FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Shinomiya, K Kobayashi, H Inokuchi, N Kobayashi, K Oshima, H Kitanaka, S Yanagidaira, K Sasaki, H Muto, M Okano, M Ito, Y AF Shinomiya, Kazufusa Kobayashi, Hiroko Inokuchi, Norio Kobayashi, Koji Oshima, Hisashi Kitanaka, Susumu Yanagidaira, Kazuhiro Sasaki, Haruo Muto, Minoru Okano, Michiharu Ito, Yoichiro TI New small-scale cross-axis coil planet centrifuge - Partition efficiency and application to purification of bullfrog ribonuclease SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article; Proceedings Paper CT 4th International Conference on Countercurrent Chromatography CY AUG 08-11, 2006 CL NIH, Bethesda, MD HO NIH DE counter-current chromatography; cross-axis coil planet centrifuge; proteins; polymer phase system; purification; ribonuclease ID COUNTER-CURRENT CHROMATOGRAPHY; PROTEIN SEPARATION; SYSTEMS; APPARATUS; DESIGN; COLUMN; ACID AB The new small-scale cross-axis coil planet centrifuge (X-axis CPC) previously designed and fabricated in our laboratory has a distinctive feature such that four separation columns of similar weight are mounted symmetrically around the rotary frame to achieve stable balancing of the centrifuge under a high revolution speed. In this column layout, neighboring columns must be rotated in the opposite direction if viewed from the center of the centrifuge to avoid twisting the interconnecting flow tubes. The effect of rotational direction of the columns on the partition efficiency was evaluated with separation of a set of test samples such as cytochrome c, myoglobin, and lysozyme using an aqueous-aqueous polymer phase system composed of 12.5% (w/w) polyethylene glycol (PEG) 1000 and 12.5% (w/w) dibasic potassium phosphate under 1000 rpm of column revolution. A series of experiments was performed using a set of two diagonally located columns (connected in series) each consisting of five coiled layers of 1 mm I.D. with a total capacity of 27.0 mL. Both right- and left-handed coils were tested each under the optimized conditions for choice of mobile phase and direction of the column rotation so that the satisfactory volume of the mobile phase was retained in the column by the aid of Archimedean screw effect. The results of these studies showed that one particular combination of handedness of the coil and direction of the rotation yielded the best peak resolution for each mobile phase. In order to demonstrate the capability of the apparatus, the purification of ribonuclease (RNase) from the extract of bullfrog egg, sialic acid binding lectin (cSBL), was carried out using both organic-aqueous and aqueous-aqueous polymer phase systems. When using the 16.0% (w/w) PEG 1000-6.3% (w/w) dibasic potassium phosphate-6.3% (w/w) monobasic potassium phosphate system, cSBL was successfully separated from other proteins present in the extract while commercial RNase A was eluted at near the solvent front by the lower phase mobile. The cSBL retained its native RNase activity. The overall results demonstrated that the present new small-scale X-axis CPC is useful for the purification of bioactive compounds without loss of their native activities. (C) 2007 Elsevier B.V. All rights reserved. C1 Nihon Univ, Coll Pharm, Funabashi, Chiba 2748555, Japan. Nihon Univ, Coll Sci & Technol, Funabashi, Chiba 2748501, Japan. NHLBI, Ctr Biochem & Biophys, NIH, Bethesda, MD 20892 USA. RP Shinomiya, K (reprint author), Nihon Univ, Coll Pharm, 7-7-1 Narashinodai, Funabashi, Chiba 2748555, Japan. EM kshino@pha.nihon-u.ac.jp NR 19 TC 7 Z9 7 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD JUN 1 PY 2007 VL 1151 IS 1-2 BP 91 EP 98 DI 10.1016/j.chroma.2007.02.116 PG 8 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 175YH UT WOS:000247049400014 PM 17400232 ER PT J AU Ito, Y Qi, L Powell, J Sharpnack, F Metger, H Host, J Cao, XL Dong, YM Huo, LS Zhu, XP Li, T AF Ito, Yoichiro Qi, Lin Powell, Jimmie Sharpnack, Frank Metger, Howard Host, James Cao, Xue-Li Dong, Yin-Mao Huo, Liang-Sheng Zhu, Xiao-Ping Li, Ting TI Mixer-settler counter-current chromatography with a barricaded spiral disk assembly with glass beads SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article; Proceedings Paper CT 4th International Conference on Countercurrent Chromatography CY AUG 08-11, 2006 CL NIH, Bethesda, MD HO NIH DE mixer-settler counter-current chromatography; barricaded spiral disk; assembly; coil planet centrifuge; purification of biopolymers AB A novel spiral disk is designed by placing barricades at 6 mm intervals in the middle of the spiral channel to divide the channel into multiple sections. Glass beads are placed in every other section so that the planetary motion produces repetitive mixing and settling of polymer phase systems. Performance of this mixer-settler spiral disk assembly was examined for separation of lysozyme and myoglobin with a polymer phase system. The best results were obtained with a spiral disk equipped with barricades with openings ranging from 1.2 to 0.4 mm on each side at a high revolution speed up to 1200 rpm. (C) 2006 Elsevier B.V. All rights reserved. C1 NHLBI, Ctr Biochem & Biophys, NIH, Bethesda, MD 20892 USA. US FDA, OPS, CDER, Off New Drug Qual Assessment, Silver Spring, MD 20993 USA. NIH, Machine Instrumentat Design & Fabricat, Bethesda, MD 20892 USA. NIST, Shady Grove, MD 20982 USA. Beijing Technol & Business Univ, Coll Chem & Environm Engn, Beijing Key Lab Plant Resource Res, Beijing 100037, Peoples R China. RP Ito, Y (reprint author), NHLBI, Ctr Biochem & Biophys, NIH, Bldg 50,Room 3334,50 S Dr, Bethesda, MD 20892 USA. EM itoy2@mail.nih.gov NR 7 TC 21 Z9 22 U1 2 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD JUN 1 PY 2007 VL 1151 IS 1-2 BP 108 EP 114 DI 10.1016/j.chroma.2006.11.078 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 175YH UT WOS:000247049400017 PM 17316660 ER PT J AU Qi, L Ito, Y AF Qi, Lin Ito, Yoichiro TI Immunoaffinity centrifugal precipitation chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article; Proceedings Paper CT 4th International Conference on Countercurrent Chromatography CY AUG 08-11, 2006 CL NIH, Bethesda, MD HO NIH DE immunoaffinity centrifugal precipitation chromatography; antibody; HSA (human serum albumin); human plasma; ammonium sufate ID AMMONIUM-SULFATE; DIALYSIS MEMBRANE; PLASMID DNA; FRACTIONATION; PROTEIN; SEPARATION; SOLUBILITY; RNA AB Purification of proteins based on immunoaffinity has been performed using a solid support coated with antibody against the target proteins. The method requires immobilizing the antibody onto the solid support using protein A or G, and has a risk of adsorptive loss of target proteins onto the solid support. Centrifugal precipitation chromatography has been successfully used to purify enzymes, such as ketosteroid isomerase and hyaluronidase without the use of solid support. The purpose of this study is to demonstrate that immunoaffinity centrifugal precipitation chromatography is capable of isolating an antigen by exploiting antigen-antibody binding. The separation was initiated by filling both channels with 40% saturated ammonium sulfate (AS) of pH 4-4.5 followed by loading 20 RI of human plasma (National Institutes of Health blood bank) mixed with 2 mg of rabbit anti-HSA (human serum protein) antibody (Sigma). Then, the sample channel was eluted with water at 0.03 ml/min and AS channel with 40% AS solution of pH 4-1.5 at 1 ml/min until all non-binding components were eluted. Then, the releasing reagent (50% AS solution containing 0.5 M glycine and 10% ammonium hydroxide at pH 10) was introduced through the AS channel to release the target protein (HSA). The retained antibody was recovered by eluting the sample channel with water at 1 ml/min. A hollow fiber membrane device at the outlet (MicroKros, Spectrum, New Brunswick, NJ, USA) was provided on-line dialysis of the eluent before fractions were collected, so that the fractions could be analyzed by SDS-PAGE (sodium dodecyl sulfate - polyacrylamide gel electrophoresis) without further dialysis. The current method does not require immobilizing the antibody onto a matrix, which is used by the conventional immunoaffinity chromatography. This method ensures full recovery of the antigen and antibody, and it may be applied to purification of other proteins. (C) 2007 Elsevier B.V. All rights reserved. C1 NHLBI, Ctr Biochem & Biophys, NIH, Bethesda, MD 20892 USA. US FDA, OPS, CDER, Off New Drug Qual Assessment, Silver Spring, MD 20993 USA. RP Ito, Y (reprint author), NHLBI, Ctr Biochem & Biophys, NIH, Bldg 50,Room 3334,50 S Dr, Bethesda, MD 20892 USA. EM itoy2@mail.nih.gov NR 17 TC 2 Z9 2 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD JUN 1 PY 2007 VL 1151 IS 1-2 BP 121 EP 125 DI 10.1016/j.chroma.2007.02.119 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 175YH UT WOS:000247049400019 PM 17416378 ER PT J AU Shiono, H Chen, HM Okada, T Ito, Y AF Shiono, Hiroyuki Chen, Hong Miao Okada, Tadashi Ito, Yoichiro TI Colony-forming cell assay for human hematopoietic progenitor cells harvested by a novel continuous-flow cell separation method SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article; Proceedings Paper CT 4th International Conference on Countercurrent Chromatography CY AUG 08-11, 2006 CL NIH, Bethesda, MD HO NIH DE cell separation; cell density; human hematopoietic progenitor cells; colony-forming cell assay ID DENSITY AB In order to prove the functional potentiality of cells separated according to their densities by a novel continuous-flow cell separation method, the colony-forming cell (CFC) assay was performed on the harvested cells from peripheral blood and umbilical cord blood. The number of colony-forming unit-granulocyte, erythroid, macrophage, megakaryocyte (CFU-GEMM), which are considered to be stem cells, was approximately 3% of colonies developed from the peripheral blood and approximately 4% of colonies from the umbilical cord blood. It appears that this new method could allow us for harvesting of hematopoietic progenitor cells without losing their native ability to proliferate. (C) 2007 Elsevier B.V. All rights reserved. C1 Aichi Med Univ, Sch Med, Dept Physiol, Nagakute, Aichi 4801195, Japan. NHLBI, Ctr Biochem & Biophys, NIH, Bethesda, MD 20892 USA. RP Shiono, H (reprint author), Aichi Med Univ, Sch Med, Dept Physiol, Nagakute, Aichi 4801195, Japan. EM shiono-h@aichi-med-u.ac.jp OI HONGMIAO, CHEN/0000-0001-5097-5664 NR 6 TC 5 Z9 5 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD JUN 1 PY 2007 VL 1151 IS 1-2 BP 153 EP 157 DI 10.1016/j.chroma.2007.01.021 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 175YH UT WOS:000247049400025 PM 17250843 ER PT J AU Shibusawa, Y Takeuchi, N Tsutsumi, K Nakano, S Yanagida, A Shindo, H Ito, Y AF Shibusawa, Yoichi Takeuchi, Naoko Tsutsumi, Kanako Nakano, Shigeru Yanagida, Akio Shindo, Heisaburo Ito, Yoichiro TI One-step purification of histone deacetylase from Escherichia coli cell-lysate by counter-current chromatography using aqueous two-phase system SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article; Proceedings Paper CT 4th International Conference on Countercurrent Chromatography CY AUG 08-11, 2006 CL NIH, Bethesda, MD HO NIH DE aqueous-aqueous two-phase systems; counter-current chromatography; proteins; maltose binding protein tagged histone deacetylase ID COIL PLANET CENTRIFUGE; POLYMER PHASE SYSTEM; NAD(+)-DEPENDENT DEACETYLASES; CRUDE EXTRACT; HUMAN SERUM; PROTEINS; GLUCOSYLTRANSFERASE; DEHYDROGENASE; LIPOPROTEINS; SEPARATION AB Aqueous-aqueous two-phase (AATP) systems composed of polyethylene glycol (PEG) (molecular mass, M-r:1000-8000) and dextran (M-r:40,000) were evaluated for purification of maltose binding protein tagged-histone deacetylase (MBP-HDAC) by counter-current chromatography (CCC). CCC purification of an MBP-HDAC from Escherichia coli cell-lysate was successfully demonstrated with a 7.0% PEG 3350-10% dextran T40 system containing 10 mM potassium phosphate buffer at pH 9.0. After CCC purification, both polymers in the CCC fractions were easily removed by ultrafiltration in a short period of time. The collected fractions containing target protein were analyzed by an HPLC-based in vitro assay as well as sodium dodecyl sulfate polyacrylamide gel electrophoresis. MBP tag was digested from fusion HDAC during the CCC separation and native HDAC was purified by one-step operation with well preserved deacetyl enzyme activity. (C) 2007 Elsevier B.V. All rights reserved. C1 Tokyo Univ Pharm & Life Sci, Div Struct Biol & Analyt Sci, Sch Pharm, Hachioji, Tokyo 1920392, Japan. NHLBI, Ctr Biochem & Biophys, NIH, Bethesda, MD 20892 USA. RP Shibusawa, Y (reprint author), Tokyo Univ Pharm & Life Sci, Div Struct Biol & Analyt Sci, Sch Pharm, 1432-1 Horinouchi, Hachioji, Tokyo 1920392, Japan. EM sibusawa@ps.toyaku.ac.jp NR 22 TC 10 Z9 10 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD JUN 1 PY 2007 VL 1151 IS 1-2 BP 158 EP 163 DI 10.1016/j.chroma.2007.01.111 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 175YH UT WOS:000247049400026 PM 17306809 ER PT J AU Han, X Ma, XF Zhang, TY Zhang, YB Liu, QH Ito, Y AF Han, Xiao Ma, Xiaofeng Zhang, Tianyou Zhang, Yabin Liu, Qinghui Ito, Yoichiro TI Isolation of high-purity casticin from Artemisia annua L. by high-speed counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article; Proceedings Paper CT 4th International Conference on Countercurrent Chromatography CY AUG 08-11, 2006 CL NIH, Bethesda, MD HO NIH DE counter-current chromatography; preparative chromatography; Artemisia annua L.; casticin AB Following an initial clean-up step on silica, high-speed counter-current chromatography (HSCCC) was used to purify a flavone, casticin (5,3 '-dihydroxy-3,6,7, 4 '-tetramethoxyflavone), from an extract of the dried leaves of Artemisia annua L. The two-phase solvent system used was composed of n-hexane-ethyl acetate-methanol-water at an optimized volume ratio of 7:10:7:10 (v/v). HSCCC separation of 226.4 mg of crude sample (containing casticin at 16.5% purity after silica gel clean-up) yielded 36.3 mg of casticin with a purity of over 99% and 96.2% recovery. Identification of the target compound was performed by H-1 NMR, C-13 NMR, two-dimensional NMR, electrospray ionization MS, IR and UV. (C) 2007 Elsevier B.V. All rights reserved. C1 Beijing UE Biotech Co Ltd, Chinese Key Lab Natl Reference Mat Nat Prod, Beijing 100035, Peoples R China. Grad Univ Chinese Acad Sci, Dept Biol, Beijing 100049, Peoples R China. NHLBI, Ctr Biochem & Biophys, NIH, Bethesda, MD 20892 USA. RP Han, X (reprint author), Beijing UE Biotech Co Ltd, Chinese Key Lab Natl Reference Mat Nat Prod, Beijing 100035, Peoples R China. EM ssisyhan@yahoo.com.cn NR 5 TC 34 Z9 37 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 EI 1873-3778 J9 J CHROMATOGR A JI J. Chromatogr. A PD JUN 1 PY 2007 VL 1151 IS 1-2 BP 180 EP 182 DI 10.1016/j.chroma.2007.02.105 PG 3 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 175YH UT WOS:000247049400030 PM 17374377 ER PT J AU De Martinis, BS Barnes, AJ Scheidweiler, KB Huestis, MA AF De Martinis, Bruno S. Barnes, Allan J. Scheidweiler, Karl B. Huestis, Marilyn A. TI Development and validation of a disk solid phase extraction and gas chromatography-mass spectrometry method for MDMA, MDA, HMMA, HMA, MDEA, methamphetamine and amphetamine in sweat SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE MDMA; amphetamine; methamphetamine; sweat patches; GC/MS ID 3,4-METHYLENEDIOXYMETHAMPHETAMINE MDMA; ECSTASY MDMA; ORAL FLUID; ABUSE; PHARMACOLOGY; HUMANS; DRUGS; PHARMACOKINETICS; METABOLITES; FATALITIES AB We describe the development and validation of a method for the simultaneous quantification of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA), 3-hydroxy-4-methoxymethamphetamine (HMMA), 3-hydroxy-4-methoxyamphetamine (HMA), 3,4-methylenedioxyethylamphetamine (MDEA), methamphetamine (MAMP) and amphetamine (AMP) in sweat. Drugs were eluted from PharmCbek (TM) sweat patches with sodium acetate buffer, extracted with disk solid phase extraction and analyzed using GC/MS-EI with selected ion monitoring. Limits of quantification (LOQ) for MDMA, MDEA, MAMP and AMP were 2.5 ng/patch, and 5 ng/patch for MDA, HMA and HMMA. This fully validated procedure was more sensitive than previously published analytical methods and permitted the simultaneous analysis of multiple amphetamine analogs in human sweat. Published by Elsevier B.V. C1 NIDA, Chem & Drug Metab Intraumal Res Program, NIH, Baltimore, MD 21224 USA. Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Pathol, BR-14051140 Ribeirao Preto, SP, Brazil. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Intraumal Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov RI De Martinis, Bruno/I-5388-2012 OI De Martinis, Bruno/0000-0002-2702-5190 FU Intramural NIH HHS [Z01 DA000412-10, Z01 DA000468-04] NR 26 TC 25 Z9 25 U1 1 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 JUN 1 PY 2007 VL 852 IS 1-2 BP 450 EP 458 DI 10.1016/j.jchromb.2007.02.017 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 179JV UT WOS:000247286700062 PM 17369000 ER PT J AU Kalkwarf, HJ Zemel, BS Gilsanz, V Lappe, JM Horlick, M Oberfield, S Mahboubi, S Fan, B Frederick, MM Winer, K Shepherd, JA AF Kalkwarf, Heidi J. Zemel, Babette S. Gilsanz, Vicente Lappe, Joan M. Horlick, Mary Oberfield, Sharon Mahboubi, Soroosh Fan, Bo Frederick, Margaret M. Winer, Karen Shepherd, John A. TI The bone mineral density in childhood study: Bone mineral content and density according to age, sex, and race SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID X-RAY ABSORPTIOMETRY; ANTIEPILEPTIC DRUGS; TOTAL-BODY; CHILDREN; MASS; DENSITOMETRY; ADOLESCENTS; ACQUISITION; GIRLS; ACCUMULATION AB Context: Low bone mass may increase risk of fracture. Several chronic medical conditions, medications, and lifestyle factors affect bone mineral accrual. Appropriate reference values are essential for identification of children with bone deficits. Objective: Our objective was to establish reference curves for bone mineral content (BMC) and density (BMD) in children. Design and Setting: The Bone Mineral Density in Childhood Study is an ongoing longitudinal study in which measurements are obtained annually at five clinical centers in the United States. Participants: Participants included 1554 healthy children (761 male, 793 female), ages 6-16 yr, of all ethnicities. Main Outcome Measures: Scans of the whole body, lumbar spine, hip, and forearm were obtained using dual-energy x-ray absorptiometry. Percentile curves based on three annual measurements were generated using the LMS statistical procedure. Results: BMC of the whole body and lumbar spine and BMD of the whole body, lumbar spine, total hip, femoral neck, and forearm are given for specific percentiles by sex, age, and race (Black vs. non-Black). BMC and BMD were higher for Blacks at all skeletal sites (P < 0.0001). BMC and BMD increased with age, and a plateau was not evident by age 16 (girls) or age 17 (boys). The variation in BMC and BMD also increased with age. Conclusions: Age-, race-, and sex-specific reference curves can be used to help identify children with bone deficits and for monitoring changes in bone in response to chronic diseases or therapies. C1 Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. Creighton Univ, Omaha, NE 68131 USA. Columbia Univ, New York, NY 10032 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Clin Trials & Surveys Corp, Baltimore, MD 21210 USA. NICHHD, Bethesda, MD 20892 USA. RP Kalkwarf, HJ (reprint author), Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. EM heidi.kalkwarf@cchmc.org RI fan, bo/A-8161-2009; Zemel, Babette/D-1117-2009 FU NCRR NIH HHS [M01 RR08084, M01 RR000240]; NICHD NIH HHS [N01 HD13228, N01 HD13329, N01 HD13330, N01 HD13331, N01 HD13332, N01 HD13333] NR 39 TC 178 Z9 183 U1 2 U2 8 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2007 VL 92 IS 6 BP 2087 EP 2099 DI 10.1210/jc.2006-2553 PG 13 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 176CX UT WOS:000247061700017 PM 17311856 ER PT J AU Feuillan, P Calis, K Hill, S Shawker, T Robey, PG Collins, MT AF Feuillan, Penelope Calis, Karim Hill, Suvimol Shawker, Thomas Robey, Pamela Gehron Collins, Michael T. TI Letrozole treatment of precocious puberty in girls with the McCune-Albright syndrome: A pilot study SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID POLYOSTOTIC FIBROUS DYSPLASIA; GROWTH-HORMONE EXCESS; BONE TURNOVER; ACTIVATING MUTATIONS; BIOCHEMICAL MARKERS; AROMATASE INHIBITOR; ADOLESCENTS; METABOLISM; PHOSPHATE; PATTERNS AB Context: Girls with McCune-Albright syndrome (MAS) and related disorders have gonadotropin-independent precocious puberty due to estrogen secretion from ovarian cysts. Their puberty does not respond to GnRH agonist therapy, and short-acting aromatase inhibitors have had limited effectiveness. Objective: Our objective was to assess the effectiveness of the potent, third-generation aromatase inhibitor letrozole in decreasing pubertal progression in girls with MAS and to assess the response of indices of bone turnover associated with the patients' polyostotic fibrous dysplasia. Design: Subjects were evaluated at baseline and every 6 months for 12-36 months while on treatment with letrozole 1.5-2.0 mg/m(2.)d. Setting: This was an open-label therapeutic trial at a single clinical center. Patients: Patients included nine girls aged 3-8 yr with MAS and/or gonadotropin-independent puberty. Main Outcome Measures: Measures included rates of linear growth, bone age advance, mean ovarian volume, estradiol, episodes of vaginal bleeding, and levels of the indices of bone metabolism: serum osteocalcin, alkaline phosphatase, urinary hydroxyproline, pyridinoline, deoxypyridinoline, and N-telopeptides. Results: Girls had decreased rates of growth (P <= 0.01) and bone age advance (P <= 0.004) and cessation or slowing in their rates of bleeding over 12-36 months of therapy. Mean ovarian volume, estradiol, and indices of bone metabolism fell after 6 months (P <= 0.05) but tended to rise by 24-36 months. Uterine volumes did not change. One girl had a ruptured ovarian cyst after 2 yr of treatment. Conclusions: This preliminary study suggests that letrozole may be effective therapy in some girls with MAS and/or gonadotropin-independent precocious puberty. Possible adverse effects include ovarian enlargement and cyst formation. C1 Natl Inst Dent & Craniofacial Res, NIH, NHGRI, Bethesda, MD 20892 USA. RP Feuillan, P (reprint author), Natl Inst Dent & Craniofacial Res, NIH, NHGRI, Bethesda, MD 20892 USA. EM feuillap@mail.nih.gov RI Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 NR 29 TC 33 Z9 39 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2007 VL 92 IS 6 BP 2100 EP 2106 DI 10.1210/jc.2006-2350 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 176CX UT WOS:000247061700018 PM 17405850 ER PT J AU Khosravi, A Cutler, CM Kelly, MH Chang, R Royal, RE Sherry, RM Wodajo, FM Fedarko, NS Collins, MT AF Khosravi, Azarmindokht Cutler, Carolee M. Kelly, Marilyn H. Chang, Richard Royal, Richard E. Sherry, Richard M. Wodajo, Felasfa M. Fedarko, Neal S. Collins, Michael T. TI Determination of the elimination half-life of fibroblast growth factor-23 SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID TUMOR-INDUCED OSTEOMALACIA; VITAMIN-D METABOLISM; ONCOGENIC OSTEOMALACIA; 1-ALPHA,25-DIHYDROXYVITAMIN D-3; PHOSPHATE HOMEOSTASIS; PARATHYROID-HORMONE; FIBROBLAST-GROWTH-FACTOR-23; FGF-23; HYPOPHOSPHATEMIA; GLYCOSYLATION AB Context: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic disease caused by mesenchymal tumors that secrete fibroblast growth factor-23 (FGF-23), a newly-described vitamin D and phosphate-regulating hormone. Surgical removal of the tumor, the ectopic source of circulating FGF-23, offers the opportunity to determine the elimination half-life of FGF-23. Objective: The aim of the study was to determine the elimination half-life of FGF-23. Patients/Methods: The tumors were removed from three patients with TIO, and serum samples were taken every 30 min for up to 72 h after the operation. FGF-23 was measured by both a C-terminal/intact assay and an intact assay, and the elimination half-life was determined by one phase exponential decay methodology. Setting: The Mark O. Hatfield Clinical Research Center of the National Institutes of Health, a tertiary referral clinical research center, was the setting for the study. Results: The elimination life of FGF-23 as determined by C-terminal/intact and intact assays was 46 +/- 12 and 58 +/- 34 min, respectively. Conclusions: The plasma half-life of serum FGF-23 is in the range of 46-58 min. C1 Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. NCI, Dept Radiol, Mark O Hatfield Clin Ctr, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Surg Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Georgetown Univ, Dept Orthoped & Pediat, Washington, DC USA. Johns Hopkins Univ, Dept Med, Div Geriatr Med & Gerontol, Baltimore, MD 21224 USA. RP Collins, MT (reprint author), Natl Inst Dent & Craniofacial Res, Skeletal Clin Studies Unit, Craniofacial & Skeletal Dis Branch, NIH, Bldg 30,Room 228 MSC 4320, Bethesda, MD 20892 USA. EM mc247k@nih.gov OI Fedarko, Neal/0000-0001-6055-6279 FU Intramural NIH HHS NR 28 TC 64 Z9 64 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD JUN PY 2007 VL 92 IS 6 BP 2374 EP 2377 DI 10.1210/jc.2006-2865 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 176CX UT WOS:000247061700062 PM 17374707 ER PT J AU Garibyan, L Lobito, AA Siegel, RM Call, ME Wucherpfennig, KW Geha, RS AF Garibyan, Lilit Lobito, Adrian A. Siegel, Richard M. Call, Matthew E. Wucherpfennig, Kai W. Geha, Raif S. TI Dominant-negative effect of the heterozygous C104R TACI mutation in common variable immunodeficiency (CVID) SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID CRYSTAL-STRUCTURE; B-CELLS; RECEPTOR; APRIL; ACTIVATION; BAFF; COMPLEX; BINDING; BLYS; IDENTIFICATION AB B cells from patients with common variable immunodeficiency (CVID) who are heterozygous for transmembrane activator and CAML interactor (TACT) mutation C104R, which abolishes ligand binding, fail to produce Igs in response to TACT ligand. It is not known whether this is due to haploinsufficiency or dominant interference. Using in vitro transfection assays, here we demonstrate that C104R and the corresponding murine TACT mutant, C76R, which also does not bind ligand, dominantly interfere with TACT signaling. This effect was dependent on preassociation of the mutants with WT TACT in the absence of ligand. The mutants did not interfere with ligand binding by WT TACT, suggesting that they may act by disrupting ligand-induced receptor rearrangement and signaling. This work demonstrates that TACT preassembles as an oligomeric complex prior to ligand binding and provides a mechanistic insight into how the heterozygous C104R TACT mutation can potentially lead to CVID. C1 Childrens Hosp, Div Immunol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA USA. NIAMSD, Immunoregulat Unit, NIH, Bethesda, MD USA. Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA USA. RP Geha, RS (reprint author), Childrens Hosp, Div Immunol, 300 Longwood Ave, Boston, MA 02115 USA. EM raif.geha@childrens.harvard.edu OI Call, Matthew/0000-0001-5846-6469 FU NIAID NIH HHS [T32 AI007512, T32-AI-007512, P01 AI031541, P01-AI-031541, R01 AI054520] NR 27 TC 57 Z9 58 U1 0 U2 0 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2007 VL 117 IS 6 BP 1550 EP 1557 DI 10.1172/JCI31023 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 175ZJ UT WOS:000247052200014 PM 17492055 ER PT J AU Galeano, B Klootwijk, R Manoli, I Sun, M Ciccone, C Darvish, D Starost, MF Zerfas, PM Hoffmann, VJ Hoogstraten-Miller, S Krasnewich, DM Gahl, WA Huizing, M AF Galeano, Belinda Klootwijk, Riko Manoli, Irini Sun, MaoSen Ciccone, Carla Darvish, Daniel Starost, Matthew F. Zerfas, Patricia M. Hoffmann, Victoria J. Hoogstraten-Miller, Shelley Krasnewich, Donna M. Gahl, William A. Huizing, Marjan TI Mutation in the key enzyme of sialic acid biosynthesis causes severe glomerular proteinuria and is rescued by N-acetylmannosamine SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID ACETYLGLUCOSAMINE 2-EPIMERASE/N-ACETYLMANNOSAMINE KINASE; INCLUSION-BODY MYOPATHY; RIMMED VACUOLES; DISTAL MYOPATHY; ALPHA-DYSTROGLYCAN; BASEMENT-MEMBRANES; POLYSIALIC ACID; MESANGIAL CELLS; GNE MUTATIONS; MICE LACKING AB Mutations in the key enzyme of sialic acid biosynthesis, uridine diphospho-N-acetylglucosamine 2-epimerase/N-acetylmannosamine (ManNAc) kinase (GNE/MNK), result in hereditary inclusion body myopathy (HIBM), an adult-onset, progressive neuromuscular disorder. We created knockin mice harboring the M712T Gne/Mnk mutation. Homozygous mutant (Gne(M712T/M712T)) mice did not survive beyond P3. At P2, significantly decreased Gne-epimerase activity was observed in Gne(M712T/M712T) muscle, but no myopathic features were apparent. Rather, homozygous mutant mice had glomerular hematuria, proteinuria, and podocytopathy. Renal findings included segmental splitting of the glomerular basement membrane, effacement of podocyte foot processes, and reduced sialylation of the major podocyte sialoprotein, podocalyxin. ManNAc administration yielded survival beyond P3 in 43% of the Gne(M712T/M712T) pups. Survivors exhibited improved renal histology, increased sialylation of podocalyxin, and increased Gne/Mnk protein expression and Gne-epimerase activities. These findings establish this Gne(M712T/M712T) knockin mouse as what we believe to be the first genetic model of podocyte injury and segmental glomerular basement membrane splitting due to hyposialylation. The results also support evaluation of ManNAc as a treatment not only for HIBM but also for renal disorders involving proteinuria and hematuria due to podocytopathy and/or segmental splitting of the glomerular basement membrane. C1 NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. Howard Hughes Med Inst, Res Scholars Program, NIH, Bethesda, MD USA. HIBM, Res Grp, Encino, CA USA. Natl Human Genome Res Inst, Div Vet Resources, Bethesda, MD USA. Natl Human Genome Res Inst, Off Lab Anim Med, Bethesda, MD USA. Natl Human Genome Res Inst, Off Rare Dis, Bethesda, MD USA. RP Huizing, M (reprint author), NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. EM mhuizing@mail.nih.gov OI Manoli, Irini/0000-0003-1543-2941 FU Intramural NIH HHS NR 58 TC 94 Z9 100 U1 0 U2 7 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2007 VL 117 IS 6 BP 1585 EP 1594 DI 10.1172/JCI30954 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 175ZJ UT WOS:000247052200018 PM 17549255 ER PT J AU Hevener, AL Olefsky, JM Reichart, D Nguyen, MTA Bandyopadyhay, G Leung, HY Watt, MJ Benner, C Febbraio, MA Nguyen, AK Folian, B Subramaniam, S Gonzalez, FJ Glass, CK Ricote, M AF Hevener, Andrea L. Olefsky, Jerrold M. Reichart, Donna Nguyen, M. T. Audrey Bandyopadyhay, Gautarn Leung, Ho-Yin Watt, Matthew J. Benner, Chris Febbraio, Mark A. Nguyen, Anh-Khoi Folian, Brian Subramaniam, Shankar Gonzalez, Frank J. Glass, Christopher K. Ricote, Mercedes TI Macrophage PPAR gamma is required for normal skeletal muscle and hepatic insulin sensitivity and full antidiabetic effects of thiazolidinediones SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID ACTIVATED-RECEPTOR-GAMMA; ADIPOSE-TISSUE; IKK-BETA; DEFICIENT MICE; FATTY-ACIDS; KAPPA-B; RESISTANCE; OBESITY; INFLAMMATION; EXPRESSION AB PPAR gamma is required for fat cell development and is the molecular target of antidiabetic thiazolidinediones (TZDs), which exert insulin-sensitizing effects in adipose tissue, skeletal muscle, and liver. Unexpectedly, we found that inactivation of PPAR gamma in macrophages results in the development of significant glucose intolerance plus skeletal muscle and hepatic insulin resistance in lean mice fed a normal diet. This phenotype was associated with increased expression of inflammatory markers and impaired insulin signaling in adipose tissue, muscle, and liver. PPAR gamma-deficient macrophages secreted elevated levels of factors that impair insulin responsiveness in muscle cells in a manner that was enhanced by exposure to FFAs. Consistent with this, the relative degree of insulin resistance became more severe in mice lacking macrophage PPAR gamma following high-fat feeding, and these mice were only partially responsive to TZD treatment. These findings reveal an essential role of PPAR gamma in macrophages for the maintenance of whole-body insulin action and in mediating the antidiabetic actions of TZDs. C1 Univ Calif Los Angeles, David Geffen Sch Med, Div Endocrinol Diabet & Hypertens, Dept Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Cellular & Mol Med, Los Angeles, CA 90095 USA. Univ Melbourne, Dept Med, St Vincents Inst Med Res, Fitzroy, Vic 3065, Australia. Univ Calif San Diego, Dept Bioengn, La Jolla, CA USA. Baker Heart Inst, Cellular & Mol Med Lab, St Kilda, Vic, Australia. NCI, Lab metab, Bethesda, MD USA. Ctr Nacl Invest Cardiovasc, Madrid, Spain. RP Hevener, AL (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Endocrinol Diabet & Hypertens, Dept Med, 900 Vet Ave,STE 24-130, Los Angeles, CA 90095 USA. EM ahevener@mednet.ucla; jolefsky@ucsd.edu; ckg@ucsd.edu; mricote@cnic.es RI Watt, Matthew/B-2089-2014; Ricote, Mercedes/L-4615-2014 OI Ricote, Mercedes/0000-0002-8090-8902 FU NHLBI NIH HHS [HL56989, P50 HL056989]; NIDDK NIH HHS [P01 DK074868, DK063491, DK074868, DK33651, DK60484, DK73227, K01 DK060484, P30 DK063491, R01 DK033651, R21 DK073227, R37 DK033651]; NIGMS NIH HHS [GM069338, U54 GM069338] NR 61 TC 296 Z9 308 U1 1 U2 18 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD JUN PY 2007 VL 117 IS 6 BP 1658 EP 1669 DI 10.1172/JCI31561 PG 12 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 175ZJ UT WOS:000247052200025 PM 17525798 ER PT J AU Siu, LL Soulieres, D Chen, EX Pond, GR Chin, SF Francis, P Harvey, L Klein, M Zhang, W Dancey, J Eisenhauer, EA Winquist, E AF Siu, Lillian L. Soulieres, Denis Chen, Eric X. Pond, Gregory R. Chin, Soo F. Francis, Peggy Harvey, Luc Klein, Meri Zhang, Wenjiang Dancey, Janet Eisenhauer, Elizabeth A. Winquist, Eric TI Phase I/II trial of erlotinib and cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck: A Princess Margaret Hospital Phase II Consortium and National Cancer Institute of Canada Clinical Trials Group study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT Symposium on Molecular Targets in Cancer Therapy CY NOV 17-21, 2003 CL Boston, MA SP Natl Cancer Inst European Org Res Res & Treatment Cancer-Amer Assoc ID COOPERATIVE-ONCOLOGY-GROUP; TYROSINE KINASE INHIBITOR; ANTIBODY CETUXIMAB; PLUS FLUOROURACIL; LUNG-CANCER; CHEMOTHERAPY; OSI-774; MULTICENTER; PACLITAXEL; CARCINOGENESIS AB Purpose To determine the phase II dose and objective response rate of erlotinib, a selective epidermal growth factor receptor tyrosine kinase inhibitor, in combination with cisplatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (HNSCC). Patients and Methods HNSCC patients with no prior chemotherapy and measurable disease were treated in three escalating-dose cohorts of daily continuous oral (PO) erlotinib and intermittent intravenous (IV) cisplatin given every 21 days. The recommended phase II dose (RPTD) was then evaluated in a two-stage trial with a primary end point of objective response rate. Results A total of 51 patients were enrolled. The RPTD was identified as erlotinib 100 mg PO daily and cisplatin 75 mg/m(2) IV every 21 days. Forty-five patients were treated at the RPTD, of which 44 and 43 were eligible for toxicity and efficacy evaluations, respectively. The intention-to-treat response rate was 21%, with one complete and eight partial responses (95% Cl, 10% to 36%), and disease stabilization was achieved in 21 patients (49%; 95% Cl, 33% to 65%). Median progression-free survival was 3.3 months (95% Cl, 2.7 to 4.8 months) and median overall survival was 7.9 (95% Cl, 5.6 to 9.5) months. The combination was well tolerated, with minimal grade 3 or higher toxicity. Subgroup analysis suggested that patients who developed higher grade skin rashes during cycle 1 had better survival outcomes (P =.034). Conclusion This schedule of erlotinib and cisplatin has a favorable toxicity profile and has antitumor activity in HNSCC comparable to standard combination chemotherapy regimens. C1 Princess Margaret Hosp, Univ Hlth Network, Dept Med Oncol & Hematol, Consortium Phase 2, Toronto, ON M5G 2M9, Canada. Natl Canc Inst, Canada Clin Trials Grp, Kingston, ON, Canada. NCI, Bethesda, MD 20892 USA. RP Siu, LL (reprint author), Princess Margaret Hosp, Univ Hlth Network, Dept Med Oncol & Hematol, Consortium Phase 2, Toronto, ON M5G 2M9, Canada. EM lillian.siu@uhn.on.ca FU NCI NIH HHS [N01-CM-17107] NR 23 TC 80 Z9 82 U1 0 U2 6 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 JUN 1 PY 2007 VL 25 IS 16 BP 2178 EP 2183 DI 10.1200/JCO.2006.07.6547 PG 6 WC Oncology SC Oncology GA 175JR UT WOS:000247010400007 PM 17538162 ER PT J AU Agulnik, M Santos, GD Hedley, D Nicklee, T dos Reis, PP Ho, J Pond, GR Chen, H Chen, S Shyr, Y Winquist, E Soulieres, D Chen, EX Squire, JA Marrano, P Kamel-Reid, S Dancey, J Siu, LL Tsao, MS AF Agulnik, Mark da Cunha Santos, Gilda Hedley, David Nicklee, Trudey dos Reis, Patricia Pintor Ho, James Pond, Gregory R. Chen, Heidi Chen, Shuo Shyr, Yu Winquist, Eric Soulieres, Denis Chen, Eric X. Squire, Jeremy A. Marrano, Paula Kamel-Reid, Suzanne Dancey, Janet Siu, Lillian L. Tsao, Ming S. TI Predictive and pharmacodynamic biomarker studies in tumor and skin tissue samples of patients with recurrent or metastatic squamous cell carcinoma of the head and neck treated with erlotinib SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Association-for-Cancer-Research/National-Cancer-Institute/Europ ean-Organization-for-Resarch-and-Treatment-of-Cancer CY NOV 14-18, 2005 CL Philadelphia, PA SP Natl Canc Inst European Org Res & Treatment Canc, Natl Canc Inst, European Org Res & Treatment Canc ID GROWTH-FACTOR-RECEPTOR; LUNG-CANCER; PHASE-II; TYROSINE KINASE; ONCOLOGY-GROUP; BREAST-CANCER; IN-SITU; KAPPA-B; EXPRESSION; GEFITINIB AB Purpose Pharmacodynamic tissue studies were conducted on a phase I/II trial of erlotinib and cisplatin in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). Levels of epidermal growth factor receptor (EGFR), downstream signaling components, and markers of angiogenesis and apoptosis were evaluated to determine the relationship between correlative end points and clinical outcomes. Patients and Methods Pretreatment and during-treatment tumor and skin biopsies, and archival tumor specimens were evaluated for EGFR, phosphorylated (p) -EGFB, extracellular signal-regulated kinase (ERK), p-ERK, Akt, p-Akt, Ki67, p27, p-nuclear factor kappa B (NF kappa B), p-signal transducer and activator of transcription 3 (STAT3), and EGFR gene copy number. Results On 37 archival samples, response to therapy was evident in two of four (50%) patients with high EGFR gene copy number tumors and in four of 27 (15%) patients with low gene copy number tumors. On nine paired tumor biopsies, elevated pretreatment levels of p27 and p-STAT3 predicted for prolonged time to progression (TTP) and overall survival (OS; P <=.03). With treatment, a decrease in p-EGFR, p-NF kappa B, and p27 correlated with increased TTP, OS, or both TTP and OS, respectively (P <=.04). Multidimensional scaling (MDS) models revealed clustering profiles of tumor markers by immunofluorescence could predict response. On 32 paired skin biopsies, suppression of p-EGFR with therapy correlated with increased OS (P =.045). Conclusion High EGFR gene copy in tumor specimens may predict which patients have an increased likelihood of response to erlotinib, and decreased p-EGFR level in skin biopsies during therapy may represent a potential surrogate marker for improved clinical outcome. MDS represents a novel way to evaluate the relationships between molecular markers and clinical outcome. Additional biomarker studies with larger sample sizes are required to elucidate HNSCC patients who may benefit from this targeted therapy. C1 Princess Margaret Hosp, Univ Hlth Network, Dept Med Oncol & Hematol, Consortium Phase 2, Toronto, ON M5G 2M9, Canada. Ontario Canc Inst, Toronto, ON M4X 1K9, Canada. Canada Clin Trials Grp, Natl Canc Inst, Kingston, ON, Canada. Vanderbilt Univ, Med Ctr, Nashville, TN USA. Natl Canc Inst, Bethesda, MD USA. RP Siu, LL (reprint author), Princess Margaret Hosp, Univ Hlth Network, Dept Med Oncol & Hematol, Consortium Phase 2, 610 Univ Ave,Suite 5-718, Toronto, ON M5G 2M9, Canada. EM lillian.siu@uhn.on.ca RI Reis, Patricia/F-4701-2012; OI Reis, Patricia/0000-0003-3775-3797; Squire, Jeremy/0000-0002-9863-468X FU NCI NIH HHS [N01-CO-124001] NR 35 TC 60 Z9 61 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 JUN 1 PY 2007 VL 25 IS 16 BP 2184 EP 2190 DI 10.1200/JCO.2006.07.6554 PG 7 WC Oncology SC Oncology GA 175JR UT WOS:000247010400008 PM 17538163 ER PT J AU Hussain, MHA MacVicar, GR Petrylak, DP Dunn, RL Vaishampayan, U Lara, PN Chatta, GS Nanus, DM Glode, LM Trump, DL Chen, H Smith, DC AF Hussain, Maha H. A. MacVicar, Gary R. Petrylak, Daniel P. Dunn, Rodney L. Vaishampayan, Ulka Lara, Primo N., Jr. Chatta, Gurkamal S. Nanus, David M. Glode, L. Michael Trump, Donald L. Chen, Helen Smith, David C. TI Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: Results of a multicenter phase II National Cancer Institute trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID METASTATIC BREAST-CANCER; TRANSITIONAL-CELL-CARCINOMA; C-ERBB-2 GENE AMPLIFICATION; URINARY-BLADDER CARCINOMA; PROGNOSTIC-SIGNIFICANCE; ADJUVANT CHEMOTHERAPY; EXTRACELLULAR DOMAIN; MONOCLONAL-ANTIBODY; 1ST-LINE TREATMENT; FACTOR RECEPTOR AB Purpose We investigated the safety and efficacy (response rates, time to disease progression, survival) of and paclitaxel in advanced urothelial carcinoma patients gemcitabine carboplatin trastuzumab,,, and prospectively evaluated human epidermal growth factor receptor-2 (Her-2/neu) overexpression rates. Patients and Methods Advanced urothelial carcinoma patients were screened for Her-2/neu overexpression. Eligibility for therapy required human epidermal growth factor receptor-2 (Her-2/neu) overexpression by immunohistochemistry (IHC), gene amplification and/or elevated serum Her-2/neu, no prior chemotherapy for metastasis, and adequate organ function including a normal cardiac function. Treatment consisted of trastuzumab (T) 4 mg/kg loading dose followed by 2 mg/kg on days 1, 8, and 15; paclitaxel (P) 200 mg/m(2) on day 1; carboplatin (C; area under the curve, 5) on day 1; and gemcitabine (G) 800 mg/m(2) on days 1 and 8. The primary end point was cardiac toxicity. Results Fifty-seven (52.3%) of 109 registered patients were Her-2/neu positive, and 48.6% were positive Her-2/neu-positive patients had more metastatic sites and visceral metastasis than did by IHC. Her-2/neu negative patients. Forty-four of 57 Her-2/neu-positive patients were treated with TPCG. The median number of cycles was six (range, I to 12 cycles). The most common grade 3/4 toxicity was myelosuppression. Grade 3 sensory neuropathy occurred in 14% of patients, and 22.7% experienced grade I to 3 cardiac toxicity (grade 3, n = 2: one left ventricular dysfunction, one tachycardia). There were two therapy-related deaths. Thirty-one (70%) of 44 patients responded (five complete and 26 partial), and 25 (57%) of 44 were confirmed responses. Median time to progression and survival were 9.3 and 14.1 months, respectively. Conclusion We prospectively characterized Her-2/neu status in advanced urothelial carcinoma patients. TPCG is feasible; cardiac toxicity rates were higher than projected, but the majority were grade two or lower. Determining the true contribution of trastuzumab requires a randomized trial. C1 Univ Michigan, Ctr Comprehens Canc, Ann Arbor, MI 48109 USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. Columbia Presbyterian Med Ctr, New York, NY 10032 USA. New York Presbyterian Med Ctr, New York, NY USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Univ Calif Davis, Ctr Canc, Sacramento, CA 95817 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Colorado, Hlth Sci Ctr, Aurora, CO USA. NCI, Canc Therapy Evaluat Program, Rockville, MD USA. RP Hussain, MHA (reprint author), Univ Michigan, Ctr Comprehens Canc, 7314 CCGC,1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM mahahuss@umich.edu FU NCI NIH HHS [5P30CA046592-17] NR 44 TC 185 Z9 188 U1 0 U2 3 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 JUN 1 PY 2007 VL 25 IS 16 BP 2218 EP 2224 DI 10.1200/JCO.2006.08.0994 PG 7 WC Oncology SC Oncology GA 175JR UT WOS:000247010400013 PM 17538166 ER PT J AU Timmers, HJLM Kozupa, A Chen, CC Carrasquillo, JA Ling, A Eisenhofer, G Adams, KT Solis, D Lenders, JWM Pacak, K AF Timmers, Henri J. L. M. Kozupa, Anna Chen, Clara C. Carrasquillo, Jorge A. Ling, Alexander Eisenhofer, Graeme Adams, Karen T. Solis, Daniel Lenders, Jacques W. M. Pacak, Karel TI Superiority of fluorodeoxyglucose positron emission tomography to other functional imaging techniques in the evaluation of metastatic SDHB-associated pheochromocytoma and paraganglioma SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ACCUMULATE METAIODOBENZYLGUANIDINE; I-123 METAIODOBENZYLGUANIDINE; MALIGNANT PHEOCHROMOCYTOMAS; GENE-MUTATIONS; LOCALIZATION; SCINTIGRAPHY; PET; TRANSPORTERS; CHEMOTHERAPY; PREVALENCE AB Purpose Germline mutations of the gene encoding subunit B of the mitochondrial enzyme succinate dehydrogenase (SDHB) predispose to malignant paraganglioma (PGL). Timely and accurate localization of these aggressive tumors is critical for guiding optimal treatment. Our aim is to evaluate the performance of functional imaging modalities in the detection of metastatic lesions of SDHB-associated PGL. Patients and Methods Sensitivities for the detection of metastases were compared between [F-18]fluorodopamine ([F-18]FDA) and F-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET), iodine-123- (I-123) and iodine-131 (I-131) -metaiodobenzylguanidine (MIBG), In-111-pentetreotide, and Tc-99m-methylene diphosphonate bone scintigraphy in 30 patients with SDHB-associated PGL. Computed tomography (CT) and magnetic resonance imaging (MRI) served as standards of reference. Results Twenty-nine of 30 patients had metastatic lesions. In two patients, obvious metastatic lesions on functional imaging were missed by CT and MRI. Sensitivity according to patient/body region was 80%/65% for I-123-MIBG and 88%/70% for [F-18]FDA-PET. False-negative results on I-123-MIBG scintigraphy and/or [F-18]FDA-PET were not predicted by genotype or biochemical phenotype. (F-18]FDG-PET yielded a by patient/by body region sensitivity of 100%/97%. At least 90% of regions that were false negative on I-123-MIBG scintigraphy or [F-18]FDA-PET were detected by [F-18]FDG-PET. in two patients, In-111-pentetreotide scintigraphy detected liver lesions that were negative on other functional imaging modalities. Sensitivities were similar before and after chemotherapy or I-131-MIBG treatment, except for a trend toward lower post- (60%/41%) versus pretreatment (80%/65%) sensitivity of I-131-MIBG scintigraphy. Conclusion With a sensitivity approaching 100%, [F-18]FDG-PET is the preferred functional imaging modality for staging and treatment monitoring of SDHB-related metastatic PGL. C1 NICHHD, Reprod Biol & Med Branch, Bethesda, MD 20892 USA. NINDS, Dept Nucl Med, NIH, Bethesda, MD 20892 USA. NINDS, Dept Diagnost Radiol, NIH, Bethesda, MD 20892 USA. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. Radboud Univ Nijmegen Med Ctr, Dept Internal Med, Div Gen Internal Med, Nijmegen, Netherlands. Radboud Univ Nijmegen Med Ctr, Dept Endocrinol, Nijmegen, Netherlands. RP Timmers, HJLM (reprint author), NICHHD, Reprod Biol & Med Branch, 10 Ctr Dr,Bldg 10,CRC,Rm 1-E 3140,MSC 1109, Bethesda, MD 20892 USA. EM h.timmers@endo.umcn.nl RI Carrasquillo, Jorge/E-7120-2010; Lenders, J.W.M./L-4487-2015; OI Carrasquillo, Jorge/0000-0002-8513-5734 NR 34 TC 165 Z9 168 U1 0 U2 7 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 JUN 1 PY 2007 VL 25 IS 16 BP 2262 EP 2269 DI 10.1200/JCO.2006.09.6297 PG 8 WC Oncology SC Oncology GA 175JR UT WOS:000247010400020 PM 17538171 ER PT J AU Birrer, MJ Johnson, ME Hao, K Wong, KK Park, DC Bell, A Welch, WR Berkowitz, RS Mok, SC AF Birrer, Michael J. Johnson, Michael E. Hao, Ke Wong, Kwong-Kwok Park, Dong-Choon Bell, Aaron Welch, William R. Berkowitz, Ross S. Mok, Samuel C. TI Whole genome oligonucleotide-based array comparative genomic hybridization analysis identified fibroblast growth factor I as a prognostic marker for advanced-stage serous ovarian adenocarcinomas SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 97th Annual Meeting of the American-Association-for-Cancer-Research (AACR) CY APR 01-05, 2006 CL Washington, DC SP Amer Assoc Canc Res ID COPY-NUMBER CHANGES; BREAST-CANCER; ANGIOGENESIS; DNA; MICROARRAY; TUMORS; CGH AB Purpose To identify markers that can predict overall survival in patients with high-grade advanced stage serous adenocarcinomas. Patients and Methods Oligonucleotide array comparative genomic hybridization (aCGH) was performed on 42 microdissected high-grade serous ovarian tumor samples. aCGH segments were obtained and a prediction Cox model was built and validated by the standard leave one out analysis. Both DNA and mRNA copy numbers of selected genes located on the candidate aCGH segments were determined by quantitative polymerase chain reaction (qPCR) and quantitative reverse transcriptase PCR (qRT-PCR) analyses. The gene that showed the highest correlation was further validated on an independent set of specimens and was selected for further functional studies. Results Two chromosomal regions, 4p16.3 and 5q31-5q35.3, exhibited the strongest correlation with overall survival (P <.01). From the 5q31 region, fibroblast growth factor 1 (FGF-1) was selected for further validation study. FGF-1 mRNA copy number was significantly correlated with DNA copy number and protein expression levels (P =.021 and <.001), and both FGF-1 mRNA and protein levels were significantly associated with overall survival (P =.018 and.042). This association was validated for protein expression on an independent set of 81 samples, significant to P =.006. Further studies showed significant correlation between FGF-1 protein expression and CD31 + staining in the tumor stroma (P =.024). Finally, both cancer cells and endothelial cells treated with exogenous FGF-1 showed a significant increase in cell motility and survival. Conclusion Amplification of FGF-1 at 5q31 in ovarian cancer tissues, leads to increased angiogenesis, and autocrine stimulation of cancer cells, which may result in poorer overall survival in patents with high-grade advanced stage serous ovarian cancer. C1 Harvard Univ, Sch Med, Brigham & Womens Hosp, Lab Gynecol Oncol,Dept Obstet & Gynecol, Boston, MA 02115 USA. NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Cambridge, MA 02138 USA. Dana Farber Harvard Canc Ctr, Gillette Ctr Womens Canc, Boston, MA USA. Univ Texas, MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. Catholic Univ Korea, St Vincent Hosp, Dept Obstet & Gynecol, Suwon, South Korea. RP Mok, SC (reprint author), Harvard Univ, Sch Med, Brigham & Womens Hosp, Lab Gynecol Oncol,Dept Obstet & Gynecol, BLI-447,221 Longwood Ave, Boston, MA 02115 USA. EM scmok@rics.bwh.harvard.edu FU Intramural NIH HHS; NCI NIH HHS [P50CA083639, P50CA105009, R33CA103595] NR 27 TC 74 Z9 76 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 JUN 1 PY 2007 VL 25 IS 16 BP 2281 EP 2287 DI 10.1200/JCO.2006.09.0795 PG 7 WC Oncology SC Oncology GA 175JR UT WOS:000247010400023 PM 17538174 ER PT J AU Faber, CA Dobolyi, A Sleeman, M Usdin, TB AF Faber, Catherine A. Dobolyi, Arpad Sleeman, Mark Usdin, Ted B. TI Distribution of tuberoinfundibular peptide of 39 residues and its receptor, parathyroid hormone 2 receptor, in the mouse brain SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE tuberoinfundibular peptide of 39 residues; parathyroid hormone 2 receptor; TIP39 and PTH2 receptor in situ hybridization and immunocytochemistry; neuropeptide; neuromodulator; neuroanatomical distribution; transgenic mouse; promoter driven expression ID PTH2 RECEPTOR; SEXUAL-BEHAVIOR; NERVOUS-SYSTEM; LACTATING RATS; EXPRESSION; FOS; HYPOTHALAMUS; ACTIVATION; FOREBRAIN; NEURONS AB Tuberoinfundibular peptide of 39 residues (TIP39) was identified as a potent parathyroid hormone 2 receptor (PTH2R) agonist. Existing anatomical data also support the suggestion that TIP39 is the PTH2R's endogenous ligand, but a comprehensive comparison of TIP39 and PTH2R distributions has not been performed. In the present study, we compared the distributions of TIP39 and PTH2R on adjacent mouse brain sections. In addition, we determined the locations of PTH2R-expressing cell bodies by in situ hybridization histochemistry and by labeling p-galactosidase driven by the PTH2R promoter in knockin mice. An excellent correlation was found between the distributions of TIP39-containing fibers and PTH2R-containing cell bodies and fibers throughout the brain. TIP39 and the PTH2R are abundant in medial prefrontal, insular, and ectorhinal cortices, the lateral septal nucleus, the bed nucleus of the stria terminalis, the fundus striati, the amygdala, the ventral subiculum, the hypothalamus, midline and intralaminar thalamic nuclei, the medial geniculate body, the periaqueductal gray, the ventral tegmental area, the superior and inferior colliculi, the parabrachial nuclei, the locus coeruleus, subcoeruleus and periolivary areas, and the nucleus of the solitary tract. Furthermore, even the subregional distribution of TIP39- and PTH2R-immunoreactive fibers in these regions showed remarkable similarities, providing anatomical evidence that TIP39 may act on the PTH2R. Based on these observations and on previous pharmacological data, we propose that TIP39 is an endogenous ligand of the PTH2R and that they form a neuromodulator system, which is optimally positioned to regulate limbic, endocrine, and auditory brain functions. C1 NIMH, Sect Fundamental Neurosci, Bethesda, MD 20892 USA. Hungarian Acad Sci, Neuromorphol & Neuroendocrinol Res Lab, H-1094 Budapest, Hungary. Semmelweis Univ, H-1094 Budapest, Hungary. Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA. RP Usdin, TB (reprint author), NIMH, Sect Fundamental Neurosci, 35 Convent Dr, Bethesda, MD 20892 USA. EM usdint@mail.nih.gov RI Dobolyi, Arpad/B-9089-2008 FU Intramural NIH HHS [Z01 MH002685-14] NR 40 TC 21 Z9 21 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD JUN 1 PY 2007 VL 502 IS 4 BP 563 EP 583 DI 10.1002/cne.21330 PG 21 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 162IZ UT WOS:000246081800006 PM 17394159 ER PT J AU Przytycka, T AF Przytycka, Teresa TI Stability of characters and construction of phylogenetic trees SO JOURNAL OF COMPUTATIONAL BIOLOGY LA English DT Article; Proceedings Paper CT 10th Annual International Conference on Research in Computational Molecular Biology CY APR 02-05, 2006 CL Venice, ITALY SP Univ Padova, Dept Informat Engn, MIT, Broad Inst, Havard Univ, Broad Inst, Coll Comp Georgia Tech, US Dept Energy, IBM Corp, Int Soc Computat Biol, Italian Assoc Informat & Automat Computat, US Natl Sci Fdn DE character overlap graph; chordal graphs; Coelomata hypothesis; Dollo parsimony; introns; multidomain proteins; promiscuous domains ID ANIMAL PHYLOGENY; GENE-SEQUENCES; CONSERVATION; MORPHOLOGY; EVOLUTION; NETWORKS AB Parsimony methods infer phylogenetic trees by minimizing number of character changes required to explain observed character states. From the perspective of applicability of parsimony methods, it is important to assess whether the characters used to infer phylogeny are likely to provide a correct tree. We introduce a graph theoretical characterization that helps to assess whether given set of characters is appropriate to use with parsimony methods. Given a set of characters and a set of taxa, we construct a network called character overlap graph. We show that the character overlap graph for characters that are appropriate to use in parsimony methods is characterized by significant under-representation of subnetworks known as holes, and provide a validation for this observation. This characterization explains success in constructing evolutionary trees using parsimony method for some characters (e.g., protein domains) and lack of such success for other characters (e.g., introns). In the latter case, the understanding of obstacles to applying parsimony methods in a direct way has lead us to a new approach for detecting inconsistent and/or noisy data. Namely, we introduce the concept of stable characters which is similar but less restrictive than the well known concept of pairwise compatible characters. Application of this approach to introns produces the evolutionary tree consistent with the Coelomata hypothesis. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Przytycka, T (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM przytyck@mail.nih.gov FU Intramural NIH HHS NR 35 TC 3 Z9 3 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1066-5277 J9 J COMPUT BIOL JI J. Comput. Biol. PD JUN PY 2007 VL 14 IS 5 BP 539 EP 549 DI 10.1089/cmb.2007.R001 PG 11 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 188NR UT WOS:000247927100002 PM 17683259 ER PT J AU Coleman, J Singh, A Pinto, P Phillips, J Pritchard, W Wray-Cahen, D Wood, BJ AF Coleman, Jonathan Singh, Amar Pinto, Peter Phillips, John Pritchard, William Wray-Cahen, Diane Wood, Bradford J. TI Radiofrequency-assisted laparoscopic partial nephrectomy: Clinical and histologic results SO JOURNAL OF ENDOUROLOGY LA English DT Article ID RADIO-FREQUENCY ABLATION; RENAL-CELL CARCINOMA; SPARING SURGERY; EXPERIENCE; DEVICE; TUMORS; MASSES; MODEL AB Purpose: To evaluate a surface conductive radiofrequency (RF) coagulation instrument (Tissuelink FB3.0) in laparoscopic and open partial nephrectomy (PN) in hereditary kidney cancer. The lesion depth and viability in the pathologic specimens from a surgical series and an acute porcine model were characterized under conditions of vascular perfusion and occlusion. Materials and Methods: A total of 19 patients underwent 20 laparoscopic and open procedures with the device. Data were acquired on tumor number, size, operative time, blood loss, length of stay, renal function, complications, pathologic diagnosis, and surgical-margin status. Renal lesions were created in pigs with the device, ultrasonic shears, and a standard electrocautery for specified time intervals and operative energy settings. These lesions were analyzed for depth, diameter, and tissue viability. Results: In 20 separate (14 laparoscopic; 6 open) procedures in 19 patients, a total of 112 tumors were removed (range 1-31 tumors per procedure). The median operative time, blood loss, and length of stay were 310 minutes, 250 mL, and 4 days, respectively. There were no positive surgical margins. Median preoperative and postoperative creatinine concentrations were similar (1.0 v 1.0 mg/dL). The average treatment margin depth was 3 mm. In the porcine experiments, the treatment depth in the unclamped vascular model was significantly less in than the clamped model (4.0 +/- 1.7 mm v 7.0 +/- 1.6 mm; P < 0.05). Lesion depth and diameter increased with treatment time. Viability depth correlated well with the depth of the visible thermal lesions (Pearson correlation 0.989). Conclusions: This RF energy device can provided adequate and uniform hemostatic control without hilar clamping during laparoscopic and open PN for hereditary renal tumors. Gross measures of renal function after surgery appeared clinically unchanged. Coagulation depth is dependent on both tissue perfusion and time in the porcine model. C1 NIH, Urol Oncol Branch, Bethesda, MD 20892 USA. NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. US FDA, Rockville, MD 20857 USA. RP Coleman, J (reprint author), NIH, Urol Oncol Branch, Bldg 10, Bethesda, MD 20892 USA. EM colemanj@mail.nih.gov OI Coleman, Jonathan/0000-0002-6428-7835 FU Intramural NIH HHS [Z99 CL999999] NR 21 TC 15 Z9 15 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0892-7790 J9 J ENDOUROL JI J. Endourol. PD JUN PY 2007 VL 21 IS 6 BP 600 EP 605 DI 10.1089/end.2006.0223 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 190SM UT WOS:000248079700006 PM 17638553 ER PT J AU Rossi, PG Beccaro, M Miccinesi, G Borgia, P Costantini, M Chini, F Baiocchi, D De Giacomi, G Grimaldi, M Montella, M AF Rossi, Paolo Giorgi Beccaro, Monica Miccinesi, Guido Borgia, Piero Costantini, Massimo Chini, Francesco Baiocchi, Diego De Giacomi, Giovanna Grimaldi, Maria Montella, Maurizio CA ISDOC Working Grp TI Dying of cancer in Italy: impact on family and caregiver. The Italian Survey of Dying of Cancer SO JOURNAL OF EPIDEMIOLOGY AND COMMUNITY HEALTH LA English DT Article ID QUALITY-OF-LIFE; HOME-CARE; HEALTH; DEATH; PATIENT; MORTALITY; SERVICES; BURDEN; SPOUSE; COSTS AB Objective: To describe the effect of terminal cancer on the patient's family, finances and daily life. Methods: A cluster sample of 2000 adults (>= 18 years old) who had died from cancer, and who were representative of Italy, was studied. 1900 caregivers were identified and 68% responded to a post-bereavement survey. Caregivers included the patient's child (46%), his/her spouse (31%), other relatives or friends (20%) or a health professional (3%). The median age of a caregiver was 54 years and 69% were females. During the last 3 months of the patient's life, 44% of caregivers reported difficulties in their regular employment. Results: Of the 68% of families who had to pay for some of the care, 37% had to pay for drugs, 36% for nursing and assistance and 22% for physicians. Paying for care was more frequent in the south of Italy (OR 2.5; 95% CI 1.0 to 6.3) and when the patient was a housewife (OR for unit increase 2.7; 95% CI 1.6 to 6.1). To cover the costs of patient care, 26% of families used all or most of their savings. Economic difficulties were greater in the south of Italy (OR 3; 95% CI 1.8 to 5.1), for female caregivers (OR 1.4; 95% CI 1.0 to 1.9) and for disadvantaged patients. The duration of time the patient was completely dependent strongly determined the effect caregiving had on their regular employment and on the family's financial situation. Conclusions: Although in Italy families are responsible for a small percentage of the overall costs of patient care, the effect of cancer on savings and daily life can be substantial. Strong geographical and gender differences emerged from this study. C1 Agcy Publ Hlth, I-00198 Rome, Italy. Natl Canc Inst, Clin Epidemiol Unit, Genoa, Italy. Ctr Study & Prevent Canc, Florence, Italy. Natl Agcy Reg Hlth Serv, Rome, Italy. G Pascale Fdn, Dept Epidemiol, Natl Canc Inst, Naples, Italy. RP Rossi, PG (reprint author), Agcy Publ Hlth, Via S Costanza 53, I-00198 Rome, Italy. EM giorgirossi@asplazio.it RI Pisanti, Renato/G-6232-2010; costantini, massimo/G-1443-2012; Giorgi Rossi, Paolo/K-6367-2016; OI Giorgi Rossi, Paolo/0000-0001-9703-2460; costantini, massimo/0000-0002-5293-7079; Bruzzi, Paolo/0000-0002-7874-2077; Pisanti, Renato/0000-0002-8153-2177 NR 31 TC 19 Z9 19 U1 0 U2 3 PU BMJ PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0143-005X EI 1470-2738 J9 J EPIDEMIOL COMMUN H JI J. Epidemiol. Community Health PD JUN PY 2007 VL 61 IS 6 BP 547 EP 554 DI 10.1136/jech.2005.045138 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 167EU UT WOS:000246434800015 ER PT J AU Heredia-Moya, J Kirk, KL AF Heredia-Moya, Jorge Kirk, Kenneth L. TI Photochemical Schiemann reaction in ionic liquids SO JOURNAL OF FLUORINE CHEMISTRY LA English DT Article DE photochemistry; ionic liquid; imidazole; Schiemann reaction ID PHOTOINDUCED ELECTRON-TRANSFER; RING-FLUORINATED IMIDAZOLES; DIAZONIUM SALTS; PHOTOLYTIC DEGRADATION; MEDIA; PHOTOISOMERIZATION; DECOMPOSITION; SOLVENTS AB Photochemical Schiemann reactions of imidazole derivatives 1 and 4 were carried out in 1-butyl-3-methylimidazolium tetrafluoroborate ionic liquid [bmim] [BF4] as solvent. The effects of temperature, co-solvent and wavelength on the rate of the reaction and product yield were examined. The use of ionic liquid increases the yield of the photochemical fluorodediazoniation reaction of 2 at 0 degrees C. Careful temperature control is necessary to minimize the photodecomposition of the ionic liquid in order to increase the yield of product. (c) 2007 Elsevier B.V. All rights reserved. C1 NIDDKD, NIH, Lab Bioorgan Chem, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Kirk, KL (reprint author), NIDDKD, NIH, Lab Bioorgan Chem, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM kennethk@intra.niddk.nih.gov FU Intramural NIH HHS [Z01 DK031113-31, Z99 DK999999] NR 28 TC 14 Z9 14 U1 1 U2 4 PU ELSEVIER SCIENCE SA PI LAUSANNE PA PO BOX 564, 1001 LAUSANNE, SWITZERLAND SN 0022-1139 J9 J FLUORINE CHEM JI J. Fluor. Chem. PD JUN PY 2007 VL 128 IS 6 BP 674 EP 678 DI 10.1016/j.jfluchem.2007.03.012 PG 5 WC Chemistry, Inorganic & Nuclear; Chemistry, Organic SC Chemistry GA 181FV UT WOS:000247423400013 PM 18079989 ER PT J AU Kotin, RM AF Kotin, Robert M. TI Production requirements for recombinant adeno-associated virus gene therapies SO JOURNAL OF GENE MEDICINE LA English DT Meeting Abstract CT 5th Meeting of the Australasian-Gene-Therapy-Society CY APR 18-20, 2007 CL Shine Dome Acad Sci, Canberra, AUSTRALIA SP Australasian Gene Therapy Soc HO Shine Dome Acad Sci C1 NHLBI, Lab Biochem Genet, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1099-498X J9 J GENE MED JI J. Gene. Med. PD JUN PY 2007 VL 9 IS 6 BP 524 EP 524 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 186CI UT WOS:000247756300012 ER PT J AU Toth, ZE Mezey, E AF Toth, Zsuzsanna E. Mezey, Eva TI Simultaneous visualization of multiple antigens with tyramide signal amplification using antibodies from the same species SO JOURNAL OF HISTOCHEMISTRY & CYTOCHEMISTRY LA English DT Article DE immunohistochemistry; multiple antigens; multiplex detection; tyramide signal amplification ID IN-SITU HYBRIDIZATION; PARAFFIN-EMBEDDED TISSUE; DIAGNOSTIC IMMUNOHISTOCHEMISTRY; MICROWAVE TREATMENT; RETRIEVAL; RAT; COLOCALIZATION; PRETREATMENT; ENDORPHIN; NUCLEAR AB After immunohistochemistry (IHC) began to be used routinely, a number of investigators worked on methods for staining multiple molecules in the same tissue sections or cells. Achieving this goal was not easy, however. One reason for this is that the majority of primary antibodies used in IHC reactions are raised in rabbits, and recognizing signals from two different rabbit antibodies is not trivial. Thus, all of the protocols described to date have serious limitations. Here we report a simple, quick, and inexpensive solution to the problem. it has two major advantages over existing methods. First, by using antibodies from the same host, two or more antigens can be visualized in the same section with commercially available fluorescent dyes. Second, because the technique relies on signal amplification, both rare and abundant antigens can be detected. C1 NIDCR, NIH, CSDB, Bethesda, MD 20892 USA. Semmelweis Univ, Dept Anat Histol & Embryol, Neuromorphol Lab, H-1085 Budapest, Hungary. Hungarian Acad Sci, Budapest, Hungary. RP Toth, ZE (reprint author), NIDCR, NIH, CSDB, Bethesda, MD 20892 USA. EM tothzs@ana.sote.hu FU Intramural NIH HHS NR 30 TC 53 Z9 53 U1 0 U2 8 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 0022-1554 J9 J HISTOCHEM CYTOCHEM JI J. Histochem. Cytochem. PD JUN PY 2007 VL 55 IS 6 BP 545 EP 554 DI 10.1369/jhc.6A7134.2007 PG 10 WC Cell Biology SC Cell Biology GA 170CW UT WOS:000246640500002 PM 17242468 ER PT J AU Rochman, I Watanabe, N Arima, K Liu, YJ Leonard, WJ AF Rochman, Irina Watanabe, Norihiko Arima, Kazuhiko Liu, Yong-Jun Leonard, Warren J. TI Cutting edge: Direct action of thymic stromal lymphopoietin on activated human CD4(+) T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SEVERE COMBINED IMMUNODEFICIENCY; IGM(+) B-CELLS; INTERLEUKIN-7 RECEPTOR; IN-VITRO; MICE; CYTOKINE; STAT5; TSLP; INFLAMMATION; EXPRESSION AB Thymic stromal lymphopoietin (TSLP) is a cytokine that promotes CD4(+) T cell homeostasis and contributes to allergic and inflammatory responses. TSLP can act directly on mouse CD4(+) T cells, but in humans, the available data have indicated that TSLP receptors are not expressed on CD4(+) T cells and that TSLP instead activates dendritic cells, which in turn promote the proliferation and differentiation of CD4(+) T cells. We now unexpectedly demonstrate the presence of TSLP receptors on activated human CD4(+) T cells. Strikingly, whereas freshly isolated peripheral blood human T cells show little if any response to TSLP, TCR stimulation allows a potent response to this cytokine. Moreover, TSLP increases the sensitivity of human CD4(+) T cells to low doses of IL-2, augmenting responsiveness of these cells to TCR engagement. Our results establish that human CD4(+) T cells are direct targets for TSLP. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Immunol, Houston, TX 77230 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10,Room 7B05, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov RI Arima, Kazuhiko/I-8962-2014 OI Arima, Kazuhiko/0000-0002-0607-8787 NR 25 TC 113 Z9 115 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2007 VL 178 IS 11 BP 6720 EP 6724 PG 5 WC Immunology SC Immunology GA 173TV UT WOS:000246896300009 PM 17513717 ER PT J AU Xu, LL Kitani, A Fuss, I Strober, W AF Xu, LiLi Kitani, Atsushi Fuss, Ivan Strober, Warren TI Cutting edge: Regulatory T cells induce CD4(+)CD25(-)Foxp3(-) T cells or are self-induced to become Th17 cells in the absence of exogenous TGF-beta SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; EXPRESSION AB Recent studies have shown that TGF-beta together with IL-6 induce the differentiation of IL-17-producing T cells (Th17) T cells. We therefore examined whether CD4(+)CD25(+)Foxp3(+) regulatory T cells, i.e., cells previously shown to produce TGF-beta, serve as Th 17 inducers. We found that upon activation purified CD25(+) T cells (or sorted GFP(+) T cells obtained from Foxp3-GFP knockin mice) produce high amounts of soluble TGF-beta and when cultured with CD4(+) CD25(+)FoxP3(-) T cells in the presence of IL-6 induce the latter to differentiate into Th17 cells. Perhaps more importantly, upon activation, CD4+ CD25(+)Foxp3(+) (GFP(+)) T cells themselves differentiate into Th17 cells in the presence of IL-6 (and in the absence of exogenous TGF-beta). These results indicate that CD4+ CD25+Foxp3+ regulatory T cells can function as inducers of Th17 cells and can differentiate into Th17 cells. They thus have important implications to our understanding of regulatory T cell function and their possible therapeutic use. C1 NIAID, Mucosal Immun Sect, Lab Host Def, NIH, Bethesda, MD 20892 USA. RP Strober, W (reprint author), NIAID, Mucosal Immun Sect, Lab Host Def, NIH, Room 5W3940,10 Ctr Dr, Bethesda, MD 20892 USA. EM wstrober@niaid.nih.gov NR 12 TC 425 Z9 454 U1 1 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2007 VL 178 IS 11 BP 6725 EP 6729 PG 5 WC Immunology SC Immunology GA 173TV UT WOS:000246896300010 PM 17513718 ER PT J AU Stephens, GL Andersson, J Shevach, EM AF Stephens, Geoffrey L. Andersson, John Shevach, Ethan M. TI Distinct subsets of FoxP3(+) regulatory T cells participate in the control of immune responses SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TRANSCRIPTION FACTOR FOXP3; EPITHELIAL-CELLS; IN-VIVO; POSITIVE SELECTION; REG CELLS; MICE; LYMPHOCYTES; CD25(+); MHC; RECEPTOR AB Expression of the transcription factor FoxP3 is the hallmark of regulatory T cells that play a crucial role in dampening immune responses. A comparison of the development and phenotype of FoxP3(+) T cells in relation to the expression of conventional MHC molecules facilitated the identification of several distinct lineages of naive and effector/memory populations of Foxp3(+) T cells. One subpopulation of effector/memory Foxp3+ T cells develops in the thymic medulla, whereas the second is thymic independent. Both lineages display a distinct activated phenotype, undergo extensive steady-state proliferation, home to sites of acute inflammation, and are unique in their capacity to mediate Ag-nonspecific suppression of T cell activation directly ex vivo. Effector FoxP3(+) T cells may act as a sentinel of tolerance, providing a first line of defense against potentially harmful responses by rapidly suppressing immunity to peripheral self-Ags. C1 NIAID, Cellular Immunol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Cellular Immunol Sect, Immunol Lab, NIH, Bldg 10,Room 11N315,10 Ctr Dr,MSC-1892, Bethesda, MD 20892 USA. EM eshevach@niaid.nih.gov RI Andersson, John/A-4436-2009; OI Andersson, John/0000-0003-2799-6349 FU Intramural NIH HHS NR 46 TC 63 Z9 65 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2007 VL 178 IS 11 BP 6901 EP 6911 PG 11 WC Immunology SC Immunology GA 173TV UT WOS:000246896300031 PM 17513739 ER PT J AU Ho, J Moir, S Kulik, L Malaspina, A Donoghue, ET Miller, NJ Wang, W Chun, TW Fauci, AS Holers, VM AF Ho, Jason Moir, Susan Kulik, Liudmila Malaspina, Angela Donoghue, Eileen T. Miller, Natalie J. Wang, Wei Chun, Tae-Wook Fauci, Anthony S. Holers, V. Michael TI Role for CD21 in the establishment of an extracellular HIV reservoir in lymphoid tissues SO JOURNAL OF IMMUNOLOGY LA English DT Article ID FOLLICULAR DENDRITIC CELLS; IMMUNODEFICIENCY-VIRUS TYPE-1; CD4(+) T-CELLS; ANTIRETROVIRAL THERAPY; MOUSE COMPLEMENT; B-CELLS; HIV-1-INFECTED PATIENTS; GERMINAL-CENTERS; INFECTIOUS HIV; RECEPTOR AB Follicular dendritic cells (FDC) represent a major extracellular reservoir for HIV. A better understanding of the mechanisms of virion attachment to FDC may offer new avenues for reducing viral burdens in infected individuals. We used a murine model to investigate the establishment of extracellular HIV reservoirs in lymph nodes (LN). Consistent with findings in human tissues, CD21 was required for trapping of HIV to LN cells, as evidenced by significantly reduced virion binding when mice were pretreated with a C3 ligand-blocking anti-CD21 mAb and absence of virion trapping in CD21 knockout mice. Also consistent with findings in human tissues, the majority of HIV virions were associated with the FDC-enriched fraction of LN cell preparations. Somewhat surprisingly, HIV-specific Abs were not essential for HIV binding to LN cells, indicating that seeding of the FDC reservoir may begin shortly after infection and before the development of HIV-specific Abs. Finally, the virion-displacing potential for anti-CD21 mAbs was investigated. Treatment of mice with anti-CD21 mAbs several days after injection of HIV significantly reduced HIV bound to LN cells. Our findings demonstrate a critical role for CD21 in HIV trapping by LN cells and suggest a new therapeutic avenue for reducing HIV reservoirs. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Univ Colorado, Hlth Sci Ctr, Dept Med & Immunol, Denver, CO 80262 USA. RP Moir, S (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 6A02,10 Ctr Dr, Bethesda, MD 20892 USA. EM smoir@niaid.nih.gov FU Intramural NIH HHS; NCI NIH HHS [R01-CA53615] NR 52 TC 21 Z9 22 U1 1 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2007 VL 178 IS 11 BP 6968 EP 6974 PG 7 WC Immunology SC Immunology GA 173TV UT WOS:000246896300038 PM 17513746 ER PT J AU Wang, W Milani, M Ostlie, N Okita, D Agarwal, RK Caspi, R Conti-Fine, BM AF Wang, Wei Milani, Monica Ostlie, Norma Okita, David Agarwal, Rajeev K. Caspi, Rachel Conti-Fine, Bianca M. TI C57BL/6 mice genetically deficient in IL-12/IL-23 and IFN-gamma are susceptible to experimental autoimmune myasthenia gravis, suggesting a pathogenic role of non-Th1 cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID REGULATORY T-CELLS; ACETYLCHOLINE-RECEPTOR EPITOPES; COLLAGEN-INDUCED ARTHRITIS; NKT CELLS; PREVENTION; TOLERANCE; CYTOKINE; ABSENCE; ENCEPHALOMYELITIS; INDUCTION AB Immunization with Torpedo acetylcholine receptor (TAChR) induces experimental autoimmune myasthenia gravis (EAMG) in C57BL/6 (B6) mice. FAMG development needs IL-12, which drives differentiation of Th1 cells. The role of IFN-gamma, an important Th1 effector, is not clear and that of IL-17, a proinflammatory cytokine produced by Th17 cells, is unknown. In this study, we examined the effect of simultaneous absence of IL-12 and IFN-gamma on EAMG susceptibility, using null mutant B6 mice for the genes of both the IL-12/IL-23 p40 subunit and IFN-gamma (dKO mice). Wild-type (WT) B6 mice served as control for EAMG induction. All mice were immunized with TAChR in Freund's adjuvant. dKO mice developed weaker anti-TAChR center dot CD4(+)T cells and Ali responses than WT mice. Yet, they developed EAMG symptoms, anti-mouse acetylcholine receptor (AChR) Ab, and CD4(+) T cell responses against mouse AChR sequences similar to those of WT mice. dKO and WT mice had similarly reduced AChR content in their muscles, and IgG and complement at the neuromuscular junction. Naive dKO mice had significantly fewer NK, NKT, and CD4(+)CD25(+)Foxp3(+) T regulatory (Treg) cells than naive WT mice. Treg cells from TAChR-immunized dKO mice had significantly less suppressive activity in vitro than Treg cells from TAChR-immunized WT mice. In contrast, TAChR-specific CD4(+) T cells from TAChR-immunized dKO and WT mice secreted comparable amounts of IL-17 after stimulation in vitro with TAChR. The susceptibility of dKO mice to EAMG may be due to reduced Treg function, in the presence of a normal function of pathogenic Th17 cells. C1 Univ Minnesota, Dept Biochem Mol Biol & Biophis, Minneapolis, MN 55455 USA. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Wang, W (reprint author), Univ Minnesota, Dept Biochem Mol Biol & Biophis, 6-155 Jackson Hall,321 Church St, Minneapolis, MN 55455 USA. EM wangx241@umn.edu FU Intramural NIH HHS [Z01 EY000184-25]; NINDS NIH HHS [NS23919, R01 NS023919] NR 43 TC 37 Z9 51 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2007 VL 178 IS 11 BP 7072 EP 7080 PG 9 WC Immunology SC Immunology GA 173TV UT WOS:000246896300048 PM 17513756 ER PT J AU Garrett, JT Rawale, S Allen, SD Phillips, G Forni, G Morris, JC Kaumaya, PTP AF Garrett, Joan T. Rawale, Sharad Allen, Stephanie D. Phillips, Gary Forni, Guido Morris, John C. Kaumaya, Pravin T. P. TI Novel engineered trastuzumab conformational epitopes demonstrate in vitro and in vivo antitumor properties against HER-2/neu SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ANTI-ERBB-2 MONOCLONAL-ANTIBODIES; HER2-POSITIVE BREAST-CANCER; TRANSGENIC MICE; ONCOGENIC PROTEIN; PEPTIDE VACCINE; NEU ONCOGENE; ADJUVANT CHEMOTHERAPY; EXTRACELLULAR DOMAIN; CIRCULAR-DICHROISM; DNA VACCINATION AB Trastuzumab is a growth-inhibitory humanized Ab targeting the oncogenic protein HER-2/neu. Although trastuzumab is approved for treatment of advanced breast cancer, a number of concerns exist with passive immunotherapy. Treatment is expensive and has a limited duration of action, necessitating repeated administrations of the mAb. Active immunotherapy with conformational B cell epitopes affords the possibility of generating an enduring immune response, eliciting protein-reactive high-affinity anti-peptide Abs. The threedimensional structure of human HER-2 in complex with trastuzumab reveals that the Ag-binding region of HER-2 spans residues 563-626 that comprises an extensive disulfide-bonding pattern. To delineate the binding region of HER-2, we have designed four synthetic peptides with different levels of conformational flexibility. Chimeric peptides incorporating the measles virus fusion '' Promiscuous '' T cell epitope via a four-residue tinker sequence were synthesized, purified, and characterized. All conformational peptides were recognized by trastuzumab and prevented the function of trastuzumab inhibiting tumor cell proliferation, with 563-598 and 597-626 showing greater reactivity. All epitopes were immunogenic in FVB/N mice with Abs against 597-626 and 613-626 recognizing HER-2. The 597-626 epitope was immunogenic in outbred rabbits eliciting Abs which recognized HER-2, competed with trastuzumab for the same epitope, inhibited proliferation of HER-2-expressing breast cancer cells in vitro and caused their Ab-dependent cell-mediated cytotoxicity. Moreover, immunization with the 597-626 epitope significantly reduced tumor burden in transgenic BALB-neuT mice. These results suggest the peptide B cell immunogen is appropriate as a vaccine for HER-2-overexpressing cancers because the resulting Abs show analogous biological properties to trastuzumab. C1 Ohio State Univ, Med Res Facil, Dept Obstet & Gynecol, Columbus, OH 43210 USA. Ohio State Univ, Chem Biol Interface Program, Columbus, OH 43210 USA. Ohio State Univ, Ohio State Biochem Program, Columbus, OH 43210 USA. Ohio State Univ, Ctr Biostat, Columbus, OH 43210 USA. Ohio State Univ, Arthur G James Comprehens Canc Ctr, Columbus, OH 43210 USA. NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Turin, Mol Biol Ctr, Dept Clin & Biol Sci, Turin, Italy. RP Kaumaya, PTP (reprint author), Ohio State Univ, Med Res Facil, Dept Obstet & Gynecol, Suite 316,420 W 12th Ave, Columbus, OH 43210 USA. EM kaumaya.1@osu.edu FU NCI NIH HHS [CA 84356] NR 58 TC 35 Z9 38 U1 2 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2007 VL 178 IS 11 BP 7120 EP 7131 PG 12 WC Immunology SC Immunology GA 173TV UT WOS:000246896300053 PM 17513761 ER PT J AU Belyakov, IM Isakov, D Zhu, Q Dzutsev, A Berzofsky, JA AF Belyakov, Igor M. Isakov, Dmitry Zhu, Qing Dzutsev, Amiran Berzofsky, Jay A. TI A novel functional CTL avidity/activity compartmentalization to the site of mucosal immunization contributes to protection of macaques against simian/human immunodeficiency viral depletion of mucosal CD4(+) T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INFECTED RHESUS-MONKEYS; MAJOR HISTOCOMPATIBILITY COMPLEX; VIRUS TYPE-1 INFECTION; EARLY HIV-1 INFECTION; GASTROINTESTINAL-TRACT; INTRANASAL IMMUNIZATION; SYSTEMIC IMMUNIZATION; VACCINE PROTECTION; POXVIRUS INFECTION; NEW-GENERATION AB The presence of high-avidity CTLs in the right compartment can greatly affect clearance of a virus infection (for example, AIDS viral infection of and dissemination from mucosa). Comparing mucosal vs systemic immunization, we observed a novel compartmentalization of CTL avidity and proportion of functionally active Ag-specific CD8(+) T cells to tissues proximal to sites of immunization. Whereas both s.c. and intrarectal routes of immunization induced tetramer(+) cells in the spleen and gut, the mucosal vaccine induced a higher percentage of functioning IFN-gamma(+) Ag-specific CD8(+) T cells in the gut mucosa in mice. Translating to the CD8(+) CTL avidity distribution in rhesus macaques, intrarectal vaccination induced more high-avidity mucosal CTL than s.c. vaccination and protection of mucosal CD4(+) T cells from AIDS viral depletion, whereas systemic immunization induced higher avidity IFN-gamma-secreting cells in the draining lymph nodes but no protection of mucosal CD4(+) T cells, after mucosal challenge with pathogenic simian/human immunodeficiency virus. Mucosal CD4(+) T cell loss is an early critical step in AIDS pathogenesis. The preservation of CD4(+) T cells in colonic lamina propria and the reduction of virus in the intestine correlated better with high-avidity mucosal CTL induced by the mucosal AIDS vaccine. This preferential localization of high-avidity CTL may explain previous differences in vaccination results and may guide future vaccination strategy. C1 NCI, Mol Immunogenet & Vaccine Res Sect, Vaccine Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Belyakov, IM (reprint author), NCI, Mol Immunogenet & Vaccine Res Sect, Vaccine Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM igorbelyakov@yahoo.com NR 75 TC 77 Z9 80 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2007 VL 178 IS 11 BP 7211 EP 7221 PG 11 WC Immunology SC Immunology GA 173TV UT WOS:000246896300062 PM 17513770 ER PT J AU Nigg, AP Zahn, S Ruckerl, D Holscher, C Yoshimoto, T Ehrchen, JM Wolbing, F Udey, MC von Stebut, E AF Nigg, Axel P. Zahn, Sabine Rueckerl, Dominik Hoelscher, Christoph Yoshimoto, Takayuki Ehrchen, Jan M. Woelbing, Florian Udey, Mark C. von Stebut, Esther TI Dendritic cell-derived IL-12p40 homodimer contributes to susceptibility in cutaneous leishmaniasis in BALB/c mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID P40 HOMODIMER; T-CELLS; INTERLEUKIN (IL)-4; C57BL/6 MICE; TH2 CELLS; IN-VIVO; IMMUNITY; INFECTION; RECEPTOR; MOUSE AB Protection against Leishmania major in resistant C57BL/6 mice is mediated by Th1 cells, whereas susceptibility in BALB/c mice is the result of Th2 development. IL-12 release by L. major-infected dendritic cells (DC) is critically involved in differentiation of Th1 cells. Previously, we reported that strain differences in the production of DC-derived factors, e.g., IL-1a beta, are in part responsible for disparate disease outcome. In the present study, we analyzed the release of IL-12 from DC in more detail. Stimulated DC from C57BL/6 and BALB/c mice released comparable amounts of IL-12p40 and p70. In the absence of IL-4, BALB/c DC produced significantly more IL-12p40 than C57BL/6 DC. Detailed analyses by Western blot and ELISA revealed that one-tenth of IL-12p40 detected in DC supernatants was released as the IL-12 antagonist IL-12p40 homodimer (IL-12p80). BALB/c DC released similar to 2-fold more IL-12p80 than C57BL/6 DC both in vitro and in vivo. Local injection of IL-12p80 during the first 3 days after infection resulted in increased lesion volumes for several weeks in both L. major-infected BALB/c or C57BL/6 mice, in higher lesional parasite burdens, and decreased Th1-cytokine production. Finally, IL-12p40-transgenic C57BL/6 mice characterized by overexpression of p40 showed increased levels of serum IL-12p80 and enhanced disease susceptibility. Thus, in addition to IL-1 alpha beta, strain-dependent differences in the release of other DC-derived factors such as IL-12p80 may influence genetically determined disease outcome. C1 Univ Mainz, Dept Dermatol, D-55131 Mainz, Germany. Forschungszentrum, Borstel, Germany. Tokyo Med Univ, Intractable Immune Syst Dis Res Ctr, Tokyo, Japan. Dept Dermatol, Munster, Germany. NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP von Stebut, E (reprint author), Univ Mainz, Dept Dermatol, Langenbeckstr 1, D-55131 Mainz, Germany. EM vonstebu@mail.uni-mainz.de FU Intramural NIH HHS NR 42 TC 23 Z9 23 U1 1 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2007 VL 178 IS 11 BP 7251 EP 7258 PG 8 WC Immunology SC Immunology GA 173TV UT WOS:000246896300066 PM 17513774 ER PT J AU Kirvan, CA Cox, CJ Swedo, SE Cunningham, MW AF Kirvan, Christine A. Cox, Carol J. Swedo, Susan E. Cunningham, Madeleine W. TI Tubulin is a neuronal target of autoantibodies in Sydenham's chorea SO JOURNAL OF IMMUNOLOGY LA English DT Article ID STREPTOCOCCAL-M-PROTEINS; BETA-D-GLUCOSAMINE; MONOCLONAL-ANTIBODIES; RHEUMATIC CARDITIS; GROUP-A; MOLECULAR ANALYSIS; MYOSIN; RECOGNIZES; EPITOPES; MIMICRY AB Sydenham's chorea is a CNS disorder and sequela of group A streptococcal infection where deposition of Abs in brain may result in movement and neuropsychiatric abnormalities. We studied human mAbs 24.3.1, 31.1.1, and 37.2.1 derived from chorea and selected for cross-reactivity with group A streptococci and brain Ags. Our novel findings reveal that Sydenham's chorea mAbs target a 55-kDa brain protein with an N-terminal amino acid sequence of MREIVHLQ corresponding to beta-tubulin. Chorea mAb specificity for purified brain tubulin was confirmed in ELISA and Western immunoblot, and significant levels of anti-tubulin IgG were found in acute chorea sera and cerebrospinal fluid. Lysoganglioside G(M1) inhibited binding of chorea mAbs to tubulin and mAb reactivity with human caudate and putamen brain sections was blocked by anti-tubulin mAb. The chorea mAbs labeled both intra- and extracellular Ags of a neuronal cell line providing evidence suggesting mimicry between intracellular brain protein tubulin and extracellular lysoganglioside. In addition, chorea mAb 24.3.1 and acute chorea sera induced calcium/calmodulindependent protein kinase II activity in human neuronal cells. Nucleotide sequence analysis of the chorea mAb V-H genes revealed that mAb 24.3.1 V-H gene was encoded by the V(H)1 germline gene family which encodes other anti-ganglioside V-H genes associated with motor neuropathies. mAb recognition of tubulin and the neuronal cell surface with initiation of cell signaling and dopamine release supports an emerging theme in autoimmnunity whereby cross-reactive or polyreactive autoantibodies against intracellular Ags recognize cell surface epitopes potentially leading to disease. C1 Univ Oklahoma, Biomed Res Ctr, Dept Microbiol & Immunol, Oklahoma City, OK 73104 USA. Calif State Univ Sacramento, Dept Biol Sci, Sacramento, CA 95819 USA. NIMH, Pediat & Dev Neuropsychiat Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Cunningham, MW (reprint author), Univ Oklahoma, Biomed Res Ctr, Dept Microbiol & Immunol, Room 217,975 NE 10th St, Oklahoma City, OK 73104 USA. EM madeleine-cunningham@ouhsc.edu FU NHLBI NIH HHS [HL35280, HL56267] NR 32 TC 53 Z9 53 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2007 VL 178 IS 11 BP 7412 EP 7421 PG 10 WC Immunology SC Immunology GA 173TV UT WOS:000246896300084 PM 17513792 ER PT J AU Jiang, CC Foley, J Clayton, N Kissling, G Jokinen, M Herbert, R Diaz, M AF Jiang, Chuancang Foley, Julie Clayton, Natasha Kissling, Grace Jokinen, Micheal Herbert, Ronald Diaz, Marilyn TI Abrogation of lupus nephritis in activation-induced deaminase-deficient MRL/lpr mice SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TERMINAL DEOXYNUCLEOTIDYL TRANSFERASE; ANTI-DNA ANTIBODIES; DECREASES AUTOIMMUNE-DISEASE; AUTOREACTIVE B-CELLS; SOMATIC HYPERMUTATION; IMMUNE-RESPONSE; AUTOANTIBODY PRODUCTION; GERMINAL-CENTERS; APOPTOTIC CELLS; RENAL-DISEASE AB We generated MRL/Ipr mice deficient in activation-induced deaminase (AID). Because AID is required for Ig hypermutation and class switch recombination, these mice lack hypermutated IgG Abs. Unlike their AID wild-type littermates, AID-deficient MRL/Ipr mice not only lacked autoreactive IgG Abs but also experienced a dramatic increase in the levels of autoreactive IgM. This phenotype in AID-deficient mice translated into a significant reduction in glomerulonephritis, minimal mononuclear cell infiltration in the kidney, and a dramatic increase in survival to levels comparable to those previously reported for MRL/Ipr mice completely lacking B cells and well below those of mice lacking secreted Abs. Therefore, this study wherein littermates with either high levels of autoreactive IgM or autoreactive IgG were directly examined proves that autoreactive IgM Abs alone are not sufficient to promote kidney disease in MRL/Ipr mice. In addition, the substantial decrease in mortality combined with a dramatic increase in autoreactive IgM Abs in AID-deficient MRL/Ipr mice suggest that autoreactive IgM Abs might not only fail to promote nephritis but may also provide a protective role in MRL/Ipr mice. This novel mouse model containing high levels of autoreactive, unmutated IgM Abs will help delineate the contribution of autoreactive IgM to autoimmunity. C1 NIEHS, Genet Mol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Expt Pathol, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. Chalk River Labs, Pathol Associates, Cary, NC 27513 USA. RP Diaz, M (reprint author), NIEHS, Genet Mol Lab, NIH, D3-01,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM diaz@niehs.nih.gov FU Intramural NIH HHS [Z01 ES101603-05] NR 75 TC 63 Z9 63 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD JUN 1 PY 2007 VL 178 IS 11 BP 7422 EP 7431 PG 10 WC Immunology SC Immunology GA 173TV UT WOS:000246896300085 PM 17513793 ER PT J AU Plummer, M Schiffman, M Castle, PE Maucort-Boulch, D Wheeler, CM AF Plummer, Martyn Schiffman, Mark Castle, Philip E. Maucort-Boulch, Delphine Wheeler, Cosette M. CA ALTS Grp TI A 2-year prospective study of human papillomavirus persistence among women with a cytological diagnosis of atypical squamous cells of undetermined significance or low-grade squamous intraepithelial lesion SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID CERVICAL-CANCER; RANDOMIZED-TRIAL; YOUNG-WOMEN; VIRAL LOAD; HPV TYPES; METAANALYSIS; RISK; CARCINOGENICITY; ACQUISITION; PREVENTION AB Background. Cervical cancer is caused by persistent infection with human papillomavirus (HPV). Most infections and associated lesions clear spontaneously. It is important to define the determinants and timing of clearance, so that viral persistence can be recognized and managed. Methods. We investigated HPV natural history among 4504 subjects from ALTS (Atypical Squamous Cells of Undetermined Significance/ Low- Grade Squamous Intraepithelial Lesions Triage Study). A discrete- time Markov model was used to simultaneously describe the prevalence, incidence, and persistence of type- specific HPV infection over 24 months in women with equivocal or mildly abnormal cytological results. Interactions between multiple HPV types infecting the same woman were examined for incidence of new infection (after an HPV- 16 infection) and persistence of a current infection within groups defined by phylogenetic relatedness or by carcinogenicity. Results. Ninety-one percent (95% credible interval [CI], 90% - 92%) of prevalent HPV infections at enrollment cleared within 24 months. The probability that an infection would persist for a further 6 months increased with the duration of infection, from 37% (95% CI, 35% - 39%) for a newly observed infection to 65% (95% CI, 61% 70%) for an infection that had already persisted for similar to 18 months. No consistent evidence of interactions was found between multiple HPV types regarding the incidence of new infection after an HPV- 16 infection or regarding persistence of current HPV infection. Conclusion. Although virtually all HPV infections clear within 2 years, the remaining infections have a high potential for persistence and, by implication, progression to precancer and cancer. Once biological and behavioral determinants are controlled for, HPV infections with different types seem to be independent of each other. C1 Int Agcy Res Canc, F-69372 Lyon 08, France. Hospices Civils Lyon, Serv Biostat Lyon, Lyon, France. Univ Lyon 1, Villeurbanne, France. CNRS UMR 5558, Lab Biosat Sante, Pierre Benite, France. NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, Dept Hlth & Human Serv,NIH, Rockville, MD USA. Univ New Mexico, Ctr Hlth Sci, Sch Med, Dept Mol Genet & Microbiol, Albuquerque, NM 87131 USA. Univ New Mexico, Ctr Hlth Sci, Sch Med, Dept Obstet & Gynecol, Albuquerque, NM 87131 USA. RP Plummer, M (reprint author), Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon 08, France. EM plummer@iarc.fr OI Plummer, Martyn/0000-0001-5130-6497 FU Intramural NIH HHS; NCI NIH HHS [CN55154, CN55105, CN55153, CN55155, CN55156, CN55157, CN55158, CN55159] NR 25 TC 197 Z9 203 U1 0 U2 6 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 JUN 1 PY 2007 VL 195 IS 11 BP 1582 EP 1589 DI 10.1086/516784 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 163ZA UT WOS:000246200700006 PM 17471427 ER PT J AU Voyich, JM Otto, M Mathema, B Kreiswirth, BN DeLeo, FR AF Voyich, Jovanka M. Otto, Michael Mathema, Barun Kreiswirth, Barry N. DeLeo, Frank R. TI How relevant were the models used to measure the impact of Panton-Valentine leukocidin in human staphylococcal infections? Reply SO JOURNAL OF INFECTIOUS DISEASES LA English DT Letter ID VIRULENCE; TOXINS C1 Montana State Univ, Dept Vet Mol Biol, Bozeman, MT 59717 USA. NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, Hamilton, MT USA. Int Ctr Publ Hlth, Publ Hlth Res Inst, TB Ctr, Newark, NJ USA. RP DeLeo, FR (reprint author), Montana State Univ, Dept Vet Mol Biol, Bozeman, MT 59717 USA. EM fdeleo@niaid.nih.gov NR 11 TC 0 Z9 0 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 JUN 1 PY 2007 VL 195 IS 11 BP 1727 EP 1728 DI 10.1086/517527 PG 2 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 163ZA UT WOS:000246200700025 ER PT J AU Knerr, I Pearl, PL Bottiglieri, T Snead, OC Jakobs, O Gibson, KM AF Knerr, I. Pearl, P. L. Bottiglieri, T. Snead, O. Carter Jakobs, O. Gibson, K. M. TI Therapeutic concepts in succinate semialdehyde dehydrogenase (SSADH; ALDH5al) deficiency (gamma-hydroxybutyric aciduria). Hypotheses evolved from 25 years of patient evaluation, studies in Aldh5a1(-/-) mice and characterization of gamma-hydroxybutyric acid pharmacology SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Review ID HYDROXYACID-OXOACID TRANSHYDROGENASE; CULTURED HUMAN-LYMPHOBLASTS; MAGNETIC-RESONANCE-SPECTROSCOPY; KETO REDUCTASE AKR7A5; ABSENCE-LIKE SEIZURES; 4-HYDROXYBUTYRIC ACIDURIA; RAT-BRAIN; RECEPTOR ANTAGONIST; GABA(B) RECEPTORS; AMINOBUTYRIC-ACID AB We overview the pathophysiological bases, clinical approaches and potential therapeutic options for succinate semialdehyde dehydrogenase (SSADH; EC1.2.1.24) deficiency (gamma-hydroxybutyric aciduria, OMIM 271980,610045) in relation to studies on SSADH gene-deleted mice, outcome data developed from 25 years of patient evaluation, and characterization of gamma-hydroxybutyric acid (GHB) pharmacology in different species. The clinical picture of this disorder encompasses a wide spectrum of neurological and psychiatric dysfunction, such as psychomotor retardation, delayed speech development, epileptic seizures and behavioural disturbances, emphasizing the multifactorial pathophysiology of SSADH deficiency. The murine SSADH(-/-)(e.g. Aldh5a1(-/-)) mouse model suffers from epileptic seizures and succumbs to early lethality. Aldh5a1(-/-) mice accumulate GHB and gamma-aminobutyric acid (GABA) in the central nervous system, exhibit alterations of amino acids such as glutamine (G1n), alanine (Ala) and arginine (Arg), and manifest disturbances in other systems including dopamine, neurosteroids and antioxidant status. Therapeutic concepts in patients with SSADH deficiency and preclinical therapeutic experiments are discussed in light of data collected from research in Aldh5a1(-/-) mice and animal studies of GHB pharmacology; these studies are the foundation for novel working approaches, including pharmacological and dietary trials, which are presented for future evaluation in this disease. C1 Childrens Hosp Pittsburgh, Div Med Genet, Pittsburgh, PA 15213 USA. Univ Erlangen Nurnberg, Childrens & Andolescents Hosp, Erlangen, Germany. George Washington Univ, Sch Med, Childrens Natl Med Ctr, Dept Neurol, Washington, DC USA. NINDS, Clin Epilepsy Branch, NIH, Maryville, MO USA. Baylor Univ, Med Ctr, Inst Metab Dis, Dallas, TX USA. Hosp Sick Children, Div Neurol, Toronto, ON M5G 1X8, Canada. Vrije Univ Amsterdam, Med Ctr, Amsterdam, Netherlands. Univ Pittsburgh, Sch Med, Div Med Genet,Dept Pediat, Childrens Hosp Pittsburg,Biochem Genet Lab, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Div Med Genet,Dept Pathol, Childrens Hosp Pittsburg,Biochem Genet Lab, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Div Med Genet,Dept Human Genet, Childrens Hosp Pittsburg,Biochem Genet Lab, Pittsburgh, PA USA. RP Gibson, KM (reprint author), Childrens Hosp Pittsburgh, Div Med Genet, Rangos Res Bldg Room 211,3460 5th Ave, Pittsburgh, PA 15213 USA. EM michael.gibson@chp.edu FU NINDS NIH HHS [R01 NS40270] NR 131 TC 29 Z9 29 U1 1 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD JUN PY 2007 VL 30 IS 3 BP 279 EP 293 DI 10.1007/s10545-007-0574-2 PG 15 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 187TR UT WOS:000247871900001 PM 17457693 ER PT J AU Qin, M Smith, CB AF Qin, M. Smith, C. Beebe TI Regionally selective decreases in cerebral glucose metabolism in a mouse model of phenylketonuria SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Article ID MENTAL-RETARDATION; PREFRONTAL CORTEX; WORKING-MEMORY; FRONTAL-CORTEX; DEFICITS; BRAIN; RAT AB Impairment of cognitive function is characteristic of untreated phenylketonuria in humans and in the pah(enu2) mouse model of phenylketonuria. We measured regional cerebral metabolic rate for glucose in the adult male pah(enu2) mouse to determine the effect of PKU on functional activity in brain and to discern what, if any, brain areas are affected. Our results demonstrate selective decreases (17-21%) in regions thought to be involved in executive function. Regions most significantly affected include prelimbic, anterior cingulate, orbital frontal and perirhinal cortex. Sensory and motor areas of cortex and hippocampus were remarkably unaffected. C1 NIH, Cerebral Metab Lab, Unit Neurodaptat & Protein Metab, Bethesda, MD 20892 USA. US PHS, NIH, Dept Hlth & Human Serv, Cerebral Metab Lab, Bethesda, MD USA. RP Smith, CB (reprint author), NIH, Cerebral Metab Lab, Unit Neurodaptat & Protein Metab, Bldg 10,Rm 2D56 10 Ctr dr, Bethesda, MD 20892 USA. EM beebec@intra.nimh.nih.gov FU Intramural NIH HHS NR 30 TC 4 Z9 4 U1 1 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD JUN PY 2007 VL 30 IS 3 BP 318 EP 325 DI 10.1007/s10545-007-0583-1 PG 8 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 187TR UT WOS:000247871900004 PM 17457692 ER PT J AU Brodsky, M Yosef, S Galit, R Albeck, M Longo, DL Albeck, A Sredni, B AF Brodsky, Miri Yosef, Sigal Galit, Rushkin Albeck, Michael Longo, Dan L. Albeck, Amnon Sredni, Benjamin TI The synthetic tellurium compound, AS101, is a novel inhibitor of IL-1 beta converting enzyme SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article ID GAMMA-INDUCING FACTOR; IMMUNOMODULATOR AS101; NITRIC-OXIDE; PROINFLAMMATORY CYTOKINE; RHEUMATOID-ARTHRITIS; TISSUE DESTRUCTION; PLASMA-LEVELS; SEPTIC SHOCK; HOST-DEFENSE; INTERLEUKIN-18 AB The organotellurium compound, trichloro(dioxoethylene-O,O') tellurate (AS101) has been shown previously to exert diverse biologic activities both in vitro and in vivo. This compound was recently found to react with thiols and to catalyze their oxidation. This property of AS101 raises the possibility that it may serve as a cysteine protease inhibitor. In the present study, using a substrate-specific enzymatic assay, we show that treatment of caspase-1 (interleukin-1 beta [IL-1 beta] converting enzyme [ICE]) with AS101 inhibits its enzymatic activity in a dose-dependent manner. Moreover, the results show that AS101 treatment causes a significant reduction in the active form of IL-18 and IL-1 beta in peripheral blood mononuclear cells (PBMC) and in human HaCat keratinocytes. We further demonstrate that the inhibitory effect of AS101 does not involve nitric oxide (NO) or interferon-gamma (IFN-gamma), two possible regulators of IL-18 production, and does not occur at the mRNA level, suggesting a posttranscriptional mechanism of action. More importantly, AS101 downregulates IL-18 and IL-1 beta serum levels in a mouse model of lipopolysaccharide (LPS)-induced sepsis, resulting in increased survival. Recent studies emphasize the pathophysiologic role of IL-18 and IL-beta in a variety of inflammatory diseases. Thus, their blockage by the nontoxic compound, AS101, currently used in clinical studies, may provide clinical advantage in the treatment of these diseases. C1 Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Safdie AIDS & Immunol Res Ctr, CAIR Inst, IL-52900 Ramat Gan, Israel. Bar Ilan Univ, Dept Chem, IL-52900 Ramat Gan, Israel. Bar Ilan Univ, Raoul Wallenberg Chair Immunochem, IL-52900 Ramat Gan, Israel. NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Sredni, B (reprint author), Bar Ilan Univ, Fac Life Sci, Safdie Inst AIDS & Immunol Res, IL-52900 Ramat Gan, Israel. EM srednib@mail.biu.ac.il NR 51 TC 18 Z9 19 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD JUN PY 2007 VL 27 IS 6 BP 453 EP 462 DI 10.1089/jir.2007.0168 PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 182TN UT WOS:000247527000002 PM 17572009 ER PT J AU Ponti, G Venesio, T Losi, L Pellacani, G Bertario, L Sala, P Pedroni, M Petti, C Maffei, S Varesco, L Lerch, E Baggio, A Bassoli, S Longo, C Seidenari, S AF Ponti, Giovanni Venesio, Tiziana Losi, Lorena Pellacani, Giovanni Bertario, Lucio Sala, Paola Pedroni, Monica Petti, Consalvo Maffei, Stefania Varesco, Liliana Lerch, Erika Baggio, Andrea Bassoli, Sara Longo, Caterina Seidenari, Stefania TI BRAF mutations in multiple sebaceous hyperplasias of patients belonging to MYH-associated polyposis pedigrees SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID MICROSATELLITE INSTABILITY; COLORECTAL NEOPLASIA; RAS MUTATIONS; K-RAS; N-RAS; MELANOMA; CARCINOMA; FREQUENCY; CANCER; GENE AB The characteristics of sebaceous gland hyperplasia (SGH) consist of yellowish or skin-colored papules and nodules. Chronic sun exposure and immunosuppressed conditions are the main environmental risk factors, whereas chronological aging regulated by hormones and molecular changes are the intrinsic risk factors. We have evaluated the contribution of BRAF, K-Ras, and N-Ras mutations to the pathogenesis of SGHs in four patients belonging to three MYH-associated polyposis (MAP) pedigrees. MAP is an autosomal-recessive disease characterized by multiple colorectal adenomas and cancer. Immunohistochemistry of mismatch repair and APC proteins was performed. DNA isolated from blood lymphocytes and formalin-fixed or paraffin-em bedded SGHs was PCR amplified and sequenced. In the SGH patients, we detected T1796A heterozygous substitution (V600E) in the BRAF gene. Compound biallelic germline MYH mutations (Y165C/G382D, R168H/379delC, and Y90X/ delGGA464) were detected in the MAP patients. In contrast to the majority of melanocytic lesions, activating hotspot mutations in BRAF have not been involved so far in the pathogenesis of SGH. BRAF mutation is not a specific marker of melanocytic cancerogenesis, and it can also be involved in SGHs. In both melanocytic and non-melanocytic skin tumors, BRAF mutation is linked to early tumorigenesis events. C1 Univ Modena, Dept Internal Med, Div Dermatol, Via Pozzo, I-41100 Modena, Italy. IRCC Inst Canc Res & Treatment, Div Pathol, Candiolo Torino, Italy. Univ Modena, Dept Pathol, I-41100 Modena, Italy. Natl Canc Inst, Dept Predict & Prevent Med, Italian Registry Hereditary Colorectal Tumors, I-20133 Milan, Italy. Univ Modena, Dept Internal Med, Div Med, I-41100 Modena, Italy. Natl Canc Inst, Hereditary Tumors Unit, Genoa, Italy. Oncol Inst So Switzerland, Div Med Oncol, Bellinzona, Switzerland. RP Ponti, G (reprint author), Univ Modena, Dept Internal Med, Div Dermatol, Via Pozzo, I-41100 Modena, Italy. EM ponti.giovanni@unimo.it RI Ponti, Giovanni/A-5565-2012; Losi, Lorena/B-2583-2012; Pedroni, Monica/C-9384-2015; Petti, Consalvo/K-9367-2016; Longo, Caterina/A-8046-2012; pellacani, giovanni/E-8573-2011 OI Ponti, Giovanni/0000-0002-1971-7306; Losi, Lorena/0000-0002-8483-3936; Pedroni, Monica/0000-0001-5374-5362; Petti, Consalvo/0000-0002-3509-3142; Longo, Caterina/0000-0002-8218-3896; pellacani, giovanni/0000-0002-7222-2951 NR 29 TC 12 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-202X EI 1523-1747 J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUN PY 2007 VL 127 IS 6 BP 1387 EP 1391 DI 10.1038/sj.jid.5700723 PG 5 WC Dermatology SC Dermatology GA 169UT UT WOS:000246618300018 PM 17273161 ER PT J AU Sugaya, M Hartley, O Root, MJ Blauvelt, A AF Sugaya, Makoto Hartley, Oliver Root, Michael J. Blauvelt, Andrew TI C34, a membrane fusion inhibitor, blocks HIV infection of Langerhans cells and viral transmission to T cells SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID ENVELOPE GLYCOPROTEIN; VAGINAL TRANSMISSION; 6-HELIX BUNDLES; DENDRITIC CELLS; VIRUS-INFECTION; TYPE-1 GP41; IMMUNODEFICIENCY; CCR5; MICROBICIDES; INDIVIDUALS AB Development of topical microbicides that prevent sexual transmission of HIV is an active area of investigation. The purpose of this study was to test the ability of the potent membrane fusion inhibitor C34, an HIV gp41 antagonist, to block HIV infection of human Langerhans cells (LCs) in an epithelia[ environment that mimics a major route of HIV infection. We incubated freshly isolated epidermal explants containing LCs with various doses of C34 before, during, and after exposing explants to HIV. Although C34 only partially blocked HIV infection of LCs when pre-incubated with skin, it displayed full, dose-dependent inhibition when present during and after viral exposure. The poor protection from HIV infectivity in pre-incubated samples is consistent with mechanism of C34 inhibition and starkly contrasts to the full protection provided by PSC-RANTES, an entry inhibitor that prevents HIV gp120 interaction with its co-receptor CCR5. Real-time PCR confirmed that C34 blocked HIV infection of LCs before reverse transcription and inhibited LC-mediated transfer of virus to T cells. We conclude that C34, if used topically at susceptible mucosal sites, and if continually present, has the potential to block sexual transmission of HIV. C1 Natl Canc Inst, Ctr Canc Res, Dermatol Branch, Bethesda, MD USA. Ctr Med Univ Geneva, Dept Biol Struct & Bioinformat, CH-1211 Geneva, Switzerland. Thomas Jefferson Univ, Dept Biochem & Mol Biol, Philadelphia, PA 19107 USA. RP Blauvelt, A (reprint author), Oregon Hlth & Sci Univ, Dept Dermatol, 3710 SW US Vet Hosp Rd,Mail Code R&D 55, Portland, OR 97239 USA. EM blauvela@ohsu.edu FU Intramural NIH HHS; NIAID NIH HHS [P01 AI 51649-01]; NIGMS NIH HHS [R01 GM66682] NR 44 TC 9 Z9 10 U1 2 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUN PY 2007 VL 127 IS 6 BP 1436 EP 1443 DI 10.1038/sj.jid.5700736 PG 8 WC Dermatology SC Dermatology GA 169UT UT WOS:000246618300024 PM 17255952 ER PT J AU Helip-Wooley, A Westbroek, W Dorward, HM Koshoffer, A Huizing, M Boissy, RE Gahl, WA AF Helip-Wooley, Amanda Westbroek, Wendy Dorward, Heidi M. Koshoffer, Amy Huizing, Marjan Boissy, Raymond E. Gahl, William A. TI Improper trafficking of melanocyte-specific proteins in Hermansky-Pudlak syndrome type-5 SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID LYSOSOME-RELATED ORGANELLES; OCULOCUTANEOUS ALBINISM; HEMORRHAGIC DIATHESIS; BIOGENESIS; COMPLEX; TYROSINASE; BLOC-2; HPS1; MELANOSOMES; ENDOSOMES AB Hermansky-Pudlak syndrome (HPS) is a disorder of lysosome-related organelle biogenesis resulting in melanosome dysfunction and absent platelet dense bodies. HPS patients have oculocutaneous albinism, bruising, and bleeding. HPS-5 results from deficiency of the HPS5 protein, a component of the biogenesis of lysosome-related organelles complex-2 (BLOC-2). HPS5 has an unknown function and lacks homology to known proteins. We performed ultrastructural studies of HPS-5 melanocytes revealing predominantly early-stage melanosomes with many small 3,4(OH)(2)-phenylalanine-positive vesicles throughout the cell body and dendrites. These findings resemble the distinct ultrastructural features of HPS-3 melanocytes; HPS3 is also a BLOC-2 component. Immunofluorescence and immunoEM studies showed decreased TYRP1 labeling in the dendrites of HPS-5 melanocytes, and the overall abundance of TYRP1 was reduced. No substantial differences were observed in the distribution or abundance of Pmel17 in HPS-5 melanocytes. In normal melanocytes, endogenous tyrosinase colocalized with Pmel17 and TYRP1 in the perinuclear area and dendritic tips; this was much reduced in HPS-5 melanocytes, particularly in the tips. We conclude that early stage melanosome formation and Pmel17 trafficking are preserved in HPS5-deficient cells. Tyrosinase and TYRP1 are mistrafficked, however, and fail to be efficiently delivered to melanosomes of HPS-5 melanocytes. C1 NHGRI, NIH, Med Genet Branch, Sect Human Biochem Genet, Bethesda, MD 20892 USA. Univ Cincinnati, Coll Med, Dept Dermatol, Cincinnati, OH USA. RP Helip-Wooley, A (reprint author), NHGRI, NIH, Med Genet Branch, Sect Human Biochem Genet, 10 Ctr Dr,MSC 1851,Bldg 10,Room 10C-103, Bethesda, MD 20892 USA. EM ahwooley@mail.nih.gov RI Koshoffer, Amy/N-2278-2014 OI Koshoffer, Amy/0000-0001-8130-103X FU Intramural NIH HHS NR 30 TC 25 Z9 26 U1 1 U2 3 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD JUN PY 2007 VL 127 IS 6 BP 1471 EP 1478 DI 10.1038/sj.jid.5700737 PG 8 WC Dermatology SC Dermatology GA 169UT UT WOS:000246618300029 PM 17301833 ER PT J AU Chen, L Calomeni, E Wen, J Ozato, K Shen, RL Gao, JX AF Chen, Li Calomeni, Edward Wen, Jing Ozato, Keiko Shen, Rulong Gao, Jian-Xin TI Natural killer dendritic cells are an intermediate of developing dendritic cells SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE differentiation; IFN-producing killer dendritic cells (IKDC); Ly6C(+) monocyles ID T-HELPER TYPE-1; IN-VIVO; IFN-GAMMA; EFFECTOR FUNCTION; MOUSE; DIFFERENTIATION; TUMOR; CD8-ALPHA(+); PRECURSORS; MONOCYTES AB NK dendritic cells (DCs; NKDCs) appear to emerge as a distinct DC subset in humans and rodents, which have the functions of NK cells and DCs. However, the developmental relationship of NKDCs (CD11c(+)NK1.1(+)) to CD11c(+)NK(1.1)DCs has not been addressed. Herein, we show that NKDCs exist exclusively in the compartment of CD11c(+)MHC II- cells in the steady state and express variable levels of DC subset markers, such as the IFN-producing killer DC marker B220, in a tissue-dependent manner. They can differentiate into NK1.1(-) DCs, which is accompanied by the up-regulation of MHC Class II molecules and downregulation of NK1.1 upon adoptive transfer. However, NK cells (NK(+)CD11c(-)) did not differentiate into NK1.1(+) CD11c(+) cells upon adoptive transfer. Bone marrow-derived Ly6C(+) monocytes can be a potential progenitor of NKDCs, as some of them can differentiate into CD11c(+)NK1.1(+) as well as CD11c(+)NK1.1(-) cells in vivo. The steady-state NKDCs have a great capacity to lyse tumor cells but little capability to present antigens. Our studies suggest that NKDCs are an intermediate of developing DCs. These cells appear to bear the unique surface phenotype of CD11c(+)NK1.1(+)MHC II- and possess strong cytotoxic function yet show a poor ability to present antigen in the steady state. These findings suggest that NKDCs may play a critical role in linking innate and adaptive immunity. C1 Ohio State Univ, Dept Pathol, Ctr Med, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Ctr Med, Columbus, OH 43210 USA. NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Gao, JX (reprint author), Ohio State Univ, Dept Pathol, Ctr Med, 129 Hamilton Hall,1645 Neil Ave, Columbus, OH 43210 USA. EM jian-xin.gao@osumc.edu RI Shen, Rulong/E-4079-2011 NR 57 TC 21 Z9 24 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0741-5400 J9 J LEUKOCYTE BIOL JI J. Leukoc. Biol. PD JUN PY 2007 VL 81 IS 6 BP 1422 EP 1433 DI 10.1189/jlb.1106674 PG 12 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 175BY UT WOS:000246988600010 PM 17332372 ER PT J AU Fuda, H Javitt, NB Mitamura, K Ikegawa, S Strott, CA AF Fuda, Hirotoshi Javitt, Normal B. Mitamura, Kuniko Ikegawa, Shigeo Strott, Charles A. TI Oxysterols are substrates for cholesterol sulfotransferase SO JOURNAL OF LIPID RESEARCH LA English DT Article DE steroid/sterol sulfotransferase; 7-ketocholesterol sulfate; cytotoxicity ID HUMAN HYDROXYSTEROID SULFOTRANSFERASE; HUMAN ATHEROSCLEROTIC LESIONS; STEROL 27-HYDROXYLASE; OXIDATION-PRODUCTS; BILE-ACID; HEPATIC-METABOLISM; ENDOTHELIAL-CELLS; LIPID-METABOLISM; 7-KETOCHOLESTEROL; EXPRESSION AB Oxysterols constitute a class of cholesterol derivatives that exhibit broad biological effects ranging from cytotoxicity to regulation of nuclear receptors. The role of oxysterols such as 7-ketocholesterol (7-KC) in the development of retinal macular degeneration and atheromatous lesions is of particular interest, but little is known of their metabolic fate. We establish that the steroid/sterol sulfotransferase SULT2B1b, known to efficiently sulfonate cholesterol, also effectively sulfonates a variety of oxysterols, including 7-KC. The cytotoxic effect of 7-KC on 293T cells was attenuated when these cells, which do not express SULT2B1b, were transfected with SULT2B1b cDNA. Importantly, protection from 7-KC-induced loss of cell viability with transfection correlated with the synthesis of SULT2B1b protein and the production of the 7-KC sulfoconjugate (7-KCS). Moreover, when 7-KCS was added to the culture medium of 293T cells in amounts equimolar to 7-KC, no loss of cell viability occurred. Additionally, MCF-7 cells, which highly express SULT2B1b, were significantly more resistant to the cytotoxic effect of 7-KC. We extended the range of oxysterol substrates for SULT2B1b to include 7 alpha/7 beta-hydroxycholesterol and 5 alpha,6 alpha/5 beta,6 beta-epoxycholesterol as well as the 7 alpha-hydroperoxide derivative of cholesterol. Thus, SULT2B1b, by acting on a variety of oxysterols, offers a potential pathway for modulating in vivo the injurious effects of these compounds. C1 NICHHD, Sect Steroid Regulat, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. Kinki Univ, Fac Pharmaceut Sci, Osaka 5778502, Japan. RP Strott, CA (reprint author), NICHHD, Sect Steroid Regulat, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. EM chastro@mail.nih.gov NR 46 TC 59 Z9 60 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0022-2275 J9 J LIPID RES JI J. Lipid Res. PD JUN PY 2007 VL 48 IS 6 BP 1343 EP 1352 DI 10.1194/jlr.M700018-JLR200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 170JH UT WOS:000246659000011 PM 17347498 ER PT J AU Subramanian, S Koscielniak, JW Devasahayam, N Pursley, RH Pohida, TJ Krishna, MC AF Subramanian, Sankaran Koscielniak, Janusz W. Devasahayam, Nallathamby Pursley, Randall H. Pohida, Thomas J. Krishna, Murali C. TI A new strategy for fast radiofrequency CW EPR imaging: Direct detection with rapid scan and rotating gradients SO JOURNAL OF MAGNETIC RESONANCE LA English DT Article DE CW EPR imaging; rapid-scan; rotating gradient; digital signal processing; DSP; direct detection ID MAGNETIC-RESONANCE; NMR-SPECTROSCOPY; CONTINUOUS-WAVE; ELECTRON; MHZ; RECONSTRUCTION; SPECTRUM AB Rapid field scan on the order of T/s using high frequency sinusoidal or triangular sweep fields superimposed on the main Zeeman field, was used for direct detection of signals without low-frequency field modulation. Simultaneous application of space-encoding rotating field gradients have been employed to perform fast CW EPR imaging using direct detection that could, in principle, approach the speed of pulsed FT EPR imaging. The method takes advantage of the well-known rapid-scan strategy in CW NMR and EPR that allows arbitrarily fast field sweep and the simultaneous application of spinning gradients that allows fast spatial encoding. This leads to fast functional EPR imaging and, depending on the spin concentration, spectrometer sensitivity and detection band width, can provide improved temporal resolution that is important to interrogate dynamics of spin perfusion, pharmacokinetics, spectral spatial imaging, dynamic oxymetry, etc. Published by Elsevier Inc. C1 NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD 21701 USA. NIH, Ctr Informat Technol, Signal Proc & Instrumentat Sect, Bethesda, MD 20892 USA. RP Krishna, MC (reprint author), NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM murali@helix.nih.gov FU Intramural NIH HHS [Z01 BC010478-04] NR 25 TC 25 Z9 25 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1090-7807 J9 J MAGN RESON JI J. Magn. Reson. PD JUN PY 2007 VL 186 IS 2 BP 212 EP 219 DI 10.1016/j.jmr.2007.01.023 PG 8 WC Biochemical Research Methods; Physics, Atomic, Molecular & Chemical; Spectroscopy SC Biochemistry & Molecular Biology; Physics; Spectroscopy GA 182FM UT WOS:000247490500006 PM 17350865 ER PT J AU Zhou, QF Shung, KK Huang, Y AF Zhou, Q. F. Shung, K. K. Huang, Y. TI Improvement electrical properties of sol-gel derived lead zirconate titanate thick films for ultrasonic transducer application SO JOURNAL OF MATERIALS SCIENCE LA English DT Article ID PIEZOELECTRIC PROPERTIES; COMPOSITE; MHZ AB In this work, a fabrication process of piezoelectric PZT [Pb(Zr0.52Ti0.48)O-3] thick films up to 60 mu m deposited on silicon and aluminum substrates is reported. Crystalline spherical modified PZT powder about 300 nm in diameter was used as filler. PZT polymeric precursor produced by Chemat Inc. was used as the matrix material. Spinning films were annealed at 700 degrees C for one hour in the furnace in air. The thickness of the thick films was measured using a scanning electron microscope (SEM). Compared with previous piezoelectric PZT composite films, the modified piezoelectric thick films exhibit better dielectric properties. The dielectric constant is over 780 and dielectric loss is 0.04 at 1 KHz. Using a PiezoCAD model, the high frequency transducer was designed and fabricated. It showed a bandwidth of 75% at 40 MHz. C1 Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. Chemat Technol Inc, Northridge, CA 91324 USA. RP Zhou, QF (reprint author), Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. EM qifazhou@usc.edu NR 12 TC 8 Z9 8 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0022-2461 J9 J MATER SCI JI J. Mater. Sci. PD JUN PY 2007 VL 42 IS 12 BP 4480 EP 4484 DI 10.1007/s10853-006-1414-8 PG 5 WC Materials Science, Multidisciplinary SC Materials Science GA 180XW UT WOS:000247402300045 ER PT J AU Luther, P Winkler, H Taylor, K Craig, R Padron, R Liu, J AF Luther, Pradeep Winkler, Hanspeter Taylor, Kenneth Craig, Roger Padron, Raul Liu, Jun TI Electron tomography reveals the structure of the C-zone in striated muscle SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Meeting Abstract CT 19th World Congress of the International-Society-for-Heart-Research CY JUN 22-25, 2007 CL Bologna, ITALY SP Int Soc Heart Res DE contractile proteins; hypertrophic cardiomyopathy; structure-function C1 Imperial Coll London, London, England. Univ Florida, Gainesville, FL 32611 USA. Univ Massachusetts, Amherst, MA 01003 USA. NIH, Bethesda, MD 20892 USA. OI Padron, Raul/0000-0002-1412-2450 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JUN PY 2007 VL 42 SU 1 BP S121 EP S122 DI 10.1016/j.yjmcc.2007.03.282 PG 2 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 184UV UT WOS:000247669000336 ER PT J AU Maltsev, VA Lakatta, EG AF Maltsev, Victor A. Lakatta, Edward G. TI Intracellular calcium clock ignites membrane clocks: A new theory of cardiac pacemaker function and regulation SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Meeting Abstract CT 19th World Congress of the International-Society-for-Heart-Research CY JUN 22-25, 2007 CL Bologna, ITALY SP Int Soc Heart Res DE calcium; cardiac function; arrhythmias C1 NIH, NIA, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JUN PY 2007 VL 42 SU 1 BP S2 EP S2 DI 10.1016/j.yjmcc.2007.03.006 PG 1 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 184UV UT WOS:000247669000007 ER PT J AU McCarthy, J Opie, L Sack, MN Essop, MF AF McCarthy, Joy Opie, Lionel Sack, Michael N. Essop, M. Faadiel TI Activated PKC epsilon overexpression protects the heart by GSK3 beta-mediated modulation of cardiac glycogen content SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Meeting Abstract CT 19th World Congress of the International-Society-for-Heart-Research CY JUN 22-25, 2007 CL Bologna, ITALY SP Int Soc Heart Res DE PKC epsilon; energy metabolism; mitochondrial function C1 Univ Cape Town, Fac Hlth Sci, Hatter Inst Heart Res, ZA-7925 Cape Town, South Africa. NIH, NHLBI, Washington, DC USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JUN PY 2007 VL 42 SU 1 BP S69 EP S69 DI 10.1016/j.yjmcc.2007.03.801 PG 1 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 184UV UT WOS:000247669000192 ER PT J AU Sun, J Steenbergen, C Murphy, E AF Sun, Junhui Steenbergen, Charles Murphy, Elizabeth TI Preconditioning increases S-nitrosylation of the L-type Ca2+ channel and SERCA2a SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Meeting Abstract CT 19th World Congress of the International-Society-for-Heart-Research CY JUN 22-25, 2007 CL Bologna, ITALY SP Int Soc Heart Res DE preconditioning; S-nitrosylation; cardioprotection C1 NHLBI, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Pathol, Baltimore, MD 21231 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JUN PY 2007 VL 42 SU 1 BP S171 EP S172 DI 10.1016/j.yjmcc.2007.03.526 PG 2 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 184UV UT WOS:000247669000469 ER PT J AU Zhu, WZ Chakir, K Koch, WJ Xiao, RP AF Zhu, Weizhong Chakir, Khalid Koch, Walter J. Xiao, Rui-Ping TI beta ARK1-directed beta(2)-adrenergic receptor coupling to G(i) signaling leads to heart failure SO JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY LA English DT Meeting Abstract CT 19th World Congress of the International-Society-for-Heart-Research CY JUN 22-25, 2007 CL Bologna, ITALY SP Int Soc Heart Res DE beta-adrenergic receptor; hear failure; protein kinase C1 NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2828 EI 1095-8584 J9 J MOL CELL CARDIOL JI J. Mol. Cell. Cardiol. PD JUN PY 2007 VL 42 SU 1 BP S145 EP S145 DI 10.1016/j.yjmcc.2007.03.473 PG 1 WC Cardiac & Cardiovascular Systems; Cell Biology SC Cardiovascular System & Cardiology; Cell Biology GA 184UV UT WOS:000247669000396 ER PT J AU McFeeters, RL Xiong, CY O'Keefe, BR Bokesch, HR McMahon, JB Ratner, DM Castelli, R Seeberger, PH Byrd, RA AF McFeeters, Robert L. Xiong, Changyun O'Keefe, Barry R. Bokesch, Heidi R. McMahon, James B. Ratner, Daniel M. Castelli, Riccardo Seeberger, Peter H. Byrd, R. Andrew TI The novel fold of scytovirin reveals a new twist for antiviral entry inhibitors SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE scytovirin; antiviral; HIV; carbohydrate; hevein ID ANTI-HIV PROTEIN; CYANOBACTERIUM SCYTONEMA-VARIUM; HIGH-MANNOSE OLIGOSACCHARIDES; CHEMICAL-SHIFT INDEX; NMR-SPECTROSCOPY; CYANOVIRIN-N; SECONDARY STRUCTURE; BINDING MODULES; POTENT; RECOGNITION AB The solution structure of the potent 95 residue anti-HIV protein scytovirin has been determined and two carbohydrate-binding sites have been identified. This unique protein, containing five structurally important disulfide bonds, demonstrates a novel fold with no elements of extended regular secondary structure. Scytovirin contains two 39 residue sequence repeats, differing in only three amino acid residues, and each repeat has primary sequence similarity to chitin binding proteins. Both sequence repeats form similarly structured domains, with the exception of one region. The result is two carbohydrate-binding sites with substantially different affinities. The unusual fold clusters aromatic residues in both sites, suggesting a binding mechanism similar to other known hevein-like carbohydrate-binding proteins but differing in carbohydrate specificity. Scytovirin, originally isolated from the cyanobacterium Scytonema varium, holds potential as an HIV entry inhibitor for both therapeutic and prophylactic anti-HIV applications. The high-resolution structural studies reported are an important initial step in unlocking the therapeutic potential of scytovirin. (C) 2007 Elsevier Ltd. All rights reserved. C1 Natl Canc Inst, Struct Biophys Lab, Frederick, MD 21702 USA. Natl Canc Inst, Mol Targets Dev Program, Frederick, MD 21702 USA. Natl Canc Inst, SAIC Frederick, Frederick, MD 21702 USA. MIT, Dept Chem, Cambridge, MA 02139 USA. ETH, Swiss Fed Inst Technol, Organ Chem Lab, CH-8092 Zurich, Switzerland. RP Byrd, RA (reprint author), Natl Canc Inst, Struct Biophys Lab, Frederick, MD 21702 USA. EM rabyrd@ncifcrf.gov RI Byrd, R. Andrew/F-8042-2015 OI Byrd, R. Andrew/0000-0003-3625-4232 FU Intramural NIH HHS [Z01 BC010346-08]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 27 TC 20 Z9 22 U1 0 U2 5 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD JUN 1 PY 2007 VL 369 IS 2 BP 451 EP 461 DI 10.1016/j.jmb.2007.03.030 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 171TF UT WOS:000246757600014 PM 17434526 ER PT J AU Dunham, EJ Holmes, EC AF Dunham, Eleca J. Holmes, Edward C. TI Inferring the timescale of dengue virus evolution under realistic models of DNA substitution SO JOURNAL OF MOLECULAR EVOLUTION LA English DT Article DE dengue virus; covarion; substitution model; molecular clock; phylogeny; natural selection ID MOLECULAR EVOLUTION; THAILAND; PHYLOGENY; BANGKOK AB Dengue virus (DENV) is the agent of the most widespread vector-borne viral disease of humans. To infer the timescale of DENV evolution with as much accuracy as possible, we compared, within a Bayesian Markov Chain Monte Carlo (MCMC) framework, estimates of phylogenetic tree length using both covarion and noncovarion models of molecular evolution, the latter also incorporating lineage-specific rate variation through a "relaxed" molecular clock. Using a data set of 32 complete genome sequences representing all four viral serotypes, we found evidence for covarion-like evolution at second codon positions in specific DENV genes, although rarely at the level of complete gene or genomes. Further, the covarion model had little effect on estimates of tree length and hence time to the Most Recent Common Ancestor (MRCA). We conclude that although covarion models can improve descriptions of the dynamics of amino acid substitution, they have little effect on estimates of the timescale of viral evolution, which in the case of DENV covers a period of no more than 2000 years. C1 Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, University Pk, PA 16802 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Holmes, EC (reprint author), Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, University Pk, PA 16802 USA. EM ech15@psu.edu OI Holmes, Edward/0000-0001-9596-3552 NR 22 TC 18 Z9 18 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0022-2844 J9 J MOL EVOL JI J. Mol. Evol. PD JUN PY 2007 VL 64 IS 6 BP 656 EP 661 DI 10.1007/s00239-006-0278-5 PG 6 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 181DA UT WOS:000247415900006 PM 17541679 ER PT J AU Chen, SN Lankin, DC Nikolic, D Fabricant, DS Lu, ZZ Ramirez, B van Breemen, RB Fong, HHS Farnsworth, NR Pauli, GF AF Chen, Shao-Nong Lankin, David C. Nikolic, Dejan Fabricant, Daniel S. Lu, Zhi-Zhen Ramirez, Benjamin van Breemen, Richard B. Fong, Harry H. S. Farnsworth, Norman R. Pauli, Guido F. TI Chlorination diversifies Cimicifuga racemosa triterpene glycosides SO JOURNAL OF NATURAL PRODUCTS LA English DT Article ID OCCURRING ORGANOHALOGEN COMPOUNDS; BLACK COHOSH EXTRACT; CLIMACTERIC SYMPTOMS; CRYSTAL-STRUCTURE; LIGHT-SCATTERING; EFFICACY; SAFETY; BIOSYNTHESIS; HEPATITIS; MECHANISM AB Extracts from the roots and rhizomes of black cohosh (Cimicifuga racemosa) are widely used as dietary supplements to alleviate menopausal symptoms. State-of-the-art quality control measures involve phytochemical fingerprinting of the triterpene glycosides for species identification and chemical standardization by HPLC. In the course of developing materials and methods for standardization procedures, the major C. racemosa triterpene glycoside (1) was isolated and initially thought to be cimicifugoside (2). Detailed HR-LC-MS and 1D and 2D NMR analysis of 1 and 2 unambiguously revealed that 1 is the chlorine-containing derivative of 2, namely, 25-chlorodeoxycimigenol-3-O-beta-d-xyloside. Accordingly, HPLC profiles of black cohosh preparations require revision of the assignments of the chlorinated (1) and nonchlorinated (2) pair. Besides explaining the substantial shift in polarity (Delta t(R)[RP-18] ca. 20 min), 25-deoxychlorination opens a new pathway of structural diversification in triterpene glycoside chemistry. As chemical conversion of 2 into 1 could be demonstrated, deoxychlorination may be interpreted as artifact formation. Simultaneously, however, it is a potentially significant pathway for the gastric in vivo conversion ("nature's prodrug") of the relatively polar triterpene glycosides into significantly less polar chlorinated derivatives with altered pharmacological properties. C1 Univ Illinois, NIH, Ctr Bot Dietary Supplements Res, Chicago, IL 60612 USA. Univ Illinois, Dept Med Chem & Pharmacognosy, Chicago, IL 60612 USA. Univ Illinois, Program Collaborat Res Pharmaceut Sci, Coll Pharm, Chicago, IL 60612 USA. Univ Illinois, Ctr Struct Biol, Chicago, IL 60612 USA. RP Pauli, GF (reprint author), Univ Illinois, NIH, Ctr Bot Dietary Supplements Res, Chicago, IL 60612 USA. EM gfp@uic.edu OI Pauli, Guido/0000-0003-1022-4326 FU NCCIH NIH HHS [P50 AT000155, P50 AT000155-04, P50 AT000155-05, P50 AT000155-06, P50 AT000155-07, P50 AT000155-08, P50 AT000155-09, P50 AT00155]; NIGMS NIH HHS [GM068944, P41 GM068944] NR 36 TC 5 Z9 7 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0163-3864 J9 J NAT PROD JI J. Nat. Prod. PD JUN PY 2007 VL 70 IS 6 BP 1016 EP 1023 DI 10.1021/np0700319 PG 8 WC Plant Sciences; Chemistry, Medicinal; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy GA 181KQ UT WOS:000247436000022 PM 17555351 ER PT J AU Mattson, MP AF Mattson, M. P. TI The fine line between neuronal plasticity and disease SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 17th European-Society-for-Neurochemistry Meeting/3rd Conference on Advances in Molecular Mechanisms of Neurological Disorder CY MAY 19-22, 2007 CL Salamanca, SPAIN SP European Soc Neurochem C1 NIA, Neurosci Lab, Baltimore, MD 21224 USA. RI Mattson, Mark/F-6038-2012 NR 4 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2007 VL 101 SU 1 BP 1 EP 1 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 160ZT UT WOS:000245984800002 ER PT J AU Hee-Yong, K AF Hee-Yong, K. TI Neurotrophic effects of docosahexaenoic acid; Involvement of phosphatidylserine SO JOURNAL OF NEUROCHEMISTRY LA English DT Meeting Abstract CT 17th European-Society-for-Neurochemistry Meeting/3rd Conference on Advances in Molecular Mechanisms of Neurological Disorder CY MAY 19-22, 2007 CL Salamanca, SPAIN SP European Soc Neurochem C1 NIAAA, Mol Signalling Lab, NIH, Bethesda, MD 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 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD JUN PY 2007 VL 101 SU 1 BP 2 EP 2 PG 1 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 160ZT UT WOS:000245984800003 ER PT J AU Zhu, PJ Lovinger, DM AF Zhu, Ping Jun Lovinger, David M. TI Persistent synaptic activity produces long-lasting enhancement of endocannabinoid modulation and alters long-term synaptic plasticity SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID CANNABINOID RECEPTOR; POTENTIATION; HIPPOCAMPUS; SYNAPSES; NEURONS; SYSTEM; GABA; INTERNEURONS; INDUCTION; TERMINALS AB Learning and memory are thought to involve activity-dependent changes in synaptic efficacy such as long- term potentiation (LTP) and long- term depression (LTD). Recent studies have indicated that endocannabinoid-dependent modulation of inhibitory transmission facilitates induction of hippocampal LTP and that endocannabinoids play a key role in certain forms of LTD. Here, we show that repetitive low-frequency synaptic stimulation (LFS) produces persistent up-regulation of endocannabinoid signaling at hippocampal CA1 GABAergic synapses. This LFS also produces LTD of inhibitory synapses and facilitates LTP at excitatory, glutamatergic synapses. These endocannabinoidmediated plastic changes could contribute to information storage within the brain. C1 NIH, NIAAA, Lab Integrat Neurosci, Bethesda, MD 20892 USA. RP Lovinger, DM (reprint author), NIH, NIAAA, Lab Integrat Neurosci, 5625 Fishers Lane,Rm TS-28, Bethesda, MD 20892 USA. EM lovindav@mail.nih.gov NR 28 TC 38 Z9 40 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD JUN PY 2007 VL 97 IS 6 BP 4386 EP 4389 DI 10.1152/jn.01228.2006 PG 4 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 188RY UT WOS:000247938200049 PM 17392410 ER PT J AU Chen, J Lee, CT Errico, SL Becker, KG Freed, WJ AF Chen, Jia Lee, Chun-Ting Errico, Stacie L. Becker, Kevin G. Freed, William J. TI Increases in expression of 14-3-3 eta and 14-3-3 zeta transcripts during neuroprotection induced by Delta(9)-tetrahydrocannabinol in AF5 cells SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE NDMA; 14-3-3 proteins; cannabinoids; neuroprotection; microarray ID CHAIN GENE YWHAH; SV40 LARGE T; PROTEINS; SCHIZOPHRENIA; APOPTOSIS; ISOFORMS; SURVIVAL; SIGNAL; 14-3-3-PROTEIN; MICROARRAYS AB The molecular mechanisms involved in N-methyl-Daspartate (NMDA)-induced cell death and Delta 9-tetrahydrocannabinol (THC)-induced neuroprotection were investigated in vitro with an AF5 neural progenitor cell line model. By microarray analysis, Ywhah, CK1, Hsp60, Pdcd 4, and Pdcd 7 were identified as being strongly regulated by both NMDA toxicity and THC neuro protection. The 14-3-3 eta (1 4-3-3 eta; gene symbol Ywhah) and 14-3-3 zeta (14-33; gene symbol Ywhaz) transcripts were deceased by NMDA treatment and increased by THC treatment prior to NMDA, as measured by cDNA microarray analysis and quantitative real-time RT-PCR. Other 14-3-3 isoforms were unchanged. Whereas up-regulation of 14-3-3 expression was observed 30 min after treatment with THC plus NMDA, down-regulation by NMDA alone was not seen until 16 hr after treatment. By Western blotting, THC increased 14-3-3 protein only in cells that were also treated with NMDA. Overexpression of 14-3-3il or 14-3-3 by transient plasmid transfection increased 14-3-3 protein levels and decreased NMDA-induced cell death. These data suggest that increases in 14-3-3 proteins mediate THC-induced neuroprotection under conditions of NMDA-induced cellular stress. (c) 2007 Wiley-Liss, Inc. C1 NIDA, Dept Hlth & Human Serv, Dev & Plast Sect,Intramural Res Program, Cellular Neurobiol Res Branch,NIH, Baltimore, MD 21224 USA. NIA, Dept Hlth & Human Serv, Gene Express & Genom Unit, Intra Mural Res Program,NIH, Baltimore, MD USA. RP Chen, J (reprint author), NIDA, Dept Hlth & Human Serv, Dev & Plast Sect,Intramural Res Program, Cellular Neurobiol Res Branch,NIH, 333 Cassell Dr,Triad Bldg,Room 3405, Baltimore, MD 21224 USA. EM jichen@mail.nih.gov FU Intramural NIH HHS [Z01 DA000410-10] NR 35 TC 16 Z9 17 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JUN PY 2007 VL 85 IS 8 BP 1724 EP 1733 DI 10.1002/jnr.21304 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 177UG UT WOS:000247177400014 PM 17455326 ER PT J AU Crooks, DR Ghosh, MC Braun-Sommargren, M Rouault, TA Smith, DR AF Crooks, Daniel R. Ghosh, Manik C. Braun-Sommargren, Michelle Rouault, Tracey A. Smith, Donald R. TI Manganese targets m-aconitase and activates iron regulatory protein 2 in AF5 GABAergic cells SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE AF5 cells; manganese; GABA; aconitase; iron regulation ID RNA-BINDING PROTEIN; ENERGY-METABOLISM; PC12 CELLS; IN-VITRO; MAGNETIC-RESONANCE; NITRIC-OXIDE; EXPOSURE; NEUROTOXICITY; MECHANISM; BRAIN AB Studies suggest that disturbances of amino acid metabolism and cellular iron regulation are important mechanisms underlying manganese (Mn) neurotoxicity, although the targets underlying these disturbances are poorly defined. Using the AF5 neural-derived cell line, which displays GABAergic properties, we showed that Mn significantly increased glutamate release to 174%-214% of that of the control and that the effects of Mn exposure on the metabolism of glutamate, glutamine, alanine, and GABA resembled the effects of fluorocitrate, an inhibitor of aconitase, but not the effects of other toxicants including paraquat, rotenone, or 3-nitropropionic acid. Consistent with this, Mn inhibited aconitase activity in AF5 cells, resulting in a 90% increase in intracellular citrate; an in vitro assay revealed that m-aconitase was significantly more sensitive to inhibition by Mn than was c-aconitase. RNA mobility shift assay and Western blot showed that Mn treatment caused c-aconitase to be converted to iron regulatory protein 1 (IRP1) and increased the abundance of IRP2, leading to reduced H-ferritin expression, increased transferrin receptor expression, and increased uptake of transferrin. To determine the relative contributions of IRP1 and IRP2 in mediating the effects of Mn on iron homeostasis, we exposed transgenic fibroblasts lacking either c-aconitase/IRP1 or IRP2 to Mn. Manganese exposure minimally altered ferritin levels in cells possessing only c-aconitase/IRP1, whereas cells possessing only IRP2 showed a robust decrease in ferritin, indicating a dominant role of IRP2 in Mn-incluced alteration of iron homeostasis. Together, these results demonstrate that m-aconitase is an important target of Mn and that Mn-incluced alteration of iron homeostasis is mediated predominantly through IRP2. (c) 2007Wiley-Liss, Inc. C1 Univ Calif Santa Cruz, Dept Environm Toxicol, Santa Cruz, CA 95064 USA. Natl Inst Child Hlth & Dev, Cell Biol & Metab Branch, Bethesda, MD USA. Univ Washington, Sch Publ Hlth, Dept Environm & Occupat Hlth Sci, Seattle, WA 98195 USA. RP Smith, DR (reprint author), Univ Calif Santa Cruz, Dept Environm Toxicol, Santa Cruz, CA 95064 USA. EM smith@etox.ucsc.edu FU Intramural NIH HHS; PHS HHS [010788] NR 51 TC 16 Z9 16 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD JUN PY 2007 VL 85 IS 8 BP 1797 EP 1809 DI 10.1002/jnr.21321 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 177UG UT WOS:000247177400021 PM 17469137 ER PT J AU Kannan, S Saadani-Makki, F Muzik, O Chakraborty, P Mangner, TJ Janisse, J Romero, R Chugani, DC AF Kannan, Sujatha Saadani-Makkil, Fadoua Muzik, Otto Chakraborty, Pulak Mangner, Thomas J. Janisse, James Romero, Roberto Chugani, Diane C. TI Microglial activation in perinatal rabbit brain induced by intrauterine inflammation: Detection with C-11-(R)-PK11195 and small-animal PET SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE perinatal brain injury; intrauterine inflammation; small-animal PET; C-11-(R)-PK11195; microglia ID PERIPHERAL BENZODIAZEPINE-RECEPTOR; NECROSIS-FACTOR-ALPHA; CEREBRAL-PALSY; IN-VIVO; MULTIPLE-SCLEROSIS; PK11195 BINDING; ISCHEMIC-STROKE; WHITE-MATTER; INJURY; LIPOPOLYSACCHARIDE AB Intrauterine infection can lead to a fetal inflammatory response syndrome that has been implicated as one of the causes of perinatal brain injury leading to periventricular leukomalacia (PVL) and cerebral palsy. The presence of activated microglial cells has been noted in autopsy specimens of patients with PVL and in models of neonatal hypoxia and ischemia. Activated microglial cells can cause oligodendrocyte damage and white matter injury by release of inflammatory cytokines and production of excitotoxic metabolites. We hypothesized that exposure to endotoxin in utero leads to microglial activation in the fetal brain that can be monitored in vivo by C-11-(R)-PK11195 (1-[2-chlorophenyl]N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide)- a positron-emitting ligand that binds peripheral benzodiazepine receptor sites in activated microglia-using small-animal PET. Methods: Pregnant New Zealand White rabbits underwent laparotomy and were injected with 20 and 30 mu g/kg of Escherichia coli lipopolysaccharide along the length of the uterus on day 28 of gestation. The pups were born spontaneously at term (31 d) and were scanned using small-animal PET after intravenous administration of C-11-(R)-PK11195 and by MRI on postnatal day 1. The standard uptake values (SUVs) of the tracer were calculated for the whole brain at 10-min intervals for 60 min after tracer injection. The pups were euthanized after the scan, and brains were fixed, sectioned, and stained for microglial cells using biotinylated tomato lectin. Results: There was increased brain retention of C-11-(R)-PK11195 - as determined by a significant difference in the slope of the SUV over time-in the endotoxin-treated pups when compared with that of age-matched controls. Immunohistochemical staining showed dose-dependent changes in activated microglia (increased number and morphologic changes) in the periventricular region and hippocampus of the brain of newborn rabbit pups exposed to endotoxin in utero. Conclusion: Intrauterine inflammation leads to activation of microglial cells that may be responsible for the development of brain injury and white matter damage in the perinatal period. C1 Wayne State Univ, Sch Med, Dept Radiol, Detroit, MI 48202 USA. Wayne State Univ, Sch Med, Dept Med, Detroit, MI 48201 USA. NICHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. NICHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Detroit, MI USA. Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI 48202 USA. RP Kannan, S (reprint author), Wayne State Univ, Childrens Hosp Michigan, Carman & Ann Adams Dept Pediat, 3901 Beaubien Blvd, Detroit, MI 48201 USA. EM skannan@med.wayne.edu FU NICHD NIH HHS [K08 HD050652] NR 39 TC 44 Z9 44 U1 1 U2 1 PU SOC NUCLEAR MEDICINE INC PI RESTON PA 1850 SAMUEL MORSE DR, RESTON, VA 20190-5316 USA SN 0161-5505 J9 J NUCL MED JI J. Nucl. Med. PD JUN PY 2007 VL 48 IS 6 BP 946 EP 954 DI 10.2967/jnumed.106.038539 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 176AJ UT WOS:000247054800019 PM 17504871 ER PT J AU Sheridan, PA Zhong, NX Carlson, BA Perella, CM Hatfield, DL Beck, MA AF Sheridan, Patricia A. Zhong, Nianxin Carlson, Bradley A. Perella, Christine M. Hatfield, Dolph L. Beck, Melinda A. TI Decreased selenoprotein expression alters the immune response during influenza virus infection in mice SO JOURNAL OF NUTRITION LA English DT Article ID SELENIUM-DEFICIENT MICE; SELENOCYSTEINE TRANSFER-RNA; REACTIVE OXYGEN; A VIRUS; NITRIC-OXIDE; PROINFLAMMATORY CYTOKINE; GLUTATHIONE-PEROXIDASE; PLASMA THIOREDOXIN; OXIDATIVE STRESS; GENE-EXPRESSION AB Previous work from our laboratory demonstrated that host selenium (Se) deficiency results in greater lung pathology and altered immune function in mice infected with influenza virus. Because selenoproteins play a key role in determining the oxidant status of the host, we utilized a transgenic mouse line carrying a mutant selenocysteine (Sec) tRNA ([Ser]Sec) transgene (t-trspi(6)A(-)). The levels of selenoproteins are decreased in these mice in a protein- and tissue-specific manner. Male t-trspi(6)A(-) and wild-type (WT) mice were infected with influenza and killed at various time points postinfection (p.i.). Lung mRNA levels for innate and pro-inflammatory cytokines increased with infection but did not differ between groups. However, at d 2 p.i., chemokine levels were greater in the t-trspi(6)A(-) mice compared with WT mice. Additionally, IFN-gamma was higher at d 7 p.i. in the t-trspi(6)A(-) mice and viral clearance slower. Despite these immune system changes, lung pathology was similar in t-trspi(6)A(-) and WT mice. Se-75 labeling experiments demonstrated that glutathione peroxidase (GPX)-1 and thioredoxin reductase, although greatly diminished in the lungs of t-trspi(6)A(-) mice, were not altered as a result of infection. GPX-1 activity in the lungs of the t-trspi(6)A(-) mice was similar to 82% of the WT mice. In addition, the GPX-1 activity in the lungs of Se-deficient mice was 125% less than in the t-trspi(6)A(-) mice. These results suggest that although selenoproteins are important for immune function, there is a threshold of GPX-1 activity that can prevent an increase in lung pathology during influenza infection. C1 Univ N Carolina, Sch Publ Hlth, Dept Nutr, Chapel Hill, NC 27599 USA. NCI, NIH, Bethesda, MD 20892 USA. Sci Applicat Int Corp Frederick Inc, Lab Anim Sci Program, NCI, Frederick, MD 21702 USA. RP Beck, MA (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Nutr, Chapel Hill, NC 27599 USA. EM melinda_beck@unc.edu FU Intramural NIH HHS; NIAID NIH HHS [AI055050]; NIDDK NIH HHS [DK56350]; NIEHS NIH HHS [ES10126] NR 50 TC 22 Z9 23 U1 0 U2 0 PU AMER SOCIETY NUTRITIONAL SCIENCE PI BETHESDA PA 9650 ROCKVILLE PIKE, RM L-2407A, BETHESDA, MD 20814 USA SN 0022-3166 J9 J NUTR JI J. Nutr. PD JUN PY 2007 VL 137 IS 6 BP 1466 EP 1471 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 173MU UT WOS:000246878000019 PM 17513408 ER PT J AU Imanguli, MM Karai, LJ Shanti, RM Stewart, DM Brahim, JS AF Imanguli, Matin M. Karai, Laszlo J. Shanti, Rabie M. Stewart, Donn M. Brahim, Jaime S. TI Myofibroblastic tumor of the lower lip in a patient with X-linked hypogammaglobulinemia and isolated growth hormone deficiency: A case report SO JOURNAL OF ORAL AND MAXILLOFACIAL SURGERY LA English DT Article ID INFLAMMATORY PSEUDOTUMOR; FIBROSARCOMA; SARCOMA; FUSION; GENE; ALK C1 NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Natl Inst Dent & Craniofacial Res, Clin Res Cores, Bethesda, MD 20892 USA. NCI, Metab Branch, Bethesda, MD 20892 USA. RP Imanguli, MM (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, 10 Ctr Dr,Bldg 10,Room 12C121, Bethesda, MD 20892 USA. EM mimanguli@mail.nih.gov NR 17 TC 2 Z9 2 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0278-2391 J9 J ORAL MAXIL SURG JI J. Oral Maxillofac. Surg. PD JUN PY 2007 VL 65 IS 6 BP 1219 EP 1222 DI 10.1016/j.joms.2005.12.041 PG 4 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 174HF UT WOS:000246932100024 PM 17517309 ER PT J AU Finkel, JC Pestieau, SR Quezado, ZMN AF Finkel, Julia C. Pestieau, Sophie R. Quezado, Zenaide M. N. TI Ketamine as an adjuvant for treatment of cancer pain in children and adolescents SO JOURNAL OF PAIN LA English DT Article DE ketamine; opioid; hyperalgesia; tolerance; cancer pain; pediatric; children ID SMALL-DOSE KETAMINE; POSTOPERATIVE PAIN; INDUCED HYPERALGESIA; ACUTE TOLERANCE; MORPHINE; ANALGESIA; HEROIN; LIFE; HYDROMORPHONE; SENSITIVITY AB In children with advanced stages of cancer, pain control remains inadequate in many patients and a solution to this problem is sorely lacking. Factors related to progression of the primary disease and side-effects of high doses of opioids, the mainstay of pain therapy, contribute to the inadequacy of pain control. In addition, few studies suggest that opioids, by inducing tolerance, having pronociceptive effects and producing hyperalgesia in some patients, can also contribute to inadequacy of pain control. Researchers have shown that N-methyl-D-aspartate (NMDA) receptor antagonists may have a role in mitigating opioid-induced tolerance and hyperalgesia in adults. However, literature on NMDA antagonists to treat cancer pain in children and adolescents is scarce. We used subanesthetic doses of ketamine to treat 11 children and adolescents who were on high doses of opioids and yet had uncontrolled cancer pain. A low-dose ketamine infusion was administered to all patients to modulate the need for rapidly escalating opioid therapy. We found that in 8 of 11 patients, ketamine infusions used as an adjuvant to opioid analgesia was associated with opioid-sparing effects and apparent improvement in pain control and in the children's ability to interact with their family. This study suggests that infusions of ketamine may offer a promising therapeutic option in the treatment of appropriately selected children and adolescents with intractable cancer pain. Perspective: in many children with advanced stages of cancer, pain control remains inadequate. We used subanesthetic doses of ketamine to treat 11 children and adolescents who were on high doses of opioids and had uncontrolled cancer pain. In the majority of patients, ketamine appeared to improve pain control and to have an opioid-sparing effect (c) 2007 by the American Pain Society. C1 George Washington Univ, Div Anesthesiol & Pain Med, Childrens Natl Med Ctr, Sch Med, Washington, DC 20010 USA. NIH, Ctr Clin, Dept Anesthesia & Surg Serv, Bethesda, MD 20892 USA. RP Finkel, JC (reprint author), George Washington Univ, Div Anesthesiol & Pain Med, Childrens Natl Med Ctr, Sch Med, 111 Michigan Ave NW, Washington, DC 20010 USA. EM jfinkel@cnmc.org RI Quezado, Zenaide/O-4860-2016 OI Quezado, Zenaide/0000-0001-9793-4368 FU NICHD NIH HHS [1U10HD45993-02] NR 37 TC 31 Z9 35 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1526-5900 J9 J PAIN JI J. Pain PD JUN PY 2007 VL 8 IS 6 BP 515 EP 521 DI 10.1016/j.jpain.2007.02.429 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 180TL UT WOS:000247388800009 PM 17434801 ER PT J AU McKenzie, FE Jeffery, GM Collins, WE AF McKenzie, F. Ellis Jeffery, Geoffrey M. Collins, William E. TI Gametocytemia and fever in human malaria infections SO JOURNAL OF PARASITOLOGY LA English DT Article ID PLASMODIUM-FALCIPARUM GAMETOCYTES; TROPHOZOITE-INDUCED INFECTIONS; BLOOD-STAGE DYNAMICS; RETROSPECTIVE EXAMINATION; GENETIC COMPLEXITY; CLINICAL IMMUNITY; PARASITE DENSITY; TRANSMISSION; GAMETOCYTOGENESIS; MICROSCOPY AB We examine the charts of 408 malaria-naive neurosyphilis patients given malaria therapy at the South Carolina USPHS facility, with daily records encompassing at least 93% of the duration of infection, and focus on the 152 patients infected with the St. Elizabeth strain of Plasmodium vivax, 82 with the McLendon strain of Plasmodium falciparum, 36 with the USPHS strain of Plasmodium malariae, and 15 with the Donaldson strain of Plasmodium ovale in whom gametocytes appeared before drug, or other, intervention. In P. vivax infections, fever and parasitemia were higher after gametocytes were first detected than before; in P. malariae infections, parasitemia was higher. In P. ovale infections, fever and parasitemia were similar before and after. In P. falciparum infections, fever, parasitemia, and fever frequency were lower after gametocytes were first detected than before. Parasitemia and temperature correlated in P. vivax infections, before and after gametocytes were first detected; parasitemia and temperature at first fever were not correlated in infections with any species. Gametocyte density correlated with parasitemia in P. malariae and sporozoite-induced P. falciparum and P. vivax infections. Fevers and detected gametocytemia coincided more often than expected by chance with P. vivax and P. ovale; fever temperature and gametocyte density were not correlated in infections with any species. C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP McKenzie, FE (reprint author), NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. EM em225k@nih.gov FU Intramural NIH HHS [Z99 TW999999] NR 32 TC 25 Z9 25 U1 0 U2 3 PU AMER SOC PARASITOLOGISTS PI LAWRENCE PA 810 EAST 10TH STREET, LAWRENCE, KS 66044 USA SN 0022-3395 J9 J PARASITOL JI J. Parasitol. PD JUN PY 2007 VL 93 IS 3 BP 627 EP 633 DI 10.1645/GE-1052R.1 PG 7 WC Parasitology SC Parasitology GA 184NJ UT WOS:000247648400023 PM 17626355 ER PT J AU Harford, JB AF Harford, Joe B. TI The Middle East Cancer Consortium and cancer incidence rates in the region SO JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY LA English DT Meeting Abstract C1 NCI, NIH, US Dept HHS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1077-4114 J9 J PEDIAT HEMATOL ONC JI J. Pediatr. Hematol. Oncol. PD JUN PY 2007 VL 29 SU 1 BP S7 EP S7 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 179BP UT WOS:000247264600012 ER PT J AU Hayward, A AF Hayward, Anthony TI Pediatric research in the era of clinical and translational science awards SO JOURNAL OF PEDIATRICS LA English DT Editorial Material C1 NIH, Div Clin Res Resources, NCCR, Bethesda, MD 20892 USA. RP Hayward, A (reprint author), NIH, Div Clin Res Resources, NCCR, DEMI-906, Bethesda, MD 20892 USA. EM HaywardA@mail.nih.gov NR 6 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JUN PY 2007 VL 150 IS 6 BP 567 EP 568 DI 10.1016/j.jpeds.2007.04.007 PG 2 WC Pediatrics SC Pediatrics GA 174KB UT WOS:000246939700001 PM 17517230 ER PT J AU Wendler, D Glantz, L AF Wendler, David Glantz, Leonard TI A standard for assessing the risks of pediatric research: Pro and con SO JOURNAL OF PEDIATRICS LA English DT Editorial Material ID MINIMAL RISK; CHILDREN; EXPERIMENTATION; BIASES C1 NIH, Dept Clin Bioeth, Ctr Clin, Bethesda, MD 20892 USA. Boston Univ, Sch Publ Hlth, Dept Hlth Law Bioeth & Human Rights, Boston, MA 02215 USA. RP Wendler, D (reprint author), NIH, Dept Clin Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM dwendler@nih.gov FU Intramural NIH HHS [Z99 CL999999] NR 25 TC 13 Z9 13 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JUN PY 2007 VL 150 IS 6 BP 579 EP 582 DI 10.1016/j.jpeds.2007.02.018 PG 4 WC Pediatrics SC Pediatrics GA 174KB UT WOS:000246939700007 PM 17517236 ER PT J AU Matura, LA Sachdev, V Bakalov, VK Rosing, DR Bondy, CA AF Matura, Lea Ann Sachdev, Vandana Bakalov, Vladimir K. Rosing, Douglas R. Bondy, Carolyn A. TI Growth hormone treatment and left ventricular dimensions in Turner syndrome SO JOURNAL OF PEDIATRICS LA English DT Article ID BLOOD-PRESSURE; ADULT HEIGHT; CHILDREN; GIRLS; ABNORMALITIES; DEFICIENCY; INTERVAL; THERAPY; IMPACT; MASS AB Objective To determine whether cardiac dimensions were different in girls with Turner syndrome (TS) who received growth hormone (GH) compared with those who did not receive GH. Study design This retrospective, cross-sectional study analyzed echocardiograms in 86 females with TS divided into GH-treated (n = 67) and untreated (n = 19) groups. The sub jects all participated in the National Institutes of Health protocol between 2001 and 2006. Results The average age was 16.2 years (range, 10 to 25 years), and average duration of GH treatment was 4.4 years (range, 1 to 14 years). The GH-treated group was taller by similar to 7 cin (P =.004), but cardiac dimensions normalized to body surface area (BSA), including septal and posterior wall thickness, and left ventricular (LV) mass and internal diameters, did not differ significantly between the 2 groups. The fractional shortening index was similar in the 2 groups. Multiple regression analyses indicated that BSA, but not duration of GH treatment, predicted LV dimensions in girls with TS. Conclusions GH treatment of girls with TS increases stature but does not disproportionately affect cardiac dimensions. