FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Zhao, B Takami, M Yamada, A Wang, X Nakao, K Tamura, T Ozato, K Takayanagi, H Kamjo, R AF Zhao, B. Takami, M. Yamada, A. Wang, X. Nakao, K. Tamura, T. Ozato, K. Takayanagi, H. Kamjo, R. TI Transcription factor IRF-8 is a negative regulator of osteoclast differentiation in vitro and in vivo. SO JOURNAL OF BONE AND MINERAL RESEARCH LA English DT Meeting Abstract CT 29th Annual Meeting of the American-Society-for-Bone-and-Mineral-Research CY SEP 16-19, 2007 CL Honolulu, HI SP Amer Soc Bone & Mineral Res C1 [Zhao, B.; Takami, M.; Yamada, A.; Wang, X.; Kamjo, R.] Showa Univ, Sch Dent, Dept Biochem, Tokyo, Japan. [Nakao, K.] RIKEN, Ctr Dev Biol, Lab Anim Resources & Genet Engn, Kobe, Hyogo, Japan. [Tamura, T.] Osaka City Univ, Grad Sch Med, Dept Physiol, Osaka, Japan. [Ozato, K.] NIH, NICHHD, Lab Mol Growth Regulat, Bethesda, MD USA. [Takayanagi, H.] Tokyo Med & Dent Univ, Grad Sch, Dept Cell Signaling, Tokyo, Japan. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC BONE & MINERAL RES PI WASHINGTON PA 2025 M ST, N W, STE 800, WASHINGTON, DC 20036-3309 USA SN 0884-0431 J9 J BONE MINER RES JI J. Bone Miner. Res. PD SEP PY 2007 VL 22 SU 1 BP S42 EP S42 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 225IA UT WOS:000250509100146 ER PT J AU Hu, JX Spiegel, AM AF Hu, Jianxin Spiegel, Allen M. TI Structure and function of the human calcium-sensing receptor: insights from natural and engineered mutations and allosteric modulators SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Review DE G protein-coupled receptor; hypercalcaemia; hypocalcaemia; receptor mutations; allosteric modulators ID HUMAN CA2+ RECEPTOR; FAMILIAL HYPOCALCIURIC HYPERCALCEMIA; AUTOSOMAL-DOMINANT HYPOCALCEMIA; NEONATAL SEVERE HYPERPARATHYROIDISM; EXTRACELLULAR CA2+-SENSING RECEPTOR; METABOTROPIC GLUTAMATE-RECEPTOR; PROTEIN-COUPLED RECEPTORS; CELL-SURFACE EXPRESSION; PARATHYROID-HORMONE SECRETION; CARBOXYL-TERMINAL TAIL AB The human extracellular Ca2+-sensing receptor (CaR), a member of the G protein-coupled receptor family 3, plays a key role in the regulation of extracellular calcium homeostasis. It is one of just a few G protein-coupled receptors with a large number of naturally occurring mutations identified in patients. In contrast to the small sizes of its agonists, this large dimeric receptor consists of domains with topologically distinctive orthosteric and allosteric sites. Information derived from studies of naturally occurring mutations, engineered mutations, allosteric modulators and crystal structures of the agonist-binding domain of homologous type 1 metabotropic glutamate receptor and G protein-coupled rhodopsin offers new insights into the structure and function of the CaR. C1 NIDDK, NIH, Mol Signalling Sect, Bioorgan Chem Lab, Bethesda, MD 20892 USA. Albert Einstein Coll Med, Off Dean, New York, NY USA. RP Hu, JX (reprint author), NIDDK, NIH, Mol Signalling Sect, Bioorgan Chem Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jianxinh@niddk.nih.gov FU Intramural NIH HHS NR 79 TC 65 Z9 66 U1 0 U2 6 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1582-1838 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD SEP-OCT PY 2007 VL 11 IS 5 BP 908 EP 922 DI 10.1111/j.1582-4934.2007.00096.x PG 15 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 226KI UT WOS:000250587500003 PM 17979873 ER PT J AU Rossner, P Terry, MB Gammon, MD Agrawal, M Zhang, FF Ferris, JS Teitelbaum, SL Eng, SM Gaudet, MM Neugut, AI Santella, RM AF Rossner, Pavel, Jr. Terry, Mary Beth Gammon, Marilie D. Agrawal, Meenakshi Zhang, Fang Fang Ferris, Jennifer S. Teitelbaum, Susan L. Eng, Sybil M. Gaudet, Mia M. Neugut, Alfred I. Santella, Regina M. TI Plasma protein carbonyl levels and breast cancer risk SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Article DE oxidative stress; protein carbonyl; breast cancer ID OXIDATIVE STRESS; LIPID-PEROXIDATION; ANTIOXIDANT STATUS; WINE CONSUMPTION; LUNG-CANCER; LONG-ISLAND; DNA-DAMAGE; INCREASES; EXERCISE; SMOKERS AB To study the role of oxidative stress in breast cancer risk, we analysed plasma levels of protein carbonyls in 1050 cases and 1107 controls. We found a statistically significant trend in breast cancer risk in relation to increasing quartiles of plasma protein carbonyl levels (OR = 1.2, 95% Cl = 0.9-1.5; OR = 1.5, 95% Cl = 1.2-2.0; OR = 1.6, 95% Cl = 1.2-2.1, for the 2(nd), 3(rd) and 4(th) quartile relative to the lowest quartile, respectively, P for trend=0.0001). The increase in risk was similar for younger (< 50 years) and older women, more pronounced among women with higher physical activity levels (= 0.7 hrs/week for 4th quartile versus lowest quartile OR = 2.0, 95% Cl = 1.4-3.0), higher alcohol consumption (= 15 grams/day for 4(th) quartile versus lowest quartile OR = 2.3, 95% Cl = 1.1-4.7), and hormone replacement therapy use (HRT, OR = 2.6, 95% Cl = 1.6-4.4 for 4(th) quartile versus lowest quartile). The multiplicative interaction terms were statistically significant only for physical activity and HRT. The positive association between plasma protein carbonyl levels and breast cancer risk was also observed when the analysis was restricted to women who had not received chemotherapy or radiation therapy prior to blood collection. Among controls, oxidized protein levels significantly increased with cigarette smoking and higher fruit and vegetable consumption, and decreased with alcohol consumption >30 grams per day. Women with higher levels of plasma protein carbonyl and urinary 15F(2t)-isoprostane had an 80% increase in breast cancer risk (OR = 1.8, 95% Cl = 1.2-2.6) compared to women with levels below the median for both markers of oxidative stress. In summary, our results suggest that increased plasma protein carbonyl levels may be associated with breast cancer risk. C1 Columbia Univ, Mailman Sch Publ Hlth, Dept Environm Hlth Sci, New York, NY USA. Hlth Inst Cent Bohemia, Lab Genet Ecotoxicol, Prague, Czech Republic. Inst Expt Med, Prague, Czech Republic. Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Mt Sinai Sch Med, Dept Community & Prevent Med, New York, NY USA. Pfizer Inc, New York, NY USA. Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD USA. RP Rossner, P (reprint author), Acad Sci Czech Republic, Inst Expt Med, Videnska 1083, Prague 14220 4, Czech Republic. EM prossner@biomed.cas.cz RI Rossner, Pavel/H-2569-2014 FU NCI NIH HHS [U01 CA/ES66572, K07 CA090685, K07CA90685-02]; NIEHS NIH HHS [P30 ES009089, P30 ES010126, P30ES09089, P30ES10126] NR 43 TC 29 Z9 30 U1 2 U2 2 PU WILEY PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1582-4934 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD SEP-OCT PY 2007 VL 11 IS 5 BP 1138 EP 1148 DI 10.1111/j.1582-4934.2007.00097.x PG 11 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 226KI UT WOS:000250587500019 PM 17979889 ER PT J AU Durkin, ME Yuan, BZ Zhou, X Zimonjic, DB Lowy, DR Thorgeirsson, SS Popescu, NC AF Durkin, Marian E. Yuan, Bao-Zhu Zhou, Xiaoling Zimonjic, Drazen B. Lowy, Douglas R. Thorgeirsson, Snorri S. Popescu, Nicholas C. TI DLC-1: a Rho GTPase-activating protein and tumour suppressor SO JOURNAL OF CELLULAR AND MOLECULAR MEDICINE LA English DT Review DE deleted in liver cancer; GTPase activating protein; tumour suppressor; metastasis suppressor; cytoskeletal organization; tensin; focal adhesion; cancer detection; cancer therapy ID HUMAN HEPATOCELLULAR-CARCINOMA; GENE-EXPRESSION PROFILE; HUMAN BREAST-CANCER; RAS-LIKE GTPASES; PROMOTER HYPERMETHYLATION; CELL-PROLIFERATION; PROSTATE-CANCER; PLC-DELTA(1)-BINDING PROTEIN; EPIGENETIC ALTERATIONS; ABERRANT METHYLATION AB The deleted in liver cancer 1 (DLC-1) gene encodes a GTPase activating protein that acts as a negative regulator of the Rho family of small GTPases. Rho proteins transduce signals that influence cell morphology and physiology, and their aberrant up-regulation is a key factor in the neoplastic process, including metastasis. Since its discovery, compelling evidence has accumulated that demonstrates a role for DLC-1 as a bona fide tumour suppressor gene in different types of human cancer. Loss of DLC-1 expression mediated by genetic and epigenetic mechanisms has been associated with the development of many human cancers, and restoration of DLC-1 expression inhibited the growth of tumour cells in vivo and in vitro. Two closely related genes, DLC-2 and DLC-3, may also be tumour suppressors. This review presents the current status of progress in understanding the biological functions of DLC-1 and its relatives and their roles in neoplasia. C1 NCI, Ctr Canc Res, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. NIOSH, Ctr Dis Control, Lab Mol Genet Toxicol, Morgantown, WV USA. NIOSH, Ctr Dis Control, Mol Biol Branch, Morgantown, WV USA. NCI, Canc Res Ctr, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Popescu, NC (reprint author), Bldg 37,Room 4128,37 Convent Dr,MSC 4262, Bethesda, MD 20832 USA. EM popescun@mail.nih.gov FU Intramural NIH HHS NR 132 TC 110 Z9 117 U1 0 U2 6 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1582-1838 J9 J CELL MOL MED JI J. Cell. Mol. Med. PD SEP-OCT PY 2007 VL 11 IS 5 BP 1185 EP 1207 DI 10.1111/j.1582-4934.2007.00098.x PG 23 WC Cell Biology; Medicine, Research & Experimental SC Cell Biology; Research & Experimental Medicine GA 226KI UT WOS:000250587500023 PM 17979893 ER PT J AU Booth, BW Boulanger, CA Smith, GH AF Booth, Brian W. Boulanger, Corinne A. Smith, Gilbert H. TI Alveolar progenitor in mouse mammary cells develop glands independent of pregnancy and lactation SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID EPIDERMAL GROWTH-FACTOR; EPITHELIAL-CELLS; TGF-BETA-1 EXPRESSION; STEM/PROGENITOR CELLS; STEM-CELLS; POPULATION; GENE; MICE; INHIBITION; HORMONE AB We have previously described pluripotent, parity-induced mammary epithelial cells (PI-MEC) marked by Rosa26-lacZ expression in the mammary glands of parous females, PI-MEC act as lobule-limited epithelial stem/progenitor cells. To determine whether parity is necessary to generate PI-MEC, we incubated mammary explant cultures from virgin mice in vitro with insulin alone (1), hydrocortisone alone (H), prolactin alone (Prl), or a combination of these lactogenic hormones (IHPrl). Insulin alone activated the WAP-Cre gene. Hydrocortisone and prolactin alone did not. Any combination of hormones that included insulin was effective. Only 1, H and PrI together were able to induce secretory differentiation and milk protein synthesis. In addition, EGF, IGF-2 and IGF- I added individually produced activated (lacZ(+)) PI-MEC in explant cultures. Neither estrogen nor progesterone induced WAP-Cre expression in the explants. None of these positive initiators of WAP-Cre expression in PI-MEC were effective in mammospheres or two-dimensional cultures of mammary epithelium, indicating the indispensability of epithelial-stromal interaction in PI-MEC activation. Like PI-MEC, lacZ(+) cells from virgin explants proliferated and contributed progeny to mammospheres in vitro and to epithelial outgrowths in vivo after transplantation. LacZ(+) cells induced in virgin mouse mammary explants were multipotent (like PI-MEC) in impregnated hosts producing lacZ+ mammary alveolar structures comprised of both myoepithelial and luminal progeny. These data demonstrate PI-MEC, a mammary epithelial sub-population of lobule-limited progenitor cells, are present in nulliparous female mice before parity and, like the PI-MEC observed following parity, are capable of proliferation, self-renewal and the capacity to produce progeny of diverse epithelial cell fates. C1 NCI, NIH, Mammary Biol & Tumorigenesis Lab, Bethesda, MD 20892 USA. RP Smith, GH (reprint author), NCI, NIH, Mammary Biol & Tumorigenesis Lab, 9000 Rockville Pike,Bldg 37,Room 1106, Bethesda, MD 20892 USA. EM gs4d@nih.gov FU Intramural NIH HHS NR 25 TC 43 Z9 43 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD SEP PY 2007 VL 212 IS 3 BP 729 EP 736 DI 10.1002/jcp.21071 PG 8 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 200NQ UT WOS:000248770500020 PM 17443685 ER PT J AU Baksh, D Tuan, RS AF Baksh, Dolores Tuan, Rocky S. TI Canonical and non-canonical wnts differentially affect the development potential of primary isolate of human bone marrow mesenchymal stem cells SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID IN-VITRO; HUMAN HEMATOPOIESIS; GROWTH; PROLIFERATION; BIOLOGY; NICHE AB This study examines the role of Wnt signaling events in regulating the differential potential of mesenchymal stem cells (MSCs) from adult bone marrow (BM). Immunohistochemical analysis of BM revealed co-localization of Wnt5a protein, a non-canonical Wnt, with CD45(+) cells and CD45(-) STRO-I+ cells, while Wnt3a expression, a canonical Wnt, was associated with the underlying stroma matrix, suggesting that Wnts may regulate MSCs in their niche in BM. To elucidate the role of Wnts in MSC development, adult human BM-derived mononuclear cells were maintained as suspension cultures to recapitulate the marrow cellular environment, in serum-free, with the addition of Wnt3a and Wnt5a protein. Results showed that Wnt3a increased cell numbers and expanded the pool of MSCs capable of colony forming unit - fibroblast (CFU-F) and CFU - osteoblast (0), while Wnt5a maintained cell numbers and CFU-F and CFU-O numbers. However, when cells were cultured directly onto tissue culture plastic, Wnt5a increased the number of CFU-O relative to control conditions. These findings suggest the potential dual role of Wnt5a in the maintenance of MSCs in BM and enhancing osteogenesis ex vivo. Our work provides evidence that Writs can function as mesenchymal regulatory factors by providing instructive cues for the recruitment, maintenance, and differentiation of MSCs. J. Cell. Physiol. 212: 817-826, 2007. (c) 2007 Wiley-Liss, Inc. C1 NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. RP Tuan, RS (reprint author), NIAMSD, Cartilage Biol & Orthopaed Branch, NIH, 50 South Dr,Room 1503,MSC 8022, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov FU NIAMS NIH HHS [Z01 AR41131] NR 29 TC 78 Z9 84 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD SEP PY 2007 VL 212 IS 3 BP 817 EP 826 DI 10.1002/jcp.21080 PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 200NQ UT WOS:000248770500030 PM 17458904 ER PT J AU Innis, RB Cunningham, VJ Delforge, J Fujita, M Giedde, A Gunn, RN Holden, J Houle, S Huang, SC Ichise, M Lida, H Ito, H Kimura, Y Koeppe, RA Knudsen, GM Knuuti, J Lammertsma, AA Laruelle, M Logan, J Maguire, RP Mintun, MA Morris, ED Parsey, R Price, JC Slifstein, M Sossi, V Suhara, T Votaw, JR Wong, DF Carson, RE AF Innis, Robert B. Cunningham, Vincent J. Delforge, Jacques Fujita, Masahiro Giedde, Albert Gunn, Roger N. Holden, James Houle, Sylvain Huang, Sung-Cheng Ichise, Masanori Lida, Hidehiro Ito, Hiroshi Kimura, Yuichi Koeppe, Robert A. Knudsen, Gitte M. Knuuti, Juhani Lammertsma, Adriaan A. Laruelle, Marc Logan, Jean Maguire, Ralph Paul Mintun, Mark A. Morris'o, Evan D. Parsey, Ramin Price, Julie C. Slifstein, Mark Sossi, Vesna Suhara, Tetsuya Votaw, John R. Wong, Dean F. Carson, Richard E. TI Consensus nomenclature for in vivo imaging of reversibly binding radioligands SO JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM LA English DT Review DE PET; SPECT; modeling; nomenclature; molecular imaging; radioligands ID POSITRON EMISSION TOMOGRAPHY; CONSTANT INFUSION; MODEL; RECEPTOR; INVIVO; VOLUME AB An international group of experts in pharmacokinetic modeling recommends a nomenclature to describe in vivo molecular imaging of reversibly binding radioligands. C1 NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. Univ London Imperial Coll Sci Technol & Med, London, England. GlaxoSmithKline Inc, London, England. CEA, DSV, SHF, Orsay, France. Univ Aarhus, Aarhus, Denmark. Univ Oxford, London, England. Univ Wisconsin, Madison, WI USA. Univ Toronto, Toronto, ON, Canada. Ctr Addict & Mental Hlth, Toronto, ON, Canada. Univ Calif Los Angeles, Sch Med, Los Angeles, CA USA. Columbia Univ, New York, NY USA. Natl Cardiovasc Ctr, Res Inst, Suita, Osaka 565, Japan. Tokyo Metropolitan Inst Gerontol, Tokyo, Japan. Univ Michigan, Ann Arbor, MI 48109 USA. Univ Copenhagen Hosp, Rigshosp, DK-2100 Copenhagen, Denmark. Turku PET Ctr, Turku, Finland. Vrije Univ Amsterdam Med Ctr, Amsterdam, Netherlands. Brookhaven Natl Lab, Upton, NY 11973 USA. Pfizer Global R&D, Groton, CT USA. Washington Univ, Sch Med, St Louis, MO USA. Indiana Univ Purdue Univ, Indianapolis, IN 46202 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. Emory Univ, Atlanta, GA 30322 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Yale Univ, New Haven, CT USA. Natl Inst Radiol Sci, Chiba 260, Japan. RP Innis, RB (reprint author), NIMH, Mol Imaging Branch, 31 Ctr Dr MSC 2035,Bldg 31,Room B2B37, Bethesda, MD 20892 USA. EM robert.innis@iiih.gov RI Bonefeld, Birgit/B-7936-2010; Kimura, Yuichi/B-3045-2008; Carson, Richard/H-3250-2011; Gunn, Roger/H-1666-2012; Iida, Hidehiro/D-4582-2011; Knudsen, Gitte/C-1368-2013 OI Carson, Richard/0000-0002-9338-7966; Gunn, Roger/0000-0003-1181-5769; Knudsen, Gitte/0000-0003-1508-6866 NR 12 TC 984 Z9 987 U1 7 U2 54 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0271-678X J9 J CEREBR BLOOD F MET JI J. Cereb. Blood Flow Metab. PD SEP PY 2007 VL 27 IS 9 BP 1533 EP 1539 DI 10.1038/sj.jcbfm.9600493 PG 7 WC Endocrinology & Metabolism; Hematology; Neurosciences SC Endocrinology & Metabolism; Hematology; Neurosciences & Neurology GA 202ZY UT WOS:000248946100001 PM 17519979 ER PT J AU Gogtay, N Ordonez, A Herman, DH Hayashi, KM Greenstein, D Vaituzis, C Lenane, M Clasen, L Sharp, W Giedd, JN Jung, D Nugent, TF Toga, AW Leibenluft, E Thompson, PM Rapoport, JL AF Gogtay, Nitin Ordonez, Anna Herman, David H. Hayashi, Kiralee M. Greenstein, Deanna Vaituzis, Cathy Lenane, Marge Clasen, Liv Sharp, Wendy Giedd, Jay N. Jung, David Nugent, Tom F., III Toga, Arthur W. Leibenluft, Ellen Thompson, Paul M. Rapoport, Judith L. TI Dynamic mapping of cortical development before and after the onset of pediatric bipolar illness SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE pediatric; bipolar; MRI; mapping; gray; matter ID SUBGENUAL PREFRONTAL CORTEX; VOXEL-BASED MORPHOMETRY; GRAY-MATTER VOLUME; TREATMENT ENHANCEMENT PROGRAM; SUPERIOR TEMPORAL GYRUS; BRAIN-DEVELOPMENT; MOOD DISORDERS; ALZHEIMERS-DISEASE; IMAGING FINDINGS; YOUNG-ADULTS AB Background: There are, to date, no pre-post onset longitudinal imaging studies of bipolar disorder at any age. We report the first prospective study of cortical brain development in pediatric bipolar illness for 9 male children, visualized before and after illness onset. Method: We contrast this pattern with that observed in a matched group of healthy children as well as in a matched group of 8 children with 'atypical psychosis' who had similar initial presentation marked by mood dysregulation and transient psychosis (labeled as 'multi-dimensionally impaired' (MDI)) as in the bipolar group, but have not, to date, developed bipolar illness. Results: Dynamic maps, reconstructed by applying novel cortical pattern matching algorithms, for the children who became bipolar I showed subtle, regionally specific, bilaterally asymmetrical cortical changes. Cortical GM increased over the left temporal cortex and decreased bilaterally in the anterior (and sub genual) cingulate cortex. This was seen most strikingly after the illness onset, and showed a pattern distinct from that seen in childhood onset schizophrenia. The bipolar neurodevelopmental trajectory was generally shared by the children who remained with MDI diagnosis without converting to bipolar I, suggesting that this pattern of cortical development may reflect affective dysregulation (lability) in general. Conclusions: These dynamic trajectories of cortical development may explain age-related disparate findings from cross-sectional studies of bipolar illness, and suggest the importance of mood disordered non-bipolar control group in future studies. C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. NIMH, Mood & Anxiety Program, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Dept Neurol, Lab Neuro Imaging, Los Angeles, CA 90024 USA. RP Gogtay, N (reprint author), NIMH, Child Psychiat Branch, Bldg 10, Bethesda, MD 20892 USA. EM gogtayn@intra.nimh.nih.gov RI Gogtay, Nitin/A-3035-2008; 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 NIMH NIH HHS [R25 MH060482] NR 76 TC 70 Z9 70 U1 3 U2 11 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0021-9630 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD SEP PY 2007 VL 48 IS 9 BP 852 EP 862 DI 10.1111/j.1469-7610.2007.01747.x PG 11 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 205QX UT WOS:000249130800002 PM 17714370 ER PT J AU Guyer, AE McClure, EB Adler, AD Brotman, MA Rich, BA Kimes, AS Pine, DS Ernst, M Leibenluft, E AF Guyer, Amanda E. McClure, Erin B. Adler, Abby D. Brotman, Melissa A. Rich, Brendan A. Kimes, Alane S. Pine, Daniel S. Ernst, Monique Leibenluft, Ellen TI Specificity of facial expression labeling deficits in childhood psychopathology SO JOURNAL OF CHILD PSYCHOLOGY AND PSYCHIATRY LA English DT Article DE emotion recognition; bipolar disorder; emotion regulation; pediatrics ID GENERALIZED ANXIETY DISORDER; PEDIATRIC BIPOLAR DISORDER; HYPERACTIVITY DISORDER; PSYCHOMETRIC CHARACTERISTICS; EMOTIONAL INFORMATION; ATTENTIONAL BIAS; JUVENILE MANIA; SOCIAL PHOBIA; RATING-SCALE; ANGRY FACES AB Background: We examined whether face-emotion labeling deficits are illness-specific or an epiphenomenon of generalized impairment in pediatric psychiatric disorders involving mood and behavioral dysregulation. Method: Two hundred fifty-two youths (7-18 years old) completed child and adult facial expression recognition subtests from the Diagnostic Analysis of Nonverbal Accuracy (DANVA) instrument. Forty-two participants had bipolar disorder (BD), 39 had severe mood dysregulation (SMD; i.e., chronic irritability, hyperarousal without manic episodes), 44 had anxiety and/or major depressive disorders (ANX/MDD), 35 had attention-deficit/hyperactivity and/or conduct disorder (ADHD/CD), and 92 were controls. Dependent measures were number of errors labeling happy, angry, sad, or fearful emotions. Results: BD and SMD patients made more errors than ANX/MDD, ADHD/CD, or controls when labeling adult or child emotional expressions. BD and SMD patients did not differ in their emotion-labeling deficits. Conclusions: Face-emotion labeling deficits differentiate BD and SMD patients from patients with ANX/MDD or ADHD/CD and controls. The extent to which such deficits cause vs. result from emotional dysregulation requires further study. C1 NIMH, Mood & Anxiety Program, NIH, DHHS, Bethesda, MD 20892 USA. Georgia State Univ, Dept Psychol, Atlanta, GA USA. NIDA, Neuroimaging Branch, NIH, DHHS, Baltimore, MD USA. RP Guyer, AE (reprint author), NIMH, Mood & Anxiety Program, NIH, DHHS, 15K N Dr,Room 208, Bethesda, MD 20892 USA. EM amandaguyer@mail.nih.gov RI Brotman, Melissa/H-7409-2013 FU Intramural NIH HHS NR 69 TC 125 Z9 125 U1 4 U2 21 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0021-9630 J9 J CHILD PSYCHOL PSYC JI J. Child Psychol. Psychiatry PD SEP PY 2007 VL 48 IS 9 BP 863 EP 871 DI 10.1111/j.1469-7610.2007.01758.x PG 9 WC Psychology, Developmental; Psychiatry; Psychology SC Psychology; Psychiatry GA 205QX UT WOS:000249130800003 PM 17714371 ER PT J AU Zhang, SM Mada, SR Mattison, D Caritis, S Venkataramanan, R AF Zhang, Shimin Mada, Sripal Reddy Mattison, Don Caritis, Steve Venkataramanan, Raman CA OPRU Network TI Development and validation of a high-performance liquid chromatography-mass spectrometric assay for the determination of 17 alpha-hydroxyprogesterone caproate (17-OHPC) in human plasma SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE 17-OHPC; MPA; liquid chromatography-mass spectrometry; pregnancy ID PRETERM DELIVERY; BIRTH; PREVENTION AB A sensitive and specific method for the determination of 17 alpha-hydroxyprogesterone caproate (17-OHPC) in human plasma using high-performance liquid chromatography and mass spectrometry has been developed and validated. Plasma samples were processed by a solid phase extraction (SPE) procedure using Oasis HLB extraction cartridge prior to chromatography. Medroxyprogesterone acetate (MPA) was used as the internal standard. Chromatography was performed using Waters C 18 Symmetry analytical column, 3.5 mu m, 2.1 mm x 10 mm, using a gradient elusion with a mobile phase consisting of acetonitrile [A] and 5% acetonitrile in water [B], with 0.1% formic acid being added to both [A] and (B], at a flow rate 0.2 ml/min. The retention times of 17-OHPC and MPA were 8.1 and 5.0 min, respectively, with a total run time of 15 min. Analysis was performed on Thermo Electron Finnigan TSQ Quantum Ultra mass spectrometer in a selected reaction-monitoring (SRM), positive mode using electron spray ionization (ESI) as an interface. Positive ions were measured using extracted ion chromatogram mode. The extracted ions following SRM transitions monitored were mlz 429.2 -> 313.13 and 429.2 -> 27 1.1, for 17-OHPC and mlz 385.1 -> 276 for MPA. The extraction recoveries at concentrations of 5, 10 and 50 ng/ml were 97.1, 92.6 and 88.7%, respectively. The assay was linear over the range 0.5-50 ng/ml for 17-OHPC. The analysis of standard samples for 17-OHPC 0.5, 1, 2.5, 5, 10, 25 and 50 ng/ml demonstrated a relative standard deviation of 16.7, 12.4, 13.7, 1.4, 5.2, 3.7 and 5.3%, respectively (n = 6). This method is simple, adaptable to routine application, and allows easy and accurate measurement of 17-OHPC in human plasma. (C) 2007 Elsevier B.V. All rights reserved. C1 Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Sch Med, Dept Pharm, Pittsburgh, PA 15261 USA. Magee Womens Hosp, Dept Obstet & Gynecol, Pittsburgh, PA 15261 USA. NICHD, Ctr Res Mothers & Children, Obstet Fetal Pharmacol Res Units, OPRU Network, Bethesda, MD USA. RP Venkataramanan, R (reprint author), Univ Pittsburgh, Sch Pharm, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. EM rv+@pitt.edu RI Mattison, Donald/C-2015-2009; Mattison, Donald/L-4661-2013; OI Mattison, Donald/0000-0001-5623-0874; caritis, steve/0000-0002-2169-0712 FU NCATS NIH HHS [UL1 TR000005]; NICHD NIH HHS [HD-047905-2, U10 HD047905, U54 HD047905] NR 11 TC 5 Z9 5 U1 0 U2 2 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 SEP 1 PY 2007 VL 856 IS 1-2 BP 141 EP 147 DI 10.1016/j.jchromb.2007.05.028 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 212RS UT WOS:000249615100021 PM 17576102 ER PT J AU Shakleya, DM Jansson, LM Huestis, MA AF Shakleya, Diaa M. Jansson, Lauren M. Huestis, Marilyn A. TI Validation of a LC-APCI-MS/MS method for quantification of methadone, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyraline (EMDP) in infant plasma following protein precipitation SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE methadone; plasma; LC-APCI-MS/MS; EDDP; EMDP ID CHROMATOGRAPHY-MASS-SPECTROMETRY; LIQUID-CHROMATOGRAPHY; PRIMARY METABOLITE; STEREOSELECTIVE DETERMINATION; MAINTENANCE TREATMENT; N-DEMETHYLATION; GC-MS; MECONIUM; PREGNANCY; ENANTIOMERS AB A validated, quantitative LC-APCI-MS/MS method for methadone, EDDP and EMDP in 200-mu L plasma is presented. Specimen preparation was limited to protein precipitation and centrifugation. Chromatographic separation was achieved on a Synergi Hydro-RP 80A (50 mm x 2.0 mm, 4 mu m) column with gradient elution. The assay was linear from 1 to 500 ng/mL, with intra- and inter-as say accuracy >= 87.5% and intra- and inter-assay precision <13.4% R.S.D. and recovery >= 87.5% for all analytes at 40 ng/mL. This analytical method is suitable for the accurate and precise determination of methadone and metabolites in human plasma specimens. Published by Elsevier B.V. C1 NIDA, Chem & Drug Metab Intramural Res Program, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21224 USA. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural NIH HHS; NIDA NIH HHS [K08DA00495] NR 28 TC 16 Z9 16 U1 1 U2 3 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 SEP 1 PY 2007 VL 856 IS 1-2 BP 267 EP 272 DI 10.1016/j.jchromb.2007.06.004 PG 6 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 212RS UT WOS:000249615100038 PM 17602899 ER PT J AU Noda, Y Mori, A AF Noda, Yasuko Mori, Akitane TI Antioxidant activities of Uyaku (Lindera strychnifolia) leaf extract: A natural extract used in traditional medicine SO JOURNAL OF CLINICAL BIOCHEMISTRY AND NUTRITION LA English DT Article DE Uyaku; natural antioxidant; lipid peroxidation ID HYDROXYL RADICALS; ROOT; COMPONENTS; VILL; PEROXIDATION; SUPEROXIDE; ACIDS; MICE AB Uyaku (Lindera strychnifolia, Sieb. et Zucc.) is used in traditional Asian medicine to treat stomach and renal diseases, neuralgia, rheumatism, and aging. In this study, the effects of lyophilized extracts on hydroxyl (OH) and superoxide (O-2(center dot-)) radicals were examined using an electron spin resonance (ESR) spectrometer with the spin trap, 5,5'-dimethyl-1-pyrroline-N-oxide. Inhibitory effects were assessed using the following reagents: for nitric oxide (NO center dot), the Griess reagent; for (Fe 21 + H2O2)-induced lipid peroxidation, 2-thiobarbituric acid; for (Fe 21 + H2O2)-induced protein carbonyl, 2,4-dinitrophenylhydrazine. Analysis of ESR data of the extracts; indicated the direct (OH)-O-center dot and O-2(center dot-) scavenging. The extracts scavenged NO center dot in a dose-dependent manner, inhibited lipid peroxidation of linolenic acid, and protein carbonyl formation in bovine serum albumin. In conclusion, the Uyaku leaf hot-water extract has potent scavenging activity against reactive oxygen species and reactive nitrogen species, and effectively inhibited lipid peroxidation. These results might contribute to understanding age-associated or free radical-related diseases induced by excess reactive oxygen and also nitrogen species. C1 Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Dept Anti Aging Food Sci, Okayama 700, Japan. RP Mori, A (reprint author), NIH, Natl Heat Lung & Blood Inst, Bldg 10, Bethesda, MD 20892 USA. EM dr-mori@cc.okayama-u.ac.jp NR 38 TC 14 Z9 14 U1 0 U2 2 PU JOURNAL CLINICAL BIOCHEMISTRY & NUTRITION PI KYOTO PA KYOTO PREFECTURAL UNIV MED, GRAD SCH MEDICAL SCIENCE, DEPT MOLECULAR GASTROENTEROLOGY & HEPATOLOGY, KYOTO, 602-8566, JAPAN SN 0912-0009 EI 1880-5086 J9 J CLIN BIOCHEM NUTR JI J. Clin. Biochem. Nutr. PD SEP PY 2007 VL 41 IS 2 BP 139 EP 145 DI 10.3164/jcbn.2007019 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 209JH UT WOS:000249384300010 PM 18193108 ER PT J AU Rodriguez, A Muller, DC Metter, EJ Maggio, M Harman, SM Blackman, MR Andres, R AF Rodriguez, Annabelle Muller, Denis C. Metter, E. Jeffrey Maggio, Marcello Harman, S. Mitchell Blackman, Marc R. Andres, Reubin TI Aging, androgens, and the metabolic syndrome in a longitudinal study of aging SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID HORMONE-BINDING GLOBULIN; MIDDLE-AGED MEN; DENSITY-LIPOPROTEIN CHOLESTEROL; POLYCYSTIC-OVARY-SYNDROME; TESTOSTERONE AB Background: Based on Adult Treatment Panel III criteria, we previously reported that the prevalence of the metabolic syndrome ( MS) increased with aging; was higher if elevated 2-h plasma postglucose challenge values were included as a criterion; and was greater in men, compared with women. The aim of this study was to evaluate the relationship between the MS and circulating androgen levels in a cohort of men in the Baltimore Longitudinal Study of Aging. Methods and Results: Study participants were Caucasian community-dwelling adult men in the Baltimore Longitudinal Study of Aging, who underwent a fasting 2-h oral glucose tolerance test and had serum concentrations of total testosterone ( T), dehydroepiandrosterone sulfate, and SHBG levels measured. The prevalence of the MS was 4, 21, 21, and 18% for men between the ages of 20 and 39, 40 and 59, 60 and 79, and 80 and 94 yr, respectively. Total T and SHBG were inversely related to the development of the MS over a mean follow-up period of 5.8 yr ( range 1.5-14.0 yr), whereas the free T index and body mass index were positively related to the incidence of the MS. Age alone did not predict the development of the MS, nor did the inclusion of abnormal 2-h plasma postglucose challenge levels in the classification of the MS. Stepwise proportional hazards regression analyses showed that among the various measurements, SHBG levels exerted the greatest influence on development of the MS. Conclusion: The prevalence of the MS increased with aging, and this was associated with lower androgen levels. Lower total T and SHBG predicted a higher incidence of the MS. C1 Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21224 USA. Johns Hopkins Univ, Bayview Med Ctr, Baltimore, MD 21224 USA. NIA, NIH, Clin Invest Lab, Baltimore, MD 21224 USA. Kronos Longev Inst, Phoenix, AZ 85013 USA. NIH, Natl Ctr Complementary & Alternat Med, Clin Invest Lab, Bethesda, MD 20892 USA. RP Rodriguez, A (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21224 USA. EM arodrig5@jhmi.edu RI Perez , Claudio Alejandro/F-8310-2010 OI Perez , Claudio Alejandro/0000-0001-9688-184X FU Intramural NIH HHS NR 20 TC 123 Z9 130 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD SEP PY 2007 VL 92 IS 9 BP 3568 EP 3572 DI 10.1210/jc.2006-2764 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 207VS UT WOS:000249279800036 PM 17595254 ER PT J AU Pasini, B Matyakhina, L Bei, T Muchow, M Boikos, S Ferrando, B Carney, JA Stratakis, CA AF Pasini, Barbara Matyakhina, Ludmila Bei, Thalia Muchow, Michael Boikos, Sosipatros Ferrando, Barbara Carney, J. Aidan Stratakis, Constantine A. TI Multiple gastrointestinal stromal and other tumors caused by platelet-derived growth factor receptor alpha gene mutations: A case associated with a germline V561D defect SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID EXTRA-ADRENAL PARAGANGLIOMA; PULMONARY CHONDROMA; CARNEY TRIAD; C-KIT; PDGFRA; LEIOMYOSARCOMA; SARCOMA AB Context: Gastrointestinal stromal tumors (GISTs) may be caused by somatic or germline mutations of the KIT and PDGFRA genes, but most GISTs associated with neuroendocrine tumors (NETs) are not, suggesting that other molecular pathways are implicated in their pathogenesis. Objective: In the course of investigating NETs and GIST genetics, we encountered a patient who had a unique combination of multiple fibrous polyps and lipomas of the small intestine and several gastric GISTs. Design: The study included the clinical description of a unique patient, DNA sequencing of germline and tumor DNA, and comparative genomic hybridization (CGH) and allelic marker analysis of tumor DNA. Results: The patient was found to carry a germline PDGFRA mutation (V561D) in the heterozygote state; it has only been seen rarely before and only in the somatic state in sporadic GISTs. CGHidentified losses of chromosomal regions 1p33-36, 9q12-24, 11q13, and 16q; loss of the 14q region that is commonly lost in NETs and GISTs was shown by DNA marker analysis. These changes are likely to point to secondary and tertiary genetic hits involved in the formation of these rare tumors. Conclusions: Multiple GISTs and other tumors may be caused by germline PDGFRA gene mutations; the V561D mutation can occur in the germline state and lead to a syndrome that should not be confused with other genetic conditions associated with a predisposition to NETs and other tumors. A number of chromosomal loci are likely to be involved in the PDGFRA V561D-dependent tumorigenesis, as shown by CGH and other DNA analyses. C1 NICHD, NIH, SEGEN, Bethesda, MD 20892 USA. NICHD, NIH, DEB, Director Pediat Endocrinol Training Program, Bethesda, MD 20892 USA. Univ Turin, Dept Genet Biol & Biochem, Turin, Italy. NICHHD, NIH, Sect Endocrinol & Genet & Pediat Endocrinol Train, Dev Endocrinol Branch, Bethesda, MD 20892 USA. Mayo Clin, Dept Lab Med & Pathol, Rochester, MN 55905 USA. RP Stratakis, CA (reprint author), NICHD, NIH, SEGEN, Bldg 10 CRC Room 1-3330,10 Ctr Dr,MSC1103, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU Intramural NIH HHS NR 20 TC 31 Z9 33 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD SEP PY 2007 VL 92 IS 9 BP 3728 EP 3732 DI 10.1210/jc.2007-0894 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 207VS UT WOS:000249279800060 PM 17566086 ER PT J AU Skoura, A Sanchez, T Claffey, K Mandala, SM Proia, RL Hla, T AF Skoura, Athanasia Sanchez, Teresa Claffey, Kevin Mandala, Suzanne M. Proia, Richard L. Hla, Timothy TI Essential role of sphingosine 1-phosphate receptor 2 in pathological angiogenesis of the mouse retina SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID NITRIC-OXIDE SYNTHASE; PROTEIN-COUPLED RECEPTOR; VASCULAR ENDOTHELIAL-CELLS; OXYGEN-INDUCED RETINOPATHY; SPHINGOSINE 1-PHOSPHATE; IN-VIVO; ISCHEMIC RETINOPATHY; BLOOD-FLOW; EXPRESSION; NEOVASCULARIZATION AB Sphingosine 1-phosphate (S1P), a multifunctional lipid mediator that signals via the S1P family of G protein-coupled receptors (S1PR), regulates vascular maturation, permeability, and angiogenesis. In this study, we explored the role of SIP 2 receptor (S1P(2)R) in normal vascularization and hypoxia-triggered pathological angiogenesis of the mouse retina. S1P(2)R is strongly induced in ECs during hypoxic stress. When neonatal mice were subjected to ischemia-driven retinopathy, pathologic neovascularization in the vitreous chamber was suppressed in S1p2(-/-) mice concomitant with reduction in endothelial gaps and inflammatory cell infiltration. In addition, EC patterning and normal revascularization into the avascular zones of the retina were augmented. Reduced expression of the proinflammatory enzyme cyclooxygenase-2 (COX-2) and increased expression of eNOS were observed in the S1p2(-/-) mouse retina. S1P(2)R activation in ECs induced COX-2 expression and suppressed the expression of eNOS. These data identify the S1P(2)R-driven inflammatory process as an important molecular event in pathological retinal angiogenesis. We propose that antagonism of the S1P(2)R maybe a novel therapeutic approach for the prevention and/or treatment of pathologic ocular neovascularization. C1 Univ Connecticut, Ctr Hlth, Ctr Vasc Biol, Farmington, CT USA. Merck Res Labs, Rahway, NJ USA. NIH, NIDDK, Genet Dis & Dev Branch, Bethesda, MD 20892 USA. RP Hla, T (reprint author), Univ Connecticut, Sch Med, Ctr Vasc Biol, 263 Farmington Ave, Farmington, CT 06030 USA. EM hla@nso2.uchc.edu RI Proia, Richard/A-7908-2012; Hla, Timothy/G-5873-2012 OI Hla, Timothy/0000-0001-8355-4065 FU Intramural NIH HHS; NCI NIH HHS [P01-CA77839, P01 CA077839]; NHLBI NIH HHS [P01 HL070694, P01-HL70694, R37 HL067330, R37HL67330] NR 63 TC 118 Z9 121 U1 0 U2 4 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 SEP PY 2007 VL 117 IS 9 BP 2506 EP 2516 DI 10.1172/JC131123 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 209JK UT WOS:000249384600022 PM 17710232 ER PT J AU Song, L Ara, T Wu, HW Woo, CW Reynolds, CP Seeger, RC DeClerck, YA Thiele, CJ Sposto, R Metelitsa, LS AF Song, Liping Ara, Tasnim Wu, Hong-Wei Woo, Chan-Wook Reynolds, C. Patrick Seeger, Robert C. DeClerck, Yves A. Thiele, Carol J. Sposto, Richard Metelitsa, Leonid S. TI Oncogene MYCN regulates localization of NKT cells to the site of disease in neuroblastoma SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID KILLER-T-CELLS; LIGAND ALPHA-GALACTOSYLCERAMIDE; CHEMOKINE RECEPTOR EXPRESSION; BONE-MARROW; TUMOR IMMUNOSURVEILLANCE; IMMUNE-RESPONSES; FLOW-CYTOMETRY; MONOCYTE CHEMOATTRACTANT; INNATE IMMUNITY; CANCER-PATIENTS AB Va24-invariant natural killer T (NKT) cells are potentially important for antitumor immunity. We and others have previously demonstrated positive associations between NKT cell presence in primary tumors and long-term survival in distinct human cancers. However, the mechanism by which aggressive tumors avoid infiltration with NKT and other T cells remains poorly understood. Here, we report that the v-myc myelocytomatosis viral related oncogene, neuroblastoma derived (MYCN), the hallmark of aggressive neuroblastoma, repressed expression of monocyte chemoattractant protein-1/CC chemokine ligand 2 (MCP-1/CCL2), a chemokine required for NKT cell chemoattraction. MYCN knockdown in AffCN-amplified neuroblastoma cell lines restored CCL2 production and NKT cell chemoattraction. Unlike other oncogenes, MYCN repressed chemokine expression in a STAT3-independent manner, requiring an E-box element in the CCL2 promoter to mediate transcriptional repression. MYCN overexpression in neuroblastoma xenografts in NOD/SCID mice severely inhibited their ability to attract human NKT cells, T cells, and monocytes. Patients with MYCN-amptified neuroblastoma metastatic to bone marrow had 4-fold fewer NKT cells in their bone marrow than did their nonamplified counterparts, indicating that the MYCN-mediated immune escape mechanism, which we believe to be novel, is operative in metastatic cancer and should be considered in tumor immunobiology and for the development of new therapeutic strategies. C1 Univ So Calif, Childrens Hosp Los Angeles, Keck Sch Med, Dept Pediat,Div Hematol Oncol, Los Angeles, CA 90089 USA. NIH, NCI, Ctr Canc Res, Pediat Oncol Branch, Bethesda, MD 20892 USA. Childrens Oncol Grp, Arcadia, CA USA. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. RP Metelitsa, LS (reprint author), Childrens Hosp Los Angeles, Dept Hematol Oncol, 4650 Sunset Blvd, Los Angeles, CA 90027 USA. EM lmetelitsa@chla.usc.edu OI Reynolds, C. Patrick/0000-0002-2827-8536 FU NCI NIH HHS [CA60104, CA116548, CA81403, P01 CA081403, R01 CA060104, R01 CA116548] NR 69 TC 44 Z9 44 U1 1 U2 1 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 SEP PY 2007 VL 117 IS 9 BP 2702 EP 2712 DI 10.1172/JCI30751 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 209JK UT WOS:000249384600040 PM 17710228 ER PT J AU Calvisi, DF Ladu, S Gorden, A Farina, M Lee, JS Conner, EA Schroeder, I Factor, VM Thorgeirsson, SS AF Calvisi, Diego F. Ladu, Sara Gorden, Alexis Farina, Miriam Lee, Ju-Seog Conner, Elizabeth A. Schroeder, Insa Factor, Valentina M. Thorgeirsson, Snorri S. TI Mechanistic and prognostic significance of aberrant methylation in the molecular pathogenesis of human hepatocellular carcinoma SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID PERICENTROMERIC SATELLITE REGIONS; TUMOR-SUPPRESSOR GENE; DNA HYPOMETHYLATION; MICROSATELLITE INSTABILITY; EPIGENETIC INACTIVATION; COLORECTAL-CANCER; BREAST-CANCER; LYSYL-OXIDASE; BETA-CATENIN; CPG ISLANDS AB Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, accounting for an estimated 600,000 deaths annually. Aberrant methylation, consisting of DNA hypomethylation and/or promoter gene CpG hypermethylation, is implicated in the development of a variety of solid tumors, including HCC. We analyzed the global levels of DNA methylation as well as the methylation status of 105 putative tumor suppressor genes and found that the extent of genome-wide hypomethylation and CpG hypermethylation correlates with biological features and clinical outcome of HCC patients. We identified activation of Ras and downstream Ras effectors (ERK, AKT, and RAL) due to epigenetic silencing of inhibitors of the Ras pathway in all HCC. Further, selective inactivation of SPRY1 and -2, DAB2, and SOCS4 and -5 genes and inhibitors of angiogenesis (BNIP3, BNIP3L, IGFBP3, and EGLN2) was associated with poor prognosis. Importantly, several epigenetically silenced putative tumor suppressor genes found in HCC were also inactivated in the nontumorous liver. Our results assign both therapeutic and chemopreventive significance to methylation patterns in human HCC and open the possibility of using molecular targets, including those identified in this study, to effectively inhibit HCC development and progression. C1 NIH, NCI, Canc Res Ctr, Lab Expt Carcinogenesis, Bethesda, MD 20892 USA. Univ Sassari, Dept Biomed Sci, Div Expt Pathol & Oncol, I-07100 Sassari, Italy. RP Thorgeirsson, SS (reprint author), NCI, Bldg 37,Room 4146A,37 Convent Dr MSC 4262, Bethesda, MD 20892 USA. EM snorri-thorgeirsson@nih.gov FU Intramural NIH HHS NR 76 TC 218 Z9 230 U1 1 U2 10 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 SEP PY 2007 VL 117 IS 9 BP 2713 EP 2722 DI 10.1172/JCI31457 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 209JK UT WOS:000249384600041 PM 17717605 ER PT J AU Highbarger, HC Hu, ZH Kottilil, S Metcalf, JA Polis, MA Vasudevachari, MB Lane, HC Dewar, RL AF Highbarger, Helene C. Hu, Zonghui Kottilil, Shyam Metcalf, Julia A. Polis, Michael A. Vasudevachari, M. B. Lane, H. Clifford Dewar, Robin L. TI Comparison of the Abbott 7000 and Bayer 340 systems for measurement of hepatitis C virus load SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; INTERNATIONAL UNIT STANDARD; HCV RNA QUANTITATION; PLUS RIBAVIRIN; ANTIVIRAL THERAPY; INFECTION; ASSAYS; INTERFERON; MANAGEMENT; STABILITY AB This study compared two commercially available assays for the measurement of hepatitis C virus (HCV) RNA levels, the Bayer HCV RNA (version 3.0) branched DNA assay and the Abbott HCV anallyte-specific reagent real-time PCR assay, to assess their quantitative relationships, ease of performance, and time to completion. The study group consisted of randomly selected patients from the NIAID human immunodeficiency virus (HIV) outpatient clinic who were infected with HIV type 1 and HCV. One hundred eighty-four samples from 66 patients coinfected with HIV and HCV receiving treatments under various protocols were analyzed for the correlation and agreement of the results. The results indicated that the two assays correlate well in the overlapping linear ranges of the assays and show good agreement. From the results obtained, we have derived a mathematical formula to compare the viral load results between the two assays, which is given as log(10) Abbott assay measure = 0.032 + 1.01 log(10) Bayer assay measure. Although it is preferable to use the same quantitation assay throughout the course of a patient's treatment, valid comparisons of the HCV RNA levels may be made between the results obtained by either of these assays in the overlapping linear range (615 to 7,700,000 IU/ml). C1 NCI, SAIC Frederick Inc, Virus Isolat & Serol Lab, Frederick, MD 21702 USA. NIH, NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. RP Highbarger, HC (reprint author), NCI, SAIC Frederick Inc, Virus Isolat & Serol Lab, Frederick, MD 21702 USA. EM hhighbarge@mail.nih.gov OI Polis, Michael/0000-0002-9151-2268 FU NCI NIH HHS [N01CO12400, N01-CO-12400] NR 22 TC 5 Z9 5 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD SEP PY 2007 VL 45 IS 9 BP 2808 EP 2812 DI 10.1128/JCM.00202-07 PG 5 WC Microbiology SC Microbiology GA 211EK UT WOS:000249506900009 PM 17596352 ER PT J AU Portera, CC Swain, SM AF Portera, Chia C. Swain, Sandra M. TI The heart of the matter SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID BREAST-CANCER PATIENTS; RETROSPECTIVE ANALYSIS; ADJUVANT THERAPY; CHEMOTHERAPY; DOXORUBICIN; DEXRAZOXANE; CYCLOPHOSPHAMIDE; CARDIOTOXICITY; AMPLIFICATION; FAILURE C1 Natl Canc Inst, Med Oncol Branch, Bethesda, MD 20814 USA. Washington Hosp Ctr, Inst Canc, Washington, DC 20010 USA. RP Portera, CC (reprint author), Natl Canc Inst, Med Oncol Branch, Bethesda, MD 20814 USA. OI Swain, Sandra/0000-0002-1320-3830 NR 21 TC 6 Z9 7 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD SEP 1 PY 2007 VL 25 IS 25 BP 3794 EP 3796 DI 10.1200/JCO.2007.11.9537 PG 3 WC Oncology SC Oncology GA 209VL UT WOS:000249416000002 PM 17664459 ER PT J AU Suter, TM Procter, M van Veldhuisen, DJ Muscholl, M Bergh, J Carlomagno, C Perren, T Passalacqua, R Bighin, C Klijn, JGM Ageev, FT Hitre, E Groetz, J Iwata, H Knap, M Gnant, M Muehlbauer, S Spence, A Gelber, RD Piccart-Gebhart, MJ AF Suter, Thomas M. Procter, Marion van Veldhuisen, Dirk J. Muscholl, Michael Bergh, Jonas Carlomagno, Chiara Perren, Timothy Passalacqua, Rodolfo Bighin, Claudia Klijn, Jan G. M. Ageev, Fail T. Hitre, Erika Groetz, Juergen Iwata, Hiroji Knap, Malgorzata Gnant, Michael Muehlbauer, Susanne Spence, Alison Gelber, Richard D. Piccart-Gebhart, Martine J. TI Trastuzumab-associated cardiac adverse effects in the herceptin adjuvant trial SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 41st Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 13-17, 2005 CL Orlando, FL SP Amer Soc Clin Oncol ID HER2-POSITIVE BREAST-CANCER; VENTRICULAR MYOCYTES; CHEMOTHERAPY; CARDIOTOXICITY; NEUREGULIN-1-BETA; DYSFUNCTION; DOXORUBICIN; THERAPY; GROWTH; ERBB2 AB Purpose The purpose of this analysis was to investigate trastuzumab- associated cardiac adverse effects in breast cancer patients after completion of ( neo) adjuvant chemotherapy with or without radiotherapy. Patients and Methods The Herceptin Adjuvant ( HERA) trial is a three- group, multicenter, open- label randomized trial that compared 1 or 2 years of trastuzumab given once every 3 weeks with observation in patients with HER-2-positive breast cancer. Only patients who after completion of ( neo) adjuvant chemotherapy with or without radiotherapy had normal left ventricular ejection fraction ( LVEF >= 55%) were eligible. A repeat LVEF assessment was performed in case of cardiac dysfunction. Results Data were available for 1,693 patients randomly assigned to 1 year trastuzumab and 1,693 patients randomly assigned to observation. The incidence of trastuzumab discontinuation due to cardiac disorders was low ( 4.3%). The incidence of cardiac end points was higher in the trastuzumab group compared with observation ( severe congestive heart failure [CHF], 0.60% v 0.00%; symptomatic CHF, 2.15% v 0.12%; confirmed significant LVEF drops, 3.04% v 0.53%). Most patients with cardiac dysfunction recovered in fewer than 6 months. Patients with trastuzumab-associated cardiac dysfunction were treated with higher cumulative doses of doxorubicin ( 287 mg/m(2) v 257 mg/m(2)) or epirubicin ( 480 mg/m(2) v 422 mg/m(2)) and had a lower screening LVEF and a higher body mass index. Conclusion Given the clear benefit in disease-free survival, the low incidence of cardiac adverse events, and the suggestion that cardiac dysfunction might be reversible, adjuvant trastuzumab should be considered for treatment of breast cancer patients who fulfill the HERA trial eligibility criteria. C1 Univ Hosp Bern, Swiss Cardiovasc Ctr, Basel, Switzerland. F Hoffmann La Roche, Basel, Switzerland. Frontier Sci, Kingussie, Scotland. Univ Groningen, Dept Cardiol, Groningen, Netherlands. Dr Daniel Den Hoed Canc Ctr, Erasmus MC, Rotterdam, Netherlands. Kardiol Praxis, Munich, Germany. Krakenhaus Gerresheim, Cardiol Wilhelm Marx Haus, Dusseldorf, Germany. Univ Hamburg Hosp, Dept Cardiol, D-2000 Hamburg, Germany. Univ Hosp Stockholm, Karolinska Inst, Dept Cardiol, Stockholm, Sweden. Univ Naples Federico 2, Dept Mol & Clin Endocrinol, Naples, Italy. Ist Ospitalieri, Div Med Oncol, Cremona, Italy. Natl Canc Inst, Genoa, Italy. UK Clin Ctr, Natl Canc Inst, Leeds, W Yorkshire, England. St James Univ Hosp, Leeds, W Yorkshire, England. Cardiol Res Complex, Moscow, Russia. Natl Inst Oncol, Budapest, Hungary. Aichi Canc Ctr Hosp, Nagoya, Aichi 464, Japan. Med Univ Vienna, Vienna, Austria. Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA. Univ Libre Bruxelles, Inst Jules Bordet, Dept Med & Breast Int Grp, Brussels, Belgium. RP Suter, TM (reprint author), Univ Hosp Bern, Swiss Cardiovasc Ctr, Inselspital, CH-3010 Bern, Switzerland. EM thomas.suter@insel.ch RI van Veldhuisen, Dirk Jan/E-8967-2014; OI Perren, Timothy/0000-0001-8472-8856; Gnant, Michael/0000-0003-1002-2118 NR 14 TC 268 Z9 278 U1 2 U2 18 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 SEP 1 PY 2007 VL 25 IS 25 BP 3859 EP 3865 DI 10.1200/JCO.2006.09.1611 PG 7 WC Oncology SC Oncology GA 209VL UT WOS:000249416000013 PM 17646669 ER PT J AU Blum, W Klisovic, RB Hackanson, B Liu, ZF Liu, SJ Devine, H Vukosavljevic, T Huynh, L Lozanski, G Kefauver, C Plass, C Devine, SM Heerema, NA Murgo, A Chan, KK Grever, MR Byrd, JC Marcucci, G AF Blum, William Klisovic, Rebecca B. Hackanson, Bjoern Liu, Zhongfa Liu, Shujun Devine, Hollie Vukosavljevic, Tamara Huynh, Lenguyen Lozanski, Gerard Kefauver, Cheryl Plass, Christoph Devine, Steven M. Heerema, Nyla A. Murgo, Anthony Chan, Kenneth K. Grever, Michael R. Byrd, John C. Marcucci, Guido TI Phase I study of decitabine alone or in combination with valproic acid in acute myeloid leukemia SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 48th Annual Meeting of the American-Society-of-Hematology CY DEC 09-12, 2006 CL Orlando, FL SP Amer Soc Hematol ID HISTONE DEACETYLASE INHIBITION; ACUTE PROMYELOCYTIC LEUKEMIA; TRANS-RETINOIC ACID; DNA METHYLATION; MYELODYSPLASTIC SYNDROMES; 5-AZA-2'-DEOXYCYTIDINE; MLL; METHYLTRANSFERASE; TRANSCRIPTION; FUSION AB Purpose To determine an optimal biologic dose ( OBD) of decitabine as a single agent and then the maximum- tolerated dose ( MTD) of valproic acid ( VA) combined with decitabine in acute myeloid leukemia ( AML). Patients and Methods Twenty-five patients ( median age, 70 years) were enrolled; 12 were untreated and 13 had relapsed AML. To determine an OBD ( based on a gene re-expression end point), 14 patients received decitabine alone for 10 days. To determine the MTD, 11 patients received decitabine ( at OBD, days 1 through 10) plus dose-escalating VA ( days 5 through 21). Results The OBD of decitabine was 20 mg/m(2)/d intravenously, with limited nonhematologic toxicity. In patients treated with decitabine plus VA, dose- limiting encephalopathy occurred in two of two patients at VA 25 mg/ kg/d and one of six patients at VA 20 mg/ kg/d. Drug- induced re- expression of estrogen receptor ( ER) was associated with clinical response ( P <=.05). ER promoter demethylation, global DNA hypomethylation, depletion of DNA methyltransferase enzyme, and histone hyperacetylation were also observed. In an intent-to-treat analysis, the response rate was 44% ( 11 of 25). Of 21 assessable patients, 11 ( 52%) responded: four with morphologic and cytogenetic complete remission ( CR; each had complex karyotype), four with incomplete CR, and three with partial remission. In untreated AML, four of nine assessable patients achieved CR. Clinical responses appeared similar for decitabine alone or with VA. Conclusion Low-dose decitabine was safe and showed encouraging clinical and biologic activity in AML, but the addition of VA led to encephalopathy at relatively low doses. On the basis of these results, additional studies of decitabine ( 20 mg/m(2)/d for 10 days) alone or with an alternative deacetylating agent are warranted. C1 Ohio State Univ, Dept Med, Dept Mol Virol, Div Hematol & Oncol, Columbus, OH 43210 USA. Ohio State Univ, Dept Mol Virol, Columbus, OH 43210 USA. Ohio State Univ, Dept Immunol, Columbus, OH USA. Ohio State Univ, Dept Med Genet, Div Human Canc Genet, Columbus, OH 43210 USA. Ohio State Univ, Ctr Comprehens Canc, Solove Res Inst, Columbus, OH 43210 USA. Ohio State Univ, Coll Pharm, Dept Pathol, Columbus, OH 43210 USA. NIH, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. Univ Freiburg, Med Ctr, Dept Hematol, Freiburg, Germany. RP Blum, W (reprint author), Ohio State Univ, Ctr Comprehens Canc, Div Hematol & Oncol, B310 Starling Loving Hall,320 W 10th Ave, Columbus, OH 43210 USA. EM william.blum@osumc.edu RI Liu, Zhongfa/G-8549-2013; Blum, William/E-2769-2011; Plass, Christoph/H-7192-2014 FU NCI NIH HHS [R01 CA102031, U01 CA 76576, K23CA120708] NR 35 TC 202 Z9 212 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 SEP 1 PY 2007 VL 25 IS 25 BP 3884 EP 3891 DI 10.1200/JCO.2006.09.4169 PG 8 WC Oncology SC Oncology GA 209VL UT WOS:000249416000017 PM 17679729 ER PT J AU Anderson, WF Reiner, AS Matsuno, RK Pfeiffer, RM AF Anderson, William F. Reiner, Anne S. Matsuno, Rayna K. Pfeiffer, Ruth M. TI Shifting breast cancer trends in the United States SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SCREENING MAMMOGRAPHY; AGE DISTRIBUTION; MORTALITY-RATES; WOMEN; EPIDEMIOLOGY; SURVEILLANCE; CARCINOMA; PATTERNS AB Purpose United States breast cancer incidence rates declined during the years 1999 to 2003, and then reached a plateau. These recent trends are impressive and may indicate an end to decades of increasing incidence. Methods To put emerging incidence trends into a broader context, we examined age incidence patterns ( frequency and rates) during five decades. We used age density plots, two-component mixture models, and age-period-cohort ( APC) models to analyze changes in the United States breast cancer population over time. Results The National Cancer Institute's Connecticut Historical Database and Surveillance, Epidemiology, and End Results program collected 600,000+ in situ and invasive female breast cancers during the years 1950 to 2003. Before widespread screening mammography in the early 1980s, breast cancer age-at-onset distributions were bimodal, with dominant peak frequency ( or mode) near age 50 years and smaller mode near age 70 years. With widespread screening mammography, bimodal age distributions shifted to predominant older ages at diagnosis. From 2000 to 2003, the bimodal age distribution returned to dominant younger ages at onset, similar to patterns before mammography screening. APC models confirmed statistically significant calendar- period ( screening) effects before and after 1983 to 1987. Conclusion Breast cancer in the general United States population has a bimodal age at onset distribution, with modal ages near 50 and 70 years. Amid a background of previously increasing and recently decreasing incidence rates, breast cancer populations shifted from younger to older ages at diagnosis, and then back again. These dynamic fluctuations between early-onset and late-onset breast cancer types probably reflect a complex interaction between age- related biologic, risk factor, and screening phenomena. C1 NIH, NCI, Dept Hlth & Human Serv, Div Canc Epidemiol Biostat Branch, Bethesda, MD 20892 USA. RP Anderson, WF (reprint author), NIH, NCI, Dept Hlth & Human Serv, Div Canc Epidemiol Biostat Branch, EPS,Room 8036,6120 Executive Blvd, Bethesda, MD 20892 USA. EM wanderso@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011 FU Intramural NIH HHS NR 34 TC 26 Z9 27 U1 0 U2 0 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 SEP 1 PY 2007 VL 25 IS 25 BP 3923 EP 3929 DI 10.1200/JCO.2007.11.6079 PG 7 WC Oncology SC Oncology GA 209VL UT WOS:000249416000022 PM 17679726 ER PT J AU Agulnik, M Cohen, EWE Cohen, RB Chen, EX Vokes, EE Hotte, SJ Winquist, E Laurie, S Hayes, DN Dancey, JE Brown, S Pond, GR Lorimer, I Daneshmand, M Ho, J Tsao, MS Siu, LL AF Agulnik, Mark Cohen, Ezra W. E. Cohen, Roger B. Chen, Eric X. Vokes, Everett E. Hotte, Sebastien J. Winquist, Eric Laurie, Scott Hayes, D. Neil Dancey, Janet E. Brown, Shirley Pond, Gregory R. Lorimer, Ian Daneshmand, Manijeh Ho, James Tsao, Ming-Sound Siu, Lillian L. TI Phase II study of lapatinib in recurrent or metastatic epidermal growth factor receptor and/or erbB2 expressing adenoid cystic carcinoma and non-adenoid cystic carcinoma malignant tumors of the salivary glands SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 42nd Annual Meeting of the American-Society-of-Clinical-Oncology CY JUN 02-06, 2006 CL Atlanta, GA SP Amer Soc Clin Oncol ID CELL NUCLEAR ANTIGEN; DUCT CARCINOMA; C-ERBB-2 ONCOPROTEIN; IMATINIB MESYLATE; KINASE INHIBITOR; SOLID TUMORS; PROTEIN; HER-2/NEU; CANCER; TRIAL AB Purpose Expression of erbB2 and/or epidermal growth factor receptor (EGFR) is associated with biologic aggressiveness and poor prognosis in malignant salivary gland tumors (MSGTs). This phase II study was conducted to determine the antitumor activity of lapatinib, a dual inhibitor of EGFR and erbB2 tyrosine kinase activity, in MSGTs. Patients and Methods Patients with progressive, recurrent, or metastatic adenoid cystic carcinoma (ACC) immunohistochemically expressing at least 1 + EGFR and/or 2 + erbB2 were treated with lapatinib 1,500 mg daily, in a two-stage cohort. Patients with non-ACC MSGTs were treated as a separate single-stage cohort. Results Of 62 patients screened, 29 of 33 (88%) ACC and 28 of 29 (97%) non-ACC patients expressed EGFR and/or erbB2. Forty patients with progressive disease were enrolled onto the study. Among 19 assessable ACC patients, there were no objective responses, 15 patients (79%) had stable disease (SD), nine patients (47%) had SD >= 6 months, and four patients (21%) had progressive disease (PD). For 17 assessable non-ACC patients, there were no objective responses, eight patients (47%) had SD, four patients (24%) had SD >= 6 months, and nine patients (53%) had PD. The most frequent adverse events were grade 1 to 2 diarrhea, fatigue, and rash. Eight paired tumor biopsies for correlative studies were procured; results did not correlate with clinical outcome. Conclusion Although no responses were observed, lapatinib was well tolerated, with prolonged tumor stabilization of >= 6 months in 36% (95% CI, 21% to 54%) of assessable patients. The antitumor effects of lapatinib in MGSTs appear mainly cytostatic, hence evaluation of other molecular targeted agents, or combinations with lapatinib, may be considered. Continued efforts should be made to gain better understanding into the biology of this heterogeneous group of malignancies. C1 Princess Margaret Hosp, Phase II Consortium, Toronto, ON M4X 1K9, Canada. Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA. Univ N Carolina, Chapel Hill, NC USA. Natl Canc Inst, Bethesda, MD USA. RP Siu, LL (reprint author), Princess Margaret Hosp, Dept Haematol & Med Oncol, 610 Univ Ave,Suite 5-718, Toronto, ON M5G 2M9, Canada. EM lillian.siu@uhn.on.ca OI Hayes, D. Neil/0000-0001-6203-7771 FU NCI NIH HHS [N01-CM-57018-16, N01-CM-62203] NR 46 TC 111 Z9 116 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 SEP 1 PY 2007 VL 25 IS 25 BP 3978 EP 3984 DI 10.1200/JCO.2007.11.8612 PG 7 WC Oncology SC Oncology GA 209VL UT WOS:000249416000030 PM 17761983 ER PT J AU Othman, AA Newman, AH Eddington, ND AF Othman, Ahmed A. Newman, Amy H. Eddington, Natalie D. TI Evaluation of the transport, metabolism, pharmacokinetics and pharmacodynamics of GA250, a novel N-substituted benztropine analog developed as a substitute medication for cocaine abuse SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Meeting Abstract CT 36th Annual Meeting of the American-College-of-Clinical-Pharmacology CY SEP 09-11, 2007 CL San Francisco, CA SP Amer Coll Clin Pharmacol C1 Univ Maryland, Sch Pharm, Baltimore, MD 21201 USA. Natl Inst Drug Abuse, Med Chem Sect, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD SEP PY 2007 VL 47 IS 9 MA 66 BP 1197 EP 1197 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 205GC UT WOS:000249101000065 ER PT J AU Sidorov, IA Prabakaran, P Dimitrov, DS AF Sidorov, Igor A. Prabakaran, Ponraj Dimitrov, Dirniter S. TI Non-covalent conjugation of nanoparticles to antibodies via electrostatic interactions - A computational model SO JOURNAL OF COMPUTATIONAL AND THEORETICAL NANOSCIENCE LA English DT Article DE nanoparticle; antibody; liposome; electrostatics; non-covalent interaction; targeted delivery ID CIRCULATION TIME; LIPOSOMES; TUMORS; BLOOD; CELLS AB Conjugation of antibodies to nanoparticles is important for the development of vehicles with targeting specificity which can be used for diagnosis and treatment of cancer and other diseases. The antibody association with nanoliposomes and other nanoparticles is achieved mostly by generation of covalent bonds based on their chemical and structural properties. Here we describe a theoretical approach that may have implications for non-covalent conjugation of antibodies to nanoparticles based on their electrostatic properties. We analyzed in detail the crystal structure of the anti-HIV antibody Fab m18 and identified basic residues in the constant domain of the light chain. Some of these residues including four lysines at the positions 126, 183, 188, and 190, histidine 189 and agrinine 211 are highly exposed and form clusters. The electrostatic potential of the antibody surface was calculated by solving the Poisson-Boltzmann equation. The results suggest the existence of a dominant positively charged surface overlapping with the basic residues. We hypothesized that these conserved charges on the constant domain of antibody may facilitate binding to a negatively charged nanoparticle surface. Our computational analysis of the electrostatic energy of antibody-nanoparticle interactions provided evidence supporting this hypothesis and the possibility to design antibodies that can be non-covalently associated with nanoparticles via electrostatic interactions. These results may provide a framework for the development of novel approaches for the generation of antibody-nanoparticle conjugates. C1 NCI, Prot Interact Grp, CCRNP, CCR,NIH, Frederick, MD 21702 USA. RP Sidorov, IA (reprint author), NCI, Prot Interact Grp, CCRNP, CCR,NIH, Frederick, MD 21702 USA. RI Ponraj, Prabakaran/D-6325-2011 NR 14 TC 12 Z9 12 U1 1 U2 8 PU AMER SCIENTIFIC PUBLISHERS PI STEVENSON RANCH PA 25650 NORTH LEWIS WAY, STEVENSON RANCH, CA 91381-1439 USA SN 1546-1955 J9 J COMPUT THEOR NANOS JI J. Comput. Theor. Nanosci. PD SEP PY 2007 VL 4 IS 6 BP 1103 EP 1107 PG 5 WC Chemistry, Multidisciplinary; Nanoscience & Nanotechnology; Materials Science, Multidisciplinary; Physics, Applied; Physics, Condensed Matter SC Chemistry; Science & Technology - Other Topics; Materials Science; Physics GA 224ML UT WOS:000250451000002 ER PT J AU Matsui, K Lie, RK Kita, Y AF Matsui, Kenji Lie, Reidar K. Kita, Yoshikuni TI Two methods of obtaining informed consent in a genetic epidemiological study: Effects on understanding SO JOURNAL OF EMPIRICAL RESEARCH ON HUMAN RESEARCH ETHICS LA English DT Article DE informed consent; warranted uncertainty; epidemiological research; comprehension; intervention ID CLINICAL-TRIALS; WRITTEN INFORMATION; VIDEO AB THIS STUDY EVALUATED THE EFFECT ON participant understanding and participation rates of two different approaches to obtaining informed consent, using 2,192 actual research subjects in a genetic cohort study. One group received the routine approach consisting of written materials and an oral explanation. The other group received a more intense approach consisting of educational lectures and group meetings in addition to the routine approach. Subjects in the intense approach group were relatively more likely to read some or all of the explanatory material. Those in the intense group who did not read the material were more likely than those in the routine group to express uncertainty about their understanding of the research. Those in the intense group who read the material perceived that they had a higher level of understanding of the research and this was associated with a higher frequency of volunteering to participate. In contrast, subjects in the routine group were less likely to read the written material, but ironically more likely to assume that they understood what the research was about. These rather paradoxical findings raised questions about what motivates potential research subjects to become sufficiently engaged to seek actual understanding of the research before volunteering. C1 [Matsui, Kenji] Univ Tokyo, Grad Sch Med, Dept Biomed Eth, Bunkyo Ku, Tokyo 1130033, Japan. [Lie, Reidar K.] Univ Bergen, N-5020 Bergen, Norway. [Lie, Reidar K.] NIH, Bethesda, MD USA. [Kita, Yoshikuni] Shiga Univ Med Sci, Shiga, Japan. RP Matsui, K (reprint author), Univ Tokyo, Grad Sch Med, Dept Biomed Eth, Bunkyo Ku, Bldg 3 Med,Hongo 7-3-1, Tokyo 1130033, Japan. EM kjmatsui@m.u-tokyo.ac.jp NR 23 TC 8 Z9 8 U1 0 U2 1 PU UNIV CALIFORNIA PRESS PI BERKELEY PA C/O JOURNALS DIVISION, 2000 CENTER ST, STE 303, BERKELEY, CA 94704-1223 USA SN 1556-2646 J9 J EMPIR RES HUM RES JI J. Empir. Res. Hum. Res. Ethics PD SEP PY 2007 VL 2 IS 3 BP 39 EP 48 DI 10.1525/JERHRE.2007.2.3.39 PG 10 WC Ethics; Medical Ethics SC Social Sciences - Other Topics; Medical Ethics GA 308JJ UT WOS:000256385300006 PM 19385850 ER PT J AU Yan, X Voutetakis, A Zheng, CY Hai, B Zhang, CM Baum, BJ Wang, SL AF Xing Yan Voutetakis, Antonis Zheng, Changyu Bo Hai Chunmei Zhang Baum, Bruce J. Songlin Wang TI Sorting of transgenic secretory proteins in miniature pig parotid glands following adenoviral-mediated gene transfer SO JOURNAL OF GENE MEDICINE LA English DT Article DE gene transfer; adenovirus; miniature pig; parotid gland; protein sorting; secretion ID RAT SUBMANDIBULAR-GLANDS; HUMAN AQUAPORIN-1 CDNA; SALIVARY-GLANDS; GROWTH-HORMONE; IN-VIVO; RETRODUCTAL DELIVERY; THERAPEUTICS; TOXICITY; VECTOR; HYDROXYCHLOROQUINE AB Background Gene transfer to salivary glands for use in treating both systemic and upper gastrointestinal tract diseases shows considerable potential. Numerous studies in rodents demonstrate that salivary glands can secrete transgenic secretory proteins either into saliva, primarily via the regulated secretory pathway (RSP), or into the bloodstream, primarily by the constitutive secretory pathway (CSP). The purpose of the present study was to assess the sorting characteristics of human growth hormone (hGH), a RSP protein, and human erythropoietin (hEpo), a CSP protein, in a large animal model of salivary gland gene transfer, the miniature pig. Methods Recombinant serotype 5 adenoviral (Ad5; 10(11) particles/gland) vectors encoding either hGH (AdCMVhGH) or hEpo (AdCMVhEpo) were administered to both parotid glands of male miniature pigs by intraductal cannulation. The secretion of hGH or hEpo was measured in both saliva and serum on days 3, 7 and 14 following administration. Detailed serum chemistry and hematological analyses were performed, and the presence of serum antibodies to hGH and hEpo was measured. For AdCMVhEpo-treated minipigs vector distribution in multiple tissues was determined by quantitative polymerase chain reaction (QPCR). Results The RSP protein hGH was secreted entirely into saliva, while the CSP protein hEpo was secreted into both saliva and serum. Most hEpo was found in saliva, but serum hEpo levels were sufficient to significantly increase hematocrit levels in treated animals by similar to-10%. Expression of both transgenes was maximal on day 3 and declined to near background by day 14. The amount of vector found in the targeted glands was 100 x more than in other tissues. Conclusions Secretion of transgenic hGH from minipig parotid glands occurred principally into saliva via the RSP, as seen in rodents, while hEpo was secreted into both saliva and serum, the latter presumably via the CSP. Even though hEpo secretion into the bloodstream was not to the extent previously observed in rodents, serum hEpo levels were considerable and the hEpo was biologically active. Ad5 vector distribution was highly restricted to the parotid glands with little vector detected elsewhere. While the results in this large animal model support the established notion that salivary gland gene transfer can be used for treating systemic single protein deficiency disorders, they also highlight differences in transgenic CSP protein sorting between rodents and miniature pigs. Copyright (c) 2007 John Wiley & Sons, Ltd. C1 NIDCR, GTTB, NIH, DHHS, Bethesda, MD 20892 USA. Capital Med Univ, Sch Stomatol, Salivary Gland Dis Ctr, Beijing 100050, Peoples R China. Capital Med Univ, Sch Stomatol, Mol Lab Gene Therapy, Beijing 100050, Peoples R China. RP Baum, BJ (reprint author), NIDCR, GTTB, NIH, DHHS, Bldg 10,Rm 1N113,MSC-1190, Bethesda, MD 20892 USA. EM bbaum@dir.nidcr.nih.gov FU Intramural NIH HHS NR 28 TC 17 Z9 19 U1 1 U2 4 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 SEP PY 2007 VL 9 IS 9 BP 779 EP 787 DI 10.1002/jgm.1081 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 213YP UT WOS:000249703500004 PM 17654745 ER PT J AU Stein, JA Andersen, R Gelberg, L AF Stein, Judith A. Andersen, Ronald Gelberg, Lillian TI Applying the Gelberg-Andersen Behavioral Model for Vulnerable Populations to health services utilization in homeless women SO JOURNAL OF HEALTH PSYCHOLOGY LA English DT Article DE gelberg-Andersen Behavioral Model for Vulnerable Populations; health services utilization; homeless women; homeless women's health ID MEDICAL-CARE; SHELTERED HOMELESS; MENTAL-ILLNESS; ADULTS; BARRIERS; OUTCOMES; COHORT; RISK AB We applied the Gelberg-Andersen Behavioral Model for Vulnerable Populations to predict health services utilization (HSU) in 875 homeless US women. Structural models assessed the impact of predisposing (demographics, psychological distress, alcohol/drug problems, homelessness severity), enabling (health insurance, source of care, barriers) and need (illness) variables on HSU (preventive care, outpatient visits, hospitalizations). Homelessness severity predicted illness, barriers and less insurance. Distress predicted more barriers, illness and less outpatient HSU. Drug problems predicted hospitalizations. Barriers predicted more illness and less outpatient HSU. Health and homelessness indicators were worse for White women. Better housing, access to care and insurance would encourage appropriate HSU. C1 Univ Calif Los Angeles, NIDA, Ctr Collaborat Res Drug Abuse, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Hlth Sci, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Family Med, Los Angeles, CA 90024 USA. RP Stein, JA (reprint author), Univ Calif Los Angeles, NIDA, Ctr Collaborat Res Drug Abuse, 3566 Franz Hall,405 Hilgard Ave, Los Angeles, CA 90095 USA. EM jastein@ucla.edu FU AHRQ HHS [R01 HS 08323]; NIAAA NIH HHS [R21AA13398-01]; NIDA NIH HHS [R01 DA14835-01, P01-DA01070-33]; NIMHD NIH HHS [P20-MD000148, P20-MD000182] NR 36 TC 60 Z9 61 U1 5 U2 20 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1359-1053 J9 J HEALTH PSYCHOL JI J. Health Psychol. PD SEP PY 2007 VL 12 IS 5 BP 791 EP 804 DI 10.1177/1359105307080612 PG 14 WC Psychology, Clinical SC Psychology GA 223NP UT WOS:000250377800009 PM 17855463 ER PT J AU Schumann, A Nyamathi, A Stein, JA AF Schumann, Anja Nyamathi, Adeline Stein, Judith A. TI HIV risk reduction in a nurse case-managed TB and HIV intervention among homeless adults SO JOURNAL OF HEALTH PSYCHOLOGY LA English DT Article DE HIV risk reduction; homelessness injection drug use; nurse-managed intervention; randomized trial ID HIV/AIDS PREVENTION; DRUG-USERS; WOMEN; BEHAVIORS; AIDS; TUBERCULOSIS; KNOWLEDGE; RELIABILITY; ATTITUDES; PROGRAMS AB This study evaluated a six-month nurse case-managed intervention against a standard care control program among 295 sheltered homeless adults from Los Angeles, USA. The primary aim of the intervention was encouraging latent tuberculosis infection treatment completion. The secondary aim was reducing HIV risk, the focus of this report. A longitudinal path model revealed that the intervention impacted cognitive factors of AIDS Knowledge, Perceived AIDS Risk and Self-efficacy for Condom Use, but did not impact substance use and risky sexual behaviors. The dual intervention program for HIV and TB provided promising synergistic effects by targeting risk factors common to both infections. C1 Cambridge Hlth Alliance, Div Addict, Medford, MA 02155 USA. Univ Calif Los Angeles, Acad Affairs, Los Angeles, CA USA. Univ Calif Los Angeles, NIDA, Ctr Collaborat Res Drug Abuse, Dept Psychol, Los Angeles, CA USA. RP Schumann, A (reprint author), Cambridge Hlth Alliance, Div Addict, 101 Stn Landing, Medford, MA 02155 USA. EM aschumann@challiance.org FU NIDA NIH HHS [DA01070-33, DA11145] NR 33 TC 7 Z9 7 U1 0 U2 1 PU SAGE PUBLICATIONS LTD PI LONDON PA 1 OLIVERS YARD, 55 CITY ROAD, LONDON EC1Y 1SP, ENGLAND SN 1359-1053 J9 J HEALTH PSYCHOL JI J. Health Psychol. PD SEP PY 2007 VL 12 IS 5 BP 833 EP 843 DI 10.1177/1359105307080618 PG 11 WC Psychology, Clinical SC Psychology GA 223NP UT WOS:000250377800012 PM 17855466 ER PT J AU Kehler, JS David, VA Schaffer, AA Bajema, K Eizirik, E Ryugo, DK Hannah, SS O'Brien, SJ Menotti-Raymond, M AF Kehler, James S. David, Victor A. Schaeffer, Alejandro A. Bajema, Kristina Eizirik, Eduardo Ryugo, David K. Hannah, Steven S. O'Brien, Stephen J. Menotti-Raymond, Marilyn TI Four independent mutations in the feline Fibroblast Growth Factor 5 gene determine the long-haired phenotype in domestic cats SO JOURNAL OF HEREDITY LA English DT Article ID GROWTH-FACTOR RECEPTOR; STRUCTURAL BASIS; MESSENGER-RNA; FACTOR-5 GENE; FACTOR FAMILY; FIBROBLAST; CYCLE; FGF-5; SPECIFICITY; ACTIVATION AB To determine the genetic regulation of "hair length" in the domestic cat, a whole-genome scan was performed in a multigenerational pedigree in which the "long-haired" phenotype was segregating. The 2 markers that demonstrated the greatest linkage to the long-haired trait (log of the odds >= 6) flanked an estimated 10-Mb region on cat chromosome B1 containing the Fibroblast Growth Factor 5 (FGF5) gene, a candidate gene implicated in regulating hair follicle growth cycle in other species. Sequence analyses of FGF5 in 26 cat breeds and 2 pedigrees of nonbreed cats revealed 4 separate mutations predicted to disrupt the biological activity of the FGF5 protein. Pedigree analyses demonstrated that different combinations of paired mutant FGF5 alleles segregated with the long-haired phenotype in an autosomal recessive manner. Association analyses of more than 380 genotyped breed and nonbreed cats were consistent with mutations in the FGF5 gene causing the long-haired phenotype in an autosomal recessive manner. In combination, these genomic approaches demonstrated that FGF5 is the major genetic determinant of hair length in the domestic cat. C1 Natl Canc Inst, Lab Genom Diversity, Frederick, MD 21702 USA. Univ Penn, Sch Vet Med, Ctr Anim Transgenesis & Germ Cell Res, Kennett Sq, PA 19348 USA. Natl Inst Hlth, Dept Hlth & Human Serv, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Pontificia Univ Catolica Rio do Grande Sul, Fac Biociencias, Ctr Biol Genom & Mol, BR-90619900 Porto Alegre, RS, Brazil. Johns Hopkins Univ, Dept Otolaryngol & Neurosci, Baltimore, MD 21205 USA. Nestle Purina PetCare Co, St Louis, MO 63134 USA. RP Kehler, JS (reprint author), Natl Canc Inst, Lab Genom Diversity, Frederick, MD 21702 USA. EM jkehler@ncifcrf.gov RI Schaffer, Alejandro/F-2902-2012; Eizirik, Eduardo/K-8034-2012; Ryugo, David/G-1940-2012 OI Eizirik, Eduardo/0000-0002-9658-0999; Ryugo, David/0000-0002-5250-7503 FU Intramural NIH HHS [Z01 BC005385-25, Z01 LM000097-07]; NCRR NIH HHS [K01 RR019677, RR019677-01]; NIDCD NIH HHS [DC00232, R01 DC000232] NR 43 TC 39 Z9 43 U1 0 U2 6 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0022-1503 J9 J HERED JI J. Hered. PD SEP-OCT PY 2007 VL 98 IS 6 BP 555 EP 566 DI 10.1093/jhered/esm072 PG 12 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 218IM UT WOS:000250009200001 PM 17767004 ER PT J AU Fedorova, OV Zhuravin, IA Agalakova, NI Yamova, LA Talan, MI Lakatta, EG Bagrov, AY AF Fedorova, Olga V. Zhuravin, Igor A. Agalakova, Natalia I. Yamova, Liubov A. Talan, Mark I. Lakatta, Edward G. Bagrov, Alexei Y. TI Intrahippocampal microinjectin of an exquisitely low dose of ouabain mimics NaCl loading and stimulates a bufadienolide Na/K-ATPase inhibitor SO JOURNAL OF HYPERTENSION LA English DT Article DE adrenal cortex; angiotensin; brain; dietary sodium; hippocampus; hypertension; inbred dahl rats; marinobufagenin; Na+K+-exchanging ATPase; ouabain ID DAHL-S RATS; SALT-SENSITIVE HYPERTENSION; ANGIOTENSIN-II; BLOOD-PRESSURE; BRAIN OUABAIN; ENDOGENOUS OUABAIN; SODIUM-CHANNELS; MARINOBUFAGENIN; NA+,K+-ATPASE; RESPONSES AB Background Brain endogenous ouabain (EOU) raises blood pressure (BP) via an angiotensin 11 (ATII)-sensitive pathway in NaCl-loaded Dahl salt-sensitive rats (DSS). Brain EOU activates central and adrenocortical renin-angiotensin systems, and stimulates marinobufagenin, a vasoconstrictor and natriuretic inhibitor of sodium pump. Methods We studied effects of acute NaCl loading (117 mmol/kg NaCl, intraperitoneally) on levels of EOU and marinobufagenin in several brain areas in DSS. We then studied effects of intrahippocampal administration of very-low-dose ouabain (60pg) on EOU, marinobufagenin, BP, sodium excretion, and sodium-pump activity in the aorta and renal medulla in the absence and presence of anti-marinobufagenin and anti-ouabain antibodies, and losartan. Results NaCl loading of DSS induced transient increases of EOU in the hippocampus and amygdala (115 min; 300%), supraoptical nucleus of hypothalamus (SON) (30 min, 230%) and pituitary (30 min; 85%), and ATII elevation in the SON (30 min). Intrahippocampal administration of ouabain (60pg) stimulated ATII in the SON, produced natriuresis, 40 mmHg rise in BP, inhibition of sodium-pump in the renal medulla (19.6%) and aorta (25%), and a two-fold increase in renal marinobufagenin excretion. Pretreatment of rats with anti-marinobufagenin antibody prevented ouabain-induced pressor and natriuretic responses and sodium-pump inhibition. Pressor responses to ouabain were also prevented by losartan (intravenously) and by administration of anti-ouabain antibody into the SON. Conclusions NaCl loading of DSS induces a cascade of events, triggered by brain EOU and ATII. Intrahippocampal administration of a low-dose ouabain mimics effects of NaCl loading and stimulates marinobufagenin, which produces natriuresis, and inhibits the vascular sodium-pump, inducing an increase in BP. C1 NIA, NIH, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. IM Sechenov Evolutionary Physiol & Biochem Inst, St Petersburg 194223, Russia. RP Bagrov, AY (reprint author), NIA, NIH, Cardiovasc Sci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM BagrovA@mail.nih.gov FU Intramural NIH HHS NR 34 TC 21 Z9 21 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0263-6352 J9 J HYPERTENS JI J. Hypertens. PD SEP PY 2007 VL 25 IS 9 BP 1834 EP 1844 DI 10.1097/HJH.0b013e328200497a PG 11 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 204OQ UT WOS:000249054300014 PM 17762648 ER PT J AU Contractor, N Louten, J Kim, L Biron, CA Kelsall, BL AF Contractor, Nikhat Louten, Jennifer Kim, Leesun Biron, Christine A. Kelsall, Brian L. TI Cutting edge: Peyer's patch plasmacytoid dendritic cells (pDCs) produce low levels of type I interferons: Possible role for IL-10, TGF beta, and prostaglandin E-2 in conditioning a unique mucosal pDC phenotype SO JOURNAL OF IMMUNOLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; IMMUNE-RESPONSE; T-CELLS; RECEPTOR; ALPHA; EXPRESSION; TOLERANCE; MICE; DIFFERENTIATION; INTERLEUKIN-10 AB The organized lymphoid tissues of the intestine likely play an important role in the balance between tolerance to harmless mucosal Ags and commensal bacteria and immunity to mucosal pathogens. We examined the pbenotype and function of plasmacytoid dendritic cells (pDCs) from murine Peyer'spatches (PPs). When stimulated with CpG-enriched oligodeoxynucleotides in vitro, PPs and spleen pDCs made equivalent levels of IL-12,yet PP pDCs were incapable of producing significant levels of type I IFNs. Three regulatory factors associated with mucosal tissues, PGE(2), IL-10, and TGF beta, inhibited the ability of spleen pDCs to produce type I IFN in a dose-dependent fashion. These studies suggest that mucosal factors may regulate the production of type I IFN as well as IL-12 by pDCs. In the intestine, this may be beneficial in preventing harmful innate and adaptive immune responses to commensal microorganisms. C1 NIAID, Mucosal Immun Sect, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. Brown Univ, Dept Mol Microbiol & Immunol, Providence, RI 02912 USA. Wyeth Nutr, Collegeville, PA 19426 USA. Schering Plough Biopharma, Palo Alto, CA 94304 USA. RP Kelsall, BL (reprint author), 10-11N111,10 Ctr Dr, Bethesda, MD 20892 USA. EM kelsall@nih.gov FU Intramural NIH HHS; NIAID NIH HHS [R01 AI 55677, R01 AI055677] NR 30 TC 88 Z9 93 U1 1 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 SEP 1 PY 2007 VL 179 IS 5 BP 2690 EP 2694 PG 5 WC Immunology SC Immunology GA 203RN UT WOS:000248991800006 PM 17709480 ER PT J AU Stewart, TJ Abrams, SI AF Stewart, Trina J. Abrams, Scott I. TI Altered immune function during long-term host-tumor interactions can be modulated to retard autochthonous neoplastic growth SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TRANSGENIC MOUSE MODEL; T-CELL RESPONSES; CANCER VACCINES; METASTATIC-DISEASE; BREAST-CANCER; BEARING MICE; INDUCED IMMUNOSUPPRESSION; SUPPRESSOR-CELLS; DENDRITIC CELLS; DOWN-REGULATION AB Ag-specific and generalized forms of immunosuppression have been documented in animal tumor models. However, much of our knowledge on tumor-induced immunosuppression was acquired using tumor implant models, which do not reiterate the protracted nature of host-tumor interactions. Therefore, a transgenic mouse model of autochthonous mammary tumor development and progression was chosen to investigate the long-term consequences of neoplastic growth on the immune system. In vitro proliferation of unfractionated splenocytes from tumor-bearing mice, as assessed by [H-3]thymidine uptake, was inhibited by the presence of suppressor cells within these splenocyte preparations, because purifying the T cells restored their biological activity. However, the level of inhibition did not correlate with either tumor load or the percentage of myeloid-derived CD11b(+)Gr1(+) cells. To evaluate tumor-specific immune dysfunction, transgenic mice were challenged with autologous tumor cells. Mice with extensive, but not minimal autochthonous tumor burdens demonstrated a significantly enhanced rate of autologous tumor growth compared with age-matched controls. In contrast, an allogeneic tumor challenge was efficiently rejected from both groups of transgenic mice. It was also noted that allogeneic tumor challenge of mice with minimal disease significantly inhibited autochthonous primary tumor growth. We therefore demonstrated that 1) a generalized form of immunosuppression occurred, but not as a result of permanent alterations to T cell function, because purified T cell subsets retained normal biological activity following polyclonal or allostimulation; and 2) tumor-specific immunosuppression emerged as a consequence of tumor progression, but could be modulated to enhance antitumor responses against autochthonous primary neoplastic growth. C1 NCI, Tumor Immunol & Biol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. RP Abrams, SI (reprint author), NCI, Tumor Immunol & Biol Lab, Canc Res Ctr, 10 Ctr Dr,Bldg 10-5B46, Bethesda, MD 20892 USA. EM sa47z@nih.gov RI Stewart, Trina/F-5967-2012 OI Stewart, Trina/0000-0003-3220-9231 FU Intramural NIH HHS NR 53 TC 31 Z9 32 U1 0 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2007 VL 179 IS 5 BP 2851 EP 2859 PG 9 WC Immunology SC Immunology GA 203RN UT WOS:000248991800025 PM 17709499 ER PT J AU Gordon, SN Klatt, NR Bosinger, SE Brenchley, JM Milush, JM Engram, JC Dunham, RM Paiardini, M Klucking, S Danesh, A Strobert, EA Apetrei, C Pandrea, IV Kelvin, D Douek, DC Staprans, SI Sodora, DL Silvestri, G AF Gordon, Shari N. Klatt, Nichole R. Bosinger, Steven E. Brenchley, Jason M. Milush, Jeffrey M. Engram, Jessica C. Dunham, Richard M. Paiardini, Mirko Klucking, Sara Danesh, Ali Strobert, Elizabeth A. Apetrei, Cristian Pandrea, Ivona V. Kelvin, David Douek, Daniel C. Staprans, Silvija I. Sodora, Donald L. Silvestri, Guido TI Severe depletion of mucosal CD4(+) T cells in AIDS-Free simian immunodeficiency virus-infected sooty Mangabeys SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SIV INFECTION; HIV-INFECTION; GASTROINTESTINAL-TRACT; DISEASE; TISSUE; HOSTS; PATHOGENESIS; RESTORATION; THERAPY AB HIV-infected humans and SIV-infected rhesus macaques experience a rapid and dramatic loss of mucosal CD4(+) T cells that is considered to be a key determinant of AIDS pathogenesis. In this study, we show that nonpathogenic SIV infection of sooty mangabeys (SMs), a natural host species for SIV, is also associated with an early, severe, and persistent depletion of memory CD4(+) T cells from the intestinal and respiratory mucosa. Importantly, the kinetics of the loss of mucosal CD4(+) T cells in SMs is similar to that of SIVmac239-infected rhesus macaques. Although the nonpathogenic SIV infection of SMs induces the same pattern of mucosal target cell depletion observed during pathogenic HIV/SIV infections, the depletion in SMs occurs in the context of limited local and systemic immune activation and can be reverted if virus replication is suppressed by antiretroviral treatment. These results indicate that a profound depletion of mucosal CD4(+) T cells is not sufficient per se to induce loss of mucosal immunity and disease progression during a primate lentiviral infection. We propose that, in the disease-resistant SIV-infected SMs, evolutionary adaptation to both preserve immune function with fewer mucosal CD4(+) T cells and attenuate the immune activation that follows acute viral infection protect these animals from progressing to AIDS. C1 Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30329 USA. Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA. Univ Hlth Network, Div Expt Therapeut, Toronto, ON, Canada. NIH, Vaccine Res Ctr, Human Immunol Sect, Bethesda, MD 20892 USA. Univ Texas SW, Dallas, TX 75390 USA. Tulane Univ, Tulane Natl Primate Res Ctr, Covington, LA USA. Merck & Co Inc, West Point, PA 19486 USA. RP Silvestri, G (reprint author), Univ Penn, Dept Pathol & Lab Med, 705 Stellar Chance Labs,422 Curie Blvd, Philadelphia, PA 19104 USA. EM gsilvest@mail.med.upenn.edu RI Dunham, Richard/B-2012-2009 OI Dunham, Richard/0000-0003-4542-2330 FU Intramural NIH HHS [Z01 AI001029-01, Z99 AI999999]; NCRR NIH HHS [P51 RR000165, RR 00165]; NHLBI NIH HHS [R01 HL 075766, R01 HL075766]; NIAID NIH HHS [R21 AI060451, 1F31 AI 066400-01A1, 5T32 AI 07520, AI 066998, F31 AI066400, R01 AI 035522, R01 AI 064066, R01 AI 52755, R01 AI035522, R01 AI052755, R01 AI064066, R01 AI066998, R21 AI 060451, R37 AI066998, T32 AI007520] NR 33 TC 191 Z9 191 U1 2 U2 9 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD SEP 1 PY 2007 VL 179 IS 5 BP 3026 EP 3034 PG 9 WC Immunology SC Immunology GA 203RN UT WOS:000248991800043 PM 17709517 ER PT J AU Pandrea, IV Gautam, R Ribeiro, RM Brenchley, JM Butler, IF Pattison, M Rasmussen, T Marx, PA Silvestri, G Lackner, AA Perelson, AS Douek, DC Veazey, RS Apetrei, C AF Pandrea, Ivona V. Gautam, Rajeev Ribeiro, Ruy M. Brenchley, Jason M. Butler, Isolde F. Pattison, Melissa Rasmussen, Terri Marx, Preston A. Silvestri, Guido Lackner, Andrew A. Perelson, Alan S. Douek, Daniel C. Veazey, Ronald S. Apetrei, Cristian TI Acute loss of intestinal CD4(+) T cells is not predictive of simian immunodeficiency virus virulence SO JOURNAL OF IMMUNOLOGY LA English DT Article ID AFRICAN-GREEN MONKEYS; IN-VIVO REPLICATION; HIV-1 INFECTION; VIRAL-LOAD; SIV INFECTION; GASTROINTESTINAL-TRACT; IMMUNE ACTIVATION; TYPE-1 INFECTION; RHESUS MACAQUE; MANDRILLUS-SPHINX AB The predictive value of acute gut-associated lymphoid tissue (GALT) CD4(+) T cell depletion in lentiviral infections was assessed by comparing three animal models illustrative of the outcomes of SIV infection: pathogenic infection (SIVsmm infection of rhesus macaques (Rh)), persistent nonprogressive infection (SIVagm infection of African green monkeys (AGM)), and transient, controlled infection (SIVagm infection of Rh). Massive acute depletion of GALT CD4(+) T cells was a common feature of acute SIV infection in all three models. The outcome of this mucosal CD4(+) T cell depletion, however, differed substantially between the three models: in SIVsmm-infected Rh, the acute GALT CD4(+) T cell depletion was persistent and continued with disease progression; in SIVagm, intestinal CD4(+) T cells were partially restored during chronic infection in the context of normal levels of apoptosis and immune activation and absence of damage to the mucosal immunologic barrier; in SIVagm-infected Rh, complete control of viral replication resulted in restoration of the mucosal barrier and immune restoration. Therefore, our data support a revised paradigm wherein severe GALT CD4(+) T cell depletion during acute pathogenic HIV and SIV infections of humans and Rh is necessary but neither sufficient nor predictive of disease progression, with levels of immune activation, proliferation and apoptosis being key factors involved in determining progression to AIDS. C1 Tulane Natl Primate Res Ctr, Covington, LA 70433 USA. Tulane Univ, Sch Publ Hlth, Dept Trop Med, New Orleans, LA 70112 USA. Tulane Univ, Sch Med, Dept Microbiol & Immunol, New Orleans, LA 70112 USA. Tulane Univ, Sch Med, Dept Pathol, New Orleans, LA 70112 USA. Los Alamos Natl Lab, Los Alamos, NM 87545 USA. NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Dept Pathol, Philadelphia, PA 19107 USA. RP Pandrea, IV (reprint author), Tulane Natl Primate Res Ctr, 18703 3 Rivers Rd, Covington, LA 70433 USA. EM ipandrea@tulanc.edu FU Intramural NIH HHS [Z99 AI999999, ZIA AI001029-02]; NCRR NIH HHS [P20 RR 020159, P20 RR020159, P51 RR 000164, P51 RR000164, R01 RR006555, RR 06555, RR 18745]; NIAID NIH HHS [AI 28433, R01 AI 064066, R01 AI 065325, R01 AI 49080, R01 AI028433, R01 AI049080, R01 AI064066, R01 AI065325, R21 AI 069935, R21 AI069935, R37 AI028433] NR 59 TC 164 Z9 164 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 SEP 1 PY 2007 VL 179 IS 5 BP 3035 EP 3046 PG 12 WC Immunology SC Immunology GA 203RN UT WOS:000248991800044 PM 17709518 ER PT J AU Soule, BP Brown, JM Kushnir-Sukhov, NM Simone, NL Mitchell, JB Metcalfe, DD AF Soule, Benjamin P. Brown, Jared M. Kushnir-Sukhov, Nataliya M. Simone, Nicole L. Mitchell, James B. Metcalfe, Dean D. TI Effects of gamma radiation on Fc epsilon RI and TLR-Mediated mast cell activation SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TOLL-LIKE RECEPTOR; IONIZING-RADIATION; BONE-MARROW; HYDROGEN-PEROXIDE; INDUCED APOPTOSIS; HUMAN-LYMPHOCYTES; IRRADIATION; MICE; TRANSPLANTATION; COMBINATION AB Ionizing gamma radiation has several therapeutic indications including bone marrow transplantation and tumor ablation. Among immune cells, susceptibility of lymphocytes to gamma radiation is well known. However, there is little information on the effects of gamma radiation on mast cells, which are important in both innate and acquired immunity. Previous studies have suggested that mast cells may release histamine in response to high doses of gamma radiation, whereas other reports suggest that mast cells are relatively radioresistant. No strong link has been established between gamma radiation and its effect on mast cell survival and activation. We examined both human and murine mast cell survival and activation, including mechanisms related to innate and acquired immune responses following gamma radiation. Data revealed that human and murine mast cells were resistant to gamma radiation-induced cytotoxicity and, importantly, that irradiation did not directly induce 13-hexosaminidase release. Instead, a transient attenuation of IgE-mediated beta-hexosaminidase release and cytokine production was observed which appeared to be the result of reactive oxygen species formation after irradiation. Mast cells retained the ability to phagocytose Escherichia coli particles and respond to TLR ligands as measured by cytokine production after irradiation. In vivo, there was no decrease in mast cell numbers in skin of irradiated mice. Additionally, mast cells retained the ability to respond to Ag in vivo as measured by passive cutaneous anaphylaxis in mice after irradiation. Mast cells are thus resistant to the cytotoxic effects and alterations in function after irradiation and, despite a transient inhibition, ultimately respond to innate and acquired immune activation signals. C1 NIAID, Lab Allerg Dis, Natl Inst Hlth, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Brown, JM (reprint author), NIAID, Lab Allerg Dis, Natl Inst Hlth, Bldg 10,Room 11C209,10 Ctr Dr,MSC 1881, Bethesda, MD 20892 USA. EM jmbrown@niaid.nih.gov FU Intramural NIH HHS NR 67 TC 21 Z9 21 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 SEP 1 PY 2007 VL 179 IS 5 BP 3276 EP 3286 PG 11 WC Immunology SC Immunology GA 203RN UT WOS:000248991800070 PM 17709544 ER PT J AU Zhang, YH Zhou, ZH Bugge, TH Wahl, LM AF Zhang, Yahong Zhou, Zhao-Hua Bugge, Thomas H. Wahl, Larry M. TI Urokinase-type plasminogen activator stimulation of monocyte matrix metalloproteinase-1 production is mediated by plasmin-dependent signaling through annexin A2 and inhibited by inactive plasmin SO JOURNAL OF IMMUNOLOGY LA English DT Article ID PROSTAGLANDIN-H SYNTHASE-2; SERINE-PROTEASE PLASMIN; AMINO-TERMINAL FRAGMENT; MATRIX METALLOPROTEINASES; CELL-SURFACE; DIFFERENTIAL REGULATION; DEFICIENT MICE; RECEPTOR; EXPRESSION; MACROPHAGES AB Chronic inflammatory diseases are associated with connective tissue turnover that involves a series of proteases, which include the plasminogen activation system and the family of matrix metalloproteinases (MMPs). Urokinase-type plasminogen activator (uPA) and plasmin, in addition to their role in fibrinolysis and activation of pro-MMPs, have been shown to transduce intracellular signals through specific receptors. The potential for uPA and plasmin to also contribute to connective tissue turnover by directly regulating MMP production was examined in human monocytes. Both catalytically active high m.w. uPA, which binds to the uPAR, and low m.w. uPA, which does not, significantly enhanced MMP-1 synthesis by activated human monocytes. In contrast, the N-terminal fragment of uPA, which binds to uPAR, but lacks the catalytic site, failed to induce MMP-1 production, indicating that uPA-stimulated MMP-1 synthesis was plasmin dependent. Endogenous plasmin generated by the action of uPA or exogenous plasmin increased MMP-1 synthesis by signaling through annexin A2, as demonstrated by inhibition of MMP-1 production with Abs against annexin A2 and S100A10, a dimeric protein associated with annexin A2. Interaction of plasmin with annexin A2 resulted in the stimulation of ERK1/2 and p38 MAPK, cyclooxygenase-2, and PGE(2), leading to increased MMP-I production. Furthermore, binding of inactive plasmin to annexin A2 inhibited plasmin induction of MMP-1, suggesting that inactive plasmin may be useful in suppressing inflammation. C1 Natl Inst Dent & Craniofacial Res, Immunopathol Sect, Natl Inst Hlth, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Expt Med Sect, Natl Inst Hlth, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Unit, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Wahl, LM (reprint author), Natl Inst Dent & Craniofacial Res, Immunopathol Sect, Natl Inst Hlth, Bldg 30,Room 3A-300, Bethesda, MD 20892 USA. EM lwahl@dir.nidcr.nih.gov NR 49 TC 27 Z9 28 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 SEP 1 PY 2007 VL 179 IS 5 BP 3297 EP 3304 PG 8 WC Immunology SC Immunology GA 203RN UT WOS:000248991800072 PM 17709546 ER PT J AU Du, X Ho, M Pastan, I AF Du, Xing Ho, Mitchell Pastan, Ira TI New immunotoxins targeting CD123, a stem cell antigen on acute myeloid leukemia cells SO JOURNAL OF IMMUNOTHERAPY LA English DT Article DE IL-3 receptor; hematologic malignancies; antibody scFv; Pseudomonas exotoxin; cytotoxicity ID ACUTE MYELOGENOUS LEUKEMIA; RECEPTOR-ALPHA CHAIN; STABILIZED FV FRAGMENTS; PHASE-I TRIAL; INTERLEUKIN-3 RECEPTOR; DIPHTHERIA-TOXIN; FUSION PROTEIN; PSEUDOMONAS EXOTOXIN; MALIGNANT PROGENITORS; RFB4(DSFV)-PE38 BL22 AB The specific alpha subunit of the interleukin-3 receptor (IL-3R alpha, CD123) is strongly expressed in various leukemic blasts and leukemic stem cells and seems to be an excellent target for the therapy of leukemias. In this study, immunotoxins were developed to target CD123 only, which bypasses the dependence on other subunits to form intact IL-3R. Three anti-CD123 hybridomas (26292, 32701, and 32716) were selected on the basis of their affinity for CD123. Total RNAs were extracted from the 3 anti-CD123 hybridomas and used to clone the fragment of variable region (Fvs). The Fvs were assembled into single chain Fvs and fused to a 38-kd fragment of Pseudomonas exotoxin A to make recombinant immunotoxins. 26292(Fv)-PE38 was found to have the highest cytotoxic activity on the CD123 expressing leukemia cell line TF-1. It bound the cells with a kd of 3.5nM. Another immunotoxin, 32716(Fv)-PE38, belonging to a different epitope group, had a similar binding ability but was less active, demonstrating the role of epitope selection in immunotoxin action. The cytotoxic activity of 26292(Fv)-PE38 was increased from 200 to about 40 ng/mL by mutating the REDLK sequence at the C terminus to KDEL. 26292(Fv)-PE38-KDEL was specifically cytotoxic to several CD123 expressing cell lines (TF-1, Molm-13, and Molm-14) with good CD123 expression but not to ML-1 or U937 with low or absent expression. In conclusion, 26292(Fv)-PE38-KDEL shows good cytotoxic activity against CD 123 expressing cell lines, and merits further development for the possible treatment of acute myeloid leukemia and other CD123 expressing malignancies. C1 NCI, Natl Inst Hlth, Ctr Canc Res, Mol Biol Lab, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Natl Inst Hlth, Ctr Canc Res, Mol Biol Lab, 37 Convent Dr,Rm 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov RI Du, Xing/B-1113-2011; Ho, Mitchell/F-5059-2015 FU Intramural NIH HHS NR 41 TC 60 Z9 64 U1 1 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1524-9557 J9 J IMMUNOTHER JI J. Immunother. PD SEP PY 2007 VL 30 IS 6 BP 607 EP 613 DI 10.1097/CJI.0b013e318053ed8e PG 7 WC Oncology; Immunology; Medicine, Research & Experimental SC Oncology; Immunology; Research & Experimental Medicine GA 194OO UT WOS:000248353900004 PM 17667524 ER PT J AU Sereti, I Sklar, P Ramchandani, MS Read, SW Aggarwal, V Imamichi, H Natarajan, V Metcalf, JA Kovacs, JA Tavel, J Davey, RT DerSimonian, R Lane, HC AF Sereti, Irini Sklar, Peter Ramchandani, Meena S. Read, Sarah W. Aggarwal, Vinay Imamichi, Hiromi Natarajan, Ven Metcalf, Julia A. Kovacs, Joseph A. Tavel, Jorge Davey, Richard T. DerSimonian, Rebecca Lane, H. Clifford TI CD4(+) T cell responses to interleukin-2 administration in HIV-infected patients are directly related to the baseline level of immune activation SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; RANDOMIZED CONTROLLED-TRIAL; INTERMITTENT IL-2 THERAPY; ANTIRETROVIRAL THERAPY; SUBCUTANEOUS INTERLEUKIN-2; CD127 EXPRESSION; VIRAL LOAD; IN-VIVO; LYMPHOCYTES; EXPANSION AB Background. Intermittent interleukin (IL)-2 administration to human immunodeficiency virus (HIV)-infected patients leads to CD4(+) T cell expansions. The factors potentially affecting these expansions were investigated in the present study. Methods. A matched (for baseline CD4(+) T cell count) case-control study was designed. Nonresponders (NRs) were defined as patients with a <= 10% increase in CD4(+) T cell count 2 months after the third IL-2 cycle (week 24), compared with that at baseline (week 0). Control subjects experienced a >= 50% increase in CD4(+) T cell count at week 24. Immunophenotype, Ki67 and forkhead box protein P3 (FoxP3) expression, and T cell receptor excision circle (TREC) measurements in T cells were evaluated at weeks 0 and 24 in both groups. Results. Control subjects and NRs did not differ significantly at baseline in age, viral load, CD4(+) T cell count, nadir CD4(+) T cell count, or CD8(+) T cell count. At week 0, NRs had lower TREC levels per 1 x 10(6) T cells and higher levels of T cell proliferation and activation than did control subjects. At week 24, both groups experienced decreases in T cell proliferation and increases in CD25 and FoxP3 expression on CD4(+) T cells, with TREC levels per 1 x 10(6) CD4(+) T cells decreasing significantly only in control subjects. Conclusions. Increased immune activation can adversely affect CD4(+) T cell expansions after IL-2 administration. Despite the lack of expansion, other evidence of IL-2-induced biological activity was observed. C1 NIAID, Clin & Mol Retrovirol Sect, Lab Immunoregulat, NIH, Bethesda, MD 20892 USA. RP Sereti, I (reprint author), NIAID, Clin & Mol Retrovirol Sect, Lab Immunoregulat, NIH, 10 Ctr Dr,Bldg 10,Rm 11B04, Bethesda, MD 20892 USA. EM isereti@niaid.nih.gov FU Intramural NIH HHS NR 28 TC 11 Z9 11 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 SEP 1 PY 2007 VL 196 IS 5 BP 677 EP 683 DI 10.1086/520087 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 197LS UT WOS:000248557600005 PM 17674308 ER PT J AU Lenroot, RK Shaw, P Clasen, LS Mackie, S Pierson, R Giedd, JN AF Lenroot, R. K. Shaw, P. Clasen, L. S. Mackie, S. Pierson, R. Giedd, J. N. TI Comparison of cerebellar anatomy in a pediatric XXY population to XY males with and without Attention Deficit and Hyperactivity Disorder (ADHD) SO JOURNAL OF INTELLECTUAL DISABILITY RESEARCH LA English DT Meeting Abstract DE XXY; Attention Deficit Disorder; MRI; cerebellum; development C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RI Shaw, Philip/A-1129-2008; 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 NR 0 TC 1 Z9 1 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0964-2633 J9 J INTELL DISABIL RES JI J. Intell. Disabil. Res. PD SEP PY 2007 VL 51 BP 655 EP 655 PN 9 PG 1 WC Education, Special; Genetics & Heredity; Clinical Neurology; Psychiatry; Rehabilitation SC Education & Educational Research; Genetics & Heredity; Neurosciences & Neurology; Psychiatry; Rehabilitation GA 206IC UT WOS:000249176100012 ER PT J AU Lowy, DR AF Lowy, Douglas R. TI Aaron Lerner: A mentor and friend - In memoriam SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Biographical-Item C1 NCI, Bethesda, MD 20892 USA. RP Lowy, DR (reprint author), NCI, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 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 SEP PY 2007 VL 127 IS 9 BP 2092 EP 2092 DI 10.1038/sj.jid.5701012 PG 1 WC Dermatology SC Dermatology GA 203SJ UT WOS:000248994000009 PM 17700616 ER PT J AU Katz, S AF Katz, Stephen TI Aaron Lerner: The quiet promoter - In memoriam SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Biographical-Item C1 NIAMSD, NIH, Bethesda, MD 20892 USA. RP Katz, S (reprint author), NIAMSD, NIH, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 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 SEP PY 2007 VL 127 IS 9 BP 2096 EP 2097 DI 10.1038/sj.jid.5701009 PG 2 WC Dermatology SC Dermatology GA 203SJ UT WOS:000248994000012 PM 17700619 ER PT J AU Gareau, DS Merlino, G Corless, C Kulesz-Martin, M Jacques, SL AF Gareau, Daniel S. Merlino, Glenn Corless, Christopher Kulesz-Martin, Molly Jacques, Steven L. TI Noninvasive imaging of melanoma with reflectance mode confocal scanning laser microscopy in a murine model SO JOURNAL OF INVESTIGATIVE DERMATOLOGY LA English DT Article ID POLARIZED-LIGHT; HUMAN SKIN AB A reflectance-mode confocal scanning laser microscope (rCSLM) was developed for imaging early-stage melanoma in a living mouse model without the addition of exogenous contrast agents. Lesions were first located by surveying the dorsum with a polarized light camera, then imaged with the rCSLM. The images demonstrated two characteristics of melanoma in this animal model: (1) melanocytes and apparent tumor nests in the epidermis at the stratum spinosum in a state of pagetoid spread and (2) architectural disruption of the dermal-epidermal junction. The epidermal melanocytes and apparent tumor nests had a high melanin content, which caused their reflectance to be fivefold greater than the surrounding epidermis. The rCSLM images illustrate the difference between normal skin and sites with apparent melanoma. This imaging modality shows promise to track the progression of melanoma lesions in animal models. C1 Oregon Hlth & Sci Univ, Dept Dermatol, Portland, OR 97201 USA. Oregon Hlth & Sci Univ, Dept Biomed Engn, Portland, OR 97201 USA. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Gareau, DS (reprint author), Mem Sloan Kettering Canc Ctr, Dept Dermatol, 160 E 66th, New York, NY 10022 USA. EM dan@dangareau.net FU NCI NIH HHS [CA98893, CA69533]; NIBIB NIH HHS [EB000224] NR 15 TC 13 Z9 14 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0022-202X J9 J INVEST DERMATOL JI J. Invest. Dermatol. PD SEP PY 2007 VL 127 IS 9 BP 2184 EP 2190 DI 10.1038/sj.jid.5700829 PG 7 WC Dermatology SC Dermatology GA 203SJ UT WOS:000248994000026 PM 17460734 ER PT J AU Rosenberg, HF AF Rosenberg, Helene F. TI Putting the brakes on leukocyte chemotaxis: an interview with Dr. Ramesh K. Ganju SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Editorial Material C1 NIH, NIAID, Lab Allerg Dis, Bethesda, MD 20892 USA. RP Rosenberg, HF (reprint author), NIH, NIAID, Lab Allerg Dis, Bldg 10, Bethesda, MD 20892 USA. EM hrosenberg@niaid.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 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 SEP PY 2007 VL 82 IS 3 BP 477 EP 478 DI 10.1189/jlb.1306678 PG 2 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 204CW UT WOS:000249022200004 ER PT J AU Gauss, KA Nelson-Overton, LK Siemsen, DW Gao, Y DeLeo, FR Quinn, MT AF Gauss, Katherine A. Nelson-Overton, Laura K. Siemsen, Daniel W. Gao, Ying DeLeo, Frank R. Quinn, Mark T. TI Role of NF-kappa B in transcriptional regulation of the phagocyte NADPH oxidase by tumor necrosis factor-alpha SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE promoter; inflammation ID CHRONIC GRANULOMATOUS-DISEASE; MARROW-DERIVED MACROPHAGES; SUPEROXIDE ANION PRODUCTION; LOW-DENSITY LIPOPROTEIN; TNF-ALPHA; HUMAN-NEUTROPHILS; SIGNAL-TRANSDUCTION; RESPIRATORY BURST; HUMAN MONOCYTES; SMOOTH-MUSCLE AB Macrophages play an important role in the pathogenesis of chronic inflammatory disease. Activation of these phagocytes induces the production of proinflammatory cytokines, such as IL-1 and TNF-alpha and the generation of reactive oxygen species (ROS), such as superoxide anion (O-2(center dot-)). Recently, we found that TNF-alpha treatment of human monocytic cells (MonoMac1) and isolated human monocytes resulted in up-regulation of the NADPH oxidase gene, neutrophil cytosolic factor 2 (NCF2). These results suggested that TNF-alpha, produced by activated macrophages, could serve as an autocrine/paracrine regulator of the oxidase, resulting in increased and/or prolonged production of O-2(center dot-). To gain a better understanding of the mechanisms involved in NADPH oxidase regulation by TNF-alpha, we evaluated transcriptional regulation of oxidase genes in MonoMac1 cells and human monocytes. We show that TNF-alpha-treated cells have increased levels of mRNA and up-regulated expression of NADPH oxidase subunits p47(phox), p67(phox), and gp91(phox), as well as increased oxidase activity. Pharmacological inhibitors of NF-kappa B activation blocked TNF-alpha-induced up-regulation of NCF1, NCF2, and CYBB message, which correlated with a reduction in expression of the corresponding oxidase proteins and decreased O-2(center dot-) production. These data demonstrate that the increase in and/or maintenance of O-2(center dot-) production in TNF-alpha-treated MonoMac1 cells and monocytes are a result, in part, of transcriptional up-regulation of three essential NADPH oxidase genes via the NF-kappa B pathway. This novel finding supports a model, whereby TNF-alpha-dependent activation of NF-kappa B up-regulates phagocyte NADPH oxidase activity, leading to enhanced ROS production and further NF-kappa B activation, potentially contributing to sustained oxidant production in chronic inflammation. C1 Montana State Univ, Dept Vet Mol Biol, Bozeman, MT 59717 USA. NIAID, Rocky Mt Labs, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. RP Gauss, KA (reprint author), Montana State Univ, Dept Vet Mol Biol, Bozeman, MT 59717 USA. EM kgauss@montana.edu FU NCRR NIH HHS [RR020185]; NIAMS NIH HHS [AR42426]; NIGMS NIH HHS [P30 GM110732] NR 61 TC 97 Z9 98 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 SEP PY 2007 VL 82 IS 3 BP 729 EP 741 DI 10.1189/jlb.1206735 PG 13 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 204CW UT WOS:000249022200032 PM 17537988 ER PT J AU Liu, Y Kruhlak, MJ Hao, JJ Shaw, S AF Liu, Yin Kruhlak, Michael J. Hao, Jian-Jiang Shaw, Stephen TI Rapid T cell receptor-mediated SHP-1S591 phosphorylation regulates SHP-1 cellular localization and phosphatase activity SO JOURNAL OF LEUKOCYTE BIOLOGY LA English DT Article DE T lymphocyte; signal transduction; lipid raft; nuclear localization ID PROTEIN-TYROSINE-PHOSPHATASE; NUCLEAR-LOCALIZATION; NEGATIVE REGULATION; KINASE-C; LIPID RAFTS; ACTIVATION; DOMAIN; SIGNAL; STIMULATION; SPECIFICITY AB Since the tyrosine phosphatase SHP-1 plays a major role in regulating T cell signaling, we investigated regulation thereof by Ser/Thr phosphorylation. We found that T cell receptor (TCR) stimulation induced fast (<= 1 min) and transient phosphorylation of SHP-1 S591 in both Jurkat and human peripheral blood T-cells (PBT). Phosphorylation of S591 in T-cells could be mediated artificially by a constitutive active PKC-theta construct, but the dose dependence of inhibition by PKC inhibitors indicated that PKCs were not the relevant basophilic kinase in the physiological response. S591 phosphorylation inhibited phosphatase function since a S591D mutant had lower activity than the S591A mutant. Additional evidence that S591 phosphorylation alters SHP-1 function was provided by studies of Jurkat cells stably expressing SHP-1 wild type or mutants. In those cells, S591D mutation reduced the capacity of transfected SHP-1 to inhibit TCR-induced phosphorylation of PLC-gamma 1. Interestingly, SHP-1 Y536 phosphorylation (previously shown to augment phosphatase activity) was also induced in PBT by TCR signal but at a much later time compared with S591 (similar to 30 min). S591 phosphorylation also altered cellular distribution of SHP-1 because: 1) SHP-1 in lipid rafts and a sheared membrane fraction was hypophosphorylated; 2) In stably transfected Jurkat cell lines, S591D mutant protein had reduced presence in both lipid raft and the sheared membrane fraction; 3) S591 phosphorylation prevented nuclear localization of a C-terminal GFP tagged SHP-1 construct. Our studies also shed light on an additional mechanism regulating SHP-1 nuclear localization, namely conformational autoinhibition. These findings highlight elegant regulation of SHP-1 by sequential phosphorylation of serine then tyrosine. C1 NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. RP Shaw, S (reprint author), NCI, NIH, Expt Immunol Branch, 9000 Rockville Pike,Bldg 10-4B05, Bethesda, MD 20892 USA. EM sshaw@nih.gov FU Intramural NIH HHS [Z01 BC010272-09, Z01 BC009257-30] NR 34 TC 23 Z9 23 U1 0 U2 0 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 SEP PY 2007 VL 82 IS 3 BP 742 EP 751 DI 10.1189/jlb.1206736 PG 10 WC Cell Biology; Hematology; Immunology SC Cell Biology; Hematology; Immunology GA 204CW UT WOS:000249022200033 PM 17575265 ER PT J AU Khalsa, PS Pearson, NJ AF Khalsa, Partap S. Pearson, Nancy J. TI Financial support for research training and career development in complementary and alternative medicine from the national institutes of health SO JOURNAL OF MANIPULATIVE AND PHYSIOLOGICAL THERAPEUTICS LA English DT Editorial Material DE research; research support; fellowships and scholarships; complementary therapies ID RESEARCH AGENDA; EDUCATION; RECOMMENDATIONS AB Research careers are a relatively new reality for complementary and alternative medicine (CAM) practitioners (eg, chiropractors, naturopaths, doctors of oriental medicine, etc). Before the establishment in 1998 of the National Center for Complementary and Alternative Medicine (NCCAM) as part of the National Institutes of Health (NIH), there were few funding resources available for those interested in a CAM research career and fewer still feasible paths. Now, however, NCCAM provides a broad array of research training and career development awards for those seeking a long-term career in CAM research. These awards include predoctoral and postdoctoral fellowships, individual career development awards, and institutional training awards. The goal of this article is to provide information about current research training funding opportunities from NCCAM and NIH as a whole that are available to CAM practitioners in the context of the historical challenges of transitioning from a clinical career in CAM practice to a CAM research career. C1 NIH, Natl Ctr Complementary & Alternat Med, Dept Hlth & Human Serv, Div Extramural & Res Training, Bethesda, MD 20892 USA. RP Khalsa, PS (reprint author), NIH, Natl Ctr Complementary & Alternat Med, 6707 Democracy Blvd,Suite 401, Bethesda, MD 20892 USA. EM khalsap@mail.nih.gov FU Intramural NIH HHS [Z99 AT999999] NR 29 TC 8 Z9 8 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-4754 J9 J MANIP PHYSIOL THER JI J. Manip. Physiol. Ther. PD SEP PY 2007 VL 30 IS 7 BP 483 EP 490 DI 10.1016/j.jmpt.2007.07.004 PG 8 WC Health Care Sciences & Services; Integrative & Complementary Medicine; Rehabilitation SC Health Care Sciences & Services; Integrative & Complementary Medicine; Rehabilitation GA 214FJ UT WOS:000249721100001 PM 17870416 ER PT J AU Mittal, P Espinoza, J Hassan, S Kusanovic, JP Edwin, SS Nien, JKA Gotsch, F Than, NG Erez, O Mazaki-Tovi, S Romero, R AF Mittal, Pooja Espinoza, Jimmy Hassan, Sonias Kusanovic, Juan Pedro Edwin, Samuel S. Nien, Jyh K. Ae Gotsch, Francesca Than, Nandor Gabor Erez, Offer Mazaki-Tovi, Shalt Romero, Roberto TI Placental growth hormone is increased in the maternal and fetal serum of patients with preeclampsia SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE pregnancy; placental growth hormone; preeclampsia; small for gestational age; fetal growth ID CIRCULATING ANGIOGENIC FACTORS; SEVERE INSULIN-RESISTANCE; ELEVATED LIVER-ENZYMES; VARIANT MESSENGER-RNA; INTRAUTERINE GROWTH; FACTOR RECEPTOR-1; NORMAL-PREGNANCY; TYROSINE KINASE-1; RESTRICTED FETUSES; SOLUBLE ENDOGLIN AB Objectives. Placental growth hormone (PGH) is a pregnancy-specific protein produced by syncytiotrophoblast and extravillous cytotrophoblast. No other cells have been reported to synthesize PGH Maternal. PGH Serum concentration increases with advancing gestational age, while quickly decreasing after delivery of the placenta. The biological properties of PGH include somatogenic, lactogenic, and lipolytic functions. The purpose of this study was to determine whether the maternal serum concentrations of PGH change in women with preeclampsia (PE), women with PE who deliver a small for gestational age neonate (PE + SGA), and those with SGA alone. Study design. This cross-sectional study included maternal serum from normal pregnant women (n = 6 1), patients with severe PE (n = 48), PE + SGA (n = 30), and SGA alone (n = 41). Fetal cord blood from uncomplicated pregnancies (n = 16) and PE (n = 16) was also analyzed. PGH concentrations were measured by ELISA. Non-parametric statistics were used for analysis. Results. (1) Women with severe PE had a median serum concentration of PGH higher than normal pregnant women (PE: median 23,076 pg/mL (3473-94 256) vs. normal pregnancy: median 12 157 pg/mL (2617-34 016); p < 0.05), pregnant women who delivered an SGA neonate (SGA: median 10 206 pg/mL (1816-34 705); p < 0.05), as well as pregnant patients with PE and SGA (PE + SGA: median 11 027 pg/mL (1232-61 702); p < 0.05). (2) No significant differences were observed in the median maternal serum concentration of PGH among pregnant women with PE and SGA, SGA alone, and normal pregnancy (p > 0.05). (3) Compared to those of the control group, the median umbilical serum concentration of PGH was significantly higher in newborns of preeclamptic women (PE: median 356.1 pg/mL (72.6-20 946), normal pregnancy: median 128.5 pg/mL (21.6-255.9); p < 0.01). (4) PGH was detected in all samples of cord blood. Conclusions. (1) PE is associated with higher median concentrations of PGH in both the maternal and fetal circulation compared to normal pregnancy. (2) Patients with PE + SGA had lower maternal serum concentrations of PGH than preeclamptic patients without SGA. (3) Contrary to previous findings, PGH was detectable in the fetal circulation. The observations reported herein are novel and suggest that PGH may play a role in the mechanisms of disease in preeclampsia and fetal growth restriction. C1 NICHD, NIH, DHHS, Detroit, MI 48201 USA. NICHD, NIH, DHHS, Perinatol Res Branch, Detroit, MI USA. Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI USA. Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI USA. RP Romero, R (reprint author), NICHD, NIH, DHHS, 3990 John R, Detroit, MI 48201 USA. EM nichdprbchiefstaff@mail.nih.gov FU Intramural NIH HHS [Z01 HD002400-16, Z99 HD999999] NR 73 TC 26 Z9 28 U1 1 U2 1 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1476-7058 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD SEP PY 2007 VL 20 IS 9 BP 651 EP 659 DI 10.1080/14767050701463571 PG 9 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 211YY UT WOS:000249561400004 PM 17701665 ER PT J AU Erez, O Hoppensteadt, D Romero, R Espinoza, J Goncalves, L Nien, JK Kusanovic, JP Fareed, J Gotsch, F Pineles, B Chaiworapongsa, T AF Erez, Offer Hoppensteadt, Debra Romero, Roberto Espinoza, Jimmy Goncalves, Luis Nien, Jyh Kae Kusanovic, Juan Pedro Fareed, Jawed Gotsch, Francesca Pineles, Beth Chaiworapongsa, Tinnakorn TI Preeclampsia is associated with low concentrations of protein Z SO JOURNAL OF MATERNAL-FETAL & NEONATAL MEDICINE LA English DT Article DE SGA; fetal demise; factor X; protein Z dependent protease inhibitor (ZPI); coagulation; pregnancy ID INTRAUTERINE GROWTH RESTRICTION; NORMAL-PREGNANCY; HEMOSTATIC SYSTEM; ANTITHROMBIN-III; SPIRAL ARTERIES; PRETERM LABOR; PRE-ECLAMPSIA; Z DEFICIENCY; FETAL LOSS; COAGULATION AB Objective. Protein Z, a vitamin K-dependent plasma protein, has an important role in the regulation of the coagulation cascade. Protein Z deficiency has been associated with unexplained pregnancy loss and adverse pregnancy outcome in patients with thrombophilia. This study was conducted to determine if preeclampsia (PE), small for gestational age (SGA), and fetal demise are associated with changes in maternal plasma concentrations of protein Z. Study design. This cross-sectional study included normal pregnant women (N=71), patients with PE (N= 130), patients who delivered an SGA neonate (N = 58), and patients with fetal demise (N = 5 8). Maternal plasma protein Z concentrations were measured by a sensitive and specific immunoassay. Protein Z deficiency was defined as maternal plasma concentrations <= 5(th) percentile of the normal pregnancy group (<= 1.59 mu g/mL). Non-parametric statistics were used for analysis. Results. (1) Patients with PE had a lower median plasma concentration of protein Z than normal pregnant women (PE: median 1.6 mu g/mL, range 0.2-3.3 mu g/mL vs. normal pregnancy: median 2.4 mu g/mL, range 1.1-3.4 mu g/mL; p < 0.0001); (2) patients with an SGA neonate (median 2.3 mu g/mL, range 0.2-3.8 mu g/mL) and fetal demise (median 2.6 mu g/mL, range 0.2-4.3 g/mL) did not have significantly different median protein Z concentrations from normal pregnant women (p > 0.05); and (3) women in the PE and fetal demise groups had significantly higher rates of protein Z deficiency than those with normal pregnancy outcome. Conclusions. (1) PE, but not SGA or fetal demise, is associated with a significantly lower maternal median plasma concentration of protein Z than normal pregnancy, and (2) a high rate of protein Z deficiency is observed in patients with PE and fetal demise. C1 Wayne State Univ, Womens Hosp, NICHD, NIH,DHHS,Perinatol Res Branch, Detroit, MI 48201 USA. Loyola Univ, Med Ctr, Dept Pathol, Chicago, IL 60611 USA. Wayne State Univ, Sch Med, Ctr Mol Med & Genet, Detroit, MI USA. Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI USA. RP Romero, R (reprint author), Wayne State Univ, Womens Hosp, NICHD, NIH,DHHS,Perinatol Res Branch, Detroit, MI 48201 USA. EM nichdprbchiefstaff@mail.nih.gov FU Intramural NIH HHS [Z01 HD002400-16] NR 46 TC 22 Z9 22 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 1476-7058 J9 J MATERN-FETAL NEO M JI J. Matern.-Fetal Neonatal Med. PD SEP PY 2007 VL 20 IS 9 BP 661 EP 667 DI 10.1080/14767050701495011 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 211YY UT WOS:000249561400005 PM 17701666 ER PT J AU Zhang, W Bouffard, GG Wallace, SS Bond, JP AF Zhang, Wei Bouffard, Gerard G. Wallace, Susan S. Bond, Jeffrey P. CA NISC Comparative Sequencing Progr TI Estimation of DNA sequence context-dependent mutation rates using primate genomic sequences SO JOURNAL OF MOLECULAR EVOLUTION LA English DT Article DE mutation; transition mutation; transversion mutation; maximum likelihood; genomics; molecular evolution; substitution; CpG dinucleotide ID HUMAN MITOCHONDRIAL-DNA; HUMAN-CHROMOSOME 7; CYTOSINE METHYLATION; NUCLEOTIDE-SEQUENCES; ESCHERICHIA-COLI; MAXIMUM-LIKELIHOOD; SUBSTITUTION RATES; CHLOROPLAST GENOME; NEIGHBORING BASES; THYMINE GLYCOLS AB It is understood that DNA and amino acid substitution rates are highly sequence context-dependent, e.g., C -> T substitutions in vertebrates may occur much more frequently at CpG sites and that cysteine substitution rates may depend on support of the context for participation in a disulfide bond. Furthermore, many applications rely on quantitative models of nucleotide or amino acid substitution, including phylogenetic inference and identification of amino acid sequence positions involved in functional specificity. We describe quantification of the context dependence of nucleotide substitution rates using baboon, chimpanzee, and human genomic sequence data generated by the NISC Comparative Sequencing Program. Relative mutation rates are reported for the 96 classes of mutations of the form 5'alpha beta gamma 3' -> 5'alpha beta gamma 3', where alpha, beta, gamma, and delta are nucleotides and beta not equal delta, based on maximum likelihood calculations. Our results confirm that C -> T substitutions are enhanced at CpG sites compared with other transitions, relatively independent of the identity of the preceding nucleotide. While, as expected, transitions generally occur more frequently than transversions, we find that the most frequent transversions involve the C at CpG sites (CpG transversions) and that their rate is comparable to the rate of transitions at non-CpG sites. A four-class model of the rates of context-dependent evolution of primate DNA sequences, CpG transitions > non-CpG transitions approximate to CpG transversions > non-CpG transversions, captures qualitative features of the mutation spectrum. We find that despite qualitative similarity of mutation rates among different genomic regions, there are statistically significant differences. C1 Univ Vermont, Markey Ctr Mol Genet, Dept Microbiol & Mol Genet, Burlington, VT 05405 USA. Univ Chicago, Dept Med, Chicago, IL 60637 USA. NHGRI, NIH, NISC Comparat Sequencing Program, Genome Technol Program, Bethesda, MD 20892 USA. NIH, NIH Intramural Sequencing Ctr, Bethesda, MD 20892 USA. RP Bond, JP (reprint author), Univ Vermont, Markey Ctr Mol Genet, Dept Microbiol & Mol Genet, 95 Carrigan Dr,Stafford Hall, Burlington, VT 05405 USA. EM jeffrey.bond@uvm.edu OI Wallace, Susan S./0000-0002-3906-0321 NR 69 TC 13 Z9 13 U1 0 U2 4 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 SEP PY 2007 VL 65 IS 3 BP 207 EP 214 DI 10.1007/s00239-007-9000-5 PG 8 WC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Evolutionary Biology; Genetics & Heredity GA 219DT UT WOS:000250065600001 PM 17676366 ER PT J AU Davis, CH Deerfield, D Wymore, T Stafford, DW Pedersen, LG AF Davis, Charles H. Deerfield, David, II Wymore, Troy Stafford, Darrel W. Pedersen, Lee G. TI A quantum chemical study of the mechanism of action of Vitamin K epoxide reductase (VKOR) - II. Transition states SO JOURNAL OF MOLECULAR GRAPHICS & MODELLING LA English DT Article DE Vitamin K; VKOR; reductase; mechanisms; transition states ID STRENGTH AMPLIFICATION MECHANISM; DISEASE AB A reaction path including transition states is generated for the Silverman mechanism [R.B. Silverman, Chemical model studies for the mechanism of Vitamin K epoxide reductase, J. Am. Chem. Soc. 103 (1981) 5939-5941] of action for Vitamin K epoxide reductase (VKOR) using quantum mechanical methods (B3LYP/6-311G**). VKOR, an essential enzymein mammalian systems, acts to convert Vitamin Kepoxide, formed by Vitamin Kcarboxylase, to its (initial) quinone form for cellular reuse. This study elaborates on a prior work that focused on the thermodynamics of VKOR [D.W. Deerfield II, C.H. Davis, T. Wymore, D.W. Stafford, L.G. Pedersen, Int. J. Quant. Chem. 106 (2006) 2944-2952]. The geometries of proposed model intermediates and transition states in the mechanism are energy optimized. We find that once a key disulfide bond is broken, the reaction proceeds largely downhill. An important step in the conversion of the epoxide back to the quinone form involves initial protonation of the epoxide oxygen. We find that the source of this proton is likely a free mercapto group rather than a water molecule. The results are consistent with the current view that the widely used drug Warfarin likely acts by blocking binding of Vitamin K at the VKOR active site and thereby effectively blocking the initiating step. These results will be useful for designing more complete QM/MM studies of the enzymatic pathway once three-dimensional structural data is determined and available for VKOR. (c) 2006 Elsevier Inc. All rights reserved. C1 Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. Biomed Grp, Pittsburgh Supercomp Ctr, Pittsburgh, PA 15213 USA. Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27009 USA. RP Pedersen, LG (reprint author), Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. EM Lee_Pedersen@unc.edu RI Pedersen, Lee/E-3405-2013 OI Pedersen, Lee/0000-0003-1262-9861 FU NCRR NIH HHS [RR06009]; NHLBI NIH HHS [HL-48318, HL-06350] NR 28 TC 12 Z9 12 U1 0 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1093-3263 J9 J MOL GRAPH MODEL JI J. Mol. Graph. PD SEP PY 2007 VL 26 IS 2 BP 401 EP 408 DI 10.1016/j.jmgm.2006.10.005 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Computer Science, Interdisciplinary Applications; Crystallography; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Computer Science; Crystallography; Mathematical & Computational Biology GA 220UI UT WOS:000250182400001 PM 17182266 ER PT J AU Davis, CH Deerfield, D Wymore, T Stafford, DW Pedersen, LG AF Davis, Charles H. Deerfield, David, II Wymore, Troy Stafford, Darrel W. Pedersen, Lee G. TI A quantum chemical study of the mechanism of action of Vitamin K carboxylase (VKC) - III. Intermediates and transition states SO JOURNAL OF MOLECULAR GRAPHICS & MODELLING LA English DT Article DE Vitamin K; VKC; carboxylase; mechanisms; transition states ID STRENGTH AMPLIFICATION MECHANISM; SINGLET OXYGEN; MYELOPEROXIDASE; OXIDATION; CELL AB A reaction path including transition states is generated for the Dowd mechanism [P. Dowd, R. Hershlne, S.W. Ham, S. Naganathan. Vitamin K and energy transduction: a base strength amplification mechanism. Science 269 (2005) 1684-1691] of action for Vitamin K carboxylase (VKC) using quantum chemical methods (B3LYP/6-311G**). VKC, an essential enzyme in mammalian systems, catalyzes the conversion of hydroquinone form of Vitamin K to the epoxide form in the presence of oxygen, An intermediate species of the oxidation of Vitamin K, an alkoxide, acts apparently to abstract the gamma hydrogen from specifically located glutamate residues. We are able to follow the Dowd proposed path to generate this alkoxide species. The geometries of the proposed model intermediates and transition states in the mechanism are energy optimized. We find that the most energetic step in the mechanism is the uni-deprotonation of tile hydroquinone - once this occurs, there is only a small barrier of 3.5 kcal/mol for the interaction of oxygen with the carbon to be attacked-and then the reaction proceeds downhill in free energy to form the critical alkoxide species. The results are consistent with the idea that the enzyme probably acts to facilitate the formation of the epoxide by reducing the energy required to deprotonate the hydroquinone form. (c) 2006 Elsevier Inc. All rights reserved. C1 Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. Biomed Grp, Pittsburgh Supercomp Ctr, Pittsburgh, PA 15213 USA. Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27009 USA. RP Pedersen, LG (reprint author), Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. EM Lee_Pedersen@unc.edu RI Pedersen, Lee/E-3405-2013 OI Pedersen, Lee/0000-0003-1262-9861 FU NCRR NIH HHS [RR06009]; NHLBI NIH HHS [HL-06350, HL-48318] NR 25 TC 7 Z9 7 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1093-3263 J9 J MOL GRAPH MODEL JI J. Mol. Graph. PD SEP PY 2007 VL 26 IS 2 BP 409 EP 414 DI 10.1016/j.jmgm.2006.10.006 PG 6 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Computer Science, Interdisciplinary Applications; Crystallography; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Computer Science; Crystallography; Mathematical & Computational Biology GA 220UI UT WOS:000250182400002 PM 17182265 ER PT J AU Chen, DF Fertig, SJ Kleitman, N Miller, RL Oliver, E Peng, GCY Shinowara, NL Weinrich, M Pancrazio, JJ AF Chen, Daofen Fertig, Stephanie J. Kleitman, Naomi Miller, Roger L. Oliver, Eugene Peng, Grace C. Y. Shinowara, Nancy L. Weinrich, Michael Pancrazio, Joseph J. TI Advances in neural interfaces: report from the 2006 NIH neural interfaces workshop SO JOURNAL OF NEURAL ENGINEERING LA English DT Article C1 NINDS, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. NICHHD, NIH, Natl Ctr Med Rehabil Res, Bethesda, MD 20892 USA. RP Pancrazio, JJ (reprint author), NINDS, NIH, 6001 Execut Blvd,MSC 9525, Bethesda, MD 20892 USA. EM pancrazj@ninds.nih.gov RI Pancrazio, Joseph/M-3206-2015; OI Pancrazio, Joseph/0000-0001-8276-3690; Kleitman, Naomi/0000-0003-1089-0257 NR 0 TC 3 Z9 3 U1 0 U2 1 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 1741-2560 J9 J NEURAL ENG JI J. Neural Eng. PD SEP PY 2007 VL 4 IS 3 BP S137 EP S142 DI 10.1088/1741-2560/4/3/S01 PG 6 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA 220UA UT WOS:000250181600002 PM 17873413 ER PT J AU Mushahwar, VK Jacobs, PL Normann, RA Triolo, RJ Kleitman, N AF Mushahwar, Vivian K. Jacobs, Patrick L. Normann, Richard A. Triolo, Ronald J. Kleitman, Naomi TI New functional electrical stimulation approaches to standing and walking SO JOURNAL OF NEURAL ENGINEERING LA English DT Article ID SPINAL-CORD-INJURY; PARASTEP(R)1 AMBULATION SYSTEM; CAT SCIATIC-NERVE; EXTREMITY BLOOD-FLOW; IMPLANTED NEUROPROSTHESIS; TRAINING-PROGRAM; MICRO STIMULATION; FATIGUE-RESISTANT; SKELETAL-MUSCLE; MICROSTIMULATION AB Spinal cord injury (SCI) is a devastating neurological trauma that is prevalent predominantly in young individuals. Several interventions in the areas of neuroregeneration, pharmacology and rehabilitation engineering/neuroscience are currently under investigation for restoring function after SCI. In this paper, we focus on the use of neuroprosthetic devices for restoring standing and ambulation as well as improving general health and wellness after SCI. Four neuroprosthetic approaches are discussed along with their demonstrated advantages and their future needs for improved clinical applicability. We first introduce surface functional electrical stimulation (FES) devices for restoring ambulation and highlight the importance of these devices for facilitating exercise activities and systemic physiological activation. Implanted muscle-based FES devices for restoring standing and walking that are currently undergoing clinical trials are then presented. The use of implanted peripheral nerve intraneural arrays of multi-site microelectrodes for providing fine and graded control of force during sit-to-stand maneuvers is subsequently demonstrated. Finally, intraspinal microstimulation (ISMS) of the lumbosacral spinal cord for restoring standing and walking is introduced and its results to date are presented. We conclude with a general discussion of the common needs of the neuroprosthetic devices presented in this paper and the improvements that may be incorporated in the future to advance their clinical utility and user satisfaction. C1 Univ Alberta, Dept Cell Biol, Edmonton, AB, Canada. Univ Alberta, Ctr Neurosci, Edmonton, AB, Canada. Florida Atlantic Univ, Dept Exercise Sci & Hlth Promot, Davie, FL USA. Univ Utah, Dept Bioengn, Salt Lake City, UT 84112 USA. Case Western Reserve Univ, Dept Orthopaed, Cleveland, OH 44106 USA. Case Western Reserve Univ, Dept Biomed Engn, Cleveland, OH 44106 USA. Natl Inst Neurol Disorders & Stroke, NIH, Div Extramural Res, Bethesda, MD USA. RP Mushahwar, VK (reprint author), Univ Alberta, Dept Cell Biol, Edmonton, AB, Canada. EM nk85q@nih.gov OI Kleitman, Naomi/0000-0003-1089-0257 FU NIBIB NIH HHS [EB-001889]; NINDS NIH HHS [R01-NS39677, R01-NS40547, R01-NS44225] NR 89 TC 46 Z9 49 U1 7 U2 27 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 1741-2560 J9 J NEURAL ENG JI J. Neural Eng. PD SEP PY 2007 VL 4 IS 3 BP S181 EP S197 DI 10.1088/1741-2560/4/3/S05 PG 17 WC Engineering, Biomedical; Neurosciences SC Engineering; Neurosciences & Neurology GA 220UA UT WOS:000250181600006 PM 17873417 ER PT J AU Schmitt, A Benninghoff, J Moessner, R Rizzi, M Paizanis, E Doenitz, C Gross, S Hermann, M Gritti, A Lanfumey, L Fritzen, S Reif, A Hamon, M Murphy, DL Vescovi, A Lesch, KP AF Schmitt, A. Benninghoff, J. Moessner, R. Rizzi, M. Paizanis, E. Doenitz, C. Gross, S. Hermann, M. Gritti, A. Lanfumey, L. Fritzen, S. Reif, A. Hamon, M. Murphy, D. L. Vescovi, A. Lesch, K.-P. TI Adult neurogenesis in serotonin transporter deficient mice SO JOURNAL OF NEURAL TRANSMISSION LA English DT Article DE adult neurogenesis; serotonin transporter; knockout; anxiety; depression; aging ID NEURAL STEM-CELLS; KNOCK-OUT MICE; CENTRAL-NERVOUS-SYSTEM; ANXIETY-LIKE BEHAVIOR; HIPPOCAMPAL NEUROGENESIS; DENTATE GYRUS; ANTIDEPRESSANT TREATMENT; MAJOR DEPRESSION; 5-HT TRANSPORTER; RAT HIPPOCAMPUS AB Serotonin (5-HT) is a regulator of morphogenetic activities during early brain development and neurogenesis, including cell proliferation, migration, differentiation, and synaptogenesis. The 5-HT transporter (5-HTT, SLC6A4) mediates high-affinity reuptake of 5-HT into presynaptic terminals and thereby fine-tunes serotonergic neurotransmission. Inactivation of the 5-HTT gene in mice reduces 5-HT clearance resulting in persistently increased concentrations of synaptic 5-HT. In the present study, we investigated the effects of elevated 5-HT levels on adult neurogenesis in the hippocampus of 5-HTT deficient mice, including stem cell proliferation, survival, and differentiation. Using an in vivo approach, we showed an increase in proliferative capacity of hippocampal adult neural stem cells in aged 5-HTT knockout mice (similar to 14.5 months) compared to wildtype controls. In contrast, in vivo and additional in vitro analyses of younger adult 5-HTT knockout mice (similar to 7 weeks and similar to 3.0 months) did not reveal significant changes in proliferation of neural stem cells or survival of newborn cells. We showed that the cellular fate of newly generated cells in 5-HTT knockout mice is not different with respect to the total number and percentage of neurons or glial cells from wildtype controls. Our findings indicate that elevated synaptic 5-HT concentration throughout early development and later life of 5-HTT deficient mice does not induce adult neurogenesis in adult mice, but that elevated 5-HT levels in aged mice influence stem cell proliferation. C1 Clin & Mol Psychobiol, Dept Psychiat & Psychotherapy, D-97080 Wurzburg, Germany. Stem Cell Res Inst, Milan, Italy. Univ Munich, Dept Psychiat & Psychotherapy, Mol & Clin Psychobiol, Munich, Germany. Univ Paris 06, INSERM, U677, Paris, France. NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. RP Schmitt, A (reprint author), Clin & Mol Psychobiol, Dept Psychiat & Psychotherapy, Fuchsleinstr 15, D-97080 Wurzburg, Germany. EM angelika.schmitt@mail.uni-wuerzburg.de RI Lanfumey, Laurence/F-7695-2013; Lesch, Klaus-Peter/J-4906-2013 OI Lesch, Klaus-Peter/0000-0001-8348-153X NR 65 TC 22 Z9 22 U1 3 U2 7 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0300-9564 J9 J NEURAL TRANSM JI J. Neural Transm. PD SEP PY 2007 VL 114 IS 9 BP 1107 EP 1119 DI 10.1007/s00702-007-0724-6 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 203WV UT WOS:000249005600001 PM 17510734 ER PT J AU Chen, JH Yao, XH Gong, W Hu, J Zhou, XD Chen, K Liu, H Ping, YF Wang, JM Bian, XW AF Chen, Jian-hong Yao, Xiao-hong Gong, Wanghua Hu, Jinyue Zhou, Xiang-dong Chen, Keqiang Liu, Hong Ping, Yi-fang Wang, Ji Ming Bian, Xiu-wu TI A novel lipoxygenase inhibitor Nordy attenuates malignant human glioma cell responses to chemotactic and growth stimulating factors SO JOURNAL OF NEURO-ONCOLOGY LA English DT Article DE Nordy; glioma; chemotaxis; formylpeptide receptor (FPR); epidermal growth factor (EGF); vascular endothelial growth factor (VEGF) ID FORMYL PEPTIDE RECEPTORS; NORDIHYDROGUAIARETIC ACID; FORMYLPEPTIDE RECEPTOR; GLIOBLASTOMA-MULTIFORME; ENDOTHELIAL-CELLS; IN-VIVO; EXPRESSION; CANCER; DIFFERENTIATION; ANGIOGENESIS AB Nordy is a chiral compound synthesized based on the structure of a natural lipoxygenase (LO) inhibitor nordihydroguaiaretic acid (NDGA) from plants. The aim of the present study is to investigate the effect of Nordy on malignant human glioma cell responses to chemoattractants and growth promoting signals. We found that Nordy, in a non-cytotoxic concentration range, potently inhibited the chemotaxis and calcium flux of a human glioblastoma cell line U87 induced by a formylpeptide receptor (FPR) agonist, formyl-methionyl-leucyl-phenylalanine (fMLF) and epidermal growth factor (EGF). U87 cells treated by Nordy also showed a significantly impaired proliferation and expression of mRNA for vascular endothelial growth factor (VEGF) induced by fMLF. The chemotactic and proliferation responses of Nordy treated U87 cells to EGF were concomitantly diminished. Further experiments revealed that Nordy did not significantly affect FPR gene expression in U87 cells, but attenuated the activation of a plethora of signaling molecules including ERK1/2, p38, JNK, and Akt when the cells were stimulated by fMLF. EGF-induced EGF receptor phosphorylation was also inhibited in Nordy-treated U87 cells. Moreover, Nordy significantly reduced the tumorigenicity of U87 cells in nude mice. Our results suggest that Nordy is capable of inhibiting glioma cell responses to signals that promote cell motility, growth and production of VEGF. Thus, Nordy may constitute a molecular basis for the development of novel anti-cancer drugs. C1 Third Mil Med Univ, SW Hosp, Inst Pathol, Chongqing 400038, Peoples R China. NCI, Ctr Canc Res, Mol Immunoregulat Lab, Frederick, MD 21702 USA. Third Mil Med Univ, SW Hosp, Dept Pharm, Chongqing 400038, Peoples R China. NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. Third Mil Med Univ, Div Basic Med Sci, Dept Pharm, Chongqing 400038, Peoples R China. RP Wang, JM (reprint author), Third Mil Med Univ, SW Hosp, Inst Pathol, Chongqing 400038, Peoples R China. EM wangji@mail.ncifcrf.gov RI Bian, Xiuwu/F-1569-2011; Bian, Xiu-wu/D-4736-2017 OI Bian, Xiu-wu/0000-0003-4383-0197 FU NCI NIH HHS [N01-CO-12400] NR 38 TC 7 Z9 8 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0167-594X J9 J NEURO-ONCOL JI J. Neuro-Oncol. PD SEP PY 2007 VL 84 IS 3 BP 223 EP 231 DI 10.1007/s11060-007-9369-4 PG 9 WC Oncology; Clinical Neurology SC Oncology; Neurosciences & Neurology GA 191ZZ UT WOS:000248171800001 PM 17377739 ER PT J AU Kostina-O'Neil, T Jirawuthiworavong, GV Podell, DN Lesser, RL AF Kostina-O'Neil, Tanina Jirawuthiworavong, Guy V. Podell, David N. Lesser, Robert L. TI Choroidal and optic nerve infarction in hepatitis C-associated polyarteritis nodosa SO JOURNAL OF NEURO-OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT 28th Annual Meeting of the North-American-Neuro-Ophthalmology-Society CY FEB 09-14, 2002 CL COPPER MT, CO SP N Amer Neuro Ophthalmol Soc ID PLACOID PIGMENT EPITHELIOPATHY; CHURG-STRAUSS-SYNDROME; MICROSCOPIC POLYANGIITIS; CEREBRAL VASCULITIS; CLINICAL-ASPECTS; MANIFESTATIONS; DISEASE AB A 39-year-old man presented with headache, weight loss, bilateral subdural hematomas, pansinusitis, and visual loss. The neuro-ophthalmologic examination disclosed deep choroidal lesions and bilateral optic disc edema. Orchiectomy for testicular torsion showed acute vasculitis consistent with polyarteritis nodosa (PAN). Polymerase chain reaction (PCR) testing revealed hepatitis C. This is the first reported case of PAN due to hepatitis C with early findings of choroidal and optic nerve infarction. C1 Yale Univ, Sch Med, Dept Ophthalmol & Visual Sci, New Haven, CT 06510 USA. Yale Univ, Sch Med, Dept Med, New Haven, CT 06510 USA. NEI, NIH, Bethesda, MD 20892 USA. Waterbury Hosp & Hlth Ctr, Dept Med, Ctr Hlth, Waterbury, CT USA. RP Kostina-O'Neil, T (reprint author), Eye Care Grp PC, 40 Temple St,Suite 5-B, New Haven, CT 06510 USA. EM ykostina@theeyecaregroup.com NR 22 TC 1 Z9 2 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1070-8022 J9 J NEURO-OPHTHALMOL JI J. Neuro-Ophthal. PD SEP PY 2007 VL 27 IS 3 BP 184 EP 188 PG 5 WC Clinical Neurology; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 209UO UT WOS:000249413700008 ER PT J AU Agoston, DV Szemes, M Dobi, A Palkovits, M Georgopoulos, K Gyorgy, A Ring, MA AF Agoston, Denes V. Szemes, Marianna Dobi, Albert Palkovits, Miklos Georgopoulos, Katia Gyorgy, Andrea Ring, Mary A. TI Ikaros is expressed in developing striatal neurons and involved in enkephalinergic differentiation SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE basal ganglia; development; gene transcription; neuron; zinc-finger ID DNA-BINDING PROTEINS; TRANSCRIPTION FACTOR DECOY; GENE-EXPRESSION; LYMPHOCYTE DEVELOPMENT; CHROMATIN IMMUNOPRECIPITATION; DOPAMINE-RECEPTOR; MUTANT MICE; CENTROMERIC HETEROCHROMATIN; LINEAGE DETERMINATION; SYSTEM DEVELOPMENT AB The Ikaros (Ik) gene encodes alternatively spliced zinc-finger proteins originally identified in developing hematopoietic organs and acts as master regulator of lymphoid development. During our search for transcription factors that control the developmental expression of the enkephalin (ENK) gene we found that Ik-1 and Ik-2 isoforms are specifically expressed in the embryonic striatum and bind the Ik-like cis-regulatory DNA element present on the ENK gene. Ik proteins are expressed by both proliferating (BrdU+/nestin+) and by post-mitotic differentiating (MAP2+) cells in the developing striatum between embryonic day 12 and post-natal day 2 and mRNAs encoding for the Ik and ENK genes are co-expressed by a subset of differentiating striatal neurons. Blocking the DNA binding of Ik proteins in differentiating embryonic striatal neuronal cultures resulted in decreased ENK expression and mutant animals lacking the DNA-binding domain of Ik had a deficit in the number of ENK but not in dynorphin or substance P mRNA+ cells. Animals lacking the protein interaction domain of Ik showed no deficit. These results demonstrate that Ik-1 and Ik-2 proteins through their DNA binding act as positive regulators of ENK gene expression in the developing striatum and participate in regulating enkephalinergic differentiation. C1 Uniformed Serv Univ Hlth Sci, APG, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. NIMH, LCB, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, MGH, Cutaneous Biol Res Ctr, Charlestown, MA USA. George Washington Univ, Grad Program Genet, Washington, DC USA. RP Agoston, DV (reprint author), Uniformed Serv Univ Hlth Sci, APG, Dept Anat Physiol & Genet, B2036, Bethesda, MD 20814 USA. EM vagoston@usuhs.edu RI Palkovits, Miklos/F-2707-2013; OI Palkovits, Miklos/0000-0003-0578-0387 FU Intramural NIH HHS NR 77 TC 25 Z9 25 U1 0 U2 2 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD SEP PY 2007 VL 102 IS 6 BP 1805 EP 1816 DI 10.1111/j.1471-4159.2007.04653.x PG 12 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 210JH UT WOS:000249452000009 PM 17504264 ER PT J AU Rao, JS Ertley, RN Rapoport, SI Bazinet, RP Lee, HJ AF Rao, Jagadeesh S. Ertley, Renee N. Rapoport, Stanley I. Bazinet, Richard P. Lee, Ho-Joo TI Chronic NMDA administration to rats up-regulates frontal cortex cytosolic phospholipase A(2) and its transcription factor, activator protein-2 SO JOURNAL OF NEUROCHEMISTRY LA English DT Article DE activator protein-2; brain; cytosolic phospholipase A(2); N-methyl-D-aspartate; NMDA receptor-3A ID D-ASPARTATE RECEPTOR; ARACHIDONIC-ACID RELEASE; MESSENGER-RNA EXPRESSION; CEREBELLAR GRANULE CELLS; GROUP-SPECIFIC ASSAYS; DNA-BINDING ACTIVITY; BIPOLAR DISORDER; GLUTAMATE RECEPTORS; HIPPOCAMPAL-NEURONS; PRIMARY CULTURES AB Excessive N-methyl-D-aspartate (NMDA) signaling is thought to contribute to bipolar disorder symptoms. Lithium and carbamazepine, effective against bipolar mania, are reported in rats to reduce brain transcription of an arachidonic acid selective calcium-dependent cytosolic phospholipase A(2) (cPLA(2)), as well as expression of one of its transcription factors, activator protein (AP)-2. In this study, we determined if chronic administration of NMDA (25 mg/kg i.p.) to rats would increase brain cPLA(2) and AP-2 expression, as these antimanic drugs are known to down-regulate excessive NMDA signaling. Administration of a daily subconvulsive dose of NMDA to rats for 21 days decreased frontal cortex NMDA receptor (NR)-1 and NR-3A subunits and increased cPLA(2) activity, phosphorylation, protein, and mRNA levels. The activity and protein levels of secretory phospholipase A(2) or calcium-independent phospholipase A(2) were not changed significantly. Chronic NMDA also increased the DNA-binding activity of AP-2 and the protein levels of its alpha and beta subunits. These changes were absent following acute (3 h earlier) NMDA administration. The changes, opposite to those found following chronic lithium or carbamazepine, are consistent with up-regulated arachidonic acid release due to excessive NR signaling and may be a contributing factor to bipolar mania. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. Univ Toronto, Fac Med, Dept Nutr Sci, Toronto, ON, Canada. RP Rao, JS (reprint author), NIA, Brain Physiol & Metab Sect, NIH, 9000 Rockville Pike,Bldg 9,1S-126, Bethesda, MD 20892 USA. EM jrao@mail.nih.gov RI Rao, Jagadeesh/C-1250-2009 FU Intramural NIH HHS NR 74 TC 47 Z9 47 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3042 J9 J NEUROCHEM JI J. Neurochem. PD SEP PY 2007 VL 102 IS 6 BP 1918 EP 1927 DI 10.1111/j.1471-4159.2007.04648.x PG 10 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 210JH UT WOS:000249452000019 PM 17550430 ER PT J AU Calabrese, M Atzori, M Bernardi, V Morra, A Romualdi, C Rinaldi, L McAuliffe, MJM Barachino, L Perini, P Fischl, B Battistin, L Gallo, P AF Calabrese, Massimiliano Atzori, Matteo Bernardi, Valentina Morra, Aldo Romualdi, Chiara Rinaldi, Luciano McAuliffe, Matthew J. M. Barachino, Luigi Perini, Paola Fischl, Bruce Battistin, Leontino Gallo, Paolo TI Cortical atrophy is relevant in multiple sclerosis at clinical onset SO JOURNAL OF NEUROLOGY LA English DT Article DE multiple sclerosis; cortical thickness; cortical atrophy; neuronal degeneration ID APPEARING WHITE-MATTER; RELAPSING-REMITTING MS; WHOLE-BRAIN ATROPHY; STATUS SCALE EDSS; DIAGNOSTIC-CRITERIA; CEREBRAL-CORTEX; GREY-MATTER; VOLUME CHANGES; DISABILITY; MRI AB Introduction Increasing evidence suggests relevant cortical gray matter pathology in patients with Multiple Sclerosis (MS), but how early this pathology begins; its impact on clinical disability and which cortical areas are primarily affected needs to be further elucidated. Methods 115 consecutive patients (10 Clinically Isolated Syndrome (CIS), 32 possible MS (p-MS), 42 Relapsing Remitting MS (RR-MS), 31 Secondary Progressive MS (SP-MS)), and 40 age/gender-matched healthy volunteers (HV) underwent a neurological examination and a 1.5 T MRI. Global and regional Cortical Thickness (CTh) measurements, brain parenchyma fraction and T2 lesion load were analyzed. Results We found a significant global cortical thinning in p-MS (2.22 +/- 0.09 mm), RR-MS (2.16 +/- 0.10 mm) and SP-MS (1.98 +/- 0.11 mm) compared to CIS (2.51 +/- 0.11 mm) and HV (2.48 +/- 0.08 mm). The correlations between mean CTh and white matter (WM) lesion load was only moderate in MS (r = -0.393, p = 0.03) and absent in p-MS (r = -0.147, p = 0.422). Analysis of regional CTh revealed that the majority of cortical areas were involved not only in MS, but also in p-MS. The type of clinical picture at onset (in particular, pyramidal signs/symptoms and optic neuritis) correlated with atrophy in the corresponding cortical areas. Discussion Cortical thinning is a diffuse and early phenomenon in MS already detectable at clinical onset. It correlates with clinical disability and is partially independent from WM inflammatory pathology. C1 Univ Hosp, Multiple Sclerosis Ctr Veneto Reg, Ist Clin Neurol, Dept Neurosci, I-35128 Padua, Italy. Neuroradiol Unit, Euganea Med, Padua, Italy. Univ Padua, Ctr Biotechnol, Dept Biol, CRIBI, Padua, Italy. NIH, Biomed Imaging Res Serv Sect, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Nucl Magnet Resonance Ctr, Harvard Med Sch, Charlestown, MA USA. RP Calabrese, M (reprint author), Univ Hosp, Multiple Sclerosis Ctr Veneto Reg, Ist Clin Neurol, Dept Neurosci, Via Giustiniani 5, I-35128 Padua, Italy. EM calabresem@hotmail.it RI Romualdi, Chiara/K-1132-2016 OI Romualdi, Chiara/0000-0003-4792-9047 NR 38 TC 120 Z9 124 U1 1 U2 2 PU DR DIETRICH STEINKOPFF VERLAG PI DARMSTADT PA PO BOX 10 04 62, D-64204 DARMSTADT, GERMANY SN 0340-5354 J9 J NEUROL JI J. Neurol. PD SEP PY 2007 VL 254 IS 9 BP 1212 EP 1220 DI 10.1007/s00415-006-0503-6 PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 216QD UT WOS:000249893200008 PM 17361339 ER PT J AU Williams-Gray, CH Goris, A Foltynie, T Brayne, CEG Robbins, TW Weinberger, DR Sawcer, SJ Barker, RA AF Williams-Gray, C. H. Goris, A. Foltynie, T. Brayne, C. E. G. Robbins, T. W. Weinberger, D. R. Sawcer, S. J. Barker, R. A. TI Incidence of dementia and factors predicting cognitive decline in Parkinson disease SO JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY LA English DT Meeting Abstract CT ABN Spring Scientific Meeting 2007 CY APR 11-13, 2007 CL Homerton Coll, Cambridge, ENGLAND SP ABN HO Homerton Coll C1 Univ Cambridge, Cambridge CB2 1TN, England. Katholieke Univ Leuven, B-3000 Louvain, Belgium. NIMH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0022-3050 J9 J NEUROL NEUROSUR PS JI J. Neurol. Neurosurg. Psychiatry PD SEP PY 2007 VL 78 IS 9 MA 025 BP 1018 EP 1018 PG 1 WC Clinical Neurology; Psychiatry; Surgery SC Neurosciences & Neurology; Psychiatry; Surgery GA 205PL UT WOS:000249127000056 ER PT J AU Oz, M Yang, KH Shippenberg, TS Renaud, LP O'Donovan, MJ AF Oz, Murat Yang, Keun-Hang Shippenberg, Toni S. Renaud, Leo P. O'Donovan, Michael J. TI Cholecystokinin B-Type receptors mediate a G-protein-dependent depolarizing action of sulphated cholecystokinin ocatapeptide (CCK-8s) on rodent neonatal spinal ventral horn neurons SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID GENE-RELATED PEPTIDE; DORSAL-ROOT GANGLIA; RAT-BRAIN-STEM; IN-VITRO; K+ CONDUCTANCE; MESSENGER-RNA; SUBSTANCE-P; CORD; MOTONEURONS; VASOPRESSIN AB Reports of cholecystokinin (CCK) binding and expression of CCK receptors in neonatal rodent spinal cord suggest that CCK may influence neuronal excitability. In patch-clamp recordings from 19/21 ventral horn motoneurons in neonatal (PN 5-12 days) rat spinal cord slices, we noted a slowly rising and prolonged membrane depolarization induced by bath-applied sulfated CCK octapeptide (CCK-8s; 1 mu M), blockable by the CCKB receptor antagonist L-365,260 (1 mu M). Responses to nonsulfated CCK-8 or CCK-4 were significantly weaker. Under voltage clamp (V-H -65 mV), 22/24 motoneurons displayed a CCK-8s-induced tetrodotoxin-resistant inward current [peak: -136 +/- 28 pA] with a similar time course, mediated via reduction in a potassium conductance. In 29/31 unidentified neurons, CCK-8s induced a significantly smaller inward current (peak: -42.8 +/- 5.6 pA), and I-V plots revealed either membrane conductance decrease with net inward current reversal at 101.3 +/- 4.4 mV (n = 16), membrane conductance increase with net current reversing at 36.1 +/- 3.8 mV (n = 4), or parallel shift (n = 9). Intracellular GTP-gamma-S significantly prolonged the effect of CCK-8s (n = 6), whereas GDP-beta-S significantly reduced the CCK-8s response (n = 6). Peak inward currents were significantly reduced after 5-min perfusion with N-ethylmaleimide. In isolated neonatal mouse spinal cord preparations, CCK-8s (30-300 nM) increased the amplitude and discharge of spontaneous depolarizations recorded from lumbosacral ventral roots. These observations imply functional postsynaptic G-protein-coupled CCKB receptors are prevalent in neonatal rodent spinal cord. C1 NIDA, IRP Integrat Neurosci Sect, Baltimore, MD 21224 USA. Natl Inst Drug Abuse, Intramural Res Program, Natl Inst Hlth,Dept Hlth & Human Serv, Integrat Neurosci Sect, Bethesda, MD USA. Natl Inst Hlth, Natl Inst Neurol Disorders & Stroke, Sect Dev Neurobiol, Neural Control Lab, Bethesda, MD USA. Univ Ottawa, Ottawa Hlth Res Inst, Ottawa, ON, Canada. RP Oz, M (reprint author), NIDA, IRP Integrat Neurosci Sect, M Oz,333 Cassell Dr, Baltimore, MD 21224 USA. EM moz@intra.nida.nih.gov RI Oz, Murat/E-2148-2012; o'donovan, michael/A-2357-2015 OI o'donovan, michael/0000-0003-2487-7547 FU Intramural NIH HHS NR 52 TC 4 Z9 4 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD SEP PY 2007 VL 98 IS 3 BP 1108 EP 1114 DI 10.1152/jn.00148.2007 PG 7 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 208XB UT WOS:000249351400007 PM 17581850 ER PT J AU Sabatinelli, D Bradley, MM Lang, PJ Costa, VD Versace, F AF Sabatinelli, Dean Bradley, Margaret M. Lang, Peter J. Costa, Vincent D. Versace, Francesco TI Pleasure rather than salience activates human nucleus accumbens and medial prefrontal cortex SO JOURNAL OF NEUROPHYSIOLOGY LA English DT Article ID ANTERIOR CINGULATE CORTEX; EVENT-RELATED FMRI; VISUAL-CORTEX; GENDER-DIFFERENCES; HUMAN AMYGDALA; ROMANTIC LOVE; PICTURE PERCEPTION; BRAIN ACTIVATION; FUNCTIONAL MRI; REWARD AB Recent human functional imaging studies have linked the processing of pleasant visual stimuli to activity in mesolimbic reward structures. However, whether the activation is driven specifically by the pleasantness of the stimulus, or by its salience, is unresolved. Here we find in two studies that free viewing of pleasant images of erotic and romantic couples prompts clear, reliable increases in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) activity, whereas equally arousing (salient) unpleasant images, and neutral pictures, do not. These data suggest that in visual perception, the human NAc and mPFC are specifically reactive to pleasant, rewarding stimuli and are not engaged by unpleasant stimuli, despite high stimulus salience. C1 Univ Florida, NIMH, Ctr Study Emot & Attent, Gainesville, FL 32611 USA. RP Sabatinelli, D (reprint author), Univ Florida, NIMH, Ctr Study Emot & Attent, POB 112766, Gainesville, FL 32611 USA. EM sabat@ufl.edu RI Costa, Vincent/E-3155-2010; Frank, David/E-8213-2012; Costa, Vincent/A-2086-2015; OI Costa, Vincent/0000-0002-5412-8945; sabatinelli, dean/0000-0001-7409-8504 NR 52 TC 96 Z9 96 U1 5 U2 24 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-3077 J9 J NEUROPHYSIOL JI J. Neurophysiol. PD SEP PY 2007 VL 98 IS 3 BP 1374 EP 1379 DI 10.1152/jn.00230.2007 PG 6 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 208XB UT WOS:000249351400029 PM 17596422 ER PT J AU Szerlip, NJ Walbridge, S Yang, L Morrison, PF Degen, JW Jarrell, ST Kouri, J Kerr, PB Kotin, R Oldfield, EH Lonser, RR AF Szerlip, Nicholas J. Walbridge, Stuart Yang, Linda Morrison, Paul F. Degen, Jeffrey W. Jarrell, S. Taylor Kouri, Joshua Kerr, P. Benjamin Kotin, Robert Oldfield, Edward H. Lonser, Russell R. TI Real-time imaging of convection-enhanced delivery of viruses and virus-sized particles SO JOURNAL OF NEUROSURGERY LA English DT Article DE adeno-associated virus; central nervous system convection-enhanced; delivery; gene therapy; Macaca fascicularis; rat; real-time magnetic resonance imaging ID RAT-BRAIN; INTRACEREBRAL HEMORRHAGE; INTERSTITIAL INFUSION; GENE-THERAPY; TISSUE; MACROMOLECULES; FLOW; IRON; EXPRESSION; TRANSPORT AB Object. Despite recent evidence showing that convection-enhanced delivery (CED) of viruses and virus-sized particles to the central nervous system (CNS) is possible, little is known about the factors influencing distribution of these vectors with convection. To better define the delivery of viruses and virus-sized particles in the CNS, and to determine optimal parameters for infusion, the authors coinfused