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Matura, LA (reprint author), NICHHD, Dev Endocrinol Branch, NIH, CRC 1-330,10 Ctr Dr, Bethesda, MD 20892 USA. EM maturale@mail.nih.gov FU Intramural NIH HHS [Z01 HD000628-18] NR 25 TC 19 Z9 19 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JUN PY 2007 VL 150 IS 6 BP 587 EP 591 DI 10.1016/j.jpeds.2007.02.009 PG 5 WC Pediatrics SC Pediatrics GA 174KB UT WOS:000246939700009 PM 17517238 ER PT J AU Hintz, SR Slovis, T Bulas, D Van Meurs, KP Perritt, R Stevenson, DK Poole, WK Das, A Higgins, RD AF Hintz, Susan R. Slovis, Thomas Bulas, Dorothy Van Meurs, Krisa P. Perritt, Rebecca Stevenson, David K. Poole, W. Kenneth Das, Abhik Higgins, Rosemary D. CA NICHD Neonatal Res Network TI Interobserver reliability and accuracy of cranial ultrasound scanning interpretation in premature infants SO JOURNAL OF PEDIATRICS LA English DT Article ID BIRTH-WEIGHT INFANTS; RISK PRETERM INFANTS; NEURODEVELOPMENTAL OUTCOMES; WEEKS GESTATION; CEREBRAL-PALSY; KAPPA; HEMORRHAGE; AGREEMENT; BRAIN; LESS AB Objective To assess interobserver reliability between 2 central readers of cranial ultrasound scanning (CUS) and accuracy of local, compared with central, interpretations. Study design The study was a retrospective analysis of CUS data from the National Institute of Child Health and Human Development (NICHD) trial of inhaled nitric oxide for premature infants. Initerobserver reliability of 2 central readers was assessed with kappa or weighted kappa. Accuracy of local, compared with central, interpretations was assessed by rising sensitivity and specificity. Results CUS from 326 infants had both central reader and local interpretations. Central reader agreement for grade 3/4 intraventricular hemorrhage (IVH), grade 3/4 IVH or periventricular leukomalacia (PVL,), grade of IVH, and degree of ventriculomegaly was very good (kappa = 0.84, 0.81, 0.79, and 0.75, respectively). Agreement was poor for lower grade lVH and for PVL alone. Local interpretations were highly accurate for grade 3/4 lVH or PVL, (sensitivity, 87%-90% specificity, 92%-93(Yo), but sensitivity was poor-to-fair for grade 1/2 IVH (48%-68%) and PVL (20%-44%). Conclusions Our findings demonstrate reliability and accuracy of highly unfavorable CUS findings, but suggest caution when interpreting mild to moderate IVH or white matter injury. C1 Stanford Univ, Sch Med, Div Neonatal & Dev Med, Palo Alto, CA 94304 USA. Childrens Hosp Michigan, Dept Pediat Imaging, Detroit, MI 48201 USA. George Washington Univ, Childrens Natl Med Ctr, Washington, DC 20052 USA. RTI Int, Res Triangle Pk, NC USA. NICHHD, Bethesda, MD 20892 USA. RP Hintz, SR (reprint author), Stanford Univ, Sch Med, Div Neonatal & Dev Med, 750 Welch Rd,Suite 315, Palo Alto, CA 94304 USA. EM srhintz@stanford.edu FU NICHD NIH HHS [U10 HD027880, U10 HD027880-16] NR 33 TC 36 Z9 37 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-3476 EI 1097-6833 J9 J PEDIATR-US JI J. Pediatr. PD JUN PY 2007 VL 150 IS 6 BP 592 EP 596 DI 10.1016/j.jpeds.2007.02.012 PG 5 WC Pediatrics SC Pediatrics GA 174KB UT WOS:000246939700011 PM 17517240 ER PT J AU Van Meurs, KP Hintz, SR Ehrenkranz, RA Lemons, JA Ball, MB Poole, WK Perritt, R Das, A Higgins, RD Stevenson, DK AF Van Meurs, K. P. Hintz, S. R. Ehrenkranz, R. A. Lemons, J. A. Ball, M. B. Poole, W. K. Perritt, R. Das, A. Higgins, R. D. Stevenson, D. K. CA Preemie Inhaled Nitric Oxide Study TI Inhaled nitric oxide in infants > 1500 g and < 34 weeks gestation with severe respiratory failure SO JOURNAL OF PERINATOLOGY LA English DT Article DE inhaled nitric oxide; respiratory failure; premature infant; bronchopulmonary dysplasia ID RANDOMIZED CONTROLLED-TRIAL; PREMATURE-INFANTS; DISTRESS-SYNDROME; PRETERM INFANTS; SMOOTH-MUSCLE; LUNG GROWTH; THERAPY; NEWBORN; OUTCOMES; DISEASE AB Objective: Inhaled nitric oxide (iNO) use in infants >1500 g, but <34 weeks gestation with severe respiratory failure will reduce the incidence of death and/or bronchopulmonary dysplasia (BPD). Study Design: Infants born at <34 weeks gestation with a birth weight > 1500 g with respiratory failure were randomly assigned to receive placebo or iNO. Results: Twenty-nine infants were randomized. There were no differences in baseline characteristics, but the status at randomization showed a statistically significant difference in the use of high-frequency ventilation (P=0.03). After adjustment for oxygenation index entry strata, there was no difference in death and/or BPD (adjusted relative risk (RR) 0.80, 95% confidence interval (CI) 0.43 to 1.48; P=0.50), death (adjusted RR 1.26, 95% CI 0.47 to 3.41; P=0.65) or BPD (adjusted RR 0.40, 95% CI 0.47 to 3.41; P=0.21). Conclusions: Although sample size limits our ability to make definitive conclusions, this small pilot trial of iNO use in premature infants >1500 g and <34 weeks with severe respiratory failure suggests that iNO does not affect the rate of BPD and/or death. C1 Stanford Univ, Sch Med, Div Neonatal & Dev Med, Palo Alto, CA 94304 USA. Stanford Univ, Lucile Packard Childrens Hosp, Palo Alto, CA 94304 USA. Indiana Univ, Sch Med, Dept Pediat, Indianapolis, IN 46202 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. NICHHD, Bethesda, MD 20892 USA. RP Van Meurs, KP (reprint author), Stanford Univ, Sch Med, Div Neonatal & Dev Med, 750 Welch Rd,Suite 315, Palo Alto, CA 94304 USA. EM vanmeurs@stanford.edu FU NCRR NIH HHS [M01RR 00039, M01 RR00044, M01 RR 08084, M01 RR 06022, M01 RR 00750, M01 RR 00070]; NICHD NIH HHS [U10 HD 21373, U10 HD40461, U10 HD27856, U10 HD40521, U10 HD27871, U10 HD27853, U10 HD36790, U10 HD40498, U10 HD27851, U10 HD34216, U10 HD27904, U10 HD40689] NR 29 TC 19 Z9 19 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0743-8346 J9 J PERINATOL JI J. Perinatol. PD JUN PY 2007 VL 27 IS 6 BP 347 EP 352 DI 10.1038/sj.jp.7211690 PG 6 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 173XM UT WOS:000246905800005 PM 17443204 ER PT J AU Wadhawan, R Oh, W Perritt, R Laptook, AR Poole, K Wright, LL Fanaroff, AA Duara, S Stoll, BJ Goldberg, R AF Wadhawan, R. Oh, W. Perritt, R. Laptook, A. R. Poole, K. Wright, L. L. Fanaroff, A. A. Duara, S. Stoll, B. J. Goldberg, R. TI Association between early postnatal weight loss and death or BPD in small and appropriate for gestational age extremely low-birth-weight infants SO JOURNAL OF PERINATOLOGY LA English DT Article DE postnatal weight loss; bronchopulmonary dysplasia; extremely low-birth-weight infants ID INTRAUTERINE GROWTH-RETARDATION; RESPIRATORY-DISTRESS SYNDROME; PATENT DUCTUS-ARTERIOSUS; BRONCHOPULMONARY DYSPLASIA; PRETERM INFANTS; PREMATURE-INFANTS; FLUID INTAKE; BODY-WATER; RESTRICTION; SODIUM AB Objective: To examine the association between weight loss during the first 10 days of life and the incidence of death or bronchopulmonary dysplasia (BPD) in small for gestational age (SGA) and appropriate for gestational age (AGA) extremely low-birth-weight infants. Design/Methods: This is a retrospective analysis of a cohort of ELBW (birth weight <1000 g) infants from the NICHD Neonatal Research Network's database. The cohort consisted of 9461 ELBW infants with gestational age of 24-29 weeks, admitted to Network's participating centers during calendar years 1994-2002 and surviving at least 72 h after birth. The cohort was divided into two groups, 1248 SGA (with birth weight below 10th percentile for gestational age) and 8213 AGA (with birth weight between 10th and 90th percentile) infants. We identified infants with or without weight loss during the first 10 days of life, which we termed as 'early postnatal weight loss' (EPWL). Univariate analyses were used to predict whether EPWL was related to the primary outcome, death or BPD, within each birth weight/gestation category (SGA or AGA). BPD and death were also analyzed separately in relation to EPWL. Logistic regression analysis was done to evaluate the risk of death or BPD in SGA and AGA groups, controlling for maternal and neonatal demographic and clinical factors found to be significant by univariate analysis. Results: SGA ELBW infants had a lower prevalence of EPWL as compared with AGA ELBW infants (81.2 vs 93.7%, respectively, P<0.001). In AGA infants, univariate analysis showed that death or BPD rate was lower in the group of infants with EPWL compared with infants without EPWL (53.4 vs 74.3%, respectively, P<0.001). The BPD (47.2 vs 64%, P<0.001) and death (13.8 vs 32.9%, P<0.001) rate were similarly lower in the EPWL group. The risk-adjusted odds ratios (ORs) showed that EPWL was associated with lower rate of death or BPD (OR 0.47, 95% CI: 0.37-0.60). In SGA infants, on univariate analysis, a similar association between EPWL and outcomes was seen as shown in AGA infants: death or BPD (55.9 vs 75.2%, P<0.001), BPD rate (48.3 vs 62.1%, P=0.002) and rate death (19 vs 40.8%, P<0.001) for those with or without EPWL, respectively. Multiple logistic regression showed that as in AGA ELBW infants, EPWL was associated with lower risk for death or BPD (OR 0.60, 95% CI: 0.41-0.89) among SGA infants. Conclusions: SGA infants experienced less EPWL when compared with their AGA counterparts. EPWL was associated with a lower risk of death or BPD in both ELBW AGA and SGA infants. These data suggest that clinicians who consider the association between EPWL and risk of death or BPD should do so independent of gestation/birth weight status. C1 All Childrens Hosp, Dept Pediat, St Petersburg, FL 33701 USA. Brown Univ, Dept Pediat, Providence, RI 02912 USA. NICHD, Neonatal Res Network, Bethesda, MD USA. Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. Univ Miami, Dept Pediat, Miami, FL 33152 USA. Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. Duke Univ, Dept Pediat, Durham, NC 27706 USA. RP Wadhawan, R (reprint author), All Childrens Hosp, Dept Pediat, 880 6th St S, St Petersburg, FL 33701 USA. EM wadhawar@allkids.org NR 21 TC 16 Z9 17 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0743-8346 J9 J PERINATOL JI J. Perinatol. PD JUN PY 2007 VL 27 IS 6 BP 359 EP 364 DI 10.1038/sj.jp.7211751 PG 6 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 173XM UT WOS:000246905800007 PM 17443198 ER PT J AU Kim, HJ Rowe, M Ren, M Hong, JS Chen, PS Chuang, DM AF Kim, Hyeon Ju Rowe, Michael Ren, Ming Hong, Jau-Shyong Chen, Po-See Chuang, De-Maw TI Histone deacetylase inhibitors exhibit anti-inflammatory and neuroprotective effects in a rat permanent ischemic model of stroke: Multiple mechanisms of action SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID NITRIC-OXIDE SYNTHASE; PROTECTS DOPAMINERGIC-NEURONS; CEREBRAL-ARTERY OCCLUSION; REDUCES BRAIN-DAMAGE; VALPROIC ACID; SODIUM-BUTYRATE; MICE; CYCLOOXYGENASE-2; EXPRESSION; INFARCTION AB The pathophysiology of cerebral ischemia involves multiple mechanisms including neuroinflammation mediated by activated microglia and infiltrating macrophages/monocytes. The present study employed a rat permanent middle cerebral artery occlusion (pMCAO) model to study effects of histone deacetylase (HDAC) inhibition on ischemia-induced brain infarction, neuroinflammation, gene expression, and neurological deficits. We found that post-pMCAO injections with HDAC inhibitors, valproic acid (VPA), sodium butyrate (SB), or trichostatin A (TSA), decreased brain infarct volume. Postinsult treatment with VPA or SB also suppressed microglial activation, reduced the number of microglia, and inhibited other inflammatory markers in the ischemic brain. The reduction in levels of acetylated histone H3 in the ischemic brain was prevented by treatment with VPA, SB, or TSA. Moreover, injections with HDAC inhibitors superinduced heat-shock protein 70 and blocked pMCAO-induced down-regulation of phospho-Akt, as well as ischemia-elicited up-regulation of p53, inducible nitric oxide synthase, and cyclooxygenase-2. The motor, sensory, and reflex performance of pMCAO rats was improved by VPA, SB, or TSA treatment. The beneficial effects of SB and VPA in reducing brain infarct volume and neurological deficits occurred when either drug was administrated at least 3 h after ischemic onset, and the behavioral improvement was long-lasting. Together, our results demonstrate robust neuroprotective effects of HDAC inhibitors against cerebral ischemia-induced brain injury. The neuroprotection probably involves multiple mechanisms including suppression of ischemia-induced cerebral inflammation. Given that there is no effective treatment for stroke, HDAC inhibitors, such as VPA, SB, and TSA, should be evaluated for their potential use for clinical trials in stroke patients. C1 NIMH, Mol Neurobiol Sect, NIH, Bethesda, MD 20892 USA. Natl Inst Environm Hlth Sci, Lab Pharmacol & Chem, Neuropharmacol Sect, NIH, Res Triangle Pk, NC USA. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, NIH, Bldg 10,Room 4C-206,10 Ctr Dr,MSC-1363, Bethesda, MD 20892 USA. EM chuang@mail.nih.gov FU Intramural NIH HHS NR 39 TC 279 Z9 300 U1 3 U2 22 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUN PY 2007 VL 321 IS 3 BP 892 EP 901 DI 10.1124/jpet.107.120188 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 167LJ UT WOS:000246452900009 PM 17371805 ER PT J AU Solinas, M Scherma, M Tanda, G Wertheim, CE Fratta, W Goldberg, SR AF Solinas, Marcello Scherma, Maria Tanda, Gianluigi Wertheim, Carrie E. Fratta, Walter Goldberg, Steven R. TI Nicotinic facilitation of Delta 9-tetrahydrocannabinol discrimination involves endogenous anandamide SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID HIPPOCAMPAL ACETYLCHOLINE-RELEASE; CANNABINOID RECEPTORS; OPIOID RECEPTORS; CB1 ANTAGONIST; MODULATION; RATS; BRAIN; MEMORY; LOCALIZATION; BEHAVIOR AB Systemic administration of the main active ingredient in cannabis, Delta 9-tetrahydrocannabinol ( THC), alters extracellular levels of acetylcholine in several brain areas, suggesting an involvement of the cholinergic system in the psychotropic effects of cannabis. Here, we investigated whether drugs acting at either nicotinic or muscarinic receptors can modulate the discriminative effects of THC. In rats that had learned to discriminate effects of 3 mg/kg i.p. injections of THC from injections of vehicle, the nicotinic agonist nicotine (0.1-0.56 mg/kg subcutaneous) and the muscarinic agonist pilocarpine (0.3-3 mg/kg i.p.) did not produce THC-like effects, but they both potentiated the discriminative effects of low doses of THC (0.3-1 mg/kg). Neither the nicotinic antagonist mecamylamine (1-5.6 mg/kg i.p.) nor the muscarinic antagonist scopolamine (0.01-0.1 mg/kg i. p.) altered the discriminative effects of THC, but they blocked the potentiation of discriminative effects of THC by nicotine and pilocarpine, respectively. The cannabinoid CB1 rimonabant (1mg/kg i.p.) reversed nicotine-but not pilocarpine-induced potentiation of THC discrimination, suggesting that nicotine potentiation is, at least in part, mediated by release of endogenous cannabinoids in the brain. In addition, when metabolic degradation of the endogenous cannabinoid anandamide was blocked by the fatty acid amide hydrolase inhibitor cyclohexyl carbamic acid 3 '-carbamoyl-biphenil-3-yl-ester (URB-597; 0.3 mg/kg i. p.) nicotine, but not pilocarpine, produced significant THC-like discriminative effects that were antagonized by rimonabant. Our results suggest that nicotinic and muscarinic cholinergic receptors modulate the discriminative effects of THC by fundamentally different mechanisms. Nicotinic, but not muscarinic, modulation of THC discrimination involves elevations in endogenous levels of anandamide. C1 Univ Poitiers, CNRS, VMR6187, Lab Biol & Physiol Cellulaires, F-86022 Poitiers, France. NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. NIDA, Psychobiol Sect, Med Discovery Res Branch, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. NIDA, Intramural Res Program, NIH, Dept Hlth & Human Serv, Baltimore, MD USA. Univ Cagliari, BB Brodie Dept Neurosci, I-09124 Cagliari, Italy. RP Solinas, M (reprint author), Univ Poitiers, CNRS, VMR6187, Lab Biol & Physiol Cellulaires, 40 Ave Recteur Pineau, F-86022 Poitiers, France. EM marcello.solinas@univ-poitiers.fr RI Tanda, Gianluigi/B-3318-2009; Solinas, Marcello/M-3500-2016 OI Tanda, Gianluigi/0000-0001-9526-9878; Solinas, Marcello/0000-0002-0664-5964 FU Intramural NIH HHS NR 40 TC 21 Z9 21 U1 0 U2 2 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD JUN PY 2007 VL 321 IS 3 BP 1127 EP 1134 DI 10.1124/jpet.106.116830 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 167LJ UT WOS:000246452900036 PM 17351107 ER PT J AU Lefman, J Morrison, R Subramaniam, S AF Lefman, Jonathan Morrison, Robert Subramaniam, Sriram TI Automated 100-position specimen loader and image acquisition system for transmission electron microscopy SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE high-throughput electron microscopy; nanotechnology; remote microscopy; electron crystallography ID LEGINON; MICROGRAPHS; TOMOGRAPHY AB We report the development of a novel, multi-specimen imaging system for high-throughput transmission electron microscopy. Our cartridge-based loading system, called the "Gatling", permits the sequential examination of as many as 100 specimens in the microscope for room temperature electron microscopy using mechanisms for rapid and automated specimen exchange. The software for the operation of the Gatling and automated data acquisition has been implemented in an updated version of our in-house program AutoEM. In the current implementation of the system, the time required to deliver 95 specimens into the microscope and collect overview images from each is about 13 h. Regions of interest are identified from a low magnification atlas generation from each specimen and an unlimited number of higher magnifications images can be subsequently acquired from these regions using fully automated data acquisition procedures that can be controlled from a remote interface. We anticipate that the availability of the Gatling will greatly accelerate the speed of data acquisition for a variety of applications in biology, materials science, and nanotechuology that require rapid screening and image analysis of multiple specimens. Published by Elsevier Inc. C1 NCI, Lab Cell Biol, NIH, Bethesda, MD 20817 USA. Gatan UK, Abingdon OX14 1RL, Oxon, England. RP Subramaniam, S (reprint author), NCI, Lab Cell Biol, NIH, Bethesda, MD 20817 USA. EM ss1@nih.gov FU Intramural NIH HHS [Z01 BC010278-09] NR 11 TC 16 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 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD JUN PY 2007 VL 158 IS 3 BP 318 EP 326 DI 10.1016/j.jsb.2006.11.007 PG 9 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 174FQ UT WOS:000246927800006 PM 17240161 ER PT J AU Hagedorn, H Dieperink, E Dingmann, D Durfee, J Ho, SB Isenhart, C Rettmann, N Lenbring, MW AF Hagedorn, Hildi Dieperink, Eric Dingmann, Debra Durfee, Janet Ho, Samuel B. Isenhart, Carl Rettmann, Nancy Lenbring, Mark W. TI Integrating hepatitis prevention services into a substance use disorder clinic SO JOURNAL OF SUBSTANCE ABUSE TREATMENT LA English DT Article DE substance abuse treatment programs; hepatitis C infections; hepatitis services; implementation; vaccinations ID CHRONIC LIVER-DISEASE; DRUG-TREATMENT PROGRAMS; C VIRUS-INFECTION; HEPATOCELLULAR-CARCINOMA; VACCINATION; EPIDEMIOLOGY; POPULATION; PREVALENCE; EDUCATION; VETERANS AB The Healthy Liver Program, established at the Minneapolis Veterans Affairs Medical Center Substance Use Disorder Clinic, provides screening for exposure to hepatitis infections, a group education class, and an individual nursing appointment to review screening results, give vaccinations for hepatitis A and hepatitis B, and make referrals to the hepatitis clinic as appropriate. A patient chart audit was completed I I months after the establishment of the Healthy Liver Program. The attendance rate for the educational group and individual feedback sessions was 66.9%, with 94.1% of attendees accepting recommended hepatitis A and/or hepatitis B vaccinations. All patients with chronic hepatitis C who attended the Healthy Liver Program received a referral for evaluation in the hepatitis clinic, as compared with only 50% of patients with chronic hepatitis C who were identified before the establishment of the program. The importance of providing comprehensive educational sessions and recommendations for how patients with substance use disorders can access hepatitis screening, vaccination, and treatment resources are stressed. (C) 2007 Elsevier Inc. All rights reserved. C1 Vet Affairs Med Ctr, Minneapolis, MN 55417 USA. Univ Minnesota, Minneapolis, MN 55455 USA. Vet Affairs Hepatitis C Resource Ctr, Minneapolis, MN 55417 USA. NIAAA, Bethesda, MD 20892 USA. RP Hagedorn, H (reprint author), Vet Affairs Med Ctr, 1 Vet Dr,116A9, Minneapolis, MN 55417 USA. EM hildi.hagedorn@va.gov NR 28 TC 12 Z9 13 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0740-5472 J9 J SUBST ABUSE TREAT JI J. Subst. Abus. Treat. PD JUN PY 2007 VL 32 IS 4 BP 391 EP 398 DI 10.1016/j.jsat.2006.10.004 PG 8 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 169EP UT WOS:000246575800008 PM 17481462 ER PT J AU Hughes, CW Emslie, GJ Crismon, ML Posner, K Birmaher, B Ryan, N Jensen, P Curry, J Vitiello, B Lopez, M Shon, SP Pliszka, SR Trivedi, MH AF Hughes, Carroll W. Emslie, Graham J. Crismon, M. Lynn Posner, Kelly Birmaher, Boris Ryan, Neal Jensen, Peter Curry, John Vitiello, Benedetto Lopez, Molly Shon, Steve P. Pliszka, Steven R. Trivedi, Madhukar H. CA Texas Consensus Conf Panel Medicat TI Texas children's medication algorithm project: Update from Texas consensus conference panel on medication treatment of childhood major depressive disorder SO JOURNAL OF THE AMERICAN ACADEMY OF CHILD AND ADOLESCENT PSYCHIATRY LA English DT Review DE medication algorithm; major depressive disorder; suicidality; childhood psychopharmacology; child and adolescent depression ID PLACEBO-CONTROLLED TRIAL; RANDOMIZED CONTROLLED-TRIAL; OBSESSIVE-COMPULSIVE DISORDER; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; SEROTONIN REUPTAKE INHIBITORS; AGGRESSIVE YOUTH TRAAY; STAR-ASTERISK-D; DOUBLE-BLIND; ADOLESCENT DEPRESSION; SUICIDAL-BEHAVIOR AB Objective: To revise and update consensus guidelines for medication treatment algorithms for childhood major depressive disorder based on new scientific evidence and expert clinical consensus when evidence is lacking. Method: A consensus conference was held January 13-14, 2005, that included academic clinicians and researchers, practicing clinicians, administrators, consumers, and families. The focus was to review, update, and incorporate the most current data to inform and recommend specific pharmacological approaches and clinical guidance for treatment of major depressive disorder in children and adolescents. Results: Consensually agreed on medication algorithms for major depression (with and without psychosis) and comorbid attention-deficit disorders were updated. These revised algorithms also incorporated approaches to address issues of suicidality, aggression, and irritability. Stages 1, 2, and 3 of the algorithm consist of selective serotonin reuptake inhibitor and norepinephrine serotonin reuptake inhibitor medications whose use is supported by controlled, acute clinical trials and clinical experience. Recent studies provide support that selective serotonin reuptake inhibitors in addition to fluoxetine are still encouraged as first-line interventions. The need for additional assessments, precautions, and monitoring is emphasized, as well as continuation and maintenance treatment. Conclusions: Evidence and expert clinical consensus support the use of selected antidepressants in the treatment of depression in youths. The use of the recommended antidepressant medications requires appropriate monitoring of suicidality and potential adverse effects and consideration of other evidence-based treatment alternatives such as cognitive behavioral therapies. C1 Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX 75390 USA. Univ Texas, Coll Pharm, Austin, TX 78712 USA. Columbia Univ, New York, NY USA. Western Psychiat Inst & Clin, Pittsburgh, PA USA. Columbia Univ, Ctr Advancement Childrens Mental Hlth, Dept Psychiat, New York, NY 10027 USA. Off Mental Hlth, New York, NY USA. Duke Univ, Durham, NC USA. NIMH, Bethesda, MD 20892 USA. Texas Dept State Hlth Serv, Austin, TX USA. Univ Texas, Hlth Sci Ctr, Dept Psychiat, San Antonio, TX 78284 USA. RP Hughes, CW (reprint author), Univ Texas, SW Med Ctr, Dept Psychiat, 5323 Harry Hines Blvd, Dallas, TX 75390 USA. EM carroll.hughes@utsouthwestern.edu OI Jensen, Peter/0000-0003-2387-0650 NR 130 TC 72 Z9 73 U1 4 U2 11 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0890-8567 J9 J AM ACAD CHILD PSY JI J. Am. Acad. Child Adolesc. Psychiatr. PD JUN PY 2007 VL 46 IS 6 BP 667 EP 686 DI 10.1097/chi.0b013e31804a859b PG 20 WC Psychology, Developmental; Pediatrics; Psychiatry SC Psychology; Pediatrics; Psychiatry GA 171KD UT WOS:000246733900002 PM 17513980 ER PT J AU Subar, AF Thompson, FE Potischman, N Forsyth, BH Buday, R Richards, D McNutt, S Hull, SG Guenther, PM Schatzkin, A Baranowski, T AF Subar, Amy F. Thompson, Frances E. Potischman, Nancy Forsyth, Barbara H. Buday, Richard Richards, Debbie McNutt, Suzanne Hull, Stephen G. Guenther, Patricia M. Schatzkin, Arthur Baranowski, Tom TI Formative research of a quick list for an automated self-administered 24-hour dietary recall SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID SYSTEM AB Twenty-four-hour dietary recalls are used to collect high-quality dietary data. Because they require highly trained interviewers, recalls are expensive and impractical for large-scale nutrition research, leading to the use of food frequency questionnaires. We are developing a computer-based, self-administered 24-hour dietary recall for use by adults. Our goal is an easy-to-use, low-cost, publicly available, Web-enabled instrument that will include elements of the Automated Multiple Pass Method developed by the US Department of Agriculture, which uses five passes to enhance recall. The initial pass is called the "quick list" and allows respondents to report foods consumed the previous day freely, in any order, and without detail. Using a crossover design, we conducted initial formative pilot testing among 18 adults in a self-administered computer environment. We tested two versions of a "quick list" (the first Automated Multiple Pass Method pass) for remembering foods consumed the previous day: "unstructured" and "meal-based." Respondents showed a strong preference for the meal-based version (13 of 18), although positive features of both were identified. Chronological reporting was most common, although many foods were sporadically reported out of order. Versions did not appreciably differ in number of foods reported, moved, or deleted. Usability issues and preferences were also identified. If these developmental efforts prove successful, the use of affordable automated recalls could be valuable in clarifying diet-disease associations in observational epidemiologic studies and measuring dietary compliance in clinical trials. This pilot work illustrates the usefulness of formative cognitive and usability testing for questionnaire and software development. C1 NCI, Risk Factor Monitoring & Methods Branch, Bethesda, MD 20892 USA. Westat Corp, Rockville, MD USA. Archimage, Houston, TX USA. Animatrix Arts, Houston, TX USA. USDA, Ctr Nutr Policy & Promot, Alexandria, VA USA. Nutr Epidemiol Branch, Bethesda, MD USA. USDA ARS, Baylor Coll Med, Childrens Nutr Res Ctr, Houston, TX USA. RP Subar, AF (reprint author), NCI, Risk Factor Monitoring & Methods Branch, 6130 Execut Blvd,MSC 7344,EPN 4005, Bethesda, MD 20892 USA. EM subara@mail.nih.gov OI Baranowski, Tom/0000-0002-0653-2222 NR 11 TC 58 Z9 58 U1 0 U2 7 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD JUN PY 2007 VL 107 IS 6 BP 1002 EP 1007 DI 10.1016/j.jada.2007.03.007 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 173PM UT WOS:000246885000021 PM 17524721 ER PT J AU Giannelli, SV Patel, KV Windham, BG Pizzarelli, F Ferrucci, L Guralnik, JM AF Giannelli, Sandra V. Patel, Kushang V. Windham, B. Gwen Pizzarelli, Francesco Ferrucci, Luigi Guralnik, Jack M. TI Magnitude of underascertainment of impaired kidney function in older adults with normal serum creatinine SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE GFR; creatinine; misclassification bias; elderly ID GLOMERULAR-FILTRATION-RATE; CONVERTING ENZYME-INHIBITORS; CHRONIC RENAL-INSUFFICIENCY; CYSTATIN-C; DISEASE; METAANALYSIS; PROGRESSION; PREDICTION; MICROALBUMINURIA; PERFORMANCE AB Objectives: To estimate in a community-dwelling elderly population the magnitude of renal function misclassification, occurring when persons with normal serum creatinine have reduced glomerular filtration rate (GFR), and to describe the participant characteristics related to misclassification. Design: Cross-sectional. Setting: Population-based study of older Italian people. Participants: Six hundred sixty participants aged 65 to 92 with normal serum creatinine. Measurements: GFR was estimated using the Cockcroft-Gault equation and creatinine clearance (CrCl) calculated from 24-hour urine collection. Results: In participants with normal serum creatinine, 39% and 25% had moderate renal function impairment (GFR < 60 mL/min) according to the Cockcroft-Gault equation and CrCl calculation, respectively. Prevalence of moderate renal impairment in those aged 65 to 74, 75 to 84, and 85 and older was 18.6%, 58.3%, and 96.8%, respectively (P for trend <.001) according to the Cockcroft-Gault equation, and 15%, 35.7%, and 58.7%, respectively (P for trend <.001) based on the CrCl calculation. In addition, female sex (P <.001) and normal or underweight (P <.05) were factors associated with high risk of misclassification. Conclusion: Serum creatinine alone is one of the most widely used methods of assessing renal function in clinical practice despite its well-known poor correlation with GFR. A large proportion of older persons with impaired renal function are not diagnosed if clinicians rely solely on normal serum creatinine as evidence of normal renal function. Opportunities may be missed for slowing progression of kidney disease, managing comorbidities and complications related to renal impairment, and adjusting drug dosage for renal function. C1 NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. Univ Hosp Geneva, Dept Rehabil & Geriatr, Geneva, Switzerland. NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. SM Annunziate Hosp, Div Nephrol, Florence, Italy. RP Giannelli, SV (reprint author), NIA, Lab Epidemiol Demog & Biometry, NIH, 7201 Wisconsin Ave,Gateway Bldg,Suite 3C309, Bethesda, MD 20892 USA. EM giannellis@mail.nih.gov RI Giannelli, Sandra/E-8637-2011 FU Intramural NIH HHS [Z99 AG999999] NR 38 TC 37 Z9 38 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUN PY 2007 VL 55 IS 6 BP 816 EP 823 DI 10.1111/j.1532-5415.2007.01196.x PG 8 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 172HI UT WOS:000246794400002 PM 17537080 ER PT J AU Richter, HE Goode, PS Kenton, K Brown, MB Burgio, KL Kreder, K Moalli, P Wright, EJ Weber, AM AF Richter, Holly E. Goode, Patricia S. Kenton, Kim Brown, Morton B. Burgio, Kathryn L. Kreder, Karl Moalli, Pamela Wright, E. James Weber, Anne M. CA Pelvic Floor Disorders Network TI The effect of age on short-term outcomes after abdominal surgery for pelvic organ prolapse SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Geriatrics-Society CY MAY 03-07, 2006 CL Chicago, IL SP Amer Geriatr Soc DE surgery; pelvic organ prolapse; older women; outcomes; quality of life; length of stay ID INCONTINENCE SURGERY; STRESS-INCONTINENCE; ELDERLY-WOMEN; UROGYNECOLOGIC SURGERY; GYNECOLOGIC SURGERY; RANDOMIZED-TRIAL; FLOOR DISORDERS; UNITED-STATES; SHORT-FORM; MORBIDITY AB Objectives: To compare perioperative morbidity and 1-year outcomes of older and younger women undergoing surgery for pelvic organ prolapse (POP). Design: Prospective ancillary analysis. Setting: Academic medical centers in National Institutes of Health, National Institute of Child Health and Human Development Colpopexy and Urinary Reduction Study. Participants: Women with POP and no symptoms of stress incontinence. Intervention: Abdominal sacrocolpopexy with randomization to receive Burch colposuspension for treatment of possible occult incontinence or not. Measurements: Perioperative complications and Pelvic Organ Prolapse Quantification and quality-of-life (QOL) questionnaires (Pelvic Floor Distress Inventory, Pelvic Floor Impact Questionnaire, and Medical Outcomes Study Short-Form Health Survey (SF-36) preoperatively, immediately postoperatively, and 6 weeks and 3 and 12 months postoperatively). Results: Three hundred twenty-two women aged 31 to 82 (21% aged >= 70), 93% white. Older women had higher baseline comorbidity (P <.001) and more severe POP (P=.003). Controlling for prolapse stage and whether Burch was performed, there were no age differences in complication rates. Older women had longer hospital stays (3.1 +/- 1.0 vs 2.7 +/- 1.5 days, P=.02) and higher prevalence of incontinence at 6 weeks (54.7% vs 37.2%, P=.005). At 3 and 12 months, there were no differences in self-reported incontinence, stress testing for incontinence, or prolapse stage. Improvements from baseline were significant on all QOL measures but with no age differences. Conclusions: Outcomes of prolapse surgery were comparable between older and younger women except that older women had slightly longer hospital stays. C1 Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35233 USA. Univ Alabama, Div Gerontol & Geriatr, Birmingham, AL 35233 USA. Dept Vet Affairs Med Ctr, Birmingham Atlanta Geriatr Res Educ & Clin Ctr, Birmingham, AL USA. Loyola Univ, Dept Obstet & Gynecol, Maywood, IL 60153 USA. Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. Univ Iowa, Dept Urol, Iowa City, IA 52242 USA. Univ Pittsburgh, Div Urogynecol & Pelv Reconstruct Surg, Pittsburgh, PA 15260 USA. Johns Hopkins Sch Med, Dept Urol, Baltimore, MD USA. NICHHD, Bethesda, MD 20892 USA. RP Richter, HE (reprint author), Univ Alabama, Dept Obstet & Gynecol, 620 20th St S,NHB 219, Birmingham, AL 35233 USA. EM hrichter@uab.edu FU NCATS NIH HHS [UL1 TR000005]; NICHD NIH HHS [U01 HD41249, U10 HD041261, U10 HD41250, U10 HD41261, U10 HD41263, U10 HD41267, U10 HD41269, U10 HD41248, U10 HD41268]; NIDDK NIH HHS [K24 DK068389] NR 26 TC 19 Z9 19 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD JUN PY 2007 VL 55 IS 6 BP 857 EP 863 DI 10.1111/j.1532-5415.2007.01178.x PG 7 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 172HI UT WOS:000246794400007 PM 17537085 ER PT J AU Milrod, B AF Milrod, Barbara TI Emptiness in agoraphobia patients SO JOURNAL OF THE AMERICAN PSYCHOANALYTIC ASSOCIATION LA English DT Article ID PANIC DISORDER; PSYCHODYNAMIC PSYCHOTHERAPY; TRIAL; ATTACHMENT; PATTERNS AB In light of new research findings about the efficacy of psychodynamic treatment for panic disorder and agoraphobia, it seems a prudent time to carefully address psychoanalytic thinking about the treatment of agoraphobia. The literature has highlighted oedipal contributions to its genesis and clinical unraveling in psychoanalysis. While those contributions are indeed central to the disorder, structural deficits in the self-representation often become a central focus of treatment once symptomatic remission has been achieved in psychoanalytic treatment. This aspect of the clinical presentation of agoraphobia has not yet been specifically addressed in the psychiatric literature. Some aspects of the phenomenon have been described by psychoanalysts. It is more difficult to treat this "emptiness" than the overt symptoms of agoraphobia, as described in DSM-IV Nonetheless, this phenomenon may be one of the contributors to the chronicity of the disorder. Two clinical cases illustrate these points. C1 Payne Whitney Psychiat Clin, New York, NY 10024 USA. NIMH, Bethesda, MD 20892 USA. RP Milrod, B (reprint author), Payne Whitney Psychiat Clin, 525 E 68th St, New York, NY 10024 USA. EM bmilrod@mail.med.cornell.edu FU NIMH NIH HHS [K23-MH01849-01/05] NR 33 TC 6 Z9 6 U1 2 U2 2 PU AMER PSYCHOANALYTIC ASSOC PI HILLSDALE PA 101 WEST STREET, HILLSDALE, NJ 07642 USA SN 0003-0651 J9 J AM PSYCHOANAL ASS JI J. Am. Psychoanal. Assoc. PD SUM PY 2007 VL 55 IS 3 BP 1007 EP 1026 PG 20 WC Psychiatry; Psychology, Psychoanalysis SC Psychiatry; Psychology GA 207NK UT WOS:000249257600020 PM 17915656 ER PT J AU Reynolds, K Gu, DF Muntner, P Kusek, JW Chen, J Wu, XG Duan, XF Chen, CS Klag, MJ Whelton, PK He, J AF Reynolds, Kristi Gu, Dongfeng Muntner, Paul Kusek, John W. Chen, Jing Wu, Xigui Duan, Xiufang Chen, Chung-Shiuan Klag, Michael J. Whelton, Paul K. He, Jiang TI A population-based, prospective study of blood pressure and risk for end-stage renal disease in China SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID HYPERTENSION; PREVALENCE; MEN AB The association between BP and risk for ESRD has not been well characterized in Asian populations. This study examined the relationship between level of BP and incidence of ESRD in a prospective cohort study of 158,365 Chinese men and women who were 40 yr and older. Measurement of BP and covariables were made in 1991 following a standard protocol. Follow-up evaluations were conducted in 1999 to 2000 and included interviewing participants or proxies and obtaining medical records and death certificates for ESRD cases. During 1,236,422 person-years of follow-up, 380 participants initiated renal replacement therapy or died from renal failure (30.7 cases per 100,000 person-years). Compared with those with normal BP, the multivariate adjusted hazard ratios (95% confidence interval) of all-cause ESRD for prehypertension and stage 1 and stage 2 hypertension were 1.30 (0.98 to 1.74), 1.47 (1.06 to 2.06), and 2.60 (1.89 to 3.57), respectively (P < 0.001 for trend). The corresponding hazard ratios (95% confidence interval) of glomerulonephritis-related ESRD were 1.32 (0.82 to 2.11), 1.48 (0.83 to 2.61), and 3.40 (2.02 to 5.74), respectively (P < 0.001 for trend). Systolic BP was a stronger predictor of ESRD than diastolic BP or pulse pressure. This study provides novel data on the incidence of ESRD and on the association between BP and glomerulonephritis-related ESRD from a nationally representative sample of adults in China. These results document the importance of high BP as a modifiable risk factor for ESRD in China. Strategies to prevent ESRD should incorporate the prevention, treatment, and control of BP. C1 Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, New Orleans, LA 70112 USA. Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. Chinese Acad Med Sci, Cardiovasc Inst, Beijing 100037, Peoples R China. Chinese Acad Med Sci, Fuwai Hosp, Beijing 100037, Peoples R China. Peking Union Med Coll, Beijing 100037, Peoples R China. Chinese Natl Ctr Cardiovasc Dis Control & Res, Beijing 100037, Peoples R China. NIDDK, Bethesda, MD USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Reynolds, K (reprint author), Tulane Univ, Sch Publ Hlth & Trop Med, Dept Epidemiol, 1440 Canal St,Suite 2036, New Orleans, LA 70112 USA. EM kristi.reynolds@tulane.edu FU NCRR NIH HHS [P20 RR 17659]; NIDDK NIH HHS [U01 DK 60963] NR 28 TC 39 Z9 44 U1 2 U2 4 PU AMERICAN SOCIETY NEPHROLOGY PI WASHINGTON PA 1725 I ST, NW STE 510, WASHINGTON, DC 20006 USA SN 1046-6673 J9 J AM SOC NEPHROL JI J. Am. Soc. Nephrol. PD JUN PY 2007 VL 18 IS 6 BP 1928 EP 1935 DI 10.1681/ASN.2006111199 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 174OV UT WOS:000246952700037 PM 17475822 ER PT J AU Raghunathan, TE Xie, D Schenker, N Parsons, VL Davis, WW Dodd, KW Feuer, EJ AF Raghunathan, Trivellore E. Xie, Dawei Schenker, Nathaniel Parsons, Van L. Davis, William W. Dodd, Kevin W. Feuer, Eric J. TI Combining information from two surveys to estimate county-level prevalence rates of cancer risk factors and screening SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE BRFSS; cancer screening; complex sample survey; Gibbs sampling; hierarchical model; mammography; NHIS; pap smear; simulation; smoking ID HEALTH INTERVIEW SURVEY; INCOME AB Cancer surveillance research requires estimates of the prevalence of cancer risk factors and screening for small areas such as counties. Two popular data sources are the Behavioral Risk Factor Surveillance System (BRFSS), a telephone survey conducted by state agencies, and the National Health Interview Survey (NHIS), an area probability sample survey conducted through face-to-face interviews. Both data sources have advantages and disadvantages. The BRFSS is a larger survey and almost every county is included in the survey, but it has lower response rates as is typical with telephone surveys and it does not include subjects who live in households with no telephones. On the other hand, the NHIS is a smaller survey, with the majority of counties not included; but it includes both telephone and nontelephone households, and has higher response rates. A preliminary analysis shows that the distributions of cancer screening and risk factors are different for telephone and nontelephone households. Thus, information from the two surveys may be combined to address both nonresponse and noncoverage errors. A hierarchical Bayesian approach that combines information from both surveys is used to construct county-level estimates. The proposed model incorporates potential noncoverage and nonresponse biases in the BRFSS as well as complex sample design features of both surveys. A Markov chain Monte Carlo method is used to simulate draws from the joint posterior distribution of unknown quantities in the model that uses design-based direct estimates and county-level covariates. Yearly prevalence estimates at the county level for 49 states. as well as for the entire state of Alaska and the District of Columbia, are developed for six outcomes using BRFSS and NHIS data from the years 1997-2000. The outcomes include smoking and use of common cancer screening procedures. The NHIS/BRFSS combined county-level estimates are substantially different from those based on the BRFSS alone. C1 Univ Michigan, Sch Publ Hlth, ISR, Ann Arbor, MI 48109 USA. Univ Penn, Dept Biostat & Epidemiol, Sch Med, Philadelphia, PA 19104 USA. Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. NCI, Stat Res & Applicat Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Raghunathan, TE (reprint author), Univ Michigan, Sch Publ Hlth, ISR, Ann Arbor, MI 48109 USA. EM teraghu@umich.edu; dxie@cceb.med.upenn.edu; nschenker@cdc.gov; vparsons@cdc.gov; feuerr@mail.nih.gov NR 39 TC 40 Z9 41 U1 1 U2 6 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 1429 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD JUN PY 2007 VL 102 IS 478 BP 474 EP 486 DI 10.1198/016214506000001293 PG 13 WC Statistics & Probability SC Mathematics GA 173FP UT WOS:000246859200012 ER PT J AU Li, Y Lahiri, P AF Li, Yan Lahiri, P. TI Robust model-based and model-assisted predictors of the finite population total SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE Box-Cox transformation; empirical best prediction; superpopulation ID EMPIRICAL BAYES ESTIMATION; IMPORT DEMAND EQUATION; BOX-COX ESTIMATION; FUNCTIONAL FORM; SAMPLE-SURVEYS; MIXED-MODEL; TRANSFORMATIONS; PARAMETERS; VARIANCE; VALUES AB The prediction approach to finite population inference has received considerable attention in recent years. Under this approach, the finite population is assumed to be a realization from a superpopulation described by a known probability model, usually a linear model. The prediction approach is often criticized for its lack of robustness against model misspecification. In this article we revisit this important issue and introduce a new robust prediction approach in which the superpopulation model is chosen adaptively from the well-known BoxCox class of probability distributions. The richness of the Box-Cox class ensures robustness in our model-based prediction approach. We explain how our robust model-based predictor can be adjusted to handle zero observations for the study variable and to achieve the design-unbiasedness and benchmarking properties. We demonstrate the robustness of our proposed predictors using a Monte Carlo simulation study and a real life example. C1 Univ Maryland, Jont Program Survey Methodol, College Pk, MD 20742 USA. NCI, Biostat Branch, US Dept HHS, NIH, Rockville, MD 20852 USA. RP Li, Y (reprint author), Univ Maryland, Jont Program Survey Methodol, College Pk, MD 20742 USA. EM plahiri@survey.umd.edu NR 60 TC 2 Z9 2 U1 0 U2 3 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 732 N WASHINGTON ST, ALEXANDRIA, VA 22314-1943 USA SN 0162-1459 EI 1537-274X J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD JUN PY 2007 VL 102 IS 478 BP 664 EP 673 DI 10.1198/016214507000000158 PG 10 WC Statistics & Probability SC Mathematics GA 173FP UT WOS:000246859200029 ER PT J AU Chen, WR Mi, RF Haughey, N Oz, M Hoke, A AF Chen, Weiran Mi, Ruifa Haughey, Norman Oz, Murat Hoeke, Ahmet TI Immortalization and characterization of a nociceptive dorsal root ganglion sensory neuronal line SO JOURNAL OF THE PERIPHERAL NERVOUS SYSTEM LA English DT Article DE DRG; high-throughput screen; nociceptive; sensory neuronal line; TRPV-1; 50B11 ID CAPSAICIN RECEPTOR; DRG NEURONS; CELLS; CHANNEL; PAIN; NEUROPATHY; IDENTIFICATION; EXPRESSION; FK506; GDNF AB Development of neuroprotective strategies for peripheral neuropathies requires high-throughput drug screening assays with appropriate cell types. Currently, immortalized dorsal root ganglion (DRG) sensory neuronal cell lines that maintain nociceptive sensory neuronal properties are not available. We generated immortalized DRG neuronal lines from embryonic day 14.5 rats. Here, we show that one of the immortalized DRG neuronal lines, 50B11, has the properties of a nociceptive neuron. When differentiated in the presence of forskolin, these cells extend long neurites, express neuronal markers, and generate action potentials. They express receptors and markers of small-diameter sensory neurons and upregulate appropriate receptor populations when grown in the presence of glial cell line-derived neurotrophic factor or nerve growth factor. Furthermore, they express capsaicin receptor transient receptor potential vanilloid family-1 (TRPV-1) and respond to capsaicin with increases in intracellular calcium. In a 96-well plate format, these neurons show a decline in ATP levels when exposed to dideoxycytosine (ddC) in a proper time- and dose-dependent manner. This ddC-induced reduction in ATP levels correlates with axonal degeneration. The immortalized DRG neuronal cell line 50B11 can be used for high-throughput drug screening for neuroprotective agents for axonal degeneration and antinociceptive drugs that block TRPV-1. C1 Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. NIDA, Integrat Neurosci Sect, Intramural Res Program, NIH, Baltimore, MD USA. RP Hoke, A (reprint author), Johns Hopkins Univ Hosp, Dept Neurol, 600 N Wolfe St,Path 509, Baltimore, MD 21287 USA. EM ahoke@jhmi.edu RI Oz, Murat/E-2148-2012; OI Hoke, Ahmet/0000-0003-1215-3373 FU NIA NIH HHS [R01 AG023471]; NIMH NIH HHS [P01 MH070056, P01MH70056, P30 MH075673, R21 MH072534]; NINDS NIH HHS [R01NS47972, R01 NS043991, R01 NS047972, R01NS43991] NR 27 TC 34 Z9 34 U1 0 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1085-9489 J9 J PERIPHER NERV SYST JI J. Peripher. Nerv. Syst. PD JUN PY 2007 VL 12 IS 2 BP 121 EP 130 DI 10.1111/j.1529-8027.2007.00131.x PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 182TI UT WOS:000247526500007 PM 17565537 ER PT J AU Grubb, RL Franks, ME Toro, J Middelton, L Choyke, L Fowler, S Torres-Cabala, C Glenn, GM Choyke, P Merino, MJ Zbar, B Pinto, PA Srinivasan, R Coleman, JA Linehan, WM AF Grubb, Robert L., III Franks, Michael E. Toro, Jorge Middelton, Lindsay Choyke, Lynda Fowler, Sarah Torres-Cabala, Carlos Glenn, Gladys M. Choyke, Peter Merino, Maria J. Zbar, Berton Pinto, Peter A. Srinivasan, Ramaprasad Coleman, Jonathan A. Linehan, W. Marston TI Hereditary leiomyomatosis and renal cell cancer: A syndrome associated with an aggressive form of inherited renal cancer SO JOURNAL OF UROLOGY LA English DT Article DE kidney; carcinoma; papillary; leiomyoma; uterus; fumarate hydratase ID PARENCHYMAL SPARING SURGERY; FUMARATE-HYDRATASE; TUMOR SIZE; FAMILIES; CARCINOMA; MUTATIONS; FH AB Purpose: Hereditary leiomyomatosis and renal cell cancer is a recently described hereditary cancer syndrome in which affected individuals are at risk for cutaneous and uterine leiomyomas, and kidney cancer. Our initial experience revealed the aggressive behavior of these renal tumors, often with early metastasis, despite small primary tumor size. We report the clinical characteristics and urological treatment of patients with hereditary leiomyomatosis and renal cell cancer associated renal tumors. Materials and Methods: A total of 19 patients with hereditary leiomyomatosis and renal cell cancer associated renal tumors were evaluated. The 11 women and 8 men had a median age at diagnosis of 39 years (range 22 to 67), and a median clinical and radiological followup of 34 months (range 6 to 141). Hereditary leiomyomatosis and renal cell cancer manifestations in patients with renal tumors included cutaneous leiomyomas in 11 of 17 evaluable patients (65%) and uterine leiomyomas in 7 of 7 evaluable females (100%). Results: Median pathological tumor size was 7.8 cm (range 1.5 to 20). Histological subtypes were consistent with hereditary leiomyomatosis and renal cell cancer renal carcinoma. Four of 7 patients with 2.0 to 6.7 cm T1 tumors had spread to regional lymph nodes or metastases at nephrectomy. Overall 9 of 19 patients (47%) presented with nodal or distant metastases. Conclusions: Renal tumors in patients with hereditary leiomyomatosis and renal cell cancer syndrome are significantly more aggressive than those in patients with other hereditary renal tumor syndromes. In contrast to other familial renal cancer syndromes, the observation of 3 cm or less renal tumors associated with hereditary leiomyomatosis and renal cell cancer is not recommended. Careful followup of affected and at risk individuals in families is necessary. C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, NIH, Bethesda, MD 20892 USA. NCI, Immunobiol Lab, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Linehan, WM (reprint author), NCI, Urol Oncol Branch, NIH, 10 Ctr Dr,MSC 1107,Bldg 10,CRC Room 1-5940, Bethesda, MD 20892 USA. EM WML@nih.gov OI Coleman, Jonathan/0000-0002-6428-7835 NR 16 TC 98 Z9 100 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD JUN PY 2007 VL 177 IS 6 BP 2074 EP 2079 DI 10.1016/j.juro.2007.01.155 PG 6 WC Urology & Nephrology SC Urology & Nephrology GA 170BJ UT WOS:000246635800016 PM 17509289 ER PT J AU Locklin, JK Yanof, J Luk, A Varro, Z Patriciu, A Wood, BJ AF Locklin, Julia K. Yanof, Jeff Luk, Alfred Varro, Zoltan Patriciu, Alexandru Wood, Bradford J. TI Respiratory biofeedback during CT-guided procedures SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article; Proceedings Paper CT 29th Annual Meeting of the Society-of-Interventional-Radiology (SIR) CY MAR 25-30, 2004 CL Phoenix, AZ SP Soc Intervent Radiol ID BREATHING CONTROL ABC; RADIATION-THERAPY; UPPER ABDOMEN; HOLD; LUNG; FEEDBACK; BIOPSY; MOTION; SYSTEM; LIVER AB PURPOSE: Respiratory motion can be a complicating factor during image-guided interventions. The ability to reproduce breath-holds may facilitate safer needle-based procedures. The purpose of this study was to evaluate if respiratory biofeedback decreased variability among breath-holds and if the signals from the respiratory bellows belt can be used to measure target motion. MATERIALS AND METHODS: In phase 1 of the study, a respiratory bellows belt was applied to patients before image-guided interventional procedures. Belt stretch from respiratory motion was converted into voltage readings and displayed on a monitor as biofeedback. Patients were asked to perform inspiratory, expiratory, and midcycle breath-holds with and without the biofeedback. The variability in voltage readings between breath-holds with and without biofeedback was compared. In phase 2, the respiratory bellows belt was used during computed tomography (CT)-guided procedures with the patients blinded to the biofeedback. Voltage readings and CT series numbers were recorded as patients were asked to hold their breath during scans. The variability of CT z-axis targets was compared with the variability of voltage readings. RESULTS: A significant decrease in variability was found during expiratory breath-holds (P = .0083) with trends toward significance with midcycle and inspiratory breath-holds. A positive correlation (Kendall tau = 0.5; P = .024) was shown between CT z-axis and belt stretch variability in subjects who received smaller doses of moderate sedation compared with those who received larger doses or general anesthesia. CONCLUSIONS: Biofeedback may help the patient to have a more consistent breath-hold. The belt could decrease the error and unpredictability from craniocaudal motion of targets during image-guided interventions. C1 NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. Philips Med Syst, Cleveland, OH USA. Oregon Hlth & Sci Univ, Portland, OR USA. RP Locklin, JK (reprint author), NIH, Dept Diagnost Radiol, Ctr Clin, Bldg 10,Room 1C367A,9000 Rockville Pike, Bethesda, MD 20892 USA. EM locklinj@cc.nih.gov FU Intramural NIH HHS [NIH0010126778]; PHS HHS [NIH0010126778] NR 18 TC 6 Z9 6 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD JUN PY 2007 VL 18 IS 6 BP 749 EP 755 DI 10.1016/j.jvir.2007.03.010 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 176MB UT WOS:000247088100008 PM 17538137 ER PT J AU Thompson, RW Schucker, B Kent, KC Clowes, AW Kraiss, LW Mannick, JA Yao, JST AF Thompson, Robert W. Schucker, Beth Kent, K. Craig Clowes, Alexander W. Kraiss, Larry W. Mannick, John A. Yao, James S. T. TI Reviving the vascular surgeon-scientist: An interim assessment of the jointly sponsored Lifeline Foundation/National heart, Lung, and Blood Institute William J. von Liebig Mentored Clinical Scientist Development (K08) Program SO JOURNAL OF VASCULAR SURGERY LA English DT Article ID PRESIDENTIAL-ADDRESS; PHYSICIAN-SCIENTIST; SURGICAL RESEARCH; CLINICAL INVESTIGATOR; RECENT TRENDS; CHALLENGES; FACULTY AB The Lifeline Foundation/National Heart, Lung, and Blood Institute William J. von Liebig Mentored Clinical Scientist Development (K08) Award program was established as a unique partnership to support vascular surgeon-scientists. Between 1999 and 2005, 39 applications were submitted, and the overall funding rate was 49% (14 von Liebig K08s and 5 additional NHLBI K08s). Vascular surgeon K08 recipients (median age, 38 years) had held faculty appointments for 2.5 +/- 0.4 years, with 2.6 +/- 0.2 years of previous research experience and 28.4 +/- 6.2 publications. These individuals subsequently authored 5.1 +/- 0.8 peer-reviewed publications per recipient per year, of which 35% were research and 65% were clinical. Six of seven holding the K08 over 3 years had received academic promotion, and all five completing the 5-year award had achieved independent investigator status with National Institutes of Health support. The von Liebig K08 program has therefore been an effective vehicle to stimulate research career development in the field of vascular surgery. C1 Washington Univ, Sch Med, Dept Surg, Vasc Surg Sect, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Radiol, Vasc Surg Sect, St Louis, MO 63110 USA. Washington Univ, Sch Med, Dept Cell Biol & Physiol, Vasc Surg Sect, St Louis, MO 63110 USA. NHLBI, Res Training & Special Programs Sci Res Grp, Div Heart & Vasc Dis, NIH, Bethesda, MD 20892 USA. New York Presbyterian Hosp, Div Vasc Surg, New York, NY USA. Cornell Univ, New York Weill Med Ctr, New York, NY 10021 USA. Univ Washington, Dept Surg, Div Vasc Surg, Seattle, WA 98195 USA. Univ Utah, Dept Surg, Div Vasc Surg, Salt Lake City, UT 84112 USA. Brigham & Womens Hosp, Dept Surg, Boston, MA 02115 USA. Harvard Univ, Sch Med, Cambridge, MA 02138 USA. Northwestern Univ, Feinberg Sch Med, Dept Surg, Evanston, IL 60208 USA. RP Thompson, RW (reprint author), Washington Univ, Sch Med, Dept Surg, Vasc Surg Sect, 5101 Queeny Tower,1 Barnes Jewish Hosp Plaza, St Louis, MO 63110 USA. EM thompson@wudosis.wustl.edu NR 25 TC 11 Z9 11 U1 2 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-5214 J9 J VASC SURG JI J. Vasc. Surg. PD JUN PY 2007 VL 45 SU A BP 2A EP 7A DI 10.1016/j.jvs.2007.02.045 PG 6 WC Surgery; Peripheral Vascular Disease SC Surgery; Cardiovascular System & Cardiology GA 175IR UT WOS:000247007800002 PM 17544018 ER PT J AU Yu, C Zimmerman, C Stone, R Engle, RE Elkins, W Nardone, GA Emerson, SU Purcell, RH AF Yu, Claro Zimmerman, Carl Stone, Roger Engle, Ronald E. Elkins, William Nardone, Glenn A. Emerson, Suzanne U. Purcell, Robert H. TI Using improved technology for filter paper-based blood collection to survey wild Sika deer for antibodies to hepatitis E virus SO JOURNAL OF VIROLOGICAL METHODS LA English DT Article DE HEV; Sika deer; filter paper discs; ELISA ID UNITED-STATES; BOAR; PREVALENCE; INFECTION; SWINE; GENOTYPE-3; MEASLES; SERUM; JAPAN; HEV AB Recent reports from Japan implicated wild Sika deer (Cervus nippon) in the zoonotic transmission of hepatitis E to humans. Seroprevalence studies were performed to determine if imported feral populations of Sika deer in Maryland and Virginia posed a similar risk of transmitting hepatitis E virus (HEV). Hunters collected blood on filter paper discs from freshly killed deer. The discs were desiccated and delivered to a collection point. The dried filters were weighed to estimate the amount of blood absorbed and were eluted and collected in one tube via a novel extraction system. The procedure was quantified and validated with negative and positive serum and blood samples obtained from domestic Sika deer before and after immunization with HEV recombinant capsid protein, respectively. None of the 155 tested samples contained antibody to HEV, suggesting that Sika deer in these populations, unlike those in Japan, do not pose a significant zoonotic threat for hepatitis E. However, the new method developed for collecting and eluting the samples should prove useful for field studies of many other pathogens. (c) 2007 Elsevier B.V. All rights reserved. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Assateague Isl Natl Seashore, Berlin, MD USA. Blackwater Natl Wildlife Refuge, Cambridge, MD USA. NIAID, NIH, Bethesda, MD 20892 USA. NIAID, NIH, Res & Technol Branch, Rockville, MD USA. RP Yu, C (reprint author), 5640 Fishers Lane,Twinbrook 1,Room 1502, Rockville, MD 20852 USA. EM clyu@niaid.nih.gov; carl_zimmerman@nps.gov; roger_stone@fws.gov; re3e@nih.gov; relkins@niaid.nih.gov; gn57d@nih.gov; semerson@niaid.nih.gov; rpurcell@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000311-24] NR 26 TC 16 Z9 16 U1 1 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-0934 J9 J VIROL METHODS JI J. Virol. Methods PD JUN PY 2007 VL 142 IS 1-2 BP 143 EP 150 DI 10.1016/j.jviromet.2007.01.016 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Virology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Virology GA 170PM UT WOS:000246675900019 PM 17336401 ER PT J AU Dey, B Pancera, M Svehla, K Shu, Y Xiang, SH Vainshtein, J Li, YX Sodroski, J Kwong, PD Mascola, JR Wyatt, R AF Dey, Barna Pancera, Marie Svehla, Krisha Shu, Yuuei Xiang, Shi-Hua Vainshtein, Jeffrey Li, Yuxing Sodroski, Joseph Kwong, Peter D. Mascola, John R. Wyatt, Richard TI Characterization of human immunodeficiency virus type 1 monomeric and trimeric gp120 glycoproteins stabilized in the CD4-bound state: Antigenicity, biophysics, and immunogenicity SO JOURNAL OF VIROLOGY LA English DT Article ID HUMAN MONOCLONAL-ANTIBODY; HIV-1 ENVELOPE GLYCOPROTEINS; CD4 BINDING-SITE; NEUTRALIZING ANTIBODIES; IMMUNE-RESPONSES; PRIMARY ISOLATE; RECEPTOR; EPITOPE; INFECTION; GP41 AB The human immunodeficiency virus type 1 exterior gp120 envelope glycoprotein is highly flexible, and this flexibility may contribute to the inability of monomeric gp120 immunogens to elicit broadly neutralizing antibodies. We previously showed that an S375W modification of a critical interfacial cavity central to the primary receptor binding site, the Phe43 cavity, stabilizes gp120 into the CD4-bound state. However, the immunological effects of this cavity-altering replacement were never tested. Subsequently, we screened other mutations that, along with the S375W alteration, might further stabilize the CD4-bound state. Here, we define a selected second cavity-altering replacement, T257S, and analyze the double mutations in several gp120 envelope glycoprotein contexts. The gp120 glycoproteins with the T257S-plus-S375W double mutation (T257S+S375W) have a superior antigenic profile compared to the originally identified single S375W replacement in terms of enhanced recognition by the broadly neutralizing CD4 binding-site antibody b12. Isothermal titration calorimetry measuring the entropy of the gp120 interaction with CD4 indicated that the double mutant was also stabilized into the CD4-bound state, with increasing relative fixation between core, full-length monomeric, and full-length trimeric versions of gp120. A significant increase in gp120 affinity for CD4 was also observed for the cavity-filling mutants relative to wild-type gp120. The most conformationally constrained T257S+S375W trimeric gp120 proteins were selected for immunogenicity analysis in rabbits and displayed a trend of improvement relative to their wild-type counterparts in terms of eliciting neutralizing antibodies. Together, the results suggest that conformational stabilization may improve the ability of gp120 to elicit neutralizing antibodies. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Wyatt, R (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,Room 4512, Bethesda, MD 20892 USA. EM richardwyatt@nih.gov FU Intramural NIH HHS NR 49 TC 83 Z9 84 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2007 VL 81 IS 11 BP 5579 EP 5593 DI 10.1128/JVI.02500-06 PG 15 WC Virology SC Virology GA 173II UT WOS:000246866300015 PM 17360741 ER PT J AU Brown, CR Czapiga, M Kabat, J Dang, Q Ourmanov, I Nishimura, Y Martin, MA Hirsch, VM AF Brown, Charles R. Czapiga, Meggan Kabat, Juraj Dang, Que Ourmanov, Ilnour Nishimura, Yoshiaki Martin, Malcolm A. Hirsch, Vanessa M. TI Unique pathology in simian immunodeficiency virus-infected rapid progressor macaques is consistent with a pathogenesis distinct from that of classical AIDS SO JOURNAL OF VIROLOGY LA English DT Article ID T-CELL DEPLETION; CHEMOKINE CORECEPTOR USAGE; POLYMERASE CHAIN-REACTION; END-STAGE DISEASE; PLASMA VIRAL LOAD; HIV-I INFECTION; RHESUS MACAQUES; GASTROINTESTINAL-TRACT; LYMPH-NODES; MACROPHAGE TROPISM AB Simian immunodeficiency virus (SM infection of macaques and human immunodeficiency virus type 1 (HIV-1) infection of humans result in variable but generally fatal disease outcomes. Most SIV-infected macaques progress to AIDS over a period of 1 to 3 years, in the face of robust SIV-specific immune responses (conventional progressors [CP]). A small number of SIV-inoculated macaques mount transient immune responses and progress rapidly to AIDS (rapid progressors [RP]). We speculated that the underlying pathogenic mechanisms may differ between RP and CP macaques. We compared the pathological lesions, virus loads, and distribution of virus and target cells in SIVsmE660- or SIVsmE543-infected RP and CP rhesus macaques at terminal disease. RP macaques developed a wasting syndrome characterized by severe SIV enteropathy in the absence of opportunistic infections. In contrast, opportunistic infections were commonly observed in CP macaques. RP and CP macaques showed distinct patterns of CD4(+) T-cell depletion, with a selective loss of memory cells in RP macaques and a generalized (naive and memory) CD4 depletion in CP macaques. In situ hybridization demonstrated higher levels of virus expression in lymphoid tissues (P < 0.001) of RP macaques and a broader distribution to include many nonlymphoid tissues. Finally, SIV was preferentially expressed in macrophages in RP macaques whereas the primary target cells in CP macaques were T lymphocytes at end stage disease. These data suggest distinct pathogenic mechanisms leading to the deaths of these two groups of animals, with CP macaques being more representative of HIV-induced AIDS in humans. C1 NIAID, LMM, NIH, Bethesda, MD 20892 USA. NIAID, Res Technol Branch, NIH, Bethesda, MD 20892 USA. RP Hirsch, VM (reprint author), NIAID, LMM, NIH, Bldg 4,Room B1-41,4 Ctr Dr, Bethesda, MD 20892 USA. EM vhirsch@niaid.nih.gov NR 82 TC 47 Z9 50 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2007 VL 81 IS 11 BP 5594 EP 5606 DI 10.1128/JVI.00202-07 PG 13 WC Virology SC Virology GA 173II UT WOS:000246866300016 PM 17376901 ER PT J AU Biacchesi, S Murphy, BR Collins, PL Buchholz, UJ AF Biacchesi, Stephane Murphy, Brian R. Collins, Peter L. Buchholz, Ursula J. TI Frequent frameshift and point mutations in the SH gene of human metapneumovirus passaged in vitro SO JOURNAL OF VIROLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; SMALL HYDROPHOBIC PROTEIN; NONHUMAN-PRIMATES; TRACT DISEASE; INFECTION; CHILDREN; CDNA; PARAMYXOVIRUS; GLYCOPROTEIN; REPLICATION AB During the preparation of recombinant derivatives of the CAN97-83 clinical isolate of human metapneumovirus (HMPV), consensus nucleotide sequencing of the recovered RNA genomes provided evidence of frequent sequence heterogeneity at a number of genome positions. This heterogeneity was suggestive of sizable subpopulations containing mutations. An analysis of molecularly cloned cDNAs confirmed the presence of mixed populations. The biologically derived virus on which the recombinant system is based also contained sizeable mutant subpopulations, whose presence was confirmed by biological cloning and nucleotide sequencing. Most of the mutations occurred in the SH gene. For example, partial consensus sequencing of 40 independent preparations of recombinant HMPV (wild-type and various derivatives) showed that 31 of these preparations contained a total of 41 instances of small insertions in the SH gene and a total of five small insertions elsewhere. In each of these 31 preparations, there was at least one insert in SH that changed the reading frame and would yield a truncated protein. Nearly all of these insertions involved adding one or more A residues to various tracks of four or more A residues, with the most frequent site being a tract of seven A residues. There were also two instances of nucleotide deletions and numerous instances of nucleotide substitution point mutations, mostly in the SH gene. The occurrence of mutant subpopulations was greatly reduced by the replacement of the SH gene with a synthetic version in which these oligonucleotide tracts were eliminated by silent nucleotide changes. We suggest that we frequently detected subpopulations in which the expression of full-length SH protein was ablated because it provided a modest selective advantage to this clinical isolate in vitro. Adaptation involving the functional loss of a gene is unusual for an RNA virus. C1 NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Buchholz, UJ (reprint author), Bldg 50,Room 6505,50 South Dr,MSC 8007, Bethesda, MD 20892 USA. EM ubuchholz@niaid.nih.gov RI Biacchesi, Stephane/A-6924-2010 FU Intramural NIH HHS NR 29 TC 26 Z9 26 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2007 VL 81 IS 11 BP 6057 EP 6067 DI 10.1128/JVI.00128-07 PG 11 WC Virology SC Virology GA 173II UT WOS:000246866300059 PM 17376897 ER PT J AU Wagenaar, TR Moss, B AF Wagenaar, Timothy R. Moss, Bernard TI Association of vaccinia virus fusion regulatory proteins with the multicomponent entry/fusion complexv SO JOURNAL OF VIROLOGY LA English DT Article ID CELL-CELL-FUSION; SERINE PROTEASE INHIBITOR; MEMBRANE-PROTEIN; BREFELDIN-A; ENDOPLASMIC-RETICULUM; ESSENTIAL COMPONENT; ENVELOPE PROTEIN; VIRION MEMBRANE; GOLGI PROTEINS; POXVIRUS ENTRY AB The proteins encoded by the A56R and K2L genes of vaccinia virus form a heterodimer (A56/K2) and have a fusion regulatory role as deletion or mutation of either causes infected cells to form large syncytia spontaneously. Here, we showed that syncytia formation is dependent on proteins of the recently described entry fusion complex (EFC), which are also required for virus-cell fusion and low-pH-triggered cell-cell fusion. This finding led us to consider that A56/K2 might prevent fusion by direct or indirect interaction with the EFC. To test this hypothesis, we made a panel of recombinant vaccinia viruses that have a tandem affinity purification tag attached to A56, K2, or the A28 EFC protein. Interaction between A56/K2 and the EFC was demonstrated by their copurification from detergent-treated lysates of infected cells and identification by mass spectrometry or Western blotting. In addition, a purified soluble transmembrane-deleted form of A56/K2 was shown to interact with the EFC. Tagged A56 (lid not interact with the EFC in the absence of K2, nor did tagged K2 interact with the EFC in the absence of A56. The finding that both A56 and K2 are required for efficient binding to the EFC fits well with prior experiments showing that mutation of either A56 or K2 results in spontaneous fusion of infected cells. Because A56 and K2 are located on the surface of infected cells, they are in position to interact with the EFC of released progeny virions and prevent back-fusion and syncytia formation. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Maryland, College Pk, MD 20742 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, Bldg 4,Room 229, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Intramural NIH HHS NR 42 TC 39 Z9 39 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2007 VL 81 IS 12 BP 6286 EP 6293 DI 10.1128/JVI.00274-07 PG 8 WC Virology SC Virology GA 175BP UT WOS:000246987500013 PM 17409143 ER PT J AU Bukreyev, A Rollin, PE Tate, MK Yang, LJ Zaki, SR Shieh, WJ Murphy, BR Collins, PL Sanchez, A AF Bukreyev, Alexander Rollin, Pierre E. Tate, Mallory K. Yang, Lijuan Zaki, Sherif R. Shieh, Wun-Ju Murphy, Brian R. Collins, Peter L. Sanchez, Anthony TI Successful topical respiratory tract immunization of primates against ebola virus SO JOURNAL OF VIROLOGY LA English DT Article ID VESICULAR STOMATITIS-VIRUS; INFLUENZA-A VIRUS; HEMORRHAGIC-FEVER; NONHUMAN-PRIMATES; VACCINE VECTORS; ATTENUATION PHENOTYPES; SECONDARY INFECTION; IMMUNOSORBENT-ASSAY; IMMUNOGLOBULIN-A; GUINEA-PIGS AB Ebola virus causes outbreaks of severe viral hemorrhagic fever with high mortality in humans. The virus is highly contagious and can be transmitted by contact and by the aerosol route. These features make Ebola virus a potential weapon for bioterrorism and biological warfare. Therefore, a vaccine that induces both systemic and local immune responses in the respiratory tract would be highly beneficial. We evaluated a common pediatric respiratory pathogen, human parainfluenza virus type 3 (HPIV3), as a vaccine vector against Ebola virus. HPIV3 recombinants expressing the Ebola virus (Zaire species) surface glycoprotein (GP) alone or in combination with the nucleocapsid protein NP or with the cytokine adjuvant granulocyte-macrophage colony-stimulating factor were administered by the respiratory route to rhesus monkeys-in which HPIV3 infection is mild and asymptomatic-and were evaluated for immunogenicity and protective efficacy against a highly lethal intraperitoneal challenge with Ebola virus. A single immunization with any construct expressing GP was moderately immunogenic against Ebola virus and protected 88% of the animals against severe hemorrhagic fever and death caused by Ebola virus. Two doses were highly immunogenic, and all of the animals survived challenge and were free of signs of disease and of detectable Ebola virus challenge virus. These data illustrate the feasibility of immunization via the respiratory tract against the hemorrhagic fever caused by Ebola virus. To our knowledge, this is the first study in which topical immunization through respiratory tract achieved prevention of a viral hemorrhagic fever infection in a primate model. C1 NIAID, NIH, Infect Dis Lab, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Special Pathogens Branch, Div Viral & Rickettsial Dis, Atlanta, GA 30329 USA. RP Bukreyev, A (reprint author), NIAID, NIH, Infect Dis Lab, Bldg 50,Room 6505,50 South Dr,MSC 8007, Bethesda, MD 20892 USA. EM AB176v@nih.gov FU Intramural NIH HHS NR 40 TC 91 Z9 101 U1 0 U2 26 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUN PY 2007 VL 81 IS 12 BP 6379 EP 6388 DI 10.1128/JVI.00105-07 PG 10 WC Virology SC Virology GA 175BP UT WOS:000246987500022 PM 17428868 ER PT J AU Ravichandran, V Jensen, PN Major, EO AF Ravichandran, Veerasamy Jensen, Peter N. Major, Eugene O. TI MEK1/2 inhibitors block basal and transforming growth factor beta 1-stimulated JC virus multiplication SO JOURNAL OF VIROLOGY LA English DT Article ID PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; SIGNAL-TRANSDUCTION; TGF-BETA; MAP KINASES; PATHWAY; PROTEIN; POLYOMAVIRUS; ACTIVATION; INFECTION; CELLS AB The multiplication of the human neurotropic polyomavirus JC virus (JCV) is regulated by cell membrane receptors and nuclear transcription factors. Signaling pathways also play a role in determining the extent to which JCV can productively infect cells. These data show that constitutively active MEK1 protein (CA-MEK1), overexpressed in cultures of human glia, supports a substantial increase in late JCV protein (Vp-1) synthesis. The specificity of this pathway was indicated by no significant enhancement of JCV multiplication through activation of other components of mitogen-activated protein kinase pathways such as p38, Jun N-terminal protein kinase, and protein kinase A. Further evidence supporting the importance of signaling in JCV infection came from addition of transforming growth factor beta 1 (TGF-beta 1), which stimulated a 200% increase of Vp-1 expression. Specific MEK1/2 inhibitors, flavenoid PD98059 and U0126, decreased the basal and TGF-beta 1-stimulated Vp-1 expression by 95% or more. TGF-beta 1 is known to phosphorylate/activate Smad DNA binding proteins that could subsequently bind or increase binding to JCV promoter sequences, linking the effects of signaling with JCV transcriptional regulation. The effectiveness with which MEK1/2 inhibitors block JCV multiplication provides insight that may contribute to development of compounds directed against JCV. C1 NINDS, Lab Mol Med & Neurosci, NIH, Bethesda, MD 20892 USA. RP Major, EO (reprint author), NINDS, Lab Mol Med & Neurosci, NIH, 10 Ctr Dr,Bldg 10,Room 3B14,MSC1296, Bethesda, MD 20892 USA. EM majorg@ninds.nih.gov FU Intramural NIH HHS NR 32 TC 11 Z9 11 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD JUN PY 2007 VL 81 IS 12 BP 6412 EP 6418 DI 10.1128/JVI.02658-06 PG 7 WC Virology SC Virology GA 175BP UT WOS:000246987500025 PM 17409139 ER PT J AU Rulli, SJ Hibbert, CS Mirro, J Pederson, T Biswal, S Rein, A AF Rulli, Samuel J., Jr. Hibbert, Catherine S. Mirro, Jane Pederson, Thoru Biswal, Shyam Rein, Alan TI Selective and nonselective packaging of cellular RNAs in retrovirus particles SO JOURNAL OF VIROLOGY LA English DT Article ID MURINE LEUKEMIA-VIRUS; ACID-CHAPERONE ACTIVITY; ROUS-SARCOMA VIRUS; MESSENGER-RNA; GENOMIC RNA; REVERSE TRANSCRIPTION; NADH DEHYDROGENASE; GAG PROTEIN; CELLS; MUTANT AB Assembly of retrovirus particles normally entails the selective encapsidation of viral genomic RNA. However, in the absence of packageable viral RNA, assembly is still efficient, and the released virus-like particles (termed "Psi(-)" particles) still contain roughly normal amounts of RNA. We have proposed that cellular mRNAs replace the genome in Psi(-) particles. We have now analyzed the mRNA content of Psi(-) and Psi(+) murine leukemia virus (MLV) particles using both microarray analysis and real-time reverse transcription-PCR. The majority of mRNA species present in the virus-producing cells were also detected in Psi(-) particles. Remarkably, nearly all of them were packaged nonselectively; that is, their representation in the particles was simply proportional to their representation in the cells. However, a small number of low-abundance mRNAs were greatly enriched in the particles. In fact, one mRNA species was enriched to the same degree as Psi(+) genomic RNA. Similar results were obtained with particles formed from the human immunodeficiency virus type 1 (HIV-1) Gag protein, and the same mRNAs were enriched in MLV and HIV-1 particles. The levels of individual cellular mRNAs were similar to 5- to 10-fold higher in Psi(-) than in Psi(+) MLV particles, in agreement with the idea that they are replacing viral RNA in the former. In contrast, signal recognition particle RNA was present at the same level in Psi(-) and Psi(+) particles; a minor fraction of this RNA was weakly associated with genomic RNA in Psi(+) MLV particles. C1 Natl Canc Inst Frederick, HIV Drug Resistance Program, Frederick, MD 21702 USA. Univ Massachusetts, Sch Med, Dept Biochem & Mol Pharmacol, Worcester, MA 01605 USA. Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. RP Rein, A (reprint author), Natl Canc Inst Frederick, HIV Drug Resistance Program, POB B, Frederick, MD 21702 USA. EM rein@ncifcrf.gov FU Intramural NIH HHS; NHLBI NIH HHS [R01 HL081205, R01 HL081205-02, R01 HL081205-03]; NIEHS NIH HHS [P30 ES003819, P30 ES03819]; NIGMS NIH HHS [R01 GM-21595] NR 39 TC 83 Z9 84 U1 0 U2 4 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUN PY 2007 VL 81 IS 12 BP 6623 EP 6631 DI 10.1128/JVI.02833-06 PG 9 WC Virology SC Virology GA 175BP UT WOS:000246987500044 PM 17392359 ER PT J AU Derse, D Crise, B Li, Y Princler, G Lum, N Stewart, C McGrath, CF Hughes, SH Munroe, DJ Wu, XL AF Derse, David Crise, Bruce Li, Yuan Princler, Gerald Lum, Nicole Stewart, Claudia McGrath, Connor F. Hughes, Stephen H. Munroe, David J. Wu, Xiaolin TI Human T-cell leukemia virus type 1 integration target sites in the human genome: Comparison with those of other retroviruses SO JOURNAL OF VIROLOGY LA English DT Article ID DNASE HYPERSENSITIVE SITES; GENE-THERAPY; IN-VIVO; SCHIZOSACCHAROMYCES-POMBE; TRANSPOSABLE ELEMENTS; LTR-RETROTRANSPOSONS; HIV INTEGRATION; RNASE-H; SELECTION; IMMUNODEFICIENCY AB Retroviral integration into the host genome is not entirely random, and integration site preferences vary among different retroviruses. Human immunodeficiency virus (HIV) prefers to integrate within active genes, whereas murine leukemia virus (MLV) prefers to integrate near transcription start sites and CpG islands. On the other hand, integration of avian sarcoma-leukosis virus (ASLV) shows little preference either for genes, transcription start sites, or CpG islands. While host cellular factors play important roles in target site selection, the viral integrase is probably the major viral determinant. It is reasonable to hypothesize that retroviruses with similar integrases have similar preferences for target site selection. Although integration profiles are well defined for members of the lentivirus, spumaretrovirus, alpharetrovirus, and gammaretrovirus genera, no members of the deltaretroviruses, for example, human T-cell leukemia virus type 1 (HTLV-1), have been evaluated. We have mapped 541 HTLV-1 integration sites in human HeLa cells and show that HTLV-1, like ASLV, does not specifically target transcription units and transcription start sites. Comparing the integration sites of HTLV-1 with those of ASLV, HIV, simian immunodeficiency virus, MLV, and foamy virus, we show that global and local integration site preferences correlate with the sequence/structure of virus-encoded integrases, supporting the idea that integrase is the major determinant of retroviral integration site selection. Our results suggest that the global integration profiles of other retroviruses could be predicted from phylogenetic comparisons of the integrase proteins. Our results show that retroviruses that engender different insertional mutagenesis risks can have similar integration profiles. C1 SAIC Frederick Inc, Lab Mol Technol, Frederick, MD 21702 USA. NCI Frederick, HIV Drug Resistance Program, Frederick, MD 21702 USA. SAIC Frederick Inc, Gene Express Lab, Frederick, MD 21702 USA. SAIC Frederick Inc, AIDS Vaccine Program, Frederick, MD 21702 USA. SAIC Frederick Inc, Lab Mol Technol, Frederick, MD 21702 USA. SAIC Frederick Inc, Target Struct Drug Discovery Grp, Frederick, MD 21702 USA. RP Wu, XL (reprint author), SAIC Frederick Inc, Lab Mol Technol, 915 Toll House Ave, Frederick, MD 21702 USA. EM forestwu@mail.nih.gov FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 58 TC 92 Z9 97 U1 1 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X EI 1098-5514 J9 J VIROL JI J. Virol. PD JUN PY 2007 VL 81 IS 12 BP 6731 EP 6741 DI 10.1128/JVI.02752-06 PG 11 WC Virology SC Virology GA 175BP UT WOS:000246987500055 PM 17409138 ER PT J AU Massad, LS Evans, CT Wilson, TE Golub, ET Sanchez-Keeland, L Minkoff, H Weber, K Watts, DH AF Massad, L. Stewart Evans, Charlesnika T. Wilson, Tracey E. Golub, Elizabeth T. Sanchez-Keeland, Lorraine Minkoff, Howard Weber, Kathleen Watts, D. Heather TI Contraceptive use among US women with HIV SO JOURNAL OF WOMENS HEALTH LA English DT Article ID INTERAGENCY HIV; SEXUAL-BEHAVIOR; INFECTED WOMEN; UNITED-STATES; HIGH-RISK; PREGNANCY; PREVENTION; DISEASE; COHORT AB Objective: To describe trends in and correlates of use of contraception and sterilization among women with the human immunodeficiency virus (HIV). Methods: This was a longitudinal cohort study of HIV-infected and uninfected women at risk for pregnancy, including structured questions on contraceptive use every 6 months. Proportions of women using contraception were calculated. Multivariate generalized estimating equation models were applied, and correlates of use were determined using logistic regression. Sterilization was assessed using a Kaplan-Meyer plot. Results: Across 26,832 visits among 2784 women from 1994 to 2005, barrier methods were used at 30.5%-36.3% of visits, sterilization at 21.8%-26.5%, hormones at < 10%, and no contraception at > 30%. Dual use of barrier and hormones or barrier and spermicide was uncommon. In multivariable analysis, HIV serostatus was not correlated with barrier use (OR 1.10, 95% CI 0.96-1.26, p = 0.18 compared with no method), but hormonal contraception was less likely in women with HIV (OR 0.73, 95% CI 0.60-0.89, p = 0.002). Among HIV-seropositive women, barrier use was more likely among women who had been pregnant (OR 1.37, 95% CI 1.03- 1.83, p = 0.03) and among those with higher CD4 lymphocyte counts (OR 1.10, 95% CI 1.04- 1.16, p = 0.0006), whereas hormone use was linked to higher CD4 counts (OR 1.12, 95% CI 1.03-1.23, p = 0.01). HAART use was not associated with barrier or hormone use. HIV serostatus was linked to sterilization in Cox analysis (HR 1.32, 95% CI 0.89-1.94, p = 0.17). Conclusions. Underuse of highly effective contraception and barriers leaves women with HIV at risk for unintended pregnancy and disease transmission. C1 So Illinois Univ, Sch Med, Dept Obstet & Gynecol, Springfield, IL 62794 USA. Univ Illinois, Chicago, IL USA. SUNY Hlth Sci Ctr, Brooklyn, NY 11203 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. Univ So Calif, Los Angeles, CA USA. Maimonides Hosp, Brooklyn, NY 11219 USA. John H Stoger Jr Hosp Cook Cty, CORE Ctr, Chicago, IL USA. NICHHD, Bethesda, MD 20892 USA. RP Massad, LS (reprint author), So Illinois Univ, Sch Med, Dept Obstet & Gynecol, POB 19640, Springfield, IL 62794 USA. EM LSMASSAD@ameritech.net FU NCI NIH HHS [CA85178-01]; NCRR NIH HHS [M01-RR00083, M01-RR00079]; NIAID NIH HHS [U01-AI-31834, U01-AI-34994, U01-AI-35004, U01-AI-34989, U01-AI-42590, U01-AI-34993]; NICHD NIH HHS [U01-HD-32632] NR 21 TC 32 Z9 32 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-9996 J9 J WOMENS HEALTH JI J. Womens Health PD JUN PY 2007 VL 16 IS 5 BP 657 EP 666 DI 10.1089/jwh.2006.0204 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal; Obstetrics & Gynecology; Women's Studies SC Public, Environmental & Occupational Health; General & Internal Medicine; Obstetrics & Gynecology; Women's Studies GA 189MH UT WOS:000247992500007 PM 17627401 ER PT J AU Ling, SM Simonsick, EM Ferrucci, L AF Ling, Shari Miura Simonsick, Eleanor M. Ferrucci, Luigi TI A painful interface between normal aging and disease SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Editorial Material ID C-REACTIVE PROTEIN; KNEE CARTILAGE DEFECTS; BONE-MARROW LESIONS; MAGNETIC-RESONANCE; MATRIX METALLOPROTEINASES; MUSCLE PROPERTIES; OSTEOARTHRITIS; ASSOCIATION; ARTHRITIS; ETIOPATHOGENESIS C1 [Ling, Shari Miura; Ferrucci, Luigi] NIA, Intramural Res Program, Clin Res Branch, Baltimore, MD 21224 USA. [Simonsick, Eleanor M.] NIA, Intramural Res Program, Longitudinal Study Sect, Baltimore, MD 21224 USA. RP Ling, SM (reprint author), Clin Res Branch NIA ASTRA Unit, 5th Floor Harbor Hosp, Baltimore, MD USA. EM lingsh@grc.nia.nih.gov FU Intramural NIH HHS [Z99 AG999999] NR 38 TC 5 Z9 5 U1 0 U2 0 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD JUN PY 2007 VL 62 IS 6 BP 613 EP 615 PG 3 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 271ZY UT WOS:000253828400005 PM 17595416 ER PT J AU Elias, JW Wagster, MV AF Elias, Jeffrey W. Wagster, Molly V. TI Developing context and background underlying cognitive intervention/training studies in older populations SO JOURNALS OF GERONTOLOGY SERIES B-PSYCHOLOGICAL SCIENCES AND SOCIAL SCIENCES LA English DT Article ID PROTEIN-KINASE-A; SOCIOECONOMIC DIFFERENCES; LIFE-STYLE; AGE; MEMORY; ADULTS; PERFORMANCE; DECLINE; HOMOCYSTEINE; EDUCATION AB Underlying the attempt to change behavior or improve performance by virtue of intervention or training is the notion that change is possible and that plasticity, life-course malleability, and compensation are well-recognized concepts of life-span development. The cognition and aging literature reveals that there are a growing number of context and background variables against which the effectiveness of intervention/training can be judged beyond the intrinsic motivations for change. In this introductory article to a special issue on cognitive intervention and training, we briefly discuss several of these background variables. C1 [Elias, Jeffrey W.; Wagster, Molly V.] NIA, NIH, Bethesda, MD 20892 USA. RP Elias, JW (reprint author), Univ Calif Davis, Sch Med, 2921 Stockton Blvd,Suite 1400, Sacramento, CA 95817 USA. EM jeffrey.elias@ucdmc.ucdavis.edu NR 60 TC 6 Z9 6 U1 1 U2 1 PU GERONTOLOGICAL SOC AMER PI WASHINGTON PA 1030 15TH ST NW, STE 250, WASHINGTON, DC 20005202-842 USA SN 1079-5014 J9 J GERONTOL B-PSYCHOL JI J. Gerontol. Ser. B-Psychol. Sci. Soc. Sci. PD JUN PY 2007 VL 62 SI 1 BP 5 EP 10 PG 6 WC Geriatrics & Gerontology; Gerontology; Psychology; Psychology, Multidisciplinary SC Geriatrics & Gerontology; Psychology GA 272CL UT WOS:000253836500001 PM 17565160 ER PT J AU Wang, XY Dakir, EH Xu, NZ Jensen-Taubman, SM DeMayo, FJ Linnoila, RI AF Wang, Xiao-Yang Dakir, El Habib Xu Naizhen Jensen-Taubman, Sandra M. DeMayo, Francesco J. Linnoila, R. Ilona TI Achaete-scute homolog-1 linked to remodeling and preneoplasia of pulmonary epithelium SO LABORATORY INVESTIGATION LA English DT Article DE achaete-scute homolog 1; apoptosis; bronchiolization of alveoli; lung; mouse model; preneoplasia; proliferation ID CELL LUNG CARCINOMAS; MATRIX-METALLOPROTEINASE; CLARA CELL; C-MYB; NEUROENDOCRINE DIFFERENTIATION; BRONCHIOLAR EPITHELIUM; 10-KDA PROTEIN; CHAIN-REACTION; CANCER CELLS; MICE LACKING AB The basic helix-loop-helix protein achaete-scute homolog-1 (ASH1) is involved in lung neuroendocrine (NE) differentiation and tumor promotion in SV40 transgenic mice. Constitutive expression of human ASH-1 (hASH1) in mouse lung results in hyperplasia and remodeling that mimics bronchiolization of alveoli (BOA), a potentially premalignant lesion of human lung carcinomas. We now show that this is due to sustained cellular proliferation in terminal bronchioles and resistance to apoptosis. Throughout the airway epithelium the expression of anti-apoptotic Bcl-2 and c-Myb was increased and Akt/mTOR pathway activated. Moreover, the expression of matrix metalloproteases (MMPs) including MMP7 was specifically enhanced at the bronchiolo-alveolar duct junction and BOA suggesting that MMPs play a key role in this microenvironment during remodeling. We also detected MMP7 in 70% of human BOA lesions. Knockdown of hASH1 gene in human lung cancer cells in vitro suppressed growth by increasing apoptosis. We also show that forced expression of hASH1 in immortalized human bronchial epithelial cells decreases apoptosis. We conclude that the impact of hASH1 is not limited to cells with NE phenotype. Rather, constitutive expression of hASH1 in lung epithelium promotes remodeling through multiple pathways that are commonly activated during lung carcinogenesis. The collective results suggest a novel model of BOA formation via hASH1-induced suppression of the apoptotic pathway. Our study yields a promising new preclinical tool for chemoprevention of peripheral lung carcinomas. C1 NCI, Expt Pathol Sect, Cell & Canc Biol Branch, CCR,NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Houston, TX 77030 USA. RP Linnoila, RI (reprint author), NCI, Expt Pathol Sect, Cell & Canc Biol Branch, CCR,NIH, 37,Convent Dr,Bg 37 Room 1056B, Bethesda, MD 20892 USA. EM linnoila@mail.nih.gov RI 2007, Secribsal/A-1556-2012; DAKIR, EL HABIB/O-1383-2015 FU Intramural NIH HHS NR 61 TC 18 Z9 19 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD JUN PY 2007 VL 87 IS 6 BP 527 EP 539 DI 10.1038/labinvest.3700552 PG 13 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 168ZA UT WOS:000246561300002 PM 17507989 ER PT J AU Shaw, P Lerch, JP Pruessner, JC Taylor, KN Rose, AB Greenstein, D Clasen, L Evans, A Rapoport, JL Giedd, JN AF Shaw, Philip Lerch, Jason P. Pruessner, Jens C. Taylor, Kristin N. Rose, A. Blythe Greenstein, Deanna Clasen, Liv Evans, Alan Rapoport, Judith L. Giedd, Jay N. TI Cortical morphology in children and adolescents with different apolipoprotein E gene polymorphisms: an observational study SO LANCET NEUROLOGY LA English DT Article ID AUTOMATED 3-D EXTRACTION; FALSE DISCOVERY RATE; ALZHEIMERS-DISEASE; ENTORHINAL CORTEX; COGNITIVE DECLINE; BRAIN-DEVELOPMENT; EPSILON-4 ALLELE; CEREBRAL-CORTEX; MRI DATA; RISK AB Background Alleles of the apolipoprotein E (APOE) gene modulate risk for Alzheimer's disease, with carriers of the epsilon 4 allele being at increased risk and carriers of the epsilon 2 allele possibly at decreased risk compared with non-carriers. Our aim was to determine whether possession of an epsilon 4 allele would confer children with a neural substrate that might render them at risk for Alzheimer's disease, and whether carriers of the epsilon 2 allele might have a so-called protective cortical morphology. Methods 239 healthy children and adolescents were genotyped and had repeated neuroanatomic MRI (total 530 scans). Mixed model regression was used to determine whether the developmental trajectory of the cortex differed by genotype. Findings Cortical thickness of the left entorhinal region was significantly thinner in epsilon 4 carriers than it was in non-epsilon 4 carriers (3 center dot 79 [SE 0 center dot 06] mm, range 1 center dot 54-5 center dot 24 vs 3 center dot 94 [0 center dot 03) mm, 2 center dot 37-6 center dot 11; p=0 center dot 03). There was a significant stepwise increase in cortical thickness in the left entorhinal regions, with epsilon 4 carriers having the thinnest cortex and epsilon 2 carriers the thickest, with epsilon 3 homozygotes occupying an intermediate position (left beta 0 center dot 11 [SE 0 center dot 05], p=0 center dot 02). Neuroanatomic effects seemed fixed and non-progressive, with no evidence of accelerated cortical loss in young healthy epsilon 4 carriers. Interpretation Alleles of the apolipoprotein E gene have distinct neuroanatomic signatures, identifiable in childhood. The thinner entorhinal cortex in individuals with the epsilon 4 allele might contribute to risk of Alzheimer's disease. C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. McGill Univ, Montreal Neurol Inst, Montreal, PQ H3A 2T5, Canada. RP Shaw, P (reprint author), 10 Ctr Dr,MSC1600,Bldg 10,Room 3N202, Bethesda, MD 20891 USA. EM shawp@mail.nih.gov RI Giedd, Jay/A-3080-2008; Giedd, Jay/B-7302-2012; Giedd, Jay/J-9644-2015 OI Giedd, Jay/0000-0003-0827-3460; Giedd, Jay/0000-0003-2002-8978 FU Intramural NIH HHS NR 57 TC 149 Z9 152 U1 0 U2 12 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1474-4422 J9 LANCET NEUROL JI Lancet Neurol. PD JUN PY 2007 VL 6 IS 6 BP 494 EP 500 DI 10.1016/S1471-4422(07)70106-0 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 175WO UT WOS:000247044900014 PM 17509484 ER PT J AU Niederhuber, JE AF Niederhuber, John E. TI Developmental biology, self-renewal, and cancer SO LANCET ONCOLOGY LA English DT Editorial Material ID STEM-CELLS; LEUKEMIA C1 NCI, Bethesda, MD 20892 USA. RP Niederhuber, JE (reprint author), NCI, Bethesda, MD 20892 USA. EM niederj@mail.nih.gov NR 4 TC 3 Z9 3 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1470-2045 J9 LANCET ONCOL JI Lancet Oncol. PD JUN PY 2007 VL 8 IS 6 BP 456 EP 457 DI 10.1016/S1470-2045(07)70150-X PG 2 WC Oncology SC Oncology GA 179AY UT WOS:000247262900002 PM 17540298 ER PT J AU Joshi, AS Janjanin, S Tanna, N Geist, C Lindsey, C AF Joshi, Arjun S. Janjanin, Sasa Tanna, Neil Geist, Craig Lindsey, Charlie TI Does suture material and technique really matter? Lessons learned from 800 consecutive blepharoplasties SO LARYNGOSCOPE LA English DT Article; Proceedings Paper CT Combined Sections Meeting of the Triological-Society CY FEB 18, 2007 CL Marco Isl, FL SP Triol Soc DE blepharoplasty; complications; suture material; incisions; scarring; milia ID WOUND CLOSURE AB Objectives: The purpose of this study was to evaluate established suture materials and techniques for blepharoplasty closure and evaluate for any differences in rates of complications between these groups. Study Design and Methods: This was a prospective study of a large sequential series of patients undergoing upper blepharoplasty who were treated by the same senior author over a 5-year period. Patients were assigned one of four techniques for closure of the incision based on the senior author's experience. After 6 weeks, rates of complications and revisions were noted and addressed. Satisfaction rates were noted at 3 months. Results: In the group whose incisions were closed with running subcuticular polypropylene (Prolene), 5 (2.5%) presented with milia, and 11 (5.5%) had a standing cone deformity (SCD). Use of running cutaneous locked Prolene resulted in 8 patients (17%) with milia and 2 patients (4.4%) requiring revision of a SCD. Use of a running 6-0 plain gut suture resulted in 12 patients (6.7%) with milia and 5 patients (2.8%) with unsightly scarring. In the group whose incisions were closed with running 6-0 fast-absorbing gut, 10 patients (2%) presented with milia, and there were no scar revisions. There were statistically significant differences between the groups with respect to formation of milia, scarring, and persistent erythema (P < .008). Conclusions: Blepharoplasty is a safe and effective procedure that can be performed successfully with several established techniques. In our experience, closure with two interrupted 6-0 Prolene sutures and a running 6-0 fast-absorbing gut resulted in the lowest rates of complications and revisions. C1 George Washington Univ, Div Otolaryngol Head & Neck Surg, Washington, DC 20052 USA. George Washington Univ, Dept Ophthalmol, Washington, DC USA. NIAMSD, NIH, Bethesda, MD 20892 USA. RP Joshi, AS (reprint author), George Washington Univ, Div Otolaryngol Head & Neck Surg, 2150 Penn Ave NW,Suite 6-301, Washington, DC 20052 USA. EM arjuns.joshi@gmail.com NR 8 TC 9 Z9 9 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0023-852X J9 LARYNGOSCOPE JI Laryngoscope PD JUN PY 2007 VL 117 IS 6 BP 981 EP 984 DI 10.1097/MLG.0b013e31804f54bd PG 4 WC Medicine, Research & Experimental; Otorhinolaryngology SC Research & Experimental Medicine; Otorhinolaryngology GA 174ET UT WOS:000246925000006 PM 17545862 ER PT J AU Slape, C Chung, YJ Soloway, PD Tessarollo, L Aplan, PD AF Slape, C. Chung, Y. J. Soloway, P. D. Tessarollo, L. Aplan, P. D. TI Mouse embryonic stem cells that express a NUP98-HOXD13 fusion protein are impaired in their ability to differentiate and can be complemented by BCR-ABL SO LEUKEMIA LA English DT Article DE NUP98; HOXD13; ES cells; oncogene; BCR-ABL ID ACUTE MYELOID-LEUKEMIA; ACUTE MYELOGENOUS LEUKEMIA; NUCLEAR-PORE COMPLEX; C-MYB; TARGETED INACTIVATION; UP-REGULATION; GENE MYF-5; MICE; CANCER; MODEL AB NUP98-HOXD13 (NHD13) fusions have been identified in patients with myelodysplastic syndrome, acute myelogenous leukemia and chronic myeloid leukemia blast crisis. We generated 'knock-in' mouse embryonic stem (ES) cells that express a NHD13 fusion gene from the endogenous murine NUP98 promoter, and used an in vitro differentiation system to differentiate the ES cells to hematopoietic colonies. Replating assays demonstrated that the partially differentiated NHD13 ES cells were immortal, and two of these cultures were transferred to liquid culture. These cell lines are partially differentiated immature hematopoietic cells, as determined by morphology, immunophenotype and gene expression profile. Despite these characteristics, they were unable to differentiate when exposed to high concentrations of erythropoietin (Epo), granulocyte colony-stimulating factor or macrophage colony-stimulating factor. The cell lines are incompletely transformed, as evidenced by their dependence on interleukin 3 (IL-3), and their failure to initiate tumors when injected into immunodeficient mice. We attempted genetic complementation of the NHD13 gene using IL-3 independence and tumorigenicity in immunodeficient mice as markers of transformation, and found that BCR-ABL successfully transformed the cell lines. These findings support the hypothesis that expression of a NHD13 fusion gene impairs hematopoietic differentiation, and that these cell lines present a model system to study the nature of this impaired differentiation. C1 NIH, Natl Ctr Inst, Genet Branch, Ctr Canc Ctr, Gaithersburg, MD 20899 USA. Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. NCI, Ctr Canc Res, Mouse Canc Genet Program, NIH, Bethesda, MD 20892 USA. RP Aplan, PD (reprint author), NIH, Natl Ctr Inst, Genet Branch, Ctr Canc Ctr, Navy 8,Room 5101,8901 Wisconsin Ave, Gaithersburg, MD 20899 USA. EM aplanp@mail.nih.gov RI Slape, Christopher/H-8586-2016; Aplan, Peter/K-9064-2016 OI Slape, Christopher/0000-0002-8407-3092; FU Intramural NIH HHS [Z01 SC010378-06] NR 32 TC 8 Z9 8 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD JUN PY 2007 VL 21 IS 6 BP 1239 EP 1248 DI 10.1038/sj.leu.2404648 PG 10 WC Oncology; Hematology SC Oncology; Hematology GA 172JD UT WOS:000246799300015 PM 17377591 ER PT J AU Brendel, C Scharenberg, C Dohse, M Robey, RW Bates, SE Shukla, S Ambudkar, SV Wang, Y Wennemuth, G Burchert, A Boudriot, U Neubauer, A AF Brendel, C. Scharenberg, C. Dohse, M. Robey, R. W. Bates, S. E. Shukla, S. Ambudkar, S. V. Wang, Y. Wennemuth, G. Burchert, A. Boudriot, U. Neubauer, A. TI Imatinib mesylate and nilotinib (AMN107) exhibit high-affinity interaction with ABCG2 on primitive hematopoietic stem cells SO LEUKEMIA LA English DT Article DE ABCG2; CML; nilotinib; imatinib; resistance ID CHRONIC MYELOID-LEUKEMIA; CHRONIC MYELOGENOUS LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; CANCER RESISTANCE PROTEIN; ABL TYROSINE KINASE; IN-VITRO ACTIVITY; BCR-ABL; PHILADELPHIA-CHROMOSOME; AMINOPYRIMIDINE INHIBITOR; CLINICAL RESISTANCE AB The majority of chronic phase chronic myeloid leukemia (CML) patients treated with the tyrosine kinase inhibitor (TKI) imatinib mesylate maintain durable responses to the drug. However, most patients relapse after withdrawal of imatinib and advanced stage patients often develop drug resistance. As CML is considered a hematopoietic stem cell cancer, it has been postulated that inherent protective mechanisms lead to relapse in patients. The ATP binding-cassette transporters ABCB1 (MDR-1; P-glycoprotein) and ABCG2 are highly expressed on primitive hematopoietic stem cells (HSCs) and have been shown to interact with TKIs. Herein we demonstrate a dose-dependent, reversible inhibition of ABCG2-mediated Hoechst 33342 dye efflux in primary human and murine HSC by both imatinib and nilotinib (AMN107), a novel aminopyrimidine inhibitor of BCR-ABL. ABCG2-transduced K562 cells were protected from imatinib and nilotinib-mediated cell death and from downregulation of P-CRKL. Moreover, photoaffinity labeling revealed interaction of both TKIs with ABCG2 at the substrate binding sites as they compete with the binding of [I-125] IAAP and also stimulate the transporter's ATPase activity. Therefore, our evidence suggests for the role of ABC transporters in resistance to TKI on primitive HSCs and CML stem cells and provides a rationale how TKI resistance can be overcome in vivo. C1 Univ Marburg, Dept Hematol Oncol & Immunol, D-35033 Marburg, Hessen, Germany. Univ Marburg, Dept Anat & Cell Biol, D-35033 Marburg, Hessen, Germany. NCI, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Marburg, Dept Orthopaed, D-35033 Marburg, Hessen, Germany. RP Brendel, C (reprint author), Univ Marburg, Dept Hematol Oncol & Immunol, Baldingerstasse, D-35033 Marburg, Hessen, Germany. EM brendelc@mailer.uni-marburg.de; christian.scharenberg@vgregion.se FU Intramural NIH HHS NR 49 TC 131 Z9 136 U1 2 U2 13 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD JUN PY 2007 VL 21 IS 6 BP 1267 EP 1275 DI 10.1038/sj.leu.2404638 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 172JD UT WOS:000246799300018 PM 17519960 ER PT J AU Lin, YW Aplan, PD AF Lin, Y-W Aplan, P. D. TI Gene expression profiling of precursor T-cell lymphoblastic leukemia/lymphoma identifies oncogenic pathways that are potential therapeutic targets SO LEUKEMIA LA English DT Article DE T-cell leukemia; SCL; Nup98; chemokine; cofilin; Pbx3 ID DOUBLE-TRANSGENIC MICE; SERINE PHOSPHATASE; CYCLE PROGRESSION; PROTEIN COFILIN; LEUKEMIA; LYMPHOCYTES; ACTIVATION; LMO1; COSTIMULATION; PP19/COFILIN AB We compared the gene expression pattern of thymic tumors from precursor T-cell lymphoblastic lymphoma/leukemia (pre-T LBL) that arose in transgenic mice that overexpressed SCL, LMO1 or NUP98-HOXD13 (NHD13) with that of thymocytes from normal littermates. Only two genes, Ccl8 and Mrpl38, were consistently more than fourfold overexpressed in pre-T LBL from all three genotypes analyzed, and a single gene, Prss16 was consistently underexpressed. However, we identified a number of genes, such as Cfl1, Tcra, Tcrb, Pbx3, Eif4a, Eif4b and Cox8b that were over or under-expressed in pre-T LBL that arose in specific transgenic lines. Similar to the situation seen with human pre-T LBL, the SCL/LMO1 leukemias displayed an expression profile consistent with mature, late cortical thymocytes, whereas the NHD13 leukemias displayed an expression profile more consistent with immature thymocytes. We evaluated two of the most differentially regulated genes as potential therapeutic targets. Cfl1 was specifically overexpressed in SCLLMO1 tumors; inactivation of Cfl1 using okadaic acid resulted in suppression of leukemic cell growth. Overexpression of Ccl8 was a consistent finding in all three transgenic lines, and an antagonist for the Ccl8 receptor-induced death of leukemic cell lines, suggesting a novel therapeutic approach. C1 NCI, Ctr Canc Res, NIH, Genet Branch, Bethesda, MD 20889 USA. Tenri Hosp, Dept Pediat, Tenri, Nara, Japan. RP Aplan, PD (reprint author), NCI, Ctr Canc Res, NIH, Genet Branch, Navy8,Rm5105,8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM aplanp@mail.nih.gov RI Aplan, Peter/K-9064-2016 FU Intramural NIH HHS [Z01 SC010378-06] NR 32 TC 11 Z9 11 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD JUN PY 2007 VL 21 IS 6 BP 1276 EP 1284 DI 10.1038/sj.leu.2404685 PG 9 WC Oncology; Hematology SC Oncology; Hematology GA 172JD UT WOS:000246799300019 PM 17429429 ER PT J AU Fishbein, KW Gluzband, YA Kaku, M Ambia-Sobhan, H Shapses, SA Yamauchi, M Spencer, RG AF Fishbein, Kenneth W. Gluzband, Yehezkiel A. Kaku, Masaru Ambia-Sobhan, Hasina Shapses, Sue A. Yamauchi, Mitsuo Spencer, Richard G. TI Effects of formalin fixation and collagen cross-linking on T-2 and magnetization transfer in bovine nasal cartilage SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE cross-link; collagen; cartilage; magnetization transfer; T-2; formaldehyde; fixation ID ARTICULAR-CARTILAGE; CHEMICAL-EXCHANGE; RESONANCE; MRI; TISSUE; WATER; FORMALDEHYDE; MODEL; RELAXATION; MICROSCOPY AB Endogenous collagen cross-links influence cartilage biomechanical properties and resistance to degradation. Formalin fixation modifies collagen residues and forms new cross-links in a dose-dependent manner. We tested the hypothesis that magnetization transfer (MT) effects and T-2 depend on collagen cross-linking in cartilage. These parameters were measured in bovine nasal cartilage (BNC) prior to fixation, after 9 weeks of immersion in formalin solutions ranging in concentration from 0% to 10%, and after NaBH3CN reduction and washing. T2 decreased by 59.4% +/- 1.1% upon fixation in 10% formalin, and was 32.2% +/- 5.2% shorter than initial values after washing. The apparent MT rate increased 25.9% +/- 3.7% and 52.8% +/- 7.1% over baseline under these conditions. Biochemical assays showed no significant differences in water, proteoglycan, natural cross-link, or collagen content between the 0% and 10% formalin-treated samples, while amino acid analysis demonstrated losses in (hydroxy)lysine and tyrosine, and new peaks consistent with methylene cross-links in fixed samples only. We conclude that formalin fixation of cartilage results in significant decreases in T2 and increases in MT parameters that persist after removal of unreacted formaldehyde. The collagen crosslinks thus created are associated with large changes in MT and T2, indicating that interpretation of T2 and MT values in terms of cartilage macromolecular content must be made with caution. C1 NIA, NIH, GRC 4D-06,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. Univ N Carolina, Dent Res Ctr, Chapel Hill, NC 27515 USA. Rutgers State Univ, Dept Nutr Sci, New Brunswick, NJ 08903 USA. RP Spencer, RG (reprint author), NIA, NIH, GRC 4D-06,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM spencerri@grc.nia.nih.gov OI Kaku, Masaru/0000-0002-7988-6435; Fishbein, Kenneth/0000-0002-6353-4603 FU Intramural NIH HHS; NIA NIH HHS [AG12161]; NIDCR NIH HHS [DE10489] NR 47 TC 40 Z9 41 U1 1 U2 5 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0740-3194 EI 1522-2594 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUN PY 2007 VL 57 IS 6 BP 1000 EP 1011 DI 10.1002/mrm.21216 PG 12 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 174YX UT WOS:000246979900004 PM 17534923 ER PT J AU Silva, AC Koretsky, AP Duyn, JH AF Silva, Afonso C. Koretsky, Alan P. Duyn, Jeff H. TI Functional MRI impulse response for BOLD and CBV contrast in rat somatosensory cortex SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE functional MRI; m-sequence; impulse response function; somatosensory cortex; animal models; temporal resolution ID CEREBRAL-BLOOD-FLOW; EVENT-RELATED FMRI; FOREPAW STIMULATION; HEMODYNAMIC-RESPONSE; TEMPORAL EVOLUTION; BARREL CORTEX; BRAIN; VOLUME; DYNAMICS; SPECTROSCOPY AB The contrast mechanism in functional MRI (fMRI) results from several vascular processes with different time scales, thus establishing a finite temporal resolution to fMRI experiments. In this work we measured the blood oxygen level-dependent (BOLD) and iron-oxide-derived cerebral blood volume (CBV) impulse response (IR) in a rat model of somatosensory brain activation at 11.7T. A binary m-sequence probe method was used to obtain high-sensitivity single-pixel estimates of the IR, from which two parameters-the full width at half maximum (FWHM) and the time to peak (TTP)-were determined as indices of the temporal resolution of the hemodynamic response (HDR). The results (N = 11) show that the CBV IR [N = 5, subset) is significantly narrower (FWHM = 1.37 +/- 0.11 s), and peaks earlier (TTP = 1.65 +/- 0.15 s) than the BOLD IR (N = 11, FWHM = 1.92 +/- 0.22 s and TTP = 2.18 +/- 0.14 s, respectively). These findings indicate that neurovascular control mechanisms have a temporal resolution better than 1.5 s FWHM, and point to a substantial contribution to BOLD of the dispersive transit of oxygenated hemoglobin across the rat vasculature, bringing important implications for the ultimately attainable temporal resolution of fMRI. C1 NINDS, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Silva, AC (reprint author), NINDS, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr,Bldg 10,Room B1D106, Bethesda, MD 20892 USA. EM silvaa@ninds.nih.gov RI Duyn, Jozef/F-2483-2010; Silva, Afonso/A-7129-2009; Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU Intramural NIH HHS [Z01 NS003041-01, Z01 NS002989-08] NR 41 TC 50 Z9 51 U1 1 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGN RESON MED JI Magn. Reson. Med. PD JUN PY 2007 VL 57 IS 6 BP 1110 EP 1118 DI 10.1002/mrm.21246 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 174YX UT WOS:000246979900015 PM 17534912 ER PT J AU Ushino, T Justus, B Huston, A Ning, H Miller, R Al-Ghazi, M AF Ushino, T. Justus, B. Huston, A. Ning, H. Miller, R. Al-Ghazi, M. TI Real-time optical fiber in vivo dosimeter with a novel method for eliminating the "stem effect" SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 49th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY JUL 22-26, 2007 CL Minneapolis, MN SP Amer Assoc Physicists Med C1 Global Dosimetry Solut, Irvine, CA USA. Naval Res Lab, Washington, DC USA. Natl Inst Hlth, Bethesda, MD USA. Natl Canc Inst, Bethesda, MD USA. Univ Calif Irvine, Irvine, CA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2007 VL 34 IS 6 BP 2486 EP 2487 DI 10.1118/1.2761094 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 182BH UT WOS:000247479600728 ER PT J AU Deye, J AF Deye, J. TI New NCRP report: General report background and formulation SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 49th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY JUL 22-26, 2007 CL Minneapolis, MN SP Amer Assoc Physicists Med C1 Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2007 VL 34 IS 6 BP 2510 EP 2510 DI 10.1118/1.2761192 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 182BH UT WOS:000247479600826 ER PT J AU Mittleman, B AF Mittleman, B. TI NIH roadmap, public-private partnerships and the biomarker consortium SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 49th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY JUL 22-26, 2007 CL Minneapolis, MN SP Amer Assoc Physicists Med C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2007 VL 34 IS 6 BP 2514 EP 2514 DI 10.1118/1.2761207 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 182BH UT WOS:000247479600841 ER PT J AU Hendee, W Deye, J Farahani, K AF Hendee, W. Deye, J. Farahani, K. TI Funding and protecting biomedical research SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 49th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY JUL 22-26, 2007 CL Minneapolis, MN SP Amer Assoc Physicists Med C1 Natl Canc Inst, Bethesda, MD USA. NIH, Bethesda, MD 20892 USA. RI Farahani, Keyvan/G-9069-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2007 VL 34 IS 6 BP 2553 EP 2553 DI 10.1118/1.2761364 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 182BH UT WOS:000247479600985 ER PT J AU Clarke, L AF Clarke, L. TI Current NIH and NCI initiatives using imaging biomarkers SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 49th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY JUL 22-26, 2007 CL Minneapolis, MN SP Amer Assoc Physicists Med C1 Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2007 VL 34 IS 6 BP 2556 EP 2556 DI 10.1118/1.2761377 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 182BH UT WOS:000247479600998 ER PT J AU Low, D Deye, J AF Low, D. Deye, J. TI Meet the expert - Therapy research SO MEDICAL PHYSICS LA English DT Meeting Abstract CT 49th Annual Meeting of the American-Association-of-Physicists-in-Medicine CY JUL 22-26, 2007 CL Minneapolis, MN SP Amer Assoc Physicists Med C1 Washington Univ, St Louis, MO USA. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC PHYSICISTS MEDICINE AMER INST PHYSICS PI MELVILLE PA STE 1 NO 1, 2 HUNTINGTON QUADRANGLE, MELVILLE, NY 11747-4502 USA SN 0094-2405 J9 MED PHYS JI Med. Phys. PD JUN PY 2007 VL 34 IS 6 BP 2569 EP 2569 DI 10.1118/1.2761430 PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 182BH UT WOS:000247479601051 ER PT J AU Armstrong, A Alvero, R Nielsen, P Deering, S Robinson, R Frattarelli, J Sarber, K Duff, P Ernest, J AF Armstrong, Alicia Alvero, Ruben Nielsen, Peter Deering, Shad Robinson, Randal Frattarelli, John Sarber, Kathleen Duff, Patrick Ernest, Joseph TI Do US Medical Licensure Examination step 1 scores correlate with Council on Resident Education in Obstetrics and Gynecology in-training examination scores and American Board of Obstetrics and Gynecology written examination performance? SO MILITARY MEDICINE LA English DT Article ID USMLE; SELECTION AB Objective: The purpose of this study was to assess the possible association between scores of > 200 on U.S. Medical Licensure Examination (USMLE) step 1 and the Council on Resident Education in Obstetrics and Gynecology (CREOG) in-training examinations and the pass rate on the American Board of Obstetrics and Gynecology (ABOG) written examination. Methods: The USMLE step 1 and postgraduate year 1 to 4 CREOG in-training examination scores for the graduating chief residents in eight accredited obstetrics and gynecology residency programs were obtained. Performance on USMLE step 1 was correlated with ABOG examination performance and CREOG in-training examination scores. The correlations between USMLE step I and CREOG in-training examination scores and ABOG examination performance were analyzed by using the Spearman correlation coefficient. Results: USMLE step 1 scores were significantly correlated with CREOG in-training examination scores (p < 0.000). None of the residents who scored > 200 on USMLE step 1 and a mean of > 200 on the CREOG in-training examinations failed the ABOG written examination. Conclusion: Program directors have used USMLE step 1 to identify trainees who are likely to perform well on the CREOG in-training examination. The CREOG in-training examination has been used to identify residents who are likely to pass the ABOG written examination. The results of this study document the strength of these associations. C1 NICHHD, Reprod Biol & Med Branch, Bethesda, MD 20892 USA. Univ Colorado, Hlth Sci Ctr, Div Reprod Endocrinol & Infertil, Denver, CO 80262 USA. Madigan Army Med Ctr, Div Maternal Fetal Med, Tacoma, WA 98431 USA. San Antonio Uniformed Serv Hlth Educ, Div Reprod Endocrinol & Infertil, Lackland AFB, TX 78236 USA. Uniformed Serv Univ Hlth Sci, Sch Med, Bethesda, MD 20814 USA. Univ Florida, Div Maternal Fetal Med, Gainesville, FL 32611 USA. Wake Forest Univ, Div Maternal Fetal Med, Winston Salem, NC 27157 USA. NR 13 TC 20 Z9 20 U1 0 U2 3 PU ASSN MILITARY SURG US PI BETHESDA PA 9320 OLD GEORGETOWN RD, BETHESDA, MD 20814 USA SN 0026-4075 J9 MIL MED JI Milit. Med. PD JUN PY 2007 VL 172 IS 6 BP 640 EP 643 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 178PV UT WOS:000247233500018 PM 17615848 ER PT J AU Galpern, WR Cudkowicz, ME AF Galpern, Wendy R. Cudkowicz, Merit E. TI Coenzyme Q treatment of neurodegenerative diseases of aging SO MITOCHONDRION LA English DT Article DE amyotrophic lateral sclerosis; Parkinson's disease; Huntington's disease; coenzyme Q; clinical trial ID AMYOTROPHIC-LATERAL-SCLEROSIS; EARLY-ONSET PARKINSONISM; COMPLEX-I DEFICIENCY; HUNTINGTONS-DISEASE; MITOCHONDRIAL DYSFUNCTION; TRINUCLEOTIDE REPEAT; H-1-NMR SPECTROSCOPY; SUPEROXIDE-DISMUTASE; OXIDATIVE DAMAGE; CLINICAL-TRIAL AB The etiology of several neurodegenerative disorders is thought to involve impaired mitochondrial function and oxidative stress. Coenzyme Q-10 (CoQ(10)) acts both as an antioxidant and as an electron acceptor at the level of the mitochondria. In several animal models of neurodegenerative diseases including amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease, CoQ(10) has shown beneficial effects. Based on its biochemical properties and the effects in animal models, several clinical trials evaluating CoQ(10) have been undertaken in many neurodegenerative diseases. CoQ(10) appears to be safe and well tolerated, and several efficacy trials are planned. (c) 2007 Elsevier B.V. and Mitochondria Research Society. All rights reserved. C1 NINDS, NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp E, Neurol Clin Trials Unit, Charlestown, MA 02129 USA. RP Galpern, WR (reprint author), NINDS, NIH, 6001 Execut Blvd,Room 2225, Bethesda, MD 20892 USA. EM galpernw@ninds.nih.gov NR 59 TC 44 Z9 46 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 J9 MITOCHONDRION JI Mitochondrion PD JUN PY 2007 VL 7 SU S BP S146 EP S153 DI 10.1016/j.mito.2007.01.004 PG 8 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 183IS UT WOS:000247567100017 PM 17485247 ER PT J AU Navas, P Villalba, JM de Cabo, R AF Navas, Placido Villalba, Jose Manuel de Cabo, Rafael TI Importance of plasma membrane coenzyme Q in aging and stress responses SO MITOCHONDRION LA English DT Article DE coenzyme Q; plasma membrane; aging; oxidative stress ID UBIQUINONE REDUCTASE-ACTIVITY; PROGRAMMED CELL-DEATH; VITAMIN-E-DEFICIENCY; RAT-LIVER; CALORIE RESTRICTION; SELENIUM DEFICIENCY; ELECTRON-TRANSPORT; DT-DIAPHORASE; REDOX SYSTEM; SACCHAROMYCES-CEREVISIAE AB The plasma membrane of eukaryotic cells is the limit to interact with the environment. This position implies receiving stress signals that affects its components such as phospholipids. Inserted inside these components is coenzyme Q that is a redox compound acting as antioxidant. Coenzyme Q is reduced by diverse dehydrogenase enzymes mainly NADH-cytochrome b(5) reductase and NAD(P)H:quinone reductase 1. Reduced coenzyme Q can prevent lipid peroxidation chain reaction by itself or by reducing other antioxidants such as alpha-tocopherol and ascorbate. The group formed by antioxidants and the enzymes able to reduce coenzyme Q constitutes a plasma membrane redox system that is regulated by conditions that induce oxidative stress. Growth factor removal, ethidium bromide-induced rho omicron cells, and vitamin E deficiency are some of the conditions where both coenzyme Q and its reductases are increased in the plasma membrane., This antioxidant system in the plasma membrane has been observed to participate in the healthy aging induced by calorie restriction. Furthermore, coenzyme Q regulates the release of ceramide from sphingomyelin, which is concentrated in the plasma membrane. This results from the non-competitive inhibition of the neutral sphingomyelinase by coenzyme Q particularly by its reduced form. Coenzyme Q in the plasma membrane is then the center of a complex antioxidant system preventing the accumulation of oxidative damage and regulating the externally initiated ceramide signaling pathway. (c) 2007 Elsevier B.V. and Mitochondria Research Society. All rights reserved. C1 Univ Pablo de Olavide, CSIC, Ctr Andaluz Biol Desarrollo, Seville 41013, Spain. Univ Cordoba, Dept Biol Celular Fisiol & Inmunol, E-14071 Cordoba, Spain. NIA, Lab Expt Gerontol, NIH, Baltimore, MD 21224 USA. RP Navas, P (reprint author), Univ Pablo de Olavide, CSIC, Ctr Andaluz Biol Desarrollo, Seville 41013, Spain. EM pnavas@upo.es RI de Cabo, Rafael/E-7996-2010; de Cabo, Rafael/J-5230-2016 OI de Cabo, Rafael/0000-0002-3354-2442 NR 83 TC 52 Z9 54 U1 0 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1567-7249 J9 MITOCHONDRION JI Mitochondrion PD JUN PY 2007 VL 7 SU S BP S34 EP S40 DI 10.1016/j.mito.2007.02.010 PG 7 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 183IS UT WOS:000247567100004 PM 17482527 ER PT J AU van de Sluis, B Muller, P Duran, K Chen, A Groot, AJ Klomp, LW Liu, PP Wijmenga, C AF van de Sluis, Bart Muller, Patricia Duran, Karen Chen, Amy Groot, Arjan J. Klomp, Leo W. Liu, Paul P. Wijmenga, Cisca TI Increased activity of hypoxia-inducible factor 1 is associated with early embryonic lethality in Commd1 null mice SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID COPPER TOXICOSIS; KAPPA-B; BEDLINGTON TERRIER; O-2 HOMEOSTASIS; GENE-EXPRESSION; FACTOR 1-ALPHA; MOUSE MURR1; PROTEIN; IDENTIFICATION; ACTIVATION AB OMMD1 (previously known as MURR1) belongs to a novel family of proteins termed the copper metabolism gene MURR1 domain (COMMD) family. The 10 COMMD family members are well conserved between vertebrates, but the functions of most of the COMMD proteins are unknown. We recently established that COMMD1 is associated with the hepatic copper overload disorder copper toxicosis in Bedlington terriers. Recent in vitro studies indicate that COMMD1 has multiple functions, including sodium transport and NF-KB signaling. To elucidate the function of Commd1 in vivo, we generated homozygous Commd1 null (Commd1(-/-)) mice. Commd1(-/-) embryos died in utero between 9.5 and 10.5 days postcoiturn. (dpc), their development was generally retarded, and placenta vascularization was absent. Microarray analysis identified transcriptional upregulation of hypoxia-inducible factor 1 (HIF-1) target genes in 9.5-dpc Commd1(-/-) embryos compared to normal embryos, a feature that was associated with increased Hif-1 alpha stability. Consistent with these observations, COMMD1 physically associates with HIF-1 alpha and inhibits HIF-1 alpha stability and HIF-1 transactivation in vitro. Thus, this study identifies COMMD1 as a novel regulator of HIF-1 activity and shows that Commd1 deficiency in mice leads to embryonic lethality associated with dysregulated placenta vascularization. C1 UMC Utrecht, Lab Metab & Endocrine Dis, NL-3584 EA Utrecht, Netherlands. Univ Utrecht, Ctr Med, DBG Dept Med Genet, Complex Genet Sect, NL-3584 CG Utrecht, Netherlands. Univ Utrecht, Med Ctr, Dept Pathol, NL-3508 GA Utrecht, Netherlands. Univ Groningen, Ctr Med, Dept Genet, NL-9700 RB Groningen, Netherlands. Natl Human Genome Res Inst, NIH, Bethesda, MD 20892 USA. RP van de Sluis, B (reprint author), UMC Utrecht, Lab Metab & Endocrine Dis, Room KC 02 069 1, NL-3584 EA Utrecht, Netherlands. EM a.j.a.vandesluis@med.uu.nl RI Liu, Paul/A-7976-2012; Wijmenga, Cisca/D-2173-2009; OI Liu, Paul/0000-0002-6779-025X; Wijmenga, Cisca/0000-0002-5635-1614 FU Intramural NIH HHS NR 46 TC 56 Z9 57 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2007 VL 27 IS 11 BP 4142 EP 4156 DI 10.1128/MCB.01932-06 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 170XA UT WOS:000246698300023 PM 17371845 ER PT J AU Shah, YA Morimura, K Yang, Q Tanabe, T Takagi, M Gonzalez, FJ AF Shah, Yatrik A. Morimura, Keiichirou Yang, Qian Tanabe, Tomotaka Takagi, Mitsuhiro Gonzalez, Frank J. TI Peroxisome proliferator-activated receptor alpha regulates a microRNA-mediated signaling cascade responsible for hepatocellular proliferation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MESSENGER-RNA DEGRADATION; RAS GENE-MUTATIONS; HUMAN LUNG CANCERS; CELL-PROLIFERATION; FVB/TG.AC MOUSE; PPAR-GAMMA; C-MYC; EXPRESSION; TARGETS; IDENTIFICATION AB Activation of peroxisome proliferator-activated receptor alpha (PPARot) leads to hepatocellular proliferation and liver carcinomas. The early events mediating these effects are unknown. A novel mechanism by which PPARot regulates gene expression and hepatocellular proliferation was uncovered. MicroRNA (miRNA) expression profiling demonstrated that activated PPARot was a major regulator of hepatic miRNA expression. Of particular interest, let-7C, an miRNA important in cell growth, was inhibited following 4-h treatment and 2-week and 11-month sustained treatment with the potent PPAR alpha agonist Wy-14,643 in wild-type mice. let-7C was shown to target c-myc via direct interaction with the 3' untranslated region of c-myc. The PPAR alpha-mediated induction of c-myc via let-7C subsequently increased expression of the oncogenic mir-17-92 cluster; these events did not occur in Ppar alpha-null mice. Overexpression of let-7C decreased c-myc and mir-17 and suppressed the growth of Hepa-1 cells. Furthermore, using the human PPAR alpha-expressing mouse model, which is responsive to Wy-14,643 effects on beta-oxidation and serum triglycerides but resistant to hepatocellular proliferation and tumorigenesis, we demonstrated a critical role for let-7C in liver oncogenesis. Wy-14,643 treatment did not inhibit let-7C or induce c-myc and mir-17 expression. These observations reveal a let-7C signaling cascade critical for PPARot agonist-induced liver proliferation and tumorigenesis. C1 NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bldg 37,Room 3106, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov FU Intramural NIH HHS NR 63 TC 165 Z9 173 U1 1 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2007 VL 27 IS 12 BP 4238 EP 4247 DI 10.1128/MCB.00317-07 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 177JS UT WOS:000247150000004 PM 17438130 ER PT J AU Sumi, K Tanaka, T Uchida, A Magoori, K Urashima, Y Ohashi, R Ohguchi, H Okamura, M Kudo, H Daigo, K Maejima, T Kojima, N Sakakibara, I Jiang, S Hasegawa, G Kim, I Osborne, TF Naito, M Gonzalez, FJ Hamakubo, T Kodama, T Sakai, J AF Sumi, Koichi Tanaka, Toshiya Uchida, Aoi Magoori, Kenta Urashima, Yasuyo Ohashi, Riuko Ohguchi, Hiroto Okamura, Masashi Kudo, Hiromi Daigo, Kenji Maejima, Takashi Kojima, Noriaki Sakakibara, Iori Jiang, Shuying Hasegawa, Go Kim, Insook Osborne, Timothy F. Naito, Makoto Gonzalez, Frank J. Hamakubo, Takao Kodama, Tatsuhiko Sakai, Juro TI Cooperative interaction between hepatocyte nuclear factor 4 alpha and GATA transcription factors regulates ATP-binding cassette sterol transporters ABCG5 and ABCG8 SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID DIETARY-CHOLESTEROL ABSORPTION; HORMONE RECEPTOR SUPERFAMILY; ORPHAN NUCLEAR RECEPTORS; HEART TUBE FORMATION; GENE-EXPRESSION; VENTRAL MORPHOGENESIS; VISCERAL ENDODERM; LIPID HOMEOSTASIS; FACTOR 4-ALPHA-1; ACID SYNTHESIS AB Cholesterol homeostasis is maintained by coordinate regulation of cholesterol synthesis and its conversion to bile acids in the liver. The excretion of cholesterol from liver and intestine is regulated by ATP-binding cassette half-transporters ABCG5 and ABCG8. The genes for these two proteins are closely linked and divergently transcribed from a common intergenic promoter region. Here, we identified a binding site for hepatocyte nuclear factor 4 alpha (HNF4 alpha) in the ABCG5/ABCG8 intergenic promoter, through which HNF4 alpha strongly activated the expression of a reporter gene in both directions. The HNF4ci-responsive element is flanked by two conserved GATA boxes that were also required for stimulation by HNF4 alpha. GATA4 and GATA6 bind to the GATA boxes, coexpression of GATA4 and HNF4 alpha leads to a striking synergistic activation of both the ABCG5 and the ABCG8 promoters, and binding sites for HNF4a and GATA were essential for maximal synergism. We also show that HNF4a, GATA4, and GATA6 colocallize in the nuclei of HepG2 cells and that a physical interaction between HNF4 alpha and GATA4 is critical for the synergistic response. This is the first demonstration that HNF4 alpha acts synergistically with GATA factors to activate gene expression in a bidirectional fashion. C1 Univ Tokyo, Adv Sci & Technol Res Ctr, Lab Syst Biol & Med, Meguro Ku, Tokyo 1538904, Japan. Niigata Univ, Grad Sch Med & Dent Sci, Div Cellular & Mol Pathol, Dept Cellular Funct, Niigata 9518510, Japan. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92717 USA. RP Sakai, J (reprint author), Univ Tokyo, Adv Sci & Technol Res Ctr, Lab Syst Biol & Med, Meguro Ku, 4-6-1 Komaba, Tokyo 1538904, Japan. EM jmsakai-tky@umin.ac.jp RI Daigo, Kenji/S-8915-2016 OI Daigo, Kenji/0000-0001-6398-3356 NR 55 TC 52 Z9 54 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD JUN PY 2007 VL 27 IS 12 BP 4248 EP 4260 DI 10.1128/MCB.01894-06 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 177JS UT WOS:000247150000005 PM 17403900 ER PT J AU Kryndushkin, D Wickner, RB AF Kryndushkin, Dmitry Wickner, Reed B. TI Nucleotide exchange factors for Hsp70s are required for [URE3] prion propagation in Saccharomyces cerevisiae SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID IN-VITRO; ANTAGONISTIC INTERACTIONS; CYTOSOLIC HSP70; CHAPERONE SSA1P; GENE DELETION; PSI+ PRION; YEAST PSI+; PROTEIN; PSI(+); HSP104 AB The [URE3] and [PSI+] prions are infectious amyloid forms of Ure2p and Sup35p. Several chaperones influence prion propagation: Hsp104p overproduction destabilizes [PSI+], whereas [URE3] is sensitive to excess of Ssa1p or Ydj1p. Here, we show that overproduction of the chaperone, Sse1p, can efficiently cure [URE3]. Sse1p and Fes1p are nucleotide exchange factors for Ssa1p. Interestingly, deletion of either SSE1 or FES1 completely blocked [URE3] propagation. In addition, deletion of SSE1 also interfered with [PSI+] propagation. C1 NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov FU Intramural NIH HHS NR 38 TC 55 Z9 56 U1 0 U2 3 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 EI 1939-4586 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUN PY 2007 VL 18 IS 6 BP 2149 EP 2154 DI 10.1091/mbc.E07-02-0128 PG 6 WC Cell Biology SC Cell Biology GA 174YA UT WOS:000246977600017 PM 17392510 ER PT J AU Cohen, LA Honda, A Varnai, P Brown, FD Balla, T Donaldson, JG AF Cohen, Lee Ann Honda, Akira Varnai, Peter Brown, Fraser D. Balla, Tamas Donaldson, Julie G. TI Active Arf6 recruits ARNO/cytohesin GEFs to the PM by binding their PH domain SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID GUANINE-NUCLEOTIDE-EXCHANGE; ADP-RIBOSYLATION FACTORS; PLECKSTRIN-HOMOLOGY DOMAINS; INOSITOL-LIPID-BINDING; FACTOR ARNO; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; PLASMA-MEMBRANE; GOLGI-COMPLEX; SEC7 DOMAIN; MAMMALIAN-CELLS AB ARNO is a soluble guanine nucleotide exchange factor (GEF) for the Arf family of GTPases. Although in biochemical assays ARNO prefers Arf1 over Arf6 as a substrate, its localization in cells at the plasma membrane (PM) suggests an interaction with Arf6. In this study, we found that ARNO activated Arf1 in HeLa and COS-7 cells resulting in the recruitment of Arf1 on to dynamic PM ruffles. By contrast, Arf6 was activated less by ARNO than EFA6, a canonical Arf6 GER Remarkably, Arf6 in its GTP-bound form recruited ARNO to the PM and the two proteins could be immunoprecipitated. ARNO binding to Arf6 was not mediated through the catalytic Sec7 domain, but via the pleckstrin homology (PH) domain. Active Arf6 also bound the PH domain of Grp1, another ARNO family member. This interaction was direct and required both inositol phospholipids and GTP. We propose a model of sequential Arf activation at the PM whereby Arf6-GTP recruits ARNO family GEFs for further activation of other Arf isoforms. C1 NICHHD, Cell Biol Lab, Natl Heart Lung & Blood Inst, NIH, Bethesda, MD 20892 USA. NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. RP Donaldson, JG (reprint author), NICHHD, Cell Biol Lab, Natl Heart Lung & Blood Inst, NIH, Bethesda, MD 20892 USA. EM jdonalds@helix.nih.gov FU Intramural NIH HHS NR 54 TC 120 Z9 120 U1 1 U2 6 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUN PY 2007 VL 18 IS 6 BP 2244 EP 2253 DI 10.1091/mbc.E06-11-0998 PG 10 WC Cell Biology SC Cell Biology GA 174YA UT WOS:000246977600025 PM 17409355 ER PT J AU Ma, XF Bao, JJ Adelstein, RS AF Ma, Xuefei Bao, Jianjun Adelstein, Robert S. TI Loss of cell adhesion causes hydrocephalus in nonmuscle myosin II-B-ablated and mutated mice SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID HEAVY-CHAIN GENE; ADHERENS JUNCTIONS; NEUROEPITHELIAL CELLS; PROTEIN COMPLEX; POLARITY; CYTOKINESIS; MUTATIONS; MIGRATION; DEFECTS; ISOFORM AB Ablation of nonmuscle myosin (NM) II-B in mice during embryonic development leads to marked enlargement of the cerebral ventricles and destruction of brain tissue, due to hydrocephalus. We have identified a transient mesh-like structure present at the apical border of cells lining the spinal canal of mice during development. This structure, which only contains the II-B isoform of NM, also contains ss-catenin and N-cadherin, consistent with a role in cell adhesion. Ablation of NM II-B or replacement of NM II-B with decreased amounts of a mutant (R709C), motor-impaired NM II-B in mice results in collapse of the mesh-like structure and loss of cell adhesion. This permits the underlying neuroepithelial cells to invade the spinal canal and obstruct cerebral spinal fluid flow. These defects in the CNS of NM II-B-ablated mice seem to be the cause of hydrocephalus. Interestingly, the mesh-like structure and patency of the spinal canal can be restored by increasing expression of the motor-impaired NM II-B, which also rescues hydrocephalus. However, the mutant isoform cannot completely rescue neuronal cell migration. These studies show that the scaffolding properties of NM II-B play an important role in cell adhesion, thereby preventing hydrocephalus during mouse brain development. C1 NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. RP Ma, XF (reprint author), NHLBI, Mol Cardiol Lab, NIH, Bethesda, MD 20892 USA. EM max@nhlbi.nih.gov OI Adelstein, Robert/0000-0002-8683-2144 FU Intramural NIH HHS NR 33 TC 49 Z9 51 U1 0 U2 3 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD JUN PY 2007 VL 18 IS 6 BP 2305 EP 2312 DI 10.1091/mbc.E07-01-0073 PG 8 WC Cell Biology SC Cell Biology GA 174YA UT WOS:000246977600031 PM 17429076 ER PT J AU Robey, RW Shukla, S Steadman, K Obrzut, T Finley, EM Ambudkar, SV Bates, SE AF Robey, Robert W. Shukla, Suneet Steadman, Kenneth Obrzut, Tomasz Finley, Elizabeth M. Ambudkar, Suresh V. Bates, Susan E. TI Inhibition of ABCG2-mediated transport by protein kinase inhibitors with a bisindolylmaleimide or indolocarbazole structure SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID CANCER RESISTANCE PROTEIN; ACUTE-MYELOID-LEUKEMIA; TOPOISOMERASE-I INHIBITORS; P-GLYCOPROTEIN; MULTIDRUG-RESISTANCE; C INHIBITOR; PHASE-I; FUNCTIONAL-CHARACTERIZATION; ORAL BIOAVAILABILITY; MONOCLONAL-ANTIBODY AB ABCG2 is a transporter with potential importance in cancer drug resistance, drug oral absorption, and stem cell biology. In an effort to identify novel inhibitors of ABCG2, we examined the ability of commercially available bisindolylmaleimides (BIM) and indolocarbazole protein kinase inhibitors (PKI) to inhibit ABCG2, given the previous demonstration that the indolocarbazole PKI UCN-01 interacted with the transporter. At a concentration of 10 mu mol/L, all of the compounds tested increased intracellular fluorescence of the ABCG2-specific substrate pheophorbide a in ABCG2-transfected HEK-293 cells by 1.3- to 6-fold as measured by flow cytometry; the ABCG2-specific inhibitor fumitremorgin C increased intracellular fluorescence by 6.6-fold. In 4-day cytotoxicity assays, wild-type ABCG2-transfected cells were not more than 2-fold resistant to any of the compounds, suggesting that the PKIs are not significantly transported by ABCG2. BIMs I, II, III, IV, and V, K252c, and arcyriaflavin A were also able to inhibit [I-125]iodoarylazidoprazosin labeling of ABCG2 by 65% to 80% at 20 mu mol/L, compared with a 50% to 70% reduction by 20 mu mol/L fumitremorgin C. K252c and arcyriaflavin A were the most potent compounds, with IC50 values for inhibition of [I-125]iodoarylazidoprazosin labeling of 0.37 and 0.23 mu mol/L, respectively. K252c and arcyriaflavin A did not have any effect on the ATPase activity of ABCG2. Four minimally toxic compounds-BIM IV, BIM V, arcyriaflavin A, and K252c-reduced the relative resistance of ABCG2-transfected cells to SN-38 in cytotoxicity assays. We find that indolocarbazole and BIM PKIs directly interact with the ABCG2 protein and may thus increase oral bioavailability of ABCG2 substrates. C1 Canc Res Ctr, NIH, Med Oncol Branch, Bethesda, MD USA. Canc Res Ctr, NIH, Lab Cell Biol, Bethesda, MD USA. RP Robey, RW (reprint author), Bldg 10,Room 12C217,9000 Rockville Pike, Bethesda, MD 20892 USA. EM robeyr@mail.nih.gov RI shukla, suneet/B-4626-2012; Steadman, Kenneth/J-3883-2013 FU Intramural NIH HHS NR 48 TC 32 Z9 32 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD JUN PY 2007 VL 6 IS 6 BP 1877 EP 1885 DI 10.1158/1535-7163.MCT-06-0811 PG 9 WC Oncology SC Oncology GA 181LS UT WOS:000247438800022 PM 17575116 ER PT J AU Strauss, KA Morton, DH Puffenberger, EG Hendrickson, C Robinson, DL Wagner, C Stabler, SP Allen, RH Chwatko, G Jakubowski, H Niculescu, MD Mudd, SH AF Strauss, Kevin A. Morton, D. Holmes Puffenberger, Erik G. Hendrickson, Christine Robinson, Donna L. Wagner, Conrad Stabler, Sally P. Allen, Robert H. Chwatko, Grazyna Jakubowski, Hieronim Niculescu, Mihai D. Mudd, S. Harvey TI Prevention of brain disease from severe 5,10-methylenetetrahydrofolate reductase deficiency SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE amish; betaine; blood-brain barrier; homocysteine; methionine; 5,10-methylenetetrahydrofolate reductase; newborn screening; S-adenosylmethionine ID S-ADENOSYLMETHIONINE; REGIONAL DISTRIBUTION; MASS-SPECTROMETRY; FOLATE-DEFICIENCY; HOMOCYSTEINE; METHIONINE; BETAINE; ADENOSYLHOMOCYSTEINE; METHYLTRANSFERASE; PERFORMANCE AB Over a four-year period, we collected clinical and biochemical data from five Amish children who were homozygous for missense mutations in 5, 10-methylenctetrahydrofolate reductase (MTHFR c. 1129C>T). The four oldest patients had irreversible brain damage prior to diagnosis. The youngest child, diagnosed and started on betaine therapy as a newborn, is healthy at her present age of three years. We compared biochemical data among four groups: 16 control subjects, eight heterozygous parents, and five affected children (for the latter group, both before and during treatment with betaine anhydrous). Plasma amino acid concentrations were used to estimate changes in cerebral methionine uptake resulting from betaine therapy. In all affected children, treatment with betaine (534 +/- 222 mg/kg/ day) increased plasma S-adenosylmethionine, improved markers of tissue methyltransferase activity, and resulted in a threefold increase of calculated brain methionine uptake. Betaine therapy did not normalize plasma total homocysteine, nor did it correct. cerebral 5-methyltetrahydrofolate deficiency. We conclude that when the 5-methyltetrahydrofolate content of brain tissue is low, dietary betaine sufficient to increase brain methionine uptake may compensate for impaired cerebral methionine recycling. To effectively support the metabolic requirements of rapid brain growth, a large dose of betaine should be started early in life. (c) 2007 Elsevier Inc. All rights reserved. C1 Clin Special Children, Strasburg, PA 17579 USA. Vanderbilt Univ, Dept Biochem, Nashville, TN 37232 USA. Dept Vet Affairs Med Ctr, Nashville, TN 37212 USA. Univ Colorado, Hlth Sci Ctr, Div Hematol, Denver, CO USA. UMDNJ, New Jersey Med Sch, Dept Microbiol & Mol Genet, Int Ctr Publ Hlth, Newark, NJ USA. Polish Acad Sci, Inst Bioorgan Chem, PL-61074 Poznan, Poland. Univ N Carolina, Dept Nutr, Chapel Hill, NC 27515 USA. NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Strauss, KA (reprint author), Clin Special Children, Strasburg, PA 17579 USA. EM kstrauss@clinicforspecialchildren.org RI Chwatko, Grazyna/R-8757-2016; OI Jakubowski, Hieronim/0000-0001-5845-4409 NR 49 TC 54 Z9 55 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUN PY 2007 VL 91 IS 2 BP 165 EP 175 DI 10.1016/j.ymgme.2007.02.012 PG 11 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 181AE UT WOS:000247408300007 PM 17409006 ER PT J AU Ziegler, SG Eblan, MJ Gutti, U Hruska, KS Stubblefield, BK Goker-Alpan, O LaMarca, ME Sidransky, E AF Ziegler, Shira G. Eblan, Michael J. Gutti, Usha Hruska, Kathleen S. Stubblefield, Barbara K. Goker-Alpan, Ozlem LaMarca, Mary E. Sidransky, Ellen TI Glucocerebrosidase mutations in Chinese subjects from Taiwan with sporadic Parkinson disease SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Gaucher disease; Parkinsonism; risk factor; sporadic parkinson disease; lysosmal enzyme; glucocerebrosidase ID ALPHA-SYNUCLEIN GENE; EARLY-ONSET PARKINSONISM; GAUCHER-DISEASE; ASHKENAZI-JEWS; LRRK2 MUTATION; G2019S; POPULATION AB Background: An association between glucocerebrosidase, the enzyme deficient in Gaucher disease, and the synucleinopathies has been suggested both by the development of parkinsonism in Gaucher probands and carriers, as well as by the presence of mutations in the gene for glucocerebrosidase (GBA) in different series of subjects with synucleinopathies. In this study, an open access Parkinson repository was used to establish the incidence of GBA alterations in a different ethnic cohort with sporadic Parkinson disease (PD). Methods: The glucocerebrosidase gene was sequenced in samples collected from 92 Chinese Parkinson disease patients from Taiwan along with 92 clinically screened controls, matched for age and ethnicity. Findings: The frequency of GBA mutations among the Chinese PD probands was 4.3%, in contrast to 1.1% in Chinese controls. Mutant alleles identified included two known mutations, L444P and D409H, and two novel mutations, L174P and Q497R. Interpretation: These results, ascertained in subjects from Taiwan collected in a standardized and clinically rigorous open access Parkinson disease repository and screened by direct sequencing of GBA, demonstrate that GBA mutations are also encountered in Chinese subjects with sporadic PD at a higher frequency than many other known PD genes. The study demonstrates that the association of GBA mutations with the development of parkinsonian pathology is not related to ethnic origin. Published by Elsevier Inc. C1 NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bethesda, MD USA. RP Sidransky, E (reprint author), NHGRI, Sect Mol Neurogenet, Med Genet Branch, NIH, Bldg 35,Room 1A21, Bethesda, MD USA. EM sidranse@mail.nih.gov OI Gutti, Usha/0000-0003-0927-0923 FU Intramural NIH HHS [Z99 HG999999, Z01 HG200336-02] NR 35 TC 74 Z9 78 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD JUN PY 2007 VL 91 IS 2 BP 195 EP 200 DI 10.1016/j.ymgme.2007.03.004 PG 6 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 181AE UT WOS:000247408300011 PM 17462935 ER PT J AU Ortiz, D Sanchez, MA Pierce, S Herrmann, T Kimblin, N Bouwer, HGA Landfear, SM AF Ortiz, Diana Sanchez, Marco A. Pierce, Steven Herrmann, Timo Kimblin, Nicola Bouwer, H. G. Archie Landfear, Scott M. TI Molecular genetic analysis of purine nucleobase transport in Leishmania major SO MOLECULAR MICROBIOLOGY LA English DT Article ID PROTOZOAN PARASITE LEISHMANIA; NUCLEOSIDE TRANSPORTER; STABLE TRANSFECTION; TRYPANOTHIONE REDUCTASE; CUTANEOUS LEISHMANIASIS; ALLOPURINOL UPTAKE; DEFICIENT MUTANT; DONOVANI; EXPRESSION; RESISTANCE AB Leishmania major and all other parasitic protozoa are unable to synthesize purines de novo and are therefore reliant upon uptake of preformed purines from their hosts via nucleobase and nucleoside transporters. L. major expresses two nucleobase permeases, NT3 that is a high affinity transporter for purine nucleobases and NT4 that is a low affinity transporter for adenine. nt3((-/-)) null mutant promastigotes were unable to replicate in medium containing 10 mu M hypoxanthine, guanine, or xanthine and replicated slowly in 10 mu M adenine due to residual low affinity uptake of that purine. The NT3 transporter mediated the uptake of the anti-leishmanial drug allopurinol, and the nt3((-/-)) mutants were resistant to killing by this drug. Expression of the NT3 permease was profoundly downregulated at the protein but not the mRNA level in stationary phase compared with logarithmic phase promastigotes. The nt4((-/-)) null mutant was quantitatively impaired in survival within murine bone marrow-derived macrophages. Extensive efforts to generate an nt3((-/-))/nt4((-/-)) dual null mutant were not successful, suggesting that one of the two nucleobase permeases must be retained for robust growth of the parasite. The phenotypes of these null mutants underscore the importance of purine nucleobase transporters in the Leishmania life cycle and pharmacology. C1 Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97239 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Vet Affairs Med Ctr Immunol Res, Earle A Chiles Res Inst, Portland, OR 97239 USA. RP Landfear, SM (reprint author), Columbia Univ, Dept Biol Sci, New York, NY 10032 USA. EM landfear@ohsu.edu OI Landfear, Scott/0000-0002-1643-6664 FU NIAID NIH HHS [AI056446, AI44138] NR 48 TC 21 Z9 21 U1 0 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUN PY 2007 VL 64 IS 5 BP 1228 EP 1243 DI 10.1111/j.1365-2958.2007.05730.x PG 16 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 177TO UT WOS:000247175600007 PM 17542917 ER PT J AU Jewett, MW Lawrence, K Bestor, AC Tilly, K Grimm, D Shaw, P VanRaden, M Gherardini, F Rosa, PA AF Jewett, Mollie W. Lawrence, Kevin Bestor, Aaron C. Tilly, Kit Grimm, Dorothee Shaw, Pamela VanRaden, Mark Gherardini, Frank Rosa, Patricia A. TI The critical role of the linear plasmid lp36 in the infectious cycle of Borrelia burgdorferi SO MOLECULAR MICROBIOLOGY LA English DT Article ID LYME-DISEASE SPIROCHETE; FIBRONECTIN-BINDING PROTEIN; OUTER SURFACE PROTEIN; WHITE-FOOTED MICE; GENE-EXPRESSION; TICK VECTOR; STRAIN B31; CLONAL POPULATIONS; ADENINE DEAMINASE; MAMMALIAN HOST AB Borrelia burgdorferi, the aetiological agent of Lyme disease, follows a life cycle that involves passage between the tick vector and the mammalian host. To investigate the role of the 36 kb linear plasmid, lp36 (also designated the B. burgdorferi K plasmid), in the infectious cycle of B. burgdorferi, we examined a clone lacking this plasmid, but containing all other plasmids known to be required for infectivity. Our results indicated that lp36 was not required for spirochete survival in the tick, but the clone lacking lp36 demonstrated low infectivity in the mammal. Restoration of lp36 to the mutant strain confirmed that the infectivity defect was due to loss of lp36. Moreover, spirochetes lacking lp36 exhibited a nearly 4-log increase in ID50 relative to the isogenic lp36(+) clone. The infectivity defect of lp36-minus spirochetes was localized, in part, to loss of the bbk17 (adeC) gene, which encodes an adenine deaminase. This work establishes a vital role for lp36 in the infectious cycle of B. burgdorferi and identifies the bbk17 gene as a component of this plasmid that contributes to mammalian infectivity. C1 NIAID, Lab Zonnot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Jewett, MW (reprint author), NIAID, Lab Zonnot Pathogens, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. EM jewettm@niaid.nih.gov FU Intramural NIH HHS NR 82 TC 74 Z9 74 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUN PY 2007 VL 64 IS 5 BP 1358 EP 1374 DI 10.1111/j.1365-2958.2007.05746.x PG 17 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 177TO UT WOS:000247175600016 PM 17542926 ER PT J AU Moon, K Sonnenburg, J Salyers, AA AF Moon, Kyung Sonnenburg, Justin Salyers, Abigail A. TI Unexpected effect of a Bacteroides conjugative transposon, CTnDOT, on chromosomal gene expression in its bacterial host SO MOLECULAR MICROBIOLOGY LA English DT Article ID TETRACYCLINE RESISTANCE ELEMENT; EXTENSIVE DNA INVERSIONS; ANAEROBIC INFECTIONS; INSERTION ELEMENT; EXCISION; REGION; IDENTIFICATION; INTEGRATION; NBU1 AB Foreign DNA elements such as plasmids and conjugative transposons are constantly entering new bacterial hosts. A possible outcome of such events that has not been considered previously is that regulatory genes carried on some of them might affect the expression of chromosomal genes of the new host. To assess this possibility, we investigated the effect of the Bacteroides conjugative transposon CTnDOT on expression of chromosomal genes in Bacteroides thetaiotaomicron 5482 (BT4001). Most of the upregulated genes were genes of unknown function, but a number of them were associated with a region of the chromosome that contained a putative conjugative transposon, which had been tentatively designated as CTn4-bt. Upregulation of CTn4-bt genes and other chromosomal genes affected by CTnDOT was controlled by two regulatory genes on CTnDOT, rteA and rteB, which encode a two-component regulatory system. Transfer of CTn4-bt was also mediated by rteA and rteB. Three other putative CTns, CTn1-bt, CTn2-bt and CTn3-bt, were mobilized by CTnERL, a CTn closely related to CTnDOT, but genes from CTnERL other than rteA and rteB were also required. Unexpectedly, homologous recombination was required for CTn1-bt, CTn2-bt, CTn3-bt and CTn4-bt to integrate in the recipient. Our results show that regulatory genes on an incoming mobile element can have multiple effects on its new host, including the activation of previously non-transmissible elements. C1 Univ Illinois, Dept Microbiol, Urbana, IL 61801 USA. NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Ctr Genome Sci, St Louis, MO 63108 USA. RP Salyers, AA (reprint author), Univ Illinois, Dept Microbiol, 131 Burrill Hall, Urbana, IL 61801 USA. EM abigails@uiuc.edu FU NIAID NIH HHS [R56 AI022383, R01 AI022383, AI 22383] NR 39 TC 7 Z9 7 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0950-382X J9 MOL MICROBIOL JI Mol. Microbiol. PD JUN PY 2007 VL 64 IS 6 BP 1562 EP 1571 DI 10.1111/j.1365-2958.2007.05756.x PG 10 WC Biochemistry & Molecular Biology; Microbiology SC Biochemistry & Molecular Biology; Microbiology GA 177TP UT WOS:000247175700014 PM 17555438 ER PT J AU Kozmin, SG Schaaper, RM AF Kozmin, Stanislav G. Schaaper, Roel M. TI Molybdenum cofactor-dependent resistance to N-hydroxylated base analogs in Escherichia coli is independent of MobA function SO MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS LA English DT Article DE base analog sensitivity; molybdenum cofactor; MobA N6-hydioxylaminopurine; hydroxylamine ID SALMONELLA-TYPHIMURIUM; XANTHINE DEHYDROGENASE; SACCHAROMYCES-CEREVISIAE; MUTAGENIC-ACTIVITY; OPERON ENCODES; 6-N-HYDROXYLAMINOPURINE; GENE; BIOSYNTHESIS; SPECIFICITY; PURINES AB Lack of molybdenum cofactor (MoCo) in Escherichia coli and related microorganisms was found to cause hypersensitivity to certain N-hydroxylated base analogs, such as HAP (6-N-hydroxylaminopurine). This observation has lead to a previous proposal that E. coli contains a molybdoenzyme capable of detoxifying such N-hydroxylated analogs. Here, we show that, unexpectedly, deletion of all known or putative molybdoenzymes in E. coli failed to reveal any base-analog sensitivity, suggesting that a novel type of MoCo-dependent activity is involved. Further, we establish that protection against the analogs does not require the common molybdopterin guanine-dinucleotide (MGD) form of the cofactor, but instead the guanosine monophosphate (GMP)-free version of MoCo (MPT) is sufficient. (c) 2007 Elsevier B.V. All rights reserved. C1 Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. St Petersburg State Univ, Dept Genet, St Petersburg 199034, Russia. RP Schaaper, RM (reprint author), Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. EM schaaper@niehs.nih.gov RI Kozmin, Stanislav/J-6849-2012 OI Kozmin, Stanislav/0000-0002-4128-4447 FU Intramural NIH HHS [Z01 ES050170-08, Z01 ES065088-10] NR 40 TC 20 Z9 20 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0027-5107 J9 MUTAT RES-FUND MOL M JI Mutat. Res.