adeno-associated virus ([AAV], 24-nm diameter) and/or ferumoxtran-10 (24 nm) by using CED during real-time magnetic resonance (MR) imaging. Methods. Sixteen rats underwent intrastriatal convective coinfusion with 4 mu l of S-35-AAV capsids (0.5-1.0 x 10(14) viral particles/ml) and increasing concentrations (0.1, 0.5, 1, and 5 mg/ml) of a similar sized iron oxide MR imaging agent (ferumoxtran-10). Five nonhuman primates underwent either convective coinfusion of S-35-AAV capsids and I mg/ml ferumoxtran-10 (striatum, one animal) or infusion of I mg/ml ferumoxtran-10 alone (striatum in two animals; frontal white matter in two). Clinical effects, MR imaging studies, quantitative autoradiography, and histological data were analyzed. Results. Real-time, T2-weighted MR imaging of ferumoxtran-10 during infusion revealed a clearly defined hypointense region of perfusion. Quantitative autoradiography confirmed that MR imaging of ferumoxtran- 10 at a concentration of 1 mg/ml accurately tracked viral capsid distribution in the rat and primate brain (the mean difference in volume of distribution [Vd] was 7 and 15% in rats and primates, respectively). The Vd increased linearly with increasing volume of infusion (Vi) (R-2 = 0.98). The mean Vd/Vi ratio was 4.1 +/- 0.2 (mean standard error of the mean) in gray and 2.3 +/- 0.1 in white matter (p < 0.01). The distribution of infusate was homogeneous. Postinfusion MR imaging revealed leakback along the cannula track at infusion rates greater than 1.5 mu l/minute in primate gray and white matter. No animal had clinical or histological evidence of toxicity. Conclusions. The CED method can be used to deliver AAV capsids and similar sized particles to the CNS safely and effectively over clinically relevant volumes. Moreover, real-time MR imaging of ferumoxtran-10 during infusion reveals that AAV capsids and similar sized particles have different convective delivery properties than smaller proteins and other compounds. C1 NINDS, Surg Neurol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. NHLBI, Lab Biochem Genet, Natl Inst Hlth, Bethesda, MD 20892 USA. Natl Inst Hlth, Off Res Serv, Div Bioengn & Phys Sci, Bethesda, MD USA. Univ Maryland, Med Ctr, Dept Neurosurg, Baltimore, MD 21201 USA. George Washington Univ, Dept Neurosurg, Washington, DC USA. RP Szerlip, NJ (reprint author), NINDS, Surg Neurol Branch, Natl Inst Hlth, Bldg 10,Room 5D37, Bethesda, MD 20892 USA. RI kotin, robert/B-8954-2008 NR 40 TC 54 Z9 54 U1 0 U2 5 PU AMER ASSOC NEUROLOGICAL SURGEONS PI CHARLOTTESVILLE PA UNIV VIRGINIA, 1224 WEST MAIN ST, STE 450, CHARLOTTESVILLE, VA 22903 USA SN 0022-3085 J9 J NEUROSURG JI J. Neurosurg. PD SEP PY 2007 VL 107 IS 3 BP 560 EP 567 DI 10.3171/JNS-07/09/0560 PG 8 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 206YZ UT WOS:000249220100013 PM 17886556 ER PT J AU Le Foll, B Chefer, SI Kimes, AS Shumway, D Goldberg, SR Stein, EA Mukhin, AG AF Le Foll, Bernard Chefer, Svetlana I. Kimes, Alane S. Shumway, Dean Goldberg, Steven R. Stein, Elliot A. Mukhin, Alexey G. TI Validation of an extracerebral reference region approach for the quantification of brain nicotinic acetylcholine receptors in squirrel monkeys with PET and 2-F-18-fluoro-A-85380 SO JOURNAL OF NUCLEAR MEDICINE LA English DT Article DE PET; nonhuman primates; radioligand; in vivo binding; nicotinic acetylcholine receptors ID POSITRON-EMISSION-TOMOGRAPHY; GRAPHICAL ANALYSIS; BLOOD-VOLUME; BINDING; LIGAND; RADIOLIGAND; SPECT; MODEL AB The aim of the present study was to explore the applicability of an extracerebral reference region for the quantification of cerebral receptors with PET. Methods: Male squirrel monkeys underwent quantitative PET studies of cerebral nicotinic acetylcholine receptors (nAChRs) with 2-F-18-fluoro-A-85380 (2-FA). Data from dynamic PET scans were analyzed with various compartment- and non-compartment-based models, including a simplified reference tissue model (SRTM). Nondisplaceable volume-of-distribution (VDnd) values were determined in regions of interest after the blockade of 2-FA-specific binding by nicotine infusion. Binding potential values, estimated with the cerebellum and muscle as reference regions, were compared and the reproducibility of measurements was determined. Results: One- and 2-tissue compartment modeling and linear graphic analysis provided similar total volume-of-distribution (VDT) values for each studied region. VDT values were high in the thalamus, intermediate in the cortex and midbrain, and low in the cerebellum and muscle, consistent with the distribution pattern of nAChR containing alpha(4) and beta(2) receptor subunits (alpha(4)beta(2)*). The administration of nicotine at 2 mg/kg/d via an osmotic pump resulted in a nearly complete saturation of 2-FA-specific binding and led to very small changes in volumes of distribution in the cerebellum and muscle (-9% +/- 4% [mean +/- SEMI and 0% +/- 6%, respectively), suggesting limited specific binding of the radioligand in these areas. VDT measured in muscle in 15 monkeys was reasonably constant (3.0 +/- 0.2, with a coefficient of variation of 8%). VDnd in studied brain regions exceeded VDT in muscles by a factor of 1.3. With this factor and with muscle as a reference region, BP* values calculated for studied brain regions with the SRTM were in good agreement with those obtained with the cerebellum as a reference region. Significant correlations were observed between BP* values estimated with these 2 approaches. The reproducibilities of BP* measurements obtained with the 2 methods were comparable, with coefficients of variation of less than 11% and 13% for the thalamus and the cortex, respectively. Conclusion: These results suggest that the accurate quantification of nAChRs can be performed with 2-FA and a reference region outside the brain, providing a novel approach for the quantification of brain receptors when no suitable cerebral reference region is available. C1 [Le Foll, Bernard; Chefer, Svetlana I.; Kimes, Alane S.; Shumway, Dean; Stein, Elliot A.; Mukhin, Alexey G.] Natl Inst Drug Abuse, Intramural Res Program, Neuroimaging Res Branch, Baltimore, MD USA. [Le Foll, Bernard] Univ Toronto, Ctr Addict & Mental Hlth, Translat Addict Res Lab, Toronto, ON, Canada. [Le Foll, Bernard; Goldberg, Steven R.] Natl Inst Drug Abuse, Intramural Res Program, Preclin Pharmacol Sect, Baltimore, MD USA. RP Mukhin, AG (reprint author), Duke Univ, Med Ctr, Ctr Nicotine & Smoking Cessat Res, Dept Psychiat, 24224 Erwin Rd,Suite 201, Durham, NC 27705 USA. EM a.mukhin@duke.edu RI Stein, Elliot/C-7349-2008; Le Foll, Bernard/K-2952-2014 OI Le Foll, Bernard/0000-0002-6406-4973 FU Intramural NIH HHS NR 35 TC 6 Z9 6 U1 0 U2 3 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 SEP PY 2007 VL 48 IS 9 BP 1492 EP 1500 DI 10.2967/jnumed.107.039776 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 258UJ UT WOS:000252894700037 PM 17704243 ER PT J AU Neggers, YH Nansel, TR Andrews, WW Schwebke, JR Yu, KF Goldenberg, RL Klebanoff, MA AF Neggers, Yasmin H. Nansel, Tonja R. Andrews, William W. Schwebke, Jane R. Yu, Kai-fun Goldenberg, Robert L. Klebanoff, Mark A. TI Dietary intake of selected nutrients affects bacterial vaginosis in women SO JOURNAL OF NUTRITION LA English DT Article ID TRACT INFECTIONS; IMMUNE-SYSTEM; VAGINAL PH; FAT INTAKE; DEFICIENCY; MODULATION; PREGNANCY; FOLATE; TRIAL AB Bacterial vaginosis (BV), a condition of altered vaginal flora, is associated with various adverse reproductive health outcomes. We evaluated the association between diet and the presence of BV in a subset of 1521 women (86% African-American) from a larger study of vaginal flora. Participants completed the Block Food Questionnaire and clinical assessments and self-report measures of sexual and hygiene behavior. A total of 42% of the women were classified as having BV (Nugent score >= 7). Severe BV (Nugent score >= 9 and vaginal pH >= 5) was present in 14.9% of the women. BV was associated [adjusted OR (AOR)] with increased dietary fat (1.5, 1.1-2.4) after adjusting for other energy nutrients and behavioral and demographic covariates. Severe BV was associated with total fat (2.3, 1.3-4.3), saturated fat (2.1, 1.2-3.9), and monounsaturated fat (2.2, 1.2-4.1). Energy intake was only marginally associated (P = 0.05) with BV (1.4, 1.0-1.8). There were significant inverse associations between severe BV and intakes of folate (0.4, 0.2-0.8), vitamin E (0.4, 0.2-0.8), and calcium (0.4, 0.3-0.7). We conclude that increased dietary fat intake is associated with increased risk of BV and severe BV, whereas increased intake of folate, vitamin A, and calcium may decrease the risk of severe BV. C1 Univ Alabama, Dept Human Nutr, Tuscaloosa, AL 35487 USA. Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35233 USA. Univ Alabama, Dept Med, Birmingham, AL 35233 USA. NICHHD, NIH, Dept Hlth & Human Serv, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. Drexel Col Med, Dept Obstet & Gynecol, Philadelphia, PA 19102 USA. RP Neggers, YH (reprint author), Univ Alabama, Dept Human Nutr, Tuscaloosa, AL 35487 USA. EM yneggers@ches.ua.edu OI Nansel, Tonja/0000-0002-8298-7595 FU Intramural NIH HHS [Z01 HD002535-09]; NICHD NIH HHS [N01-HD-8-3293] NR 25 TC 23 Z9 23 U1 0 U2 5 PU AMER SOC 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 SEP PY 2007 VL 137 IS 9 BP 2128 EP 2133 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 205JU UT WOS:000249110600022 PM 17709453 ER PT J AU Johnson-Taylor, WL Hubbard, VS AF Johnson-Taylor, Wendy L. Hubbard, Van S. TI The need for research in the delivery of nutrition education SO JOURNAL OF NUTRITION EDUCATION AND BEHAVIOR LA English DT Editorial Material C1 US PHS, Div Nutr Res Coordinat, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Hubbard, VS (reprint author), US PHS, Div Nutr Res Coordinat, Dept Hlth & Human Serv, NIH, 2 Democracy Pl,Room 631,6707 Democracy Blvd,MSC, Bethesda, MD 20892 USA. EM van.hubbard@nih.hhs.gov NR 2 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1499-4046 J9 J NUTR EDUC BEHAV JI J. Nutr. Educ. Behav. PD SEP-OCT PY 2007 VL 39 IS 5 SU S PG 1 WC Education, Scientific Disciplines; Nutrition & Dietetics SC Education & Educational Research; Nutrition & Dietetics GA 216PA UT WOS:000249889500001 ER PT J AU Seifried, HE Anderson, DE Fisher, EI Milner, JA AF Seifried, Harold E. Anderson, Darrell E. Fisher, Evan I. Milner, John A. TI A review of the interaction among dietary antioxidants and reactive oxygen species SO JOURNAL OF NUTRITIONAL BIOCHEMISTRY LA English DT Review DE review; reactive oxygen species; antioxidants; cancer; cardiovascular disease ID NF-KAPPA-B; ACTIVATED PROTEIN-KINASE; LOW-DENSITY-LIPOPROTEIN; OXIDATIVE DNA-DAMAGE; SMOOTH-MUSCLE-CELL; NITRIC-OXIDE; HYDROGEN-PEROXIDE; GENE-EXPRESSION; SIGNAL-TRANSDUCTION; DEGENERATIVE DISEASES AB During normal cellular activities, various processes inside of cells produce reactive oxygen species (ROS). Some of the most common ROS are hydrogen peroxide (H2O2), superoxide ion (O-2(-)), and hydroxide radical (OH-). These compounds, when present in a high enough concentration, can damage cellular proteins and lipids or form DNA adducts that may promote carcinogenic activity. The purpose of antioxidants in a physiological setting is to prevent ROS concentrations from reaching a high-enough level within a cell that damage may occur. Cellular antioxidants may be enzymatic (catalase, glutathione peroxidase, superoxide dismutase) or nonenzymatic (glutathione, thiols, some vitamins and metals, or phytochemicals such as isoflavones, polyphenols, and flavanoids). Reactive oxygen species are a potential double-edged sword in disease prevention and promotion. Whereas generation of ROS once was viewed as detrimental to the overall health of the organism, advances in research have shown that ROS play crucial roles in normal physiological processes including response to growth factors, the immune response, and apoptotic elimination of damaged cells. Notwithstanding these beneficial functions, aberrant production or regulation of ROS activity has been demonstrated to contribute to the development of some prevalent diseases and conditions, including cancer and cardiovascular disease (CVD). The topic of antioxidant usage and ROS is currently receiving much attention because of studies linking the use of some antioxidants with increased mortality in primarily higher-risk populations and the lack of strong efficacy data for protection against cancer and heart disease, at least in populations with adequate baseline dietary consumption. In normal physiological processes, antioxidants effect signal transduction and regulation of proliferation and the immune response. Reactive oxygen species have been linked to cancer and CVD, and antioxidants have been considered promising therapy for prevention and treatment of these diseases, especially given the tantalizing links observed between diets high in fruits and vegetables (and presumably antioxidants) and decreased risks for cancer. (c) 2007 Elsevier Inc. All rights reserved. C1 NCI, Div Canc Prevent, Rockville, MD 20862 USA. Sci Consulting Grp Inc, Gaithersburg, MD 20878 USA. RP Seifried, HE (reprint author), NCI, Nutr Sci Res Grp, Div Canc, NIH, Bethesda, MD 20892 USA. EM hs41s@nih.gov NR 100 TC 318 Z9 339 U1 7 U2 82 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0955-2863 J9 J NUTR BIOCHEM JI J. Nutr. Biochem. PD SEP PY 2007 VL 18 IS 9 BP 567 EP 579 DI 10.1016/j.jnutbio.2006.10.007 PG 13 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 204HW UT WOS:000249035600001 PM 17360173 ER PT J AU Naito, H Kamijima, M Yamanoshita, O Nakahara, A Katoh, T Tanaka, N Aoyama, T Gonzalez, FJ Nakajima, T AF Naito, Hisao Kamijima, Michihiro Yamanoshita, Osamu Nakahara, Ai Katoh, Takahiko Tanaka, Naoki Aoyama, Toshifumi Gonzalez, Frank J. Nakajima, Tamie TI Differential effects of aging, drinking and exercise on serum cholesterol levels dependent on the PPARA-V227A polymorphism SO JOURNAL OF OCCUPATIONAL HEALTH LA English DT Article DE peroxisome proliferator-activated receptor alpha; alcohol drinking; aging; exercise; polymorphism; molecular epidemiology; cholesterol; sex; Japanese ID PROLIFERATOR-ACTIVATED RECEPTOR; CORONARY HEART-DISEASE; ALCOHOLIC LIVER-DISEASE; ESTER TRANSFER PROTEIN; ALPHA PPAR-ALPHA; JAPANESE POPULATION; LIPOPROTEIN CONCENTRATIONS; CARDIOVASCULAR-DISEASE; LIPID CONCENTRATIONS; RISK-FACTORS AB Peroxisome proliferator-activated receptor alpha (PPAR alpha) plays a pivotal role in lipid metabolism. Our previous study reported that PPARA-V227A was a major polymorphism in Japanese, which was associated with markedly lower serum total cholesterol (TC) levels, which were significantly affected by alcohol drinking compared to subjects with the wild-type (PPARA-WT) allele. However, serum lipids are also associated with aging and exercise frequency. The objective of the present study was to evaluate the relationship between PPARA-V227A and these factors. Genetic analysis of the polymorphism was performed in 1058 Japanese men and 281 women, and the relationship with aging, drinking and exercise on serum lipids was analyzed in 989 men and 245 women after exclusion criteria had been applied. In men, drinking increased high-density lipoprotein cholesterol (HDL-C) levels in both PPARA-WT and A227 carriers, but to a significantly higher degree in the latter. In women, TC and low-density lipoprotein cholesterol (LDL-C) levels in the A227 carriers drinking at least once a week were significantly higher than in PPARA-WT carriers. TC and LDL-C levels in males with PPARA-WT increased with aging regardless of drinking habit, while LDL-C levels in the A227 drinking carriers were significantly lower in 45-yr-old or older subjects than in 35- to 45-yr-olds. In addition, no effect of exercising was observed in the A227 carriers, while increase in the HDL-C of the PPARA-WT carriers was exercise frequency dependent. These results suggest that the influence of drinking, aging or exercise on TC, LDL-C and HDL-C levels in the A227 carriers may be different from those in the PPARA-WT subjects. C1 Nagoya Univ, Grad Sch Med, Dept Environm & Occupat Hlth, Showa Ku, Nagoya, Aichi 4668550, Japan. Chubu Univ, Coll Life & Hlth Sci, Dept Biomed Sci, Kasugai, Aichi 487, Japan. Miyazaki Univ, Miyazaki Med Coll, Dept Publ Hlth, Miyazaki, Japan. Shinshu Univ, Grad Sch Med, Inst Aging & Adaptat, Inst Metab Regulat, Nagano, Japan. Natl Canc Inst, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Nakajima, T (reprint author), Nagoya Univ, Grad Sch Med, Dept Environm & Occupat Hlth, Showa Ku, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan. EM tnasu23@med.nagoya-u.ac.jp NR 45 TC 10 Z9 10 U1 1 U2 2 PU JAPAN SOC OCCUPATIONAL HEALTH PI TOKYO PA 1-29-8 SHINJUKU, SHINJUKU-KU, TOKYO, 160, JAPAN SN 1341-9145 J9 J OCCUP HEALTH JI J. Occup. Health PD SEP PY 2007 VL 49 IS 5 BP 353 EP 362 DI 10.1539/joh.49.353 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 218KP UT WOS:000250014700002 PM 17951966 ER PT J AU Beverage, JN Sissung, TM Sion, AM Danesi, R Figg, WD AF Beverage, Jacob N. Sissung, Tristan M. Sion, Amy M. Danesi, Romano Figg, William D. TI CYP2D6 Polymorphisms and the impact on tamoxifen therapy SO JOURNAL OF PHARMACEUTICAL SCIENCES LA English DT Review DE cYP2D6; tamoxifen; pharmacogenetics; polymorphisms; endoxifen ID DEBRISOQUINE SPARTEINE-TYPE; RECEPTOR-POSITIVE TUMORS; BREAST-CANCER-TREATMENT; POSTMENOPAUSAL WOMEN; ESTROGEN-RECEPTOR; GENETIC-POLYMORPHISM; ADJUVANT BREAST; DRUG-THERAPY; HOT FLASHES; METABOLISM AB The cytochrome P450 2D6 (CYP2D6) is an enzyme known to metabolize a variety of xenobiotics and drugs. Inter-individual variation in the metabolic capacity of this enzyme has been extensively studied and associations with genotype have been established. Genetic polymorphisms have been grouped as nonfunctional, reduced function, functional, and multiplication alleles phenotypically. Individuals carrying these alleles are presumed to correspond to poor, intermediate, extensive, and ultrarapid metabolizers (UM), respectively. Tamoxifen has been shown to be metabolized by CYP2D6 to the more potent metabolite endoxifen. Poor metabolizers (PM) of tamoxifen have lower levels of endoxifen and poorer clinical outcomes as compared to extensive metabolizers (EM). Here, we will provide an overview of the history and application of CYP2D6 pharmacogenetics, and will discuss the clinical implications of recent developments relating to the involvement of CYP2D6 in tamoxifen treatment. (c) 2007 Wiley-Liss, Inc. C1 NCI, Clin Pharmacol Res Core, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Pisa, Dept Oncol Transplants & Adv Technol Med, Pisa, Italy. RP Figg, WD (reprint author), NCI, Clin Pharmacol Res Core, Med Oncol Branch, Ctr Canc Res, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 NR 41 TC 53 Z9 57 U1 1 U2 3 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0022-3549 J9 J PHARM SCI-US JI J. Pharm. Sci. PD SEP PY 2007 VL 96 IS 9 BP 2224 EP 2231 DI 10.1002/jps.20892 PG 8 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Pharmacology & Pharmacy; Chemistry GA 206LB UT WOS:000249183800004 PM 17518364 ER PT J AU Yadav, H Jain, S Prasad, GBKS Yadav, M AF Yadav, Hariom Jain, Shalini Prasad, G. B. K. S. Yadav, Mukesh TI Preventive effect of diabegon, a polyherbal preparation, during progression of diabetes induced by high-fructose feeding in rats SO JOURNAL OF PHARMACOLOGICAL SCIENCES LA English DT Article DE diabetes; diabegon; high fructose; herbal; antidiabetic plant ID INSULIN-RESISTANCE; LIPOPROTEIN-LIPASE; MEDICINAL-PLANTS; OBESE RATS; HYPERTENSION; METABOLISM; ROSIGLITAZONE; MODEL AB In the present study, the polyherbal preparation diabegon, containing 18 plant extracts with hypoglycemic activity, was evaluated for its preventive effect during progression of type 2 diabetes in high-fructose-diet-fed rats. Oral administration of diabegon (100 mg/kg body weight) delayed development of glucose intolerance for 4 weeks in comparison with the diabetic control group, and the effect of diabegon was compared to that of the standard insulin sensitizer drug rosiglitazone. Diabegon treatment also ameliorated the elevation of glycosylated haemoglobin, liver glycogen content, plasma insulin, homeostasis model assessment, free fatty acids, triglycerides, total cholesterol, LDL-cholesterol, and VLDL-cholesterol, whereas it increased HDL-cholesterol after 56 days of treatment (P<0.05). The mechanism of action by which diabegon attenuates insulin resistance and dyslipidemia may be through induction of peroxisome proliferator-activated receptor-gamma and lipoprotein lipase activity in peripheral tissues (muscles). Moreover, diabegon administration for 56 days also produced no alteration in liver and kidney function tests, which seems to indicate its non-toxicity during treatment. Our present results suggest that diabegon may be included in diabetes mellitus treatment regimens, as a drug with good antidiabetic actions but no toxic manifestations. C1 Jiwaji Univ, Sch Studies Biochem, Gwalior 474011, India. Natl Dairy Res Inst, Anim Biochem Div, Karnal 132001, Haryana, India. Jiwaji Univ, Sch Studies Chem, Gwalior 474011, India. RP Yadav, H (reprint author), NIDDKD, Diabet Branch, NIH,W Labs, Regenerat Biol Sect,Clin Res Ctr, Bldg 10,5-5872 S Dr & Old Georgetown Rd, Bethesda, MD 20892 USA. EM yadavh@mail.nih.gov OI Yadav, Hariom/0000-0003-4504-1597 NR 32 TC 8 Z9 12 U1 0 U2 3 PU JAPANESE PHARMACOLOGICAL SOC PI KYOTO PA EDITORIAL OFF, KANTOHYA BLDG GOKOMACHI-EBISUGAWA NAKAGYO-KU, KYOTO, 604, JAPAN SN 1347-8613 J9 J PHARMACOL SCI JI J. Pharmacol. Sci. PD SEP PY 2007 VL 105 IS 1 BP 12 EP 21 DI 10.1254/jphs.FP0060092 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 215GI UT WOS:000249795900003 PM 17878707 ER PT J AU Sforcin, JM Nunes, GA Missima, F Sa-Nunes, A Faccioli, LH AF Sforcin, Jose Mauricio Nunes, Gladston A. Missima, Fabiane Sa-Nunes, Anderson Faccioli, Lucia H. TI Effect of a leukotriene inhibitor (MK886) on nitric oxide and hydrogen peroxide production by macrophages of acutely and chronically stressed mice SO JOURNAL OF PHARMACY AND PHARMACOLOGY LA English DT Article ID SALMONELLA-TYPHIMURIUM; MURINE MACROPHAGES; INFECTION; HORMONES; SUSCEPTIBILITY; BIOSYNTHESIS; PHAGOCYTOSIS; CYTOKINES; PROTEIN; STRAIN AB We evaluated the effect of a leukotriene inhibitor (MK886) on nitric oxide (NO) and hydrogen peroxide (H2O2) production by peritoneal macrophages of mice subjected to acute and chronic stress. Acute stress was induced by keeping mice immobilized in a tube for 2 h. Chronic stress was induced over a 7-day period by the same method, but with increasing duration of immobilization. The effects of MK886 were investigated in-vitro after incubation with peritoneal macrophages, and in-vivo by submitting mice to stress and treating them daily with MK886. Supernatants of macrophage cultures were collected for NO determination and adherent cells were used for H2O2 determination. Macrophages from mice submitted to acute or chronic stress showed no alterations in H2O2 production. However, macrophages of acutely and chronically stressed mice showed inhibition of NO after incubation with MK886 in-vitro. Administration of MK886 to chronically stressed mice increased generation of H2O2 and inhibited production of NO. Our data suggest an important role of leukotrienes in NO synthesis, which is important in controlling replication of several infectious agents, mainly in stressed and immunosuppressed animals. C1 UNESP, Inst Biociencias, Dept Microbiol & Imunol, BR-18618000 Botucatu, SP, Brazil. NIAID, Sect Med Biol, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. Fac Ciencias Farmaceut Ribeirao Preto, Dept Anal Clin Toxicol & Bromatol, BR-14040903 Ribeirao Preto, SP, Brazil. RP Sforcin, JM (reprint author), UNESP, Inst Biociencias, Dept Microbiol & Imunol, BR-18618000 Botucatu, SP, Brazil. EM sforcin@ibb.unesp.br RI Sa-Nunes, Anderson/D-8667-2012; SFORCIN, JOSE/F-4263-2012; Lucia , Faccioli/G-8976-2015 OI Sa-Nunes, Anderson/0000-0002-1859-4973; Lucia , Faccioli/0000-0002-4999-8305 NR 29 TC 9 Z9 9 U1 0 U2 0 PU PHARMACEUTICAL PRESS-ROYAL PHARMACEUTICAL SOC GREAT BRITIAN PI LONDON PA 1 LAMBETH HIGH ST, LONDON SE1 7JN, ENGLAND SN 0022-3573 J9 J PHARM PHARMACOL JI J. Pharm. Pharmacol. PD SEP PY 2007 VL 59 IS 9 BP 1249 EP 1254 DI 10.1211/jpp.59.9.0009 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 217TQ UT WOS:000249970600009 PM 17883896 ER PT J AU Zhou, XW Mudannayake, M Green, M Gigena, MS Wang, GH Shen, RF Rogers, TB AF Zhou, Xing Wang Mudannayake, Malkanthi Green, Mariah Gigena, Marisa S. Wang, Guanghui Shen, Rong-Fong Rogers, Terry B. TI Proteomic. studies of PP2A-B56 gamma 1 phosphatase complexes reveal phosphorylation-regulated partners in cardiac local signaling SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE B56 gamma 1; phosphatase; PP2A; proteomics; cardiac function; heart disease; signal transduction; splicing; EC coupling ID VENTRICULAR MYOCYTES; RYANODINE RECEPTOR; NUCLEAR SPECKLES; BINDING-PROTEINS; SPLICING FACTORS; 2A; SUBUNIT; PHOSPHOLAMBAN; DEPHOSPHORYLATION; FAMILY AB Defects of kinase-phosphatase signaling in cardiac myocytes contribute to human heart disease. The activity of one phosphatase, PP2A, is governed by B targeting subunits, including B56 gamma 1, expressed in heart cells. As the role of PP2A/B56 gamma 1 on the heart function remains largely unknown, this study sought to identify protein partners through unbiased, affinity purification-based proteomics combined with the functional validation. The results reveal multiple interactors that are localized in strategic cardiac sites to participate in Ca2+ homeostasis and gene expression, exemplified by the Ca pump, SERCA2a, and the splicing factor ASF/SF2. These results are corroborated by confocal imaging where adenovirally overexpressed B56 gamma 1 is found in z-line/t-tubule region and nuclear speckles. Importantly, overexpression of B56 gamma 1 in Cultured myocytes dramatically impairs cell contractility. These results provide a global view of B56 gamma 1-regulated local signaling and heart function. C1 Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. Natl Inst Hlth, NHLBI, Proteom Core Facil, Bethesda, MD 20892 USA. RP Zhou, XW (reprint author), Univ Maryland, Sch Med, Dept Biochem & Mol Biol, 108 N Greene St, Baltimore, MD 21201 USA. EM xzhou@som.umaryland.edu; trogers@som.umaryland.edu FU NHLBI NIH HHS [HL070709]; NIA NIH HHS [AG14637] NR 59 TC 6 Z9 6 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD SEP PY 2007 VL 6 IS 9 BP 3433 EP 3442 DI 10.1021/pr0606191 PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 209EE UT WOS:000249371000009 PM 17663574 ER PT J AU Hoffert, JD Wang, GH Pisitkun, T Shen, RF Knepper, MA AF Hoffert, Jason D. Wang, Guanghui Pisitkun, Trairak Shen, Rong-Fong Knepper, Mark A. TI An automated platform for analysis of phosphoproteomic datasets: Application to kidney collecting duct phosphoproteins SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE phosphoproteomics; neutral loss; target-decoy; LC-MS/MS; collecting duct; IMCD; mass spectrometry; label-free; phosphoPIC; proteomics ID TANDEM MASS-SPECTRA; QUANTITATIVE PHOSPHOPROTEOMICS; WATER PERMEABILITY; PHOSPHORYLATION; IDENTIFICATION; LOCALIZATION; SPECTROMETRY; PROTEOMICS; CHANNEL; SITES AB Large-scale phosphoproteomic analysis employing liquid chromatography-tandem mass spectrometry (LC-MS/MS) often requires a significant amount of manual manipulation of phosphopeptide datasets in the post-acquisition phase. To assist in this process, we have created software, PhosphoPIC (PhosphoPeptide Identification and Compilation), which can perform a variety of useful functions including automated selection and compilation of phosphopeptide identifications from multiple MS levels, estimation of dataset false discovery rate, and application of appropriate cross-correlation (XCorr) filters. In addition, the output files generated by this program are compatible with downstream phosphorylation site assignment using the Ascore algorithm, as well as phosphopepticle quantification via QUOIL. In this report, we utilized this software to analyze phosphoproteins from short-term vasopressin-treated rat kidney inner medullary collecting duct (IMCD). A total of 925 phosphopeptides representing 173 unique proteins were identified from membrane-enriched fractions of IMCD with a false discovery rate of 1.5%. Of these proteins, 106 were found only in the membrane-enriched fraction of IMCD cells and not in whole IMCD cell lysates. These identifications included a number of well-studied ion and solute transporters including CIC-1, LAT4, MCT2, NBC3, and NHE1, all of which contained novel phosphorylation sites. Using a label-free quantification approach, we identified phosphoproteins that changed in abundance with vasopressin exposure including aquaporin-2 (AQP2), Hnrpa3, IP3 receptor 3, and pur-beta. C1 NHLBI, Kidney & Electrolyte Metab Lab, Proteom Core Facil, Bethesda, MD 20892 USA. RP Knepper, MA (reprint author), NHLBI, Kidney & Electrolyte Metab Lab, Proteom Core Facil, NIH Bldg 10,Rm 6N260,10 Ctr Dr MSC 1603, Bethesda, MD 20892 USA. EM knep@heliy-nih.gov OI Pisitkun, Trairak/0000-0001-6677-2271 FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999]; NHLBI NIH HHS [Z01 HL001285] NR 18 TC 46 Z9 48 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD SEP PY 2007 VL 6 IS 9 BP 3501 EP 3508 DI 10.1021/pr0701153 PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 209EE UT WOS:000249371000017 PM 17683130 ER PT J AU Taylor, MM Stokes, WS Bajuscak, R Serdula, M Siegel, KL Griffin, B Keiser, J Agate, L Kite-Powell, A Roach, D Humbert, N Brusuelas, K Shekar, SS AF Taylor, Melanie M. Stokes, William S. Bajuscak, Ronald Serdula, Mary Siegel, Karen L. Griffin, Brian Keiser, Jeffrey Agate, Lisa Kite-Powell, Aaron Roach, David Humbert, Nancy Brusuelas, Kristin Shekar, Sam S. TI Mobilizing mobile medical units for hurricane relief: The United States Public Health Service and Broward County Health Department response to hurricane Wilma, Broward county, Florida SO JOURNAL OF PUBLIC HEALTH MANAGEMENT AND PRACTICE LA English DT Article DE disaster relief; hurricane; mobile medical units; syndromic surveillance ID KATRINA AB Objectives: To describe the outcomes Of a collaborative response of federal, state, county, and local agencies in conducting syndromic surveillance and delivering medical care to persons affected by the storm through the use of mobile medical units. Methods: Nine mobile medical vans were staffed with medical personnel to deliver care in communities affected by the storm. Individual patient encounter information was collected. Results: A total of 14 033 housing units were approached and checked for occupants. Of residents with whom contact was made, approximately 10 percent required medical assessment in their homes; 3 218 clients were medically evaluated on the mobile medical vans. Sixty-two percent of clients were female. The most common presenting complaints included normal health maintenance (59%), upper respiratory tract illness (10%), and other illness (10%). Injuries occurred in 9 percent. A total of 1 531 doses of medications were dispensed from the mobile medical units during the response. Conclusion: Mobile medical units provided an efficient means to conduct syndromic surveillance and to reach populations in need of medical care who were unable to access fixed local medical facilities. C1 United States Publ Hlth Serv Commissioned Corps, Rockville, MD USA. Ctr Dis Control & Prevent, Natl Ctr HIV Viral Hepatitis STD & TB Prevent, Div STD Prevent, Atlanta, GA USA. Natl Inst Environm Hlth Sci, Natl Inst Hlth, Natl Toxicol Program Interagency Evaluat Alternat, Res Triangle Pk, NC USA. United States Publ Hlth Serv Commissioned Corps, Natl Consultant Oral Med Pathol, Rockville, MD USA. Broward Ctr Hlth Dept, Florida Dept Hlth, Ft Lauderdale, FL USA. Broward Epidemiol Florida, Dept Hlth, Tallahassee, FL USA. Bureau Epidemiol Florida, Dept Hlth, Ft Lauderdale, FL USA. Ctr Dis Control & Prevent, Atlanta, GA USA. US Publ Hlth Serv Commiss Corps, Bethesda, MD USA. Natl Inst Hlth, Clin Res Grants, Off Extramural Res, Bethesda, MD USA. RP Taylor, MM (reprint author), Arizona Dept Hlth Serv, United States Publ Hlth Serv, Off Infect Dis Serv, 150 N 18th Ave,Suite 140, Phoenix, AZ 85007 USA. EM taylorm@azdhs.gov RI Siegel, Karen Lohmann/B-5898-2008; OI Siegel, Karen Lohmann/0000-0002-0788-6612 NR 8 TC 6 Z9 6 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1078-4659 J9 J PUBLIC HEALTH MAN JI J. Public Health Manag. Pract. PD SEP-OCT PY 2007 VL 13 IS 5 BP 447 EP 452 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 203RU UT WOS:000248992500003 PM 17762687 ER PT J AU Castaneda-Sceppa, C Sarnak, MJ Wang, XL Greene, T Madero, M Kusek, JW Beck, G Kopple, JD Levey, AS Menon, V AF Castaneda-Sceppa, Carmen Sarnak, Mark J. Wang, Xuelei Greene, Tom Madero, Magdalena Kusek, John W. Beck, Gerald Kopple, Joel D. Levey, Andrew S. Menon, Vandana TI Role of adipose tissue in determining muscle mass in patients with chronic kidney disease SO JOURNAL OF RENAL NUTRITION LA English DT Article ID C-REACTIVE PROTEIN; CHRONIC-RENAL-FAILURE; HEMODIALYSIS-PATIENTS; INSULIN-RESISTANCE; NUTRITIONAL-STATUS; CARDIOVASCULAR MORTALITY; ALL-CAUSE; ADIPONECTIN; MALNUTRITION; INFLAMMATION AB Objective: Malnutrition is a powerful predictor of mortality in chronic kidney disease (CKD). However, its etiology is unclear. We hypothesized that the adipocyte-derived proteins leptin and adiponectin, inflammation (as measured by C-reactive protein, CRP), and insulin resistance (as measured by homeostasis model assessment, HOMA), implicated in the malnutrition-inflammation complex syndrome commonly seen in maintenance dialysis patients, would be associated with the loss of muscle mass in earlier stages of CKD. Arm muscle area was used as an indicator of muscle mass. Patients and Setting: The Modification of Diet in Renal Disease Study cohort of people with CKD stages 3 and 4 was used for analysis (N = 780). Main Outcome Measures: Regression models were carried out to examine the relationships of leptin, adiponectin, CRP, and HOMA with arm muscle area (the main study outcome). Results: Arm muscle area was 39 +/- 15 cm(2) (mean +/- SD), and adiponectin levels were 13 +/- 7 mu g/mL. Median and interquartile range (IQR) concentrations were: 9.0 (13.6) ng/mL for leptin, 2.3 (4.9) mg/L for CRP, and 2.4 (2.0) for HOMA. Higher leptin (beta coefficient and 95% confidence interval, -6.9 [-8.7 to -5.1], P < .001) and higher CRP (beta coefficient and 95% confidence interval, -2.7 [-3.9 to -1.4], P < .001) were associated with lower arm muscle area. There was a trend toward lower arm muscle area with higher adiponectin (P = .07), but no association with HOMA (P = .80). Conclusion: Leptin and CRP were associated with lower muscle mass in subjects with CKD at stages 3 and 4. Further studies are needed to understand the mechanisms underlying these associations, and to develop targeted interventions for this patient population. (C) 2007 by the National Kidney Foundation, Inc. C1 Tufts Univ, USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA. Tufs New England Med Ctr, Div Nephrol, Dept Med, Boston, MA USA. Cleveland Clin Fdn, Dept Biostat & Epidemiol, Cleveland, OH 44195 USA. Univ Utah, Div Clin Epidemiol, Salt Lake City, UT USA. Natl Inst Hlth, Bethesda, MD USA. Harbor Univ Calif, Los Angeles Med Ctr, Los Angeles Biomed Res Inst, Torrance, CA USA. Univ Calif Los Angeles, Sch Publ Hlth, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA USA. RP Castaneda-Sceppa, C (reprint author), Tufts Univ, USDA, Human Nutr Res Ctr Aging, 711 Washington St, Boston, MA 02111 USA. EM cvsceppa@comcast.net FU NIDDK NIH HHS [U01 DK 35073, K23 DK67303, U01 DK035073, K23 DK067303-05, K23 DK067303, U01 DK035073-14] NR 36 TC 12 Z9 12 U1 1 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 1051-2276 J9 J RENAL NUTR JI J. Renal Nutr. PD SEP PY 2007 VL 17 IS 5 BP 314 EP 322 DI 10.1053/j.jrn.2007.05.006 PG 9 WC Nutrition & Dietetics; Urology & Nephrology SC Nutrition & Dietetics; Urology & Nephrology GA 213SW UT WOS:000249688400004 PM 17720100 ER PT J AU Ness, RB Bass, D Hill, L Klebanoff, MA Zhang, J AF Ness, Roberta B. Bass, Debra Hill, Lyndon Klebanoff, Mark A. Zhang, Jun TI Diagnostic test characteristics of placental weight in the prediction of small-for-gestational-age neonates SO JOURNAL OF REPRODUCTIVE MEDICINE LA English DT Article DE placenta; infant; small for gestation age; fetal growth retardation ID INTRAUTERINE GROWTH-RETARDATION; LOW-BIRTH-WEIGHT; UNITED-STATES; FETAL-GROWTH; INFANTS BORN; ADULT LIFE; RATIO; ULTRASOUND; PREGNANCY; VOLUME AB OBJECTIVE: To assess the diagnostic test characteristics of placental weight as a clinical predictor of small-for-gestational-age (SGA) neonates. STUDY DESIGN: Placentas were weighed at 45,846 deliveries. Predictive values and likelihood ratios (LRs) were calculated assessing placental weight (lowest tertile vs. top 2 or mid/high tertiles) as a predictor of SGA both overall and by maternal age, gestational age, maternal weight, reported early pregnancy smoking, race, neonatal sex and parity. RESULTS: Although the positive predictive value (PPV) of low placental weight was poor (0.19), the negative predictive value (NPV) was high (0.97). Both NPV and LR- were powerfully predictive in women at earlier gestational ages. At gestational ages < 32 weeks, LR-was 0.11, showing that among women with mid/high placental weight, the proportion with SGA (false negative) was about 1/10 that without SGA (true negative). CONCLUSION: Placental weight in the mid or tipper tertile has strong NPV and LR-for delivery of an SGA neonate. Further study of the value of placental size in prediction of SGA is warranted. C1 Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. Magee Womens Res Inst, Pittsburgh, PA USA. NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Ness, RB (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Crabtree Hall,Room A527,130 DeSoto St, Pittsburgh, PA 15261 USA. EM repro@pitt.edu FU NICHD NIH HHS [P01 HD30367] NR 47 TC 4 Z9 4 U1 0 U2 1 PU SCI PRINTERS & PUBL INC PI ST LOUIS PA PO DRAWER 12425 8342 OLIVE BLVD, ST LOUIS, MO 63132 USA SN 0024-7758 J9 J REPROD MED JI J. Reprod. Med. PD SEP PY 2007 VL 52 IS 9 BP 793 EP 800 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 212VL UT WOS:000249624800009 PM 17939595 ER PT J AU Thomas, YF Compton, WM AF Thomas, Yonette F. Compton, Wilson M. TI Rural populations are not protected from drug use and abuse SO JOURNAL OF RURAL HEALTH LA English DT Editorial Material C1 [Thomas, Yonette F.; Compton, Wilson M.] NIDA, NIH, Div Epidemiol Serv & Prevent Res, Dept Hlth & Human Serv,Epidemiol Res Branch, Bethesda, MD 20892 USA. RP Thomas, YF (reprint author), NIDA, NIH, Div Epidemiol Serv & Prevent Res, Dept Hlth & Human Serv,Epidemiol Res Branch, 6001 Execut Blvd,Rm 5153, Bethesda, MD 20892 USA. EM ythomas@mail.nih.gov NR 3 TC 6 Z9 6 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0890-765X J9 J RURAL HEALTH JI J. Rural Health PD FAL PY 2007 VL 23 SU S BP 1 EP 3 DI 10.1111/j.1748-0361.2007.00116.x PG 3 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 245MR UT WOS:000251939700001 PM 18237317 ER PT J AU Clayton, RR McBride, D Roberts, LW Hartsock, P AF Clayton, Richard R. McBride, Duane Roberts, Laura Weiss Hartsock, Peter TI Drug abuse research in rural communities: Current knowledge and future directions SO JOURNAL OF RURAL HEALTH LA English DT Editorial Material C1 [Clayton, Richard R.] Univ Kentucky, Ctr Prevent Res, Lexington, KY 40536 USA. [McBride, Duane] Andrews Univ, Inst Prevent Addict, Berrien Springs, MI 49104 USA. [Roberts, Laura Weiss] Med Coll Wisconsin, Dept Psychiat & Behav Med, Milwaukee, WI 53226 USA. [Hartsock, Peter] NIDA, Epidemiol Res Branch, Rockville, MD USA. RP Clayton, RR (reprint author), Univ Kentucky, Ctr Prevent Res, 121 Washington Ave,Suite B110, Lexington, KY 40536 USA. EM clayton@uky.edu NR 14 TC 6 Z9 6 U1 0 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0890-765X J9 J RURAL HEALTH JI J. Rural Health PD FAL PY 2007 VL 23 SU S BP 4 EP 9 DI 10.1111/j.1748-0361.2007.00117.x