-Fundam. Mol. Mech. Mutagen. PD JUN 1 PY 2007 VL 619 IS 1-2 BP 9 EP 15 DI 10.1016/j.mrfmmm.2006.12.005 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 170MP UT WOS:000246667800002 PM 17349664 ER PT J AU Kobayashi, H Hama, Y Koyama, Y Barrett, T Regino, CAS Urano, Y Choyke, PL AF Kobayashi, Hisataka Hama, Yukihiro Koyama, Yoshinori Barrett, Tristan Regino, Celeste A. S. Urano, Yasuteru Choyke, Peter L. TI Simultaneous multicolor imaging of five different lymphatic basins using quantum dots SO NANO LETTERS LA English DT Article ID MAGNETIC RESONANCE LYMPHANGIOGRAPHY; IN-VIVO; CANCER; NODE AB Quantum dots can be used to perform multicolor images with high fluorescent intensity and are of a nanosize suitable for lymphatic imaging via direct interstitial injection. Here simultaneous multicolor in vivo wavelength-resolved spectral fluorescence lymphangiography is shown using five quantum dots with similar physical sizes but different emission spectra. This allows noninvasive and simultaneous visualization of five separate lymphatic flows draining and may have implications for predicting the route of cancer metastasis into the lymph nodes. C1 NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bldg 10,Room 1B40,MSC 1088, Bethesda, MD 20892 USA. EM Kobayash@mail.nih.gov RI Urano, Yasuteru/H-1380-2012 FU Intramural NIH HHS NR 13 TC 220 Z9 226 U1 6 U2 40 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1530-6984 J9 NANO LETT JI Nano Lett. PD JUN PY 2007 VL 7 IS 6 BP 1711 EP 1716 DI 10.1021/nl0707003 PG 6 WC Chemistry, Multidisciplinary; Chemistry, Physical; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 177XW UT WOS:000247186800050 PM 17530812 ER PT J AU Resnik, DB Tinkle, SS AF Resnik, David B. Tinkle, Sally S. TI Ethics in nanomedicine SO NANOMEDICINE LA English DT Editorial Material ID ULTRAFINE PARTICLES; NANOTECHNOLOGY; SYSTEM; SAFETY AB As the science and technology of nanomedicine speed ahead, ethics, policy and the law are struggling to keep up. It is important to proactively address the ethical, social and regulatory aspects of nanomedicine in order to minimize its adverse impacts on the environment and public health and also to avoid a public backlash. At present, the most significant concerns involve risk assessment, risk management of engineered nanomaterials and risk communication. Although in vivo animal experiments and ex vivo laboratory analyses can increase our understanding of the interaction of engineered nanomaterials in biological systems, they cannot eliminate all of the uncertainty surrounding the exposure of a human subject to nanomedicine products in clinical trials. Significant risks can still materialize after a product has cleared the Phase I hurdle and is in Phase II or III clinical trials. Furthermore, as the use of engineered nanomaterials in nanomedicine increases, questions of social justice, access to healthcare and the use of nanotechnology for physical enhancement become increasingly important. C1 NIEHS, Res Triangle Pk, NC 27709 USA. NIH, Res Triangle Pk, NC 27709 USA. RP Resnik, DB (reprint author), NIEHS, Box 12233,Mail Drop NH06, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 28 TC 31 Z9 32 U1 3 U2 9 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1743-5889 J9 NANOMEDICINE-UK JI Nanomedicine PD JUN PY 2007 VL 2 IS 3 BP 345 EP 350 DI 10.2217/17435889.2.3.345 PG 6 WC Biotechnology & Applied Microbiology; Nanoscience & Nanotechnology SC Biotechnology & Applied Microbiology; Science & Technology - Other Topics GA 193CE UT WOS:000248250400012 PM 17716179 ER PT J AU Masui, S Nakatake, Y Toyooka, Y Shimosato, D Yagi, R Takahashi, K Okochi, H Okuda, A Matoba, R Sharov, AA Ko, MSH Niwa, H AF Masui, Shinji Nakatake, Yuhki Toyooka, Yayoi Shimosato, Daisuke Yagi, Rika Takahashi, Kazue Okochi, Hitoshi Okuda, Akihiko Matoba, Ryo Sharov, Alexei A. Ko, Minoru S. H. Niwa, Hitoshi TI Pluripotency governed by Sox2 via regulation of Oct3/4 expression in mouse embryonic stem cells SO NATURE CELL BIOLOGY LA English DT Article ID SELF-RENEWAL; ES CELLS; TRANSCRIPTIONAL REGULATION; GENE; OCT-3/4; NANOG; OCT4; DIFFERENTIATION; COMPLEX; IDENTIFICATION AB The pluripotency of embryonic stem (ES) cells is thought to be maintained by a few key transcription factors, including Oct3/4 and Sox2. The function of Oct3/4 in ES cells has been extensively characterized, but that of Sox2 has yet to be determined. Sox2 can act synergistically with Oct3/4 in vitro to activate Oct-Sox enhancers, which regulate the expression of pluripotent stem cell-specific genes, including Nanog, Oct3/4 and Sox2 itself. These findings suggest that Sox2 is required by ES cells for its Oct-Sox enhancer activity. Using inducible Sox2-null mouse ES cells, we show that Sox2 is dispensable for the activation of these Oct-Sox enhancers. In contrast, we demonstrate that Sox2 is necessary for regulating multiple transcription factors that affect Oct3/4 expression and that the forced expression of Oct3/4 rescues the pluripotency of Sox2-null ES cells. These results indicate that the essential function of Sox2 is to stabilize ES cells in a pluripotent state by maintaining the requisite level of Oct3/4 expression. C1 RIKEN, Ctr Dev Biol, Lab Pluripotent Cell Studies, Chuo Ku, Kobe, Hyogo 6500047, Japan. CREST, Japan Sci & Technol Agcy, Kawaguchi, Saitama 3320012, Japan. Int Med Ctr Japan, Div Mol Biol & Cell Engn, Dept Regenerat Med, Res Inst,Shinjuku Ku, Tokyo 1628655, Japan. Kobe Univ, Lab Dev & Regenerat Med, Grad Sch Med, Chuo Ku, Kobe, Hyogo 6500017, Japan. Saitama Med Univ, Div Dev Biol, Res Ctr Genom Med, Hidaka, Saitama 3501241, Japan. NIA, NIH, Dev Genom & Aging Sect, Genet Lab, Baltimore, MD 21224 USA. RP Masui, S (reprint author), RIKEN, Ctr Dev Biol, Lab Pluripotent Cell Studies, Chuo Ku, Minatojima Minamimachi 2-2-3, Kobe, Hyogo 6500047, Japan. EM masui@ri.imcj.go.jp; niwa@cdb.riken.jp RI Ko, Minoru/B-7969-2009; Nakatake, Yuhki/K-5405-2013 OI Ko, Minoru/0000-0002-3530-3015; FU Intramural NIH HHS NR 50 TC 571 Z9 610 U1 7 U2 63 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD JUN PY 2007 VL 9 IS 6 BP 625 EP U26 DI 10.1038/ncb1589 PG 15 WC Cell Biology SC Cell Biology GA 174DY UT WOS:000246922700007 PM 17515932 ER PT J AU Soutoglou, E Dorn, JF Sengupta, K Jasin, M Nussenzweig, A Ried, T Danuser, G Misteli, T AF Soutoglou, Evi Dorn, Jonas F. Sengupta, Kundan Jasin, Maria Nussenzweig, Andre Ried, Thomas Danuser, Gaudenz Misteli, Tom TI Positional stability of single double-strand breaks in mammalian cells SO NATURE CELL BIOLOGY LA English DT Article ID LIVING CELLS; DNA BREAKS; HISTONE H2AX; TRANSLOCATIONS; REPAIR; VISUALIZATION; ORGANIZATION; CANCER; SITES; ENDONUCLEASE AB Formation of cancerous translocations requires the illegitimate joining of chromosomes containing double-strand breaks (DSBs). It is unknown how broken chromosome ends find their translocation partners within the cell nucleus. Here, we have visualized and quantitatively analysed the dynamics of single DSBs in living mammalian cells. We demonstrate that broken ends are positionally stable and unable to roam the cell nucleus. Immobilization of broken chromosome ends requires the DNA-end binding protein Ku80, but is independent of DNA repair factors, H2AX, the MRN complex and the cohesion complex. DSBs preferentially undergo translocations with neighbouring chromosomes and loss of local positional constraint correlates with elevated genomic instability. These results support a contact-first model in which chromosome translocations predominantly form among spatially proximal DSBs. C1 NCI, NIH, Genet Branch, Bethesda, MD 20892 USA. Scripps Res Inst, La Jolla, CA 92037 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, Genet Branch, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov OI Dorn, Jonas/0000-0001-6696-0117 FU Intramural NIH HHS [Z01 BC010309-09]; NIGMS NIH HHS [GM68956, R01 GM068956] NR 41 TC 279 Z9 285 U1 0 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1465-7392 J9 NAT CELL BIOL JI Nat. Cell Biol. PD JUN PY 2007 VL 9 IS 6 BP 675 EP U121 DI 10.1038/ncb1591 PG 20 WC Cell Biology SC Cell Biology GA 174DY UT WOS:000246922700013 PM 17486118 ER PT J AU Martin, MP Qi, Y Gao, XJ Yamada, E Martin, JN Pereyra, F Colombo, S Brown, EE Shupert, WL Phair, J Goedert, JJ Buchbinder, S Kirk, GD Telenti, A Connors, M O'Brien, SJ Walker, BD Parham, P Deeks, SG McVicar, DW Carrington, M AF Martin, Maureen P. Qi, Ying Gao, Xiaojiang Yamada, Eriko Martin, Jeffrey N. Pereyra, Florencia Colombo, Sara Brown, Elizabeth E. Shupert, W. Lesley Phair, John Goedert, James J. Buchbinder, Susan Kirk, Gregory D. Telenti, Amalio Connors, Mark O'Brien, Stephen J. Walker, Bruce D. Parham, Peter Deeks, Steven G. McVicar, Daniel W. Carrington, Mary TI Innate partnership of HLA-B and KIR3DL1 subtypes against HIV-1 SO NATURE GENETICS LA English DT Article ID NATURAL-KILLER-CELLS; MAJOR HISTOCOMPATIBILITY COMPLEX; IMMUNOGLOBULIN-LIKE RECEPTOR; IMMUNODEFICIENCY-VIRUS TYPE-1; CLASS-I MOLECULES; MHC CLASS-I; INHIBITORY RECEPTORS; SELF-TOLERANCE; AIDS; INFECTION AB Allotypes of the natural killer ( NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV)(+) individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes. The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection. C1 Sci Applicat Int Corp Frederick Inc, NCI, Lab Genom Divers, Frederick, MD 21702 USA. Sci Applicat Int Corp Frederick Inc, NCI, Lab Expt Immunol, Frederick, MD 21702 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94105 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, AIDS Res Ctr, Boston, MA 02129 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Infect Dis Div, Boston, MA 02129 USA. Univ Lausanne, Inst Microbiol, CH-1011 Lausanne, Switzerland. NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. NIAID, Rocky Mt Lab, Hamilton, MT 59840 USA. Northwestern Univ, Sch Med, Dept Med, Chicago, IL 60611 USA. HIV Res Sect, San Francisco Dept Publ Hlth, San Francisco, CA 94102 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Dept Biol Struct, Stanford, CA 94305 USA. San Francisco Gen Hosp, San Francisco, CA 94110 USA. RP Carrington, M (reprint author), Sci Applicat Int Corp Frederick Inc, NCI, Lab Genom Divers, POB B,Bldg 560, Frederick, MD 21702 USA. EM carringt@ncifcrf.gov RI Kirk, Gregory/A-8484-2009; SHCS, all/G-4072-2011; SHCS, int. coll. A/G-4083-2011; McVicar, Daniel/G-1970-2015 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400]; NIAID NIH HHS [P30 AI027763]; NIDA NIH HHS [R01 DA004334, R01-DA04334, R56 DA004334] NR 45 TC 407 Z9 416 U1 0 U2 15 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD JUN PY 2007 VL 39 IS 6 BP 733 EP 740 DI 10.1038/ng2035 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 173FO UT WOS:000246859100017 PM 17496894 ER PT J AU Rogozin, IB Iyer, LM Liang, LZ Glazko, GV Liston, VG Pavlov, YI Aravind, L Pancer, Z AF Rogozin, Igor B. Iyer, Lakshminarayan M. Liang, Lizhi Glazko, Galina V. Liston, Victoria G. Pavlov, Youri I. Aravind, L. Pancer, Zeev TI Evolution and diversification of lamprey antigen receptors: evidence for involvement of an AID-APOBEC family cytosine deaminase SO NATURE IMMUNOLOGY LA English DT Article ID INDUCED CYTIDINE DEAMINASE; POLYNUCLEOTIDE (DEOXY)CYTIDINE DEAMINASES; IMMUNOGLOBULIN GENE CONVERSION; VARIABLE LYMPHOCYTE RECEPTORS; SOMATIC DIVERSIFICATION; AID/APOBEC FAMILY; RECOMBINATION; HYPERMUTATION; MUTATIONS; REPERTOIRE AB The variable lymphocyte receptors (VLRs) of jawless vertebrates such as lamprey and hagfish are composed of highly diverse modular leucine-rich repeats. Each lymphocyte assembles a unique VLR by rearrangement of the germline gene. In the lamprey genome, we identify here about 850 distinct cassettes encoding leucine-rich repeat modules that serve as sequence templates for the hypervariable VLR repertoires. The data indicate a gene conversion-like process in VLR diversification. Genomic analysis suggested a link between the VLR and platelet glycoprotein receptors. Lamprey lymphocytes express two putative deaminases of the AID-APOBEC family that may be involved in VLR diversification, as indicated by in vitro mutagenesis and recombination assays. Vertebrate acquired immunity could have therefore originated from lymphocyte receptor diversification by an ancestral AID-like DNA cytosine deaminase. C1 Univ Maryland, Inst Biotechnol, Ctr Marine Biotechnol, Baltimore, MD 21202 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Russian Acad Sci, Inst Cytol & Genet, Novosibirsk 630090, Russia. Univ Rochester, Med Ctr, Dept Biostat & Computat Biol, Rochester, NY 14642 USA. Univ Nebraska Med Ctr, Eppley Inst Res Canc & Allied Dis, Omaha, NE 68198 USA. RP Pancer, Z (reprint author), Univ Maryland, Inst Biotechnol, Ctr Marine Biotechnol, 600 E Lombard St, Baltimore, MD 21202 USA. EM pancer@comb.umbi.umb.edu FU Intramural NIH HHS NR 49 TC 144 Z9 150 U1 2 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD JUN PY 2007 VL 8 IS 6 BP 647 EP 656 DI 10.1038/ni1463 PG 10 WC Immunology SC Immunology GA 170YY UT WOS:000246703300019 PM 17468760 ER PT J AU Wood, KC Gladwin, MT AF Wood, Katherine C. Gladwin, Mark T. TI The hydrogen highway to reperfusion therapy SO NATURE MEDICINE LA English DT Editorial Material ID MITOCHONDRIA; RADICALS AB Hydrogen gas debuts as a selective antioxidant with explosive potential as cytoprotective therapy for ischemiareperfusion injury and stroke. C1 Natl Heart Lung & Blood Inst, Intramural Res Div, NIH, Bethesda, MD 20892 USA. RP Wood, KC (reprint author), Natl Heart Lung & Blood Inst, Intramural Res Div, NIH, Bethesda, MD 20892 USA. EM mgladwin@mail.nih.gov NR 12 TC 34 Z9 43 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUN PY 2007 VL 13 IS 6 BP 673 EP 674 DI 10.1038/nm0607-673 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 176KQ UT WOS:000247084300017 PM 17554332 ER PT J AU Amadi-Obi, A Yu, CR Liu, XB Mahdi, RM Clarke, GL Nussenblatt, RB Gery, I Lee, YS Egwuagu, CE AF Amadi-Obi, Ahjoku Yu, Cheng-Rong Liu, Xuebin Mahdi, Rashid M. Clarke, Grace Levy Nussenblatt, Robert B. Gery, Igal Lee, Yun Sang Egwuagu, Charles E. TI T(H)17 cells contribute to uveitis and scleritis and are expanded by IL-2 and inhibited by IL-27/STAT1 SO NATURE MEDICINE LA English DT Article ID EXPERIMENTAL AUTOIMMUNE UVEITIS; CD4(+) T-CELLS; BEHCETS-DISEASE; TH1 DIFFERENTIATION; RECEPTOR ANTAGONIST; FAMILY CYTOKINES; INDUCTION; MICE; ENCEPHALOMYELITIS; INTERLEUKIN-12 AB T-helper type 17 cells (T(H)17) are implicated in rodent models of immune- mediated diseases. Here we report their involvement in human uveitis and scleritis, and validate our findings in experimental autoimmune uveoretinitis (EAU), a model of uveitis. T(H)17 cells were present in human peripheral blood mononuclear cells (PBMC), and were expanded by interleukin (IL)- 2 and inhibited by interferon (IFN)-alpha. Their numbers increased during active uveitis and scleritis and decreased following treatment. IL-17 was elevated in EAU and upregulated tumor necrosis factor (TNF)- a in retinal cells, suggesting a mechanism by which T(H)17 may contribute to ocular pathology. Furthermore, IL-27 was constitutively expressed in retinal ganglion and photoreceptor cells, was upregulated by IFN-gamma and inhibited proliferation of T(H)17. These findings suggest that T(H)1 cells may mitigate uveitis by antagonizing the T(H)17 phenotype through the IFN-gamma mediated induction of IL- 27 in target tissue. The finding that IL-2 promotes T(H)17 expansion provides explanations for the efficacy of IL- 2R antibody therapy in uveitis, and suggests that antagonism of T(H)17 by IFN-gamma and/ or IL- 27 could be used for the treatment of chronic inflammation. C1 NEI, NIH, Mol Immunol Sect, Bethesda, MD 20892 USA. NEI, NIH, Clin Immunol Sect, Bethesda, MD 20892 USA. NEI, NIH, Expt Immunol Sect, Bethesda, MD 20892 USA. RP Egwuagu, CE (reprint author), NEI, NIH, Mol Immunol Sect, Bethesda, MD 20892 USA. EM egwuaguc@nei.nih.gov FU Intramural NIH HHS [Z01 EY000262-12] NR 46 TC 458 Z9 487 U1 2 U2 14 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD JUN PY 2007 VL 13 IS 6 BP 711 EP 718 DI 10.1038/nm1585 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 176KQ UT WOS:000247084300034 PM 17496900 ER PT J AU Samanez-Larkin, GR Gibbs, SEB Khanna, K Nielsen, L Carstensen, LL Knutson, B AF Samanez-Larkin, Gregory R. Gibbs, Sasha E. B. Khanna, Kabir Nielsen, Lisbeth Carstensen, Laura L. Knutson, Brian TI Anticipation of monetary gain but not loss in healthy older adults SO NATURE NEUROSCIENCE LA English DT Article ID DECISION-MAKING; BRAIN; AGE; FMRI; VISUALIZATION; COGNITION; OUTCOMES AB Although global declines in structure have been documented in the aging human brain, little is known about the functional integrity of the striatum and prefrontal cortex in older adults during incentive processing. We used event-related functional magnetic resonance imaging to determine whether younger and older adults differed in both self-reported and neural responsiveness to anticipated monetary gains and losses. The present study provides evidence for intact striatal and insular activation during gain anticipation with age, but shows a relative reduction in activation during loss anticipation. These findings suggest that there is an asymmetry in the processing of gains and losses in older adults that may have implications for decision-making. C1 Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. Univ Calif Berkeley, Helen Wills Neurosci Inst, Berkeley, CA 94720 USA. NIA, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. Stanford Ctr Longev, Stanford, CA 94305 USA. Stanford Univ, Inst Neurosci, Stanford, CA 94305 USA. RP Samanez-Larkin, GR (reprint author), Stanford Univ, Dept Psychol, Bldg 420,Jordan Hall, Stanford, CA 94305 USA. EM glarkin@stanford.edu RI Samanez-Larkin, Gregory/A-1139-2007; OI Samanez-Larkin, Gregory/0000-0001-7846-3804; Knutson, Brian/0000-0002-7669-426X FU NIA NIH HHS [P30 AG017253-09, AG008816, AG017253, AG024957, P30 AG017253, P30 AG024957, P30 AG024957-04, R01 AG008816, R37 AG008816, R37 AG008816-17] NR 30 TC 173 Z9 178 U1 2 U2 13 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD JUN PY 2007 VL 10 IS 6 BP 787 EP 791 DI 10.1038/nn1894 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 172JI UT WOS:000246799800022 PM 17468751 ER PT J AU Li, G Zou, LY Jack, CR Yang, YH Yang, ES AF Li, Geng Zou, Liangyu Jack, Clifford R., Jr. Yang, Yihong Yang, Edward S. TI Neuroprotective effect of Coenzyme Q10 on ischemic hemisphere in aged mice with mutations in the amyloid precursor protein SO NEUROBIOLOGY OF AGING LA English DT Article DE APP/PS1 double transgenic mice; antioxidant; stroke; Alzheimer's disease; cerebral infarction ID FOCAL CEREBRAL-ISCHEMIA; ALZHEIMERS-DISEASE; PARKINSONS-DISEASE; RESPIRATORY-CHAIN; BRAIN INFARCTION; GLOBAL-ISCHEMIA; MR MICROSCOPY; RAT-BRAIN; Q(10); DEMENTIA AB This study was designed to test whether Coenzyme Q10 (CoQ10) supplementation has neuroprotective effect in aged, double-transgenic amyloid precursor protein (APP)/presenilin 1 (PS1), single transgenic APP and PS1 mice exposed to ischemic injury of the brain. Forty-eight mice (12 each of APP/PS1, APP, PS1 and wild-type) were studied. Half of each genotype groups (n = 6 per group) was treated with CoQ10 (1200 mg/kg/day) after ischemic injury and the other half with placebo. Magnetic resonance (MR) images were used to measure the volume of induced infarction (TFV), as well as the volume of the hemispheres and hippocampi. Significantly greater volumes of infarction and lesser volumes of hemisphere/hippocampus on the ischemic side were observed in APP/PS1 and APP mice than in PS1 and wild-type mice. This is consistent with amplification of the effect of ischemia in APP carriers. After 28 days of CoQ10 treatment, APP/PS1 or APP mutations have smaller infarct volumes, while the volumes of hemisphere and hippocampus on the infarcted side were larger than those treated with placebo. No differences between CoQ10- and placebo-treated groups in volumes of infarct, hemisphere and hippocampus were observed in PS1 and wild-type mice. We conclude that CoQ10 has a protective effect on the brain from infarction and atrophy induced by ischemic injury in aged and susceptible transgenic mice. (c) 2006 Elsevier Inc. All rights reserved. C1 Univ Hong Kong, Fac Med, Jockey Club MRI Ctr, Hong Kong, Hong Kong, Peoples R China. Harbin Med Coll, Affiliated Hosp 1, Dept Neurol, Harbin, Peoples R China. Mayo Clin & Mayo Fdn, Dept Diagnost Radiol, Rochester, MN 55905 USA. NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. RP Li, G (reprint author), Univ Hong Kong, Fac Med, Jockey Club MRI Ctr, Room 204,Chow Yei Ching Bldg,Pokfulam Rd, Hong Kong, Hong Kong, Peoples R China. EM ligeng@eee.hku.hk RI Jack, Clifford/F-2508-2010 OI Jack, Clifford/0000-0001-7916-622X NR 45 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 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUN PY 2007 VL 28 IS 6 BP 877 EP 882 DI 10.1016/j.neurobiolaging.2006.05.005 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 164SB UT WOS:000246253300008 PM 16806588 ER PT J AU Moffat, SD Resnick, SM AF Moffat, Scott D. Resnick, Susan M. TI Long-term measures of free testosterone predict regional cerebral blood flow patterns in elderly men SO NEUROBIOLOGY OF AGING LA English DT Article DE testosterone; steroid hormones PET; regional cerebral blood flow; aging; neuroimaging ID MILD COGNITIVE IMPAIRMENT; HEALTH INITIATIVE MEMORY; OLDER MEN; POSTMENOPAUSAL WOMEN; HORMONE REPLACEMENT; ALZHEIMERS-DISEASE; ANDROGEN RECEPTOR; RAT-BRAIN; STEROIDS; HIPPOCAMPUS AB We previously reported that high circulating free testosterone (T) was associated with better performance on tests of memory, executive function, and spatial ability, and with a reduced risk for Alzheimer's disease. In this study, we report that free T levels, measured on multiple occasions over 14 years, predict regional cerebral blood flow (rCBF) measured by PET in 40 older men. Voxel-based regression, indicated that higher Free T was associated with increased rCBF in the hippocampus bilaterally (extending to the parahippocampal gyrus on the right), anterior cingulate gyrus, and right inferior frontal cortex. Total T concentrations were positively correlated with rCBF in the left putamen, bilateral thalamus, and left inferior frontal cortex and negatively correlated with amygdala rCBF bilaterally. These findings suggest that endogenous T influences brain physiology in regions critical for memory and attention and provide one mechanism through which T may affect cognitive function. Published by Elsevier Inc. C1 NIA, Lab Personal & Cognit, Intramural Res Program, Baltimore, MD 21224 USA. Wayne State Univ, Inst Gerontol, Detroit, MI 48202 USA. Wayne State Univ, Dept Psychol, Detroit, MI 48202 USA. RP Resnick, SM (reprint author), NIA, Lab Personal & Cognit, Ctr Gerontol Res, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM resnicks@grc.nia.nih.gov FU Intramural NIH HHS [Z01 AG000191-11]; NIA NIH HHS [N01-AG-3-2124] NR 42 TC 20 Z9 21 U1 3 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD JUN PY 2007 VL 28 IS 6 BP 914 EP 920 DI 10.1016/j.neurobiolaging.2006.04.001 PG 7 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 164SB UT WOS:000246253300013 PM 16698125 ER PT J AU Zhou, Y Resnick, SM Ye, WG Fan, H Holt, DP Klunk, WE Mathis, CA Dannals, R Wong, DF AF Zhou, Yun Resnick, Susan M. Ye, Weiguo Fan, Hong Holt, Daniel P. Klunk, William E. Mathis, Chester A. Dannals, Robert Wong, Dean F. TI Using a reference tissue model with spatial constraint to quantify [C-11]Pittsburgh compound BPET for early diagnosis of Alzheimer's disease SO NEUROIMAGE LA English DT Article ID POSITRON-EMISSION-TOMOGRAPHY; DISTRIBUTION VOLUME RATIOS; MILD COGNITIVE IMPAIRMENT; BETA-AMYLOID PLAQUES; COMPARTMENTAL-MODELS; DYNAMIC PET; NEUROFIBRILLARY TANGLES; PARAMETRIC IMAGES; BRAIN-TUMORS; OLDER-ADULTS AB Introduction: Reference tissue model (RTM) is a compartmental modeling approach that uses reference tissue time activity curve (TAC) as input for quantification of ligand-receptor dynamic PET without blood sampling. There are limitations in applying the RTM for kinetic analysis of PET studies using [C-11]Pittsburgh compound B ([C-11]PIB). For region of interest (ROI) based kinetic modeling, the low specific binding of [C-11]PIB in a target ROI can result in a high linear relationship between the output and input. This condition may result in amplification of errors in estimates using RTM. For pixel-wise quantification, due to the high noise level of pixel kinetics, the parametric images generated by RTM with conventional linear or nonlinear regression may be too noisy for use in clinical studies. Methods: We applied RTM with parameter coupling and a simultaneous fitting method as a spatial constraint for ROI kinetic analysis. Three RTMs with parameter coupling were derived from a classical compartment model with plasma input: an RTM of 4 parameters (R], k '(2R), k(4), BP) (RTM4P); an RTM of 5 parameters (R-1, k(2R), NS, k(6), BP) (RTM5P); and a simplified RTM (SRTM) of 3 parameters (R-1, k '(2R), BP) (RTM3P). The parameter sets [k '(2R), k(4)], [k(2R), NS, k(6)], and k '(2R) are coupled among ROIs for RTM4P, RTM5P, and RTM3P, respectively. A linear regression with spatial constraint (LRSC) algorithm was applied to the SRTM for parametric imaging. Logan plots were used to estimate the distribution volume ratio (DVR) (=1+BP (binding potential)) in ROI and pixel levels. Ninety-minute [C-11]PIB dynamic PET was performed in 28 controls and 6 individuals with mild cognitive impairment (MCI) on a GE Advance scanner. ROIs of cerebellum (reference tissue) and 15 other regions were defined on coregistered MRIs. Results: The coefficients of variation of DVR estimates from RTM3P obtained by the simultaneous fitting method were lower by 77-89% (in striatum, frontal, occipital, parietal, and cingulate cortex) as compared to that by conventional single ROI TAC fitting method. There were no significant differences in both TAC fitting and DVR estimates between the RTM3P and the RTM4P or RTM5P. The DVR in striatum, lateral temporal, frontal and cingulate cortex for MCI group was 25% to 38% higher compared. to the control group (p <= 0.05), even in this group of individuals with generally low PIB retention. The DVR images generated by the SRTM with LRSC algorithm had high linear correlations with those from the Logan plot (R-2=0.99). Conclusion: In conclusion, the RTM3P with simultaneous fitting method is shown to be a robust compartmental modeling approach that may be useful in [C-11]PIB PET studies to detect early markers of Alzheimer's disease where specific ROIs have been hypothesized. In addition, the SRTM with LRSC algorithm may be useful in generating R-1 and DVR images for pixel-wise quantification of [C-11]PIB dynamic PET. (c) 2007 Elsevier Inc. All rights reserved. C1 Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Univ Pittsburgh, Pittsburgh, PA 15213 USA. RP Zhou, Y (reprint author), Johns Hopkins Univ, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, 601 N Caroline St,JHOC Room 3245, Baltimore, MD 21287 USA. EM yunzhou@jhmi.edu RI Mathis, Chester/A-8607-2009; OI Klunk, William/0000-0001-5512-0251 FU Intramural NIH HHS [Z01 AG000191-11]; NIA NIH HHS [N01-AG-3-2124] NR 60 TC 43 Z9 43 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD JUN PY 2007 VL 36 IS 2 BP 298 EP 312 DI 10.1016/j.neuroimage.2007.03.004 PG 15 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 171WS UT WOS:000246766700005 PM 17449282 ER PT J AU Keil, A Stolarova, M Moratti, S Ray, WJ AF Keil, Andreas Stolarova, Margarita Moratti, Stephan Ray, William J. TI Adaptation in human visual cortex as a mechanism for rapid discrimination of aversive stimuli SO NEUROIMAGE LA English DT Article DE electroencephalography; classical conditioning; emotion; perception; large-scale brain oscillations; adaptation ID EXPERIENCE-DEPENDENT PLASTICITY; OSCILLATORY BRAIN ACTIVITY; AUDITORY-CORTEX; HUMAN EEG; GAMMA-RESPONSES; STARTLE REFLEX; ATTENTION; TASK; EMOTION; MODULATION AB The ability to react rapidly and efficiently to adverse stimuli is crucial for survival. Neuroscience and behavioral studies have converged to show that visual information associated with aversive content is processed quickly and accurately and is associated with rapid amplification of the neural responses. In particular, unpleasant visual information has repeatedly been shown to evoke increased cortical activity during early visual processing between 60 and 120 ms following the onset of a stimulus. However, the nature of these early responses is not well understood. Using neutral versus unpleasant colored pictures, the current report examines the time course of short-term changes in the human visual cortex when a subject is repeatedly exposed to simple grating stimuli in a classical conditioning paradigm. We analyzed changes in amplitude and synchrony of large-scale oscillatory activity across 2 days of testing, which included baseline measurements, 2 conditioning sessions, and a final extinction session. We found a gradual increase in amplitude and synchrony of very early cortical oscillations in the 20-35 Hz range across conditioning sessions, specifically for conditioned stimuli predicting aversive visual events. This increase for conditioned stimuli affected stimulus-locked cortical oscillations at a latency of around 60-90 ms and disappeared during extinction. Our findings suggest that reorganization of neural connectivity on the level of the visual cortex acts to optimize early perception of specific features indicative of emotional relevance. (c) 2007 Elsevier Inc. All rights reserved. C1 Univ Florida, NIMH, Ctr Study Emot & Attent, Gainesville, FL 32611 USA. Univ Konstanz, D-7750 Constance, Germany. Univ Complutense Madrid, Madrid, Spain. Penn State Univ, University Pk, PA 16802 USA. RP Keil, A (reprint author), Univ Florida, NIMH, Ctr Study Emot & Attent, POB 112766, Gainesville, FL 32611 USA. EM akeil@ufl.edu RI Stolarova, Margarita/A-3953-2009; Keil, Andreas/F-9427-2011; OI Keil, Andreas/0000-0002-4064-1924; Moratti, Stephan/0000-0003-0824-8759 FU NIMH NIH HHS [P50 MH052384, P50 MH052384-10] NR 46 TC 60 Z9 62 U1 5 U2 12 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 JUN PY 2007 VL 36 IS 2 BP 472 EP 479 DI 10.1016/j.neuroimage.2007.02.048 PG 8 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 171WS UT WOS:000246766700021 PM 17451974 ER PT J AU Olive, M Armstrong, J Miralles, F Pou, A Fardeau, M Gonzalez, L Martinez, F Fischer, D Matos, JAM Shatunov, A Goldfarb, L Ferrer, I AF Olive, Montse Armstrong, Judith Miralles, Francesc Pou, Adolf Fardeau, Michel Gonzalez, Laura Martinez, Francesca Fischer, Dirk Martinez Matos, Juan Antonio Shatunov, Alexey Goldfarb, Lev Ferrer, Isidre TI Phenotypic patterns of desminopathy associated with three novel mutations in the desmin gene SO NEUROMUSCULAR DISORDERS LA English DT Article DE myofibrillar myopathy; desminopathy; DES mutations; phenotype; muscle imaging ID DILATED CARDIOMYOPATHY; INTERMEDIATE-FILAMENTS; AUTOSOMAL-DOMINANT; SKELETAL MYOPATHY; DOMAIN; ACCUMULATION; DISEASE; DENSE AB Desminopathy represents a subgroup of myofibrillar myopathies caused by mutations in the desmin gene. Three novel disease-associated mutations in the desmin gene were identified in unrelated Spanish families affected by cardioskeletal myopathy. A selective pattern of muscle involvement, which differed from that observed in myofibrillar myopathy resulting from mutations in the myotilin gene, was observed in each of the three families with novel mutations and each of three desminopathy patients with known desmin mutations. Prominent joint retractions at the ankles and characteristic nasal speech were observed early in the course of illness. These findings suggest that muscle imaging in combination with routine clinical and pathological examination may be helpful in distinguishing desminopathy from other forms of myofibrillar myopathy and ordering appropriate molecular investigations. (c) 2007 Elsevier B.V. All rights reserved. C1 Bellvitge Hosp, Inst Neuropatol, IDIBELL, Barcelona, Spain. Hosp Son Dureta, Serv Neurol, Palma de Mallorca, Spain. Hosp del Mar, Serv Neurol, Barcelona, Spain. Grp Hosp Pitie Salpetriere, Inst Myol, F-75634 Paris, France. Bellvitge Hosp, Serv Radiol, IDIBELL, Barcelona, Spain. Kantonsspital, Muskelzentrum ALS Clin, St Gallen, Switzerland. Bellvitge Hosp, Serv Neurol, IDIBELL, Barcelona, Spain. NINDS, NIH, Bethesda, MD 20892 USA. RP Olive, M (reprint author), Bellvitge Hosp, Inst Neuropatol, IDIBELL, Hospitalet Llobregat, Barcelona, Spain. EM 25169mop@comb.es RI Shatunov, Aleksey/E-6946-2011; OI Olive, Montse/0000-0001-5727-0165 FU Intramural NIH HHS [Z01 NS002973-10] NR 29 TC 30 Z9 32 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-8966 J9 NEUROMUSCULAR DISORD JI Neuromusc. Disord. PD JUN PY 2007 VL 17 IS 6 BP 443 EP 450 DI 10.1016/j.nmd.2007.02.009 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 186CY UT WOS:000247757900003 PM 17418574 ER PT J AU Shrimpton, AE Schelper, RL Linke, RP Hardy, J Crook, R Dickson, DW Ishizawa, T Davis, RL AF Shrimpton, Antony E. Schelper, Robert L. Linke, Reinhold P. Hardy, John Crook, Richard Dickson, Dennis W. Ishizawa, Takashi Davis, Richard L. TI A presenilin 1 mutation (L420R) in a family with early onset Alzheimer disease, seizures and cotton wool plaques, but not spastic paraparesis SO NEUROPATHOLOGY LA English DT Article DE Alzheimer disease; amyloid beta protein; presenilin 1; senile plaques; spastic paraparesis ID MISSENSE MUTATIONS; GENE AB Over 100 mutations in the presenilin-1 gene (PSEN1) have been shown to result in familial early onset Alzheimer disease (EOAD), but only a relatively few give rise to plaques with an appearance like cotton wool (CWP) and/or spastic paraparesis (SP). A family with EOAD, seizures and CWP was investigated by neuropathological study and DNA sequencing of the PSEN1 gene. A beta was identified in leptomeningeal vessels and in cerebral plaques. A single point mutation, p.L420R (g.1508T > G) that gives rise to a missense mutation in the eighth transmembrane (TM8) domain of PS1 was identified in two affected members of the family. p.L420R (g.1508T > G) is the mutation responsible for EOAD, seizures and CWP without SP in this family. C1 SUNY Upstate Med Univ, Dept Pathol, Syracuse, NY 13210 USA. Reference Ctr Amyloid Dis, Martinsried, Germany. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Mayo Clin Jacksonville, Dept Neurosci, Jacksonville, FL 32224 USA. RP Shrimpton, AE (reprint author), SUNY Upstate Med Univ, Dept Pathol, 750 E Adams St, Syracuse, NY 13210 USA. EM shrimpta@upstate.edu RI Hardy, John/C-2451-2009; OI Dickson, Dennis W/0000-0001-7189-7917 FU Medical Research Council [G0701075] NR 16 TC 25 Z9 25 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0919-6544 J9 NEUROPATHOLOGY JI Neuropathology PD JUN PY 2007 VL 27 IS 3 BP 228 EP 232 DI 10.1111/j.1440-1789.2007.00766.x PG 5 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 170TC UT WOS:000246686200003 PM 17645236 ER PT J AU Crawley, JN Chen, T Puri, A Washburn, R Sullivan, TL Hill, JM Young, NB Nadler, JJ Moy, SS Young, LJ Caldwell, HK Young, WS AF Crawley, Jacqueline N. Chen, Thomas Puri, Amit Washburn, Richard Sullivan, Timothy L. Hill, Joanna M. Young, Nancy B. Nadler, Jessica J. Moy, Sheryl S. Young, Larry J. Caldwell, Heather K. Young, W. Scott TI Social approach behaviors in oxytocin knockout mice: Comparison of two independent lines tested in different laboratory environments SO NEUROPEPTIDES LA English DT Article DE social interaction; knockout mice; autism; sociability; social memory; olfaction; neuropeptide ID OVEREXPRESSING TRANSGENIC MICE; INBRED MOUSE STRAINS; AUTISTIC DISORDER; TASKS RELEVANT; ANIMAL-MODELS; GENETICS; DEFICITS; RECOGNITION; VASOPRESSIN; PHENOTYPE AB Oxytocin mediates social affiliation behaviors and social memory in rodents. It has been suggested that disruptions in oxytocin contribute to the deficits in reciprocal social interactions that characterize autism. The present experiments employed a new social approach task for mice which is designed to detect low levels of sociability, representing the first diagnostic criterion for autism. Two lines of oxytocin knockout mice were tested, the National Institute of Mental Health line in Bethesda, and the Baylor/Emory line at the University of North Carolina in Chapel Hill. Similar methods were used for each line to evaluate tendencies to spend time with a stranger mouse versus with an inanimate novel object with no social valence. Adult C57BL/6J males were tested identically, as controls to confirm the robustness of the methods used in the social task. Comprehensive phenotyping of general health, neurological reflexes, olfactory and other sensory abilities, and motor functions was employed to assess both lines. No genotype differences were detected in any of the control measures for either line. Normal sociability, measured as time spent with a novel stranger mouse as compared to time spent with a novel object, was seen in both the NIMH and the Baylor/Emory lines of oxytocin null mutants, heterozygotes.. and wild-type littermate controls. Normal preference for social novelty, measured as time spent with a second novel stranger as compared to time spent with a more familiar mouse, was seen in both the NIMH and the Baylor/Emory lines of oxytocin null mutants, heterozygotes, and wild-type littermate controls, with minor exceptions. Similar behavioral results from two independent targeted gene mutations. generated with different targeting vectors, bred on different genetic backgrounds, and tested in different laboratory environments, corroborates the negative findings on sociability in oxytocin mutant mice. Intact tendencies to spend time with another mouse versus with a novel object, in both lines of oxytocin knockouts, supports an interpretation that oxytocin plays a highly specific role in social memory, but is not essential for general spontaneous social approach in mice. (C) 2007 Elsevier Ltd. All rights reserved. C1 NIMH, Intramural Res Program, Lab Behav Neurosci, Bethesda, MD 20892 USA. Univ N Carolina, Sch Med, Mouse Behav Phenotyping Lab, Neurodev Disorders Res Ctr, Chapel Hill, NC USA. Univ N Carolina, Sch Med, Autism Res Ctr, Chapel Hill, NC USA. Univ N Carolina, Sch Med, Dept Genet, Chapel Hill, NC USA. Emory Univ, Sch Med, Yerkes Natl Primate Ctr, Ctr Behav Neurosci, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Yerkes Natl Primate Ctr, Dept Psychiat, Atlanta, GA 30322 USA. NIMH, Intramural Res Program, Sect Neural Gene Express, Bethesda, MD 20892 USA. RP Crawley, JN (reprint author), NIMH, Intramural Res Program, Lab Behav Neurosci, Bethesda, MD 20892 USA. EM crawleyj@intra.nimh.nih.gov RI Young, W Scott/A-9333-2009 OI Young, W Scott/0000-0001-6614-5112 FU Intramural NIH HHS; NICHD NIH HHS [P30 HD 03110]; NIMH NIH HHS [U54 MH66418] NR 69 TC 117 Z9 118 U1 3 U2 20 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4179 J9 NEUROPEPTIDES JI Neuropeptides PD JUN PY 2007 VL 41 IS 3 BP 145 EP 163 DI 10.1016/j.npep.2007.02.002 PG 19 WC Endocrinology & Metabolism; Neurosciences SC Endocrinology & Metabolism; Neurosciences & Neurology GA 175UY UT WOS:000247040700003 PM 17420046 ER PT J AU Gould, TD O'Donnell, KC Picchini, AM Manji, HK AF Gould, Todd D. O'Donnell, Kelley C. Picchini, Alyssa M. Manji, Husseini K. TI Strain differences in lithium attenuation of d-amphetamine-induced hyperlocomotion: A mouse model for the genetics of clinical response to lithium SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE hyperactivity; endophenotype; bipolar disorder; stimulant; manic-depressive illness; depression ID INDUCED LOCOMOTOR STIMULATION; GLYCOGEN-SYNTHASE KINASE-3; PLACEBO-CONTROLLED TRIAL; OPEN-FIELD ACTIVITY; BIPOLAR DISORDER; NUCLEUS-ACCUMBENS; INBRED STRAINS; BRAIN; DOPAMINE; RATS AB Lithium attenuation of stimulant-induced hyperlocomotion is a rodent model that may be useful both to understand the mechanism of the therapeutic action of lithium and to develop novel lithium-mimetic compounds. To lay the foundation for future investigations into the neurobiology and genetics of lithium as a therapeutic agent, we studied the effect of lithium on d-amphetamine-induced hyperlocomotion in 12 ( 3 outbred) mouse strains. In our initial screening, mice received either ( 1) no drugs, ( 2) LiCl only, ( 3) d-amphetamine only, or ( 4) d-amphetamine and LiCl. Whereas there was no significant effect of LiCl alone on locomotion in any strain, there was a large degree of strain variation in the effects of LiCl combined with d-amphetamine. LiCl attenuated d-amphetamine-induced hyperlocomotion in C57BL/6J, C57BL/6Tac, Black Swiss, and CBA/J mice, whereas CD-1, FVB/NJ, SWR/J, and NIH Swiss mice, which were responsive to d-amphetamine, showed no significant effect of LiCl. d-Amphetamine-induced hyperlocomotion in the C3H/HeJ strain was increased by pretreatment with lithium. A subset of strains were treated for 4 weeks with lithium carbonate before the damphetamine challenge, and in each of these strains, lithium produced effects identical to those seen following acute administration. Strain responsiveness to lithium was not dependent upon the dose of either d-amphetamine or LiCl. Further, the results are not explained by brain lithium levels, which suggests that these behavioral responses to lithium are under the control of inherent genetic or other biological mechanisms specific to the effects of lithium on brain function. C1 NIMH, Lab Mol Pathophysiol, Mood & Anxiety Disorders Program, NIH,HHS, Bethesda, MD 20892 USA. RP Gould, TD (reprint author), NIMH, Lab Mol Pathophysiol, Mood & Anxiety Disorders Program, NIH,HHS, Bldg 35,Rm 1C-912,35 Convent Dr, Bethesda, MD 20892 USA. EM gouldt@mail.nih.gov FU Intramural NIH HHS NR 49 TC 76 Z9 77 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2007 VL 32 IS 6 BP 1321 EP 1333 DI 10.1038/sj.npp.1301254 PG 13 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 169PG UT WOS:000246603500013 PM 17151598 ER PT J AU Xu, J Mendrek, A Cohen, MS Monterosso, J Simon, S Jarvik, M Olmstead, R Brody, AL Ernst, M London, ED AF Xu, Jiansong Mendrek, Adrianna Cohen, Mark S. Monterosso, John Simon, Sara Jarvik, Murray Olmstead, Richard Brody, Arthur L. Ernst, Monique London, Edythe D. TI Effect of cigarette smoking on prefrontal cortical function in nondeprived smokers performing the stroop task SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE fMRI; tobacco; nicotine; attention; brain imaging; prefrontal cortex ID ABSTINENT COCAINE ABUSERS; ANTERIOR CINGULATE CORTEX; SELECTIVE ATTENTION; COGNITIVE PERFORMANCE; INTRAVENOUS NICOTINE; NEURAL MECHANISMS; BRAIN ACTIVATION; SIGNAL RESPONSE; INTERFERENCE; FMRI AB Some reports indicate that cigarette smoking can help smokers focus attention, even when they have not abstained from smoking for a substantial period of time (eg, > 1 h). Understanding the mechanisms by which smoking affects attention may help in designing smoking cessation treatments. Thirteen nonsmokers and nine smokers participated in two tests of blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). During fMRI, the participants performed the Stroop Task. There was a 15-min break between the two tests. During the break, each smoker smoked one cigarette. For smokers, the first test began 45-60 min after the last cigarette of ad libitum smoking. The differences in BOLD signal changes between Stroop conditions (ie, incongruent minus congruent) showed a group x test interaction in the right precentral sulcus, including the putative human frontal eye field (FEF). Smokers, but not nonsmokers, showed greater changes ( relative to rest) in BOLD signal in the incongruent than in the congruent condition in the first fMRI test but not in the second. Even after brief abstinence from smoking, therefore, smokers exhibit compromised functional efficiency in the right FEF and adjacent precentral sulcus in a test of selective attention; and smoking ameliorates this condition. C1 Univ Calif Los Angeles, David Geffen Sch Med, NPI Semel Inst Neurosci, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol Radiol Sci & Biomed Phys, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA 90024 USA. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90024 USA. RP London, ED (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, NPI Semel Inst Neurosci, Dept Psychiat & Biobehav Sci, 760 Westwood Plaza,C8-528, Los Angeles, CA 90024 USA. EM elondon@mednet.ucla.edu RI Cohen, Mark/C-6610-2011 OI Cohen, Mark/0000-0001-6731-4053 FU NCRR NIH HHS [M01 RR000865, M01 RR 00865]; NIDA NIH HHS [R01 DA014093, R01 DA015059, R01 DA015059-04, T32 DA007272, R01 DA020872, T32 DA 07272, R01 DA020872-02] NR 60 TC 34 Z9 34 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD JUN PY 2007 VL 32 IS 6 BP 1421 EP 1428 DI 10.1038/sj.npp.1301272 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 169PG UT WOS:000246603500022 PM 17164821 ER PT J AU Bagot, KS Heishman, SJ Moolchan, ET AF Bagot, Kara S. Heishman, Stephen J. Moolchan, Eric T. TI Tobacco craving predicts lapse to smoking among adolescent smokers in cessation treatment SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID FAGERSTROM TOLERANCE QUESTIONNAIRE; NICOTINE DEPENDENCE; WITHDRAWAL SYMPTOMS; CIGARETTE SMOKERS; ADDICTION; RELAPSE; ABSTINENCE; THERAPY; URGES; MODEL AB Previous research indicates that tobacco craving predicts relapse to smoking among adult smokers attempting to quit. We hypothesized a similar relationship between craving and lapse (any smoking following a period of abstinence) among adolescent smokers during the treatment phase of a clinical trial. A visit was considered a lapse visit if the participant reported smoking or had a carbon monoxide level of 7 ppm or greater subsequent to an abstinent visit. A total of 34 participants (mean age=14.9 years [SD=1.3]; mean cigarettes/day=18.0 [SD=7.6]; mean Fagerstrom Test for Nicotine Dependence score = 6.8 [SD = 1.34]; 65% female), were included in the present analysis of 167 treatment visits. Logistic regression analyses showed a positive relationship between degree of craving, measured by the Questionnaire on Smoking Urges, and lapse during smoking cessation treatment (p=.013). Additionally, linear regression analyses demonstrated a strong positive association between cigarettes smoked per day and craving scores (p <.001). Taken together with other data, these findings suggest that degree of craving might influence tobacco abstinence for adolescent smokers. Thus monitoring and addressing craving appears useful to increase the success of adolescent smoking cessation. C1 NIDA, Teen Tobacco Addict Treatment Res Clin, Intramural Res Program, Baltimore, MD 21224 USA. RP Moolchan, ET (reprint author), NIDA, Teen Tobacco Addict Treatment Res Clin, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM emoolcha@intra.nida.nih.gov FU Intramural NIH HHS NR 36 TC 38 Z9 38 U1 0 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD JUN PY 2007 VL 9 IS 6 BP 647 EP 652 DI 10.1080/14622200701365178 PG 6 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 186KY UT WOS:000247778800003 PM 17558821 ER PT J AU Lawrence, D Fagan, P Backinger, CL Gibson, JT Hartman, A AF Lawrence, Deirdre Fagan, Pebbles Backinger, Cathy L. Gibson, James T. Hartman, Anne TI Cigarette smoking patterns among young adults aged 18-24 years in the United States SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID INTERMITTENT SMOKERS; BRITISH DOCTORS; UNEMPLOYMENT; HEALTH; PREDICTORS; MORTALITY; CANCER; SCHOOL; WOMEN AB Most tobacco control programs focus on prevention for children or cessation for adults. Little is known about cigarette smoking among young adults. This study examined sociodemographic variables associated with current, daily, heavy, and light smoking among young adults in the United States. Data from the 1998-1999 Tobacco Use Supplement to the Current Population Survey (TUS-CPS) were used to examine cigarette smoking patterns and correlates of smoking among 15,371 young adults aged 18-24 years. We found that 26% of young adults were current smokers, 20% were daily smokers, and 80/0 were former smokers. Current smoking rates were higher among American Indians/Alaska Natives (330/4) and Whites (31%) than among other racial/ethnic groups. Compared with white-collar workers, blue-collar and service workers were more likely to report current and daily smoking. Blue-collar workers also were more likely to report heavy smoking (OR=1.97). The unemployed (those in the labor force but not currently working) and those reporting an annual household income of less than US$20,000 were more likely to report current, daily, and heavy smoking, compared with those not in the labor force and those reporting an annual household income of $20,000 or more, respectively. Young adults not currently enrolled in school were more than twice as likely to report current (OR=2.36) and daily (OR=2.90) smoking, compared with those currently enrolled in school. Differential cigarette smoking patterns by race/ethnicity, occupation, employment status, household income, and school enrollment status should be considered when developing interventions to reduce smoking among young adults. C1 NCI, Appl Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. NCI, Behav Res Program, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. IMS, Silver Spring, MD USA. RP Lawrence, D (reprint author), NCI, Appl Res Program, Div Canc Control & Populat Sci, NIH, 6130 Execut Blvd,MSC 7344,EPN 4005, Bethesda, MD 20892 USA. EM dl177n@nih.gov NR 42 TC 45 Z9 45 U1 2 U2 7 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1462-2203 J9 NICOTINE TOB RES JI Nicotine Tob. Res. PD JUN PY 2007 VL 9 IS 6 BP 687 EP 697 DI 10.1080/14622200701365319 PG 11 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 186KY UT WOS:000247778800008 PM 17558826 ER PT J AU Ritkind, JM Nagababu, E Barbiro-Michaely, E Ramasamy, S Pluta, RM Mayevsky, A AF Ritkind, Joseph M. Nagababu, Enika Barbiro-Michaely, Efrat Ramasamy, Somasundaram Pluta, Ryszard M. Mayevsky, Avraham TI Nitrite infusion increases cerebral blood flow and decreases mean arterial blood pressure in rats: A role for red cell NO SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Article DE cerebral circulation; erythrocytm nitric oxide; nitrite; vasodilation ID HYPOXIC CONDITIONS; OXIDE; BRAIN; DEOXYHEMOGLOBIN; REDUCTION; AUTOREGULATION; KINETICS; MECHANISM; INVIVO; CORD AB It has been proposed that the reduction of nitrite by red cells producing NO plays a role in the regulation of vascular tone. This hypothesis was investigated in rats by measuring the effect of nitrite infusion on mean arterial blood pressure (MAP), cerebral blood flow (CBF) and cerebrovascular resistance (CVR) in conjunction with the accumulation of red cell NO. The relative magnitude of the effects on MAP and CBF as well as the time dependent changes during nitrite infusion are used to distinguish between the effects on the peripheral circulation and the effects on the cerebral circulation undergoing cerebral autoregulation. The nitrite infusion was found to reverse the 96% increase in MAP and the 13% decrease in CBF produced by L-NAME inhibition of e-NOS. At the same time there was a 20-fold increase in oxygen stable red cell NO. Correlations of the red cell NO for individual rats support a role for red cell nitrite reduction in regulating vascular tone in both the peripheral and the cerebral circulation. Furthermore, data obtained prior to treatment is consistent with a contribution of red cell reduced nitrite in regulating vascular tone even under normal conditions. (c) 2007 Published by Elsevier Inc. C1 NIA, Mol Dynam Sect, Baltimore, MD 21224 USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Bar Ilan Univ, Mina & Everard Goodman Fac Life Sci, Ramat Gan, Israel. RP Ritkind, JM (reprint author), NIA, Mol Dynam Sect, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM rifkindj@mail.nih.gov NR 41 TC 0 Z9 0 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 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD JUN PY 2007 VL 16 IS 4 BP 448 EP 456 DI 10.1016/j.niox.2007.04.002 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 179EE UT WOS:000247271600008 ER PT J AU Wu, TY Heilman-Miller, SL Levin, JG AF Wu, Tiyun Heilman-Miller, Susan L. Levin, Judith G. TI Effects of nucleic acid local structure and magnesium ions on minus-strand transfer mediated by the nucleic acid chaperone activity of HIV-1 nucleocapsid protein SO NUCLEIC ACIDS RESEARCH LA English DT Article ID STRONG-STOP DNA; KISSING HAIRPIN COMPLEX; RECOMBINATION HOT-SPOT; ZINC-FINGER STRUCTURES; PRIMER BINDING-SITE; REVERSE TRANSCRIPTION; SECONDARY STRUCTURE; DESTABILIZING ACTIVITY; CTAR DNA; COMPLEMENTARY SEQUENCE AB HIV-1 nucleocapsid protein (NC) is a nucleic acid chaperone, which is required for highly specific and efficient reverse transcription. Here, we demonstrate that local structure of acceptor RNA at a potential nucleation site, rather than overall thermodynamic stability, is a critical determinant for the minus-strand transfer step (annealing of acceptor RNA to (2) strong-stop DNA followed by reverse transcriptase (RT)-catalyzed DNA extension). In our system, destabilization of a stem-loop structure at the 50 end of the transactivation response element (TAR) in a 70-nt RNA acceptor (RNA 70) appears to be the major nucleation pathway. Using a mutational approach, we show that when the acceptor has a weak local structure, NC has little or no effect. In this case, the efficiencies of both annealing and strand transfer reactions are similar. However, when NC is required to destabilize local structure in acceptor RNA, the efficiency of annealing is significantly higher than that of strand transfer. Consistent with this result, we find that Mg 21 (required for RT activity) inhibits NC-catalyzed annealing. This suggests that Mg 21 competes with NC for binding to the nucleic acid substrates. Collectively, our findings provide new insights into the mechanism of NC-dependent and -independent minus-strand transfer. C1 NICHHD, Sect Viral Gene Regulat, Mol Genet Lab, Bethesda, MD 20892 USA. RP Levin, JG (reprint author), NICHHD, Sect Viral Gene Regulat, Mol Genet Lab, Bethesda, MD 20892 USA. EM levinju@mail.nih.gov FU Intramural NIH HHS NR 82 TC 22 Z9 22 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUN PY 2007 VL 35 IS 12 BP 3974 EP 3987 DI 10.1093/nar/gkm375 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 186ZS UT WOS:000247817700010 PM 17553835 ER PT J AU Wong, HK Muftuoglu, M Beck, G Imam, SZ Bohr, VA Wilson, DM AF Wong, Heng-Kuan Muftuoglu, Meltem Beck, Gad Imam, Syed Z. Bohr, Vilhelm A. Wilson, David M., III TI Cockayne syndrome B protein stimulates apurinic endonuclease 1 activity and protects against agents that introduce base excision repair intermediates SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RNA-POLYMERASE-II; TRANSCRIPTION-COUPLED REPAIR; HUMAN APURINIC ENDONUCLEASE; ABASIC SITE RECOGNITION; STRAND BREAK REPAIR; CSB GENE-PRODUCT; DNA-REPAIR; XERODERMA-PIGMENTOSUM; POLY(ADP-RIBOSE) POLYMERASE; MAJOR HUMAN AB The Cockayne syndrome B (CSB) protein-defective in a majority of patients suffering from the rare autosomal disorder CS-is a member of the SWI2/SNF2 family with roles in DNA repair and transcription. We demonstrate herein that purified recombinant CSB and the major human apurinic/apyrimidinic (AP) endonuclease, APE1, physically and functionally interact. CSB stimulates the AP site incision activity of APE1 on normal (i.e. fully paired) and bubble AP-DNA substrates, with the latter being more pronounced ( =up to 6-fold). This activation is ATP-independent, and specific for the human CSB and full-length APE1 protein, as no CSB-dependent stimulation was observed with Escherichia coli endonuclease IV or an N-terminal truncated APE1 fragment. CSB and APE1 were also found in a common protein complex in human cell extracts, and recombinant CSB, when added back to CSB-deficient whole cell extracts, resulted in increased total AP site incision capacity. Moreover, human fibroblasts defective in CSB were found to be hypersensitive to both methyl methanesulfonate (MMS) and 5-hydroxymethyl 20-deoxyuridine, agents that introduce base excision repair (BER) DNA substrates/intermediates. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Univ Texas, Hlth Sci Ctr, S Texas Vet Hlth Care Syst, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Pharmacol, San Antonio, TX 78229 USA. RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM wilsonda@grc.nia.nih.gov FU Intramural NIH HHS NR 81 TC 63 Z9 66 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUN PY 2007 VL 35 IS 12 BP 4103 EP 4113 DI 10.1093/nar/gkm404 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 186ZS UT WOS:000247817700022 PM 17567611 ER PT J AU Clark, AB Deterding, L Tomer, KB Kunkel, TA AF Clark, Alan B. Deterding, Leesa Tomer, Kenneth B. Kunkel, Thomas A. TI Multiple functions for the N-terminal region of Msh6 SO NUCLEIC ACIDS RESEARCH LA English DT Article ID CELL NUCLEAR ANTIGEN; REPAIR PROTEIN MUTS; DNA MISMATCH REPAIR; SACCHAROMYCES-CEREVISIAE; COLORECTAL-CANCER; MUTATIONS; YEAST; RECOMBINATION; RECOGNITION; COMPLEXES AB The eukaryotic mismatch repair protein Msh6 shares five domains in common with other MutS members. However, it also contains several hundred additional residues at its N-terminus. A few of these residues bind to PCNA, but the functions of the other amino acids in the N-terminal region (NTR) are unknown. Here we demonstrate that the Msh6 NTR binds to duplex DNA in a salt-sensitive, mismatch-independent manner. Partial proteolysis, DNA affinity chromatography and mass spectrometry identified a fragment comprised of residues 228-299 of yeast Msh6 that binds to DNA and is rich in positively charged residues. Deleting these residues, or replacing lysines and arginines with glutamate, reduces DNA binding in vitro and elevates spontaneous mutation rates and resistance to MNNG treatment in vivo. Similar in vivo defects are conferred by alanine substitutions in a highly conserved motif in the NTR that immediately precedes domain I of MutS proteins, the domain that interacts with mismatched DNA. These data suggest that, in addition to PCNA binding, DNA binding and possibly other functions in the amino terminal region of Msh6 are important for eukaryotic DNA mismatch repair and cellular response to alkylation damage. C1 Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Kunkel, TA (reprint author), Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov RI Tomer, Kenneth/E-8018-2013 FU Intramural NIH HHS NR 24 TC 15 Z9 16 U1 3 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD JUN PY 2007 VL 35 IS 12 BP 4114 EP 4123 DI 10.1093/nar/gkm409 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 186ZS UT WOS:000247817700023 PM 17567610 ER PT J AU Lykidis, D Van Noorden, S Armstrong, A Spencer-Dene, B Li, J Zhuang, ZP Stamp, GWH AF Lykidis, Dimitrios Van Noorden, Susan Armstrong, Alan Spencer-Dene, Bradley Li, Jie Zhuang, Zhengping Stamp, Gordon W. H. TI Novel zinc-based fixative for high quality DNA, RNA and protein analysis SO NUCLEIC ACIDS RESEARCH LA English DT Article ID EMBEDDED TISSUES; PRESERVATION; EXTRACTION; AMPLIFICATION; HOPE AB We have developed a reliable, cost-effective and non-toxic fixative to meet the needs of contemporary molecular pathobiology research, particularly in respect of RNA and DNA integrity. The effects of 25 different fixative recipes on the fixed quality of tissues from C57BL/6 mice were investigated. Results from IHC, PCR, RT-PCR, RNA Agilent Bioanalyser and Real-Time PCR showed that a novel zinc-based fixative (Z7) containing zinc trifluoroacetate, zinc chloride and calcium acetate was significantly better than the standard zinc-based fixative (Z2) and neutral buffered formalin (NBF) for DNA, RNA and protein preservation. DNA sequences up to 2.4 kb in length and RNA fragments up to 361 bp in length were successfully amplified from Z7 fixed tissues, as demonstrated by PCR, RT-PCR and Real-Time PCR. Total protein analysis was achieved using 2-D gel electrophoresis. In addition, nucleic acids and proteins were very stable over a 6-14-month period. This improved, non-toxic and economical tissue fixative could be applied for routine use in pathology laboratories to permit subsequent genomic/proteomic studies. C1 Univ London Imperial Coll Sci Technol & Med, Div Invest Sci, Dept Histopathol, London W12 0NN, England. Univ London Imperial Coll Sci Technol & Med, Dept Chem, London SW7 2AZ, England. Canc Res UK London Res Inst, Expt Pathol Lab, Lincolns Inn Fields Labs, London WC2A 3PX, England. NINDS, Mol Pathogenesis Unit, NIH, Bethesda, MD 20892 USA. RP Lykidis, D (reprint author), Univ London Imperial Coll Sci Technol & Med, Div Invest Sci, Dept Histopathol, Hammersmith Hosp Campus,Ducane Rd, London W12 0NN, England. EM dimitrios.lykidis00@ic.ac.uk NR 11 TC 41 Z9 41 U1 1 U2 16 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 JUN PY 2007 VL 35 IS 12 AR e85 DI 10.1093/nar/gkm433 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 186ZS UT WOS:000247817700034 PM 17576663 ER PT J AU Gonzalez, FJ AF Gonzalez, Frank J. TI Animal models for human risk assessment: The peroxisome proliferator-activated receptor alpha-humanized mouse SO NUTRITION REVIEWS LA English DT Article; Proceedings Paper CT 6th Nestle Nutrition Conference CY NOV 16-17, 2006 CL Mexico City``, MEXICO SP Mexican Hlth Fdn, Nestle Nutr Fund, Natl Inst Med Sci & Nutr Salvador Zubiran DE hepatocarcinogenesis; hyperlipidemic fibrate drugs; nuclear receptors; peroxisome proliferator-activated receptor alpha; PPAR alpha ID PPAR-ALPHA; MICE; SUPERFAMILY; MECHANISM; LIVER AB The hyperlipidemic fibrate drugs mediate their lipid-lowering effects through binding to and activating the peroxisome proliferator-activated receptor alpha (PPAR alpha). PPAR alpha ligands are potent hepatocarcinogens in rats and mice; after 11 months of feeding a fibrate drug, there is 100% incidence of adenomas and carcinomas. However, there is no evidence that humans chronically administered fibrates have increased cancer risk. Recent studies on PPAR alpha-humanized mice have revealed a potential mechanism for the species differences in response to PPAR alpha ligands. These models will be of great value in human risk assessment and in determining the mechanism of hepatocarcinogenesis. C1 NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bldg 37,Room 3106, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov FU Intramural NIH HHS NR 17 TC 7 Z9 7 U1 0 U2 2 PU INT LIFE SCIENCES INST NORTH AMERICA PI WASHINGTON PA ONE THOMAS CIRCLE, N W, 9TH FLOOR, WASHINGTON, DC 20005 USA SN 0029-6643 J9 NUTR REV JI Nutr. Rev. PD JUN PY 2007 VL 65 IS 6 BP S2 EP S6 DI 10.1301/nr.2007.jun.S2-S6 PN 2 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 179WN UT WOS:000247321100002 PM 17605307 ER PT J AU Tanofsky-Kraff, M Wilfley, DE Young, JF Mufson, L Yanovski, SZ Glasofer, DR Salaita, CG AF Tanofsky-Kraff, Marian Wilfley, Denise E. Young, Jami F. Mufson, Laura Yanovski, Susan Z. Glasofer, Deborah R. Salaita, Christine G. TI Preventing excessive weight gain in adolescents: Interpersonal psychotherapy for binge eating SO OBESITY LA English DT Review DE adolescents; psychosocial behavior; binge eating; weight maintenance; prevention ID COGNITIVE-BEHAVIORAL THERAPY; BODY-MASS INDEX; QUALITY-OF-LIFE; EMPIRICALLY SUPPORTED TREATMENTS; LOW CALORIE DIET; RISK-FACTORS; ANOREXIA-NERVOSA; BULIMIA-NERVOSA; FOLLOW-UP; OVERWEIGHT CHILDREN AB The most prevalent disordered eating pattern described in overweight youth is loss of control (LOC) eating, during which individuals experience an inability to control the type or amount of food they consume. LOC eating is associated cross-sectionally with greater adiposity in children and adolescents and seems to predispose youth to gain weight or body fat above that expected during normal growth, thus likely contributing to obesity in susceptible individuals. No prior studies have examined whether LOC eating can be decreased by interventions in children or adolescents without full-syndrome eating disorders or whether programs reducing LOC eating prevent inappropriate weight gain attributable to LOC eating. Interpersonal psychotherapy, a form of therapy that was designed to treat depression and has been adapted for the treatment of eating disorders, has shown efficacy in reducing binge eating episodes and inducing weight stabilization among adults diagnosed with binge eating disorder. In this paper, we propose a theoretical model of excessive weight gain in adolescents at high risk for adult obesity who engage in LOC eating and associated overeating patterns. A rationale is provided for interpersonal psychotherapy as an intervention to slow the trajectory of weight gain in at-risk youth, with the aim of preventing or ameliorating obesity in adulthood. C1 NICHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH,Dept Hlth & Human Serv, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Dept Med & Clin Physiol, Bethesda, MD 20814 USA. Washington Univ, Sch Med, Dept Psychiat, Weight Management & Eating Disorders Program, St Louis, MO 63110 USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. NIDDKD, Div Digest Dis & Nutr, NIH, US Dept HHS, Bethesda, MD USA. RP Tanofsky-Kraff, M (reprint author), NICHD, Unit Growth & Obes, Dev Endocrinol Branch, NIH,Dept Hlth & Human Serv, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM mtanofsky@usubs.edu FU Intramural NIH HHS; NICHD NIH HHS [Z01 HD000641]; NIMH NIH HHS [K24 MH070446, K24 MH070446-03] NR 131 TC 40 Z9 40 U1 7 U2 16 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1930-7381 J9 OBESITY JI Obesity PD JUN PY 2007 VL 15 IS 6 BP 1345 EP 1355 DI 10.1038/oby.2007.162 PG 11 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 180ZG UT WOS:000247405900003 PM 17557971 ER PT J AU Safaeian, M Solomon, D Wacholder, S Schiffman, M Castle, P AF Safaeian, Mahboobeh Solomon, Diane Wacholder, Sholom Schiffman, Mark Castle, Philip TI Risk of precancer and follow-up management strategies for women with human papillomavirus-negative atypical squamous cells of undetermined significance SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID ASCUS-LSIL TRIAGE; CYTOLOGIC ABNORMALITIES; CERVICAL NEOPLASIA; RANDOMIZED-TRIAL; ABSOLUTE RISK; PARTICIPANTS; PROGRAM; DNA AB Objective: To investigate the relative performances of follow-up cytology and carcinogenic human papillomavirus (HPV) DNA testing among carcinogenic HPV-negative women with atypical squamous cells of undetermined significance (ASCUS), for detection of cervical precancer. Methods: Twelve-month follow-up management strategies to detect cervical intraepithelial neoplasia grade 3 (CIN3) or worse using cytology or HPV testing or both were compared among women with HPV-negative ASCUS in the Atypical Squamous Cells of Undetermined Significance-Low-Grade Squamous Intraepithelial Lesion (ASCUS-LSIL) Triage Study. Results: Overall only 22 of 1,559 (1.4%) HPV-negative ASCUS women developed CIN grade 3 or worse during follow-up compared with 269 of 1,767 (15.2%) HPV-positive ASCUS wc men (P<.001). Because of the low risk of disease among HPV-negative ASCUS women, only 7 cases of CIN3 were diagnosed between 12 and 24 months of follow-up, limiting power to distinguish meaningful differences in sensitivity among 12-month testing strategies. The specificity of HPV testing (84%) was significantly higher than cytology using an ASCUS threshold (71%) (P<.001). Cotesting with cytology and HPV testing at 12 months resulted in even lower specificity (61%). Because cases were uncommon, the positive predictive value for subsequent CIN3 or worse was low for cytology (2.6%), Hybrid Capture 2 (3.8%), and cotesting with cytology and HPV testing (2.2%). The negative predictive value for all three management strategies was very high (99.70%, 99.82%, and 100.0% for HPV testing, cytology, or cotesting, respectively.) Conclusion: Women with HPV-negative ASCUS have very low absolute risk of subsequently detected CIN3 or worse in the subsequent 2 years, similar to women with a negative cytology in the absence of HPV testing. The results suggest that women with HPV-negative ASCUS should return to routine screening intervals which may be longer than 1 year depending on age and screening history. However, if increased surveillance is chosen, a single HPV test for carcinogenic types at 12 months has significantly higher specificity and lower referrals than cytology. C1 NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epdiemiol Branch, NIH, Rockville, MD 20852 USA. NCI, Div Canc Prevent, Hormonal & Reprod Epdiemiol Branch, NIH, Rockville, MD 20852 USA. RP Safaeian, M (reprint author), NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epdiemiol Branch, NIH, 6120 Execut Blvd,suite 550, Rockville, MD 20852 USA. EM safaeianm@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [CN-55155, CN-55158, CN-55105, CN-55157, CN-55153, CN-55159, CN-55156, CN-55154] NR 18 TC 45 Z9 48 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 JUN PY 2007 VL 109 IS 6 BP 1325 EP 1331 DI 10.1097/01.AOG.0000263461.71732.40 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 175JP UT WOS:000247010200011 PM 17540804 ER PT J AU Read, JS Cahn, P Losso, M Pinto, J Joao, E Duarte, G Cardoso, E Freimanis-Hance, L Stoszek, SK AF Read, Jennifer S. Cahn, Pedro Losso, Marcelo Pinto, Jorge Joao, Esau Duarte, Geraldo Cardoso, Edmundo Freimanis-Hance, Laura Stoszek, Sonia K. CA NIDSI Perinatal STudy Grp TI Management of human immunodeficiency virus-infected pregnant women at Latin American and Caribbean sites SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 12th Conference on Retroviruses and Opportunistic Infections CY FEB 22-25, 2005 CL Boston, MA ID GESTATIONAL AGE; HIV-1 INFECTION; NEWBORN-INFANT; TRANSMISSION; AFRICA; COHORT; HEALTH AB Objective: To describe the management of a population of human immunodeficiency virus (HIV)-infected pregnant women in Latin America and the Caribbean, and to assess factors associated with maternal viral load of 1,000 copies/mL or more and with infant HIV-1 infection. Methods: Eligibility criteria were enrollment in the prospective cohort study as of March 2006; delivery of a liveborn, singleton infant; and completion of the 6-month postpartum or postnatal visit. Results: Of 955 women enrolled in Argentina, the Bahamas, Brazil, and Mexico, 770 mother-infant pairs were eligible. At enrollment, most women were relatively healthy (87% asymptomatic, 59% with viral load less than 1,000 copies/mL, 62% with CD4(+)% of 25% or more). Most (99%) received antiretrovirals during pregnancy (56% prophylaxis, 44% treatment), and 38% delivered by cesarean before labor and before ruptured membranes. Only 18% of women had a viral load of 1,000 copies/mL or more after delivery (associated in adjusted analyses with receipt of antiretrovirals at conception, CD4(+)% [lower], viral load [higher], and country at enrollment, enrollment late in pregnancy, and inversely related to antiretroviral regimen [two nucleoside or nucleotide analogue reverse transcriptase inhibitors plus one nonnucleoside reverse transcriptase inhibitor] during pregnancy). None of the infants breastfed, and all received antiretroviral prophylaxis. Seven infants became infected (0.91%; 95% confidence interval 0.37-1.86). Low birth weight infants and those whose mothers had a low CD4(+)% at hospital discharge after delivery and were not receiving antiretrovirals at enrollment were at higher risk of HIV infection. Conclusion: Only a minority of women had a viral load of 1,000 copies/mL or more around delivery, and mother-to-child transmission of HIV occurred rarely (1%). C1 NICHHD, NIH, Bethesda, MD 20892 USA. Hosp Juan Fernandez, Buenos Aires, DF, Argentina. Hosp Gen Agudos Jose Maria Ramos Meja, Buenos Aires, DF, Argentina. Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. Hosp SErv Do Estado Rio de Janeiro, Rio De Janeiro, Brazil. Univ Sao Paulo, Sch Med, Ribeirao Preto, Brazil. Hosp Conceicao, Rockville, MD USA. RP Read, JS (reprint author), NICHHD, NIH, Execut Bldg,Room 4B11F,6100 Execut Blvd, Bethesda, MD 20892 USA. EM jennifer_read@nih.gov RI Duarte, Geraldo/J-7906-2012 FU NICHD NIH HHS [N01-HD-3-3345] NR 19 TC 29 Z9 29 U1 0 U2 3 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 JUN PY 2007 VL 109 IS 6 BP 1358 EP 1367 DI 10.1097/01.AOG.0000265211.76196.ac PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 175JP UT WOS:000247010200015 PM 17540808 ER PT J AU Kang, Y Hong, JA Chen, GA Nguyen, DM Schrump, DS AF Kang, Y. Hong, J. A. Chen, G. A. Nguyen, D. M. Schrump, D. S. TI Dynamic transcriptional regulatory complexes including BORIS, CTCF and Sp1 modulate NY-ESO-1 expression in lung cancer cells SO ONCOGENE LA English DT Article DE lung cancer; epigenetics; NY-ESO-1; BORIS; CTCF; Sp1 ID GC-RICH DNA; GENE-TRANSCRIPTION; BINDING; FAMILY; IDENTIFICATION; DEREPRESSION; EPIGENETICS; ANTIGEN; DOMAIN; P300 AB Previously, we reported that the paralogous zinc-finger proteins-CTCF and brother of the regulator of imprinted sites (BORIS), directly contribute to transcriptional regulation of NY-ESO-1 in lung cancer cells. To further examine mechanisms that mediate expression of this cancer-testis gene, we performed software-guided analysis of the NY-ESO-1 promoter region, which revealed several potential Sp1- binding motifs. Sequential 5-aza-2 ' deoxycytidine/ depsipeptide FK228 treatment markedly induced BORIS expression and enhanced nuclear translocation of Sp1 in lung cancer cells. Transient transfection assays using promoter-reporter constructs, as well as gel-shift and chromatin immunoprecipitation experiments revealed that NY-ESO-1 promoter activity coincided with occupancy of the proximal Spi-binding site in lung cancer cells. Mutations within the Sp1 recognition sequence specifi. cally eliminated binding of Sp1 to this motif in vitro, and markedly diminished NY-ESO-1 promoter activity in vivo. siRNA-mediated inhibition of Sp1 expression decreased NY-ESO-1 promoter activity, whereas knock down of CTCF expression augmented NY-ESO-1 transcription in lung cancer cells. Co-immunoprecipitation experiments indicated that Sp1 physically interacts with BORIS but not with CTCF in vivo. Collectively, these. findings suggest that BORIS recruits Sp1 to mediate de-repression of NY-ESO-1 during pulmonary carcinogenesis. C1 NCI, Ctr Canc Res, Surg Branch, Thorac Oncol Sect, Bethesda, MD 20892 USA. RP Schrump, DS (reprint author), NCI, Ctr Canc Res, Surg Branch, Thorac Oncol Sect, Bldg 10,Rm 4-3942,10 Ctr Dr, Bethesda, MD 20892 USA. EM David_Schrump@nih.gov NR 27 TC 35 Z9 36 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 JUN PY 2007 VL 26 IS 30 BP 4394 EP 4403 DI 10.1038/sj.onc.1210218 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 184CZ UT WOS:000247620000007 PM 17260018 ER PT J AU Feng, YD Wu, JH Feng, XL Tao, DD Hu, JB Qin, JC Li, XL Xiao, W Gardner, K Judge, SIV Li, QDQ Gong, JP AF Feng, Yongdong Wu, Jianhong Feng, Xiaolan Tao, Deding Hu, Junbo Qin, Jichao Li, Xiaolan Xiao, Wei Gardner, Kevin Judge, Susan I. V. Li, Qingdi Q. Gong, Jianping TI Timing of apoptosis onset depends on cell cycle progression in peripheral blood lymphocytes and lymphocytic leukemia cells SO ONCOLOGY REPORTS LA English DT Article DE apoptosis; cell cycle phase specificity; apoptotic pattern; lymphocytes; leukemia cells; Chinese medicine; Jinke ID FISSION YEAST; G1 PHASE; CHECKPOINT; PROLIFERATION; STARVATION; CONFLUENT; ONCOGENES; DEATH; PATHWAYS; KINASES AB Apoptosis results in cell death within 10 min after initiation by Bcl-2 family proteins and mitochondria; however, cells enter the apoptotic pathway at different elapsed times after being triggered. Intrinsic factors related to chemical or physical cell damage can initiate apoptosis at a specific cell cycle phase; it is not clear whether cells insulted via an extrinsic pathway also die at a specific cell cycle phase, or how apoptosis is related to cell cycle progression in cells. To illustrate the kinetic changes of apoptosis during cell cycle progression, we examined both intrinsically and extrinsically induced apoptosis in MOLT-4 and Jurkat lymphocytic leukemia cells and in cultured peripheral blood lymphocytes (PBLs) using a recently modified annexin V and propidium iodide method, which detects cell cycle-specific apoptosis. Apoptosis predominantly occurred at a specific cell cycle phase. Leukemia cells were sensitive to induction by both intrinsic (X-rays, UV light, camptothecin, arsenic trioxide, and the traditional Chinese medicine Jinke, which is an extract of Aitricularia auricula) and extrinsic factors (via Fas and TNF receptor pathways). The phase at which leukemia cells entered apoptosis depended on the nature of the insult (X-ray or UV, G1-phase; camptothecin, S-phase; arsenic, G1/S phases; Jinke, G1/S phases; and TNF or Fas ligand, G1/S phases), whereas PBLs did not exhibit such insult-dependent differences. PHA-stimulated PBLs entered apoptosis, and additional cells were recruited following additional insults, Unstimulated PBLs remained unresponsive to apoptosis, and proliferating cells became insensitive to the insults after the cell cycle checkpoint was abolished by caffeine. Confluent or starving PBLs were also unresponsive to apoptotic triggers. Thus, apoptotic cell death is a cell cycle event with most, if not all, apoptosis being initiated during a particular cell cycle phase, and changes in the cell cycle result in changes in the apoptotic pattern and schedule. The coordination of apoptosis and proliferation in cells offers a mechanism for the integration of both cell cycle and apoptotic signals. C1 NCI, Lab Receptor Biol & Gene Express, NIH, Canc Res Ctr, Bethesda, MD 20892 USA. Cent China Univ Sci & Technol, Tongji Med Coll, Ctr Canc, Tongji Hosp, Wuhan 430030, Peoples R China. Univ Maryland, Dept Neurol, Baltimore, MD 21201 USA. VA Maryland Hlth Care Syst, MS Ctr Excellence E, Baltimore, MD 21201 USA. RP Gong, JP (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Canc Res Ctr, Bldg 41,Room D305, Bethesda, MD 20892 USA. EM jpgong@tjh.tjmu.edu.cn NR 37 TC 11 Z9 14 U1 0 U2 7 PU PROFESSOR D A SPANDIDOS PI ATHENS PA 1, S MERKOURI ST, EDITORIAL OFFICE,, ATHENS 116 35, GREECE SN 1021-335X J9 ONCOL REP JI Oncol. Rep. PD JUN PY 2007 VL 17 IS 6 BP 1437 EP 1444 PG 8 WC Oncology SC Oncology GA 171ZN UT WOS:000246774000023 PM 17487402 ER PT J AU Derfoul, A Miyoshi, AD Freeman, DE Tuan, RS AF Derfoul, A. Miyoshi, A. D. Freeman, D. E. Tuan, R. S. TI Glucosamine promotes chondrogenic phenotype in both chondrocytes and mesenchymal stem cells and inhibits MMP-13 expression and matrix degradation SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE glucosamine; osteoarthritis; mesenchymal stem cells; chondrocytes; matrix metalloproteinase 13; cartilage ID HUMAN TRABECULAR BONE; ARTICULAR-CARTILAGE EXPLANTS; CHONDROITIN SULFATE; KNEE OSTEOARTHRITIS; PROGENITOR CELLS; N-ACETYLGLUCOSAMINE; GENE-EXPRESSION; IN-VITRO; DIFFERENTIATION; METAANALYSIS AB Objectives: Glucosamine (GIcN), a natural amino monosaccharide, is a constituent of glycosaminoglycans (GAGs) found in hyaline cartilage. GIcN salts constitute a new class of nutraceutical components with putative chondroprotective activity, which may target chondrocytes as well as chondroprogenitors cells, such as mesenchymal stem cells (MSCs), during cartilage turnover and repair. In the present study, we examined the effects of GIcN on chondrogenesis of human MSCs (hMSCs) and the phenotype of normal and osteoarthritic human articular chondrocytes, using an in vitro pellet culture model maintained in a defined medium. Methods: hMSCs and normal and osteoarthritic human chondrocytes grown as pellet cultures, stimulated or not with interieukin-1 beta (IL-1 beta), were treated with varying doses of GIcN. Expression of cartilage matrix genes and cartilage degrading enzymes was determined by semiquantitative and quantitative real-time reverse transcription polymerase chain reaction (RT-PCR), and by histological staining of cartilage markers, as well as sulfated GAG (sGAG) analysis and Western blotting. Results: Chondrocytes grown in the presence of serum for 11 days showed decreased expression of the cartilage matrix genes, collagen type 11 (collagen II) and aggrecan, as early as day 3, which was reversed with GIcN treatment by day 11. Both hMSCs and choncrocytes grown as pellet cultures in defined medium and treated with 100 mu M GIcN exhibited enhanced expression of collagen II and aggrecan as well as increased content of sGAG, when compared to control untreated pellets. However, high doses of GIcN (10-20 mM) were inhibitory. GIcN treatment partially blocked IL-1 beta mediated downregulation of collagen II and aggrecan expression and inhibited expression of the matrix degrading enzyme, matrix metalloproteinase 13 (MMP-13), in both chondrocytes and hMSCs undergoing chondrogenesis. Conclusions: These observations suggest that GIcN treatment enhances hMSC chondrogenesis and maintains cartilage matrix gene expression in chondrocytes, which may account for some of the reported chondroprotective properties of GIcN on cartilage. (c) 2007 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, US Dept HHS, 50 Ctr dr,Room 1503,MSC 8022, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov NR 37 TC 53 Z9 57 U1 4 U2 13 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 1063-4584 J9 OSTEOARTHR CARTILAGE JI Osteoarthritis Cartilage PD JUN PY 2007 VL 15 IS 6 BP 646 EP 655 DI 10.1016/j.joca.2007.01.014 PG 10 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 179UF UT WOS:000247314900007 PM 17337215 ER PT J AU Shaffer, JR Kammerer, CM Reich, D McDonald, G Patterson, N Goodpaster, B Bauer, DC Li, J Newman, AB Cauley, JA Harris, TB Tylavsky, F Ferrell, RE Zmuda, JM AF Shaffer, J. R. Kammerer, C. M. Reich, D. McDonald, G. Patterson, N. Goodpaster, B. Bauer, D. C. Li, J. Newman, A. B. Cauley, J. A. Harris, T. B. Tylavsky, F. Ferrell, R. E. Zmuda, J. M. CA Hlth ABC Study TI Genetic markers for ancestry are correlated with body composition traits in older African Americans SO OSTEOPOROSIS INTERNATIONAL LA English DT Article DE admixture mapping; body composition; genetic ancestry; linkage analysis; osteoporosis; single nucleotide polymorphisms (SNPs) ID BONE-MINERAL DENSITY; X-RAY ABSORPTIOMETRY; MUSCLE MASS; POPULATION-STRUCTURE; GENDER-DIFFERENCES; DISEASE GENES; WHITE WOMEN; ADMIXTURE; HEALTH; ADULTS AB Individual-specific percent European ancestry was assessed in 1,277 African Americans. We found significant correlations between proportion of European ancestry and several musculoskeletal traits, indicating that admixture mapping may be a useful strategy for locating genes affecting these traits. Introduction Genotype data for admixed populations can be used to detect chromosomal regions influencing disease risk if allele frequencies at disease-related loci differ between parental populations. We assessed evidence for differentially distributed alleles affecting bone and body composition traits in African Americans. Methods Bone mineral density (BMD) and body composition data were collected for 1,277 African and 1,790 European Americans (aged 70-79). Maximum likelihood methods were used to estimate individual-specific percent European ancestry for African Americans genotyped at 37 ancestry-informative genetic markers. Partial correlations between body composition traits and percent European ancestry were calculated while simultaneously adjusting for the effects of covariates. Results Percent European ancestry (median = 18.7%) in African Americans was correlated with femoral neck BMD in women (r = -0.18, p < 10(-5)) and trabecular spine BMD in both sexes (r = -0.18, p < 10(-5)) independently of body size, fat, lean mass, and other covariates. Significant associations of European ancestry with appendicular lean mass (r = -0.19, p < 10(-10)), total lean mass (r = -0.12, p < 10(-4)), and total body fat (r = 0.09, p < 0.002) were also observed for both sexes. Conclusions These results indicate that some population differences in body composition may be due to population-specific allele frequencies, suggesting the utility of admixture mapping for identifying susceptibility genes for osteoporosis, sarcopenia, and obesity. C1 Univ Pittsburgh, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA USA. Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. MIT, Cambridge, MA 02139 USA. Univ Pittsburgh, Dept Endocrinol, Pittsburgh, PA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NIA, Bethesda, MD 20892 USA. Univ Tennessee, Ctr Hlth Sci, Memphis, TN 38163 USA. RP Shaffer, JR (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, 130 DeSoto St, Pittsburgh, PA 15261 USA. EM john.shaffer@hgen.pitt.edu RI Cauley, Jane/N-4836-2015; Newman, Anne B./C-6408-2013 OI Cauley, Jane/0000-0003-0752-4408; Newman, Anne B./0000-0002-0106-1150 FU ASPE HHS [AE-2-1024]; Intramural NIH HHS; NCRR NIH HHS [U54 RR020278-01]; NIA NIH HHS [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] NR 33 TC 36 Z9 38 U1 1 U2 1 PU SPRINGER LONDON LTD PI ARTINGTON PA ASHBOURNE HOUSE, THE GUILDWAY, OLD PORTSMOUTH ROAD, ARTINGTON GU3 1LP, GUILDFORD, ENGLAND SN 0937-941X J9 OSTEOPOROSIS INT JI Osteoporosis Int. PD JUN PY 2007 VL 18 IS 6 BP 733 EP 741 DI 10.1007/s00198-006-0316-6 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 163QF UT WOS:000246175600003 PM 17235662 ER PT J AU Lee, YS Kim, H Brahim, JS Rowan, J Lee, G Dionne, RA AF Lee, Yun-Sil Kim, Hyungsuk Brahim, Jaime S. Rowan, Janet Lee, Gloria Dionne, Raymond A. TI Acetaminophen selectively suppresses peripheral prostaglandin E-2 release and increases COX-2 gene expression in a clinical model of acute inflammation SO PAIN LA English DT Article DE gene expression; NSAIDs; acetaminophen; selective COX-2 inhibitor ID ANTIINFLAMMATORY DRUGS; PARACETAMOL EXERTS; H SYNTHASE-1; IN-VIVO; CYCLOOXYGENASE; PAIN; INHIBITORS; IDENTIFICATION; BIOSYNTHESIS; FIBROBLASTS AB Acetaminophen is widely used for pain management as an alternative to NSAIDs and selective COX-2 inhibitors, but its action at a molecular level is still unclear. We evaluated acetaminophen's effect on PG release and the expression patterns of genes related to PG production in a clinical model of tissue injury and acute inflammation. Subjects (119 outpatients) received either 1000 mg acetaminophen, 50 mg rofecoxib (a selective COX-2 inhibitor), 30 mg ketorolac (a dual COX-1/COX-2 inhibitor), or placebo before the surgical removal of two impacted mandibular third molars. Microdialysis was used to collect inflammatory transudate from the surgical site for measurement of PGE(2) and TXB2 levels at the site of injury. Biopsies were collected to investigate the expression patterns of genes related to PG production at baseline prior to surgery and at 3 or 24 h following surgery. PGE2 release was suppressed by ketorolac, rofecoxib and acetaminophen compared to placebo at 3 h coincident with increased COX-2 gene expression in biopsies collected from the surgical site. TXB2 release was suppressed only by ketorolac. COX-2 gene expression remained elevated at 24 h with continued ketorolac and acetaminophen treatment. COX-1 gene expression was significantly down-regulated at 24 h by ketorolac, rofecoxib and acetaminophen. Acetaminophen suppression of PGE2 without inhibiting TXB2 release, when COX-2 gene expression is up-regulated, suggests that acetaminophen is a selective COX-2 inhibitor in vivo. The up-regulation of COX-2 gene and down-regulation of COX-1 gene expression suggests that acetaminophen may result in changes in COX-derived prostanoids with repeated doses. (c) 2007 Published by Elsevier B.V. on behalf of International Association for the Study of Pain. C1 Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mech Branch, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Clin Res Core, Bethesda, MD USA. Natl Inst Nursing Res, Bethesda, MD USA. Magnuson Clin Res Ctr, Dept Nursing, NIH, Bethesda, MD USA. RP Dionne, RA (reprint author), Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mech Branch, Bethesda, MD 20892 USA. EM dionner@mail.nih.gov FU Intramural NIH HHS NR 39 TC 43 Z9 44 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD JUN PY 2007 VL 129 IS 3 BP 279 EP 286 DI 10.1016/j.pain.2006.10.020 PG 8 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 179JQ UT WOS:000247286200007 PM 17175104 ER PT J AU Kim, H Dionne, RA AF Kim, Hyungsuk Dionne, Raymond A. TI Comment on Diatchenko et al. Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli. Pain 2006;125 : 216-24 SO PAIN LA English DT Letter ID SENSITIVITY; RESPONSES; DISEASES; HUMANS; GENOME C1 NINR, Lab Symptom Management, NIH, Bethesda, MD 20892 USA. RP Dionne, RA (reprint author), NINR, Lab Symptom Management, NIH, Bldg 10 CRC 2-1339,10 Ctr Dr, Bethesda, MD 20892 USA. EM dionner@mail.nih.gov FU Intramural NIH HHS [Z01 NR000015-02] NR 12 TC 7 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD JUN PY 2007 VL 129 IS 3 BP 365 EP 366 DI 10.1016/j.pain.2007.02.011 PG 2 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 179JQ UT WOS:000247286200018 PM 17407801 ER PT J AU Diatchenko, L Nackley, AG Slade, GD Belfer, I Max, MB Goldman, D Maixner, W AF Diatchenko, Luda Nackley, Andrea G. Slade, Gary D. Belfer, Inna Max, Mitchell B. Goldman, David Maixner, William TI Comment on Diatchenko et al. Catechol-O-methyltransferase gene polymorphisms are associated with multiple pain-evoking stimuli. Pain 2006;125:216-24 - Response SO PAIN LA English DT Letter ID MODALITIES C1 Univ N Carolina, Ctr Neurosensory Disorders, Chapel Hill, NC 27515 USA. Univ Adelaide, Sch Dent, Australian Res Ctr Populat Oral Hlth, Adelaide, SA 5005, Australia. NIAAA, NIH, DHHS, Rockville, MD 20852 USA. NIDCR, NIH, DHHS, Bethesda, MD USA. RP Diatchenko, L (reprint author), Univ N Carolina, Ctr Neurosensory Disorders, Chapel Hill, NC 27515 USA. EM lbdiatch@email.unc.edu RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU NIDCR NIH HHS [R01 DE016558, P01 DE007509, P01 DE007509-15, R01 DE016558-01, R01 DE016558-02, R01 DE016558-03, U01 DE017018, U01 DE017018-02]; NINDS NIH HHS [P01 NS045685, P01 NS045685-03] NR 9 TC 13 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-3959 J9 PAIN JI Pain PD JUN PY 2007 VL 129 IS 3 BP 366 EP 370 DI 10.1016/j.pain.2007.02.012 PG 5 WC Anesthesiology; Clinical Neurology; Neurosciences SC Anesthesiology; Neurosciences & Neurology GA 179JQ UT WOS:000247286200019 PM 17851590 ER PT J AU Kim, SY Walsh, MP Guimond, M Fry, TJ Mackall, CL Briggs, J Khanna, C O'Mard, DL Jones, B Aziz, N Helman, LJ AF Kim, Su Young Walsh, Meghaan P. Guimond, Martin Fry, Terry J. Mackall, Crystal L. Briggs, Joseph Khanna, Chand O'Mard, Danielle L. Jones, Barry Aziz, Nazneen Helman, Lee J. TI In vivo suppression of metastatic murine osteosarcoma SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 NIH, Pediat Oncol Branch, Bethesda, MD 20892 USA. Point Therapeut, Boston, MA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN 1 PY 2007 VL 48 IS 6 BP 601 EP 601 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 161KN UT WOS:000246013900005 ER PT J AU Giri, N Savage, S Khaghani, S Alter, BP AF Giri, Neelam Savage, Sharon Khaghani, Sara Alter, Blanche P. TI The clinical spectrum of dyskeratosis congenita SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 NCI, Clin Genet Branch DCEG, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN 1 PY 2007 VL 48 IS 6 BP 604 EP 604 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 161KN UT WOS:000246013900018 ER PT J AU Al-Rahawan, MM Alter, BP Bryant, BJ Elghetany, MT AF Al-Rahawan, Mohamad M. Alter, Blanche P. Bryant, Barbara J. Elghetany, M. Tarek TI Predictive markers of myelodysplastic syndrome in the bone marrow of patients with inherited bone marrow failure syndromes SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 NCI, DCEG, CGB, Rockville, MD USA. Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. Univ Texas, Med Branch, Dept Pathol, Galveston, TX 77550 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN 1 PY 2007 VL 48 IS 6 BP 605 EP 605 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 161KN UT WOS:000246013900019 ER PT J AU Kim, SY Garfield, SH Wincovitch, SM Hong, SH Darko, IA Li, WJ Tuan, RS Khanna, C Helman, LJ AF Kim, Su Young Garfield, Susan H. Wincovitch, Stephen M. Hong, Sony Hyeok Darko, Isaac A. Li, Wan-Ju Tuan, Rocky S. Khanna, Chand Helman, Lee J. TI A 3-dimensional blo-mimetic model of metastases SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN 1 PY 2007 VL 48 IS 6 BP 611 EP 611 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 161KN UT WOS:000246013900044 ER PT J AU Hayward, RM Patronas, NJ Baker, EH Vezina, LG Albert, PS Warren, KE AF Hayward, Robert M. Patronas, Nicholas J. Baker, Eva H. Vezina, Louis-Gilbert Albert, Paul S. Warren, Katherine E. TI Variability in the measurement of diffuse intrinsic pontine gliomas (DIPG) on magnetic resonance imaging (MRI) SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 NIH, NCI, Neuro Oncol Branch, Bethesda, MD 20892 USA. NIH, Dept Diagnost Radiol, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. NIH, Biomet Res Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN 1 PY 2007 VL 48 IS 6 BP 638 EP 638 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 161KN UT WOS:000246013900155 ER PT J AU Warren, K Steffen-Smith, E Albert, P Shimoda, K Draper, D Wolters, P AF Warren, Katherine Steffen-Smith, Emilie Albert, Paul Shimoda, Kim Draper, David Wolters, Pam TI Proton magnetic resonance spectroscopic imaging (H-1-MRSI) and neuropsychological (NP) function in cancer patients: Pilot study SO PEDIATRIC BLOOD & CANCER LA English DT Meeting Abstract C1 NIH, NCI, Bethesda, MD 20892 USA. Childrens Hosp SW Florida, Lee Mem Hlth Syst, Ft Myers, FL USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD JUN 1 PY 2007 VL 48 IS 6 BP 641 EP 641 PG 1 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 161KN UT WOS:000246013900168 ER PT J AU Darmstadt, GL Hossain, MM Jana, AK Saha, SK Choi, Y Sridhar, S Thomas, N Miller-Bell, M Edwards, D Aranda, J Willis, J Coffey, P AF Darmstadt, Gary L. Hossain, M. Monir Jana, Atanu Kumar Saha, Samir K. Choi, Yoonjoung Sridhar, S. Thomas, Niranjan Miller-Bell, Mary Edwards, David Aranda, Jacob Willis, Jefftey Coffey, Patricia TI Determination of extended-interval gentamicin dosing for neonatal patients in developing countries SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article DE extended-interval; neonatal sepsis; developing country; gentamicin; Uniject ID AMINOGLYCOSIDE PLASMA-LEVELS; REFERENCE RANGES; DOSAGE REGIMEN; INFANTS; PHARMACOKINETICS; NEPHROTOXICITY; IMMUNIZATION; ASSOCIATION; TOBRAMYCIN; CREATININE AB Background: Infectious diseases account for an estimated 36% of neonatal deaths globally. The purpose of this study was to determine safe, effective, simplified dosing regimens of gentamicin for treatment of neonatal sepsis in developing countries. Methods: Neonates with suspected sepsis in the neonatal intensive care unit (NICU) at Christian Medical College and Hospital (CMC), Vellore, India (n = 49), and Dhaka Shishu Hospital (DSH), Bangladesh (n = 59), were administered gentamicin intravenously according to the following regimens: (1) 10 mg every 48 hours for neonates < 2000 g; (2) 10 mg every 24 hours for neonates 20002249 g; and (3) 13.5 mg every 24 hours for neonates >= 2500 g. Serum gentamicin concentration (SGC) at steady state and pharmacokinetic indices were determined. Renal function was followed while under treatment and hearing was examined 6 weeks to 3 months after discharge. Results: All neonates, except 1 weighing 2000-2249 g at DSH, had a peak SGC >4 mu g/mL. Overall, 5 (10%) and 17 (29%) infants had a peak SGC level >= 12 mu g/mL from CMC and DSH, respectively, and 10 (20%) and 4 (7%) cases from CMC and DSH, respectively, had a trough SGC level >= 2 mu g/mL. However, no infant < 2000 g had a trough SGC level >= 2 mu g/mL. We found no evidence of gentamicin nephrotoxicity or ototoxicity. Conclusion: Safe, therapeutic gentamicin dosing regimens were identified for treatment of neonatal sepsis in developing country settings. Administration of these doses could be simplified through use of Uniject, a prefilled, single injection device designed to make injections safe and easy to deliver in developing country settings. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21218 USA. Dhaka Shishu Hosp, Dept Neonatol, Inst Child Hlth, Dhaka, Bangladesh. Dhaka Shishu Hosp, Dept Microbiol, Inst Child Hlth, Dhaka, Bangladesh. Christian Med Coll & Hosp, Vellore 632004, Tamil Nadu, India. Duke Univ, Dept Pharmacol, Durham, NC 27706 USA. Wayne State Univ, Dept Pharm Practice, Detroit, MI 48202 USA. Wayne State Univ, Childrens Hosp Michigan, NIH NICHD, Pediat Pharmacol Res Unit Network, Detroit, MI 48202 USA. PATH, Seattle, WA USA. RP Darmstadt, GL (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Baltimore, MD 21218 USA. EM gdarmsta@jhsph.edu NR 52 TC 17 Z9 17 U1 0 U2 2 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 JUN PY 2007 VL 26 IS 6 BP 501 EP 507 DI 10.1097/INF.0b013e318059c25b PG 7 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 174HA UT WOS:000246931600009 PM 17529867 ER PT J AU Aggarwal, R Sentz, J Miller, MA AF Aggarwal, Rakesh Sentz, John Miller, Mark A. TI Role of zinc administration in prevention of childhood diarrhea and respiratory illnesses: A meta-analysis SO PEDIATRICS LA English DT Article DE diarrhea; respiratory illness; meta-analysis; nutrition; supplementation; zinc ID RANDOMIZED CONTROLLED-TRIAL; LOW-BIRTH-WEIGHT; UNDERNOURISHED JAMAICAN CHILDREN; PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; BANGLADESHI CHILDREN; DEVELOPING-COUNTRIES; PERSISTENT DIARRHEA; PUBLICATION BIAS; IMMUNE FUNCTION AB Background. The quantified effect of zinc supplementation to prevent childhood diarrhea and respiratory illnesses is unclear. We conducted a meta- analysis of randomized, controlled trials on the subject. Methods. We searched PubMed, Science Citation Index, and the Cochrane Database of Controlled Trials and hand- searched the reference lists of identified articles. All randomized, controlled trials of zinc supplementation for >= 3 months for children < 5 years of age, using blinded assessment, were eligible. The outcome measures studied were number of episodes of illness, number of days with illness, and number of episodes of severe illness. Data from 17 studies were pooled by using random- effects and fixed- effects models for data with and without significant heterogeneity, respectively. Results. Children who received a zinc supplement had fewer episodes of diarrhea (rate ratio: 0.86) and respiratory tract infections (rate ratio: 0.92) and significantly fewer attacks of severe diarrhea or dysentery (rate ratio: 0.85), persistent diarrhea (rate ratio: 0.75), and lower respiratory tract infection or pneumonia (rate ratio: 0.80) than did those who received placebo. They also had significantly fewer total days with diarrhea (rate ratio: 0.86) but not days with respiratory illness (rate ratio: 0.95). Published studies showed a publication bias and significant heterogeneity; however, no cause for the latter could be identified. Conclusions. Zinc supplementation reduced significantly the frequency and severity of diarrhea and respiratory illnesses and the duration of diarrheal morbidity. The relatively limited reduction in morbidity and the presence of significant heterogeneity and of publication bias indicate the need for larger, high- quality studies to identify subpopulations most likely to benefit. C1 Sanjay Gandhi Postgrad Inst Med Sci, Dept Gastroenterol, Lucknow, Uttar Pradesh, India. All India Inst Med Sci, Dept Gastroenterol, New Delhi, India. NIH, Fogarty Int Ctr, Div Int Epidemiol & Populat Studies, Bethesda, MD 20892 USA. RP Miller, MA (reprint author), NIH, Div Int Epidemiol & Populat Studies, Fogaarty Int Ctr, 16 Ctr, Bethesda, MD 20892 USA. EM millemar@nih.gov OI Aggarwal, Rakesh/0000-0001-9689-494X NR 52 TC 108 Z9 110 U1 0 U2 13 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUN PY 2007 VL 119 IS 6 BP 1120 EP 1130 DI 10.1542/peds.2006-3481 PG 11 WC Pediatrics SC Pediatrics GA 174NL UT WOS:000246948900011 PM 17545379 ER PT J AU Hemachandra, AH Howards, PP Furth, SL Klebanoff, MA AF Hemachandra, Anusha H. Howards, Penelope P. Furth, Susan L. Klebanoff, Mark A. TI Birth weight, postnatal growth, and risk for high blood pressure at 7 years of age: Results from the collaborative perinatal project SO PEDIATRICS LA English DT Article DE hypertension; Barker hypothesis; catch-up growth; intrauterine growth restriction ID CORONARY-HEART-DISEASE; CATCH-UP GROWTH; INSULIN-RESISTANCE; CHILDHOOD GROWTH; GESTATIONAL-AGE; ADULT DISEASE; FETAL ORIGINS; TASK-FORCE; CHILDREN; HYPERTENSION AB Objective. A physiologic predisposition toward hypertension is theorized to result from the combination of intrauterine growth restriction followed by rapid catch-up growth. The objective of this study was to evaluate the effects of birth weight and weight gain during childhood on the risk for high blood pressure in childhood and to identify discrete periods of catch-up growth that put children with intrauterine growth restriction at increased risk for the development of high blood pressure later in life. Methods. The US Collaborative Perinatal Project (1959-1974) studied 55 908 pregnancies in an observational cohort at 12 medical centers in the United States and followed the offspring through 7 years of age. All white or black children who were born at term and completed the follow-up without kidney or heart disease were included in this posthoc analysis. z scores were calculated for weight at birth, 4 months, 1 year, 4 years, and 7 years on the basis of study means and SD. Changes in z scores were calculated for each interval. RESULTS. Each 1-kg increase in birth weight increased the odds for high systolic blood pressure by 2.19 and high diastolic blood pressure by 1.82 when race and change in weight z scores were also included in the regression model. An increase in weight z score of 1 SD above the previous weight z score increased the odds for high systolic blood pressure at 7 years by 1.65 (birth to 4 months), 1.79 (4 months to 1 year), 1.71 (1 - 4 years), and 1.94 (4 - 7 years) in the full model. White race increased the odds for high systolic blood pressure by 1.51. Conclusions. In this large biracial US cohort, infants who were small for gestational age were not at increased risk for high blood pressure at 7 years of age. However, children who crossed weight percentiles upward during early childhood did demonstrate an increased risk. C1 NICHD, DESPR, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Div Neonatol, Baltimore, MD 21218 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Div Pediat Nephrol, Baltimore, MD 21218 USA. Johns Hopkins Med Inst, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21205 USA. RP Hemachandra, AH (reprint author), NICHD, DESPR, NIH, Dept Hlth & Human Serv, 6100 Bldg,Room 7B05,MSC 7510, Bethesda, MD 20892 USA. EM ahemachandra@hotmail.com FU Intramural NIH HHS; NIDDK NIH HHS [K24 DK078737, U01DK66174] NR 33 TC 57 Z9 60 U1 1 U2 2 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUN PY 2007 VL 119 IS 6 BP E1264 EP E1270 DI 10.1542/peds.2005-2486 PG 7 WC Pediatrics SC Pediatrics GA 174NL UT WOS:000246948900068 PM 17545358 ER PT J AU Mei, ZG Grummer-Strawn, M Wang, J Thornton, JC Freedman, DS Pierson, RN Dietz, WH Horlick, M AF Mei, Zuguo Grummer-Strawn, M. Wang, Jack Thornton, John C. Freedman, David S. Pierson, Richard N., Jr. Dietz, William H. Horlick, Mary TI Do skinfold measurements provide additional information to body mass index in the assessment of body fatness among children and adolescents? SO PEDIATRICS LA English DT Article DE dual-energy radiograph absorptiometry; BMI; skinfold; anthropometry; receiver operating characteristic curve; sensitivity; specificity ID X-RAY ABSORPTIOMETRY; FAT-FREE MASS; CROSS-CALIBRATION; OVERWEIGHT; OBESITY; BONE; VALIDATION; ACCURACY; VALIDITY; WEIGHT AB Objectives. The purpose of this work was to validate the performance of age- and gender-specific BMI, triceps, and subscapular skinfold for the classification of excess of body fat in children and adolescents and to examine how much additional information these 2 skinfold measurements provide to BMI-for-age. Methods. The receiver operating characteristic curve was used to characterize the sensitivity and specificity of these 3 indices in classifying excess body fat. Percentage of body fat was determined by dual-energy radiograph absorptiometry. Both >= 85th and >= 95th percentile of percentage of body fat were used to define excess body fat. Data from the New York Pediatric Rosetta Body Composition Project were examined (n = 1196; aged 5 - 18 years). Results. For children aged 5 to 18 years, BMI-for-age, triceps skinfold-for-age, and subscapular skinfold- for- age each performed equally well alone in the receiver operating characteristic curves in the identification of excess body fat defined by either the >= 85th or >= 95th percentile of percentage of body fat by dual-energy radiograph absorptiometry. However, if BMI-for-age was already known and was >95th percentile, the additional measurement of skinfolds did not significantly increase the sensitivity or specificity in the identification of excess body fat. Conclusions. In contrast to the recommendations of expert panels, skinfold measurements do not seem to provide additional information about excess body fat beyond BMI-for-age alone if the BMI-for-age is >95th percentile. C1 Ctr Dis Control & Prevent, Div Nutr & Phys Activ, Atlanta, GA 30341 USA. St Lukes Roosevelt Hosp, Obes Res Ctr, Dept Med, Body Composit Unit, New York, NY 10025 USA. NIDDK, NIH, Bethesda, MD 20892 USA. RP Mei, ZG (reprint author), Ctr Dis Control & Prevent, Div Nutr & Phys Activ, Mailstop K-25,4770 Buford Hwy, Atlanta, GA 30341 USA. EM zmei@cdc.gov FU NIDDK NIH HHS [DK37352] NR 35 TC 49 Z9 53 U1 0 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD JUN PY 2007 VL 119 IS 6 BP E1306 EP E1313 DI 10.1542/peds.2006-2546 PG 8 WC Pediatrics SC Pediatrics GA 174NL UT WOS:000246948900074 PM 17545361 ER PT J AU Kusalik, A Bickis, M Lewis, C Li, Y Lucchese, G Marincola, FM Kanduc, D AF Kusalik, Anthony Bickis, Mikelis Lewis, Christopher Li, Ying Lucchese, Guglielmo Marincola, Francesco M. Kanduc, Darja TI Widespread and ample peptide overlapping between HCV and Homo sapiens proteomes SO PEPTIDES LA English DT Article DE similarity analysis; sequence-sequence peptide; matching; viral versus human proteome; overlapping; HCV-related autoirnmunity ID HEPATITIS-C VIRUS; MOLECULAR MIMICRY; HEPATOCELLULAR-CARCINOMA; AUTOIMMUNE HEPATITIS; CYTOCHROME-P450 2A6; INSULIN-RESISTANCE; INFECTION; AUTOANTIBODIES; IDENTIFICATION; SEQUENCE AB Alignment of protein sequences is fundamental in analyzing homology, evolutionary events and functional relationships. Searching for the epitopic peptide platform underlying hepatitis C virus (HCV) infection and autoimmune phenomena, we have used sequence-sequence peptide matching to compare the HCV polyprotein sequence to the human proteome. The following results were obtained: (1) pentamers from HCV polyprotein have a widespread and high level of similarity to a large number of human proteins (19,605 human proteins, that is 57.6% of the human proteome); (2) remarkable similarity between the two proteomes persists even using longer peptide motifs as probes for identity scanning; (3) only a limited number of HCV pentameric fragments have no similarity to the human host, so representing molecular sequence signatures of the virus. We conclude that the widespread sharing of numerous perfect exact matches between HCV and human proteomes might explain HCV persistence in humans. (c) 2007 Elsevier Inc. All rights reserved. C1 NIH, Immunogenet Lab, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. Univ Saskatchewan, Dept Comp Sci, Saskatoon, SK S7N 0W0, Canada. Univ Saskatchewan, Math Sci Grp, Saskatoon, SK, Canada. Univ Bari, Dept Biochem & Mol Biol Ernesto Quagliariello, Bari, Italy. RP Kanduc, D (reprint author), NIH, Immunogenet Lab, Dept Transfus Med, Ctr Clin, Bldg 10,10 Ctr Dr,Room 1N224, Bethesda, MD 20892 USA. EM kanducd@cc.nih.gov OI Kanduc, Darja/0000-0003-2111-4608 NR 51 TC 16 Z9 16 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD JUN PY 2007 VL 28 IS 6 BP 1260 EP 1267 DI 10.1016/j.peptides.2007.04.001 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 185HH UT WOS:000247701500014 PM 17485143 ER PT J AU Cacioppo, JT Amaral, DG Blanchard, JJ Cameron, JL Carter, CS Crews, D Fiske, S Heatherton, T Johnson, MK Kozak, MJ Levenson, RW Lord, C Miller, EK Ochsner, K Raichle, ME Shea, MT Taylor, SE Young, LJ Quinn, KJ AF Cacioppo, John T. Amaral, David G. Blanchard, Jack J. Cameron, Judy L. Carter, C. Sue Crews, David Fiske, Susan Heatherton, Todd Johnson, Marcia K. Kozak, Michael J. Levenson, Robert W. Lord, Catherine Miller, Earl K. Ochsner, Kevin Raichle, Marcus E. Shea, M. Tracie Taylor, Shelley E. Young, Larry J. Quinn, Kevin J. TI Social Neuroscience Progress and Implications for Mental Health SO PERSPECTIVES ON PSYCHOLOGICAL SCIENCE LA English DT Review AB Social neuroscience is a new, interdisciplinary field devoted to understanding how biological systems implement social processes and behavior. Social neuroscience capitalizes on biological concepts and methods to inform and refine theories of social behavior, and it uses social and behavioral constructs and data to inform and refine theories of neural organization and function. We focus here on the progress and potential of social neuroscience in the area of mental health. Research in social neuroscience has grown dramatically in recent years. Among the most active areas of research we found are brain-imaging studies in normal children and adults; animal models of social behavior; studies of stroke patients; imaging studies of psychiatric patients; and research on social determinants of peripheral neural, neuroendocrine, and immunological processes. We also found that these areas of research are proceeding along largely independent trajectories. Our goals in this article are to review the development of this field, examine some currently promising approaches, identify obstacles and opportunities for future advances and integration, and consider how this research can inform work on the diagnosis and treatment of mental disorders. C1 [Cacioppo, John T.] Univ Chicago, Ctr Cognit & Social Neurosci, Chicago, IL 60637 USA. [Amaral, David G.] Univ Calif Davis, Davis, CA 95616 USA. [Blanchard, Jack J.] Univ Maryland, College Pk, MD 20742 USA. [Cameron, Judy L.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Carter, C. Sue] Univ Illinois, Chicago, IL USA. [Crews, David] Univ Texas Austin, Austin, TX 78712 USA. [Fiske, Susan] Princeton Univ, Princeton, NJ 08544 USA. [Johnson, Marcia K.] Yale Univ, New Haven, CT 06520 USA. [Kozak, Michael J.; Quinn, Kevin J.] NIMH, Bethesda, MD 20892 USA. [Levenson, Robert W.] Univ Calif Berkeley, Berkeley, CA 94720 USA. [Lord, Catherine] Univ Michigan, Ann Arbor, MI 48109 USA. [Miller, Earl K.] MIT, Cambridge, MA 02139 USA. [Ochsner, Kevin] Columbia Univ, New York, NY 10027 USA. [Raichle, Marcus E.] Washington Univ, St Louis, MO 63130 USA. [Shea, M. Tracie] Brown Univ, Providence, RI 02912 USA. [Taylor, Shelley E.] Univ Calif Los Angeles, Los Angeles, CA USA. [Young, Larry J.] Emory Univ, Sch Med, Atlanta, GA 30322 USA. RP Cacioppo, JT (reprint author), Univ Chicago, Ctr Cognit & Social Neurosci, 5848 S Univ Ave, Chicago, IL 60637 USA. EM cacioppo@uchicago.edu; kquinn@mail.nih.gov RI Heatherton, Todd/H-5478-2011; Cameron, Judy/J-6682-2013 NR 306 TC 58 Z9 60 U1 20 U2 29 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1745-6916 J9 PERSPECT PSYCHOL SCI JI Perspect. Psychol. Sci. PD JUN PY 2007 VL 2 IS 2 BP 99 EP 123 DI 10.1111/j.1745-6916.2007.00032.x PG 25 WC Psychology, Multidisciplinary SC Psychology GA V10FR UT WOS:000207450400001 PM 26151956 ER PT J AU Raja, AS Pandeya, SN Panda, SS Stables, JP AF Raja, A. S. Pandeya, S. N. Panda, S. S. Stables, J. P. TI SYNTHESIS AND ANTICONVULSANT EVALUATION OF SEMICARBAZONES OF ACETOPHENONE MANNICH BASES SO PHARMACEUTICAL CHEMISTRY JOURNAL LA English DT Article AB Several semicarbazones of acetophenone and p-chloroacetophenone Mannich bases were designed and synthesized to meet the pharmacophore requirements essential for anticonvulsant activity. Mannich bases of acetophenone and p-chloroacetophenone were prepared by reacting formaldehyde with various secondary amines and then condensed with several aryl semicarbazides to yield the corresponding semicarbazones. All compounds were evaluated for their anticonvulsant activity by maximal electroshock (MES) and by subcutaneous metrazole (ScMet) and strychnine (ScSty) induced seizure methods, and their neurotoxic effects were determined using the rotorod test. The title compounds were also investigated for antidepressant and sedative-hypnotic potentiation properties. It is established that 3-[3-chlorophenyl(beta-dimethylaminopropiophenone)semicarbazone] has excellent anticonvulsant activity in MES, ScSty, and ScMet tests and exhibits a potent antidepressant effect in the absence of sedative-hypnotic potentiation. The present study has proved our earlier hypothesis concerning the pharmacophore model with essential binding sites for semicarbazones. The inclusion of an additional moiety (CH2-CH2-N<) at the electron donor acceptor group retained the anticonvulsant activity. C1 [Raja, A. S.; Pandeya, S. N.; Panda, S. S.] Banaras Hindu Univ, Inst Technol, Dept Pharmaceut, Varanasi 221005, Uttar Pradesh, India. [Stables, J. P.] NINDS, Epilepsy Branch, NIH, Bethesda, MD 20892 USA. RP Raja, AS (reprint author), Banaras Hindu Univ, Inst Technol, Dept Pharmaceut, Varanasi 221005, Uttar Pradesh, India. EM asraja.phe@itbhu.ac.in FU UGC (New Delhi) FX The authors are thankful to the Head of the Department of Pharmaceutics, Institute of Technology, Banaras Hindu University for providing laboratory facilities. The award of JRF to one of the authors (S. S. P) by UGC (New Delhi) is cordially acknowledged. NR 22 TC 3 Z9 3 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0091-150X EI 1573-9031 J9 PHARM CHEM J+ JI Pharm. Chem. J. PD JUN PY 2007 VL 41 IS 6 BP 302 EP 307 DI 10.1007/s11094-007-0068-4 PG 6 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA V38JU UT WOS:000209340500004 ER PT J AU Steagall, WK Barrow, BJ Glasgow, CG Mendoza, JW Ehrmantraut, M Lin, JP Insel, PA Moss, J AF Steagall, Wendy K. Barrow, Bethany J. Glasgow, Connie G. Mendoza, Jennifer Woo Ehrmantraut, Mary Lin, Jing-Ping Insel, Paul A. Moss, Joel TI Beta-2-adrenergic receptor polymorphisms in cystic fibrosis SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE beta(2)-adrenergic receptor; bronchodilator response; cystic fibrosis; single nucleotide polymorphism ID ALVEOLAR EPITHELIAL-CELLS; BETA(2)-ADRENERGIC RECEPTOR; ADRENERGIC-RECEPTOR; SODIUM-CHANNELS; IN-VIVO; CFTR; ASTHMA; HAPLOTYPES; EXPRESSION; AIRWAY AB Objectives Cystic fibrosis (CF), an autosomal recessive disease affecting the lung, pancreas, gut, liver, and reproductive tract, is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a cyclic adenosine 3', 5' monophosphate-regulated chloride channel. The variability of disease progression among patients with CF suggests effects of genetic modifiers of disease. Beta-2 adrenergic receptors (beta(2)AR), which are abundant in airway epithelial cells, accelerate the formation of cyclic adenosine 3', 5' monophosphate, which can modulate CFTR activity and affect smooth muscle contractility. We tested the hypothesis that genetic variants of the beta(2)AR gene, which have been shown to influence receptor desensitization, are more frequent in patients than in controls. Methods We genotyped 130 adult CF patients and 1 : 1 age-matched, sex-matched, and ethnicity-matched normal volunteers for Gly(16)Arg and Gln(27) Glu beta(2)AR. Results We found that CF patients were more likely than controls to be Gly(16) homozygotes (48 and 32%, respectively) (P<0.01) and Glu(27) homozygotes (29 and 10%, respectively) (P<0.01). Conclusions Our results, showing a higher frequency of Gly(16) and Glu(27) PAR alleles in adult CF patients than in the control population, contrast with data from children with CF, who are reported to have lower frequency of Gly(16) and similar frequency of G1u(27), and with data from young adults with CF, who showed no differences in frequencies Of beta(2)AR variants. The Gly(16)Glu(27) variant of beta(2)AR may have properties that lead to enhanced beta(2)AR function, resulting in the upregulation of CFTR activity and the improvement of CF disease. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Off biostat Res, NIH, Bethesda, MD 20892 USA. Univ Calif San Diego, Dept Pharmacol, La Jolla, CA 92093 USA. Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA. RP Moss, J (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10,Room 6D03,MSC 1590, Bethesda, MD 20892 USA. EM mossj@nhlbi.nih.gov FU Intramural NIH HHS [Z01 HL000659-15] NR 38 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1744-6872 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD JUN PY 2007 VL 17 IS 6 BP 425 EP 430 DI 10.1097/FPC.0b013e3280119349 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 174HD UT WOS:000246931900005 PM 17502834 ER PT J AU Sauna, ZE Kimchi-Sarfaty, C Ambudkar, SV Gottesman, MM AF Sauna, Zuben E. Kimchi-Sarfaty, Chava Ambudkar, Suresh V. Gottesman, Michael M. TI The sounds of silence: synonymous mutations affect function SO PHARMACOGENOMICS LA English DT Editorial Material ID CODON USAGE; P-GLYCOPROTEIN; MDR1 GENE; PROTEIN EXPRESSION; POLYMORPHISMS; TRANSLATION; HAPLOTYPES; EVOLUTION; DISEASE; GENOME C1 NCI, Cell Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, Canc Res Ctr, NIH, Bldg 37, Bethesda, MD 20892 USA. EM mgottesman@nih.gov FU Intramural NIH HHS NR 41 TC 32 Z9 35 U1 0 U2 4 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 J9 PHARMACOGENOMICS JI Pharmacogenomics PD JUN PY 2007 VL 8 IS 6 BP 527 EP 532 DI 10.2217/14622416.8.6.527 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 183QD UT WOS:000247586400001 PM 17559340 ER PT J AU Lal, S Wong, ZW Jada, SR Xiang, XQ Shu, XC Ang, PCS Figg, WD Lee, EJD Chowbay, B AF Lal, Suman Wong, Zee Wan Jada, Srinivasa Rao Xiang, Xiaoqiang Shu, Xiao Chen Ang, Peter Cher Siang Figg, William D. Lee, Edmund J. D. Chowbay, Balram TI Novel SLC22A16 polymorphisms and influence on doxorubicin pharmacokinetics in Asian breast cancer patients SO PHARMACOGENOMICS LA English DT Article DE asian breast cancer patients; doxorubicinol; doxorubicin pharmacokinetics; hCT2; hOCT6; influx transporters; SLC22A16 ID ORGANIC ANION TRANSPORTER; CARNITINE DEFICIENCY; DRUG; RESISTANCE; CELLS; PHARMACOGENETICS; IDENTIFICATION AB Objective: To identify novel polymorphisms in the solute carrier SLC22A16 gene and determine their influence on the pharmacokinetics of doxorubicin and doxorubicinol in Asian breast cancer patients. Methods: SLC22A16 coding regions were screened in a total of 400 healthy subjects belonging to three distinct Asian ethnic groups (Chinese [n = 100], Malays [n = 100] and Indians [n = 100]) and in the Caucasian population (n = 100). Pharmacokinetic parameters of doxorubicin and doxorubicinol were estimated in Asian breast cancer patients undergoing adjuvant chemotherapy to investigate genotype-phenotype correlations. Results: Four novel polymorphisms (c.146A > G [exon 2], c.312T > C, c.755T > C [exon 4] and c.1226T > C [exon 51) were identified. The genotypic frequency of the homozygous c.146GG polymorphism was approximately twofold higher in the healthy Chinese (13%) & Malay (18%) populations compared with the Indian (7%) and Caucasian (9%) populations. The genotypic frequency of the c.1226T > C polymorphism was observed to be significantly higher among the Caucasian (11 %) and Indian (8%) study subjects compared with the Chinese (1 %) and Malay (1 %) ethnic groups (p < 0.005 in each case). Breast cancer patients harboring the 146GG genotype showed a trend towards higher exposure levels to doxorubicin (AUC(0-infinity)/dose/body surface area [BSA] [hM(-5)]: 21.6; range: 18.8-27.7) compared with patients with either the reference genotype (AUC(0-infinity)/dose/BSA[hM(-5)]: 17.4; range: 8.2-26.3, p = 0.066) or heterozygotes (AUC(0-infinity)/dose/BSA[hM(-5)]: 15.4; range: 6.2-38.0, p = 0.055). The exposure levels of doxorubicinol were also higher in patients harboring the variant 146GG genotype (AUC(0-infinity)/dose/BSA[hm(-5)]: 13.3; range: 8.8-21.7) when compared with patients harboring the reference genotype (AUC(0-infinity)Jdose/BSA[hm(-5)]): 9.8; range: 6.1-24.3, p = 0.137) or heterozygotes (AUC(0-infinity)/dose/BSA[hm(-5)]: 8.98; range: 3.7-20.6, p = 0.047). Conclusion: Among the four novel SLC22A16 polymorphisms identified, the c.146A > G and c.1226T > C polymorphisms exhibited interethnic variations in allele and genotype frequencies. This exploratory study suggests that the c.146A > G variation could contribute to the variations in the pharmacokinetics of doxorubicin and doxorubicinol in Asian cancer patients. Further in vitro studies are required to determine the functional impact of these novel polymorphisms on doxorubicin pharmacokinetics in cancer patients. C1 Natl Canc Ctr, Div Med Sci, Singapore 169610, Singapore. Natl Canc Ctr, Dept Med Oncol, Singapore, Singapore. NCI, Med Oncol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. Natl Univ Singapore, Dept Pharmacol, Singapore 117548, Singapore. RP Chowbay, B (reprint author), Natl Canc Ctr, Div Med Sci, 11 Hosp Dr, Singapore 169610, Singapore. EM ctebal@nccs.com.sg RI Xiang, Xiaoqiang/L-6763-2014; Figg Sr, William/M-2411-2016 NR 30 TC 39 Z9 43 U1 0 U2 6 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 J9 PHARMACOGENOMICS JI Pharmacogenomics PD JUN PY 2007 VL 8 IS 6 BP 567 EP 575 DI 10.2217/14622416.8.6.567 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 183QD UT WOS:000247586400010 PM 17559346 ER PT J AU Warren, LL Hughes, AR Lai, EH Zaykin, DV Haneline, SA Bansal, AT Wooster, AW Spreen, WR Hernandez, JE Scott, TR Roses, AD Mosteller, M AF Warren, L. L. Hughes, A. R. Lai, E. H. Zaykin, D. V. Haneline, S. A. Bansal, A. T. Wooster, A. W. Spreen, W. R. Hernandez, J. E. Scott, T. R. Roses, A. D. Mosteller, M. CA CNA30027 CNA30032 study teams TI Use of pairwise marker combination and recursive partitioning in a pharmacogenetic genome-wide scan SO PHARMACOGENOMICS JOURNAL LA English DT Article DE pairwise marker combinations; sensitivity; specificity; recursive partitioning; candidate genes; genome scan ID ADVERSE DRUG-REACTIONS; GENETIC ASSOCIATION; HYPERSENSITIVITY REACTIONS; ABACAVIR HYPERSENSITIVITY; DISEASE; SUSCEPTIBILITY; HLA-B-ASTERISK-5701; BREAST; CANCER; REGION AB The objective of pharmacogenetic research is to identify a genetic marker, or a set of genetic markers, that can predict how a given person will respond to a given medicine. To search for such marker combinations that are predictive of adverse drug events, we have developed and applied two complementary methods to a pharmacogenetic study of the hypersensitivity reaction (HSR) associated with treatment with abacavir, a medicine that is used to treat HIV-infected patients. Our results show that both of these methods can be used to uncover potentially useful predictive marker combinations. The pairwise marker combination method yielded a collection of marker pairs that featured a spectrum of sensitivities and specificities. Recursive partitioning results led to the genetic delineation of multiple risk categories, including those with extremely high and extremely low risk of HSR. These methods can be readily applied in pharmacogenetic candidate gene studies as well as in genome-wide scans. C1 GlaxoSmithKline Inc, Genet Res, Genet Analysis, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. GlaxoSmithKline Inc, Harlow, Essex, England. RP Mosteller, M (reprint author), GlaxoSmithKline Inc, Genet Res, Genet Analysis, 5 Moore Dr, Res Triangle Pk, NC 27709 USA. EM mike.m.mosteller@gsk.com FU Intramural NIH HHS NR 33 TC 9 Z9 9 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1470-269X J9 PHARMACOGENOMICS J JI Pharmacogenomics J. PD JUN PY 2007 VL 7 IS 3 BP 180 EP 189 DI 10.1038/sj.tpj.6500414 PG 10 WC Genetics & Heredity; Pharmacology & Pharmacy SC Genetics & Heredity; Pharmacology & Pharmacy GA 172PI UT WOS:000246815900002 PM 16969363 ER PT J AU Adib, AB AF Adib, Artur B. TI Algebraic perturbation theory for dense liquids with discrete potentials SO PHYSICAL REVIEW E LA English DT Article ID SQUARE-WELL FLUID; MEAN SPHERICAL APPROXIMATION; INTERMOLECULAR FORCES; EQUILIBRIUM STRUCTURE; SOLVENT MODEL; STATE; WATER; EQUATION AB A simple theory for the leading-order correction g(1)(r) to the structure of a hard-sphere liquid with discrete (e.g., square-well) potential perturbations is proposed. The theory makes use of a general approximation that effectively eliminates four-particle correlations from g(1)(r) with good accuracy at high densities. For the particular case of discrete perturbations, the remaining three-particle correlations can be modeled with a simple volume-exclusion argument, resulting in an algebraic and surprisingly accurate expression for g(1)(r). The structure of a discrete "core-softened" model for liquids with anomalous thermodynamic properties is reproduced as an application. C1 NIH, NIDDK, Phys Chem Lab, Bethesda, MD 20892 USA. RP Adib, AB (reprint author), NIH, NIDDK, Phys Chem Lab, Bethesda, MD 20892 USA. EM adiba@mail.nih.gov NR 27 TC 7 Z9 7 U1 0 U2 5 PU AMERICAN 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 JUN PY 2007 VL 75 IS 6 AR 061204 DI 10.1103/PhysRevE.75.061204 PN 1 PG 5 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 184EN UT WOS:000247624000047 PM 17677248 ER PT J AU Hallsson, JH Haflidadottir, BS Schepsky, A Arnheiter, H Steingrimsson, E AF Hallsson, Jon Hallsteinn Haflidadottir, Benedikta S. Schepsky, Alexander Arnheiter, Heinz Steingrimsson, Eirikur TI Evolutionary sequence comparison of the Mitf gene reveals novel conserved domains SO PIGMENT CELL RESEARCH LA English DT Article DE Mitf; transcription factor; melanocyte; conservation; domains ID TRANSCRIPTION FACTOR GENE; WAARDENBURG-SYNDROME TYPE-2; RETINAL-PIGMENT EPITHELIUM; MOUSE MICROPHTHALMIA LOCUS; LOOP-HELIX PROTEINS; SYNDROME TYPE-II; MESSENGER-RNA; MICRORNA TARGETS; LOCAL ALIGNMENT; FACTOR ISOFORM AB The microphthalmia-associated transcription factor (MITF) is a member of the MYC family of basic helix-loop-helix leucine zipper transcription factors. The corresponding gene was initially discovered in the mouse based on mutations which affect the development of several different cell types, including melanocytes and retinal pigment epithelium cells. Subsequently, it was shown to be associated with deafness and hypo-pigmentation disorders in humans. More recently, the gene has been shown to be critical in melanoma formation and to play a role in melanocyte stem cell maintenance. Thus, the mouse Mitf gene represents an important model system for the study of human disease as well as an interesting model for the study of transcription factor function in the organism. Here we use the evolutionary relationship of Mitf genes from numerous distantly related species, including vertebrates and invertebrates, to identify novel conserved domains in the Mitf protein and regions of possible functional importance in the 3' untranslated region. We also characterize the nine different 5' exons of the Mitf gene and identify a new 5' exon in the Drosophila Mitf gene. Our analysis sheds new light on the conservation of the Mitf gene and protein and opens the door for further functional analysis. C1 Univ Iceland, Dept Biochem & Mol Biol, Fac Med, IS-101 Reykjavik, Iceland. NINDS, Lab Dev Neurogenet, NIH, Bethesda, MD 20892 USA. RP Steingrimsson, E (reprint author), Univ Iceland, Dept Biochem & Mol Biol, Fac Med, Vatnsmyrarvegur 16, IS-101 Reykjavik, Iceland. EM eirikurs@hi.is OI Hallsson, Jon/0000-0002-9127-2137 FU Intramural NIH HHS NR 84 TC 21 Z9 24 U1 0 U2 6 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0893-5785 J9 PIGM CELL RES JI Pigm. Cell. Res. PD JUN PY 2007 VL 20 IS 3 BP 185 EP 200 DI 10.1111/j.1600-0749.2007.00373.x PG 16 WC Cell Biology; Dermatology SC Cell Biology; Dermatology GA 169XC UT WOS:000246624400007 PM 17516926 ER PT J AU Baxter, LL Hsu, BJ Umayam, L Wolfsberg, TG Larson, DM Frith, MC Kawai, J Hayashizaki, Y Carninci, P Pavan, WJ AF Baxter, Laura L. Hsu, Benjamin J. Umayam, Lowell Wolfsberg, Tyra G. Larson, Denise M. Frith, Martin C. Kawai, Jun Hayashizaki, Yoshihide Carninci, Piero Pavan, William J. TI Informatic and genomic analysis of melanocyte cDNA libraries as a resource for the study of melanocyte development and function SO PIGMENT CELL RESEARCH LA English DT Article DE melanocyte; cDNA library; development; B16F10Y; melan-c ID CREST-DERIVED MELANOCYTES; HERMANSKY-PUDLAK-SYNDROME; NEURAL CREST; FULL-LENGTH; IN-VITRO; CAP-TRAPPER; PROTEIN; GENE; CLONING; CELL AB As part of the RIKEN mouse encyclopedia project, two cDNA libraries were prepared from melanocyte-derived cell lines, using techniques of full-length clone selection and subtraction/normalization to enrich for rare transcripts. End sequencing showed that these libraries display over 83% complete coding sequence at the 5' end and 96-97% complete coding sequence at the 3' end. Evaluation of the libraries, derived from B16F10Y tumor cells and melan-c cells, revealed that they contain clones for a majority of the genes previously demonstrated to function in melanocyte biology. Analysis of genomic locations for transcripts revealed that the distribution of melanocyte genes is non-random throughout the genome. Three genomic regions identified that showed significant clustering of melanocyte-expressed genes contain one or more genes previously shown to regulate melanocyte development or function. A catalog of genes expressed in these libraries is presented, providing a valuable resource of cDNA clones and sequence information that can be used for identification of new genes important for melanocyte development, function, and disease. C1 NHGRI, Genet Dis Res Branch, NIH, Rockville, MD 20855 USA. NHGRI, Genome Technol Branch, NIH, Rockville, MD 20855 USA. Univ Queensland, ARC Ctr Bioinformat, Brisbane, Qld 4072, Australia. Univ Queensland, Inst Mol Biosci, Brisbane, Qld 4072, Australia. RIKEN, Yokohama Inst, Genom Sci Ctr,Genome Network Project Core Grp, Genome Explorat Res Grp,Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan. RIKEN, Wako Inst, Genome Res Lab, Discovery & Res Inst, Wako, Saitama 3510198, Japan. RP Pavan, WJ (reprint author), NHGRI, Genet Dis Res Branch, NIH, Rockville, MD 20855 USA. EM bpavan@mail.nih.gov RI Carninci, Piero/K-1568-2014; Kawai, Jun/A-6451-2016; OI Carninci, Piero/0000-0001-7202-7243; Frith, Martin/0000-0003-0998-2859 NR 39 TC 3 Z9 4 U1 1 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0893-5785 J9 PIGM CELL RES JI Pigm. Cell. Res. PD JUN PY 2007 VL 20 IS 3 BP 201 EP 209 DI 10.1111/j.1600-0749.2007.00372.x PG 9 WC Cell Biology; Dermatology SC Cell Biology; Dermatology GA 169XC UT WOS:000246624400008 PM 17516927 ER PT J AU Matera, I Cockroft, JL Moran, JL Beier, DR Goldowitz, D Pavan, WJ AF Matera, Ivana Cockroft, Jody L. Moran, Jennifer L. Beier, David R. Goldowitz, Dan Pavan, William J. TI A mouse model of Waardenburg syndrome type IV resulting from an ENU-induced mutation in endothelin 3 SO PIGMENT CELL RESEARCH LA English DT Article DE endothelin 3; Waardenburg syndrome; white spotting; ENU mutagenesis; furin ID HIRSCHSPRUNG-DISEASE; B RECEPTOR; FRAMESHIFT MUTATION; SOX10 MUTATIONS; GENE-MUTATIONS; MUTAGENESIS; MELANOCYTE; ASSIGNMENT; MUTANTS; GENOME AB A line of mutant mice (114-CH19) exhibiting white spotting and preweaning lethality was identified during an N-ethyl-N-nitrosourea (ENU) mutagenesis screen. The trait segregated as a semidominant bellyspot with reduced penetrance. Homozygous mutant mice showed preweaning lethality, and exhibited white spotting over the majority of the body surface, with pigmented patches remaining around the pinnae, eyes and tail. Linkage analysis localized 114-CH19 on mouse chromosome 2, suggesting endothelin 3 (Edn3) as a candidate gene. Sequence analysis of Edn3 identified a G > A transversion that encodes an arginine to histidine substitution (R96H). This mutation is predicted to disrupt furin-mediated proteolytic cleavage of pro-endothelin that is necessary to form biologically active EDN3. This mutation is novel among human and mouse EDN3 mutants, is the first reported EDN3 ENU mutant, and is the second reported EDN3 point mutation. This study demonstrates the power of using ENU mutagenesis screens to generate new animal models of human disease, and expands the spectrum of EDN3 mutant alleles. C1 NHGRI, Genet Dis Res Branch, NIH, Rockville, MD 20855 USA. Inst G Gaslini, Lab Genet Mol, Genoa, Italy. Univ Tennessee, Ctr Hlth Sci, Res Ctr Excellence Genom & Bioinformat, Memphis, TN 38163 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Genet, Boston, MA 02115 USA. RP Pavan, WJ (reprint author), NHGRI, Genet Dis Res Branch, NIH, Rockville, MD 20855 USA. EM bpavan@mail.nih.gov OI Moran, Jennifer/0000-0002-5664-4716 NR 29 TC 6 Z9 6 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0893-5785 J9 PIGM CELL RES JI Pigm. Cell. Res. PD JUN PY 2007 VL 20 IS 3 BP 210 EP 215 DI 10.1111/j.1600-0749.2007.00371.x PG 6 WC Cell Biology; Dermatology SC Cell Biology; Dermatology GA 169XC UT WOS:000246624400009 PM 17516928 ER PT J AU Tarca, AL Carey, VJ Chen, XW Romero, R Draghici, S AF Tarca, Adi L. Carey, Vincent J. Chen, Xue-Wen Romero, Roberto Draghici, Sorin TI Machine learning and its applications to biology SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID ORGANIZING NEURAL NETWORK; GENE-EXPRESSION PATTERNS; FEATURE-SELECTION; MICROARRAY DATA; CLASSIFICATION; PREDICTION; CANCER; RECOGNITION; INFORMATION; VALIDATION C1 NIH, NICHD, DHHS, Perinatol Res Branch, Detroit, MI USA. Wayne State Univ, Dept Comp Sci, Detroit, MI USA. Harvard Med Sch, Channing Lab, Boston, MA USA. Univ Kansas, Dept Elect Engn & Comp Sci, Bioinformat & Computat Life Sci Lab, Lawrence, KS 66045 USA. RP Draghici, S (reprint author), NIH, NICHD, DHHS, Perinatol Res Branch, Detroit, MI USA. EM sorin@wayne.edu RI Draghici, Sorin/B-3074-2013 OI Draghici, Sorin/0000-0002-0786-8377 FU Intramural NIH HHS; NCI NIH HHS [1R21CA100740-01, 1U01CA117478-01, 2P30 CA022453-24, P30 CA022453, R21 CA100740, U01 CA117478]; NCRR NIH HHS [P20 RR017708, P20 RR17708]; NHGRI NIH HHS [1 P41 HG004059, 1R01HG003491-01A1, P41 HG004059, R01 HG003491]; NIBIB NIH HHS [5R21EB000990-03, R21 EB000990]; NINDS NIH HHS [1R01NS045207-01, R01 NS045207] NR 40 TC 105 Z9 107 U1 2 U2 16 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 JUN PY 2007 VL 3 IS 6 BP 953 EP 963 AR e116 DI 10.1371/journal.pcbi.0030116 PG 11 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 205HV UT WOS:000249105500005 PM 17604446 ER PT J AU Hu, ZJ Bowen, D Southerland, WM del Sol, A Pan, YP Nussinov, R Ma, BY AF Hu, Zengjian Bowen, Donnell Southerland, William M. del Sol, Antonio Pan, Yongping Nussinov, Ruth Ma, Buyong TI Ligand binding and circular permutation modify residue interaction network in DHFR SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID COLI DIHYDROFOLATE-REDUCTASE; ESCHERICHIA-COLI; PROTEIN STRUCTURES; FOLDING ELEMENTS; MECHANICAL STABILITY; CHAIN CONNECTIVITY; DYNAMICS; LOOP; PREDICTION; CATALYSIS AB Residue interaction networks and loop motions are important for catalysis in dihydrofolate reductase ( DHFR). Here, we investigate the effects of ligand binding and chain connectivity on network communication in DHFR. We carry out systematic network analysis and molecular dynamics simulations of the native DHFR and 19 of its circularly permuted variants by breaking the chain connections in ten folding element regions and in nine nonfolding element regions as observed by experiment. Our studies suggest that chain cleavage in folding element areas may deactivate DHFR due to large perturbations in the network properties near the active site. The protein active site is near or coincides with residues through which the shortest paths in the residue interaction network tend to go. Further, our network analysis reveals that ligand binding has ''network-bridging effects'' on the DHFR structure. Our results suggest that ligand binding leads to a modification, with most of the interaction networks now passing through the cofactor, shortening the average shortest path. Ligand binding at the active site has profound effects on the network centrality, especially the closeness. C1 Howard Univ, Coll Med, Dept Biochem & Mol Biol, Washington, DC 20059 USA. Div Res & Dev, Bioinformat Res Project, Tokyo, Japan. NCI, Frederick Inc, Ctr Canc Res Nanobiol Program, Sci Applicat Int Corp,Basic Res Program, Frederick, MD 21701 USA. Tel Aviv Univ, Sackler Sch Med, Sackler Inst Mol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Southerland, WM (reprint author), Howard Univ, Coll Med, Dept Biochem & Mol Biol, Washington, DC 20059 USA. EM wsoutherland@howard.edu; mab@ncifcrf.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400]; NCRR NIH HHS [2G12RR03048, G12 RR003048] NR 29 TC 29 Z9 30 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7358 J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD JUN PY 2007 VL 3 IS 6 BP 1097 EP 1107 AR e117 DI 10.1371/journal.pcbi.0030117 PG 11 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 205HV UT WOS:000249105500017 PM 17571919 ER PT J AU Sanjuan, R Cuevas, JM Furio, V Holmes, EC Moya, A AF Sanjuan, Rafael Cuevas, Jose M. Furio, Victoria Holmes, Edward C. Moya, Andres TI Selection for robustness in mutagenized RNA viruses SO PLOS GENETICS LA English DT Article ID GENETIC ROBUSTNESS; DROSOPHILA-MELANOGASTER; DIGITAL ORGANISMS; ERROR CATASTROPHE; MUTATION-RATES; FITNESS; POPULATION; EPISTASIS; VIABILITY; EVOLUTION AB Mutational robustness is defined as the constancy of a phenotype in the face of deleterious mutations. Whether robustness can be directly favored by natural selection remains controversial. Theory and in silico experiments predict that, at high mutation rates, slow-replicating genotypes can potentially outcompete faster counterparts if they benefit from a higher robustness. Here, we experimentally validate this hypothesis, dubbed the "survival of the flattest,'' using two populations of the vesicular stomatitis RNA virus. Characterization of fitness distributions and genetic variability indicated that one population showed a higher replication rate, whereas the other was more robust to mutation. The faster replicator outgrew its robust counterpart in standard competition assays, but the outcome was reversed in the presence of chemical mutagens. These results show that selection can directly favor mutational robustness and reveal a novel viral resistance mechanism against treatment by lethal mutagenesis. C1 Univ Valencia, Inst Cavanilles Biodiver & Biol Evolut, E-46003 Valencia, Spain. Univ Valencia, Dept Genet, E-46003 Valencia, Spain. Univ Politecn Valencia, Inst Biol Mol & Celular Plant, Consejo Super Invest Cientif, E-46071 Valencia, Spain. Univ Oxford, Dept Zool, Oxford OX1 2JD, England. Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. NIH, Fogarty Int Ctr, Bethesda, MD USA. RP Moya, A (reprint author), Univ Valencia, Inst Cavanilles Biodiver & Biol Evolut, E-46003 Valencia, Spain. EM andres.moya@uv.es RI Moya, Andres/A-8190-2008; Cuevas, Jose/C-6271-2016; OI Moya, Andres/0000-0002-2867-1119; Cuevas, Jose/0000-0003-2049-3554; Holmes, Edward/0000-0001-9596-3552 FU Wellcome Trust [071979] NR 44 TC 95 Z9 96 U1 2 U2 8 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 JUN PY 2007 VL 3 IS 6 BP 939 EP 946 AR e93 DI 10.1371/journal.pgen.0030093 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 194MU UT WOS:000248349300008 PM 17571922 ER PT J AU van de Leemput, J Chandran, J Knight, MA Holtzclaw, LA Scholz, S Cookson, MR Houlden, H Gwinn-Hardy, K Fung, HC Lin, X Hernandez, D Simon-Sanchez, J Wood, NW Giunti, P Rafferty, I Hardy, J Storey, E Gardner, RJM Forrest, SM Fisher, EMC Russell, JT Cai, H Singleton, AB AF van de Leemput, Joyce Chandran, Jayanth Knight, Melanie A. Holtzclaw, Lynne A. Scholz, Sonja Cookson, Mark R. Houlden, Henry Gwinn-Hardy, Katrina Fung, Hon-Chung Lin, Xian Hernandez, Dena Simon-Sanchez, Javier Wood, Nick W. Giunti, Paola Rafferty, Ian Hardy, John Storey, Elsdon Gardner, R. J. McKinlay Forrest, Susan M. Fisher, Elizabeth M. C. Russell, James T. Cai, Huaibin Singleton, Andrew B. TI Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans SO PLOS GENETICS LA English DT Article ID INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR; MULTIPLE SULFATASE DEFICIENCY; GENE; MOUSE; DISCOVERY; LOCUS AB We observed a severe autosomal recessive movement disorder in mice used within our laboratory. We pursued a series of experiments to define the genetic lesion underlying this disorder and to identify a cognate disease in humans with mutation at the same locus. Through linkage and sequence analysis we show here that this disorder is caused by a homozygous in-frame 18-bp deletion in Itpr1 (Itpr1D18/D18), encoding inositol 1,4,5- triphosphate receptor 1. A previously reported spontaneous Itpr1 mutation in mice causes a phenotype identical to that observed here. In both models in- frame deletion within Itpr1 leads to a decrease in the normally high level of Itpr1 expression in cerebellar Purkinje cells. Spinocerebellar ataxia 15 (SCA15), a human autosomal dominant disorder, maps to the genomic region containing ITPR1; however, to date no causal mutations had been identified. Because ataxia is a prominent feature in Itpr1 mutant mice, we performed a series of experiments to test the hypothesis that mutation at ITPR1 may be the cause of SCA15. We show here that heterozygous deletion of the 59 part of the ITPR1 gene, encompassing exons 1-10, 1-40, and 1-44 in three studied families, underlies SCA15 in humans. C1 NIH, Neurogenet Lab, Mol Genet Unit, Bethesda, MD 20892 USA. Inst Neurol, Dept Neurodegenerat Dis, London WC1N 3BG, England. NIH, NIA, Neurogenet Lab, Transgen Unit, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Biol, Baltimore, MD 21218 USA. NIH, NINDS, Neurogenet Branch, Bethesda, MD 20892 USA. NIH, NICHD, Sect Cell Biol & Signal Transduct, Bethesda, MD 20892 USA. UCL, Reta Lila Weston Inst Neurol Studies, London, England. NIH, NIA, Neurogenet Lab, Cell Biol & Gene Express Unit, Bethesda, MD 20892 USA. Inst Neurol, Dept Mol Neurosci, London WC1N 3BG, England. NIH, NINDS, Bethesda, MD 20892 USA. NIH, NIA, Neurogenet Lab, Bethesda, MD 20892 USA. Chang Gung Univ, Chang Gung Mem Hosp, Coll Med, Dept Neurol, Taipei, Taiwan. Inst Biomed, Consejo Super Invest Cientif, Dept Genom & Proteom, Unit Genet Mol, Valencia, Spain. Monash Univ, Alfred Hosp, Dept Med, Melbourne, Vic 3004, Australia. Genet Hlth Serv, Melbourne, Vic, Australia. Royal Childrens Hosp, Murdoch Childrens Res Inst, Melbourne, Vic, Australia. Walter & Eliza Hall Inst Med Res, Australian Genome Res Facil, Melbourne, Vic 3050, Australia. RP Singleton, AB (reprint author), NIH, Neurogenet Lab, Mol Genet Unit, Bldg 10, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Houlden, Henry/C-1532-2008; Gwinn, Katrina/C-2508-2009; Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; Giunti, Paola /E-5526-2012; Wood, Nicholas/C-2505-2009; OI Houlden, Henry/0000-0002-2866-7777; Giunti, Paola /0000-0003-3508-4788; Wood, Nicholas/0000-0002-9500-3348; Scholz, Sonja/0000-0002-6623-0429; Gwinn, Katrina/0000-0002-8277-651X FU Intramural NIH HHS; Medical Research Council [G0500288, G0701075, G108/638] NR 15 TC 105 Z9 107 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD JUN PY 2007 VL 3 IS 6 BP 1076 EP 1082 AR e108 DI 10.1371/journal.pgen.0030108 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 194MU UT WOS:000248349300020 PM 17590087 ER PT J AU Spierings, E Hendriks, M Absi, L Canossi, A Chhaya, S Crowley, J Dolstra, H Eliaou, JF Ellis, T Enczmann, J Fasano, ME Gervais, T Gorodezky, C Kircher, B Laurin, D Leffell, MS Loiseau, P Malkki, M Markiewicz, M Martinetti, M Maruya, E Mehra, N Oguz, F Oudshoorn, M Pereira, N Rani, R Sergeant, R Thomson, J Tran, TH Turpeinen, H Yang, KL Zunec, R Carrington, M de Knijff, P Goulmy, E AF Spierings, Eric Hendriks, Matthijs Absi, Lena Canossi, Angelica Chhaya, Sonal Crowley, John Dolstra, Harry Eliaou, Jean-Francois Ellis, Tom Enczmann, Juergen Fasano, Maria E. Gervais, Thibaut Gorodezky, Clara Kircher, Brigitte Laurin, David Leffell, Mary S. Loiseau, Pascale Malkki, Mari Markiewicz, Miroslaw Martinetti, Miryam Maruya, Etsuko Mehra, Narinder Oguz, Fatma Oudshoorn, Machteld Pereira, Noemi Rani, Rajni Sergeant, Ruhena Thomson, Jackie Tran, Thuong Hien Turpeinen, Hannu Yang, Kuo-Liang Zunec, Renata Carrington, Mary de Knijff, Peter Goulmy, Els TI Phenotype frequencies of autosomal minor histocompatibility antigens display significant differences among populations SO PLOS GENETICS LA English DT Article ID STEM-CELL TRANSPLANTATION; CYTOTOXIC T-LYMPHOCYTES; HA-1; CANCER; GENE; IDENTIFICATION; EXPRESSION; IMMUNOTHERAPY; RECOGNITION; LEUKEMIA AB Minor histocompatibility (H) antigens are allogeneic target molecules having significant roles in alloimmune responses after human leukocyte antigen-matched solid organ and stem cell transplantation (SCT). Minor H antigens are instrumental in the processes of transplant rejection, graft- versus-host disease, and in the curative graft-versus- tumor effect of SCT. The latter characteristic enabled the current application of selected minor H antigens in clinical immunotherapeutic SCT protocols. No information exists on the global phenotypic distribution of the currently identified minor H antigens. Therefore, an estimation of their overall impact in human leukocyte antigen-matched solid organ and SCT in the major ethnic populations is still lacking. For the first time, a worldwide phenotype frequency analysis of ten autosomal minor H antigens was executed by 31 laboratories and comprised 2,685 randomly selected individuals from six major ethnic populations. Significant differences in minor H antigen frequencies were observed between the ethnic populations, some of which appeared to be geographically correlated. C1 Leiden Univ, Med Ctr, Leiden, Netherlands. EFS Auvergne Loire, Lab Histocompatibil, St Etienne, France. Ist CNR Trapianti Organ Immunocitol, Laquila, Italy. Tata Mem Hosp, Bombay 400012, Maharashtra, India. Natl Blood Ctr, Natl Histocompatibil & Immunogenet Reference Lab, Dublin, Ireland. Radboud Univ Nijmegen, Nijmegen Med Ctr, Cent Hematol Lab, Nijmegen, Netherlands. Hop St Eloi, CHU Montpellier, Unit Immunogenet, Immunol Lab, Montpellier, France. Blood Ctr SE Wisconsin Inc, Milwaukee, WI USA. Univ Hosp, Inst Transplantat Immunol, Dusseldorf, Germany. Az Osped S Giovanni Battista Torino UOADU, Turin, Italy. Catholic Univ Louvain, Clin St Luc, Brussels, Belgium. Inst Diagnost & Reference Epidemiol, Dept Immunol & Immunogenet, Mexico City, DF, Mexico. Innsbruck Med Univ, Div Hematol & Oncol, Innsbruck, Austria. Establissement Francais Sang Rhone Alpes, Lab Immunol Res & Dev, Grenoble, France. Johns Hopkins Univ, Sch Med, Immunogenet Lab, Baltimore, MD 21218 USA. Hop St Louis, Immunol Lab, Paris, France. Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA USA. L Warynski Silesian Med Acad, Hematol & BMT Dept, Katowice, Poland. IRCCS, Policlin San Matteo, Serv Immunoematol & Transfus, Lab HLA, Pavia, Italy. HLA Lab, Sakyo Ku, Kyoto, Japan. All India Inst Med Sci, Dept Transplant Immunol & Immunogenet, New Delhi, India. Istanbul Univ, Istanbul Fac Med, Dept Med Biol, Istanbul, Turkey. Stichting Europdonor, Leiden, Netherlands. Univ Fed Parana, Hosp Clin, Immunogenet Lab, BR-80060000 Curitiba, Parana, Brazil. Natl Inst Immunol, New Delhi 110067, India. Hammersmith Hosp, Clin Immunol Lab, London, England. Univ Cape Town, Sch Med, Lab Tissue Immunol, ZA-7700 Rondebosch, South Africa. Univ Heidelberg, Inst Immunol, Dept Transplantat Immunol, D-6900 Heidelberg, Germany. Finnish Red Cross Blood Serv, Res & Dev, Helsinki, Finland. Tsu Chi Stem Cells Ctr, Cord Blood Bank, Hualien, Taiwan. Clin Hosp Zagreb, Tissue Typing Ctr, Zagreb, Croatia. Sci Applicat Int Corp, Lab Genom Divers, Frederick, MD USA. Frederick Canc Res & Dev, Natl Canc Inst, Frederick, MD USA. Leiden Univ, Med Ctr, Dept Human Genet, Leiden, Netherlands. RP Spierings, E (reprint author), Leiden Univ, Med Ctr, Leiden, Netherlands. EM eric.spierings@lumc.nl RI Laurin, David/M-7895-2014; Dolstra, H./L-4276-2015; OI Laurin, David/0000-0001-9339-8369; Spierings, Eric/0000-0001-9441-1019 FU Intramural NIH HHS; NCI NIH HHS [N01CO12400, N01-CO-12400] NR 38 TC 55 Z9 58 U1 0 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD JUN PY 2007 VL 3 IS 6 BP 1108 EP 1119 AR e103 DI 10.1371/journal.pgen.0030103 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 194MU UT WOS:000248349300023 PM 17604453 ER PT J AU An, P Wang, LH Hutcheson-Dilks, H Nelson, G Donfield, S Goedert, JJ Rinaldo, CR Buchbinder, S Kirk, GD O'Brien, SJ Winkler, CA AF An, Ping Wang, Li Hua Hutcheson-Dilks, Holli Nelson, George Donfield, Sharyne Goedert, James J. Rinaldo, Charles R. Buchbinder, Susan Kirk, Gregory D. O'Brien, Stephen J. Winkler, Cheryl A. TI Regulatory polymorphisms in the cyclophilin A gene, PPIA, accelerate progression to AIDS SO PLOS PATHOGENS LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; HIV-1 INFECTION; TRIM5-ALPHA RESTRICTION; HUMAN-CELLS; DRUG-USERS; ASSOCIATION; RESISTANCE; HEMOPHILIA; VARIANTS; VIRIONS AB Human cyclophilin A, or CypA, encoded by the gene peptidyl prolyl isomerase A (PPIA), is incorporated into the HIV type 1 (HIV-1) virion and promotes HIV-1 infectivity by facilitating virus uncoating. We examined the effect of single nucleotide polymorphisms (SNPs) and haplotypes within the PPIA gene on HIV-1 infection and disease progression in five HIV-1 longitudinal history cohorts. Kaplan- Meier survival statistics and Cox proportional hazards model were used to assess time to AIDS outcomes. Among eight SNPs tested, two promoter SNPs (SNP3 and SNP4) in perfect linkage disequilibrium were associated with more rapid CD4(+) T- cell loss (relative hazard = 3.7, p = 0.003) in African Americans. Among European Americans, these alleles were also associated with a significant trend to more rapid progression to AIDS in a multi-point categorical analysis (p = 0.005). Both SNPs showed differential nuclear protein- binding efficiencies in a gel shift assay. In addition, one SNP (SNP5) located in the 5 ' UTR previously shown to be associated with higher ex vivo HIV-1 replication was found to be more frequent in HIV-1-positive individuals than in those highly exposed uninfected individuals. These results implicate regulatory PPIA polymorphisms as a component of genetic susceptibility to HIV-1 infection or disease progression, affirming the important role of PPIA in HIV-1 pathogenesis. C1 Natl Canc Frederick, Sci Applicat Int Corp, Lab Genom Divers, Frederick, MD USA. Natl Canc Inct, Lab Genome Divers, Frederick, MD USA. Rho Inc, Chapel Hill, NC USA. NCI, Div Canc, Vira Epidemiol Branch, Bethesda, MD USA. Univ Pittsburgh, Dept Infect Dis & Microbiol, Grad Sch Publ Hlth, Pittsburgh, PA 15260 USA. San Francisco, Dept Publ Hlth, San Francisco, CA USA. Johns Hopkins Univ, Dept Epidemiol, Sch Publ Hlth, Baltimore, MD 21218 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. RP Winkler, CA (reprint author), NCI, Sci Applicat Int Corp, Lab Genom Divers, Frederick, MD 21701 USA. EM winkler@mail.ncifcrf.gov RI Kirk, Gregory/A-8484-2009 FU Intramural NIH HHS; NCATS NIH HHS [UL1 TR000005]; NCI NIH HHS [N01CO12400, N01-CO-12400]; NIDA NIH HHS [DA-04334, R01 DA004334, R37 DA004334, R56 DA004334] NR 45 TC 42 Z9 44 U1 0 U2 8 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 JUN PY 2007 VL 3 IS 6 BP 849 EP 857 AR e88 DI 10.1371/journal.ppat.0030088 PG 9 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 196VX UT WOS:000248511400015 PM 17590083 ER PT J AU Carmen, J Magnus, T Cassiani-Ingoni, R Sherman, L Rao, MS Mattson, MR AF Carmen, Jessica Magnus, Tim Cassiani-Ingoni, Riccardo Sherman, Larry Rao, Mahendra S. Mattson, Mark R. TI Revisiting the astrocyte-oligodendrocyte relationship in the adult CNS SO PROGRESS IN NEUROBIOLOGY LA English DT Review DE astrocytes; oligodendrocytes; CNS injury; glial scar; CNS damage; stem cell; glial precursor ID CENTRAL-NERVOUS-SYSTEM; NEURAL STEM-CELLS; FIBRILLARY ACIDIC PROTEIN; SPINAL-CORD-INJURY; BONE-MARROW CELLS; GLIAL PROGENITOR-CELL; GROWTH-FACTOR PDGF; SUBVENTRICULAR ZONE; IN-VIVO; PRECURSOR CELLS AB The lineages of both astrocytes and oligodendrocytes have been popular areas of research in the last decade. The source of these cells in the mature CNS is relevant to the study of the cellular response to CNS injury. A significant amount of evidence exists to suggest that resident precursor cells proliferate and differentiate into mature glial cells that facilitate tissue repair and recovery. Additionally, the re-entry of mature astrocytes into the cell cycle can also contribute to the pool of new astrocytes that are observed following CNS injury. In order to better understand the glial response to injury in the adult CNS we must revisit the astrocyte-oligodendrocyte relationship. Specifically, we argue that there is a common glial precursor cell from which astrocytes and oligodendrocytes differentiate and that the microenvironment surrounding the injury determines the fate of the stimulated precursor cell. Ideally, better understanding the origin of new glial cells in the injured CNS will facilitate the development of therapeutics targeted to alter the glial response in a beneficial way. (C) 2007 Elsevier Ltd. All rights reserved. C1 NIA, Neurosci Lab, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NINDS, Cellular Immunol Sect, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Oregon Hlth & Sci Univ, Oregon Natl Primate Res Ctr, Div Neurosci, Beaverton, OR 97006 USA. Invitrogen Corp, Corp Res Labs, Carlsbad, CA 92008 USA. RP Carmen, J (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, 600 N Wolfe St, Baltimore, MD 21287 USA. EM jcarmen1@jhmi.edu FU Intramural NIH HHS NR 143 TC 15 Z9 15 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0301-0082 J9 PROG NEUROBIOL JI Prog. Neurobiol. PD JUN PY 2007 VL 82 IS 3 BP 151 EP 162 DI 10.1016/j.pneurobio.2007.03.001 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 185WL UT WOS:000247741000004 PM 17448587 ER PT J AU Kouprina, N Noskov, VN Solomon, G OtStot, J Isaacs, W Xu, JF Schleutker, J Larionov, V AF Kouprina, Natalay Noskov, Vladimir N. Solomon, Greg OtStot, John Isaacs, William Xu, Jianfeng Schleutker, Johanna Larionov, Vladimir TI Mutational analysis of SPANXGenes in families with X-linked prostate cancer SO PROSTATE LA English DT Article DE SPANX gene cluster; HPCX; prostate cancer; TAR cloning ID SUSCEPTIBILITY LOCUS HPCX; GENOME-WIDE SCAN; CELL-LINES; CANCER/TESTIS ANTIGENS; RECOMBINATION CLONING; SELECTIVE ISOLATION; HUMAN SPERMATOZOA; LINKAGE ANALYSIS; GENE; EXPRESSION AB BACKGROUND. Previous genetic linkage studies identified a locus for susceptibility to prostate cancer called HPCX at Xq27. The candidate region contains two clusters of SPANX genes. The first cluster called SPANX-A/D includes SPANX-A1, SPANX-A2, SPANX-B, SPANX-C, and SPANX-D; the second cluster called SPANX-N includes SPANX-N1, SPANX-N2, SPANX-N3, and SPANX-N4. The SPANX genes encode cancer-testis (CT) specific antigens. Previous studies identified SPANX-B and SPANX-D variants produced by gene conversion events, none of which are associated with X-linked prostate cancer. METHODS. In this study we applied transformation-associated recombination cloning (TAR) in yeast to analyze sequence variations in SPANX-A1, SPANX-A2, and SPANX-C genes that are resided within large chromosomal duplications. A SPANX-N1/N4 cluster was analyzed by a routine PCR analysis. RESULTS. None of the sequence variations in the coding regions of these genes is associated with susceptibility to prostate cancer. CONCLUSIONS. Therefore, genetic variation in the SPANX genes is not the actual target variants explaining HPCX. However, it is possible that they play a modifying role in susceptibility to prostate cancer through complex recombinational interaction. C1 NCI, Lab Mol Pathol, NIH, Bethesda, MD 20892 USA. NIEHS, Lab Mol Carcinogenesis, NIH, Res Triangle Pk, NC USA. Johns Hopkins Univ, Dept Urol, Baltimore, MD USA. Wake Forest Univ, Sch Med, Ctr Human Genom, Winston Salem, NC USA. Tampere Univ, Inst Med Technol, Lab Canc Genet, Tampere, Finland. Tampere Univ Hosp, Tampere, Finland. RP Kouprina, N (reprint author), NCI, Lab Mol Pathol, NIH, Bethesda, MD 20892 USA. EM kouprinn@mail.nih.gov FU Intramural NIH HHS NR 41 TC 13 Z9 15 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 JUN 1 PY 2007 VL 67 IS 8 BP 820 EP 828 DI 10.1002/pros.20561 PG 9 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 170BO UT WOS:000246636300003 PM 17373721 ER PT J AU Daugherty, SE Hayes, RB Yeager, M Andriole, GL Chatterjee, NJ Huang, WY Isaacs, WB Platz, EA AF Daugherty, Sarah E. Hayes, Richard B. Yeager, Meredith Andriole, Gerald L. Chatterjee, Nilan-Jan Huang, Wen-Yi Isaacs, William B. Platz, Elizabeth A. TI RNASEL Arg462Gln polymorphism and prostate cancer in PLCO SO PROSTATE LA English DT Article DE RNASEL; prostate cancer; non-steroidal anti-inflammatory drugs; inflammation ID GENE; FAMILIES; METAANALYSIS; HEREDITARY; MUTATIONS; LINKAGE; HPC1; MEN AB BACKGROUND. The Gln allele of the Arg162Gln polymorphism in RNASEL results in a threefold decrease in enzymatic activity, a reported deficiency in apoptotic response, and has been associated with prostate cancer in some high-risk family studies. The relationship of this variant to sporadic prostate cancer remain,; uncertain. METHODS. We conducted a nested case-control study of 1,317 prostate cancer cases and 1,842 controls from the screening arm of the prostate, lung, colorectal, and ovarian (PLCO) cancer screening trial. Conditional logistic regression was used to evaluate the association between the RNASEL Arg462Gln polymorphism and prostate cancer. RESULTS. No statistically significant association was observed between the Arg462Gln polymorphism and prostate cancer (compared to Arg/Arg, Gln/Arg: OR 0.99 95% CI 0.84-1.16; Gln/Gln: OR = 0.95 95% CI 0.74-1.21), although slight non-significant differences in risk were observed among men with the Gln/Gln genotype by stage and grade. CONCLUSIONS. These results suggest that the RNASEL Gln/Gln genotype does not play an important role in the etiology of prostate cancer in the general population. C1 NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. NCI, SAIC Frederick, Core Genotyping Facil, NIH, Bethesda, MD USA. Washington Univ, Sch Med, Div Urol Surg, St Louis, MO USA. James Buchanan Brady Urol Inst, Baltimore, MD USA. Johns Hopkins Med Inst, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RP Daugherty, SE (reprint author), 6120 Executive Blvd,EPS 8121,MSC 724, Bethesda, MD USA. EM daughers@mail.nih.gov OI Hayes, Richard/0000-0002-0918-661X FU Intramural NIH HHS; NCI NIH HHS [T32 CA09314] NR 22 TC 14 Z9 14 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 JUN 1 PY 2007 VL 67 IS 8 BP 849 EP 854 DI 10.1002/pros.20537 PG 6 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 170BO UT WOS:000246636300006 PM 17407163 ER PT J AU Wang, T Zhou, Z Bunagan, MR Du, DG Bai, YW Gai, F AF Wang, Ting Zhou, Zheng Bunagan, Michelle R. Du, Deguo Bai, Yawen Gai, Feng TI Probing the folding intermediate of Rd-apocyt b(562) by protein engineering and infrared T-jump SO PROTEIN SCIENCE LA English DT Article DE T-jump; infrared; Rd-apocyt b(562); intermediate; protein folding ID LIMITING TRANSITION-STATE; 4-HELIX BUNDLE PROTEIN; HYDROGEN-EXCHANGE; STRUCTURAL CHARACTERIZATION; HIDDEN INTERMEDIATE; HELIX FORMATION; 3-HELIX BUNDLE; CYTOCHROME-C; SPEED LIMIT; KINETICS AB Small proteins often fold in an apparent two-state manner with the absence of detectable early-folding intermediates. Recently, using native-state hydrogen exchange, intermediates that exist after the rate-limiting transition state have been identified for several proteins. However, little is known about the folding kinetics from these post-transition intermediates to their corresponding native states. Herein, we have used protein engineering and a laser-induced temperature-jump (T-jump) technique to investigate this issue and have applied it to Rd-apocyt b(562), a four-helix bundle protein. Previously, it has been shown that Rd-apocyt b(562) folds via an on-pathway hidden intermediate, which has only the N-terminal helix unfolded. In the present study, a double mutation (V16G/I17A) in the N-terminal helix of Rd-apocyt b(562) was made to further increase the relative population of this intermediate state at high temperature by selectively destabilizing the native state. In the circular dichroism thermal melting experiment, this mutant showed apparent two-state folding behavior. However, in the T-jump experiment, two kinetic phases were observed. Therefore, these results are in agreement with the idea that a folding intermediate is populated on the folding pathway of Rd-apocyt b(562). Moreover, it was found that the exponential growth rate of the native state from this intermediate state is roughly (25 mu sec)(-1) at 65 degrees C. C1 Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Gai, F (reprint author), Univ Penn, Dept Chem, 231 S 34th St, Philadelphia, PA 19104 USA. EM yawen@helix.nih.gov; gai@sas.upenn.edu FU Intramural NIH HHS NR 35 TC 7 Z9 7 U1 0 U2 11 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD JUN PY 2007 VL 16 IS 6 BP 1176 EP 1183 DI 10.1110/ps.062505607 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 171HP UT WOS:000246727100016 PM 17473017 ER PT J AU Kann, MG Jothi, R Cherukuri, PF Przytycka, TM AF Kann, Maricel G. Jothi, Raja Cherukuri, Praveen F. Przytycka, Teresa M. TI Predicting protein domain interactions from coevolution of conserved regions SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE protein domain interactions; phylogenetic trees; co-evolution; information theory; speciation ID CO-EVOLUTIONARY ANALYSIS; MULTIPLE SEQUENCE ALIGNMENT; SACCHAROMYCES-CEREVISIAE; INTERACTION NETWORK; REVEALS INSIGHTS; COMPLEXES; DATABASE; INFORMATION; ACCURACY; GENOMES AB The knowledge of protein and domain interactions provide crucial insights into their function within a cell. Several computational methods have been proposed to detect interactions between proteins and their constitutive domains. In this work, we focus on approaches based on correlated evolution (coevolution) of sequences of interacting proteins. In this type of approach, often referred to as the mirrortree method, a high correlation of evolutionary histories of two proteins is used as an indicator to predict protein interactions. Recently, it has been observed that subtracting the underlying speciation process by separating coevolution due to common speciation divergence from that due to common function of interacting pairs greatly improves the predictive power of the mirrortree approach. In this article, we investigate possible improvements and limitations of this method. In particular, we demonstrate that the performance of the mirrortree method that can be further improved by restricting the coevolution analysis to the relatively conserved regions in the protein domain sequences (disregarding highly divergent regions). We provide a theoretical validation of our results leading to new insights into the interplay between coevolution and speciation of interacting proteins. Proteins 2007;67:811-820. (C) 2007 Wiley-Liss, Inc.*. C1 NIH, Natl Ctr Biotechnol Informat, Dept Hlth & Human Serv, Natl Lib Med, Bethesda, MD 20894 USA. RP Przytycka, TM (reprint author), NIH, Natl Ctr Biotechnol Informat, Dept Hlth & Human Serv, Natl Lib Med, Bldg 38A,Room 812, Bethesda, MD 20894 USA. EM przytyck@ncbi.nlm.nih.gov RI Kann, Maricel/E-5701-2012; Jothi, Raja/G-3780-2015 FU Intramural NIH HHS NR 38 TC 28 Z9 32 U1 0 U2 6 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 JUN PY 2007 VL 67 IS 4 BP 811 EP 820 DI 10.1002/prot.21347 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 166YA UT WOS:000246415700004 PM 17357158 ER PT J AU Zheng, WJ Liao, JC Brooks, BR Doniach, S AF Zheng, Wenjun Liao, Jung-Chi Brooks, Bernard R. Doniach, Sebastian TI Toward the mechanism of dynamical couplings and translocation in hepatitis C virus NS3 helicase using elastic network model SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE normal mode analysis; elastic network model; dynamical coupling; helicase; allostery ID BOX RNA HELICASE; MUTATIONAL ANALYSIS; DNA HELICASE; CRYSTAL-STRUCTURE; DOMAIN MOTIONS; MOTOR; PROTEINS; ATP; COORDINATION; SYNTHASE AB Hepatitis C virus NS3 helicase is an enzyme that unwinds double-stranded polynucleotides in an ATP-dependent reaction. It provides a promising target for small molecule therapeutic agents against hepatitis C. Design of such drugs requires a thorough understanding of the dynamical nature of the mechanochemical functioning of the helicase. Despite recent progress, the detailed mechanism of the coupling between ATPase activity and helicase activity remains unclear. Based on an elastic network model (ENM), we apply two computational analysis tools to probe the dynamical mechanism underlying the allosteric coupling between ATP binding and polynucleotide binding in this enzyme. The correlation analysis identifies a network of hot-spot residues that dynamically couple the ATP-binding site and the polynucleotide-binding site. Several of these key residues have been found by mutational experiments as functionally important, while our analysis also reveals previously unexplored hot-spot residues that are potential targets for future mutational studies. The conformational changes between different crystal structures of NS3 helicase are found to be dominated by the lowest frequency mode solved from the ENM. This mode corresponds to a hinge motion of the highly flexible domain 2. This motion simultaneously modulates the opening/closing of the domains 1-2 cleft where ATP binds, and the domains 2-3 cleft where the polynucleotide binds. Additionally, a small twisting motion of domain 1, observed in both mode 1 and the computed ATP binding induced conformational change, fine-tunes the binding affinity of the domains 1-3 interface for the polynucleotide. The combination of these motions facilitates the translocation of a single-stranded polynucleotide in an inchworm-like manner. Proteins 2007;67:886-896. (C) 2007 Wiley-Liss, Inc.dagger. C1 NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. Stanford Univ, Dept Bioengn, Stanford, CA 94305 USA. Stanford Univ, Dept Appl Phys, Stanford, CA 94305 USA. RP Zheng, WJ (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM zhengwj@helix.nih.gov RI Liao, Jung-Chi/B-3336-2014; OI Zheng, Wenjun/0000-0002-6236-9765 FU NIGMS NIH HHS [U54 GM072970] NR 46 TC 35 Z9 35 U1 0 U2 5 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 JUN PY 2007 VL 67 IS 4 BP 886 EP 896 DI 10.1002/prot.21326 PG 11 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 166YA UT WOS:000246415700009 PM 17373706 ER PT J AU Forlino, A Tani, C Rossi, A Lupi, A Campari, E Gualeni, B Bianchi, L Armini, A Cetta, G Bini, L Marini, JC AF Forlino, Antonella Tani, Chiara Rossi, Antonio Lupi, Anna Campari, Elena Gualeni, Benedetta Bianchi, Laura Armini, Alessandro Cetta, Giuseppe Bini, Luca Marini, Joan C. TI Differential expression of both extracellular and intracellular proteins is involved in the lethal or nonlethal phenotypic variation of BrtIIV, a murine model for osteogenesis imperfecta SO PROTEOMICS LA English DT Article; Proceedings Paper CT 2nd International Workshop on 2-D DIGE Applications in Proteomics CY FEB 27-MAR 02, 2007 CL Ruhr Univ Bochum, Bochum, GERMANY HO Ruhr Univ Bochum DE 2-DE; allele specific real-time PCR; microarray; osteogenesis imperfecta; phenotypic variability ID COLLAGEN MUTATION DATABASE; I COLLAGEN; 2-DIMENSIONAL ELECTROPHORESIS; POLYACRYLAMIDE-GELS; PLATELET ANTIGENS; PROTEOME ANALYSIS; BONE; IDENTIFICATION; CHAIN; MICE AB This study used proteomic and transcriptomic techniques to understand the molecular basis of the phenotypic variability in the bone disorder osteogenesis imperfecta (01). Calvarial bone mRNA expression was evaluated by microarray, real-time, and comparative RT-PCR and the bone proteome profile was analyzed by 2-DE, MS, and immunoblotting in the 01 murine model BrtlIV, which has either a moderate or a lethal 01 outcome. Differential expression analysis showed significant changes for eight proteins. The expression of the ER stress-related protein Gadd153 was increased in lethal mice, whereas expression of the chaperone alpha B crystallin was increased in nonlethal mice, suggesting that the intracellular machinery is involved in the modulation of the 01 phenotype. Furthermore, in lethal BrdlIV, the increased expression of the cartilaginous proteins Pre1p, Bmp6, and Bmp7 and the lower expression of the bone matrix proteins matrilin 4, microfibril-associated glycoprotein 2, and thrombospondin 3 revealed that both a delay in skeletal development and an alteration in extracellular matrix composition influence 01 outcomes. Differentially expressed proteins identified in this model offer a starting point for elucidating the molecular basis of phenotypic variability, a characteristic common to many genetic disorders. The first reference 2-DE map for murine calvarial tissue is also reported. C1 Univ Pavia, Dept Biochem A Castellani, Sect Med & Pharm, I-27100 Pavia, Italy. Univ Siena, Dept Mol Biol, I-53100 Siena, Italy. NICHD, Bone & Extracellular Matrix Bracnh, NIH, Bethesda, MD USA. RP Forlino, A (reprint author), Univ Pavia, Dept Biochem A Castellani, Sect Med & Pharm, Via Taramelli 3-B, I-27100 Pavia, Italy. EM aforlino@unipv.it RI Rossi, Antonio/E-9935-2012; Forlino, Antonella/H-5385-2015 OI Forlino, Antonella/0000-0002-6385-1182 NR 48 TC 29 Z9 30 U1 0 U2 2 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD JUN PY 2007 VL 7 IS 11 BP 1877 EP 1891 DI 10.1002/pmic.200600919 PG 15 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 179YF UT WOS:000247325800014 PM 17520686 ER PT J AU Vega, WA Pollitt, A Mays, RA AF Vega, William A. Pollitt, Anthony Mays, Robert A., Jr. TI Hispanics and telepsychiatry - Reply SO PSYCHIATRIC SERVICES LA English DT Letter C1 [Vega, William A.] Rutgers State Univ, Robert Wood Johnson Med Sch, Piscataway, NJ 08854 USA. [Pollitt, Anthony; Mays, Robert A., Jr.] NIMH, ORMHR, Rural Res Program, Bethesda, MD USA. RP Vega, WA (reprint author), Rutgers State Univ, Robert Wood Johnson Med Sch, Piscataway, NJ 08854 USA. NR 1 TC 3 Z9 3 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD JUN PY 2007 VL 58 IS 6 BP 878 EP 878 DI 10.1176/appi.ps.58.6.878 PG 1 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 265LJ UT WOS:000253360100025 ER PT J AU Wheatley, T Milleville, SC Martin, A AF Wheatley, Thalia Milleville, Shawn C. Martin, Alex TI Understanding animate agents - Distinct roles for the social network and mirror system SO PSYCHOLOGICAL SCIENCE LA English DT Article ID NEURAL SYSTEMS; IMITATION; MECHANISMS; PERCEPTION; ACTIVATION; COGNITION; OBJECTS; SELF AB How people understand the actions of animate agents has been vigorously debated. This debate has centered on two hypotheses focused on anatomically distinct neural substrates: The mirror-system hypothesis proposes that the understanding of others is achieved via action simulation, and the social-network hypothesis proposes that such understanding is achieved via the integration of critical biological properties (e.g., faces, affect). In this study, we assessed the areas of the brain that were engaged when people interpreted and imagined moving shapes as animate or inanimate. Although observing and imagining the moving shapes engaged the mirror system, only activation of the social network was modulated by animacy. C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Wheatley, T (reprint author), Dartmouth Coll, Dept Psychol & Brain Sci, Moore Hall, Hanover, NH 03755 USA. EM thalia.p.wheatley@dartmouth.edu RI martin, alex/B-6176-2009 FU Intramural NIH HHS NR 30 TC 102 Z9 102 U1 1 U2 17 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0956-7976 J9 PSYCHOL SCI JI Psychol. Sci. PD JUN PY 2007 VL 18 IS 6 BP 469 EP 474 DI 10.1111/j.1467-9280.2007.01923.x PG 6 WC Psychology, Multidisciplinary SC Psychology GA 179BH UT WOS:000247263800001 PM 17576256 ER PT J AU Ruo, B Liu, K Tian, L Tan, J Ferrucci, L Guralnik, JM McDermott, MM AF Ruo, Bernice Liu, Kiang Tian, Lu Tan, Jin Ferrucci, Luigj Guralnik, Jack M. McDermott, Mary M. TI Persistent depressive symptoms and functional decline among patients with peripheral arterial disease SO PSYCHOSOMATIC MEDICINE LA English DT Article DE depression; functional status; peripheral arterial disease; intermittent claudication ID LOWER-EXTREMITY FUNCTION; CHRONIC HEART-FAILURE; ANKLE BRACHIAL INDEX; OLDER PERSONS; PHYSICAL PERFORMANCE; OCCLUSIVE DISEASE; TREADMILL WALKING; LONGITUDINAL DATA; 6-MINUTE WALK; LEG SYMPTOMS AB Objective: Because depressive symptoms are prevalent among patients with peripheral arterial disease (PAD), our goal was to study the effect of depressive symptoms over time on functional decline among patients with PAD. Methods: We conducted a prospective cohort study of 417 patients with PAD followed annually for 2 years. A Geriatric Depression Scale Short Form (GDS-S) score > 5 was considered positive for depressive symptoms. Depressive symptom categories based on annual GDS-S measures included persistent, new, resolved, and no depressive symptoms. Outcome variables were change in 6-minute walk distance, 4-meter fast walking velocity, and short physical performance battery (0-12 scale, 12 = best). Results are adjusted for age, sex, race, body mass index, marital status, exercise level, smoking, ankle brachial index, leg symptoms, comorbidities, beta-blocker medication use, anti-depressant medications, and interim medical events. Results: In adjusted analyses, patients with new depressive symptoms had greater annual decline in fast walking velocity compared with that of patients with no depressive symptoms (-0.08 versus -0.01 meters/second per year, p = .02). Patients with persistent depressive symptoms had greater annual decline in 6-minute walk distance (-86.4 versus -41.5 feet/yr, p = .04), fast walking velocity (-0.08 versus -0.01 meters/second per year, p = .004), and short physical performance battery (-0.73 versus -0.18 per year, p = .005) compared with that of patients with no depressive symptoms. Conclusions: Among patients with PAD, persistent and new depressive symptoms are associated with greater annual decline in functional performance. Further study is needed to determine the mechanisms of these associations and whether treatment of depressive symptoms prevents functional decline in persons with PAD. C1 Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. Lab Clin Epidemiol, Baltimore, MD USA. NIA, Lab Epidemiol Demog & Biometry, Baltimore, MD 21224 USA. RP Ruo, B (reprint author), 676 N St Clair St,Suite 200, Chicago, IL 60611 USA. EM bruo@nmff.org FU Intramural NIH HHS [Z99 AG999999]; NCRR NIH HHS [M01 RR000048, RR-00048]; NHLBI NIH HHS [R01 HL064739, R01 HL071223, R01-HL071223, R01-HL58099, R01-HL64739] NR 44 TC 14 Z9 15 U1 3 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0033-3174 J9 PSYCHOSOM MED JI Psychosom. Med. PD JUN PY 2007 VL 69 IS 5 BP 415 EP 424 DI 10.1097/PSY.0b013e318063ef5c PG 10 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 184KY UT WOS:000247641500005 PM 17556643 ER PT J AU Beatty, PC Willis, GB AF Beatty, Paul C. Willis, Gordon B. TI Research synthesis: The practice of cognitive interviewing SO PUBLIC OPINION QUARTERLY LA English DT Article ID SURVEY QUESTIONS; VERBAL REPORTS AB Cognitive interviewing has emerged as one of the more prominent methods for identifying and correcting problems with survey questions. We define cognitive interviewing as the administration of draft survey questions while collecting additional verbal information about the survey responses, which is used to evaluate the quality of the response or to help determine whether the question is generating the information that its author intends. But beyond this general categorization, cognitive interviewing potentially includes a variety of activities that may be based on different assumptions about the type of data that are being collected and the role of the interviewer in that process. This synthesis reviews the range of current cognitive interviewing practices, focusing on three considerations: (1) what are the dominant paradigms of cognitive interviewing-what is produced under each, and what are their apparent advantages; (2) what key decisions about cognitive interview study design need to be made once the general approach is selected (e.g., who should be interviewed, how many interviews should be conducted, and how should probes be selected), and what bases exist for making these decisions; and (3) how cognitive interviewing data should be evaluated, and what standards of evidence exist for making questionnaire design decisions based on study findings. In considering these issues, we highlight where standards for best practices are not clearly defined, and suggest broad areas worthy of additional methodological research. C1 Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Beatty, PC (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, 3311 Toeldo Rd,Room 3218, Hyattsville, MD 20782 USA. EM pbb5@cdc.gov NR 62 TC 221 Z9 222 U1 5 U2 70 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0033-362X J9 PUBLIC OPIN QUART JI Public Opin. Q. PD SUM PY 2007 VL 71 IS 2 BP 287 EP 311 DI 10.1093/poq/nfm006 PG 25 WC Communication; Political Science; Social Sciences, Interdisciplinary SC Communication; Government & Law; Social Sciences - Other Topics GA 223DT UT WOS:000250350500006 ER PT J AU Bhatti, P Preston, DL Doody, MM Hauptmann, M Kampa, D Alexander, BH Petibone, D Simon, SL Weinstock, RM Bouville, A Yong, LC Freedman, DM Mabuchi, K Linet, MS Edwards, AA Tucker, JD Sigurdson, AJ AF Bhatti, Parveen Preston, Dale L. Doody, Michele Morin Hauptmann, Michael Kampa, Diane Alexander, Bruce H. Petibone, Dayton Simon, Steven L. Weinstock, Robert M. Bouville, Andre Yong, Lee C. Freedman, D. Michal Mabuchi, Kiyohiko Linet, Martha S. Edwards, Alan A. Tucker, James D. Sigurdson, Alice J. TI Retrospective biodosimetry among United States radiologic technologists SO RADIATION RESEARCH LA English DT Article ID RADIATION-INDUCED TRANSLOCATIONS; CHROMOSOME-ABERRATION ANALYSIS; FISH-DETECTED TRANSLOCATIONS; PERIPHERAL-BLOOD LYMPHOCYTES; SELLAFIELD NUCLEAR FACILITY; BIOLOGICAL DOSIMETRY; IONIZING-RADIATION; CANCER INCIDENCE; CLEANUP WORKERS; SMOKING-HABITS AB Measurement of chromosome translocations in peripheral blood lymphocytes has been used to quantify prior exposure to ionizing radiation, including for workers exposed to low, chronic doses. We assessed translocation frequencies in a subset of U.S. radiologic technologists to substantiate ionizing radiation dose estimates developed for 110,418 technologists who worked between 1916 and 1984. From 3,441 cohort members known to have begun working before 1950, we selected a sample of 152, stratified by estimated cumulative dose, oversampling from higher-dose categories and excluding persons with a prior cancer diagnosis, a personal or family history of chromosomal instability disorders, or a current history of smoking. Estimates of film-badge dose ranged from less than 10 cSv to more than 30 cSv. Blood samples, obtained in 2004, were analyzed by fluorescence in situ hybridization (FISH) whole chromosome painting by simultaneously labeling chromosomes 1, 2 and 4 in red and 3, 5 and 6 in green. Translocations were scored in 1800 well-spread metaphase cells and expressed per 100 cell equivalents (CE) per person. Linear Poisson regression models with allowance for overdispersion were used to assess the relationship between estimated occupational red bone marrow absorbed dose in cGy and translocation frequency, adjusted for age, gender and estimated red bone marrow absorbed dose score from personal diagnostic procedures. We observed 0.09 excess translocations per 100 CE per cGy red bone marrow dose (95% CI: -0.01, 0.2; P = 0.07), which is similar to the expected estimate based on previous cytogenetic studies (0.05 excess translocations per 100 CE per cGy). Despite uncertainty in the estimates of occupational red bone marrow absorbed doses, we found good general agreement between the doses and translocation frequencies, lending support to the credibility of the dose assessment for this large cohort of U.S. radiologic technologists. (C) 2007 by Radiation Research Society C1 NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, DHHS,NIH, Bethesda, MD 20892 USA. HiroSoft Int Corp, Seattle, WA USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, DHHS,NIH, Bethesda, MD USA. Netherlands Canc Inst, Amsterdam, Netherlands. Univ Minnesota, Minneapolis, MN USA. Wayne State Univ, Dept Biol Sci, Detroit, MI 48202 USA. NIOSH, Cincinnati, OH 45226 USA. Hlth Protect Agcy, Radiat Protect Div, Didcot, Oxon, England. RP Sigurdson, AJ (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, DHHS,NIH, 6120 Execut Blvd,EPS 7060,MSC 7238, Bethesda, MD 20892 USA. EM sigurdsa@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01 CP31018, N02 CP31003, N02 CP31013, Y1 CP9012] NR 35 TC 26 Z9 26 U1 1 U2 3 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD JUN PY 2007 VL 167 IS 6 BP 727 EP 734 DI 10.1667/RR0894.1 PG 8 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 172RQ UT WOS:000246822100011 PM 17523852 ER PT J AU Schell, MJ Yankaskas, BC Ballard-Barbash, R Qaqish, BF Barlow, WE Rosenberg, RD Smith-Bindman, R AF Schell, Michael J. Yankaskas, Bonnie C. Ballard-Barbash, Rachel Qaqish, Bahjat F. Barlow, William E. Rosenberg, Robert D. Smith-Bindman, Rebecca TI Evidence-based target recall rates for screening mammography SO RADIOLOGY LA English DT Article ID FALSE-POSITIVE MAMMOGRAMS; PERFORMANCE; GUIDELINES; PROGRAMS AB Purpose: To retrospectively identify target recall rates for screening mammography on the basis of how sensitivity shifts with recall rate. Materials and Methods: The study group included 1 872 687 subsequent and 171 104 first screening mammograms from 1996 to 2001 from 172 and 139 facilities, respectively, in six sites of the Breast Cancer Surveillance Consortium. Institutional review board ( IRB) approval was obtained from each site. Informed consent requirements of the IRBs were followed. The study was HIPAA compliant. Recall rate was defined as the percentage of screening studies for which further work-up was recommended by the radiologist. Sensitivity was defined as the proportion of cancers that were detected at screening mammography. Piecewise linear regression was used to model sensitivity as a function of recall rate. This model allows detection of critical recall rates in which significant changes ( shifts) occurred in the rates that sensitivity increased with increasing recall rate. Rates were interpreted as number of additional work-ups per additional cancer detected ( AW/ACD) or, in other words, the estimated number of additional women needed to be recalled at a given rate to detect one additional cancer. Results: For first mammograms, a single shift in the estimated AW/ACD rate occurred at a recall rate of 10.0%, with the rate jumping dramatically from 35 to 172. For subsequent mammograms, four shifts were identified. At a recall rate of 6.7%, the estimated AW/ACD increased from 80 to 132, which rendered it the highest desirable target recall rate. At a recall rate of 12.3%, the estimated AW/ACD was 304, which suggests little benefit for any higher recall rate. Conclusion: Recall rates of 10.0% for first and 6.7% for subsequent mammograms are recommended targets on the basis of their AW/ACD rates ( less than 100). (c) RSNA, 2007. C1 Moffitt Res Ctr, Dept Interdisciplinary Oncol, Div Biostat, Tampa, FL 33612 USA. Univ N Carolina, Dept Radiol, Chapel Hill, NC USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. NCI, Div Canc Control & Populat Studies, Appl Res Program, Bethesda, MD 20892 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Univ New Mexico, Hlth Sci Ctr, Dept Radiol, Albuquerque, NM 87131 USA. Univ Calif San Francisco, Dept Radiol Epidemiol & Biostat, San Francisco, CA 94143 USA. RP Schell, MJ (reprint author), Moffitt Res Ctr, Dept Interdisciplinary Oncol, Div Biostat, 12902 Magnolia Dr, Tampa, FL 33612 USA. EM michael.schell@moffitt.org FU NCI NIH HHS [U01 CA69976, U01 CA63740, U01 CA63731, U01 CA70013, U01 CA70040, U01 CA86076, U01 CA63736, U01 CA86082] NR 22 TC 42 Z9 44 U1 1 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD JUN PY 2007 VL 243 IS 3 BP 681 EP 689 DI 10.1148/radiol.2433060372 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 170UQ UT WOS:000246691600010 PM 17517927 ER PT J AU Aragon-Ching, JB Li, HQ Gardner, ER Figg, WD AF Aragon-Ching, Jeanny B. Li, Haiqing Gardner, Erin R. Figg, William D. TI Thalidomide analogues as anticancer drugs SO RECENT PATENTS ON ANTI-CANCER DRUG DISCOVERY LA English DT Review DE thalidomide analogues; CC-5013; lenalidomide; CC-4047; CPS49; CPS11; multiple myeloma; prostate cancer ID MULTIPLE-MYELOMA CELLS; PHASE-II TRIAL; INDEPENDENT PROSTATE-CANCER; NEWLY-DIAGNOSED MYELOMA; DEEP-VEIN THROMBOSIS; TNF-ALPHA; TUMOR ANGIOGENESIS; MYELODYSPLASTIC SYNDROMES; THERAPEUTIC APPLICATIONS; INHIBITS ANGIOGENESIS AB The evolution of thalidomide as an effective treatment in several neoplasms has led to the search for compounds with increased antiangiogenic and anti-tumor effects, but decreased side-effects. The development of thalidomide analogues which retain the immunomodulatory effects of the parent compound, while minimizing the adverse reactions, brought about a class of agents termed the Immunomodulatory drugs (IMiDs). The IMiDs have undergone significant advances in recent years as evidenced by the recent FDA-approvals of one of the lead compounds, CC-5013 (lenalidomide), for 5q- myelodysplasia and for multiple myeloma (MM). Actimid (CC-4047), another IMiD lead compound, has also undergone clinical testing in MM. Apart from hematologic malignancies, these drugs are actively under investigation in solid tumor malignancies including prostate cancer, melanoma, and gliomas, in which potent activity has been demonstrated, The preclinical and clinical data relating to these analogues, as well as ENMD-0995, are reviewed herein. Encouraging results with these thalidomide analogues brought forth synthesis and screening of additional novel thalidomide analogues in the N-substituted and tetrafluorinated classes, including CPSI 1 and CPS49. This review also discusses the patents and preclinical findings for these agents. C1 NCI, Med Oncol Branch, CCR, NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Sect, CCR, Med Oncol Branch, Bethesda, MD 20892 USA. SAIC Frederick Inc, Clin Pharmacol Program, NCI, Frederick, MD USA. RP Figg, WD (reprint author), NCI, Med Oncol Branch, CCR, NIH, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016; OI Aragon-Ching, Jeanny/0000-0002-6714-141X FU Intramural NIH HHS [, 001-1802-535, NIH0011335962, NIH0011802535]; NCI NIH HHS [N01-CO-12400, N01CO12400]; PHS HHS [001-1802-535, NIH0011335962, NIH0011802535] NR 80 TC 37 Z9 41 U1 0 U2 7 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1574-8928 J9 RECENT PAT ANTI-CANC JI Recent Patents Anti-Canc. Drug Discov. PD JUN PY 2007 VL 2 IS 2 BP 167 EP 174 PG 8 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 178ZS UT WOS:000247259700006 PM 17975653 ER PT J AU Illei, GG Yarboro, CH Kuroiwa, T Schlimgen, R Austin, HA Tisdale, JF Chitkara, P Fleisher, T Klippel, JH Balow, JE Boumpas, DT AF Illei, G. G. Yarboro, C. H. Kuroiwa, T. Schlimgen, R. Austin, H. A. Tisdale, J. F. Chitkara, P. Fleisher, T. Klippel, J. H. Balow, J. E. Boumpas, D. T. TI Long-term effects of combination treatment with fludarabine and low-dose pulse cyclophosphamide in patients with lupus nephritis SO RHEUMATOLOGY LA English DT Article DE systemic lupus erythematosus; chemotherapy; myelosuppression; remission; safety ID CONTROLLED TRIAL; THERAPY; METHYLPREDNISOLONE; ERYTHEMATOSUS AB Objectives. To determine the safety and efficacy of a short course of fludarabine combined with cyclophoshamide in lupus nephritis. Methods. A phase I/II open label pilot study. Thirteen patients with active proliferative lupus nephritis received monthly oral boluses of low-dose cyclophoshamide (0.5gm/m(2) on day 1) and subcutaneous fludarabine (30 mg/m(2) on days 1-3) for 3-6 cycles. Concomitant prednisone was aggressively tapered from 0.5 mg/kg/day to a low-dose, alternate-day schedule. Patients were followed for at least 24 months after therapy. The primary outcome was the number of patients achieving renal remission defined as stable creatinine, proteinuria <1 gm/day and inactive urine sediment for at least 6 months. Results. The study was terminated early because of bone marrow toxicity. Eleven patients who received at least three cycles were evaluated for efficacy. Ten patients improved markedly with seven patients achieving complete remission and three patients achieving partial remission. There were three serious haematological adverse events during the treatment with one death due to transfusion-associated graft vs host disease. Profound and prolonged CD4 (mean CD4: 98/mu l at 7 months and 251/mu l at 12 months) and CD20 lymphocytopenia was noted in most patients. Three patients developed Herpes zoster infections. Conclusions. A short course of low-dose fludarabine and cyclophoshamide can induce long-lasting remissions in patients with proliferative lupus nephritis, but severe myelosuppression limits its widespread use. C1 NIDDKD, NIH, Bethesda, MD 20892 USA. NIAMSD, NIH, Bethesda, MD 20892 USA. NIH, Ctr Canc, Bethesda, MD 20892 USA. Univ Crete, Sch Med, Div Rheumatol Allergy & Clin Immunol, Iraklion, Greece. RP Illei, GG (reprint author), NIDCR, Sjogrens Syndrome Clin, NIH, 10 Ctr Dr,Bldg 10,Room 9S205, Bethesda, MD 20892 USA. EM illeig@mail.nih.gov NR 14 TC 6 Z9 7 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1462-0324 J9 RHEUMATOLOGY JI RHEUMATOLOGY PD JUN PY 2007 VL 46 IS 6 BP 952 EP 956 DI 10.1093/rheumatology/kem001 PG 5 WC Rheumatology SC Rheumatology GA 182VD UT WOS:000247531200013 PM 17317716 ER PT J AU Howard, MT Moyle, MW Aggarwal, G Carlson, BA Anderson, CB AF Howard, Michael T. Moyle, Mark W. Aggarwal, Gaurav Carlson, Bradley A. Anderson, Christine B. TI A recoding element that stimulates decoding of UGA codons by Sec tRNA([Ser]Sec) SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE selenocysteine; selenoprotein; SEPN1; readthrough; SRE; recoding ID SELENOCYSTEINE TRANSFER-RNA; ELONGATION-FACTOR SELB; MESSENGER-RNA; SELENOPROTEIN SYNTHESIS; FORMATE DEHYDROGENASE; TRANSFER RNASEC; ESCHERICHIA-COLI; MAMMALIAN-CELLS; GENETIC-CODE; IDENTIFICATION AB Selenocysteine insertion during decoding of eukaryotic selenoprotein mRNA requires several trans-acting factors and a cis-acting selenocysteine insertion sequence (SECIS) usually located in the 39 UTR. A second cis-acting selenocysteine codon redefinition element (SRE) has recently been described that resides near the UGA-Sec codon of selenoprotein N (SEPN1). Similar phylogenetically conserved elements can be predicted in a subset of eukaryotic selenoprotein mRNAs. Previous experimental analysis of the SEPN1 SRE revealed it to have a stimulatory effect on readthrough of the UGA-Sec codon, which was not dependent upon the presence of a SECIS element in the 39 UTR; although, as expected, readthrough efficiency was further elevated by inclusion of a SECIS. In order to examine the nature of the redefinition event stimulated by the SEPN1 SRE, we have modified an experimentally tractable in vitro translation system that recapitulates efficient selenocysteine insertion. The results presented here illustrate that the SRE element has a stimulatory effect on decoding of the UGA-Sec codon by both the methylated and unmethylated isoforms of Sec tRNA([Ser]Sec), and confirm that efficient selenocysteine insertion is dependent on the presence of a 3'-UTR SECIS. The variation in recoding elements predicted near UGA-Sec codons implies that these elements may play a differential role in determining the amount of selenoprotein produced by acting as controllers of UGA decoding efficiency. C1 Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA. NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Howard, MT (reprint author), Univ Utah, Dept Human Genet, 15 N 2030 E,Rm 2100, Salt Lake City, UT 84112 USA. EM mhoward@genetics.utah.edu FU Intramural NIH HHS; NIGMS NIH HHS [R01GM077462, R01 GM077462] NR 34 TC 37 Z9 38 U1 0 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1355-8382 J9 RNA JI RNA-Publ. RNA Soc. PD JUN PY 2007 VL 13 IS 6 BP 912 EP 920 DI 10.1261/rna.473907 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 170IP UT WOS:000246657000013 PM 17456565 ER PT J AU Yoo, MH Xu, XM Turanov, AA Carlson, BA Gladyshev, VN Hatfield, DL AF Yoo, Min-Hyuk Xu, Xue-Ming Turanov, Anton A. Carlson, Bradley A. Gladyshev, Vadim N. Hatfield, Dolph L. TI A new strategy for assessing selenoprotein function: siRNA knockdown/knock-in targeting the 3'-UTR SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE glutathione peroxidase 1; knockdown/knock-in; siRNA; selenophosphate synthetase 2; thioredoxin reductase 1 ID SELENOCYSTEINE TRANSFER-RNA; THIOREDOXIN REDUCTASE; MAMMALIAN SELENOPROTEIN; INSERTION-SEQUENCE; GENE REPLACEMENT; INTERFERENCE; PHENOTYPE; THIOREDOXIN-REDUCTASE-1; EXPRESSION; ELEMENTS AB Selenocysteine insertion into protein in mammalian cells requires RNA elements in the 3'-untranslated regions (3'-UTRs) of selenoprotein genes. The occurrence of these conserved sequences should make selenoproteins particularly amenable for knockdown/ knock-in strategies to examine selenoprotein functions. Herein, we utilized the 3'-UTR of various selenoproteins to knock down their expression using siRNAs and then knock in expression using constructs containing mutations within the target region. Thioredoxin reductase 1 (TR1) knockdown in a mouse kidney cell line resulted in the cells growing about 10% more slowly, being more sensitive to UV radiation, and having increased apoptosis in response to UV than control cells. The knockdown cells transfected with a construct encoding the wild-type TR1 gene and having mutations in the sequences targeted by siRNA restored TR1 expression and catalytic activity, rendered the knockdown cells less sensitive to UV, and protected the cells against apoptosis. We also applied this technique to other selenoproteins, selenophosphate synthetase 2 and glutathione peroxidase 1, and found that mRNA and protein levels were restored following transfection of knockdown cells with the corresponding knock-in constructs. In addition to important new insights into the functions of key mammalian selenoproteins, the data suggest that the RNAi-based knock-in technology could distinguish phenotypes due to off-targeting and provide a new method for examining many of the subtleties of selenoprotein function not available using RNAi technology alone. C1 NIH, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. RP Hatfield, DL (reprint author), NIH, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res, Bldg 37,Room 6032, Bethesda, MD 20892 USA. EM hatfield@mail.nih.gov RI Gladyshev, Vadim/A-9894-2013 FU NIGMS NIH HHS [R01 GM065204, R37 GM065204, GM061603, R01 GM061603, GM065204] NR 30 TC 14 Z9 15 U1 0 U2 1 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1355-8382 J9 RNA JI RNA-Publ. RNA Soc. PD JUN PY 2007 VL 13 IS 6 BP 921 EP 929 DI 10.1261/rna.533007 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 170IP UT WOS:000246657000014 PM 17468436 ER PT J AU Cravens, PD Hayashida, K Davis, LS Nanki, T Lipsky, PE AF Cravens, P. D. Hayashida, K. Davis, L. S. Nanki, T. Lipsky, P. E. TI Human peripheral blood dendritic cells and monocyte subsets display similar chemokine receptor expression profiles with differential migratory responses SO SCANDINAVIAN JOURNAL OF IMMUNOLOGY LA English DT Article ID INFLAMMATORY PROTEIN 3-ALPHA; T-CELLS; RHEUMATOID-ARTHRITIS; CUTTING EDGE; MATURE; SYNOVIUM; TRAFFICKING; IMMATURE; LINEAGE; CCR7 AB Human antigen presenting cells (APC) found in peripheral blood are considered to be precursors that have been released from the bone marrow and are in transit to the peripheral tissues. These APC populations include myeloid dendritic cells (mDC), plasmacytoid DC (pDC) and monocytes (Mo). To assign specialized functional roles and stages of development for APCs, CD33 expressing APC subsets were examined for their capacity to respond to chemokines. Three major CD33(+) subsets including CD33(bright)CD14(bright) Mo, CD33(bright)CD14(-) CD11c(+) mDC and CD33(dim)CD14(-) pDC were present. Dendritic cells subsets and Mo expressed low levels of CC and CXC receptors, but distinctive chemokine receptor expression profiles were not observed. The percentage of cells expressing a particular chemokine receptor varied from donor to donor and over time in the same donor. Myeloid DC and Mo but not pDC migrated toward CXCL12 in a concentration dependent manner. Monocytes and pDC, but not myeloid DC, were attracted by high concentrations of CXCL10. All CD33(+) subsets migrated in a concentration dependent manner toward CCL19, but responded less robustly to CCL21. CCL20 was not chemoattractant for any population. Despite the finding that APC did not exhibit unique surface chemokine receptor expression patterns, they exhibited differential migration to CXCL12, CXCL10 and CCL21 but not to CCL20 or CCL19. C1 NIAMSD, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Harold C Simmons Arthritis Res Ctr, Dept Internal Med, Dallas, TX 75230 USA. RP Lipsky, PE (reprint author), NIAMSD, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lipskyp@mail.nih.gov FU NIAID NIH HHS [AI-39230]; NIAMS NIH HHS [AR-45293] NR 33 TC 14 Z9 14 U1 0 U2 1 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 JUN PY 2007 VL 65 IS 6 BP 514 EP 524 DI 10.1111/j.1365-3083.2007.01933.x PG 11 WC Immunology SC Immunology GA 171CY UT WOS:000246713700004 PM 17523943 ER PT J AU Brindle, TJ Nyland, JA Nitz, AJ Shapiro, R AF Brindle, T. J. Nyland, J. A. Nitz, A. J. Shapiro, R. TI Scapulothoracic latent muscle reaction timing comparison between trained overhead throwers and untrained control subjects SO SCANDINAVIAN JOURNAL OF MEDICINE & SCIENCE IN SPORTS LA English DT Article DE shoulder; electromyography; muscle latency; biomechanics ID SHOULDER PROPRIOCEPTION; SERRATUS ANTERIOR; MOVEMENT; KINESTHESIA; CONTRACTION; INSTABILITY; RECEPTORS; TRAPEZIUS; PATTERNS; POSITION AB Aim: This study evaluated select scapulothoracic muscles for training-induced latent muscle reaction timing (LMRT) changes. Comparisons were also made between the dominant and non-dominant upper extremities and between individual muscles. Materials and methods: Fifteen male trained overhead throwers (college baseball pitchers) and 15 male untrained, age-matched control subjects participated in this study. Scapulothoracic muscle activation data were collected as subjects attempted to stop a variably timed, sudden glenohumeral joint internal rotation perturbation. Results: Training group differences were not evident for LMRT (P = 0.56), however upper extremity dominance (P = 0.003) and test muscle (P = 0.0002) displayed significant differences. Dominant upper extremity upper trapezius muscle LMRT (72.5 +/- 26 ms) occurred later than nondominant upper trapezius muscle LMRT (60.0 +/- 14.1 ms, P = 0.001). Dominant upper extremity middle trapezius-rhomboid muscle LMRT (60.0 +/- 16.2 ms) occurred later than non-dominant middle trapezius-rhomboid muscle LMRT (50.2 +/- 12.6 ms, P = 0.004). Dominant upper extremity upper trapezius muscle LMRT also occurred later than serratus anterior (55.7 +/- 16.0 ms, P = 0.001) and middle trapezius-rhomboid LMRT (60.2 +/- 16 ms, P = 0.003). Mean overall dominant upper extremity LMRT (62.7 +/- 19.4 ms) was delayed compared with mean overall non-dominant upper extremity LMRT (53.9 +/- 12.4 ms, P = 0.003). Clinical consequences: Although training was not found to influence scapulothoracic LMRT, differences were observed between the dominant and nondominant upper extremities. Consistent LMRT delays at the dominant upper extremity suggest possible neuromuscular timing differences to enable prolonged glenohumeral joint and scapulothoracic articulation acceleration before deceleration through eccentric muscle activation. Both trained and untrained overhead throwers displayed this response. Variable perturbation test velocities, and in-season testing of larger subject groups may be needed to better elucidate the more subtle differences associated with training. C1 Univ Louisville, Dept Orthopaed Surg, Div Sports Med, Louisville, KY 40202 USA. NIH, Phys Disabilit Branch, Bethesda, MD USA. Univ Kentucky, Coll Allied Hlth, Div Phys Therapy, Lexington, KY USA. Univ Kentucky, Coll Educ, Lexington, KY USA. RP Nyland, JA (reprint author), Univ Louisville, Dept Orthopaed Surg, Div Sports Med, 210 E Gray St,Suite 1003, Louisville, KY 40202 USA. EM john.nyland@louisville.edu NR 42 TC 3 Z9 3 U1 0 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0905-7188 J9 SCAND J MED SCI SPOR JI Scand. J. Med. Sci. Sports PD JUN PY 2007 VL 17 IS 3 BP 252 EP 259 DI 10.1111/j.1600-0838.2006.00574.x PG 8 WC Sport Sciences SC Sport Sciences GA 166RW UT WOS:000246398700010 PM 16774649 ER PT J AU Scott, LJ Mohlke, KL Bonnycastle, LL Willer, CJ Li, Y Duren, WL Erdos, MR Stringham, HM Chines, PS Jackson, AU Prokunina-Olsson, L Ding, CJ Swift, AJ Narisu, N Hu, T Pruim, R Xiao, R Li, XY Conneely, KN Riebow, NL Sprau, AG Tong, M White, PP Hetrick, KN Barnhart, MW Bark, CW Goldstein, JL Watkins, L Xiang, F Saramies, J Buchanan, TA Watanabe, RM Valle, TT Kinnunen, L Abecasis, GR Pugh, EW Doheny, KF Bergman, RN Tuomilehto, J Collins, FS Boehnke, M AF Scott, Laura J. Mohlke, Karen L. Bonnycastle, Lori L. Willer, Cristen J. Li, Yun Duren, William L. Erdos, Michael R. Stringham, Heather M. Chines, Peter S. Jackson, Anne U. Prokunina-Olsson, Ludmila Ding, Chia-Jen Swift, Amy J. Narisu, Narisu Hu, Tianle Pruim, Randall Xiao, Rui Li, Xiao-Yi Conneely, Karen N. Riebow, Nancy L. Sprau, Andrew G. Tong, Maurine White, Peggy P. Hetrick, Kurt N. Barnhart, Michael W. Bark, Craig W. Goldstein, Janet L. Watkins, Lee Xiang, Fang Saramies, Jouko Buchanan, Thomas A. Watanabe, Richard M. Valle, Timo T. Kinnunen, Leena Abecasis, Gonalo R. Pugh, Elizabeth W. Doheny, Kimberly F. Bergman, Richard N. Tuomilehto, Jaakko Collins, Francis S. Boehnke, Michael TI A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants SO SCIENCE LA English DT Article ID PANCREATIC BETA-CELLS; BODY-MASS INDEX; INSULIN-SECRETION; ZINC TRANSPORTER; RISK LOCI; GENE; EXPRESSION; IDENTIFICATION AB Identifying the genetic variants that increase the risk of type 2 diabetes (T2D) in humans has been a formidable challenge. Adopting a genome-wide association strategy, we genotyped 1161 Finnish T2D cases and 1174 Finnish normal glucose tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. We carried out association analysis with these SNPs to identify genetic variants that predispose to T2D, compared our T2D association results with the results of two similar studies, and genotyped 80 SNPs in an additional 1215 Finnish T2D cases and 1258 Finnish NGT controls. We identify T2D-associated variants in an intergenic region of chromosome 11p12, contribute to the identification of T2D-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings the number of T2D loci now confidently identified to at least 10. C1 Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. Univ Michigan, Ctr State Genet, Ann Arbor, MI 48109 USA. Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA. NHGRI, Genome Technol Branch, Bethesda, MD 20892 USA. Calvin Coll, Dept Math & Stat, Grand Rapids, MI 49546 USA. Johns Hopkins Univ, Sch Med, Inst Med Genet, Ctr Inherited Dis Res, Baltimore, MD 21224 USA. Savitaipale Hlth Ctr, Savitaipate 54800, Finland. Univ So Calif, Keck Sch Med, Div Endocrinol, Los Angeles, CA 90033 USA. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. Univ So Calif, Keck Sch Med, Dept Physiol & Biophys, Los Angeles, CA 90033 USA. Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Diabet Unit, SF-00300 Helsinki, Finland. Univ Helsinki, Dept Publ Hlth, Helsinki 00014, Finland. S Ostrobothnia Cent Hosp, Seinajoki 60220, Finland. RP Boehnke, M (reprint author), Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. EM francisc@mail.nih.gov; boehnke@umich.edu RI Abecasis, Goncalo/B-7840-2010; Hu, Tianle/H-9105-2012; kinnunen, leena/B-7059-2012; OI kinnunen, leena/0000-0001-8739-4812; Willer, Cristen/0000-0001-5645-4966; Prokunina-Olsson, Ludmila/0000-0002-9622-2091; Abecasis, Goncalo/0000-0003-1509-1825 FU Intramural NIH HHS [Z01 HG000024-13]; NHGRI NIH HHS [Z01 HG000024, HG002651, N01 HG065403, N01HG65403, R01 HG002651, R01 HG002651-01]; NHLBI NIH HHS [HL084729, U01 HL084729, U01 HL084729-01]; NIDA NIH HHS [U54 DA021519, U54 DA021519-02]; NIDDK NIH HHS [DK062370, DK072193, R01 DK029867, R01 DK062370, R01 DK062370-04, R01 DK072193, R01 DK072193-04, R56 DK062370, U01 DK062370] NR 31 TC 1694 Z9 1769 U1 17 U2 129 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 JUN 1 PY 2007 VL 316 IS 5829 BP 1341 EP 1345 DI 10.1126/science.1142382 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 173PS UT WOS:000246885600051 PM 17463248 ER PT J AU Choi, S Schwartz, RH AF Choi, Seeyoung Schwartz, Ronald H. TI Molecular mechanisms for adaptive tolerance and other T cell anergy models SO SEMINARS IN IMMUNOLOGY LA English DT Review DE clonal anergy; Adaptive tolerance; T cell receptor signaling; ionomycin; superantigen ID NF-KAPPA-B; IMMUNOLOGICAL SELF-TOLERANCE; PROTEIN-TYROSINE KINASE; E3 UBIQUITIN LIGASE; IN-VIVO; CLONAL ANERGY; IL-2 GENE; INTERLEUKIN-2 PRODUCTION; PERIPHERAL TOLERANCE; ANTIGEN PRESENTATION AB Since the original description of T cell anergy in CD4 clones from mice and humans, a number of different unresponsive states have been described, both in vivo and in vitro, that have been called anergic. While initial attempts were made to understand the similarities between the different models, it has now become clear from biochemical experiments that many of them have different molecular mechanisms underlying their unresponsiveness. In this review we will detail our own work on the in vivo model referred to as adaptive tolerance and then attempt to compare this biochemical state to the multitude of other states that have been described in the literature. (C) 2007 Elsevier Ltd. All rights reserved. C1 NIAID, NIH, LCMI, Bethesda, MD 20892 USA. RP Schwartz, RH (reprint author), NIAID, NIH, LCMI, Bldg 4,Rm 111,MsC-0420,4 Ctr Dr,9000 Rockville Pi, Bethesda, MD 20892 USA. EM rs34r@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000485-21] NR 95 TC 57 Z9 59 U1 0 U2 5 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1044-5323 J9 SEMIN IMMUNOL JI Semin. Immunol. PD JUN PY 2007 VL 19 IS 3 BP 140 EP 152 DI 10.1016/j.smim.2007.02.005 PG 13 WC Immunology SC Immunology GA 181WE UT WOS:000247466200002 PM 17400472 ER PT J AU Mazaki-Tovi, S Romero, R Kusanovic, JP Erez, O Pineles, BL Gotsch, F Mittal, P Than, NG Espinoza, J Hassan, SS AF Mazaki-Tovi, Shali Romero, Roberto Kusanovic, Juan Pedro Erez, Offer Pineles, Beth L. Gotsch, Francesca Mittal, Pooja Than, Nandor Gabor Espinoza, Jimmy Hassan, Sonia S. TI Recurrent preterm birth SO SEMINARS IN PERINATOLOGY LA English DT Review DE recurrent preterm birth; indicated preterm birth; spontaneous preterm birth; rupture of membranes; parturition ID CERVICOVAGINAL FETAL FIBRONECTIN; RANDOMIZED CONTROLLED-TRIAL; HIGH-RISK PREGNANCIES; ASYMPTOMATIC BACTERIAL VAGINOSIS; ULTRASONOGRAPHIC CERVICAL LENGTH; BLOOD-CELL COUNT; PREMATURE RUPTURE; MICROBIAL INVASION; INTACT MEMBRANES; AMNIOTIC-FLUID AB Recurrent preterm birth is frequently defined as two or more deliveries before 37 completed weeks of gestation. The recurrence rate varies as a function of the antecedent for preterm birth: spontaneous versus indicated. Spontaneous preterm birth is the result of either preterm labor with intact membranes or preterm prelabor rupture of the membranes. This article reviews the body of literature describing the risk of recurrence of spontaneous and indicated preterm birth. Also discussed are the factors which modify the risk for recurrent spontaneous preterm birth (a short sonographic cervical length and a positive cervicovaginal fetal fibronectin test). Patients with a history of an indicated preterm birth are at risk not only for recurrence of this subtype, but also for spontaneous preterm birth. Individuals of black origin have a higher rate of recurrent preterm birth. C1 Hutzel Womens Hosp, NIH, NICHD, DHHS,Intramural Div,Perinatol Res Branch, Detroit, MI 48201 USA. Wayne State Univ, Hutzel Womens Hosp, Dept Obstet & Gynecol, Detroit, MI 48202 USA. Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48202 USA. RP Romero, R (reprint author), Hutzel Womens Hosp, NIH, NICHD, DHHS,Intramural Div,Perinatol Res Branch, 3990 John R St,Box No4, Detroit, MI 48201 USA. EM warfiela@mail.nih.gov FU Intramural NIH HHS [ZIA HD002401-17] NR 294 TC 34 Z9 34 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 0146-0005 J9 SEMIN PERINATOL JI Semin. Perinatol. PD JUN PY 2007 VL 31 IS 3 BP 142 EP 158 DI 10.1053/j.semperi.2007.04.001 PG 17 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 176XN UT WOS:000247118300004 PM 17531896 ER PT J AU Williams, A Scharf, SM AF Williams, Antoinette Scharf, Steven M. TI Obstructive sleep apnea, cardiovascular disease, and inflammation - is NF-kappa B the key? SO SLEEP AND BREATHING LA English DT Review DE obstructive sleep apnea; NF-kappa B; inflammation; atherosclerosis ID POSITIVE AIRWAY PRESSURE; CHRONIC INTERMITTENT HYPOXIA; OXIDATIVE STRESS; ENDOTHELIAL FUNCTION; NITRIC-OXIDE; LIPID-PEROXIDATION; TRANSCRIPTION FACTORS; ADHESION MOLECULES; CIRCULATING ICAM-1; SERUM HOMOCYSTEINE AB Obstructive sleep apnea (OSA) affects a large portion of the population and is associated with repeated airway collapse leading to chronic intermittent hypoxia, exaggerated swings in intrathoracic pressure and post apneic arousal. OSA is associated with heightened sympathoadrenal tone and is a risk factor for cardiovascular mortality and morbidity. In addition to well-known mechanical and autonomic effects, OSA appears to be associated with systemic inflammation. This could provide one mechanism leading to cardiovascular disease (CVD). A central factor in the inflammatory cascade is nuclear factor kappa B (NF-kappa B), which is involved in the transcription of numerous genes involved in the inflammatory cascade. The object of this article is to review recent literature on some of the aspects of OSA related to a proinflammatory state and the possible role of NF-kappa B as one mechanism providing a link between sleep apnea and CVD. C1 Univ Maryland, Sleep Disorders Ctr, Div Pulm & Crit Care Med, Baltimore, MD 21201 USA. NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Scharf, SM (reprint author), Univ Maryland, Sleep Disorders Ctr, Div Pulm & Crit Care Med, Baltimore, MD 21201 USA. EM sscharf@medicine.umaryland.edu NR 74 TC 47 Z9 60 U1 0 U2 6 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1520-9512 J9 SLEEP BREATH JI Sleep Breath. PD JUN PY 2007 VL 11 IS 2 BP 69 EP 76 DI 10.1007/s11325-007-0106-1 PG 8 WC Clinical Neurology; Respiratory System SC Neurosciences & Neurology; Respiratory System GA 164KU UT WOS:000246233400002 PM 17380355 ER PT J AU Boyd, SJ Armstrong, KM Fang, LJ Medoff, DR Dixon, LB Gorelick, DA AF Boyd, Susan J. Armstrong, Kevin M. Fang, Li Juan Medoff, Deborah R. Dixon, Lisa B. Gorelick, David A. TI Use of a "microecologic technique" to study crime around substance abuse treatment centers SO SOCIAL SCIENCE COMPUTER REVIEW LA English DT Article DE substance abuse; treatment; crime mapping; GIS; geocoding; buffers AB Whether substance abuse treatment centers affect neighborhood crime is hotly debated. Empirical evidence on this issue is lacking because of the difficulty of distinguishing the crime effect of treatment centers in high-crime areas, the inability to make before-and-after comparisons for clinics founded before computerized crime data, and the need for appropriate control sites. The authors present an innovative method (without an actual data analysis) to overcome these challenges. Clinic addresses and crime data are geocoded by street address. Crimes are counted within concentric-circular, 25-meter '' buffers '' around the clinics. Regression analyses are used to calculate the '' crime slope '' (beta) among the buffers. A negative beta indicates more crimes closer to the site. A similar process is used to evaluate crimes around control sites: convenience stores, hospitals, and residential points. This innovative technique provides valid empirical evidence on crime around substance abuse treatment centers. C1 Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. Univ Maryland, Sch Med, Dept Psychiat, Div Hlth Serv Res, Baltimore, MD 21201 USA. NIDA, NIH, Bethesda, MD 20892 USA. RP Boyd, SJ (reprint author), Univ Maryland, Sch Med, Baltimore, MD 21201 USA. EM sboyd@psych.umaryland.edu; kevin@gcsllc.com; lfang@psych.umaryland.edu; dmedoff@psych.umaryland.edu; ldixon@psych.umaryland.edu; DGORELIC@intra.nida.nih.gov NR 14 TC 4 Z9 4 U1 0 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0894-4393 J9 SOC SCI COMPUT REV JI Soc. Sci. Comput. Rev. PD SUM PY 2007 VL 25 IS 2 BP 163 EP 173 DI 10.1177/0894439307298928 PG 11 WC Computer Science, Interdisciplinary Applications; Information Science & Library Science; Social Sciences, Interdisciplinary SC Computer Science; Information Science & Library Science; Social Sciences - Other Topics GA 172KP UT WOS:000246803500003 ER PT J AU Baksh, D Yao, R Tuan, RS AF Baksh, Dolores Yao, Raphael Tuan, Rocky S. TI Comparison of proliferative and multilineage differentiation potential of human mesenchymal stem cells derived from umbilical cord and bone marrow SO STEM CELLS LA English DT Article DE perivascular cells; bone marrow stromal cells; multi differentiation ID ENDOTHELIAL-CELLS; PROGENITOR CELLS; IN-VITRO; OSTEOGENIC DIFFERENTIATION; GENE-TRANSFER; MATRIX CELLS; THERAPY; TRANSPLANTATION; TRANSFECTION; SCAFFOLDS AB Human umbilical cord perivascular cells (HUCPVCs) have been shown to have a high proliferative potential and the capacity to differentiate into an osteogenic phenotype. HUCPVCs have thus been considered a possible extra-embryonic mesenchymal stem cell (MSC) source for cell-based therapies. To assess this potential, we compared HUCPVCs to the "gold standard" bone marrow mesenchymal stromal cells (BMSCs) with respect to their proliferation, differentiation, and transfection capacities. HUCPVCs showed a higher proliferative potential than BMSCs and were capable of osteogenic, chondrogenic, and adipogenic differentiation. Interestingly, osteogenic differentiation of HUCPVCs proceeded more rapidly than BMSCs. Additionally, HUCPVCs expressed higher levels of CD146, a putative MSC marker, relative to BMSCs. HUCPVCs showed comparable transfection efficiency as BMSCs using a nucleofection method but were more amenable to transfection with liposomal methods (FuGENE). Gene array analysis showed that HUCPVCs also expressed Wnt signaling pathway genes that have been implicated in the regulation of MSCs. The similar characteristics between HUCPVCs and MSCs support the applicability of HUCPVCs for cell-based therapies. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, 50 S Dr,Room 1503,BMSC 8022, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov FU Intramural NIH HHS NR 26 TC 440 Z9 536 U1 6 U2 49 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD JUN PY 2007 VL 25 IS 6 BP 1384 EP 1392 DI 10.1634/stemcells.2006-0709 PG 9 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 173XT UT WOS:000246906500006 PM 17332507 ER PT J AU Gudmundsson, KO Thorsteinsson, L Sigurjonsson, OE Keller, JR Olafsson, K Egeland, T Gudmundsson, S Rafnar, T AF Gudmundsson, Kristbjorn Orri Thorsteinsson, Leifur Sigurjonsson, Olafur E. Keller, Jonathan R. Olafsson, Karl Egeland, Torstein Gudmundsson, Sveinn Rafnar, Thorunn TI Gene expression analysis of hematopoietic progenitor cells identifies Dlg7 as a potential stem cell gene SO STEM CELLS LA English DT Article DE human; hematopoietic progenitor cells; embryonic stem cells; gene expression ID REGULATED PROTEIN; DENDRITIC CELLS; AURORA-KINASE; SELF-RENEWAL; IN-VITRO; DIFFERENTIATION; HURP; DROSOPHILA; CARCINOMA; LINE AB Inducible hematopoietic stem/progenitor cell lines represent a model for studying genes involved in self-renewal and differentiation. Here, gene expression was studied in the inducible human CD34+ acute myelogenous leukemia cell line KG1 using oligonucleotide arrays and suppression subtractive cloning. Using this approach, we identified Dlg7, the homolog of the Drosophila Dlg1 tumor suppressor gene, as downregulated at the early stages of KG1 differentiation. Similarly, Dlg7 was expressed in normal purified umbilical cord blood CD34+CD38- progenitors but not in the more committed CD34+CD38+ population. Dlg7 expression was not detected in differentiated cells obtained from hematopoietic colonies, nor was expression detected in purified T-cells, B-cells, and monocytes. When analyzed in different types of stem cells, Dlg7 expression was detected in purified human bone marrow-derived CD133+ progenitor cells, human mesenchymal stem cells, and mouse embryonic stem (ES) cells. Overexpression of Dlg7 in mouse ES cells increased their growth rate and reduced the number of EBs emerging upon differentiation. In addition, the EBs were significantly smaller, indicating an inhibition in differentiation. This inhibition was further supported by higher expression of Bmp4, Oct4, Rex1, and Nanog in EBs overexpressing Dlg7 and lower expression of Brachyury. Finally, the Dlg7 protein was detected in liver and colon carcinoma tumors but not in normal adjacent tissues, suggesting a role for the gene in carcinogenesis. In conclusion, our results suggest that Dlg7 has a role in stem cell survival, in maintaining stem cell properties, and in carcinogenesis. C1 NCI, Ctr Canc Res, Canc & Dev Biol Lab, NIH, Frederick, MD USA. Landspitali Univ Hosp, Blood Bank, Reykjavik, Iceland. Landspitali Univ Hosp, Dept Obstet & Gynecol, Reykjavik, Iceland. Univ Hosp, Inst Immunol, Oslo, Norway. Iceland Genom Corp, Reykjavik, Iceland. RP Gudmundsson, KO (reprint author), NCI, Ctr Canc Res, Canc & Dev Biol Lab, NIH, Frederick, MD USA. EM orri@ncifcrf.gov FU NCI NIH HHS [N01-CO12400] NR 47 TC 18 Z9 19 U1 0 U2 1 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD JUN PY 2007 VL 25 IS 6 BP 1498 EP 1506 DI 10.1634/stemcells.2005-0479 PG 9 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 173XT UT WOS:000246906500019 PM 17322106 ER PT J AU Kawai, T Choi, U Liu, PC Whiting-Theobald, NL Linton, GF Malech, HL AF Kawai, Toshinao Choi, Uimook Liu, Po-Ching Whiting-Theobald, Narda L. Linton, Gilda F. Malech, Harry L. TI Diprotin A infusion into nonobese diabetic/severe combined immunodeficiency mice markedly enhances engraftment of human mobilized CD34(+) peripheral blood cells SO STEM CELLS AND DEVELOPMENT LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; TERMINUS-TRUNCATED CXCR4; NATURAL-KILLER-CELLS; RECEPTOR BETA-CHAIN; GENE-THERAPY; PROGENITOR CELLS; STEM-CELLS; BONE-MARROW; MONOCLONAL-ANTIBODY; FUNCTIONAL-ROLE AB Hematopoietic stem cell (HSC) graft cell dose impacts significantly on allogeneic transplant. Similarly, HSC gene therapy outcome is affected by loss of repopulating cells during culture required for ex vivo retrovirus transduction. Stromal cell-derived factor-1 (SDF-1) and its receptor CXCR4 play a central role in marrow trafficking of HSCs, and maneuvers that enhance CXCR4 activation might positively impact outcome in settings of limiting graft dose. CD26/dipeptidyl peptidase IV (DPP-IV) is an ectoenzyme protease that cleaves SDF-1, thus reducing CXCR4 activation. We show that injection of irradiated nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mice with >= 2 mu mol Diprotin A (a tripeptide specific inhibitor of CD26 protease activity) at the time of transplant of human granulocyte colony-stimulating factor (G-CSF) mobilized CD34(+) peripheral blood cells (CD34(+) PBCs) results in a >3.4-fold enhancement of engraftment of human cells. We also show that CD26 on residual stromal cells in the irradiated recipient marrow milieu, and not any CD26 activity in the human CD34(+) PBC graft itself, plays the critical role in regulating receptivity of this environment for the incoming graft. Human marrow stromal cells also express CD26, raising the possibility that Diprotin A treatment could significantly enhance engraftment of HSCs in humans in settings of limiting graft dose just as we observed in the NOD/SCID mouse human xenograft model. C1 NIH, NIAID, Host Def Lab, Bethesda, MD 20892 USA. Jikei Univ, Sch Med, Inst DNA Med, Dept Gene Therapy, Tokyo, Japan. RP Malech, HL (reprint author), NIH, NIAID, Host Def Lab, Bethesda, MD 20892 USA. EM hmalech@nih.gov OI Malech, Harry/0000-0001-5874-5775 NR 44 TC 28 Z9 28 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1547-3287 J9 STEM CELLS DEV JI Stem Cells Dev. PD JUN PY 2007 VL 16 IS 3 BP 361 EP 370 DI 10.1089/scd.2007.9997 PG 10 WC Cell & Tissue Engineering; Hematology; Medicine, Research & Experimental; Transplantation SC Cell Biology; Hematology; Research & Experimental Medicine; Transplantation GA 185PB UT WOS:000247721800004 PM 17610366 ER PT J AU Kidwell, CS Warach, S AF Kidwell, Chelsea S. Warach, Steven TI Mismatch and defuse - Harvesting the riches of multicenter neuroimaging-based stroke studies SO STROKE LA English DT Editorial Material DE acute stroke; magnetic resonance; thrombolysis ID WEIGHTED MRI; DIFFUSION; PERFUSION; THROMBOLYSIS C1 Georgetown Univ, Washington, DC USA. Washington Hosp Ctr, Washington, DC 20010 USA. NINDS, NIH, Bethesda, MD 20892 USA. RP Kidwell, CS (reprint author), 110 Irving St NW,E Bldg Rm 6126, Washington, DC 20010 USA. EM Ck256@georgetown.edu NR 10 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUN PY 2007 VL 38 IS 6 BP 1718 EP 1719 DI 10.1161/STROKEAHA.107.487215 PG 2 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 172TK UT WOS:000246827100003 PM 17495213 ER PT J AU Beason-Held, LL Moghekar, A Zonderman, AB Kraut, MA Resnick, SM AF Beason-Held, Lori L. Moghekar, Abhay Zonderman, Alan B. Kraut, Michael A. Resnick, Susan M. TI Longitudinal changes in cerebral blood flow in the older hypertensive brain SO STROKE LA English DT Article DE aging; brain imaging; hypertension ID AGE-RELATED-CHANGES; COGNITIVE FUNCTION; PREFRONTAL CORTEX; WORKING-MEMORY; PRESSURE; DISEASE; DISSOCIATION; PERFORMANCE; ACTIVATION; DEMENTIA AB Background and Purpose - Changes in patterns of regional cerebral blood flow ( rCBF) were assessed over a period of 6 years in 14 treated hypertensive participants ( HTNs) and 14 age-matched healthy older participants ( healthy controls [ HCs]) in the Baltimore Longitudinal Study of Aging. Methods - Resting-state PET scans collected at years 1, 3, 5, and 7 were used to determine differences in longitudinal patterns of rCBF change in HTNs relative to HCs. Pulse pressure, arterial pressure, systolic/diastolic blood pressure, and hypertension duration were also correlated with patterns of rCBF change in the HTN group. Results - Relative to HCs, the HTN group shows greater rCBF decreases in prefrontal, anterior cingulate, and occipital areas over time, suggesting that these regions are more susceptible to hypertension-related dysfunction with advancing age. The HTN group also fails to show preservation of function over time in motor regions and in the temporal cortex and hippocampus as observed in HC. Although pulse pressure, mean arterial pressure, and systolic and diastolic pressure all correlate similarly with longitudinal rCBF changes, increased duration of hypertension is associated with decreased rCBF in prefrontal and anterior cingulate areas of functional vulnerability observed in the HTN group. Conclusions - These results show that hypertension significantly affects resting brain function in older individuals and suggest that duration of hypertension contributes significantly to the patterns of change over time. C1 NIA, Lab Personal & Cognit, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Radiol, Baltimore, MD 21205 USA. RP Beason-Held, LL (reprint author), NIA, Lab Personal & Cognit, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM heldlo@grc.nia.nih.gov OI Zonderman, Alan B/0000-0002-6523-4778 FU Intramural NIH HHS [Z01 AG000191-11]; NIA NIH HHS [N01-AG-3-2124] NR 37 TC 85 Z9 87 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUN PY 2007 VL 38 IS 6 BP 1766 EP 1773 DI 10.1161/STROKEAHA.106.477109 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 172TK UT WOS:000246827100017 PM 17510458 ER PT J AU Johnston, KC Wagner, DP Wang, XQ Newman, GC Thijs, V Sen, S Warach, S AF Johnston, Karen C. Wagner, Douglas P. Wang, Xin-Qun Newman, George C. Thijs, Vincent Sen, Souvik Warach, Steven CA GAIN Citicoline ASAP Investigators TI Validation of an acute ischemic stroke model - Does diffusion-weighted imaging lesion volume offer a clinically significant improvement in prediction of outcome? SO STROKE LA English DT Article; Proceedings Paper CT 30th International Stroke Conference CY FEB 02-04, 2005 CL New Orleans, LA SP Amer Stroke Assoc DE cerebral ischemia; prognosis; stroke outcome; models; statistical ID RANDOMIZED CONTROLLED-TRIAL; INDEPENDENT PREDICTOR; GLYCINE ANTAGONIST; RISK; SCALE; NEUROPROTECTION; INFORMATION; CITICOLINE; SCORE; MRI AB Background and Purpose - Prediction models for ischemic stroke outcome have the potential to contribute prognostic information in the clinical and/ or research setting. The importance of diffusion- weighted magnetic resonance imaging ( DWI) in the prediction of clinical outcome, however, is unclear. The purpose of this study was to combine acute clinical data and DWI lesion volume for ischemic stroke patients to determine whether DWI improves the prediction of clinical outcome. Methods - Patients ( N = 382) with baseline DWI data from the Glycine Antagonist In Neuroprotection and citicoline ( 010 and 018) trials were used to develop the prediction models by multivariable logistic regression. Data from prospectively collected patients ( N = 266) from the Acute Stroke Accurate Prediction Study were used to externally validate the model equations. The models predicted either full recovery or nursing home - level disability/ death, as defined by the National Institutes of Health Stroke Scale, Barthel Index, or modified Rankin Scale. Results - The full- recovery models with DWI lesion volume had areas under the receiver operating characteristic curves ( AUCs) of 0.799 to 0.821, and those without DWI lesion volume had AUCs of 0.758 to 0.798. The nursing home - level disability/ death models with DWI had AUCs of 0.832 to 0.882, and those without DWI had AUCs of 0.827 to 0.867. All models had mean absolute errors <= 0.4 for calibration. Conclusions - All 12 models had excellent discrimination and calibration, with 8 of 12 meeting prespecified performance criteria ( AUC >= 0.8, mean absolute error <= 0.4). Although DWI lesion volume significantly increased model explanatory power, the magnitude of increase was not large enough to be clinically important. C1 Univ Virginia, Dept Neurol, Charlottesville, VA USA. Univ Virginia, Dept Publ Hlth Sci, Charlottesville, VA USA. Albert Einstein Med Ctr, Dept Neurol, New York, NY USA. Univ Hosp Louvain, Louvain, Belgium. Univ N Carolina, Dept Neurol, Chapel Hill, NC USA. NINDS, Bethesda, MD 20892 USA. RP Johnston, KC (reprint author), Univ Virginia Hlth Syst, Dept Neurol, 800394, Charlottesville, VA 22908 USA. EM kj4v@virginia.edu RI Thijs, Vincent/C-3647-2009 OI Thijs, Vincent/0000-0002-6614-8417 FU NINDS NIH HHS [K23NS02168, K23 NS002168] NR 25 TC 59 Z9 61 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUN PY 2007 VL 38 IS 6 BP 1820 EP 1825 DI 10.1161/STROKEAHA.106.479154 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 172TK UT WOS:000246827100025 PM 17446421 ER PT J AU Janjua, N Nasar, A Lynch, JK Qureshi, AI AF Janjua, Nazli Nasar, Abu Lynch, John K. Qureshi, Adnan I. TI Thrombolysis for ischemic stroke in children - Data from the nationwide inpatient sample SO STROKE LA English DT Article DE ischemic; pediatric; stroke; thrombolysis ID TISSUE-PLASMINOGEN ACTIVATOR; RISK-FACTORS; INTRAARTERIAL THROMBOLYSIS; PEDIATRIC STROKE; ARTERY-OCCLUSION; CHILDHOOD; THROMBOSIS; ADOLESCENT; SURVIVORS; ACCURACY AB Background and Purpose - Few pediatric reports of thrombolysis exist. We sought to determine national rates of thrombolysis among pediatric ischemic stroke patients using a national database. Methods - Patients between the ages of 1 and 17 years, entered in the Nationwide Inpatient Sample between 2000 and 2003, with International Classification of Diseases codes for ischemic stroke were included in the study. Differences in mean age, gender distribution, ethnicity, secondary diagnoses, medical complications, associated procedure rates, modes of discharge, and hospital costs between pediatric stroke patients receiving and not receiving thrombolysis were estimated. Results - In the United States, between 2000 and 2003 an estimated 2904 children were admitted with ischemic stroke, of which 46 children ( 1.6%) received thrombolytic therapy. Children who received thrombolysis were on the average older ( 11 versus 9 years), more likely to be male ( 100% versus 53.8%), with significantly higher hospital costs ($ 81 800 versus $ 38 700). These children were also less likely to be discharged home with higher rates of death and dependency, although differences in clinical severity between the 2 groups was not known. Conclusion - Thrombolysis, though not indicated for patients <18 years of age, is currently being administered to children, with unclear benefit. Larger studies are needed to evaluate the safety and efficacy of this treatment for children. C1 Long Isl Coll Hosp, Dept Neurol, Brooklyn, NY 11201 USA. Suny Downstate Med Ctr, Brooklyn, NY 11203 USA. Univ Minnesota, Zeenat Qureshi Stroke Res Ctr, Minneapolis, MN USA. Columbia Univ, Med Ctr, Dept Surg, New York, NY USA. NINDS, Off Minor Hlth & Res, NIH, Bethesda, MD 20892 USA. RP Janjua, N (reprint author), Long Isl Coll Hosp, Dept Neurol, 339 Hicks St, Brooklyn, NY 11201 USA. EM NJanjua@chpnet.org NR 27 TC 87 Z9 88 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD JUN PY 2007 VL 38 IS 6 BP 1850 EP 1854 DI 10.1161/STROKEAHA.106.473983 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 172TK UT WOS:000246827100030 PM 17431210 ER PT J AU Ali, M Bath, PMW Curram, J Davis, SM Diener, HC Donnan, GA Fisher, M Gregson, BA Grotta, J Hacke, W Hennerici, MG Hommel, M Kaste, M Marler, JR Sacco, RL Teal, P Wahlgren, NG Warach, S Weir, CJ Lees, KR AF Ali, Myzoon Bath, Philip M. W. Curram, John Davis, Stephen M. Diener, Hans-Christoph Donnan, Geoffrey A. Fisher, Marc Gregson, Barbara A. Grotta, James Hacke, Werner Hennerici, Michael G. Hommel, Marc Kaste, Markku Marler, John R. Sacco, Ralph L. Teal, Philip Wahlgren, Nils-Gunnar Warach, Steven Weir, Christopher J. Lees, Kennedy R. TI The virtual international stroke trials archive SO STROKE LA English DT Article DE clinical trials; trial design; natural history; database; modified Rankin Scale; National Institutes of Health Stroke Scale ID ACUTE ISCHEMIC-STROKE; RANDOMIZED CONTROLLED-TRIAL; TISSUE-PLASMINOGEN ACTIVATOR; INTRACEREBRAL HEMORRHAGE; THROMBOLYTIC THERAPY; GLYCINE ANTAGONIST; NEUROPROTECTION; EFFICACY; PLACEBO; DESIGN AB Background and Purpose - Stroke has global importance and it causes an increasing amount of human suffering and economic burden, but its management is far from optimal. The unsuccessful outcome of several research programs highlights the need for reliable data on which to plan future clinical trials. The Virtual International Stroke Trials Archive aims to aid the planning of clinical trials by collating and providing access to a rich resource of patient data to perform exploratory analyses. Methods - Data were contributed by the principal investigators of numerous trials from the past 16 years. These data have been centrally collated and are available for anonymized analysis and hypothesis testing. Results - Currently, the Virtual International Stroke Trials Archive contains 21 trials. There are data on > 15 000 patients with both ischemic and hemorrhagic stroke. Ages range between 18 and 103 years, with a mean age of 69 +/- 12 years. Outcome measures include the Barthel Index, Scandinavian Stroke Scale, National Institutes of Health Stroke Scale, Orgogozo Scale, and modified Rankin Scale. Medical history and onset- to- treatment time are readily available, and computed tomography lesion data are available for selected trials. Conclusions - This resource has the potential to influence clinical trial design and implementation through data analyses that inform planning. C1 Univ Glasgow, Dept Med & Therapuet, Div Cardiovasc & Med Sci, Glasgow G11 6NT, Lanark, Scotland. W Infirm, Gardiner Inst, Glasgow, Lanark, Scotland. Inst Neurosci, Glasgow, Lanark, Scotland. Univ Nottingham, Nottingham NG7 2RD, England. Nayer Plc, Newbury, Berks, England. Univ Melbourne, Royal Melbourne Hosp, Parkville, Vic 3052, Australia. Univ Melbourne, Dept Neurol, Parkville, Vic 3052, Australia. Univ Duisburg Essen, Dept Neurol, Essen, Germany. Univ Melbourne, Dept Neurol, Melbourne, Vic 3002, Australia. Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01605 USA. Univ Newcastle, Newcastle Gen Hosp, Dept Neurosurg, Newcastle Upon Tyne, Tyne & Wear, England. Univ Texas, Houston Med Sch, Dept Neurol, Houston, TX 77025 USA. Heidelberg Univ, Dept Neurol, D-6900 Heidelberg, Germany. Univ Klinikum, Dept Neurol, Mannheim, Germany. Heidelberg Univ, D-6900 Heidelberg, Germany. Univ Grenoble 1, F-38026 Grenoble, France. Univ Helsinki, Cent Hosp, Dept Neurol, FIN-00014 Helsinki, Finland. Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. Columbia Univ, Dept Neurol, New York, NY 10027 USA. Columbia Univ, Dept Epidemiol, New York, NY 10027 USA. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. Karolinska Hosp, S-10401 Stockholm, Sweden. NINDS, Bethesda, MD 20892 USA. Robertson Ctr Biostat, Glasgow, Lanark, Scotland. Western Infirm & Associated Hosp, Gardiner Inst, Glasgow, Lanark, Scotland. RP Lees, KR (reprint author), Univ Glasgow, Dept Med & Therapuet, Div Cardiovasc & Med Sci, Glasgow G11 6NT, Lanark, Scotland. EM k.r.lees@clinmed.gla.ac.uk RI Davis, Stephen/L-5260-2013 OI Gregson, Barbara/0000-0003-4868-9137; Bath, Philip/0000-0003-2734-5132; Weir, Christopher/0000-0002-6494-4903; Donnan, Geoffrey/0000-0001-6324-3403; Kaste, Markku/0000-0001-6557-6412; Davis, Stephen/0000-0003-0962-2300 FU Medical Research Council [G0501444] NR 31 TC 68 Z9 68 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD JUN PY 2007 VL 38 IS 6 BP 1905 EP 1910 DI 10.1161/STROKEAHA.106.473579 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 172TK UT WOS:000246827100039 PM 17446430 ER PT J AU Bradley, CM Jones, S Huang, Y Suzuki, Y Kvaratskhelia, M Hickman, AB Craigie, R Dyda, F AF Bradley, Christina Marchetti Jones, Sarah Huang, Ying Suzuki, Youichi Kvaratskhelia, Mamuka Hickman, Alison Burgess Craigie, Robert Dyda, Fred TI Structural basis for dimerization of LAP2 alpha, a component of the nuclear lamina SO STRUCTURE LA English DT Article ID C-TERMINAL DOMAIN; POLYPEPTIDE 2-ALPHA; COILED COILS; LEM-DOMAIN; DIFFRACTION DATA; PROTEIN; BAF; PROGRAM; BINDS; CARDIOMYOPATHY AB Lamina-associated polypeptides (LAPs) are important components of the nuclear lamina, the dense network of filaments that supports the nuclear envelope and also extends into the nucleoplasm. The main protein constituents of the nuclear lamina are the constitutively expressed B-type lamins and the developmentally regulated A- and C-type lamins. LAP2 alpha is the only non-membrane-associated member of the LAP family. It preferentially binds laminA/C, has been implicated in cell-cycle regulation and chromatin organization, and has also been found to be a component of retroviral preintegration complexes. As an approach to understanding the role of LAP2 alpha in cellular pathways, we have determined the crystal structure of the C-terminal domain of LAP2 alpha, residues 459-693. The C-terminal domain is dimeric and possesses an extensive four-stranded, antiparallel coiled coil. The surface involved in binding lamin A/C is proposed based on results from alanine-scanning mutagenesis and a solid-phase overlay binding assay. C1 NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Ohio State Univ, Hlth Sci Ctr, Columbus, OH 43210 USA. RP Dyda, F (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM fred.dyda@nih.gov FU Intramural NIH HHS NR 41 TC 10 Z9 11 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0969-2126 J9 STRUCTURE JI Structure PD JUN PY 2007 VL 15 IS 6 BP 643 EP 653 DI 10.1016/j.str.2007.04.007 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 179ZM UT WOS:000247329400002 PM 17562312 ER PT J AU Comoletti, D Grishaev, A Whitten, AE Tsigelny, I Taylor, P Trewhella, J AF Comoletti, Davide Grishaev, Alexander Whitten, Andrew E. Tsigelny, Igor Taylor, Palmer Trewhella, Jill TI Synaptic arrangement of the neuroligin/beta-neurexin complex revealed by X-ray and neutron scattering SO STRUCTURE LA English DT Article ID SMALL-ANGLE SCATTERING; BETA-NEUREXINS; CELL-ADHESION; BIOLOGICAL MACROMOLECULES; CRYSTAL-STRUCTURE; AUTISM REVEALS; CA2+ BINDING; LNS DOMAIN; PROTEIN; ACETYLCHOLINESTERASE AB Neuroligins are postsynaptic cell-adhesion proteins that associate with their presynaptic partners, the neurexins. Using small-angle X-ray scattering, we determined the shapes of the extracellular region of several neuroligin isoforms in solution. We conclude that the neuroligins dimerize via the characteristic four-helix bundle observed in cholinesterases, and that the connecting sequence between the globular lobes of the dimer and the cell membrane is elongated, projecting away from the dimer interface. X-ray scattering and neutron contrast variation data show that two neurexin monomers, separated by 107 A, bind at symmetric locations on opposite sides of the long axis of the neuroligin dimer. Using these data, we developed structural models that delineate the spatial arrangements of different neuroligin domains and their partnering molecules. As mutations of neurexin and neuroligin genes appear to be linked to autism, these models provide a structural framework for understanding altered recognition by these proteins in neurodevelopmental disorders. C1 Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, Dept Pharmacol, La Jolla, CA 92093 USA. NIDDK, Bethesda, MD 20892 USA. Australian Nucl Sci & Technol Org, Bragg Inst, Menai, NSW 2234, Australia. Univ Sydney, Sch Mol & Microbial Biosci, Sydney, NSW 2006, Australia. Univ Utah, Dept Chem, Salt Lake City, UT 84112 USA. RP Comoletti, D (reprint author), Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, Dept Pharmacol, La Jolla, CA 92093 USA. EM dcomolet@ucsd.edu OI Trewhella, Jill/0000-0002-8555-6766; Whitten, Andrew/0000-0001-8856-3120 FU Intramural NIH HHS; NIEHS NIH HHS [P42 ES 10337, P42 ES010337, P42 ES010337-01]; NIGMS NIH HHS [R37 GM 18360, R37 GM018360-28, R37 GM018360] NR 47 TC 47 Z9 47 U1 0 U2 15 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0969-2126 J9 STRUCTURE JI Structure PD JUN PY 2007 VL 15 IS 6 BP 693 EP 705 DI 10.1016/j.str.2007.04.010 PG 13 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 179ZM UT WOS:000247329400006 PM 17562316 ER PT J AU Giomarelli, B Washington, VA Chisholm, MM Quigley, L McMahon, JB Mori, T McVicar, DW AF Giomarelli, Barbara Washington, Valance A. Chisholm, Maia M. Quigley, Laura McMahon, James B. Mori, Toshiyuki McVicar, Daniel W. TI Inhibition of thrombin-induced platelet aggregation using human single-chain Fv antibodies specific for TREM-like transcript-I SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE triggering receptors expressed on myeloid cells (TREM)-like; transcript-I (TLT-I); anti-thrombosis therapy; human antibodies; single chain fragments (scFvs); phage display ID PHAGE DISPLAY; RECEPTOR; FRAGMENTS; LIBRARY; SHP-2; ATHEROTHROMBOSIS; ANGIOPLASTY; ACTIVATION; SELECTION; PROTEINS AB TREM-like transcript-1 (TLT-1) is a novel platelet membrane receptor, which has been recently characterized in mice.TLT-1 is expressed exclusively in platelets and megakaryocytes, and its expression is dramatically upregulated upon platelet activation, suggesting that it plays a unique role in hemostasis and/or thrombosis. In this study we identified and characterized highly specific human monoclonal antibodies that bind to TLT-1 by screening a naive library of single chain Fv fragments (scFvs) displayed on filamentous phage (Thomlinson I library).These scFvs detected plate-bound TLT-1, captured soluble TLT-1, and readily reacted with cell-bound TLT-1 on transfectants and primary human platelets. Most importantly, anti-TLT-1 scFvs inhibited thrombin-mediated human platelet aggregation. This inhibition was specific for thrombin-induced aggregation and was reversible with higher doses of agonist.These data are the first to demonstrate a biological role for TLT-1 and its potential as a therapeutic target.The human scFvs isolated in this study may represent novel anti-platelet therapeutic agents. C1 NCI, Mol Targets Dev Program, Frederick, MD 21702 USA. NCI, Canc & Inflammat Program, Ctr Canc Res, Frederick, MD 21702 USA. Univ Cent Caribe, Dept Anat & Cell Biol, Bayamon, PR USA. RP McVicar, DW (reprint author), NCI, Mol Targets Dev Program, 560 Rm 31-46, Frederick, MD 21702 USA. EM McvicarD@mail.nih.gov RI McVicar, Daniel/G-1970-2015 FU NCRR NIH HHS [2G12RR3035] NR 31 TC 11 Z9 12 U1 0 U2 1 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD JUN PY 2007 VL 97 IS 6 BP 955 EP 964 DI 10.1160/TH06-08-0456 PG 10 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 179RY UT WOS:000247309000013 PM 17549298 ER PT J AU Falanga, V Iwamoto, S Chartier, M Yufit, T Butmarc, J Kouttab, N Shrayer, D Carson, P AF Falanga, Vincent Iwamoto, Satori Chartier, Molly Yufit, Tatyana Butmarc, Janet Kouttab, Nicholas Shrayer, David Carson, Polly TI Autologous bone marrow-derived cultured mesenchymal stem cells delivered in a fibrin spray accelerate healing in murine and human cutaneous wounds SO TISSUE ENGINEERING LA English DT Article ID VENOUS ULCERS; IN-VITRO; DERMAL FIBROBLASTS; EXPRESSION; PROLIFERATION; SURGERY; SKIN; DEPENDENCE; BEHAVIOR; CLOSURE AB The nonhematopoietic component of bone marrow includes multipotent mesenchymal stem cells (MSC) capable of differentiating into fat, bone, muscle, cartilage, and endothelium. In this report, we describe the cell culture and characterization, delivery system, and successful use of topically applied autologous MSC to accelerate the healing of human and experimental murine wounds. A single bone marrow aspirate of 35-50 mL was obtained from patients with acute wounds (n = 5) from skin cancer surgery and from patients with chronic, long-standing, nonhealing lower extremity wounds (n = 8). Cells were grown in vitro under conditions favoring the propagation of MSC, and flow cytometry and immunostaining showed a profile (CD29+, CD44+, CD105+, CD166+, CD34-, CD45-) highly consistent with published reports of human MSC. Functional induction studies confirmed that the MSC could differentiate into bone, cartilage, and adipose tissue. The cultured autologous MSC were applied up to four times to the wounds using a fibrin polymer spray system with a double-barreled syringe. Both fibrinogen (containing the MSC) and thrombin were diluted to optimally deliver a polymerized gel that immediately adhered to the wound, without run-off, and yet allowing the MSC to remain viable and migrate from the gel. Sequential adjacent sections from biopsy specimens of the wound bed after MSC application showed elongated spindle cells, similar to their in vitro counterparts, which immunostained for MSC markers. Generation of new elastic fibers was evident by both special stains and antibodies to human elastin. The application of cultured cells was safe, without treatment-related adverse events. A strong direct correlation was found between the number of cells applied (greater than 1 x 10(6) cells per cm(2) of wound area) and the subsequent decrease in chronic wound size (p = 0.0058). Topical application of autologous MSC also stimulated closure of full-thickness wounds in diabetic mice (db/db). Tracking of green fluorescent protein (GFP)+ MSC in mouse wounds showed GFP+ blood vessels, suggesting that the applied cells may persist as well as act to stimulate the wound repair process. These findings indicate that autologous bone marrow-derived MSC can be safely and effectively delivered to wounds using a fibrin spray system. C1 Roger Williams Canc Med Ctr, Dept Dermatol & Skin Surg, Providence, RI 02908 USA. Roger Williams Canc Med Ctr, Dept Pathol, Providence, RI 02908 USA. Roger Williams Canc Med Ctr, Ctr Biomed Res Excellence, COBRE, Providence, RI 02908 USA. Boston Univ, Sch Med, Dept Dermatol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Biochem, Boston, MA 02118 USA. RP Falanga, V (reprint author), Roger Williams Canc Med Ctr, Dept Dermatol & Skin Surg, Elmhurst Bldg,50 Maude St, Providence, RI 02908 USA. EM vfalanga@bu.edu NR 31 TC 318 Z9 332 U1 8 U2 39 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1076-3279 J9 TISSUE ENG JI Tissue Eng. PD JUN PY 2007 VL 13 IS 6 BP 1299 EP 1312 DI 10.1089/ten.2006.0278 PG 14 WC Cell & Tissue Engineering SC Cell Biology GA 178RK UT WOS:000247237600016 PM 17518741 ER PT J AU Eisenberg, E Greene, LE AF Eisenberg, Evan Greene, Lois E. TI Multiple roles of auxilin and Hsc70 in clathrin-mediated endocytosis SO TRAFFIC LA English DT Review DE auxilin; clathrin; endocytosis; energetics; GAK; Hsc70; uncoating ID G-ASSOCIATED KINASE; COATED VESICLES; UNCOATING ATPASE; IN-VIVO; LIVING CELLS; PROTEIN; DOMAIN; IDENTIFICATION; DISSOCIATION; RECRUITMENT AB The ATP-dependent dissociation of clathrin from clathrin-coated vesicles (CCVs) by the molecular chaperone Hsc70 requires J-domain cofactor proteins, either auxilin or cyclin-G-associated kinase (GAK). Both the nerve-specific auxilin and the ubiquitous GAK induce CCVs to bind to Hsc70. The removal of auxilin or GAK from various organisms and cells has provided definitive evidence that Hsc70 uncoats CCVs in vivo. In addition, evidence from various studies has suggested that Hsc70 and auxilin are involved in several other key processes that occur during clathrin-mediated endocytosis. First, Hsc70 and auxilin are required for the clathrin exchange that occurs during coated-pit invagination and constriction; this clathrin exchange may catalyze any rearrangement of the clathrin-coated pit (CCP) structure that is required during invagination and constriction. Second, Hsc70 and auxilin may chaperone clathrin after it dissociates from CCPs so that it does not aggregate in the cytosol. Third, auxilin and Hsc70 may be involved in the rebinding of clathrin to the plasma membrane to form new CCPs and independently appear to chaperone adaptor proteins so that they can also rebind to membranes to nucleate the formation of new CCPs. Finally, if formation of the curved clathrin coat induces membrane curvature, then Hsc70 and auxilin provide the energy for this curvature by inducing ATP-dependent clathrin exchange and rearrangement during endocytosis and ATP-dependent dissociation of clathrin at the end of the cycle so that it is energetically primed to rebind to the plasma membrane. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Greene, LE (reprint author), NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM greenel@helix.nih.gov NR 52 TC 105 Z9 107 U1 0 U2 14 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1398-9219 J9 TRAFFIC JI Traffic PD JUN PY 2007 VL 8 IS 6 BP 640 EP 646 DI 10.1111/j.1600-0854.2007.00568.x PG 7 WC Cell Biology SC Cell Biology GA 169XV UT WOS:000246626300002 PM 17488288 ER PT J AU Gupta, S Almyroudis, NG Battiwalla, M Bambach, BJ McCarthy, PL Proefrock, AD Ball, D Paplham, P Varma, A Kwon-Chung, J Segal, BH AF Gupta, S. Almyroudis, N. G. Battiwalla, M. Bambach, B. J. McCarthy, P. L. Proefrock, A. D. Ball, D. Paplham, P. Varma, A. Kwon-Chung, J. Segal, B. H. TI Successful treatment of disseminated fusariosis with posaconazole during neutropenia and subsequent allogeneic hematopoietic stem cell transplantation SO TRANSPLANT INFECTIOUS DISEASE LA English DT Article DE Fusarium; mold; transplant; posaconazole; hematopoietic stem cell transplantation ID HEMATOLOGIC MALIGNANCY; CANCER CENTER; RECIPIENTS; INFECTION AB We report the case of a 16-year-old girl with acute myelogenous leukemia with disseminated fusariosis, who responded to salvage posaconazole therapy. She subsequently received additional cytotoxic chemotherapy and allogeneic hematopoietic stem cell transplantation with posaconazole continued as secondary prophylaxis. Despite intensive immunosuppressive therapy for graft-versus-host disease, no recrudescence of infection occurred. C1 Roswell Pk Canc Inst, Dept Med, Div Infect Dis, Buffalo, NY 14263 USA. SUNY Buffalo, Sch Med & Biochem Sci, Dept Med, Buffalo, NY 14260 USA. Roswell Pk Canc Inst, Div Bone Marrow Transplantat, Buffalo, NY 14263 USA. NIAID, Mol Microbiol Sect, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Segal, BH (reprint author), Roswell Pk Canc Inst, Dept Med, Div Infect Dis, Elm & Carlton St, Buffalo, NY 14263 USA. EM brahm.segal@roswellpark.org NR 16 TC 14 Z9 14 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1398-2273 J9 TRANSPL INFECT DIS JI Transpl. Infect. Dis. PD JUN PY 2007 VL 9 IS 2 BP 156 EP 160 DI 10.1111/j.1399-3062.2006.00189.x PG 5 WC Immunology; Infectious Diseases; Transplantation SC Immunology; Infectious Diseases; Transplantation GA 161CQ UT WOS:000245992300014 PM 17462004 ER PT J AU Schirmer, JM Miyagi, N Rao, VP Ricci, D Federspiel, MJ Kotin, RM Russell, SJ McGregor, CGA AF Schirmer, Johannes M. Miyagi, Naoto Rao, Vinay P. Ricci, Davide Federspiel, Mark J. Kotin, Robert M. Russell, Stephen J. McGregor, Christopher G. A. TI Recombinant adeno-associated virus vector for gene transfer to the transplanted rat heart SO TRANSPLANT INTERNATIONAL LA English DT Article DE adeno-associated virus vector; cold perfusion system; gene therapy; heart transplantation; rat ID IN-VIVO; REPLICATION-DEFICIENT; TRANSGENE EXPRESSION; ADENOVIRUS VECTORS; DIRECT-INJECTION; IMMUNE-RESPONSE; EFFICIENT; TRANSDUCTION; DELIVERY; MYOCARDIUM AB Efficient durable viral vector transduction of the transplanted heart remains elusive. This study assesses the potential of recombinant adeno-associated virus (rAAV) mediated gene delivery to the transplanted rat heart. rAAV serotype 1, 2 and 5 vectors encoding the green fluorescent protein (GFP) gene (1 x 10(11) viral particles/ml) were diluted in cold University of Wisconsin solution and circulated through the coronary vasculature of the donor organs for 30 min before syngeneic rat heterotopic heart transplantation was performed. Study 1: animals (n = 5 each serotype) were killed at 21 days post-transplant to evaluate the efficiency of GFP transduction using RT-PCR and expression by fluorescence microscopy. Study 2: using rAAV-1, animals (n = 5 each group) were killed at 7, 21 and 84 days to evaluate the durability of GFP expression. The maximum cardiac GFP expression at 21 days was observed in rAAV-1. GFP expression by rAAV-1 was detectable at 7 days, improved at 21 days, and was still evident at 84 days. This study demonstrates cardiac rAAV gene transduction with a cold perfusion preservation system of the donor heart. These data show that AAV-1 is superior to AAV-2 and AAV-5 for this purpose and that durable expression is achievable. C1 Mayo Clin, Coll Med, William J von Liebig Transplant Ctr, Rochester, MN 55905 USA. Mayo Clin, Program Mol Med, Rochester, MN USA. NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. Univ Pavia, Fdn Policlin San Matteo, I-27100 Pavia, Italy. RP McGregor, CGA (reprint author), Mayo Clin, Coll Med, William J von Liebig Transplant Ctr, 200 1st St SW, Rochester, MN 55905 USA. EM mcgregor.christopher@mayo.edu RI kotin, robert/B-8954-2008; OI Ricci, Davide/0000-0003-0015-6374 FU NHLBI NIH HHS [HL66958 P2] NR 33 TC 10 Z9 13 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0934-0874 J9 TRANSPL INT JI Transpl. Int. PD JUN PY 2007 VL 20 IS 6 BP 550 EP 557 DI 10.1111/j.1432-2277.2007.00479.x PG 8 WC Surgery; Transplantation SC Surgery; Transplantation GA 164PC UT WOS:000246245100010 PM 17403107 ER PT J AU Mukhopadhyay, D Dasso, M AF Mukhopadhyay, Debaditya Dasso, Mary TI Modification in reverse: the SUMO proteases SO TRENDS IN BIOCHEMICAL SCIENCES LA English DT Review ID NUCLEAR-PORE COMPLEX; SACCHAROMYCES-CEREVISIAE; SUBSTRATE-SPECIFICITY; MODIFIED PROTEINS; TOPOISOMERASE-II; YEAST; SUMOYLATION; CONJUGATION; PATHWAY; IDENTIFICATION AB SUMOs (small ubiquitin-like modifiers) are ubiquitin-related proteins that become covalently conjugated to cellular target proteins that are involved in a variety of processes. Frequently, this modification has a key role in regulating the activities of those targets and, thus, their cellular functions. SUMO conjugation is a highly dynamic process that can be rapidly reversed by the action of members of the Ubl (ubiquitin-like protein)-specific protease (Ulp) family. The same family of enzymes is also responsible for maturation of newly synthesized SUMOs prior to their initial conjugation. Recent advances in structural, biochemical and cell biological analysis of Ulp/SENPs reveal their high degree of specificity towards SUMO paralogs, in addition to discrimination between processing, deconjugation and chain-editing reactions. The dissimilar sub-nuclear localization patterns of Ulp/SENPs and phenotypes of Ulp/ SENP mutants further indicate that different Ulp/SENPs have distinct and non-redundant roles. C1 NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Dasso, M (reprint author), NICHD, Lab Gene Regulat & Dev, NIH, Bldg 18,Room 106, Bethesda, MD 20892 USA. EM mdasso@helix.nih.gov OI Dasso, Mary/0000-0002-5410-1371 FU Intramural NIH HHS [Z01 HD001902-13] NR 71 TC 301 Z9 315 U1 5 U2 29 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0968-0004 J9 TRENDS BIOCHEM SCI JI Trends Biochem.Sci. PD JUN PY 2007 VL 32 IS 6 BP 286 EP 295 DI 10.1016/j.tibs.2007.05.002 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 184PN UT WOS:000247654100007 PM 17499995 ER PT J AU Cellmer, T Bratko, D Prausnitz, JM Blanch, HW AF Cellmer, Troy Bratko, Dusan Prausnitz, John M. Blanch, Harvey W. TI Protein aggregation in silico SO TRENDS IN BIOTECHNOLOGY LA English DT Review ID AMYLOID BETA-PROTEIN; MOLECULAR-DYNAMICS SIMULATIONS; SPONTANEOUS FIBRIL FORMATION; NEURODEGENERATIVE DISEASES; CONFORMATIONAL CONVERSION; POLYALANINE PEPTIDES; GLOBULAR-PROTEINS; MONOMER STRUCTURE; SHEET STRUCTURE; LATTICE-MODEL AB Protein aggregation is a challenge to the successful manufacture of protein therapeutics; it can impose severe limitations on purification yields and compromise formulation stability. Advances in computer power, and the wealth of computational studies pertaining to protein folding, have facilitated the development of molecular simulation as a tool to investigate protein misfolding and aggregation. Here, we highlight the successes of protein aggregation studies carried out in silico, with a particular emphasis on studies related to biotechnology. To conclude, we discuss future prospects for the field, and identify several biotechnology-related problems that would benefit from molecular simulation. C1 Univ Calif Berkeley, Dept Chem Engn, Berkeley, CA 94720 USA. NIH, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Dept Chem, Richmond, VA 23284 USA. Lawrence Berkeley Lab, Div Chem Sci, Berkeley, CA 94720 USA. RP Blanch, HW (reprint author), Univ Calif Berkeley, Dept Chem Engn, Berkeley, CA 94720 USA. EM blanch@berkeley.edu FU NIGMS NIH HHS [R01 GM070919, R01 GM070919-02] NR 65 TC 43 Z9 43 U1 2 U2 16 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0167-7799 J9 TRENDS BIOTECHNOL JI Trends Biotechnol. PD JUN PY 2007 VL 25 IS 6 BP 254 EP 261 DI 10.1016/j.tibtech.2007.03.011 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 178WY UT WOS:000247252200005 PM 17433843 ER PT J AU Graham, AL Cattadori, IM Lloyd-Smith, JO Ferrari, MJ Bjornstad, ON AF Graham, Andrea L. Cattadori, Isabella M. Lloyd-Smith, James O. Ferrari, Matthew J. Bjornstad, Ottar N. TI Transmission consequences of coinfection: cytokines writ large? SO TRENDS IN PARASITOLOGY LA English DT Review ID CONCURRENT NEMATODE INFECTION; BLOOD-STAGE MALARIA; SUB-SAHARAN AFRICA; ACTIVATED T-CELLS; IMMUNE-RESPONSES; SCHISTOSOMA-MANSONI; TNF-ALPHA; HOST; HELMINTH; DISEASES AB Coinfection of a host by multiple parasite species is commonly observed and recent epidemiological work indicates that coinfection can enhance parasite transmission. This article proposes an immunoepidemiological framework to understand how within-host interactions during coinfection might affect between-host transmission. Cytokines, immune signalling molecules with a fundamental role in the amplification of antiparasitic effector mechanisms, provide a useful way to simplify immunological complexity for this endeavour - focusing on cytokines offers analytical tractability without sacrificing realism. Testable predictions about the epidemiological consequences of coinfection are generated by this conceptual framework. C1 Univ Edinburgh, Sch Biol Sci, Inst Evolut, Edinburgh EH9 3JT, Midlothian, Scotland. Univ Edinburgh, Sch Biol Sci, Inst Immunol & Infect Res, Edinburgh EH9 3JT, Midlothian, Scotland. Univ Glasgow, Fac Vet Med, Div Anim Prod & Publ Hlth, Glasgow G61 1QH, Lanark, Scotland. Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Graham, AL (reprint author), Univ Edinburgh, Sch Biol Sci, Inst Evolut, Edinburgh EH9 3JT, Midlothian, Scotland. EM andrea.graham@ed.ac.uk RI Graham, Andrea/A-8808-2010; Bjornstad, Ottar/I-4518-2012; Lloyd-Smith, James/K-4080-2012 OI Graham, Andrea/0000-0002-6580-2755; Lloyd-Smith, James/0000-0001-7941-502X NR 66 TC 70 Z9 71 U1 0 U2 22 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4922 J9 TRENDS PARASITOL JI Trends Parasitol. PD JUN PY 2007 VL 23 IS 6 BP 284 EP 291 DI 10.1016/j.pt.2007.04.005 PG 8 WC Parasitology SC Parasitology GA 177PW UT WOS:000247166000012 PM 17466597 ER PT J AU Hansen-Schwartz, J Vajkoczy, P Macdonald, RL Pluta, RM Zhang, JH AF Hansen-Schwartz, Jacob Vajkoczy, Peter Macdonald, Robert Loch Pluta, Ryszard M. Zhang, John H. TI Cerebral vasospasm: looking beyond vasoconstriction SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID EXPERIMENTAL SUBARACHNOID HEMORRHAGE; CEREBROSPINAL-FLUID; BRAIN-INJURY; INFLAMMATION; MECHANISMS; CLAZOSENTAN; ENDOTHELIN; PREVENTION; ISCHEMIA; KINASE AB Cerebral vasospasm is an important syndrome that afflicts 30% of patients in the aftermath of, and secondary to, subarachnoid hemorrhage. Starting approximately one week after the hemorrhage, the condition worsens the prognosis of the hemorrhage significantly. Apart from general supportive care, no treatment exists for cerebral vasospasm. During the past 50 years, it was thought that the ischernia that signifies poor outcome is more or less exclusively caused by arterial narrowing. However, this idea has recently been challenged by the failure of the drug clazosentan to improve patient outcome, despite reversing vasoconstriction. In this article, we discuss the opinion that factors other than vasoconstriction are important in the pathophysiology and prognosis of cerebral vasospasm. Such factors include global ischernia, disruption of the blood-brain barrier, activation of apoptotic and inflammatory pathways, and cortical spreading depression. C1 Univ Copenhagen Hosp, Rigshosp, Dept Neurosurg, DK-2100 Copenhagen, Denmark. Univ Heidelberg, Univ Hosp Mannheim, Fac Med, Dept Neurosurg, D-68167 Mannheim, Germany. Univ Toronto, St Michaels Hosp, Div Neurosurg, Toronto, ON M5B 1W8, Canada. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Loma Linda Univ, Dept Neurosurg, Loma Linda, CA 92350 USA. RP Zhang, JH (reprint author), Univ Copenhagen Hosp, Rigshosp, Dept Neurosurg, DK-2100 Copenhagen, Denmark. EM johnzhang3910@yahoo.cont OI Hansen-Schwartz, Jacob/0000-0002-2736-4942; Zhang, John H./0000-0002-4319-4285 NR 38 TC 69 Z9 72 U1 0 U2 5 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD JUN PY 2007 VL 28 IS 6 BP 252 EP 256 DI 10.1016/j.tips.2007.04.002 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 179GL UT WOS:000247277600002 PM 17466386 ER PT J AU Mehta, GU Shively, SB Glasker, S Bechert, CJ Zhuang, Z Raffeld, M Lonser, RI Oldfield, EH Vortmeyer, AO AF Mehta, Gautam U. Shively, Sharon B. Glaesker, Sven Bechert, Charles J. Zhuang, Zhengping Raffeld, Mark Lonser, Russell R. Oldfield, Edward H. Vortmeyer, Alexander O. TI von Hippel-Lindau disease: Epididymal cystadenoma targeted by metastatic events SO UROLOGY LA English DT Article ID RENAL-CELL CARCINOMA; OF-THE-LITERATURE; CEREBELLAR HEMANGIOBLASTOMA AB Cases of renal clear cell carcinoma in patients with. von Hippel-Lindau disease often exhibit extensive metastasis. Several investigators have shown these tumors to specifically invade central nervous system hemangioblastomas, which are commonly associated with the disease. We report on multiple metastatic events within a single von Hippel-Lindau disease-associated tumor outside the central nervous system, epididymal cystadenoma. The multiplicity of these metastatic events suggests the epididydymal castadenoma as a preferential site of metastasis for von Hippel-Lindau disease-associated renal clear cell carcinoma. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Vortmeyer, AO (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 5D37, Bethesda, MD 20892 USA. EM gum@georgetown.edu OI Mehta, Gautam/0000-0002-8009-6430 FU Intramural NIH HHS NR 14 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 0090-4295 J9 UROLOGY JI Urology PD JUN PY 2007 VL 69 IS 6 AR 1209.e9 DI 10.1016/j.urology.2007.03.047 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 188KC UT WOS:000247917800050 PM 17572225 ER PT J AU Whitney, MS Schwan, TG Sultemeier, KB McDonald, PS Brillhart, MN AF Whitney, Marlyn S. Schwan, Tom G. Sultemeier, Katherine B. McDonald, Polly S. Brillhart, Martin N. TI Spirochetemia caused by Borrelia turicatae infection in 3 dogs in Texas SO VETERINARY CLINICAL PATHOLOGY LA English DT Article DE Borrelia turicatae; dog; hematology; spirochetemia ID BORNE RELAPSING FEVER; LINKED-IMMUNOSORBENT-ASSAY; LYME-DISEASE; SEROLOGICAL DISCRIMINATION; PHYLOGENETIC ANALYSIS; BURGDORFERI VLSE; SERODIAGNOSIS; FLORIDA; REGION; HUMANS AB Spirochetemia was diagnosed in 2 Siberian Huskies and a Rottweiler from the northwestern region of Texas between June 1999 and October 2001. Clinical findings were nonspecific; tick exposure was documented in 2 of the dogs. Hematologic abnormalities included anemia (n = 2), neutrophilia (n = 2, including 1 with a left shift), lymphopenia (n = 3), eosinopenia (n = 3), and thrombocytopenia (n = 2). One anemic dog had a positive Coombs' test. In 1 dog, Western blot analysis of serum yielded multiple positive bands with B turicatae lysate, indicating the spirochetemia most likely was due to B turicatae infection. In 2 dogs, spirochetes were cultured from the blood and identified using DNA analysis as Borrelia turicatae; 1 of these dogs also was seropositive for Ehrlichia canis and B burgdorferi. In 2 cases, spirochetemia was more prominent in blood smears prepared immediately after sample collection than in smears prepared from EDTA blood. Two dogs recovered with doxycycline treatment; 1 dog declined clinically despite treatment and was euthanized. B turicatae is the agent of tick-borne ( endemic) relapsing fever in humans and is distinct from B burgdorferi, the agent of Lyme disease; however, serologic cross-reactivity may occur. B turicatae is transmitted by the soft tick, Ornithodoros turicata, and infection should be considered in dogs with spirochetemia and possible exposure to the tick vector. C1 [Schwan, Tom G.] NIAID, Rocky Mt Labs, NIH, Hamilton, MT 59840 USA. [Sultemeier, Katherine B.] Colonial Pk Vet Clin, Wichita Falls, TX USA. [McDonald, Polly S.] Dry Fork Vet Clin, Henrietta, TX USA. [Brillhart, Martin N.] Brillhart Vet Clin, Slaton, TX USA. [Whitney, Marlyn S.] Texas A&M Univ, Texas Vet Med Diagnost Lab, Amarillo, TX USA. RP Whitney, MS (reprint author), Univ Missouri, Coll Vet Med, Vet Med Diagnost Lab, Columbia, MO 65211 USA. EM whitneym@missouri.edu NR 18 TC 17 Z9 19 U1 1 U2 2 PU AMER SOC VETERINARY CLINICAL PATHOLOGY PI MADISON PA 2810 CROSSROADS DR, STE 3800, MADISON, WI 53718 USA SN 0275-6382 J9 VET CLIN PATH JI Vet. Clin. Pathol. PD JUN PY 2007 VL 36 IS 2 BP 212 EP 216 DI 10.1111/j.1939-165X.2007.tb00213.x PG 5 WC Veterinary Sciences SC Veterinary Sciences GA 296PN UT WOS:000255558400018 PM 17523100 ER PT J AU Jeffries, SM Kusunoki, M Bisley, JW Cohen, IS Goldberg, ME AF Jeffries, S. Morgan Kusunoki, Makoto Bisley, James W. Cohen, Ian S. Goldberg, Michael E. TI Rhesus monkeys mislocalize saccade targets flashed for 100 ms around the time of a saccade SO VISION RESEARCH LA English DT Article DE saccade; oculomotor; monkey; psychophysics; localization ID LATERAL INTRAPARIETAL AREA; EYE-MOVEMENTS; VISUAL MISLOCALIZATION; APPARENT POSITION; STIMULI; PERCEPTION; LOCALIZATION; DISPLACEMENT; DIRECTION; SPACE AB Humans and monkeys mislocalize targets flashed around the time of a saccade. Here, we present data from three monkeys on a double-step task with a 100 ms target duration. All three subjects mislocalized targets that were flashed around the time of the first saccade, in spite of long intersaccadic intervals. The error was consistently in the direction opposite that of the saccade, and occurred in some cases when the target presentation was entirely presaccadic. This is inconsistent with a theory invoking a damped representation of eye position, but it is consistent with the hypothesis that it is due to an error in peri-saccadic remapping. (c) 2007 Elsevier Ltd. All rights reserved. C1 Columbia Univ Coll Phys & Surg, Ctr Neurobiol & Behav, Mahoney Ctr Brain & Behav, New York, NY 10032 USA. NEI, Sensorimotor Res Lab, Bethesda, MD 20892 USA. Georgetown Univ, Sch Med, Dept Neurol, Washington, DC 20007 USA. Columbia Univ Coll Phys & Surg, Dept Neurol, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. RP Goldberg, ME (reprint author), Columbia Univ Coll Phys & Surg, Ctr Neurobiol & Behav, Mahoney Ctr Brain & Behav, 630 W 168th St, New York, NY 10032 USA. EM meg2008@columbia.edu OI Bisley, James/0000-0002-2841-0306 FU NEI NIH HHS [R01 EY014978-04, R01 EY014978-01, R24 EY015634, R24 EY015634-01, R24 EY015634-04, R01 EY014978-03, R24 EY015634-03, R01 EY014978-05, P30 EY019007, R01 EY014978, R01 EY014978-02, R24 EY015634-02, R24 EY015634-05] NR 45 TC 18 Z9 18 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PD JUN PY 2007 VL 47 IS 14 BP 1924 EP 1934 DI 10.1016/j.visres.2007.02.021 PG 11 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 185LW UT WOS:000247713500007 PM 17499832 ER PT J AU Currier, JS Kendall, MA Henry, WK Beverly, AS Torriani, FJ Tebas, P Li, YJ Hodis, HN AF Currier, Judith S. Kendall, Michelle A. Henry, W. Keith Beverly, Alston-Smith Torriani, Francesca J. Tebas, Pablo Li, Yanjie Hodis, Howard N. CA ACTG 5078 Study Team TI Progression of carotid artery intima-media thickening in HIV-infected and uninfected adults SO AIDS LA English DT Article DE intima-media thickness; carotid artery; protease inhibitors; HIV ID HUMAN-IMMUNODEFICIENCY-VIRUS; PROTEASE INHIBITOR THERAPY; COMBINATION ANTIRETROVIRAL THERAPY; C-REACTIVE PROTEIN; CARDIOVASCULAR-DISEASE; HIV-1-INFECTED PATIENTS; MYOCARDIAL-INFARCTION; INSULIN-RESISTANCE; RISK-FACTORS; THICKNESS AB Objectives: To compare the rate of change in intima-media thickness (IMT) of the carotid artery among uninfected subjects and HIV-infected subjects receiving or not receiving protease inhibitor (PI) regimens over a 144 week period. Design: This prospective, matched cohort study enrolled 133 subjects into 45 triads (groups of three subjects matched by age, sex, race/ethnicity, smoking status, blood pressure, and menopause) from university based outpatient HIV clinics. Each triad consisted of one subject from each of the following groups: 1, HIV-infected subjects with continuous use of PI therapy for >= 2 years; 2, HIV-infected subjects without prior PI use; 3, HIV-uninfected subjects. Methods: Standardized ultrasound images of carotid IMT were collected at weeks 0, 2, 24, 48, 72, 96, and 144. The main outcome was the yearly progression rate of carotid IMT (mm/year). Results: The median yearly IMT progression rate in groups 1, 2, and 3 was 0.0096, 0.0058, and 0.0085 mm/year, respectively. There were no statistically significant differences in progression between groups 1 and 2, or between the combined HIV-positive groups and the HIV-negative control group. A multicovariate model examining predictors of progression in carotid IMT among all subjects contained low density lipoprotein cholesterol and homocysteine. Among HIV subjects, predictors included nadir CD4 cell count and ritonavir use. Conclusions: HIV infection and PI use did not contribute substantially to the rate of carotid IMT progression in our matched study. (C) 2007 Lippincott Williams & Wilkins. C1 Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Infect Dis,Ctr Cllin AIDS Res & Educ, Los Angeles, CA 90024 USA. Harvard Univ, Sch Publ Hlth, Stat & Data Anal Ctr, Boston, MA 02115 USA. Univ Minnesota, Hennepin Cty Med Ctr, HIV Program, Minneapolis, MN 55415 USA. NIAID, Div AIDS, Bethesda, MD 20892 USA. Univ Calif San Diego, Dept Med, Div Infect Dis, San Diego, CA 92103 USA. Univ Penn, Div Infect Dis, Philadelphia, PA 19104 USA. Univ So Calif, Keck Sch Med, Div Cardiovasc Med, Atherosclerosis Res Unit, Los Angeles, CA USA. RP Currier, JS (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Infect Dis,Ctr Cllin AIDS Res & Educ, Los Angeles, CA 90024 USA. EM jscurrier@mednet.ucla.edu RI Tebas, Pablo/A-7061-2008; Kendall, Michelle/B-7665-2016 OI Kendall, Michelle/0000-0001-9160-4544 FU NIAID NIH HHS [U01 AI 27660, K24 AI 56933] NR 42 TC 72 Z9 76 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 MAY 31 PY 2007 VL 21 IS 9 BP 1137 EP 1145 DI 10.1097/QAD.0b013e32811ebf79 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 175VY UT WOS:000247043300007 PM 17502724 ER PT J AU Eshleman, SH Husnik, M Hudelson, S Donnell, D Huang, YJ Huang, W Hart, S Jackson, B Coates, T Chesney, M Koblin, B AF Eshleman, Susan H. Husnik, Maria Hudelson, Sarah Donnell, Deborah Huang, Yijian Huang, Wei Hart, Stephen Jackson, Brooks Coates, Thomas Chesney, Margaret Koblin, Beryl TI Antiretroviral drug resistance, HIV-1 tropism, and HIV-1 subtype among men who have sex with men with recent HIV-1 infection SO AIDS LA English DT Article DE HIV; seroconverter; resistance; tropism; men who have sex with men; United States; recent infection; subtype ID IMMUNODEFICIENCY-VIRUS TYPE-1; PREVENTION TRIALS; TRANSMISSION; PREVALENCE; INTERVENTION; EXPLORE; INDIVIDUALS; ZIDOVUDINE; NEVIRAPINE AB Objective: Antiretroviral drug treatment may be complicated in individuals infected with antiretroviral drug-resistant or non-subtype B HIV-1 strains. HIV-1 tropism may also affect disease progression. We analyzed antiretroviral drug resistance, HIV-1 subtype, and HIV-1 tropism among 195 men who have sex with men from six major cities in the United States, using samples collected within 6 months of HIV-1 seroconversion (1999-2003). Methods: HIV-1 genotyping was performed using the ViroSeq HIV-1 Genotyping System. HIV-1 tropism was determined using a commercial assay. HIV-1 subtyping was performed by phylogenetic analysis of pol region sequences. Results: Thirty-one (15.9%) of the men had evidence of antiretroviral drug resistance. Seven (3.6%) men had multi-class resistance, including three (1.5%) with resistance to all three antiretroviral drug classes. We found no statistically significant association of antiretroviral drug resistance with demographic factors, sexual practices, self-reported sexually transmitted infections, use of recreational drugs, or use of antiretroviral drug post-exposure prophylaxis. All samples were HIV-1 subtype B. Four men had CXCR4-using HIV-1 strains. One man with a CXCR4-using strain also had antiretroviral drug resistance. Conclusions: Antiretroviral drug resistance is relatively common among recently infected men who have sex with men in the United States. CXCR4-using strains were detected in a small number of these infections, which were all subtype B HIV-1. (C) 2007 Lippincott Williams & Wilkins. C1 Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98104 USA. Emory Univ, Atlanta, GA 30322 USA. Monogram Biosci, San Francisco, CA USA. Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. Univ Calif Los Angeles, Los Angeles, CA USA. NIH, Bethesda, MD 20892 USA. New York Blood Ctr, New York, NY 10021 USA. RP Eshleman, SH (reprint author), Johns Hopkins Med Inst, Dept Pathol, Ross Bldg 646,720 Rutland Ave, Baltimore, MD 21205 USA. EM seshlem@jhmi.edu OI Donnell, Deborah/0000-0002-0587-7480 FU NIAID NIH HHS [U01 AI068613, 5U01 AI 46749, N01 AI 35176, N01 AI 45200, U01 AI 068613, U01 AI 46745, U01 AI 47981, U01 AI 47995, U01 AI 48016, U01 AI 48040, U01 AI068613-01] NR 19 TC 39 Z9 43 U1 0 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAY 31 PY 2007 VL 21 IS 9 BP 1165 EP 1174 DI 10.1097/QAD.0b013e32810fd72e PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 175VY UT WOS:000247043300010 PM 17502727 ER PT J AU Carrico, AW Johnson, MO Morin, SF Remien, RH Charlebois, ED Steward, WT Chesney, MA AF Carrico, Adam W. Johnson, Mallory O. Morin, Stephen F. Remien, Robert H. Charlebois, Edwin D. Steward, Wayne T. Chesney, Margaret A. CA NIMH Hlth Living Project Team TI Correlates of suicidal ideation among HIV-positive persons SO AIDS LA English DT Article DE AIDS; coping; depression; HIV; marijuana; substance use; suicidal ideation ID HUMAN-IMMUNODEFICIENCY-VIRUS; HEALTHY LIVING PROJECT; RISK-FACTORS; VIRAL LOAD; DRUG-USE; MEN; HIV/AIDS; INTERVENTION; AIDS; GAY AB Objectives: The present investigation sought to determine the extent to which demographic characteristics, illness-related burdens, alcohol and other substance use, and psychosocial factors are independently associated with suicidal ideation in HIV-positive individuals. Design: HIV-positive individuals in four US cities (San Francisco, Los Angeles, Milwaukee, and New York City) were screened between July 2000 and January 2002 for recruitment into a randomized behavioral prevention trial. Utilizing data from this screening visit, rates and correlates of suicidal ideation were examined in a diverse sample of 2909 HIV-positive individuals. Methods: Using binary logistic regression study sites, demographic characteristics, illness-related burdens, alcohol and substance use, and psychosocial factors were entered as predictors of suicidal ideation. This cross-sectional model thus examined the independent effects of each factor. Results: Approximately one-fifth (19%) of participants reported thoughts of suicide in the past week. We observed that participants who were not heterosexual, rated HIV-related symptoms and medication side effects as more severe, reported regular marijuana use, and described elevated affective symptoms of depression were those who were more likely to report suicidal ideation. Conversely, participants who identified as Hispanic/Latino, individuals in a primary romantic relationship, and those who reported greater self-efficacy for coping were less likely to report suicidal ideation. Conclusion: Suicidal ideation among HIV-positive individuals is relatively common and is associated with multiple factors. These independent correlates may assist with identifying HIV-positive individuals who are at increased risk of suicidal ideation so that they may be assessed regularly and referred for psychological treatment when appropriate. (C) 2007 Lippincott Williams & Wilkins. C1 Univ Calif San Francisco, Hlth Psychol Program, San Francisco Dept Psychiat, San Francisco, CA 94143 USA. Univ Calif San Francisco, San Francisco Ctr AIDS Prevent Studies, San Francisco, CA 94143 USA. Columbia Univ, New York State Psychiat Inst, New York, NY USA. NIH, Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Carrico, AW (reprint author), Univ Calif San Francisco, Hlth Psychol Program, San Francisco Dept Psychiat, 3333 Calif St,Suite 465,Box 0848, San Francisco, CA 94143 USA. EM adam.carrico@ucsf.edu FU NIMH NIH HHS [P30 MH 058107, T32 MH 019391, U10 MH 57615, U10 MH 57631, P30 MH043520, P30 MH 062246, P30 MH 43520, P30 MH 57226, U10 MH 57616, U10 MH 57636] NR 33 TC 42 Z9 46 U1 4 U2 9 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD MAY 31 PY 2007 VL 21 IS 9 BP 1199 EP 1203 DI 10.1097/QAD.0b013e3281532c96 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 175VY UT WOS:000247043300013 PM 17502730 ER PT J AU Kagaayi, J Makumbi, F Nakigozi, G Wawer, MJ Gray, RH Serwadda, D Reynolds, SJ AF Kagaayi, Joseph Makumbi, Fredrick Nakigozi, Gertrude Wawer, Maria J. Gray, Ronald H. Serwadda, David Reynolds, Steven J. TI WHOHIV clinical staging or CD4 cell counts for antiretroviral therapy eligibility assessment? An evaluation in rural Rakai district, Uganda SO AIDS LA English DT Article AB The ability of WHO clinical staging to predict CD4 cell counts of 200cells/mu l or less was evaluated among 1221 patients screened for antiretroviral therapy (ART). Sensitivity was 51% and specificity was 88%. The positive predictive value was 64% and the negative predictive value was 81%. Clinical criteria missed half the patients with CD4 cell counts of 200 cells/mu l or less, highlighting the importance of CD4 cell measurements for the scale-up of ART provision in resource-limited settings. C1 Rakai Hlth Sci Programme, Rakai, Uganda. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. Makerere Univ, Inst Publ Hlth, Kampala, Uganda. NIAID, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Kagaayi, J (reprint author), Rakai Hlth Sci Programme, Rakai, Uganda. NR 5 TC 25 Z9 25 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 MAY 31 PY 2007 VL 21 IS 9 BP 1208 EP 1210 DI 10.1097/QAD.0b013e32810c8dce PG 3 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 175VY UT WOS:000247043300016 PM 17502733 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI The cosmological model of eternal inflation and the transition from chance to biological evolution in the history of life SO BIOLOGY DIRECT LA English DT Article ID TRANSFER-RNA SYNTHETASES; GENETIC-CODE; PROTEIN EVOLUTION; AMINOACYL-RNA; ORIGIN; RIBOZYME; UNIVERSE; WORLD; TRANSLATION; HYPOTHESIS AB Background: Recent developments in cosmology radically change the conception of the universe as well as the very notions of "probable" and "possible". The model of eternal inflation implies that all macroscopic histories permitted by laws of physics are repeated an infinite number of times in the infinite multiverse. In contrast to the traditional cosmological models of a single, finite universe, this worldview provides for the origin of an infinite number of complex systems by chance, even as the probability of complexity emerging in any given region of the multiverse is extremely low. This change in perspective has profound implications for the history of any phenomenon, and life on earth cannot be an exception. Hypothesis: Origin of life is a chicken and egg problem: for biological evolution that is governed, primarily, by natural selection, to take off, efficient systems for replication and translation are required, but even barebones cores of these systems appear to be products of extensive selection. The currently favored (partial) solution is an RNA world without proteins in which replication is catalyzed by ribozymes and which serves as the cradle for the translation system. However, the RNA world faces its own hard problems as ribozyme-catalyzed RNA replication remains a hypothesis and the selective pressures behind the origin of translation remain mysterious. Eternal inflation offers a viable alternative that is untenable in a finite universe, i.e., that a coupled system of translation and replication emerged by chance, and became the breakthrough stage from which biological evolution, centered around Darwinian selection, took off. A corollary of this hypothesis is that an RNA world, as a diverse population of replicating RNA molecules, might have never existed. In this model, the stage for Darwinian selection is set by anthropic selection of complex systems that rarely but inevitably emerge by chance in the infinite universe (multiverse). Conclusion: The plausibility of different models for the origin of life on earth directly depends on the adopted cosmological scenario. In an infinite universe (multiverse), emergence of highly complex systems by chance is inevitable. Therefore, under this cosmology, an entity as complex as a coupled translation-replication system should be considered a viable breakthrough stage for the onset of biological evolution. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov NR 66 TC 12 Z9 14 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD MAY 31 PY 2007 VL 2 AR 15 DI 10.1186/1745-6150-2-15 PG 21 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 179JM UT WOS:000247285800001 PM 17540027 ER PT J AU Wolf, YI Koonin, EV AF Wolf, Yuri I. Koonin, Eugene V. TI On the origin of the translation system and the genetic code in the RNA world by means of natural selection, exaptation, and subfunctionalization SO BIOLOGY DIRECT LA English DT Review ID GROUP-II INTRONS; RIBOSOMAL PEPTIDYL TRANSFERASE; AMINO-ACID INTERACTIONS; COMPARATIVE GENOMICS; DIRECTED EVOLUTION; FUNDAMENTAL NATURE; PROTEIN EVOLUTION; BOND FORMATION; RIBOZYME; LIFE AB Background: The origin of the translation system is, arguably, the central and the hardest problem in the study of the origin of life, and one of the hardest in all evolutionary biology. The problem has a clear catch-22 aspect: high translation fidelity hardly can be achieved without a complex, highly evolved set of RNAs and proteins but an elaborate protein machinery could not evolve without an accurate translation system. The origin of the genetic code and whether it evolved on the basis of a stereochemical correspondence between amino acids and their cognate codons (or anticodons), through selectional optimization of the code vocabulary, as a "frozen accident" or via a combination of all these routes is another wide open problem despite extensive theoretical and experimental studies. Here we combine the results of comparative genomics of translation system components, data on interaction of amino acids with their cognate codons and anticodons, and data on catalytic activities of ribozymes to develop conceptual models for the origins of the translation system and the genetic code. Results: Our main guide in constructing the models is the Darwinian Continuity Principle whereby a scenario for the evolution of a complex system must consist of plausible elementary steps, each conferring a distinct advantage on the evolving ensemble of genetic elements. Evolution of the translation system is envisaged to occur in a compartmentalized ensemble of replicating, co-selected RNA segments, i.e., in a RNA World containing ribozymes with versatile activities. Since evolution has no foresight, the translation system could not evolve in the RNA World as the result of selection for protein synthesis and must have been a by-product of evolution drive by selection for another function, i.e., the translation system evolved via the exaptation route. It is proposed that the evolutionary process that eventually led to the emergence of translation started with the selection for ribozymes binding abiogenic amino acids that stimulated ribozyme-catalyzed reactions. The proposed scenario for the evolution of translation consists of the following steps: binding of amino acids to a ribozyme resulting in an enhancement of its catalytic activity; evolution of the amino-acid-stimulated ribozyme into a peptide ligase (predecessor of the large ribosomal subunit) yielding, initially, a unique peptide activating the original ribozyme and, possibly, other ribozymes in the ensemble; evolution of self-charging proto-tRNAs that were selected, initially, for accumulation of amino acids, and subsequently, for delivery of amino acids to the peptide ligase; joining of the peptide ligase with a distinct RNA molecule (predecessor of the small ribosomal subunit) carrying a built-in template for more efficient, complementary binding of charged proto-tRNAs; evolution of the ability of the peptide ligase to assemble peptides using exogenous RNAs as template for complementary binding of charged proteo-tRNAs, yielding peptides with the potential to activate different ribozymes; evolution of the translocation function of the protoribosome leading to the production of increasingly longer peptides (the first proteins), i.e., the origin of translation. The specifics of the recognition of amino acids by proto-RNAs and the origin of the genetic code depend on whether not there is a physical affinity between amino acids and their cognate codons or anticodons, a problem that remains unresolved. Conclusion: We describe a stepwise model for the origin of the translation system in the ancient RNA world such that each step confers a distinct advantage onto an ensemble of co-evolving genetic elements. Under this scenario, the primary cause for the emergence of translation was the ability of amino acids and peptides to stimulate reactions catalyzed by ribozymes. Thus, the translation system might have evolved as the result of selection for ribozymes capable of, initially, efficient amino acid binding, and subsequently, synthesis of increasingly versatile peptides. Several aspects of this scenario are amenable to experimental testing. Reviewers: This article was reviewed by Rob Knight, Doron Lancet, Alexander Mankin (nominated by Arcady Mushegian), and Arcady Mushegian. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM wolf@ncbi.nlm.nih.gov; koonin@ncbi.nlm.nih.gov NR 154 TC 57 Z9 62 U1 1 U2 17 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD MAY 31 PY 2007 VL 2 AR 14 DI 10.1186/1745-6150-2-14 PG 25 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 181TH UT WOS:000247458500001 PM 17540026 ER PT J AU Brynczka, C Labhart, P Merrick, BA AF Brynczka, Christopher Labhart, Paul Merrick, B. Alex TI NGF-mediated transcriptional targets of p53 in PC12 neuronal differentiation SO BMC GENOMICS LA English DT Article ID NERVE GROWTH-FACTOR; TUMOR-SUPPRESSOR P53; WILD-TYPE P53; FACTOR-BINDING-SITES; CELL-DIFFERENTIATION; PHEOCHROMOCYTOMA CELLS; THERAPEUTIC STRATEGY; P53-DEFICIENT MICE; SERIAL ANALYSIS; HIGH-FREQUENCY AB Background: p53 is recognized as a critical regulator of the cell cycle and apoptosis. Mounting evidence also suggests a role for p53 in differentiation of cells including neuronal precursors. We studied the transcriptional role of p53 during nerve growth factor-induced differentiation of the PC12 line into neuron-like cells. We hypothesized that p53 contributed to PC12 differentiation through the regulation of gene targets distinct from its known transcriptional targets for apoptosis or DNA repair. Results: Using a genome-wide chromatin immunoprecipitation cloning technique, we identified and validated 14 novel p53-regulated genes following NGF treatment. The data show p53 protein was transcriptionally activated and contributed to NGF-mediated neurite outgrowth during differentiation of PC12 cells. Furthermore, we describe stimulus-specific regulation of a subset of these target genes by p53. The most salient differentiation-relevant target genes included wnt7b involved in dendritic extension and the tfcp214/grhl3 grainyhead homolog implicated in ectodermal development. Additional targets included brk, sdk2, sesn3, txnl2, dusp5, pon3, lect1, pkcbpb15 and other genes. Conclusion: Within the PC12 neuronal context, putative p53-occupied genomic loci spanned the entire Rattus norvegicus genome upon NGF treatment. We conclude that receptor-mediated p53 transcriptional activity is involved in PC12 differentiation and may suggest a contributory role for p53 in neuronal development. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27606 USA. Genpathway Inc, San Diego, CA 92121 USA. RP Merrick, BA (reprint author), NIEHS, NIH, Res Triangle Pk, NC 27709 USA. EM brynczka@niehs.nih.gov; plabhart@genpathway.com; merrick@niehs.nih.gov FU Intramural NIH HHS NR 91 TC 31 Z9 33 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD MAY 31 PY 2007 VL 8 AR 139 DI 10.1186/1471-2164-8-139 PG 17 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 181EJ UT WOS:000247419400001 PM 17540029 ER PT J AU Jiao, R Harrigan, JA Shevelev, I Dietschy, T Selak, N Indig, FE Piotrowski, J Janscak, P Bohr, VA Stagljar, I AF Jiao, R. Harrigan, J. A. Shevelev, I. Dietschy, T. Selak, N. Indig, F. E. Piotrowski, J. Janscak, P. Bohr, V. A. Stagljar, I. TI The Werner syndrome protein is required for recruitment of chromatin assembly factor 1 following DNA damage SO ONCOGENE LA English DT Article DE WRN; CAF-1; DNA damage; chromatin assembly; genome stability ID SYNDROME GENE-PRODUCT; NUCLEOTIDE EXCISION-REPAIR; BLOOM-SYNDROME HELICASES; FUNCTIONAL INTERACTION; IN-VIVO; HUMAN-CELLS; FLAP ENDONUCLEASE-1; POLYMERASE-BETA; WRN HELICASES; STRAND BREAKS AB The Werner syndrome protein (WRN) and chromatin assembly factor 1 (CAF-1) are both involved in the maintenance of genome stability. In response to DNA-damaging signals, both of these proteins relocate to sites where DNA synthesis occurs. However, the interaction between WRN and CAF-1 has not yet been investigated. In this report, we show that WRN interacts physically with the largest subunit of CAF-1, hp150, in vitro and in vivo. Although hp150 does not alter WRN catalytic activities in vitro, and the chromatin assembly activity of CAF-1 is not affected in the absence of WRN in vivo, this interaction may have an important role during the cellular response to DNA replication fork blockage and/or DNA damage signals. In hp150 RNA-mediated interference (RNAi) knockdown cells, WRN partially formed foci following hydroxyurea (HU) treatment. However, in the absence of WRN, hp150 did not relocate to form foci following exposure to HU and ultraviolet light. Thus, our results demonstrate that WRN responds to DNA damage before CAF-1 and suggest that WRN may recruit CAF-1, via interaction with hp150, to DNA damage sites during DNA synthesis. C1 Univ Toronto, Terrence Donnelly Ctr Cellular & Biomol Res, Dept Biochem, Toronto, ON M5S 3E1, Canada. Univ Toronto, Dept Med Genet & Microbiol, Toronto, ON M5S 3E1, Canada. Chinese Acad Sci, Natl Lab Biomacromol, Inst Biophys, Beijing 100080, Peoples R China. Chinese Acad Sci, State Key Lab Brain & Cognit Sci, Inst Biophys, Beijing 100080, Peoples R China. NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Univ Toronto, Dept Med Genet & Microbiol, Toronto, ON M4X 1K9, Canada. Friedrich Miescher Inst Biomed Res, Basel, Switzerland. NIA, Res Resources Branch, NIH, Baltimore, MD 21224 USA. Univ Zurich, Inst Mol Canc Res, CH-8006 Zurich, Switzerland. RP Jiao, R (reprint author), Univ Toronto, Terrence Donnelly Ctr Cellular & Biomol Res, Dept Biochem, 160 Coll St, Toronto, ON M5S 3E1, Canada. EM rjiao@sun5.ibp.ac.cn; igor.stagljar@utoronto.ca RI Janscak, Pavel/G-6189-2014 NR 69 TC 13 Z9 13 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 MAY 31 PY 2007 VL 26 IS 26 BP 3811 EP 3822 DI 10.1038/sj.onc.1210150 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 175PV UT WOS:000247026400005 PM 17173071 ER PT J AU Leotlela, PD Wade, MS Duray, PH Rhode, MJ Brown, HF Rosenthal, DT Dissanayake, SK Earley, R Indig, FE Nickoloff, BJ Taub, DD Kallioniemi, OP Meltzer, P Morin, PJ Weeraratna, AT AF Leotlela, P. D. Wade, M. S. Duray, P. H. Rhode, M. J. Brown, H. F. Rosenthal, D. T. Dissanayake, S. K. Earley, R. Indig, F. E. Nickoloff, B. J. Taub, D. D. Kallioniemi, O. P. Meltzer, P. Morin, P. J. Weeraratna, A. T. TI Claudin-1 overexpression in melanoma is regulated by PKC and contributes to melanoma cell motility SO ONCOGENE LA English DT Article DE claudin; melanoma; PKC; motility; tissue array ID PROTEIN-KINASE-C; TIGHT JUNCTION PROTEINS; OVARIAN-CANCER; INVASION; ACTIVATION; EXPRESSION; ADHESION; BARRIER; MICE AB Serial analysis of gene expression followed by pathway analysis implicated the tight junction protein claudin-1 (CLDN1) in melanoma progression. Tight junction proteins regulate the paracellular transport of molecules, but staining of a tissue microarray revealed that claudin-1 was overexpressed in melanoma, and aberrantly expressed in the cytoplasm of malignant cells, suggesting a role other than transport. Indeed, melanoma cells in culture demonstrate no tight junction function. It has been shown that protein kinase C (PKC) can affect expression of claudin-1 in rat choroid plexus cells, and we observed a correlation between levels of activated PKC and claudin expression in our melanoma cells. To determine if PKC could affect the expression of CLDN1 in human melanoma, cells lacking endogenous claudin-1 were treated with 200 nM phorbol myristic acid (PMA). PKC activation by PMA caused an increase in CLDN1 transcription in 30 min, and an increase in claudin-1 protein by 12 h. Inhibition of PKC signaling in cells with high claudin-1 expression resulted in decreased claudin-1 expression. CLDN1 appears to contribute to melanoma cell invasion, as transient transfection of melanoma cells with CLDN1 increased metalloproteinase 2 (MMP-2) secretion and activation, and subsequently, motility of melanoma cells as demonstrated by wound-healing assays. Conversely, knockdown of CLDN1 by siRNA resulted in the inhibition of motility, as well as decreases in MMP-2 secretion and activation. These data implicate claudin-1 in melanoma progression. C1 NIA, Immunol Lab, NIH, Gerontol Res Ctr, Baltimore, MD 21224 USA. VA Healthcare Syst, Boston, MA USA. Univ Maryland Eastern Shore, MARC Scholar, Princess Anne, MD USA. Univ N Carolina, Dept Biol & Marine Biol, Wilmington, NC 28401 USA. NIA, Res Resources Branch, Gerontol Res Ctr, Baltimore, MD 21224 USA. Loyola Univ, Med Ctr, Dept Pathol, Maywood, IL 60153 USA. Univ Turku, VTT Tech Res Ctr Finland, Med Biotechnol Dept, SF-20500 Turku, Finland. Natl Human Genome Res Inst, Canc Genet Branch, Bethesda, MD USA. NIA, Lab Cellular & Mol Biol, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Weeraratna, AT (reprint author), NIA, Immunol Lab, NIH, Gerontol Res Ctr, 5600 Nathan Shock Dr,Box 21, Baltimore, MD 21224 USA. EM weerarat@grc.nia.nih.gov RI Kallioniemi, Olli/H-5111-2011; Kallioniemi, Olli/H-4738-2012 OI Kallioniemi, Olli/0000-0002-3231-0332; Kallioniemi, Olli/0000-0002-3231-0332 FU Intramural NIH HHS NR 23 TC 87 Z9 90 U1 2 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 31 PY 2007 VL 26 IS 26 BP 3846 EP 3856 DI 10.1038/sj.onc.1210155 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 175PV UT WOS:000247026400008 PM 17160014 ER PT J AU Simone, NL Soule, BP Gerber, L Augustine, E Smith, S Altemus, RM Mitchell, JB Camphausen, KA AF Simone, Nicole L. Soule, Benjamin P. Gerber, Lynn Augustine, Elizabeth Smith, Sharon Altemus, Rosemary M. Mitchell, James B. Camphausen, Kevin A. TI Oral Pirfenidone in patients with chronic fibrosis resulting from radiotherapy: a pilot study SO RADIATION ONCOLOGY LA English DT Article ID RADIATION-INDUCED FIBROSIS; IDIOPATHIC PULMONARY-FIBROSIS; PLACEBO-CONTROLLED TRIAL; PAIN DISABILITY INDEX; INDUCED LUNG FIBROSIS; SUBCUTANEOUS FIBROSIS; PHASE-II; SOFT-TISSUE; HUMAN SKIN; VITAMIN-E AB Background: Fibrosis is a common side effect after treatment with ionizing radiation. Several methods to ameliorate debilitating fibrosis have been employed but without consistent results. The goal of this pilot study is to determine if Pirfenidone, a novel regulator of cytokine gene expression, has the potential to ameliorate established radiation-induced fibrosis. Methods: Open label, prospective pilot study of 800 mg three times/day, orally administered Pirfenidone was administered to enrolled patients who were had completed radiation therapy and who had established radiation-induced fibrosis. Range of motion (ROM) was assessed using standard measures, and subjective measures of pain, fatigue, disability and global health were measured every three months. Results: Seven patients were enrolled of whom 3 had ROM assessments of 1 site and 2 had ROM assessments of 2 sites. Of these assessments, 6 revealed increased ROM during drug intervention while 1 revealed a decreased ROM. There was an overall improvement in the mental composite score of the SF36 while physical composite score was decreased and the vitality score was unchanged. Two patients were removed from the study because of syncopal episodes. Conclusion: Several patients experienced improved function of at least 25% and reported subjective improvement. Pirfenidone may benefit patients with radiation-induced fibrosis and is worthy of a larger well controlled trial. C1 [Simone, Nicole L.; Smith, Sharon; Altemus, Rosemary M.; Camphausen, Kevin A.] NCI, NIH, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Soule, Benjamin P.; Mitchell, James B.] NCI, NIH, Radiat Biol Branch, Bethesda, MD 20892 USA. [Gerber, Lynn; Augustine, Elizabeth] George Mason Univ, Dept Global & Community Hlth, Ctr Chron Illness & Disabil, Fairfax, VA 22030 USA. RP Simone, NL (reprint author), NCI, NIH, Radiat Oncol Branch, 9000 Rockville Pike,Bldg 10-CRC,Room B2-3561, Bethesda, MD 20892 USA. EM simonen@mail.nih.gov; souleb@mail.nih.gov; ngerber1@gmu.edu; augustine_elizabeth@yahoo.com; smiths@mail.nih.gov; raltemus@cox.net; jbm@helix.nih.gov; camphauk@mail.nih.gov FU NIH; National Cancer Institute; Center for Cancer Research FX This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. NR 38 TC 19 Z9 19 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND J9 RADIAT ONCOL JI Radiat. Oncol. PD MAY 31 PY 2007 VL 2 AR 19 DI 10.1186/1748-717X-2-19 PG 6 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 363YO UT WOS:000260303600001 PM 17540023 ER PT J AU Yingling, YG Garrison, BJ AF Yingling, Yaroslava G. Garrison, Barbara J. TI Incorporation of chemical reactions into UV photochemical ablation of coarse-grained material SO APPLIED SURFACE SCIENCE LA English DT Article; Proceedings Paper CT 5th International Conference on Photo-Excited Processes and Applications CY SEP, 2006 CL Charlotteville, VA SP Univ Virginia, US Natl Sci Fdn, US Off Naval Res Global, Thomas Jefferson Natl Accelerat Fac DE laser ablation; simulations; coarse-grained; photochemistry ID ASSISTED LASER-DESORPTION; ORGANIC-SOLIDS; MOLECULAR-DYNAMICS; EJECTION; MODEL; FRAGMENTATION; CHLOROBENZENE; SIMULATIONS AB A coarse-grained representation of material can significantly speed up molecular dynamics simulations. The difficulty arises when the simulations need to include chemical reactions. We have developed a methodology for including the effects of chemical reactions in coarse-grained molecular dynamics simulations, namely the Coarse-Grained Chemical Reactions Model (CGCRM). The model adopts physically and experimentally based parameters of a specific material, such as photochemical passways, the probabilities, and the exothermicities of chemical reactions. We have applied this approach to elucidate the effects of photochemical reactions on laser ablation of organic and polymeric materials. We find that the model provides a plausible description of the essential processes. (C) 2007 Elsevier B.V. All rights reserved. C1 Penn State Univ, Dept Chem, University Pk, PA 16802 USA. RP Yingling, YG (reprint author), Natl Canc Inst, Ctr Canc Res Nanobiol Program, NIH, Frederick, MD 21702 USA. EM yaray@ncifcrf.gov RI Yingling, Yaroslava/B-2901-2008; Garrison, Barbara/P-1807-2014 OI Yingling, Yaroslava/0000-0002-8557-9992; Garrison, Barbara/0000-0002-7053-5284 NR 26 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-4332 J9 APPL SURF SCI JI Appl. Surf. Sci. PD MAY 30 PY 2007 VL 253 IS 15 SI SI BP 6377 EP 6381 DI 10.1016/j.apsusc.2007.01.100 PG 5 WC Chemistry, Physical; Materials Science, Coatings & Films; Physics, Applied; Physics, Condensed Matter SC Chemistry; Materials Science; Physics GA 178KX UT WOS:000247220700021 ER PT J AU Soubias, O Gawrisch, K AF Soubias, Olivier Gawrisch, Klaus TI Docosahexaenoyl chains isomerize on the sub-nanosecond time scale SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; SPIN-LATTICE-RELAXATION; LIPID-BILAYERS; DYNAMICS; PROTEIN; NMR; MEMBRANES AB The dynamics of docosahexaenoyl acyl chains (DHA) in 18:0-22:6n3-PC bilayers were studied by C-13 MAS NMR relaxation measurements. A Lipari-Szabo-type analysis yielded site-specific correlation times of DHA chain isomerization and C-H bond order parameters. It is concluded that DHA chains perform rapid isomerization with correlation times from 80 ps near the carbonyl group to 8 ps near the terminal methyl group. Spin-lattice relaxation rates remained unaltered after rhodopsin incorporation into the bilayers, indicating that the majority of lipids maintain their rapid chain isomerization in the presence of the protein. However, spin-spin relaxation rates revealed that rhodopsin increased motional correlation times of slow collective DHA motions. C1 NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. RP Gawrisch, K (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. EM gawrisch@helix.nih.gov FU Intramural NIH HHS NR 14 TC 27 Z9 27 U1 0 U2 3 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 MAY 30 PY 2007 VL 129 IS 21 BP 6678 EP + DI 10.1021/ja068856c PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 170TG UT WOS:000246686700008 PM 17477528 ER PT J AU Stroncek, DF Jin, P Wang, E Jett, B AF Stroncek, David F. Jin, Ping Wang, Ena Jett, Betsy TI Potency analysis of cellular therapies: the emerging role of molecular assays SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Review ID BLOOD MONONUCLEAR-CELLS; GENE-EXPRESSION PROFILES; HEMATOPOIETIC STEM-CELLS; UMBILICAL-CORD BLOOD; PROGENITOR CELLS; PROSTATE-CANCER; T-CELLS; G-CSF; TRANSPLANTATION; DIFFERENTIATION AB Potency testing is an important part of the evaluation of cellular therapy products. Potency assays are quantitative measures of a product-specific biological activity that is linked to a relevant biological property and, ideally, a product's in vivo mechanism of action. Both in vivo and in vitro assays can be used for potency testing. Since there is often a limited period of time between the completion of production and the release from the laboratory for administration to the patient, in vitro assays such are flow cytometry, ELISA, and cytotoxicity are typically used. Better potency assays are needed to assess the complex and multiple functions of cellular therapy products, some of which are not well understood. Gene expression profiling using microarray technology has been widely and effectively used to assess changes of cells in response to stimuli and to classify cancers. Preliminary studies have shown that the expression of noncoding microRNA which play an important role in cellular development, differentiation, metabolism and signal transduction can distinguish different types of stem cells and leukocytes. Both gene and microRNA expression profiling have the potential to be important tools for testing the potency of cellular therapies. Potency testing, the complexities associated with potency testing of cellular therapies, and the potential role of gene and microRNA expression microarrays in potency testing of cellular therapies is discussed. C1 NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov; PJin@cc.nih.gov; EWang@cc.nih.gov; bjett@cc.nih.gov NR 58 TC 13 Z9 13 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD MAY 30 PY 2007 VL 5 AR 24 DI 10.1186/1479-5876-5-24 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 185CC UT WOS:000247687900001 PM 17537259 ER PT J AU Zarghooni, S Wunsch, J Bodenbenner, M Bruggmann, D Grando, SA Schwantes, U Wess, J Kummer, W Lips, KS AF Zarghooni, Shirin Wunsch, Julia Bodenbenner, Martin Brueggmann, Doerthe Grando, Sergei A. Schwantes, Ulrich Wess, Juergen Kummer, Wolfgang Lips, Katrin S. TI Expression of muscarinic and nicotinic acetylcholine receptors in the mouse urothelium SO LIFE SCIENCES LA English DT Article; Proceedings Paper CT 2nd International Symposium on Non-Neuronal Acetylcholine CY AUG 31-SEP 02, 2006 CL Mainz, GERMANY DE non-neuronal cholinergic system; urothelium; muscarinic receptors; nicotinic receptors ID CHOLINERGIC SYSTEM; KNOCKOUT MICE; KERATINOCYTE ADHESION; BLADDER; DETRUSOR; SUBTYPES; PHARMACOLOGY; ALPHA-10 AB Acetylcholine (ACh) and its receptors play a crucial role in bladder physiology. Here, we investigated the presence of muscarinic receptor subtypes (MR) and nicotinic acetylcholine receptor (nAChR) alpha-subunits in the mouse urothelium by RT-PCR and immunohistochemistry. With RT-PCR, we detected mRNAs coding for all of the five different MR subtypes and for the nicotinic receptor subunits alpha 2, alpha 4, alpha 5, alpha 6, alpha 7, alpha 9 and alpha 10, whereas the alpha 3-subunit was not expressed. Using immunohistochemistry, we localised a panel of acetylcholine receptors in the different layers of the murine bladder urothelium, with predominant appearance in the basal plasma membrane of the basal cell layer and in the apical membrane of the umbrella cells. M2R and subunit alpha 9 were observed exclusively in the umbrella cells, whereas the MR subtypes 3-5 and the nAChR subunits alpha 4, alpha 7 and alpha 10 were also detected in the intermediate and basal cell layers. The subunit alpha 5 was localised only in the basal cell layer. In conclusion, the murine urothelium expresses multiple cholinergic receptors, including several subtypes of both MR and nAChR, which are differentially distributed among the urothelial cell types. Since these receptors have different electrophysio logical and pharmacological properties, and therefore are considered to be responsible for different cellular responses to ACh, this differential distribution is expected to confer cell type-specificity of cholinergic regulation in the bladder urothelium. (c) 2007 Elsevier Inc. All rights reserved. C1 Univ Giessen, Inst Anat & Cell Biol, D-35385 Giessen, Germany. Univ Giessen, Dept Obstet & Gynecol, D-35385 Giessen, Germany. Univ Calif Davis, Dept Dermatol, Sacramento, CA 95817 USA. Dr R Pfleger GmbH, D-96045 Bamberg, Germany. NIDDK, Bioorgan Chem Lab, Bethesda, MD 20892 USA. RP Lips, KS (reprint author), Univ Giessen, Inst Anat & Cell Biol, Aulweg 123, D-35385 Giessen, Germany. EM Katrin.S.Lips@anatomie.med.uni-giessen.de NR 30 TC 63 Z9 63 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD MAY 30 PY 2007 VL 80 IS 24-25 BP 2308 EP 2313 DI 10.1016/j.lfs.2007.01.046 PG 6 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 182RE UT WOS:000247520900027 PM 17337281 ER PT J AU Vezys, V Masopust, D Desmarets, M Wess, J Zimring, JC AF Vezys, Vaiva Masopust, David Desmarets, Maxime Wess, Juergen Zimring, James C. TI Analysis of CD8(+) T cell-mediated anti-viral responses in mice with targeted deletions of the M-1 or M-5 muscarinic cholinergic receptors SO LIFE SCIENCES LA English DT Article; Proceedings Paper CT 2nd International Symposium on Non-neuronal Acetylcholine CY AUG 31-SEP 02, 2006 CL Mainz, GERMANY DE CD8(+) T cells ID HUMAN MONONUCLEAR LEUKOCYTES; ACETYLCHOLINE-RECEPTOR; MESSENGER-RNA; SYSTEM; LYMPHOCYTES; DIFFERENTIATION; EXPRESSION; INDUCTION; LINES AB A number of studies have demonstrated that non-neuronal acetylcholine can play a role in the regulation of T cell function. Recently, we reported that CD8+ T cells, from mice with a targeted deletion of the M-1 muscarinic receptor, had a defect in differentiating into cytolytic T lymphocytes when stimulated in vitro. In the current report, we analyze the in vivo function of CD8+ T cells from mice with targeted deletions of either M-1 or M-5 muscarinic receptors. M-1 or M-5 knockout mice were infected with either lymphocytic choriomeningitis virus or vesicular stomatitis virus. Expansion of anti-viral CD8+ T cells was monitored by staining with tetramer reagents specific for the immunodominant peptides of the viruses. No defect in expansion of CD8+ T cells was observed in either M-1 or M-5 knockout mice. The extent to which one can draw a generalized conclusion that M-1 and M-5 are not involved in anti-viral immunity depends upon issues of antigen strength, genetic background, induction of redundant receptors, and the potential for qualitative defects in the expanded CD8+ T cells. (c) 2007 Elsevier Inc. All rights reserved. C1 Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. NIDDK, NIH, Bioorgan Chem Lab, DHHS, Bethesda, MD 20892 USA. RP Zimring, JC (reprint author), Emory Univ, Sch Med, Dept Pathol, Woodruff Mem Res Bldg,Room 7301,101 Woodruff Circ, Atlanta, GA 30322 USA. EM jzimrin@emory.edu RI masopust, david/B-5027-2008; vezys, vaiva/N-3144-2013; OI Vezys, Vaiva/0000-0002-2520-809X; Zimring, James/0000-0002-1063-4010 FU NIAID NIH HHS [R03 AI060017-02, R03 AI060017] NR 19 TC 6 Z9 6 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD MAY 30 PY 2007 VL 80 IS 24-25 BP 2330 EP 2333 DI 10.1016/j.lfs.2007.01.001 PG 4 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 182RE UT WOS:000247520900031 PM 17286988 ER PT J AU Humphries, A Wells, T Baler, R Klein, DC Carter, DA AF Humphries, Ann Wells, Tim Baler, Ruben Klein, David C. Carter, David A. TI Rodent Aanat: Intronic E-box sequences control tissue specificity but not rhythmic expression in the pineal gland SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE arylalkylamine N-acetyltransferase; pineal gland; transgenic rat; E-box; circadian rhythm ID SEROTONIN N-ACETYLTRANSFERASE; PHOTORECEPTOR CONSERVED ELEMENTS; CIRCADIAN EXPRESSION; MELATONIN SYNTHESIS; GENE; CLOCK; MECHANISM; PROMOTER; TRANSCRIPTION; ACTIVATION AB Arylalkylamine N-acetyltransferase (Aanat) is the penultimate enzyme in the serotonin-N-acetylserotonin-melatonin pathway. It is nearly exclusively expressed in the pineal gland and the retina. A marked rhythm of Aanat gene expression in the rat pineal is mediated by cyclic AMP response elements located in the promoter and first intron. Intron I also contains E-box elements, which mediate circadian gene expression in other cells. Here we examined whether these elements contribute to rhythmic Aanat expression in the pineal gland. This was done using transgenic rats carrying Aanat transgenes with mutant E-box elements. Circadian expression of Aanat transgenes was not altered by these mutations. However, these mutations enhanced ectopic expression establishing that the intronic Aanat E-box elements contribute to the gene's pineal specific expression. A similar role of the Aanat E-box has been reported in zebrafish, indicating that Aanat E-box mediated silencing is a conserved feature of vertebrate biology. (C) 2007 Elsevier Ireland Ltd. All rights reserved. C1 Univ Cardiff Wales, Sch Biosci, Cardiff CF10 3US, Wales. NICHHD, Sect Neuroendocrinol, Off Sci Director, NIH, Bethesda, MD 20892 USA. RP Carter, DA (reprint author), Univ Cardiff Wales, Sch Biosci, POB 91,Museum Ave, Cardiff CF10 3US, Wales. EM smbdac@cardiff.ac.uk RI Wells, Timothy/A-6484-2010; Carter, David/A-4479-2010; OI Carter, David/0000-0002-8419-3975; Wells, Timothy/0000-0003-3618-0595 FU Medical Research Council [G9724886]; Wellcome Trust NR 25 TC 12 Z9 12 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD MAY 30 PY 2007 VL 270 IS 1-2 BP 43 EP 49 DI 10.1016/j.mce.2007.02.003 PG 7 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 174DD UT WOS:000246920500006 PM 17363136 ER PT J AU Morton, RA Geras-Raaka, E Wilson, LM Raaka, BM Gershengorn, MC AF Morton, Russell A. Geras-Raaka, Elizabeth Wilson, Leah M. Raaka, Bruce M. Gershengorn, Marvin C. TI Endocrine precursor cells from mouse islets are not generated by epithelial-to-mesenchymal transition of mature beta cells SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE mouse islet-derived precursor cells; human islet-derived precursor cells; beta cells; epithelial-to-mesenchymal transition; insulin; islet hormones; transgenic mouse models; genetically marked beta cells ID CULTURE; REDIFFERENTIATION; DIFFERENTIATION; EXPANSION; PANCREAS; TISSUE; VIVO AB We previously presented evidence that proliferative human islet precursor cells may be derived in vitro from adult islets by epithelial-to-mesenchymal transition (EMT) and show here that similar fibroblast-like cells can be derived from mouse islets. These mouse cell populations exhibited changes in gene expression consistent with EMT. Both C-peptide and insulin mRNAs were undetectable in expanded cultures of mouse islet-derived precursor cells (mIPCs). After expansion, mIPCs could be induced to migrate into clusters and differentiate into hormone-expressing islet-like aggregates. Although early morphological changes suggesting EMT were observed by time-lapse microscopy when green fluorescent protein-labeled beta cells were placed in culture, the expanded precursor cell population was not fluorescent. Using two mouse models in which beta cells were permanently made either to express alkaline phosphatase or to have a deleted M-3 muscarinic receptor, we provide evidence that mIPCs in long term culture are not derived from beta cells. Published by Elsevier Ireland Ltd. C1 NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Gershengorn, MC (reprint author), NIDDK, Clin Endocrinol Branch, NIH, 50 S Dr, Bethesda, MD 20892 USA. EM marving@intra.niddk.nih.gov FU Intramural NIH HHS [Z01 DK011007-06, Z99 DK999999] NR 16 TC 50 Z9 51 U1 0 U2 3 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 MAY 30 PY 2007 VL 270 IS 1-2 BP 87 EP 93 DI 10.1016/j.mce.2007.02.005 PG 7 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 174DD UT WOS:000246920500012 PM 17363142 ER PT J AU Hu, ZH Follmann, D AF Hu, Zonghui Follmann, Dean TI Statistical methods for active extension trials SO STATISTICS IN MEDICINE LA English DT Article DE ANCOVA; change score; maximum likelihood; pretest-posttest design ID 2-PERIOD; DESIGN; WITHDRAWAL AB This paper develops methods of analysis for active extension clinical trials. Under this design, patients are randomized to treatment or placebo for a period of time (period 1), and then all patients receive treatment for an additional period of time (period 2). We assume a continuous outcome is measured at baseline and at the end of the two consecutive periods. If only period 1 data is available, classic estimators of the treatment effect include the change score, analysis of covariance, and maximum likelihood (ML). We show how to extend these estimators by incorporating period 2 data which we refer to as the period 2 estimators. Under the assumption that the mean responses for treatment and placebo arms are the same at the end of period 2, the new estimators are unbiased and more efficient than estimators that ignore period 2 data. If this assumption is not met, the period 2 tests may be more powerful than period 1 tests, but the estimators are biased downward (upward) if the treatment effect during period 2 is larger (smaller) in treatment arm than the placebo arm. In general, the proposed period 2 procedure can provide an efficient way to supplement but not supplant the usual period 1 analysis. Copyright (C) 2006 John Wiley & Sons, Ltd. C1 NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Hu, ZH (reprint author), NIAID, Biostat Res Branch, NIH, 6700A rockledge Dr,MSC 7609, Bethesda, MD 20892 USA. EM huzo@niaid.nih.gov NR 12 TC 0 Z9 0 U1 0 U2 2 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 MAY 30 PY 2007 VL 26 IS 12 BP 2433 EP 2448 DI 10.1002/sim.2720 PG 16 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 167CI UT WOS:000246428000001 PM 17066400 ER PT J AU Vega-Rocha, S Gronenborn, B Gronenborn, AM Campos-Olivas, R AF Vega-Rocha, Susana Gronenborn, Bruno Gronenborn, Angela M. Campos-Olivas, Ramon TI Solution structure of the endonuclease domain from the master replication initiator protein of the nanovirus faba bean necrotic yellows virus and comparison with the corresponding geminivirus and circovirus structures SO BIOCHEMISTRY LA English DT Article ID TORSION ANGLE DYNAMICS; CIRCLE DNA-REPLICATION; LEAF CURL GEMINIVIRUS; REP PROTEIN; GENOME COMPONENTS; CONJUGATIVE RELAXASE; NUCLEASE DOMAIN; VIRAL ORIGIN; AMINO-ACID; IN-VITRO AB Nanoviruses are a family of plant viruses that possess a genome of multiple circular single-stranded DNA (ssDNA) components and are strikingly similar in their replication mode to the plant geminiviruses and to the circoviruses that infect birds or mammals. These viruses multiply by rolling circle replication using virus-encoded multifunctional replication initiator proteins (Rep proteins) that catalyze the initiation of replication on a double-stranded DNA (dsDNA) intermediate and the resolution of the ssDNA into circles. Here we report the solution NMR three-dimensional structure of the endonuclease domain from the master Rep (M-Rep) protein of faba bean necrotic yellows virus (FBNYV), a representative of the nanoviruses. The domain comprises amino acids 2-95 (M-Rep(2-95)), and its global fold is similar to those previously described for the gemini- and circovirus Rep endonuclease domains, consisting of a central 5-stranded antiparallel beta-sheet covered on one side by an alpha-helix and irregular loops and on the other, more open side of the domain, by an alpha-helix containing the catalytic tyrosine residue (the catalytic helix). Longer domain constructs extending to amino acids 117 and 124 were also characterized. They contain an additional alpha-helix, are monomeric, and exhibit catalytic activity indistinguishable from that of M-Rep(2-95). The binding site for the catalytic metal was identified by paramagnetic broadening and maps to residues on the exposed face of the central beta-sheet. A comparison with the previously determined Rep endonuclease domain structures of tomato yellow leaf curl Sardinia virus (TYLCSV), a geminivirus, and that of porcine circovirus type 2 (PCV2) Rep allows the identification of a positively charged surface that is most likely involved in dsDNA binding, and reveals common features shared by all endonuclease domains of nanovirus, geminivirus, and circovirus Rep proteins. C1 CNIO, Spanish Natl Canc Ctr, Struct & Computat Biol Program, Madrid 28029, Spain. CNRS, Inst Sci Vegetal, F-91198 Gif Sur Yvette, France. NIDDKD, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Dept Biol Struct, Pittsburgh, PA 15261 USA. RP Campos-Olivas, R (reprint author), CNIO, Spanish Natl Canc Ctr, Struct & Computat Biol Program, C Melchor Fernandex Almagro 3, Madrid 28029, Spain. EM rcampos@cnio.es RI Campos-Olivas, Ramon/L-9173-2014; OI Campos-Olivas, Ramon/0000-0002-5743-2221; Gronenborn, Angela M/0000-0001-9072-3525 FU Intramural NIH HHS [Z01 DK029025-16]; NIDDK NIH HHS [Z01 DK029025] NR 51 TC 21 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 MAY 29 PY 2007 VL 46 IS 21 BP 6201 EP 6212 DI 10.1021/bi700159q PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 170ER UT WOS:000246645700005 PM 17472345 ER PT J AU Kronmal, RA McClelland, RL Detrano, R Shea, S Lima, JA Cushman, M Bild, DE Burke, GL AF Kronmal, Richard A. McClelland, Robyn L. Detrano, Robert Shea, Steven Lima, Joao A. Cushman, Mary Bild, Diane E. Burke, Gregory L. TI Risk factors for the progression of coronary artery calcification in asymptomatic subjects - Results from the Multi-Ethnic Study of Atherosclerosis (MESA) SO CIRCULATION LA English DT Article DE arteries; calcium; coronary disease; epidemiology; imaging; risk factors ID BEAM COMPUTED-TOMOGRAPHY; HEART-DISEASE EVENTS; CARDIOVASCULAR RISK; CALCIUM SCORE; YOUNG-ADULTS; FOLLOW-UP; PREDICTION; CT; DIALYSIS; THERAPY AB Background - The Multi-Ethnic Study of Atherosclerosis (MESA) provides an opportunity to study the association of traditional cardiovascular risk factors with the incidence and progression of coronary artery calcium (CAC) in a large community-based cohort with no evidence of clinical cardiovascular disease. Methods and Results - Follow-up CAC measurements were available for 5756 participants with an average of 2.4 years between scans. The incidence of newly detectable CAC averaged 6.6% per year. Incidence increased steadily across age, ranging from < 5% annually in those < 50 years of age to > 12% in those > 80 years of age. Median annual change in CAC for those with existing calcification at baseline was 14 Agatston units for women and 21 Agatston units for men. Most traditional cardiovascular risk factors were associated with both the risk of developing new incident coronary calcium and increases in existing calcification. These included age, male gender, white race/ethnicity, hypertension, body mass index, diabetes mellitus, glucose, and family history of heart attack. Factors also existed that were related only to incident CAC risk, such as low- and high-density lipoprotein cholesterol and creatinine. Diabetes mellitus had the strongest association with CAC progression for blacks and the weakest for Hispanics, with intermediate associations for whites and Chinese. Conclusions - This is the first large multiethnic study reporting on the incidence and progression of CAC. Standard coronary risk factors were generally related to both CAC incidence and progression. Whites had more incident CAC and CAC progression than the other 3 racial/ethnic groups. Except for diabetes mellitus, risk factor relationships were similar across racial/ethnic groups. C1 Univ Washington, Dept Biostat, Collaborat Hlth Studies Coordinating Ctr, Seattle, WA 98115 USA. Harbor UCLA Med Ctr, Div Cardiol, Los Angeles, CA USA. Columbia Univ, Dept Med, New York, NY USA. Columbia Univ, Dept Epidemiol, New York, NY USA. Johns Hopkins Univ, Dept Cardiol, Baltimore, MD USA. Univ Vermont, Dept Med, Burlington, VT USA. NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. RP McClelland, RL (reprint author), Univ Washington, Dept Biostat, Collaborat Hlth Studies Coordinating Ctr, Bldg 29,Suite 310,6200 NE 74th St, Seattle, WA 98115 USA. EM rmcclell@u.washington.edu FU NHLBI NIH HHS [N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95169] NR 33 TC 236 Z9 245 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 29 PY 2007 VL 115 IS 21 BP 2722 EP 2730 DI 10.1161/CIRCULATIONHA.106.674143 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 172LA UT WOS:000246804600007 PM 17502571 ER PT J AU Heegaard, AM Corsi, A Danielsen, CC Nielsen, KL Jorgensen, HL Riminucci, M Young, MF Bianco, P AF Heegaard, Anne-Marie Corsi, Alessandro Danielsen, Carl Christian Nielsen, Karina L. Jorgensen, Henrik L. Riminucci, Mara Young, Marian F. Bianco, Paolo TI Biglycan deficiency causes spontaneous aortic dissection and rupture in mice SO CIRCULATION LA English DT Article DE aneurysm; biglycan; gene targeting ID GENE-EXPRESSION; TARGETED DISRUPTION; COLLAGEN FIBRILS; TERNARY COMPLEX; ANEURYSMS; DECORIN; PROTEOGLYCANS; LOCALIZATION; TISSUES; LOCUS AB Background - For the majority of cases, the cause of spontaneous aortic dissection and rupture is unknown. An inherited risk is associated with Marfan syndrome, Ehlers-Danlos syndrome type IV, and loci mapped to diverse autosomal chromosomes. Analysis of pedigrees however has indicated that it may be also inherited as an X-linked trait. The biglycan gene, found on chromosome X in humans and mice, encodes a small leucine- rich proteoglycan involved in the integrity of the extracellular matrix. A vascular phenotype has never been described in mice deficient in the gene for small leucine-rich proteoglycans. In the breeding of BALB/cA mice homozygous for a null mutation of the biglycan gene, we observed that 50% of biglycan- deficient male mice died suddenly within the first 3 months of life. Methods and Results - Necropsies revealed a major hemorrhage in the thoracic or abdominal cavity, and histology showed aortic rupture that involved an intimal and medial tear as well as dissection between the media and adventitia. By transmission electron microscopy and biomechanical testing, the aortas of biglycan-deficient mice showed structural abnormalities of collagen fibrils and reduced tensile strength. Similar collagen fibril changes were observed in male as well as in female biglycan-deficient mice, which implies a role of additional determinants such as gender- related response to stress in the development of this vascular catastrophe only in male mice. Conclusions - The spontaneous death of biglycan-deficient male mice from aortic rupture implicates biglycan as essential for the structural and functional integrity of the aortic wall and suggests a potential role of biglycan gene defects in the pathogenesis of aortic dissection and rupture in humans. C1 Univ Copenhagen, Dept Pharmacol & Pharmacotherapy, Fac Pharmaceut Sci, Copenhagen, Denmark. Nordic Biosci AS, Herlev, Denmark. Univ Roma La Sapienza, Dept Expt Med & Pathol, Rome, Italy. Univ Aarhus, Inst Anat, Dept Connect Tissue Biol, Aarhus, Denmark. Bispebjerg Hosp, Dept Clin Biochem, Copenhagen, Denmark. Univ Aquila, Dept Expt Med, I-67100 Laquila, Italy. Parco Sci Biomed San Raffaele, Rome, Italy. Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD USA. RP Heegaard, AM (reprint author), Danish Univ Pharmaceut Sci, Dept Pharmacol & Pharmacotherapy, Univ Pk 2, DK-2100 Copenhagen, Denmark. EM amhe@farma.ku.dk; p.bianco@flashnet.it NR 47 TC 57 Z9 60 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 29 PY 2007 VL 115 IS 21 BP 2731 EP 2738 DI 10.1161/CIRCULATIONHA.106.653980 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 172LA UT WOS:000246804600008 PM 17502576 ER PT J AU Tan, ZS Beiser, AS Vasan, RS Roubenoff, R Dinarello, CA Harris, TB Benjamin, EJ Au, R Kiel, DP Wolf, PA Seshadri, S AF Tan, Z. S. Beiser, A. S. Vasan, R. S. Roubenoff, R. Dinarello, C. A. Harris, T. B. Benjamin, E. J. Au, R. Kiel, D. P. Wolf, P. A. Seshadri, S. TI Inflammatory markers and the risk of Alzheimer disease - The Framingham study SO NEUROLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; C-REACTIVE PROTEIN; AMYLOID PRECURSOR PROTEIN; GENE POLYMORPHISMS; RECEPTOR ANTAGONIST; INTERLEUKIN-1; DEMENTIA; AGE; IMMUNOREACTIVITY; ASSOCIATION AB Objective: To examine whether serum cytokines and spontaneous production of peripheral blood mononuclear cell ( PBMC) cytokines are associated with the risk of incident Alzheimer disease (AD). Methods: We followed 691 cognitively intact community-dwelling participants (mean age 79 years, 62% women) and related PBMC cytokine production ( tertiles of spontaneous production of interleukin 1 [IL-1], IL-1 receptor antagonist, and tumor necrosis factor alpha [ TNF-alpha]) and serum C-reactive protein and interleukin 6 (IL- 6) to the risk of incident AD. Results: Adjusting for clinical covariates, individuals in the top two tertiles (T2 and T3) of PBMC production of IL-1 or the top tertile (T3) of PBMC production of TNF-alpha were at increased risk of developing AD (multivariable-adjusted hazard ratio [HR] for IL- 1 T2 = 2.84, 95% CI 1.09 to 7.43; p = 0.03 and T3 = 2.61, 95% CI 0.96 to 7.07; p = 0.06; for TNF-alpha, adjusted HR for T2 = 1.30, 95% CI 0.53 to 3.17; p = 0.57 and T3 = 2.59, 95% CI 1.09 to 6.12; p = 0.031]) compared with those in the lowest tertile (T1). Interpretation: Higher spontaneous production of interleukin 1 or tumor necrosis factor alpha by peripheral blood mononuclear cells may be a marker of future risk of Alzheimer disease ( AD) in older individuals. These data strengthen the evidence for a pathophysiologic role of inflammation in the development of clinical AD. C1 Beth Israel Deaconess Med Ctr, Hebrew Sr Life Dept Med, Inst Aging Res, Boston, MA 02131 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol & Biostat, Boston, MA 02118 USA. Tufts Univ, Sch Med, Boston, MA 02111 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. NIA, Bethesda, MD 20892 USA. RP Tan, ZS (reprint author), Beth Israel Deaconess Med Ctr, Hebrew Sr Life Dept Med, Inst Aging Res, 1200 Ctr St, Boston, MA 02131 USA. EM ztan@hms.harvard.edu OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336; Kiel, Douglas/0000-0001-8474-0310 FU NHLBI NIH HHS [N01-HC-25195]; NIA NIH HHS [5R01-AG08122, 5R01-AG16495, P30 AG13846]; NINDS NIH HHS [5R01-NS17950] NR 39 TC 222 Z9 230 U1 1 U2 10 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAY 29 PY 2007 VL 68 IS 22 BP 1902 EP 1908 DI 10.1212/01.wnl.0000263217.36439.da PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 172QD UT WOS:000246818100005 PM 17536046 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI An RNA-making reactor for the origin of life SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID ENVIRONMENTS C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM koonin@ncbi.nlm.nih.gov NR 19 TC 11 Z9 11 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 29 PY 2007 VL 104 IS 22 BP 9105 EP 9106 DI 10.1073/pnas.0702699104 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 174IN UT WOS:000246935700002 PM 17519331 ER PT J AU Goncalvez, AP Engle, RE St Claire, M Purcell, RH Lai, CJ AF Goncalvez, Ana P. Engle, Ronald E. St. Claire, Marisa Purcell, Robert H. Lai, Ching-Juh TI Monoclonal antibody-mediated enhancement of dengue virus infection in vitro and in vivo and strategies for prevention SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE antibody-dependent enhancement; nonhuman primate model; Fc mutations; cross-reactive mAb ID JAPANESE ENCEPHALITIS-VIRUS; IMMUNOGLOBULIN G1 ANTIBODY; CHIMPANZEE FAB FRAGMENTS; WEST-NILE-VIRUS; DEPENDENT ENHANCEMENT; ENVELOPE GLYCOPROTEIN; HEMORRHAGIC-FEVER; DISEASE SEVERITY; TYPE-2 VIRUSES; DV INFECTION AB Infection with dengue virus (DENV) or any other flavivirus induces cross-reactive, but weakly neutralizing or nonneutralizing, antibodies that recognize epitopes involving the fusion peptide in the envelope glycoprotein. Humanized mAb IgG 1A5, derived from a chimpanzee, shares properties of cross-reactive antibodies. mAb IgG 1A5 up-regulated DENV infection by a mechanism of antibody-dependent enhancement (ADE) in a variety of Fc receptor-bearing cells in vitro. A 10- to 1,000-fold increase of viral yield in K562 cells, dependent on the DENV serotype, was observed over a range of subneutralizing concentrations of IgG 1A5. A significant increase of DENV-4 viremia titers (up to 100-fold) was also demonstrated in juvenile rhesus monkeys immunized with passively transferred dilutions of IgG 1A5. These results, together with earlier findings of AIDE of DENV-2 infection by a polyclonal serum, establish the primate model for analysis of ADE. Considering the abundance of these cross-reactive antibodies, our observations confirm that significant viral amplification could occur during DENV infections in humans with prior infection or with maternally transferred immunity, possibly leading to severe dengue. Strategies to eliminate ADE were explored by altering the antibody Fc structures responsible for binding to Fc receptors. IgG 1A5 variants, containing amino acid substitutions from the Fc region of IgG2 or IgG4 antibodies, reduced but did not eliminate DENV-4-enhancing activity in K562 cells. Importantly, a 9-aa deletion at the N terminus of the CH2 domain in the Fc region abrogated the enhancing activity. C1 NIAID, Mol Viral Biol Sect, NIH, Rockville, MD 20850 USA. NIAID, Hepatitis Viruses Sect, NIH, Rockville, MD 20850 USA. Bioqual Inc, Rockville, MD 20850 USA. RP Goncalvez, AP (reprint author), NIAID, Mol Viral Biol Sect, NIH, Rockville, MD 20850 USA. EM agoncalvez@niaid.nih.gov; rpurcell@niaid.nih.gov; clai@niaid.nih.gov FU Intramural NIH HHS NR 35 TC 184 Z9 196 U1 1 U2 14 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 29 PY 2007 VL 104 IS 22 BP 9422 EP 9427 DI 10.1073/pnas.0703498104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 174IN UT WOS:000246935700061 PM 17517625 ER PT J AU De Ferrari, GV Papassotiropoulos, A Biechele, T De-Vrieze, FW Avila, ME Major, MB Myers, A Saez, K Henriquez, JP Zhao, A Wollmer, MA Nitsch, RM Hock, C Morris, CM Hardy, J Moon, RT AF De Ferrari, Giancarlo V. Papassotiropoulos, Andreas Biechele, Travis De-Vrieze, Fabienne Wavrant Avila, Miguel E. Major, Michael B. Myers, Amanda Saez, Katia Henriquez, Juan P. Zhao, Alice Wollmer, M. Axel Nitsch, Roger M. Hock, Christoph Morris, Chris M. Hardy, John Moon, Randall T. TI Common genetic variation within the Low-Density Lipoprotein Receptor-Related Protein 6 and late-onset Alzheimer's disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE neurodegenerative; LRP-6; single-nucleotide polymorphism; APOE; Wnt ID GLYCOGEN-SYNTHASE KINASE-3-BETA; RECEPTOR-RELATED PROTEIN-5; AMYLOID PRECURSOR PROTEIN; WNT SIGNALING PATHWAY; FAMILY-BASED TESTS; ALPHA-T-CATENIN; APOLIPOPROTEIN-E; CHROMOSOME 12; HIPPOCAMPAL-NEURONS; SEQUENCE VARIANTS AB Genome-wide linkage studies have defined a broad susceptibility region for late-onset Alzheimer's disease on chromosome 12, which contains the Low-Density Lipoprotein Receptor-Related Protein 6 (LRP6) gene, a coreceptor for Wnt signaling. Here, we report the association between common LRP6 variants and late-onset Alzheimer's disease in a multicenter case-control series as well as in a large family-based series ascertained by the National Institute of Mental Health-National Institute on Aging Genetics Initiative. As shown in the genome-wide linkage studies, our association depends mainly on apolipoprotein E-epsilon 4 (APOE-epsilon 4) carrier status. Haplotype tagging single-nucleotide polymorphisms (SNPs) with a set of seven allelic variants of LRP6 identified a putative risk haplotype, which includes a highly conserved coding sequence SNP: Ile-1062 -> Val. Functional analyses revealed that the associated allele Val-1062, an allele previously linked to low bone mass, has decreased beta-catenin signaling in HEK293T cells. Our study unveils a genetic relationship between LRP6 and APOE and supports the hypothesis that altered Wnt/beta-catenin signaling may be involved in this neuroclegenerative disease. C1 Univ Washington, Howard Hughes Med Inst, Sch Med, Seattle, WA 98195 USA. Univ Washington, Dept Pharmacol, Sch Med, Seattle, WA 98195 USA. Univ Washington, Inst Stem Cell & Regenerat Med, Sch Med, Seattle, WA 98195 USA. Univ Concepcion, Dept Bioquim & Biol Mol, Concepcion 4089100, Chile. Univ Concepcion, Dept Estadist, Concepcion 4089100, Chile. Univ Concepcion, Dept Biol Celular, Concepcion 4089100, Chile. Univ Basel, Biozentrum, Div Mol Psychol, CH-4055 Basel, Switzerland. Univ Basel, Biozentrum, Life Sci Training Facil, CH-4055 Basel, Switzerland. Univ Zurich, Dept Psychiat Res, CH-8029 Zurich, Switzerland. NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA. Newcastle Gen Hosp, Inst Aging & Hlth, Newcastle Upon Tyne N64 6BE, Tyne & Wear, England. RP De Ferrari, GV (reprint author), Univ Washington, Howard Hughes Med Inst, Sch Med, Seattle, WA 98195 USA. EM gdeferrari@udec.cl; rtmoon@u.washington.edu RI Wollmer, Marc /B-5038-2009; Myers, Amanda/B-1796-2010; Hardy, John/C-2451-2009; Moon, Randall/B-1743-2014; OI Myers, Amanda/0000-0002-3100-9396; Moon, Randall/0000-0002-9352-1408; Major, Michael/0000-0002-6753-8513 FU Medical Research Council [G0701075]; NIA NIH HHS [U24 AG021886]; NIMH NIH HHS [U01 MH 46281, U01 MH 46290, U01 MH 46372, U01 MH046281, U01 MH046290] NR 69 TC 149 Z9 150 U1 1 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 MAY 29 PY 2007 VL 104 IS 22 BP 9434 EP 9439 DI 10.1073/pnas.0603523104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 174IN UT WOS:000246935700063 PM 17517621 ER PT J AU Li, M Lai, YP Villaruz, AE Cha, DJ Sturdevant, DE Otto, M AF Li, Min Lai, Yuping Villaruz, Amer E. Cha, David J. Sturdevant, Daniel E. Otto, Michael TI Gram-positive three-component antimicrobial peptide-sensing system SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE innate host defense; Staphylococcus epidermidis ID STAPHYLOCOCCUS-AUREUS; SALMONELLA-TYPHIMURIUM; LISTERIA-MONOCYTOGENES; DLT OPERON; CONFERS RESISTANCE; LIPOTEICHOIC ACID; D-ALANINE; VIRULENCE; IDENTIFICATION; EPIDERMIDIS AB To survive during colonization or infection of the human body, microorganisms must circumvent mechanisms of innate host defense. Antimicrobial peptides represent a key component of innate host defense, especially in phagocytes and on epithelial Surfaces. However, it is not known how the clinically important group of Gram-positive bacteria sense antimicrobial peptides to coordinate a directed defensive response. By determining the genome-wide gene regulatory response to human P-defensin 3 in the nosocomial pathogen Staphylococcus epidermidis, we discovered an antimicrobial peptide sensor system that controls major specific resistance! mechanisms of Gram-positive bacteria and is unrelated to the Gram-negative PhoP/PhoQ system. It contains a classical two-component signal transducer and an unusual third protein, all of which are indispensable for signal transduction and antimicrobial peptide resistance. Furthermore, our data indicate that a very short, extracellular loop with a high density of negative charges in the sensor protein is responsible for antimicrobial peptide binding and the observed specificity for cationic antimicrobial peptides. Our study shows that Gram-positive bacteria have developed an efficient and unique way of controlling resistance mechanisms to antimicrobial peptides, which may provide a promising target for antimicrobial drug development. C1 NIAID, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. NIAID, Res & Technol Branch, Res Technol Sect, Genom Unit,Rocky Mtn Labs,NIH, Hamilton, MT 59840 USA. E China Normal Univ, Sch Life Sci, Shanghai 200062, Peoples R China. RP Otto, M (reprint author), NIAID, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115 FU Intramural NIH HHS NR 28 TC 154 Z9 159 U1 5 U2 29 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 MAY 29 PY 2007 VL 104 IS 22 BP 9469 EP 9474 DI 10.1073/pnas.0702159104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 174IN UT WOS:000246935700069 PM 17517597 ER PT J AU Wilson, PWF Meigs, JB Sullivan, L Fox, CS Nathan, DM D'Agostino, RB AF Wilson, Peter W. F. Meigs, James B. Sullivan, Lisa Fox, Caroline S. Nathan, David M. D'Agostino, Ralph B., Sr. TI Prediction of incident diabetes mellitus in middle-aged adults - The Framingham Offspring Study SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID INSULIN-RESISTANCE ATHEROSCLEROSIS; GLUCOSE-TOLERANCE TEST; METABOLIC SYNDROME; CARDIOVASCULAR-DISEASE; HIGH-RISK; ALTERNATIVE DEFINITIONS; FASTING GLUCOSE; HEART; MODEL; VALIDATION AB Background: Prediction rules for type 2 diabetes mellitus (T2DM) have been developed, but we lack consensus for the most effective approach. Methods: We estimated the 7-year risk of T2DM in middle-aged participants who had an oral glucose tolerance test at baseline. There were 160 cases of new T2DM, and regression models were used to predict new T2DM, starting with characteristics known to the subject (personal model, ie, age, sex, parental history of diabetes, and body mass index [calculated as the weight in kilograms divided by height in meters squared]), adding simple clinical measurements that included metabolic syndrome traits (simple clinical model), and, finally, assessing complex clinical models that included (1) 2-hour post-oral glucose tolerance test glucose, fasting insulin, and C-reactive protein levels; (2) the Gutt insulin sensitivity index; or (3) the homeostasis model insulin resistance and the homeostasis model insulin resistance beta- cell sensitivity indexes. Discrimination was assessed with area under the receiver operating characteristic curves (AROCs). Results: The personal model variables, except sex, were statistically significant predictors of T2DM (AROC, 0.72). In the simple clinical model, parental history of diabetes and obesity remained significant predictors, along with hyper-tension, low levels of high-density lipoprotein cholesterol, elevated triglyceride levels, and impaired fasting glucose findings but not a large waist circumference (AROC, 0.85). Complex clinical models showed no further improvement in model discriminations (AROC, 0.850-0.854) and were not superior to the simple clinical model. Conclusion: Parental diabetes, obesity, and metabolic syndrome traits effectively predict T2DM risk in a middleaged white population sample and were used to develop a simple T2DM prediction algorithm to estimate risk of new T2DM during a 7-year follow-up interval. C1 Emory Univ, Sch Med, Emory Program Cardiovasc Outcomes Res & Epidemiol, Atlanta, GA 30306 USA. Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Ctr Diabet, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. RP Wilson, PWF (reprint author), Emory Univ, Sch Med, Emory Program Cardiovasc Outcomes Res & Epidemiol, 1256 Briarcliff Rd,Suite 1N, Atlanta, GA 30306 USA. EM pwwilso@emory.edu OI Sullivan, Lisa/0000-0003-0726-7149 FU NHLBI NIH HHS [N01-HC-25195] NR 36 TC 367 Z9 385 U1 0 U2 19 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 MAY 28 PY 2007 VL 167 IS 10 BP 1068 EP 1074 DI 10.1001/archinte.167.10.1068 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 172AE UT WOS:000246775700011 PM 17533210 ER PT J AU Ward, MM AF Ward, Michael M. TI Laboratory abnormalities at the onset of treatment of end-stage renal disease - Are there racial or socioeconomic disparities in care? SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID INCIDENT HEMODIALYSIS-PATIENTS; CHRONIC KIDNEY-DISEASE; UNITED-STATES; MAINTENANCE DIALYSIS; INITIATION; MORTALITY; TRANSPLANTATION; MORBIDITY; ESRD; RACE AB Background: Laboratory abnormalities at the start of treatment of end-stage renal disease ( ESRD) have been reported as worse in racial/ethnic minorities than in white patients, suggesting racial disparities in care. It is not known whether these differences are attributable to racial/ethnic differences in socioeconomic status (SES). Methods: We tested associations between race/ethnicity, SES, and type of medical insurance and serum creatinine level, estimated glomerular filtration rate, serum albumin level, and hematocrit at the start of treatment of ESRD and use of epoietin before ESRD treatment in a large national population-based sample. Data on 515 561 patients beginning ESRD treatment between January 1, 1996, and June 30, 2004, were obtained for this cross-sectional survey from the United States Renal Data System. Results: Race/ethnicity had a much stronger association than SES with each laboratory measure. Adjusted mean serum creatinine levels were lowest in white patients (7.5 mg/dL [663.0 mu mol/L]; 95% confidence interval [CI], 7.45-7.49) and highest in black patients (8.9 mg/dL [786.7 mu mol/ L]; 95% CI, 8.92-8.97) (P <. 001 across racial/ethnic groups). Adjusted mean hematocrit for white patients ( 29.5%; 95% CI, 29.4%-29.6%) was significantly higher and for black patients (28.3%; 95% CI, 28.2%-28.4%) significantly lower than that of all other racial/ethnic groups (P <. 001 across racial/ethnic groups). Less marked differences were present for estimated glomerular filtration rate and serum albumin level. In contrast, predialysis use of epoietin was associated with race/ethnicity (black vs white: odds ratio, 0.80; 95% CI, 0.78-0.81; Hispanic vs white: odds ratio, 0.87; 95% CI, 0.85-0.89) and showed a graded decrease with decreasing SES ( odds ratio for the lowest vs highest socioeconomic quartile 0.68; 95% CI, 0.67-0.70). Patients without medical insurance had more abnormal laboratory values than those with insurance, but these associations were weaker than those of race/ethnicity. Conclusions: Minorities, particularly black patients, had more severe laboratory abnormalities at the start of ESRD treatment than white patients. These differences were not readily attributable to SES differences. Absence of medical insurance, SES, and race/ethnicity were associated with the likelihood of predialysis use of epoietin. C1 NIAMSD, Intramural Res Program, NIH, Bethesda, MD 20892 USA. RP Ward, MM (reprint author), NIAMSD, Intramural Res Program, NIH, 10 Ctr Dr,Bldg 10 CRC,Room 4-1339,MSC 1468, Bethesda, MD 20892 USA. EM wardm1@mail.nih.gov FU Intramural NIH HHS NR 50 TC 20 Z9 20 U1 0 U2 2 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 MAY 28 PY 2007 VL 167 IS 10 BP 1083 EP 1091 DI 10.1001/archinte.167.10.1083 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 172AE UT WOS:000246775700013 PM 17533212 ER PT J AU Koshiji, M Kumamoto, K Morimura, K Utsumi, Y Aizawa, M Hoshino, M Ohki, S Takenoshita, S Costa, M Commes, T Piquemal, D Harris, CC Tchou-Wong, KM AF Koshiji, Minori Kumamoto, Kensuke Morimura, Keiichirou Utsumi, Yasufumi Aizawa, Michiko Hoshino, Masami Ohki, Shinji Takenoshita, Seiichi Costa, Max Commes, Therese Piquemal, David Harris, Curtis C. Tchou-Wong, Kam-Meng TI Correlation of N-myc downstream-regulated gene 1 expression with clinical outcomes of colorectal cancer patients of different race/ethnicity. SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE NDRG1 expression; colorectal cancer; race; ethnicity; clinical outcomes ID VASCULAR ENDOTHELIAL-CELLS; COLON-CANCER; TUMOR-METASTASIS; PROSTATE-CANCER; SUPPRESSOR GENE; DRG-1; HYPOXIA; PROTEIN; HOMOCYSTEINE; GROWTH AB AIM: To evaluate the role of N-myc downstream-regulated gene 1 (NDRG1) expression in prognosis and survival of colorectal cancer patients with different ethnic backgrounds. METHODS: Because NDRG1 is a downstream target of p53 and hypoxia inducible factor-1 alpha (HIF-1 alpha), we examined NDRG1 expression together with 053 and HIF-1 alpha by immunohistochemistry. A total of 157 colorectal cancer specimens including 80 from Japanese patients and 77 from US patients were examined. The correlation between protein expression with clinicopathological features and survival after surgery was analyzed. RESULTS: NDRG1 protein was significantly increased in colorectal tumor compared with normal epithelium in both Japanese and US patient groups. Expression of NDRG1 protein was significantly correlated with lymphatic invasion, venous invasion, depth of invasion, histopathological type, and Dukes' stage in Japanese colorectal cancer patients. NDRG1 expression was correlated to histopathological type, Dukes' stage and HIF-1 alpha expression in US-Caucasian patients but not in US-African American patients. Interestingly, Kaplan-Meier survival analysis demonstrated that NDRG1 expression correlated significantly with poorer survival in US-African American patients but not in other patient groups. However, in p53-positive US cases, NDRG1 positivity correlated significantly with better survival. In addition, NDRG1 expression also correlated significantly with improved survival in US patients with stages III and IV tumors without chemotherapy. In Japanese patients with stages U and M tumors, strong NDRG1 staining in p53-positive tumors correlated significantly with improved survival but negatively in patients without chemotherapy. CONCLUSION: NDRG1 expression was correlated with various clinicopathological features and clinical outcomes in colorectal cancer depending on the race/ethnicity of the patients. NDRG1 may serve as a biological basis for the disparity of clinical outcomes of colorectal cancer patients with different ethnic backgrounds. (c) 2007 The WJG Press. All rights reserved. C1 NYU, Sch Med, Dept Environm Med, Tuxedo Pk, NY 10987 USA. Fukushima Med Univ, Dept Surg 2, Fukushima 9601295, Japan. NCI, NIH, Bethesda, MD 20892 USA. Osaka City Univ, Dept Pathol, Osaka 558, Japan. Ohara Gen Hosp, Dept Pathol, Fukushima 9608611, Japan. Ohara Gen Hosp, Dept Surg, Fukushima 9608611, Japan. Univ Montpellier 2, Montpellier, France. RP Tchou-Wong, KM (reprint author), NYU, Sch Med, Dept Environm Med, 57 Old Forge Rd, Tuxedo Pk, NY 10987 USA. EM tchouk02@med.nyu.edu RI costa, max/H-1754-2012 FU NCI NIH HHS [CA101234, CA16087, P30 CA016087, R01 CA101234]; NIDDK NIH HHS [R21 DK063603, DK63603]; NIEHS NIH HHS [ES00260, ES05512, ES10344, P30 ES000260, P42 ES010344, R01 ES005512, T32 ES007324, T32-ES07324] NR 26 TC 22 Z9 26 U1 2 U2 2 PU W J G PRESS PI BEIJING PA PO BOX 2345, BEIJING 100023, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD MAY 28 PY 2007 VL 13 IS 20 BP 2803 EP 2810 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 179XX UT WOS:000247325000005 PM 17569115 ER PT J AU Schneider, D Liaw, L Daniel, C Athanasopoulos, AN Herrmann, M Preissner, KT Nawroth, PP Chavakis, T AF Schneider, Darius Liaw, Lucy Daniel, Carolin Athanasopoulos, Athanasios N. Herrmann, Mathias Preissner, Klaus T. Nawroth, Peter P. Chavakis, Triantafyllos TI Inhibition of breast cancer cell adhesion and bone metastasis by the extracellular adherence protein of Staphylococcus aureus SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE breast cancer; bone metastasis; integrin; osteopontin; adhesion ID INTEGRIN ALPHA-V-BETA-3; TUMOR-METASTASIS; HOST-DEFENSE; OSTEOPONTIN; EXPRESSION; IDENTIFICATION; INVOLVEMENT; MECHANISMS; RECEPTORS; FRAGMENT AB Bone metastasis is a common sequelae of breast cancer and the interaction of alpha v beta 3-integrin with osteopontin (OPN) found in the extracellular matrix of mineralized tissues is implicated in this process. The integrin-dependent proadhesive and promigratory functions of OPN are particularly attributed to the 40 kD N-terminal fragment that derives upon matrix metalloproteinase (MMPP) cleavage. Based on the broad repertoire of interactions between Staphylococcus aureus extracellular adherence protein (Eap) and host components, we here characterized Eap to specifically interact with recombinant full-length OPN and the 40 kD N-terminal MMP cleavage fragment, but not with the 32 W or the 25 kD C-terminal fragments of OPN. Eap thereby prevented the OPN/alpha v beta 3-integrin interaction, as well as the alpha v beta 3-integrin-dependent adhesion of MDA-MB-231 breast cancer cells to full-length OPN or to the 40 kD fragment and the migration of these cells towards OPN. Furthermore, Eap treatment markedly impaired the development of osseous metastasis of human MDA-MB-231 cells in vivo. Taken together, Eap may represent an attractive novel treatment for the prevention of breast cancer bone metastasis. Published by Elsevier Inc. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Univ Heidelberg, Dept Internal Med, D-69120 Heidelberg, Germany. Maine Med Ctr, Res Inst, Ctr Mol Med, Scarborough, ME 04074 USA. Univ Frankfurt, Div Gastroenterol & Clin Nutr, Dept Internal Med, D-60590 Frankfurt, Germany. Univ Saarland, Inst Med Microbiol, D-66421 Homburg, Germany. Univ Giessen, Inst Biochem, D-35392 Giessen, Germany. RP Chavakis, T (reprint author), NCI, Expt Immunol Branch, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM chavakist@mail.nih.gov RI Herrmann, Mathias/B-6475-2013; Daniel, Carolin/M-4624-2014 OI Daniel, Carolin/0000-0003-4698-7069 FU Intramural NIH HHS [, NIH0012066627]; PHS HHS [NIH0012066627] NR 32 TC 8 Z9 9 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 MAY 25 PY 2007 VL 357 IS 1 BP 282 EP 288 DI 10.1016/j.bbrc.2007.03.143 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 161PW UT WOS:000246028800046 PM 17418809 ER PT J AU Marchionini, DM Lehrmann, E Chu, YP He, B Sortwell, CE Becker, KG Kordower, JH Collier, TJ AF Marchionini, Deanna M. Lehrmann, Elin Chu, Yaping He, Bin Sortwell, Caryl E. Becker, Kevin G. Kordower, Jeffrey H. Collier, Timothy J. TI Role of heparin binding growth factors in nigrostriatal dopamine system development and Parkinson's disease SO BRAIN RESEARCH LA English DT Article DE Parkinson's disease; striaturn; human; HB-GAM; microarray; development ID ANAPLASTIC LYMPHOMA KINASE; ACTIVATED PROTEIN-KINASE; AFFIN REGULATORY PEPTIDE; MOLECULE HB-GAM; NEUROTROPHIC FACTOR; NEURITE OUTGROWTH; SUBSTANTIA-NIGRA; VENTRAL MESENCEPHALON; CELL-DEATH; IN-VITRO AB The developmental biology of the dopamine (DA) system may hold important clues to its reconstruction. We hypothesized that factors highly expressed during nigrostriatal development and re-expressed after injury and disease may play a role in protection and reconstruction of the nigrostriatal system. Examination of gene expression in the developing striatum suggested an important role for the heparin binding growth factor family at time points relevant to establishment of dopaminergic innervation. Midkine, pleiotrophin (PTN), and their receptors syndecan-3 and receptor protein tyrosine phosphatase beta/zeta, were highly expressed in the striatum during development. Furthermore, PTN was up-regulated in the degenerating substantia nigra of Parkinson's patients. The addition of PTN to ventral mesencephalic cultures augmented DA neuron survival and neurite outgrowth. Thus, PTN was identified as a factor that plays a role in the nigrostriatal system during development and in response to disease, and may therefore be useful for neuroprotection or reconstruction of the DA system. (c) 2007 Elsevier B.V. All rights reserved. C1 Rush Univ, Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. NIDA, Cellular Neurobiol Res Branch, DHHS, NIH, Baltimore, MD 21224 USA. NIA, Res Resources Branch, Gene Express & Genom Unit, DHHS,NIH, Baltimore, MD 21224 USA. RP Marchionini, DM (reprint author), Rush Univ, Med Ctr, Dept Neurol Sci, 1735 W Harrison St,Suite 300, Chicago, IL 60612 USA. EM deanna_marchionini@rush.edu OI Lehrmann, Elin/0000-0002-9869-9475; Becker, Kevin/0000-0002-6794-6656 FU NINDS NIH HHS [NS42125] NR 88 TC 41 Z9 41 U1 1 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 MAY 25 PY 2007 VL 1147 BP 77 EP 88 DI 10.1016/j.brainres.2007.02.028 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 171EP UT WOS:000246718000008 PM 17368428 ER PT J AU Saavedra, JM AF Saavedra, Juan M. TI The challenge of genetic studies in hypertension SO CIRCULATION RESEARCH LA English DT Editorial Material DE endothelin; VEGF; human hypertension; haplotype analysis; salt sensitivity ID ANGIOTENSIN-II RECEPTOR; BLOOD-PRESSURE; K+-ATPASE; ENDOTHELIN RECEPTOR; NA,K-ATPASE GENE; BINDING-SITE; RAT MODEL; DAHL; NA+; SEQUENCE C1 NIMH, Pharmacol Sect, DIRP, NIH,DHHS, Bethesda, MD 20892 USA. RP Saavedra, JM (reprint author), NIMH, Pharmacol Sect, DIRP, NIH,DHHS, 10 Ctr Dr,Bldg 10,Room 2D-57, Bethesda, MD 20892 USA. EM saavedrj@mail.nih.gov FU Intramural NIH HHS NR 53 TC 2 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD MAY 25 PY 2007 VL 100 IS 10 BP 1389 EP 1393 DI 10.1161/01.RES.0000269420.81524.05 PG 5 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 171HO UT WOS:000246727000001 PM 17525374 ER PT J AU Hsueh, W Abel, ED Breslow, JL Maeda, N Davis, RC Fisher, EA Dansky, H McClain, DA McIndoe, R Wassef, MK Rabadan-Diehl, C Goldberg, IJ AF Hsueh, Willa Abel, E. Dale Breslow, Jan L. Maeda, Nobuyo Davis, Richard C. Fisher, Edward A. Dansky, Hayes McClain, Donald A. McIndoe, Richard Wassef, Momtaz K. Rabadan-Diehl, Cristina Goldberg, Ira J. TI Recipes for creating animal models of diabetic cardiovascular disease SO CIRCULATION RESEARCH LA English DT Review DE atherosclerosis; diabetes mellitus; diabetic cardiomyopathy; transgenic mice ID E-DEFICIENT MICE; APOLIPOPROTEIN-A-II; ADVANCED ATHEROSCLEROTIC LESIONS; FATTY-ACID OXIDATION; DENSITY-LIPOPROTEIN RECEPTOR; INSULIN-RESISTANCE; TRANSGENIC MICE; CARDIAC-HYPERTROPHY; KNOCKOUT MICE; LIPOTOXIC CARDIOMYOPATHY AB For more than 50 years, investigators have unsuccessfully tried to recreate in experimental animals the cardiovascular complications of diabetes seen in humans. In particular, accelerated atherosclerosis and dilated cardiomyopathy, the major causes of mortality in patients with diabetes, have been conspicuously absent in many mouse models of the disease. Under the auspices of the NIH, the Animal Models of Diabetic Complications Consortium has worked to address this issue. This effort has focused on the development of mouse models because of the high level of genomic information available and the many well-developed genetic manipulations that may be performed in mice. Importantly, the consortium has also worked to standardize many methods to assess metabolic and cardiovascular end points for measurement of the diabetic state and its macrovascular complications. Finally, for maximum benefits from these animal models in the study of atherosclerosis and of other diabetic complications, the consortium has created a system for sharing both the animal models and the accumulated phenotypic data with the greater scientific community. C1 Columbia Univ, Dept Med, New York, NY 10032 USA. NYU, Sch Med, Leon H Charney Div Cardiol, Marc & Ruti Bell Program Vasc Biol,Dept Med, New York, NY 10032 USA. Med Coll Georgia, Ctr Biotechnol & Genom Med, Augusta, GA 30912 USA. NHLBI, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. Univ Calif Los Angeles, David Geffen Sch Med, Div Endocrinol Diabet & Hypertens, Los Angeles, CA USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Cardiol, Los Angeles, CA USA. Univ Utah, Div Endocrinol Metab & Diabet, Salt Lake City, UT USA. Univ Utah, Program Human Mol Biol & Genet, Salt Lake City, UT USA. Rockefeller Univ, Biochem Genet & Metab Lab, New York, NY 10021 USA. Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC USA. RP Goldberg, IJ (reprint author), Columbia Univ, Dept Med, 630 W 168th St,PH10-305, New York, NY 10032 USA. EM ijg3@columbia.edu RI Breslow, Jan/B-7544-2008; OI Fisher, Edward/0000-0001-9802-143X FU NHLBI NIH HHS [HL70523, HL70524, HL70525, HL70526, HL87944, HL87945, HL87947, U01 HL087946]; NIDDK NIH HHS [DK60966, DK76169] NR 150 TC 122 Z9 125 U1 0 U2 6 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 MAY 25 PY 2007 VL 100 IS 10 BP 1415 EP 1427 DI 10.1161/01.RES.0000266449.37396.1f PG 13 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 171HO UT WOS:000246727000008 PM 17525381 ER PT J AU Isenberg, JS Jia, YF Fukuyama, J Switzer, CH Wink, DA Roberts, DD AF Isenberg, Jeff S. Jia, Yifeng Fukuyama, Julia Switzer, Christopher H. Wink, David A. Roberts, David D. TI Thrombospondin-1 inhibits nitric oxide signaling via CD36 by inhibiting myristic acid uptake SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ENDOTHELIAL-CELL RESPONSES; N-TERMINAL MYRISTOYLATION; PROTEIN-TYROSINE KINASES; ANGIOGENESIS IN-VIVO; CHAIN FATTY-ACIDS; METHIONINE AMINOPEPTIDASE-2; SELECTIVE REQUIREMENT; DEPENDENT MANNER; GROWTH-FACTOR; MEMBRANE AB Although CD36 is generally recognized to be an inhibitory signaling receptor for thrombospondin- 1 (TSP1), the molecular mechanism for transduction of this signal remains unclear. Based on evidence that myristic acid and TSP1 each modulate endothelial cell nitric oxide signaling in a CD36-dependent manner, we examined the ability of TSP1 to modulate the fatty acid translocase activity of CD36. TSP1 and a CD36 antibody that mimics the activity of TSP1 inhibited myristate uptake. Recombinant TSP1 type 1 repeats were weakly inhibitory, but an anti-angiogenic peptide derived from this domain potently inhibited myristate uptake. This peptide also inhibited membrane translocation of the myristoylated CD36 signaling target Fyn and activation of Src family kinases. Myristate uptake stimulated cGMP synthesis via endothelial nitric-oxide synthase and soluble guanylyl cyclase. CD36 ligands blocked myristate-stimulated cGMP accumulation in proportion to their ability to inhibit myristate uptake. TSP1 also inhibited myristate-stimulated cGMP synthesis by engaging its receptor CD47. Myristate stimulated endothelial and vascular smooth muscle cell adhesion on type I collagen via the NO/cGMP pathway, and CD36 ligands that inhibit myristate uptake blocked this response. Therefore, the fatty acid translocase activity of CD36 elicits pro-angiogenic signaling in vascular cells, and TSP1 inhibits this response by simultaneously inhibiting fatty acid uptake via CD36 and downstream cGMP signaling via CD47. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Roberts, DD (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Rm 2A33,10 Ctr Dr,MSC1500, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008; Switzer, Christopher/D-9203-2013 OI Roberts, David/0000-0002-2481-2981; FU Intramural NIH HHS [Z01 SC009172-04, Z01 SC009174-04] NR 66 TC 65 Z9 66 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 25 PY 2007 VL 282 IS 21 BP 15404 EP 15415 DI 10.1074/jbc.M701638200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 169JX UT WOS:000246589600016 PM 17416590 ER PT J AU Don, AS Martinez-Lamenca, C Webb, WR Proia, RL Roberts, E Rosen, H AF Don, Anthony S. Martinez-Lamenca, Carolina Webb, William R. Proia, Richard L. Roberts, Ed Rosen, Hugh TI Essential requirement for sphingosine kinase 2 in a sphingolipid apoptosis pathway activated by FTY720 analogues SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID IMMUNOMODULATORY DRUG FTY720; 1-PHOSPHATE RECEPTOR AGONIST; MRL-LPR/LPR-MICE; ENDOPLASMIC-RETICULUM; KINASE TYPE-2; IN-VIVO; SACCHAROMYCES-CEREVISIAE; IMMUNOSUPPRESSIVE AGENT; LYMPHOCYTE EGRESS; TUMOR-GROWTH AB The clinical immunosuppressant FTY720 is a sphingosine analogue that, once phosphorylated by sphingosine kinase 2(Sphk2), is an agonist of multiple receptor subtypes for sphingosine 1-phosphate. Short exposures to FTY720 afford long term protection in lymphoproliferative and autoimmune disease models, presumably by inducing apoptosis in subsets of cells essential for pathogenesis. Sphingosine itself is pro-apoptotic, and apoptosis induced with FTY720 or sphingosine is thought to proceed independently of their phosphorylation. Following chemical mutagenesis of Jurkat cells we isolated mutants that are selectively resistant to FTY720 analogue AAL(R), as well as natural sphingolipid bases, including sphingosine. Cells lacking functional Sphk2 were resistant to apoptosis induced with AAL(R), indicating that apoptosis proceeds through AAL(R) phosphorylation. Phosphorylation of AAL(R) was also required for induction of lymphocyte apoptosis in mice, as apoptosis was not induced with the non-phosphorylatable chiral analogue, AAL(S). Apoptosis was induced in the spleen but not the thymus of mice administered 1 mg/ kg AAL(R), correlating with levels of AAL(R)-phosphate (AFD(R)) in organ extracts. AFD(R) did not induce apoptosis when added to the cell culture medium, indicating that it induces apoptosis through an intracellular target. NBD-labeled AAL(R) localized to the endoplasmic reticulum, and AAL(R) treatment resulted in elevated cytosolic calcium, Bax redistribution from cytosol to mitochondrial and endoplasmic reticulum membranes, and caspase-independent mitochondrial permeabilization in Jurkat cells. We therefore describe an apoptotic pathway triggered by intracellular accumulation of sphingolipid base phosphates and suggest that sphingoid base substrates for Sphk2 acting intracellularly could be useful in the treatment of lymphoproliferative diseases. C1 Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA. Scripps Res Inst, Dept Chem, La Jolla, CA 92037 USA. NIDDK, NIH, Bethesda, MD 20892 USA. RP Rosen, H (reprint author), ICND118,10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM hrosen@scripps.edu RI Proia, Richard/A-7908-2012 FU NIAID NIH HHS [AI055509]; PHS HHS [NIMH-074404] NR 50 TC 51 Z9 53 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 MAY 25 PY 2007 VL 282 IS 21 BP 15833 EP 15842 DI 10.1074/jbc.M609124200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 169JX UT WOS:000246589600058 PM 17400555 ER PT J AU Shimizu, R Trainor, CD Nishikawa, K Kobayashi, M Ohneda, K Yamamoto, M AF Shimizu, Ritsuko Trainor, Cecelia D. Nishikawa, Keizo Kobayashi, Makoto Ohneda, Kinuko Yamamoto, Masayuki TI GATA-1 self-association controls erythroid development in vivo SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSCRIPTION FACTOR GATA-1; CREB-BINDING PROTEIN; DNA-BINDING; ZINC-FINGER; HEMATOPOIETIC TRANSCRIPTION; GENE; DIFFERENTIATION; ACETYLATION; DOMAIN; EXPRESSION AB GATA-1 is the key transcription factor for the development of the erythroid, megakaryocytic, eosinophilic, and mast cell lineages. GATA-1 possesses the ability to self-associate, and this characteristic has been suggested to be important for GATA-1 function. To elucidate the roles self-associated GATA-1 plays during hematopoietic cell development in vivo, in this study we prepared GATA-1 mutants in which three lysine residues potentially contributing to the self-association (Lys-245, Lys-246, and Lys-312) are substituted in combination with alanines. Of the mutants, 3KA harboring alanine substitutions in all three lysines showed reduced self-association activity without considerable interference in the modification of GATA-1 by acetylation. We generated transgenic mouse lines that express these GATA-1 mutants utilizing the Gata1 hematopoietic regulatory domain, and crossed the mice to Gata1 knockdown (GATA-1.05) mutant mice. Although NKA (K245A and K246A) and CKA (K312A) mutants almost fully rescued the GATA-1.05 mice from anemia and embryonic lethality, the 3KA mutant only partially rescued the GATA-1.05 mutant mice. Even with the higher than endogenous level expression, GATA-1.05/Y::3KA embryos were prone to die at various stages in mid-to-late gestation. Live birth and an anemic phenotype were restored in some embryos depending on the expression level of the 3KA transgene. The expression of the transferrin receptor and heme biosynthesis enzymes was impaired in the yolk sac and liver of the 3KA-rescued embryos. Immature erythroid cells with insufficient expression of the transferrin receptor accumulated in the livers of 3KA-rescued embryos. These results provide the first convincing line of evidence that the self-association of GATA-1 is important for proper mammalian erythroid development in vivo. C1 Univ Tsukuba, Grad Sch Comprehens Human Sci, Tsukuba, Ibaraki 3058577, Japan. Univ Tsukuba, Ctr Tsukuba Adv Res Alliance, Tsukuba, Ibaraki 3058577, Japan. Univ Tsukuba, Japan Sci & Technol Agcy, Explorat Res Adv Technol Environm Response Projec, Tsukuba, Ibaraki 3058577, Japan. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Yamamoto, M (reprint author), Univ Tsukuba, Grad Sch Comprehens Human Sci, Tennoudai 1-1-1, Tsukuba, Ibaraki 3058577, Japan. EM masi@tara.tsukuba.ac.jp RI Yamamoto, Masayuki/A-4873-2010; Kobayashi, Makoto/B-2537-2008 FU Intramural NIH HHS NR 47 TC 19 Z9 20 U1 1 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 MAY 25 PY 2007 VL 282 IS 21 BP 15862 EP 15871 DI 10.1074/jbc.M701936200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 169JX UT WOS:000246589600061 PM 17374603 ER PT J AU Iwamoto, H Oiwa, K Kovacs, M Sellers, JR Suzuki, T Wakayama, J Tamura, T Yagi, N Fujisawa, T AF Iwamoto, Hiroyuki Oiwa, Kazuhiro Kovacs, Mihaly Sellers, James R. Suzuki, Takuya Wakayama, Jun'ichi Tamura, Takumi Yagi, Naoto Fujisawa, Tetsuro TI Diversity of structural behavior in vertebrate conventional Myosins complexed with actin SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE myosin subfragment-1; myosin-II; ADP; X-ray fiber diffraction; actomyosin complex ID SMOOTH-MUSCLE MYOSIN; X-RAY-DIFFRACTION; INSECT FLIGHT-MUSCLE; SKELETAL-MUSCLE; ADP RELEASE; KINETIC CHARACTERIZATION; 3-DIMENSIONAL STRUCTURE; ELECTRON-MICROSCOPY; CROSS-BRIDGES; MOTOR DOMAIN AB Low-resolution three-dimensional structures of acto-myosin subfragment-1 (S1) complexes were retrieved from X-ray fiber diffraction patterns, recorded either in the presence or absence of ADP. The S1 was obtained from various myosin-II isoforms from vertebrates, including rabbit fast-skeletal and cardiac, chicken smooth and human non-muscle IIA and IIB species, and was diffused into an array of overstretched, skinned skeletal muscle fibers. The SI attached to the exposed actin filaments according to their helical symmetry. Upon addition of ADP, the diffraction patterns from acto-Sl showed an increasing magnitude of response in the order as listed above, with features of a lateral compression of the whole diffraction pattern (indicative of increased radius of the acto-Sl complex) and an enhancement of the fifth layer-line reflection. The structure retrieval indicates that these changes are mainly due to the swing of the light chain (LC) domain in the direction consistent with the cryo-electron microscopic results. In the nonmuscle isoforms, the swing is large enough to affect the manner of quasicrystal packing of the SI-decorated actin filaments and their lattice dimension, with a small change in the twist of actin filaments. Variations also exist in the behavior of the 50K-cleft, which apparently opens upon addition of ADP to the non-muscle isoforms but not to other isoforms. The fast-skeletal S1 remains as the only isoform that does not clearly exhibit either of the structural changes. The results indicate that the "conventional" myosin-II isoforms exhibit a wide variety of structural behavior, possibly depending on their functions and/or the history of molecular evolution. (C) 2007 Elsevier Ltd. All rights reserved. C1 Kansai Adv Res Ctr, Natl Inst Informat & Commun Technol, Kobe, Hyogo 6512492, Japan. NHLBI, Lab Mol Physiol, NIH, Bethesda, MD 20892 USA. Eotvos Lorand Univ, Dept Biochem, H-1117 Budapest, Hungary. EM iwamoto@spring8.or.jp RI Kovacs, Mihaly/A-6841-2011; Oiwa, Kazuhiro/D-7721-2011 OI Oiwa, Kazuhiro/0000-0002-1281-113X FU FIC NIH HHS [1 R01 TW007241-01, D43 TW006230, R01 TW006230, R01 TW007241, R01 TW007241-02] NR 51 TC 11 Z9 11 U1 1 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 25 PY 2007 VL 369 IS 1 BP 249 EP 264 DI 10.1016/j.jmb.2007.03.031 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 170KA UT WOS:000246661100020 PM 17433365 ER PT J AU Trus, BL Newcomb, WW Cheng, NQ Cardone, G Marekov, L Horna, FL Brown, JC Steven, AC AF Trus, Benes L. Newcomb, William W. Cheng, Naiqian Cardone, Giovanni Marekov, Lyuben Horna, Fred L. Brown, Jay C. Steven, Alasdair C. TI Allosteric signaling and a nuclear exit strategy: Binding of UL25/UL17 heterodimers to DNA-filled HSV-1 capsids SO MOLECULAR CELL LA English DT Article ID HERPES-SIMPLEX-VIRUS; PACKAGING PROTEIN UL17; CRYOELECTRON MICROSCOPY; ELECTRON CRYOMICROSCOPY; 3-DIMENSIONAL STRUCTURE; EXTERNAL SURFACE; GENE-PRODUCT; UL25 GENE; TYPE-1; MATURATION AB UL25 and UL17 are two essential minor capsid proteins of HSV-1, implicated in DNA packaging and capsid maturation. We used cryo-electron microscopy to examine their binding to capsids, whose architecture observes T = 16 icosahedral geometry. C-capsids (mature DNA-filled capsids) have an elongated two-domain molecule present at a unique, vertex-adjacent site that is not seen at other quasiequivalent sites or on unfilled capsids. Using SDS-PAGE and mass spectrometry to analyze wild-type capsids, UL25 null capsids, and denaturant-extracted capsids, we conclude that (1) the C-capsid-specific component is a heterodimer of UL25 and UL17, and (2) capsids have additional populations of UL25 and UL17 that are invisible in reconstructions because of sparsity and/or disorder. We infer that binding of the ordered population reflects structural changes induced on the outer surface as pressure builds up inside the capsid during DNA packaging. Its binding may signal that the C-capsid is ready to exit the nucleus. C1 NIAMSD, Lab Struct Biol Res, Bethesda, MD 20892 USA. NIH, Imaging Sci Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. Univ Virginia Hlth Syst, Dept Microbiol, Charlottesville, VA 22908 USA. Univ Virginia Hlth Syst, Ctr Canc, Charlottesville, VA 22908 USA. Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA. RP Steven, AC (reprint author), NIAMSD, Lab Struct Biol Res, Bethesda, MD 20892 USA. EM alasdair_steven@nih.gov FU Intramural NIH HHS [Z01 AR027002-29, Z01 CT000090-27, Z99 AR999999]; NIAID NIH HHS [AI060836, AI41644-10, R01 AI041644, R01 AI041644-10, R01 AI060836, R01 AI060836-02, R56 AI041644, R56 AI060836] NR 49 TC 96 Z9 100 U1 0 U2 3 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD MAY 25 PY 2007 VL 26 IS 4 BP 479 EP 489 DI 10.1016/j.molcel.2007.04.010 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 174XF UT WOS:000246975500005 PM 17531807 ER PT J AU Gorry, PR Dunfee, RL Mefford, ME Kunstman, K Morgan, T Moore, JP Mascola, JR Agopian, K Holm, GH Mehle, A Taylor, J Farzan, M Wang, H Ellery, P Willey, SJ Clapham, PR Wolinsky, SM Crowe, SM Gabuzda, D AF Gorry, Paul R. Dunfee, Rebecca L. Mefford, Megan E. Kunstman, Kevin Morgan, Tom Moore, John P. Mascola, John R. Agopian, Kristin Holm, Geoffrey H. Mehle, Andrew Taylor, Joann Farzan, Michael Wang, Hui Ellery, Philip Willey, Samantha J. Clapham, Paul R. Wolinsky, Steven M. Crowe, Suzanne M. Gabuzda, Dana TI Changes in the V3 region of gp 120 contribute to unusually broad coreceptor usage of an HIV-1 isolate from a CCR5 Delta 32 heterozygote SO VIROLOGY LA English DT Article DE HIV-1; CCR5 Delta 32; ENV; V3; CCR5 ID HUMAN-IMMUNODEFICIENCY-VIRUS; CHEMOKINE RECEPTOR D6; HUMAN MONOCLONAL-ANTIBODIES; LONG-TERM SURVIVOR; DISEASE PROGRESSION; GP120 GLYCOPROTEIN; TYPE-1 INFECTION; SMALL-MOLECULE; IN-VIVO; SEROPOSITIVE INDIVIDUALS AB Heterozygosity for the CCR5 Delta 32 allele is associated with delayed progression to AIDS in human immunodeficiency virus type 1 (HIV-1) infection. Here we describe an unusual HIV-1 isolate from the blood of an asymptomatic individual who was heterozygous for the CCR5 Delta 32 allele and had reduced levels of CCR5 expression. The primary virus used CCR5, CXCR4, and an unusually broad range of alternative coreceptors to enter transfected cells. However, only CXCR4 and CCR5 were Used to enter primary T cells and monocyte-derived macrophages, respectively. Full-length Env clones had an unusually long V1/V2 region and rare amino acid variants in the V3 and C4 regions. Mutagenesis studies and structural models suggested that Y308, D321, and to a lesser extent K442 and E444, contribute to the broad coreceptor usage of these Envs, whereas 1317 is likely to be a compensatory change. Furthermore, database analysis suggests that covariation can occur at positions 308/317 and 308/321 in vivo. Y308 and D321 reduced dependence on the extracellular loop 2 (ECL2) region of CCR5, while these residues along with Y330, K442, and E444 enhanced dependence on the CCR5 N-terminus compared to clade B consensus residues at these positions. These results suggest that expanded coreceptor usage of HIV-1 can occur in some individuals without rapid progression to AIDS as a consequence of changes in the V3 region that reduce dependence on the ECL2 region of CCR5 by enhancing interactions with conserved structural elements in G-protein-coupled receptors. (C) 2006 Elsevier Inc. All rights reserved. C1 Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Neurol, Boston, MA 02115 USA. Northwestern Univ, Sch Med, Dept Med, Chicago, IL 60611 USA. Cornell Univ, Weill Med Coll, New York, NY 10021 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Macfarlane Burnet Inst Med Res & Publ Hlth, Melbourne, Vic, Australia. Monash Univ, Dept Med, Clayton, Vic 3168, Australia. Univ Massachusetts, Sch Med, Dept Mol Genet & Microbiol, Program Mol Med, Worcester, MA 01655 USA. RP Gabuzda, D (reprint author), Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Immunol & AIDS, 44 Binney St JF816, Boston, MA 02115 USA. EM dana_gabuzda@dfci.harvard.edu RI Holm, Geoffrey/C-3188-2009; Wolinsky, Steven/B-2893-2012 FU NIAID NIH HHS [R21 AI054207, AI41420, R01 AI041420, R01 AI041420-08, R01 AI041420-09, R01 AI041420-10, R21 AI054207-01A1, R21 AI054207-02]; NIMH NIH HHS [MH64408, R01 MH064408, R01 MH064408-02, R01 MH064408-03, R01 MH064408-04]; NIMHD NIH HHS [L60 MD003100]; NINDS NIH HHS [NS37277, R01 NS037277, R01 NS037277-05A1, R01 NS037277-06, R01 NS037277-07, R01 NS037277-08, R01 NS037277-09] NR 76 TC 29 Z9 29 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAY 25 PY 2007 VL 362 IS 1 BP 163 EP 178 DI 10.1016/j.virol.2006.11.025 PG 16 WC Virology SC Virology GA 168ZU UT WOS:000246563300018 PM 17239419 ER PT J AU Grewal, SIS Elgin, SCR AF Grewal, Shiv I. S. Elgin, Sarah C. R. TI Transcription and RNA interference in the formation of heterochromatin SO NATURE LA English DT Review ID POSITION-EFFECT VARIEGATION; DROSOPHILA-MELANOGASTER DEVELOPMENT; DOMAIN-CONTAINING PROTEINS; DOUBLE-STRANDED-RNA; FISSION YEAST; HISTONE H3; EPIGENETIC CONTROL; CHROMOSOME SEGREGATION; LYSINE-9 METHYLATION; CHROMODOMAIN PROTEIN AB Transcription in heterochromatin seems to be an oxymoron - surely the 'silenced' form of chromatin should not be transcribed. But there have been frequent reports of low-level transcription in heterochromatic regions, and several hundred genes are found in these regions in Drosophila. Most strikingly, recent investigations implicate RNA interference mechanisms in targeting and maintaining heterochromatin, and these mechanisms are inherently dependent on transcription. Silencing of chromatin might involve transacting sources of the crucial small RNAs that carry out RNA interference, but in some cases, transcription of the region to be silenced seems to be required - an apparent contradiction. C1 Washington Univ, Dept Biol, St Louis, MO 63130 USA. NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Elgin, SCR (reprint author), Washington Univ, Dept Biol, CB1137, St Louis, MO 63130 USA. EM grewals@mail.nih.gov; selgin@biology.wustl.edu FU NIGMS NIH HHS [R01 GM068388-19, R01 GM068388] NR 83 TC 272 Z9 283 U1 6 U2 33 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 24 PY 2007 VL 447 IS 7143 BP 399 EP 406 DI 10.1038/nature05914 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 170VA UT WOS:000246693100034 PM 17522672 ER PT J AU Kovtun, IV Liu, Y Bjoras, M Klungland, A Wilson, SH McMurray, CT AF Kovtun, Irina V. Liu, Yuan Bjoras, Magnar Klungland, Arne Wilson, Samuel H. McMurray, Cynthia T. TI OGG1 initiates age-dependent CAG trinucleotide expansion in somatic cells SO NATURE LA English DT Article ID BASE-EXCISION-REPAIR; TRIPLET-REPEAT EXPANSION; DNA-POLYMERASE BETA; HUNTINGTON-DISEASE; SUBSTRATE-SPECIFICITY; NEURODEGENERATIVE DISEASE; TRANSGENIC MICE; DEFICIENT MICE; INSTABILITY; GLYCOSYLASE AB Although oxidative damage has long been associated with ageing and neurological disease, mechanistic connections of oxidation to these phenotypes have remained elusive. Here we show that the age-dependent somatic mutation associated with Huntington's disease occurs in the process of removing oxidized base lesions, and is remarkably dependent on a single base excision repair enzyme, 7,8-dihydro-8-oxoguanine-DNA glycosylase (OGG1). Both in vivo and in vitro results support a 'toxic oxidation' model in which OGG1 initiates an escalating oxidation - excision cycle that leads to progressive age-dependent expansion. Age-dependent CAG expansion provides a direct molecular link between oxidative damage and toxicity in post-mitotic neurons through a DNA damage response, and error-prone repair of single-strand breaks. C1 Mayo Clin & Mayo Fdn, Dept Pharmacol & Expt Therapeut, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Program Neurosci, Rochester, MN 55905 USA. Univ Oslo, Ctr Mol Biol & Neurosci, Rikshosp Radiumhosp HF, N-0027 Oslo, Norway. Univ Oslo, Inst Med Microbiol, Rikshosp Radiumhosp HF, N-0027 Oslo, Norway. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP McMurray, CT (reprint author), Mayo Clin & Mayo Fdn, Dept Pharmacol & Expt Therapeut, 200 1st St SW, Rochester, MN 55905 USA. EM mcmurray.cynthia@mayo.edu FU Intramural NIH HHS [Z01 ES050158-11]; NIGMS NIH HHS [R01 GM066359, R01 GM066359-05A1]; NINDS NIH HHS [R01 NS040738, R01 NS040738-05] NR 44 TC 240 Z9 248 U1 2 U2 15 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 24 PY 2007 VL 447 IS 7143 BP 447 EP U2 DI 10.1038/nature05778 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 170VA UT WOS:000246693100041 PM 17450122 ER PT J AU Albo, ME Richter, HE Brubaker, L Norton, P Kraus, SR Zimmern, PE Zyczynski, H Diokno, AC Tennstedt, S Nager, C Lloyd, LK FitzGerald, M Lemack, GE Johnson, HW Leng, W Mallett, V Stoddard, AM Menefee, S Varner, RE Kenton, K Moalli, P Sirls, L Dandreo, KJ Kusek, JW Nyberg, LM Steers, W Steers, W Diokno, A Khandwala, S Brubaker, L FitzGerald, M Richter, HE Lloyd, LK Albo, M Nager, C Chai, T Johnson, HW Zyczynski, HM Leng, W Zimmern, P Lemack, G Kraus, S Rozanski, T Norton, P Kerr, L Tennstedt, S Stoddard, A Chang, D Kusek, JW Nyberg, LM Weber, AM Ashford, RS Baker, J Borello-France, D Burgio, KL Chiang, S Dabbous, A Goode, PS Hammontree, LN Kenton, K Lesser, D Luber, K Lukacz, E Markland, A Menefee, S Moalli, P Peters, K Sagan, E Schaffer, J Simsiman, A Sirls, L Starr, R Varner, RE Bradt, R Debes, K Dinh, R Gruss, J Hall, L Howell, A Jesse, K Kalinoski, DL Koches, K Leemon, B Mislanovich, K O'Meara, S Parent, J Pope, N Prather, C Rogers, T Sluder, S Tulke, M Dandreo, KJ Leifer, CJ McDermott, S Stoddard, A Tennstedt, S Tinsley, L Wruck, L Xu, Y Gormley, EA Abrams, P Bland, D Clemens, JQ Connett, J Henderson, W Fenner, D Kelsey, S Myers, D Mostwin, J Wadie, B AF Albo, Michael E. Richter, Holly E. Brubaker, Linda Norton, Peggy Kraus, Stephen R. Zimmern, Philippe E. Zyczynski, Halina Diokno, Ananias C. Tennstedt, Sharon Nager, Charles Lloyd, L. Keith FitzGerald, MaryPat Lemack, Gary E. Johnson, Harry W. Leng, Wendy Mallett, Veronica Stoddard, Anne M. Menefee, Shawn Varner, R. Edward Kenton, Kimberly Moalli, Pam Sirls, Larry Dandreo, Kimberly J. Kusek, John W. Nyberg, Leroy M. Steers, William Steers, W. Diokno, A. Khandwala, S. Brubaker, L. FitzGerald, M. Richter, H. E. Lloyd, L. K. Albo, M. Nager, C. Chai, T. Johnson, H. W. Zyczynski, H. M. Leng, W. Zimmern, P. Lemack, G. Kraus, S. Rozanski, T. Norton, P. Kerr, L. Tennstedt, S. Stoddard, A. Chang, D. Kusek, J. W. Nyberg, L. M. Weber, A. M. Ashford, R. S., II Baker, J. Borello-France, D. Burgio, K. L. Chiang, S. Dabbous, A. Goode, P. S. Hammontree, L. N. Kenton, K. Lesser, D. Luber, K. Lukacz, E. Markland, A. Menefee, S. Moalli, P. Peters, K. Sagan, E. Schaffer, J. Simsiman, A. Sirls, L. Starr, R. Varner, R. E. Bradt, R. Debes, K. Dinh, R. Gruss, J. Hall, L. Howell, A. Jesse, K. Kalinoski, D. L. Koches, K. Leemon, B. Mislanovich, K. O'Meara, S. Parent, J. Pope, N. Prather, C. Rogers, T. Sluder, S. Tulke, M. Dandreo, K. J. Leifer, C. J. McDermott, S. Stoddard, A. Tennstedt, S. Tinsley, L. Wruck, L. Xu, Y. Gormley, E. A. Abrams, P. Bland, D. Clemens, J. Q. Connett, J. Henderson, W. Fenner, D. Kelsey, S. Myers, D. Mostwin, J. Wadie, B. CA Urinary Incontinence Treatment Net TI Burch colposuspension versus fascial sling to reduce urinary stress incontinence SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID INTERNATIONAL CONTINENCE SOCIETY; UNITED-STATES; FOLLOW-UP; WOMEN; SURGERY; STANDARDIZATION; TERMINOLOGY; IMPACT; DYSFUNCTION; DEFINITION AB Background: Many surgical procedures are available for women with urinary stress incontinence, yet few randomized clinical trials have been conducted to provide a basis for treatment recommendations. Methods: We performed a multicenter, randomized clinical trial comparing two procedures - the pubovaginal sling, using autologous rectus fascia, and the Burch colposuspension - among women with stress incontinence. Women were eligible for the study if they had predominant symptoms associated with the condition, a positive stress test, and urethral hypermobility. The primary outcomes were success in terms of overall urinary-incontinence measures, which required a negative pad test, no urinary incontinence (as recorded in a 3-day diary), a negative cough and Valsalva stress test, no self-reported symptoms, and no retreatment for the condition, and success in terms of measures of stress incontinence specifically, which required only the latter three criteria. We also assessed postoperative urge incontinence, voiding dysfunction, and adverse events. Results: A total of 655 women were randomly assigned to study groups: 326 to undergo the sling procedure and 329 to undergo the Burch procedure; 520 women (79%) completed the outcome assessment. At 24 months, success rates were higher for women who underwent the sling procedure than for those who underwent the Burch procedure, for both the overall category of success (47% vs. 38%, P=0.01) and the category specific to stress incontinence (66% vs. 49%, P < 0.001). However, more women who underwent the sling procedure had urinary tract infections, difficulty voiding, and postoperative urge incontinence. Conclusions: The autologous fascial sling results in a higher rate of successful treatment of stress incontinence but also greater morbidity than the Burch colposuspension. C1 Univ Calif San Diego, San Diego Med Ctr, Div Urol, San Diego, CA 92103 USA. Univ Alabama, Birmingham, AL USA. Loyola Univ, Med Ctr, Maywood, IL 60153 USA. Univ Utah, Hlth Sci Ctr, Salt Lake City, UT USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX USA. Univ Texas SW, Dallas, TX USA. Univ Maryland, Baltimore, MD 21201 USA. Univ Pittsburgh, Magee Womens Hosp, Pittsburgh, PA 15213 USA. Beaumont Hosp, Med Ctr, Royal Oak, MI USA. New England Res Inst, Watertown, MA 02172 USA. Oakwood Hosp, Dearborn, MI USA. NIDDKD, Bethesda, MD 20892 USA. Univ Virginia Hlth Syst, Charlottesville, VA USA. RP Albo, ME (reprint author), Univ Calif San Diego, San Diego Med Ctr, Div Urol, 200 W Arbor Dr, San Diego, CA 92103 USA. OI Wadie, Bassem/0000-0002-6977-6849 FU NCATS NIH HHS [UL1 TR000005]; NIDDK NIH HHS [U01 DK60393, U01 DK60379, U01 DK60401, U01 DK058225, U01 DK58231, U01 DK58225, U01 DK58234, U01 DK60397, U01 DK58229, U01 DK60395, U01 DK60380] NR 41 TC 208 Z9 211 U1 1 U2 8 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 24 PY 2007 VL 356 IS 21 BP 2143 EP 2155 DI 10.1056/NEJMoa070416 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 170ON UT WOS:000246673100004 PM 17517855 ER PT J AU Jothi, R Przytycka, TM Aravind, L AF Jothi, Raja Przytycka, Teresa M. Aravind, L. TI Discovering functional linkages and uncharacterized cellular pathways using phylogenetic profile comparisons: a comprehensive assessment SO BMC BIOINFORMATICS LA English DT Article ID PROTEIN-PROTEIN INTERACTIONS; COMPARATIVE GENOME ANALYSIS; CO-EVOLUTIONARY ANALYSIS; INTERACTION NETWORK; MYCOBACTERIUM-TUBERCULOSIS; INTERACTION MAP; SACCHAROMYCES-CEREVISIAE; INTERACTING PROTEINS; HALOPHILIC ARCHAEON; BACTERIAL GENOMES AB Background: A widely-used approach for discovering functional and physical interactions among proteins involves phylogenetic profile comparisons (PPCs). Here, proteins with similar profiles are inferred to be functionally related under the assumption that proteins involved in the same metabolic pathway or cellular system are likely to have been co-inherited during evolution. Results: Our experimentation with E. coli and yeast proteins with 16 different carefully composed reference sets of genomes revealed that the phyletic patterns of proteins in prokaryotes alone could be adequate enough to make reasonably accurate functional linkage predictions. A slight improvement in performance is observed on adding few eukaryotes into the reference set, but a noticeable drop-off in performance is observed with increased number of eukaryotes. Inclusion of most parasitic, pathogenic or vertebrate genomes and multiple strains of the same species into the reference set do not necessarily contribute to an improved sensitivity or accuracy. Interestingly, we also found that evolutionary histories of individual pathways have a significant affect on the performance of the PPC approach with respect to a particular reference set. For example, to accurately predict functional links in carbohydrate or lipid metabolism, a reference set solely composed of prokaryotic (or bacterial) genomes performed among the best compared to one composed of genomes from all three super-kingdoms; this is in contrast to predicting functional links in translation for which a reference set composed of prokaryotic (or bacterial) genomes performed the worst. We also demonstrate that the widely used random null model to quantify the statistical significance of profile similarity is incomplete, which could result in an increased number of false-positives. Conclusion: Contrary to previous proposals, it is not merely the number of genomes but a careful selection of informative genomes in the reference set that influences the prediction accuracy of the PPC approach. We note that the predictive power of the PPC approach, especially in eukaryotes, is heavily influenced by the primary endosymbiosis and subsequent bacterial contributions. The over-representation of parasitic unicellular eukaryotes and vertebrates additionally make eukaryotes less useful in the reference sets. Reference sets composed of highly non-redundant set of genomes from all three super-kingdoms fare better with pathways showing considerable vertical inheritance and strong conservation (e. g. translation apparatus), while reference sets solely composed of prokaryotic genomes fare better for more variable pathways like carbohydrate metabolism. Differential performance of the PPC approach on various pathways, and a weak positive correlation between functional and profile similarities suggest that caution should be exercised while interpreting functional linkages inferred from genome-wide large-scale profile comparisons using a single reference set. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Jothi, R (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM jothi@ncbi.nlm.nih.gov; przytyck@ncbi.nlm.nih.gov; aravind@ncbi.nlm.nih.gov RI Jothi, Raja/G-3780-2015 FU Intramural NIH HHS NR 95 TC 42 Z9 46 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD MAY 23 PY 2007 VL 8 AR 173 DI 10.1186/1471-2105-8-173 PG 17 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 186PG UT WOS:000247790000001 PM 17521444 ER PT J AU Solinas, M Scherma, M Fattore, L Stroik, J Wertheim, C Tanda, G Fratta, W Goldberg, SR AF Solinas, Marcello Scherma, Maria Fattore, Liana Stroik, Jessica Wertheim, Carrie Tanda, Gianluigi Fratta, Walter Goldberg, Steven R. TI Nicotinic alpha(7) receptors as a new target for treatment of cannabis abuse SO JOURNAL OF NEUROSCIENCE LA English DT Article DE abuse; acetylcholine receptor; cannabinoids; dopamine; behavior; nucleus accumbens ID HIPPOCAMPAL ACETYLCHOLINE-RELEASE; NUCLEUS-ACCUMBENS SHELL; VENTRAL TEGMENTAL AREA; EXTRACELLULAR DOPAMINE; ANTAGONIST; MICE; MODULATION; MECHANISMS; SUBUNIT; RATS AB Increasing use of cannabis makes the search for medications to reduce cannabis abuse extremely important. Here, we show that homomeric alpha(7) nicotinic receptors are novel molecular entities that could be targeted in the development of new drugs for the treatment of cannabis dependence. In rats, systemic administration of the selective alpha 7 nicotinic acetylcholine receptor antagonist methyllycaconitine ( MLA), but not the selective heteromeric non-alpha(7) nicotinic acetylcholine receptor antagonist dihydrobetaerythroidine, ( 1) antagonized the discriminative effects of delta-9-tetrahydrocannabinol ( THC), the main active ingredient in cannabis, ( 2) reduced intravenous self-administration of the synthetic cannabinoid CB1 receptor agonist WIN55,212-2 [( R)-( +)-[ 2,3-dihydro-5-methyl-3[( 4-morpholinyl)methyl] pyrrolo[ 1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl) methanone, mesylate salt], and ( 3) decreased THC-induced dopamine elevations in the shell of the nucleus accumbens. Altogether, our results indicate that blockade of alpha(7) nicotinic receptors reverses abuse-related behavioral and neurochemical effects of cannabinoids. Importantly, MLA reversed the effects of cannabinoids at doses that did not produce depressant or toxic effects, further pointing to alpha(7) nicotinic antagonists as potentially useful agents in the treatment of cannabis abuse in humans. C1 Univ Poitiers, Inst Biol & Physiol, CNRS 6187, F-86022 Poitiers, France. Natl Inst Drug Abuse, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Baltimore, MD 21224 USA. Natl Inst Drug Abuse, Preclin Pharmacol Sect, Intramural Res Program,Psychobiol Sect, NIH,Dept Hlth & Human Serv,Medicat Discovery Res, Baltimore, MD 21224 USA. RP Goldberg, SR (reprint author), Natl Inst Drug Abuse, Preclin Pharmacol Sect, Intramural Res Program,Psychobiol Sect, NIH,Dept Hlth & Human Serv,Medicat Discovery Res, 5500 Nathan Stock Dr, Baltimore, MD 21224 USA. EM sgoldber@intra.nida.nih.gov RI Tanda, Gianluigi/B-3318-2009; Solinas, Marcello/M-3500-2016 OI Tanda, Gianluigi/0000-0001-9526-9878; Solinas, Marcello/0000-0002-0664-5964 FU Intramural NIH HHS NR 44 TC 48 Z9 48 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 MAY 23 PY 2007 VL 27 IS 21 BP 5615 EP 5620 DI 10.1523/JNEUROSCI.0027-07.2007 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 171FM UT WOS:000246720700009 PM 17522306 ER PT J AU Geisler, S Derst, C Veh, RW Zahm, DS AF Geisler, Stefanie Derst, Christian Veh, Ruediger W. Zahm, Daniel S. TI Glutamatergic afferents of the ventral tegmental area in the rat SO JOURNAL OF NEUROSCIENCE LA English DT Article DE VTA; excitatory; VGLUT; connections; hypothalamus; reward ID MIDBRAIN DOPAMINE NEURONS; IN-SITU HYBRIDIZATION; VESICULAR GLUTAMATE; PHOSPHATE TRANSPORTER; EXCITATORY NEURONS; PREFRONTAL CORTEX; NUCLEUS-ACCUMBENS; STRIA TERMINALIS; COCAINE-SEEKING; BED NUCLEUS AB Glutamatergic inputs to the ventral tegmental area ( VTA), thought crucial to the capacity of the VTA to detect and signal stimulus salience, have been reported to arise in but a few structures. However, the afferent system of the VTA comprises very abundant neurons within a large formation extending from the prefrontal cortex to the caudal brainstem. Neurons in nearly all parts of this continuum may be glutamatergic and equivalently important to VTA function. Thus, we sought to identify the full range of glutamatergic inputs to the VTA by combining retrograde transport of wheat germ agglutinin-bound gold after injections into the VTA with nonisotopic in situ hybridization of the vesicular glutamate transporters ( VGLUTs) 1, 2, and 3. We found glutamatergic neurons innervating the VTA in almost all structures projecting there and that a majority of these are subcortical and VGLUT2 mRNA positive. The tremendous convergence of glutamatergic afferents from many brain areas in the VTA suggests that ( 1) the function of the VTA requires integration of manifold and diverse bits of information and ( 2) the activity of the VTA reflects the ongoing activities of various combinations of its afferents. C1 St Louis Univ, Sch Med, Dept Pharmacol & Physiol Sci, St Louis, MO 63104 USA. Univ Berlin Med, Charite, Inst Integrat Neuroant, D-10098 Berlin, Germany. RP Geisler, S (reprint author), NIDA, Intramural Res Program, Behav Neurosci Branch, Baltimore, MD 21224 USA. EM GeislerS@mail.nih.gov; zahmds@slu.edu OI Zahm, Daniel/0000-0002-2943-7906 FU NIDA NIH HHS [DA-15207, R01 DA015207]; NINDS NIH HHS [NS-23805, R01 NS023805] NR 45 TC 234 Z9 235 U1 0 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD MAY 23 PY 2007 VL 27 IS 21 BP 5730 EP 5743 DI 10.1523/JNEUROSCI.0012-07.2007 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 171FM UT WOS:000246720700020 PM 17522317 ER PT J AU Meyers, JH Justement, JS Hallahan, CW Blair, ET Sun, YMA O'Shea, MA Roby, G Kottilil, S Moir, S Kovacs, CM Chun, TW Fauci, AS AF Meyers, Jennifer Hartt Justement, J. Shawn Hallahan, Claire W. Blair, Eric T. Sun, Yongming A. O'Shea, M. Angeline Roby, Gregg Kottilil, Shyam Moir, Susan Kovacs, Colin M. Chun, Tae-Wook Fauci, Anthony S. TI Impact of HIV on Cell Survival and Antiviral Activity of Plasmacytoid Dendritic Cells SO PLOS ONE LA English DT Article AB Plasmacytoid dendritic cells (pDCs) are important mediators of innate immunity that act mainly through secretion of interferon (IFN)-alpha. Previous studies have found that these cells can suppress HIV in vitro; additionally, pDCs have been shown to be severely reduced in the peripheral blood of HIV-infected individuals. In the present study, we sought to determine the ability of pDCs to directly suppress viral replication ex vivo and to delineate the potential mechanisms whereby pDCs are depleted in HIV-infected individuals. We demonstrate that activated pDCs strongly suppress HIV replication in autologous CD4(+) T cells via a mechanism involving IFN-alpha as well as other antiviral factors. Of note, unstimulated pDCs from infected individuals who maintain low levels of plasma viremia without antiretroviral therapy were able to suppress HIV ex vivo via a mechanism requiring cell-to-cell contact. Our data also demonstrate that death of pDCs by both apoptosis and necrosis is induced by fusion of HIV with pDCs. Taken together, our data suggest that pDCs play an important role in the control of HIV replication and that high levels of viral replication in vivo are associated with pDC cell death via apoptosis and necrosis. Elucidation of the mechanism by which pDCs suppress HIV replication in vivo may have clinically relevant implications for future therapeutic strategies. C1 [Meyers, Jennifer Hartt; Justement, J. Shawn; O'Shea, M. Angeline; Roby, Gregg; Kottilil, Shyam; Moir, Susan; Chun, Tae-Wook; Fauci, Anthony S.] NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. [Blair, Eric T.; Sun, Yongming A.] Appl Biosyst Inc, Foster City, CA 94404 USA. [Hallahan, Claire W.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. [Kovacs, Colin M.] Univ Toronto, Dept Med, Toronto, ON, Canada. RP Chun, TW (reprint author), NIAID, Immunoregulat Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM twchun@nih.gov FU National Institutes of Health FX This research was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 40 TC 58 Z9 59 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 MAY 23 PY 2007 VL 2 IS 5 AR e458 DI 10.1371/journal.pone.0000458 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10DZ UT WOS:000207446000006 PM 17520017 ER PT J AU Watson, LE Kuo, SR Katki, K Dang, TY Park, SK Dostal, DE Tang, WJ Leppla, SH Frankel, AE AF Watson, Linley E. Kuo, Shu-ru Katki, Khurshed Dang, Tongyun Park, Seong Kyu Dostal, David E. Tang, Wei-jen Leppla, Stephen H. Frankel, Arthur E. TI Anthrax Toxins Induce Shock in Rats by Depressed Cardiac Ventricular Function SO PLOS ONE LA English DT Article AB Anthrax infections are frequently associated with severe and often irreversible hypotensive shock. The isolated toxic proteins of Bacillus anthracis produce a non-cytokine-mediated hypotension in rats by unknown mechanisms. These observations suggest the anthrax toxins have direct cardiovascular effects. Here, we characterize these effects. As a first step, we administered systemically anthrax lethal toxin (LeTx) and edema toxin (EdTx) to cohorts of three to twelve rats at different doses and determined the time of onset, degree of hypotension and mortality. We measured serum concentrations of the protective antigen (PA) toxin component at various time points after infusion. Peak serum levels of PA were in the mg/mL range with half-lives of 10-20 minutes. With doses that produced hypotension with delayed lethality, we then gave bolus intravenous infusions of toxins to groups of four to six instrumented rats and continuously monitored blood pressure by telemetry. Finally, the same doses used in the telemetry experiments were given to additional groups of four rats, and echocardiography was performed pretreatment and one, two, three and twenty-four hours post-treatment. LeTx and EdTx each produced hypotension. We observed a doubling of the velocity of propagation and 20% increases in left ventricular diastolic and systolic areas in LeTx-treated rats, but not in EdTx-treated rats. EdTx-but not LeTx-treated rats showed a significant increase in heart rate. These results indicate that LeTx reduced left ventricular systolic function and EdTx reduced preload. Uptake of toxins occurs readily into tissues with biological effects occurring within minutes to hours of serum toxin concentrations in the mu g/mL range. LeTx and EdTx yield an irreversible shock with subsequent death. These findings should provide a basis for the rational design of drug interventions to reduce the dismal prognosis of systemic anthrax infections. C1 [Watson, Linley E.] Scott & White Mem Hosp & Clin, Div Cardiol, Scott Sherwood & Brindley Fdn, Temple, TX 76508 USA. [Watson, Linley E.; Katki, Khurshed; Dostal, David E.; Frankel, Arthur E.] Texas A&M Univ Syst, Hlth Sci Ctr, Coll Med, Dept Med, Temple, TX USA. [Kuo, Shu-ru; Dang, Tongyun; Park, Seong Kyu; Frankel, Arthur E.] Scott & White Canc Res Inst, Temple, TX USA. [Watson, Linley E.; Dostal, David E.] Texas A&M Univ Syst, Div Mol Cardiol, Hlth Sci Ctr, Coll Med, Temple, TX USA. [Watson, Linley E.; Dostal, David E.] Cent Texas Vet Hlth Care Syst, Temple, TX USA. [Tang, Wei-jen] Univ Chicago, Ben May Inst Canc Res, Chicago, IL 60637 USA. [Leppla, Stephen H.] NIAID, Bacterial Toxins & Therapeut Sect, Bethesda, MD 20892 USA. RP Frankel, AE (reprint author), Scott & White Mem Hosp & Clin, Div Cardiol, Scott Sherwood & Brindley Fdn, Temple, TX 76508 USA. EM AFRANKEL@swmail.sw.org OI Tang, Wei-Jen/0000-0002-8267-8995 NR 37 TC 41 Z9 41 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 MAY 23 PY 2007 VL 2 IS 5 AR e466 DI 10.1371/journal.pone.0000466 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10DZ UT WOS:000207446000014 PM 17520025 ER PT J AU Mitchell, GF Guo, CY Benjamin, EJ Larson, MG Keyes, MJ Vita, JA Vasan, RS Levy, D AF Mitchell, Gary F. Guo, Chao-Yu Benjamin, Emelia J. Larson, Martin G. Keyes, Michelle J. Vita, Joseph A. Vasan, Ramachandran S. Levy, Daniel TI Cross-sectional correlates of increased aortic stiffness in the community - The Framingham Heart Study SO CIRCULATION LA English DT Article DE arteriosclerosis; blood pressure; hypertension; obesity; population; risk factors; vasculature ID PULSE-WAVE VELOCITY; ARTERIAL STIFFNESS; SYSTOLIC HYPERTENSION; OLDER-ADULTS; PRESSURE; HEALTH; ATHEROSCLEROSIS; SMOKING; DISEASE; RISK AB Background - Increased aortic stiffness is associated with numerous common diseases of aging, including heart disease, stroke, and renal disease. However, the prevalence and correlates of abnormally high aortic stiffness are incompletely understood. Methods and Results - We evaluated 2 aortic stiffness measures, carotid-femoral pulse wave velocity and forward pressure wave amplitude, in a pooled sample of the Framingham Original, Offspring, and minority Omni cohorts ( mean age, 62 years; 56% women). Abnormal stiffness of each measure was defined as a value exceeding the sex-specific 90th percentile of a reference group with a low burden of conventional cardiovascular disease risk factors. Applying this criterion to the entire sample identified a 24% to 33% prevalence of abnormal stiffness measures. The prevalence of abnormal stiffness increased markedly with age, eg, for pulse wave velocity, from a few percent in both sexes aged < 50 years to 64% (men) to 74% (women) in those aged >= 70 years. With adjustment for age, important correlates of abnormal aortic stiffness included higher mean arterial pressure, greater body mass index, impaired glucose metabolism, and abnormal lipids. Correlates of aortic stiffness were similar if we used age-specific rather than fixed criteria for defining abnormal stiffness. Conclusions - The prevalence of abnormal aortic stiffness increases steeply with advancing age in the community, especially in the presence of obesity or diabetes. Our data suggest that the burden of disease attributable to aortic stiffness is likely to increase considerably over the next few years as the population ages. C1 Cardiovasc Engn Inc, Waltham, MA 02453 USA. NHLBI, Framingham Study, Framingham, MA USA. Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02215 USA. Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02215 USA. Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02215 USA. NHLBI, Bethesda, MD 20892 USA. RP Mitchell, GF (reprint author), Cardiovasc Engn Inc, 52 Sawyer Rd,Suite 100, Waltham, MA 02453 USA. EM GaryFMitchell@mindspring.com OI Vita, Joseph/0000-0001-5607-1797; Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [HL60040, HL70100, HL71039, K24-HL-04334, N01-HC-25195, N01-HV28178] NR 28 TC 113 Z9 118 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 22 PY 2007 VL 115 IS 20 BP 2628 EP 2636 DI 10.1161/CIRCULATIONAHA.106.667733 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 170LF UT WOS:000246664200008 PM 17485578 ER PT J AU Loria, CM Liu, K Lewis, CE Hulley, SB Sidney, S Schreiner, PJ Williams, OD Bild, DE Detrano, R AF Loria, Catherine M. Liu, Kiang Lewis, Cora E. Hulley, Stephen B. Sidney, Stephen Schreiner, Pamela J. Williams, O. Dale Bild, Diane E. Detrano, Robert TI Early adult risk factor levels and subsequent coronary artery calcification - The CARDIA study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID BEAM COMPUTED-TOMOGRAPHY; ASSOCIATION DETECTION PROJECT; ALL-CAUSE MORTALITY; BODY-MASS INDEX; QUALITY-OF-LIFE; YOUNG-ADULTS; CARDIOVASCULAR-DISEASE; RACIAL-DIFFERENCES; BLOOD-PRESSURE; HEART-DISEASE AB Objectives We sought to determine whether early adult levels of cardiovascular risk factors predict subsequent coronary artery calcium (CAC) better than concurrent or average 15-year levels and independent of a 15-year change in levels. Background Few studies have used multiple measures over the course of time to predict subclinical atherosclerosis. Methods African American and white adults, ages 18 to 30 years, in 4 U.S. cities were enrolled in the prospective CARDIA (Coronary Artery Risk Development in Young Adults) study from 1985 to 1986. Risk factors were measured at years 0, 2, 5, 7, 10, and 15, and CAC was assessed at year 15 (n = 3,043). Results Overall, 9.6% adults had any CAC, with a greater prevalence among men than women (15.0% vs. 5.1%), white than African American men (17.6% vs. 11.3%), and ages 40 to 45 years than 33 to 39 years (13.3% vs. 5.5%). Baseline levels predicted CAC presence (C = 0.79) equally as well as average 15-year levels (C = 0.79; p = 0.8262) and better than concurrent levels (C = 0.77; p = 0.019), despite a 15-year change in risk factor levels. Multivariate-adjusted odds ratios of having CAC by ages 33 to 45 years were 1.5 (95% confidence interval [Cl] 1.3 to 1.7) per 10 cigarettes, 1.5 (95% Cl 1.3 to 1.8) per 30 mg/dl low-density lipoprotein cholesterol, 1.3 (95% Cl 1.1 to 1.5) per 10 mm Hg systolic blood pressure, and 1.2 (95% Cl 1.1 to 1.4) per 15 mg,/dl glucose at baseline. Young adults with above optimal risk factor levels at baseline were 2 to 3 times as likely to have CAC. Conclusions Early adult levels of modifiable risk factors, albeit low, were equally or more informative about odds of CAC in middle age than subsequent levels. Earlier risk assessment and efforts to achieve and maintain optimal risk factor levels may be needed. C1 NHLBI, Div Prevent & Populat Sci, Bethesda, MD 20892 USA. Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. Univ Alabama, Sch Med, Div Prevent Med, Birmingham, AL USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Kaiser Permanente, Div Res, Oakland, CA USA. Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. Harbor UCLA Med Ctr, Res & Educ Inst, Torrance, CA 90509 USA. RP Loria, CM (reprint author), NHLBI, Div Prevent & Populat Sci, 6701 Rockledge Dr,Room 10116, Bethesda, MD 20892 USA. EM loriac@mail.nih.gov FU NHLBI NIH HHS [N01-HC-05187, N01-HC-48047, N01-HC-48048, N01-HC-48049, N01-HC-48050, N01-HC-95095] NR 44 TC 113 Z9 116 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAY 22 PY 2007 VL 49 IS 20 BP 2013 EP 2020 DI 10.1016/j.jacc.2007.03.009 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 171KF UT WOS:000246734100005 PM 17512357 ER PT J AU Bruno, MK Lee, HY Auburger, GWJ Friedman, A Nielsen, JE Lang, AE Bertini, E Van Bogaert, P Averyanov, Y Hallett, M Gwinn-Hardy, K Sorenson, B Pandolfo, M Kwiecinski, H Servidei, S Fu, YH Ptacek, L AF Bruno, M. K. Lee, H.-Y. Auburger, G. W. J. Friedman, A. Nielsen, J. E. Lang, A. E. Bertini, E. Van Bogaert, P. Averyanov, Y. Hallett, M. Gwinn-Hardy, K. Sorenson, B. Pandolfo, M. Kwiecinski, H. Servidei, S. Fu, Y.-H. Ptacek, L. TI Genotype-phenotype correlation of paroxysmal nonkinesigenic dyskinesia SO NEUROLOGY LA English DT Article ID FRONTAL-LOBE EPILEPSY; EXERCISE-INDUCED DYSTONIA; MYOFIBRILLOGENESIS REGULATOR-1; KINESIGENIC DYSKINESIA; GENETIC-LINKAGE; CHROMOSOME 2Q; CHOREOATHETOSIS; FAMILY; MIGRAINE; MUTATION AB Background: Paroxysmal nonkinesigenic dyskinesia (PNKD) is a rare disorder characterized by episodic hyperkinetic movement attacks. We have recently identified mutations in the MR-1 gene causing familial PNKD. Methods: We reviewed the clinical features of 14 kindreds with familial dyskinesia that was not clearly induced by movement or during sleep. Of these 14 kindreds, 8 had MR-1 mutations and 6 did not. Results: Patients with PNKD with MR-1 mutations had their attack onset in youth ( infancy and early childhood). Typical attacks consisted of a mixture of chorea and dystonia in the limbs, face, and trunk, and typical attack duration lasted from 10 minutes to 1 hour. Caffeine, alcohol, and emotional stress were prominent precipitants. Attacks had a favorable response to benzodiazepines, such as clonazepam and diazepam. Attacks in families without MR-1 mutations were more variable in their age at onset, precipitants, clinical features, and response to medications. Several were induced by persistent exercise. Conclusions: Paroxysmal nonkinesigenic dyskinesia ( PNKD) should be strictly defined based on age at onset and ability to precipitate attacks with caffeine and alcohol. Patients with this clinical presentation ( which is similar to the phenotype initially reported by Mount and Reback) are likely to harbor myofibrillogenesis regulator 1 (MR-1) gene mutations. Other "PNKD-like" families exist, but atypical features suggests that these subjects are clinically distinct from PNKD and do not have MR-1 mutations. Some may represent paroxysmal exertional dyskinesia. C1 Univ Calif San Francisco, Howard Hughes Med Inst, Dept Neurol, San Francisco, CA 94158 USA. NINDS, NIH, Bethesda, MD 20892 USA. Univ Frankfurt, D-6000 Frankfurt, Germany. Med Acad Warsaw, Dept Neurol, Warsaw, Poland. Univ Copenhagen, Panum Inst, Inst Med Biochem & Genet, DK-2200 Copenhagen, Denmark. Univ Toronto, Toronto, ON, Canada. Bambino Gesu Res Hosp, IRCCS, Dept Neurosci, Rome, Italy. Erasme Univ Hosp, Brussels, Belgium. Moscow Med Acad, Clin Nervous Dis, Moscow, Russia. Univ Cattolica Sacro Cuore, Inst Neurol, Rome, Italy. Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA. RP Ptacek, L (reprint author), Univ Calif San Francisco, Howard Hughes Med Inst, Dept Neurol, San Francisco, CA 94158 USA. EM ljp@ucsf.edu RI Gwinn, Katrina/C-2508-2009; Pandolfo, Massimo/B-2853-2010 FU NINDS NIH HHS [NS43533] NR 37 TC 69 Z9 75 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAY 22 PY 2007 VL 68 IS 21 BP 1782 EP 1789 DI 10.1212/01.wnl.0000262029.91552.e0 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 170LI UT WOS:000246664500005 PM 17515540 ER PT J AU Chen, Q Espey, MG Sun, AY Lee, JH Krishna, MC Shacter, E Choyke, PL Pooput, C Kirk, KL Buettner, GR Levine, M AF Chen, Qi Espey, Michael Graham Sun, Andrew Y. Lee, Je-Hyuk Krishna, Murali C. Shacter, Emily Choyke, Peter L. Pooput, Chaya Kirk, Kenneth L. Buettner, Garry R. Levine, Mark TI Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE ascorbic acid; cancer; vitamin C; pharmacokinetics ID RECOMMENDED DIETARY ALLOWANCE; VITAMIN-C PHARMACOKINETICS; TERMINAL HUMAN CANCER; SUPPLEMENTAL ASCORBATE; SUPPORTIVE TREATMENT; OXIDATIVE STRESS; SURVIVAL TIMES; CELLS; ACID; APOPTOSIS AB Ascorbate (ascorbic acid, vitamin C) in pharmacologic concentrations easily achieved in humans by i.v. administration, selectively kills some cancer cells but not normal cells. We proposed that pharmacologic ascorbate is a prodrug for preferential steady-state formation of ascorbate radical (Asc(.-)) and H2O2 in the extracellular space compared with blood. Here we test this hypothesis in vivo. Rats were administered parenteral (i.v. or i.p.) or oral ascorbate in typical human pharmacologic doses (approximate to 0.25-0.5 mg per gram of body weight). After i.v. injection, ascorbate baseline concentrations of 50-100 mu M in blood and extracellular fluid increased to peaks of > 8 mM. After i.p. injection, peaks approached 3 mM in both fluids. By gavage, the same doses produced ascorbate concentrations of < 150 mu M in both fluids. In blood, Asc(.-)concentrations measured by EPR were undetectable with oral administration and always < 50 nM with parenteral administration, even when corresponding ascorbate concentrations were > 8 mM. After parenteral dosing, Asc(.-) concentrations in extracellular fluid were 4- to 12-fold higher than those in blood, were as high as 250 nM, and were a function of ascorbate concentrations. By using the synthesized probe peroxyxanthone, H2O2 in extracellular fluid was detected only after parenteral administration of ascorbate and when Asc(.-) concentrations in extracellular fluid exceeded 100 nM. The data show that pharmacologic ascorbate is a prodrug for preferential steady-state formation of Asc- and H2O2 in the extracellular space but not blood. These data provide a foundation for pursuing pharmacologic ascorbate as a prooxidant therapeutic agent in cancer and infections. C1 NIDDK, Mol & Clin Nutr Sect, NIH, Bethesda, MD 20892 USA. NIDDK, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, Bethesda, MD 20892 USA. US FDA, Ctr Drug Evaluat & Res, Biochem Lab, Bethesda, MD 20892 USA. Univ Iowa, Free Rad & Radiat Biol Program, Iowa City, IA 52242 USA. RP Levine, M (reprint author), NIDDK, Mol & Clin Nutr Sect, NIH, Bethesda, MD 20892 USA. EM markL@mail.nih.gov RI Chen, Qi/D-8278-2015; OI Chen, Qi/0000-0002-7173-8411; Buettner, Garry/0000-0002-5594-1903 FU NIDDK NIH HHS [Z01 DK054506, Z01 DK54506] NR 42 TC 224 Z9 234 U1 3 U2 18 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 22 PY 2007 VL 104 IS 21 BP 8749 EP 8754 DI 10.1073/pnas.0702854104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 173DM UT WOS:000246853700015 PM 17502596 ER PT J AU Kulman, JD Harris, JE Xie, L Davie, EW AF Kulman, John D. Harris, Jeff E. Xie, Ling Davie, Earl W. TI Proline-rich Gla protein 2 is a cell-surface vitamin K-dependent protein that binds to the transcriptional coactivator Yes-associated protein SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Gla domain; warfarin; WW domain ID GAMMA-CARBOXYGLUTAMIC ACID; WW DOMAIN; C4B-BINDING PROTEIN; BLOOD-COAGULATION; EPOXIDE REDUCTASE; RECOGNITION SITE; MEMBRANE-BINDING; FACTOR-IX; COMPLEX; IDENTIFICATION AB Proline-rich Gla protein 2 (PRGP2) is one of four known vertebrate transmembrane gamma-carboxyglutamic acid (Gla) proteins. Members of this protein family are broadly expressed in fetal and adult human tissues and share a common architecture consisting of a predicted propeptide and Gla domain, a single-pass transmembrane segment, and tandem Pro/Leu-Pro-Xaa-Tyr (PY) motifs near their C termini. Using a methodology developed for the regulated expression of enzymatically biotinylated proteins in mammalian cells, we demonstrate that PRGP2 undergoes gamma-glutamyl carboxylation in a manner that is both dependent upon the presence of a proteolytically cleavable propeptide and sensitive to warfarin, a vitamin K antagonist that is widely used as an antithrombotic agent. When expressed at physiologically relevant levels, the majority of PRGP2 is present in the gamma-glutamyl carboxylated, propeptide-cleaved (mature) form. We additionally demonstrate, by Western blotting and flow cytometry, that mature PRGP2 is predominantly located on the cell surface with the Gla domain exposed extracellularly. In a yeast two-hybrid screen that used the C-terminal cytoplasmic region of PRGP2 as bait, we identified the WW domain-containing transcriptional coactivator Yes-associated protein (YAP) as a binding partner for PRGP2. In GST pull-down experiments, both PRGP2 PY motifs and both YAP WW domains were essential for complex formation, as were residues proximal to the core sequence of the first PY motif. These findings suggest that PRGP2 may be involved in a signal transduction pathway, the impairment of which may be an unintended consequence of warfarin therapy. C1 Univ Washington, Dept Biochem, Seattle, WA 98195 USA. NIAMSD, Bethesda, MD 20892 USA. RP Davie, EW (reprint author), Univ Washington, Dept Biochem, Seattle, WA 98195 USA. EM ewd@u.washington.edu FU NHLBI NIH HHS [HL071599, HL16919, R01 HL016919, R01 HL071599] NR 47 TC 14 Z9 14 U1 1 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 MAY 22 PY 2007 VL 104 IS 21 BP 8767 EP 8772 DI 10.1073/pnas.0703195104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 173DM UT WOS:000246853700018 PM 17502622 ER PT J AU Stan, G Lorimer, GH Thirumalai, D Brooks, BR AF Stan, George Lorimer, George H. Thirumalai, D. Brooks, Bernard R. TI Coupling between allosteric transitions in GroEL and assisted folding of a substrate protein SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE native state yield; soft nanomachine; force-induced stretching ID 4-HELIX BUNDLE PROTEIN; CHAPERONIN GROEL; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; NATIVE-STATE; MECHANISM; KINETICS; ATP; THERMODYNAMICS; ENHANCEMENT AB Escherichia coli chaperonin, GroEL, helps proteins fold under nonpermissive conditions. During the reaction cycle, GroEL undergoes allosteric transitions in response to binding of a substrate protein (SP), ATP, and the cochaperonin GroES. Using coarse-grained representations of the GroEL and GroES structures, we explore the link between allosteric transitions and the folding of a model SP, a de novo-designed four-helix bundle protein, with low spontaneous yield. The ensemble of GroEL-bound SIR is less structured than the bulk misfolded structures. Upon binding, which kinetically occurs in two stages, the SP loses not only native tertiary contacts but also experiences a decrease in helical content. During multivalent binding and the subsequent ATP-driven transition of GroEL the SP undergoes force-induced stretching. Upon encapsulation, which occurs upon GroES binding, the SP finds itself in a "hydrophilic" cavity in which it can reach the folded conformation. Surprisingly, we find that the yield of the native state in the expanded GroEL cavity is relatively small even after it remains in it for twice the spontaneous folding time. Thus, in accord with the iterative annealing mechanism, multiple rounds of binding, partial unfolding, and release of the SIP are required to enhance the yield of the folded SP. C1 NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. Univ Maryland, Biophys Program, Inst Phys Sci & Technol, College Pk, MD 20742 USA. RP Stan, G (reprint author), NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. EM george.stan@uc.edu; glorimer@umd.edu; thirum@glue.umd.edu; brb@nih.gov FU Intramural NIH HHS; NIGMS NIH HHS [R01 GM067851, 1R01GM067851-01] NR 44 TC 28 Z9 28 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 22 PY 2007 VL 104 IS 21 BP 8803 EP 8808 DI 10.1073/pnas.0700607104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 173DM UT WOS:000246853700024 PM 17496143 ER PT J AU Saporito, RA Donnelly, MA Norton, RA Garraffo, HM Spande, TF Daly, JW AF Saporito, Ralph A. Donnelly, Maureen A. Norton, Roy A. Garraffo, H. Martin Spande, Thomas F. Daly, John W. TI Oribatid mites as a major dietary source for alkaloids in poison frogs SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chemical defense; dendrobatid frogs; indoliziclines; myrmicine ants; pumiliotoxins ID COLLOHMANNIA-GIGANTEA ACARI; DENDROBATES-PUMILIO; CHEMICAL DEFENSE; ARTHROPOD SOURCE; AMPHIBIAN SKIN; OIL GLANDS; DART FROGS; SPECIALIZATION; CHEMISTRY; EVOLUTION AB Alkaloids in the skin glands of poison frogs serve as a chemical defense against predation, and almost all of these alkaloids appear to be sequestered from dietary arthropods. Certain alkaloid-containing ants have been considered the primary dietary source, but dietary sources for the majority of alkaloids remain unknown. Herein we report the presence of approximate to 80 alkaloids from extracts of oribatid mites collected throughout Costa Rica and Panama, which represent 11 of the approximate to 24 structural classes of alkaloids known in poison frogs. Forty-one of these alkaloids also occur in the dendrobatid poison frog, Oophaga pumilio, which co-occurs with the collected mites. These shared alkaloids include twenty-five 5,8-disubstituted or 5,6,8-trisubstituted indolizidines; one 1,4-disubstituted quinolizidine; three pumiliotoxins; and one homopumiliotoxin. All but the last of these alkaloid classes occur widely in poison frogs. In addition, nearly 40 alkaloids of unknown structure were detected in mites; none of these alkaloids have been identified in frog extracts. Two of these alkaloids are homopumiliotoxins, five appear to be izidines, four appear to be tricyclics, and six are related in structure to poison frog alkaloids that are currently unclassified as to structure. Mites are common in the diet of O. pumilio, as well as in the diets of other poison frogs. The results of this study indicate that mites are a significant arthropod repository of a variety of alkaloids and represent a major dietary source of alkaloids in poison frogs. C1 Florida Int Univ, Dept Biol Sci, Miami, FL 33199 USA. SUNY Syracuse, Coll Environm Sci & Forestry, Syracuse, NY 13210 USA. NIDDK, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. RP Saporito, RA (reprint author), Florida Int Univ, Dept Biol Sci, Miami, FL 33199 USA. EM saporito@fiu.edu; jdaly@nih.gov FU Intramural NIH HHS NR 47 TC 90 Z9 95 U1 3 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 MAY 22 PY 2007 VL 104 IS 21 BP 8885 EP 8890 DI 10.1073/pnas.0702851104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 173DM UT WOS:000246853700038 PM 17502597 ER PT J AU Oliveira, JB Bidere, N Niemela, JE Zheng, LX Sakai, K Nix, CP Danner, RL Barb, J Munson, PJ Puck, JM Dale, J Straus, SE Fleisher, TA Lenardo, MJ AF Oliveira, Joao B. Bidere, Nicolas Niemela, Julie E. Zheng, Lixin Sakai, Keiko Nix, Cynthia P. Danner, Robert L. Barb, Jennifer Munson, Peter J. Puck, Jennifer M. Dale, Janet Straus, Stephen E. Fleisher, Thomas A. Lenardo, Michael J. TI NRAS mutation causes a human autoimmune lymphoproliferative syndrome SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE autoimmunity; B cell lymphoma 2-interacting mediator of cell death; intrinsic apoptosis; lymphoma; lymphoproliferation ID FACIO-CUTANEOUS SYNDROME; N-RAS; NOONAN-SYNDROME; SIGNAL-TRANSDUCTION; GERMLINE MUTATIONS; GENE-EXPRESSION; IMMUNE-RESPONSE; CELL-DEATH; BIM; APOPTOSIS AB The p21 RAS subfamily of small GTPases, including KRAS, HRAS, and NRAS, regulates cell proliferation, cytoskeletal organization, and other signaling networks, and is the most frequent target of activating mutations in cancer. Activating germline mutations of KRAS and HRAS cause severe developmental abnormalities leading to Noonan, cardio-facial-cutaneous, and Costello syndrome, but activating germline mutations of NRAS have not been reported. Autoimmune lymphoproliferative syndrome (ALPS) is the most common genetic disease of lymphocyte apoptosis and causes autoimmunity as well as excessive lymphocyte accumulation, particularly of CD4(-), CD8(-) alpha beta T cells. Mutations in ALPS typically affect CD95 (Fas/APO-1)-mediated apoptosis, one of the extrinsic death pathways involving TNF receptor superfamily proteins, but certain ALPS individuals have no such mutations. We show here that the salient features of ALPS as well as a predisposition to hematological malignancies can be caused by a heterozygous germline Glyl 3Asp activating mutation of the NRAS oncogene that does not impair CD95-mediated apoptosis. The increase in active, GTP-bound NRAS augments RAF/MEK/ERK signaling, which markedly decreases the proapoptotic protein BIM and attenuates intrinsic, nonreceptor-mediated mitochondrial apoptosis. Thus, germline activating mutations in NRAS differ from other p2l Ras oncoproteins by causing selective immune abnormalities without general developmental defects. Our observations on the effects of NRAS activation indicate that RAS-inactivating drugs, such as farnesyltransferase inhibitors should be examined in human autoimmune and lymphocyte homeostasis disorders. C1 NIAID, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. NIAID, Mol Dev Sect, Immunol Lab, Bethesda, MD 20892 USA. NHGRI, Funct Genom & Proteom Facil, Crit Care Med Dept, Ctr Clin, Bethesda, MD 20892 USA. NHGRI, Math & Stat Comp Lab, Ctr Informat Technol, Bethesda, MD 20892 USA. NHGRI, Genet & Mol Biol Branch, Ctr Informat Technol, Bethesda, MD 20892 USA. NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Fleisher, TA (reprint author), NIAID, Dept Lab Med, Ctr Clin, MSC 1508, Bethesda, MD 20892 USA. EM tfleishe@mail.nih.gov; mlenardo@niaid.nih.gov RI sakai, Keiko/F-5807-2013; bidere, nicolas/K-8887-2015; OI bidere, nicolas/0000-0001-9177-0008; Niemela, Julie/0000-0003-4197-3792; Oliveira, Joao/0000-0001-9388-8173 FU Intramural NIH HHS NR 34 TC 103 Z9 106 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 22 PY 2007 VL 104 IS 21 BP 8953 EP 8958 DI 10.1073/pnas.0702975104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 173DM UT WOS:000246853700050 PM 17517660 ER PT J AU Qian, XL Li, GR Asmussen, HK Asnaghi, L Vass, WC Braverman, R Yamada, KM Popescu, NC Papageorge, AG Lowy, DR AF Qian, Xiaolan Li, Guorong Asmussen, Holly K. Asnaghi, Laura Vass, William C. Braverman, Richard Yamada, Kenneth M. Popescu, Nicholas C. Papageorge, Alex G. Lowy, Douglas R. TI Oncogenic inhibition by a deleted in liver cancer gene requires cooperation between tensin binding and Rho-specific GTPase-activating protein activities SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE DLC1; Src homology 2 and phosphotyrosine binding domains; tumor suppressor gene ID HEPATOCELLULAR-CARCINOMA; SH2 DOMAIN; PLC-DELTA(1)-BINDING PROTEIN; DLC-1; SUPPRESSOR; EXPRESSION; GROWTH; LOCALIZATION; METHYLATION; ADHESIONS AB The three deleted in liver cancer genes (DLC1-3) encode RhoGTPase-activating proteins (RhoGAPs) whose expression is frequently down-regulated or silenced in a variety of human malignancies. The RhoGAP activity is required for full DLC-dependent tumor suppressor activity. Here we report that DLC1 and DLC3 bind to human tensin1 and its chicken homolog. The binding has been mapped to the tensin Src homology 2 (SH2) and phosphotyrosine binding (PTB) domains at the C terminus of tensin proteins. Distinct DLC1 sequences are required for SH2 and PTB binding. DCL binding to both domains is constitutive under basal conditions. The SH2 binding depends on a tyrosine in DCL1 (Y442) but is phosphotyrosine-independent, a highly unusual feature for SH2 binding. DLC1 competed with the binding of other proteins to the tensin C terminus, including beta 3-integrin binding to the PTB domain. Point mutation of a critical tyrosine residue (Y442F) in DLC1 rendered the protein deficient for binding the tensin SH2 domain and binding full-length tensin. The Y442F protein was diffusely cytoplasmic, in contrast to the localization of wild-type DLC1 to focal adhesions, but it retained the ability to reduce the intracellular levels of Rho-GTP. The Y442F mutant displayed markedly reduced biological activity, as did a mutant that was RhoGAP-deficient. The results suggest that DLC1 is a multifunctional protein whose biological activity depends on cooperation between its tensin binding and RhoGAP activities, although neither activity depends on the other. C1 NCI, Cellular Oncol Lab, NIH, Lab Cellular Oncol,Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Cellular Oncol Lab, NIH, Lab Expt Carcinogenesis,Ctr Canc Res, Bethesda, MD 20892 USA. Natl Inst Dent & Cranopfacial Res, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Lowy, DR (reprint author), NCI, Cellular Oncol Lab, NIH, Lab Cellular Oncol,Ctr Canc Res, Bldg 37,Room 4106, Bethesda, MD 20892 USA. EM drl@helix.nih.gov OI Yamada, Kenneth/0000-0003-1512-6805 FU Intramural NIH HHS NR 29 TC 97 Z9 102 U1 1 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 MAY 22 PY 2007 VL 104 IS 21 BP 9012 EP 9017 DI 10.1073/pnas.0703033104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 173DM UT WOS:000246853700060 PM 17517630 ER PT J AU Baker, CI Liu, J Wald, LL Kwong, KK Benner, T Kanwisher, N AF Baker, Chris I. Liu, Jia Wald, Lawrence L. Kwong, Kenneth K. Benner, Thomas Kanwisher, Nancy TI Visual word processing and experiential origins of functional selectivity in human extrastriate cortex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE learning; vision; fMRI; experience; ventral visual pathway ID LETTER-STRING PERCEPTION; SURFACE-BASED ANALYSIS; LEFT FUSIFORM GYRUS; FORM AREA; INFEROTEMPORAL CORTEX; LETTER RECOGNITION; ADULT MONKEYS; FACE AREA; OBJECT; DYSLEXIA AB How do category-selective regions arise in human extrastriate cortex? Visually presented words provide an ideal test of the role of experience: Although individuals have extensive experience with visual words, our species has only been reading for a few thousand years, a period not thought to belong enough for natural selection to produce a genetically specified mechanism dedicated to visual word recognition per se. Using relatively high-resolution functional magnetic resonance imaging (1.4 x 1.4 x 2-mm voxels), we identified a small region of extrastriate cortex in most participants that responds selectively to both visually presented words and consonant strings, compared with line drawings, digit strings, and Chinese characters. Critically, we show that this pattern of selectivity is dependent on experience with specific orthographies: The same region responds more strongly to Hebrew words in Hebrew readers than in nonreaders of Hebrew. These results indicate that extensive experience with a given visual category can produce strong selectivity for that category in discrete cortical regions. C1 NIMH, Lab Brain & Cognit, NIH, Bethesda, MD 20892 USA. Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing 100875, Peoples R China. Harvard Univ, Massachusetts Gen Hosp, MIT, Sch Med,Athinoula A Martinos Ctr Biomed Imaging, Charlestown, MA 02129 USA. MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. MIT, Dept Brain & Cognit Sci, Cambridge, MA 02139 USA. RP Baker, CI (reprint author), NIMH, Lab Brain & Cognit, NIH, Bldg 10,Room 4C104, Bethesda, MD 20892 USA. EM bakerchris@mail.nih.gov; ngk@mit.edu RI Liu, Jia/C-5630-2011; Wald, Lawrence/D-4151-2009; OI Baker, Chris/0000-0001-6861-8964 FU NCRR NIH HHS [P41 RR014075, P41-RR14075]; NEI NIH HHS [EY13455, R01 EY013455]; NINDS NIH HHS [NS049052] NR 58 TC 174 Z9 181 U1 1 U2 28 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 22 PY 2007 VL 104 IS 21 BP 9087 EP 9092 DI 10.1073/pnas.0703300104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 173DM UT WOS:000246853700073 PM 17502592 ER PT J AU Perry, AS Loftus, B Moroose, R Lynch, TH Hollywood, D Watson, RWG Woodson, K Lawler, M AF Perry, A. S. Loftus, B. Moroose, R. Lynch, T. H. Hollywood, D. Watson, R. W. G. Woodson, K. Lawler, M. TI In silico mining identifies IGFBP3 as a novel target of methylation in prostate cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE methylation; prostate cancer; prostatic intraepithelial neoplasia; insulin-like growth factor binding protein 3; glutathione-S-transferase pi ID FACTOR-BINDING PROTEIN-3; CELL LUNG-CANCER; INTRAEPITHELIAL NEOPLASIA; PROMOTER METHYLATION; MULTIPLE GENES; CPG-ISLANDS; HUMAN GENOME; EXPRESSION; HYPERMETHYLATION; PROGRESSION AB Promoter hypermethylation is central in deregulating gene expression in cancer. Identification of novel methylation targets in specific cancers provides a basis for their use as biomarkers of disease occurrence and progression. We developed an in silico strategy to globally identify potential targets of promoter hypermethylation in prostate cancer by screening for 5 ' CpG islands in 631 genes that were reported as downregulated in prostate cancer. A virtual archive of 338 potential targets of methylation was produced. One candidate, IGFBP3, was selected for investigation, along with glutathione-S-transferase pi (GSTP1), a well-known methylation target in prostate cancer. Methylation of IGFBP3 was detected by quantitative methylation-specific PCR in 49/79 primary prostate adenocarcinoma and 7/14 adjacent preinvasive high-grade prostatic intraepithelial neoplasia, but in only 5/37 benign prostatic hyperplasia (P < 0.0001) and in 0/39 histologically normal adjacent prostate tissue, which implies that methylation of IGFBP3 may be involved in the early stages of prostate cancer development. Hypermethylation of IGFBP3 was only detected in samples that also demonstrated methylation of GSTP1 and was also correlated with Gleason score >= 7 (P=0.01), indicating that it has potential as a prognostic marker. In addition, pharmacological demethylation induced strong expression of IGFBP3 in LNCaP prostate cancer cells. Our concept of a methylation candidate gene bank was successful in identifying a novel target of frequent hypermethylation in early-stage prostate cancer. Evaluation of further relevant genes could contribute towards a methylation signature of this disease. C1 St James Hosp, Dept Haematol, Dublin, Ireland. St James Hosp, Acad Unit Clin & Mol Oncol, Inst Mol Med, Dublin, Ireland. Trinity Coll Dublin, Dublin, Ireland. AMNCH, Dept Histopathol, Dublin, Ireland. Florida Hosp, Ctr Canc, Orlando, FL USA. St James Hosp, Dept Urol, Dublin 8, Ireland. Univ Coll Dublin, Conway Inst Biomol Biomed Res, Sch Med & Med Sci, Dublin, Ireland. NCI, Genet Branch, Bethesda, MD 20892 USA. RP Perry, AS (reprint author), St James Hosp, Dept Haematol, Dublin, Ireland. EM aperry@tcd.ie OI Perry, Antoinette/0000-0002-6108-512X NR 44 TC 30 Z9 32 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD MAY 21 PY 2007 VL 96 IS 10 BP 1587 EP 1594 DI 10.1038/sj.bjc.6603767 PG 8 WC Oncology SC Oncology GA 168YS UT WOS:000246560500015 PM 17453001 ER PT J AU Glushakova, S Yin, D Gartner, N Zimmerberg, J AF Glushakova, Svetlana Yin, Dan Gartner, Nicole Zimmerberg, Joshua TI Quantification of malaria parasite release from infected erythrocytes: inhibition by protein-free media SO MALARIA JOURNAL LA English DT Article ID CULTURE AB Background: Intracellular malaria parasites leave their host erythrocytes to infect neighbouring cells after each cycle of asexual replication. No method is currently available for the direct quantification of parasite release. Method and results: To quantify parasite release process, human erythrocytves infected with Plasmodium falciparum were injected into sealed chambers at optimal density, where they progressed through the end of the erythrocyte cycle. Each event of parasite release inside the chamber at the site of erythrocyte rupture leaves on the chamber wall a footprint, composed of 1) separated parasites, 2) a digestive vacuole with haemozoin, and 3) fragments of the ruptured membranes. These footprints are stable for hours, allowing precise identification using differential interference contrast (DIC) microscopy. The relative rate of parasite release is defined as the percent of such footprints out of all schizonts injected and incubated into chamber at 37 C for two hours. The method is highly reproducible, easy to perform, and does not require expensive equipment. Additionally, this method allows one to analyse cell and release site morphology, which adds information about the release process and the quality of the culture. The method is used here to show that swelling of schizonts caused by protein-free media inhibits parasite release. Conclusion: In this study, a novel method is described to count sites of parasite release by microscopy. Besides the direct estimation of parasite release from infected erythrocytes, this method provides a morphological evaluation of normal infected cells approaching the end of the plasmodial life cycle, or pathological forms accumulated as the result of experimental intervention in the parasite release process. One may now accurately estimate the relative parasite release rate at the time of cycle transition, without any obligatory coupling to parasite invasion. C1 NICHHD, Dept Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Zimmerberg, J (reprint author), NICHHD, Dept Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. EM glushaks@mail.nih.gov; dan_yin@nymc.edu; nicolegar@pcom.edu; joshz@helix.nih.gov OI Spare, Nicole/0000-0002-7009-7210 FU Intramural NIH HHS NR 5 TC 15 Z9 15 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD MAY 21 PY 2007 VL 6 AR 61 DI 10.1186/1475-2875-6-61 PG 5 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 175TN UT WOS:000247037000001 PM 17517141 ER PT J AU Kristinsson, SY Landgren, O Dickman, PW Derolf, AR Bjorkholm, M AF Kristinsson, Sigurdur Yngvi Landgren, Ola Dickman, Paul W. Derolf, Asa Rangert Bjorkholm, Magnus TI Patterns of survival in multiple myeloma: A population-based study of patients diagnosed in Sweden from 1973 to 2003 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 46th Annual Meeting of the American-Society-of-Hematology CY DEC 04-07, 2004 CL San Diego, CA SP Amer Soc Hematol ID STEM-CELL TRANSPLANTATION; HIGH-DOSE MELPHALAN; BONE-MARROW-TRANSPLANTATION; PROGNOSTIC-FACTORS; COMBINATION CHEMOTHERAPY; RANDOMIZED-TRIALS; RELATIVE SURVIVAL; PHASE-III; THERAPY; LEUKEMIA AB Purpose To define patterns of survival among all multiple myeloma (MM) patients diagnosed in Sweden during a 30-year period. Patients and Methods A total of 14,381 MM patients (7,643 males; 6,738 females) were diagnosed in Sweden from 1973 to 2003 (median age, 69.9 years; range 19 to 101 years). Patients were categorized into six age categories and four calendar periods (1973 to 1979, 1980 to 1986, 1987 to 1993, and 1994 to 2003). We computed relative survival ratios (BSRs) as measures of patient survival. Results One-year survival improved (P <.001) over time in all age groups and RSBs were 0.73, 0.78, 0.80, and 0.82 for the four calendar periods; however, improvement in 5-year (P <.001) and 10-year (P <.001) RSR was restricted to patients younger than 70 years and younger than 60 years, respectively. For the first time, in analyses restricted to MM patients diagnosed at age younger than 60 years, we found a 29% (P <.001) reduced 10-year mortality in the last calendar period (1994 to 2003) compared with the preceding calendar period (1987 to 1993). Females with MM had a 3% (P =.024) lower excess mortality than males. Conclusion One-year MM survival has increased for all age groups during the last decades; 5-year and 10-year MM survival has increased in younger patients (younger than 60 to 70 years). High-dose melphalan with subsequent autologous stem-cell transplantation, thalidomide, and a continuous improvement in supportive care measures are probably the most important factors contributing to this finding. New effective agents with a more favorable toxicity profile are needed to improve survival further, particularly in the elderly. C1 Karolinska Univ Hosp & Inst, Dept Med, Div Hematol, Stockholm, Sweden. Karolinska Univ Hosp & Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Bjorkholm, M (reprint author), Karolinska Univ Hosp, Dept Med, Div Hematol, SE-17176 Stockholm, Sweden. EM magnus.bjorkholm@karolinska.se RI Dickman, Paul/B-4572-2013; Kristinsson, Sigurdur /M-2910-2015 OI Dickman, Paul/0000-0002-5788-3380; Kristinsson, Sigurdur /0000-0002-4964-7476 NR 58 TC 158 Z9 163 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 MAY 20 PY 2007 VL 25 IS 15 BP 1993 EP 1999 DI 10.1200/JCO.2006.09.0100 PG 7 WC Oncology SC Oncology GA 172KW UT WOS:000246804200010 PM 17420512 ER PT J AU Goss, PE Ingle, JN Martino, S Robert, NJ Muss, HB Piccart, MJ Castiglione, M Tu, DH Shepherd, LE Pritchard, KI Livingston, RB Davidson, NE Norton, L Perez, EA Abrams, JS Cameron, DA Palmer, MJ Pater, JL AF Goss, Paul E. Ingle, James N. Martino, Silvana Robert, Nicholas J. Muss, Hyman B. Piccart, Martine J. Castiglione, Monica Tu, Dongsheng Shepherd, Lois E. Pritchard, Kathleen I. Livingston, Robert B. Davidson, Nancy E. Norton, Larry Perez, Edith A. Abrams, Jeffrey S. Cameron, David A. Palmer, Michael J. Pater, Joseph L. TI Efficacy of letrozole extended adjuvant therapy according to estrogen receptor and progesterone receptor status of the primary tumor: National Cancer Institute of Canada Clinical Trials Group MA.17 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 28th Annual San Antonio Breast Cancer Symposium CY DEC 08-11, 2005 CL San Antonio, TX SP San Antonio Canc Inst, Baylor Coll Med, Canc Therapy & Res Ctr, Univ Texas San Antonio, Hlth Sci Ctr ID EARLY BREAST-CANCER; POSTMENOPAUSAL WOMEN; RANDOMIZED-TRIAL; ENDOCRINE THERAPY; TAMOXIFEN THERAPY; UPDATED FINDINGS; PHASE-III; ANASTROZOLE; MULTICENTER; COMBINATION AB Purpose Controversy exists regarding estrogen (ER) and progesterone (PgR) receptor expression on efficacy of adjuvant endocrine therapy. In the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial, the benefit of anastrozole over tamoxifen was substantially greater in ER+/PgR- than ER+/PgR+ tumors. In BIG 1-98 (Breast International Group), the benefits of letrozole over tamoxifen were the same in ER+ tumors irrespective of PgR. MA.17 randomized postmenopausal women after 5 years of tamoxifen, to letrozole or placebo. We present outcomes according to tumor receptor status. Patients and Methods Disease-free survival (DFS) and other outcomes were assessed in subgroups by ER and PgR status using Cox's proportional hazards model, adjusting for nodal status and prior adjuvant chemotherapy. Results The DFS hazard ratio (HB) for letrozole versus placebo in ER+/PgR+ tumors (N = 3,809) was 0.49 (95% Cl, 0.36 to 0.67) versus 1.21 (95% Cl, 0.63 to 2.34) in ER+/PgR- tumors (n = 636). ER+/PgR+ letrozole patients experienced significant benefit in distant DFS (DDFS; HR = 0.53, 95% Cl, 0.35 to 0.80) and overall survival (OS, HR = 0.58; 95% Cl, 0.37 to 0.90). A statistically significant difference in treatment effect between EB+/PgR+ and ER+/PgR- subgroups for DFS was observed (P =.02), but not for DDFS (P =.06) or CS (P =.09). Conclusion These results suggest greater benefit for letrozole in DFS DDFS and OS in patients with,, ER+/PgR+ tumors, implying greater activity of letrozole in tumors with a functional ER. However, because this is a subset analysis and receptors were not measured centrally we caution against, using these results for clinical decision making. C1 Massachusetts Gen Hosp, Ctr Canc, Div Hematol & Oncol, Boston, MA 02114 USA. Mayo Clin, Rochester, MN USA. John Wayne Canc Inst, Santa Monica, CA USA. Inova Fairfax Hosp, Falls Church, VA USA. Univ Vermont, Burlington, VT USA. Inst Jules Bordet, B-1000 Brussels, Belgium. SIBCSG Coordinating Ctr, Bern, Switzerland. Natl Canc Inst Canada, Clin Trials Grp, Kingston, ON, Canada. Univ Toronto, Toronto Sunnybrook Reg Canc Ctr, Toronto, ON, Canada. Univ Washington, Seattle, WA 98195 USA. Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. NCI, Clin Invest Branch, Rockville, MD USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Mayo Clin, Jacksonville, FL 32224 USA. Western Gen Hosp, Edinburgh Breast Unit, Edinburgh EH4 2XU, Midlothian, Scotland. RP Goss, PE (reprint author), Massachusetts Gen Hosp, Ctr Canc, Div Hematol & Oncol, 55 Fruit St,Lawrence House,LRH-302, Boston, MA 02114 USA. EM pgoss@partners.org OI Norton, Larry/0000-0003-3701-9250 NR 25 TC 79 Z9 81 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 MAY 20 PY 2007 VL 25 IS 15 BP 2006 EP 2011 DI 10.1200/JCO.2006.09.4482 PG 6 WC Oncology SC Oncology GA 172KW UT WOS:000246804200012 PM 17452676 ER PT J AU Freidlin, B Korn, EL Hunsberger, S Gray, R Saxman, S Zujewski, LA AF Freidlin, Boris Korn, Edward L. Hunsberger, Sally Gray, Robert Saxman, Scott Zujewski, Lo Anne TI Proposal for the use of progression-free survival in unblinded randomized trials SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CLINICAL-TRIALS; LOGRANK TEST; PROPORTIONS; CANCER AB Progression-free survival is an attractive end point for clinical trials when an overall survival end point may be confounded by additional treatments administered after progression. When a trial is performed in an unblinded manner, however, there is the potential for bias between the treatment arms because of the subjective aspects of the progression end point. We discuss the magnitude of this potential bias and suggest methods for lessening it. We propose the carrying forward of any progression information to two designated time points for the statistical analysis for trials that are not blinded. This proposal, possibly combined with central review of progression scans for these two time points, essentially eliminates any bias, with little risk of major efficiency loss compared with using the reported progression times. C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. NCI, Clin Invest Branch, Div Canc Treatment & Diagnosis, Bethesda, MD 20892 USA. Harvard Univ, Sch Publ Hlth, Eastern Cooperat Oncol Grp, Boston, MA 02115 USA. Peace Corps, Washington, DC USA. RP Freidlin, B (reprint author), NCI, Biometr Res Branch, EPN-8122, Bethesda, MD 20892 USA. EM freidlinb@ctep.nci.nih.gov NR 14 TC 35 Z9 40 U1 1 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 MAY 20 PY 2007 VL 25 IS 15 BP 2122 EP 2126 DI 10.1200/JCO.2006.09.6198 PG 5 WC Oncology SC Oncology GA 172KW UT WOS:000246804200028 PM 17513819 ER PT J AU Hudis, CA Barlow, WE Costantino, JP Gray, RJ Pritchard, KI Chapman, JAW Sparano, JA Hunsberger, S Enos, RA Gelber, RD Zujewski, JA AF Hudis, Clifford A. Barlow, William E. Costantino, Joseph P. Gray, Robert J. Pritchard, Kathleen I. Chapman, Judith-Anne W. Sparano, Joseph A. Hunsberger, Sally Enos, Rebecca A. Gelber, Richard D. Zujewski, Jo Anne TI Proposal for standardized definitions for efficacy end points in adjuvant breast cancer trials: The STEEP system SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID POSTMENOPAUSAL WOMEN; RANDOMIZED-TRIAL; TAMOXIFEN THERAPY; ANASTROZOLE; LETROZOLE AB Purpose Standardized definitions of breast cancer clinical trial end points must be adopted to permit the consistent interpretation and analysis of breast cancer clinical trials and to facilitate cross-trial comparisons and meta-analyses. Standardizing terms will allow for uniformity in data collection across studies, which will optimize clinical trial utility and efficiency. A given end point term (eg, overall survival) used in a breast cancer trial should always encompass the same set of events (eg, death attributable to breast cancer, death attributable to cause other than breast cancer, death from unknown cause), and, in turn, each event within that end point should be commonly defined across end points and studies. Methods A panel of experts in breast cancer clinical trials representing medical oncology, biostatistics, and correlative science convened to formulate standard definitions and address the confusion that nonstandard definitions of widely used end point terms for a breast cancer clinical trial can generate. We propose standard definitions for efficacy end points and events in early-stage adjuvant breast cancer clinical trials. In some cases, it is expected that the standard end points may not address a specific trial question, so that modified or customized end points would need to be prospectively defined and consistently used. Conclusion The use of the proposed common end point definitions will facilitate interpretation of trial outcomes. This approach may be adopted to develop standard outcome definitions for use in trials involving other cancer sites. C1 Mem Sloan Kettering Canc Ctr, Breast Canc Med Serv, New York, NY 10021 USA. Montefiore Med Ctr, Albert Einstein Coll Med, Bronx, NY 10467 USA. Canc Res & Biostat, Seattle, WA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Ctr Biostat, Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Div Canc Treatment & Diag, Biometr Res Branch, Rockville, MD USA. EMMES Corp, Rockville, MD USA. NCI, Div Canc Treatment & Diag, Canc Therapy Evaluat Program, Rockville, MD USA. Univ Toronto, Toronto, ON, Canada. Sunnybrook Hlth Sci Ctr, Toronto, ON M4N 3M5, Canada. Queens Univ, Kingston, ON, Canada. RP Hudis, CA (reprint author), Mem Sloan Kettering Canc Ctr, Breast Canc Med Serv, 1275 York Ave,Box 206, New York, NY 10021 USA. EM hudisc@mskcc.org NR 7 TC 273 Z9 276 U1 1 U2 5 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 MAY 20 PY 2007 VL 25 IS 15 BP 2127 EP 2132 DI 10.1200/JCO.2006.10.3523 PG 6 WC Oncology SC Oncology GA 172KW UT WOS:000246804200029 PM 17513820 ER PT J AU Edgren, G Hjalgrim, H Reilly, M Tran, TN Rostgaard, K Shanwell, A Titlestad, K Adami, J Wikman, A Jersild, C Gridley, G Wideroff, L Nyren, O Melbye, M AF Edgren, Gustaf Hjalgrim, Henrik Reilly, Marie Tran, Trung Nam Rostgaard, Klaus Shanwell, Agneta Titlestad, Kjell Adami, Johanna Wikman, Agneta Jersild, Casper Gridley, Gloria Wideroff, Louise Nyren, Olof Melbye, Mads TI Risk of cancer after blood transfusion from donors with subclinical cancer: a retrospective cohort study SO LANCET LA English DT Article ID NON-HODGKINS-LYMPHOMA; TRAUMA PATIENTS; OLDER WOMEN; RECIPIENTS; TRANSMISSION; MICROCHIMERISM; LEUKEMIA; HISTORY; MORBIDITY; REGISTRY AB Background Although mechanisms for detection of short-term complications after blood transfusions are well developed, complications with delayed onset, notably transmission of chronic diseases such as cancer, have been difficult to assess. Our aim was to investigate the possible risk of cancer transmission from blood donors to recipients through blood transfusion. Methods We did a register-based retrospective cohort study of cancer incidence among patients who received blood from donors deemed to have a subclinical cancer at the time of donation. These precancerous donors were diagnosed with a cancer within 5 years of the donation. Data from all computerised blood bank registers in Sweden and Denmark gathered between 1968 and 2002 were merged into a common database. Demographic and medical data, including mortality and cancer incidence, were ascertained through linkages with nationwide, and essentially complete, population and health-care registers. The risk of cancer in exposed recipients relative to that in recipients who received blood from non-cancerous donors was estimated with multivariate Poisson regression, adjusting for potential confounding factors. Findings Of the 354094 transfusion recipients eligible for this analysis, 12012 (3%) were exposed to blood products from precancerous donors. There was no excess risk of cancer overall (adjusted relative risk 1.00, 95% CI 0.94-1.07) or in crude anatomical subsites among recipients of blood from precancerous donors compared with recipients of blood from non-cancerous donors. Interpretation Our data provide no evidence that blood transfusions from precancerous blood donors are associated with increased risk of cancer among recipients compared with transfusions from non-cancerous donors. C1 Karolinska Inst, Dept Med Epidemiol & Biostat, SE-17177 Stockholm, Sweden. Karolinska Inst, Dept Clin Immunol & Transfus Med, SE-17177 Stockholm, Sweden. Karolinska Inst, Dept Med, Clin Epidemiol Unit, SE-17177 Stockholm, Sweden. Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark. Odense Univ Hosp, Dept Clin Immunol, DK-5000 Odense, Denmark. Aarhus Univ Hosp, Dept Clin Immunol, DK-8000 Aarhus, Denmark. NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Nyren, O (reprint author), Karolinska Inst, Dept Med Epidemiol & Biostat, Box 281, SE-17177 Stockholm, Sweden. EM olof.nyren@ki.se RI Hernandez, Jessica/G-6527-2011; Edgren, Gustaf/F-4013-2014; OI Edgren, Gustaf/0000-0002-2198-4745; Rostgaard, Klaus/0000-0001-6220-9414 FU NCI NIH HHS [N01-CP-21175] NR 40 TC 35 Z9 35 U1 0 U2 5 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD MAY 20 PY 2007 VL 369 IS 9574 BP 1724 EP 1730 DI 10.1016/S0140-6736(07)60779-X PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 169ZT UT WOS:000246631300028 PM 17512857 ER PT J AU Yu, LR Chan, KC Tahara, H Lucas, DA Chatterjee, K Issaq, HJ Veenstra, TD AF Yu, Li-Rong Chan, King C. Tahara, Hidetoshi Lucas, David A. Chatterjee, Koushik Issaq, Haleem J. Veenstra, Timothy D. TI Quantitative proteomic analysis of human breast epithelial cells with differential telomere length SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE breast epithelial cells; ICAT; mass spectrometry; quantitative proteomics; telomere length ID REVERSE-TRANSCRIPTASE; HUMAN FIBROBLASTS; PROTEIN TRF2; DNA-DAMAGE; EXPRESSION; CAPACITY; DYSFUNCTION; ACTIVATION; RESISTANCE; MUTATION AB Telomeres play important functional roles in cell proliferation, cell cycle regulation, and genetic stability, in which telomere length is critical. In this study, quantitative proteome comparisons for the human breast epithelial cells with short and long telomeres (hTERT(L) vs. 184-hTERT(S) and 90P-hTERT(L) vs. 90P-hTERT(S)), resulting from transfection of the human telomerase reverse transcriptase (hTERT) gene, were performed using cleavable isotope-coded affinity tags. More than 2000 proteins were quantified in each comparative experiment, with approximately 77% of the proteins identified in both analyses. In the cells with long telomeres, significant and consistent alterations were observed in metabolism (amino acid, nucleotide, and lipid metabolism), genetic information transmission (transcription and translation regulation, spliceosome and ribosome complexes), and cell signaling. Interestingly, the DNA excision repair pathway is enhanced, while integrin and its ligands are downregulated in the cells with long telomeres. These results may provide valuable information related to telomere functions. (c) 2007 Elsevier Inc. All rights reserved. C1 NCI, Lab Proteom & Analyt Technol, SAIC Frederick, Frederick, MD 21702 USA. Hiroshima Univ, Dept Cellular & Mol Biol, Hiroshima 7348551, Japan. RP Yu, LR (reprint author), NCI, Lab Proteom & Analyt Technol, SAIC Frederick, Frederick, MD 21702 USA. EM lyu@ncifcrf.gov; veenstra@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400, N01 CO12400/CO/NCI, N01CO12400] NR 26 TC 8 Z9 8 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 MAY 18 PY 2007 VL 356 IS 4 BP 942 EP 947 DI 10.1016/j.bbrc.2007.03.069 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 158ZD UT WOS:000245833500019 PM 17395154 ER PT J AU Koh, E Bandle, R Clair, T Roberts, DD Stracke, ML AF Koh, Eunjin Bandle, Russell Clair, Timothy Roberts, David D. Stracke, Mary L. TI Trichostatin A and 5-aza-2 '-deoxycytidine switch S1P from an inhibitor to a stimulator of motility through epigenetic regulation of S1P receptors SO CANCER LETTERS LA English DT Article DE sphingosine-1-phosphate; S1P(1); S1P(2); S1P(3); trichostatin A; motility; epigenetic ID HISTONE DEACETYLASE INHIBITORS; GASTRIC-CANCER CELLS; SPHINGOSINE 1-PHOSPHATE; LYSOPHOSPHATIDIC ACID; GENE-EXPRESSION; MELANOMA-CELLS; SPHINGOSINE-1-PHOSPHATE; MIGRATION; PROLIFERATION; ANGIOGENESIS AB The histone deacetylase inhibitor, trichostatin A (TSA), and the DNA methyltransferase inhibitor, 5-aza-2-deoxycytidine (Aza-dC), induced epigenetic regulation of sphingosine-1-phosphate (S1P) receptors in human melanoma cells, switching SIP from motility inhibitor to stimulator. Quantitative PCR revealed increased expression of S1P(1) and S1P(3), associated with S1P-induced chemotaxis, and decreased expression of S1P(2,) associated with motility inhibition. Expression of lysophosphatidic acid (LPA) receptors was less affected. The TSA effect was reversible suggesting no mutational change, and Aza-dC treatment resulted in demethylation of a putative S1P(1) promoter. S1P receptors, therefore, appear to be susceptible to epigenetic regulation, accompanied by altered cellular functionality. Published by Elsevier Ireland Ltd. C1 NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Koh, E (reprint author), NCI, Pathol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM kohe@mail.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU Intramural NIH HHS NR 41 TC 7 Z9 8 U1 0 U2 0 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 MAY 18 PY 2007 VL 250 IS 1 BP 53 EP 62 DI 10.1016/j.canlet.2006.09.017 PG 10 WC Oncology SC Oncology GA 164UM UT WOS:000246260100007 PM 17189669 ER PT J AU Barski, A Cuddapah, S Cui, KR Roh, TY Schones, DE Wang, ZB Wei, G Chepelev, I Zhao, KJ AF Barski, Artern Cuddapah, Suresh Cui, Kairong Roh, Tae-Young Schones, Dustin E. Wang, Zhibin Wei, Gang Chepelev, Iouri Zhao, Keji TI High-resolution profiling of histone methylations in the human genome SO CELL LA English DT Article ID EMBRYONIC STEM-CELLS; ACTIVE GENES; T-CELLS; DEVELOPMENTAL REGULATORS; SACCHAROMYCES-CEREVISIAE; MAMMALIAN CHROMATIN; CODING REGIONS; WIDE; H2A.Z; H3 AB Histone modifications are implicated in influencing gene expression. We have generated high-resolution maps for the genome-wide distribution of 20 histone lysine and arginine methylations as well as histone variant H2A.Z, RNA polymerase II, and the insulator binding protein CTCF across the human genome using the Solexa 1G sequencing technology. Typical patterns of histone methylations exhibited at promoters, insulators, enhancers, and transcribed regions are identified. The monomethylations of H3K27, H3K9, H4K20, H3K79, and H2BK5 are all linked to gene activation, whereas trimethylations of H3K27, H3K9, and H3K79 are linked to repression. H2A.Z associates with functional regulatory elements, and CTCF marks boundaries of histone methylation domains. Chromosome banding patterns are correlated with unique patterns of histone modifications. Chromosome breakpoints detected in T cell cancers frequently reside in chromatin regions associated with H3K4 methylations. Our data provide new insights into the function of histone methylation and chromatin organization in genome function. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Gonda Neurosci & Genet Res Ctr, Dept Human Genet, Los Angeles, CA 90095 USA. RP Zhao, KJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM zhaok@nhlbi.nih.gov RI Wei, Gang/A-3291-2011; OI Barski, Artem/0000-0002-1861-5316 FU Intramural NIH HHS NR 54 TC 3264 Z9 3354 U1 43 U2 361 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD MAY 18 PY 2007 VL 129 IS 4 BP 823 EP 837 DI 10.1016/j.cell.2007.05.009 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 172FA UT WOS:000246788300025 PM 17512414 ER PT J AU Zhu, TN He, HJ Kole, S D'Souza, T Agarwal, R Morin, PJ Bernier, M AF Zhu, Tie-Nian He, Hua-Jun Kole, Sutapa D'Souza, Theresa Agarwal, Rachana Morin, Patrice J. Bernier, Michel TI Filamin A-mediated down-regulation of the exchange factor Ras-GRF1 correlates with decreased matrix metalloproteinase-9 expression in human melanoma cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GUANINE-NUCLEOTIDE EXCHANGE; MATRIX METALLOPROTEINASE-2 AND-9; GTPASE-ACTIVATING PROTEIN; DEPENDENT ACTIVATION; GENE-EXPRESSION; METASTATIC MELANOMA; KINASE ACTIVATION; CANCER CELLS; GELATINASE-B; KAPPA-B AB The actin-binding protein filamin A (FLNa) is associated with diverse cellular processes such as cell motility and signaling through its scaffolding properties. Here we examine the effect of FLNa on the regulation of signaling pathways that control the expression of matrix metalloproteinases (MMPs). The lack of FLNa in human M2 melanoma cells was associated with constitutive and phorbol ester-induced expression and secretion of active MMP-9 in the absence of MMP-2 up-regulation. M2 cells displayed stronger MMP-9 production and activity than their M2A7 counterparts where FLNa had been stably reintroduced. Using an MMP-9 promoter construct (pMMP-9-Luc), in vitro kinase assays, and genetic and pharmacological approaches, we demonstrate that FLNa mediated transcriptional down-regulation of pMMP-9-Luc by suppressing the constitutive hyperactivity of the Ras/MAPK extracellular signal-regulated kinase (ERK) cascade. Experimental evidence indicated that this phenomenon was associated with destabilization and ubiquitylation of Ras-GRF1, a guanine nucleotide exchange factor that activates H-Ras by facilitating the release of GDP. Ectopic expression of Ras-GRF1 was accompanied by ERK activation and elevated levels of MMP-9 in M2A7 cells, whereas a catalytically inactive dominant negative Ras-GRF1, which prevented ERK activation, reduced MMP-9 expression in M2 cells. Our results indicate that expression of FLNa regulates constitutive activation of the Ras/ERK pathway partly through a Ras-GRF1 mechanism to modulate the production of MMP-9. C1 NIA, Diabet Sect, NIH, Clin Invest Lab, Baltimore, MD 21224 USA. NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. RP Bernier, M (reprint author), NIA, Diabet Sect, NIH, Clin Invest Lab, Box 23,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM Bernierm@mail.nih.gov OI Bernier, Michel/0000-0002-5948-368X FU Intramural NIH HHS NR 72 TC 36 Z9 44 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 MAY 18 PY 2007 VL 282 IS 20 BP 14816 EP 14826 DI 10.1074/jbc.M611430200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 169JR UT WOS:000246589000017 PM 17389601 ER PT J AU Lemieux, GA Blumenkron, F Yeung, N Zhou, P Williams, J Grammer, AC Petrovich, R Lipsky, PE Moss, ML Werb, Z AF Lemieux, George A. Blumenkron, Fernando Yeung, Nolan Zhou, Pei Williams, Jason Grammer, Amrie C. Petrovich, Robert Lipsky, Peter E. Moss, Marcia L. Werb, Zena TI The low affinity IgE receptor (CD23) is cleaved by the metalloproteinase ADAM10 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FC-EPSILON-RII; PRIMARY HUMAN MONOCYTES; SOLUBLE CD23; B-CELLS; PRECURSOR PROTEIN; FC-EPSILON-RII/CD23; DISEASE; CD11B; ACTIVATION; INHIBITION AB The low affinity IgE receptor, Fc epsilon RII (CD23), is both a positive and negative regulator of IgE synthesis. The proteinase activity that converts the membrane-bound form of CD23 into a soluble species (sCD23) is an important regulator of the function of CD23 and may be an important therapeutic target for the control of allergy and inflammation. We have characterized the catalytic activity of ADAM (a disintegrin and metalloproteinase) 10 toward human CD23. We found that ADAM10 efficiently catalyzes the cleavage of peptides derived from two distinct cleavage sites in the CD23 backbone. Tissue inhibitors of metalloproteinases and a specific prodomain-based inhibitor of ADAM10 perturb the release of endogenously produced CD23 from human leukemia cell lines as well as primary cultures of human B-cells. Expression of a mutant metalloproteinase- deficient construct of ADAM10 partially inhibited the production of sCD23. Similarly, small inhibitory RNA knockdown of ADAM10 partially inhibited CD23 release and resulted in the accumulation of the membrane-bound form of CD23 on the cells. ADAM10 contributes to CD23 shedding and thus could be considered a potential therapeutic target for the treatment of allergic disease. C1 Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Program Biomed Sci, San Francisco, CA 94143 USA. Cognosci, Durham, NC 27710 USA. Duke Univ, Med Ctr, Durham, NC 27710 USA. NIAMS, B Cell Biol Grp, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. NIEHS, NIH, Durham, NC 27710 USA. BioZyme Inc, Apex, NC 27523 USA. RP Moss, ML (reprint author), Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. EM mmoss@biozyme-inc.com; zena.werb@ucsf.edu OI Zhou, Pei/0000-0002-7823-3416 FU NHLBI NIH HHS [T32 HL007731, HL07731, HL75602, R01 HL075602, R01 HL075602-01]; NIAID NIH HHS [AI053194, P01 AI053194, P01 AI053194-01] NR 45 TC 58 Z9 62 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 MAY 18 PY 2007 VL 282 IS 20 BP 14836 EP 14844 DI 10.1074/jbc.M608414200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 169JR UT WOS:000246589000019 PM 17389606 ER PT J AU Adams, VH McBryant, SJ Wade, PA Woodcock, CL Hansen, JC AF Adams, Valerie H. McBryant, Steven J. Wade, Paul A. Woodcock, Christopher L. Hansen, Jeffrey C. TI Intrinsic disorder and autonomous domain function in the multifunctional nuclear protein, MeCP2 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CPG-BINDING PROTEIN; SEDIMENTATION-VELOCITY ANALYSIS; CHROMATIN-REMODELING COMPLEX; RETT-SYNDROME; TRANSCRIPTIONAL REPRESSION; METHYLATED DNA; HISTONE DEACETYLASE; UNSTRUCTURED PROTEINS; CHROMOSOMAL PROTEIN; SEQUENCE AB To probe the tertiary structure and domain organization of native methyl CpG-binding protein 2 ( MeCP2), the recombinant human e2 isoform was purified to homogeneity and characterized by analytical ultracentrifugation, CD, and protease digestion. The location of intrinsic disorder in the MeCP2 sequence was predicted using the FoldIndex algorithm. MeCP2 was found to be monomeric in low and high salt and over a nearly 1000-fold concentration range. CD indicated that the MeCP2 monomer was nearly 60% unstructured under conditions where it could preferentially recognize CpG dinucleotides and condense chromatin. Protease digestion experiments demonstrate that MeCP2 is composed of at least six structurally distinct domains, two of which correspond to the well characterized methyl DNA binding domain and transcriptional repression domain. These domains collectively are organized into a tertiary structure with coil-like hydrodynamic properties, reflecting the extensive disorder in the MeCP2 sequence. When expressed as individual fragments, the methyl DNA binding domain and transcriptional repression domain both could function as nonspecific DNA binding domains. The unusual structural features of MeCP2 provide a basis for understanding MeCP2 multifunctionality in vitro and in vivo. These studies also establish an experimental paradigm for characterizing the tertiary structures of other highly disordered proteins. C1 Colorado State Univ, Dept Biochem & Mol Biol, Ft Collins, CO 80523 USA. Univ Massachusetts, Dept Biol, Amherst, MA 01003 USA. NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Hansen, JC (reprint author), Colorado State Univ, Dept Biochem & Mol Biol, 1870 Campus Delivery, Ft Collins, CO 80523 USA. EM Jeffrey.C.Hansen@colostate.edu FU Intramural NIH HHS; NIGMS NIH HHS [GM45916, GM66834, GM70897] NR 53 TC 70 Z9 74 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 18 PY 2007 VL 282 IS 20 BP 15057 EP 15064 DI 10.1074/jbc.M700855200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 169JR UT WOS:000246589000045 PM 17371874 ER PT J AU Maynard, EL Berg, JM AF Maynard, Ernest L. Berg, Jeremy M. TI Quantitative analysis of peroxisomal targeting signal type-1 binding to wild-type and pathogenic mutants of Pex5p supports an affinity threshold for peroxisomal protein targeting SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE PTS1; Pex5p; peroxisomal targeting; Zellweger spectrum ID IMPORT RECEPTOR PEX5P; RECOGNITION; BIOGENESIS; TRIPEPTIDE AB Peroxisomal biogenesis disorders (PBDs) are caused by mutations in 12 distinct genes that encode the components of the peroxisome assembly machinery. Three mutations in the gene encoding Pex5p, the peroxisomal targeting signal type-1 (PTS1) receptor, have been reported, each associated with a disorder of the Zellweger spectrum of different severity. Here, we report studies of the affinities of mutated forms of Pex5p for a series of PTS1 peptides and conclude that PTS1-affinity reductions are correlated with disease severity and cell biological phenotype. A quantitative model has been developed that allows estimation of the dissociation constants for complexes with a wide range of,PTSI sequences bound to wild-type and mutant Pex5p. In the context of this model, the binding measurements suggest that no PTSI-containing proteins are targeted by Pex5p(N489K) and only a relatively small subset of PTS1-containing proteins with the highest affinity for Pex5p are targeted to peroxisomes by Pex5p(S563W). Furthermore, the results of the analysis are consistent with an approximate dissociation constant threshold near 500 nM required for efficient protein targeting to peroxisomes.(C) 2007 Published by Elsevier Ltd. C1 NIDDKD, Bethesda, MD 20892 USA. Johns Hopkins Univ, Dept Biophys & Biophys Chem, Sch Med, Baltimore, MD 21205 USA. Uniformed Serv Univ Hlth Sci, Dept Biochem & Mol Biol, F Edward Hebert Sch Med, Bethesda, MD 20814 USA. RP Berg, JM (reprint author), NIDDKD, 45 Ctr Dr, Bethesda, MD 20892 USA. EM bergj@mail.nih.gov OI Berg, Jeremy/0000-0003-3022-0963 FU NIGMS NIH HHS [5P01GM051362] NR 17 TC 10 Z9 10 U1 1 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAY 18 PY 2007 VL 368 IS 5 BP 1259 EP 1266 DI 10.1016/j.jmb.2007.03.005 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 167HU UT WOS:000246443200005 PM 17399738 ER PT J AU Doppalapudi, RS Riccio, ES Rausch, LL Shimon, JA Lee, PS Mortelmans, KE Kapetanovic, IM Crowell, JA Mirsalis, JC AF Doppalapudi, Rupa S. Riccio, Edward S. Rausch, Linda L. Shimon, Julie A. Lee, Pam S. Mortelmans, Kristien E. Kapetanovic, Izet M. Crowell, James A. Mirsalis, Jon C. TI Evaluation of chemopreventive agents for genotoxic activity SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE chemopreventive agents; mutagenesis; chromosomal aberrations; micronuclei ID BOWMAN-BIRK INHIBITOR; PLANT ESSENTIAL OILS; CHROMOSOME-ABERRATIONS; CYTOGENETIC BIOMARKERS; MUTATION ASSAY; DNA-SYNTHESIS; TUMOR BURDEN; CANCER CELLS; VITAMIN-E; INDOLE-3-CARBINOL AB We conducted genetic toxicity evaluations of 11 candidate chemopreventive agents with the potential for inhibiting carcinogenesis in humans at increased risk of cancer. The compounds were evaluated for bacterial mutagenesis in the Salmonella-E. coli assay, for mammalian mutagenesis in mouse lymphoma cells, for chromosome aberrations in Chinese Hamster Ovary (CHO) cells, and for micronucleus induction in mouse bone marrow. Tested agents were indole 3-carbinol (I3C), bowman-birk inhibitor concentrate (BBIC), black tea polyphenols (BTP), farnesol, geraniol, L-Se-methylselenocysteine (SeMC), 5,6-dihydro-4H-cyclopenta[1,2]-dithiol-3-thione(DC-D3T), 4'-bromoflavone, 2,5,7,8-tetramethyl-(2R-[4R,8R,12-trimethyltridecyl] chroman-6-yloxy) acetic acid (alpha-TEA), SR13668 (2,10-dicarbethoxy-6-methoxy-5,7-dihydro-indolo[2,3-b] carbazole and SR16157 (3-O-sulfamoyloxy-7 alpha-methyl-21-(2-N,N-diethylaminoethoxy)-19-norpregna-1,3,5(10)-triene). All these agents, except I3C and BTP, were negative in the Salmonella-E. coli assay in the presence and absence of metabolic activation (S9). I3C and BTP induced a weak mutagenic response in the presence and absence of S9 with strains TA100 and TA98, respectively. Of the three compounds tested in the mouse lymphoma assay (I3C, BBIC, and BTP), only BTP was mutagenic in the presence of S9. In the chromosomal aberration assay, of the 8 compounds that were tested, 4'-bromoflavone elicited a positive response in the.absence of S9 only, while SR16157 was positive in the presence of S9. The results with geraniol remain inconclusive. I3C, BBIC and BTP were not tested in the chromosomal aberration assay. None of the 11 agents induced micronuclei in mouse bone marrow erythrocytes. (c) 2007 Elsevier B.V. All rights reserved. C1 SRI Int, Biosci Div, Menlo Pk, CA 94025 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Doppalapudi, RS (reprint author), SRI Int, Biosci Div, PN 171, Menlo Pk, CA 94025 USA. EM rupa.doppalapudi@sri.com FU NCI NIH HHS [N01-CN-95033, N01-CN-15010] NR 42 TC 25 Z9 25 U1 0 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD MAY 18 PY 2007 VL 629 IS 2 BP 148 EP 160 DI 10.1016/j.mrgentox.2007.02.004 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 169ZJ UT WOS:000246630300009 PM 17387038 ER PT J AU Feng, BY Simeonov, A Jadhav, A Babaoglu, K Inglese, J Shoichet, BK Austin, CP AF Feng, Brian Y. Simeonov, Anton Jadhav, Ajit Babaoglu, Kerim Inglese, James Shoichet, Brian K. Austin, Christopher P. TI A high-throughput screen for aggregation-based inhibition in a large compound library SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID AMPC BETA-LACTAMASE; PROMISCUOUS INHIBITORS; FALSE POSITIVES; MECHANISM; DRUGS; BIOAVAILABILITY; IDENTIFICATION; LEADLIKENESS; MOLECULES; DISCOVERY AB High-throughput screening (HTS) is the primary technique for new lead identification in drug discovery and chemical biology. Unfortunately, it is susceptible to false-positive hits. One common mechanism for such false-positives is the congregation of organic molecules into colloidal aggregates, which nonspecifically inhibit enzymes. To both evaluate the feasibility of large-scale identification of aggregate-based inhibition and quantify its prevalence among screening hits, we tested 70 563 molecules from the National Institutes of Health Chemical Genomics Center (NCGC) library for detergent-sensitive inhibition. Each molecule was screened in at least seven concentrations, such that dose-response curves were obtained for all molecules in the library. There were 1274 inhibitors identified in total, of which 1204 were unambiguously detergent-sensitive. We identified these as aggregate-based inhibitors. Thirty-one library molecules were independently purchased and retested in secondary low-throughput experiments; 29 of these were confirmed as either aggregators or nonaggregators, as appropriate. Finally, with the dose-response information collected for every compound, we could examine the correlation between aggregate-based inhibition and steep dose-response curves. Three key results emerge from this study: first, detergent-dependent identification of aggregate-based inhibition is feasible on the large scale. Second, 95% of the actives obtained in this screen are aggregate-based inhibitors. Third, aggregate-based inhibition is correlated with steep dose-response curves, although not absolutely. The results of this screen are being released publicly via the PubChem database. C1 NHGRI, Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94158 USA. Univ Calif San Francisco, Grad Grp Chem & Chem Biol, San Francisco, CA 94158 USA. RP Shoichet, BK (reprint author), NHGRI, Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. EM shoichet@cgl.ucsf.edu; austinc@mail.nih.gov NR 31 TC 186 Z9 188 U1 2 U2 17 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 MAY 17 PY 2007 VL 50 IS 10 BP 2385 EP 2390 DI 10.1021/jm061317y PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 165XO UT WOS:000246341000013 PM 17447748 ER PT J AU Yogeeswari, P Ragavendran, JV Sriram, D Nageswari, Y Kavya, R Sreevatsan, N Vanitha, K Stables, J AF Yogeeswari, Perumal Vaigunda Ragavendran, Jegadeesan Sriram, Dharmarajan Nageswari, Yarravarapu Kavya, Ramkumar Sreevatsan, Narayanan Vanitha, Kaliappan Stables, James TI Discovery of 4-aminobutyric acid derivatives possessing anticonvulsant and antinociceptive activities: A hybrid pharmacophore approach SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ANTIEPILEPTIC DRUG DEVELOPMENT; NEUROPATHIC PAIN; PERIPHERAL NEUROPATHY; MECHANICAL ALLODYNIA; DYNAMIC COMPONENTS; ANIMAL-MODELS; NERVE INJURY; DOUBLE-BLIND; RAT; SEMICARBAZONES AB Antiepileptic drugs are often utilized in the treatment of neuropathic pain. The present study aims at the design and synthesis of newer gamma-aminobutyric acid (GABA) derivatives with the combination of aryl semicarbazone and the GABA pharmacophores in order to develop a multifunctional drug useful in the treatment of neurological disorders like epilepsy and neuropathic pain. Various GABA semicarbazones were synthesized and screened for anticonvulsant, peripheral analgesic, antiallodynic, and antihyperalgesic activities. The structures of the synthesized compounds were confirmed by the use of their spectral data in addition to elemental analysis. The synthesized derivatives of the inhibitory neurotransmitter GABA produced anticonvulsant and antinociceptive actions in the acetic acid induced writhing test and peripheral nerve injury (chronic constriction injury and L5 spinal nerve ligation) models of neuropathic pain. The underlying mechanisms are expected to be enhancement of peripheral GABAergic neurotransmission owing to their activity in the scPIC screen and due to various reports on the involvement of GABAergic pathway in peripheral models of neuropathic pain. C1 Birla Inst Technol & Sci, Pharm Grp, Med Chem Res Lab, Pilani 333031, Rajasthan, India. NIH, Epilepsy Branch, Preclin Pharmacol Sect, Bethesda, MD 20892 USA. RP Yogeeswari, P (reprint author), Birla Inst Technol & Sci, Pharm Grp, Med Chem Res Lab, Pilani 333031, Rajasthan, India. EM pyogee@bits-pilani.ac.in NR 37 TC 11 Z9 11 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 17 PY 2007 VL 50 IS 10 BP 2459 EP 2467 DI 10.1021/jm061431g PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 165XO UT WOS:000246341000022 PM 17451232 ER PT J AU Flores-Ortega, A Casanovas, J Zanuy, D Nussinov, R Aleman, C AF Flores-Ortega, Alejandra Casanovas, Jordi Zanuy, David Nussinov, Ruth Aleman, Carlos TI Conformations of proline analogues having double bonds in the ring SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID CIS-TRANS ISOMERIZATION; AMINO-ACIDS; CYCLOPROPANE ANALOG; DIPEPTIDE ANALOGS; AQUEOUS-SOLUTION; PEPTIDE MODELS; SIDE-CHAIN; RESIDUES; PROLYL; INITIO AB The intrinsic conformational preferences of proline analogues having double bonds between carbon atoms in their rings have been investigated using quantum mechanical calculations at the B3LYP/6-31+G(d,p) level. For this purpose, the potential energy surface of the N-acety-N'-methylamide derivatives of three dehydroprolines (proline analogues unsaturated at alpha,beta; beta,gamma; and gamma,delta) and pyrrole (proline analogue with unsaturations at both alpha,beta and gamma,delta) have been explored, and the results are compared with those obtained for the derivative of the nonmodified proline. We found that the double bonds affect the ring puckering and the geometric internal parameters, even though the backbone conformation was influenced the most. Results indicate that the formation of double bonds between carbon atoms in the pyrrolidine ring should be considered as an effective procedure to restrict the conformational flexibility of prolines. Interestingly, we also found that the N-acetyl-N'-methylamide derivative of pyrrole shows a high probability of having a cis peptide bond preceding the proline analogue. C1 Univ Lleida, Dept Quim, Escola Politecn Catalunya, E-25001 Lleida, Spain. Univ Politecn Cataluna, Dept Engn Quim, ETS Engn Ind Barcelona, E-08028 Barcelona, Spain. NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. Tel Aviv Univ, Dept Human Genet Sackler, Sch Med, IL-69978 Tel Aviv, Israel. RP Casanovas, J (reprint author), Univ Lleida, Dept Quim, Escola Politecn Catalunya, C Jaume 2 69, E-25001 Lleida, Spain. EM jcasanovas@quimica.udl.es; carlos.aleman@upc.edu RI Casanovas, Jordi/B-5435-2013; Zanuy, David/G-3930-2014 OI Casanovas, Jordi/0000-0002-4914-9194; Zanuy, David/0000-0001-7704-2178 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 57 TC 18 Z9 18 U1 1 U2 14 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAY 17 PY 2007 VL 111 IS 19 BP 5475 EP 5482 DI 10.1021/jp0712001 PG 8 WC Chemistry, Physical SC Chemistry GA 165XQ UT WOS:000246341300060 PM 17458993 ER PT J AU Storici, F Bebenek, K Kunkel, TA Gordenin, DA Resnick, MA AF Storici, Francesca Bebenek, Katarzyna Kunkel, Thomas A. Gordenin, Dmitry A. Resnick, Michael A. TI RNA-templated DNA repair SO NATURE LA English DT Article ID DOUBLE-STRAND BREAKS; REVERSE-TRANSCRIPTASE; SACCHAROMYCES-CEREVISIAE; POLYMERASE-ETA; RECA PROTEIN; RECOMBINATION; RIBONUCLEOTIDES; REPLICATION; OLIGONUCLEOTIDES; RETROTRANSPOSONS AB RNA can act as a template for DNA synthesis in the reverse transcription of retroviruses and retrotransposons(1) and in the elongation of telomeres(2). Despite its abundance in the nucleus, there has been no evidence for a direct role of RNA as a template in the repair of any chromosomal DNA lesions, including DNA double-strand breaks (DSBs), which are repaired in most organisms by homologous recombination or by non-homologous end joining(3). An indirect role for RNA in DNA repair, following reverse transcription and formation of a complementary DNA, has been observed in the non-homologous joining of DSB ends(4,5). In the yeast Saccharomyces cerevisiae, in which homologous recombination is efficient(3), RNA was shown to mediate recombination, but only indirectly through a cDNA intermediate(6,7) generated by the reverse transcriptase function of Ty retrotransposons in Ty particles in the cytoplasm(8). Although pairing between duplex DNA and single-strand (ss) RNA can occur in vitro(9,10) and in vivo(11), direct homologous exchange of genetic information between RNA and DNA molecules has not been observed. We show here that RNA can serve as a template for DNA synthesis during repair of a chromosomal DSB in yeast. The repair was accomplished with RNA oligonucleotides complementary to the broken ends. This and the observation that even yeast replicative DNA polymerases such as alpha and delta can copy short RNA template tracts in vitro demonstrate that RNA can transfer genetic information in vivo through direct homologous interaction with chromosomal DNA. C1 NIEHS, Mol Biol Lab, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Resnick, MA (reprint author), NIEHS, Mol Biol Lab, NIH, US Dept HHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM resnick@niehs.nih.gov OI Gordenin, Dmitry/0000-0002-8399-1836 FU Intramural NIH HHS [Z01 ES065072-17] NR 29 TC 74 Z9 78 U1 1 U2 22 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAY 17 PY 2007 VL 447 IS 7142 BP 338 EP 341 DI 10.1038/nature05720 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 168JK UT WOS:000246520300050 PM 17429354 ER PT J AU Johnston, MI Fauci, AS AF Johnston, Margaret I. Fauci, Anthony S. TI Current concepts: An HIV vaccine - Evolving concepts SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Review ID IMMUNODEFICIENCY-VIRUS TYPE-1; CD4(+) T-CELLS; PLASMA VIRAL LOAD; NEUTRALIZING ANTIBODIES; HETEROSEXUAL TRANSMISSION; GASTROINTESTINAL-TRACT; MONOCLONAL-ANTIBODIES; IMMUNE-RESPONSES; SIV INFECTION; LYMPHOCYTES C1 NIAID, Off Director, Bethesda, MD 20892 USA. NIAID, Div AIDS, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, Off Director, 31 Ctr Dr,MSC 2520,Bldg 31,Rm 7A03, Bethesda, MD 20892 USA. EM afauci@niaid.nih.gov NR 56 TC 176 Z9 185 U1 2 U2 9 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD MAY 17 PY 2007 VL 356 IS 20 BP 2073 EP 2081 DI 10.1056/NEJMra066267 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 167ZD UT WOS:000246490500008 PM 17507706 ER PT J AU Mehta, SA Christopherson, KW Bhat-Nakshatri, P Goulet, RJ Broxmeyer, H Kopelovich, L Nakshatri, H AF Mehta, S. A. Christopherson, K. W. Bhat-Nakshatri, P. Goulet, R. J., Jr. Broxmeyer, He Kopelovich, L. Nakshatri, H. TI Negative regulation of chemokine receptor CXCR4 by tumor suppressor p53 in breast cancer cells: implications of p53 mutation or isoform expression on breast cancer cell invasion SO ONCOGENE LA English DT Article DE CXCR4; p53; breast cancer; invasion; PRIMA-1 ID GENE-EXPRESSION; MUTANT P53; GROWTH SUPPRESSION; METASTASIS; TRANSCRIPTION; REPRESSION; MIGRATION; APOPTOSIS; PRIMA-1; AP-1 AB Chemokine receptor CXCR4 and its ligand CXCL12 are suggested to be involved in migration, invasion and metastasis of breast cancer cells. Mutation of the tumor suppressor gene p53 in breast cancer is associated with metastasis and aggressive clinical phenotype. In this report, we demonstrate that wild type but not the dominant-negative mutant (V143A)or cancer-specific mutants (R175H or R280K) of p53 repress CXCR4 expression. Recently described cancer-specific p53 isoform, Delta 133p53, also failed to repress CXCR4 promoter activity. Short-interfering RNA-mediated depletion of p53 increased endogenous CXCR4 expression in MCF-7 breast cancer cells that contain wild-type p53. Basal CXCR4 promoter activity in HCT116 colon carcinoma cells deleted of p53 [HCT116(p53KO)] was 10-fold higher compared to that in parental HCT116 cells with functional wild-type p53. Deletion analysis of CXCR4 promoter identified a seven-base pair p53-repressor element homologous to cyclic AMP/AP-1 response (CRE/AP-1) element. Electrophoretic mobility shift and chromatin immunoprecipitation assays revealed binding of ATF-1 and cJun to the CRE/AP-1 element. The p53 rescue drug PRIMA-1 reduced CXCR4 mRNA and cell surface expression in MDA-MB-231 cells, which express R280K mutant p53. CP-31398, another p53 rescue drug, similarly reduced cell surface levels of CXCR4. PRIMA-1-mediated decrease in CXCR4 expression correlated with reduced invasion of MDA-MB-231 cells through matrigel. These results suggest a mechanism for elevated CXCR4 expression and metastasis of breast cancers with p53 mutations or isoform expression. We propose that p53 rescue drugs either alone or in combination with chemotherapeutic drugs may be effective in reducing CXCR4-mediated metastasis. C1 Indiana Univ, Sch Med, Dept Microbiol & Immunol, Bloomington, IN 47405 USA. Indiana Univ, Sch Med, Walther Oncol Ctr, Bloomington, IN 47405 USA. Natl Canc Inst, DCP, CADRG, Bethesda, MD USA. Walther Canc Inst, Indianapolis, IN USA. RP Nakshatri, H (reprint author), Indiana Canc Res Inst, Dept Surg Biochem & Mol Biol, R4-202,1044 W Walnut St,R4-268, Indianapolis, IN 46202 USA. EM hnakshat@iupui.edu FU NCI NIH HHS [N01-CN-15133, R01 CA89153]; NHLBI NIH HHS [R01 HL67384]; NIDDK NIH HHS [R01 DK53674] NR 38 TC 61 Z9 61 U1 0 U2 9 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 17 PY 2007 VL 26 IS 23 BP 3329 EP 3337 DI 10.1038/sj.onc.1210120 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 169GB UT WOS:000246579600003 PM 17130833 ER PT J AU Buchanan, SK Lukacik, P Grizot, S Ghirlando, R Ali, MMU Barnard, TJ Jakes, KS Kienker, PK Esser, L AF Buchanan, Susan K. Lukacik, Petra Grizot, Sylvestre Ghirlando, Rodolfo Ali, Maruf M. U. Barnard, Travis J. Jakes, Karen S. Kienker, Paul K. Esser, Lothar TI Structure of colicin I receptor bound to the R-domain of colicin Ia: implications for protein import SO EMBO JOURNAL LA English DT Article DE active transport; colicin; outer membrane protein; protein import; TonB ID MEMBRANE TRANSPORTER FECA; CHANNEL-FORMING COLICINS; ESCHERICHIA-COLI; OUTER-MEMBRANE; VITAMIN-B12 TRANSPORT; CRYSTAL-STRUCTURE; TONB PROTEIN; BTUB AFFECT; CELLS; TRANSLOCATION AB Colicin Ia is a 69 kDa protein that kills susceptible Escherichia coli cells by binding to a specific receptor in the outer membrane, colicin I receptor (70 kDa), and subsequently translocating its channel forming domain across the periplasmic space, where it inserts into the inner membrane and forms a voltage-dependent ion channel. We determined crystal structures of colicin I receptor alone and in complex with the receptor binding domain of colicin Ia. The receptor undergoes large and unusual conformational changes upon colicin binding, opening at the cell surface and positioning the receptor binding domain of colicin Ia directly above it. We modelled the interaction with full-length colicin Ia to show that the channel forming domain is initially positioned 150 angstrom above the cell surface. Functional data using full-length colicin Ia show that colicin I receptor is necessary for cell surface binding, and suggest that the receptor participates in translocation of colicin Ia across the outer membrane. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Albert Einstein Coll Med, Dept Physiol & Biophys, Bronx, NY 10467 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Buchanan, SK (reprint author), NIDDKD, Mol Biol Lab, NIH, 50 S Dr,Room 4503, Bethesda, MD 20892 USA. EM skbuchan@helix.nih.gov RI Ghirlando, Rodolfo/A-8880-2009 FU Intramural NIH HHS; NIGMS NIH HHS [GM31986, R01 GM031986] NR 59 TC 62 Z9 63 U1 2 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 MAY 16 PY 2007 VL 26 IS 10 BP 2594 EP 2604 DI 10.1038/sj.emboj.7601693 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 176KF UT WOS:000247083100014 PM 17464289 ER PT J AU Allison, RD Bryant, BJ Vasu, S Leitman, SF AF Allison, Robert D. Bryant, Barbara J. Vasu, Sumithira Leitman, Susan F. TI Iron reduction and cardiovascular outcomes SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIH, Warren G Magnuson Clin Res Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. RP Allison, RD (reprint author), NIH, Warren G Magnuson Clin Res Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. EM allisonr@mail.nih.gov NR 2 TC 0 Z9 0 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 MAY 16 PY 2007 VL 297 IS 19 BP 2075 EP 2076 DI 10.1001/jama.297.19.2075-b PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 167UG UT WOS:000246477400012 PM 17507338 ER PT J AU Zarin, DA Ide, NC Tse, T Harlan, WR West, JC Lindberg, DAB AF Zarin, Deborah A. Ide, Nicholas C. Tse, Tony Harlan, William R. West, Joyce C. Lindberg, Donald A. B. TI Issues in the registration of clinical trials SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID MEDICAL-JOURNAL-EDITORS; PUBLICATION BIAS; RANDOMIZED-TRIALS; INTERNATIONAL-COMMITTEE; CONSORT STATEMENT; REPORT CARD; INFORMATION; CLINICALTRIALS.GOV; PRINCIPLES; DATABASE AB Public concerns about the perils associated with incomplete or delayed reporting of results from clinical trials has heightened interest in trial registries and results databases. Here we review the current status of trial registration efforts and the challenges in developing a comprehensive system of trial registration and reporting of results. ClinicalTrials. gov, the largest trial registry with 36 249 trials from approximately 140 countries, has procedures in place to help ensure that records are valid and informative. Key challenges include the need to minimize inadvertent duplicate registrations, to ensure that interventions have unambiguous names, and to have a search engine that identifies all trials that meet a user's specifications. Recent policy initiatives have called for the development of a database of trial results. Several issues confound the implementation of such a database, including the lack of an accepted format or process for providing summaries of trial results to the public and concerns about disseminating data in the absence of independent scientific review. C1 Natl Lib Med, Clin Trials Gov, Bethesda, MD 20894 USA. NIH, Off Biotechnol Act, US Dept HHS, Bethesda, MD 20892 USA. Amer Psychiat Inst Res & Educ, Arlington, VA USA. Thoughtful Solut Inc, McLean, VA USA. RP Zarin, DA (reprint author), Natl Lib Med, Clin Trials Gov, 8600 Rockville Pike,Bldg 38A,Room 75706, Bethesda, MD 20894 USA. EM dzarin@mail.nih.gov FU Intramural NIH HHS [, NIH0010298972]; PHS HHS [NIH0010298972] NR 61 TC 107 Z9 111 U1 3 U2 11 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 MAY 16 PY 2007 VL 297 IS 19 BP 2112 EP 2120 DI 10.1001/jama.297.19.2112 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 167UG UT WOS:000246477400024 PM 17507347 ER PT J AU Emanuel, EJ AF Emanuel, Ezekiel J. TI What cannot be said on television about health care SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material C1 NIH, Dept Clin Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Emanuel, EJ (reprint author), NIH, Dept Clin Bioeth, Ctr Clin, Bldg 10 Room 1C118, Bethesda, MD 20892 USA. EM eemanuel@nih.gov NR 24 TC 16 Z9 16 U1 0 U2 1 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 MAY 16 PY 2007 VL 297 IS 19 BP 2131 EP 2133 DI 10.1001/jama.297.19.2131 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 167UG UT WOS:000246477400026 PM 17507349 ER PT J AU Comin, MJ Agbaria, R Ben-Kasus, T Huleihel, M Liao, CZ Sun, GY Nicklaus, MC Deschamps, JR Parrish, DA Marquez, VE AF Comin, Maria J. Agbaria, Riad Ben-Kasus, Tsipi Huleihel, Mahmoud Liao, Chenzhong Sun, Guangyu Nicklaus, Marc C. Deschamps, Jeffrey R. Parrish, Damon A. Marquez, Victor E. TI Sculpting the bicyclo[3.1.0]hexane template of carbocyclic nucleosides to improve recognition by herpes thymidine kinase SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ACCURATE DOCKING; SUGAR; DISCRIMINATE; ANALOGS; GLIDE AB The replacement of the furanose ring by a cyclopentane in nucleosides generates a group of analogues known generically as carbocyclic nucleosides. These compounds have increased chemical and enzymatic stability due to the absence of a true glycosyl bond that characterizes conventional nucleosides. The additional fusion of a cyclopropane ring to the cyclopentane produces a bicyclo[3.1.0]hexane system that depending on its location relative to the nucleobase is able to lock the embedded cyclopentane ring into conformations that mimic the typical north and south conformations of the furanose ring in conventional nucleosides. These bicyclo[3.1.0]hexane templates have already provided important clues to differentiate the contrasting conformational preferences between kinases and polymerases. Herein, we describe the design, synthesis, and phosphorylation pattern of a new bicyclo[3.1.0]hexane thymidine analogue that seems to possess an ideal spatial distribution of pharmacophores for an optimal interaction with herpes simplex 1 thymidine kinase. The bicyclo[3.1.0]hexane template represents a privileged rigid template for sculpting other carbocyclic nucleosides to meet the demands of specific receptors. C1 Natl Canc Inst, Med Chem Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. Ben Gurion Univ Negev, Fac Hlth Sci, Dept Clin Pharmacol, IL-84105 Beer Sheva, Israel. Ben Gurion Univ Negev, Fac Hlth Sci, Natl Inst Biotechnol, IL-84105 Beer Sheva, Israel. Ben Gurion Univ Negev, Fac Hlth Sci, Dept Virol, IL-84105 Beer Sheva, Israel. USN, Res Lab, Washington, DC 20375 USA. RP Marquez, VE (reprint author), Natl Canc Inst, Med Chem Lab, Ctr Canc Res, 376 Boyles St, Ft Detrick, MD 21702 USA. EM marquezv@dc37a.nci.nih.gov RI Nicklaus, Marc/N-4183-2014; OI Deschamps, Jeffrey/0000-0001-5845-0010; Nicklaus, Marc/0000-0002-4775-7030 FU Intramural NIH HHS; NIDA NIH HHS [DA6002-01] NR 20 TC 15 Z9 15 U1 0 U2 4 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 MAY 16 PY 2007 VL 129 IS 19 BP 6216 EP 6222 DI 10.1021/ja0688732 PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA 166XU UT WOS:000246415100035 PM 17451242 ER PT J AU Hashibe, M Brennan, P Benhamou, S Castellsague, X Chu, C Curado, MP Dal Maso, L Dauct, AW Fabianova, E Wunsch, V Franceschi, S Hayes, RB Herrero, R Koifman, S La Vecchia, C Lazarus, P Levi, F Mates, D Matos, E Menezes, A Muscat, J Eluf, J Olshan, AF Rudnai, P Schwartz, SM Smith, E Sturgis, EM Szeszenia-Dabrowska, N Talamini, R Wei, QY Winn, DM Zaridze, D Zatonski, W Zhang, ZF Berthiller, J Boffetta, P AF Hashibe, Mia Brennan, Paul Benhamou, Simone Castellsague, Xavier Chu Chen Paula Curado, Maria Dal Maso, Luigino Dauct, Alexander W. Fabianova, Eleonora Wunsch-Filho, Victor Franceschi, Silvia Hayes, Richard B. Herrero, Rolando Koifman, Sergio La Vecchia, Carlo Lazarus, Philip Levi, Fabio Mates, Dana Matos, Elena Menezes, Ana Muscat, Joshua Eluf-Neto, Jose Olshan, Andrew F. Rudnai, Peter Schwartz, Stephen M. Smith, Elaine Sturgis, Erich M. Szeszenia-Dabrowska, Neonilia Talamini, Renato Wei, Qingyi Winn, Deborah M. Zaridze, David Zatonski, Witold Zhang, Zuo-Feng Berthiller, Julien Boffetta, Paolo TI Alcohol drinking in never users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: Pooled analysis in the international head and neck cancer epidemiology consortium SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID UPPER AERODIGESTIVE TRACT; SQUAMOUS-CELL CARCINOMAS; HUMAN-PAPILLOMAVIRUS INFECTION; ORAL-CANCER; PHARYNGEAL CANCER; LARYNX; POLYMORPHISMS; CONSUMPTION; CAVITY; DIET AB Background At least 75% of head and neck cancers are attributable to a combination of cigarette smoking and alcohol drinking. A precise understanding of the independent association of each of these factors in the absence of the other with the risk of head and neck cancer is needed to elucidate mechanisms of head and neck carcinogenesis and to assess the efficacy of interventions aimed at controlling either risk factor. Methods We examined the extent to which head and neck cancer is associated with cigarette smoking among never drinkers and with alcohol drinking among never users of tobacco. We pooled individual-level data from 15 case-control studies that included 10244 head and neck cancer case subjects and 15227 control subjects, of whom 1072 case subjects and 5775 control subjects were never users of tobacco and 1598 case subjects and 4051 control subjects were never drinkers of alcohol. Odds ratios (ORs) and 95% confidence intervals (Cls) were estimated using unconditional logistic regression models. All statistical tests were two-sided. Results Among never drinkers, cigarette smoking was associated with an increased risk of head and neck cancer (OR for ever versus never smoking = 2.13, 95% Cl = 1.52 to 2.98), and there were clear dose-response relationships for the frequency, duration, and number of pack-years of cigarette smoking. Approximately 24% (95% Cl = 16% to 31%) of head and neck cancer cases among nondrinkers in this study would have been prevented if these individuals had not smoked cigarettes. Among never users of tobacco, alcohol consumption was associated with an increased risk of head and neck cancer only when alcohol was consumed at high frequency (OR for three or more drinks per day versus never drinking = 2.04, 95% Cl = 1.29 to 3.21). The association with high-frequency alcohol intake was limited to cancers of the oropharynx/hypopharynx and larynx. Conclusions Our results represent the most precise estimates available of the independent association of each of the two main risk factors of head and neck cancer, and they exemplify the strengths of large-scale consortia in cancer epidemiology. C1 Int Agcy Res Canc, Geneenvironm Epidemiol Grp, F-69008 Lyon, France. INSERM U794, Evry, France. Inst Catala Oncol, Barcelona, Spain. Fred Hutchinson Canc Res Ctr, Seattle, WA USA. Hosp Araujo Jorge, Goiania, Go, Brazil. Aviano Canc Ctr, Aviano, Italy. Hosp Clin Porto Alegre, Porto Alegre, RS, Brazil. Specialized State Hlth Inst, Banska Bystrica, Slovakia. Univ Sao Paulo, BR-05508 Sao Paulo, Brazil. NCI, Bethesda, MD 20892 USA. Inst Invest Epidemiol, San Jose, Costa Rica. Escola Nacl Saude Publica, Rio De Janeiro, Brazil. Ist Ric Farmacol Mario Negri, Milan, Italy. Univ Milan, Milan, Italy. Penn State Coll Med, Hershey, PA USA. Univ Lausanne, Inst Med Sociale & Prevent, Lausanne, Switzerland. RP Hashibe, M (reprint author), Int Agcy Res Canc, Geneenvironm Epidemiol Grp, 150 Cours Albert Thomas, F-69008 Lyon, France. EM hashibe@iarc.fr RI Wunsch Filho, Victor/C-4475-2012; Eluf-Neto, Jose/B-2522-2009; Szeszenia-Dabrowska, Neonila/F-7190-2010; Castellsague Pique, Xavier/N-5795-2014; Benhamou, Simone/K-6554-2015; Curado, Maria Paula/M-6200-2013; OI Hayes, Richard/0000-0002-0918-661X; Eluf-Neto, Jose/0000-0001-7504-2115; Castellsague Pique, Xavier/0000-0002-0802-3595; Curado, Maria Paula/0000-0001-8172-2483; mates, dana/0000-0002-6219-9807; dal maso, luigino/0000-0001-6163-200X; La Vecchia, Carlo/0000-0003-1441-897X FU FIC NIH HHS [TW01500]; NCI NIH HHS [K07CA104231, P01CA068384, P50CA90388, R01CA048896, R01CA100264, R01CA61188, R03CA113157, R03CA77954, T32CA09142, U01CA96134]; NIDA NIH HHS [R01DA11386]; NIDCR NIH HHS [R01DE012609, R01DE11979, R01DE13110]; NIEHS NIH HHS [P30ES010126, R01ES11740, R21ES011667] NR 45 TC 372 Z9 384 U1 4 U2 52 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 MAY 16 PY 2007 VL 99 IS 10 BP 777 EP 789 DI 10.1093/jnci/djk179 PG 13 WC Oncology SC Oncology GA 170VJ UT WOS:000246694000009 PM 17505073 ER PT J AU Lee, JE Hunter, DJ Spiegelman, D Adami, HO Albanes, D Bernstein, L van den Brandt, PA Buring, JE Cho, EY Folsom, AR Freudenheim, JL Giovannucci, E Graham, S Horn-Ross, PL Leitzmann, MF McCullough, ML Miller, AB Parker, AS Rodriguez, C Rohan, TE Schatzkin, A Schouten, LJ Virtanen, M Willett, WC Wolk, A Zhang, SM Smith-Warner, SA AF Lee, Jung Eun Hunter, David J. Spiegelman, Donna Adami, Hans-Olov Albanes, Demetrius Bernstein, Leslie van den Brandt, Piet A. Buring, Julie E. Cho, Eunyoung Folsom, Aaron R. Freudenheim, Jo L. Giovannucci, Edward Graham, Saxon Horn-Ross, Pamela L. Leitzmann, Michael F. McCullough, Marjorie L. Miller, Anthony B. Parker, Alexander S. Rodriguez, Carmen Rohan, Thomas E. Schatzkin, Arthur Schouten, Leo J. Virtanen, Mikko Willett, Walter C. Wolk, Alicja Zhang, Shumin M. Smith-Warner, Stephanie A. TI Alcohol intake and renal cell cancer in a pooled analysis of 12 prospective studies SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID LOGISTIC-REGRESSION MODELS; FOOD FREQUENCY QUESTIONNAIRE; MEASUREMENT ERROR-CORRECTION; COVARIANCE STRUCTURE MODELS; POPULATION-BASED COHORT; DIETARY ASSESSMENT; RISK-FACTORS; INSULIN SENSITIVITY; DIABETES-MELLITUS; COLORECTAL-CANCER AB Background The association between alcohol intake and risk of renal cell cancer has been inconsistent in case-control studies. An inverse association between alcohol intake and risk of renal cell cancer has been suggested in a few prospective studies, but each of these studies included a small number of cases. Methods We performed a pooled analysis of 12 prospective studies that included 530469 women and 229575 men with maximum follow-up times of 7-20 years. All participants had completed a validated food-frequency questionnaire at baseline. Using the primary data from each study, the study-specific relative risks (RRs) for renal cell cancer were calculated using Cox proportional hazards models and then pooled using a random-effects model. All statistical tests were two-sided. Results A total of 1430 (711 women and 719 men) cases of incident renal cell cancer were identified. The study-standardized incidence rates of renal cell cancer were 23 per 100000 person-years among nondrinkers and 15 per 100000 person-years among those who drank 15 g/day or more of alcohol. Compared with non-drinking, alcohol consumption (>= 15 g/day, equivalent to slightly more than one alcoholic drink per day) was associated with a decreased risk of renal cell cancer (pooled multivariable RR = 0.72, 95% confidence interval = 0.60 to 0.86; P-trend <.001); statistically significant inverse trends with increasing intake were seen in both women and men. No difference by sex was observed (P-heterogeneity = .89). Associations between alcohol intake and renal cell cancer were not statistically different across alcoholic beverage type (beer versus wine versus liquor) (P = .40). Conclusion Moderate alcohol consumption was associated with a lower risk of renal cell cancer among both women and men in this pooled analysis. C1 Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. Karolinska Inst, Dept Med Epidemiol & Biostat, Div Nutr Epidemiol, Natl Inst Environm Med, Stockholm, Sweden. NCI, Div Canc Epidemiol & Genet, Dept Hlth & Hlth Serv, NIH, Bethesda, MD USA. Univ So Calif, Dept Prevent Med, Los Angeles, CA USA. Univ So Calif, Norriss Comprehens Canc Ctr, Los Angeles, CA USA. Maastricht Univ, Dept Epidemiol, Nutr & Toxicol Res Inst, Maastricht, Netherlands. Univ Minnesota, Sch Publ Hlth, Dept Epidemiol & Community Hlth, Minneapolis, MN USA. SUNY Buffalo, Dept Social & Prevent Med, Buffalo, NY 14260 USA. No Calif Canc Ctr, Fremont, CA USA. Amer Canc Soc, Epidemiol & Surveillance Res, Atlanta, GA USA. Univ Toronto, Dept Publ Hlth Sci, Toronto, ON, Canada. Mayo Clin, Coll Med, Dept Urol, Jacksonville, FL USA. Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. Natl Publ Hlth Inst, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland. RP Lee, JE (reprint author), Brigham & Womens Hosp, Channing Lab, Dept Med, 75 Francis St, Boston, MA 02115 USA. EM jung.lee@channing.harvard.edu RI Schouten, Leo/G-3713-2012; Albanes, Demetrius/B-9749-2015 FU NCI NIH HHS [CA55075, R01 CA077398] NR 78 TC 51 Z9 51 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAY 16 PY 2007 VL 99 IS 10 BP 801 EP 810 DI 10.1093/jnci/djk181 PG 10 WC Oncology SC Oncology GA 170VJ UT WOS:000246694000011 PM 17505075 ER PT J AU Boyce-Rustay, JM Cameron, HA Holmes, A AF Boyce-Rustay, Janel M. Cameron, Heather A. Holmes, Andrew TI Chronic swim stress alters sensitivity to acute behavioral effects of ethanol in mice SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE ethanol; stress; drinking; anxiety; sedation; mouse; hypothermia; ataxia; forced swim; depression; alcohol; pentobarbital ID VOLUNTARY ALCOHOL INTAKE; DRUG-USE DISORDERS; GABA(A) RECEPTOR; SOCIAL STRESS; RESTRAINT STRESS; FAMILY-HISTORY; A RECEPTOR; RAT LINES; SUBUNIT; CONSUMPTION AB Epidemiological data support a strong link between stress, stress-related disorders and risk for alcoholism. However, precisely how stress might impact sensitivity to the intoxicating effects of ethanol or the willingness to voluntary consume ethanol remains unclear. The present study assessed the effects of daily exposure to forced swim stress on subsequent sensitivity to the sedative/hypnotic, hypothermic, ataxic (measured using accelerating rotarod), and anxiolytic-like (measured using elevated plus-maze) effects of ethanol, and ethanol consumption and preference in a two-bottle choice paradigm, in male C57BL/6J mice. Stress effects on the sedative/hypnotic effects of the barbiturate pentobarbital were also tested. Results showed that chronic (fourteen days) but not acute (one or three days) swim stress significantly potentiated the sedative/hypnotic and hypothermic effects of 4 g/kg, but not 3 g/kg, ethanol. The sedative/bypnotic effects of pentobarbital were attenuated by chronic swim stress. Irrespective of chronicity, swim stress did not alter the ataxic or anxiolytic-like effects of ethanol, or alter ethanol self-administration either during or after stress. These data provide further evidence that stress alters the intoxicating effects of high doses of ethanol in a behaviorally selective manner. Published by Elsevier Inc. C1 NIMH, Unit Neuroplast Mood & Anxiety & Disorders Progra, Bethesda, MD 20892 USA. RP Boyce-Rustay, JM (reprint author), Abbott Labs, R4N5,AP9A,L018,100 Abbott Pk Rd, Abbott Pk, IL 60064 USA. EM janel.boyce-rustay@abbott.com RI Cameron, Heather/E-6221-2011 OI Cameron, Heather/0000-0002-3245-5777 FU NIAAA NIH HHS [Z01-AA000411]; NIMH NIH HHS [Z01-MH002784] NR 72 TC 36 Z9 37 U1 4 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD MAY 16 PY 2007 VL 91 IS 1 BP 77 EP 86 DI 10.1016/j.physbeh.2007.01.024 PG 10 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 171NT UT WOS:000246743400011 PM 17363014 ER PT J AU Sulima, A Folk, J Jacobson, AE Rice, KC AF Sulima, Agnieszka Folk, John Jacobson, Arthur E. Rice, Kenner C. TI A new approach to the synthesis of the nonpeptide NOP receptor antagonist J-113397 SO SYNTHESIS-STUTTGART LA English DT Article DE NOP antagonist; receptor; synthesis; enantiomeric resolution; beta-enaminoester reduction ID KAPPA-OPIOID RECEPTOR; NOCICEPTIN/ORPHANIN FQ; ORL1 RECEPTOR; CDNA CLONING; GENE FAMILY; ORPHANIN-FQ; POTENT; MEMBER; IDENTIFICATION; DISCOVERY AB A new synthesis that eliminates the need for chromatographic separation in order to obtain multigram quantities of J-113397, a competitive antagonist of the N/OFQ-NOP receptor system, is reported. N-Benzyl protected 4-oxopiperidinecarboxylate was used as the starting material to obtain an N-benzyl intermediate that could be resolved at a relatively early stage in the synthesis. The crucial step in the synthesis was reduction of the double bond of the beta-enaminoester functionality of 1-benzyl-4-(3-ethyl-2-oxo-2,3-dihydrobenzoimidazol-1-yl)-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester, since Pd/C reduction gave inseparable mixtures. It could be reduced and epimerized to the desired trans diastereoisomer in a one-pot reaction by treatment with magnesium metal in methanol. C1 NIH, Natl Inst Drug Abuse, Chem Biol Res Branch, Drug Design & Synthesis Sect,Dept Hlth & Human S, Bethesda, MD 20892 USA. RP Rice, KC (reprint author), NIH, Natl Inst Drug Abuse, Chem Biol Res Branch, Drug Design & Synthesis Sect,Dept Hlth & Human S, Bldg 10, Bethesda, MD 20892 USA. EM kr21f@nih.gov NR 30 TC 5 Z9 5 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0039-7881 J9 SYNTHESIS-STUTTGART JI Synthesis PD MAY 16 PY 2007 IS 10 BP 1547 EP 1553 DI 10.1055/s-2007-966037 PG 7 WC Chemistry, Organic SC Chemistry GA 176OV UT WOS:000247095700020 ER PT J AU Qian, F Wu, YM Muratova, O Zhou, H Dobrescu, G Duggan, P Lynn, L Song, GH Zhang, YL Reiter, K MacDonald, N Narum, DL Long, CA Miller, LH Saul, A Mullen, GED AF Qian, Feng Wu, Yimin Muratova, Olga Zhou, Hong Dobrescu, Gelu Duggan, Peter Lynn, Lambert Song, Guanhong Zhang, Yanling Reiter, Karine MacDonald, Nicholas Narum, David L. Long, Carole A. Miller, Louis H. Saul, Allan Mullen, Gregory E. D. TI Conjugating recombinant proteins to Pseudomonas aeruginosa ExoProtein A: A strategy for enhancing immunogenicity of malaria vaccine candidates SO VACCINE LA English DT Article DE malaria; Pseudomonas aeruginosa ExoProtein A; AMA1; Pfs25 ID PLASMODIUM-FALCIPARUM MALARIA; APICAL MEMBRANE ANTIGEN-1; INFLUENZAE TYPE-B; TRANSMISSION-BLOCKING VACCINE; MEROZOITE SURFACE PROTEIN-1; ANTIBODY-RESPONSES; ESCHERICHIA-COLI; PICHIA-PASTORIS; CLINICAL-TRIAL; IN-VITRO AB Conjugation of polysaccharides to carrier proteins has been a successful approach for producing safe and effective vaccines. In an attempt to increase the immunogenicity of two malarial vaccine candidate proteins of Plasmodium falciparum, apical membrane antigen I (AMA1) to a blood stage vaccine candidate and surface protein 25 (Pfs25) a mosquito stage vaccine candidate, were each independently chemically conjugated to the mutant, nontoxic Pseudomonas aeruginosa ExoProtein A (rEPA). AMA1 is a large (66 kD) relatively good immunogen in mice; Pfs25 is a poorly immunogenic protein when presented on alum to mice. Mice were immunized on days 0 and 28 with AMA1- or Pfs25-rEPA conjugates or unconjugated AMA1 or Pfs25, all formulated on Alhydrogel. Remarkably, sera from mice 14 days after the second immunization with Pfs25-rEPA conjugates displayed over a 1000-fold higher antibody titers as compared to unconjugated Pfs25. In contrast, AMA1 conjugated under the same conditions induced only a three-fold increase in antibody titers. When tested for functional activity, antibodies elicited by the AMA1-rEPA inhibited invasion of erythrocytes by blood-stage parasites and antibodies elicited by the Pfs25-rEPA conjugates blocked the development of the sexual stage parasites in the mosquito midgut. These results demonstrate that conjugation to rEPA induces a marked improvement in the antibody titer in mice for the poor immunogen (Pfs25) and for the larger protein (AMA1). These conjugates now need to be tested in humans to determine if mice are predictive of the response in humans. Published by Elsevier Ltd. C1 NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD 20852 USA. RP Mullen, GED (reprint author), Kings Coll London, Div Imaging Sci, 5th Floor Thomas Guy House,Guys Hosp Campus,St Th, London SE1 9RT, England. EM gregory.mullen@kcl.ac.uk RI Saul, Allan/I-6968-2013 OI Saul, Allan/0000-0003-0665-4091 FU Intramural NIH HHS [, NIH0012094647]; PHS HHS [NIH0012094647] NR 44 TC 42 Z9 47 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 MAY 16 PY 2007 VL 25 IS 20 BP 3923 EP 3933 DI 10.1016/j.vaccine.2007.02.073 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 172WT UT WOS:000246835900001 PM 17428587 ER PT J AU Catanzaro, AT Roederer, M Koup, RA Bailer, RT Enama, ME Nason, MC Martin, JE Rucker, S Andrews, CA Gomez, PL Mascola, JR Nabel, GJ Graham, BS AF Catanzaro, Andrew T. Roederer, Mario Koup, Richard A. Bailer, Robert T. Enama, Mary E. Nason, Martha C. Martin, Julie E. Rucker, Steve Andrews, Charla A. Gomez, Phillip L. Mascola, John R. Nabel, Gary J. Graham, Barney S. TI Phase I clinical evaluation of a six-plasmid multiclade HIV-1 DNA candidate vaccine SO VACCINE LA English DT Article DE promoter; T cell response; AIDS; prevention; envelope; Gag; Pol; Nef ID MEMORY T-CELLS; IMMUNOGENICITY EVALUATION; VIRUS; IMMUNITY; HUMANS; IMMUNIZATION; INDUCTION; MONKEYS; VECTOR; SAFETY AB Needle-free delivery of a six-plasmid HIV-1 DNA vaccine encoding EnvA, EnvB, EnvC, and subtype B Gag, Pol, and Nef underwent open-label evaluation in 15 subjects; 14 completed the 0, 1, 2 month vaccination schedule. T cell responses to HIV-specific peptide pools were detected by intracellular cytokine staining of CD4(+) [13/14 (93%)] and CD8(+) [5/14 (36%)], and by ELISpot in 11/14 (79%). Ten of 14 (71%) had ELISA antibody responses to Env proteins. Compared to a four-plasmid product, Gag- and Nef-specific T cell responses were improved, while Env-specific responses were maintained. This candidate vaccine has now advanced to Phase II evaluation. Published by Elsevier Ltd. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Graham, BS (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,MSC 3017,Bldg 40,Rm 2502, Bethesda, MD 20892 USA. EM bgraham@nih.gov RI Roederer, Mario/G-1887-2011 FU Intramural NIH HHS NR 17 TC 105 Z9 108 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 MAY 16 PY 2007 VL 25 IS 20 BP 4085 EP 4092 DI 10.1016/j.vaccine.2007.02.050 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 172WT UT WOS:000246835900019 PM 17391815 ER PT J AU Taylor, HA Penman, AD Han, H Dele-Michael, A Skelton, TN Fox, ER Benjamin, EJ Arnett, DK Mosley, TH AF Taylor, Herman A. Penman, Alan D. Han, Hui Dele-Michael, Abiola Skelton, Thomas N. Fox, Ervin R. Benjamin, Emelia J. Arnett, Donna K. Mosley, Thomas H., Jr. TI Left ventricular architecture and survival in African-Americans free of coronary heart disease (from the atherosclerosis risk in communities [ARIC] study) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID ESSENTIAL-HYPERTENSION; GEOMETRIC PATTERNS; PROGNOSTIC VALUE; WALL THICKNESS; MASS; HYPERTROPHY; ECHOCARDIOGRAPHY AB Published studies of the prognostic value of left ventricular (LV) hypertrophy and LV geometric pattern in African-Americans were based on referred or hospitalized patients with hypertension or coronary heart disease. All-cause mortality rates and survival associated with LV geometric pattern were determined using echocardiography in a population-based sample of middle-aged and elderly African-American men and women. During the third (1993 to 1995) visit of the ARIC Study, echocardiography was performed at the Jackson, Mississippi, field center on the cohort of 2,445 African-Americans aged 49 to 75 years. M-Mode LV echocardiographic measurements were available for 1,722 persons. Mortality data were available through December 31, 2003. During the follow-up period (median 8.8 years, maximum 10.4), 160 deaths were identified. In men, multivariable-adjusted hazard ratios for all-cause mortality (compared with men with normal LV geometry) were 1.75 (95% confidence interval [CI] 0.71 to 4.33) in those with concentric LV hypertrophy, 0.38 (95% CI 0.08 to 1.88) in those with eccentric LV hypertrophy, and 0.79 (95% CI 0.41 to 1.54) in those with concentric remodeling. In women, multivariable7adjusted hazard ratios for all-cause mortality (compared with women with normal LV geometry) were 1.17 (95% CI 0.48 to 2.84) in those with concentric LV hypertrophy, 1.23 (95% CI 0.46 to 3.28) in those with eccentric LV hypertrophy, and 1.17 (95% CI 0.60 to 2.28) in those with concentric remodeling. In conclusion, in this population-based cohort of middle-aged and elderly African-Americans free of coronary heart disease, adjustment for baseline differences in cardiovascular disease risk factors and LV mass greatly attenuated the strength of the association between LV pattern and all-cause mortality risk in women. In men, an association between concentric LV hypertrophy and mortality risk remained. (c) 2007 Elsevier Inc. All rights reserved. C1 Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. Univ Rochester, Med Ctr, Rochester, NY 14627 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Univ Alabama, Birmingham, AL USA. RP Penman, AD (reprint author), Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. EM apenman@medicine.umsmed.edu OI Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [N01 HC095171, N01 HC 55015, N01 HC 55016, N01 HC 55018, N01 HC 55019, N01 HC 55020, N01 HC 55021, N01 HC 55022, N01 HC 95171, N01 HC 95172, N01 HC 97570, N01HC55015, N01HC55016, N01HC55018, N01HC55019, N01HC55020, N01HC55021, N01HC55022, N01HC95170, N01HC95171, N01HC95172] NR 24 TC 31 Z9 31 U1 0 U2 2 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAY 15 PY 2007 VL 99 IS 10 BP 1413 EP 1420 DI 10.1016/j.amjcard.2006.12.065 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 171DU UT WOS:000246715900014 PM 17493471 ER PT J AU Domanski, M Coady, S Fleg, J Tian, X Sachdev, V AF Domanski, Michael Coady, Sean Fleg, Jerome Tian, Xin Sachdev, Vandana TI Effect of statin therapy on survival in patients with nonischemic dilated cardiomyopathy (from the beta blocker evaluation of survival trial [BEST]) SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID HEART-FAILURE AB To determine whether statin therapy improves survival in patients with heart failure (HF) secondary to nonischemic dilated cardiomyopathy (non-IDC), data from 1,024 patients with non-IDC (New York Heart Association functional class III and IV HF) and left ventricular ejection fraction <= 0.35 who were enrolled in the BEST were analyzed. The association of statin therapy at the initial screening visit with all-cause and cardiovascular mortality was evaluated using multivariate Cox proportional hazards models. After adjusting for age, gender, race, systolic blood pressure, total cholesterol, New York Heart Association functional class IV, estimated glomerular filtration rate, current cigarette smoking, left ventricular ejection fraction, angiotensin-converting enzyme inhibitor use, antiplatelet therapy, diabetes mellitus, treatment group (beta blocker or placebo), and hypertension, statin use was independently associated with decreased all-cause mortality (hazard ratio 0.38, confidence interval 0.18 to 0.82, p = 0.0134) and also with decreased cardiovascular death (hazard ratio 0.42, confidence interval 0.18 to 0.95, p = 0.037). In conclusion, in patients with moderate or severe BF due to non-IDC entered into BEST, statin therapy at entry was independently associated with a decrease in all-cause and cardiovascular mortality. (c) 2007 Elsevier Inc. All rights reserved. C1 NHLBI, Atherothrombosis & Coronary Artery Dis Branch, Div Cardiovasc Dis, Bethesda, MD 20892 USA. NHLBI, Div Epidemiol & Populat Sci, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. NHLBI, Cardiol Branch, Bethesda, MD 20892 USA. RP Domanski, M (reprint author), NHLBI, Atherothrombosis & Coronary Artery Dis Branch, Div Cardiovasc Dis, Bldg 10, Bethesda, MD 20892 USA. EM domasnkm@nih.gov NR 7 TC 19 Z9 19 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD MAY 15 PY 2007 VL 99 IS 10 BP 1448 EP 1450 DI 10.1016/j.amjcard.2006.12.080 PG 3 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 171DU UT WOS:000246715900020 PM 17493477 ER PT J AU Ruhl, CE Everhart, JE AF Ruhl, Constance E. Everhart, James E. TI Risk factors for inguinal hernia among adults in the US population SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE adult; hernia; inguinal; prospective studies; risk factors; United States ID SMOKING AB The authors examined risk factors for incident inguinal hernia among US adults (5,316 men and 8,136 women) participating in the First National Health and Nutrition Examination Survey (1971-1975) who were followed through 1992-1993 for a hospital (International Classification of Diseases, Ninth Revision, Clinical Modification, code 550) or physician diagnosis of inguinal hernia. Ninety-six percent of the baseline cohort was recontacted, with a median follow-up of 18.2 years (range, 0.02-22.1 years). Because the cumulative incidence of inguinal hernia was higher among men (13.9%) than among women (2.1%), more detailed analyses were conducted in men. Among men in multivariate analysis, a higher incidence (p < 0.05) of inguinal hernia was associated with an age of 40-59 years (hazard ratio (HR) = 2.2, 95% confidence interval (CI): 1.7, 2.8), an age of 60-74 years (HR = 2.8, 95% CI: 2.2, 3.6), and hiatal hernia (HR = 1.8, 95% CI: 1.2, 2.7), while Black race (HR = 0.58, 95% CI: 0.42, 0.79), being overweight (HR = 0.79, 95% CI: 0.66, 0.95), and obesity (HR = 0.51, 95% CI: 0.36, 0.71) were associated with a lower incidence. Among women, older age, rural residence, greater height, chronic cough, and umbilical hernia were associated with inguinal hernia. In the United States, inguinal hernias are common among men, especially with aging. The lower risk among heavier men was unexpected and bears further study. C1 Social & Sci Syst Inc, Silver Spring, MD 20910 USA. NIDDKD, Bethesda, MD 20892 USA. RP Ruhl, CE (reprint author), Social & Sci Syst Inc, 8757 Georgia Ave,12th Floor, Silver Spring, MD 20910 USA. EM cruhl@s-3.com FU NIDDK NIH HHS [N01-DK-1-2478] NR 21 TC 70 Z9 70 U1 1 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 MAY 15 PY 2007 VL 165 IS 10 BP 1154 EP 1161 DI 10.1093/aje/kwm011 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 162WK UT WOS:000246120000008 PM 17374852 ER PT J AU Toro, JR Pautler, SE Stewart, L Glenn, GM Weinreich, M Toure, O Wei, MH Schmidt, LS Davis, L Zbar, B Choyke, P Steinberg, SM Nguyen, DM Linehan, WM AF Toro, Jorge R. Pautler, Stephen E. Stewart, Laveta Glenn, Gladys M. Weinreich, Michael Toure, Ousmane Wei, Ming-Hui Schmidt, Laura S. Davis, Lewis Zbar, Berton Choyke, Peter Steinberg, Seth M. Nguyen, Dao M. Linehan, W. Marston TI Lung cysts, spontaneous pneumothorax, and genetic associations in 89 families with Birt-Hogg-Dube syndrome SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE Birt-Hogg-Dube syndrome; familial spontaneous pneumothorax; lung cysts; fibrofolliculomas; renal neoplasms ID BHD GENE; KIDNEY NEOPLASIA; INHERITANCE; MUTATIONS; FIBROSIS; TUMORS; RISK AB Rationale: Birt-Hogg-Dube syndrome (BHDS) is an autosomal, dominantly inherited genodermatosis that predisposes to fibrofolliculomas, kidney neoplasms, lung cysts, and spontaneous pneumothorax. Objectives: We evaluated 198 patients from 89 families with BHDS to characterize the risk factors for pneumothorax and genotype-pulmonary associations. Methods: Helical computed tomography scans of the chest were used to screen for pulmonary abnormalities. BHD mutation data were used for genotype-pulmonary associations. We examined the relationship of pneumothorax with categorical parameters (sex, smoking history, and lung cysts) and continuous parameters (number of cysts, lung cyst volume, and largest Cyst diameter and volume). Logistic regression analyses were used to identify the risk factors associated with pneumothorax. Measurements and Main Results: Twenty-four percent (48/198) of patients with BHDS had a history of pneumothorax. The presence of lung cysts was significantly associated with pneumothorax (p = 0.006). Total lung cyst volume, largest cyst diameter and volume, and every parameter related to the number of lung cysts were significantly associated (p < 0.0001) with pneumothorax. A logistic regression analysis showed that only the total number of cysts in the right parenchymal lower lobe and the total number of cysts located on the pleural surface in the right middle lobe were needed to classify a patient as to whether or not he or she was likely to have a pneumothorax. Exon location of the BHD mutation was associated with the numbers of cysts (p = 0.0002). Conclusions: This study indicates that patients with BHDS have a significant association between lung cysts and spontaneous pneumothorax. C1 NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. SAIC Frederick Inc, Basic Res Program, NCI Frederick, Frederick, MD USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. NCI, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Toro, JR (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Execut Plaza S,Room 7012, Rockville, MD 20892 USA. EM torojo@exchange.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 35 TC 112 Z9 113 U1 0 U2 2 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD MAY 15 PY 2007 VL 175 IS 10 BP 1044 EP 1053 DI 10.1164/rccm.200610-1483OC PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 168BL UT WOS:000246497100011 PM 17322109 ER PT J AU Moaddel, R Calleri, E Massolini, G Frazier, CR Wainer, IW AF Moaddel, Ruin Calleri, Enrica Massolini, Gabriella Frazier, Chester R. Wainer, Irving W. TI The synthesis and initial characterization of an immobilized purinergic receptor (P2Y(1)) liquid chromatography stationary phase for online screening SO ANALYTICAL BIOCHEMISTRY LA English DT Editorial Material ID PROTEIN-COUPLED RECEPTOR; ANTAGONISTS C1 NIA, Ctr Gerontol Res, NIH, Baltimore, MD 21224 USA. Univ Pavia, Dipartimento Chim Farmaceut, I-27100 Pavia, Italy. RP Moaddel, R (reprint author), NIA, Ctr Gerontol Res, NIH, Baltimore, MD 21224 USA. EM moaddelru@grc.nia.nih.gov OI CALLERI, ENRICA/0000-0002-4246-460X FU Intramural NIH HHS [Z99 AG999999] NR 14 TC 23 Z9 23 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAY 15 PY 2007 VL 364 IS 2 BP 216 EP 218 DI 10.1016/j.ab.2007.02.014 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 160RQ UT WOS:000245960400016 PM 17391632 ER PT J AU Xu, XM Carlson, BA Irons, R Mix, H Zhong, NX Gladyshev, VN Hatfield, DL AF Xu, Xue-Ming Carlson, Bradley A. Irons, Robert Mix, Heiko Zhong, Nianxin Gladyshev, Vadim N. Hatfield, Dolph L. TI Selenophosphate synthetase 2 is essential for selenoprotein biosynthesis SO BIOCHEMICAL JOURNAL LA English DT Article DE RNA interference; selenocysteine; selenocysteine synthesis; selenoprotein; selenoprotein synthesis; selenophosphate synthetase ID SYNTHETASE 2 SPS2; ESCHERICHIA-COLI; TRANSFER-RNA; SELENOCYSTEINE; EUKARYOTES; IDENTIFICATION; EXPRESSION; MACHINERY; MECHANISM; ARCHAEA AB Selenophosphate synthetase (SelD) generates the selenium donor for selenocysteine biosynthesis in eubacteria. One homologue of SelD in eukaryotes is SPS1 (selenophosphate synthetase 1) and a second one, SPS2, was identified as a selenoprotein in mammals. Earlier in vitro studies showed SPS2, but not SPS1, synthesized selenophosphate from selenide, whereas SPS1 may utilize a different substrate. The roles of these enzymes in selenoprotein synthesis in vivo remain unknown. To address their function in vivo, we knocked down SPS2 in NIH3T3 cells using small interfering RNA and found that selenoprotein biosynthesis was severely impaired, whereas knockdown of SPS1 had no effect. Transfection of SPS2 into SPS2 knockdown cells restored selenoprotein biosynthesis, but SPS1 did not, indicating that SPS1 cannot complement SPS2 function. These in vivo studies indicate that SPS2 is essential for generating the selenium donor for selenocysteine biosynthesis in mammals, whereas SPS1 probably has a more specialized, non-essential role in selenoprotein metabolism. C1 Natl Canc Inst, Mol Biol Selenium Sect, Lab Canc Prevent, NIH, Bethesda, MD 20892 USA. Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. RP Hatfield, DL (reprint author), Natl Canc Inst, Mol Biol Selenium Sect, Lab Canc Prevent, NIH, Bethesda, MD 20892 USA. EM hatfield@mail.nih.gov RI Gladyshev, Vadim/A-9894-2013 FU NIGMS NIH HHS [GM061603, GM065204, R01 GM061603, R01 GM065204, R37 GM065204] NR 21 TC 79 Z9 81 U1 2 U2 5 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD MAY 15 PY 2007 VL 404 BP 115 EP 120 DI 10.1042/BJ20070165 PN 1 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 168TQ UT WOS:000246547300013 PM 17346238 ER PT J AU Nissley, DV Radzio, J Ambrose, Z Sheen, CW Hamamouch, N Moore, KL Tachedjian, G Sluis-Cremer, N AF Nissley, Dwight V. Radzio, Jessica Ambrose, Zandrea Sheen, Chih-Wei Hamamouch, Noureddine Moore, Katie L. Tachedjian, Gilda Sluis-Cremer, Nicolas TI Characterization of novel non-nucleoside reverse transcriptase (RT) inhibitor resistance mutations at residues 132 and 135 in the 51 kDa subunit of HIV-1 RT SO BIOCHEMICAL JOURNAL LA English DT Article DE chimaeric Ty 1/HIV-1 reverse transcriptase phenotypic assay; HIV-1; non-nucleoside reverse transcriptase inhibitor; resistance; reverse transcriptase ID IMMUNODEFICIENCY-VIRUS TYPE-1; IN-VITRO SELECTION; HIGHLY RESISTANT; DRUG-RESISTANCE; AMINO-ACID; PURIFICATION; VARIANTS; GW678248; THERAPY; ISOLATE AB Several rare and novel NNRTI [non-nucleoside reverse transcriptase (RT) inhibitor] resistance mutations were recently detected at codons 132 and 135 in RTs from clinical isolates using the yeast-based chimaeric TyHRT (Ty1/HIV-1 RT) phenotypic assay. Ile(132) and Ile(135) form part of the beta 7-beta 8 loop of HIV-1 RT (residues 132-140). To elucidate the contribution of these residues in RT structure-function and drug resistance, we constructed twelve recombinant enzymes harbouring mutations at codons 132 and 135-140. Several of the mutant enzymes exhibited reduced DNA polymerase activities. Using the yeast two-hybrid assay for HIV-1 RT dimerization we show that in some instances this decrease in enzyme activity could be attributed to the mutations, in the context of the 5 1 kDa subunit of HIV-1 RT, disrupting the subunit-subunit interactions of the enzyme. Drug resistance analyses using purified RT, the TyHRT assay and antiviral assays demonstrated that the I132M mutation conferred high-level resistance (> 10-fold) to nevirapine and delavirdine and low-level resistance (similar to 2-3-fold) to efavirenz. The I135A and I135M mutations also conferred low level NNRTI resistance (similar to 2-fold). Subunit selective mutagenesis studies again demonstrated that resistance was conferred via the p51 subunit of HIV-1RT. Taken together, our results highlight a specific role of residues 132 and 135 in NNRTI resistance and a general role for residues in the beta 7-beta 8 loop in the stability of HIV-1RT. C1 Univ Pittsburgh, Sch Med, Dept Med, Div Infect Dis, Pittsburgh, PA 15261 USA. NCI Frederick, Gene Regulat & Chromosome Biol Lab, Ft Detrick, MD 21702 USA. SAIC Frederick Inc, Basic Res Program, Ft Detrick, MD 21702 USA. Natl Canc Inst, HIV Drug Resistance Program, Ft Detrick, MD 21702 USA. Macfarlane Burnet Inst Med Res & Publ Hlth, Mol Interact Grp, Melbourne, Vic 3004, Australia. Monash Univ, Dept Microbiol, Melbourne, Vic 3168, Australia. RP Sluis-Cremer, N (reprint author), Univ Pittsburgh, Sch Med, Dept Med, Div Infect Dis, Pittsburgh, PA 15261 USA. EM cremern@dom.pitt.edu OI Tachedjian, Gilda/0000-0002-7733-7037 FU NCI NIH HHS [N01-CO-12400, N01CO12400]; NIGMS NIH HHS [R01 GM068406-01, R01 GM068406] NR 31 TC 19 Z9 19 U1 1 U2 2 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD MAY 15 PY 2007 VL 404 BP 151 EP 157 DI 10.1042/BJ20061814 PN 1 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 168TQ UT WOS:000246547300017 PM 17286555 ER PT J AU Li, LP Liang, Y Bass, RL AF Li, Leping Liang, Yu Bass, Robert L. TI GAPWM: a genetic algorithm method for optimizing a position weight matrix SO BIOINFORMATICS LA English DT Article ID FACTOR-BINDING-SITES; EMBRYONIC STEM-CELLS; REGULATORY ELEMENTS; DNA; IDENTIFICATION; GENOME; DISCOVERY; SEQUENCES; REPRESENTATION; MODELS AB Motivation: Position weight matrices (PMWs) are simple models commonly used in motif-finding algorithms to identify short functional elements, such as cis-regulatory motifs, on genes. When few experimentally verified motifs are available, estimation of the PWM may be poor. The resultant PW`M may not reliably discriminate a true motif from a false one. While experimentally identifying such motifs remains time-consuming and expensive, low-resolution binding data from techniques such as ChIP-on-chip and ChlP-PET have become available. We propose a novel but simple method to improve a poorly estimated PWM using ChIP data. Methodology: Starting from an existing PWM, a set of ChIP sequences, and a set of background sequences, our method, GAPWM, derives an improved PWM via a genetic algorithm that maximizes the area under the receiver operating characteristic (ROG) curve. GAPWM can easily incorporate prior information such as base conservation. We tested our method on two PMWs (Oct4/Sox2 and p53) using three recently published ChIP data sets (human Oct4, mouse Oct4 and human p53). Results: GAPWM substantially increased the sensitivity/specificity of a poorly estimated PWM and further improved the quality of a good PWM. Furthermore, it still functioned when the starting PWM contained a major error. The ROG performance of GAPWM compared favorably with that of MEME and others. With increasing availability of ChlP data, our method provides an alternative for obtaining high-quality PWMs for genome-wide identification of transcription factor binding sites. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. NIEHS, Computat Biol Fac, Res Triangle Pk, NC 27709 USA. RP Li, LP (reprint author), NIEHS, Biostat Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM li3@niehs.nih.gov FU Intramural NIH HHS NR 33 TC 20 Z9 21 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD MAY 15 PY 2007 VL 23 IS 10 BP 1188 EP 1194 DI 10.1093/bioinformatics/btm080 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 180FQ UT WOS:000247348300002 PM 17341493 ER PT J AU DeRosse, P Hodgkinson, CA Lencz, T Burdick, KE Kane, JM Goldman, D Malhotra, AK AF DeRosse, Pamela Hodgkinson, Colin A. Lencz, Todd Burdick, Katherine E. Kane, John M. Goldman, David Malhotra, Anil K. TI Disrupted in schizophrenia 1 genotype and positive symptoms in schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Article DE DISC1; haplotype; schizophrenia; SNP ID HIPPOCAMPAL; DISC1; ASSOCIATION AB Background: Converging evidence has demonstrated an association between the Disrupted in Schizophrenia 1 (DISC1) gene and Schizophrenia (SZ). Within the DISC1 gene, a single nucleotide polymorphism (SNP), Ser704Cys, has been associated with the structure and function of the hippocampus. Because positive symptoms in SZ have also been associated with hippocampal structure and function, we hypothesized that variation in a DISC1 haplotype containing Ser704Cys would be significantly associated with positive symptomatology in SZ. Methods: We tested for an association between variation in a haplotype block within the DISC1 gene containing Ser704Cys and lifetime history of positive symptoms in 199 Caucasian patients with SZ. Results: We detected significant associations between a DISC1 haplotype containing Ser704Cys and Ser704Cys genotype and lifetime severity of delusions in SZ. Conclusions: These data suggest that that the effect of DISC1 genetic variation might be associated with positive symptoms in patients with SZ. C1 N Shore Long Isl Jewish Hlth Syst, Zucker Hillside Hosp, Dept Psychiat Res, Glen Oaks, NY 11004 USA. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. RP DeRosse, P (reprint author), N Shore Long Isl Jewish Hlth Syst, Zucker Hillside Hosp, Dept Psychiat Res, 75-59 263rd St, Glen Oaks, NY 11004 USA. EM pderosse@lij.edu RI Burdick, Katherine/G-6124-2012; Goldman, David/F-9772-2010; Lencz, Todd/J-3418-2014 OI Goldman, David/0000-0002-1724-5405; Lencz, Todd/0000-0001-8586-338X FU Intramural NIH HHS; NIMH NIH HHS [MH001760] NR 13 TC 50 Z9 53 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAY 15 PY 2007 VL 61 IS 10 BP 1208 EP 1210 DI 10.1016/j.biopsych.2006.07.023 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 165VV UT WOS:000246335100015 PM 17054920 ER PT J AU Zeng, R Spolski, R Casas, E Zhu, W Levy, DE Leonard, WJ AF Zeng, Rong Spolski, Rosanne Casas, Esther Zhu, Wei Levy, David E. Leonard, Warren J. TI The molecular basis of IL-21-mediated proliferation SO BLOOD LA English DT Article ID ALPHA CHAIN EXPRESSION; RECEPTOR-BETA CHAIN; COMMON GAMMA-CHAIN; T-CELL-ACTIVATION; NK CELLS; B-CELLS; IMMUNODEFICIENCY DISEASES; SIGNAL-TRANSDUCTION; INNATE IMMUNITY; IL-21 RECEPTOR AB Interleukin-21 (IL-21) is a type I cytokine that modulates functions of T, B, natural killer (NK), and myeloid cells. The IL-21 receptor (IL-21 R) is closely related to the IL-2 receptor beta chain and is capable of transducing signals through its dimerization with the common cytokine receptor gamma chain (gamma(c)), the protein whose expression is defective in humans with X-linked severe combined immunodeficiency. To clarity the molecular basis of IL-21 actions, we investigated the role of tyrosine residues in the IL-21R cytoplasmic domain. Simultaneous mutation of all 6 tyrosines greatly diminished IL-21-mediated proliferation, whereas retention of tyrosine 510 (Y510) allowed full proliferation. Y510 efficiently mediated IL-21-induced phosphorylation of Stat1 and Stat3, but not of Stat5, and CD8(+) T cells from Stat1/Stat3 double knock-out mice exhibited decreased proliferation in response to IL-21 + IL-15. In addition, IL-21 weakly induced phosphorylation of Shc and Akt, and consistent with this, specific inhibitors of the MAPK and PI3K pathways inhibited IL-21-mediated proliferation. Collectively, these data indicate the involvement of the Jak-STAT, MAPK, and PI3K pathways in IL-21 signaling. C1 NHLBI, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. NYU, Sch Med, Dept Pathol, New York, NY 10003 USA. NYU, Sch Med, Dept Microbiol, New York, NY 10003 USA. RP Leonard, WJ (reprint author), NHLBI, Lab Mol Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM wjl@helix.nih.gov OI Levy, David/0000-0002-7320-7788 FU Intramural NIH HHS; NIAID NIH HHS [AI28900, R01 AI028900] NR 56 TC 136 Z9 149 U1 1 U2 8 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 MAY 15 PY 2007 VL 109 IS 10 BP 4135 EP 4142 DI 10.1182/blood-2006-10-054973 PG 8 WC Hematology SC Hematology GA 169RJ UT WOS:000246609100013 PM 17234735 ER PT J AU Biancotto, A Grivel, JC Iglehart, SJ Vanpouille, C Lisco, A Sieg, SF Debernardo, R Garate, K Rodriguez, B Margolis, LB Lederman, MM AF Biancotto, Angelique Grivel, Jean-Charles Iglehart, Sarah J. Vanpouille, Christophe Lisco, Andrea Sieg, Scott F. Debernardo, Robert Garate, Kristen Rodriguez, Benigno Margolis, Leonid B. Lederman, Michael M. TI Abnormal activation and cytokine spectra in lymph nodes of people chronically infected with HIV-1 SO BLOOD LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CD4(+) T-CELLS; IMMUNE ACTIVATION; PREDICTIVE-VALUE; ANTIRETROVIRAL THERAPY; VIRAL LOAD; RNA LEVEL; TISSUE; LYMPHOCYTES; DISEASE AB There is growing recognition that HIV-1 infection leads to an activation of the immune system that includes perturbations of cytokine expression, redistribution of lymphocyte subpopulations, cell dysfunction, and cell death. Here, we explored the relationships between HIV-1 infection and immune activation in chronically HIV-1-infected human lymph nodes. In addition to CD4 T-cell depletion, we found increased effector T-cell frequencies associated with profound up-regulation of an activation marker CD38 in naive, central memory, and effector CD4(+) and CD8(+) T cells. Likewise, Fas death receptor (CD95) was more frequently detectable on T cells from HIV-1 nodes. Dendritic cell (DC) depletion was dramatic, with plasmacytoid DCs (PDCs) 40-fold and myeloid DCs (MDCs) 20-fold less frequent in HIV+ nodes than in control nodes. Cytokine dysregulation was evident, with IL-2 and IL-15 as much as 2 or 3 logs greater in infected nodes than in control nodes. Thus, activated effector cells are inappropriately attracted and/or retained in lymphoid tissue in chronic HIV-1 infection. High-level cytokine expression in turn activates and retains more cells at these sites, leading to lymphadenopathy and massive bystander activation that characterizes HIV-1 infection. Strategies targeting these activation pathways may lead to new therapies. C1 NICHHD, Lab Cellular & Mol Biol, NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Univ Case Med Ctr, Ctr AIDS Res, Cleveland, OH 44106 USA. RP Margolis, LB (reprint author), NICHHD, Lab Cellular & Mol Biol, NIH, Bldg 10,Rm 9D58, Bethesda, MD 20892 USA. EM margolis@helix.nih.gov RI Rodriguez, Benigno/C-3365-2009 OI Rodriguez, Benigno/0000-0001-9736-7957 FU Intramural NIH HHS; NIAID NIH HHS [AI 36219, P30 AI036219] NR 56 TC 130 Z9 135 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAY 15 PY 2007 VL 109 IS 10 BP 4272 EP 4279 DI 10.1182/blood-2006-11-055764 PG 8 WC Hematology SC Hematology GA 169RJ UT WOS:000246609100033 PM 17289812 ER PT J AU Yao, Z Kanno, Y Kerenyi, M Stephens, G Durant, L Watford, WT Laurence, A Robinson, GW Shevach, EM Moriggl, R Hennighausen, L Wu, CY O'Shea, JJ AF Yao, Zhengju Kanno, Yuka Kerenyi, Marc Stephens, Geoffrey Durant, Lydia Watford, Wendy T. Laurence, Arian Robinson, Gertraud W. Shevach, Ethan M. Moriggl, Richard Hennighausen, Lothar Wu, Changyou O'Shea, John J. TI Nonredundant roles for Stat5a/b in directly regulating Foxp3 SO BLOOD LA English DT Article ID TRANSCRIPTION FACTOR FOXP3; IMMUNOLOGICAL SELF-TOLERANCE; T-CELL HOMEOSTASIS; LYMPHOID DEVELOPMENT; LETHAL AUTOIMMUNITY; NEONATAL THYMECTOMY; GENE-EXPRESSION; CUTTING EDGE; IN-VITRO; IL-2 AB Stats (signal transducers and activators of transcription) regulate multiple aspects of T-cell fate. T regulatory (Treg) cells are a critical subset that limits immune responses, but the relative importance of Stat5a/b versus Stat3 for Treg cell development has been contentious. We observed that peripheral CD25(+)CD4(+) T cells were reduced in StatS(Delta N) mice; however, the levels of Foxp3, a transcription factor that is critical for Treg cells, were normal in splenic CD4(+) T cells even though they were reduced in the thymus. In contrast, complete deletion of Stat5a/b (Stat5(-/-)) resulted in dramatic reduction in CD25- or Foxp3-expressing CD4(+) T cells. An intrinsic requirement was demonstrated by reduction of Stat5a/b in CD4-expressing cells and by stem cell transplantation using Stat5(-/-) fetal liver cells. Stat5a/b were also required for optimal induction of Foxp3 in vitro and bound directly to the Foxp3 gene. Reduction of Stat3 in T cells did not reduce the numbers of Treg cells in the thymus or spleen; however, Stat3 was required for IL-6-dependent down-regulation of Foxp3. Therefore, we conclude that Stat5a/b have an essential, nonredundant role in regulating Treg cells, and that Stat3 and Stat5a/b appear to have opposing roles in the regulation of Foxp3. C1 NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. Ludwig Boltzmann Inst Canc Res, Vienna, Austria. Med Univ Vienna, Dept Med Biochem, Max F Perutz Labs, Vienna, Austria. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Wu, CY (reprint author), NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bldg 10,Rm 9N262,10 Ctr Dr,MSC-1820, Bethesda, MD 20892 USA. EM changyou_wu@yahoo.com; osheajo@mail.nih.gov RI Laurence, Arian/A-8770-2009; Robinson, Gertraud/I-2136-2012; Kanno, Yuka/B-5802-2013; OI Laurence, Arian/0000-0003-0942-8292; Moriggl, Richard/0000-0003-0918-9463 FU Intramural NIH HHS NR 46 TC 298 Z9 309 U1 0 U2 10 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 MAY 15 PY 2007 VL 109 IS 10 BP 4368 EP 4375 DI 10.1182/blood-2006-11-055756 PG 8 WC Hematology SC Hematology GA 169RJ UT WOS:000246609100045 PM 17227828 ER PT J AU Alter, BR Rosenberg, PS AF Alter, Blanche R. Rosenberg, Philip S. TI Granulocyte colony-stimulating factor and severe aplastic anemia SO BLOOD LA English DT Letter ID MYELODYSPLASTIC SYNDROME; G-CSF; LEUKEMIA; EVOLUTION; CHILDREN; THERAPY C1 NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Alter, BR (reprint author), NCI, Clin Genet Branch, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room EPS 70209, Bethesda, MD 20892 USA. EM alterb@mail.nih.gov NR 6 TC 3 Z9 3 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 MAY 15 PY 2007 VL 109 IS 10 BP 4589 EP 4589 DI 10.1182/blood-2007-01-068866 PG 1 WC Hematology SC Hematology GA 169RJ UT WOS:000246609100072 PM 17483301 ER PT J AU Rodrigues, J Agrawal, N Sharma, A Malhotra, P Adak, T Chauhan, VS Bhatnagar, RK AF Rodrigues, Janneth Agrawal, Neema Sharma, Anil Malhotra, Pawan Adak, Tridibes Chauhan, Virander S. Bhatnagar, Raj K. TI Transcriptional analysis of an immune-responsive serine protease from Indian malarial vector, Anopheles culicifacies SO BMC MOLECULAR BIOLOGY LA English DT Article ID PLASMODIUM-CYNOMOLGI B; MOLECULAR CHARACTERIZATION; GENOMIC ORGANIZATION; REFRACTORY STRAIN; SEPHADEX BEADS; DEFENSIN GENE; AEDES-AEGYPTI; GAMBIAE; MOSQUITO; MELANIZATION AB Background: The main vector for transmission of malaria in India is the Anopheles culicifacies mosquito species, a naturally selected subgroup of which is completely refractory (R) to transmission of the malaria parasite, Plasmodium vivax; Results: Here, we report the molecular characterization of a serine protease (acsp30)-encoding gene from A. culicifacies, which was expressed in high abundance in the refractory strain compared to the susceptible (S) strain. The transcriptional upregulation of acsp30 upon Plasmodium challenge in the refractory strain coincided with ookinete invasion of mosquito midgut. Gene organization and primary sequence of acsp30 were identical in the R and S strains suggesting a divergent regulatory status of acsp30 in these strains. To examine this further, the upstream regulatory sequences of acsp30 were isolated, cloned and evaluated for the presence of promoter activity. The 702 bp upstream region of acsp30 from the two strains revealed sequence divergence. The promoter activity measured by luciferase- based reporter assay was shown to be 1.5-fold higher in the R strain than in the S. Gel shift experiments demonstrated a differential recruitment of nuclear proteins to upstream sequences of acsp30 as well as a difference in the composition of nuclear proteins in the two strains, both of which might contribute to the relative abundance of acsp30 in the R strain; Conclusion: The specific upregulation of acsp30 in the R strain only in response to Plasmodium infection is suggestive of its role in contributing the refractory phenotype to the A. culicifacies mosquito population. C1 Int Ctr Genet Engn & Biotechnol, Insect Resistance Grp, New Delhi 110067, India. ICGEB, Malaria Grp, New Delhi 67, India. Natl Inst Malaria Res 2, New Delhi 110009, India. NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. RP Bhatnagar, RK (reprint author), Int Ctr Genet Engn & Biotechnol, Insect Resistance Grp, POB 10504, New Delhi 110067, India. EM rodriguesj@niaid.nih.gov; neema@icgeb.res.in; anil.mrc@gmail.com; pawan@icgeb.res.in; adak.mrc@gmail.com; virander@icgeb.res.in; raj@icgeb.res.in RI Adak, Tridibes/C-2501-2011; OI Sharma, Anil/0000-0003-2264-2007 NR 46 TC 10 Z9 11 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2199 J9 BMC MOL BIOL JI BMC Mol. Biol. PD MAY 15 PY 2007 VL 8 AR 33 DI 10.1186/1471-2199-8-33 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 170XP UT WOS:000246699800001 PM 17502004 ER PT J AU Vikis, H Sato, M James, M Wang, DL Wang, Y Wang, M Jia, DM Liu, Y Bailey-Wilson, JE Amos, CI Pinney, SM Petersen, GM de Andrade, M Yang, P Wiest, JS Fain, PR Schwartz, AG Gazdar, A Gaba, C Rothschild, H Mandal, D Kupert, E Seminara, D Viswanathan, A Govindan, R Minna, J Anderson, MW You, M AF Vikis, Haris Sato, Mitsuo James, Michael Wang, Daolong Wang, Yian Wang, Min Jia, Dongmei Liu, Yan Bailey-Wilson, Joan E. Amos, Christopher I. Pinney, Susan M. Petersen, Gloria M. de Andrade, Mariza Yang, Ping Wiest, Jonathan S. Fain, Pamela R. Schwartz, Ann G. Gazdar, Adi Gaba, Colette Rothschild, Henry Mandal, Diptasri Kupert, Elena Seminara, Daniela Viswanathan, Avinash Govindan, Ramaswamy Minna, John Anderson, Marshall W. You, Ming TI EGFR-T790M is a rare lung cancer susceptibility allele with enhanced kinase activity SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-RECEPTOR; EGF RECEPTOR; ACQUIRED-RESISTANCE; GEFITINIB; MUTATIONS; INHIBITORS; GENE; SENSITIVITY; EXPRESSION; ERLOTINIB AB The use of tyrosine kinase inhibitors (TKI) has yielded great success in treatment of lung adenocarcinomas. However, patients who develop resistance to TKI treatment often acquire a somatic resistance mutation (T790M) located in the catalytic cleft of the epidermal growth factor receptor (EGFR) enzyme. Recently, a report describing EGFR-T790M as a germ-fine mutation suggested that this mutation may be associated with inherited susceptibility to lung cancer. Contrary to previous reports, our analysis indicates that the T790M mutation confers increased Y992 and Y1068 phosphorylation levels. In a human bronchial epithelial cell line, overexpression of EGFR-T790M displayed a growth advantage over wild-type (WT) EGFR. We also screened 237 lung cancer family probands, in addition to 45 bronchoalveolar tumors, and found that none of them contained the EGFR-T790M mutation. Our observations show that EGFR-T790M provides a proliferative advantage with respect to WT EGFR and suggest that the enhanced kinase activity of this mutant is the basis for rare cases of inherited susceptibility to lung cancer. C1 Washington Univ, Dept Surg, St Louis, MO 63110 USA. Univ Texas, SW Med Ctr, Dallas, TX 75230 USA. NHGRI, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Cincinnati, Cincinnati, OH USA. Mayo Clin, Coll Med, Rochester, MN USA. NCI, Rockville, MD USA. Univ Colorado, Denver, CO 80202 USA. Karmanos Canc Inst, Detroit, MI USA. Med Univ Ohio, Toledo, OH USA. Louisiana State Univ, Hlth Sci Ctr, New Orleans, LA USA. RP You, M (reprint author), Washington Univ, Dept Surg, 660 Euclid Ave,Box 8109, St Louis, MO 63110 USA. EM youm@wustl.edu RI Sato, MITSUO/I-7280-2014; OI Bailey-Wilson, Joan/0000-0002-9153-2920 FU Intramural NIH HHS [ZIA BC010448-09]; NCI NIH HHS [R01CA099147, P50 CA070907, P50CA70907, R01 CA058554, R01 CA080127, R01 CA093643, R01 CA099147, R01 CA099187, R01CA058554, R01CA093643, R01CA099187, R01CA80127, R03 CA077118, U01 CA076293, U01CA76293]; NHGRI NIH HHS [N01HG65404]; NIEHS NIH HHS [P30 ES006096, P30ES06096, R01 ES012063, R01 ES013340, R01ES012063, R01ES013340] NR 23 TC 56 Z9 57 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2007 VL 67 IS 10 BP 4665 EP 4670 DI 10.1158/0008-5472.CAN-07-0217 PG 6 WC Oncology SC Oncology GA 172BG UT WOS:000246778500014 PM 17510392 ER PT J AU Bai, RK Leal, SM Covarrubias, D Liu, A Wong, LJC AF Bai, Ren-Kui Leal, Suzanne M. Covarrubias, Daniel Liu, Aiyi Wong, Lee-Jun C. TI Mitochondrial genetic background modifies breast cancer risk SO CANCER RESEARCH LA English DT Article ID HEREDITARY OPTIC NEUROPATHY; DNA G10398A POLYMORPHISM; WOLFRAM DIDMOAD SYNDROME; AFRICAN-AMERICAN WOMEN; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; REGION SEQUENCES; MTDNA; MUTATIONS; HAPLOGROUPS AB Inefficient mitochondrial electron transport chain (ETC) function has been implicated in the vicious cycle of reactive oxygen species (ROS) production that may predispose an individual to late onset diseases, such as diabetes, hypertension, and cancer. Mitochondrial DNA (mtDNA) variations may affect the efficiency of ETC and ROS production, thus contributing to cancer risk. To test this hypothesis, we genotyped 69 mtDNA variations in 156 unrelated European-American females with familial breast cancer and 260 age-matched European-American female controls. Fisher's exact test was done for each single-nucleotide polymorphism (SNP)/haplogroup and the P values were adjusted for multiple testing using permutation. Odds ratio (OR) and its 95% confidence interval (95% CI) were calculated using the Sheehe correction. Among the 69 variations, 29 were detected in the study subjects. Three SNPs, G9055A (OR, 3.03; 95% CI, 1.63-5.63; P = 0.0004, adjusted P = 0.0057), A10398G (OR, 1.79; 95% CI, 1.14-2.81; P = 0.01, adjusted P = 0.19), and T16519C (OR, 1.98; 95% CI, 1.25-3.12; P = 0.0030, adjusted P = 0.0366), were found to increase breast cancer risk, whereas T3197C (OR, 0.31; 95% CI, 0.13-0.75; P = 0.0043, adjusted P = 0.0526) and G13708A (OR, 0.47; 95% CI, 0.24-0.92; P = 0.022, adjusted P = 0.267) were found to decrease breast cancer risk. Overall, individuals classified as haplogroup K show a significant increase in the risk of developing breast cancer (OR, 3.03; 95% CI, 1.63-5.63; P = 0.0004, adjusted P = 0.0057), whereas individuals bearing haplogroup U have a significant decrease in breast cancer risk (OR, 0.37; 95% CI, 0.19-0.73; P = 0.0023, adjusted P = 0.03). Our results suggest that mitochondrial genetic background plays a role in modifying an individual's risk to breast cancer. C1 Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Rice Univ, Dept Stat, Houston, TX 77251 USA. NICHHD, Biometry & Math Stat Branch, NIH, Rockville, MD USA. RP Wong, LJC (reprint author), Baylor Coll Med, Dept Mol & Human Genet, 1 Baylor Plaza,NAB 2015, Houston, TX 77030 USA. EM ljwong@bcm.edu OI Liu, Aiyi/0000-0002-6618-5082 FU NCI NIH HHS [CA87327, CA10023] NR 50 TC 131 Z9 140 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2007 VL 67 IS 10 BP 4687 EP 4694 DI 10.1158/0008-5472.CAN-06-3554 PG 8 WC Oncology SC Oncology GA 172BG UT WOS:000246778500017 PM 17510395 ER PT J AU Wang, SS Cozen, W Cerhan, JR Colt, JS Morton, LM Engels, EA Davis, S Severson, RK Rothman, N Chanock, SJ Hartge, P AF Wang, Sophia S. Cozen, Wendy Cerhan, James R. Colt, Joanne S. Morton, Lindsay M. Engels, Eric A. Davis, Scott Severson, Richard K. Rothman, Nathaniel Chanock, Stephen J. Hartge, Patricia TI Immune mechanisms in non-Hodgkin lymphoma: Joint effects of the TNF G308A and IL10 T3575A polymorphisms with non-Hodgkin lymphoma risk factors SO CANCER RESEARCH LA English DT Article ID EPIDEMIOLOGY CONSORTIUM INTERLYMPH; FRANCISCO BAY AREA; C VIRUS-INFECTION; MALIGNANT-LYMPHOMA; POOLED ANALYSIS; ULTRAVIOLET-RADIATION; GENETIC-VARIATION; MEDICATION USE; CARPET DUST; SPAIN AB Two common single nucleotide polymorphisms in immunoregulatory genes (TAT G308A, rs1800629 and IL10 T3575A, rs1800890) have been recently reported as risk factors for non-Hodgkin lymphoma (NHL) in a large pooled analysis. We systematically investigated the effects of other established NHL risk factors in relation to the tumor necrosis factor (TAW) G308A or interleukin 10 (IL10) T3575A genotypes. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) from 1,172 cases and 982 population-based controls in a U.S. multicenter study. We investigated NHL overall and two common subtypes [diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma]. NHL risks were increased among those with both an autoimmune condition and the TNF G308A GA/AA (ORNHL, 2.1; 95% CI, 1.0-4.2) or the IL10 T3575A TA/AA genotype (ORNHL, 1.6; 95% CI, 0.9-2.6) compared with individuals without an autoimmune condition and with the common TAT G308A GG or IL10 T3575A TT genotype, respectively; results were similar for DLBCL and follicular lymphoma. We found that elevated DLBCL risk associated with last-born status was more pronounced among those with TNF G308A GA/AA (ORDLBCL, 2.7; 95% CI, 1.1-6.4) or IL10 T3575A TA/AA (ORDLBCL, 2.9; 95% Cl, 1.6-5.2). Similarly, elevated DLBCL risk associated with obesity (body mass index, >= 35 versus < 25 kg/m(2)) was observed only among those with TAT G308A GA/AA (ORDLBCL, 2.5; 95% CI, 1.1-5.7) or IL.10 T3575A TA/AA genotypes (ORDLBCL, 2.0; 95% Cl, 1.1-3.5). These exploratory results require replication but provide evidence that autoimmune conditions, late birth order, and obesity act partly through a common inflammatory pathway, posing a greater risk to individuals with variant TNF and IL-10 genotypes than those with wild-type alleles. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Univ So Calif, Los Angeles, CA USA. Mayo Clin & Mayo Fdn, Coll Med, Dept Hlth Sci Res, Rochester, MN 55905 USA. Univ Iowa, Iowa City, IA USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Washington, Seattle, WA 98195 USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Wayne State Univ, Dept Family Med, Detroit, MI USA. NCI, Adv Technol Corp, Core Genotyping Facil, Gaithersburg, MD USA. RP Wang, SS (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS MSC 7234, Bethesda, MD 20892 USA. EM wangso@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-65064, N01-PC-67008, N01-PC-67009, N01-PC-67010, N01-PC-71105] NR 50 TC 52 Z9 54 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 MAY 15 PY 2007 VL 67 IS 10 BP 5042 EP 5054 DI 10.1158/0008-5472.CAN-06-4752 PG 13 WC Oncology SC Oncology GA 172BG UT WOS:000246778500060 PM 17510437 ER PT J AU Malone, KE Doody, DR Hsu, L Ostrander, EA AF Malone, Kathleen E. Doody, David R. Hsu, Li Ostrander, Elaine A. TI How reliable are BRCA1/2 mutation estimates? In response SO CANCER RESEARCH LA English DT Letter ID BREAST-CANCER C1 Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Malone, KE (reprint author), Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. NR 3 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2007 VL 67 IS 10 BP 5057 EP 5058 DI 10.1158/0008-5472.CAN-07-0100 PG 2 WC Oncology SC Oncology GA 172BG UT WOS:000246778500064 ER PT J AU Inoue, S Scott, D Golding, B Leitner, WW AF Inoue, Satoshi Scott, Dorothy Golding, Basil Leitner, Wolfgang W. TI Regulatory B cells inhibit antitumor immunity SO CANCER RESEARCH LA English DT Letter C1 US FDA, Div Hematol, Off Blood Res & Review, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. NCI, Dermatol Branch, NIH, Bethesda, MD 20892 USA. RP Inoue, S (reprint author), US FDA, Div Hematol, Off Blood Res & Review, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. RI Leitner, Wolfgang/F-5741-2011 OI Leitner, Wolfgang/0000-0003-3125-5922 NR 4 TC 0 Z9 2 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAY 15 PY 2007 VL 67 IS 10 BP 5059 EP 5059 DI 10.1158/0008-5472.CAN-06-4780 PG 1 WC Oncology SC Oncology GA 172BG UT WOS:000246778500066 ER PT J AU Caretti, G Lei, EP Sartorelli, V AF Caretti, Giuseppina Lei, Elissa P. Sartorelli, Vittorio TI The DEAD-box p68/p72 proteins and the noncoding RNA steroid receptor activator SRA - Eclectic regulators of disparate biological functions SO CELL CYCLE LA English DT Article DE RNA helicases; noncoding RNA; transcription; nuclear hormone receptors; MyoD; Rm62; epithelial-mesenchymal transition ID NUCLEAR-ORGANIZATION; CHROMATIN INSULATOR; HELICASE P68; EXPRESSION; COACTIVATOR; GENE; PROLIFERATION; BINDING; CELLS; DIFFERENTIATION AB p68 and p72 are RNA-binding proteins endowed with RNA helicase and RNA-protein complex remodeling activities. One of the RNAs associated with p68/p72 is the noncoding Steroid Receptors RNA Activator (SRA). Here we review recent findings on the cellular processes regulated by either p68/p72 alone or in combination with SRA and discuss the transcriptional events influenced by these molecules. C1 NIAMS, Lab Muscle Stem Cells & Gene Regulat, NIH, Bethesda, MD 20892 USA. NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Sartorelli, V (reprint author), NIAMS, Lab Muscle Stem Cells & Gene Regulat, NIH, 50 South Dr, Bethesda, MD 20892 USA. EM sartorev@mail.nih.gov FU Intramural NIH HHS NR 37 TC 26 Z9 27 U1 0 U2 3 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAY 15 PY 2007 VL 6 IS 10 BP 1172 EP 1176 DI 10.4161/cc.6.10.4228 PG 5 WC Cell Biology SC Cell Biology GA 174QF UT WOS:000246956700008 PM 17495528 ER PT J AU de Gramont, A Barbour, L Ross, KE Cohen-Fix, O AF de Gramont, Armand Barbour, Leslie Ross, Karen E. Cohen-Fix, Orna TI The spindle midzone microtubule-associated proteins Ase1p and Cin8p affect the number and orientation of astral microtubules in Saccharomyces cerevisiae SO CELL CYCLE LA English DT Article DE nuclear positioning; cytoplasmic microtubules; Spindle Pole Body; ASE1; CIN8; SPB; SCC1-RRDD; FEAR pathway ID FISSION YEAST; MITOTIC SPINDLE; CHROMOSOME SEGREGATION; DYNAMIC MICROTUBULES; SELF-ORGANIZATION; NUCLEAR DIVISION; CELL-DIVISION; ANAPHASE; ARRAYS; CYTOKINESIS AB The nucleus of the budding yeast S. cerevisiae has to move to the bud neck during mitosis in order for proper DNA segregation to take place. This movement is mediated by spindle and astral microtubules, and it relies on forces generated by microtubule - associated motor proteins. When budding yeast cells express the non - cleavable cohesin subunit, Scc1-RRDD, sister chromatid separation is blocked, preventing the spindle from elongating. Thus, in the presence of Scc1-RRDD nuclear positioning is mediated solely by forces acting through astral microtubules. We have previously shown that under these conditions cells exit mitosis with the nucleus in the mother cells, and that the position of the nucleus is determined, at least in part, by the FEAR pathway, which regulates various aspects of mitotic exit. When the FEAR pathway is inactivated, cells expressing Scc1-RRDD exit mitosis with the nucleus in the daughter cells (referred to as a "daughterly phenotype"). In order to find additional proteins that participate in nuclear positioning, we screened a series of mutant strains for those that displayed a daughterly phenotype when Scc1-RRDD was expressed. The most prominent defects were seen in ase1 Delta and cin8 Delta mutant cells. Both Ase1p and Cin8p were previously shown to be nuclear and to be involved in spindle function. We show here that deletion of ASE1 or CIN8 causes a defect in SPB separation and leads to an abnormal number of astral microtubules and a change in their orientation within the cell. Taken together, these results suggest that in budding yeast Ase1p and Cin8p affect nuclear positioning through astral micro tubule - dependent mechanisms. C1 NIDDKD, NIH, Mol & Cellular Biol Lab, Bethesda, MD 20892 USA. RP Cohen-Fix, O (reprint author), NIDDKD, NIH, Mol & Cellular Biol Lab, 8 Ctr Dr,Bldg 8,Room 319, Bethesda, MD 20892 USA. EM ornacf@helix.nih.gov FU Intramural NIH HHS NR 37 TC 10 Z9 10 U1 0 U2 2 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD MAY 15 PY 2007 VL 6 IS 10 BP 1231 EP 1241 DI 10.4161/cc.6.10.4181 PG 11 WC Cell Biology SC Cell Biology GA 174QF UT WOS:000246956700016 PM 17495529 ER PT J AU Faraday, N Yanek, LR Mathias, R Herrera-Galeano, JE Vaidya, D Moy, TF Fallin, MD Wilson, AF Bray, PF Becker, LC Becker, DM AF Faraday, Nauder Yanek, Lisa R. Mathias, Rasika Herrera-Galeano, J. Enrique Vaidya, Dhananjay Moy, Taryn F. Fallin, M. Daniele Wilson, Alexander F. Bray, Paul F. Becker, Lewis C. Becker, Diane M. TI Heritability of platelet responsiveness to aspirin in activation pathways directly and indirectly related to cyclooxygenase-1 SO CIRCULATION LA English DT Article DE antiplatelet agents; aspirin; genetics; platelets ID CORONARY-ARTERY-DISEASE; LOW-DOSE ASPIRIN; CARDIOVASCULAR-DISEASE; ARACHIDONIC-ACID; MYOCARDIAL-INFARCTION; PRIMARY PREVENTION; CIGARETTE-SMOKING; RESISTANCE; THROMBOXANE; RISK AB Background - The inability of aspirin (acetylsalicylic acid [ASA]) to adequately suppress platelet function is associated with future risk of myocardial infarction, stroke, and cardiovascular death. Genetic variation is a proposed but unproved mechanism for insufficient ASA responsiveness. Methods and Results - We examined platelet ASA responsiveness in 1880 asymptomatic subjects (mean age, 44 +/- 13 years; 58% women) recruited from 309 white and 208 black families with premature coronary heart disease. Ex vivo platelet function was determined before and after ingestion of ASA (81 mg/d for 2 weeks) with the use of a panel of measures that assessed platelet activation in pathways directly and indirectly related to cyclooxygenase-1, the enzyme inhibited by ASA. The proportion of phenotypic variance related to CHD risk factor covariates was determined by multivariable regression. Heritability of phenotypes was determined with the use of variance components models unadjusted and adjusted for covariates. ASA inhibited arachidonic acid - induced aggregation and thromboxane B-2 production by >= 99% (P < 0.0001). Inhibition of urinary thromboxane excretion and platelet activation in pathways indirectly related to cyclooxygenase-1 was less pronounced and more variable (inhibition of 0% to 100%). Measured covariates contributed modestly to variability in ASA response phenotypes (r(2) = 0.001 to 0.133). Phenotypes indirectly related to cyclooxygenase-1 were strongly and consistently heritable across races (h(2) = 0.266 to 0.762; P < 0.01), but direct cyclooxygenase-1 phenotypes were not. Conclusions - Heritable factors contribute prominently to variability in residual platelet function after ASA exposure. These data suggest a genetic basis for the adequacy of platelet suppression by ASA and potentially for differences in the clinical efficacy of ASA. C1 Johns Hopkins Med Inst, Dept Anesthesiol & Crit Care Med, Div Cardiac Surg Intens Care, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Med, Div Gen Internal Med, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Med, Div Cardiol, Baltimore, MD 21205 USA. NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Jefferson Med Coll, Div Hematol, Dept Med, Philadelphia, PA USA. RP Faraday, N (reprint author), Johns Hopkins Univ Hosp, 298 Meyer Bldg,600 N Wolfe St, Baltimore, MD 21287 USA. EM nfaraday@jhmi.edu RI Wilson, Alexander/C-2320-2009; OI Vaidya, Dhananjay/0000-0002-7164-1601 FU Intramural NIH HHS; NCRR NIH HHS [M01-RR000052, RR03655]; NHLBI NIH HHS [HL65229, U01 HL72518] NR 35 TC 86 Z9 91 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAY 15 PY 2007 VL 115 IS 19 BP 2490 EP 2496 DI 10.1161/CIRCULATIONAHA.106.667584 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 167LN UT WOS:000246453300008 PM 17470694 ER PT J AU Koyama, Y Hama, Y Urano, Y Nguyen, DM Choyke, PL Kobayashi, H AF Koyama, Yoshinori Hama, Yukihiro Urano, Yasuteru Nguyen, Dao M. Choyke, Peter L. Kobayashi, Hisataka TI Spectral fluorescence molecular imaging of lung metastases targeting HER2/neu SO CLINICAL CANCER RESEARCH LA English DT Article ID PRIMARY BREAST-CANCER; ANTITUMOR-ACTIVITY; PULMONARY NODULES; ANTIBODY; LOCALIZATION; SURGERY; SITES; CELLS AB Purpose: Surgical resection of pulmonary metastases is now a clinically accepted cancer therapy but its success depends on the accurate localization and removal of all tumor foci. To enhance the detection of pulmonary metastases during surgery, we developed an i.v. administered optical probe that uses a monoclonal antibody, Herceptin (trastuzumab), conjugated to a fluorophore, rhodamine green (RhodG), to specifically detect human epidermal growth factor receptor type 2 (HER2/neu) -expressing pulmonary lesions in an animal model of lung metastases. Experimental Design: Pulmonary metastases were induced by i.v. injection of gene-transfected murine embryonic fibroblasts (3T3) cells in a murine model to produce a mixed population of HER2+ and HER2- tumors. To image these tumors, an anti-HER2 (Herceptin) or a control (HUT) complementarity-determining region-grafted antibody was conjugated to RhodG and injected i.v. into mice. Spectral fluorescence imaging was done after thoracotomy and images were correlated with gross and microscopic pathology to assess sensitivity and specificity. Results: HER2+ tumors injected with Herceptin-RhodG were more fluorescent than either HER2- tumors or HER2+ tumors injected with HUT-RhodG at all time points. The maximal fluorescence signal in HER2+ tumors injected with Herceptin-RhodG was observed at 1 day postinjection. The tumors fluoresced primarily at the rim and not their center, reflecting the binding-site barrier that is commonly seen with high-affinity antibodies. Conclusion: A HER2-targeted optical imaging probe shows the ability to specifically enhance HER2+ pulmonary metastases but not HER2- pulmonary metastases. The high sensitivity and specificity of this probe is encouraging for the development of antigen-targeted optical probes to assist in the resection of pulmonary metastases. C1 NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo, Japan. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Room 1B40,Bldg 10,MSC1088, Bethesda, MD 20892 USA. EM Kobayash@mail.nih.gov RI Urano, Yasuteru/H-1380-2012 FU Intramural NIH HHS NR 14 TC 52 Z9 54 U1 1 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 MAY 15 PY 2007 VL 13 IS 10 BP 2936 EP 2945 DI 10.1158/1078-0432.CCR-06-2240 PG 10 WC Oncology SC Oncology GA 169DJ UT WOS:000246572600017 PM 17504994 ER PT J AU Albert, JM Cao, C Kim, KW Willey, CD Geng, L Xiao, DK Wang, H Sandler, A Johnson, DH Colevas, AD Low, J Rothenberg, ML Lu, B AF Albert, Jeffrey M. Cao, Carolyn Kim, Kwang Woon Willey, Christopher D. Geng, Ling Xiao, Dakai Wang, Hong Sandler, Alan Johnson, David H. Colevas, Alexander D. Low, Jennifer Rothenberg, Mace L. Lu, Bo TI Inhibition of poly (ADP-ribose) polymerase enhances cell death and improves tumor growth delay in irradiated lung cancer models SO CLINICAL CANCER RESEARCH LA English DT Article ID BASE EXCISION-REPAIR; DNA-DAMAGE-RESPONSE; POLY(ADP-RIBOSE) POLYMERASE; IONIZING-RADIATION; FUNCTIONAL INTERACTION; PARP INHIBITORS; STRAND BREAKS; DOMAINS; RADIOSENSITIZATION; RADIOTHERAPY AB Purpose: Poly (ADP-ribose) polymerase-1 (RARP-1) is the founding member of a family of enzymes that catalyze the addition of ADP-ribose units to proteins that mediate DNA repair pathways. Ionizing radiation induces DNA strand breaks, suggesting that PARP-1 inhibition may sensitize tumor cells to radiation. Experimental Design: We investigated the combination of PARP-1 inhibition with radiation in lung cancer models. ABT-888, a novel potent PARP-1 inhibitor, was used to explore the effects of PARP-1 inhibition on irradiated tumors and tumor vasculature. Results: ABT-888 reduced clonogenic survival in H460 lung cancer cells, and inhibited DNA repair as shown by enhanced expression of DNA strand break marker histone gamma-H2AX. Both apoptosis and autophagy contributed to the mechanism of increased cell death. Additionally, ABT-888 increased tumor growth delay at well-tolerated (loses in murine models. For a 5-fold increase in tumor volume, tumor growth delay was 1 day for ABT-888 alone, 7 days for radiation alone, and 13.5 days for combination treatment. Immunohistochemical staining of tumor sections revealed an increase in terminal deoxyribonucleotide transferase-mediated nick-end labeling apoptotic staining, and a decrease in Ki-67 proliferative staining after combination treatment. Matrigel assay showed a decrease in in vitro endothelial tubule formation with ABT-888/radiation combination treatment, and von Willebrand factor staining of tumor sections revealed decreased vessel formation in vivo, suggesting that this strategy may also target tumor angiogenesis. Conclusions: We conclude that PARP-1 inhibition shows promise as an effective means of enhancing tumor sensitivity to radiation, and future clinical studies are needed to determine the potential of ABT-888 as a radiation enhancer. C1 Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Vanderbilt Clin B902,Dept Radiat Oncol, Nashville, TN 37232 USA. NCI, Bethesda, MD 20892 USA. RP Lu, B (reprint author), Vanderbilt Univ, Sch Med, Vanderbilt Ingram Canc Ctr, Vanderbilt Clin B902,Dept Radiat Oncol, 1301 22nd Ave S, Nashville, TN 37232 USA. EM bo.lu@vanderbilt.edu RI Johnson, David/A-7437-2009; lu, bo/G-4573-2010; OI Willey, Christopher/0000-0001-9953-0279 FU NCI NIH HHS [5 U01 CA099177-04] NR 42 TC 167 Z9 177 U1 4 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 MAY 15 PY 2007 VL 13 IS 10 BP 3033 EP 3042 DI 10.1158/1078-0432.CCR-06-2872 PG 10 WC Oncology SC Oncology GA 169DJ UT WOS:000246572600029 PM 17505006 ER PT J AU Stopfer, M AF Stopfer, Mark TI Olfactory processing: Massive convergence onto sparse codes SO CURRENT BIOLOGY LA English DT Editorial Material ID OSCILLATING NEURAL ASSEMBLIES; ODOR REPRESENTATIONS; ANTENNAL LOBE; MUSHROOM BODY; NEURONS; SYSTEM C1 NIH, NICHD, Bethesda, MD 20892 USA. RP Stopfer, M (reprint author), NIH, NICHD, 35 Lincoln Dr,Rm 3A-102,msc 3715, Bethesda, MD 20892 USA. EM stopferm@mail.nih.gov NR 13 TC 9 Z9 9 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD MAY 15 PY 2007 VL 17 IS 10 BP R363 EP R364 DI 10.1016/j.cub.2007.03.019 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 169DM UT WOS:000246572900014 PM 17502089 ER PT J AU Song, N Schwab, KR Patterson, LT Yamaguchi, T Lin, XH Potter, SS Lang, RA AF Song, Ni Schwab, Kristopher R. Patterson, Larry T. Yamaguchi, Terry Lin, Xinhua Potter, Steven S. Lang, Richard A. TI pygopus 2 has a crucial, Wnt pathway-independent function in lens induction SO DEVELOPMENT LA English DT Article DE Pax6; pygopus 2; Wnt; lens induction; mesenchyme; neural crest; mouse ID BETA-CATENIN GENE; ARMADILLO/BETA-CATENIN; MOUSE; PAX6; EYE; PROTEIN; MORPHOGENESIS; ECTODERM; CELLS; MICE AB Drosophila Pygopus was originally identified as a core component of the canonical Wnt signaling pathway and a transcriptional coactivator. Here we have investigated the microophthalmia that arises in mice with a germline null mutation of pygopus 2. We show that this phenotype is a consequence of defective lens development at inductive stages. Using a series of regionally limited Cre recombinase transgenes for conditional deletion of Pygo2(flox), we show that Pygo2 activity in pre-placodal presumptive lens ectoderm, placodal ectoderm and ocular mesenchyme all contribute to lens development. In each case, Pygo2 is required for normal expression levels of the crucial transcription factor Pax6. Finally, we provide multiple lines of evidence that although Pygo2 can function in the Wnt pathway, its activity in lens development is Wnt pathway-independent. C1 Childrens Hosp Res Fdn, Div Pediat Ophthalmol, Cincinnati, OH 45229 USA. Childrens Hosp Res Fdn, Div Dev Biol, Cincinnati, OH 45229 USA. Univ Cincinnati, Dept Ophthalmol, Cincinnati, OH 45229 USA. Univ Cincinnati, Coll Med, Grad Program Mol & Dev Biol, Cincinnati, OH 45229 USA. Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA. Childrens Hosp Res Fdn, Div Nephrol, Cincinnati, OH 45229 USA. NCI, Cell Signaling Vertebrate Dev Sect, Canc & Dev Biol Lab, Frederick, MD 21701 USA. RP Lang, RA (reprint author), Childrens Hosp Res Fdn, Div Pediat Ophthalmol, Cincinnati, OH 45229 USA. EM Richard.Lang@cchmc.org RI Lang, Richard/E-5578-2011 FU NEI NIH HHS [R01 EY015766, R01 EY015766-03, R01 EY14102, R01 EY15766, R01 EY16241, R03 EY14826] NR 62 TC 50 Z9 53 U1 1 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 MAY 15 PY 2007 VL 134 IS 10 BP 1873 EP 1885 DI 10.1242/dev.001495 PG 13 WC Developmental Biology SC Developmental Biology GA 163DK UT WOS:000246138700007 PM 17428831 ER PT J AU Toth, ZE Shahar, T Leker, R Szalayova, I Bratincsak, A Key, S Lonyai, A Nemeth, K Mezey, E AF Toth, Zsuzsanna E. Shahar, Tal Leker, Ronen Szalayova, Ildiko Bratincsak, Andras Key, Sharon Lonyai, Anna Nemeth, Krisztian Mezey, Eva TI Sensitive detection of GFP utilizing tyramide signal amplification to overcome gene silencing SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE hematopoetic stem cell; stem cell transplantation; lineage tracking; green fluorescent protein; immunohistochemistry; cell fate ID GREEN FLUORESCENT PROTEIN; CEREBRAL-ARTERY OCCLUSION; CATALYZED REPORTER DEPOSITION; HEMATOPOIETIC STEM-CELLS; BONE-MARROW-CELLS; IN-VIVO; ES CELLS; MOUSE; MICE; EXPRESSION AB The green fluorescent protein (GFP) is among the most commonly used expression markers in biology. GFP-tagged cells have played a particularly important role in studies of cell lineage. Sensitive detection of GFP is crucially important for such studies to be successful, and problems with detection may account for discrepancies in the literature regarding the possible fate choices of stem cells. Here we describe a very sensitive technique for visualization of GFP. Using it we can detect about 90% of cells of donor origin while we could only see about 50% of these cells when we employ the methods that are in general use in other laboratories. In addition, we provide evidence that some cells permanently silence GFP expression. In the case of the progeny of bone marrow stem cells, it appears that the more distantly related they are to their precursors, the more likely it is that they will turn off the lineage marker. Published by Elsevier Inc. C1 NIDCR, CSDB, NIH, Bethesda, MD 20892 USA. Semmelweis Univ, Neuromorphol Lab, H-1094 Budapest, Hungary. Hungarian Acad Sci, H-1094 Budapest, Hungary. NINDS, NIH, Bethesda, MD 20892 USA. NIMH, NIH, Bethesda, MD 20892 USA. Hebrew Univ Jerusalem, Hadassah Med Ctr, Stroke Serv, Jerusalem, Israel. Hebrew Univ Jerusalem, Hadassah Med Ctr, Cerebrovasc Dis Res Lab, Jerusalem, Israel. Semmelweis Univ, Dept Dermatovenereol & Oncol, H-1085 Budapest, Hungary. RP Mezey, E (reprint author), NIDCR, CSDB, NIH, Bldg 49,Room 5A-76,49 Convent Dr, Bethesda, MD 20892 USA. EM ztoth@mail.nih.gov; mezeye@mail.nih.gov FU Intramural NIH HHS [Z01 NS002996-04] NR 41 TC 16 Z9 16 U1 0 U2 4 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD MAY 15 PY 2007 VL 313 IS 9 BP 1943 EP 1950 DI 10.1016/j.yexcr.2007.02.024 PG 8 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 166AE UT WOS:000246348400018 PM 17428464 ER PT J AU Engblom, D Kornfeld, JW Schwake, L Tronche, F Reimann, A Beug, H Hennighausen, L Moriggl, R Schutz, G AF Engblom, David Kornfeld, Jan-Wilhelm Schwake, Lukas Tronche, Francois Reimann, Andreas Beug, Hartmut Hennighausen, Lothar Moriggl, Richard Schuetz, Guenther TI Direct glucocorticoid receptor-Stat5 interaction in hepatocytes controls body size and maturation-related gene expression SO GENES & DEVELOPMENT LA English DT Article DE somatomedin; liver; Cre-loxP; growth hormone; microarray ID GROWTH-FACTOR-I; DNA-BINDING; LYMPHOID DEVELOPMENT; SIGNAL TRANSDUCER; BONE-GROWTH; STAT5; TRANSCRIPTION; DIFFERENTIATION; REPRESSION; ACTIVATOR AB The glucocorticoid receptor regulates transcription through DNA binding as well as through cross-talk with other transcription factors. In hepatocytes, the glucocorticoid receptor is critical for normal postnatal growth. Using hepatocyte- specific and domain-selective mutations in the mouse we show that Stat5 in hepatocytes is essential for normal postnatal growth and that it mediates the growth- promoting effect of the glucocorticoid receptor through a direct interaction involving the N-terminal tetramerization domain of Stat5b. This interaction mediates a selective and unexpectedly extensive part of the transcriptional actions of these molecules since it controls the expression of gene sets involved in growth and sexual maturation. C1 German Canc Res Ctr, Div Mol Biol Cell 1, D-69120 Heidelberg, Germany. Ludwig Boltzmann Inst Canc Res, A-1090 Vienna, Austria. CNRS, Coll France, UMR 7148, F-75231 Paris, France. CNRS, Dept Dev Biol, Pasteur FRE 2850, F-75014 Paris, France. Inst Mol Pathol, A-1030 Vienna, Austria. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Moriggl, R (reprint author), German Canc Res Ctr, Div Mol Biol Cell 1, D-69120 Heidelberg, Germany. EM richard.moriggl@lbicr.lbg.ac.at; g.schuetz@dkfz-heidelberg.de RI TRONCHE, Francois/F-3895-2011; OI Moriggl, Richard/0000-0003-0918-9463 NR 23 TC 63 Z9 63 U1 0 U2 4 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD MAY 15 PY 2007 VL 21 IS 10 BP 1157 EP 1162 DI 10.1101/gad.426007 PG 6 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 168NR UT WOS:000246531800004 PM 17504935 ER PT J AU Cheung, YN Maag, D Mitchell, SF Fekete, CA Algire, MA Takacs, JE Shirokikh, N Pestova, T Lorsch, JR Hinnebusch, AG AF Cheung, Yuen-Nei Maag, David Mitchell, Sarah F. Fekete, Christie A. Algire, Mikkel A. Takacs, Julie E. Shirokikh, Nikolay Pestova, Tatyana Lorsch, Jon R. Hinnebusch, Alan G. TI Dissociation of eIF1 from the 40S ribosomal subunit is a key step in start codon selection in vivo SO GENES & DEVELOPMENT LA English DT Article DE AUG selection; Saccharomyces cerevisiae; translation initiation; eIF1 ID EUKARYOTIC TRANSLATION INITIATION; YEAST SACCHAROMYCES-CEREVISIAE; C-TERMINAL DOMAIN; MULTIFACTOR COMPLEX; PREINITIATION COMPLEX; SITE SELECTION; ASSAY SYSTEM; RECOGNITION; BINDING; PROTEIN AB Selection of the AUG start codon is a key step in translation initiation requiring hydrolysis of GTP in the eIF2 circle GTP circle Met- tRNA(i) Met ternary complex (TC) and subsequent Pi release from eIF2 circle GDP circle Pi. It is thought that eIF1 prevents recognition of non-AUGs by promoting scanning and blocking Pi release at non-AUG codons. We show that Sui(-) mutations in Saccharomyces cerevisiae eIF1, which increase initiation at UUG codons, reduce interaction of eIF1 with 40S subunits in vitro and in vivo, and both defects are diminished in cells by overexpressing the mutant proteins. Remarkably, Sui-mutation ISQLG(93-97)ASQAA (abbreviated 93-97) accelerates eIF1 dissociation and Pi release from reconstituted preinitiation complexes (PICs), whereas a hyperaccuracy mutation in eIF1A (that suppresses Sui- mutations) decreases the eIF1 off-rate. These findings demonstrate that eIF1 dissociation is a critical step in start codon selection, which is modulated by eIF1A. We also describe Gcd(-) mutations in eIF1 that impair TC loading on 40S subunits or destabilize the multifactor complex containing eIF1, eIF3, eIF5, and TC, showing that eIF1 promotes PIC assembly in vivo beyond its important functions in AUG selection. C1 NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Biophys & Biophys Chem, Baltimore, MD 21205 USA. SUNY Hlth Sci Ctr, Dept Microbiol & Immunol, Brooklyn, NY 11203 USA. RP Lorsch, JR (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. EM jlorsch@jhmi.edu; ahinnebusch@nih.gov OI Shirokikh, Nikolay/0000-0001-8249-358X; Lorsch, Jon/0000-0002-4521-4999 FU Intramural NIH HHS; NIGMS NIH HHS [R01 GM062128, GM59660, GM62128, R01 GM059660] NR 35 TC 84 Z9 85 U1 1 U2 2 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0890-9369 J9 GENE DEV JI Genes Dev. PD MAY 15 PY 2007 VL 21 IS 10 BP 1217 EP 1230 DI 10.1101/gad.1528307 PG 14 WC Cell Biology; Developmental Biology; Genetics & Heredity SC Cell Biology; Developmental Biology; Genetics & Heredity GA 168NR UT WOS:000246531800010 PM 17504939 ER PT J AU Wassif, CA Brownson, KE Sterner, AL Forlino, A Zerfas, PM Wilson, WK Starost, MF Porter, FD AF Wassif, Christopher A. Brownson, Kirstyn E. Sterner, Allison L. Forlino, Antonella Zerfas, Patricia M. Wilson, William K. Starost, Matthew F. Porter, Forbes D. TI HEM dysplasia and ichthyosis are likely laminopathies and not due to 3 beta-hydroxysterol Delta(14)-reductase deficiency SO HUMAN MOLECULAR GENETICS LA English DT Article ID B RECEPTOR GENE; CHOLESTEROL-SYNTHESIS; EXPRESSION; MUTATIONS; STEROLS; MODEL AB Mutations of the lamin B receptor (LBR) have been shown to cause HEM dysplasia in humans and ichthyosis in mice. LBR is a bifunctional protein with both a lamin B binding and a sterol Delta(14)-reductase domain. It previously has been proposed that LBR is the primary sterol Delta(14)-reductase and that HEM dysplasia and ichthyosis are inborn errors of cholesterol synthesis. However, DHCR14 also encodes a sterol Delta(14)-reductase and could provide enzymatic redundancy with respect to cholesterol synthesis. To test the hypothesis that LBR and DHCR14 both function as sterol Delta(14)-reductases, we obtained ichthyosis mice (Lbr(-/-)) and disrupted Dhcr14. Heterozygous Lbr and Dhcr14 mice were intercrossed to test for a digenic phenotype. Lbr(-/-), Dhcr14(Delta 4-7/Delta 4-7) and Lbr(+/-):Dhcr14(Delta 4-7/Delta 4-7) mutant mice have distinct physical and biochemical phenotypes. Dhcr14(Delta 4-7/Delta 4-7) mice are essentially normal, whereas Lbr(+/-):Dhcr14(Delta 4-7/Delta 4-7) mice are growth retarded and neurologically abnormal. Neither of these mutants resembles the ichthyosis mouse and biochemically, no sterol abnormalities were detected in either liver or kidney tissue. In contrast, relatively small transient elevations of Delta(14)-sterols were observed in Lbr(-/-) and Dhcr14(Delta 4-7/Delta 4-7) brain tissue, and marked elevations were seen in Lbr(+/-):Dhcr14(Delta 4-7/Delta 4-7) brain. Pathological evaluation demonstrated vacuolation and swelling of the myelin sheaths in the spinal cord of Lbr(+/-):Dhcr14(Delta 4-7/Delta 4-7) mice consistent with a demyelinating process. This was not observed in either Lbr(-/-) or Dhcr14(Delta 4-7/Delta 4-7) mice. Our data support the conclusions that LBR and DHCR14 provide substantial enzymatic redundancy with respect to cholesterol synthesis and that HEM dysplasia and ichthyosis are laminopathies rather than inborn errors of cholesterol synthesis. C1 NICHD, HDB, DHHS, NIH, Bethesda, MD 20892 USA. Diagnost & Res Serv Branch, OD, DHHS, NIH, Bethesda, MD 20892 USA. Univ Pavia, Sch Med & Pharm, Dept Biochem, I-27100 Pavia, Italy. Rice Univ, Dept Biochem & Cell Biol, Houston, TX 77005 USA. RP Porter, FD (reprint author), NICHD, HDB, DHHS, NIH, Bld 10,Room 9D42 10 Ctr Dr, Bethesda, MD 20892 USA. EM fdporter@mail.nih.gov RI Forlino, Antonella/H-5385-2015; OI Forlino, Antonella/0000-0002-6385-1182; Wassif, Christopher/0000-0002-2524-1420 FU Intramural NIH HHS NR 22 TC 35 Z9 35 U1 0 U2 1 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 MAY 15 PY 2007 VL 16 IS 10 BP 1176 EP 1187 DI 10.1093/hmg/ddm065 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 182VC UT WOS:000247531100005 PM 17403717 ER PT J AU Wang, XT Tomso, DJ Chorley, BN Cho, HY Cheung, VG Kleeberger, SR Bell, DA AF Wang, Xuting Tomso, Daniel J. Chorley, Brian N. Cho, Hye-Youn Cheung, Vivian G. Kleeberger, Steven R. Bell, Douglas A. TI Identification of polymorphic antioxidant response elements in the human genome SO HUMAN MOLECULAR GENETICS LA English DT Article ID HUMAN GENE-EXPRESSION; CONSENSUS SEQUENCE; OXIDATIVE STRESS; OLIGONUCLEOTIDE MICROARRAY; OXIDOREDUCTASE-1 GENE; CONFERRING PROTECTION; MEDIATED EXPRESSION; BASE SUBSTITUTION; PROMOTER; BINDING AB Single nucleotide polymorphisms (SNPs) in transcription factor binding sites (TFBSs) may affect the binding of transcription factors, lead to differences in gene expression and phenotypes and therefore affect susceptibility to environmental exposure. We developed an integrated computational system for discovering functional SNPs in TFBSs in the human genome and predicting their impact on the expression of target genes. In this system, we (i) construct a position weight matrix (PWM) from a collection of experimentally discovered TFBSs; (ii) predict TFBSs in SNP sequences using the PWM and map SNPs to the upstream regions of genes; (iii) examine the evolutionary conservation of putative TFBSs by phylogenetic footprinting; (iv) prioritize candidate SNPs based on microarray expression profiles from tissues in which the transcription factor of interest is either deleted or over-expressed and (v) finally, analyze association of SNP genotypes with gene expression phenotypes. The application of our system has been tested to identify functional polymorphisms in the antioxidant response element (ARE), a cis-acting enhancer sequence found in the promoter region of many genes that encode antioxidant and Phase II detoxification enzymes/proteins. In response to oxidative stress, the transcription factor NRF2 (nuclear factor erythroid-derived 2-like 2) binds to AREs, mediating transcriptional activation of its responsive genes and modulating in vivo defense mechanisms against oxidative damage. Using our novel computational tools, we have identified a set of polymorphic AREs with functional evidence, showing the utility of our system to direct further experimental validation of genomic sequence variations that could be useful for identifying high-risk individuals. C1 NIEHS, Environm Genom Sect, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. Univ Penn, Dept Pediat, Philadelphia, PA 19104 USA. RP Bell, DA (reprint author), NIEHS, Environm Genom Sect, Mol Genet Lab, NIH, Mail Drop C3-03,111 TW Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM bell1@niehs.nih.gov OI Wang, Xuting/0000-0001-6781-8008 FU Intramural NIH HHS [Z01 ES100475-06]; NIEHS NIH HHS [R01 ES015733, R01 ES015733-01]; NIGMS NIH HHS [R01 GM081930, R01 GM081930-08] NR 41 TC 95 Z9 98 U1 0 U2 7 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 MAY 15 PY 2007 VL 16 IS 10 BP 1188 EP 1200 DI 10.1093/hmg/ddm066 PG 13 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 182VC UT WOS:000247531100006 PM 17409198 ER PT J AU Catena, R Muniz-Medina, V Moralejo, B Javierre, B Best, CJM Emmert-Buck, MR Greens, JE Baker, CC Calvo, A AF Catena, Raul Muniz-Medina, Vanessa Moralejo, Beatriz Javierre, Biola Best, Carolyn J. M. Emmert-Buck, Michael R. Greens, Jeffrey E. Baker, Carl C. Calvo, Alfonso TI Increased expression of VEGF(121)/VEGF(165-189) ratio results in a significant enhancement of human prostate tumor angiogenesis SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE prostate cancer; gene expression; VEGF; real time QRT-PCR; morpholino; isoform ID ENDOTHELIAL GROWTH-FACTOR; METASTATIC COLORECTAL-CANCER; CELL LUNG-CANCER; FACTOR VEGF; FACTOR ISOFORMS; IN-VIVO; EXTRACELLULAR-MATRIX; SPLICE VARIANTS; TRANSGENIC MICE; HIGH-GRADE AB Vascular endothelial growth factor (VEGF) is a proangiogenic factor upregulated in many tumors. The alternative splicing of VEGF mRNA renders 3 major isoforms of 121, 165 and 189 amino-acids in humans (1 less amino-acid for each mouse VEGF isoform). We have designed isoform specific real time QRT-PCR assays to quantitate VEGF transcripts in mouse and human normal and malignant prostates. In the human normal prostate, VEGF(165) was the predominant isoform (62.8% +/- 5.2%), followed by VEGF(121) (22.5% 6.3%) and VEGF(189) (p < 0.001) (14.6% +/- 2.1%). Prostate tumors showed a significant increase in the percentage of VEGF(121) and decreases in VEGF(165) (p < 0.01) and VEGF(189) (p < 0.05). However, the amount of total VEGF mRNA was similar between normal and malignant prostates. VEGF(164) was the transcript with the highest expression in the mouse normal prostate. Unlike human prostate cancer, tumors from TRAMP mice demonstrated a significant increase in total VEGF mRNA levels and in each of the VEGF isoforms, without changes in the relative isoform ratios. Morpholino phosphorodiamide antisense oligonucleotide technology was used to increase the relative amount of VEGF(121) while proportionally decreasing VEGF(165) and VEGF(189) levels in human prostate cell lines, through the modification of alternative splicing, without changing transcription levels and total amount of VEGF. The increase in the VEGF(121)/VEGF(165-189) ratio in PC3 cells resulted in a dramatic increase in prostate tumor angiogenesis in vivo. Our results underscore the importance of VEGF(121) in human prostate carcinoma and demonstrate that the relative expression of the different VEGF isoforms has an impact on prostate carcinogenesis. (c) 2007 Wiley-Liss, Inc. C1 Univ Navarra, Calvo Lab 1 05, Div Oncol, Ctr Appl Med Res,CIMA, Pamplona 31008, Spain. Univ Navarra, Dept Histol & Pathol, Pamplona 31008, Spain. NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Pathogenet Unit, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, LCRC, NIH, Bethesda, MD 20892 USA. RP Calvo, A (reprint author), Univ Navarra, Calvo Lab 1 05, Div Oncol, Ctr Appl Med Res,CIMA, Pio 12,55, Pamplona 31008, Spain. EM acalvo@unav.es RI JAVIERRE, BIOLA/A-2974-2017 OI JAVIERRE, BIOLA/0000-0002-8682-6748 NR 45 TC 25 Z9 27 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAY 15 PY 2007 VL 120 IS 10 BP 2096 EP 2109 DI 10.1002/ijc.22461 PG 14 WC Oncology SC Oncology GA 155GE UT WOS:000245565100005 PM 17278099 ER PT J AU Nesti, LJ Caterson, EJ Li, WJ Chang, R McCann, TD Hoek, JB Tuan, RS AF Nesti, Leon J. Caterson, E. J. Li, Wan-Ju Chang, Richard McCann, Thane D. Hoek, Jan B. Tuan, Rocky S. TI TGF-beta 1 calcium signaling in osteoblasts SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE TGF-beta 1; Ca2+ signaling; osteoblast; cell adhesion; Ca2+ channel; Smad; Fura-2 ID GROWTH-FACTOR-BETA; TGF-BETA; CELL-ADHESION; MATRIX MINERALIZATION; INTEGRIN EXPRESSION; OSTEOSARCOMA CELLS; SMAD PROTEINS; RAT BONE; IN-VITRO; IGF-I AB Transforming growth factor-beta 1 (TGF-beta 1) action is known to be initiated by its binding to multiple cell surface receptors containing serine/threonine kinase domains that act to stimulate a cascade of signaling events in a variety of cell types. We have previously shown that TGF-beta 1 and BMP-2 treatment of primary human osteoblasts (HOBs) enhances cell-substrate adhesion. In this report, we demonstrate that TGF-beta 1 elicits a rapid, transient, and oscillatory rise in the intracellular Ca2+ concentration, [Ca2+](i), that is necessary for enhancement of cell adhesion in HOBs but does not alter the phosphorylation state of Smad proteins. This rise in [Ca2+](i) in HOB is not observed in the absence of extracellular calcium or when the cells are treated with the L-type Ca2+ channel blocker, nifeclipine, but is stimulated upon treatment with the L-type Ca2+ channel agonist, Bay K 8644, or under high K+ conditions. The rise in [Ca2+](i) is severely attenuated after treatment of the cells with thapsigargin, a selective encloplasmic reticulum Ca2+ PUMP inhibitor. TGF-beta 1 enhancement of HOB adhesion to tissue culture polystyrene is also inhibited in cells treated with nifeclipine. These data suggest that intracellular Ca2+ signaling is an important second messenger of the TGF-beta 1 signal transcluction pathway in osteoblast function. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Dept Orthopaed & Rehabil, Washington, DC 20307 USA. Harvard Univ, Sch Med, Dept Plast & Reconstruct Surg, Boston, MA 02114 USA. Thomas Jefferson Univ, Dept Orthopaed Surg, Philadelphia, PA 19107 USA. Thomas Jefferson Univ, Dept Pathol Anat & Cell Biol, Philadelphia, PA 19107 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Dept Hlth & Human Serv, Bldg 50,Room 1523,50 S Dr,MSC 8022, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov RI Li, Wan-Ju/A-7002-2008 FU Intramural NIH HHS; NIAAA NIH HHS [AA07186, AA07215, F30 AA05516, AA08714]; NIAMS NIH HHS [AR Z01 41113, AR44501]; NIDCR NIH HHS [DE11327, DE16864] NR 60 TC 24 Z9 24 U1 1 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD MAY 15 PY 2007 VL 101 IS 2 BP 348 EP 359 DI 10.1002/jcb.21180 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 162XP UT WOS:000246123100007 PM 17211850 ER PT J AU MacArthur, PH Shiva, S Gladwin, MT AF MacArthur, Peter H. Shiva, Sruti Gladwin, Mark T. TI Measurement of circulating nitrite and S-nitrosothiols by reductive chemiluminescence SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Review DE reviews; nitric oxide; S-nitrosohemoglobin; tri-iodide; copper(I)/cysteine ID RED-BLOOD-CELLS; PROTEIN-CONTAINING SAMPLES; OXIDE SYNTHASE ACTIVITY; HUMAN PLASMA; GAS-CHROMATOGRAPHY; BIOLOGICAL SAMPLES; RELAXING FACTOR; SMOOTH-MUSCLE; GRIESS METHOD; IN-VIVO AB Considerable disparities in the reported levels of basal human nitrite and S-nitrosothiols (RSNO) in blood have brought methods of quantifying these nitric oxide (NO) metabolites to the forefront of NO biology. Ozone-based chemiluminescence is commonly used and is a robust method for measuring these species when combined with proper reductive chemistry. The goal of this article is to review existing methodologies for the measurement of nitrite and RSNO by reductive chemiluminescence. Specifically, we discuss in detail the measurement of nitrite and RSNO in biological matrices using tri-iodide and copper(I)/cysteine-based reduction methods coupled to chemiluminescence. The underlying reaction mechanisms, as well as the potential pitfalls of each method are discussed. (C) 2006 Elsevier B.V. All rights reserved. C1 NHLBI, Vasc Med Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Ctr Clin, Dept Crit Care Med, NIH, Bethesda, MD 20892 USA. RP Gladwin, MT (reprint author), NHLBI, Ctr Clin, Dept Crit Care Med, Vasc Med Branch,NIH, Bldg 10 CRC,Room 5-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM mgladwin@nih.gov NR 67 TC 128 Z9 128 U1 1 U2 16 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 MAY 15 PY 2007 VL 851 IS 1-2 BP 93 EP 105 DI 10.1016/j.jchromb.2006.12.012 PG 13 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 178BR UT WOS:000247196700010 PM 17208057 ER PT J AU Chen, X Howard, OMZ Oppenheim, JJ AF Chen, Xin Howard, O. M. Zack Oppenheim, Joost J. TI Pertussis toxin by inducing IL-6 promotes the generation of IL-17-producing CD4 cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; REGULATORY T-CELLS; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; CENTRAL-NERVOUS-SYSTEM; INFLAMMATORY CYTOKINES; DENDRITIC CELLS; IN-VIVO; BORDETELLA-PERTUSSIS; MULTIPLE-SCLEROSIS; TH1 CELLS AB Compelling evidence has now demonstrated that IL-17-producing CD4 cells (Th17) are a major contributor to autoimmune pathogenesis, whereas CD4(+)CD25(+) T regulatory cells (Treg) play a major role in suppression of autoimmunity. Differentiation of proinflammatory Th17 and immunosuppressive Treg from naive CD4 cells is reciprocally related and contingent upon the cytokine environment. We and others have reported that in vivo administration of pertussis toxin (PTx) reduces the number and function of mouse Treg. In this study, we have shown that supernatants from PTx-treated mouse splenic cells, which contained IL-6 and other proinflammatory cytokines, but not PTx itself, overcame the inhibition of proliferation seen in cocultures of Treg and CD4(+)CD25(-) T effector cells. This stimulatory effect could be mimicked by individual inflammatory cytokines such as IL-1 beta, IL-6, and TNF-a. The combination of these cytokines synergistically stimulated the proliferation of CD4+CD25- T effector cells despite the presence of Treg with a concomitant reduction in the percentage of FoxP3(+) cells and generation of IL-17-expressing cells. PTx generated Th17 cells, while inhibiting the differentiation of FoxP(+) cells, from naive CD4 cells when cocultured with bone marrow-derived dendritic cells from wild-type mice, but not from IL-6(-/-) mice. In vivo treatment with PTx induced IL-17-secreting cells in wild-type mice, but not in IL-6(-/-) mice. Thus, in addition to inhibiting the development of Treg, the immunoadjuvant activity of PTx can be attributable to the generation of IL-6-dependent IL-17-producing CD4 cells. The Journal of Immunology, 2007, 178: 6123-6129. C1 NCI, Basic Res Program, SAIC Frederick Inc, Mol Immunoregulat Lab, Frederick, MD 21702 USA. NCI, Mol Immunoregulat Lab, Ctr Canc Res, Frederick, MD 21702 USA. RP Chen, X (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Mol Immunoregulat Lab, POB B,Bldg 560,Room 31-19, Frederick, MD 21702 USA. EM chenxin@mail.nih.gov RI Howard, O M Zack/B-6117-2012; Chen, Xin/I-6601-2015 OI Howard, O M Zack/0000-0002-0505-7052; Chen, Xin/0000-0002-2628-4027 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 47 TC 64 Z9 66 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2007 VL 178 IS 10 BP 6123 EP 6129 PG 7 WC Immunology SC Immunology GA 165EG UT WOS:000246286200016 PM 17475838 ER PT J AU Zarember, KA Sugui, JA Chang, YC Kwon-Chung, KJ Gallin, JI AF Zarember, Kol A. Sugui, Janyce A. Chang, Yun C. Kwon-Chung, Kyung J. Gallin, John I. TI Human polymorphonuclear leukocytes inhibit Aspergillus fumigatus conidial growth by lactoferrin-mediated iron depletion SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; FUNGAL-INFECTIONS; ANTIMICROBIAL ACTIVITY; GRANULE DEFICIENCY; HOST-DEFENSE; NEUTROPHILS; METABOLISM; VIRULENCE; HEPCIDIN; TRANSPLANTATION AB Aspergillus fumigatus, a common mold, rarely infects humans, except during prolonged neutropenia or in cases of chronic granulomatous disease (CGD), a primary immunodeficiency caused by mutations in the NADPH oxidase that normally produces fungicidal reactive oxygen species. Filamentous hyphae of Aspergillus are killed by normal, but not CGD polymorphonuclear leukocytes (PMN); however, the few studies on PMN-mediated host defenses against infectious conidia (spores) of this organism have yielded conflicting results, some showing that PMN do not inhibit conidial growth, with others showing that they do, most likely using reactive oxygen species. Given that CGD patients are exposed daily to hundreds of viable A. fumigatus conidia, yet considerable numbers of them survive years without infection, we reasoned that PMN use ROS-independent mechanisms to combat Aspergillus. We show that human PMN from both normal controls and CGD patients are equipotent at arresting the growth of Aspergillus conidia in vitro, indicating the presence of a reactive oxygen species-independent factor(s). Cell-free supernatants of degranulated normal and CGD neutrophils both suppressed fungal growth and were found to be rich in lactoferrin, an abundant PMN secondary granule protein. Purified iron-poor lactoferrin at concentrations occurring in PMN supernatants (and reported in human mucosal secretions in vivo) decreased fungal growth, whereas saturation of lactoferrin or PMN supernatants with iron, or testing in the presence of excess iron in the form of ferritin, completely abolished activity against conidia. These results demonstrate that PMN lactoferrin sequestration of iron is important for host defense against Aspergillus. C1 NIAID, Host Def Lab, NIH, Bethesda, MD 20892 USA. NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Kwon-Chung, KJ (reprint author), 10 Ctr Dr,RM 6-2551,MSC 1504, Bethesda, MD 20892 USA. EM june_kwon-chung@nih.gov; jgallin@cc.nih.gov FU Intramural NIH HHS NR 58 TC 107 Z9 113 U1 0 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2007 VL 178 IS 10 BP 6367 EP 6373 PG 7 WC Immunology SC Immunology GA 165EG UT WOS:000246286200044 PM 17475866 ER PT J AU Park, H Teja, K O'Shea, JJ Siegel, RM AF Park, Heiyoung Teja, Kabir O'Shea, John J. Siegel, Richard M. TI The Yersinia effector protein YpkA induces apoptosis independently of actin depolymerization SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PLASMA-MEMBRANE LOCALIZATION; DETACHMENT-INDUCED APOPTOSIS; CELL-DEATH; KINASE ACTIVATION; TRIGGER APOPTOSIS; BUBONIC PLAGUE; T-LYMPHOCYTES; IMMUNE CELLS; V-ANTIGEN; MACROPHAGES AB The pathogenicity of the plague agent Yersinia pestis is largely due to the injection of effector proteins that potently block immune responses into host cells through a type III secretion apparatus. One Yersinia effector protein, YpkA, a putative serine/threonine kinase, has been reported to act by depolymerizing actin and disrupting actin microfilament organization. Using YpkA-GFP fusion proteins to directly visualize cells expressing YpkA, we found instead that YpkA triggered rapid cell death that can be blocked by caspase inhibitors and Bcl-x(L) but was not dependent on caspase-8. The actin depolymerization promoted by YpkA was only seen in cells with other features of apoptosis, and was blocked by inhibiting apoptosis, indicating that actin filament disruption is likely to be a result, rather than a cause of YpkA-induced apoptosis. A region including aa 133-262 in YpkA was sufficient for inducing apoptosis independent of localization to the plasma membrane. These data suggest that YpkA can act as a direct inducer of cell death. C1 NIAMSD, Immunoregulat Unit, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. NIAMSD, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Siegel, RM (reprint author), NIAMSD, Immunoregulat Unit, Autoimmun Branch, NIH, Bldg 10,Room 9N238,10 Ctr Dr, Bethesda, MD 20892 USA. EM rsiegel@nih.gov RI Siegel, Richard/C-7592-2009 OI Siegel, Richard/0000-0001-5953-9893 FU Intramural NIH HHS NR 52 TC 10 Z9 11 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2007 VL 178 IS 10 BP 6426 EP 6434 PG 9 WC Immunology SC Immunology GA 165EG UT WOS:000246286200050 PM 17475872 ER PT J AU Alaedini, A Okamoto, H Briani, C Wollenberg, K Shill, HA Bushara, KO Sander, HW Green, PHR Hallett, M Latov, N AF Alaedini, Armin Okamoto, Haruka Briani, Chiara Wollenberg, Kurt Shill, Holly A. Bushara, Khalafalla O. Sander, Howard W. Green, Peter H. R. Hallett, Mark Latov, Norman TI Immune cross-reactivity in Celiac disease: Anti-gliadin antibodies bind to neuronal synapsin I SO JOURNAL OF IMMUNOLOGY LA English DT Article ID 2-DIMENSIONAL GEL-ELECTROPHORESIS; CEREBELLAR-ATAXIA; GLUTEN ATAXIA; NERVOUS-SYSTEM; MASS-SPECTROMETRY; DIETARY-TREATMENT; PROTEIN; PHOSPHORYLATION; SENSITIVITY; TRANSMISSION AB Celiac disease is an immune-mediated disorder triggered by ingestion of wheat gliadin and related proteins in genetically susceptible individuals. In addition to the characteristic enteropathy, celiac disease is associated with various extraintestinal manifestations, including neurologic complications such as neuropathy, ataxia, seizures, and neurobehavioral changes. The cause of the neurologic manifestations is unknown, but autoimmunity resulting from molecular mimicry between gliadin and nervous system proteins has been proposed to play a role. In this study, we sought to investigate the immune reactivity of the anti-gliadin Ab response toward neural proteins. We characterized the binding of affinity-purified anti-gliadin Abs from immunized animals to brain proteins by one- and two-dimensional gel electrophoresis, immunoblotting, and peptide mass mapping. The major immunoreactive protein was identified as synapsin I. Anti-gliadin Abs from patients with celiac disease also bound to the protein. Such cross-reactivity may provide clues into the pathogenic mechanism of the neurologic deficits that are associated with gluten sensitivity. The Journal of Immunology, 2007, 178: 6590-6595. C1 Cornell Univ, Dept Neurol & Neurosci, New York, NY 10021 USA. Columbia Univ, Dept Med, New York, NY 10032 USA. Columbia Univ, Inst Human Nutr, New York, NY 10032 USA. Univ Padua, Dept Neurosci, Padua, Italy. NIAID, Bioinformat & Sci Informat Technol Program, Off Technol Informat Syst, NIH, Bethesda, MD 20892 USA. NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. St Vincents Hosp, Dept Neurol, New York, NY 10011 USA. RP Alaedini, A (reprint author), Cornell Univ, Dept Neurol & Neurosci, 1300 York Ave, New York, NY 10021 USA. EM ara2004@med.cornell.edu NR 40 TC 48 Z9 49 U1 1 U2 2 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD MAY 15 PY 2007 VL 178 IS 10 BP 6590 EP 6595 PG 6 WC Immunology SC Immunology GA 165EG UT WOS:000246286200068 PM 17475890 ER PT J AU French, AL Operskalski, E Peters, M Strickler, HD Tien, PC Sharp, GB Glesby, MJ Young, M Augenbraun, M Seaberg, E Kovacs, A AF French, Audrey L. Operskalski, Eva Peters, Marion Strickler, Howard D. Tien, Phyllis C. Sharp, Gerald B. Glesby, Marshall J. Young, Mary Augenbraun, Michael Seaberg, Eric Kovacs, Andrea TI Isolated hepatitis B core antibody is associated with HIV and ongoing but not resolved hepatitis C virus infection in a cohort of US women SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 45th Interscience Conference on Antimicrobial Agents and Chemotherapy CY DEC 16-19, 2005 CL Washington, DC ID CLINICAL-SIGNIFICANCE; INTERAGENCY HIV; INDIVIDUALS; ANTIGEN AB To characterize predictors of isolated hepatitis B core antibody (anti-HBc) among human immunodeficiency virus (HIV)-infected and HIV-uninfected women, we compared 702 women with anti-HBc and hepatitis B surface antibody (anti-HBs) with 490 women with isolated anti-HBc (1.8% of whom had detectable hepatitis B virus [HBV] DNA). Factors independently associated with isolated anti-HBc without viremia were detectable hepatitis C virus (HCV) RNA, HIV positivity, history of injection drug use, >10 lifetime sex partners, and HIV RNA level >100,000 copies/mL. Anti-HBs levels were lower among anti-HCV-positive women. Isolated anti-HBc was rarely explained by occult HBV in this cohort but may be explained by the influence of viral coinfections on anti-HBs level or durability. C1 Rush Med Coll, Cook Cty Hosp, Chicago, IL 60612 USA. Univ So Calif, Keck Sch Med, Dept Pediat, Los Angeles, CA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Dept Vet Affairs Med Ctr, San Francisco, CA USA. Albert Einstein Coll Med, Bronx, NY 10467 USA. Cornell Univ, Weill Med Coll, Ithaca, NY 14853 USA. SUNY, Downstate Med Ctr, Brooklyn, NY USA. Natl Inst Allergy Infect Dis, Div AIDS, NIH, Bethesda, MD USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD USA. Georgetown Univ, Sch Med, Washington, DC USA. RP French, AL (reprint author), Rush Med Coll, Cook Cty Hosp, 637 S Wood St Durand 115, Chicago, IL 60612 USA. EM Audrey_French@rush.edu FU NCRR NIH HHS [M01 RR000071, M01 RR000079, M01 RR000083, M01-RR-00071, M01-RR00083, MO1-RR00079]; NIAID NIH HHS [U01 AI034994, R01 AI052065, R01 AI052065-01, R01 AI057006, R01-AI-034993, R01-AI-052065, R01-AI-057006, U01 AI031834, U01 AI034989, U01 AI034993, U01 AI035004, U01 AI042590, U01-AI-034993, U01-AI-33834, U01-AI-34989, U01-AI-34993, U01-AI-34994, U01-AI-35004, U01-AI-42590]; NIDDK NIH HHS [P30 DK026743, P30-DK-26743]; OID CDC HHS [U01-CH-32632] NR 16 TC 22 Z9 22 U1 0 U2 0 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 MAY 15 PY 2007 VL 195 IS 10 BP 1437 EP 1442 DI 10.1086/515578 PG 6 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 158HG UT WOS:000245781800008 PM 17436223 ER PT J AU Wen, ZM Kim, HY AF Wen, Zhiming Kim, Hee-Yong TI Inhibition of phosphatidylserine biosynthesis in developing rat brain by maternal exposure to ethanol SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE ethanol; phosphaticlylserine; phosphatidylserine synthase; mass spectrometry; phosphatidylethanolamine; rat brain ID POLYUNSATURATED FATTY-ACIDS; FETAL ALCOHOL SYNDROME; DOCOSAHEXAENOIC ACID; SUBSTRATE PREFERENCE; MAMMALIAN-CELLS; GLIOMA-CELLS; SYNTHASE-II; PROTEIN; MEMBRANES; PHOSPHOLIPIDS AB Phosphatidylserine (PtdSer), major acidic phospholipids in neuronal membranes, participate in important cell signaling processes. The PtdSer in brain is highly enriched with docosahexaenoic acid (DHA; 22:6n-3), and the DHA status or ethanol exposure has been shown to influence the PtdSer level. This study shows that ethanol exposure during prenatal and developmental period significantly attenuates microsomal PtdSer biosynthetic activities and reduces PtdSer, particularly 18:0, 22:6-PtdSer, in developing rat brain cortices. Brain microsomes were incubated with deuterium labeled exogenous substrates in vitro and the products formed were detected by reversed phase HPLC-electrospray ionization mass spectrometry (ESI-MS). These in vitro bioassays showed that 1-stearoyl-2-docosahexaenoyl (18:0, 22:6) species is the best substrate for PtdSer synthesis from both phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn). The PtdSer biosynthetic activity of brain, especially for 18:0, 22:6-PtdSer production, was hampered significantly by maternal exposure to ethanol. PtdSer levels were consistently reduced significantly in brain cortices of the pups from ethanol-exposed dams, due mainly to the depletion of 18:0, 22:6-PtdSer. The mRNA expression of PtdSer synthase 1 (PSS1) and PtdSer synthase 2 (PSS2) was not reduced by ethanol. Similarly, the PSS1 enzyme level did not change after ethanol exposure but PSS2 could not be probed with the antibody available currently. Degradation of PtdSer by mitochondrial PtdSer decarboxylation was not enhanced but also inhibited. Taken together, attenuated PtdSer biosynthetic activities are largely responsible for the PtdSer reduction observed in developing rat brains after maternal exposure to ethanol. (c) 2007 Wiley-Liss, lnc. C1 NIAAA, Sect Mass Spect, LMBB, NIH,Lab Mol Signaling, Bethesda, MD 20892 USA. RP Kim, HY (reprint author), NIAAA, Sect Mass Spect, LMBB, NIH,Lab Mol Signaling, 5625 Fishers Lane Rm 3N-07, Bethesda, MD 20892 USA. EM hykim@nih.gov FU Intramural NIH HHS NR 48 TC 11 Z9 11 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD MAY 15 PY 2007 VL 85 IS 7 BP 1568 EP 1578 DI 10.1002/jnr.21263 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 174GJ UT WOS:000246929900021 PM 17387686 ER PT J AU Chiba-Falek, O Lopez, GJ Nussbaum, RL AF Chiba-Falek, Ornit Lopez, Grisel J. Nussbaum, Robert L. TI Reply: Expression of a-synuclein mRNA in Parkinson's disease SO MOVEMENT DISORDERS LA English DT Letter C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Chiba-Falek, O (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM ochibafa@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD MAY 15 PY 2007 VL 22 IS 7 BP 1057 EP 1057 DI 10.1002/mds.21498 PG 1 WC Clinical Neurology SC Neurosciences & Neurology GA 174BU UT WOS:000246917000031 ER PT J AU Scher, AI Xu, Y Korf, ESC White, LR Scheltens, P Toga, AW Thompson, PM Hartley, SW Witter, MP Valentino, DJ Launer, LJ AF Scher, A. I. Xu, Y. Korf, E. S. C. White, L. R. Scheltens, P. Toga, A. W. Thompson, P. M. Hartley, S. W. Witter, M. P. Valentino, D. J. Launer, L. J. TI Hippocampal shape analysis in Alzheimer's disease: A population-based study SO NEUROIMAGE LA English DT Article DE hippocampal atrophy; Alzheimer's disease; hippocampus; volumetric MRI ID LONGITUDINAL VOLUMETRIC MRI; ISCHEMIC VASCULAR DEMENTIA; MILD COGNITIVE IMPAIRMENT; JAPANESE-AMERICAN MEN; NEURONAL LOSS; CARDIOVASCULAR-HEALTH; ENTORHINAL CORTEX; PREDICT DEMENTIA; ELDERLY-PEOPLE; ATROPHY AB Background. Hippocampal atrophy - particularly of the CA1 region may be useful as a biomarker for Alzheimer's disease (AD) or the risk for AD. The extent to which the AD hippocampus can be distinguished in vivo from changes due to normal aging or other processes that affect the hippocampus is of clinical importance and is an area of active research. In this study, we use structural imaging techniques to model hippocampal size and regional shape differences between elderly men with incident AD and a non-demented comparison group of elderly men. Methods: Participants are Japanese-American men from the Honolulu Asia Aging Study (HAAS). The HAAS cohort has been followed since 1965. The following analysis is based on a sub-group of men who underwent MRI examination in 1994-1996. Participants were diagnosed with incident AD (n = 24: age= 82.5 +/-:4.6) or were not demented (n = 102: age = 83.0 +/- 5.9). One reader, blinded to dementia diagnosis, manually outlined the left and right hippocampal formation using published criteria. We used 3D structural shape analysis methods developed at the Laboratory of Neuro Imaging (LONI) to compare regional variation in hippocampal diameter between the AD cases and the non-demented comparison group. Results: Mean total hippocampal volume was 11.5% smaller in the AD cases than the non-demented controls (4903 +/- 857 mm(3) vs. 5540 +/- 805 mm(3)), with a similar size difference for the median left (12.0%) and median right (11.6%) hippocampus. Shape analysis showed a regional pattern of shape difference between the AD and nondemented hippocampus, more evident for the hippocampal body than the head, and the appearance of more consistent differences in the left hippocampus than the right. While assignment to a specific sub-region is not possible with this method, the surface changes primarily intersect the area of the hippocampus body containing the CA1 region (and adjacent CA2 and distal CA3), subiculum, and the dentate gyrus-hilar region. (C) 2006 Elsevier Inc. All rights reserved. C1 Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med, Dept Neurol, Lab Neuroimaging, Los Angeles, CA USA. Vrije Univ Amsterdam, Med Ctr, Ctr Alzheimers, Dept Neurol, Amsterdam, Netherlands. Pacific Hlth Res Inst, Honolulu, HI USA. Vrije Univ Amsterdam, Med Ctr, Dept Anat & Neurosci, Amsterdam, Netherlands. RP Scher, AI (reprint author), Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, 4201 Jones Bridge Rd, Bethesda, MD 20814 USA. EM ascher@usuhs.mil NR 55 TC 62 Z9 68 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD MAY 15 PY 2007 VL 36 IS 1 BP 8 EP 18 DI 10.1016/j.neuroimage.2006.12.036 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 168YI UT WOS:000246559500002 PM 17434756 ER PT J AU Loucks, TMJ Poletto, CJ Simonyan, K Reynolds, CL Ludlow, CL AF Loucks, Torrey M. J. Poletto, Christopher J. Simonyan, Kristina Reynolds, Catherine L. Ludlow, Christy L. TI Human brain activation during phonation and exhalation: Common volitional control for two upper airway functions SO NEUROIMAGE LA English DT Article DE phonation; exhalation; speech; fMRI ID SPEECH MOTOR CONTROL; CEREBRAL BLOOD-FLOW; EVENT-RELATED FMRI; VERBAL RESPONSES; MUSCLE-ACTIVITY; RHESUS-MONKEY; CORTEX; VOCALIZATION; NEUROANATOMY; CEREBELLUM AB Phonation is defined as a laryngeal motor behavior used for speech production, which involves a highly specialized coordination of laryngeal and respiratory neuromuscular control. During speech, brief periods of vocal fold vibration for vowels are interspersed by voiced and unvoiced consonants, glottal stops and glottal fricatives (/h/). It remains unknown whether laryngeal/respiratory coordination of phonation for speech relies on separate neural systems from respiratory control or whether a common system controls both behaviors. To identify the central control system for human phonation, we used event-related fMRI to contrast brain activity during phonation with activity during prolonged exhalation in healthy adults. Both whole-brain analyses and region of interest comparisons were conducted. Production of syllables containing glottal stops and vowels was accompanied