PG 6 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 245MR UT WOS:000251939700002 PM 18237318 ER PT J AU Sousa, AA Aronova, MA Kim, YC Dorward, LM Zhang, G Leapman, RD AF Sousa, A. A. Aronova, M. A. Kim, Y. C. Dorward, L. M. Zhang, G. Leapman, R. D. TI On the feasibility of visualizing ultrasmall gold labels in biological specimens by STEM tomography SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article DE scanning transmission electron microscopy; STEM; electron tomography; nanogold; undecagold; labeling; protein ID TRANSMISSION ELECTRON-MICROSCOPY; 3-DIMENSIONAL ORGANIZATION; CRYOELECTRON TOMOGRAPHY; NANOMETER-SCALE; UNDECAGOLD; CELLS; IMMUNOCYTOCHEMISTRY; RECONSTRUCTION; ARCHITECTURE; SECTIONS AB Labeling with heavy atom clusters attached to antibody fragments is an attractive technique for determining the 3D distribution of specific proteins in cells using electron tomography. However, the small size of the labels makes them very difficult to detect by conventional bright-field electron tomography. Here, we evaluate quantitative scanning transmission electron microscopy (STEM) at a beam voltage of 300 kV for detecting 11-gold atom clusters (Undecagold) and 1.4 nm-diameter nanoparticles (Nanogold) for a variety of specimens and imaging conditions. STEM images as well as tornographic tilt series are simulated by means of the NIST Elastic-Scattering Cross-Section Database for gold clusters embedded in carbon. The simulations indicate that the visibility in 2D of Undecagold clusters in a homogeneous matrix is maximized for low inner collection semi-angles of the STEM annular dark-field detector (15-20 mrad). Furthermore, our calculations show that the visibility of Undecagold in 3D reconstructions is significantly higher than in 2D images for an inhomogeneous matrix corresponding to fluctuations in local density. The measurements demonstrate that it is possible to detect Nanogold particles in plastic sections of tissue freeze-substituted in the presence of osmium. STEM tomography has the potential to localize specific proteins in permeabilized cells using antibody fragments tagged with small heavy atom clusters. Our quantitative analysis provides a framework for determining the detection limits and optimal experimental conditions for localizing these small clusters. Published by Elsevier Inc. C1 Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Leapman, RD (reprint author), Natl Inst Biomed Imaging & Bioengn, NIH, Bldg 13,Room 3N17,13 South Dr, Bethesda, MD 20892 USA. EM leapmanr@mail.nih.gov FU Intramural NIH HHS [Z01 EB000017-01] NR 47 TC 14 Z9 14 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD SEP PY 2007 VL 159 IS 3 BP 507 EP 522 DI 10.1016/j.jsb.2007.06.006 PG 16 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 210RE UT WOS:000249472500018 PM 17689263 ER PT J AU McCabe, SE Boyd, CJ Cranford, JA Slayden, J Lange, JE Reed, MB Ketchie, JM Scott, MS AF McCabe, Sean Esteban Boyd, Carol J. Cranford, James A. Slayden, Janie Lange, James E. Reed, Mark B. Ketchie, Julie M. Scott, Marcia S. TI Alcohol involvement and participation in residential learning communities among first-year college students SO JOURNAL OF STUDIES ON ALCOHOL AND DRUGS LA English DT Article ID SUBSTANCE USE; AGES 18-24; DRINKING; CONSUMPTION; ARRANGEMENT; MAGNITUDE; MORBIDITY; MORTALITY; SELECTION; OUTCOMES AB Objective: Residential learning communities (RLCs) on U.S. college campuses are assumed to build connections between formal learning opportunities and students' living environment. The objective of this longitudinal study was to examine the association between living in RLCs and alcohol misuse among first-year undergraduate students. Method: A Web-based survey was self-administered to a stratified random sample of 923 first-year undergraduate students (52.7% women) attending a large Midwestern research university. The sample included 342 students who lived and participated in RLCs (termed RLC) and 581 students who did not participate in RLCs (termed non-RLC). First-year students were asked about their drinking behaviors before college, during their first semester, and approximately 6 months later during their second semester. Results: RLC students reported lower rates of drinking than non-RLC students before college. RLC students reported lower rates of drinking and fewer alcohol-related consequences than non-RLC students during the first and second semesters. Maximum drinks in I day increased from precollege to first semester, and this increase was larger among non-RLC students than RLC students. The number of drinks per occasion and alcohol-related consequences increased between first semester and second semester for all students regardless of RLC status. Conclusions: Lower rates of alcohol misuse among RLC students predate their entrance into college, and the increase in drinking from precollege to first semester is lower in magnitude among RLC students. RLCs' influence involves selection and socialization processes. These findings have implications for prevention and intervention efforts aimed at incoming first-year undergraduate students. C1 Univ Michigan, Subst Abuse Res Ctr, Ann Arbor, MI 48105 USA. San Diego State Univ, Res Fdn, AOD Initiat Res, San Diego, CA 92182 USA. NIAAA, Div Epidemiol & Prevent Res, Bethesda, MD USA. RP McCabe, SE (reprint author), Univ Michigan, Subst Abuse Res Ctr, 2025 Traverwood Dr,Suite C, Ann Arbor, MI 48105 USA. EM plius@umich.edu RI Croff, Julie/I-6861-2012; OI McCabe, Sean/0000-0002-9622-4652 FU NIAAA NIH HHS [AA015275, AA014738, U01 AA014738, U18 AA015275, U18 AA015275-01, U18 AA015275-02, U18 AA015275-02S1, U18 AA015275-03] NR 31 TC 8 Z9 8 U1 3 U2 4 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 1937-1888 J9 J STUD ALCOHOL DRUGS JI J. Stud. Alcohol Drugs PD SEP PY 2007 VL 68 IS 5 BP 722 EP 726 PG 5 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 202HC UT WOS:000248891600013 PM 17690806 ER PT J AU DeWitt, CA Collins, MT Cowen, EW AF DeWitt, Christine A. Collins, Michael T. Cowen, Edward W. TI Diffuse pain, hypophosphatemia, and a subcutaneous nodule SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID TUMOR-INDUCED OSTEOMALACIA; ONCOGENIC OSTEOMALACIA; MESENCHYMAL TUMORS; FIBROUS DYSPLASIA; RICKETS; FIBROBLAST-GROWTH-FACTOR-23; FGF23; BONE C1 NCI, Ctr Canc Res, Dermatol Branch, Bethesda, MD 20892 USA. Natl Inst Dental & Craniofacial Res, Craniofacial & Skeletal Dis Branch, Skeletal Clin Studies Unit, Bethesda, MD USA. RP Cowen, EW (reprint author), NCI, Ctr Canc Res, Dermatol Branch, Bldg 10 Room 12N238,10 Ctr Dr,MSC 1908, Bethesda, MD 20892 USA. EM cowene@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 14 TC 4 Z9 4 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD SEP PY 2007 VL 57 IS 3 BP 509 EP 512 DI 10.1016/j.jaad.2007.05.010 PG 4 WC Dermatology SC Dermatology GA 203RW UT WOS:000248992700016 PM 17707153 ER PT J AU Levy, RM Ming, ME Shapiro, M Tucker, M Guerry, D Cirillo-Hyland, VA Elenitsas, R AF Levy, Ross M. Ming, Michael E. Shapiro, Michael Tucker, Margaret Guerry, DuPont Cirillo-Hyland, Victoria A. Elenitsas, Rosalie TI Eruptive disseminated spitz nevi SO JOURNAL OF THE AMERICAN ACADEMY OF DERMATOLOGY LA English DT Article ID JUVENILE MELANOMA C1 Northwestern Univ, Feinberg Sch Med, Dept Dermatol, Chicago, IL USA. Univ Penn, Div Hematol Oncol, Dept Med, Philadelphia, PA 19104 USA. Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. NCI, Bryn Mawr Skin & Canc Inst, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol, Bethesda, MD 20892 USA. RP Elenitsas, R (reprint author), Div Dermatopathol, Dept Dermatol, 2 Maloney Bldg,3600 Spruce St, Philadelphia, PA 19104 USA. EM rosalie.elenitsas@uphs.upenn.edu RI Tucker, Margaret/B-4297-2015 FU Intramural NIH HHS NR 16 TC 19 Z9 20 U1 0 U2 2 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0190-9622 J9 J AM ACAD DERMATOL JI J. Am. Acad. Dermatol. PD SEP PY 2007 VL 57 IS 3 BP 519 EP 523 DI 10.1016/j.jaad.2007.02.031 PG 5 WC Dermatology SC Dermatology GA 203RW UT WOS:000248992700019 PM 17467853 ER PT J AU Tilburt, JC Miller, FG AF Tilburt, Jon C. Miller, Franklin G. TI Responding to medical pluralism in practice: A principled ethical approach SO JOURNAL OF THE AMERICAN BOARD OF FAMILY MEDICINE LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Society-for-Bioethics-and-Humanities CY OCT 26-29, 2006 CL Denver, CO SP Amer Soc Bioeth & Humanities ID SHARED DECISION-MAKING; ALTERNATIVE MEDICINE; COMPLEMENTARY; THERAPIES; CANCER; LIFE AB The popularity of complementary and alternative medicine ( CAM) raises a range of ethical issues for practicing clinicians. Principles of biomedical ethics define obligations of health care professionals, but applying principles in particular cases at the interface of CAM and biomedicine may be particularly challenging. "Recognition of medical pluralism" can help clinicians' ethical deliberations related to CAM. Here we outline a 3-point practical approach to applying basic principles of biomedical ethics in light of medical pluralism: ( 1) inquiring about CAM use and the scientific evidence related to CAM, ( 2) acknowledging the health beliefs and practices of patients, and ( 3) accommodating diverse healing practices. Construed as such, recognition of medical pluralism encourages pragmatic willingness to examine the personal and cultural meaning associated with CAM use, the biases and assumptions of biomedicine, as well as the risk-benefit ratio of CAM practices. In this way, recognition of medical pluralism can help clinicians enhance patient care in a manner consistent with basic ethical principles. C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Tilburt, JC (reprint author), NIH, Dept Clin Bioeth, Bldg 10,Room 1C, Bethesda, MD 20892 USA. EM tilburtj@cc.nih.gov NR 19 TC 3 Z9 3 U1 4 U2 7 PU AMER BOARD FAMILY MEDICINE PI LEXINGTON PA 2228 YOUNG DR, LEXINGTON, KY 40505 USA SN 1557-2625 J9 J AM BOARD FAM MED JI J. Am. Board Fam. Med. PD SEP-OCT PY 2007 VL 20 IS 5 BP 489 EP 494 DI 10.3122/jabfm.2007.05.060205 PG 6 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 207YC UT WOS:000249286000009 PM 17823467 ER PT J AU Karanja, N Lancaster, KJ Vollmer, WM Lin, PH Most, MM Ard, JD Swain, JF Sacks, FM Obarzanek, E AF Karanja, Njeri Lancaster, Kristie J. Vollmer, William M. Lin, Pao-Hwa Most, Marlene M. Ard, Jamy D. Swain, Janis F. Sacks, Frank M. Obarzanek, Eva TI Acceptability of sodium-reduced research diets, including the dietary approaches to stop hypertension diet, among adults with prehypertension and stage 1 hypertension SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID ELEVATED BLOOD-PRESSURE; DASH-SODIUM; SALT RESTRICTION; UNITED-STATES; VEGETABLE CONSUMPTION; BLACK CHURCHES; CLINICAL-TRIAL; PREVENTION; REDUCTION; FEASIBILITY AB Objective Examine the acceptability of sodium-reduced research diets. Design Randomized crossover trial of three sodium levels for 30 days each among participants randomly assigned to one of two dietary patterns. Participants/setting Three hundred fifty-four adults with prehypertension or stage 1 hypertension who were participants in the Dietary Approaches to Stop Hypertension (DASH-Sodium) outpatient feeding trial. Intervention Participants received their assigned diet (control or DASH, rich in fruits, vegetables, and low-fat dairy products), each at three levels of sodium (higher, intermediate, and lower) corresponding to 3,500, 2,300, and 1,200 mg/day (150, 100, and 50 mmol/day) per 2,100 kcal. Main outcome measures Nine-item questionnaire on liking and willingness to continue the assigned diet and its level of saltiness using a nine-point scale, ranging from one to nine. Statistical analyses performed Generalized estimating equations to test participant ratings as a function of sodium level and diet while adjusting for site, feeding cohort, carryover effects, and ratings during run-in. Results Overall, participants rated the saltiness of the intermediate level sodium as most acceptable (DASH group: 5.5 for intermediate vs 4.5 and 4.4 for higher and lower sodium; control group: 5.7 for intermediate vs 4.9 and 4.7 for higher and lower sodium) and rated liking and willing to continue the DASH diet more than the control diet by about one point (ratings range from 5.6 to 6.6 for DASH diet and 5.2 to 6.1 for control diet). Small race differences were observed in sodium and diet acceptability. Conclusions Both the intermediate and lower sodium levels of each diet are at least as acceptable as the higher sodium level in persons with or at risk for hypertension. C1 NHLBI, Bethesda, MD 20892 USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. NYU, Dept Nutr Food Studies & Publ Hlth, New York, NY USA. Duke Univ, Med Ctr, Ctr Nutr Studies, Durham, NC 27706 USA. Pennington Biomed Res Ctr, Baton Rouge, LA USA. Univ Alabama, Dept Nutr Sci, Birmingham, AL USA. Brigham & Womens Hosp, Clin Res Ctr, Natl Inst Hlth Gen, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med, Boston, MA 02115 USA. NHLBI, Bethesda, MD 20892 USA. RP Obarzanek, E (reprint author), NHLBI, 6701 Rockledge Dr,Room 10018, Bethesda, MD 20892 USA. EM obarzane@nhlbi.nih.gov FU NCRR NIH HHS [M01 RR000722, M01 RR002635, M01-RR02635]; NHLBI NIH HHS [K08 HL03857, U01 HL057114, U01-HL57114, U01-HL57139, U01-HL57156, U01-HL57173, U01-HL57190]; NIDDK NIH HHS [P30 DK040561, P30 DK040561-12] NR 42 TC 19 Z9 21 U1 3 U2 11 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 SEP PY 2007 VL 107 IS 9 BP 1530 EP 1538 DI 10.1016/j.jada.2007.06.013 PG 9 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 210EO UT WOS:000249439700019 PM 17761230 ER PT J AU Semba, RD Ferrucci, L Sun, K Walston, J Varadhan, R Guralnik, JM Fried, LP AF Semba, Richard D. Ferrucci, Luigi Sun, Kai Walston, Jeremy Varadhan, Ravi Guralnik, Jack M. Fried, Linda P. TI Oxidative stress is associated with greater mortality in older women living in the community SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE aging; mortality; oxidative stress; protein carbonyls; women ID PROTEIN CARBONYL GROUPS; KAPPA-B; SERUM; BIOMARKERS; OBESITY; DAMAGE; CONSEQUENCES; CONSUMPTION; ACTIVATION; MECHANISMS AB OBJECTIVES: To determine whether oxidative stress, as implied by oxidative damage to proteins, is associated with greater mortality in older women living in the community. DESIGN: Longitudinal. SETTING: Women's Health and Aging Study I, Baltimore, Maryland. PARTICIPANTS: Seven hundred forty-six moderately to severely disabled women, aged 65 and older, with baseline measures of serum protein carbonyls. MEASUREMENTS: Serum protein carbonyls, which consist of chemically stable aldehyde and ketone groups produced on protein side chains when they are oxidized, were measured using enzyme-linked immunosorbent assay. Multivariate logistic regression was used to adjust for potential confounders. RESULTS: During 5 years of follow-up, 202 (27.1%) participants died. Geometric mean serum protein carbonyls were 0.091 nmol/mg in women who died and 0.083 nmol/mg in those who survived (P=.02). Log(e) protein carbonyls (nmol/mg) were associated with greater risk of mortality (hazards ratio=1.34, 95% confidence interval=1.01-1.79, P=.04) in a multivariate Cox proportional hazards model adjusting for age, current smoking, and body mass index. CONCLUSION: Greater oxidative stress, as indicated by elevated serum protein carbonyl concentrations, was associated with greater risk of death in older women living in the community who were moderately to severely disabled. Prevention of oxidative stress may reduce the risk of mortality. C1 NIA, Clin Res Branch, Dept Ophthalmol, Baltimore, MD 21224 USA. NIA, Clin Res Branch, Dept Longitudinal Studies, Baltimore, MD 21224 USA. Johns Hopkins Med Inst, Dept Med, Baltimore, MD 21205 USA. NIA, Demog & Biometry Branch, Dept Epidemiol, Bethesda, MD 20892 USA. RP Semba, RD (reprint author), 550 N Broadway,Suite 700, Baltimore, MD 21205 USA. EM rdsemba@jhmi.edu FU Intramural NIH HHS [Z99 AG999999]; NCRR NIH HHS [M01 RR000722]; NIA NIH HHS [R37 AG019905, N01 AG012112, N01-AG12112, R01 AG027012] NR 30 TC 18 Z9 18 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 SEP PY 2007 VL 55 IS 9 BP 1421 EP 1425 DI 10.1111/j.1532-5415.2007.01308.x PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 206IZ UT WOS:000249178400015 PM 17767685 ER PT J AU Kim, YJ Jones, M Greenberg, NL Popovic, ZB Sitges, M Bauer, F Thomas, JD Shiota, T AF Kim, Yong Jin Jones, Michael Greenberg, Neil L. Popovic, Zoran B. Sitges, Marta Bauer, Fabrice Thomas, James D. Shiota, Takahiro TI Evaluation of left ventricular contractile function using noninvasively determined single-beat end-systolic elastance in mitral regurgitation: Experimental validation and clinical application SO JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY LA English DT Article ID PRESSURE-VOLUME RELATION; CANINE LEFT-VENTRICLE; ECHOCARDIOGRAPHIC PREDICTION; VALVULAR REGURGITATION; VALVE REPLACEMENT; WALL STRESS; PERFORMANCE; RATIO; EJECTION; HEART AB Objective: We performed this study to validate the single-beat estimation of end-systolic elastance (E-es) in an animal model of chronic mitral regurgitation (MR) and to use E-es to predict postoperative left ventricular (IV) systolic function with the noninvasively derived single-beat E-es (Ees-s) in patients with MR. Methods: Eight sheep with MR were studied under 4 different loading conditions. E-s was measured as the slope of the end-systolic pressure-volume relationship with a conductance catheter during inferior vena cava occlusion. Ees-s was calculated using a bilinearly approximated time-varying elastance curve. We also studied 105 patients with MR who had undergone mitral valve repair. All measurements in these patients were performed before surgery and repeated at about 1 week after surgery. Results: In the animals in a total of 23 different stages, Ees-s showed a good correlation and agreement with invasively determined Ees (y = 0.84 x + 0.38; r = 0.8; P < .01, mean difference 0.1 +/- 0.6 nun Hg/mL). In the clinical study, preoperative Ees-s (r = 0.77; P < .001) and end-systolic volume index correlated well with postoperative ejection fraction (r = -0.69; P < .001). Multivariate analyses revealed that only Ees-s was an independent predictor of postoperative LV function. Preoperative Ees-s less than or equal. to 1.0 mm Hg/mL was most predictive for identifying patients with LV dysfunction after surgery (sensitivity 87%; specificity 76%). Conclusions. LV end-systolic elastance can be estimated noninvasively and is useful to detect latent LV dysfunction in patients with MR before surgery. C1 Cleveland Clin Fdn, Div Cardiol, Cleveland, OH 44195 USA. Seoul Natl Univ Hosp, Seoul, South Korea. Natl Heart Lung & Blood Inst Hlth, Bethesda, MD USA. RP Shiota, T (reprint author), Cleveland Clin Fdn, Div Cardiol, Desk F 15,9500 Euclid Ave, Cleveland, OH 44195 USA. EM shiotat@ccf.org NR 34 TC 6 Z9 7 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0894-7317 J9 J AM SOC ECHOCARDIOG JI J. Am. Soc. Echocardiogr. PD SEP PY 2007 VL 20 IS 9 BP 1086 EP 1092 DI 10.1016/j.echo.2007.02.009 PG 7 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 210KK UT WOS:000249454900009 PM 17566701 ER PT J AU Lakatta, EG AF Lakatta, Edward G. TI Central arterial aging and the epidemic of systolic hypertension and atherosclerosis SO JOURNAL OF THE AMERICAN SOCIETY OF HYPERTENSION LA English DT Review DE Aging; arterial remodeling; arterial inflammation; arterial disease ID SMOOTH-MUSCLE-CELLS; RENIN-ANGIOTENSIN SYSTEM; INTIMA-MEDIA THICKNESS; PULSE-WAVE VELOCITY; GROWTH-FACTOR-BETA; CARDIOVASCULAR-DISEASE ENTERPRISES; AORTIC INPUT IMPEDANCE; NITRIC-OXIDE SYNTHASE; MONOCYTE CHEMOATTRACTANT PROTEIN-1; IMPROVES ENDOTHELIAL FUNCTION AB The structure and function of central arteries change throughout the lifetime of humans and animals. Since atherosclerosis and hypertension are prevalent in epidemic proportion among older persons, it is reasonable to hypothesize that specific mechanisms that underlie the arterial substrate that has been altered by an "aging process" are intimately linked to arterial diseases. Indeed, recent studies reveal a profile of arterial cell and matrix properties that emerges with advancing age within the grossly normal appearing aortic wall of both animals and humans. This profile is proinflammatory, and is manifested by intimal infiltration of fetal cells, increased production of angiotensin II (Ang II)-signaling pathway molecules, eg, matrix metalloproteases (MMPs), and monocyte chemoattractant protein (MCP-1), transforming growth factor B1 (TGF-beta 1), enhanced activation of MMPs, TGF-beta, and NADPH oxidase, and reduced nitric oxide (NO) bioavailability. This profile is similar to that induced at younger ages in experimental animal models of hypertension or atherosclerosis. In humans, this proinflammatory state, which occurs in the absence of lipid deposition, appears to be attributable to aging, per se. Other well known human risk factors, eg, altered lipid metabolism, smoking, and lack of exercise, interact with this arterial substrate that is altered by aging and render the aging human artery fertile soil for facilitation of the initiation and progression of arterial diseases. Therapies to reduce or retard this age-associated proinflammatory state within the grossly appearing arterial wall central arteries, in addition to slowing arterial aging, per se, may have a substantial impact on the quintessential age-associated arterial diseases of our society. (C) 2007 American Society of Hypertension. All rights reserved. C1 NIA, Lab Cardiovasc Sci, Gerontol Res Ctr, Intramural Res Program,NIH, Baltimore, MD 21224 USA. RP Lakatta, EG (reprint author), NIA, Lab Cardiovasc Sci, Gerontol Res Ctr, Intramural Res Program,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. FU National Institutes of Health, National Institute on Aging FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Aging. NR 223 TC 18 Z9 19 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1933-1711 J9 J AM SOC HYPERTENS JI J. Am. Soc. Hypertens. PD SEP-OCT PY 2007 VL 1 IS 5 BP 302 EP 340 DI 10.1016/j.jash.2007.05.001 PG 39 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA V18KP UT WOS:000208004000003 PM 20409863 ER PT J AU Dvorak, MM De Joussineau, C Carter, DH Pisitkun, T Knepper, MA Gamba, G Kemp, PJ Riccardi, D AF Dvorak, Melita M. De Joussineau, Cyrille Carter, D. Howard Pisitkun, Trairak Knepper, Mark A. Gamba, Gerardo Kemp, Paul J. Riccardi, Daniela TI Thiazide diuretics directly induce osteoblast differentiation and mineralized nodule formation by interacting with a sodium chloride co-transporter in bone SO JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY LA English DT Article ID RESORPTION IN-VITRO; NA-CL COTRANSPORTER; URINARY CALCIUM; HYDROCHLOROTHIAZIDE; CELLS; DENSITY; HYPERCALCIURIA; MECHANISMS; EXPRESSION; BINDING AB Thiazide diuretics are used worldwide as a first-choice drug for patients with uncomplicated hypertension. In addition to their anti hypertensive effect, thiazides increase bone mineral density and reduce the prevalence of fractures. Traditionally, these effects have been attributed to increased renal calcium reabsorption that occurs secondary to the inhibition of the thiazide-sensitive sodium chloride cotransporter (NCC) in the distal tubule. The aim of the current study was to determine whether thiazides exert a direct bone-forming effect independent of their renal action. We found that the osteoblasts of human and rat bone also express NCC, suggesting that these bone-forming cells may be an additional target for thiazides. In vitro, NCC protein was virtually absent in proliferating human and fetal rat osteoblasts, whereas its expression dramatically increased during differentiation. Thiazides did not affect osteoblast proliferation, but directly stimulated the production of the osteoblast differentiation markers runtrelated transcription factor 2 (runx2) and osteopontin. Using overexpression/knockdown studies in fetal rat calvarial cells, we show that thiazides increase the formation of mineralized nodules, but loop diuretics do not. Overall, our study demonstrates that thiazides directly stimulate osteoblast differentiation and bone mineral formation independent of their effects in the kidney. Therefore, in addition to their use as anti hypertensive drugs, our results suggest that thiazides may find a role in the prevention and treatment of osteoporosis. C1 Cardiff Univ, Sch Biosci, Cardiff CF10 3US, Wales. Cardiff Inst Tissue Engn & Repair, Cardiff, Wales. Univ Calif San Francisco, Dept Med, Endocrine Res Unit, San Francisco, CA 94143 USA. Univ Manchester, Tumer Dent Sch, Manchester M13 9PL, Lancs, England. NIH, NHLBI, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. Univ Nacl Autonoma Mexico, Inst Invest Biomed, Inst Nacl Ciencias Med & Nutr Salvador Zubiran, Mol Physiol Unit, Mexico City 04510, DF, Mexico. RP Riccardi, D (reprint author), Cardiff Univ, Sch Biosci, Museum Ave, Cardiff CF10 3US, Wales. EM riccardi@cardiff.ac.uk RI Kemp, Paul/A-4634-2010; Riccardi, Daniela/A-4674-2010; OI Kemp, Paul/0000-0003-2773-973X; Riccardi, Daniela/0000-0002-7322-3163; Pisitkun, Trairak/0000-0001-6677-2271 FU Arthritis Research UK [16269]; Intramural NIH HHS [Z99 HL999999]; Medical Research Council [G0600821]; Wellcome Trust [CRIG070159] NR 24 TC 43 Z9 50 U1 2 U2 4 PU AMER SOC 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 SEP PY 2007 VL 18 IS 9 BP 2509 EP 2516 DI 10.1681/ASN.2007030348 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 231YV UT WOS:000250986000014 PM 17656470 ER PT J AU Waber, DP De Moor, C Forbes, PW Almli, CR Botteron, KN Leonard, G Milovan, D Paus, T Rumsey, J AF Waber, Deborah P. De Moor, Carl Forbes, Peter W. Almli, C. Robert Botteron, Kelly N. Leonard, Gabriel Milovan, Denise Paus, Tomas Rumsey, Judith CA BRAIN DEV Cooperative Grp TI The NIH MRI study of normal brain development: Performance of a population based sample of healthy children aged 6 to 18 years on a neuropsychological battery SO JOURNAL OF THE INTERNATIONAL NEUROPSYCHOLOGICAL SOCIETY LA English DT Article DE psychol tests; child behavior; child development; adolescent development; MRI scans; neuropsychology ID PURDUE PEGBOARD; EARLY-CHILDHOOD; FRONTAL-LOBE; KINDERGARTEN; ACHIEVEMENT; RELIABILITY; VALIDITY; FLUENCY; YOUNG AB The National Institutes of Health (NIH) Magnetic Resonance Imaging (MRI) Study of Normal Brain Development is a landmark study in which structural and metabolic brain development and behavior are followed longitudinally from birth to young, adulthood in a population-based sample of healthy children. The neuropsychological assessment protocol for children aged 6 to 18 years is described and normative data are presented for participants in that age range (N = 385). For many measures. raw score performance improved steeply from 6 to 10 years, decelerating during adolescence. Sex differences were documented for Block Design (male advantage), CVLT, Pegboard and Coding (female advantage). Household income predicted IQ and achievement, as well as externalizing problems and social competence, but not the other cognitive or behavioral measures. Performance of this healthy sample was,generally better than published norms. This linked imaging-clinical/behavioral database will be an invaluable public resource for researchers for many years to come. C1 Harvard Univ, Sch Med, Childrens Hosp, Dept Psychiat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Childrens Hosp, Clin Res Program, Boston, MA 02115 USA. Washington Univ, Sch Med, Program Occupat Therapy Neurol & Psychol, St Louis, MO USA. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO USA. McGill Univ, Cognit Neurosci Unit, Montreal, PQ, Canada. Univ Nottingham, Brain & Body Ctr, Nottingham NG7 2RD, England. NIMH, Neurodev Disorders Branch, Bethesda, MD 20892 USA. RP Waber, DP (reprint author), Harvard Univ, Sch Med, Childrens Hosp, Dept Psychiat, 300 Longwood Ave, Boston, MA 02115 USA. EM deborah.waber@childrens.harvard.edu FU NICHD NIH HHS [N01-HD02-3343]; NIMH NIH HHS [N01-MH9-0002]; NINDS NIH HHS [N01-NS-9-2314, N01-NS-9-2315, N01-NS-9-2316, N01-NS-9-2317, N01-NS-9-2319, N01-NS-9-2320] NR 33 TC 122 Z9 124 U1 3 U2 18 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 32 AVENUE OF THE AMERICAS, NEW YORK, NY 10013-2473 USA SN 1355-6177 J9 J INT NEUROPSYCH SOC JI J. Int. Neuropsychol. Soc. PD SEP PY 2007 VL 13 IS 5 BP 729 EP 746 DI 10.1017/S1355617707070841 PG 18 WC Clinical Neurology; Neurosciences; Psychiatry; Psychology SC Neurosciences & Neurology; Psychiatry; Psychology GA 205UQ UT WOS:000249140500001 PM 17511896 ER PT J AU Shavers, VL AF Shavers, Vickie L. TI Measurement of socioeconomic status in health disparities research SO JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION LA English DT Article DE socioeconomic status; health disparities; minorities; race/ethnicity ID UNITED-STATES; RACIAL DISPARITIES; AFRICAN-AMERICANS; SOCIAL-CLASS; LIFE-COURSE; CANCER; MORTALITY; DEPRIVATION; INDICATORS; SURVIVAL AB Socioeconomic status (SES) is frequently implicated as a contributor to the disparate health observed among racial/ ethnic minorities, women and elderly populations. Findings from studies that examine the role of SES and health disparities, however, have provided inconsistent results. This is due in part to the: 1) lack of precision and reliability of measures; 2) difficulty with the collection of individual SES data; 3) the dynamic nature of SES over a lifetime; 4) the classification of women, children, retired and unemployed persons; 5) lack of or poor correlation between individual SES measures; and 6) and inaccurate or misleading interpretation of study results. Choosing the best variable or approach for measuring SES is dependent in part on its relevance to the population and outcomes under study. Many of the commonly used compositional and contextual SES measures are limited in terms of their usefulness for examining the effect of SES on outcomes in analyses of data that include population subgroups known to experience health disparities. This article describes SES measures, strengths and limitations of specific approaches and methodological issues related to the analysis and interpretation of studies that examine SES and health disparities. C1 NCI, Div Canc Control & Populat Sci, Appl Res Program, Hlth Serv & Econ Branch, Bethesda, MD 20892 USA. RP Shavers, VL (reprint author), NCI, Div Canc Control & Populat Sci, Appl Res Program, Hlth Serv & Econ Branch, 6130 Execut Blvd,MSC-7344,EPN Room 4005, Bethesda, MD 20892 USA. EM shaversv@mail.nih.gov NR 70 TC 227 Z9 230 U1 8 U2 44 PU NATL MED ASSOC PI WASHINGON PA 1012 10TH ST, N W, WASHINGON, DC 20001 USA SN 0027-9684 J9 J NATL MED ASSOC JI J. Natl. Med. Assoc. PD SEP PY 2007 VL 99 IS 9 BP 1013 EP 1023 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 212XO UT WOS:000249630500006 PM 17913111 ER PT J AU Maynard, DM Heijnen, HFG Horne, MK White, JG Gahl, WA AF Maynard, D. M. Heijnen, H. F. G. Horne, M. K. White, J. G. Gahl, W. A. TI Proteomic analysis of platelet alpha-granules using mass spectrometry SO JOURNAL OF THROMBOSIS AND HAEMOSTASIS LA English DT Article DE alpha-granules; mass spectrometry; platelets; proteomics ID HERMANSKY-PUDLAK-SYNDROME; ACTIVATED PLATELETS; GLYCOPROTEIN-IB; ENDOTHELIAL-CELLS; PROTEIN; MEMBRANE; PEPTIDE; DISORDERS; SURFACE; FAMILY AB Background: Platelets have three major types of secretory organelles: lysosomes, dense granules, and a-granules. alpha-Granules contain several adhesive proteins involved in hemostasis, as well as glycoprotems involved in inflammation, wound healing, and cell-matrix interactions. This article represents the first effort to define the platelet a-granule proteome using mass spectrometry (MS). Methods: We prepared a subcellular fraction enriched in intact a-granules from human platelets using sucrose gradient ultracentrifugation. a-Granule proteins were separated and identified using sodium dodecylsulfate polyacrylamide gel electrophoresis and liquid chromatography-tandem MS. Results: In the sucrose fraction enriched in a-granules, we identified 284 non-redundant proteins, 44 of which appear to be new a-granule proteins, on the basis of a literature review. Immunoelectron microscopy confirmed the presence of Scamp2, APLP2, ESAM and LAMA5 in platelet a-granules for the first time. We identified 65% of the same proteins that were detected in the platelet releasate (J. A. Coppinger et al. [Blood 2004; 103: 2096-104]) as well as additional soluble and membrane proteins. Our method provides a suitable tool for analyzing the granule proteome of patients with storage pool deficiencies. C1 NHGRI, NIH, Med Genet Branch, Sect Human Biochem Genet, Bethesda, MD 20892 USA. Univ Utrecht, Med Ctr, Lab Clin Chem & Haematol, Utrecht, Netherlands. Univ Utrecht, Med Ctr, Cell Microscopy Ctr, Utrecht, Netherlands. NIH, WG Magnuson Clin Ctr, Dept Lab Med, Hematol Serv, Bethesda, MD 20892 USA. Univ Minnesota, Dept Lab Med, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Pathol, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. RP Maynard, DM (reprint author), NHGRI, NIH, Med Genet Branch, Sect Human Biochem Genet, 10 Ctr Dr,10-10C103,MSC 1851, Bethesda, MD 20892 USA. EM maynardd@mail.nih.gov NR 51 TC 100 Z9 101 U1 1 U2 6 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1538-7933 J9 J THROMB HAEMOST JI J. Thromb. Haemost. PD SEP PY 2007 VL 5 IS 9 BP 1945 EP 1955 DI 10.1111/j.1538-7836.2007.02690.x PG 11 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 207KR UT WOS:000249250500024 PM 17723134 ER PT J AU Espinoza, J Romero, R Kusanovic, JP Gotsch, F Erez, O Lee, W Goncalves, LF Schoen, ML Hassan, SS AF Espinoza, Jimmy Romero, Roberto Kusanovic, Juan Pedro Gotsch, Francesca Erez, Offer Lee, Wesley Goncalves, Luis F. Schoen, Mary Lou Hassan, Sonia S. TI The role of the sagittal view of the ductal arch in identification of fetuses with conotruncal anomalies using 4-dimensional ultrasonography SO JOURNAL OF ULTRASOUND IN MEDICINE LA English DT Article DE congenital heart disease; ductus arteriosus; fetal echocardiograph; prenatal diagnosis; spatiotemporal; spatiotemporal image correlation; 3-dimensional ultrasonography ID SPATIOTEMPORAL IMAGE CORRELATION; 3-DIMENSIONAL FETAL ECHOCARDIOGRAPHY; CONGENITAL HEART-DISEASE; COLOR DOPPLER ULTRASOUND; PRENATAL-DIAGNOSIS; OUTFLOW TRACT; GREAT-ARTERIES; VOLUME; 3D; DEFECTS AB Objective. Conotruncal anomalies represent one fifth of all congenital heart defects (CHDs) detected in the fetus. However, the spatial relationship of the great vessels is incorrectly defined in about 20% of these cases. The sagittal view of the ductal arch is considered a standard ultrasonographic view in fetal echocardiography and can be easily visualized using 4-dimensional (4D) ultrasonography. This study was designed to determine the role of this ultrasonographic plane for the prenatal diagnosis of conotruncal anomalies. Methods. We reviewed 4D volume data sets, acquired with the spatiotemporal image correlation technique, from fetuses with and without confirmed conotruncal anomalies. The visualization rate of the sagittal view of the ductal arch was compared among groups using standardized multiplanar views. Results. This study included 183 volume data sets from fetuses in the following groups: (1) normal echocardiographic findings (n = 130); (2) conotruncal anomalies (n = 18); and (3) other CHDs (n = 35). Volumes of poor image quality were excluded from analysis (8.2% [15/183]). The visualization rate of the sagittal view of the ductal arch was significantly lower in fetuses with conotruncal anomalies (5.6% [1/18]) than that in fetuses without abnormalities (93.1 % [108/116]) and that in fetuses with other CHDs (79.4% [27/34]; P <.01). Absence of visualization of the sagittal view of the ductal arch was associated with a likelihood ratio of 9.44 (95% confidence interval, 5.8-15.5) to have conotruncal anomalies. Conclusions. The sagittal view of the ductal arch may play an important role in the screening and prenatal diagnosis of conotruncal anomalies in 4D ultrasonography. C1 NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. William Beaumont Hosp, Div Fetal Imaging, Royal Oak, MI 48072 USA. RP Espinoza, J (reprint author), Wayne State Univ, Hutzel Womens Hosp, NICHD NIH DHHS, Perinatol Res Branch, 3990 John R,Box 4, Detroit, MI 48201 USA. EM espinoz@med.wayne.edu FU Intramural NIH HHS [Z01 HD002401-15] NR 70 TC 13 Z9 15 U1 0 U2 1 PU AMER INST ULTRASOUND MEDICINE PI LAUREL PA SUBSCRIPTION DEPT, 14750 SWEITZER LANE, STE 100, LAUREL, MD 20707-5906 USA SN 0278-4297 J9 J ULTRAS MED JI J. Ultrasound Med. PD SEP PY 2007 VL 26 IS 9 BP 1181 EP 1188 PG 8 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 207BO UT WOS:000249226800008 PM 17715312 ER PT J AU Propert, KJ Mayer, R Nickel, JC Payne, CK Peters, KM Teal, V Burks, D Kusek, JW Nyberg, LM Foster, HE AF Propert, Kathleen Joy Mayer, Robert Nickel, J. Curtis Payne, Christopher K. Peters, Kenneth M. Teal, Valerie Burks, David Kusek, John W. Nyberg, Leroy M. Foster, Harris E. CA Interstitial Cystitis Clin Trial G TI Did patients with interstitial cystitis who failed to respond to initial treatment with bacillus Calmette-Guerin or placebo in a randomized clinical trial benefit from a second course of open label bacillus Calmette-Guerin? SO JOURNAL OF UROLOGY LA English DT Article DE bladder; Mycobacterium bovis; cystitis; interstitial; quality of life; pain ID SUPERFICIAL BLADDER-CANCER; IMMUNOTHERAPY; EFFICACY; BCG AB Purpose: We evaluated safety and efficacy outcomes in a case series of subjects who received open label intravesical bacillus Calmette-Guerin after failing to respond to bacillus Calmette-Guerin or intravesical placebo in a randomized clinical trial. Materials and Methods: Subjects who met National Institutes of Health-National Institute of Diabetes and Digestive and Kidney Diseases criteria for IC and reported at least moderate pain and frequency were initially randomized to 6 weekly intravesical instillations of bacillus Calmette-Guerin or placebo and followed for a total of 34 weeks. At 34 weeks subjects who reported that they had not responded to treatment were offered treatment with open label bacillus Calmette-Guerin, using the same course of treatment and followup. Outcomes included a patient reported global response assessment, a 24-hour voiding diary, pain, urgency, validated interstitial cystitis symptom indexes and adverse events. Results: A total of 156 subjects elected open label bacillus Calmette-Guerin, of whom 18 (12%) withdrew during the open label series. The response rate based on the global response assessment was 18% and it was identical between those initially randomized to placebo (first course of bacillus Calmette-Guerin in the open label series) and those initially randomized to bacillus Calmette-Guerin (second course). Small improvements were observed for most secondary efficacy outcomes. Most participants reported at least 1 adverse event, primarily pain, genitourinary symptoms and gastrointestinal disturbances. However, there was no difference in adverse events between those who received the first course of bacillus Calmette-Guerin in this series compared to those who received 2 courses. Conclusions: The low response rate for bacillus Calmette-Guerin in this open label case series further argues against the routine use of bacillus Calmette-Guerin as treatment for interstitial cystitis. C1 Univ Penn, Sch Med, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. Univ Penn, Philadelphia, PA 19104 USA. Univ Rochester, Rochester, NY USA. Queens Univ, Kingston, ON, Canada. Stanford Univ, Stanford, CA 94305 USA. William Beaumont Hosp, Royal Oak, MI 48072 USA. Henry Ford Hosp, Detroit, MI 48202 USA. NIDDK, NIH, Bethesda, MD USA. Yale Univ, New Haven, CT USA. RP Propert, KJ (reprint author), Univ Penn, Sch Med, Dept Biostat & Epidemiol, Blockley Hall,6th Floor, Philadelphia, PA 19104 USA. EM propert@mail.med.upenn.edu OI Teal, Valerie/0000-0001-7116-5353 FU NCRR NIH HHS [M01 RR16500]; NIDDK NIH HHS [U01 DK54127, U01 DK54133, U01 DK54138, U01 DK54158, U01 DK54125, U01 DK54108] NR 12 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD SEP PY 2007 VL 178 IS 3 BP 886 EP 890 DI 10.1016/j.juro.2007.05.052 PN 1 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 198PZ UT WOS:000248641300042 PM 17631335 ER PT J AU Richter, HE Nygaard, I Burgio, KL Handa, VL FitzGerald, MP Wren, P Zyczynski, H Fine, P Brown, MB Weber, AM AF Richter, Holly E. Nygaard, Ingrid Burgio, Kathryn L. Handa, Victoria L. FitzGerald, Mary Pat Wren, Patricia Zyczynski, Halina Fine, Paul Brown, Morton B. Weber, Anne M. CA Pelvic Floor Disorders Network TI Lower urinary tract symptoms, quality of life and pelvic organ prolapse: Irritative bladder and obstructive voiding symptoms in women planning to undergo abdominal sacrocolpopexy for advanced pelvic organ prolapse SO JOURNAL OF UROLOGY LA English DT Article DE prolapse; urinary incontinence; stress; urinary tract; quality of life; questionnaires ID GENITOURINARY PROLAPSE; STRESS-INCONTINENCE; PREVALENCE; CONTINENT AB Purpose: We compared lower urinary tract and voiding symptoms in women with and without symptoms of stress urinary incontinence who were planning to undergo abdominal sacrocolpopexy for pelvic organ prolapse. Materials and Methods: Subjects without stress urinary incontinence included 293 women in the Colpopexy and Urinary Reduction Efforts Trial. Subjects with stress urinary incontinence included 82 women who met trial inclusion criteria except for having stress urinary incontinence symptoms. We assessed symptoms and quality of life using validated measures. Results: After adjusting for age, race and site subjects with stress urinary incontinence had higher irritative and obstructive symptom subscale scores and reported greater symptom bother, greater impact of colorectal and prolapse symptoms, and poorer physical and mental health. Conclusions: Women with prolapse and stress urinary incontinence had more lower urinary tract symptoms and reported more functional impact. This is contrary to our hypothesis that women with prolapse and stress urinary incontinence would have fewer irritative, obstructive and voiding symptoms because of the relief valve effect of the less resistant urethra. C1 Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL 35233 USA. Univ Alabama, Dept Med, Div Gerontol & Geriatr Med, Birmingham, AL 35294 USA. Dept Vet Affairs Med Ctr, Birmingham Atlanta Geriatr Res Educ & Clin Ctr, Birmingham, AL USA. Univ Utah, Salt Lake City, UT USA. Johns Hopkins Sch Med, Baltimore, MD USA. NICHHD, Bethesda, MD 20892 USA. Loyola Univ, Dept Obstet & Gynecol, Chicago, IL 60611 USA. Oakland Univ, Sch Hlth Sci, Rochester, MI 48309 USA. Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. Univ Pittsburgh, Magee Womens Hosp, Div Urogynecol & Reconstruct Pelv Surg, Pittsburgh, PA 15213 USA. Baylor Coll Med, Houston, TX 77030 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 NICHD NIH HHS [U10 HD41261, U10 HD041263, U10 HD41267, U10 HD41269, U10 HD41248, U10 HD41263, U01 HD41249, U10 HD041261, U10 HD41250, U10 HD41268]; NIDDK NIH HHS [K24 DK068389] NR 20 TC 8 Z9 9 U1 1 U2 4 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 SEP PY 2007 VL 178 IS 3 BP 965 EP 969 DI 10.1016/j.juro.2007.05.045 PN 1 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 198PZ UT WOS:000248641300065 PM 17632167 ER PT J AU Krucker, J Xu, S Glossop, N Viswanathan, A Borgert, J Schulz, H Wood, BJ AF Kruecker, Jochen Xu, Sheng Glossop, Neil Viswanathan, Anand Borgert, Joern Schulz, Heinrich Wood, Bradford J. TI Electromagnetic tracking for thermal ablation and biopsy guidance: Clinical evaluation of spatial accuracy SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID PERCUTANEOUS RADIOFREQUENCY ABLATION; RENAL-CELL CARCINOMA; LIVER-TUMORS; FREEHAND ULTRASOUND; HEPATIC-TUMORS; METASTASES; FEASIBILITY; NAVIGATION; PROTOCOL; US AB PURPOSE: To evaluate the spatial accuracy of electromagnetic needle tracking and demonstrate the feasibility of ultrasonography (US)-computed tomography (CT) fusion during CT- and US-guided biopsy and radiofrequency ablation procedures. MATERIALS AND METHODS: The authors performed a 20-patient clinical trial to investigate electromagnetic needle tracking during interventional procedures. The study was approved by the institutional investigational review board, and written informed consent was obtained from all patients. Needles were positioned by using CT and US guidance. A commercial electromagnetic tracking device was used in combination with prototype internally tracked needles and custom software to record needle positions relative to previously obtained CT scans. Position tracking data were acquired to evaluate the tracking error, defined as the difference between tracked needle position and reference standard needle position on verification CT scans. Registration between tracking space and image space was obtained by using reference markers attached to the skin ("fiducials"), and different registration methods were compared. The US transducer was tracked to demonstrate the potential use of real-time US-CT fusion for imaging guidance. RESULTS: One patient was excluded from analysis because he was unable to follow breathing instructions during the acquisition of CT scans. Nineteen of the 20 patients were evaluable, demonstrating a basic tracking error of 5.8 mm +/- 2.6, which improved to 3.5 mm +/- 1.9 with use of nonrigid registrations that used previous internal needle positions as additional fiducials. Fusion of tracked US with CT was successful. Patient motion and distortion of the tracking system by the CT table and gantry were identified as sources of error. CONCLUSIONS: The demonstrated spatial tracking accuracy is sufficient to display clinically relevant preprocedural imaging information during needle-based procedures. Virtual needles displayed within preprocedural images may be helpful for clandestine targets such as arterial phase enhancing liver lesions or during thermal ablations when obscuring gas is released. Electromagnetic tracking may help improve imaging guidance for interventional procedures and warrants further investigation, especially for procedures in which the outcomes are dependent on accuracy. C1 Philips Res N Amer, Briarcliff Manor, NY USA. Traxtal Inc, Toronto, ON, Canada. NIH, Ctr Clin, Dept Diagnost Radiol, Bethesda, MD 20892 USA. Res Sector Med Imaging Syst, Philips Res Europe Hamburg, Hamburg, Germany. RP Krucker, J (reprint author), NIH, Bldg 10,Rm 2N-236,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jochen.kruecker@philips.com OI Viswanathan, Anand/0000-0003-3810-6217 FU Intramural NIH HHS [Z99 CL999999] NR 30 TC 101 Z9 105 U1 1 U2 13 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 SEP PY 2007 VL 18 IS 9 BP 1141 EP 1150 DI 10.1016/j.jvir.2007.06.014 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 211TX UT WOS:000249547300013 PM 17804777 ER PT J AU Bolton, DL Lenardo, MJ AF Bolton, Diane L. Lenardo, Michael J. TI Vpr cytopathicity independent of G(2)/M cell cycle arrest in human immunodeficiency virus type 1-infected CD4(+) T cells SO JOURNAL OF VIROLOGY LA English DT Article ID REGULATORY PROTEIN VPR; C-TERMINAL DOMAIN; HIV-1 VPR; NUCLEAR-LOCALIZATION; DISTINCT MECHANISMS; MUTATIONAL ANALYSIS; VIRAL EXPRESSION; INFECTED-CELLS; NMR STRUCTURE; G(1) PHASE AB The mechanism of CD4(+) T-cell depletion in human immunodeficiency virus type 1 (HIV-1)-infected individuals remains unknown, although mounting evidence suggests that direct viral cytopathicity contributes to this loss. The HIV-1 Vpr accessory protein causes cell death and arrests cells in the G(2)/M phase; however, the molecular mechanism underlying these properties is not clear. Mutation of hydrophobic residues on the surface of its third alpha-helix disrupted Vpr toxicity, G,/M arrest induction, nuclear localization, and self-association, implicating this region in multiple Vpr functions. Cytopathicity by virion-delivered mutant Vpr protein correlated with G(2)/M arrest induction but not nuclear localization or self-association. However, infection with whole virus encoding these Vpr mutants did not abrogate HIV-1-induced cell killing. Rather, mutant Vpr proteins that are impaired for G(2)/M block still prevented infected cell proliferation, and this property correlated with the death of infected cells. Chemical agents that inhibit infected cells from entering G(2)/M also did not reduce HIV-1 cytopathicity. Combined, these data implicate Vpr in HIV-1 killing through a mechanism involving inhibiting cell division but not necessarily in G(2)/M. Thus, the hydrophobic region of the third alpha-helix of Vpr is crucial for mediating G(2)/M arrest, nuclear localization, and self-association but dispensable for HIV-1 cytopathicity due to residual cell proliferation blockade mediated by a separate region of the protein. C1 NIAID, Immunol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Lenardo, MJ (reprint author), NIAID, Immunol Lab, Natl Inst Hlth, Bldg 10,Rm 11N311,10 Ctr Dr, Bethesda, MD 20892 USA. EM lenardo@nih.gov FU Intramural NIH HHS NR 75 TC 35 Z9 35 U1 0 U2 2 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 SEP PY 2007 VL 81 IS 17 BP 8878 EP 8890 DI 10.1128/JVI.00122-07 PG 13 WC Virology SC Virology GA 202SL UT WOS:000248923700003 PM 17553871 ER PT J AU Kuwata, T Byrum, R Whitted, S Goeken, R Buckler-White, A Plishka, R Iyengar, R Hirsch, VM AF Kuwata, Takeo Byrum, Russell Whitted, Sonya Goeken, Robert Buckler-White, Alicia Plishka, Ronald Iyengar, Ranjini Hirsch, Vanessa M. TI Rapid progressor-specific variant clone of simian immunodeficiency virus replicates efficiently in vivo only in the absence of immune reponses SO JOURNAL OF VIROLOGY LA English DT Article ID CD4(+) T-CELLS; END-STAGE DISEASE; NEUTRALIZING ANTIBODIES; RHESUS MACAQUES; ENVELOPE GLYCOPROTEIN; VIRAL REPLICATION; SIV INFECTION; MACROPHAGE TROPISM; 1-INFECTED PATIENT; CORECEPTOR USAGE AB A subset of simian immunodeficiency virus (SIV)-infected macaques progresses rapidly to disease with transient SIV-specific immune responses and high viral loads. Unique SIV variants with convergent Env mutations evolve in these rapid progressor (RP) macaques. To address the pathogenic significance of RP-specific variants, we generated infectious molecular clones from the terminal-phase plasma of an RP macaque. Inoculation of macaques with a representative clone, SIVsmH635FC, resulted in a persistent viremia, comparable to that produced by pathogenic SIVsmE543-3, and a chronic disease with progressive loss of CD4(+) T cells. However, SIVsmH635FC did not reproduce the rapid-disease phenomenon. Molecular analyses of viruses from these macaques revealed rapid reversion to the wild-type SIVsmE543-3 sequence at two RP-specific sites and slower reversion at another three sites. SIVsmH635FC infection was not sufficient to cause rapid progression even following coinoculation with SIVsmE543-3, despite acute depletion of memory CD4(+) T cells. SIVsmH635FC competed efficiently during primary infection in the coinoculated macaques, but SIVsmE543-3 predominated after the development of SIV-specific immune responses. These data suggest that the replication fitness of the R-P variant was similar to that of SIVsmE543-3 in a naive host; however, SIVsmH635FC was at a disadvantage following the development of SIV-specific immune responses. Consistent with these findings, neutralization assays revealed that SIVsmH635FC was highly sensitive to neutralization but that the parental SIVsmE543-3 strain was highly resistant. This study suggests that the evolution of RP-specific variants is the result of replication in a severely immunocompromised host, rather than the direct cause of rapid progression. C1 NIAID, Mol Microbiol Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. Bioqual Inc, Rockville, MD USA. RP Hirsch, VM (reprint author), NIAID, Mol Microbiol Lab, Natl Inst Hlth, Bldg 4,Rm B1-33,4Ctr Dr, Bethesda, MD 20892 USA. EM vhirsch@nih.gov RI Kuwata, Takeo/F-5809-2013 FU Intramural NIH HHS NR 62 TC 11 Z9 11 U1 0 U2 2 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 SEP PY 2007 VL 81 IS 17 BP 8891 EP 8904 DI 10.1128/JVI.00614-07 PG 14 WC Virology SC Virology GA 202SL UT WOS:000248923700004 PM 17596304 ER PT J AU Chen, ZC Earl, P Americo, J Damon, I Smith, SK Yu, FJ Sebrell, A Emerson, S Cohen, G Eisenberg, RJ Gorshkova, I Schuck, P Satterfield, W Moss, B Purcell, R AF Chen, Zhaochun Earl, Patricia Americo, Jeffrey Damon, Inger Smith, Scott K. Yu, Fujuan Sebrell, Andrew Emerson, Suzanne Cohen, Gary Eisenberg, Roselyn J. Gorshkova, Inna Schuck, Peter Satterfield, William Moss, Bernard Purcell, Robert TI Characterization of chimpanzee/human monoclonal antibodies to vaccinia virus A33 glycoprotein and its variola virus homolog in vitro and in a vaccinia virus mouse protection model SO JOURNAL OF VIROLOGY LA English DT Article ID 2 INFECTIOUS FORMS; EXTRACELLULAR ENVELOPED VIRUS; OUTER-MEMBRANE PROTEINS; TO-CELL SPREAD; SMALLPOX VACCINE; NEUTRALIZING ACTIVITIES; POXVIRUS CHALLENGE; NONHUMAN-PRIMATES; MICE; RESPONSES AB Three distinct chimpanzee Fabs against the A33 envelope glycoprotein of vaccinia virus were isolated and converted into complete monoclonal antibodies (MAbs) with human gamma 1 heavy-chain constant regions. The three MAbs (6C, 12C, and 12F) displayed high binding affinities to A33 (K, of 0.14 nM to 20 nM) and may recognize the same epitope, which was determined to be conformational and located within amino acid residues 99 to 185 at the C terminus of A33. One or more of the MAbs were shown to reduce the spread of vaccinia virus as well as variola virus (the causative agent of smallpox) in vitro and to more effectively protect mice when administered before or 2 days after intranasal challenge with virulent vaccinia virus than a previously isolated mouse anti-A33 MAb (IG10) or vaccinia virus immunoglobulin. The protective efficacy afforded by anti-A33 MAb was comparable to that of a previously isolated chimpanzee/human anti-B5 MAb. The combination of anti-A33 MAb and anti-B5 MAb did not synergize the protective efficacy. These chimpanzee/human anti-A33 MAbs may be useful in the prevention and treatment of vaccinia virus-induced complications of vaccination against smallpox and may also be effective in the immunoprophylaxis and immunotherapy of smallpox and other orthopoxvirus diseases. C1 NIH, Hepatitis Viruses Sect, Bethesda, MD 20892 USA. NIH, Mol Hepatitis Sect, Bethesda, MD 20892 USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Atlanta, GA 30333 USA. Univ Penn, Sch Dent Med, Dept Microbiol, Philadelphia, PA 19104 USA. Univ Texas, MD Anderson Canc Ctr, Dept Vet Sci, Bastrop, TX 78602 USA. RP Chen, ZC (reprint author), NIH, Infect Dis Lab, 50 S Dr,MSC 8009, Bethesda, MD 20892 USA. EM zc20a@nih.gov OI Schuck, Peter/0000-0002-8859-6966 FU Intramural NIH HHS; NIAID NIH HHS [N01-AO-62713, U54 AI057168, N01AO62713]; ORS NIH HHS [N02-OR-04021] NR 48 TC 36 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 SEP PY 2007 VL 81 IS 17 BP 8989 EP 8995 DI 10.1128/JVI.00906-07 PG 7 WC Virology SC Virology GA 202SL UT WOS:000248923700012 PM 17581986 ER PT J AU Fukumoto, R Dundr, M Nicot, C Adams, A Valeri, VW Samelson, LE Franchini, G AF Fukumoto, Risaku Dundr, Miroslav Nicot, Christophe Adams, Anthony Valeri, Valerio W. Samelson, Lawrence E. Franchini, Genoveffa TI Inhibition of T-cell receptor signal transduction and viral expression by the linker for activation of T cells-interacting p12(I) protein of human T-cell leukemia/lymphoma virus type 1 SO JOURNAL OF VIROLOGY LA English DT Article ID TROPICAL SPASTIC PARAPARESIS; BLOOD MONONUCLEAR-CELLS; READING FRAME-I; IMMUNOLOGICAL SYNAPSE; NUCLEAR FACTOR; LIPID RAFTS; HIV-1 NEF; HTLV-I; LEUKEMIA; LYMPHOCYTES AB The p12(I) protein of human T-cell leukemia/lymphoma virus type 1 (HTLV-1) is a small oncoprotein that increases calcium release following protein kinase C activation by phorbol myristate acetate, and importantly, this effect is linker for activation of T cells (LAT) independent. Here, we demonstrate that p12(I) inhibits the phosphorylation of LAT, Vav, and phospholipase C-gamma 1 and decreases NFAT (nuclear factor of activated T cells) activation upon engagement of the T-cell receptor (TCR) with anti-CD3 antibody. Furthermore, we demonstrate that p12(I) localizes to membrane lipid rafts and, upon engagement of the TCR, relocalizes to the interface between T cells and antigen-presenting cells, defined as the immunological synapse. A p12(I) knockout molecular clone of HTLV-1 expresses more virus upon antigen stimulation than the isogenic wild type, suggesting that, by decreasing T-cell responsiveness, p12(I) curtails viral expression. Thus, p12(I) has contrasting effects on TCR signaling: it down-regulates TCR in a LAT-dependent manner on one hand, and on the other, it increases calcium release in a LAT-independent manner. The negative regulation of T-cell activation by p12(I) may have evolved to minimize immune recognition of infected CD4(+) T cells, to impair the function of infected cytotoxic CD8(+) T cells, and to favor viral persistence in the infected host. C1 NCI, Anim Models & Retroviral Vaccines Sect, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. NCI, Cellular & Mol Biol Lab, Bethesda, MD 20892 USA. RP Franchini, G (reprint author), NCI, Basic Res Lab, NIH, Bldg 41,RM D804, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [R01 CA115398, CA115398] NR 58 TC 35 Z9 36 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 SEP PY 2007 VL 81 IS 17 BP 9088 EP 9099 DI 10.1128/JVI.02703-06 PG 12 WC Virology SC Virology GA 202SL UT WOS:000248923700022 PM 17582004 ER PT J AU Belov, GA Habbersett, C Franco, D Ehrenfeld, E AF Belov, George A. Habbersett, Courtney Franco, David Ehrenfeld, Ellie TI Activation of cellular Arf GTPases by poliovirus protein 3CD correlates with virus replication SO JOURNAL OF VIROLOGY LA English DT Article ID NUCLEOTIDE EXCHANGE FACTOR; ADP-RIBOSYLATION FACTOR; DEPENDENT RNA-POLYMERASE; VIRAL PROTEIN; BREFELDIN-A; IN-VITRO; 3A PROTEINS; FACTOR GBF1; INHIBITION; PRECURSOR AB We have previously shown that synthesis of poliovirus protein 3CD in uninfected HeLa cell extracts induces an increased association with membranes of the cellular Arf GTPases, which are key players in cellular membrane traffic. Arts cycle between an inactive, cytoplasmic, GDP-bound form and an active, membrane-associated, GTP-bound form. 3CD promotes binding of Arf to membranes by initiating recruitment to membranes of guanine nucleotide exchange factors (GEFs), BIG1 and BIG2. GEFs activate Arf by replacing GDP with GTP. In poliovirus-infected cells, there is a dramatic redistribution of cellular Arf pools that coincides with the reorganization of membranes used to form viral RNA replication complexes. Here we demonstrate that Arf translocation in vitro can be induced by purified recombinant 3CD protein; thus, concurrent translation of viral RNA is not required. Coexpression of 3C and 3D proteins was not sufficient to target Arf to membranes. 3CD expressed in HeLa cells was retained after treatment of the cells with digitonin, indicating that it may interact with a membrane-bound host factor. A F441S mutant of 3CD was shown previously to have lost Arf translocation activity and was also defective in attracting the corresponding GEFs to membranes. A series of other mutations were introduced at 3CD residue F441. Mutations that retained Arf translocation activity of 3CD also supported efficient growth of virus, regardless of their effects on 3D pollymerase elongation activity. Those that abrogated Arf activation by 3CD generated quasi-infectious RNAs that produced some plaques from which revertants that always restored the Arf activation property of 3CD were rescued. C1 NIAID, LID, NIH, Bethesda, MD 20892 USA. RP Ehrenfeld, E (reprint author), NIAID, LID, NIH, 50 South Dr,Room 6120, Bethesda, MD 20892 USA. EM eehrenfeld@niaid.nih.gov RI Belov, George/B-4625-2008 OI Belov, George/0000-0002-0892-1731 NR 44 TC 38 Z9 39 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 SEP PY 2007 VL 81 IS 17 BP 9259 EP 9267 DI 10.1128/JVI.00840-07 PG 9 WC Virology SC Virology GA 202SL UT WOS:000248923700038 PM 17567696 ER PT J AU Krempl, CD Wnekowicz, A Lamirande, EW Nayebagha, G Collins, PL Buchholz, UJ AF Krempl, Christine D. Wnekowicz, Anna Lamirande, Elaine W. Nayebagha, Giw Collins, Peter L. Buchholz, Ursula J. TI Identification of a novel virulence factor in recombinant pneumonia virus of mice SO JOURNAL OF VIROLOGY LA English DT Article ID RESPIRATORY SYNCYTIAL VIRUS; TRANSCRIPTION ELONGATION-FACTOR; HUMAN METAPNEUMOVIRUS LACKING; NONSTRUCTURAL PROTEINS NS1; SMALL HYDROPHOBIC SH; G-GLYCOPROTEIN; MESSENGER-RNA; IN-VITRO; PNEUMOVIRUS INFECTIONS; EPITHELIAL-CELLS AB Pneumonia virus of mice (PVM) is a murine relative of human respiratory syncytial virus (HRSV). Here we developed a reverse genetics system for PVM based on a consensus sequence for virulent strain 15. Recombinant PVM and a version engineered to express green fluorescent protein replicated as efficiently as the biological parent in vitro but were 4- and 12.5-fold attenuated in vivo, respectively. The G proteins of HRSV and PVM have been suggested to contribute to viral pathogenesis, but this had not been possible to study in a defined manner in a fully permissive host. As a first step, we evaluated recombinant mutants bearing a deletion of the entire G gene (Delta G) or expressing a G protein lacking its cytoplasmic tail (Gt). Both G mutants replicated as efficiently in vitro as their recombinant parent, but both were nonpathogenic in mice at doses that would otherwise be lethal. We could not detect replication of the Delta G mutant in mice, indicating that its attenuation is based on a severe reduction in the virus load. In contrast, the Gt mutant appeared to replicate as efficiently in mice as its recombinant parent. Thus, the reduction in virulence associated with the Gt mutant could not be accounted for by a reduction in viral replication. These results identified the cytoplasmic tail of G as a virulence factor whose effect is not mediated solely by the viral load. In addition to its intrinsic interest, a recombinant virus that replicates with wild-type-like efficiency but does not cause disease defines optimal properties for vaccine development. C1 Univ Freiburg, Inst Med Microbiol & Hyg, Dept Virol, Freiburg, Germany. NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. RP Krempl, CD (reprint author), Univ Wurzburg, Inst Immunol & Virol, Versbacher Str 7, D-97078 Wurzburg, Germany. EM ckrempl@vim.uni-wuerzburg.de RI Krempl, Christine/O-2081-2015 FU Intramural NIH HHS NR 48 TC 18 Z9 19 U1 1 U2 3 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 SEP PY 2007 VL 81 IS 17 BP 9490 EP 9501 DI 10.1128/JVI.00364-07 PG 12 WC Virology SC Virology GA 202SL UT WOS:000248923700062 PM 17567693 ER PT J AU Vasilakis, N Holmes, EC Fokam, EB Faye, O Diallo, M Sall, AA Weaver, SC AF Vasilakis, Nikos Holmes, Edward C. Fokam, Eric B. Faye, Ousinane Diallo, Mawlouth Sall, Arnadou A. Weaver, Scott C. TI Evolutionary processes among sylvatic dengue type 2 viruses SO JOURNAL OF VIROLOGY LA English DT Article ID MOLECULAR EVOLUTION; EMERGENCE; SENEGAL; THAILAND; BANGKOK; HOST AB Sylvatic dengue viruses (DEW) are transmitted in an enzootic cycle between nonhuman primates and arboreal Aedes mosquitoes in Southeast Asia and West Africa. Although previous analyses have revealed the evolutionary processes among endemic (human) DEW, little is known about viral evolution in the sylvatic cycle. Through an analysis of 14 complete coding regions of sylvatic Dengue type 2 virus sampled over a 33-year period, we show that both the rate of evolutionary change and the pattern of natural selection are similar among endemic and sylvatic DEW, although the latter have a uniquely high frequency of positive selection in the NS4B protein gene. Our findings support a recent cross-species transmission event and suggest the possibility of future DENV reemergence from the sylvatic cycle. C1 Univ Texas, Med Branch, Ctr Biodefense & Emerging Infect Dis, Galveston, TX 77555 USA. Univ Texas, Med Branch, Dept Pathol, Galveston, TX 77555 USA. Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. Penn State Univ, Dept Biol, University Pk, PA 16802 USA. NCI, Fogarty Int Ctr, Bethesda, MD 20892 USA. Inst Pasteur, Dakar, Senegal. Univ Buea, Dept Bot & Zool, Buea, Cameroon. RP Weaver, SC (reprint author), Univ Texas, Med Branch, Ctr Biodefense & Emerging Infect Dis, 301 Univ Blvd, Galveston, TX 77555 USA. EM sweaver@utmb.edu RI Weaver, Scott/D-6490-2011; OI Holmes, Edward/0000-0001-9596-3552 FU PHS HHS [T01/CCT622892] NR 30 TC 45 Z9 47 U1 0 U2 4 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 SEP PY 2007 VL 81 IS 17 BP 9591 EP 9595 DI 10.1128/JVI.02776-06 PG 5 WC Virology SC Virology GA 202SL UT WOS:000248923700076 PM 17553878 ER PT J AU McAlister, VJ Owens, RA AF McAlister, Victor J. Owens, Roland A. TI Preferential integration of adeno-associated virus type 2 into a Polypyrimidine/Polypurine-Rich region within AAVS1 SO JOURNAL OF VIROLOGY LA English DT Article ID SITE-SPECIFIC INTEGRATION; DEPENDENT PROTEIN-KINASE; REPLICATION IN-VITRO; HUMAN-CHROMOSOME 19; REP PROTEIN; DNA-BINDING; PUR-ALPHA; TARGETED INTEGRATION; HUMAN GENOME; HUMAN-CELLS AB Adeno-associated virus type 2 (AAV2) preferentially integrates its genome into the AAVSI locus on human chromosome 19. Preferential integration requires the AAV2 Rep68 or Rep78 protein (Rep68/78), a Rep68/78 binding site (RBS), and a nicking site within AAVSI and may also require an RBS within the virus genome. To obtain further information that might help to elucidate the mechanism and preferred substrate configurations of preferential integration, we amplified junctions between AAV2 DNA and AAVS] from AAV2-infected HeLaJW cells and cells with defective Artemis or xeroderma pigmentosum group A genes. We sequenced 61 distinct junctions. The integration junction sequences show the three classical types of nonhomologous-endjoining joints: microhomology at junctions (57%), insertion of sequences that are not normally contiguous with either the AAV2 or the AAVSI sequences at the junction (31%, and direct joining (11%). These junctions were spread over 750 bases and were all downstream of the Rep68/78 nicking site within AAVSL Two-thirds of the junctions map to 350 bases of AAVS] that are rich in polypyrimidine tracts on the nicked strand. The majority of AAV2 breakpoints were within the inverted terminal repeat (ITR) sequences, which contain RBSs. We never detected a complete ITR at a junction. Residual ITRs at junctions never contained more than one RBS, suggesting that the hairpin form, rather than the linear ITR, is the more frequent integration substrate. Our data are consistent with a model in which a cellular protein other than Artemis cleaves AAV2 hairpins to produce free ends for integration. C1 NIDDK, Mol & Cellular Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Owens, RA (reprint author), NIDDK, Mol & Cellular Biol Lab, NIH, Dept Hlth & Human Serv, Bldg 8,Rm 307,8 Ctr Dr,MSC 0840, Bethesda, MD 20892 USA. EM ro6n@nih.gov FU Intramural NIH HHS [Z01 DK057501-31] NR 70 TC 8 Z9 8 U1 0 U2 2 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 SEP PY 2007 VL 81 IS 18 BP 9718 EP 9726 DI 10.1128/JVI.00746-07 PG 9 WC Virology SC Virology GA 208JI UT WOS:000249315200010 PM 17626070 ER PT J AU Heidecker, G Lloyd, PA Soheilian, F Nagashima, K Derse, D AF Heidecker, Gisela Lloyd, Patricia A. Soheilian, Ferri Nagashima, Kunio Derse, David TI The role of WWP1-Gag interaction and gag ubiquitination in assembly and release of human T-Cell leukemia virus type 1 SO JOURNAL OF VIROLOGY LA English DT Article ID ROUS-SARCOMA-VIRUS; INFECTIOUS-ANEMIA VIRUS; PROTEIN-SORTING PATHWAY; IMMUNODEFICIENCY-VIRUS; PARTICLE RELEASE; MATRIX PROTEIN; LATE DOMAIN; BUDDING PROCESS; SWISS-MODEL; TSG101 AB The PPPY motif in the matrix (MA) domain of human T-cell leukemia virus type 1 (HTLV-1) Gag associates with WWP1, a member of the HECT domain containing family of E3 ubiquitin ligases. Mutation of the PPPY motif arrests particle assembly at an early stage and abolishes ubiquitination of MA. Similar effects are seen when Gag is expressed in the presence of a truncated form of WNW1 that lacks the catalytically active HECT domain (C2WW). To understand the role of ubiquitination in budding, we mutated the four lysines in MA to arginines and identified lysine 74 as the unique site of ubiquitination. Virus-like particles produced by the K74R mutant did not contain ubiquitinated MA and showed a fourfold reduction in the release of infectious particles. Furthermore, the K74R mutation rendered assembly hypersensitive to C2WW inhibition; K74R Gag budding was inhibited at significantly lower levels of expression of C2WW compared with wild-type Gag. This finding indicates that the interaction between Gag and WWPI is required for functions other than Gag ubiquitination. Additionally, we show that the PPPY- mutant Gag exerts a strong dominant-negative effect on the budding of wild-type Gag, further supporting the importance of recruitment of WWP1 to achieve particle assembly. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. SAIC Frederick, Image Anal Lab, Frederick, MD 21702 USA. RP Heidecker, G (reprint author), NCI, HIV Drug Resistance Program, Bldg 535,Rm 111, Frederick, MD 21702 USA. EM heidecke@ncifcrf.gov FU Intramural NIH HHS; NCI NIH HHS [N01CO12400]; PHS HHS [N01 C0 12400] NR 64 TC 23 Z9 23 U1 0 U2 2 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 SEP PY 2007 VL 81 IS 18 BP 9769 EP 9777 DI 10.1128/JVI.00642-07 PG 9 WC Virology SC Virology GA 208JI UT WOS:000249315200015 PM 17609263 ER PT J AU Lin, G Bertolotti-Ciarlet, A Haggarty, B Romano, J Nolan, KM Leslie, GJ Jordan, APO Huang, CC Kwong, PD Doms, RW Hoxie, JA AF Lin, George Bertolotti-Ciarlet, Andrea Haggarty, Beth Romano, Josephine Nolan, Katrina M. Leslie, George J. Jordan, Andrea P. -O. Huang, Chih-chin Kwong, Peter D. Doms, Robert W. Hoxie, James A. TI Replication-competent variants of human immunodeficiency virus type 2 lacking the V3 loop exhibit resistance to chemokine receptor antagonists SO JOURNAL OF VIROLOGY LA English DT Article ID GP120 ENVELOPE GLYCOPROTEIN; CORECEPTOR-BINDING-SITE; MOLECULE CCR5 INHIBITOR; CELL FUSION ASSAY; ENTRY INHIBITOR; HIV-1 ENTRY; NEUTRALIZATION EPITOPE; MONOCLONAL-ANTIBODY; CD4 INDEPENDENCE; VARIABLE DOMAIN AB Entry of human immunodeficiency virus type 1 (HIV-1) and HIV-2 requires interactions between the envelope glycoprotein (Env) on the virus and CD4 and a chemokine receptor, either CCR5 or CXCR4, on the cell surface. The V3 loop of the HIV gp120 glycoprotein plays a critical role in this process, determining tropism for CCR5- or CXCR4-expres sing cells, but details of how V3 interacts with these receptors have not been defined. Using an iterative process of deletion mutagenesis and in vitro adaptation of infectious viruses, variants of HIV-2 were derived that could replicate without V3, either with or without a deletion of the VIN2 variable loops. The generation of these functional but markedly minimized Envs required adaptive changes on the gp120 core and gp41 transmembrane glycoprotein. W-deleted Envs exhibited tropism for both CCR5- and CXCR4-expressing cells, suggesting that domains on the gp120 core were mediating interactions with determinants shared by both coreceptors. Remarkably, HIV-2 Envs with V3 deletions became resistant to smallmolecule inhibitors of CCR5 and CXCR4, suggesting that these drugs inhibit wild-type viruses by disrupting a specific V3 interaction with the coreceptor. This study represents a proof of concept that HIV Envs lacking V3 alone or in combination with V1/V2 that retain functional domains required for viral entry can be derived. Such minimized Envs may be useful in understanding Env function, screening for new inhibitors of gp120 core interactions with chemokine receptors, and designing novel immunogens for vaccines. C1 Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. Natl Inst Allerg & Infect Dis, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Hoxie, JA (reprint author), Univ Penn, Sch Med, Dept Med, Room 356,Biomed Res Bldg 2 3, Philadelphia, PA 19104 USA. EM hoxie@mail.med.upenn.edu FU Intramural NIH HHS; PHS HHS [R21 065234, R37 457800, R01 40880] NR 72 TC 22 Z9 22 U1 1 U2 2 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 SEP PY 2007 VL 81 IS 18 BP 9956 EP 9966 DI 10.1128/JVI.00385-07 PG 11 WC Virology SC Virology GA 208JI UT WOS:000249315200033 PM 17609282 ER PT J AU Zou, P Kawada, J Pesnicak, L Cohen, JI AF Zou, Ping Kawada, Junichi Pesnicak, Lesley Cohen, Jeffrey I. TI Bortezomib induce aoptosis of Epstein-Barr virus (EBV)-transformed B cells and prolongs survival of mice inoculated with EBV-transformed B cells SO JOURNAL OF VIROLOGY LA English DT Article ID NF-KAPPA-B; PROTEASOME INHIBITOR PS-341; TRAF-BINDING-SITE; LATENT MEMBRANE-PROTEIN-1; BURKITTS-LYMPHOMA; SIGNALING PATHWAY; NF-KAPPA-B2 P100; TUMOR-GROWTH; ACTIVATION; APOPTOSIS AB Bortezomib, an inhibitor of the 26S proteasome, is currently approved for treatment of multiple myeloma and is being studied for therapy of non-Hodgkin's lymphoma. We found that Epstein-Barr virus (EBV) -positive B cells with type III latency were more susceptible to killing by bortezomib than those with type I latency. Bortezomib induced apoptosis of EBV lymphoblastoid cell lines (LCLs) by inducing cleavage of caspases 8 and 9; apoptosis was inhibited by pretreatment with a pan-caspase inhibitor. Bortezomib reduced the levels of the p50 and p65 components of the canonical NF-kappa B pathway and reduced the level of p52 in the noncanonical NF-kappa B pathway, which is induced by EBV LMP1. Bortezomib inhibited expression of cIAP-1, cIAP-2, and XIAP, which are regulated by NF-kappa B and function as inhibitors of apoptosis. Bortezomib did not inhibit expression of several other antiapoptotic proteins, including Bcl-2 and Bcl-XL. Finally, bortezomib significantly prolonged the survival of severe combined immunodeficiency mice inoculated with LCLs. These findings suggest that bortezomib may represent a novel strategy for the treatment of certain EBV-associated lymphomas. C1 NIH, Lab Clin Infect Dis, Med Virol Sect, Bethesda, MD 20892 USA. RP Cohen, JI (reprint author), NIH, Lab Clin Infect Dis, Med Virol Sect, 10 Ctr Dr,Bldg 10,Room 11N234, Bethesda, MD 20892 USA. EM jcohen@niaid.nih.gov RI Kawada, Jun-ichi/I-7322-2014 FU Intramural NIH HHS NR 50 TC 53 Z9 58 U1 0 U2 3 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 SEP PY 2007 VL 81 IS 18 BP 10029 EP 10036 DI 10.1128/JVI.02241-06 PG 8 WC Virology SC Virology GA 208JI UT WOS:000249315200040 PM 17626072 ER PT J AU Coren, LV Thomas, JA Chertova, E Sowder, RC Gagliardi, TD Gorelick, RJ Ott, DE AF Coren, Lori V. Thomas, James A. Chertova, Elena Sowder, Raymond C., II Gagliardi, Tracy D. Gorelick, Robert J. Ott, David E. TI Mutational analysis of the C-terminal Gag cleavage sites in human immunodeficiency virus type 1 SO JOURNAL OF VIROLOGY LA English DT Article ID HIV-1 NUCLEOCAPSID PROTEIN; IN-VITRO; REVERSE TRANSCRIPTION; INFECTION PROCESSES; CDNA INTEGRATION; SPACER PEPTIDE; ZINC-FINGER; GENOMIC RNA; RESISTANCE; SPECIFICITY AB Human immunodeficiency virus type 1 (HIV-1) Gag is expressed as a polyprotein that is cleaved into six proteins by the viral protease in a maturation process that begins during assembly and budding. While processing of the N terminus of Gag is strictly required for virion maturation and infectivity, the necessity for the C-terminal cleavages of Gag is less well defined. To examine the importance of this process, we introduced a series of mutations into the C terminus of Gag that interrupted the cleavage sites that normally produce in the nucleocapsid (NC), spacer 2 (SP2), or p6(Gag) proteins. Protein analysis showed that all of the mutant constructs produced virions efficiently upon transfection of cells and appropriately processed Gag polyprotein at the nonmutated sites. Mutants that produced a p9(NC/SP2) protein exhibited only minor effects on HIV-1 infectivity and replication. In contrast, mutants that produced only the p8(SP2/p6) or p15(NC/SP2/p6) protein had severe defects in infectivity and replication. To identify the key defective step, we quantified reverse transcription and integration products isolated from infected cells by PCR. All mutants tested produced levels of reverse transcription products either similar to or only somewhat lower than that of wild type. In contrast, mutants that failed to cleave the SP2-p6(Gag) site produced drastically less provirus than the wild type. Together, our results show that processing of the SP2-p6(Gag) and not the NC-SP2 cleavage site is important for efficient viral DNA integration during infection in vitro. In turn, this finding suggests an important role for the p9(NC/SP2) species in some aspect of integration. C1 SAIC Frederick Inc, AIDS Vaccine Program, Natl Canc Inst, Frederick, MD 21702 USA. RP Ott, DE (reprint author), SAIC Frederick Inc, AIDS Vaccine Program, Natl Canc Inst, Frederick, MD 21702 USA. EM ott@ncifcrf.gov OI Thomas, James/0000-0002-2509-490X FU NCI NIH HHS [N01 CO 12400, N01CO12400] NR 55 TC 36 Z9 37 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 SEP PY 2007 VL 81 IS 18 BP 10047 EP 10054 DI 10.1128/JVI.02496-06 PG 8 WC Virology SC Virology GA 208JI UT WOS:000249315200042 PM 17634233 ER PT J AU Hurst, SA Danis, M AF Hurst, Samia A. Danis, Marion TI A framework for rationing by clinical judgment SO KENNEDY INSTITUTE OF ETHICS JOURNAL LA English DT Article ID COST-EFFECTIVENESS ANALYSIS; EVIDENCE-BASED MEDICINE; QUALITY-OF-LIFE; HEALTH-CARE; PHYSICIANS RESPONSES; MANAGED CARE; BEDSIDE; VALUES; CONSTRAINTS; GUIDELINES AB Although rationing by clinical judgment is controversial, its acceptability partly depends on how it is practiced. In this paper, rationing by clinical judgment is defined in three different circumstances that represent increasingly wider circles of resource pools in which the rationing decision takes place: triage during acute shortage, comparison to other potential patients in a context of limited but not immediately strained resources, and determination of whether expected benefit of an intervention is deemed sufficient to warrant its cost by reference to published population based thresholds. Notions of procedural justice are applied along with an analytical framework of six minimal requisites in order to facilitate fair bedside rationing: (1) a closed system that offers reciprocity, (2) attention to general concerns of justice, (3) respect for individual variations, (4) application of a consistent process, (5) explicitness, and (6) review of decisions. The process could be monitored for its applicability and appropriateness. C1 Univ Geneva, Sch Med, Inst Biomed Eth, CH-1211 Geneva 4, Switzerland. NIH, Sect Eth & Hlth Policy, Dept Bioeth, Bethesda, MD 20892 USA. NIH, Clin Bioeth Consultat Serv, Bethesda, MD 20892 USA. RP Hurst, SA (reprint author), Univ Geneva, Sch Med, Inst Biomed Eth, CH-1211 Geneva 4, Switzerland. RI Hurst, Samia/A-9661-2008 OI Hurst, Samia/0000-0002-1980-5226 NR 39 TC 27 Z9 27 U1 0 U2 2 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 1054-6863 J9 KENNEDY INST ETHIC J JI Kennedy Inst. Ethics J. PD SEP PY 2007 VL 17 IS 3 BP 247 EP 266 DI 10.1353/ken.2007.0021 PG 20 WC Ethics; Philosophy; Social Issues SC Social Sciences - Other Topics; Philosophy; Social Issues GA 237SD UT WOS:000251395800004 PM 18210983 ER PT J AU Erickson, HS Albert, PS Gillespie, JW Wallis, BS Rodriguez-Canales, J Linehan, WM Gonzalez, S Velasco, A Chuaqui, RF Emmert-Buck, MR AF Erickson, Heidi S. Albert, Paul S. Gillespie, John W. Wallis, Benjamin S. Rodriguez-Canales, Jaime Linehan, W. Marston Gonzalez, Sergio Velasco, Alfredo Chuaqui, Rodrigo F. Emmert-Buck, Michael R. TI Assessment of normalization strategies for quantitative RT-PCR using microdissected tissue samples SO LABORATORY INVESTIGATION LA English DT Article ID GENE-EXPRESSION ANALYSIS; CANCER-CELL-LINES; HOUSEKEEPING GENES; PROSTATE-CANCER; MESSENGER-RNA; ENDOGENOUS CONTROLS; RENAL BIOPSIES; VALIDATION; SELECTION; CARCINOMA AB Gene expression measurement techniques such as quantitative reverse transcriptase (qRT)-PCR require a normalization strategy to allow meaningful comparisons across biological samples. Typically, this is accomplished through the use of an endogenous housekeeping gene that is presumed to show stable expression levels in the samples under study. There is concern regarding how precisely specific genes can be measured in limited amounts of mRNA such as those from microdissected (MD) tissues. To address this issue, we evaluated three different approaches for qRT-PCR normalization of dissected samples; cell count during microdissection, total RNA measurement, and endogenous control genes. The data indicate that both cell count and total RNA are useful in calibrating input amounts at the outset of a study, but do not provide enough precision to serve as normalization standards. However, endogenous control genes can accurately determine the relative abundance of a target gene relative to the entire cellular transcriptome. Taken together, these results suggest that precise gene expression measurements can be made from MD samples if the appropriate normalization strategy is employed. C1 NCI, Pathogenet Unit, Pathol Lab, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Biomet Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. NCI, SAIC Frederick Inc, Frederick, MD 21701 USA. Catholic Univ Chile, Dept Pathol, Santiago, Chile. Catholic Univ Chile, Dept Urol, Santiago, Chile. RP Erickson, HS (reprint author), NCI, Pathogenet Unit, Pathol Lab, Bethesda, MD 20892 USA. EM HSE@nih.gov; mbuck@helix.nih.gov OI Rodriguez-Canales, Jaime/0000-0002-0885-2377 FU Intramural NIH HHS NR 33 TC 31 Z9 32 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD SEP PY 2007 VL 87 IS 9 BP 951 EP 962 DI 10.1038/labinvest.3700659 PG 12 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 202ZM UT WOS:000248943900010 PM 17643124 ER PT J AU Choi, WJ Xang, SU Burke, TR AF Choi, W. J. Xang, S.