by activity in left sensorimotor, bilateral temporoparietal and medial motor areas. Prolonged exhalation similarly involved activity in left sensorimotor and temporoparietal areas but not medial motor areas. Significant differences between phonation and exhalation were found primarily in the bilateral auditory cortices with whole-brain analysis. The ROI analysis similarly indicated task differences in the auditory cortex with differences also detected in the inferolateral motor cortex and dentate nucleus of the cerebellum. A second experiment confirmed that activity in the auditory cortex only occurred during phonation for speech and did not depend upon sound production. Overall, a similar central neural system was identified for both speech phonation and voluntary exhalation that primarily differed in auditory monitoring. (C) 2007 Elsevier Inc. All rights reserved. C1 NINDS, Laryngeal & Speech Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Ludlow, CL (reprint author), NINDS, Laryngeal & Speech Sect, Med Neurol Branch, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM LudlowC@ninds.nih.gov OI Simonyan, Kristina/0000-0001-7444-0437; Ludlow, Christy/0000-0002-2015-6171 FU Intramural NIH HHS [Z01 NS002980-08] NR 51 TC 61 Z9 61 U1 2 U2 6 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 MAY 15 PY 2007 VL 36 IS 1 BP 131 EP 143 DI 10.1016/j.neuroimage.2007.01.049 PG 13 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 168YI UT WOS:000246559500013 PM 17428683 ER PT J AU Yang, H Long, XY Yang, YH Yan, H Zhu, CZ Zhou, XP Zang, YF Gong, QY AF Yang, Hong Long, Xiang-Yu Yang, Yihong Yan, Hao Zhu, Chao-Zhe Zhou, Xiang-Ping Zang, Yu-Feng Gong, Qi-Yong TI Amplitude of low frequency fluctuation within visual areas revealed by resting-state functional MRI SO NEUROIMAGE LA English DT Article ID DEFAULT-MODE; MAGNETIC-RESONANCE; BRAIN-FUNCTION; MOTOR CORTEX; ALPHA-RHYTHM; BOLD SIGNAL; CONNECTIVITY; FMRI; ACTIVATION; HYPOTHESIS AB Most studies of resting-state functional magnetic resonance imaging (fMRI) have applied the temporal correlation in the time courses to investigate the functional connectivity between brain regions. Alternatively, the power of low frequency fluctuation (LFF) may also be used as a biomarker to assess spontaneous activity. The purpose of the current study is to evaluate whether the amplitude of the LFF (ALFF) relates to cerebral physiological states. Ten healthy subjects underwent four resting-state fMRI scanning sessions, two for eyes-open (EO) and two for eyes-closed (EC) conditions, with two sets of parameters (TR=400 ms and 2 s, respectively). After data preprocessing, ALFF was obtained by calculating the square root of the power spectrum in the frequency range of 0.01-0.08 Hz. Our results showed that the ALFF in EO was significantly higher than that in EC (P<0.05, corrected) in the bilateral visual cortices. Furthermore, the ALFF in EO was significantly reduced in the right paracentral lobule (PCL) than in EC (P<0.05, corrected). Region of interest (ROI) analysis showed that the ALFF differences between EO and EC were consistent for each subject. In contrast, no significant ALFF differences were found between EO and EC (P<0.381) in the posterior cingulate cortex. All these results agree well with previous studies comparing EO and EC states. Our finding of the distinct ALFF difference between EO and EC in the visual cortex implies that the ALFF may be a novel biomarker for physiological states of the brain. (C) 2007 Elsevier Inc. All rights reserved. C1 Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing 100875, Peoples R China. Sichuan Univ, W China Hosp, Dept Radiol, HMRRC, Chengdu, Peoples R China. NIDA, Neuroimaging Res Branch, NIH, Baltimore, MD 21042 USA. Peking Univ, Inst Mental Hlth, Beijing 100871, Peoples R China. Univ Liverpool, Fac Med, Div Med Imaging, Liverpool L69 3GB, Merseyside, England. RP Gong, QY (reprint author), Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing 100875, Peoples R China. EM zangyf@263.net; cjr.gongqiyong@vip.163.com RI ZANG, Yu-Feng/J-1558-2012 OI ZANG, Yu-Feng/0000-0003-1833-8010 NR 36 TC 187 Z9 218 U1 2 U2 23 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 MAY 15 PY 2007 VL 36 IS 1 BP 144 EP 152 DI 10.1016/j.neuroimage.2007.01.054 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 168YI UT WOS:000246559500014 PM 17434757 ER PT J AU Vasconcelos, OM Prokhorenko, OA Salajegheh, MK Kelley, KF Livornese, K Olsen, CH Vo, AH Dalakas, MC Halstead, LS Jabbari, B Campbell, WW AF Vasconcelos, O. M. Prokhorenko, O. A. Salajegheh, M. K. Kelley, K. F. Livornese, K. Olsen, C. H. Vo, A. H. Dalakas, M. C. Halstead, L. S. Jabbari, B. Campbell, W. W. TI Modafinil for treatment of fatigue in post-polio syndrome - A randomized controlled trial SO NEUROLOGY LA English DT Article ID PLACEBO-CONTROLLED TRIAL; DOUBLE-BLIND; DAYTIME SLEEPINESS; MULTIPLE-SCLEROSIS; PARKINSONS-DISEASE; MYOTONIC-DYSTROPHY; POLIO SURVIVORS; PYRIDOSTIGMINE; SOMNOLENCE; AMANTADINE AB Objective: To determine if modafinil can improve fatigue in patients with post-polio syndrome. Methods: We used a randomized, placebo-controlled crossover trial. Intervention with modafinil (400 mg/ day) and placebo occurred over 6-week periods. Primary endpoint (fatigue) was assessed using the Fatigue Severity Scale as the main outcome measure. Other measures included the Visual Analog Scale for Fatigue and the Fatigue Impact Scale. Secondary endpoint (health-related quality of life) was assessed using the 36-Item Short-Form. Analysis of variance for repeated measures was applied to assess treatment, period, and carryover effects. Results: Thirty-six patients were randomized, 33 of whom (mean age: 61 years) completed required interventions. Treatment with modafinil was safe and well-tolerated. After adjusting for periods and order effects, no difference was observed between treatments. Conclusion: Based on the utilized measures of outcome modafinil was not superior to placebo in alleviating fatigue or improving quality of life in the studied post-polio syndrome population. C1 Uniformed Serv Univ Hlth Sci, Dept Neurol, Bethesda, MD 20814 USA. NIH, Neuromuscular Dis Sect, Bethesda, MD 20892 USA. Natl Rehabil Hosp, Dept Neurosci, Washington, DC USA. RP Vasconcelos, OM (reprint author), 4301 Jones Bridge Rd,Bldg 53,Room 101, Bethesda, MD 20814 USA. EM ovasconcelos@usuhs.mil NR 41 TC 18 Z9 20 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAY 15 PY 2007 VL 68 IS 20 BP 1680 EP 1686 DI 10.1212/01.wnl.0000261912.53959.b4 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 167KL UT WOS:000246450500007 PM 17502549 ER PT J AU McKay, MM Morrison, DK AF McKay, M. M. Morrison, D. K. TI Integrating signals from RTKs to ERK/MAPK SO ONCOGENE LA English DT Review DE RTKs; ERK/MA PK; Ras; Raf; ERK scaffolds ID NUCLEOTIDE EXCHANGE FACTORS; RECEPTOR TYROSINE KINASES; PROTEIN PHOSPHATASE 2A; RAS ACTIVATOR SON; MAP KINASE; EPITHELIAL MORPHOGENESIS; PHOSPHORYLATION SITES; SCAFFOLD COMPLEX; RAF-1 ACTIVATION; PLASMA-MEMBRANE AB Signals received at the cell surface must be properly transmitted to critical targets within the cell to achieve the appropriate biological response. This process of signal transduction is often initiated by receptor tyrosine kinases (RTKs), which function as entry points for many extracellular cues and play a critical role in recruiting the intracellular signaling cascades that orchestrate a particular response. Essential for most RTK-mediated signaling is the engagement and activation of the mitogen-activated protein kinase (MAPK) cascade comprised of the Raf, MEK and extracellular signal-regulated kinase (ERK) kinases. For many years, it was thought that signaling from RTKs to ERK occurred only at the plasma membrane and was mediated by a simple, linear Ras-dependent pathway. However, the limitation of this model became apparent with the discovery that Ras and ERK can be activated at various intracellular compartments, and that RTKs can modulate Ras/ERK signaling from these sites. Moreover, ERK scaffolding proteins and signaling modulators have been identified that play critical roles in determining the strength, duration and location of RTK-mediated ERK signaling. Together, these factors contribute to the diversity of biological responses generated by RTK signaling. C1 NCI Frederick, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. RP Morrison, DK (reprint author), NCI Frederick, Lab Cell & Dev Signaling, POB B, Frederick, MD 21702 USA. EM dmorrison@ncifcrf.gov NR 76 TC 272 Z9 278 U1 2 U2 41 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 15 PY 2007 VL 26 IS 22 BP 3113 EP 3121 DI 10.1038/sj.onc.1210394 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 169PH UT WOS:000246603600003 PM 17496910 ER PT J AU Turjanski, AG Vaque, JP Gutkind, JS AF Turjanski, A. G. Vaque, J. P. Gutkind, J. S. TI MAP kinases and the control of nuclear events SO ONCOGENE LA English DT Review DE signal transduction; Ras GTPases; Rho GTPases; chromatin remodeling; transcription factors; growth factors ID ACTIVATED PROTEIN-KINASE; SIGNAL-TRANSDUCTION PATHWAY; EPIDERMAL-GROWTH-FACTOR; STRESS-INDUCED PHOSPHORYLATION; HISTONE H3 PHOSPHORYLATION; RECEPTOR TYROSINE KINASES; JUN NH2-TERMINAL KINASE; SERUM RESPONSE ELEMENT; C-MYC EXPRESSION; DOCKING SITES AB The mitogen-activated protein kinases (MAPKs) are a family of serine/threonine kinases that play an essential role in signal transduction by modulating gene transcription in the nucleus in response to changes in the cellular environment. They include the extracellular signal-regulated protein kinases (ERK1 and ERK2); c-Jun N-terminal kinases (JNK1, JNK2, JNK3); p38s (p38a, p38b, p38c, p38d) an d ERK5. The molecular events in which MAPKs function can be separated in discrete and yet interrelated steps: activation of the MAPK by their upstream kinases, changes in the subcellular localization of MAPKs, and recognition, binding and phosphorylation of MAPK downstream targets. The resulting pattern of gene expression will ultimately depend on the integration of the combinatorial signals provided by the temporal activation of each group of MAPKs. This review will focus on how the specificity of signal transmission by MAPKs is achieved by scaffolding molecules and by the presence of structural motifs in MAPKs that are dynamically regulated by phosphorylation and protein-protein interactions. We discuss also how MAPKs recognize and phosphorylate their target nuclear proteins, including transcription factors, co-activators and repressors and chromatin-remodeling molecules, thereby affecting an intricate balance of nuclear regulatory molecules that ultimately control gene expression in response to environmental cues. C1 Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. RP Gutkind, JS (reprint author), Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009; Vaque, Jose/H-8413-2015 OI Vaque, Jose/0000-0002-3913-2495 FU Intramural NIH HHS NR 159 TC 239 Z9 248 U1 1 U2 19 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 15 PY 2007 VL 26 IS 22 BP 3240 EP 3253 DI 10.1038/sj.onc.1210415 PG 14 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 169PH UT WOS:000246603600012 PM 17496919 ER PT J AU Drake, JW AF Drake, John W. TI Mutations in clusters and showers SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID MULTIPLE MUTATIONS; RATES; MICE C1 Natl Inst Environm Hlth Sci, Lab Mol Genet, NIH, Res Triangle Pk, NC 27709 USA. RP Drake, JW (reprint author), Natl Inst Environm Hlth Sci, Lab Mol Genet, NIH, Res Triangle Pk, NC 27709 USA. EM drake@niehs.nih.gov NR 19 TC 16 Z9 18 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 15 PY 2007 VL 104 IS 20 BP 8203 EP 8204 DI 10.1073/pnas.0703089104 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 169NW UT WOS:000246599900003 PM 17495029 ER PT J AU Elmowalid, GA Qiao, M Jeong, SH Borg, BB Baumert, TF Sapp, RK Hu, ZY Murthy, K Liang, TJ AF Elmowalid, Gamal A. Qiao, Ming Jeong, Sook-Hyang Borg, Brian B. Baumert, Thomas F. Sapp, Ronda K. Hu, Zongyi Murthy, Krishna Liang, T. Jake TI Immunization with hepatitis C virus-like particles results in control of hepatitis C virus infection in chimpanzees SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE envelope proteins; prevention; protective immunity; vaccine; viral clearance ID CELLULAR IMMUNE-RESPONSES; HUMAN-PAPILLOMAVIRUS TYPE-16; CONTROLLED-TRIAL; DENDRITIC CELLS; INSECT CELLS; VACCINE; PERSISTENCE; PROTEIN; HCV; CHALLENGE AB Recombinant hepatitis C virus (HCV)-like particles (HCV-LPs) containing HCV structural proteins (core, E1, and E2) produced in insect cells resemble the putative HCV virions and are capable of inducing strong and broad humoral and cellular immune responses in mice and baboons. Here, we present evidence on the immunogenicity and induction of protective immunity by HCV-LPs in chimpanzees. Chimpanzees (two in each group), were immunized with HCV-LPs or HCV-LPs plus AS01B adjuvant. After immunizations, all animals developed an HCV-specific immune response including IFN-gamma(+), IL-2(+), CD4(+), and CD8(+) T cell and proliferative lymphocyte responses against core, E1, and E2. Upon challenge with an infectious HCV inoculum, one chimpanzee developed transient viremia with low HCV RNA titers (10(3) to 10(4) copies per ml) in the third and fourth weeks after the challenge. The three other chimpanzees became infected with higher levels of viremia (10(4) to 10(5) copies per ml), but their viral levels became unquantifiable (< 10(3) copies per ml) 10 weeks after the challenge. After the HCV challenge, all four chimpanzees demonstrated a significant increase in peripheral and intrahepatic T cell and proliferative responses against the HCV structural proteins. These T cell responses coincided with the fall in HCV RNA levels. Four naive chimpanzees were infected with the same HCV inoculum, and three developed persistent infection with higher viremia in the range of 105 to 106 copies per ml. Our study suggests that HCV-LP immunization induces HCV-specific cellular immune responses that can control HCV challenge in the chimpanzee model. C1 NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. SW Fdn Biomed Res, San Antonio, TX 78245 USA. Univ Freiburg, Dept Virol & Immunol, D-79085 Freiburg, Germany. RP Liang, TJ (reprint author), NIDDK, Liver Dis Branch, NIH, Bldg 10,Room 9B16,10 Ctr Dr, Bethesda, MD 20892 USA. EM jliang@nih.gov RI Jeong, Sook-Hyang/D-5726-2012; Jeong, Sook-Hyang/J-5642-2012 FU Intramural NIH HHS; NHLBI NIH HHS [N01-HB-27091, N01HB27091] NR 32 TC 97 Z9 103 U1 1 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 MAY 15 PY 2007 VL 104 IS 20 BP 8427 EP 8432 DI 10.1073/pnas.0702162104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 169NW UT WOS:000246599900043 PM 17485666 ER PT J AU Zhang, ML Yao, ZS Patel, H Garmestani, K Zhang, Z Talanov, VS Plascjak, PS Goldman, CK Janik, JE Brechbiel, MW Waldmann, TA AF Zhang, Meili Yao, Zhengsheng Patel, Hiral Garmestani, Kayhan Zhang, Zhuo Talanov, Vladimir S. Plascjak, Paul S. Goldman, Carolyn K. Janik, John E. Brechbiel, Martin W. Waldmann, Thomas A. TI Effective therapy of murine models of human leukemia and lymphoma with radiolabeled anti-CD30 antibody, HeFi-1 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE monoclonal antibody; radioimmunotherapy; alpha-emitter; beta-emitter ID LARGE-CELL LYMPHOMA; MONOCLONAL-ANTIBODY; HODGKINS-DISEASE; FACTOR-RECEPTOR; SIGNAL-TRANSDUCTION; CHEMOTHERAPY PLUS; XENOGRAFTED MICE; CD30 EXPRESSION; ALPHA-EMITTER; IN-VITRO AB CD30 is a member of the TNF receptor superfamily. Overexpression of CD30 on some neoplasms versus limited expression on normal tissues makes this receptor a promising target for antibody-based therapy. Radioimmunotherapy of cancer with radiolabeled antibodies has shown promise. In this study, we evaluated the therapeutic efficacy of an anti-CD30 antibody, HeFi-1, armed with At-211 in a leukemia (karpas299) model and with Y-90 in a lymphoma (SUDHL-1) model. Furthermore, we investigated the combination therapy of At-211-HeFi-1 with unmodified HeFi-1 in the leukemia model. Treatment with unmodified HeFi-1 significantly prolonged the survival of the karpas299-bearing mice compared with the controls (P < 0.001). Treatment with At-211-HeFi-1 showed greater therapeutic efficacy than that with unmodified HeFi-1 as shown by survival of the mice (P < 0.001). Combining these two agents further improved the survival of the mice compared with the groups treated with either At-211-HeFi-1 (P < 0.05) or unmodified HeFi-1 (P < 0.001) alone. In the lymphoma model, the survival of the SUDHL-1-bearing mice was significantly prolonged by the treatment with Y-90-HeFi-1 compared with the controls (P < 0.001). In summary, radiolabeled HeFi-1 is very promising for the treatment of CD30-expressing leukemias and lymphomas, and the combination regimen of At-211-HeFi-1 with unmodified HeFi-1 enhanced the therapeutic efficacy. C1 NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NIH, PET Dept, Clin Ctr, Bethesda, MD 20892 USA. NCI, Lab Anim Sci Program, Ft Detrick, MD 21702 USA. NCI, Appl Dev Res Support Program, Sci Applicat Int Corp, Frederick, MD 21702 USA. RP Waldmann, TA (reprint author), NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01CO12400, N01-CO-12400] NR 47 TC 14 Z9 15 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 MAY 15 PY 2007 VL 104 IS 20 BP 8444 EP 8448 DI 10.1073/pnas.0702496104 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 169NW UT WOS:000246599900046 PM 17488826 ER PT J AU Zhang, P Wu, CG Mihalik, K Virata-Theimer, ML Yu, MYW Alter, HJ Feinstone, SM AF Zhang, Pei Wu, Charles G. Mihalik, Kathleen Virata-Theimer, Maria Luisa Yu, Mei-Ying W. Alter, Harvey J. Feinstone, Stephen M. TI Hepatitis C virus epitope-specific neutralizing antibodies in Igs prepared from human plasma SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE anti-hepatitis C virus-positive plasma; Ig intravenous ID HUMAN MONOCLONAL-ANTIBODIES; LIVER-TRANSPLANTATION; ENVELOPE GLYCOPROTEIN; IMMUNE GLOBULIN; CELL-CULTURE; IN-VITRO; HCV; INFECTION; PROTEIN; PSEUDOPARTICLES AB Neutralizing antibodies directed against hepatitis C virus (HCV) are present in Igs made from anti-HCV-positive plasma. However, these HCV-specific Igs are largely ineffective in vivo. The mechanism for the poor effectiveness is currently unknown. We hypothesize that the presence of nonneutralizing antibodies in HCV-specific Igs interferes with the function of neutralizing antibodies, resulting in the reduction or blockage of their effect. In the present study, we identified at least two epitopes at amino acid residues 412-419 (epitope I) and 434-446 (epitope II), located downstream of the hypervariable region I within the HCV E2 protein. We demonstrated that epitope I, but not epitope II, was implicated in HCV neutralization and that binding of a nonneutralizing antibody to epitope II completely disrupted virus neutralization mediated by antibody binding at epitope I. The dynamic interaction between nonneutralizing and neutralizing antibodies may thus play a key role in determining the outcomes of HCV infection. Further exploration of this interplay should lead to a better understanding of the mechanisms of neutralization and immune escape and may indicate pathways for the manufacture of an effective HCV-specific Ig product for immune prophylaxis of HCV infection. C1 US FDA, Div Hematol, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. US FDA, Div Viral Prod, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. US FDA, Div Gastroenterol Prodl, Ctr Drug Evaluat & Res, Silver Spring, MD 20993 USA. NIH, Dept Transfus Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Zhang, P (reprint author), US FDA, Div Hematol, Ctr Biol Evaluat & Res, 29 Lincoln Dr, Bethesda, MD 20892 USA. EM pei.zhang@fda.hhs.gov; halter@dtm.cc.nih.gov NR 27 TC 84 Z9 87 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 MAY 15 PY 2007 VL 104 IS 20 BP 8449 EP 8454 DI 10.1073/pnas.0703039104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 169NW UT WOS:000246599900047 PM 17494735 ER PT J AU Waheed, AA Ablan, SD Roser, JD Sowder, RC Schaffner, CP Chertova, E Freed, EO AF Waheed, Abdul A. Ablan, Sherimay D. Roser, James D. Sowder, Raymond C. Schaffner, Carl P. Chertova, Elena Freed, Eric O. TI HIV-1 escape from the entry-inhibiting effects of a cholesterol-binding compound via cleavage of gp41 by the viral protease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE drug resistance; viral entry; viral evolution ID IMMUNODEFICIENCY-VIRUS TYPE-1; VIRION-ASSOCIATED CHOLESTEROL; CYTOPLASMIC DOMAIN; LIPID RAFTS; TRANSMEMBRANE PROTEIN; ENVELOPE PROTEIN; ENV PROTEIN; MEMBRANE CHOLESTEROL; MOLECULAR CLONE; GLYCOPROTEIN AB HIV-1 virions are highly enriched in cholesterol relative to the cellular plasma membrane. We recently reported that a cholesterol-binding compound, amphotericin B methyl ester (AME), blocks HIV-1 entry and that single amino acid substitutions in the cytoplasmic tail of the transmembrane envelope glycoprotein gp41 confer resistance to AME. In this study, we defined the mechanism of resistance to AME. We observed that the gp41 in AME-resistant virions is substantially smaller than wild-type gp41. Remarkably, we found that this shift in gp41 size is due to cleavage of the gp41 cytoplasmic tail by the viral protease. We mapped the protease-mediated cleavage to two sites in the cytoplasmic tail and showed that gp41 truncations in this region also confer AME resistance. Thus, to escape the inhibitory effects of AME, HIV-1 evolved a mechanism of protease-mediated envelope glycoprotein cleavage used by several other retroviruses to activate envelope glycoprotein fusogenicity. In contrast to the mechanism of AME resistance observed for HIV-1, we demonstrate that simian immunodeficiency virus can escape from AME via the introduction of premature termination codons in the gp41 cytoplasmic tail coding region. These findings demonstrate that in human T cell lines, HIV-1 and simian immunodeficiency virus can evolve distinct strategies for evading AME, reflecting their differential requirements for the gp41 cytoplasmic tail in virus replication. These data reveal that HIV-1 can escape from an inhibitor of viral entry by acquiring mutations that cause the cytoplasmic tail of gp41 to be cleaved by the viral protease. C1 NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. NCI, AIDS Vaccine Program, Basic Res Program, Sci Applicat Int Corp, Frederick, MD 21702 USA. Rutgers State Univ, Dept Microbiol & Biochem, Waksman Inst, New Brunswick, NJ 08903 USA. RP Freed, EO (reprint author), NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM efreed@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 49 TC 25 Z9 26 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 MAY 15 PY 2007 VL 104 IS 20 BP 8467 EP 8471 DI 10.1073/pnas.0701443104 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 169NW UT WOS:000246599900050 PM 17483482 ER PT J AU Andrade, N Komnenovic, V Blake, SM Jossin, Y Howell, B Goffinet, A Schneider, WJ Nimpf, J AF Andrade, Nuno Komnenovic, Vukoslav Blake, Sophia M. Jossin, Yves Howell, Brian Goffinet, Andre Schneider, Wolfgang J. Nimpf, Johannes TI ApoER2/VLDL receptor and Dab1 in the rostral migratory stream function in postnatal neuronal migration independently of Reelin SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Reelin signaling; postnatal neurogenesis; tangential neuronal migration ID CENTRAL-NERVOUS-SYSTEM; SUBVENTRICULAR ZONE; OLFACTORY-BULB; TYROSINE PHOSPHORYLATION; BRAIN-DEVELOPMENT; CHAIN-MIGRATION; CELL-MIGRATION; VLDL RECEPTOR; MOUSE; PRECURSORS AB Postnatal migration of interneuron precursors from the subventricular zone to the olfactory bulb occurs in chains that form the substrate for the rostral migratory stream. Reelin is suggested to induce detachment of neuroblasts from the chains when they arrive at the olfactory bulb. Here we show that ApoER2 and possibly very-low-density lipoprotein receptor (VLDLR) and their intracellular adapter protein Dab1 are involved in chain formation most likely independent of Reelin. F-spondin, which is present in the stream, may act as ligand for ApoER2 and VLDLR. In mice lacking either both receptors or Dab1 chain formation is severely compromised, and as a consequence the rostral migratory stream is virtually absent and neuroblasts accumulate in the subventricular zone. The mutant animals exhibit severe neuroanatomical defects in the subventricular zone and in the olfactory bulb. These data demonstrate a cell-autonomous function of ApoER2, and most likely VLDLR and Dab1, in postnatal migration of neuroblasts in the forebrain, which is suggested to depend on ligands other than Reelin. C1 Med Univ Vienna, Max F Perutz Labs, Dept Med Biochem, Univ Dept Vienna Bioctr, A-1030 Vienna, Austria. Austrian Acad Sci, Inst Mol Biotechnol, A-1030 Vienna, Austria. Katholieke Univ Leuven, Sch Med, Dev Neurobiol Unit, B-3000 Louvain, Belgium. NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Nimpf, J (reprint author), Med Univ Vienna, Max F Perutz Labs, Dept Med Biochem, Univ Dept Vienna Bioctr, A-1030 Vienna, Austria. EM johannes.nimpf@meduniwien.ac.at OI Howell, Brian/0000-0002-0204-0773; Jossin, Yves/0000-0001-8466-7432 NR 36 TC 41 Z9 46 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 15 PY 2007 VL 104 IS 20 BP 8508 EP 8513 DI 10.1073/pnas.0611391104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 169NW UT WOS:000246599900057 PM 17494763 ER PT J AU Johanneson, B Deutsch, K McIntosh, L Friedrichsen-Karyadi, DM Jarier, M Kwon, EM Iwasaki, L Hood, L Ostrander, EA Stanford, JL AF Johanneson, Bo Deutsch, Kerry McIntosh, Laura Friedrichsen-Karyadi, Danielle M. Jarier, Marta Kwon, Erika M. Iwasaki, Lori Hood, Leroy Ostrander, Elaine A. Stanford, Janet L. TI Suggestive genetic linkage to chromosome 11p11.2-q12.2 in hereditary prostate cancer families with primary kidney cancer SO PROSTATE LA English DT Article DE hereditary prostate cancer; kidney cancer; renal cancer; linkage analysis ID AUTOSOMAL-DOMINANT INHERITANCE; MALIGNANT HUMAN TISSUES; RENAL-CELL CARCINOMA; MEMBRANE ANTIGEN; SEGREGATION ANALYSIS; SUSCEPTIBILITY LOCUS; BREAST-CANCER; GENOMIC SCAN; RISK; POPULATION AB BACKGROUND. The Seattle-based PROGRESS study was started in 1995 to ascertain hereditary prostate cancer (HPC) families for studies of genetic susceptibility. Subsequent studies by several research groups, including our own, suggest that HPC is a genetically D heterogeneous disease. To be successful in mapping loci for such a complex disease, one must consider ways of grouping families into subsets that likely share the same genetic origin. Towards that end, we analyzed a genome-wide scan of HPC families with primary kidney cancer. METHODS. An 8.1 cM genome-wide scan including 441 microsatellite markers was analyzed by both parametric and non-parametric linkage approaches in fifteen HPC families with the cooccurrence of kidney cancer. RESULTS. There was no evidence for significant linkage in the initial findings. However, two regions of suggestive linkage were observed at 11q12 and 4q21, with HLOD scores of 2.59 and 2.10, respectively. The primary result on chromosome 11 was strengthened after excluding two families with members who had rare transitional cell carcinoma (TCC). Specifically, we observed a non-parametric Kong and Cox P-value of 0.004 for marker D11S1290 at 11p11.2. The 8 cM region between 11p11.2 and 11q12.2 was refined by the addition of 16 new markers. The subset of HPC families with a median age of diagnosis > 65 years demonstrated the strongest evidence for linkage, with an HLOD = 2.50. The P-values associated with non-parametric analysis ranged from 0.004 to 0.05 across five contiguous markers. CONCLUSIONS. Analysis of HPC families with members diagnosed with primary renal cell carcinoma demonstrates suggestive linkage to chromosome 11p11.2-q12.2. C1 Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98109 USA. Fred Hutchinson Canc Res Ctr, Div Human Biol, Seattle, WA 98109 USA. Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. Inst Syst Biol, Seattle, WA USA. NHGRI, Canc Genet Branch, NIH, Bethesda, MD 20892 USA. RP Stanford, JL (reprint author), Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, M4-B874,POB 19024, Seattle, WA 98109 USA. EM jstanfor@fhcrc.org OI Ostrander, Elaine/0000-0001-6075-9738 FU NCI NIH HHS [R01 CA089600, R01 CA080122, R01 CA78836] NR 65 TC 6 Z9 6 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 MAY 15 PY 2007 VL 67 IS 7 BP 732 EP 742 DI 10.1002/pros.20528 PG 11 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 161NM UT WOS:000246022200006 PM 17372923 ER PT J AU Ziolkowska, NE Shenoy, SR O'Keefe, BR McMahon, JB Palmer, KE Dwek, RA Wormald, MR Wlodawer, A AF Ziolkowska, Natasza E. Shenoy, Shilpa R. O'Keefe, Barry R. McMahon, James B. Palmer, Kenneth E. Dwek, Raymond A. Wormald, Mark R. Wlodawer, Alexander TI Crystallographic, thermodynamic, and molecular modeling studies of the mode of binding of oligosaccharides to the potent antiviral protein griffithsin SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE lectin; anti-HIV; anti-viral; oligosaccharide binding; carbohydrate modeling ID ANTI-HIV PROTEIN; HUMAN-IMMUNODEFICIENCY-VIRUS; CRYSTAL-STRUCTURES; STRUCTURAL BASIS; CYANOVIRIN-N; GLYCOPROTEIN; RECOGNITION; ENVELOPE; LECTINS; NMR AB The mode of binding of oligosaccharides to griffithsin, ark antiviral lectin from the red alga Griffithsia sp., wits investigated by a combination of X-ray crystallography, isothermal titration calorimetry, and molecular modeling. The structures of complexes of griffithsin with 1 -> 6 alpha-mannobiose and With maltose were solved and refined at the resolution of 2.0 and 1.5 angstrom, respectively. The thermodynamic parameters of binding of 1 -> 6 alpha-mannobiose, maltose, and mannose to griffithsin were determined. Binding profiles of 1 6 alpha-mannobiose and mainnose were similar with K-d values of 83.3 mu M and 102 mu M, respectively. The binding of maltose to griffithsin was significantly weaker, with a fourfold lower affinity,(K-d = 394 mu M). In all cases the binding at 30 degrees C was entropically rather than enthalpically driven. On the basis of the experimental crystal structures, as well as on previously determined structures of complexes with monosaccharides, it was possible to create a model of a tridentate complex of griffithsin with MangGIcNAC(2), a high mannose oligosaccharide commonly found on the surface of viral glycoproteins. All shorter oligomannoses could be modeled only as bidentate or monodentate complexes with griffithsin. The ability to mediate tight multivalent and multisite interactions with high-mannose oligosaccharides helps to explain the potent antiviral activity of griffithsin. C1 NCI, Macromol Crystallog Lab, Prot Struct Sect, Frederick, MD 21702 USA. SAIC Frederick Inc, Mol Targets Dev Program, NCI, Ft Detrick, MD 21702 USA. NCI, Mol Targets Dev Program, Canc Res Ctr, Ft Detrick, MD 21702 USA. Univ Louisville, James Graham Brown Canc Ctr, Dept Pharmacol & Toxicol, Louisville, KY 40202 USA. Univ Oxford, Dept Biochem, Oxford Glycobiol Inst, Oxford OX1 3QU, England. RP Wlodawer, A (reprint author), NCI, Macromol Crystallog Lab, Prot Struct Sect, Frederick, MD 21702 USA. EM wlodawer@ncifcrf.gov RI Wormald, Mark/G-2785-2011; OI Wormald, Mark/0000-0002-4853-2773; Palmer, Kenneth/0000-0002-2811-1111 FU NCI NIH HHS [N01-CO-12400]; NIAID NIH HHS [R01 AI076169-01A2, R01 AI076169] NR 26 TC 31 Z9 31 U1 1 U2 9 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 MAY 15 PY 2007 VL 67 IS 3 BP 661 EP 670 DI 10.1002/prot.21336 PG 10 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 157TE UT WOS:000245743100015 PM 17340634 ER PT J AU Pearl, JP Xu, H Leopardi, F Preston, E Kirk, AD AF Pearl, Jonathan P. Xu, He Leopardi, Frank Preston, Edwin Kirk, Allan D. TI CD154 blockade, sirolimus, and donor-specific transfusion prevents renal allograft rejection in cynomolgus monkeys despite homeostatic T-cell activation SO TRANSPLANTATION LA English DT Article DE primate models; costimulation; renal transplantation ID LONG-TERM SURVIVAL; INTRAHEPATIC ISLET ALLOGRAFTS; NONHUMAN PRIMATE MODEL; MEMORY-LIKE PHENOTYPE; MONOCLONAL-ANTIBODY; TRANSPLANTATION TOLERANCE; ANTI-CD154 ANTIBODY; COSTIMULATORY REQUIREMENTS; HUMANIZED ANTI-CD154; SKIN ALLOGRAFTS AB Background. CD154-specific antibodies have been shown to prevent acute rejection in many preclinical models including nonhuman primates (NHPs). However, they have been ineffective in pilot clinical trials, suggesting a need for more robust preclinical analysis. One factor affecting the disparate results may be related to the recipient's immune activation state. Specifically, adult humans have a high percentage of memory-phenotype T cells compared to young animals. Postdepletional homeostatic repopulation has been shown to enrich for memory-phenotype T cells and interfere with CD154-based therapies in rodents. Methods. We developed a NHP model nonspecifically enriched for peripheral memory-phenotype T cells. Thymectomized cynomolgus macaques underwent depletion with polyclonal anti-thymocyte globulin followed by repopulation. Peripheral phenotype was serially determined using polychromatic flow cytometry. In vitro response to donor and environmental antigens was also confirmed before and after manipulation. We then tested a regimen previously successful in rhesus monkeys combining anti-CD154, sirolimus, and donor-specific blood transfusion (DST), in a second primate species with and without the provocation of increased peripheral homeostatic T-cell activation. Results. Monkeys that were thymectomized (n=3) and depleted recovered via homeostatic repopulation with a repertoire enriched for cells with a memory surface phenotype compared to unmanipulated controls (n=3). Despite a repertoire markedly enriched for memory-phenotype cells, the regimen effectively prevented acute rejection for the duration of therapy. Conclusions. Cynomolgus monkeys can be rendered memory phenotype enriched using homeostatic repopulation. Despite a generally activated T-cell repertoire, anti-CD154, sirolimus, and DST effectively prevents rejection in cynomoigus monkeys. C1 NIDDK, Transplantat Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD USA. USN, Natl Med Ctr, Dept Surg, Bethesda, MD 20084 USA. Georgetown Univ Hosp, Dept Surg, Washington, DC 20007 USA. RP Kirk, AD (reprint author), Room 5-5752,Bldg 10CRC,10 Ctr Dr, Bethesda, MD 20892 USA. EM allank@intra.niddk.nih.gov RI Kirk, Allan/B-6905-2012 FU Intramural NIH HHS NR 43 TC 15 Z9 18 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD MAY 15 PY 2007 VL 83 IS 9 BP 1219 EP 1225 DI 10.1097/01.tp.0000259929.04596.d5 PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 170MW UT WOS:000246668500014 PM 17496539 ER PT J AU Dhingra, R Sullivan, LM Fox, CS Wang, TJ D'Agostino, RB Gaziano, JM Vasan, RS AF Dhingra, Ravi Sullivan, Lisa M. Fox, Caroline S. Wang, Thomas J. D'Agostino, Ralph B. Gaziano, J. Michael Vasan, Ramachandran S. TI Relations of serum phosphorus and calcium levels to the incidence of cardiovascular disease in the community SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID CORONARY-ARTERY-DISEASE; PARATHYROID-HORMONE; MORTALITY RISK; HEMODIALYSIS-PATIENTS; BLOOD-PRESSURE; RENAL-DISEASE; YOUNG-ADULTS; KLOTHO GENE; PHOSPHATE; CALCIFICATION AB Background: Higher levels of serum phosphorus and the calcium-phosphorus product are associated with increased mortality from cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) or prior CVD. However, it is unknown if serum phosphorus levels influence vascular risk in individuals without CKD or CVD. Methods: We prospectively evaluated 3368 Framingham Offspring study participants (mean age, 44 years; 51% were women) free of CVD and CKD. We used multivariable Cox models to relate serum phosphorus and calcium levels to CVD incidence. Results: On follow-up (mean duration, 16.1 years), there were 524 incident CVD events (159 in women). In multivariable analyses and adjusting for established risk factors and additionally for glomerular filtration rate and for hemoglobin, serum albumin, proteinuria, and C-reactive protein levels, a higher level of serum phosphorus was associated with an increased CVD risk in a continuous fashion (adjusted hazard ratio per increment of milligrams per deciliter, 1.31; 95% confidence interval, 1.05-1.63; P = .02; P value for trend across quartiles =. 004). Individuals in the highest serum phosphorus quartile experienced a multivariable-adjusted 1.55-fold CVD risk (95% confidence interval, 1.16%-2.07%; P = .004) compared with those in the lowest quartile. These findings remained robust in time-dependent models that up-dated CVD risk factors every 4 years and in analyses restricted to individuals without proteinuria and an estimated glomerular filtration rate greater than 90 mL/min per 1.73 m(2). Serum calcium was not related to CVD risk. Conclusion: Higher serum phosphorus levels are associated with an increased CVD risk in individuals free of CKD and CVD in the community. These observations emphasize the need for additional research to elucidate the potential link between phosphorus homeostasis and vascular risk. C1 NHLBI, Framingham Heart Study, Framingham, MA 01702 USA. Brigham & Womens Hosp, Masachusetts Vet Epidemiol Res & Informat Ctr, Vet Adm Boston Healthcare Syst, Boston, MA 02115 USA. Brigham & Womens Hosp, Div Aging, Boston, MA 02115 USA. Alice Peck Day Mem Hosp, Dept Med, Lebanon, NH USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02215 USA. Boston Univ, Cardiol Sect, Boston, MA 02215 USA. Boston Univ, Dept Prevent Med & Epidemiol, Sch Med, Boston, MA 02215 USA. NHLBI, Bethesda, MD USA. RP Vasan, RS (reprint author), NHLBI, Framingham Heart Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM vasan@bu.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [K23HL74077, 1R01HL67288, 2K24HL04334, N01-HC-25195] NR 46 TC 397 Z9 413 U1 3 U2 11 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 MAY 14 PY 2007 VL 167 IS 9 BP 879 EP 885 DI 10.1001/archinte.167.9.879 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 167LX UT WOS:000246454300004 PM 17502528 ER PT J AU Prabhu, Y Muller, R Anjard, C Noegel, AA AF Prabhu, Yogikala Mueller, Rolf Anjard, Christophe Noegel, Angelika A. TI GrIJ, a Dictyostelium GABA(B)-like receptor with roles in post-aggregation development SO BMC DEVELOPMENTAL BIOLOGY LA English DT Article ID CELL-ADHESION MOLECULE; PROTEIN-COUPLED RECEPTORS; TERMINAL DIFFERENTIATION; ENDOCYTIC PATHWAY; GENE-EXPRESSION; DISCOIDEUM; BINDING; ACTIN; MORPHOGENESIS; MUTANTS AB Background: The G-protein-coupled receptor (GPCR) family represents the largest and most important group of targets for chemotherapeutics. They are extremely versatile receptors that transduce signals as diverse as biogenic amines, purins, odorants, ions and pheromones from the extracellular compartment to the interior via biochemical processes involving GTP-binding proteins. Until recently, the cyclic AMP receptors (cARs) were the only known G protein coupled receptors in Dictyostelium discoideum. The completed genome sequence revealed the presence of several families of GPCRs in Dictyostelium, among them members of the family 3 of GPCRs, the GABA(B)/ glutamate like receptor family, which in higher eukaryotes is involved in neuronal signaling. Results: D. discoideum has seventeen Family 3 members of GPCRs, denoted GrlA through GrlR. Their transcripts are detected throughout development with increased levels during early and late development. We have examined here GrlJ. GFP- tagged GrlJ localises to the plasmamembrane and to internal membranes. Inactivation of the grlJ gene leads to precocious development, and the mutant completes development similar to 6 hours earlier. Alterations were also noted at the slug stage and in spore formation. grlJ- slugs were longer and broke apart several times on their way to culmination forming smaller but proportionate fruiting bodies. Spores from grlJ- fruiting bodies were malformed and less viable, although the spore differentiation factors were synthesized and sensed normally. Expression of a GFP- tagged full length GrlJ rescued the phenotype. Conclusion: Our data suggest that GrlJ acts at several stages of Dictyostelium development and that it is a negative regulator in Dictyostelium development. C1 Univ Cologne, Fac Med, Ctr Biochem, Inst Biochem, D-50931 Cologne, Germany. Univ Cologne, Ctr Mol Med Cologne, D-50931 Cologne, Germany. Univ Calif San Diego, Ctr Mol Genet, Div Biol Sci, La Jolla, CA 92093 USA. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Noegel, AA (reprint author), Univ Cologne, Fac Med, Ctr Biochem, Inst Biochem, Joseph Stelzmann Str 52, D-50931 Cologne, Germany. EM prabhuyo@mail.nih.gov; rolf.mueller@uni-koeln.de; canjard@biomail.ucsd.edu; noegel@uni-koeln.de NR 52 TC 10 Z9 28 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-213X J9 BMC DEV BIOL JI BMC Dev. Biol. PD MAY 14 PY 2007 VL 7 AR 44 DI 10.1186/1471-213X-7-44 PG 14 WC Developmental Biology SC Developmental Biology GA 174XY UT WOS:000246977400001 PM 17501984 ER PT J AU Difilippantonio, S Celeste, A Kruhlak, M Lee, Y Difilippantonio, MJ Feigenbaum, L Jackson, SP McKinnon, PJ Nussenzweig, A AF Difilippantonio, Simone Celeste, Arkady Kruhlak, Michael Lee, Youngsoo Difilippantonio, Michael J. Feigenbaum, Lionel Jackson, Stephen P. McKinnon, Peter J. Nussenzweig, Andre TI Distinct domains in Nbs1 regulate irradiation-induced checkpoints and apoptosis SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID NIJMEGEN-BREAKAGE-SYNDROME; DOUBLE-STRAND BREAKS; DNA-DAMAGE-RESPONSE; FORKHEAD-ASSOCIATED DOMAIN; S-PHASE CHECKPOINT; ATM ACTIVATION; ATAXIA-TELANGIECTASIA; MRE11 COMPLEX; IONIZING-RADIATION; MRE11-RAD50-NBS1 COMPLEX AB The chromosomal instability syndromes Nijmegen breakage syndrome (NBS) and ataxia telangiectasia (AT) share many overlapping phenotypes, including cancer predisposition, radiation sensitivity, cell-cycle checkpoint defects, immunodeficiency, and gonadal dysfunction. The NBS protein Nbs1 is not only a downstream target of AT mutated (ATM) kinase but also acts upstream, promoting optimal ATM activation, ATM recruitment to breaks, and ATM accessibility to substrates. By reconstituting Nbs1 knockout mice with bacterial artificial chromosomes, we have assessed the contribution of distinct regions of Nbs1 to the ATM-dependent DNA damage response. We fi nd that T cell and oocyte development, as well as DNA damage-induced G2/M and S phase checkpoint arrest and radiation survival are dependent on the N-terminal forkhead-associated domain, but not on the principal residues phosphorylated by ATM (S278 and S343) or on the evolutionarily conserved C-terminal region of Nbs1. However, the C-terminal region regulates irradiation-induced apoptosis. These studies provide insight into the complex interplay between Nbs1 and ATM in the DNA damage response. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. St Jude Childrens Res Hosp, Dept Genet & Tumor Cell Biol, Memphis, TN 38105 USA. Natl Canc Inst, Frederick Canc Res & Dev Ctr, SAIC Frederick, Ft Detrick, MD 21702 USA. Univ Cambridge, Dept Zool, Cambridge CB2 1QN, England. Univ Cambridge, Wellcome Trust Canc Res UK Gurdon Inst, Cambridge CB2 1QN, England. RP Nussenzweig, A (reprint author), NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. EM andre_nussenzweig@nih.gov RI Dry, Kate/I-2328-2014; OI Jackson, Stephen Philip/0000-0001-9317-7937 FU Cancer Research UK [A5290]; Intramural NIH HHS [Z99 CA999999] NR 56 TC 56 Z9 58 U1 0 U2 2 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 MAY 14 PY 2007 VL 204 IS 5 BP 1003 EP 1011 DI 10.1084/jem.20070319 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 167RA UT WOS:000246467600006 PM 17485521 ER PT J AU Crouch, EE Li, ZY Takizawa, M Fichtner-Feigl, S Gourzi, P Montano, C Feigenbaum, L Wilson, P Janz, S Papavasiliou, FN Casellas, R AF Crouch, Elizabeth E. Li, Zhiyu Takizawa, Makiko Fichtner-Feigl, Stefan Gourzi, Polyxeni Montano, Carolina Feigenbaum, Lionel Wilson, Patrick Janz, Siegfried Papavasiliou, F. Nina Casellas, Rafael TI Regulation of AID expression in the immune response SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID INDUCED CYTIDINE DEAMINASE; CENTER B-CELLS; CLASS SWITCH RECOMBINATION; SOMATIC HYPERMUTATION; GENE-EXPRESSION; LAMINA PROPRIA; PLASMA-CELLS; MICE LACKING; MU-CHAIN; IMMUNOGLOBULIN AB The B cell-specific enzyme activation-induced cytidine deaminase (AID) has been shown to be essential for isotype switching and affinity maturation of antibody genes during the immune response. Conversely, AID activity has also been linked to autoimmunity and tumorigenesis. Determining how AID expression is regulated in vivo is therefore central to understanding its role in health and disease. Here we use phylogenetic footprinting and high-resolution histone acetylation mapping to accurately demarcate AID gene regulatory boundaries. Based on this strategy, we identify a novel, positive regulatory element required for AID transcription. Furthermore, we generate two AID indicator mouse strains using bacterial artificial chromosomes that faithfully recapitulate endogenous AID expression. The first strain uses a green fluorescent protein reporter to identify B cells that actively express AID during the immune response. In the second strain, AID transcription affects the permanent expression of a yellow fluorescent protein reporter in post-germinal center and terminally differentiated lymphocytes. We demonstrate the usefulness of these novel strains by resolving recent contradictory observations on AID expression during B cell ontogeny. C1 NCI, Genom Integr & Immun, NIAMS, NIH, Bethesda, MD 20892 USA. NCI, NIAID, Mucosal Immun Sect, NIH, Bethesda, MD 20892 USA. NCI, Lab Genet, NIH, Bethesda, MD 20892 USA. Rockefeller Univ, Lab Lymphocyte Biol, New York, NY 10021 USA. NCI, Lab Anim Sci Program, Sci Applicat Int Corp, SAIC,NIH, Ft Detrick, MD 21702 USA. Oklahoma Med Res Fdn, Mol Immunogenet, Oklahoma City, OK 73104 USA. RP Casellas, R (reprint author), NCI, Genom Integr & Immun, NIAMS, NIH, Bethesda, MD 20892 USA. EM casellar@mail.nih.gov FU Intramural NIH HHS NR 55 TC 136 Z9 142 U1 0 U2 6 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 MAY 14 PY 2007 VL 204 IS 5 BP 1145 EP 1156 DI 10.1084/jem.20061952 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 167RA UT WOS:000246467600018 PM 17452520 ER PT J AU Umhau, JC AF Umhau, John C. TI Folate and ageing SO LANCET LA English DT Letter ID DOCOSAHEXAENOIC ACID; ALZHEIMER-DISEASE; PLASMA C1 NIAAA, Lab Clin & Translat Studies, NIH, CRC, Bethesda, MD 20892 USA. RP Umhau, JC (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, CRC, 10 Ctr Dr,Room 1-5330, Bethesda, MD 20892 USA. EM umhau@nih.gov NR 5 TC 1 Z9 1 U1 0 U2 0 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD MAY 12 PY 2007 VL 369 IS 9573 BP 1602 EP 1602 DI 10.1016/S0140-6736(07)60745-4 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 167YO UT WOS:000246488800027 PM 17499600 ER PT J AU Brogly, SB Ylitalo, N Mofenson, LM Oleske, J Van Dyke, R Crain, MJ Abzug, MJ Brady, M Jean-Philippe, P Hughes, MD Seage, GR AF Brogly, Susan B. Ylitalo, Nathalie Mofenson, Lynne M. Oleske, James Van Dyke, Russell Crain, Marilyn J. Abzug, Mark J. Brady, Michael Jean-Philippe, Patrick Hughes, Michael D. Seage, George R., III TI In utero nucleoside reverse transcriptase inhibitor exposure and signs of possible mitochondrial dysfunction in HIV-uninfected children SO AIDS LA English DT Article DE children; HIV; mitochondria; zidovudine; lamivudine; pregnancy; toxicity ID ANTIEPILEPTIC DRUGS; COCAINE EXPOSURE; ZIDOVUDINE; TRANSMISSION; THERAPY; INFANTS; MOTHER; NEURODEVELOPMENT; CARDIOMYOPATHY; LAMIVUDINE AB Background: There is equivocal evidence of in utero nucleoside reverse transcriptase inhibitor (NRTI) exposure and the occurrence of mitochondrial dysfunction (MD) in HIV-uninfected children born of HIV-infected women. Methods: The primary analysis included 1037 HIV-uninfected children born in 19912002 and enrolled in Pediatric AIDS Clinical Trials Group protocols 219/219C. Possible cases with unexplained signs of MD according to the Enquete Perinatale Francaise criteria were identified through retrospective review. Associations between overall in utero NRTI exposure, and trimester of first in utero NRTI exposure and possible MD were estimated with exact logistic regression. Results: Cases (n = 20) were significantly more likely to be male and to be born in earlier years than non-cases (n = 1017). There was no association between overal I in utero NRTI exposure and MD. In unadjusted models there were higher odds of first in utero exposure in the third trimester to lamivudine (3TC) [odds ratio (OR), 3.76 versus 3TC unexposed; 95% confidence interval (CI), 1.09-11.78] and to zidovudine (ZDV) and 3TC in combination (ZDV/3TC) (OR, 3.29 vs. ZDV/3TC unexposed; 95% CI, 0.96-10.25) among cases than noncases. When adjusted for year of birth the odds of first exposure in the third trimester to 3TC (OR, 10.57; 95% CI, 1.93-75.61) and ZDV/3TC (OR, 9.84; 95% CI, 1.77-71.68) were significantly higher among cases than non-cases. Incomplete data precluded control of possible confounding by maternal viral load and psychoactive drug use. Conclusions: Our study suggests that first exposure to 3TC or ZDV/3TC in the third trimester may be associated with the occurrence of possible MD. Further studies that rigorously assess MD and better control confounding are needed. (C) 2007 Lippincott Williams & Wilkins. C1 Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. NICHHD, Pediat Adolescent & Maternal AIDS Branch, Rockville, MD USA. Univ Med & Dent New Jersey, Dept Pediat, Newark, NJ 07103 USA. Tulane Univ, Hlth Sci Ctr, Dept Pediat, New Orleans, LA 70118 USA. Univ Alabama, Dept Pediat Infect Dis, Birmingham, AL USA. Univ Colorado, Sch Med, Dept Pediat Infect Dis, Denver, CO 80202 USA. Childrens Hosp, Denver, CO 80218 USA. Childrens Hosp, Dept Infect Dis, Columbus, OH 43205 USA. NIAID, Div Aids, Henry M Jackson Fdn, Bethesda, MD 20892 USA. RP Seage, GR (reprint author), Harvard Univ, Sch Publ Hlth, Dept Epidemiol, 677 Huntington Ave, Boston, MA 02115 USA. EM gseage@hsph.harvard.edu OI Mofenson, Lynne/0000-0002-2818-9808 FU NIAID NIH HHS [5 U01 AI41110] NR 32 TC 68 Z9 71 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 MAY 11 PY 2007 VL 21 IS 8 BP 929 EP 938 DI 10.1097/QAD.0b013e3280d5a786 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 171RW UT WOS:000246754100005 PM 17457086 ER PT J AU Liang, ZQ Li, YL Zhao, XL Han, R Wang, XX Wang, Y Chase, TN Bennett, MC Qin, ZH AF Liang, Zhong-Qin Li, Yun-Lin Zhao, Xi-Lin Han, Rong Wang, Xiaom-Xia Wang, Yumei Chase, Thomas N. Bennett, M. Catherine Qin, Zheng-Hong TI NF-kappa B contributes to 6-hydroxydopainine-induced apoptosis of nigral dopaminergic neurons through p53 SO BRAIN RESEARCH LA English DT Article DE 6-hydroxydopamine; oxidative stress; Parkinson's disease; NF-kappa B; p53; c-Myc ID PARKINSONS-DISEASE; ALPHA-SYNUCLEIN; CELL-DEATH; NUCLEAR TRANSLOCATION; OXIDATIVE STRESS; RAT STRIATUM; PC12 CELLS; NEURODEGENERATIVE DISEASES; MITOCHONDRIAL DYSFUNCTION; TRANSGENIC MICE AB To evaluate the contribution of NF-kappa B and the NF-kappa B target gene p53 to nigral dopaminergic neuron degeneration in rodent models of Parkinson's disease, time-course of dopaminergic neuron loss as well as changes in the expression of some NF-kappa B-regulated proapoptotic proteins were assayed after unilateral infusion of 6-hydroxydopamine into rat medial forebrain bundle. Substantial loss of tyrosine hydroxylase immunoreactivity in nigral was observed 24 h after 6-hydroxydopamine treatment. The degenerative processes began 12 h after 6-hydroxydopamine administration as evidenced by a positive silver staining. Apoptotic death of dopaminergic neurons was suggested by the appearance of TUNEL-positive nuclei in substantia nigra and internucleosomal DNA fragmentation as detected by agarose gel electrophoresis. NF-kappa B activation in dopaminergic neurons as revealed by immunohistochemistry and electrophoresis mobility shift assay, began at 12 h after 6-hydroxydopamine administration. Levels of c-Myc and p53 immunore activities increased after 6-hydroxydopamine treatment, mainly in dopaminergic neurons as indicated by co-localization with tyrosine hydroxylase immunoreactivity. Blockade of NF-kappa B nuclear translocation with recombinant cell-permeable peptide NF-kappa B SN50 inhibited NF-kappa B nuclear translocation and p53 induction. SN50 and the p53 antagonist pifithrin-alpha significantly reduced nigral dopaminergic neuron degeneration. These results suggest that NF-kappa B activation contributes, at least in part, to oxidative stress-induced degeneration of dopaminergic neurons through a NF-kappa B-dependent p53-signaling pathway. (c) 2007 Elsevier B.V. All rights reserved. C1 Soochow Univ, Sch Med, Dept Pharmacol, Suzhou 215123, Peoples R China. NINDS, Expt Therapeut Branch, NIH, Bethesda, MD 20892 USA. Blanchette Rockefeller Neurosci Inst, Rockville, MD USA. RP Qin, ZH (reprint author), Soochow Univ, Sch Med, Dept Pharmacol, Suzhou Singapore Ind Pk, Suzhou 215123, Peoples R China. EM zhqin5@hotmail.com NR 58 TC 50 Z9 55 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAY 11 PY 2007 VL 1145 BP 190 EP 203 DI 10.1016/j.brainres.2007.01.130 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 164UR UT WOS:000246260600020 PM 17368433 ER PT J AU Staniszewska, I Zaveri, S Del Valle, L Oliva, I Rothman, VL Croul, SE Roberts, DD Mosher, DF Tuszynski, GP Marcinkiewicz, C AF Staniszewska, Izabela Zaveri, Shachi Del Valle, Luis Oliva, Isabela Rothman, Vicki L. Croul, Sidney E. Roberts, David D. Mosher, Deane F. Tuszynski, George P. Marcinkiewicz, Cezary TI Interaction of alpha 9 beta 1 integrin with thrombospondin-1 promotes angiogenesis SO CIRCULATION RESEARCH LA English DT Article DE integrins; thrombospondin; angiogenesis ID ENDOTHELIAL-CELL RESPONSES; IN-VITRO; STRUCTURAL REQUIREMENTS; TENASCIN-C; III REPEAT; ALPHA-4-BETA-1; LIGAND; FIBRONECTIN; MIGRATION; MATRIX AB Thrombospondin-1 is a multifunctional protein interacting with several cell surface receptors including integrins. We found that it is a ligand for alpha 9 beta 1 integrin, and has an integrin binding site within its N-terminal domain (NoC1). Interaction of thrombospondin- 1 and its recombinant NoC1 domain with alpha 9 beta 1 integrin was confirmed in ELISA and cell adhesion assays. Binding of NoC1 to cells expressing alpha 9 beta 1 integrin activated signaling proteins such as Erk1/2 and paxillin. Blocking of this integrin by monoclonal antibody and the met-leu-asp-disintegrin inhibited dermal human microvascular endothelial cell proliferation and NoC1-induced migration of these cells. Immunohistochemical studies revealed that alpha 9 beta 1 is expressed on microvascular endothelium in several organs including skin, lung, heart and brain. NoC1 induced neovascularization in an experimental quail chorioallantoic membrane system and Matrigel plug formation assay in mice. This proangiogenic activity of NoC1 in vivo was inhibited by alpha 9 beta 1 inhibitors. In summary, our results revealed that alpha 9 beta 1 integrin expressed on microvascular endothelial cells interacts with thrombospondin-1, and this interaction is involved in modulation of angiogenesis. C1 Temple Univ, Sch Med, Dept Neurosci, Ctr Neurovirol, Philadelphia, PA 19122 USA. Univ Toronto, Dept Med & Pathobiol, Toronto, ON, Canada. Natl Canc Inst, Pathol Lab, NIH, Bethlehem, PA USA. Univ Wisconsin, Dept Med, Madison, WI 53706 USA. RP Marcinkiewicz, C (reprint author), Temple Univ, Sch Med, Dept Neurosci, Ctr Neurovirol, 1900n 12th St, Philadelphia, PA 19122 USA. EM cmarcink@temple.edu RI Roberts, David/A-9699-2008; Del Valle, Luis/J-4085-2015 OI Roberts, David/0000-0002-2481-2981; Del Valle, Luis/0000-0003-3894-9206 FU NCI NIH HHS [5R01CA100145, R01CA88931]; NHLBI NIH HHS [R01HL54462] NR 38 TC 63 Z9 67 U1 1 U2 2 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 MAY 11 PY 2007 VL 100 IS 9 BP 1308 EP 1316 DI 10.1161/01.RES.0000266662.98355.66 PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 166SA UT WOS:000246399100008 PM 17413041 ER PT J AU Zofall, M Grewal, SIS AF Zofall, Martin Grewal, Shiv I. S. TI HULC, a histone H2B ubiquitinating complex, modulates heterochromatin independent of histone methylation in fission yeast SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RNA-POLYMERASE-II; H3 LYSINE-4 METHYLATION; JMJC DOMAIN PROTEIN; SCHIZOSACCHAROMYCES-POMBE; CHROMOSOME SEGREGATION; TRANSCRIPTIONAL ACTIVATION; SACCHAROMYCES-CEREVISIAE; CHROMODOMAIN PROTEIN; CONJUGATING ENZYMES; EPIGENETIC CONTROL AB Heterochromatin in fission yeast is targeted dynamically by opposing chromatin-modifying activities capable of alleviating or promoting transcriptional gene silencing. In this study, we report the biochemical and genetic characterization of a ubiquitin-conjugating enzyme Rhp6 (a homolog of budding yeast Rad6), which has been shown to negatively affect stability of heterochromatic structures. We show that Rhp6 is a component of the multisubunit protein complex (termed HULC) that also contains two RING finger proteins Rfp1 and Rfp2, sharing homology with budding yeast Bre1 protein and a unique serine-rich protein Shf1. HULC is required for ubiquitination of histone H2B at lysine 119 (H2B-K119), and it localizes to heterochromatic sequences. Moreover, our analyses suggest that Rhp6-induced changes in heterochromatic silencing are mediated predominantly through H2B ubiquitination (ubH2B), and they correlate with increased RNA polymerase II levels at repeat elements embedded within heterochromatin domains. Interestingly, heterochromatic derepression caused by Rhp6 occurs independently of the involvement of HULC subunits and ubH2B in methylation of histone H3 at lysine 4 (H3K4me). These analyses implicate ubH2B in modulation of heterochromatin, which has important implications for dynamics and many functions associated with heterochromatic structures. C1 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 FU Intramural NIH HHS NR 74 TC 24 Z9 29 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 MAY 11 PY 2007 VL 282 IS 19 BP 14065 EP 14072 DI 10.1074/jbc.M700292200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 164PJ UT WOS:000246245800016 PM 17363370 ER PT J AU Gloyd, M Ghirlando, R Matthews, LA Guarne, A AF Gloyd, Melanie Ghirlando, Rodolfo Matthews, Lindsay A. Guarne, Alba TI MukE and MukF form two distinct high affinity complexes SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ESCHERICHIA-COLI; DNA INTERACTIONS; SMC PROTEINS; BACTERIAL; KLEISINS; HINGE; ULTRACENTRIFUGATION; ARCHITECTURE; CHROMOSOMES; ACTIVATION AB The MukBFE complex is essential for chromosome segregation and condensation in Escherichia coli. MukB is functionally related to the structural maintenance of chromosomes (SMC) proteins. Similar to SMCs, MukB requires accessory proteins (MukE and MukF) to form a functional complex for DNA segregation. MukF is a member of the kleisin family, which includes proteins that commonly mediate the interaction between SMCs and other accessory proteins, suggesting that the similarities between the MukBFE and the SMC complexes extend beyond MukB. Although SMCs have been carefully studied, little is known about the roles of their accessory components. In the present work, we characterize the oligomeric states of MukE and MukF using size exclusion chromatography and analytical ultracentrifugation. MukE self-associates to form dimers (K-D 18 +/- 3 mu M), which in turn interact with the MukF dimer to form two distinct high affinity complexes having 2: 2 and 2: 4 stoichiometries (F: E). Intermediate complexes are not found, and thus we propose that the equilibrium between these two complexes determines the formation of a functional MukBFE with stoichiometry 2:2:2. C1 McMaster Univ, Dept Biochem & Biomed Sci, Hamilton, ON L8N 3Z5, Canada. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Guarne, A (reprint author), McMaster Univ, Dept Biochem & Biomed Sci, HSC 4N57A,1200 Main St W, Hamilton, ON L8N 3Z5, Canada. EM guarnea@mcmaster.ca RI Ghirlando, Rodolfo/A-8880-2009 FU Intramural NIH HHS NR 26 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 11 PY 2007 VL 282 IS 19 BP 14373 EP 14378 DI 10.1074/jbc.M701402200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 164PJ UT WOS:000246245800049 PM 17355972 ER PT J AU Cai, ML Huang, Y Suh, JY Louis, JM Ghirlando, R Craigie, R Clore, GM AF Cai, Mengli Huang, Ying Suh, Jeong-Yong Louis, John M. Ghirlando, Rodolfo Craigie, Robert Clore, G. Marius TI Solution NMR structure of the barrier-to-autointegration factor-emerin complex SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DREIFUSS MUSCULAR-DYSTROPHY; NUCLEAR-MAGNETIC-RESONANCE; MACROMOLECULAR STRUCTURE DETERMINATION; RESIDUAL DIPOLAR COUPLINGS; STRUCTURE REFINEMENT; LEM-DOMAIN; 3-DIMENSIONAL STRUCTURES; MOLECULAR-DYNAMICS; PROTEIN COMPLEXES; MEMBRANE PROTEIN AB The barrier-to-autointegration factor BAF binds to the LEM domain (Em(LEM)) of the nuclear envelope protein emerin and plays an essential role in the nuclear architecture of metazoan cells. In addition, the BAF(2) dimer bridges and compacts double-stranded DNA nonspecifically via two symmetry-related DNA binding sites. In this article we present biophysical and structural studies on a complex of BAF(2) and EmLEM. Light scattering, analytical ultracentrifugation, and NMR indicate a stoichiometry of one molecule of EmLEM bound per BAF(2) dimer. The equilibrium dissociation constant (K-d) for the interaction of the BAF(2) dimer and Em(LEM), determined by isothermal titration calorimetry, is 0.59 +/- 0.03 mu M. Z-exchange spectroscopy between corresponding cross-peaks of the magnetically non-equivalent subunits of the BAF(2) dimer in the complex yields a dissociation rate constant of 78 +/- 2 s(-1). The solution NMR structure of the BAF(2)-Em(LEM) complex reveals that the LEM and DNA binding sites on BAF(2) are non-overlapping and that both subunits of the BAF(2) dimer contribute approximately equally to the EmLEM binding site. The relevance of the implications of the structural and biophysical data on the complex in the context of the interaction between the BAF(2) dimer and EmLEM at the nuclear envelope is discussed. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. EM mariusc@intra.niddk.nih.gov RI Ghirlando, Rodolfo/A-8880-2009; Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 55 TC 43 Z9 45 U1 1 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 11 PY 2007 VL 282 IS 19 BP 14525 EP 14535 DI 10.1074/jbc.M700576200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 164PJ UT WOS:000246245800066 PM 17355960 ER PT J AU Galeeva, A Treuter, E Tomarev, S Pelto-Huikko, M AF Galeeva, A. Treuter, E. Tomarev, S. Pelto-Huikko, M. TI A prospero-related homeobox gene Prox-1 is expressed during postnatal brain development as well as in the adult rodent brain SO NEUROSCIENCE LA English DT Article DE embryonic transcription factors; Prox-1 homeobox gene; brain; postnatal development; rat; mouse ID CENTRAL-NERVOUS-SYSTEM; DENTATE GYRUS; MIGRATION; PROTEINS; CELLS; RAT; NEUROGENESIS; PATTERNS; SUMO AB Prox-1, a prospero-related homeobox gene, is known to be an important transcription factor during embryogenesis. However, very little is known about Prox-1 expression and functions in the adult nervous system. Here we have investigated the expression pattern of Prox-1 mRNA and protein during postnatal brain development and in adult rat and mouse brains using in situ hybridization (ISH), immunohistochemistry (IHC) and Western blotting. In the developing and adult brain, we found prominent, but restricted Prox-1 mRNA expression in the dentate gyrus of the hippocampus, in some thalamic nuclei, notably in the anterior thalamus, and in the cerebellar cortex. Other brain regions, such as the hypothalamus and nuclei belonging to the midbrain, revealed a moderate level of Prox-1 mRNA expression. In developing cerebral cortex, Prox-1 mRNA was seen only in the thin layer under the pial surface postnatally, and the signal almost disappeared by the 28th postnatal day (PD). Using IHC and ISH approaches, we demonstrated rather restricted, but intense Prox-1 labeling in adult brain of both rat and mouse species. During postnatal brain development Prox-1 proteins by IHC, were below the detection limit at PD 14, while Prox-1 mRNA remained at a high level. Western blotting demonstrated the existence of two different variants of Prox-1 protein, one of which was about 20 kDa larger than ordinary size. During the first PDs, the larger variant predominated. At PD 14, neither protein variant could be detected. From PD 16 onwards the smaller variant started to predominate and by PD 30 the larger size protein had almost disappeared. The prominent but limited distribution of Prox-1 in the brain suggests its potentially important role during postnatal brain development and in adult CNS, which remains to be ascertained in future studies. (C) 2006 Published by Elsevier Ltd on behalf of IBRO. C1 Tampere Univ, Dept Dev Biol, Sch Med, FIN-33014 Tampere, Finland. Karolinska Inst, Dept Biosci, Huddinge, Sweden. NEI, Sect Mol Mech Glaucoma, Lab Mol & Dev Biol, Bethesda, MD 20892 USA. RAS, Pavlov Inst Physiol, Dept Neuroendocrinol, St Petersburg, Russia. Tampere Univ Hosp, Dept Pathol, Tampere, Finland. RP Galeeva, A (reprint author), Tampere Univ, Dept Dev Biol, Sch Med, FIN-33014 Tampere, Finland. EM loanga@uta.fi NR 28 TC 25 Z9 26 U1 0 U2 4 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 MAY 11 PY 2007 VL 146 IS 2 BP 604 EP 616 DI 10.1016/j.neuroscience.2007.02.002 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 168OX UT WOS:000246535000015 PM 17368742 ER PT J AU Frayling, TM Timpson, NJ Weedon, MN Zeggini, E Freathy, RM Lindgren, CM Perry, JRB Elliott, KS Lango, H Rayner, NW Shields, B Harries, LW Barrett, JC Ellard, S Groves, CJ Knight, B Patch, AM Ness, AR Ebrahim, S Lawlor, DA Ring, SM Ben-Shlomo, Y Jarvelin, MR Sovio, U Bennett, AJ Melzer, D Ferrucci, L Loos, RJF Barroso, I Wareham, NJ Karpe, F Owen, KR Cardon, LR Walker, M Hitman, GA Palmer, CNA Doney, ASF Morris, AD Smith, GD Hattersley, AT McCarthy, MI AF Frayling, Timothy M. Timpson, Nicholas J. Weedon, Michael N. Zeggini, Eleftheria Freathy, Rachel M. Lindgren, Cecilia M. Perry, John R. B. Elliott, Katherine S. Lango, Hana Rayner, Nigel W. Shields, Beverley Harries, Lorna W. Barrett, Jeffrey C. Ellard, Sian Groves, Christopher J. Knight, Bridget Patch, Ann-Marie Ness, Andrew R. Ebrahim, Shah Lawlor, Debbie A. Ring, Susan M. Ben-Shlomo, Yoav Jarvelin, Marjo-Riitta Sovio, Ulla Bennett, Amanda J. Melzer, David Ferrucci, Luigi Loos, Ruth J. F. Barroso, Ines Wareham, Nicholas J. Karpe, Fredrik Owen, Katharine R. Cardon, Lon R. Walker, Mark Hitman, Graham A. Palmer, Colin N. A. Doney, Alex S. F. Morris, Andrew D. Smith, George Davey Hattersley, Andrew T. McCarthy, Mark I. CA Wellcome Trust Case Control TI A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity SO SCIENCE LA English DT Article ID FUSED TOES FT; CANDIDATE; ENPP1; GAD2 AB Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO ( fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass. C1 Peninsula Med Sch, Inst Biomed & Clin Sci, Exeter, Devon, England. Univ Oxford, Wellcome Trust, Ctr Human Genet, Oxford, England. Univ Bristol, MRC, Ctr Casual Anal Translat Epidemiol, Bristol, Avon, England. Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. Royal Devon & Exeter Natl Hlth Serv Fdn Trust, Mol Genet Lab, Exeter, Devon, England. Univ Bristol, Dept Oral & Dent Sci, Sch Dent, Bristol, Avon, England. London Sch Hyg & Trop Med, Dept Epidemiol & Populat Hlth, London WC1, England. Univ Bristol, Dept Social Med, Bristol, Avon, England. Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, London W2 1PG, England. Univ Oulu, Dept Publ Hlth Sci & Gen Practice, FIN-90014 Oulu, Finland. Peninsula Med Sch, Epidemiol & Publ Hlth Grp, Exeter, Devon, England. NIA, Lonitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21224 USA. Strangeways Res Labs, MRC, Epidemiol Unit, Cambridge, England. Sanger Inst, Metab Dis Grp, Wellcome Trust, Cambridge, England. Univ Newcastle, Diabet Res Grp, Sch Clin Med Sci, Newcastle Upon Tyne, Tyne & Wear, England. Barts & London Royal London Hosp, Dept Diabet & Metab Med, London, England. Univ Dundee, Populat Pharmacogenet Grp, Ninewells Hosp & Med Sch, Biomed Res Ctr, Dundee DD1 9SY, Scotland. Univ Dundee, Ninewells Hosp & Med Sch, Diabet Res Grp, Div Med & Therapeut,Sch Med, Dundee DD1 9SY, Scotland. RP Hattersley, AT (reprint author), Peninsula Med Sch, Inst Biomed & Clin Sci, Magdalen Rd, Exeter, Devon, England. EM Andrew.Hattersley@pms.ac.uk RI Palmer, Colin/C-7053-2008; Morris, Andrew/C-2837-2009; Patch, Ann-Marie/F-8060-2011; Lango Allen, Hana/G-9026-2012; Ness, Andy/M-7612-2013; Harries, Lorna/D-2241-2014; Berryman, Katie/J-4236-2014; Study, GoDARTS/K-9448-2016; Fox, Laura /C-6249-2016; Davey Smith, George/A-7407-2013; OI Palmer, Colin/0000-0002-6415-6560; Lango Allen, Hana/0000-0002-7803-8688; Ness, Andy/0000-0003-3548-9523; Davey Smith, George/0000-0002-1407-8314; Freathy, Rachel/0000-0003-4152-2238; Monsalve, Beatriz Elena/0000-0002-5994-866X; Zeggini, Eleftheria/0000-0003-4238-659X; Barrett, Jeffrey/0000-0002-1152-370X; Melzer, David/0000-0002-0170-3838; Jarvelin, Marjo-Riitta/0000-0002-2149-0630; Karpe, Fredrik/0000-0002-2751-1770; Timpson, Nicholas/0000-0002-7141-9189; Lawlor, Debbie A/0000-0002-6793-2262 FU Intramural NIH HHS [Z99 AG999999]; Medical Research Council [G0000934, G0500070, G0600705, G9815508, MC_U106179471, MC_U106188470]; Wellcome Trust [, 079557, 090532] NR 18 TC 2088 Z9 2205 U1 44 U2 316 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 MAY 11 PY 2007 VL 316 IS 5826 BP 889 EP 894 DI 10.1126/science.1141634 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 166HM UT WOS:000246369800038 PM 17434869 ER PT J AU Tseng, GN Sonawane, KD Korolkova, YV Zhang, M Liu, J Grishin, EV Guy, HR AF Tseng, Gea-Ny Sonawane, Kailas D. Korolkova, Yuliya V. Zhang, Mei Liu, Jie Grishin, Eugene V. Guy, H. Robert TI Probing the outer mouth structure of the hERG channel with peptide toxin footprinting and molecular modeling SO BIOPHYSICAL JOURNAL LA English DT Article ID C-TYPE INACTIVATION; K+ CHANNEL; POTASSIUM CHANNEL; SELECTIVITY FILTER; CRYSTAL-STRUCTURE; GATING MODIFIER; FUNCTIONAL-ROLE; SCORPION TOXIN; MUTANT CYCLES; BINDING-SITE AB Previous studies have shown that the unusually long S5-P linker lining human ether a-go-go related gene's ( hERG's) outer vestibule is critical for its channel function: point mutations at high-impact positions here can interfere with the inactivation process and, in many cases, also reduce the pore's K 1 selectivity. Because no data are available on the equivalent region in the available K channel crystal structures to allow for homology modeling, we used alternative approaches to model its three-dimensional structure. The first part of this article describes mutant cycle analysis used to identify residues on hERG's outer vestibule that interact with specific residues on the interaction surface of BeKm-1, a peptide toxin with known NMR structure and a high binding affinity to hERG. The second part describes molecular modeling of hERG's pore domain. The transmembrane region was modeled after the crystal structure of KvAP pore domain. The S5-P linker was docked to the transmembrane region based on data from previous NMR and mutagenesis experiments, as well as a set of modeling criteria. The models were further restrained by contact points between hERG's outer vestibule and the bound BeKm-1 toxin molecule deduced from the mutant cycle analysis. Based on these analyses, we propose a working model for the open conformation of the outer vestibule of the hERG channel, in which the S5-P linkers interact with the pore loops to influence ion flux through the pore. C1 Virginia Commonwealth Univ, Dept Physiol, Richmond, VA 23298 USA. NCI, Lab Cell Biol, NIH, Bethesda, MD USA. Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow, Russia. RP Tseng, GN (reprint author), Virginia Commonwealth Univ, Dept Physiol, 1101 E Marshall Rd, Richmond, VA 23298 USA. EM gtseng@vcu.edu OI Sonawane, Kailas/0000-0003-0156-7466 FU Intramural NIH HHS; NHLBI NIH HHS [HL 46451, HL 67840, R01 HL046451, R01 HL067840] NR 55 TC 58 Z9 60 U1 0 U2 3 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAY 10 PY 2007 VL 92 IS 10 BP 3524 EP 3540 DI 10.1529/biophysj.106.097360 PG 17 WC Biophysics SC Biophysics GA 159GE UT WOS:000245852600017 PM 17293393 ER PT J AU Caudle, RM Mannes, AJ Keller, J Perez, FM Suckow, SK Neubert, JK AF Caudle, Robert M. Mannes, Andrew J. Keller, Jason Perez, Federico M. Suckow, Shelby K. Neubert, John K. TI Sensitization of spinal cord nociceptive neurons with a conjugate of substance P and cholera toxin SO BMC NEUROSCIENCE LA English DT Article ID HAMSTER OVARY CELLS; PROTEIN-COUPLED RECEPTORS; EXPRESSING NEURONS; ADP-RIBOSYLATION; OPIOID RECEPTORS; PERSISTENT PAIN; HYPERALGESIA; SAPORIN; NEUROKININ-1; STIMULATION AB Background: Several investigators have coupled toxins to neuropeptides for the purpose of lesioning specific neurons in the central nervous system. By producing deficits in function these toxin conjugates have yielded valuable information about the role of these cells. In an effort to specifically stimulate cells rather than kill them we have conjugated the neuropeptide substance P to the catalytic subunit of cholera toxin (SP-CTA). This conjugate should be taken up selectively by neurokinin receptor expressing neurons resulting in enhanced adenylate cyclase activity and neuronal firing. Results: The conjugate SP-CTA stimulates adenylate cyclase in cultured cells that are transfected with either the NK1 or NK2 receptor, but not the NK3 receptor. We further demonstrate that intrathecal injection of SP-CTA in rats induces the phosphorylation of the transcription factor cyclic AMP response element binding protein (CREB) and also enhances the expression of the immediate early gene c-Fos. Behaviorally, low doses of SP-CTA (1 mu g) injected intrathecally produce thermal hyperalgesia. At higher doses (10 mu g) peripheral sensitivity is suppressed suggesting that descending inhibitory pathways may be activated by the SP-CTA induced sensitization of spinal cord neurons. Conclusion: The finding that stimulation of adenylate cyclase in neurokinin receptor expressing neurons in the spinal cord produces thermal hyperalgesia is consistent with the known actions of these neurons. These data demonstrate that cholera toxin can be targeted to specific cell types by coupling the catalytic subunit to a peptide agonist for a g-protein coupled receptor. Furthermore, these results demonstrate that SP-CTA can be used as a tool to study sensitization of central neurons in vivo in the absence of an injury. C1 Univ Florida, Coll Dent, Dept Oral & Maxillofacial Surg & Diagnost Sci, Gainesville, FL 32610 USA. Univ Florida, Coll Dent, Dept Orthodont, Gainesville, FL 32610 USA. Univ Florida, Coll Med, McKnight Brain Inst, Dept Neurosci, Gainesville, FL 32610 USA. Natl Inst Dent & Craniofacial Res, Pain & Neurosensory Mech Branch, NIH, Bethesda, MD 20892 USA. RP Caudle, RM (reprint author), Univ Florida, Coll Dent, Dept Oral & Maxillofacial Surg & Diagnost Sci, Gainesville, FL 32610 USA. EM caudle@ufl.edu; amannes@nidcr.nih.gov; jakeller@nidcr.nih.gov; fperez@dental.ufl.edu; ssuckow@ufl.edu; jneubert@dental.ufl.edu OI Mannes, Andrew/0000-0001-5834-5667 FU NIDA NIH HHS [DA016562, R21 DA016562] NR 32 TC 4 Z9 4 U1 1 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2202 J9 BMC NEUROSCI JI BMC Neurosci. PD MAY 10 PY 2007 VL 8 AR 30 DI 10.1186/1471-2202-8-30 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 175NI UT WOS:000247019900001 PM 17493276 ER PT J AU Eichler, EE Nickerson, DA Altshuler, D Bowcock, AM Brooks, LD Carter, NP Church, DM Felsenfeld, A Guyer, M Lee, C Lupski, JR Mullikin, JC Pritchard, JK Sebat, J Sherry, ST Smith, D Valle, D Waterston, RH AF Eichler, Evan E. Nickerson, Deborah A. Altshuler, David Bowcock, Anne M. Brooks, Lisa D. Carter, Nigel P. Church, Deanna M. Felsenfeld, Adam Guyer, Mark Lee, Charles Lupski, James R. Mullikin, James C. Pritchard, Jonathan K. Sebat, Jonathan Sherry, Stephen T. Smith, Douglas Valle, David Waterston, Robert H. CA Human Genome Structural Variation TI Completing the map of human genetic variation SO NATURE LA English DT Article ID COPY-NUMBER POLYMORPHISMS; HUMAN GENOME; STRUCTURAL VARIATION; LINKAGE DISEQUILIBRIUM; SEGMENTAL DUPLICATIONS; DELETION POLYMORPHISMS; Y-CHROMOSOMES; IDENTIFICATION; DISEASE; REARRANGEMENTS C1 Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. Harvard Univ, Broad Inst, Cambridge, MA 02142 USA. MIT, Cambridge, MA 02142 USA. Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Wellcome Trust Sanger Inst, Hinxton CB4 5RW, England. Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA. Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA. Texas Childrens Hosp, Baylor Coll Med, Houston, TX 77030 USA. Univ Chicago, Dept Human Genet, Chicago, IL 60637 USA. Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. Agencourt Biosci Corp, Beverly, MA 01915 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21025 USA. RP Eichler, EE (reprint author), Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA. EM eee@gs.washington.edu RI Altshuler, David/A-4476-2009; OI Altshuler, David/0000-0002-7250-4107; Bowcock, Anne/0000-0001-8691-9090; Sebat, Jonathan/0000-0002-9087-526X NR 46 TC 120 Z9 131 U1 1 U2 12 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 EI 1476-4687 J9 NATURE JI Nature PD MAY 10 PY 2007 VL 447 IS 7141 BP 161 EP 165 DI 10.1038/447161a PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 165WT UT WOS:000246338700034 ER PT J AU D'Souza, G Kreimer, AR Viscidi, R Pawlita, M Fakhry, C Koch, WM Westra, WH Gillison, ML AF D'Souza, Gypsyamber Kreimer, Aimee R. Viscidi, Raphael Pawlita, Michael Fakhry, Carole Koch, Wayne M. Westra, William H. Gillison, Maura L. TI Case-control study of human papillomavirus and oropharyngeal cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID SQUAMOUS-CELL CARCINOMA; INVASIVE CERVICAL-CANCER; ORAL-CANCER; NECK-CANCER; SOUTHERN SWEDEN; US POPULATION; UNITED-STATES; RISK; HEAD; INFECTION AB BACKGROUND: Substantial molecular evidence suggests a role for human papillomavirus (HPV) in the pathogenesis of oropharyngeal squamous-cell carcinoma, but epidemiologic data have been inconsistent. METHODS: We performed a hospital-based, case-control study of 100 patients with newly diagnosed oropharyngeal cancer and 200 control patients without cancer to evaluate associations between HPV infection and oropharyngeal cancer. Multivariate logistic-regression models were used for case-control comparisons. RESULTS: A high lifetime number of vaginal-sex partners (26 or more) was associated with oropharyngeal cancer (odds ratio, 3.1; 95% confidence interval [CI], 1.5 to 6.5), as was a high lifetime number of oral-sex partners (6 or more) (odds ratio, 3.4; 95% CI, 1.3 to 8.8). The degree of association increased with the number of vaginal-sex and oral-sex partners (P values for trend, 0.002 and 0.009, respectively). Oropharyngeal cancer was significantly associated with oral HPV type 16 (HPV-16) infection (odds ratio, 14.6; 95% CI, 6.3 to 36.6), oral infection with any of 37 types of HPV (odds ratio, 12.3; 95% CI, 5.4 to 26.4), and seropositivity for the HPV-16 L1 capsid protein (odds ratio, 32.2; 95% CI, 14.6 to 71.3). HPV-16 DNA was detected in 72% (95% CI, 62 to 81) of 100 paraffin-embedded tumor specimens, and 64% of patients with cancer were seropositive for the HPV-16 oncoprotein E6, E7, or both. HPV-16 L1 seropositivity was highly associated with oropharyngeal cancer among subjects with a history of heavy tobacco and alcohol use (odds ratio, 19.4; 95% CI, 3.3 to 113.9) and among those without such a history (odds ratio, 33.6; 95% CI, 13.3 to 84.8). The association was similarly increased among subjects with oral HPV-16 infection, regardless of their tobacco and alcohol use. By contrast, tobacco and alcohol use increased the association with oropharyngeal cancer primarily among subjects without exposure to HPV-16. CONCLUSIONS: Oral HPV infection is strongly associated with oropharyngeal cancer among subjects with or without the established risk factors of tobacco and alcohol use. C1 Johns Hopkins Univ, Div Viral Oncol, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Univ Hosp, Dept Pediat, Baltimore, MD 21287 USA. Johns Hopkins Univ Hosp, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21287 USA. Johns Hopkins Univ Hosp, Dept Pathol, Baltimore, MD 21287 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. German Canc Res Ctr, Infect & Canc Control Program, D-6900 Heidelberg, Germany. RP Gillison, ML (reprint author), Johns Hopkins Univ, Div Viral Oncol, Sidney Kimmel Comprehens Canc Ctr, Canc Res Bldg 1,Rm 3M 54A,1650 Orleans St, Baltimore, MD 21231 USA. EM gillima@jhmi.edu RI Pawlita, Labor/C-9720-2011; Kreimer, Aimee/H-1687-2015; Waterboer, Tim/G-1252-2010 FU NIAID NIH HHS [T32 AI050056, T32AI50056]; NIDCR NIH HHS [DE016631-01, R01 DE016631] NR 39 TC 1210 Z9 1230 U1 11 U2 98 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 MAY 10 PY 2007 VL 356 IS 19 BP 1944 EP 1956 DI 10.1056/NEJMoa065497 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 165KX UT WOS:000246305500006 PM 17494927 ER PT J AU Pacak, K Eisenhofer, G Grossman, A AF Pacak, Karel Eisenhofer, Graeme Grossman, Ashley TI The incidentally discovered adrenal mass SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID BIOCHEMICAL-DIAGNOSIS; PHEOCHROMOCYTOMA C1 NIH, Bethesda, MD 20892 USA. Barts & London, London E1 2AD, England. RP Pacak, K (reprint author), NIH, Bethesda, MD 20892 USA. EM karel@mail.nih.gov NR 5 TC 3 Z9 3 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 MAY 10 PY 2007 VL 356 IS 19 BP 2005 EP 2005 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 165KX UT WOS:000246305500030 PM 17494941 ER PT J AU Cardone, G Winkler, DC Trus, BL Cheng, NQ Heuser, JE Newcomb, WW Brown, JC Steven, AC AF Cardone, Giovanni Winkler, Dennis C. Trus, Benes L. Cheng, Naiqian Heuser, John E. Newcomb, William W. Brown, Jay C. Steven, Alasdair C. TI Visualization of the herpes simplex virus portal in situ by cryo-electron tomography SO VIROLOGY LA English DT Article DE capsid assemby; portal protein; cryo-electron microscopy; immuno-gold labelling; three-dimentional image reconsruction ID 3-DIMENSIONAL STRUCTURE; ELECTRON TOMOGRAPHY; ANGSTROM RESOLUTION; BACTERIAL-VIRUS; DNA; PROTEIN; CAPSIDS; TYPE-1; MATURATION; MICROSCOPY AB Herpes simplex virus type I (HSV-1), the prototypical herpesvirus, has an icosahedral nucleocapsid surrounded by a proteinaceous tegument and a lipoprotein envelope. As in tailed bacteriophages, the icosahedral symmetry of the capsid is broken at one of the 12 vertices, which is occupied by a dodecameric ring of portal protein, UL6, instead of a pentamer of the capsid protein, UL19. The portal ring serves as a conduit for DNA entering and exiting the capsid. From a cryo-EM reconstruction of capsids immuno-gold-labeled with anti-UL6 antibodies, we confirmed that UL6 resides at a vertex. To visualize the portal in the context of the assembled capsid, we used cryo-electron tomography to determine the three-dimensional structures of individual A-capsids (empty, mature capsids). The similarity in size and overall shape of the portal and a UL19 pentamer - both are cylinders of similar to 800 kDa - combined with residual noise in the tomograms, prevented us from identifying the portal vertices directly; however, this was accomplished by a computational classification procedure. Averaging the portal-containing subtomograms produced a structure that tallies with the isolated portal, as previously reconstructed by cryo-EM. The portal is mounted on the outer surface of the capsid floor layer, with its narrow end pointing outwards. This disposition differs from that of known phage portals in that the bulk of its mass lies outside, not inside, the floor. This distinction may be indicative of divergence at the level of portal-related functions other than its role as a DNA channel. Published by Elsevier Inc. C1 NIAMSD, Struct Biol Res Lab, NIH, Bethesda, MD 20892 USA. NIH, Imaging Sci Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Cell Biol, St Louis, MO 63110 USA. Univ Virginia, Hlth Syst, Dept Microbiol, Charlottesville, VA 22908 USA. Univ Virginia, Hlth Syst, Ctr Canc, Charlottesville, VA 22908 USA. RP Steven, AC (reprint author), NIAMSD, Struct Biol Res Lab, NIH, Bldg 50,Rm 1517,MSC 8025,50 S Dr, Bethesda, MD 20892 USA. EM Alasdair_Steven@nih.gov RI Heuser, John/H-5940-2012 FU Intramural NIH HHS; NIAID NIH HHS [AI41644-10, R01 AI041644, R56 AI041644]; NIGMS NIH HHS [GM29647-23, R01 GM029647] NR 55 TC 66 Z9 66 U1 3 U2 12 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 MAY 10 PY 2007 VL 361 IS 2 BP 426 EP 434 DI 10.1016/j.virol.2006.10.047 PG 9 WC Virology SC Virology GA 161SI UT WOS:000246035700019 PM 17188319 ER PT J AU Giordano, TP Henderson, L Landgren, O Chiao, EY Kramer, JR El-Serag, H Engels, EA AF Giordano, Thomas P. Henderson, Louise Landgren, Ola Chiao, Elizabeth Y. Kramer, Jennifer R. El-Serag, Hashem Engels, Eric A. TI Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID ADMINISTRATION MEDICAL SYSTEM; THYROID-CANCER; UNITED-STATES; WALDENSTROM MACROGLOBULINEMIA; MONOCLONAL GAMMOPATHY; INFECTION; PREVALENCE; CRYOGLOBULINEMIA; ASCERTAINMENT; REGRESSION AB Context Hepatitis C virus (HCV) infection causes liver cancer and cirrhosis and may also increase the risk of other tumors, particularly hematopoietic malignancies and thyroid cancer. Previous studies have been too small to adequately assess these risks. Objective To test the hypothesis that HCV infection is associated with increased risk for hematological malignancies, related lymphoproliferative disorders, and thyroid cancer. Design, Setting, and Patients A retrospective cohort study of users of US Veterans Affairs health care facilities from 1997-2004, which included 146 394 patients infected with HCV who had at least 2 visits with a diagnostic code for HCV infection, and 572 293 patients uninfected with HCV. To assemble the HCV-uninfected cohort, we randomly selected up to 4 patients per patient infected with HCV from all veterans who matched on age, sex, and baseline visit date and type (inpatient or outpatient). Individuals with human immunodeficiency virus were excluded. Main Outcome Measures Risks of hematopoietic malignancies, related lymphoproliferative precursor diseases, and thyroid cancer, adjusting for selection factors, race, era of military service, and use of medical services. Results The mean (SD) age of the patients was 52 (8) years, and 97% were men. Risks for non-Hodgkin lymphoma (n = 1359), Waldenstrom macroglobulinemia (n = 165), and cryoglobulinemia (n = 551) were increased with HCV infection (adjusted hazard ratio [ HR], 1.28; 95% confidence interval [ CI], 1.12-1.45; adjusted HR, 2.76; 95% CI, 2.01-3.79; and adjusted HR, 3.98; 95% CI, 3.36-4.72; respectively). We found no significantly increased risk for other hematological malignancies. Although thyroiditis risk was slightly increased, risk for thyroid cancer (n = 320) was not (adjusted HR, 0.72; 95% CI, 0.52-0.99). Adjusted P values for non-Hodgkin lymphoma, Waldenstrom macroglobulinemia, cryoglobulinemia, and thyroiditis were all < .0038, the Bonferroni threshold for statistical significance considering multiple comparisons. Conclusions Hepatitis C virus infection confers a 20% to 30% increased risk of non-Hodgkin lymphoma overall, and a 3-fold higher risk of Waldenstrom macroglobulinemia, a low-grade lymphoma. Risks were also increased for cryoglobulinemia. These results support an etiological role for HCV in causing lymphoproliferation and causing non-Hodgkin lymphoma. C1 Michael E DeBakey Vet Affairs Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Hlth Serv Res & Dev Serv, Houston, TX 77030 USA. Baylor Coll Med, Dept Med, Houston, TX 77030 USA. NCI, NIH, Rockville, MD USA. RP Giordano, TP (reprint author), Michael E DeBakey Vet Affairs Med Ctr, Houston Ctr Qual Care & Utilizat Studies, Hlth Serv Res & Dev Serv, VA152,2002 Holcombe Blvd, Houston, TX 77030 USA. EM tpg@bcm.tmc.edu FU Intramural NIH HHS; NCI NIH HHS [K23CA124318]; NIMH NIH HHS [K23MH67505] NR 27 TC 167 Z9 174 U1 0 U2 4 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 MAY 9 PY 2007 VL 297 IS 18 BP 2010 EP 2017 DI 10.1001/jama.297.18.2010 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 165JM UT WOS:000246301800023 PM 17488966 ER PT J AU Taubenberger, JK Morens, DM Fauci, AS AF Taubenberger, Jeffery K. Morens, David M. Fauci, Anthony S. TI The next influenza pandemic - Can it be predicted? SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID H5N1 INFLUENZA; A VIRUSES; TRANSMISSION; ASIA; VIRULENCE; EVOLUTION; IMMUNE; HUMANS; GENE C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Morens, DM (reprint author), Bldg 31,Room 7A-10,31 Ctr Dr,MSC 2520, Bethesda, MD 20892 USA. EM dmorens@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000995-01] NR 24 TC 53 Z9 55 U1 0 U2 3 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 MAY 9 PY 2007 VL 297 IS 18 BP 2025 EP 2027 DI 10.1001/jama.297.18.2025 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 165JM UT WOS:000246301800025 PM 17488968 ER PT J AU Efroni, S Schaefer, CF Buetow, KH AF Efroni, Sol Schaefer, Carl F. Buetow, Kenneth H. TI Identification of Key Processes Underlying Cancer Phenotypes Using Biologic Pathway Analysis SO PLOS ONE LA English DT Article AB Cancer is recognized to be a family of gene-based diseases whose causes are to be found in disruptions of basic biologic processes. An increasingly deep catalogue of canonical networks details the specific molecular interaction of genes and their products. However, mapping of disease phenotypes to alterations of these networks of interactions is accomplished indirectly and non-systematically. Here we objectively identify pathways associated with malignancy, staging, and outcome in cancer through application of an analytic approach that systematically evaluates differences in the activity and consistency of interactions within canonical biologic processes. Using large collections of publicly accessible genome-wide gene expression, we identify small, common sets of pathways - Trka Receptor, Apoptosis response to DNA Damage, Ceramide, Telomerase, CD40L and Calcineurin - whose differences robustly distinguish diverse tumor types from corresponding normal samples, predict tumor grade, and distinguish phenotypes such as estrogen receptor status and p53 mutation state. Pathways identified through this analysis perform as well or better than phenotypes used in the original studies in predicting cancer outcome. This approach provides a means to use genome-wide characterizations to map key biological processes to important clinical features in disease. C1 [Efroni, Sol; Schaefer, Carl F.; Buetow, Kenneth H.] NCI, Ctr Bioinformat, Rockville, MD USA. [Buetow, Kenneth H.] NCI, Lab Populat Genet, Bethesda, MD 20892 USA. RP Buetow, KH (reprint author), NCI, Ctr Bioinformat, Rockville, MD USA. EM buetowk@mail.nih.gov RI Efroni, Sol/I-6752-2012 OI Efroni, Sol/0000-0001-7927-6349 FU NIH, National Cancer Institute FX This research was supported by the intramural research program of the NIH, National Cancer Institute. NR 47 TC 58 Z9 58 U1 0 U2 3 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAY 9 PY 2007 VL 2 IS 5 AR e425 DI 10.1371/journal.pone.0000425 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10DX UT WOS:000207445800007 PM 17487280 ER PT J AU Meijers, R Adolph, HW Dauter, Z Wilson, KS Lamzin, VS Cedergren-Zeppezauer, ES AF Meijers, Rob Adolph, Hans-Werner Dauter, Zbigniew Wilson, Keith S. Lamzin, Victor S. Cedergren-Zeppezauer, Eila S. TI Structural evidence for a ligand coordination switch in liver alcohol dehydrogenase SO BIOCHEMISTRY LA English DT Article ID TERNARY COMPLEX; SUBSTITUTED COBALT(II); SITE; PROTEIN; BINDING; RESOLUTION; CATALYSIS; ENZYME; NADH; CRYSTALLOGRAPHY AB The use of substrate analogues as inhibitors provides a way to understand and manipulate enzyme function. Here we report two 1 A resolution crystal structures of liver alcohol dehydrogenase in complex with NADH and two inhibitors: dimethyl sulfoxide and isobutyramide. Both structures present a dynamic state of inhibition. In the dimethyl sulfoxide complex structure, the inhibitor is caught in transition on its way to the active site using a flash-freezing protocol and a cadmium-substituted enzyme. One inhibitor molecule is partly located in the first and partly in the second coordination sphere of the active site metal. A hydroxide ion bound to the active site metal lies close to the pyridine ring of NADH, which is puckered in a twisted boat conformation. The cadmium ion is coordinated by both the hydroxide ion and the inhibitor molecule, providing structural evidence of a coordination switch at the active site metal ion. The structure of the isobutyramide complex reveals the partial formation of an adduct between the isobutyramide inhibitor and NADH. It provides evidence of the contribution of a shift from the keto to the enol tautomer during aldehyde reduction. The different positions of the inhibitors further refine the knowledge of the dynamics of the enzyme mechanism and explain how the crowded active site can facilitate the presence of a substrate and a metal-bound hydroxide ion. C1 Care Of DESY, European Mol Biol Lab, Hamburg Outstn, D-22603 Hamburg, Germany. Univ Saarland, D-66041 Saarbrucken, Germany. Argonne Natl Lab, NCI, MCL, Synchrotron Radiat Res Stn, Argonne, IL 60439 USA. Univ York, Dept Chem, York Struct Biol Lab, York YO10 5YW, N Yorkshire, England. Lund Univ, Ctr Chem & Chem Engn, Dept Biochem, SE-22100 Lund, Sweden. RP Meijers, R (reprint author), Lorme Merisiers, Div Experiences, Synchrotron Soleil, St Aubin BP 48, F-91192 Gif Sur Yvette, France. EM rob.meijers@synchrotron-soleil.fr; eila.cedergren@telia.com RI Adolph, Hans/A-2104-2008; Meijers, Rob/D-5521-2011; OI Lamzin, Victor/0000-0002-6058-7793; Meijers, Rob/0000-0003-2872-6279 NR 43 TC 26 Z9 27 U1 1 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAY 8 PY 2007 VL 46 IS 18 BP 5446 EP 5454 DI 10.1021/bi6023594 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 162FH UT WOS:000246071700018 PM 17429946 ER PT J AU Ruggiero, C Metter, EJ Cherubini, A Maggio, M Sen, R Najjar, SS Windham, GB Ble, A Senin, U Ferrucci, L AF Ruggiero, Carmelinda Metter, E. Jeffrey Cherubini, Antonio Maggio, Marcello Sen, Ranjan Najjar, Samer S. Windham, Gwen B. Ble, Alessandro Senin, Umberto Ferrucci, Luigi TI White blood cell count and mortality in the Baltimore Longitudinal Study of Aging SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID SUBCLINICAL CAROTID ATHEROSCLEROSIS; CORONARY-ARTERY-DISEASE; LEUKOCYTE COUNT; UNITED-STATES; PHYSICAL-ACTIVITIES; INSULIN-RESISTANCE; MEN; INFLAMMATION; RISK; POPULATION AB We investigated the secular trend in white blood cell (WBC) count and the relationship between WBC count and mortality between 1958 and 2002. The WBC count is a clinical marker of inflammation and a strong predictor of mortality. Limited data exist on the WBC count secular trend and the relationship between WBC and mortality. One thousand eighty-three women and 1,720 men were evaluated longitudinally in the Baltimore Longitudinal Study of Aging. Blood samples and medical information were collected at the study entry and every 2 years during follow-up visits. The WBC count and all-cause, cardiovascular, and cancer mortality were assessed. Results A downward trend in WBC count was observed from 1958 to 2002. The secular downward trend was independent of age, gender, race, smoking, body mass index, and physical activity. The WBC count was nonlinearly associated with all-cause mortality and almost linearly associated with cardiovascular mortality. Participants with baseline WBC < 3,500 cells/mm(3) and WBC > 6,000 cells/mm(3) had higher mortality than those with 3,500 to 6,000 WBC/mm(3). Within each WBC group, age-adjusted mortality rates declined in successive cohorts from the 1960s to the 1990s. Participants who died had higher WBC than those who survived, and the difference was statistically significant within 5 years before death. Our study provides evidence for a secular downward trend in WBC count over the period from 1958 to 2002. Higher WBC counts are associated with higher mortality in successive cohorts. We found no evidence that the decline of age-specific mortality rates that occurred from 1960 to 2000 was attributable to a secular downward trend in WBC. (J Am Coll Cardiol 2007;49:1841-50) (C) 2007 by the American College of Cardiology Foundation. C1 NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Baltimore, MD 21225 USA. NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21225 USA. NIA, Human Cardiovasc Studies Unit, Cardiovasc Sci Lab, NIH, Baltimore, MD 21225 USA. Univ Perugia, Dept Geriatr & Gerontol, I-06100 Perugia, Italy. RP Ruggiero, C (reprint author), NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, 3001 S Hanover St, Baltimore, MD 21225 USA. EM ruggieroc07@hotmail.it OI Cherubini, Antonio/0000-0003-0261-9897 FU Intramural NIH HHS [Z01 AG000015-49] NR 34 TC 70 Z9 72 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAY 8 PY 2007 VL 49 IS 18 BP 1841 EP 1850 DI 10.1016/j.jacc.2007.01.076 PG 10 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 165CR UT WOS:000246282000004 PM 17481443 ER PT J AU Lees, AJ Singleton, AB AF Lees, Andrew J. Singleton, Andrew B. TI Clinical heterogeneity of ATP13A2 linked disease (Kufor-Rakeb) justifies a PARK designation SO NEUROLOGY LA English DT Editorial Material ID MUTATIONS; PARKINSONISM C1 NIA, Mol Genet Unit, NIH, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. UCL, Reta Lila Weston Inst Neurol Studies, London WC1E 6BT, England. RP Singleton, AB (reprint author), NIA, Mol Genet Unit, NIH, Porter Neurosci Res Ctr, Room 1A1000,35 Lincoln Dr, Bethesda, MD 20892 USA. EM singleta@mail.nih.gov RI Singleton, Andrew/C-3010-2009; Lees, Andrew/A-6605-2009 NR 6 TC 25 Z9 25 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAY 8 PY 2007 VL 68 IS 19 BP 1553 EP 1554 DI 10.1212/01.wnl.0000265228.66664.f4 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 164ZW UT WOS:000246274600001 PM 17485640 ER PT J AU Novoselov, SV Lobanov, AV Hua, D Kasaikina, MV Hatfield, DL Gladyshev, VN AF Novoselov, Sergey V. Lobanov, Alexey V. Hua, Deame Kasaikina, Marina V. Hatfield, Dolph L. Gladyshev, Vadim N. TI A highly efficient form of the selenocysteine insertion sequence element in protozoan parasites and its use in mammalian cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE genome; RNA structure; selenocysteine; selenoprotein ID SELENOPROTEIN MESSENGER-RNAS; THIOREDOXIN REDUCTASE; ESCHERICHIA-COLI; STRUCTURAL MOTIF; SECIS ELEMENTS; IN-SILICO; TRANSLATION; EUKARYOTES; PROTEIN; MACHINERY AB Selenoproteins are an elite group of proteins containing a rare amino acid, selenocysteine (Sec), encoded by the codon, UGA. In eukaryotes, incorporation of Sec requires a Sec insertion sequence (SECIS) element, a stem-loop structure located in the 3'-untranslated regions of selenoprotein mRNAs. Here we report identification of a noncanonical form of SECIS element in Toxoplasma gondii and Neospora canine, single-celled apicomplexan parasites of humans and domestic animals. This SECIS has a GGGA sequence in the SBP2-binding site in place of AUGA previously considered invariant. Using a combination of computational and molecular techniques, we show that Toxoplasma and Neospora possess both canonical and noncanonical SECIS elements. The GGGA-type SECIS element supported Sec insertion in mammalian HEK 293 and NIH 3T3 cells and did so more efficiently than the natural mammalian SECIS elements tested. In addition, mammalian type I and type II SECIS elements mutated into the GGGA forms were functional but manifested decreased Sec insertion efficiency. We carried out computational searches for both AUGA and GGGA forms of SECIS elements in Toxoplasma and detected five selenoprotein genes, including one coding for a previously undescribed selenoprotein, designated SeIQ, and two containing the GGGA form of the SECIS element. In contrast, the GGGA-type SECIS elements were not detected in mammals and nematodes. As a practical outcome of the study, we developed pSelExpress1, a vector for convenient expression of selenoproteins in mammalian cells. It contains an SBP2 gene and the most efficient tested SECIS element: an AUGA mutant of the GGGA-type Toxoplasma SeIT structure. C1 Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. NCI, Lab Canc Prevent, Sect Mol Biol Selenium, NIH, Bethesda, MD 20892 USA. RP Gladyshev, VN (reprint author), Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. EM vgladyshev1@unl.edu RI Gladyshev, Vadim/A-9894-2013; OI Novoselov, Sergey/0000-0003-0104-6492 FU NIGMS NIH HHS [GM061603, R01 GM061603] NR 36 TC 35 Z9 36 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 MAY 8 PY 2007 VL 104 IS 19 BP 7857 EP 7862 DI 10.1073/pnas.0610683104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 167OR UT WOS:000246461500025 PM 17470795 ER PT J AU Hasan, UA Caux, C Perrot, I Doffin, AC Menetrier-Caux, C Trinchieri, G Tommasino, M Vlach, J AF Hasan, Uzma A. Caux, Christophe Perrot, Ivan Doffin, Anne-Claire Menetrier-Caux, Christine Trinchieri, Giorgio Tommasino, Massimo Vlach, Jaromir TI Cell proliferation and survival induced by toll-like receptors is antagonized by type IIFNs SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cell cycle; p27 ID NF-KAPPA-B; DOUBLE-STRANDED-RNA; EPSTEIN-BARR-VIRUS; APOPTOSIS IN-VIVO; DENDRITIC CELLS; IFN-BETA; CYTOPLASMIC LOCALIZATION; SIGNALING PATHWAYS; ENDOTHELIAL-CELLS; P27(KIP1) AB TRIF is an adaptor protein associated with the signaling by Toll-like receptor (TLR)3 and TLR4 for the induction of type I IFNs. Here, we demonstrate a mechanism by which TLR signaling controls cell proliferation and survival. We show that TLR3 and TLR4 can induce cell cycle entry via TRIF, which targets the cell cycle inhibitor p27(kip1) for relocalization, phosphorylation by cyclin/cdk complexes, and proteasome degradation. These events are antagonized by type I IFN induced by the TRIF pathway. Furthermore, in human dendritic cells treated with TLR3, TLR4, or TLR5 ligands, we demonstrate that IFN signaling modulates p27kipl degradation and apoptosis, identifying an immunoregulatory "switching" function of type I IFNs. These findings reveal a previously uncharacterized function of TLR signaling in cell proliferation and survival. C1 Int Agcy Res Canc, Infect & Canc Biol Grp, F-69372 Lyon 08, France. Ctr Leon Berard, F-69373 Lyon, France. Innate Pharma, F-69573 Dardilly, France. NCI, Canc & Inflammat Program, Canc Res Ctr, Ft Detrick, MD 21702 USA. Schering Plough Res Inst, Kenilworth, NJ 07033 USA. RP Hasan, UA (reprint author), Int Agcy Res Canc, Infect & Canc Biol Grp, 150 Cours Albert Thomas, F-69372 Lyon 08, France. EM hasan@iarc.fr RI hasan, uzma/G-3247-2013; Caux, Christophe/G-2851-2013 NR 48 TC 50 Z9 52 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAY 8 PY 2007 VL 104 IS 19 BP 8047 EP 8052 DI 10.1073/pnas.0700664104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 167OR UT WOS:000246461500057 PM 17463087 ER PT J AU Moore, DF Gelderman, MP Ferreira, PA Fuhrmann, SR Yi, HQ Elkahloun, A Lix, LM Brady, RO Schiffmann, R Goldin, E AF Moore, David F. Gelderman, Monique P. Ferreira, Paulo A. Fuhrmann, Steven R. Yi, Haiqing Elkahloun, Abdel Lix, Lisa M. Brady, Roscoe O. Schiffmann, Raphael Goldin, Ehud TI Genomic abnormalities of the murine model of Fabry disease after disease-related perturbation, a systems biology approach SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE glycolipids; growth factor; lysosomal; reactive oxygen species ID ALPHA-GALACTOSIDASE; ENZYME REPLACEMENT; SUBCELLULAR-LOCALIZATION; CEREBRAL HYPERPERFUSION; MICE; DEFICIENCY; PROTEOLYSIS; THROMBOSIS; PROTEINS; REVERSAL AB Fabry disease is a disorder of alpha-D-galactosyl-containing glycolipids resulting from a deficiency of alpha-galactosidase A. Patients have a poorly understood vascular dysregulation. We hypothesized that disease-related perturbation by using enzyme replacement therapy in the murine model of Fabry disease would provide insight into abnormal biological processes in Fabry disease. Gene expression analyses of the heart, aorta, and liver of male alpha-galactosidase A knockout mice 28 weeks of age were compared with that of WT mice. Microarray analyses were performed before and after six weekly injections of a-galactosidase A. Alteration of Rpgrip1 ranked highest statistically in all three organs when knockout mice were compared with WT, and its splice variants responded in a unique way to alpha-galactosidase A. Enzyme replacement therapy tended to not only normalize gene expression, e.g., reduce the overexpression of securin, but also specifically modified gene expression in each tissue examined. Following multiple comparison analysis, gene expression correlation graphs were constructed, and a priori hypotheses were examined by using structural equation modeling. This systems biology approach demonstrated multiple and complex parallel cellular abnormalities in Fabry disease. These abnormalities form the basis for informed, in a Bayesian sense, sequential, hypothesis-driven research that can be subsequently tested experimentally. C1 Univ Manitoba, Neurol Sect, Winnipeg, MB R3T 2N2, Canada. Univ Manitoba, Dept Community Hlth Sci, Winnipeg, MB R3T 2N2, Canada. US FDA, Ctr Biol Evaluat & Res, Lab Cellular Hematol, Rockville, MD 20857 USA. IOMAI Corp, Gaithersburg, MD 20878 USA. Duke Univ, Med Ctr, Dept Ophthalmol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. Natl Inst Neurol Disorders & Strokes, Microarray Core Facil, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Strokea, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Goldin, E (reprint author), Univ Manitoba, Neurol Sect, Winnipeg, MB R3T 2N2, Canada. EM rb57v@nih.gov RI Ferreira, Paulo/A-3893-2008; Ferreira, Paulo/S-4209-2016 OI Ferreira, Paulo/0000-0003-4585-1717 FU Intramural NIH HHS; NEI NIH HHS [2P30-EY 005722-21, EY 11993, P30 EY005722, R01 EY011993, R01 EY012665] NR 46 TC 11 Z9 11 U1 1 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 MAY 8 PY 2007 VL 104 IS 19 BP 8065 EP 8070 DI 10.1073/pnas.0701991104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 167OR UT WOS:000246461500060 PM 17470787 ER PT J AU Bennett, RS Ton, DR Hanson, CT Murphy, BR Whitehead, SS AF Bennett, Richard S. Ton, David R. Hanson, Christopher T. Murphy, Brian R. Whitehead, Stephen S. TI Genome sequence analysis of La Crosse virus and in vitro and in vivo phenotypes SO VIROLOGY JOURNAL LA English DT Article ID NONSTRUCTURAL PROTEIN NSS; DUALLY INFECTED MOSQUITOS; CALIFORNIA ENCEPHALITIS; AEDES-TRISERIATUS; LACROSSE VIRUS; UNITED-STATES; BUNYAVIRUSES; REGIONS; PATHOGENESIS; CHIPMUNKS AB Background: La Crosse virus (LACV), family Bunyaviridae, is a mosquito-borne virus recognized as a major cause of pediatric encephalitis in North America with 70-130 symptomatic cases each year. The virus was first identified as a human pathogen in 1960 after its isolation from a 4 year-old girl who suffered encephalitis and died in La Crosse, Wisconsin. The majority of LACV infections are mild and never reported, however, serologic studies estimate infection rates of 10-30/100,000 in endemic areas. Results: In the present study, sequence analysis of the complete LACV genomes of low-passage LACV/human/1960, LACV/mosquito/1978, and LACV/human/1978 strains and of biologically cloned derivatives of each strain, indicates that circulating LACVs are genetically stable over time and geographic distance with 99.6-100%, 98.9-100%, 97.8-99.6%, and 99.2-99.7% amino acid identity for N, NsS, M polyprotein, and L proteins respectively. We identified 5 amino acid differences in the RNA polymerase and 4 nucleotide differences in the non- coding region of the L segment specific to the human virus isolates, which may result in altered disease outcomes. Conclusion: All three wild type viruses had similar in vitro growth kinetics and phenotypes in mosquito C6/36 and Vero cells, and similar levels of neurovirulence and neuroinvasiveness in Swiss Webster mice. The biologically cloned derivative of LACV/human/1960 was significantly less neuroinvasive than its uncloned parent and differed in sequence at one amino acid position in the G(N) glycoprotein, identifying this residue as an attenuating mutation. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Bennett, RS (reprint author), NIAID, Infect Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bennettri@niaid.nih.gov; tond@niaid.nih.gov; chanson@niaid.nih.gov; bmurphy@niaid.nih.gov; swhitehead@niaid.nih.gov OI Bennett, Richard/0000-0002-7227-4831 FU Intramural NIH HHS NR 30 TC 11 Z9 15 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD MAY 8 PY 2007 VL 4 AR 41 DI 10.1186/1743-422X-4-41 PG 10 WC Virology SC Virology GA 182RQ UT WOS:000247522100001 PM 17488515 ER PT J AU Vatten, LJ Forman, MR Nilsen, TIL Barrett, JC Romundstad, PR AF Vatten, L. J. Forman, M. R. Nilsen, T. I. L. Barrett, J. C. Romundstad, P. R. TI The negative association between pre-eclampsia and breast cancer risk may depend on the offspring's gender SO BRITISH JOURNAL OF CANCER LA English DT Article DE pre-eclampsia; offspring's gender; breast cancer; epidemiology ID PREGNANCY AB If the negative association between pre-eclampsia and subsequent breast cancer risk differs by gender, this would strengthen the hypothesis that factors intrinsic to the particular pregnancy may explain the association. The study included 701 006 parous Norwegian women with follow-up for breast cancer through the Cancer Registry of Norway. Breast cancer risk was lower in women with pre-eclampsia/hypertension in their first pregnancy, compared to other women ( relative risk, 0.86, 95% CI, 0.78-0.94), after adjustment for age at first birth, maternal birth year, length of gestation, marital status, and parity. The risk reduction was slightly greater if the woman delivered a son as opposed to a daughter ( relative risks of 0.79 vs 0.94, P-value for interaction, 0.06), and if preeclampsia/hypertension was combined with pre-term delivery, these differences were more pronounced (relative risks, 0.62 vs 1.07, P-value for interaction 0.03). A subanalysis among 176 036 primiparous women showed a substantial risk reduction if the mother delivered a son (relative risk, 0.62, 95% CI, 0.47-0.82), but essentially null if she delivered a daughter (relative risk, 0.92, 95% CI, 0.72-1.18; P-value for interaction, 0.05). These results suggest that the effect of pre- eclampsia/ hypertension may be attributed to factors associated with the particular pregnancy rather than an underlying biological trait of the mother. The stronger risk reduction related to having a son suggests a role for sex-dependent hormones in pregnancy. C1 Norwegian Univ Sci & Technol, Fac Med, Dept Publ Hlth, N-7034 Trondheim, Norway. MD Anderson Canc Ctr, Houston, TX USA. NCI, Lab Biosyst & Canc, Bethesda, MD 20892 USA. RP Vatten, LJ (reprint author), Norwegian Univ Sci & Technol, Fac Med, Dept Publ Hlth, N-7034 Trondheim, Norway. EM lars.vatten@ntnu.no OI Romundstad, Pal Richard/0000-0003-2061-4336 NR 11 TC 20 Z9 20 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD MAY 7 PY 2007 VL 96 IS 9 BP 1436 EP 1438 DI 10.1038/sj.bjc.6603688 PG 3 WC Oncology SC Oncology GA 163LZ UT WOS:000246162600019 PM 17387346 ER PT J AU Brinton, LA Sakoda, LC Lissowska, J Sherman, ME Chatterjee, N Peplonska, B Szeszenia-Dabrowska, N Zatonski, W Garcia-Closas, M AF Brinton, L. A. Sakoda, L. C. Lissowska, J. Sherman, M. E. Chatterjee, N. Peplonska, B. Szeszenia-Dabrowska, N. Zatonski, W. Garcia-Closas, M. TI Reproductive risk factors for endometrial cancer among Polish women SO BRITISH JOURNAL OF CANCER LA English DT Article DE endometrial cancer; reproduction; risk; abortion; breastfeeding ID YOUNG-WOMEN; INDUCED-ABORTION; INFERTILE WOMEN; BREAST-CANCER; POPULATION; AGE; TIME; CARCINOMA; PREGNANCY; LACTATION AB We conducted a population-based case-control study of reproductive factors in Warsaw and Looz, Poland, in 551 incident endometrial cancer cases and 1925 controls. The reproductive variable most strongly related to risk was multiparity, with subjects with three or more births having a 70% lower risk than the nulliparous women. The reduced risk was particularly strong below 55 years of age. Subjects with older ages at a first birth were also at reduced risk even after adjustment for number of births. Ages at last birth or intervals since last birth were not strongly related to risk. Spontaneous abortions were unrelated to risk, but induced abortions were associated with slight risk increases (odds ratios = 1.28, 95% confidence intervals 0.8-2.1 for 3+ vs no abortions). The absence of effects on risk of later ages at, or short intervals since, a last birth fails to support the view that endometrial cancer is influenced by mechanical clearance of initiated cells. Alternative explanations for reproductive effects should be sought, including alterations in endogenous hormones. C1 Natl Canc Inst, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, Rockville, MD 20852 USA. Canc Ctr & M Sklodowska Curie Inst Oncol, Dept Canc Epidemiol & Prevent, PL-02781 Warsaw, Poland. Natl Canc Inst, Div Canc Epidemiol & Genet, Biostat Branch, Rockville, MD 20852 USA. Nofer Inst Occupat Med, Dept Occupat & Environm Epidemiol, Lodz, Poland. RP Brinton, LA (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, 6120 Execut Blvd,Suite 550, Rockville, MD 20852 USA. EM brinton@nih.gov RI Peplonska, Beata/F-6004-2010; Szeszenia-Dabrowska, Neonila/F-7190-2010; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Lissowska, Jolanta/0000-0003-2695-5799 FU Intramural NIH HHS NR 32 TC 30 Z9 31 U1 0 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 MAY 7 PY 2007 VL 96 IS 9 BP 1450 EP 1456 DI 10.1038/sj.bjc.6603731 PG 7 WC Oncology SC Oncology GA 163LZ UT WOS:000246162600022 PM 17426703 ER PT J AU Freedman, ND Schatzkin, A Leitzmann, MF Hollenbeck, AR Abnet, CC AF Freedman, N. D. Schatzkin, A. Leitzmann, M. F. Hollenbeck, A. R. Abnet, C. C. TI Alcohol and head and neck cancer risk in a prospective study SO BRITISH JOURNAL OF CANCER LA English DT Article DE head and neck cancer; alcohol; cohort ID POPULATION-BASED COHORT; LARYNGEAL-CANCER; TOBACCO; TRACT; ASSOCIATION; CONSUMPTION; DRINKING; ETHANOL; SMOKING; MODELS AB We investigated the relation between head and neck cancer risk and alcohol consumption in the NIH-AARP Diet and Health Study. During 2 203 500 person-years of follow-up, 611 men and 183 women developed head and neck cancer. With moderate drinking ( up to one alcoholic drink per day) as the referent group, non-drinkers showed an increased risk of head and neck cancer (men: hazard ratio (HR) 1.68, 95% confidence interval (95% CI) 1.37-2.06; women: 1.46, 1.02-2.08). Among male and female alcohol drinkers, we observed a significant dose-response relationship between alcohol consumption and risk. The HR for consuming 43 drinks per day was significantly higher in women ( 2.52, 1.46-4.35) than in men (1.48, 1.15-1.90; P for interaction = 0.0036). The incidence rates per 100 000 person-years for those who consumed 43 drinks per day were similar in men (77.6) and women (75.3). The higher HRs observed in women resulted from lower incidence rates in the referent group: women (14.7), men (34.4). In summary, drinking 43 alcoholic beverages per day was associated with increased risk in men and women, but consumption of up to one drink per day may be associated with reduced risk relative to non-drinking. C1 NCI, Canc Prevent Fellowship Program, Div Canc Prevent, NIH, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, NIH, Bethesda, MD 20892 USA. AARP, Washington, DC 20049 USA. RP Freedman, ND (reprint author), NCI, Canc Prevent Fellowship Program, Div Canc Prevent, NIH, Exeuct Plaza N,Suite 3109,6130 Execut Blvd,MSC 73, Bethesda, MD 20892 USA. EM freedmanne@mail.nih.gov RI Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015 OI Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098 FU Intramural NIH HHS NR 30 TC 37 Z9 38 U1 0 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 MAY 7 PY 2007 VL 96 IS 9 BP 1469 EP 1474 DI 10.1038/sj.bjc.6603713 PG 6 WC Oncology SC Oncology GA 163LZ UT WOS:000246162600025 PM 17387340 ER PT J AU Kang, D Chokkalingam, AP Gridley, G Nyren, O Johansson, JE Adami, HO Silverman, D Hsing, AW AF Kang, D. Chokkalingam, A. P. Gridley, G. Nyren, O. Johansson, J. E. Adami, H. O. Silverman, D. Hsing, A. W. TI Benign prostatic hyperplasia and subsequent risk of bladder cancer SO BRITISH JOURNAL OF CANCER LA English DT Article DE benign prostatic hyperplasia; prostate cancer; population-based; standardised incidence ratio ID POPULATION-BASED COHORT; SWEDEN AB We evaluated the risk of bladder cancer in a cohort of 79 280 Swedish men hospitalised for benign prostatic hyperplasia (BPH), identified in the Swedish Inpatient Register between 1964 and 1983 and followed until 1989 via multiple record linkages with nationwide data on cancer registry, death and emigration. Standardised incidence ratios (SIRs), the ratios of the observed to the expected numbers of incident bladder cancers, were used to calculate the risk associated with BPH. The expected number was calculated by multiplying the number of person-years by the age-specific cancer incidence rates in Sweden for each 5-year age group and calendar year of observation. Analyses were stratified by BPH treatment, latency, calendar year and presence of genitourinary (GU) comorbid conditions. After excluding the first 3 years of follow-up after the index hospitalisation, we observed 506 incident bladder cancer cases during follow-up in the cohort. No overall increased risk of bladder cancer was apparent in our main analysis involving the entire BPH cohort. However, among BPH patients with transurethral resection of the prostate ( TURP), there was an increased risk in all follow-up periods; SIRs of bladder cancer during years 4-6 of follow-up was 1.22 (95% confidence interval = 1.02-1.46), 1.32 for 7-9 years of follow-up, and 1.47 for 10-26 years of follow-up. SIRs of bladder cancer among TURP-treated BPH patients were particularly elevated among those with comorbid conditions of the GU tract ( e. g., stone, infection, etc.); 1.72, 1.74 and 2.01 for 4-6, 7-9, 10-26 years of follow-up, respectively, and also for those whose diagnoses occurred before 1975, when TURP was more likely to be performed by a urologist than a general practitioner: 1.87, 1.90 and 1.74, respectively. These findings suggest that BPH overall is not associated with bladder cancer risk. However, among men treated with TURP, particularly those with other comorbid GU tract conditions, risk of bladder cancer was elevated. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. Seoul Natl Univ, Coll Med, Seoul, South Korea. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. Obrebro Univ Hosp, Dept Urol & Clin Med, Obrebro, Sweden. Obrebro Univ Hosp, Ctr Assessment Med Technol, Obrebro, Sweden. RP Hsing, AW (reprint author), NCI, Div Canc Epidemiol & Genet, EPS 5024,MSC 7234,6120 Execut Blvd, Bethesda, MD 20892 USA. EM hsinga@mail.nih.gov RI Kang, Dae Hee/E-8631-2012 FU Intramural NIH HHS NR 19 TC 10 Z9 14 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD MAY 7 PY 2007 VL 96 IS 9 BP 1475 EP 1479 DI 10.1038/sj.bjc.6603730 PG 5 WC Oncology SC Oncology GA 163LZ UT WOS:000246162600026 PM 17473820 ER PT J AU Tsujimoto, S Sawaguchi, T AF Tsujimoto, Satoshi Sawaguchi, Toshiyuki TI Prediction of relative and absolute time of reward in monkey prefrontal neurons SO NEUROREPORT LA English DT Article DE decision-making; frontal lobe; learning; motivation; neuroeconomics; primate; reward; short-term memory; timing; working memory ID CORTEX; EXPECTATION; REPRESENTATION; PERCEPTION; IMMEDIATE; CONTEXT; MACAQUE; BRAIN AB We studied single-neuron activity in the monkey dorsolateral prefrontal cortex during a saccade task, in which correct responses were rewarded after a delay of 0.5 or 1.5s in one trial-block, and after 1.5 or 3-s delay in the other trial-block. Activity of some neurons depended on the relative length of the delays (longer or shorter) within each block, and activity for the 1.5-s trials was significantly different between the blocks. Activity of another group of neurons reflected the absolute length of delay: hence, the activity in the 1.5-s trials did not differ between the blocks. These results indicate that both relative and absolute time of future reward is represented in subsets of neurons in the dorsolateral prefrontal cortex. C1 Hokkaido Univ, Grad Sch Med, Lab Cognit Neurobiol, Sapporo, Hokkaido, Japan. RP Tsujimoto, S (reprint author), NIMH, Lab Syst Neurosci, Bldg 49,Room B1EE17,49 Convent Dr,MSC 4401, Bethesda, MD 20892 USA. EM tsujimotos@mail.nih.gov RI Tsujimoto, Satoshi/B-8223-2011 NR 24 TC 6 Z9 6 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD MAY 7 PY 2007 VL 18 IS 7 BP 703 EP 707 DI 10.1097/WNR.0b013e3280d943a1 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 159HK UT WOS:000245856000017 PM 17426603 ER PT J AU Conlan, AJK Grenfell, BT AF Conlan, Andrew J. K. Grenfell, Bryan T. TI Seasonality and the persistence and invasion of measles SO PROCEEDINGS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES LA English DT Article DE measles; persistence; critical community size; birth rate; invasion; vaccination ID CRITICAL COMMUNITY SIZE; INFECTIOUS PERIODS; REALISTIC DISTRIBUTIONS; DEVELOPING-COUNTRIES; VACCINATION PROGRAM; EPIDEMIC MODELS; UNITED-STATES; DYNAMICS; IMPACT; PATTERNS AB The critical community size (CCS) for measles, which separates persistent from extinction-prone populations, is arguably the best understood stochastic threshold in ecology. Using simple models, we explore a relatively neglected relationship of how the CCS scales with birth rate. A predominantly positive relationship of persistence with birth rate is complicated by the accompanying dynamical transitions of the underlying deterministic process. We show that these transitions imply a lower CCS for high birth rate less developed countries and contrary to the experience in lower birth rate, industrial countries, the CCS may increase after vaccination. We also consider the evolutionary implications of the CCS for the origin of measles; this analysis explores how the deterministic and stochastic thresholds for invasion and persistence set limits on the mechanism by which this highly infectious pathogen could have successfully colonized its human host. C1 DAMTP, Ctr Math Sci, Cambridge CB3 0WA, England. Penn State Univ, Ctr Infect Dis Dynam, Mueller Lab 208, University Pk, PA 16802 USA. US Nih, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Conlan, AJK (reprint author), DAMTP, Ctr Math Sci, Wilberforce Rd, Cambridge CB3 0WA, England. EM a.j.k.conlan@damtp.cam.ac.uk FU Wellcome Trust NR 57 TC 35 Z9 35 U1 0 U2 11 PU ROYAL SOCIETY PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 0962-8452 J9 P R SOC B JI Proc. R. Soc. B-Biol. Sci. PD MAY 7 PY 2007 VL 274 IS 1614 BP 1133 EP 1141 DI 10.1098/rspb.2006.0030 PG 9 WC Biology; Ecology; Evolutionary Biology SC Life Sciences & Biomedicine - Other Topics; Environmental Sciences & Ecology; Evolutionary Biology GA 156CZ UT WOS:000245627000002 PM 17327206 ER PT J AU Nagy, A Turner, RJ AF Nagy, Akos Turner, R. James TI The membrane integration of a naturally occurring alpha-helical hairpin SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE membrane protein structure; trans-membrane topology; cation-chloride cotransporter; translocon ID IN-VITRO TRANSLATION; INTACT MAMMALIAN-CELLS; TURN PROPENSITY SCALE; TRANSMEMBRANE HELICES; TOPOLOGY; BIOGENESIS AB Helical hairpins, two closely spaced helical membrane spanning segments separated by a short surface turn, are thought to be common in integral membrane proteins. Her:, we study the membrane integration of a naturally occurring helical hairpin from the secretory Na+-K+-2Cl(-) cotransporter NKCC1. This sequence is only slightly longer and significantly less hydrophobic than a previously identified minimal poly-leucine model hairpin structure. Using site directed mutagenesis we document the importance of the turn propensity of the amino acids in the intervening surface turn but, somewhat surprisingly, our results indicate that the formation of this natural hairpin apparently does not depend on specific helix-helix interactions. Our results suggest that helical hairpins may be formed quite readily from even minimally hydrophobic sequences separated by a short, sufficiently strong, turn signal, and that current methods for predicting integral membrane protein topology may miss many similar short helical hairpin sequences. Thus the occurrence of these structures may be much more common than presently thought. (c) 2007 Elsevier Inc. All rights reserved. C1 Natl Inst Dent & Craniofacial Res, Membrane Biol Sect, Gene Therapy & Therapeut Branch, NIH,DHHS, Bethesda, MD 20892 USA. RP Turner, RJ (reprint author), Natl Inst Dent & Craniofacial Res, Membrane Biol Sect, Gene Therapy & Therapeut Branch, NIH,DHHS, Bethesda, MD 20892 USA. EM rjturner@nih.gov FU Intramural NIH HHS NR 15 TC 2 Z9 2 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 MAY 4 PY 2007 VL 356 IS 2 BP 392 EP 397 DI 10.1016/j.bbrc.2007.02.149 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 155FY UT WOS:000245564500012 PM 17367760 ER PT J AU Peter, ME Budd, RC Desbarats, J Hedrick, SM Hueber, AO Newell, MK Owen, LB Tschopp, J Wajant, H Wallach, D Wiltrout, RH Zornig, M Lynch, DH AF Peter, Marcus E. Budd, Ralph C. Desbarats, Julie Hedrick, Stephen M. Hueber, Anne-Odile Newell, M. Karen Owen, Laurie B. Tschopp, Juerg Wajant, Harald Wallach, David Wiltrout, Robert H. Zornig, Martin Lynch, David H. TI The CD95 receptor: Apoptosis revisited SO CELL LA English DT Article ID HEMATOPOIETIC PROGENITOR CELLS; FAS LIGAND; DEATH; ACTIVATION; PROLIFERATION; CASPASE-8; SIGNALS; INJURY; LEADS; FADD AB CD95 is the quintessential death receptor and, when it is bound by ligand, cells undergo apoptosis. Recent evidence suggests, however, that CD95 mediates not only apoptosis but also diverse nonapoptotic functions depending on the tissue and the conditions. C1 Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA. Univ Vermont, Coll Med, Dept Med, Burlington, VT 05405 USA. McGill Univ, Dept Physiol, Montreal, PQ, Canada. Univ Calif San Diego, La Jolla, CA 92093 USA. CNRS, UMR 6543, Inst Signaling Dev Biol & Canc Res, F-06189 Nice, France. Univ Colorado, Inst Bioenerget, Colorado Springs, CO 80907 USA. Univ Calif Riverside, Riverside, CA 92521 USA. Northwestern Univ, Feinberg Sch Med, Div Rheumatol, Chicago, IL 60611 USA. Univ Lausanne, Dept Biochem, CH-1066 Epalinges, Switzerland. Univ Wurzburg, Dept Mol Internal Med, Med Clin & Polyclin 2, D-97070 Wurzburg, Germany. Weizmann Inst Sci, Dept Biol Chem, IL-76100 Rehovot, Israel. NCI, Ctr Canc Res, Expt Immunol Lab, Ft Detrick, MD 21702 USA. Bainbridge Biopharma Consulting, Bainbridge Is, WA 98110 USA. RP Peter, ME (reprint author), Univ Chicago, Ben May Dept Canc Res, Chicago, IL 60637 USA. EM mpeter@uchicago.edu RI HUEBER, Anne-Odile/G-4352-2013; Wajant, Harald/A-3020-2017 OI Wajant, Harald/0000-0002-2005-3949 NR 31 TC 246 Z9 253 U1 1 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAY 4 PY 2007 VL 129 IS 3 BP 447 EP 450 DI 10.1016/j.cell.2007.04.031 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 166IY UT WOS:000246373600007 PM 17482535 ER PT J AU Kostelansky, MS Schluter, C Tam, YYC Lee, S Ghirlando, R Beach, B Conibear, E Hurley, JH AF Kostelansky, Michael S. Schluter, Cayetana Tam, Yuen Yi C. Lee, Sangho Ghirlando, Rodolfo Beach, Bridgette Conibear, Elizabeth Hurley, James H. TI Molecular architecture and functional model of the complete yeast ESCRT-I heterotetramer SO CELL LA English DT Article ID UBIQUITIN-BINDING DOMAINS; SORTING COMPLEX; SACCHAROMYCES-CEREVISIAE; TRAFFICKING COMPLEX; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; GLUE DOMAIN; PROTEIN; ENDOSOME; RECOGNITION AB The endosomal sorting complex required for transport-1 (ESCRT-1) complex, which is conserved from yeast to humans, directs the lysosomal degradation of ubiquitinated transmembrane proteins and the budding of the HIV virus. Yeast ESCRT-1 contains four subunits, Vps23, Vps28, Vps37, and Mvb12. The crystal structure of the heterotetrameric ESCRT-1 complex reveals a highly asymmetric complex of 1:1:1:1 subunit stoichiometry. The core complex is nearly 18 nm long and consists of a headpiece attached to a 13 nm stalk. The stalk is important for cargo sorting by ESCRT-1 and is proposed to serve as a spacer regulating the correct disposition of cargo and other ESCRT components. Hydrodynamic constraints and crystallographic structures were used to generate a model of intact ESCRT-1 in solution. The results show how ESCRT-1 uses a combination of a rigid stalk and flexible tethers to interact with lipids, cargo, and other ESCRT complexes over a span of similar to 25 nm. C1 NIDDKD, Mol Biol Lab, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ British Columbia, Ctr Mol Med & Therapeut, Child & Family Res Inst, Dept Med Genet, Vancouver, BC V5Z 4H4, Canada. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov RI Ghirlando, Rodolfo/A-8880-2009; Conibear, Elizabeth/G-5297-2010 FU Intramural NIH HHS [Z01 DK036118-14] NR 43 TC 83 Z9 89 U1 2 U2 12 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAY 4 PY 2007 VL 129 IS 3 BP 485 EP 498 DI 10.1016/j.cell.2007.03.016 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 166IY UT WOS:000246373600016 PM 17442384 ER PT J AU Zhang, F Yim, YI Scarselletta, S Norton, M Eisenberg, E Greene, LE AF Zhang, Fang Yim, Yang-In Scarselletta, Sarah Norton, Mark Eisenberg, Evan Greene, Lois E. TI Clathrin adaptor GGA1 polymerizes clathrin into tubules SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANS-GOLGI NETWORK; VHS DOMAINS; ENDOSOME TRANSPORT; GAMMA-ADAPTIN; PROTEINS; AP-1; TGN; LOCALIZATION; TRAFFICKING; RECEPTORS AB GGAs, a class of monomeric clathrin adaptors, are involved in the sorting of cargo at the trans-Golgi network of eukaryotic cells. They are modular structures consisting of the VHS, the GAT, hinge, and GAEdomains, which have been shown to interact directly with cargo, ARF, clathrin, and accessory proteins, respectively. Previous studies have shown that GGAs interact with clathrin both in solution and in the cell, but it has yet been shown whether they assemble clathrin. We find that GGA1 promoted assembly of clathrin with complete assembly achieved when one GGA1 molecule is bound per heavy chain. In the presence of excess GGA1, we obtained the unusual stoichiometry of five GGA1s per heavy chain, and even at this stoichiometry the binding was not saturated. The assembled structures were mostly baskets, but similar to 10% of the structures were tubular with an average length of 180 similar to 40 nm and width of similar to 50 nm. The truncated GGA1 fragment consisting of the hinge+GAE domains bound to clathrin with similar affinity as the full-length molecule and polymerized clathrin into baskets. Unlike the full-length molecule, this fragment saturated the lattices at one molecule per heavy chain and assembled clathrin only into baskets. The separated hinge and GAE domains bound much weaker to clathrin than the intact molecule, and these domains do not significantly polymerize clathrin into baskets. We conclude that clathrin adaptor GGA1 is a clathrin assembly protein, but it is unique in its ability to polymerize clathrin into tubules. C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Greene, LE (reprint author), NHLBI, Cell Biol Lab, NIH, 50 S Dr,Rm 2737,MSC 8017, Bethesda, MD 20892 USA. EM greenel@helix.nih.gov NR 28 TC 11 Z9 12 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 MAY 4 PY 2007 VL 282 IS 18 BP 13282 EP 13289 DI 10.1074/jbc.M700936200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 162BC UT WOS:000246060300016 PM 17344219 ER PT J AU Grodnitzky, JA Syed, N Kimber, MJ Day, TA Donaldson, JG Hsu, WH AF Grodnitzky, Justin A. Syed, Nasser Kimber, Michael J. Day, Tim A. Donaldson, Julie G. Hsu, Walter H. TI Somatostatin receptors signal through EFA6A-ARF6 to activate phospholipase D in clonal beta-cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ADP-RIBOSYLATION FACTOR; PROTEIN-KINASE-C; NUCLEOTIDE EXCHANGE FACTOR; SMOOTH-MUSCLE CELLS; GTP-BINDING PROTEIN; PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATE; PLASMA-MEMBRANE; INSULIN-SECRETION; P115 RHOGEF; HL-60 CELLS AB Somatostatin (SS) is a peptide hormone that inhibits insulin secretion in beta-cells by activating its G(i/o)-coupled receptors. Our previous work indicated that a beta gamma-dimer of G(i/o) coupled to SS receptors can activate phospholipase D1 ( PLD1) ( Cheng, H., Grodnitzky, J. A., Yibchok-anun, S., Ding, J., and Hsu, W. H. (2005) Mol. Pharmacol. 67, 2162-2172). The aim of the present study was to elucidate the mechanisms underlying SS-induced PLD activation. We demonstrated the presence of ADP-ribosylation factor Arf1 and Arf6 in clonal beta-cells, HIT-T15. We also determined that the activation of PLD1 was mediated through Arf6. Overexpression of dominant-negative (dn) Arf6 mutant, Arf6( T27N), and suppression of mRNA levels using siRNA, both abolished SS-induced PLD activation, while overexpression of wild type Arf6 further enhanced this PLD activation. In contrast, overexpression of dn-Arf1 mutant Arf1(T31N) or dn-Arf5 mutant Arf5(T31N) failed to reduce SS-induced PLD activation. These findings suggested that Arf6, but not Arf1 or Arf5, mediates the effect of SS. We further determined the involvement of the Arf6 guanine nucleotide exchange factor (GEF) EFA6A, a GEF previously thought to be found predominantly in the brain, in the activation of PLD1 in HIT-T15 cells. Using Northern and Western blot analyses, both mRNA and protein of EFA6A were found in these cells. Overexpression of dn-EFA6A mutant, EFA6A( E242K), and suppression of mRNA levels using siRNA, both abolished SS-induced PLD activation, whereas overexpression of dn-EFA6B mutant, EFA6B( E651K), failed to reduce SS-induced PLD activation. In addition, overexpression of dn-ARNO mutant, ARNO(E156K), another GEF of Arf6, had no effect on SS-induced activation of PLD. Taken together, these results suggest that SS signals through EFA6A to activate Arf6-PLD cascade. C1 Iowa State Univ, Dept Biomed Sci, Ames, IA 50011 USA. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hsu, WH (reprint author), Iowa State Univ, Dept Biomed Sci, Ames, IA 50011 USA. EM whsu@iastate.edu NR 63 TC 6 Z9 8 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAY 4 PY 2007 VL 282 IS 18 BP 13410 EP 13418 DI 10.1074/jbc.M701940200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 162BC UT WOS:000246060300030 PM 17353194 ER PT J AU Liu, YA Prasad, R Beard, WA Kedar, PS Hou, EW Shock, DD Wilson, SH AF Liu, Yuan Prasad, Rajendra Beard, William A. Kedar, Padmini S. Hou, Esther W. Shock, David D. Wilson, Samuel H. TI Coordination of steps in single-nucleotide base excision repair mediated by apurinic/apyrimidinic endonuclease 1 and DNA polymerase beta SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PURIFIED HUMAN PROTEINS; CELL NUCLEAR ANTIGEN; ABASIC SITE REPAIR; POLY(ADP-RIBOSE) POLYMERASE-1; LIGASE I; DEGENERATIVE DISEASES; INDUCED CYTOTOXICITY; MAMMALIAN-CELLS; DAMAGE; ENZYMES AB The individual steps in single-nucleotide base excision repair (SN-BER) are coordinated to enable efficient repair without accumulation of cytotoxic DNA intermediates. The DNA transactions and various proteins involved in SN-BER of abasic sites are well known in mammalian systems. Yet, despite a wealth of information on SN-BER, the mechanism of step-by-step coordination is poorly understood. In this study we conducted experiments toward understanding step-by-step coordination during BER by comparing DNA binding specificities of two major human SN-BER enzymes, apurinic/aprymidinic endonuclease 1 (APE) and DNA polymerase beta (Pol beta). It is known that these enzymes do not form a stable complex in solution. For each enzyme, we found that DNA binding specificity appeared sufficient to explain the sequential processing of BER intermediates. In addition, however, we identified at higher enzyme concentrations a ternary complex of APE center dot Pol beta center dot DNA that formed specifically at BER intermediates containing a 5'-deoxyribose phosphate group. Formation of this ternary complex was associated with slightly stronger Pol beta gap-filling and much stronger 5'-deoxyribose phosphate lyase activities than was observed with the Pol beta center dot DNA binary complex. These results indicate that step-by step coordination in SN-BER can rely on DNA binding specificity inherent in APE and Pol beta, although coordination also may be facilitated by APE center dot Pol beta center dot DNA ternary complex formation with appropriate enzyme expression levels or enzyme recruitment to sites of repair. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, 111 TW Alexander Dr,POB 12233,MD F3-01, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU Intramural NIH HHS [Z01 ES050158-11] NR 57 TC 67 Z9 72 U1 2 U2 9 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 MAY 4 PY 2007 VL 282 IS 18 BP 13532 EP 13541 DI 10.1074/jbc.M611295200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 162BC UT WOS:000246060300042 PM 17355977 ER PT J AU Kim, JA Formoso, G Li, YH Potenza, MA Marasciulo, FL Montagnani, M Quon, MJ AF Kim, Jeong-a Formoso, Gloria Li, Yunhua Potenza, Maria A. Marasciulo, Flora L. Montagnani, Monica Quon, Michael J. TI Epigallocatechin gallate, a green tea polyphenol, mediates NO-dependent vasodilation using signaling pathways in vascular endothelium requiring reactive oxygen species and Fyn SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NITRIC-OXIDE SYNTHASE; CORONARY-ARTERY-DISEASE; SPONTANEOUSLY HYPERTENSIVE-RATS; INSULIN-STIMULATED PRODUCTION; MUSCLE GLUCOSE-UPTAKE; PROTEIN-KINASE-B; PHOSPHATIDYLINOSITOL 3-KINASE; MICROVASCULAR RECRUITMENT; TYROSINE PHOSPHORYLATION; RECEPTOR SUBSTRATE-1 AB Green tea consumption is associated with reduced cardiovascular mortality in some epidemiological studies. Epigallocatechin gallate (EGCG), a bioactive polyphenol in green tea, mimics metabolic actions of insulin to inhibit gluconeogenesis in hepatocytes. Because signaling pathways regulating metabolic and vasodilator actions of insulin are shared in common, we hypothesized that EGCG may also have vasodilator actions to stimulate production of nitric oxide (NO) from endothelial cells. Acute intra-arterial administration of EGCG to mesenteric vascular beds isolated ex vivo from WKY rats caused dose-dependent vasorelaxation. This was inhibitable by L-NAME (NO synthase inhibitor), wortmannin (phosphatidylinositol 3-kinase inhibitor), or PP2 (Src family kinase inhibitor). Treatment of bovine aortic endothelial cells (BAEC) with EGCG (50 mu m) acutely stimulated production of NO(assessed with NO-specific fluorescent dye DAF-2) that was inhibitable by L-NAME, wortmannin, or PP2. Stimulation of BAEC with EGCG also resulted in dose- and time-dependent phosphorylation of eNOS that was inhibitable by wortmannin or PP2 (but not by MEK inhibitor PD98059). Specific knockdown of Fyn (but not Src) with small interfering RNA inhibited both EGCG-stimulated phosphorylation of Akt and eNOS as well as production of NO in BAEC. Treatment of BAEC with EGCG generated intracellular H2O2 ( assessed with H2O2-specific fluorescent dye CM-H2DCF-DA), whereas treatment with N-acetylcysteine inhibited EGCG-stimulated phosphorylation of Fyn, Akt, and eNOS. We conclude that EGCG has endothelial-dependent vasodilator actions mediated by intracellular signaling pathways requiring reactive oxygen species and Fyn that lead to activation of phosphatidylinositol 3-kinase, Akt, and eNOS. This mechanism may explain, in part, beneficial vascular and metabolic health effects of green tea consumption. C1 NCCAM, Diabet Unit, Bethesda, MD 20892 USA. Univ Bari, Dept Pharmacol & Human Physiol, I-70124 Bari, Italy. RP Quon, MJ (reprint author), Bldg 10,Room 6C-205, Bethesda, MD 20892 USA. EM quonm@nih.gov RI Quon, Michael/B-1970-2008; OI Potenza, Maria Assunta/0000-0002-9995-1468; Quon, Michael/0000-0002-9601-9915; montagnani, monica/0000-0002-5697-8185; Quon , Michael /0000-0002-5289-3707 FU Intramural NIH HHS NR 66 TC 122 Z9 127 U1 2 U2 20 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 MAY 4 PY 2007 VL 282 IS 18 BP 13736 EP 13745 DI 10.1074/jbc.M609725200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 162BC UT WOS:000246060300063 PM 17363366 ER PT J AU Li, X Ghandri, N Piancatelli, D Adams, S Chen, D Robbins, FM Wang, E Monaco, A Selleri, S Bouaouina, N Stroncek, D Adorno, D Chouchane, L Marincola, FM AF Li, Xin Ghandri, Nahla Piancatelli, Daniela Adams, Sharon Chen, Deborah Robbins, Fu-Meei Wang, Ena Monaco, Alessandro Selleri, Silvia Bouaouina, Noureddine Stroncek, David Adorno, Domenico Chouchane, Lotfi Marincola, Francesco M. TI Associations between HLA Class I alleles and the prevalence of nasopharyngeal carcinoma (NPC) among Tunisians SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID EWENS SAMPLING DISTRIBUTION; PEPTIDE-BASED IMMUNOTHERAPY; ETHNIC-GROUPS; B ALLELES; AFRICAN POPULATIONS; MOROCCAN PATIENTS; SOUTHERN CHINESE; A LOCUS; POLYMORPHISM; HAPLOTYPES AB The high prevalence of nasopharyngeal cancer (NPC) in Southern Asia and Mediterranean Northern Africa suggests genetic predisposition among other factors. While Human Leukocyte Antigen (HLA) haplotypes have been conclusively associated with NPC predisposition in Asians, Northern African Maghrebians have been less intensely studied. However, low resolution serological methods identified weak positive associations with HLA-B5, B13 and B18 and a negative with HLA-B14. Using sequence based typing (SBT), we performed a direct comparison of HLA class I frequencies in a cohort of 136 Tunisian patients with NPC matched for gender, age and geographical residence to 148 normal Tunisians. The bimodal age distribution of NPC in Maghrebians was also taken into account. HLA frequencies in normal Tunisians were also compared with those of Northern Moroccan Berbers (ME) to evaluate whether the Tunisian population in this study could be considered representative of other Maghrebian populations. HLA-B14 and - Cw08 were negatively associated with NPC (odd ratio = 0.09 and 0.18 respectively, Fisher p(2)-value = 0.0001 and = 0.003). Moreover, positive associations were observed for HLA-B-18, - B51 (split of -B5) and -B57 (p(2)-value < 0.025 in all) confirming previous findings in Maghrebs. The HLA-B14/Cw*08 haplotype frequency (HF) was 0.007 in NPC patients compared to 0.057 in both Tunisian (OR = 0.12; p(2)-value = 0.001) and Moroccan controls. This study confirms several previous associations noted by serologic typing between HLA class I alleles and the prevalence of NPC in Maghrebians populations. In addition, we identified a putative haplotype rare in Tunisian patients with NPC that may serve as a genetic marker for further susceptibility studies. C1 NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. Fac Med Monastir, Lab Mol Immunol & oncol, Monastir, Tunisia. Inst Organ Transplant & Immunocytol, CNR, Laquila, Italy. RP Marincola, FM (reprint author), NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM Lixin2@cc.nih.gov; nahnouna@yahoo.fr; d.piancatelli@itoi.cnr.it; SAdams1@cc.nih.gov; DSChen@cc.nih.gov; FRobbins@cc.nih.gov; EWang@cc.nih.gov; monacoal@cc.nih.gov; selleris@cc.nih.gov; noueddine.bouaouina@rns.tn; DStroncek@cc.nih.gov; d.adorno@itoi.cnr.it; lotfi.chouchane@planet.tn; FMarincola@cc.nih.gov RI Monaco, Alessandro/O-5338-2015 OI Monaco, Alessandro/0000-0002-9941-7003 NR 65 TC 19 Z9 22 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD MAY 4 PY 2007 VL 5 AR 22 DI 10.1186/1479-5876-5-22 PG 13 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 175TJ UT WOS:000247036600001 PM 17480220 ER PT J AU Ko, H Fricks, I Ivanov, AA Harden, TK Jacobson, KA AF Ko, Hyojin Fricks, Ingrid Ivanov, Andrei A. Harden, T. Kendall Jacobson, Kenneth A. TI Structure-activity relationship of uridine 5'-diphosphoglucose analogues as agonists of the human P2Y(14) receptor SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; HUMAN P2Y(6) RECEPTOR; P2 RECEPTORS; MOLECULAR RECOGNITION; NUCLEOTIDE RECEPTORS; PHOSPHOLIPASE-C; UDP-GLUCOSE; FUNCTIONAL EXPRESSION; PURINERGIC RECEPTORS; CLONING AB UDP-glucose (UDPG) and derivatives are naturally occurring agonists of the G(i) protein-coupled P2Y(14) receptor, which occurs in the immune system. We synthesized and characterized pharmacologically novel analogues of UDPG modified on the nucleobase, ribose, and glucose moieties, as the basis for designing novel ligands in conjunction with modeling. The recombinant human P2Y(14) receptor expressed in COS-7 cells was coupled to phospholipase C through an engineered G alpha-q/i protein. Most modifications of the uracil or ribose moieties abolished activity; this is among the least permissive P2Y receptors. However, a 2-thiouracil modification in 15 (EC50 49 +/- 2 nM) enhanced the potency of UDPG (but not UDP-glucuronic acid) by 7-fold. 4-Thio analogue 13 was equipotent to UDPG, but S-alkylation was detrimental. Compound 15 was docked in a rhodposin-based receptor homology model, which correctly predicted potent agonism of UDP-fructose, UDP-mannose, and UDP-inositol. The hexose moiety of UDPG interacts with multiple H-bonding and charged residues and provides a fertile region for agonist modification. C1 NIDDK, Mol Recognit Sect, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Dept Pharmacol, Sch Med, Chapel Hill, NC 27599 USA. RP Jacobson, KA (reprint author), NIDDK, Mol Recognit Sect, Lab Bioorgan Chem, NIH, 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 [Z01 DK031116-20]; NHLBI NIH HHS [HL34322, P01 HL034322]; NIGMS NIH HHS [GM38213, R01 GM038213] NR 41 TC 39 Z9 41 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 3 PY 2007 VL 50 IS 9 BP 2030 EP 2039 DI 10.1021/jm061222w PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 160PK UT WOS:000245954600005 PM 17407275 ER PT J AU Morrell, A Placzek, MS Steffen, JD Antony, S Agama, K Pommier, Y Cushman, M AF Morrell, Andrew Placzek, Michael S. Steffen, Jamin D. Antony, Smitha Agama, Keli Pommier, Yves Cushman, Mark TI Investigation of the lactam side chain length necessary for optimal indenoisoquinoline topoisomerase i inhibition and cytotoxicity in human cancer cell cultures SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID DNA COVALENT COMPLEX; BIOLOGICAL EVALUATION; MJ-III-65 NSC-706744; ANTICANCER ACTIVITY; CLEAVAGE COMPLEXES; SERUM-ALBUMIN; CAMPTOTHECIN; MECHANISM; DESIGN; TOPOTECAN AB Indenoisoquinolines with lactam substituents such as ethylamino, propylamino, and butylamino have previously demonstrated potent biological activity, but an optimal length has never been established. In the present study, a series of simplified indenoisoquinoline analogues possessing a linker spacing of 0-12 carbon atoms between the lactam nitrogen and the terminal amino group have been prepared, determining that 2-4-atom lengths are optimal for topoisomerase I inhibition and cytotoxicity. Using these lengths, analogues were prepared with the amino group and portions of the linker replaced by a pyridine ring. A three-carbon spacer within the pyridine series still demonstrated potent topoisomerase I inhibition. C1 Purdue Univ, Sch Pharm & Pharmaceut Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. Purdue Univ, Purdue Canc Ctr, W Lafayette, IN 47907 USA. NCI, Canc Res Ctr, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Cushman, M (reprint author), Purdue Univ, Sch Pharm & Pharmaceut Sci, Dept Med Chem & Mol Pharmacol, W Lafayette, IN 47907 USA. EM cushman@pharmacy.purdue.edu FU Intramural NIH HHS; NCI NIH HHS [U01 CA89566, ST32 CA09634-12, T32 CA009634, U01 CA089566, U01 CA089566-01A1, U01 CA089566-02, U01 CA089566-03, U01 CA089566-04, U01 CA089566-05, U01 CA089566-06]; PHS HHS [C06-14400] NR 41 TC 46 Z9 46 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 3 PY 2007 VL 50 IS 9 BP 2040 EP 2048 DI 10.1021/jm0613119 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 160PK UT WOS:000245954600006 PM 17402722 ER PT J AU Burnett, JC Opsenica, D Sriraghavan, K Panchal, RG Ruthel, G Hermone, AR Nguyen, TL Kenny, TA Lane, DJ McGrath, CF Schmidt, JJ Vennerstrom, JL Gussio, R Solaja, BA Bavari, S AF Burnett, James C. Opsenica, Dejan Sriraghavan, Kamaraj Panchal, Rekha G. Ruthel, Gordon Hermone, Ann R. Nguyen, Tam L. Kenny, Tara A. Lane, Douglas J. McGrath, Connor F. Schmidt, James J. Vennerstrom, Jonathan L. Gussio, Rick Solaja, Bogdan A. Bavari, Sina TI A refined pharmacophore identifies potent 4-amino-7-chloroquinoline-based inhibitors of the botulinum neurotoxin serotype a metalloprotease SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID SMALL-MOLECULE INHIBITORS; TOXIN TYPE-A; CLOSTRIDIUM-BOTULINUM; ZINC ENDOPEPTIDASE; NEUROTRANSMITTER RELEASE; ANTIMALARIAL ACTIVITY; CRYSTAL-STRUCTURE; PROTEASE ACTIVITY; MEDICAL ASPECTS; BINDING AB We previously identified structurally diverse small molecule (non-peptidic) inhibitors (SMNPIs) of the botulinum neurotoxin serotype A (BoNT/A) light chain (LC). Of these, several (including antimalarial drugs) contained a 4-amino-7-chloroquinoline (ACQ) substructure and a separate positive ionizable amine component. The same antimalarials have also been found to interfere with BoNT/A translocation into neurons, via pH elevation of the toxin-mediated endosome. Thus, this structural class of small molecules may serve as dual-function BoNT/A inhibitors. In this study, we used a refined pharmacophore for BoNT/A LC inhibition to identify four new, potent inhibitors of this structural class (IC(50)'s ranged from 3.2 to 17 mu M). Molecular docking indicated that the binding modes for the new SMNPIs are consistent with those of other inhibitors that we have identified, further supporting our structure-based pharmacophore. Finally, structural motifs of the new SMNPIs, as well as two structure-based derivatives, were examined for activity, providing valuable information about pharmacophore component contributions to inhibition. C1 Univ Belgrade, Fac Chem, Belgrade 11001, Serbia. SAIC Frederick Inc, Target Struct Based Discovery Grp, Natl Canc Inst, Frederick, MD 21702 USA. Inst Chem Technol & Met, Belgrade 11001, Serbia. Univ Nebraska, Med Ctr, Coll Pharm, Omaha, NE 68198 USA. USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. NCI Frederick, Dev Therapeut Program, Ft Detrick, MD 21702 USA. RP Solaja, BA (reprint author), Univ Belgrade, Fac Chem, Studentski Trg 16,POB 158, Belgrade 11001, Serbia. EM bsolaja@chem.bg.ac.yu; sina.bavari@us.army.mil OI Solaja, Bogdan/0000-0002-9975-2725 FU NCI NIH HHS [N01-CO-12400] NR 60 TC 40 Z9 40 U1 0 U2 2 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 MAY 3 PY 2007 VL 50 IS 9 BP 2127 EP 2136 DI 10.1021/jm061446e PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 160PK UT WOS:000245954600015 PM 17417831 ER PT J AU Romagnoli, R Baraldi, PG Carrion, MD Cara, CL Preti, D Fruttarolo, F Pavani, MG Tabrizi, MA Tolomeo, M Grimaudo, S Di Cristina, A Balzarini, J Hadfield, JA Brancale, A Hamel, E AF Romagnoli, Romeo Baraldi, Pier Giovanni Carrion, Maria Dora Cara, Carlota Lopez Preti, Delia Fruttarolo, Francesca Pavani, Maria Giovanna Tabrizi, Mojgan Aghazadeh Tolomeo, Manlio Grimaudo, Stefania Di Cristina, Antonella Balzarini, Jan Hadfield, John A. Brancale, Andrea Hamel, Ernest TI Synthesis and biological evaluation of 2-and 3-aminobenzo[b]thiophene derivatives as antimitotic agents and inhibitors of tubulin polymerization SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ANTINEOPLASTIC AGENTS; ANTITUBULIN AGENTS; COMBRETASTATIN-A-4; COLCHICINE; THIOPHENES; BINDING; ANALOGS; GROWTH AB Two new series of inhibitors of tubulin polymerization based on the 2-amino-3-(3,4,5-trimethoxybenzoyl)benzo[b]thiophene molecular skeleton and its 3-amino positional isomer were synthesized and evaluated for antiproliferative activity, inhibition of tubulin polymerization, and cell cycle effects. Although many more 3-amino derivatives have been synthesized so far, the most promising compound in this series was 2-amino-6-methyl-3-(3,4,5-trimethoxybenzoyl)benzo[b]thiophene, which inhibits cancer cell growth at subnanomolar concentrations and interacts strongly with tubulin by binding to the colchicine site. C1 Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. Univ Palermo, Policlin P Giaccone, Div Ematol, Palermo, Italy. Univ Palermo, Policlin P Giaccone, Serv AIDS, Palermo, Italy. Katholieke Univ Leuven, Rega Inst Med Res, Lab Virol & Chemotherapy, B-3000 Louvain, Belgium. Univ Salford, Ctr Mol Drug Design, Salford M5 4W5, Lancs, England. Cardiff Univ, Welsh Sch Pharm, Cardiff CF10 3XF, Wales. NCI, Frederick Canc Res & Dev Ctr, Div Canc Treatment & Diag,Dev Therapeut Program, Toxicol & Pharmacol Branch,NIH, Frederick, MD 21702 USA. RP Romagnoli, R (reprint author), Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. EM rmr@unife.it; baraldi@unife.it RI antonietta, di cristina/I-9251-2012; Aghazadeh Tabrizi, Mojgan/I-9169-2014; Brancale, Andrea/N-9445-2014; LOPEZ-CARA, LUISA CARLOTA/F-9686-2014; Carrion, M. Dora/G-8638-2015; Romagnoli, Romeo/G-9887-2015; Baraldi, Pier Giovanni/B-7933-2017 OI Grimaudo, Stefania/0000-0003-3225-4112; Brancale, Andrea/0000-0002-9728-3419; LOPEZ-CARA, LUISA CARLOTA/0000-0003-1142-6448; Carrion, M. Dora/0000-0002-6794-3949; NR 23 TC 83 Z9 84 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAY 3 PY 2007 VL 50 IS 9 BP 2273 EP 2277 DI 10.1021/jm070050f PG 5 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 160PK UT WOS:000245954600033 PM 17419607 ER PT J AU Klauda, JB Wu, XW Pastor, RW Brooks, BR AF Klauda, Jeffery B. Wu, Xiongwu Pastor, Richard W. Brooks, Bernard R. TI Long-range Lennard-Jones and electrostatic interactions in interfaces: Application of the isotropic periodic sum method SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID MOLECULAR-DYNAMICS SIMULATIONS; LIPID-BILAYERS; COMPUTER-SIMULATION; ALKANES; SURFACE; WATER; MONOLAYERS; TREHALOSE; INSIGHTS; SYSTEM AB Molecular dynamics (MD) simulations of heptane/vapor, hexadecane/vapor, water/vapor, hexadecane/water, and dipalmitoylphosphatidylcholine (DPPC) bilayers and monolayers are analyzed to determine the accuracy of treating long-range interactions in interfaces with the isotropic periodic sum (IPS) method. The method and cutoff (r(c)) dependences of surface tensions, density profiles, water dipole orientation, and electrostatic potential profiles are used as metrics. The water/vapor, heptane/vapor, and hexadecane/vapor interfaces are accurately and efficiently calculated with 2D IPS (r(c) = 10 A). It is demonstrated that 3D IPS is not practical for any of the interfacial systems studied. However, the hybrid method PME/IPS [Particle Mesh Ewald for electrostatics and 3D IPS for Lennard-Jones (LJ) interactions] provides an efficient way to include both types of long-range forces in simulations of large liquid/vacuum and all liquid/liquid interfaces, including lipid monolayers and bilayers. A previously published pressure-based long-range LJ correction yields results similar to those of PME/IPS for liquid/liquid interfaces. The contributions to surface tension of LJ terms arising from interactions beyond 10 A range from 13 dyn/cm for the hexadecane/vapor interface to approximately 3 dyn/cm for hexadecane/water and DPPC bilayers and monolayers. Surface tensions of alkane/vapor, hexadecane/water, and DPPC monolayers based on the CHARMM lipid force fields agree very well with experiment, whereas surface tensions of the TIP3P and TIP4P-Ew water models underestimate experiment by 16 and 11 dyn/cm, respectively. Dipole potential drops (Delta Psi) are less sensitive to long-range LJ interactions than surface tensions. However, Delta Psi for the DPPC bilayer (845 +/- 3 mV proceeding from water to lipid) and water (547 +/- 2 mV for TIP4P-Ew and 521 +/- 3 mV for TIP3P) overestimate experiment by factors of 3 and 5, respectively, and represent expected deficiencies in nonpolarizable force fields. C1 NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP Klauda, JB (reprint author), NHLBI, Lab Computat Biol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM klauda@helix.nih.gov RI Klauda, Jeffery/A-4345-2008 FU Intramural NIH HHS NR 34 TC 51 Z9 52 U1 0 U2 23 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAY 3 PY 2007 VL 111 IS 17 BP 4393 EP 4400 DI 10.1021/jp068767m PG 8 WC Chemistry, Physical SC Chemistry GA 160PM UT WOS:000245954800016 PM 17425357 ER PT J AU Low, NC Hardy, J AF Low, Nancy C. Hardy, John TI What is a schizophrenic mouse? SO NEURON LA English DT Editorial Material ID TRANSLOCATION; GENES AB In this issue of Neuron, Clapcote et al. examine mice containing missense mutations of the DISCI gene, a locus associated with major mental illness in at least one large Scottish family. Genetic manipulation of mouse homologs of genes implicated in the etiology of psychiatric disorders is a promising avenue of research, but also one that is fraught with interpretative difficulties. C1 Inst Neurol, Reta Lila Western Labs, Dept Mol Biosci, London WC1N 3BG, England. McGill Univ, Dept Psychiat, Montreal, PQ H3A 1A1, Canada. NIA, Neurogenet Lab, Bethesda, MD 20892 USA. RP Hardy, J (reprint author), Inst Neurol, Reta Lila Western Labs, Dept Mol Biosci, Queen Sq, London WC1N 3BG, England. EM hardyj@mail.nih.gov RI Hardy, John/C-2451-2009 FU Medical Research Council [G0701075] NR 13 TC 18 Z9 18 U1 2 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD MAY 3 PY 2007 VL 54 IS 3 BP 348 EP 349 DI 10.1016/j.neuron.2007.04.014 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 173EG UT WOS:000246855700003 PM 17481386 ER PT J AU Li, J Wood, WH Becker, KG Weeraratna, AT Morin, PJ AF Li, J. Wood, W. H., III Becker, K. G. Weeraratna, A. T. Morin, P. J. TI Gene expression response to cisplatin treatment in drug-sensitive and drug-resistant ovarian cancer cells SO ONCOGENE LA English DT Article DE cisplatin; connexin; p53; microarrays; ovarian cancer; expression profling ID P53 STATUS; INTERCELLULAR COMMUNICATION; REDUCED EXPRESSION; ANTICANCER AGENTS; CARCINOMA CELLS; LINES; IDENTIFICATION; APOPTOSIS; BCL-2; CHEMOTHERAPY AB The molecular pathways activated in response to acute cisplatin exposure, as well as the mechanisms involved in the long-term development of cisplatin-resistant cancer cells remain unclear. Using whole genome oligonucleotide microarrays, we have examined the kinetics of gene expression changes in a cisplatin-sensitive cell line, A2780, and its cisplatin-resistant derivative, ACRP. Both sensitive and resistant cell lines exhibited a very similar response of p53-inducible genes as early as 16 h after treatment. This p53 response was further increased at the 24-h time point. These experiments identify p53 as the main pathway producing a large-scale transcriptional response after cisplatin treatment in these cells containing wild-type p53. Consistent with a role for the p53 response in cisplatin sensitivity, knock down of the p53 protein with small interfering RNA led to a twofold decrease in cell survival in the resistant cells. In addition, our analysis also allowed the identification of several genes that are differentially expressed between sensitive and resistant cells. These genes include GJA1 (encoding connexin 43 (Cx43)) and TWIST1, which are highly upregulated in cisplatin-resistant cells. The importance of Cx43 in drug resistance was demonstrated through functional analyses, although paradoxically, inhibition of Cx43 function in high expressing cells led to an increase in drug resistance. The pathways important in cisplatin response, as well as the genes found differentially expressed between cisplatin-resistant and -sensitive cells, may represent targets for therapy aimed at reversing drug resistance. C1 NIA, Gerontol Res Ctr, Cellular & Mol Biol Lab, Baltimore, MD 21224 USA. NIA, Gerontol Res Ctr, Resources Res Branch, Baltimore, MD 21224 USA. NIA, Gerontol Res Ctr, Immunol Lab, Baltimore, MD 21224 USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. RP Morin, PJ (reprint author), NIA, Gerontol Res Ctr, Cellular & Mol Biol Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM morinp@grc.nia.nih.gov OI Becker, Kevin/0000-0002-6794-6656 FU Intramural NIH HHS NR 51 TC 43 Z9 45 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAY 3 PY 2007 VL 26 IS 20 BP 2860 EP 2872 DI 10.1038/sj.onc.1210086 PG 13 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 164CR UT WOS:000246210800006 PM 17072341 ER PT J AU Bjork, JM Smith, AR Danube, CL Hommer, DW AF Bjork, James M. Smith, Ashley R. Danube, Cinnamon L. Hommer, Daniel W. TI Developmental differences in posterior mesofrontal cortex recruitment by risky rewards SO JOURNAL OF NEUROSCIENCE LA English DT Article DE adolescence; development; reward; risk taking; decision making; cortex ID ANTERIOR CINGULATE CORTEX; MEDIAL FRONTAL-CORTEX; COGNITIVE-DEVELOPMENT; ADOLESCENT BRAIN; DECISION-MAKING AB Might increased risk taking in adolescence result in part from underdeveloped conflict-monitoring circuitry in the posterior mesofrontal cortex (PMC)? Adults and adolescents underwent functional magnetic resonance imaging during a monetary game of "chicken." As subjects watched ostensible winnings increase over time, they decided when to press a button to bank their winnings, knowing that if they did not stop pursuing money reward before a secret varying time limit, they would "bust" and either lose the money accrued on the current trial (low-penalty trials) or forfeit trial winnings plus a portion of previous winnings (high-penalty trials). Reward accrual at risk of low penalty (contrasted with guaranteed reward) activated the PMC in adults but not in adolescents. Across all subjects, this activation (1) correlated positively with age but negatively with risk exposure and (2) was greater when subjects busted on the previous low-penalty trial. Reward accrual at risk of high penalty was terminated sooner and recruited the PMC in both adults and adolescents when contrasted with guaranteed reward. Predecision PMC activation in the high-penalty trials was significantly reduced in trials when subjects busted. These data suggest that (1) under threat of an explicit severe penalty, recruitment of the PMC is similar in adolescents and adults and correlates with error avoidance, and (2) when potential penalties for a rewarding behavior are mild enough to encourage some risk taking, predecision PMC activation by a reward/risk conflict is sensitive to previous error outcomes, predictive of risk-aversive behavior in that trial, and underactive in adolescents. C1 NIAAA, NIH, Lab Clin & Translat Studies, Bethesda, MD 20892 USA. RP Bjork, JM (reprint author), NIAAA, NIH, Lab Clin & Translat Studies, 10 Ctr Dr,CRC Room 1-5330, Bethesda, MD 20892 USA. EM jbjork@mail.nih.gov OI Bjork, James/0000-0003-0593-3291 FU Intramural NIH HHS NR 23 TC 59 Z9 59 U1 1 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 MAY 2 PY 2007 VL 27 IS 18 BP 4839 EP 4849 DI 10.1523/JNEUROSCI.5469-06.2007 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 163RO UT WOS:000246180800006 PM 17475792 ER PT J AU Hu, KF Vogeli, B Clore, GM AF Hu, Kaifeng Vogeli, Beat Clore, G. Marius TI Spin-state selective carbon-detected HNCO with TROSY optimization in all dimensions and double echo-antiecho sensitivity enhancement in both indirect dimensions SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID TRIPLE-RESONANCE EXPERIMENTS; PROTONLESS NMR-SPECTROSCOPY; RESIDUAL DIPOLAR COUPLINGS; LARGE PROTEINS; SEQUENTIAL ASSIGNMENTS; DEUTERATED PROTEINS; CROSS-CORRELATION; METHYL-TROSY; C-13; RELAXATION AB A carbon-detected TROSY-optimized experiment correlating H-1(N), N-15, and C-13' resonances, referred to as c-TROSY-HNCO is presented, in which the H-1(N) and N-15 TROSY effects are maintained in both indirect dimensions, while the directly detected C-13' is doubly TROSY-optimized with respect to H-1(N) and N-15. A new strategy for sensitivity enhancement, the so-called double echo-antiecho (dEA), is described and implemented in the c-TROSY-HNCO experiment. dEA offers sensitivity enhancement of root 2 in both indirect dimensions and is generally applicable to many multidimensional experiments. A carbon-detected HNCO experiment, c-HNCO, without TROSY optimization and sensitivity enhancement is also designed for comparison purposes. Relaxation simulations show that for a protein with a rotational correlation time of 10 ns or larger, the c-TROSY-HNCO experiment displays comparable or higher signal-to-noise (S/N) ratios than the c-HNCO experiment, although the former selects only 1/4 of the initial magnetization relative to the later. The high resolution afforded in the directly detected carbon dimension allows direct measurement of the doublet splitting to extract (1)J(C alpha C') scalar and D-1(C alpha C') residual dipolar couplings. Simulations indicate that the c-TROSY-HNCO experiment offers higher precision (lower uncertainty) compared to the c-HNCO experiment for larger proteins. The experiments are applied to N-15/C-13/H-2/[Leu,Val]-methyl-protonated IIBMannose, a protein of molecular mass 18.6 kDa with a correlation time of similar to 10 ns at 30 degrees C. The experimental pairwise root-mean-square deviation for the measured (1)J(C alpha C') couplings obtained from duplicate experiments is 0.77 Hz. By directly measuring the doublet splitting, the experiments described here are expected to be much more tolerant to nonuniform values of (1)J(C alpha C') (or (1)J(C alpha C') + D-1(C alpha C') for aligned samples) and pulse imperfections due to the smaller number of applied pulses in the "out-and-stay" coherence transfer in the c-HNCO-TROSY experiment relative to conventional H-1-detected "out-and-back" quantitative J correlation experiments. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@intra.niddk.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU Intramural NIH HHS NR 48 TC 17 Z9 17 U1 0 U2 3 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 MAY 2 PY 2007 VL 129 IS 17 BP 5484 EP 5491 DI 10.1021/ja067981I PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA 160MR UT WOS:000245946400054 PM 17417840 ER PT J AU Marincola, FM AF Marincola, Francesco M. TI In support of descriptive studies; relevance to translational research SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Editorial Material ID ANTITUMOR; VACCINE; IL-23; MELANOMA AB The contemporary scientific establishment equates hypothesis testing to good science. This stance bypasses the preliminary need to identify a worthwhile hypothesis through rigorous observation of natural processes. If alleviation of human suffering is claimed as the goal of a scientific undertaking, it would be unfair to test a hypothesis whose relevance to human disease has not been satisfactorily proven. Here, we argue that descriptive investigations based on direct human observation should be highly valued and regarded essential for the selection of worthwhile hypotheses while the pursuit of costly scientific investigations without such evidence is a desecration of the cause upon which biomedical research is grounded. There are good things so in the tide pools and interesting thoughts to be generated from the seeing. Every new eye applied to the peephole which looks out at the world may fish in some new beauty and some new pattern, and the world of the human mind must be enriched by such fishing. C1 NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. RP Marincola, FM (reprint author), NIH, Infect Dis & Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM FMarincola@mail.cc.nih.gov NR 17 TC 31 Z9 31 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD MAY 2 PY 2007 VL 5 AR 21 DI 10.1186/1479-5876-5-21 PG 3 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 169JA UT WOS:000246587300001 PM 17474987 ER PT J AU Arai, Y Mentis, GZ Wu, JY O'Donovan, MJ AF Arai, Yoshiyasu Mentis, George Z. Wu, Jiang-young O'Donovan, Michael J. TI Ventrolateral Origin of Each Cycle of Rhythmic Activity Generated by the Spinal Cord of the Chick Embryo SO PLOS ONE LA English DT Article AB Background. The mechanisms responsible for generating rhythmic motor activity in the developing spinal cord of the chick embryo are poorly understood. Here we investigate whether the activity of motoneurons occurs before other neuronal populations at the beginning of each cycle of rhythmic discharge. Methodology/Principal Findings. The spatiotemporal organization of neural activity in transverse slices of the lumbosacral cord of the chick embryo (E8-E11) was investigated using intrinsic and voltage-sensitive dye (VSD) imaging. VSD signals accompanying episodes of activity comprised a rhythmic decrease in light transmission that corresponded to each cycle of electrical activity recorded from the ipsilateral ventral root. The rhythmic signals were widely synchronized across the cord face, and the largest signal amplitude was in the ventrolateral region where motoneurons are located. In unstained slices we recorded two classes of intrinsic signal. In the first, an episode of rhythmic activity was accompanied by a slow decrease in light transmission that peaked in the dorsal horn and decayed dorsoventrally. Superimposed on this signal was a much smaller rhythmic increase in transmission that was coincident with each cycle of discharge and whose amplitude and spatial distribution was similar to that of the VSD signals. At the onset of a spontaneously occurring episode and each subsequent cycle, both the intrinsic and VSD signals originated within the lateral motor column and spread medially and then dorsally. By contrast, following a dorsal root stimulus, the optical signals originated within the dorsal horn and traveled ventrally to reach the lateral motor column. Conclusions/Significance. These findings suggest that motoneuron activity contributes to the initiation of each cycle of rhythmic activity, and that motoneuron and/or R-interneuron synapses are a plausible site for the activity-dependent synaptic depression that modeling studies have identified as a critical mechanism for cycling within an episode. C1 [Arai, Yoshiyasu; Mentis, George Z.; Wu, Jiang-young; O'Donovan, Michael J.] NINDS, Neural Control Lab, Sect Dev Neurobiol, NIH, Bethesda, MD 20892 USA. [Wu, Jiang-young] Georgetown Univ, Dept Physiol & Biophys, Washington, DC USA. RP O'Donovan, MJ (reprint author), NINDS, Neural Control Lab, Sect Dev Neurobiol, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM odonovm@ninds.nih.gov RI o'donovan, michael/A-2357-2015 OI o'donovan, michael/0000-0003-2487-7547 FU National Institute of Neurological Disorders and Stroke; JSPS [2000] FX This study was supported by the National Institute of Neurological Disorders and Stroke Intramural Research Program, and a JSPS Postdoctoral Fellowships for Research Abroad (to Y. A. 2000). NR 47 TC 16 Z9 16 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 MAY 2 PY 2007 VL 2 IS 5 AR e417 DI 10.1371/journal.pone.0000417 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10DW UT WOS:000207445700019 PM 17479162 ER PT J AU Jaskolski, M Gilski, M Dauter, Z Wlodawer, A AF Jaskolski, Mariusz Gilski, Miroslaw Dauter, Zbigniew Wlodawer, Alexander TI Stereochemical restraints revisited: how accurate are refinement targets and how much should protein structures be allowed to deviate from them? SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID 3-DIMENSIONAL FOURIER SYNTHESIS; ULTRAHIGH-RESOLUTION STRUCTURE; FREE R-VALUE; X-RAY; MACROMOLECULAR STRUCTURES; CRYSTAL-STRUCTURES; ATOMIC-RESOLUTION; DIFFRACTION DATA; 0.75 ANGSTROM; PEPTIDE-BOND AB The Protein Data Bank and Cambridge Structural Database were analyzed with the aim of verifying whether the restraints that are most commonly used for protein structure refinement are still appropriate 15 years after their introduction. From an analysis of selected main-chain parameters in well ordered fragments of ten highest resolution protein structures, it was concluded that some of the currently used geometrical target values should be adjusted somewhat (the C-N bond and the N-C(alpha)-C angle) or applied with less emphasis (peptide planarity). It was also found that the weighting of stereochemical information in medium-resolution refinements is often overemphasized at the cost of the experimental information in the diffraction data. A correctly set balance will be reflected in root-mean-square deviations from ideal bond lengths in the range 0.015-0.020 angstrom for structures refined to R factors of 0.15-0.20. At ultrahigh resolution, however, the diffraction terms should be allowed to dominate, with even higher acceptable deviations from idealized standards in the well defined fragments of the protein. It is postulated that modern refinement programs should accommodate variable restraint weights that are dependent on the occupancies and B factors of the atoms involved. C1 NCI, Protein Struct Sect, Macromol Crystallog Lab, Ft Detrick, MD 21702 USA. Adam Mickiewicz Univ Poznan, Polish Acad Sci, Fac Chem, Ctr Biocrystallog Res,Inst Bioorgan Chem,Dept Cry, Poznan, Poland. Argonne Natl Lab, NCI, Synchrotron Radiat Res Sect, Biosci Div,Macromol Crystallog Lab, Argonne, IL 60439 USA. RP Wlodawer, A (reprint author), NCI, Protein Struct Sect, Macromol Crystallog Lab, Ft Detrick, MD 21702 USA. EM wlodawer@ncifcrf.gov FU Intramural NIH HHS NR 51 TC 48 Z9 49 U1 0 U2 5 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD MAY PY 2007 VL 63 BP 611 EP 620 DI 10.1107/S090744490700978X PN 5 PG 10 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 189SO UT WOS:000248009000007 PM 17452786 ER PT J AU Nolen, WA Kupka, RW Hellemann, G Frye, MA Altshuler, LL Leverich, GS Suppes, T Keck, PE McElroy, S Grunze, H Mintz, J Post, RM AF Nolen, W. A. Kupka, R. W. Hellemann, G. Frye, M. A. Altshuler, L. L. Leverich, G. S. Suppes, T. Keck, P. E., Jr. McElroy, S. Grunze, H. Mintz, J. Post, R. M. TI Tranylcypromine vs. lamotrigine in the treatment of refractory bipolar depression: a failed but clinically useful study SO ACTA PSYCHIATRICA SCANDINAVICA LA English DT Article DE bipolar disorder; bipolar depression; tranylcypromine; lamotrigine; lithium; anticonvulsant ID MOOD STABILIZERS; MAINTENANCE TREATMENT; VENLAFAXINE; DISORDER; MANIA; ANTIDEPRESSANTS; IMIPRAMINE; SERTRALINE; BUPROPION; CROSSOVER AB Objective: To compare the efficacy and tolerability of tranylcypromine vs. lamotrigine in bipolar depression not responding to conventional antidepressants. Method: Bipolar depressed patients received open randomized treatment with tranylcypromine or lamotrigine as add-on to a mood stabilizer during 10 weeks. In a second treatment phase, non-responding patients could receive the opposite drug. Outcome criteria were response (measured with CGI-BP and IDS-C), switch into mania, and completion of the study. Results: Only 20 of 70 planned patients were randomized, due to problems with recruitment, and 19 patients received any medication. During the first treatment phase 5/8 patients (62.5%) responded to tranylcypromine without switch into mania, compared with 4/11 patients (36.4%) on lamotrigine with two switches (statistically not significant). Over both treatment phases, 8/10 patients (80%) receiving tranylcypromine completed the study vs. 5/13 (38.5%) on lamotrigine (likelihood 0.02). Conclusions: There still appears to be a role for tranylcypromine in the treatment of refractory bipolar depression. Larger controlled studies are demanded. C1 Univ Groningen, Dept Psychiat, Univ Med Ctr Groningen, NL-9700 RB Groningen, Netherlands. Altrecht Inst Mental Hlth Care, Utrecht, Netherlands. Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, David Geffen Sch Med, Los Angeles, CA 90024 USA. W Los Angeles VA Med Ctr, Los Angeles, CA USA. NIMH, Dept Hlth & Human Serv, Biol Psychiat Branch, NIH, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Univ Cincinnati, Coll Med, Dept Psychiat, Psychopharmacol Res Program, Cincinnati, OH USA. Univ Munich, Munich, Germany. RP Nolen, WA (reprint author), Univ Groningen, Dept Psychiat, Univ Med Ctr Groningen, POB 30-001, NL-9700 RB Groningen, Netherlands. EM w.a.nolen@med.umcg.nl RI Nolen, Willem/E-9006-2014; OI Grunze, Heinz/0000-0003-4712-8979 NR 23 TC 30 Z9 31 U1 0 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0001-690X J9 ACTA PSYCHIAT SCAND JI Acta Psychiatr. Scand. PD MAY PY 2007 VL 115 IS 5 BP 360 EP 365 DI 10.1111/j.1600-0447.2007.00993.x PG 6 WC Psychiatry SC Psychiatry GA 152VM UT WOS:000245390100004 PM 17430413 ER PT J AU Ghitza, UE Epstein, DH Preston, KL AF Ghitza, Udi E. Epstein, David H. Preston, Kenzie L. TI Nonreporting of cannabis use: Predictors and relationship to treatment outcome in methadone maintained patients SO ADDICTIVE BEHAVIORS LA English DT Article DE cocaine; heroin; marijuana; THC; substance use; self-report ID REPORTED DRUG-USE; COCAINE USE; SELF-REPORT; VALIDITY; MAINTENANCE; PSYCHOPATHY; ABSTINENCE; MARIJUANA; URINE AB Underreporting of drug use is common and influenced by multiple factors. Cannabis (THC) use nonreporting and its relationship to heroin and cocaine use were investigated in 690 patients enrolled in 25-to 29-week clinical trials of contingency management plus methadone maintenance. Urine specimens and self-reports of drug use were collected 3 times/week. Potential predictors of THC use nonreporting were analyzed by multiple logistic regression; relationships between THC use nonreporting and % cocaine- and opiate-positive urines were analyzed by multiple regression. Compared to non-THC users (n = 317), patients with THC-positive urines (n = 373) were more likely to be male and have more years of THC use, but were not different on other characteristics. Nonreporting to user ratios were: THC 191/373 (51.2%); opiates 17/686 (2.5%); cocaine 21/681 (3.1%). Predictors of THC use nonreporting were low rate of THC-positive urines during treatment, fewer days of THC use in the last 30 before treatment, African-American race, and absence of antisocial personality disorder. Nonreporting of THC use was associated with significantly greater opiate and cocaine use. Contingency management decreased cocaine use in THC nonreporters to the level of reporters. Nonreporting of THC use is a significant predictor of greater cocaine and heroin use. This association can be eliminated with contingency management therapy. (c) 2006 Elsevier Ltd. All fights reserved. C1 NIDA, Clin Pharmacol & Therapeut Branch, Treatment Sect, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Preston, KL (reprint author), NIDA, Clin Pharmacol & Therapeut Branch, Treatment Sect, Intramural Res Program,NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM kpreston@intra.nida.nih.gov RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 FU Intramural NIH HHS NR 30 TC 6 Z9 6 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD MAY PY 2007 VL 32 IS 5 BP 938 EP 949 DI 10.1016/j.addbeh.2006.06.034 PG 12 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 150YO UT WOS:000245255700005 PM 16887281 ER PT J AU Bos, AM Bos, AJ AF Bos, Antonio M. Bos, Angelo J. TI The socio-economic determinants of older people's health in Brazil: the importance of marital status and income SO AGEING & SOCIETY LA English DT Article DE older people; marital status; health; income; Brazil ID SELF-RATED HEALTH; ASSESSED HEALTH; GENDER INEQUALITIES; HOUSEHOLD STRUCTURE; ELDERLY POPULATION; MARRIAGE SELECTION; METROPOLITAN-AREA; FUNCTIONAL STATUS; PERCEIVED HEALTH; MORTALITY AB Studies in various countries have reported that older people who are married have better health than older widows. This paper reports a replication of these analyses with Brazilian data. The main objective was to explore the relationships between marital status, individual and household income, and the health of men and women using ordered logistic regression with self-assessed health as the dependent variable. The explanatory variables of interest were gender, marital status, and individual and family income. The data are from a survey of 7,920 non-institutionalised older people resident in the southern state of Rio Grande do Sul in 1995. The survey used a structured, multi-disciplinary questionnaire, which collected information on demographic attributes, household composition, social relations, occupation, income and health status. The results show that widows were 20 per cent more likely to report better health than married women. The women without individual income had worse health than those who did, even after controlling for family income. For men, there were no significant differences in health by marital status. The main recommendation is that the health status and economic circumstances of married elderly women should be given more attention in both research and policy, certainly in Brazil and probably in other Latin American countries. Programmes of income support to the poorest households should include specific transfers to these elderly women. Brazil's Family Health and Older People's Health public programmes should place more emphasis on the health of elderly home-makers. C1 Tusculum Coll, Greeneville, TN 37743 USA. Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD USA. NIA, Clin Res Branch, Longitudinal Studies Sect, Bethesda, MD 20892 USA. RP Bos, AM (reprint author), Tusculum Coll, 60 Shiloh Rd, Greeneville, TN 37743 USA. EM abos@tusculum.edu NR 86 TC 5 Z9 5 U1 2 U2 8 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 0144-686X J9 AGEING SOC JI Ageing Soc. PD MAY PY 2007 VL 27 BP 385 EP 405 DI 10.1017/S0144686X06005472 PN 3 PG 21 WC Gerontology SC Geriatrics & Gerontology GA 163VR UT WOS:000246191800004 ER PT J AU Wiener, LS Battles, HB Wood, LV AF Wiener, Lori S. Battles, Haven B. Wood, Lauren V. TI A longitudinal study of adolescents with perinatally or transfusion acquired HIV infection: Sexual knowledge, risk reduction self-efficacy and sexual behavior SO AIDS AND BEHAVIOR LA English DT Article DE HIV; adolescents; knowledge; sexual behavior; condoms ID OLDER CHILDREN AB As HIV-positive children are surviving to adolescence and beyond, understanding their HIV knowledge and sexual behavior is critical. Forty HIV+ adolescents/young adults were interviewed twice, approximately 21 months apart (mean age 16.6 and 18.3 years, respectively). Data on demographics, safer sex knowledge, sexual risk behaviors, risk reduction self-efficacy, and Tanner stage were collected. Twenty-eight percent of HIV+ youth at Time 1 and 41% at Time 2 reported being sexually active. HIV transmission/safer sex knowledge was low, increased with age, and both self-efficacy for and actual condom use was relatively high. Secondary prevention messages should be incorporated into routine medical settings. C1 NCI, HIV AIDS Malignancy Branch, NIH, Pediat Clin, Bethesda, MD 20892 USA. RP Wiener, LS (reprint author), NCI, HIV AIDS Malignancy Branch, NIH, Pediat Clin, 9000 Rockville Pike,Bldg 10,I-SE,Room I-6466, Bethesda, MD 20892 USA. EM wienerl@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 14 TC 40 Z9 40 U1 1 U2 4 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1090-7165 J9 AIDS BEHAV JI AIDS behav. PD MAY PY 2007 VL 11 IS 3 BP 471 EP 478 DI 10.1007/s10461-006-9162-y PG 8 WC Public, Environmental & Occupational Health; Social Sciences, Biomedical SC Public, Environmental & Occupational Health; Biomedical Social Sciences GA 153TP UT WOS:000245458400012 PM 17028994 ER PT J AU Lovinger, DM Homanics, GE AF Lovinger, David M. Homanics, Gregg E. TI Tonic for what ails us? high-affinity GABA(A) receptors and alcohol SO ALCOHOL LA English DT Editorial Material DE ethanol; synaptic inhibition; intoxication; RO15-4513 ID GABAERGIC SYNAPTIC-TRANSMISSION; CEREBELLAR GRANULE CELLS; ALPHA 6 SUBUNIT; A-RECEPTOR; DELTA-SUBUNIT; CORTICAL-NEURONS; ANTAGONIST RO15-4513; BASOLATERAL AMYGDALA; BEHAVIORAL-RESPONSES; ETHANOL SENSITIVITY AB Ethanol interactions with gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, play key roles in acute intoxication. However, the exact mechanisms of these ethanol interactions have been the subject of considerable confusion and controversy. Many studies suggest that ethanol potentiates the function of the type A GABA receptor (GABA(A)-R). However, these findings have not been consistently replicated in experiments that directly examined the effects of ethanol on GABA(A)-R-mediated ion current. Differences in ethanol sensitivity of different GABAA-R subtypes have been invoked as a potential explanation for the inconsistent findings, and recent work suggests that GABA(A)-Rs that contain the delta subunit and/or mediate tonic extrasynaptic GABA responses may be especially ethanol sensitive. However, considerable disagreement has arisen over these findings. This special issue of Alcohol contains articles from eight research groups that are examining this issue. The authors present their work, their views on the present state of this area of alcohol research, and their ideas about how to proceed with future studies that may help to address the present confusion and controversy. This editorial provides an introduction to this line of research and the current findings and controversies. (c) 2007 Elsevier Inc. All rights reserved. C1 NIAAA, Lab Integrat Neurosci, Rockville, MD 20852 USA. Univ Pittsburgh, Dept Anesthesiol, Pittsburgh, PA USA. RP Lovinger, DM (reprint author), NIAAA, Lab Integrat Neurosci, 4625 Fishers Lane, Rockville, MD 20852 USA. EM lovindav@mail.nih.gov OI Homanics, Gregg/0000-0003-3641-8153 FU Intramural NIH HHS [Z01 AA000407-06] NR 64 TC 43 Z9 43 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-8329 J9 ALCOHOL JI Alcohol PD MAY PY 2007 VL 41 IS 3 BP 139 EP 143 DI 10.1016/j.alcohol.2007.03.008 PG 5 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 187ZH UT WOS:000247887500001 PM 17521844 ER PT J AU Goldstein, RB Dawson, DA Saha, TD Ruan, WJ Compton, WM Grant, BF AF Goldstein, Rise B. Dawson, Deborah A. Saha, Tulshi D. Ruan, W. June Compton, Wilson M. Grant, Bridget F. TI Antisocial behavioral syndromes and DSM-IV alcohol use disorders: Results from the National Epidemiologic Survey on Alcohol and Related Conditions SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE antisocial personality disorder; conduct disorder; alcohol consumption; alcohol use disorders ID SUBSTANCE USE DISORDERS; COMORBID PSYCHIATRIC-DIAGNOSIS; INTERVIEW SCHEDULE AUDADIS; GENERAL-POPULATION SAMPLE; DRUG-USE DISORDERS; PERSONALITY-DISORDERS; UNITED-STATES; CONDUCT PROBLEMS; ANXIETY DISORDERS; SOCIAL COMPETENCE AB Background: Antisocial personality disorder (ASPD), syndromal adult antisocial behavior (AABS) without conduct disorder (CD) before age 15, and CD without progression to ASPD ("CD only") are highly prevalent among adults with alcohol use disorders (AUDs). Among patients in AUD treatment, antisocial behavioral syndromes are associated with more severe AUDs and poorer treatment outcomes. Comparative data concerning associations of antisocial syndromes with clinical characteristics of AUDs and the sociodemographic and clinical correlates of these syndromes among general population adults with AUDs have not previously been available. This study examines prevalences and correlates of antisocial syndromes among adults with lifetime Diagnostic and Statistical Manual-Version IV (DSM-IV) AUDs, and describes associations of these syndromes with clinical characteristics of AUDs, in the general U.S. population. Methods: This report is based on the 2001-2002 National Epidemiologic Survey on Alcohol and Related Conditions (n=43,093, response rate=81%). Respondents (n=11,843) with lifetime AUDs were classified according to whether they met criteria for ASPD, AABS, "CD only," or no antisocial syndrome. Correlates of antisocial syndromes were examined using contingency table approaches and normal theory analyses of variance. Associations of antisocial syndromes with clinical characteristics of AUDs, including number of lifetime episodes, duration of longest or only episode, and alcohol consumption during period of heaviest drinking were examined using normal theory and logistic regression. Results: Sociodemographic and clinical correlates of antisocial syndromes among respondents with AUDs were consistent with results from prior studies. Antisocial syndromes were significantly associated with phenomenology of AUDs, particularly ASPD with the most severe clinical presentations. Associations with AABS were similar to but more modest than those with ASPD; those with "CD only" were weaker and less consistent. Patterns of associations between antisocial syndromes and clinical characteristics of AUDs were generally similar between men and women. Conclusions: Antisocial syndromes, particularly ASPD, appear to identify a more pernicious clinical profile of AUDs among adults in the general U.S. population. C1 NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIDA, Div Epidemiol Serv & Prevent Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Goldstein, RB (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH,Dept Hlth & Human Serv, Room 3068,MS 9304,5635 Fusgers Ln, Bethesda, MD 20892 USA. EM goldster@mail.nih.gov OI Goldstein, Rise/0000-0002-9603-9473 FU Intramural NIH HHS NR 82 TC 51 Z9 51 U1 3 U2 6 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 MAY PY 2007 VL 31 IS 5 BP 814 EP 828 DI 10.1111/j.1530-0277.2007.00364.x PG 15 WC Substance Abuse SC Substance Abuse GA 155TL UT WOS:000245601000011 PM 17391341 ER PT J AU Srivastava, VK Hiney, JK Mattison, JA Bartke, A Dees, WL AF Srivastava, Vinod K. Hiney, Jill K. Mattison, Julie A. Bartke, Andrej Dees, W. Les TI The alcohol-induced suppression of ovarian insulin-like growth factor-1 gene transcription is independent of growth hormone and its receptor SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE alcohol; ovary; IGF-1 ID ACUTE REGULATORY PROTEIN; PREPUBERTAL FEMALE RATS; IGF-I; INDUCED DIFFERENTIATION; GRANULOSA-CELLS; FOLLICULAR DEVELOPMENT; TRANSGENIC MICE; RHESUS-MONKEY; ETHANOL; EXPRESSION AB Background: Insulin-like growth factor-1 (IGF-1) plays an important role in ovarian development and function. Alcohol (ALC) is a gonadal toxin and capable of causing depressed ovarian IGF-1 and suppressed estradiol. The mechanism by which ALC affects IGF-1 transcription is not well understood, and more information is needed to better understand the interrelationships between ALC, growth hormone (GH) and its ovarian receptor, and the gene expression of ovarian IGF-1. Methods: Prepubertal transgenic mice carrying the bovine GH (bGH) gene were fed either a liquid diet containing ALC, pair-fed the companion isocaloric control liquid diet, or fed chow and water. A fourth group consisted of normal (nontransgenic) littermates fed chow and water. Mice received their diets for 5 days, were then killed and tissues collected and frozen. Results: Alcohol did not alter circulating levels of bGH held constant by the promoter. Real-time polymerase chain reaction (PCR) showed elevated (p < 0.05) ovarian IGF-1 mRNA levels in both groups of transgenic control mice, compared with normal mice. Insulin-like growth factor-1 expression in the ALC-treated transgenic mice was suppressed (p < 0.01) compared with both transgenic controls. Insulin-like growth factor-1 receptor (IGF-1R) gene expression was also decreased (p < 0.01) in ALC-treated transgenic mice compared with transgenic controls. Growth hormone-receptor (GH-R) synthesis revealed that all transgenic mice, including those exposed to ALC, showed increased (p < 0.05) GH-R mRNA compared with normal controls, and ALC did not alter protein levels of the GH-R. Conclusions: These results suggest that the ALC-induced suppression of ovarian IGF-1 gene transcription is independent of alterations in serum GH. C1 Texas A&M Univ, Coll Vet Med, Dept Vet Integrat Biosci, College Stn, TX 77843 USA. So Illinois Univ, Sch Med, Dept Internal Med, Springfield, IL USA. NIA, NIH, Bethesda, MD 20892 USA. RP Srivastava, VK (reprint author), Texas A&M Univ, Coll Vet Med, Dept Vet Integrat Biosci, College Stn, TX 77843 USA. EM vsrivastava@cvm.tamu.edu RI Bartke, Andzej/D-6640-2017 OI Bartke, Andzej/0000-0002-2569-557X FU NIAAA NIH HHS [AA07216, R01 AA007216]; NICHD NIH HHS [HD37672]; PHS HHS [ESO-9106] NR 40 TC 2 Z9 2 U1 0 U2 0 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 MAY PY 2007 VL 31 IS 5 BP 880 EP 886 DI 10.1111/j.1530-0277.2007.00368.x PG 7 WC Substance Abuse SC Substance Abuse GA 155TL UT WOS:000245601000017 PM 17386070 ER PT J AU Sapienza, JN Corbie-Smith, G Keim, S Fleischman, AR AF Sapienza, Jessica N. Corbie-Smith, Giselle Keim, Sarah Fleischman, Alan R. TI Community engagement in epidemiological research SO AMBULATORY PEDIATRICS LA English DT Article DE community engagement; epidemiology; community-based participatory research; longitudinal studies ID PARTICIPATORY RESEARCH; ENVIRONMENTAL-HEALTH; PUBLIC-HEALTH; PARTNERSHIP; CHILDRENS; LESSONS AB Objective. - Engaging communities has become a critical aspect of planning and implementing health research. The role community engagement should play in epidemiological and observational research remains unclear since much of this research is not directly generated by community concerns and is not interventional in nature. The National Children's Study (NCS), an observational longitudinal study of 100,000 children and their families, provides a model to help guide the development of community engagement strategies in epidemiologic research. Methodology. - This manuscript describes community engagement activities of the NCS during the planning phases of the study. Results. - There are many challenges of community engagement in epidemiologic research particularly before the actual research sites are determined. After communities of interest are designated many further issues must be resolved, including: defining the specific community, determining which residents or institutions represent the identified community, and developing trust and rapport through respectful engagement. Conclusions. - Community engagement is critical to the longterm success of any longitudinal epidemiologic study. A partnership with the community should be formed to ensure mutual respect and the establishment of an enduring relationship. Genuine community engagement offers the hope of enhancing recruitment, retention, and participant satisfaction. C1 NICHHD, Natl Childrens Study, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Dept Med, Chapel Hill, NC 27515 USA. Univ N Carolina, Dept Social Med, Chapel Hill, NC 27515 USA. Albert Einstein Coll Med, New York, NY USA. RP Sapienza, JN (reprint author), NICHHD, Natl Childrens Study, NIH, 6100 Execut Blvd,Room 5CO1, Bethesda, MD 20892 USA. EM sapienzj@mail.nih.gov RI Keim, Sarah/F-8929-2013 OI Keim, Sarah/0000-0003-3490-3649 FU Intramural NIH HHS [NIH0012083628, 001-2083-628]; PHS HHS [NIH0012083628, 001-2083-628] NR 37 TC 21 Z9 21 U1 0 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1530-1567 J9 AMBUL PEDIATR JI Ambul. Pediatr. PD MAY-JUN PY 2007 VL 7 IS 3 BP 247 EP 252 DI 10.1016/j.ambp.2007.01.004 PG 6 WC Pediatrics SC Pediatrics GA 171OR UT WOS:000246745800009 PM 17512886 ER PT J AU Schatzkin, A Mouw, T Park, Y Subar, AF Kipnis, V Hollenbeck, A Leitzmann, MF Thompson, FE AF Schatzkin, Arthur Mouw, Traci Park, Yikyung Subar, Amy F. Kipnis, Victor Hollenbeck, Albert Leitzmann, Michael F. Thompson, Frances E. TI Dietary fiber and whole-grain consumption in relation to colorectal cancer in the NIH-AARP Diet and Health Study SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE dietary fiber; whole grain; colorectal cancer; fiber sources; cohort study ID BREAST-CANCER; PROSPECTIVE COHORT; REGRESSION-MODELS; RANDOMIZED TRIAL; HEART-DISEASE; UNITED-STATES; COLON-CANCER; LOW-FAT; RISK; WOMEN AB Background: Whether the intake of dietary fiber can protect against colorectal cancer is a long-standing question of considerable public health import, but the epidemiologic evidence has been inconsistent. Objective: The objective was to investigate the relation between dietary fiber and whole-grain food intakes and invasive colorectal cancer in the prospective National Institutes of Health-AARP Diet and Health Study. Design: The analytic cohort consisted of 291988 men and 197 623 women aged 50-71 y, Diet was assessed with a self-administered food-frequency questionnaire at baseline in 1995-1996; 2974 incident colorectal cancer cases were identified during 5 y of follow-up. The Cox proportional hazards model was used to estimate the relative risks (RRs) and 95% CIs. Results: Total dietary fiber intake was not associated with colorectal cancer. The multivariate RR for the highest compared with the lowest intake quintile (RRQ5-Q1) was 0.99 (95% CI: 0.85, 1.15; P for trend = 0.96). In analyses of fiber from different food sources, only fiber from grains was associated with a lower risk of colorectal cancer (multivariate RRQ5-Q1: 0.86; 95% CI: 0.76, 0.98; P for trend = 0.01). Whole-grain intake was inversely associated with colorectal cancer risk: the multivariate RRQ5-Q1 was 0.79 (95% CI: 0.70, 0.89) for the whole cohort (P for trend < 0.001). The association with whole grain was stronger for rectal than for colon cancer. Conclusions: In this large prospective cohort study, total dietary fiber intake was not associated with colorectal cancer risk, whereas whole-grain consumption was associated with a modest reduced risk. C1 NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. AARP, Washington, DC USA. RP Schatzkin, A (reprint author), 6120 Execut Blvd, Rockville, MD 20852 USA. EM schatzka@mail.nih.gov OI Park, Yikyung/0000-0002-6281-489X FU Intramural NIH HHS NR 41 TC 138 Z9 145 U1 2 U2 22 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 MAY PY 2007 VL 85 IS 5 BP 1353 EP 1360 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 168GN UT WOS:000246511400025 PM 17490973 ER PT J AU Castle, PE Stoler, MH Solomon, D Schiffman, M AF Castle, Philip E. Stoler, Mark H. Solomon, Diane Schiffman, Mark CA ALTS Grp TI The relationship of community biopsy-diagnosed cervical intraepithelial neoplasia grade 2 to the quality control pathology-reviewed diagnoses - An ALTS report SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE cervical intraepithelial neoplasia; CIN; human papillomavirus; HPV; loop electrosurgical excision procedure; biopsy; cytology; colposcopy ID ATYPICAL SQUAMOUS-CELLS; HUMAN-PAPILLOMAVIRUS TYPES; TRANS-RETINOIC ACID; ASCUS-LSIL TRIAGE; RANDOMIZED-TRIAL; UNDETERMINED SIGNIFICANCE; CYTOLOGY INTERPRETATIONS; MANAGEMENT STRATEGIES; LESIONS; CANCER AB We examined the predictors (cytologic interpretations, pathology review, human papillomavirus [HPV] testing results, and colposcopic impressions) of precancer among 545 women with clinical center biopsy diagnoses of cervical intraepithelial neoplasia (CIN) 2 in the ASCUS LSIL Triage Study. Among women with a CIN 2 biopsy result, there was an increasing likelihood that the loop electrosurgical excision procedure (LEEP) tissue sample was diagnosed as precancer (CIN 3) with an increasing number of clinical risk factors of cervical precancer (high-grade squamous intraepithelial lesion [HSIL] cytology, high-grade colposcopy, detection of HPV type 16; P-trend <.0005). In a multivariate model, using a case definition of worst histologic diagnosis made by the quality control pathology review of biopsy and LEEP tissue samples, HPV-16 was positively associated (odds ratio [OR], 4.8; 95% confidence interval [CI], 2.6-8.8) with a CIN 3 diagnosis, whereas testing negative for HPV or positive for noncarcinogenic HPV types was negatively associated (OR, 0.32; 95% CI, 0.14-0.75) with a CIN 3 diagnosis. Although we found clear evidence that HPV-16 detection helped clarify whether a biopsy specimen diagnosed as CIN 2 represented HPV infection or cervical precancer, this relationship was not sufficiently robust to be clinically useful for reducing the overtreatment of women with HPV infection. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Virginia, Hlth Syst, Robert E Fechner Lab Surg Pathol, Charlottesville, VA USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 7074,EPS MSC 7234, Bethesda, MD 20892 USA. FU CSP VA [CU-55178, CU-55179]; NCI NIH HHS [CN-55156, CN-55105, CN-55153, CN-55154, CN-55155, CN-55157] NR 33 TC 105 Z9 111 U1 0 U2 1 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD MAY PY 2007 VL 127 IS 5 BP 805 EP 815 DI 10.1309/PT3PNC1QL2F4D2VL PG 11 WC Pathology SC Pathology GA 159OH UT WOS:000245875100016 PM 17439841 ER PT J AU Saczynski, JS White, L Peila, RL Rodriguez, BL Launer, LJ AF Saczynski, Jane S. White, Lon Peila, Rita L. Rodriguez, Beatriz L. Launer, Lenore J. TI The relation between apolipoprotein A-I and dementia - The Honolulu-Asia aging study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE apolipoproteins; apolipoproteins E; dementia; lipids ID HIGH-DENSITY-LIPOPROTEIN; JAPANESE-AMERICAN MEN; CORONARY-HEART-DISEASE; ALZHEIMERS-DISEASE; MYOCARDIAL-INFARCTION; VASCULAR DEMENTIA; HDL CHOLESTEROL; PLASMA-LIPIDS; RISK; ATHEROSCLEROSIS AB The association between apolipoproteins and neurodegeneration is unclear. The authors examined the association of dementia with serum levels of apolipoprotein A-I (ApoA-I) alone and in combination with the apolipoprotein E genotype (ApoE). Subjects were Japanese-American men in Hawaii followed since 1965 in the Honolulu Heart Program cohort and the Honolulu-Asia Aging Study. Lipid levels were assessed in 1980-1982. Dementia was diagnosed in 1991-1993, 1994-1996, and 1997-1999 by using a multistep procedure and international guidelines. The sample consisted of 929 men (107 dementia cases). The relation between ApoA-I and dementia was examined by using Cox proportional hazards models adjusted for age, education, and cardiovascular risk factors. Compared with men in the lowest quartile, men in the highest quartile of ApoA-I concentration had a significantly lower risk of dementia (hazard ratio = 0.25, 95% confidence interval: 0.08, 0.78). Compared with men with both risk factors, those with a high ApoA-I concentration and no ApoE epsilon 4 had a significantly lower risk of dementia (hazard ratio = 0.21, 95% confidence interval: 0.08, 0.52). Previous work has demonstrated an inverse relation between ApoA-I and cardiovascular disease, and the authors extended these findings to the risk of dementia. These results raise the possibility that different lipoprotein components of cholesterol may be differentially associated with dementia. C1 NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. Univ Hawaii Manoa, John A Burns Sch Med, Dept Geriatr Med, Honolulu, HI USA. Pacific Hlth Res Inst, Honolulu, HI USA. RP Saczynski, JS (reprint author), NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Gateway Bldg,Room 3C-309,7201 Wisconsin Ave, Bethesda, MD 20892 USA. EM saczynsj@mail.nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [N01-HC-05102]; NIA NIH HHS [U01AG09349, R01AG07155] NR 52 TC 34 Z9 34 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 MAY 1 PY 2007 VL 165 IS 9 BP 985 EP 992 DI 10.1093/aje/kwm027 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 159VY UT WOS:000245896900002 PM 17298957 ER PT J AU Chen, HL O'Reilly, E McCullough, ML Rodriguez, C Schwarzschild, MA Calle, EE Thun, MJ Ascherio, A AF Chen, Honglei O'Reilly, Ellis McCullough, Marjorie L. Rodriguez, Carmen Schwarzschild, Michael A. Calle, Eugenia E. Thun, Michael J. Ascherio, Alberto TI Consumption of dairy products and risk of Parkinson's disease SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE dairy products; diet; milk; Parkinson disease ID FOOD-FREQUENCY QUESTIONNAIRE; SOCIETY CANCER PREVENTION; URIC-ACID LEVELS; ENDOGENOUS AMINE; DIETARY FACTORS; COHORT; BRAIN; MEN; 1-BENZYL-1,2,3,4-TETRAHYDROISOQUINOLINE; TETRAHYDROISOQUINOLINE AB The authors prospectively investigated the association between intake of dairy products and risk of Parkinson's disease among 57,689 men and 73,175 women from the American Cancer Society's Cancer Prevention Study 11 Nutrition Cohort. A total of 250 men and 138 women with Parkinson's disease were identified during follow-up (1992-2001). Dairy product consumption was positively associated with risk of Parkinson's disease: Compared with the lowest intake quintile, the corresponding relative risks for quintiles 2-5 were 1.4, 1.4, 1.4, and 1.6 (95 percent confidence interval (CI): 1.1, 2.2; p for trend = 0.05). A higher risk among dairy product consumers was found in both men and women, although the association in women appeared nonlinear. Meta-analysis of all prospective studies confirmed a moderately elevated risk of Parkinson's disease among persons with high dairy product consumption: For extreme intake categories, relative risks were 1.6 (95 percent CI: 1.3, 2.0) for both sexes, 1.8 for men (95 percent CI: 1.4, 2.4), and 1.3 for women (95 percent CI: 0.8, 2.1). These data suggest that dairy consumption may increase the risk of Parkinson's disease, particularly in men. More studies are needed to further examine these findings and to explore underlying mechanisms. C1 Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. Amer Canc Soc, Epidemiol & Surveillance Res dept, Atlanta, GA 30329 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. RP Ascherio, A (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave,Bldg 2,Room 335, Boston, MA 02115 USA. EM aascheri@hsph.harvard.edu OI Chen, Honglei/0000-0003-3446-7779 FU Intramural NIH HHS [Z01 ES101986-02]; NINDS NIH HHS [K08 NS048468, NS48468] NR 29 TC 59 Z9 61 U1 2 U2 9 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 MAY 1 PY 2007 VL 165 IS 9 BP 998 EP 1006 DI 10.1093/aje/kwk089 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 159VY UT WOS:000245896900004 PM 17272289 ER PT J AU Longnecker, MP Gladen, BC Cupul-Uicab, LA Romano-Riquer, SP Weber, JP Chapin, RE Hernandez-Avila, M AF Longnecker, Matthew P. Gladen, Beth C. Cupul-Uicab, Lea A. Romano-Riquer, S. Patricia Weber, Jean-Phillipe Chapin, Robert E. Hernandez-Avila, Mauricio TI In utero exposure to the antiandrogen 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) in relation to anogenital distance in male newborns from Chiapas, Mexico SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE androgens; DDT; developmental biology; dichlorodiphenyl dichloroethylene; endocrine system diseases; genitalia; male; prenatal exposure delayed effects ID MATERNAL SERUM-LEVEL; MALARIA CONTROL; ORGANOCHLORINE PESTICIDES; UMBILICAL-CORD; MALE-RAT; P,P'-DDE; METABOLITE; HYPOSPADIAS; ANOMALIES; PREGNANCY AB The insecticide 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane (DDT) is still used for disease control in some areas, resulting in high levels of human exposure. The main degradation product of DDT is 1,1-dichloro-2,2bis(p-chlorophenyl)ethylene (DDE), an antiandrogen. In animal experiments, in utero exposure to DDE decreases anogenital distance in male offspring. In these models, anogenital distance serves as a measure of fetal androgen action. The authors designed the present study to examine the hypothesis that in utero exposure to DDE decreases anogenital distance in newborn human males. A cross-sectional study of 781 newly delivered male infants was conducted in 2002-2003 in Chiapas, Mexico, where DDT had recently been used for malaria control. Measurements of anogenital distance and penile dimensions were taken, and a sample of the mother's blood was drawn. In this population, the range of serum DDE levels was large (0.8-398 pg/liter). The authors, using two-sided tests, found no evidence that exposure in utero to DDE was related to reduced androgen action as reflected by anogenital distance or penile dimensions at birth. If DDE has important antiandrogenic action in humans, it may be manifest only at higher levels of exposure or via effects on other outcomes. C1 NIEHS, Epidemiol Branch, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. Inst Nacl Salud Publ, Ctr Populat Hlth Res, Cuernavaca, Morelos, Mexico. Natl Inst Publ Hlth Quebec, Toxicol Ctr, Ste Foy, PQ, Canada. NIEHS, Natl Toxicol Program, NIH, US Dept HHS, Res Triangle Pk, NC 27709 USA. RP Longnecker, MP (reprint author), NIEHS, Epidemiol Branch, NIH, US Dept HHS, POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. EM longnec1@niehs.nih.gov RI CUPUL UICAB, LEA/C-8699-2014; OI CUPUL UICAB, LEA/0000-0001-6190-4474; Chapin, Robert/0000-0002-5997-1261; Longnecker, Matthew/0000-0001-6073-5322 FU Intramural NIH HHS; NIEHS NIH HHS [N01-ES-15468, Z01 ES044009-05]; NINDS NIH HHS [R01 NS044623-05] NR 39 TC 51 Z9 56 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 MAY 1 PY 2007 VL 165 IS 9 BP 1015 EP 1022 DI 10.1093/aje/kwk109 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 159VY UT WOS:000245896900006 PM 17272288 ER PT J AU Lynch, E Liu, K Spring, B Hankinson, A Wei, GS Greenland, P AF Lynch, Elizabeth Liu, Kiang Spring, Bonnie Hankinson, Arlene Wei, Gina S. Greenland, Philip TI Association of ethnicity and socioeconomic status with judgments of body size - The Coronary Artery Risk Development in Young Adults (CARDIA) Study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE body composition; body image; body mass index; body size; ethnic groups; social class ID WEIGHT CONTROL PRACTICES; SOCIAL-CLASS; BLACK-WOMEN; US ADULTS; OBESITY; IMAGE; WHITE; DISSATISFACTION; AMERICAN; PERCEPTIONS AB The authors assessed the associations of ethnicity and socioeconomic status (SES) with body size judgments in Black and White young adults. Self-perceived and ideal body size judgments were measured using the Stunkard nine-figure scale (higher value = larger body) at the year 7 examination (1992-1993) of the Coronary Artery Risk Development in Young Adults (CARDIA) Study. In sex-specific adjusted multiple regression models, the difference between self-perceived and ideal body size judgments was largerfor Whites than for Blacks: 0.74 vs. 0.57 forWhite men vs. Black men (p < 0.05) and 1.48 vs. 0.96 for White women vs. Black women (p < 0.0001). This ethnic difference was evident in all body mass index-stratified adjusted models (all p's < 0.05). In ethnicity/sex-specific adjusted models, lower education was associated with a smaller difference between self-perceived and ideal body size for all groups except White women (p's for trend: White women, 0.57; Black women, < 0.0001; White men, 0.0007; Black men, 0.016). Judgments of self-perceived body size differed by ethnicity but not by SES, and judgments of ideal body size differed by SES but not by ethnicity. Learning to make medically accurate judgments of healthy body size may increase the motivation to lose weight in some persons. C1 Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60601 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Lynch, E (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60601 USA. EM bethlynch@northwestern.edu FU NHLBI NIH HHS [N01-HC-48047, N01-HC-48048, N01-HC-95095] NR 31 TC 39 Z9 40 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 MAY 1 PY 2007 VL 165 IS 9 BP 1055 EP 1062 DI 10.1093/aje/kwk114 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 159VY UT WOS:000245896900011 PM 17327218 ER PT J AU Harris, TB Launer, LJ Eiriksdottir, G Kjartansson, O Jonsson, PV Sigurdsson, G Thorgeirsson, G Aspelund, T Garcia, ME Cotch, MF Hoffman, HJ Gudnason, V AF Harris, Tamara B. Launer, Lenore J. Eiriksdottir, Gudny Kjartansson, Olafur Jonsson, Palmi V. Sigurdsson, Gunnar Thorgeirsson, Gudmundur Aspelund, Thor Garcia, Melissa E. Cotch, Mary Frances Hoffman, Howard J. Gudnason, Vilmundur CA Age GeneEnvironm Susceptibility-R TI Age, Gene/Environment Susceptibility-Reykjavik Study: Multidisciplinary applied phenomics SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE aging; body composition; cardiovascular diseases; cognition; genetics; population; osteoporosis; phenotype ID CORONARY-HEART-DISEASE; UNRECOGNIZED MYOCARDIAL-INFARCTION; COGNITIVE FUNCTION; ARTERY-DISEASE; RISK-FACTORS; ATHEROSCLEROSIS; INFLAMMATION; WOMEN; POPULATION; PREVALENCE AB In anticipation of the sequencing of the human genome and description of the human proteome, the Age, Gene/ Environment Susceptibility-Reykjavik Study (AGES-Reykjavik) was initiated in 2002. AGES-Reykjavik was designed to examine risk factors, including genetic susceptibility and gene/environment interaction, in relation to disease and disability in old age. The study is multidisciplinary, providing detailed phenotypes related to the cardiovascular, neurocognitive (including sensory), and musculoskeletal systems, and to body composition and metabolic regulation. Relevant quantitative traits, subdinical indicators of disease, and medical diagnoses are identified by using biomarkers, imaging, and other physiologic indicators. The AGES-Reykjavik sample is drawn from an established population-based cohort, the Reykjavik Study. This cohort of men and women born between 1907 and 1935 has been followed in Iceland since 1967 by the Icelandic Heart Association. The AGES-Reykjavik cohort, with cardiovascular risk factor assessments earlier in life and detailed late-life phenotypes of quantitative traits, will create a comprehensive study of aging nested in a relatively genetically homogeneous older population. This approach should facilitate identification of genetic factors that contribute to healthy aging as well as the chronic conditions common in old age. C1 NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, Bethesda, MD 20892 USA. Icelandic Heart Assoc, Kopavogur, Iceland. Landspitali Univ Hosp, Dept Radiol, Reykjavik, Iceland. Landspitali Univ Hosp, Dept Geriatr, Reykjavik, Iceland. Univ Iceland, Fac Med, Reykjavik, Iceland. Landspitali Univ Hosp, Dept Endocrinol & Metab, Reykjavik, Iceland. Landspitali Univ Hosp, Dept Med, Reykjavik, Iceland. NEI, Div Epidemiol & Clin Res, Bethesda, MD 20892 USA. NIDCD, Epidemiol & Biostat Program, Bethesda, MD USA. RP Harris, TB (reprint author), NIA, Lab Epidemiol Demog & Biometry, Intramural Res Program, 7201 Wisconsin Ave,Suite 3C309, Bethesda, MD 20892 USA. EM Harris99@mail.nih.gov; LaunerL@mail.nih.gov; v.gudnason@hjarta.is RI Aspelund, Thor/C-5983-2008; Aspelund, Thor/F-4826-2011; Gudnason, Vilmundur/K-6885-2015; OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084; Cotch, Mary Frances/0000-0002-2046-4350 FU Intramural NIH HHS [Z01 AG007380-02, Z01 EY000401-06, Z01 EY000401-07, Z99 EY999999, ZIA EY000401-08, ZIA EY000401-09, ZIA EY000401-10]; NIA NIH HHS [N01 AG012100, N01AG12100] NR 41 TC 225 Z9 227 U1 5 U2 22 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 MAY 1 PY 2007 VL 165 IS 9 BP 1076 EP 1087 DI 10.1093/aje/kwk115 PG 12 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 159VY UT WOS:000245896900014 PM 17351290 ER PT J AU Stanford, JB Dunson, DB AF Stanford, Joseph B. Dunson, David B. TI Effects of sexual intercourse patterns in time to pregnancy studies SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE coitus; confounding factors (epidemiology); fertility; fertilization ID DAY-SPECIFIC PROBABILITIES; LONG-TERM RECALL; MENSTRUAL-CYCLE; CIGARETTE-SMOKING; HUMAN-FERTILITY; TO-PREGNANCY; 1ST-PREGNANCY PLANNERS; LUTEINIZING-HORMONE; DELAYED CONCEPTION; CLINICAL PREGNANCY AB Time to pregnancy,. typically defined as the number of menstrual cycles required to achieve a clinical pregnancy, is widely used as a measure of couple fecundity in epidemiologic studies. Time to pregnancy studies seldom utilize detailed data on the timing and frequency of sexual intercourse and the timing of ovulation. However, the simulated models in this paper illustrate that intercourse behavior can have a large impact on time to pregnancy and, likewise, on fecunclability ratios, especially under conditions of low intercourse frequency or low fecundity. Because intercourse patterns in the menstrual cycles may vary substantially among groups, it is important to consider the effects of sexual behavior. Where relevant and feasible, an assessment should be made of the timing and frequency of intercourse relative to ovulation. Day-specific probabilities of pregnancy can be used to account for the effects of intercourse patterns. Depending on the research hypothesis, intercourse patterns may be considered as a potential confounder, mediator, or outcome. C1 Univ Utah, Dept Family & Prevent Med, Salt Lake City, UT 84108 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Stanford, JB (reprint author), Univ Utah, Dept Family & Prevent Med, 375 Chipeta Way,Suite A, Salt Lake City, UT 84108 USA. EM joseph.stanford@utah.edu NR 83 TC 24 Z9 24 U1 2 U2 9 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 MAY 1 PY 2007 VL 165 IS 9 BP 1088 EP 1095 DI 10.1093/aje/kwk111 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 159VY UT WOS:000245896900015 PM 17289774 ER PT J AU Awumey, EM Howlett, AC Putney, JW Diz, DI Bukoski, RD AF Awumey, Emmanuel M. Howlett, Allyn C. Putney, James W., Jr. Diz, Debra I. Bukoski, Richard D. TI Ca2+ mobilization through dorsal root ganglion Ca2+-sensing receptor stably expressed in HEK293 cells SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE desensitization; protein kinase C ID CALCIUM-SENSING RECEPTOR; PROTEIN-KINASE-C; BOVINE PARATHYROID CELLS; CA2+-INDUCED RELAXATION; MOLECULAR-CLONING; KERATINOCYTE DIFFERENTIATION; FUNCTIONAL EXPRESSION; INTRACELLULAR CALCIUM; GLUTAMATE-RECEPTOR; HORMONE-SECRETION AB The rat dorsal root ganglion ( DRG) Ca2+-sensing receptor ( CaR) was stably expressed in- frame as an enhanced green fluorescent protein ( EGFP) fusion protein in human embryonic kidney ( HEK) 293 cells, and is functionally linked to changes in intracellular Ca2+ concentration ([ Ca2+](i)). RT- PCR analysis indicated the presence of the message for the DRG CaR cDNA. Western blot analysis of membrane proteins showed a doublet of 168 - 175 and 185 kDa, consistent with immature and mature forms of the CaR. EGFP fusion protein, respectively. Increasing extracellular [ Ca2+] ([ Ca2+](e)) from 0.5 to 1 mM resulted in increases in [ Ca2+](i) levels, which were blocked by 30 mu M 2-aminoethyldiphenyl borate. [ Ca2+](e)- response studies indicate a Ca2+-sensitivity with an EC50 of 1.75 +/- 0.10 mM. NPS R- 467 and Gd3+ activated the CaR. When [ Ca2+](e) was successively raised from 0.25 to 4 mM, peak [ Ca2+](i), attained with 0.5 mM, was reduced by similar to 50%. Similar reductions were observed with repeated applications of 10 mM Ca2+, 1 and 10 mu M NPS R- 467, or 50 and 100 mu MGd3+, indicating desensitization of the response. Furthermore, Ca2+ mobilization increased phosphorylated protein kinase C ( PKC)alpha levels in the cells. However, the PKC activator, phorbol myristate acetate did not inhibit CaR-mediated Ca2+ signaling. Rather, a spectrum of PKC inhibitors partially reduced peak responses to Ca-e(2+). Treatment of cells with 100 nM PMA for 24 h, to downregulate PKC, reduced [ Ca2+](i) transients by 49.9 +/- 5.2% ( at 1 mM Ca-2(+)) and 40.5 +/- 6.5% ( at 2 mM Ca-2(+)), compared with controls. The findings suggest involvement of PKC in the pathway for Ca-2(+) mobilization following CaR activation. C1 N Carolina Cent Univ, Julius L Chambers Biomed Biotechnol Res Inst, Cardiovasc Dis Res Program, Durham, NC 27707 USA. N Carolina Cent Univ, Julius L Chambers Biomed Biotechnol Res Inst, Neurosci Drug Abuse Res Program, Durham, NC 27707 USA. Natl Inst Environm Hlth Sci, Lab Signal Transduct, Res Triangle Pk, NC USA. Wake Forest Univ, Sch Med, Hypertens Vasc Dis Ctr, Winston Salem, NC USA. Wake Forest Univ, Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC USA. RP Awumey, EM (reprint author), N Carolina Cent Univ, Julius L Chambers Biomed Biotechnol Res Inst, Cardiovasc Dis Res Program, 700 George St, Durham, NC 27707 USA. EM eawumey@nccu.edu OI Howlett, Allyn/0000-0002-2810-0164 FU NHLBI NIH HHS [R01 HL-64761, 5UH1 HL-05968] NR 58 TC 11 Z9 11 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD MAY PY 2007 VL 292 IS 5 BP C1895 EP C1905 DI 10.1152/ajpcell.00404.2006 PG 11 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 188RH UT WOS:000247936500035 PM 17267550 ER PT J AU Potenza, MA Marasciulo, FL Tarquinio, M Tiravanti, E Colantuono, G Federici, A Kim, JA Quon, MJ Montagnani, M AF Potenza, Maria A. Marasciulo, Flora L. Tarquinio, Mariela Tiravanti, Edy Colantuono, Giuseppe Federici, Antonio Kim, Jeong-a Quon, Michael J. Montagnani, Monica TI EGCG, a green tea polyphenol, improves endothelial function and insulin sensitivity, reduces blood pressure, and protects against myocardial I/R injury in SHR SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE epigallocatechin gallate; insulin resistance; endothelial dysfunction; nitric oxide; metabolic syndrome; spontaneously hypertensive rats; ischemia-reperfusion ID SPONTANEOUSLY HYPERTENSIVE-RATS; CORONARY-ARTERY-DISEASE; NITRIC-OXIDE SYNTHASE; ISCHEMIA-REPERFUSION INJURY; CONVERTING-ENZYME-INHIBITOR; EPIGALLOCATECHIN GALLATE; HYPERCHOLESTEROLEMIC PATIENTS; CARDIOVASCULAR-DISEASE; STIMULATED PRODUCTION; METABOLIC SYNDROME AB Epigallocatechin gallate (EGCG), a bioactive polyphenol in green tea, may augment metabolic and vascular actions of insulin. Therefore, we investigated effects of EGCG treatment to simultaneously improve cardiovascular and metabolic function in spontaneously hypertensive rats (SHR; model of metabolic syndrome with hypertension, insulin resistance, and overweight). In acute studies, EGCG (1-100 mu M) elicited dose-dependent vasodilation in mesenteric vascular beds (MVB) isolated from SHR ex vivo that was inhibitable by N-omega-nitro-L-arginine methyl ester (L-NAME; nitric oxide synthase antagonist) or wortmannin [phosphatidylinositol (PI) 3-kinase inhibitor]. In chronic studies, 9-wk-old SHR were treated by gavage for 3 wk with EGCG (200 mg center dot kg(-1) center dot day -1), enalapril (30 mg center dot kg(-1) center dot day(-1)), or vehicle. A separate group of SHR receiving L-NAME (80 mg/l in drinking water) was treated for 3 wk with either EGCG or vehicle. Vasodilator actions of insulin were significantly improved in MVB from EGCG- or enalapril-treated SHR (when compared with vehicle-treated SHR). Both EGCG and enalapril therapy significantly lowered systolic blood pressure (SBP) in SHR. EGCG therapy of SHR significantly reduced infarct size and improved cardiac function in Langendorff-perfused hearts exposed to ischemia-reperfusion (I/R) injury. In SHR given L-NAME, beneficial effects of EGCG on SBP and I/R were not observed. Both enalapril and EGCG treatment of SHR improved insulin sensitivity and raised plasma adiponectin levels. We conclude that acute actions of EGCG to stimulate production of nitric oxide from endothelium using PI 3-kinase-dependent pathways may explain, in part, beneficial effects of EGCG therapy to simultaneously improve metabolic and cardiovascular pathophysiology in SHR. These findings may be relevant to understanding potential benefits of green tea consumption in patients with the metabolic syndrome. C1 Univ Bari, Policlin, Dept Pharmacol & Human Physiol, Sch Med, I-70124 Bari, Italy. Univ Bari, Sch Med, Dept Emergency & Organ Transplantat, I-70124 Bari, Italy. NIH, Natl Ctr Complementary & Alternat Med, Diabet Unit, Bethesda, MD 20892 USA. RP Montagnani, M (reprint author), Univ Bari, Policlin, Dept Pharmacol & Human Physiol, Sch Med, Piazza Giulio Cesare 11, I-70124 Bari, Italy. EM monica@farmacol.uniba.it RI Quon, Michael/B-1970-2008; OI federici, antonio/0000-0001-5102-9995; Quon, Michael/0000-0002-9601-9915; Potenza, Maria Assunta/0000-0002-9995-1468; montagnani, monica/0000-0002-5697-8185; Quon , Michael /0000-0002-5289-3707 FU Intramural NIH HHS NR 60 TC 166 Z9 178 U1 8 U2 45 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 MAY PY 2007 VL 292 IS 5 BP E1378 EP E1387 DI 10.1152/ajpendo.00698.2006 PG 10 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 188SF UT WOS:000247938900017 PM 17227956 ER PT J AU Zhang, JH Wright, W Bernlohr, DA Cushman, SW Chen, XL AF Zhang, Jinhui Wright, Wendy Bernlohr, David A. Cushman, Samuel W. Chen, Xiaoli TI Alterations of the classic pathway of complement in adipose tissue of obesity and insulin resistance SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE C1 complement; gene expression ID NECROSIS-FACTOR-ALPHA; ACYLATION-STIMULATING PROTEIN; C-REACTIVE PROTEIN; 3T3-L1 ADIPOCYTES; TRIACYLGLYCEROL SYNTHESIS; EXTRACELLULAR-MATRIX; ALTERNATIVE PATHWAY; GLUCOSE-TRANSPORT; GENE-EXPRESSION; C1Q AB Adipose tissue inflammation has recently been linked to the pathogenesis of obesity and insulin resistance. C1 complex comprising three distinct proteins, C1q, C1r, and C1s, involves the key initial activation of the classic pathway of complement and plays an important role in the initiation of inflammatory process. In this study, we investigated adipose expression and regulation of C1 complement subcomponents and C1 activation regulator decorin in obesity and insulin resistance. Expression of C1q in epididymal adipose tissue was increased consistently in ob/ob mice, Zucker obese rats, and high fat-diet-induced obese (HF-DIO) mice. Decorin was found to increase in expression in Zucker obese rats and HF-DIO mice but decrease in ob/ob mice. After TZD administration, C1q and decorin expression was reversed in Zucker obese rats and HF-DIO mice. Increased expression of C1 complement and decorin was observed in both primary adipose and stromal vascular cells isolated from Zucker obese rats. Upregulation of C1r and C1s expression was also perceived in adipose cells from insulin-resistant humans. Furthermore, expression of C1 complement and decorin is dysregulated in TNF-alpha-induced insulin resistance in 3T3-L1 adipocytes and cultured rat adipose cells as they become insulin resistant after 24-h culture. These data suggests that both adipose and immune cells are the sources for abnormal adipose tissue production of C1 complement and decorin in obesity. Our findings also demonstrate that excessive activation of the classic pathway of complement commonly occurs in obesity, suggesting its possible role in adipose tissue inflammation and insulin resistance. C1 Univ Minnesota, Dept Food Sci & Nutr, St Paul, MN 55108 USA. Univ Minnesota, Dept Biochem Mol Biol & Biophys, St Paul, MN 55108 USA. NIDDKD, Expt Diabet Metab & Nutr Sci, Diabet Branch, NIH, Bethesda, MD 20892 USA. RP Chen, XL (reprint author), Univ Minnesota, Dept Food Sci & Nutr, Rm 139,1334 Eckles Ave, St Paul, MN 55108 USA. EM xlchen@umn.edu FU NIDDK NIH HHS [R01 DK080743-01, DK-053189, R01 DK080743] NR 47 TC 32 Z9 32 U1 0 U2 2 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 MAY PY 2007 VL 292 IS 5 BP E1433 EP E1440 DI 10.1152/ajpendo.00664.2006 PG 8 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 188SF UT WOS:000247938900024 PM 17244723 ER PT J AU Hasegawa, T Ito, Y Wijeweera, J Liu, J Malle, E Farhood, A McCuskey, RS Jaeschke, H AF Hasegawa, Tadashi Ito, Yoshiya Wijeweera, Jayanthika Liu, Jie Malle, Ernst Farhood, Anwar McCuskey, Robert S. Jaeschke, Hartmut TI Reduced inflammatory response and increased microcirculatory disturbances during hepatic ischemia-reperfusion injury in steatotic livers of ob/ob mice SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE liver blood flow; microvascular dysfunction; heme oxygenase-1; neutrophils; hypochlorous acid; steatosis ID HYPOCHLORITE-MODIFIED PROTEINS; CD4(+) T-LYMPHOCYTES; ISCHEMIA/REPERFUSION INJURY; RAT-LIVER; HEME OXYGENASE-1; KUPFFER CELLS; FATTY LIVER; THERAPEUTIC STRATEGIES; SUPEROXIDE GENERATION; MONOCLONAL-ANTIBODY AB Steatosis is a major risk factor for complications after liver surgery. Since neutrophil cytotoxicity is critical for ischemia-reperfusion injury in normal livers, the aim of the present study was to evaluate whether an exaggerated inflammatory response could cause the increased injury in steatotic livers. In C57B1/6 mice, 60 min of warm hepatic ischemia triggered a gradual increase in hepatic neutrophil accumulation during reperfusion with peak levels of 100- fold over baseline at 12 h of reperfusion. Neutrophil extravasation and a specific neutrophil-induced oxidant stress ( immunostaining for hypochlorous acid- modified epitopes) started at 6 h of reperfusion and peaked at 12 - 24 h. Ob/ob mice, which had a severe macrovesicular steatosis, suffered significantly higher injury ( alanine transaminase activity: 18,000 +/- 2,100 U/1; 65% necrosis) compared with lean littermates ( alanine transaminase activity: 4,900 +/- 720 U/1; 24% necrosis) at 6 h of reperfusion. However, 62% fewer neutrophils accumulated in steatotic livers. This correlated with an attenuated increase in mRNA levels of several proinflammatory genes in ob/ ob mice during reperfusion. In contrast, sham- operated ob/ ob mice had a 50% reduction in liver blood flow and 35% fewer functional sinusoids compared with lean littermates. These deficiencies in liver blood flow and the microcirculation were further aggravated only in ob/ ob mice during reperfusion. The attenuated inflammatory response and reduced neutrophil- induced oxidant stress observed in steatotic livers during reperfusion cannot be responsible for the dramatically increased injury in ob/ ob mice. In contrast, the aggravated injury appears to be mediated by ischemic necrosis due to massive impairment of blood and oxygen supply in the steatotic livers. C1 Univ Kansas, Ctr Med, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66160 USA. Univ Arizona, Coll Med, Liver Res Inst, Tucson, AZ USA. Univ Arizona, Coll Med, Dept Cell Biol & Anat, Tucson, AZ USA. Natl Inst Environm Hlth Sci, Lab Comparat Carcinogenesis, Inorgan Carcinogenesis Sect, NCI, Res Triangle Pk, NC USA. Med Univ Graz, Ctr Mol Med, Inst Mol Biol & Biochem, Graz, Austria. Brackenridge Hosp, Dept Pathol, Austin, TX USA. RP Hasegawa, T (reprint author), Univ Kansas, Ctr Med, Dept Pharmacol Toxicol & Therapeut, 3901 Rainbow Blvd,MS 1018, Kansas City, KS 66160 USA. EM hjaeschke@kumc.edu RI Malle, Ernst/D-3071-2013 FU Austrian Science Fund FWF [P 17013]; Intramural NIH HHS; NIAAA NIH HHS [AA-12436, AA-12916, R01 AA012436, R01 AA012916, R56 AA012916]; NIDDK NIH HHS [DK-070195, R01 DK070195] NR 54 TC 34 Z9 36 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD MAY PY 2007 VL 292 IS 5 BP G1385 EP G1395 DI 10.1152/ajpgi.00246.2006 PG 11 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 188RA UT WOS:000247935800022 PM 17307725 ER PT J AU Imahashi, K Mraiche, F Steenbergen, C Murphy, E Fliegel, L AF Imahashi, Kenichi Mraiche, Fatima Steenbergen, Charles Murphy, Elizabeth Fliegel, Larry TI Overexpression of the Na+/H+ exchanger and ischemia-reperfusion injury in the myocardium SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE transgenic mice; sodium/hydrogen exchange; intracellular pH; intracellular sodium ID SODIUM-HYDROGEN EXCHANGER; DIABETIC-RAT HEARTS; H+ EXCHANGE; INTRACELLULAR PH; VENTRICULAR MYOCYTES; CARDIAC ISCHEMIA; MOUSE HEART; EXPRESSION; INHIBITION; CARIPORIDE AB In the myocardium, the Na+/H+ exchanger isoform-1 (NHE1) activity is detrimental during ischemia-reperfusion (I/R) injury, causing increased intracellular Na+ (Na-i(+)) accumulation that results in subsequent Ca2+ overload. We tested the hypothesis that increased expression of NHE1 would accentuate myocardial I/R injury. Transgenic mice were created that increased the Na+/H+ exchanger activity specifically in the myocardium. Intact hearts from transgenic mice at 10-15 wk of age showed no change in heart performance, resting intracellular pH (pH(i)) or phosphocreatine/ ATP levels. Transgenic and wild-type (WT) hearts were subjected to 20 min of ischemia followed by 40 min of reperfusion. Surprisingly, the percent recovery of rate-pressure product (%RPP) after I/R improved in NHE1-overexpressing hearts (64 +/- 5% vs. 41 +/- 5% in WT; P < 0.05). In addition, NMR spectroscopy revealed that NHE1 overexpressor hearts contained higher ATP during early reperfusion (levels P < 0.05), and there was no difference in Na+ accumulation during I/R between transgenic and WT hearts. HOE642 (cariporide), an NHE1 inhibitor, equivalently protected both WT and NHE1-overexpressing hearts. When hearts were perfused with bicarbonate-free HEPES buffer to eliminate the contribution of HCO3- transporters to pHi regulation, there was no difference in contractile recovery after reperfusion between controls and transgenics, but NHE1-overexpressing hearts showed a greater decrease in ATP during ischemia. These results indicate that the basal activity of NHE1 is not rate limiting in causing damage during I/R, therefore, increasing the level of NHE1 does not enhance injury and can have some small protective effects. C1 Univ Alberta, Dept Biochem, Edmonton, AB T6G 2H7, Canada. Natl Inst Environm Hlth Sci, NIH, Lab Signal Transduct, Res Triangle Pk, NC USA. Duke Univ, Med Ctr, Dept Pathol, Durham, NC USA. Univ Alberta, Dept Biochem, Edmonton, AB, Canada. RP Imahashi, K (reprint author), Univ Alberta, Dept Biochem, Edmonton, AB T6G 2H7, Canada. EM lfiegel@ualberta.ca FU Intramural NIH HHS; NHLBI NIH HHS [R01 HL039752] NR 48 TC 31 Z9 31 U1 1 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 MAY PY 2007 VL 292 IS 5 BP H2237 EP H2247 DI 10.1152/ajpheart.00855.2006 PG 11 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 186KI UT WOS:000247777200027 PM 17209001 ER PT J AU Wang, Z Armando, I Asico, LD Escano, C Wang, XY Lu, QS Felder, RA Schnackenberg, CG Sibley, DR Eisner, GM Jose, PA AF Wang, Zheng Armando, Ines Asico, Laureano D. Escano, Crisanto Wang, Xiaoyan Lu, Quansheng Felder, Robin A. Schnackenberg, Christine G. Sibley, David R. Eisner, Gilbert M. Jose, Pedro A. TI The elevated blood pressure of human GRK4 gamma A142V transgenic mice is not associated with increased ROS production SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article; Proceedings Paper CT 9th Cardiovascular-Kidney Interactions in Health and Disease Meeting CY MAY 26, 2006 CL Amelia Isl, FL DE hGRK4 polymorphism; hypertension; reactive oxygen species; G protein-coupled receptor kinases ID SINGLE-NUCLEOTIDE POLYMORPHISMS; COUPLED RECEPTOR KINASE-4; SPONTANEOUSLY HYPERTENSIVE-RATS; RENIN-ANGIOTENSIN SYSTEM; D-5 DOPAMINE-RECEPTORS; HUMAN HEME OXYGENASE-1; SMOOTH-MUSCLE-CELLS; OXIDATIVE STRESS; NITRIC-OXIDE; NAD(P)H OXIDASE AB G protein-coupled receptor (GPCR) kinases (GRKs) regulate the sensitivity of GPCRs, including dopamine receptors. The GRK4 locus is linked to, and some of its polymorphisms are associated with, human essential hypertension. Transgenic mice overexpressing human (h) GRK4 gamma A142V on a mixed genetic background (C57BL/6J and SJL/J) have impaired renal D-1-dopamine receptor (D1R) function and increased blood pressure. We now report that hGRK4 gamma A142V transgenic mice, in C57BL/6J background, are hypertensive and have higher blood pressures than hGRK4 gamma wild-type transgenic and nontransgenic mice. The hypertensive phenotype is stable because blood pressures in transgenic founders and F6 offspring are similarly increased. To determine whether the hypertension is associated with increased production of reactive oxygen species (ROS), we measured renal NADPH oxidase (Nox2 and Nox4) and heme oxygenase (HO-1 and HO-2) protein expressions and urinary excretion of 8-isoprostane and compared the effect of Tempol on blood pressure in hGRK4 gamma A142V transgenic mice and D5R knockout (D-5(-/-)) mice in which hypertension is mediated by increased ROS. The expressions of Nox isoforms and HO-2 and the urinary excretion of 8-isoprostane were similar in hGRK4 gamma A142V transgenic mice and their controls. HO-1 expression was increased in hGRK4 gamma A142V relative to hGRK4 gamma wild-type transgenic mice. In contrast with the hypotensive effect of Tempol in D5-/- mice, it had no effect in hGRK4 gamma A142V transgenic mice. We conclude that the elevated blood pressure of hGRK4 gamma A142V transgenic mice is due mainly to the effect of hGRK4 gamma A142V transgene acting via D1R and increased ROS production is not a contributor. C1 Georgetown Univ, Sch Med, Dept Pediat & Physiol & Biophys, Washington, DC USA. Univ Virginia, Hlth Sci Ctr, Dept Pathol, Charlottesville, VA USA. GlaxoSmithKline Inc, Dept Investigat & Cardiac Biol, King Of Prussia, PA USA. NINDS, Mol Neuropharmacol Sect, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Med, Washington, DC 20007 USA. RP Wang, Z (reprint author), Georgetown Univ, Sch Med, Bldg D Room 366,4000 Reservoir Rd, Washington, DC 20057 USA. EM wangz10@georgetown.edu FU NHLBI NIH HHS [HL 68686, HL 23081, HL 07490]; NIDDK NIH HHS [DK 39308, DK 52612] NR 67 TC 23 Z9 23 U1 0 U2 0 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 MAY PY 2007 VL 292 IS 5 BP H2083 EP H2092 DI 10.1152/ajpheart.00944.2006 PG 10 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 186KI UT WOS:000247777200009 PM 17259440 ER PT J AU Cheruvanky, A Zhou, H Pisitkun, T Kopp, JB Knepper, MA Yuen, PST Star, RA AF Cheruvanky, Anita Zhou, Hua Pisitkun, Trairak Kopp, Jeffrey B. Knepper, Mark A. Yuen, Peter S. T. Star, Robert A. TI Rapid isolation of urinary exosomal biomarkers using a nanomembrane ultrafiltration concentrator SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE urinary exosomes; ultracentrifugation; diagnostic method ID DISCOVERY; PROTEIN; INJURY AB Urinary exosomes are excreted from all nephron segments and may serve as biomarkers for classifying renal diseases. Isolation of urinary exosomes by the established ultracentrifugation method has some limitations for use in a clinical laboratory. We sought a rapid and simple way to obtain urinary exosomes. We used a commercially available nanomembrane concentrator to enrich exosomes from urine by centrifugation at 3,000 g for 10 - 30 min. Urinary exosomal markers tumor susceptibility gene 101, aquaporin- 2, neuron- specific enolase, annexin V, angiotensin-converting enzyme, and podocalyxin ( PODXL) were recovered from the nanomembrane concentrator and detected by Western blotting, and typical features of urinary vesicles were found by electron microscopy. Exosomal markers were detected in as little as 0.5 ml of urine. By the nanomembrane method, exosomal proteins could be recovered from urine samples frozen at -80 degrees C or refrigerated overnight at 4 degrees C then stored at -80 degrees C. By enriching exosomes we could detect PODXL, a podocyte marker, which decreased by 71% in five male patients with focal segmental glomerulosclerosis and abundant proteinuria. We conclude that 1) use of a nanomembrane concentrator simplifies and accelerates the enrichment of urinary exosomes; and 2) the nanomembrane concentrator can concentrate exosomal proteins from clinical urine samples. This enhanced method may accelerate the translation of urinary exosomal biomarkers from bench to bedside for the diagnosis, classification, and prognostication of renal diseases. C1 NIDDKD, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD 20892 USA. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Star, RA (reprint author), NIDDKD, Renal Diagnost & Therapeut Unit, NIH, 10 Ctr Dr,bldg 10,Rm 3N108, Bethesda, MD 20892 USA. EM Robert_Star@nih.gov RI Yuen, Peter/B-1954-2008; OI Yuen, Peter/0000-0001-9557-3909; Pisitkun, Trairak/0000-0001-6677-2271; Kopp, Jeffrey/0000-0001-9052-186X FU Intramural NIH HHS [Z01 DK043400-08, Z01 HL001285-21, Z99 HL999999] NR 7 TC 89 Z9 99 U1 1 U2 21 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 MAY PY 2007 VL 292 IS 5 BP F1657 EP F1661 DI 10.1152/ajprenal.00434.2006 PG 5 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 188SU UT WOS:000247940400040 PM 17229675 ER PT J AU Nakaya, K Harbidge, DG Wangemann, P Schultz, BD Green, ED Wall, SM Marcus, DC AF Nakaya, Kazuhiro Harbidge, Donald G. Wangemann, Philine Schultz, Bruce D. Green, Eric D. Wall, Susan M. Marcus, Daniel C. TI Lack of pendrin HCO(3)over-bar transport elevates vestibular endolymphatic [Ca(2+)] by inhibition of acid-sensitive TRPV5 and TRPV6 channels SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE epithelial calcium channel; vitamin D; SLC26a4; HCO(3)over-bar secretion ID EPITHELIAL CALCIUM-CHANNEL; SYNDROME GENE; INNER-EAR; NA+/I-SYMPORTER; HAIR-CELLS; GUINEA-PIG; EXPRESSION; ABSORPTION; SECRETION; MICE AB The low Ca(2+) concentration ([Ca(2+)]) of mammalian endolymph in the inner ear is required for normal hearing and balance. We reported (Yamauchi et al., Biochem Biophys Res Commun 331: 1353-1357, 2005) that the epithelial Ca(2+) channels TRPV5 and TRPV6 (transient receptor potential types 5 and 6) are expressed in the vestibular system and that TRPV5 expression is stimulated by 1,25-dihydroxyvitamin D(3), as also reported in kidney. TRPV5/6 channels are known to be inhibited by extracellular acidic pH. Endolymphatic pH, [Ca(2+)], and transepithelial potential of the utricle were measured in Cl(-)/HCO(3)(-) exchanger pendrin (SLC26A4) knockout mice in vivo. Slc26a4(-/-) mice exhibit reduced pH and utricular endolymphatic potential and increased [Ca(2+)]. Monolayers of primary cultures of rat semicircular canal duct cells were grown on permeable supports, and cellular uptake of (45)Ca(2+) was measured individually from the apical and basolateral sides. Net uptake of (45)Ca(2+) was greater after incubation with 1,25-dihydroxyvitamin D(3). Net (45)Ca(2+) absorption was dramatically inhibited by low apical pH and was stimulated by apical alkaline pH. Gadolinium, lanthanum, and ruthenium red reduced apical uptake. These observations support the notion that one aspect of vestibular dysfunction in Pendred syndrome is a pathological elevation of endolymphatic [Ca(2+)] due to luminal acidification and consequent inhibition of TRPV5/6-mediated Ca(2+) absorption. C1 Kansas State Univ, Dept Anat & Physiol, Cellular Biophys Lab, Manhattan, KS 66506 USA. Kansas State Univ, Dept Anat & Physiol, Cell Physiol Lab, Manhattan, KS 66506 USA. Kansas State Univ, Dept Anat & Physiol, Epithelial Cell Biol Lab, Manhattan, KS 66506 USA. Tohoku Univ, Dept Otolaryngol Head & Neck Surg, Grad Sch Med, Sendai, Miyagi 980, Japan. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Emory Univ, Sch Med, Div Renal, Atlanta, GA 30322 USA. RP Marcus, DC (reprint author), Kansas State Univ, Dept Anat & Physiol, Cellular Biophys Lab, 228 Coles Hall, Manhattan, KS 66506 USA. EM marcus@ksu.edu RI Wangemann, Philine/N-2826-2013; Schultz, Bruce/F-8854-2013 FU NIDCD NIH HHS [R01 DC-00212, R01 DC-01098, R01 DC000212, R01 DC000212-24, R01 DC001098]; NIDDK NIH HHS [P01 DK-061521, P01 DK061521] NR 46 TC 64 Z9 67 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAY PY 2007 VL 292 IS 5 BP F1314 EP F1321 DI 10.1152/ajpreanl.00432.2006 PG 8 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 188SU UT WOS:000247940400002 PM 17200157 ER PT J AU Norregaard, R Jensen, BL Topcu, SO Diget, M Schweer, H Knepper, MA Nielsen, S Frokiaer, J AF Norregaard, Rikke Jensen, Boye L. Topcu, Sukru Oguzkan Diget, Maria Schweer, Horst Knepper, Mark A. Nielsen, Soren Frokiaer, Jorgen TI COX-2 activity transiently contributes to increased water and NaCl excretion in the polyuric phase after release of ureteral obstruction SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE cyclooxygenase; ureteral obstruction; PGE(2); parecoxib; AQP2; NKCC2; urine-concentrating capacity ID MEDULLARY INTERSTITIAL-CELLS; THICK ASCENDING LIMB; DOWN-REGULATION; CYCLOOXYGENASE-2 INHIBITOR; ALTERED EXPRESSION; RAT-KIDNEY; AQUAPORIN-2; LOCALIZATION; TRANSPORT; PHOSPHORYLATION AB Release of bilateral ureteral obstruction (BUO) is associated with reduced expression of renal aquaporins (AQPs), polyuria, and impairment of urine-concentrating capacity. Recently, we demonstrated that 24 h of BUO is associated with increased cyclooxygenase (COX)-2 expression in the inner medulla (IM) and that selective COX-2 inhibition prevents downregulation of AQP2. In the present study, we tested the hypothesis that COX-2 activity increases in the postobstructive phase and that this increase in COX-2 activity contributes to polyuria and impaired urine-concentrating capacity. We examined the effect of the selective COX-2 inhibitor parecoxib (5 mg (.) kg(-1) (.) day(-1) via osmotic minipumps) on renal functions and protein abundance of AQP2, AQP3, Na-K-2Cl cotransporter type 2 (NKCC2), and Na-K-ATPase 3 days after release of BUO. At 3 days after release of BUO, rats exhibited polyuria, dehydration and urine and IM tissue osmolality were decreased. There were inverse changes of COX-1 and COX-2 in the IM: COX- 2 mRNA, protein, and activity increased, while COX- 1 mRNA and protein decreased. Parecoxib reduced urine output 1 day after release of BUO, but sodium excretion and glomerular filtration rate were unchanged. Parecoxib normalized urinary PGE2 and PGI2 excretion and attenuated downregulation of AQP2 and AQP3, while phosphorylated AQP2 and NKCC2 remained suppressed. Parecoxib did not improve urine-concentrating capacity in response to 24 h of water deprivation. We conclude that decreased NKCC2 and collapse of the IM osmotic gradient, together with suppressed phosphorylated AQP2, are likely causes for the impaired urine-concentrating capacity and that COX-2 activity is not likely to mediate these changes in the chronic postobstructive phase after ureteral obstruction. C1 Univ Aarhus, Water & Salt Res Ctr, Inst Clin Med, Dept Clin Physiol & Nucl Med,Hosp Skejby, DK-8200 Aarhus N, Denmark. Univ Aarhus, Inst Clin Med, Aarhus, Denmark. Univ Aarhus, Inst Anat, Aarhus, Denmark. Aarhus Univ Hosp, Dept Clin Physiol & Nucl Med, DK-8000 Aarhus, Denmark. Univ So Denmark, Dept Physiol & Pharmacol, Odense, Denmark. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. Univ Marburg, Dept Pediat, Marburg, Germany. RP Frokiaer, J (reprint author), Univ Aarhus, Water & Salt Res Ctr, Inst Clin Med, Dept Clin Physiol & Nucl Med,Hosp Skejby, DK-8200 Aarhus N, Denmark. EM JF@ki.au.dk FU Intramural NIH HHS [Z99 HL999999, Z01 HL001285-21] NR 38 TC 19 Z9 19 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD MAY PY 2007 VL 292 IS 5 BP F1322 EP F1333 DI 10.1152/ajprenal.00394.2006 PG 12 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 188SU UT WOS:000247940400003 PM 17229676 ER PT J AU Atienza, AA Hesse, BW Baker, TB Abrams, DB Rimer, BK Croyle, RT Volckmann, LN AF Atienza, Audie A. Hesse, Bradford W. Baker, Timothy B. Abrams, David B. Rimer, Barbara K. Croyle, Robert T. Volckmann, Lindsey N. TI Critical issues in eHealth research SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Editorial Material ID HEALTH INFORMATION; INTERNET; SYSTEM; EDUCATION; ADULTS; IMPACT C1 NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. Univ Wisconsin, Dept Psychol, Madison, WI 53706 USA. Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. RP Atienza, AA (reprint author), NIH, NIH 6130-4074, Bethesda, MD 20892 USA. EM AtienzaA@mail.nih.gov OI Hesse, Bradford/0000-0003-1142-1161 FU Intramural NIH HHS [Z99 CA999999] NR 44 TC 18 Z9 18 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD MAY PY 2007 VL 32 IS 5 SU S BP S71 EP S74 DI 10.1016/j.amepre.2007.02.013 PG 4 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 168LX UT WOS:000246527200001 PM 17466821 ER PT J AU Hesse, BW Shneiderman, B AF Hesse, Bradford W. Shneiderman, Ben TI eHealth research from the user's perspective SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID HEALTH INFORMATION; DECISION-SUPPORT; BREAST-CANCER; COMMUNICATION; CARE; SYSTEMS; PHYSICIANS; LITERACY; SCIENCE; IMPACT AB The application of information technology (IT) to issues of healthcare delivery has had a long and tortuous history in the United States. Within the field of eHealth, vanguard applications of advanced computing techniques, such as applications in artificial intelligence or expert systems, have languished in spite of a track record of scholarly publication and decisional accuracy. The problem is one of purpose, of asking the right questions for the science to solve. Historically, many computer science pioneers have been tempted to ask '' what can the computer do?'' New advances in eHealth are prompting developers to ask 14 what can people do?'' How can eHealth take part in national goals for healthcare reform to empower relationships between healthcare professionals and patients, healthcare teams and families, and hospitals and communities to improve health equitably throughout the population? To do this, eHealth researchers must combine best evidence from the user sciences (human factors engineering, human-computer interaction, psychology, and usability) with best evidence in medicine to create transformational improvements in the quality of care that medicine offers. These improvements should follow recommendations from the Institute of Medicine to create a healthcare system that is (1) safe, (2) effective (evidence based), (3) patient centered, and (4) timely. Relying on the eHealth researcher's intuitive grasp of systems issues, improvements should be made with considerations of users and beneficiaries at the individual (patient-physician), group (family-staff), community, and broad environmental levels. C1 NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Univ Maryland, Dept Comp Sci, College Pk, MD 20742 USA. RP Hesse, BW (reprint author), NCI, Div Canc Control & Populat Sci, 6130 Execut Blvd,MSC 7365, Bethesda, MD 20892 USA. EM hesseb@mail.nih.gov OI Hesse, Bradford/0000-0003-1142-1161 FU Intramural NIH HHS [Z99 CA999999] NR 94 TC 48 Z9 50 U1 4 U2 21 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 MAY PY 2007 VL 32 IS 5 SU S BP S97 EP S103 DI 10.1016/j.amepre.2007.01.019 PG 7 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 168LX UT WOS:000246527200005 PM 17466825 ER PT J AU Lutz, CK Davis, EB Ruggiero, AM Suomi, SJ AF Lutz, Corrine K. Davis, Ernie B. Ruggiero, Angela M. Suomi, Stephen J. TI Early predictors of self-biting in socially-housed rhesus Macaques (Macaca mulatta) SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Article DE Macaca mulatta; rearing; self-biting; social behavior ID INJURIOUS-BEHAVIOR; MONKEYS; ENVIRONMENT AB The development of self-biting behavior in captive monkeys is little understood and poses a serious risk to their well-being. Although early rearing conditions may influence the expression of this behavior, not all animals reared under similar conditions self-bite. The purpose of this study was to examine the effects of three rearing conditions on biting behavior and to determine whether early infant behavior can predict later self-biting. The subjects were 370 rhesus macaques born at the National Institutes of Health (NIH) Animal Center between 1994 and 2004. They were reared under three conditions: mother-reared in social groups (n = 183), peer-reared in groups of four (n = 84), and surrogatepeer-reared (n = 103). Significantly more surrogate-peer-reared animals self-bit compared to peer-only or mother-reared animals. There was no sex difference in self-biting, but this result may have been affected by a sex bias in the number of observations. The durations of behaviors exhibited by the surrogate-peer-reared subjects were recorded in 5-min sessions twice a week from 2 to 6 months of age while the animals were in their home cages and play groups. In the play-group situation, surrogatepeer-reared subjects who later self-bit were found to be less social and exhibited less social clinging than those that did not self-bite. Home-cage behavior did not predict later self-biting, but it did change with increasing age: surrogate clinging and self-mouthing decreased, while environmental exploration increased. Our findings suggest that surrogate rearing in combination with lower levels of social contact during play may be risk factors for the later development of self-biting behavior. C1 NICHD, NIH Anim Ctr, Comparat Ethol Lab, NIH, Poolesville, MD USA. RP Lutz, CK (reprint author), SW Natl Primate Res Ctr, POB 760549, San Antonio, TX 78245 USA. EM clutz@sfbr.org FU Intramural NIH HHS NR 17 TC 21 Z9 21 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD MAY PY 2007 VL 69 IS 5 BP 584 EP 590 DI 10.1002/ajp.20370 PG 7 WC Zoology SC Zoology GA 172MG UT WOS:000246807800008 PM 17216620 ER PT J AU Volkow, ND O'Brien, CP AF Volkow, Nora D. O'Brien, Charles P. TI Issues for DSM-V: Should obesity be included as a brain disorder? SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Editorial Material ID UNITED-STATES; ADDICTION; MECHANISMS; PREVALENCE; REWARD; FOOD C1 NIDA, Bethesda, MD 20892 USA. RP Volkow, ND (reprint author), NIDA, 6001 Execut Blvd,Room 5274, Bethesda, MD 20892 USA. EM nvolkow@nida.nih.gov NR 12 TC 127 Z9 131 U1 6 U2 57 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 MAY PY 2007 VL 164 IS 5 BP 708 EP 710 DI 10.1176/appi.ajp.164.5.708 PG 3 WC Psychiatry SC Psychiatry GA 166HR UT WOS:000246370300006 PM 17475727 ER PT J AU Wisniewski, SR Fava, M Trivedi, MH Thase, ME Warden, D Niederehe, G Friedman, ES Biggs, MM Sackeim, HA Shores-Wilson, K McGrath, PJ Lavori, PW Miyahara, S Rush, AJ AF Wisniewski, Stephen R. Fava, Maurizio Trivedi, Madhukar H. Thase, Michael E. Warden, Diane Niederehe, George Friedman, Edward S. Biggs, Melanie M. Sackeim, Harold A. Shores-Wilson, Kathy McGrath, Patrick J. Lavori, Philip W. Miyahara, Sachiko Rush, A. John TI Acceptability of second-step treatments to depressed outpatients: A STAR*D report SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID SEQUENCED TREATMENT ALTERNATIVES; MEDICATION ALGORITHM PROJECT; ILLNESS RATING-SCALE; REPORT QIDS-SR; QUICK INVENTORY; PSYCHOMETRIC EVALUATION; SYMPTOMATOLOGY IDS; DISORDER; RATIONALE AB Objective: Treatment of major depressive disorder typically entails implementing treatments in a stepwise fashion until a satisfactory outcome is achieved. This study sought to identify factors that affect patients' willingness to accept different second-step treatment approaches. Method: Participants in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial who had unsatisfactory outcomes after initial treatment with citalopram were eligible for a randomized second-step treatment trial. An equipoise-stratified design allowed participants to exclude or include specific treatment strategies. Analyses were conducted to identify factors associated with the acceptability of the following second-step treatments: cognitive therapy versus no cognitive therapy, any switch strategy versus any augmentation strategy (including cognitive therapy), and a medication switch strategy only versus a medication augmentation strategy only. Results: Of the 1,439 participants who entered second-step treatment, 1% accepted all treatment strategies, 3% accepted only cognitive therapy, and 26% accepted cognitive therapy (thus, 71% did not accept cognitive therapy). Those with higher educational levels or a family history of a mood disorder were more likely to accept cognitive therapy. Participants in primary care settings and those who experienced a greater side effect burden or a lower reduction in symptom severity with citalopram were more likely to accept a switch strategy as compared with an augmentation strategy. Those with concurrent drug abuse and recurrent major depressive disorder were less likely to accept a switch strategy. Conclusions: Few participants accepted all treatments. Acceptance of cognitive therapy was primarily associated with sociodemographic characteristics, while acceptance of a treatment switch was associated with the results of the initial treatment. C1 Univ Pittsburgh, Epidemiol Data Ctr, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX USA. Massachusetts Gen Hosp, Clin Psychopharmacol Unit, Boston, MA 02114 USA. Univ Pittsburgh, Dept Psychiat, Med Ctr, Pittsburgh, PA 15261 USA. NIMH, Bethesda, MD 20892 USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, New York, NY 10032 USA. VA Cooperat Studies Program, Palo Alto, CA USA. Stanford Univ, Dept Hlth Res & Policy, Stanford, CA 94305 USA. RP Wisniewski, SR (reprint author), Univ Pittsburgh, Epidemiol Data Ctr, Grad Sch Publ Hlth, 127 Parran Hall,130 DeSoto St, Pittsburgh, PA 15261 USA. RI Biggs, Dr. Melanie/C-1468-2010; McGrath, Patrick/I-6410-2013; OI McGrath, Patrick/0000-0001-7217-7321; Wisniewski, Stephen/0000-0002-3877-9860; Rush, Augustus/0000-0003-2004-2382 FU NIMH NIH HHS [N01 MH-90003] NR 23 TC 47 Z9 47 U1 1 U2 2 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 MAY PY 2007 VL 164 IS 5 BP 753 EP 760 DI 10.1176/appi.ajp.164.5.753 PG 8 WC Psychiatry SC Psychiatry GA 166HR UT WOS:000246370300015 PM 17475734 ER PT J AU Kakko, J Gronbladh, L Svanborg, KD von Wachenfeldt, J Ruck, C Rawlings, B Nilsson, LH Heilig, M AF Kakko, Johan Groenbladh, Leif Svanborg, Kerstin Dybrandt von Wachenfeldt, Joachim Rueck, Christian Rawlings, Bob Nilsson, Lars-Hakan Heilig, Markus TI A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: A randomized controlled trial SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID OPIOID DEPENDENCE; CONTINGENCY MANAGEMENT; RELAPSE PREVENTION; ADDICTION; OVERDOSE; RETENTION; MORTALITY; IMPACT; DEATH; MODEL AB Objective: Both methadone and buprenorphine are effective therapy for heroin dependence. Efficacy is best documented for methadone maintenance therapy, but safety concerns limit its use. Buprenorphine offers lower overdose risk and improved access, but efficacy may be lower. The authors compared adaptive, buprenorphine-based stepped care to optimal methadone maintenance treatment. Method: This randomized controlled trial was undertaken 2004-2006. It consisted of a 24-day uniform double-blind induction phase followed by single-blind flexible dosing based on structured clinical criteria, for a total of 6 months. Ninety-six self-referred subjects with heroin dependence were randomly assigned to methadone or to stepped treatment initiated with buprenorphine/naloxone and escalated to methadone if needed. All subjects received intensive behavioral treatment. Primary outcome was retention in treatment. Secondary outcomes were completer analyses of problem severity (Addiction Severity Index) and proportion of urine samples free of illicit drugs. Results: Overall, 6-month retention was 78%. Stepped treatment and methadone maintenance therapy outcomes were virtually identical. Among completers of stepped therapy, 46% remained on buprenorphine/naloxone. Proportion of urine samples free of illicit opiates increased over time and ultimately reached approximately 80% in both arms. Problem severity decreased significantly and uniformly in both arms. Conclusions: A stepped treatment of heroin dependence as described here appears equally efficacious compared to optimally delivered methadone maintenance therapy. Together with prior data on the advantageous safety of buprenorphine, this suggests that broad implementation of strategies using buprenorphine as first-line treatment should be considered. C1 NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. Karolinska Inst, Dept Clin Neurosci, Stockholm, Sweden. Uppsala Univ, Dept Neurosci, Uppsala, Sweden. RP Heilig, M (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, 10 Ctr Dr,10-1-5334, Bethesda, MD 20892 USA. EM markus.heilig@mail.nih.gov RI Ruck, Christian/J-4396-2012; OI Ruck, Christian/0000-0002-8742-0168; Heilig, Markus/0000-0003-2706-2482 NR 34 TC 96 Z9 98 U1 1 U2 9 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD MAY PY 2007 VL 164 IS 5 BP 797 EP 803 DI 10.1176/appi.ajp.164.5.797 PG 7 WC Psychiatry SC Psychiatry GA 166HR UT WOS:000246370300020 PM 17475739 ER PT J AU Avila, NA Dwyer, AJ Rabel, A Pinto, P Moss, J AF Avila, N. A. Dwyer, A. J. Rabel, A. Pinto, P. Moss, J. TI Nonfatty Renal Masses in Patients with Lymphangioleiomyomatosis (LAM): Diagnosis and Management SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Meeting Abstract C1 [Avila, N. A.; Dwyer, A. J.] NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. [Rabel, A.; Moss, J.] NHLBI, Pulm Crit Care Med Branch, Bethesda, MD 20892 USA. [Pinto, P.] NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. EM navila@nih.gov NR 0 TC 0 Z9 0 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 MAY PY 2007 VL 188 IS 5 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA V04XA UT WOS:000207089900532 ER PT J AU Gai, N Yao, L AF Gai, N. Yao, L. TI MRI Evaluation of Idiopathic Inflammatory Myopathy: Improved Fat-Muscle Separation Using A Modified Dual Flip Angle Dixon Technique SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Meeting Abstract C1 [Gai, N.; Yao, L.] NIH, Bethesda, MD 20892 USA. EM gaind@cc.nih.gov NR 0 TC 0 Z9 0 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 MAY PY 2007 VL 188 IS 5 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA V04XA UT WOS:000207089900011 ER PT J AU O'Kane, P Brill, A McAuliffe, M Shelkovoy, E Nayda, Y Shpak, V Markov, V McConnell, R Ephstein, O AF O'Kane, P. Brill, A. McAuliffe, M. Shelkovoy, E. Nayda, Y. Shpak, V Markov, V McConnell, R. Ephstein, O. TI Comparison of Thyroid Nodule Detectability Using 7.5 MHz and 10 MHz Ultrasound Systems: Results from the Ukrainian-American Study of Thyroid Cancer and Other Thyroid Diseases Following the Chernobyl Accident SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Meeting Abstract C1 [McConnell, R.] Columbia Univ, New York, NY 19107 USA. [McAuliffe, M.] NIH, Rockville, MD USA. [O'Kane, P.] Thomas Jefferson Univ, Philadelphia, PA USA. [Shelkovoy, E.; Nayda, Y.; Markov, V; Ephstein, O.] Ukraine Acad Med Sci, VP Komisarenko Inst Endocrinol & Metab, Kiev, Ukraine. [Brill, A.; Shpak, V] Vanderbilt Univ, Nashville, TN USA. EM patrick.okane@jefferson.edu NR 0 TC 0 Z9 0 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 MAY PY 2007 VL 188 IS 5 SU S PG 1 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA V04XA UT WOS:000207089900666 ER PT J AU Prasad, SR Surabhi, V Vibhute, P Fatterpekar, M Som, PM Choyke, PL Chintapalli, KN AF Prasad, S. R. Surabhi, V Vibhute, P. Fatterpekar, M. Som, P. M. Choyke, P. L. Chintapalli, K. N. TI Hypoxia and Cancer-Strange Bedfellows: A Genophenotype Update on the Role of Hypoxia in Carcinogenesis and Implications on Diagnosis and Management SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Meeting Abstract C1 [Fatterpekar, M.; Som, P. M.] Mt Sinai Med Ctr, New York, NY 10029 USA. [Choyke, P. L.] NIH, Bethesda, MD 20892 USA. [Prasad, S. R.; Surabhi, V; Vibhute, P.; Chintapalli, K. N.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX 78229 USA. EM prasads@uthscsa.edu NR 0 TC 0 Z9 0 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 MAY PY 2007 VL 188 IS 5 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA V04XA UT WOS:000207089900695 ER PT J AU Cheng, OH Curfman, B Abend, J Imperiale, M Major, E Mannon, RB AF Cheng, Orlena H. Curfman, B. Abend, J. Imperiale, M. Major, E. Mannon, Roslyn B. TI The molecular impact of BK polyomavirus infection on renal tubular epithelium. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT Annual American Transplant Congress CY MAY 05-09, 2007 CL San Francisco, CA C1 NIH, NIDDK, Bethesda, MD 20892 USA. NIH, NIDDK, Lab Mol Med & Neurosci, Bethesda, MD USA. Univ Michigan, Ann Arbor, MI 48109 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2007 VL 7 SU 2 MA 18 BP 151 EP 151 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 166HQ UT WOS:000246370200019 ER PT J AU Thuillier, R Mannon, RB AF Thuillier, Raphael Mannon, Roslyn B. TI Big mac uncovered: Macrophage induced epithelial-mesenchymal transformation (EMT) contributes to late kidney allograft failure. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT Annual American Transplant Congress CY MAY 05-09, 2007 CL San Francisco, CA C1 NIH, NIDDK, Transplantat Branch, Bethesda, MD 20892 USA. RI thuillier, raphael/P-5709-2016 OI thuillier, raphael/0000-0002-7482-0031 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 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2007 VL 7 SU 2 MA 32 BP 154 EP 155 PG 2 WC Surgery; Transplantation SC Surgery; Transplantation GA 166HQ UT WOS:000246370200033 ER PT J AU Cherikh, W Ring, M Kauffman, HM Burke, G Kaufman, D Knechtle, S Potdar, S Shapiro, R Kirk, A AF Cherikh, Wida Ring, Michael Kauffman, H. M. Burke, George Kaufman, Dixon Knechtle, Stuart Potdar, Santosh Shapiro, Ron Kirk, Allan TI Updated analysis of dissociation of depletion and PTLD in kidney recipients treated with alemzutumab induction therapy. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT Annual American Transplant Congress CY MAY 05-09, 2007 CL San Francisco, CA C1 UNOS, Richmond, VA USA. NIH, NIDDK, Transplantat Branch, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2007 VL 7 SU 2 MA 332 BP 233 EP 233 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 166HQ UT WOS:000246370200333 ER PT J AU Gorbach, A Wang, H Alemozaffar, M Gage, F Dhanani, N Smith, P Liu, J Pinto, P Kirk, A Tadaki, D Elster, E AF Gorbach, A. Wang, H. Alemozaffar, M. Gage, F. Dhanani, N. Smith, P. Liu, J. Pinto, P. Kirk, A. Tadaki, D. Elster, E. TI Intraoperative imaging of global and focal perfusion deficit in the kidney. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT Annual American Transplant Congress CY MAY 05-09, 2007 CL San Francisco, CA C1 NIH, NIBIB, Bethesda, MD 20892 USA. NMRC, Silver Spring, MD USA. NCI, Bethesda, MD 20892 USA. NIH, NIDDK, 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 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2007 VL 7 SU 2 MA 406 BP 252 EP 252 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 166HQ UT WOS:000246370200406 ER PT J AU Cheng, OH Kampen, RL Kleiner, DE Kirk, AD Mannon, RB AF Cheng, Orlena H. Kampen, Robert L. Kleiner, David E. Kirk, Allan D. Mannon, Roslyn B. TI Gloms away! The molecular signature of transplant glomerulopathy (TG). SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT Annual American Transplant Congress CY MAY 05-09, 2007 CL San Francisco, CA C1 NIH, NIDDK, Transplantat Branch, Bethesda, MD 20892 USA. NIH, NCI, Pathol Lab, Bethesda, MD 20892 USA. RI Kirk, Allan/B-6905-2012 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 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2007 VL 7 SU 2 MA 431 BP 259 EP 259 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 166HQ UT WOS:000246370200431 ER PT J AU Xu, BY Ford, E Crawford, S Kampen, R Kirk, AD AF Xu, Biying Ford, Elizabeth Crawford, Sean Kampen, Robert Kirk, Allan D. TI Soluble CD154 (sCD154) in renal transplantation. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT Annual American Transplant Congress CY MAY 05-09, 2007 CL San Francisco, CA C1 NIH, NIDDK, Transplantat Branch, Bethesda, MD 20892 USA. RI Kirk, Allan/B-6905-2012 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 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2007 VL 7 SU 2 MA 742 BP 339 EP 339 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 166HQ UT WOS:000246370201178 ER PT J AU Chamberlain, CE Peretti, J Cropper, T Hale, L Kirk, AD Mannon, RB AF Chamberlain, Christine E. Peretti, Julie Cropper, Tracy Hale, Liz Kirk, Allan D. Mannon, Roslyn B. TI Is it all for the better? Clarifying the impact of cinacalcet in post kidney transplant hyperparathyroidism. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT Annual American Transplant Congress CY MAY 05-09, 2007 CL San Francisco, CA C1 NIH, Clin Ctr Pharm Dept, Bethesda, MD 20892 USA. NIH, Clin Ctr Nursing Dept, Bethesda, MD 20892 USA. NIH, NIDDK, Transplantat Branch, Bethesda, MD 20892 USA. RI Kirk, Allan/B-6905-2012 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 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2007 VL 7 SU 2 MA 830 BP 362 EP 362 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 166HQ UT WOS:000246370201266 ER PT J AU Hanna, B Agrawal, S Gorbach, A Wang, H Smith, P Tadaki, D Gage, F Elster, E AF Hanna, B. Agrawal, S. Gorbach, A. Wang, H. Smith, P. Tadaki, D. Gage, F. Elster, E. TI Real-time intraoperative assessment of critical structures using visible-range/infrared image fusion. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT Annual American Transplant Congress CY MAY 05-09, 2007 CL San Francisco, CA C1 Sarnoff Corp, Princeton, NJ USA. NIBIB, NIH, Bethesda, MD USA. NMRC, Silver Spring, MD 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 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2007 VL 7 SU 2 MA 1121 BP 435 EP 435 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 166HQ UT WOS:000246370201557 ER PT J AU Girlanda, R Ford, E Ring, M Salcedo, E Wright, E Kleiner, D Mannon, R Kirk, A AF Girlanda, Raffaele Ford, Elizabeth Ring, Michael Salcedo, Edgardo Wright, Elizabeth Kleiner, David Mannon, Roslyn Kirk, Allan TI The ultrasound resistive index is a function of systemic hemodynamics, not intragraft pathology. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT Annual American Transplant Congress CY MAY 05-09, 2007 CL San Francisco, CA C1 NIDDK, Transplantat Branch, NIH, Bethesda, MD USA. NIDDK, Off Director, NIH, Bethesda, MD USA. NCI, Pathol Lab, NIH, 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 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2007 VL 7 SU 2 MA 1494 BP 532 EP 532 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 166HQ UT WOS:000246370202359 ER PT J AU Bohl, DL Storch, GA Gaudreault-Keener, M Ryschkewitsch, C Major, EO Brennan, DC AF Bohl, Daniel L. Storch, Gregory A. Gaudreault-Keener, Monique Ryschkewitsch, Caroline Major, Eugene O. Brennan, Daniel C. TI JC virus in kidney transplantation and relationship to BK virus. SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Meeting Abstract CT Annual American Transplant Congress CY MAY 05-09, 2007 CL San Francisco, CA C1 Washington Univ, Sch Med, St Louis, MO USA. St Louis Childrens Hosp, St Louis, MO 63178 USA. NINDS, Lab Mol Med & Neurosci, 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 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAY PY 2007 VL 7 SU 2 MA 1520 BP 538 EP 538 PG 1 WC Surgery; Transplantation SC Surgery; Transplantation GA 166HQ UT WOS:000246370202385 ER PT J AU Takala, SL Smith, DL Thera, MA Coulibaly, D Doumbo, OK Plowe, CV AF Takala, Shannon L. Smith, David L. Thera, Mahamadou A. Coulibaly, Drissa Doumbo, Ogobara K. Plowe, Christopher V. TI Short report: Rare Plasmodium falciparum merozoite surface protein 1 19-kDa (MSP-1(19)) haplotypes identified in mali using high-throughput genotyping methods SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID MALARIA VACCINE ANTIGEN; C-TERMINAL FRAGMENT; IN-FIELD SAMPLES; SEQUENCE DIVERSITY; LINKAGE DISEQUILIBRIUM; PARASITE POPULATIONS; SERUM ANTIBODIES; RICH REGION; POLYMORPHISM; GENE AB Genetic diversity in malaria vaccine antigens may compromise malaria vaccine efficacy, so it is important to understand this diversity and the processes that generate it. By applying new high-throughput genotyping methods to a large sample of infections from Mali (N = 1369), seven new 19-kDa merozoite surface protein 1 (MSP-1(19)) haplotypes were identified. Herein we report the sequences of these new haplotypes and discuss their possible origins. Although they are present in < 1% of the samples examined, the existence of these rare haplotypes reveals a greater degree of diversity at this locus than previously reported and highlights the potential for Plasmodium to evolve under selective pressure from the immune system and from such interventions as vaccines and drugs. C1 Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. Univ Bamako, Malaria Res & Training Ctr, Bamako, Mali. RP Plowe, CV (reprint author), Univ Maryland, Sch Med, Ctr Vaccine Dev, Baltimore, MD 21201 USA. EM cplowe@medicine.umaryland.edu RI Smith, David/L-8850-2013 OI Smith, David/0000-0003-4367-3849 FU NIAID NIH HHS [N01AI85346, U19 AI065683, U19 AI065683-02] NR 34 TC 5 Z9 5 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD MAY PY 2007 VL 76 IS 5 BP 855 EP 859 PG 5 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 165SR UT WOS:000246326300014 PM 17488904 ER PT J AU Dodd, LE Korn, EL AF Dodd, Lori E. Korn, Edward L. TI The bootstrap variance of the square of a sample mean SO AMERICAN STATISTICIAN LA English DT Article DE bootstrap failure; double bootstrap; microarray; resampling AB A motivating microarray analysis leads to examining the bootstrap variance estimator of the square of a sample mean of independent and identically distributed observations. This variance is approximately three times too large when the true mean is zero, even when the observations are normally distributed and the sample size is large. A double bootstrap variance estimator as well as other suggested modifications to the bootstrap for this problem are examined. C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Dodd, LE (reprint author), NCI, Biometr Res Branch, EPN 8140, Bethesda, MD 20892 USA. EM doddl@mail.nih.gov; korne@ctep.nci.nih.gov NR 21 TC 2 Z9 2 U1 1 U2 2 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 1429 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0003-1305 J9 AM STAT JI Am. Stat. PD MAY PY 2007 VL 61 IS 2 BP 127 EP 131 DI 10.1198/000313007X1877-58 PG 5 WC Statistics & Probability SC Mathematics GA 158AD UT WOS:000245762200004 ER PT J AU Grady, C AF Grady, Christine TI Quality improvement and ethical oversight SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID HEALTH-SERVICES RESEARCH; CHALLENGES; PROJECT; PROGRAM; IMPACT; IRB C1 NIH, Dept Clin Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Grady, C (reprint author), NIH, Dept Clin Bioeth, Ctr Clin, Bldg 10-1C118, Bethesda, MD 20892 USA. NR 18 TC 16 Z9 16 U1 1 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD MAY 1 PY 2007 VL 146 IS 9 BP 680 EP 681 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 162EV UT WOS:000246070500009 PM 17438309 ER PT J AU Dalakas, MC Rakocevic, G Shatunov, A Goldfarb, L Raju, R Salajegheh, M AF Dalakas, Marinos C. Rakocevic, Goran Shatunov, Alexey Goldfarb, Lev Raju, Raghavan Salajegheh, Mohammad TI Inclusion body myositis with human immunodeficiency virus infection: Four cases with clonal expansion of viral-specific T cells SO ANNALS OF NEUROLOGY LA English DT Article ID INFLAMMATORY MYOPATHIES; INFILTRATING LYMPHOCYTES; COSTIMULATORY MOLECULE; MUSCLE BIOPSIES; AMYLOID-BETA; POLYMYOSITIS; EXPRESSION; CHEMOKINES; PROTEINS; PATHOGENESIS AB Objective: Sporadic inclusion body myositis (sIBM), a common adult-onset myositis, is characterized by an antigen-driven inflammatory response and vacuolar degeneration. The cause is unknown. We report the association of sIBM with human immunodeficiency virus (HIV) infection and explore the clonality and viral specificity of the autoinvasive T cells. Methods: Clinicopathological studies in four HIV-infected patients with IBM were performed. The clonal restriction of endomysial T cells, compared with peripheral blood, was examined by spectratyping. Immunohistochemical studies using human leukocyte antigen-A* 0201-gag tetramers and the most dominant Vb families were performed in serial muscle biopsy sections to examine whether clonally expanded autoinvasive T cells are viral specific and invade muscle fibers expressing the allele-specific monomorphic major histocompatibility complex class I antigen. Results: Prominent clonal restriction of certain Vb families was noted among the endomysial T cells with evidence of in situ expansion. Approximately 10% of the autoinvasive CD8(+) cells were human leukocyte antigen-A* 0201-HIV-gag specific and invaded muscle fibers expressing the specific human leukocyte antigen-A* 0201 allele. These cells belonged to restricted Vb families. The HIV gag antigen was present on several endomysial macrophages but not within the muscle fibers. Interpretation: sIBM develops in patients who harbor HIV. In HIV-IBM, a subset of CD8(+) T cells surrounding muscle fibers are viral specific and may play a role in the disease mechanism by cross-reacting with antigens on the surface of muscle fibers. This study provides a paradigm that a chronic viral infection in genetically susceptible individuals can trigger viral specific T cell clones that persist within the muscle and lead to development of sIBM. C1 NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, NIH, Bldg 10,Room 4N248,10 Ctr Dr,MSC 1382, Bethesda, MD 20892 USA. EM dalakasm@ninds.nih.gov RI Shatunov, Aleksey/E-6946-2011; Raju, Raghavan/E-9219-2011 FU Intramural NIH HHS NR 40 TC 29 Z9 29 U1 0 U2 0 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 MAY PY 2007 VL 61 IS 5 BP 466 EP 475 DI 10.1002/ana.21103 PG 10 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 175CX UT WOS:000246991300014 PM 17366634 ER PT J AU Lunemann, JD Schmidt, J Schmid, D Barthel, K Wrede, A Dalakas, MC Munz, C AF Lunemann, Jan D. Schmidt, Jens Schmid, Dorothee Barthel, Konstanze Wrede, Arne Dalakas, Marinos C. Munz, Christian TI beta-amyloid is a substrate of autophagy in sporadic inclusion body myositis SO ANNALS OF NEUROLOGY LA English DT Article ID PROTEASOME INHIBITION; DISEASE; MUSCLE; MICE; DYSFUNCTION; ANTIGEN; MARKER; LC3 AB Objective: Sporadic Inclusion Body Myositis (sIBM) is the most common acquired muscle disease in patients above 50 years of age. Apart from inflammation in the skeletal muscle, overexpression of amyloid precursor protein (APP) and intracellular accumulation of its proteolytic fragment fi-amyloid play a central role in the pathogenesis of sIBM. In neurodegenerative disorders, similar aggregations of aberrant proteins have recently been shown to be susceptible to autophagic degradation. Therefore, we analyzed macroautophagy of APP in human muscle cell lines and sIBM muscle biopsies. Methods: Colocalization of APP with the essential autophagy protein Atg8/LC3, which associates with preautophagosomal and autophagosomal membranes via lipidation, was analyzed in the CCL-136 muscle cell line and muscle biopsies by immunofluorescence. While APP was visualized with specific antibodies in the muscle cell line and in tissue sections. Atg8/LC3 localization was analyzed after GFP-Atg8/LC3 transfection or with an Atg8/LC3 specific antiserum, respectively. Results: We demonstrate here that Atg8/LC3 colocalizes with APP in cultured human muscle cells. In addition, APP/beta-amyloid-containing autophagosomes can be observed at increased frequency in muscle fibers of sIBM muscle biopsies, but not in non-myopathic muscle or non-vacuolated myopathic controls. APP/beta-amyloid and Ata8/LC3 double-positive compartments were almost exclusively observed in degenerating muscle fibers of the type II (fast-twitching) and were in part associated with overexpression of major histocompatibility complex (MHC) class I and II on myofibers and invasion by CD4(+) and CD8(+) cells. Interpretation: These findings indicate that APP/beta-amyloid is targeted for lysosomal degradation via macroautophagy and suggest that the autophagy pathway should be explored for its potential therapeutic merit in sIBM. C1 Rockefeller Univ, Christopher H Browne Ctr Immunol & Immune Dis, Lab Viral Immunobiol, New York, NY 10021 USA. Univ Gottingen, Dept Neuroimmunol, Muscle Immunobiol Grp, D-3400 Gottingen, Germany. Univ Gottingen, Dept Neurol, Muscle Immunobiol Grp, D-3400 Gottingen, Germany. Univ Gottingen, Inst Neuropathol, D-3400 Gottingen, Germany. NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. RP Munz, C (reprint author), Rockefeller Univ, Christopher H Browne Ctr Immunol & Immune Dis, Lab Viral Immunobiol, Box 390,1230 York Ave, New York, NY 10021 USA. EM munzc@rockefeller.edu RI Schmidt, Jens/B-5791-2013; Lunemann, Jan/G-8729-2011 OI Lunemann, Jan/0000-0002-3007-708X FU NCI NIH HHS [R01CA101741, R01CA108609]; NCRR NIH HHS [1UL1RR024143, U54RR023419]; PHS HHS [DAIDS-BAA-06-19] NR 20 TC 72 Z9 76 U1 0 U2 4 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 MAY PY 2007 VL 61 IS 5 BP 476 EP 483 DI 10.1002/ana.21115 PG 8 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 175CX UT WOS:000246991300015 PM 17469125 ER PT J AU Pena, MT Aujla, PK Zudaire, E Watson, AM Przygodzki, R Zalzal, GH Rose, MC AF Pena, Maria T. Aujla, Pawandeep K. Zudaire, Enrique Watson, Alan M. Przygodzki, Ronald Zalzal, George H. Rose, Mary C. TI Localization and expression pediatric of MUC5B and MUC7 mucins in sintis mucosa SO ANNALS OF OTOLOGY RHINOLOGY AND LARYNGOLOGY LA English DT Article DE chronic rhinosinusitis; goblet cell; MUC5B; MUC7; mucin; submucosal gland ID HUMAN RESPIRATORY-TRACT; CHRONIC RHINOSINUSITIS; SUBMUCOSAL GLANDS; CHRONIC SINUSITIS; UP-REGULATION; GENES; AIRWAYS; CHILDREN; DISEASES; CLONING AB Objectives: The purpose of this study was to analyze the secretory cell population and distribution of MUC5B and MUC7 mucins in the sinus mucosa of pediatric patients with and without chronic rhinosinusitis (CRS). Methods: Sinus mucosal specimens were collected at surgery in a pediatric tertiary care facility. Histologic, immunohistochemical, and morphometric analyses were performed on sinus mucosa of 20 children with CRS and 7 children without CRS. Results: A significant increase in the area of submucosal glands was evident in the sinus mucosa of children with CRS as compared to controls. MUC5B and MUC7 mucins were expressed in the submucosal glands, as well as in goblet cells, in the sinus mucosa of both populations. No differences in MUC5B or MUC7 expression were observed when mucin expression was normalized to glandular area. Conclusions: Children with CRS have an increased number of submucosal glands, indicating that glandular mucins contribute to mucus overproduction in CRS. MUC5B and MUC7 mucins, which have previously been considered only glandular mucins, are also expressed in goblet cells in the sinus mucosa. C1 Childrens Natl Med Ctr, Dept Otolaryngol, Washington, DC 20010 USA. Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA. Childrens Natl Med Ctr, Dept Anat Pathol, Washington, DC 20010 USA. NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. RP Pena, MT (reprint author), Childrens Natl Med Ctr, Dept Otolaryngol, 111 Michigan Ave NW, Washington, DC 20010 USA. NR 40 TC 8 Z9 8 U1 0 U2 1 PU ANNALS PUBL CO PI ST LOUIS PA 4507 LACLEDE AVE, ST LOUIS, MO 63108 USA SN 0003-4894 J9 ANN OTO RHINOL LARYN JI Ann. Otol. Rhinol. Laryngol. PD MAY PY 2007 VL 116 IS 5 BP 389 EP 397 PG 9 WC Otorhinolaryngology SC Otorhinolaryngology GA 168QM UT WOS:000246539100013 ER PT J AU Lee, W Reveille, JD Davis, JC Learch, TJ Ward, MM Weisman, MH AF Lee, Wonuk Reveille, John D. Davis, John C., Jr. Learch, Thomas J. Ward, Michael M. Weisman, Michael H. TI Are there gender differences in severity of ankylosing spondylitis? Results from the PSOAS cohort SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID FUNCTIONAL INDEX; RHEUMATOID-ARTHRITIS; CLINICAL-FEATURES; DISEASE-ACTIVITY; WOMEN; MEN; ONSET; SPONDYLOARTHROPATHIES; SUSCEPTIBILITY; DISABILITY AB Objective: To examine the clinical and radiographic features in men and women in the Prospective Study of Outcomes in Ankylosing Spondylitis cohort, a large well-defined cross-sectional study of patients with AS, in order to understand the influence of gender in determining the severity of ankylosing spondylitis. Methods: Extensive clinical assessments and spine radiographs were performed in 302 men and 100 women with AS of >= 20 years duration. Radiographs were scored using the Bath Ankylosing Spondylitis Radiographic Index Spine (BASRI-spine) score ( range 2-12). Functional impairment was measured by the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Health Assessment Questionnaire for the Spondyloarthropathies (HAQ-S). Results: Radiographic severity was worse among men. The unadjusted median BASRI-spine score for men was 10, compared with 6.5 for women (p<0.001). Functional disability, as measured by the BASFI and HAQ-S, was not different between men and women. However, after adjusting for radiographic spinal damage, women were found to report worse functioning than men at any given level of radiographic damage. Women had a slightly earlier age of disease onset; however, disease duration was identical in both groups. Women more frequently reported family histories of AS in first-degree relatives and were more likely to be treated with intra-articular steroids, sulphasalazine and prednisone. Conclusions: Among patients with longstanding AS, men have more severe radiographic changes; findings of treatment differences suggest that women may have more peripheral arthritis. At any given level of radiographic damage, self-reported functional limitations were worse for women. C1 Cedars Sinai Med Ctr, Div Rheumatol, Los Angeles, CA 90048 USA. Univ Texas, Hlth Sci Ctr, Div Rheumatol & Clin Immunogenet, Houston, TX USA. Univ Calif San Francisco, Div Rheumatol, San Francisco, CA 94143 USA. Univ So Calif, Keck Sch Med, Dept Radiol, Los Angeles, CA USA. NIAMSD, NIH, Bethesda, MD 20892 USA. RP Weisman, MH (reprint author), Cedars Sinai Med Ctr, Div Rheumatol, 8700 Beverly Blvd,B-131, Los Angeles, CA 90048 USA. EM weisman@cshs.org NR 40 TC 85 Z9 89 U1 0 U2 3 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 MAY 1 PY 2007 VL 66 IS 5 BP 633 EP 638 DI 10.1136/ard.2006.060293 PG 6 WC Rheumatology SC Rheumatology GA 161LZ UT WOS:000246018000010 PM 17127685 ER PT J AU Fryar-Tita, EB Das, JR Davis, JH Desoto, JA Green, S Southerland, WM Bowen, D AF Fryar-Tita, Elizabeth B. Das, Jharna R. Davis, J. H. Desoto, J. A. Green, Sidney Southerland, William M. Bowen, Donnell TI Raloxifene and selective cell cycle specific agents: A case for the inclusion of raloxifene in current breast cancer treatment therapies SO ANTICANCER RESEARCH LA English DT Article DE selective estrogen receptor modulator; raloxifene; trimetrexate; 5-fluorouracil; breast cancer; osteoporosis ID HUMAN BONE-MARROW; POSTMENOPAUSAL WOMEN; METHOTREXATE CYTOTOXICITY; RANDOMIZED-TRIAL; SEQUENCE; 5-FU/METHOTREXATE; OSTEOPOROSIS; ATTENUATION; RISK AB Background: Breast cancer patients are at increased risk of osteoporosis. Contributing factors include age and/or chemotherapy. The selective estrogen modulator, raloxifene (RAL), effective in the prevention of breast cancer and approved for the treatment and prevention of osteoporosis, may prove beneficial in current breast cancer treatment modules. The purpose of this study was to evaluate RAL in combination with 5-fluorouracil (5-FU) and trimetrexate (TMX) to determine the most effective sequence in which to administer these cell cycle specific agents while taking into consideration the cellular mechanism of action. The goal was to maintain cytotoxicity to breast cancer cells and capitalize on the selective estrogen receptor modulatory effects of RAL. Materials and Methods: MCF-7 cells were exposed to (i) TM)(, 5-FU or RAL alone, or (ii) RAL 24 It prior to 5-FU followed 2 It later by TMX, or (iii) 5-FU 2 h prior to TMX followed 24 h later by RAL. The cell viability was determined using the Quick Cell Proliferation Assay. Results: The growth rate of MCF-7 cells exposed to early RAL was 68.25 +/- 4.11% that of the control, however, late RAL exposure produced a growth of 34.75 +/- 4.79% that of the control. Late RAL maintained the cytotoxicity of the regimen. The findings were further supported by cell flow cytometry and Western blot analysis data. Conclusion: RAL given prior to 5-FU/TMX significantly compromised cytotoxicity to breast cancer cells. C1 Howard Univ, Coll Med, Dept Biochem, Washington, DC 20059 USA. Howard Univ, Coll Med, Dept Pharmacol, Washington, DC 20059 USA. Univ N Carolina, Dept Environm Sci & Engn, Chapel Hill, NC 27515 USA. Hampton Univ, Sch Pharm, Hampton, VA 23668 USA. NIDDK, NIH, Bethesda, MD USA. RP Southerland, WM (reprint author), Howard Univ, Coll Med, Dept Biochem, Suite 3430,Adams Bldg,520 W St NW, Washington, DC 20059 USA. EM wsoutherland@howard.edu FU NCRR NIH HHS [G12RR003048-18] NR 16 TC 1 Z9 1 U1 0 U2 0 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD MAY-JUN PY 2007 VL 27 IS 3B BP 1393 EP 1399 PG 7 WC Oncology SC Oncology GA 170GL UT WOS:000246650700002 PM 17595753 ER PT J AU Chen, XC Yu, B Dong, JC Gu, YX Chen, L Wu, QZ Hou, NP Liu, JX Xu, JT Jin, RX Jin, GQ Yang, XD Cao, YW Tan, JJ Zhu, B Shen, JC Xu, Z Varticovski, L Wang, XW AF Chen, Xian-Cheng Yu, Bo Dong, Jing-Cheng Gu, Yu-Xiang Chen, Lei Wu, Qing-Zhen Hou, Nan-Ping Liu, Jun-Xiong Xu, Jia-Ting Jin, Rui-Xie Jin, Guan-Qiu Yang, Xue-Dong Cao, Yong-Wei Tan, Jia-Ju Zhu, Bin Shen, Jia-Chuan Xu, Zheng Varticovski, Lyuba Wang, Xin Wei TI A phase II clinical trial with cytotropic heterogeneous molecular lipids (CHML((R))) for patients with hepatic malignancies SO ANTICANCER RESEARCH LA English DT Article DE biological anticancer agent; cytotropic heterogeneous; molecular lipids (CHML) hepatocellular carcinoma; liver metastasis ID SMALL HEPATOCELLULAR-CARCINOMA; CELL-DEATH; APOPTOSIS; CANCER; HEPATECTOMY; METASTASES; EXPERIENCE; GADD45 AB Hepatocellular carcinoma (HCC) and other forms of metastatic liver cancer (MLC) have poor outcomes due to the limited treatment options. Surgery, radiotherapy and chemotherapy have a limited success. Thus, there is an urgent need for novel therapies for patients with advanced HCC and MLC. The response and toxicity profile of a novel biological anticancer agent, cytotropic heterogeneous molecular lipids (CHML), in 135 Asian patients with hepatic malignancies treated at five different hospitals in China from April 1998 to August 2003 is described. This trial included 97 patients with HCC and 38 with MLC. The majority of these patients had received conventional therapies and many had failed to respond or relapsed. CHML was administered by intra-arterial (i. a.) infusion with or without simultaneous intravenous (i. v.) infusion for 25 days with a rest of 2-4 weeks between each cycle. Fifty three percent of patients received two cycles, and 47% received three cycles. The complete response (CR) rates were 23% for HCC and 29% for MLC with an overall CR of 24%. The overall partial response (PR) was 53%. The patients with earlier stages and limited tumor burden had a better response, but a few patients with advanced disease also achieved PR. The patients who achieved CR or PR had a significant increase in long-term survival for up to five years. The treatment with CHML resulted in minimal toxicity and the reported adverse reactions were not higher than grade II. CHML is an effective therapy for hepatic malignancies, showing responses and increases in survival in patients in whom other therapies have failed. CHML is well tolerated and is an excellent candidate for Phase III clinical trials. C1 NCI, Liver Carcinogenesis Sect, Lab Human Carcinogenesis, Canc Res Ctr, Bethesda, MD 20892 USA. Fudan Univ, Huashan Hosp, Shanghai 200040, Peoples R China. Second Med Univ, Rujing Hosp, Shanghai 200025, Peoples R China. Navy 421 Hosp, Guangzhou 510318, Guangdong, Peoples R China. Navy 411 Hosp, Shanghai 200081, Peoples R China. Foshan Hosp, Foshan 52800, Peoples R China. Glory F&D Co Ltd, Vienna, VA 22180 USA. RP Wang, XW (reprint author), NCI, Liver Carcinogenesis Sect, Lab Human Carcinogenesis, Canc Res Ctr, Bethesda, MD 20892 USA. EM xcchen@hsh.stn.sh.cn; xw3u@nih.gov RI Wang, Xin/B-6162-2009 FU Intramural NIH HHS NR 26 TC 0 Z9 0 U1 0 U2 4 PU INT INST ANTICANCER RESEARCH PI ATHENS PA EDITORIAL OFFICE 1ST KM KAPANDRITIOU-KALAMOU RD KAPANDRITI, PO BOX 22, ATHENS 19014, GREECE SN 0250-7005 J9 ANTICANCER RES JI Anticancer Res. PD MAY-JUN PY 2007 VL 27 IS 3B BP 1593 EP 1600 PG 8 WC Oncology SC Oncology GA 170GL UT WOS:000246650700030 PM 17595781 ER PT J AU Okusanya, O Forrest, A DiFrancesco, R Bilic, S Rosenkranz, S Para, MF Adams, E Yarasheski, KE Reichman, RC Morse, GD AF Okusanya, Olanrewaju Forrest, Alan DiFrancesco, Robin Bilic, Sanela Rosenkranz, Susan Para, Michael F. Adams, Elizabeth Yarasheski, Kevin E. Reichman, Richard C. Morse, Gene D. CA ACTG 5043 Protocol Team TI Compartmental pharmacokinetic analysis of oral amprenavir with secondary peaks SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID PROTEASE INHIBITOR AMPRENAVIR; DRUG-INTERACTIONS; FOSAMPRENAVIR; RITONAVIR; PLASMA; PRODRUG; IMPACT; SAFETY; MODEL AB Amprenavir is a protease inhibitor that has been shown to have secondary peaks postulated to be due to enterohepatic recycling. We propose a model to describe the pharmacokinetics of amprenavir which accommodates the secondary peak(s). A total of 82 healthy human immunodeficiency virus (HM-seronegative subjects were administered a single 600-mg dose of amprenavir as part of adult AIDS Clinical Trials Group protocol A5043. Serial blood samples were obtained over 24 It. Samples were analyzed for amprenavir and fit to a compartmental model using ADAPT II software, with all relevant parameters conditional with respect to bioavailability. The model accommodated secondary peaks by incorporating clearance out of the central compartment with delayed instantaneous release back into the gut compartment. The data were weighted by the inverse of the estimated measurement error variance; model discrimination was determined using Akaike's Information Criteria. A total of 76 subjects were evaluable in the study analysis. The data were best fit by a two-compartment model, with 98.7% of the subjects demonstrating a secondary peak. Amprenavir had a mean total clearance of 1.163 liters/h/kg of body weight (0.7), a central volume of distribution of 1.208 liters/kg (0.8), a peripheral volume of distribution of 8.2 liters/kg (0.81), and distributional clearance of 0.04 liters/h/kg (0.81). The time to the secondary peak was 7.86 It (0.17), and clearance into a recycling compartment was 0.111 liters/kg/h (0.74). Amprenavir pharmacokinetics has been well described using a two-compartment model with clearance to a recycling compartment and release back into the gut. The nature of the secondary peaks may be an important consideration for the interpretation of amprenavir plasma concentrations during therapeutic drug monitoring. C1 SUNY Buffalo, Sch Pharm, Buffalo, NY 14260 USA. Harvard Univ, Boston, MA 02115 USA. Ohio State Univ, Columbus, OH 43210 USA. NIAID, Div AIDS, Bethesda, MD 20892 USA. Washington Univ, St Louis, MO 63130 USA. Univ Rochester, Rochester, NY 14627 USA. RP Morse, GD (reprint author), SUNY Buffalo, Sch Pharm & Pharmaceut Sci, Dept Pharm Practice, 317 Hochstetter Hall, Buffalo, NY 14260 USA. EM emorse@buffalo.edu RI Yarasheski, Kevin/A-3025-2008; OI Yarasheski, Kevin/0000-0001-5436-2451 FU NCRR NIH HHS [M01 RR000034, M01 RR00034, M01 RR00036, M01 RR00037, M01 RR00044, M01 RR00051, M01 RR00052, M01 RR00070, M01 RR00750]; NIAID NIH HHS [U01 AI38858, U01 AI025859, U01 AI25859, U01 AI25903, U01 AI25924, U01 AI27658, U01 AI27664, U01 AI27666, U01 AI27668, U01 AI32770, U01 AI38855]; NIDDK NIH HHS [R01 DK049393, R01 DK049393-09A1, R01 DK059531, R01 DK059531-01, R01 DK059531-02, R01 DK059531-03, R01 DK059531-04, R01 DK059531-05] NR 24 TC 14 Z9 15 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD MAY PY 2007 VL 51 IS 5 BP 1822 EP 1826 DI 10.1128/AAC.00570-06 PG 5 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 168RK UT WOS:000246541500033 PM 17283195 ER PT J AU Dhungana, S Anthony, CR Hersman, LE AF Dhungana, Suraj Anthony, Charles R., III Hersman, Larry E. TI Effect of exogenous reductant on growth and iron mobilization from ferrihydrite by the Pseudomonas mendocina ymp strain SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID GOETHITE DISSOLUTION; SIDEROPHORES; OXALATE; ACQUISITION; SOLUBILITY; KINETICS AB Growth of the Pseudomonas mendocina ymp strain on insoluble ferrihydrite is enhanced by exogenous reductants with concurrent increase in soluble iron concentrations. This shows that exogenous reductants play a substantial role in the overall microbial iron bioavailability. The exogenous reductants may work together with the siderophores, Fe-scavenging agents, to facilitate ferrihydrite dissolution. C1 Los Alamos Natl Lab, Biosci Div, Los Alamos, NM 87544 USA. RP Dhungana, S (reprint author), NIEHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM dhunganas@niehs.nih.gov NR 17 TC 15 Z9 15 U1 1 U2 6 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 MAY PY 2007 VL 73 IS 10 BP 3428 EP 3430 DI 10.1128/AEM.02586-06 PG 3 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 170RA UT WOS:000246680500036 PM 17384310 ER PT J AU Merikangas, KR Akiskal, HS Angst, J Greenberg, PE Hirschfeld, RMA Petukhova, M Kessler, RC AF Merikangas, Kathleen R. Akiskal, Hagop S. Angst, Jules Greenberg, Paul E. Hirschfeld, Robert M. A. Petukhova, Maria Kessler, Ronald C. TI Lifetime and 12-month prevalence of bipolar spectrum disorder in the national comorbidity survey replication SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID WORLD-HEALTH-ORGANIZATION; NCS-R; EPIDEMIOLOGIC SURVEY; GENERAL-POPULATION; MAJOR DEPRESSION; MENTAL-DISORDERS; RATING-SCALE; II-DISORDER; BURDEN; DISABILITY AB Context: There is growing recognition that bipolar disorder (BPD) has a spectrum of expression that is substantially more common than the 1% BP-I prevalence traditionally found in population surveys. Objective: To estimate the prevalence, correlates, and treatment patterns of bipolar spectrum disorder in the US population. Design: Direct interviews. Setting: Households in the continental United States. Participants: A nationally representative sample of 9282 English-speaking adults (aged >= 18 years). Main Outcome Measures: Version 3.0 of the World Health Organization's Composite International Diagnostic interview, a fully structured lay-administered diagnostic interview, was used to assess DSM-1V lifetime and 12-month Axis I disorders. Subthreshold BPD was defined as recurrent hypomania without a major depressive episode or with fewer symptoms than required for threshold hypomania. Indicators of clinical severity included age at onset, chronicity, symptom severity, role impairment, comorbidity, and treatment. Results: Lifetime (and 12-month) prevalence estimates are 1.0% (0.6%) for BP-I, 1.1% (0.8%) for BP-II, and 2.4% (1.4%) for subthreshold BPD. Most respondents with threshold and subthreshold BPD had lifetime comorbidity with other Axis I disorders, particularly anxiety disorders. Clinical severity and role impairment are greater for threshold than for subthreshold BPD and for BP-II than for BP-I episodes of major depression, but subthreshold cases still have moderate to severe clinical severity and role impairment. Although most people with BPD receive lifetime professional treatment for emotional problems, use of antimanic medication is uncommon, especially in general medical settings. Conclusions: This study presents the first prevalence estimates of the BPD spectrum in a probability sample of the United States. Subthreshold BPD is common, clinically significant, and underdetected in treatment settings. Inappropriate treatment of BPD is a serious problem in the US population. Explicit criteria are needed to define subthreshold BPD for future clinical and research purposes. C1 NIMH, Intramural Res Program, Sect Dev Genet Epidemiol, Bethesda, MD 20892 USA. Univ Calif San Diego, Int Mood Ctr, San Diego, CA 92103 USA. VA Psychiat Serv, San Diego, CA USA. Univ Zurich, Hosp Psychiat, Zurich, Switzerland. Anal Grp, Boston, MA USA. Univ Texas, Med Branch, Dept Psychiat & Behav Sci, Galveston, TX 77550 USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. RP Merikangas, KR (reprint author), NIMH, Intramural Res Program, Sect Dev Genet Epidemiol, 35 Convent Dr,MSC 3720, Bethesda, MD 20892 USA. EM kathleen.merikangas@nih.gov FU NIDA NIH HHS [R01 DA016558, R01 DA016558-04]; NIMH NIH HHS [U01 MH060220-06A1, R01 MH069864, R01 MH069864-03, R13 MH066849, R13 MH066849-04, U01 MH060220, U01 MH60220, U13 MH066849] NR 54 TC 978 Z9 1014 U1 14 U2 79 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0003-990X EI 1538-3636 J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD MAY PY 2007 VL 64 IS 5 BP 543 EP 552 DI 10.1001/archpsyc.64.5.543 PG 10 WC Psychiatry SC Psychiatry GA 164VQ UT WOS:000246263300004 PM 17485606 ER PT J AU Compton, WM Thomas, YF Stinson, FS Grant, BF AF Compton, Wilson M. Thomas, Yonette F. Stinson, Frederick S. Grant, Bridget F. TI Prevalence, correlates, disability, and comorbidity of DSM-IV drug abuse and dependence in the United States - Results from the National Epidemiologic Survey on Alcohol and Related Conditions SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Review ID SUBSTANCE USE DISORDERS; INTERVIEW SCHEDULE AUDADIS; GENERAL-POPULATION SAMPLE; MAJOR DEPRESSIVE DISORDER; MENTAL-HEALTH-SURVEY; AGE-OF-ONSET; PSYCHIATRIC-DISORDERS; ANXIETY DISORDERS; PERSONALITY-DISORDERS; SURVEY REPLICATION AB Background: Current and comprehensive information on the epidemiology of DSM-IV 12-month and lifetime drug use disorders in the United States has not been available. Objectives: To present detailed information on drug abuse and dependence prevalence, correlates, and comorbidity with other Axis I and II disorders. Design, Setting, and Participants: Face-to-face interviews using the Alcohol Use Disorder and Associated Disabilities Interview Schedule of the National Institute on Alcohol Abuse and Alcoholism in a large representative sample of US adults (N = 43 093). Main Outcome Measures: Twelve-month and lifetime prevalence of drug abuse and dependence and the associated correlates, treatment rates, disability, and comorbidity with other Axis I and II disorders. Results: Prevalences of 12-month and lifetime drug abuse (1.4% and 7.7%, respectively) exceeded rates of drug dependence (0.6% and 2.6%, respectively). Rates of abuse and dependence were generally greater among men, Native Americans, respondents aged 18 to 44 years, those of lower socioeconomic status, those residing in the West, and those who were never married or widowed, separated, or divorced (all P<.05). Associations of drug use disorders with other substance use disorders and antisocial personality disorder were diminished but remained strong when we controlled for psychiatric disorders. Dependence associations with most mood disorders and generalized anxiety disorder also remained significant. Lifetime treatment- or help-seeking behavior was uncommon (8.1%, abuse; 37.9%, dependence) and was not associated with sociodemographic characteristics but was associated with psychiatric comorbidity. Conclusions: Most individuals with drug use disorders have never been treated, and treatment disparities exist among those at high risk, despite substantial disability and comorbidity. Comorbidity of drug use disorders with other substance use disorders and antisocial personality disorder, as well as dependence with mood disorders and generalized anxiety disorder, appears to be due in part to unique factors underlying each pair of these disorders studied. The persistence of low treatment rates despite the availability of effective treatments indicates the need for vigorous educational efforts for the public and professionals. C1 NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Natl Inst Drug Abuse, Div Epidemiol Serv & Prevent Res, Bethesda, MD 20892 USA. RP Grant, BF (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, NIH,Dept Hlth & Human Serv, Room 3077,Mailstop 9304,5635 Fishers Ln, Bethesda, MD 20892 USA. EM bgrant@willco.niaaa.nih.gov FU Intramural NIH HHS NR 106 TC 572 Z9 581 U1 16 U2 86 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 MAY PY 2007 VL 64 IS 5 BP 566 EP 576 DI 10.1001/archpsyc.64.5.566 PG 11 WC Psychiatry SC Psychiatry GA 164VQ UT WOS:000246263300006 PM 17485608 ER PT J AU Saika, S Yamanaka, O Nishikawa-Ishida, I Kitano, A Flanders, KC Okada, Y Ohnishi, Y Nakajima, Y Ikeda, K AF Saika, Shizuya Yamanaka, Osamu Nishikawa-Ishida, Iku Kitano, Ai Flanders, Kathleen C. Okada, Yuka Ohnishi, Yoshitaka Nakajima, Yuji Ikeda, Kazuo TI Effect of Smad7 gene overexpression on transforming growth factor beta-induced retinal pigment fibrosis in a proliferative vitreoretinopathy mouse model SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID MUSCLE ACTIN EXPRESSION; HEPATIC STELLATE CELLS; EPITHELIAL-CELLS; TGF-BETA; MESENCHYMAL TRANSITION; IN-VIVO; DETACHMENT; FIBRONECTIN; RECEPTOR; KINASE AB Objective: To determine the effects of Smad7 gene transfer in the prevention of fibrogenic responses by the retinal pigment epithelium, a major cause of proliferative vitreoretinopathy after retinal detachment, in mice. Methods: Retinal detachment-induced proliferative vitreoretinopathy in a mouse model. Forty-eight eyes received either an adenoviral gene transfer of Smad7 or Cre recombinase gene only. The eyes were histologically analyzed. A retinal pigment epithelial cell line, ARPE-19, was used to determine whether Smad7 gene transfection suppresses the fibrogenic response to transforming growth factor (TGF) beta 2 exposure. Results: The Smad7 gene transfer inhibited TGF-beta 2/Smad signaling in ARPE-19 cells and expression of collagen type I and TGF-beta 1 but had no effect on their basal levels. In vivo Smad7 overexpression resulted in suppression of Smad2/3 signals and of the fibrogenic response to epithelial-mesenchymal transition by the retinal pigment epithelium. Conclusion: Smad7 gene transfer suppresses fibrogenic responses to TGF-beta 2 by retinal pigment epithelial cells in vitro and in vivo. Clinical Relevance: Smad7 gene transfer might be a new strategy to prevent and treat proliferative vitreoretinopathy. C1 Wakayama Med Univ, Dept Ophthalmol, Wakayama 6410012, Japan. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. Osaka City Univ, Grad Sch Med, Dept Anat, Osaka 558, Japan. RP Saika, S (reprint author), Wakayama Med Univ, Dept Ophthalmol, 811-1 Kimiidera, Wakayama 6410012, Japan. EM shizuya@wakayama-med.ac.jp NR 38 TC 31 Z9 47 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD MAY PY 2007 VL 125 IS 5 BP 647 EP 654 DI 10.1001/archopht.125.5.647 PG 8 WC Ophthalmology SC Ophthalmology GA 165XI UT WOS:000246340200008 PM 17502504 ER PT J AU Bryant, BJ Klein, HG AF Bryant, Barbara J. Klein, Harvey G. TI Pathogen inactivation - The definitive safeguard for the blood supply SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Review ID FRESH-FROZEN PLASMA; ULTRAVIOLET-A-LIGHT; WEST-NILE-VIRUS; THROMBOTIC THROMBOCYTOPENIC PURPURA; NON-B HEPATITIS; PHOTOACTIVE PHENOTHIAZINE DYES; HUMAN-IMMUNOGLOBULIN PRODUCTS; FACTOR-VIII CONCENTRATE; CELL STORAGE PROPERTIES; PHASE-III TRIAL AB Context.-Pathogen inactivation provides a proactive approach to cleansing the blood supply. In the plasma fractionation and manufacturing industry, pathogen inactivation technologies have been successfully, implemented resulting in no transmission of human immunodeficiency, hepatitis C, or hepatitis 13 viruses by US-licensed plasma derivatives since 1985. However, these technologies cannot be used to pathogen inactivate cellular blood components. Although current blood donor screening and disease testing has drastically reduced the incidence of transfusion-transmitted diseases, there still looms the threat to the blood supply of a new or reemerging pathogen. Of particular concern is the silent emergence of a new agent with a prolonged latent period in which asymptornatic infected carriers would donate and spread infection. Objective.-To review and summarize the principles, challenges, achievements, prospective technologies, and future goals of pathogen inactivation of the blood supply. Data Sources.-The current published English-language literature from 1968 through 2006 and a historical landmark article from 1943 are integrated into a review of this subject. Conclusions.-The ultimate goal of pathogen inactivation is to maximally reduce the transmission of potential pathogens without significantly compromising the therapeutic efficacy of the cellular and protein constituents of blood. This must be accomplished without introducing toxicities into the blood supply and without causing neoantigen formation and subsequent antibody production. Several promising pathogen inactivation technologies are being developed and clinically tested, and others are currently in use. Pathogen inactivation offers additional layers of protection from infectious agents that threaten the blood supply and has the potential to impact the safety of blood transfusions worldwide. C1 Natl Inst Hlth, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20894 USA. RP Bryant, BJ (reprint author), Natl Inst Hlth, Warren G Magnuson Clin Ctr, Dept Transfus Med, 10 Center Dr,MSC 1184,Bldg 10,Room 1C711, Bethesda, MD 20894 USA. EM bryantb2@cc.nih.gov NR 110 TC 48 Z9 54 U1 0 U2 2 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD MAY PY 2007 VL 131 IS 5 BP 719 EP 733 PG 15 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 164VO UT WOS:000246263100010 PM 17488157 ER EF