-U. Burke, T. R., Jr. TI Preparation of orthogonally-protected 3-methoxy-4-phosphonomethyl-L-phenylalanine, a new reagent for the synthesis of phosphotyrosyl mimetic-containing peptides SO LETTERS IN ORGANIC CHEMISTRY LA English DT Article DE amino acid; asymmetric; chiral auxiliaries; peptides; stereoselective synthesis ID GRB2 SH2 DOMAIN; HYDROLYTICALLY STABLE ANALOG; SOLID-PHASE SYNTHESIS; ALPHA-AMINO-ACIDS; O-PHOSPHOTYROSINE; ENANTIOSELECTIVE SYNTHESIS; ASYMMETRIC-SYNTHESIS; SIGNAL-TRANSDUCTION; BINDING LIGANDS; DESIGN AB [(4-Hydroxymethyl-2-methoxyphenyl)methyl]phosphonic acid di-tert-butyl ester (8) served as a key intermediate in the stereoselective preparation of N-Fmoc-3-methoxy-4-(di-tert-butyl)phosphonomethyl-L-phenylalanine (5). Reagent 5 may be useful for the solid-phase synthesis of phosphotyrosyl mimetic-containing peptides. C1 NCI, Frederick Canc Res & Dev Ctr, Natl Inst Hlth, Med Chem Lab, Frederick, MD 21702 USA. RP Burke, TR (reprint author), NCI, Frederick Canc Res & Dev Ctr, Natl Inst Hlth, Med Chem Lab, Bldg 376 Boyles St, Frederick, MD 21702 USA. EM tburke@helix.nih.gov RI Burke, Terrence/N-2601-2014 NR 40 TC 1 Z9 1 U1 0 U2 2 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1570-1786 J9 LETT ORG CHEM JI Lett. Org. Chem. PD SEP PY 2007 VL 4 IS 6 BP 433 EP 439 PG 7 WC Chemistry, Organic SC Chemistry GA 216GR UT WOS:000249867000011 ER PT J AU Mesa, RA Camoriano, JK Geyer, SM Wu, W Kaufmann, SH Rivera, CE Erlichman, C Wright, J Pardanani, A Lasho, T Finke, C Li, CY Tefferi, A AF Mesa, R. A. Camoriano, J. K. Geyer, S. M. Wu, W. Kaufmann, S. H. Rivera, C. E. Erlichman, C. Wright, J. Pardanani, A. Lasho, T. Finke, C. Li, C. Y. Tefferi, A. TI A phase II trial of tipifarnib in myelofibrosis: primary, post-polycythemia vera and post-essential thrombocythemia SO LEUKEMIA LA English DT Article DE primary myelofibrosis; myelofibrosis; myeloproliferative; disorder; JAK2V617F ID FARNESYLTRANSFERASE INHIBITOR R115777; AGNOGENIC MYELOID METAPLASIA; TYROSINE KINASE JAK2; MYELOPROLIFERATIVE DISORDERS; TRANSFERASE INHIBITOR; CELL TRANSPLANTATION; IN-VITRO; THERAPY; MUTATION; PROTEIN AB Patients with primary myelofibrosis ( PMF) or post- polycythemia vera or post- essential thrombocythemia myelofibrosis ( post- PV/ ET MF) have limited therapeutic options. The farnesyltransferaseinhibitor tipifarnib inhibits in vitro proliferation of myeloid progenitors from such patients. In the current phase II clinical trial, single- agent oral tipifarnib ( 300mg twice daily *21 of 28 days) was given to 34 symptomatic patients with either PMF ( n 28) or post- PV/ ET MF ( n 6). Median time to discontinuation of protocol therapy was 4.6 months; reasons for early termination ( n 19; 56%) included disease progression ( 21%) and adverse drug effects ( 18%). Toxicities ( >= grade 3) included myelosuppression ( n 16), neuropathy ( n 2), fatigue ( n 1), rash ( n 1) and hyponatremia ( n 1). Response rate was 33% for hepatosplenomegaly and 38% for transfusion- requiring anemia. No favorable changes occurred in bone marrow fibrosis, angiogenesis or cytogenetic status. Pre- and post- treatment patient sample analysis for in vitro myeloid colony growth revealed substantial reduction in the latter. Clinical response did not correlate with either degree of colony growth, measurable decrease in quantitative JAK2 (V617F) levels or tipifarnib IC50 values ( median 11.8 nM) seen in pretreatment samples. The current study indicates both in vitro and in vivo tipifarnib activity in PMF and post- PV/ ET MF. C1 Mayo Clin, Div Hematol & Internal Med, Rochester, MN 55905 USA. Div Hematol, Rochester, MN USA. Div Hematol, Scottsdale, AZ USA. Mayo Clin, Canc Ctr Stat, Rochester, MN USA. Div Hematol, Jacksonville, FL USA. Mayo Clin, Coll Med, Dept Oncol, Rochester, MN USA. Natl Canc Inst, Canc Therapy Evaluat Program, Bethesda, MD USA. Mayo Clin, Coll Med, Div Hematopathol, Rochester, MN USA. RP Mesa, RA (reprint author), Mayo Clin, Div Hematol & Internal Med, 200 First St SW, Rochester, MN 55905 USA. EM mesa.ruben@mayo.edu RI Geyer, Susan/E-3112-2011; OI Kaufmann, Scott/0000-0002-4900-7145 FU NCI NIH HHS [CA15083, N01CM62205] NR 33 TC 26 Z9 30 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0887-6924 J9 LEUKEMIA JI Leukemia PD SEP PY 2007 VL 21 IS 9 BP 1964 EP 1970 DI 10.1038/sj.leu.2404816 PG 7 WC Oncology; Hematology SC Oncology; Hematology GA 205NY UT WOS:000249122200016 PM 17581608 ER PT J AU Arons, E Suntum, T Sunshine, J Stetler-Stevenson, M Kreitman, RJ AF Arons, Evgeny Suntum, Tara Sunshine, Joel Stetler-Stevenson, Maryalice Kreitman, Robert J. TI Immunoglobulin light chain repertoire in hairy cell leukemia SO LEUKEMIA RESEARCH LA English DT Article DE kappa chain; lambda chain; gene usage; chronic lymphocytic leukemia ID CHRONIC LYMPHOCYTIC-LEUKEMIA; V-LAMBDA REPERTOIRE; FLOW-CYTOMETRY; PROGNOSTIC-SIGNIFICANCE; SOMATIC MUTATION; TUMOR-CELLS; KAPPA-LIGHT; GENE USAGE; B-CELLS; IMMUNOLOGICAL PHENOTYPE AB Of 166 hairy cell leukemia (HCL) patients, 81 had kappa and 80 had lambda expression. IGKV-J and IGLV-J rearrangement structure was analyzed in 21 HCL patients (11 kappa, 10 lambda). For kappa, IGKV 1-5 was most frequent, and the KJ2 gene was over-utilized. For lambda HCL, LJ3 was over-utilized compared to normal. This study significantly adds to previous studies of light chain usage in HCL and is the first to report light chain gene usage. In HCL, we confirm the lack of kappa predominance observed in normal lymphocytes and in chronic lymphocytic leukemia, and note over-representation of several light chain genes. Published by Elsevier Ltd. C1 NCI, Labs Mol Biol & Pathol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kreitman, RJ (reprint author), Clin Immunotherapy Sect, Mol Biol Lab, 9000 Rockville Pike,Bldg 37,Room 5124B, Bethesda, MD 20892 USA. EM kreitmar@mail.nih.gov FU Intramural NIH HHS NR 60 TC 2 Z9 2 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0145-2126 J9 LEUKEMIA RES JI Leuk. Res. PD SEP PY 2007 VL 31 IS 9 BP 1231 EP 1236 DI 10.1016/j.leukres.2006.11.019 PG 6 WC Oncology; Hematology SC Oncology; Hematology GA 189UC UT WOS:000248013000010 PM 17462732 ER PT J AU Peng, YW Taylor, JMG Yu, BB AF Peng, Yingwei Taylor, Jeremy M. G. Yu, Binbing TI A marginal regression model for multivariate failure time data with a surviving fraction SO LIFETIME DATA ANALYSIS LA English DT Article DE copula; cure; logit link; mixture model; proportional hazards; sandwich variance estimate; semiparametric; tonsil cancer ID CURE RATE ESTIMATION; MIXTURE MODEL; COX REGRESSION; LIFE-TABLES; ASSOCIATION; ESTIMATORS; CARCINOMA; INFERENCE; VARIANCE AB A marginal regression approach for correlated censored survival data has become a widely used statistical method. Examples of this approach in survival analysis include from the early work by Wei et al. (J Am Stat Assoc 84:1065-1073, 1989) to more recent work by Spiekerman and Lin (J Am Stat Assoc 93:1164-1175, 1998). This approach is particularly useful if a covariate's population average effect is of primary interest and the correlation structure is not of interest or cannot be appropriately specified due to lack of sufficient information. In this paper, we consider a semiparametric marginal proportional hazard mixture cure model for clustered survival data with a surviving or "cure" fraction. Unlike the clustered data in previous work, the latent binary cure statuses of patients in one cluster tend to be correlated in addition to the possible correlated failure times among the patients in the cluster who are not cured. The complexity of specifying appropriate correlation structures for the data becomes even worse if the potential correlation between cure statuses and the failure times in the cluster has to be considered, and thus a marginal regression approach is particularly attractive. We formulate a semiparametric marginal proportional hazards mixture cure model. Estimates are obtained using an EM algorithm and expressions for the variance-covariance are derived using sandwich estimators. Simulation studies are conducted to assess finite sample properties of the proposed model. The marginal model is applied to a multi-institutional study of local recurrences of tonsil cancer patients who received radiation therapy. It reveals new findings that are not available from previous analyses of this study that ignored the potential correlation between patients within the same institution. C1 Queens Univ, Dept Epidemiol & Community Hlth, Kingston, ON K7L 3N6, Canada. Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. NIA, Bethesda, MD 20892 USA. RP Peng, YW (reprint author), Queens Univ, Dept Epidemiol & Community Hlth, Kingston, ON K7L 3N6, Canada. EM pengp@queensu.ca; jmgt@umich.edu; yubi@mail.nih.gov NR 28 TC 15 Z9 15 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1380-7870 J9 LIFETIME DATA ANAL JI Lifetime Data Anal. PD SEP PY 2007 VL 13 IS 3 BP 351 EP 369 DI 10.1007/s10985-007-9042-4 PG 19 WC Mathematics, Interdisciplinary Applications; Statistics & Probability SC Mathematics GA 210LY UT WOS:000249458900004 PM 17641970 ER PT J AU Lee, SH Yang, S AF Lee, Seung-Hwan Yang, Song TI Checking the censored two-sample accelerated life model using integrated cumulative hazard difference SO LIFETIME DATA ANALYSIS LA English DT Article DE accelerated life; censored data; lack-of-fit tests; martingale residuals ID REGRESSION-MODELS; SURVIVAL-DATA AB In this paper, new statistical tests for the censored two-sample accelerated life model are discussed. From the estimating functions using integrated cumulative hazard difference, stochastic processes are constructed. They can be described by martingale residuals, and, given the data, conditional distributions can be approximated by zero mean Gaussian processes. The new methods, based on these processes, provide asymptotically consistent tests against a general departure from the model. A graphical method is also discussed. In various numerical studies, the new tests performed better than the existing method, especially when the hazard curves cross. The proposed procedures are illustrated with two real data sets. C1 Illinois Wesleyan Univ, Dept Math & Comp Sci, Bloomington, IL 61702 USA. NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. RP Lee, SH (reprint author), Illinois Wesleyan Univ, Dept Math & Comp Sci, Bloomington, IL 61702 USA. EM slee2@iwu.edu; yangso@nhlbi.nih.gov NR 10 TC 3 Z9 3 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1380-7870 J9 LIFETIME DATA ANAL JI Lifetime Data Anal. PD SEP PY 2007 VL 13 IS 3 BP 371 EP 380 DI 10.1007/s10985-007-9039-z PG 10 WC Mathematics, Interdisciplinary Applications; Statistics & Probability SC Mathematics GA 210LY UT WOS:000249458900005 PM 17530398 ER PT J AU Kipervaser, ZG Pelled, G Goelman, G AF Kipervaser, Zeev Gideon Pelled, Galit Goelman, Gadi TI Statistical framework and noise sensitivity of the amplitude radial correlation contrast method SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE radial correlation contrast (RCC); fMRI; cluster size statistic; connectivity; rat forepaw stimulation ID FUNCTIONAL CONNECTIVITY; NEURONAL-ACTIVITY; BOLD; FMRI; BRAIN; MRI; ACTIVATION; CLUSTERS; CORTEX; SIGNAL AB A statistical framework for the amplitude radial correlation contrast (RCC) method, which integrates a conventional pixel threshold approach with cluster-size statistics, is presented. The RCC method uses functional MRI (fMRI) data to group neighboring voxels in terms of their degree of temporal cross correlation and compares coherences in different brain states (e.g., stimulation OFF vs. ON). By defining the RCC correlation map as the difference between two RCC images, the map distribution of two OFF states is shown to be normal, enabling the definition of the pixel cutoff. The empirical cluster-size null distribution obtained after the application of the pixel cutoff is used to define a cluster-size cutoff that allows 5% false positives. Assuming that the MRI signal equals the task-induced response plus noise, an analytical expression of amplitude-RCC dependency on noise is obtained and used to define the pixel threshold. In vivo and ex vivo data obtained during rat forepaw electric stimulation are used to fine-tune this threshold. Calculating the spatial coherences within in vivo and ex vivo images shows enhanced coherence in the in vivo data, but no dependency on the anesthesia method, magnetic field strength, or depth of anesthesia, strengthening the generality of the proposed cutoffs. C1 Hadassah Univ Hosp, Med Ctr, Dept Med Biophys, Human Biol Res Ctr,MRI MRS Lab, IL-91120 Jerusalem, Israel. NINDS, Lab Funct & Mol Imaging, Bethesda, MD 20892 USA. RP Goelman, G (reprint author), Hadassah Univ Hosp, Med Ctr, Dept Med Biophys & Nucl Med, POB 1200, IL-91120 Jerusalem, Israel. EM gadig@hadassah.org.il NR 34 TC 1 Z9 1 U1 1 U2 1 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 SEP PY 2007 VL 58 IS 3 BP 554 EP 561 DI 10.1002/mrm.21278 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 207OK UT WOS:000249260200015 PM 17763348 ER PT J AU Lu, H Scholl, CA Zuo, Y Stein, EA Yang, YH AF Lu, Hanbing Scholl, Clara A. Zuo, Yantao Stein, Elliot A. Yang, Yihong TI Quantifying the blood oxygenation level dependent effect in cerebral blood volume-weighted functional MRI at 9.4T SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE BOLD; CBV; fMRI; BOLD contamination; superparamagnetic contrast agent ID CONTRAST AGENT; CBV RESPONSES; SPIN-ECHO; FMRI; BOLD; SIZE; SPECIFICITY; RESOLUTION AB In cerebral blood volume (CBV)-weighted functional MRI (fMRI) employing superparamagnetic contrast agent, iron dose and blood oxygenation level dependent (BOLD) contamination are two important issues for experimental design and CBV quantification. Both BOLD and CBV-weighted fMRI are based upon the susceptibility effect, to which spin-echo and gradient-echo sequences have different sensitivities. In the present study, CBV-weighted fMRI was conducted using spin-echo and gradient-echo sequences at 9.4T by systematically changing the doses of contrast agent. Results suggest that BOLD contamination is a significant component in CBV-weighted fMRI at high field, particularly when relatively low dose of contrast agent is administered. A mathematical model was developed to quantify the extravascular (EV) BOLD effect. With a TE of 35 ms, the EV BOLD effect was estimated to account for 76 +/- 12% of the observed spin-echo fMRI signal at 9.4T. These data suggest that correcting BOLD effect may be necessary for accurately quantifying activation-induced CBV changes at high field. C1 Natl Inst Drug Abuse, Neuroimaging Res Branch, NIH, Baltimore, MD 21224 USA. RP Lu, H (reprint author), Natl Inst Drug Abuse, Neuroimaging Res Branch, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM luha@intra.nida.nih.gov RI Stein, Elliot/C-7349-2008 FU Intramural NIH HHS NR 20 TC 26 Z9 26 U1 2 U2 2 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 SEP PY 2007 VL 58 IS 3 BP 616 EP 621 DI 10.1002/mrm.21354 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 207OK UT WOS:000249260200023 PM 17763339 ER PT J AU Wodarz, D Hamer, DH AF Wodarz, Dominik Hamer, Dean H. TI Infection dynamics in HIV-specific CD4 T cells: Does a CD4 T cell boost benefit the host or the virus? SO MATHEMATICAL BIOSCIENCES LA English DT Article DE HIV; dynamics; mathematical models; CD4 T cells; vaccination ID ACTIVE ANTIRETROVIRAL THERAPY; PROLIFERATION PROGRAM; CD8-T-CELL MEMORY; CD4-T-CELL HELP; VIRAL DYNAMICS; RESPONSES; LYMPHOCYTE; VIREMIA; MODELS; DIFFERENTIATION AB Recent experimental data have shown that HIV-specific CD4 T cells provide a very important target for HIV replication. We use mathematical models to explore the effect of specific CD4 T cell infection on the dynamics of virus spread and immune responses. Infected CD4 T cells can provide antigen for their own stimulation. We show that such autocatalytic cell division can significantly enhance virus spread, and can also provide an additional reservoir for virus persistence during anti-viral drug therapy. In addition, the initial number of HIV-specific CD4 T cells is an important determinant of acute infection dynamics. A high initial number of HIV-specific CD4 T cells can lead to a sudden and fast drop of the population of HIV-specific CD4 T cells which results quickly in their extinction. On the other hand, a low initial number of HIV-specific CD4 T cells can lead to a prolonged persistence of HIV-specific CD4 T cell help at higher levels. The model suggests that boosting the population of HIV-specific CD4 T cells can increase the amount of virus-induced immune impairment, lead to less efficient anti-viral effector responses, and thus speed up disease progression, especially if effector responses such as CTL have not been sufficiently boosted at the same time. (C) 2007 Elsevier Inc. All rights reserved. C1 Univ Calif Irvine, Dept Ecol & Evolutionary Biol, Irvine, CA 92697 USA. NCI, DDR, Biochem Lab, Bethesda, MD USA. RP Wodarz, D (reprint author), Univ Calif Irvine, Dept Ecol & Evolutionary Biol, 321 Steinhaus Hall, Irvine, CA 92697 USA. EM dwodarz@uci.edu FU NIAID NIH HHS [R01 AI058153-02, R01 AI058153, 1R01AI058153-01A2] NR 32 TC 11 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0025-5564 J9 MATH BIOSCI JI Math. Biosci. PD SEP PY 2007 VL 209 IS 1 BP 14 EP 29 DI 10.1016/j.mbs.2007.01.007 PG 16 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 211GC UT WOS:000249511300002 PM 17379260 ER PT J AU Theruvathu, JA Jaruga, P Dizdaroglu, M Brooks, PJ AF Theruvathu, Jacob A. Jaruga, Pawel Dizdaroglu, Miral Brooks, P. J. TI The oxidatively induced DNA lesions 8,5'-cyclo-2'-deoxyadenosine and 8-hydroxy-2'-deoxyadenosine are strongly resistant to acid-induced hydrolysis of the glycosidic bond SO MECHANISMS OF AGEING AND DEVELOPMENT LA English DT Article DE xeroderma pigmentosum; neurodegeneration; DNA repair; oxidative stress ID CHROMATOGRAPHY MASS-SPECTROMETRY; HUMAN-CELLS; XERODERMA-PIGMENTOSUM; GENE-EXPRESSION; REPAIR PATHWAY; ABASIC SITES; BASE DAMAGE; DHFR GENE; IN-VITRO; EXCISION AB The 8,5'-cyclopurine-2-deoxynucleosides (cPu) are unique oxidatively induced DNA lesions in that they are specifically repaired by NER. In the absence of NER, a possible mechanism for cPu removal is spontaneous glycosidic bond hydrolysis followed by enzymic processing. Such a mechanism could be significant if the glycosidic bond in cPu were substantially destabilized, as shown for other DNA lesions. Therefore, we investigated the stability of the glycosidic bond in a cPu, (5'S)-8,5-cyclo-2'-deoxyadenosine (S-cdA) against acid hydrolysis. For comparison, we also studied 8-hydroxy-2-deoxyadenosine (8-OH-dA). We found that the glycosidic bond in S-cdA is approximate to 40-fold more resistant to glycosidic bond hydrolysis compared to dA. Interestingly, under the same conditions, the glycosidic bond in 8-OH-dA was even more stable than in S-cdA. These studies effectively rule out any mechanism for the removal of S-cdA or 8-OH-dA from DNA that requires spontaneous glycosidic bond hydrolysis, and further support the proposed role of cPu in the neurodegeneration observed in xeroderma pigmentosum patients who lack NER. Of broader significance, since NER does not function in non-transcribed DNA sequences of terminally differentiated cells, including neurons, cPu are expected to accumulate in such sequences even in individuals with normal NER, which could be important in the ageing process. Published by Elsevier Ireland Ltd. C1 NIAAA, Mol Neurobiol Sect, Neurogenet Lab, Bethesda, MD 20952 USA. Univ Maryland, Dept Chem & Biochem Engn, Baltimore, MD 21250 USA. Nicholas Copernicus Univ, Coll Med, Dept Clin Biochem, Bydgoszcz, Poland. NIST, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. RP Brooks, PJ (reprint author), NIAAA, Mol Neurobiol Sect, Neurogenet Lab, 5625 Fishers Lane,Room 3S-32,MSC 9412, Bethesda, MD 20952 USA. EM pjbrooks@mail.nih.gov RI Jaruga, Pawel/M-4378-2015 FU Intramural NIH HHS [Z01 AA000083-14, Z99 AA999999] NR 40 TC 19 Z9 19 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0047-6374 J9 MECH AGEING DEV JI Mech. Ageing Dev. PD SEP PY 2007 VL 128 IS 9 BP 494 EP 502 DI 10.1016/j.mad.2007.06.006 PG 9 WC Cell Biology; Geriatrics & Gerontology SC Cell Biology; Geriatrics & Gerontology GA 218LL UT WOS:000250016900003 PM 17692895 ER PT J AU Holmes-Rovner, M Nelson, WL Pignone, M Elwyn, G Rovner, DR O'Connor, AM Coulter, A Correa-De-Araujo, R AF Holmes-Rovner, Margaret Nelson, Wndy L. Pignone, Michael Elwyn, Glyn Rovner, David R. O'Connor, Annette M. Coulter, Angela Correa-de-Araujo, Rosaly TI Are patient decision aids the best way to improve clinical decision making? Report of the IPDAS symposium SO MEDICAL DECISION MAKING LA English DT Article; Proceedings Paper CT 26th Annual Meeting of the Society-for-Medical-Decision-Making CY OCT 17-20, 2004 CL Atlanta, GA SP Soc Med Decis Making ID PATIENTS PREFERENCES; SUPPORT FRAMEWORK; CARE OUTCOMES; THINKING TOO; INTROSPECTION; INFORMATION; CRITERIA; THERAPY; QUALITY; ISSUES AB This article reports on the International Patient Decision Aid Standards Symposium held in 2006 at the annual meeting of the Society for Medical Decision Making in Cambridge, Massachusetts. The symposium featured a debate regarding the proposition that "decision aids are the best way to improve clinical decision making." The formal debate addressed the theoretical Problem of the appropriate gold standard for an improved decision, efficacy of decision aids, and prospects for implementation. Audience comments and questions focused on both theory and practice: the often unacknowledged roots of decision aids in expected utility theory and the practical problems of limited patient decision aid implementation in health care. The participants' vote on the proposition was approximately half for and half against. C1 Michigan State Univ, Hlth Serv Res, Ctr Eth & Humanities Life Sci, Coll Human Med, E Lansing, MI 48824 USA. Natl Canc Inst, Div Canc Control & Populat Sci, Behav Res Program, Bethesda, MD USA. Univ N Carolina, Chapel Hill, NC USA. Univ Cardiff, Dept Primary Care & Publ Hlth, Cardiff, Wales. Univ Ottawa, Ottawa, ON K1N 6N5, Canada. Ottawa Hlth Res Inst, Ottawa, ON, Canada. Picker Inst Europe, Oxford, England. Off Global Hlth Affairs, Dept Hlth & Human Serv, Rockville, MD USA. RP Holmes-Rovner, M (reprint author), Michigan State Univ, Hlth Serv Res, Ctr Eth & Humanities Life Sci, Coll Human Med, C203 E Fee Hall, E Lansing, MI 48824 USA. EM mholmes@msu.edu RI Elwyn, Glyn/B-4798-2009; Elwyn, G./L-4292-2015; OI Elwyn, Glyn/0000-0002-0917-6286; Coulter, Angela/0000-0002-6308-8375; Pignone, Michael/0000-0002-6657-7342 FU AHRQ HHS [1 R13 HS016486-01] NR 51 TC 33 Z9 33 U1 3 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X EI 1552-681X J9 MED DECIS MAKING JI Med. Decis. Mak. PD SEP-OCT PY 2007 VL 27 IS 5 BP 599 EP 608 DI 10.1177/0272989x07307272 PG 10 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 223BS UT WOS:000250345200010 PM 17873257 ER PT J AU Nelson, WL Han, PKJ Fagerlin, A Stefanek, M Ubel, PA AF Nelson, Wendy L. Han, Paul K. J. Fagerlin, Angela Stefanek, Michael Ubel, Peter A. TI Rethinking the objectives of decision aids: A call for conceptual clarity SO MEDICAL DECISION MAKING LA English DT Article ID RANDOMIZED CONTROLLED-TRIAL; QUALITY-OF-LIFE; BREAST-CANCER; MECHANICAL VENTILATION; TREATMENT PREFERENCES; POSTMENOPAUSAL WOMEN; HORMONE-THERAPY; PROSTATE-CANCER; DURABILITY BIAS; HEALTH VALUES AB Health decision aids are a potentially valuable adjunct to patient-physician communication and decision making. Although the overarching goal of decision aids to help patients make informed, preference-sensitive choices-is widely accepted, experts do not agree on the means to achieve this end. In this article, the authors critically examine the theoretical basis and appropriateness of 2 widely accepted criteria used to evaluate decision aids: values clarification and reduction of decisional conflict. First, they argue that although clarifying values is central to decision making under uncertainty, it is not clear that decision aids-as they have been be used to achieve this goal, The pursuit of clarifying values, particularly values clarification exercises, raises a number of ethical, methodological, and conceptual issues, and the authors suggest research questions that should be addressed before values clarification is routinely endorsed. Second, the authors argue that the goal of reducing, decisional conflict is conceptually untenable and propose that it be eliminated as an objective of decision aids. C1 NCI, NIH, Div Canc Control & Populat Sci, Basic & Biobehav Res Branch,Behav Res Program, Bethesda, MD 20892 USA. VA Ann Arbor Healthcare Syst, VA Hlth Serv Res & Dev Ctr Practice Management &, Ann Arbor, MI USA. Univ Michigan, Div Gen Internal Med, Ann Arbor, MI 48109 USA. Ctr Behav & Decis Sci Med, Ann Arbor, MI 48109 USA. Amer Canc Soc, Behav Res Ctr, Atlanta, GA 30329 USA. RP Nelson, WL (reprint author), NCI, NIH, Div Canc Control & Populat Sci, Basic & Biobehav Res Branch,Behav Res Program, 6130 Execut Blvd,MSC 7363, Bethesda, MD 20892 USA. EM nelsonw@mail.nih.gov OI Han, Paul/0000-0003-0165-1940 FU NCI NIH HHS [R01 CA87595] NR 93 TC 56 Z9 56 U1 2 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X J9 MED DECIS MAKING JI Med. Decis. Mak. PD SEP-OCT PY 2007 VL 27 IS 5 BP 609 EP 618 DI 10.1177/0272989x07306780 PG 10 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 223BS UT WOS:000250345200011 PM 17873251 ER PT J AU Politi, MC Han, PKJ Col, NF AF Politi, Mary C. Han, Paul K. J. Col, Nananda F. TI Communicating the uncertainty of harms and benefits of medical interventions SO MEDICAL DECISION MAKING LA English DT Review ID INFORMED DECISION-MAKING; BREAST-CANCER; INDIVIDUAL-DIFFERENCES; PERCEIVED AMBIGUITY; RISK PERCEPTION; HEALTH-CARE; PROBABILITY; INFORMATION; PREFERENCES; PREVENTION AB Background. There is growing interest in shared medical decision making among patients, physicians, and policy makers. This requires patients to interpret increasing amounts Of medical information, much of which is uncertain. Little is known about the optimal approaches to or outcomes of communicating uncertainty about the risks and benefits of treatments. Methods. The authors reviewed the literature on various issues related to uncertainty in decision making: conceptualizing uncertainty, identifying its potential sources, assessing uncertainty, potential methods of communicating uncertainty potential outcomes of communicating uncertainty, and current practices and recommendations by expert groups on communicating uncertainty. Results. There are multiple sources of uncertainty in most medical decisions. There are conceptual differences in how researchers define uncertainty and its sources, as well as in its measurement. The few studies that have assessed alternate means of communicating uncertainty dealt mostly with presenting uncertainty about probabilities. Both patients' and physicians' interpretation of and responses to uncertainty may depend on their personal characteristics and values and may be affected by the manner in which uncertainty is communicated. Conclusions. Research has not yet identified best practices for communicating uncertainty to patients about harms and benefits of treatment. More conceptual, qualitative, and quantitative studies are needed to explore fundamental questions about how people process, interpret, and respond to various types of uncertainty inherent in clinical decisions. C1 Brown Univ, Sch Med, Rhode Isl Hosp, Providence, RI 02912 USA. NCI, Appl Res Program, Div Canc Control & Populat Sci, Outcomes Res Branch, Rockville, MD USA. RP Col, NF (reprint author), Maine Med Ctr, Ctr Outcomes Res & Evaluat, 39 Forest Ave, Portland, ME 04101 USA. EM coln@mmc.org OI Politi, Mary/0000-0001-9103-6495; Han, Paul/0000-0003-0165-1940 FU PHS HHS [HHSA29020050013C] NR 108 TC 136 Z9 137 U1 5 U2 21 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0272-989X J9 MED DECIS MAKING JI Med. Decis. Mak. PD SEP-OCT PY 2007 VL 27 IS 5 BP 681 EP 695 DI 10.1177/0272989x07307270 PG 15 WC Health Care Sciences & Services; Medical Informatics SC Health Care Sciences & Services; Medical Informatics GA 223BS UT WOS:000250345200019 PM 17873256 ER PT J AU Moaddel, R Jozwiak, K Wainer, IW AF Moaddel, Ruin Jozwiak, Krzyztof Wainer, Iraing W. TI Allosteric modifiers of neuronal nicotinic acetylcholine receptors: New methods, new opportunities SO MEDICINAL RESEARCH REVIEWS LA English DT Article DE affinity chromatography; molecular modeling; non-competitive inhibition; quinacrine-binding site; ethidium-binding site ID CHROMATOGRAPHIC STATIONARY PHASES; IMMOBILIZED P-GLYCOPROTEIN; PROTEIN-COUPLED RECEPTOR; NONCOMPETITIVE INHIBITORS; AFFINITY-CHROMATOGRAPHY; CONFORMATIONAL MOBILITY; LIQUID-CHROMATOGRAPHY; DRUG DISCOVERY; BINDING-SITES; ALPHA-3-BETA-4 AB Allosteric, non-competitive inhibitors (NCIs) of neuronal nicotinic acetylcholine receptors (nAChRs) have been shown to produce a wide variety of clinically relevant responses. Many of the observed effects are desired as the nAChR is the therapeutic target, while others are undesired consequences due to off-target binding at the nAChR. Thus, the determination of whether or not a lead drug candidate is an NCI should play an important role in drug discovery programs. However, the current experimental techniques used to identify NCIs are challenging, expensive, and time consuming. This review focuses on an alternative approach to the investigation of interactions between test compounds and nAChRs based upon liquid chromatographic stationary phases containing cellular fragments from cell lines expressing nAChRs. The development and validation of these phases as well as their use in drug discovery and pharmacophore modeling are discussed. (c) 2007 Wiley Periodicals, Inc. C1 NIA, Bioanalyt & Drug Discovery Unit, Gerontol Res Ctr, NIH,Lab Clin Investigat, Baltimore, MD 21224 USA. Med Univ Lublin, Dept Chem, Lublin, Poland. RP Wainer, IW (reprint author), NIA, Bioanalyt & Drug Discovery Unit, Gerontol Res Ctr, NIH,Lab Clin Investigat, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM Wainerir@grc.nia.nih.gov FU Intramural NIH HHS NR 76 TC 25 Z9 25 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0198-6325 J9 MED RES REV JI Med. Res. Rev. PD SEP PY 2007 VL 27 IS 5 BP 723 EP 753 DI 10.1002/med.20091 PG 31 WC Chemistry, Medicinal; Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 201VS UT WOS:000248861300006 PM 17238157 ER PT J AU Troiano, RP AF Troiano, Richard P. TI Large-scale applications of accelerometers: New frontiers and new questions SO MEDICINE AND SCIENCE IN SPORTS AND EXERCISE LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. RP Troiano, RP (reprint author), NCI, Bethesda, MD 20892 USA. OI Troiano, Richard/0000-0002-6807-989X NR 8 TC 39 Z9 39 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0195-9131 J9 MED SCI SPORT EXER JI Med. Sci. Sports Exerc. PD SEP PY 2007 VL 39 IS 9 BP 1501 EP 1501 DI 10.1097/mss.0b013e318150d42e PG 1 WC Sport Sciences SC Sport Sciences GA 210GW UT WOS:000249445700009 PM 17805080 ER PT J AU Fiehn, O Robertson, D Griffin, J van der Werf, M Nikolau, B Morrison, N Sumner, LW Goodacre, R Hardy, NW Taylor, C Fostel, J Kristal, B Kaddurah-Daouk, R Mendes, P van Ommen, B Lindon, JC Sansone, SA AF Fiehn, Oliver Robertson, Don Griffin, Jules van der Werf, Mariet Nikolau, Basil Morrison, Norman Sumner, Lloyd W. Goodacre, Roy Hardy, Nigel W. Taylor, Chris Fostel, Jennifer Kristal, Bruce Kaddurah-Daouk, Rima Mendes, Pedro van Ommen, Ben Lindon, John C. Sansone, Susanna-Assunta TI The metabolomics standards initiative (MSI) SO METABOLOMICS LA English DT Article DE standardization; metabolomics; metabonomics; metabolite profiling; databases ontology ID GENOMICS; WORK AB In 2005, the Metabolomics Standards Initiative has been formed. An outline and general introduction is provided to inform about the history, structure, working plan and intentions of this initiative. Comments on any of the suggested minimal reporting standards are welcome to be sent to the open email list Msi-workgroups-feedback@lists.sourceforge.net C1 Univ Calif Davis, Genome Ctr, Davis, CA 95616 USA. Pfizer Global Res & Dev, Mol Profiling, Ann Arbor, MI 48105 USA. Univ Cambridge, Dept Biochem, Cambridge CB2 1QW, England. TNO Qual Life, Zeist, Netherlands. Iowa State Univ, Ames, IA USA. Univ Manchester, Sch Comp Sci, Manchester M13 9PL, Lancs, England. NERC, Environm Bioinformat Ctr, Oxford Ctr Ecol & Hydrol, Oxford OX1 3SR, England. Samuel Roberts Noble Fdn Inc, Ardmore, OK USA. Univ Manchester, Sch Chem, Manchester, Lancs, England. Univ Coll Wales, Dept Comp Sci, Aberystwyth SY23 3DB, Dyfed, Wales. EMBL EBI European Bioinformat Inst, Cambridge CB10 1SD, England. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Neurosurg, Boston, MA 02115 USA. Duke Univ, Dept Psychiat & Behav Sci, Durham, NC USA. Virginia Bioinformat Inst, Blacksburg, VA USA. Univ London Imperial Coll Sci Technol & Med, Dept Biomol Med, London SW7 2AZ, England. RP Fiehn, O (reprint author), Univ Calif Davis, Genome Ctr, Davis, CA 95616 USA. EM ofiehn@ucdavis.edu RI Goodacre, Roy/J-1600-2012; Sumner, Lloyd/A-3270-2013; Smith, Barry/A-9525-2011; OI Goodacre, Roy/0000-0003-2230-645X; Smith, Barry/0000-0003-1384-116X; Sansone, Susanna-Assunta/0000-0001-5306-5690 NR 13 TC 122 Z9 124 U1 7 U2 63 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1573-3882 J9 METABOLOMICS JI Metabolomics PD SEP PY 2007 VL 3 IS 3 BP 175 EP 178 DI 10.1007/s11306-007-0070-6 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 217JZ UT WOS:000249945500001 ER PT J AU van der Werf, MJ Takors, R Smedsgaard, J Nielsen, J Ferenci, T Portais, JC Wittmann, C Hooks, M Tomassini, A Oldiges, M Fostel, J Sauer, U AF van der Werf, Mariet J. Takors, Ralf Smedsgaard, Jorn Nielsen, Jens Ferenci, Tom Portais, Jean Charles Wittmann, Christoph Hooks, Mark Tomassini, Alberta Oldiges, Marco Fostel, Jennifer Sauer, Uwe TI Standard reporting requirements for biological samples in metabolomics experiments: microbial and in vitro biology experiments SO METABOLOMICS LA English DT Article DE microbiology; in vitro biology; metabolomics; minimal reporting standards; sample context ID PLANT METABOLOMICS AB With the increasing use of metabolomics as a means to study a large number of different biological research questions, there is a need for a minimal set of reporting standards that allow the scientific community to evaluate, understand, repeat, compare and re-investigate metabolomics studies. Here we propose, a first draft of minimal requirements to effectively describe the biological context of metabolomics studies that involve microbial or in vitro biological subjects. This recommendation has been produced by the microbiology and in vitro biology working subgroup of the Metabolomics Standards Initiative in collaboration with the yeast systems biology network as part of a wider standardization initiative led by the Metabolomics Society. Microbial and in vitro biology metabolomics is defined by this sub-working group as studies with any cell or organism that require a defined external medium to facilitate growth and propagation. Both a minimal set and a best practice set of reporting standards for metabolomics experiments have been defined. The minimal set of reporting standards for microbial or in vitro biology metabolomics experiments includes those factors that are specific for metabolomics experiments and that critically determine the outcome of the experiments. The best practice set of reporting standards contains both the factors that are specific for metabolomics experiments and general aspects that critically determine the outcome of any microbial or in vitro biological experiment. C1 TNO Qual Life, Dept Microbiol, Zeist, Netherlands. Degussa AG, Hanau, Germany. Tech Univ Denmark, Ctr Microbial Biotechnol, DK-2800 Lyngby, Denmark. Univ Sydney, Sydney, NSW 2006, Australia. Inst Natl Sci Appl, Biosyst Adn Proc Engn Lab, F-31077 Toulouse, France. Univ Saarland, Syst Biotechnol Grp, D-6600 Saarbrucken, Germany. Univ Coll N Wales, Sch Biol Sci, Bangor LL57 2UW, Gwynedd, Wales. Sigma Tau Pharmaceut Co, Sci Dept, Rome, Italy. Forschungszentrum Julich, D-5170 Julich, Germany. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. ETH, Inst Mol Syst Biol, Zurich, Switzerland. RP van der Werf, MJ (reprint author), TNO Qual Life, Dept Microbiol, POB 360, Zeist, Netherlands. EM Mariet.vanderwerf@tno.n1; ralf.takors@degussa.com; js@biocentrum.dtu.dk; jn@biocentrum.dtu.dk; t.ferenci@microbio.usyd.edu.au; jean-charles.portais@insa-toulouse.fr; e.wittmann@mx.uni-saarland.de; bss606@bangro.ac.uk; alfredo.miccheli@uniromal.it; m.oldiges@fz-juelich.de; Fostel@niehs.nih.gov; sauer@imsb.biol.ethz.ch RI Ferenci, Tom/A-1177-2010; Oldiges, Marco/C-8871-2013; OI Wittmann, Christoph/0000-0002-7952-985X; Oldiges, Marco/0000-0003-0704-5597 NR 11 TC 23 Z9 23 U1 4 U2 30 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1573-3882 J9 METABOLOMICS JI Metabolomics PD SEP PY 2007 VL 3 IS 3 BP 189 EP 194 DI 10.1007/s11306-007-0080-4 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 217JZ UT WOS:000249945500003 ER PT J AU Wang, CZ Li, M Dong, D Wang, JP Ren, J Otto, M Gao, Q AF Wang, Chongzhen Li, Min Dong, Dandan Wang, Jianping Ren, Jun Otto, Michael Gao, Qian TI Role of ClpP in biofilm formation and virulence of Staphylococcus epidermidis SO MICROBES AND INFECTION LA English DT Article DE Staphylococcus epidermidis; biofilms; ClpP protease ID ESCHERICHIA-COLI; STRESS TOLERANCE; PROTEASES; AUREUS; DEGRADATION; PROTEINS; INSIGHTS AB Infections caused by the leading nosocomial pathogen Staphylococcus epidermidis are characterized by biofilm formation on implanted medical devices. However, the molecular basis of biofilm formation and its regulation are not completely understood. Here, we describe an important role of the ClpP protease in biofilm development and virulence of S. epidermidis. We constructed an isogenic clpP mutant strain of a biofilm-forming clinical isolate of S. epidermidis. The mutant strain showed decreased biofilm formation in vitro and reduced virulence in a rat model of biofilm-associated infection. Biofilm forming ability of the mutant strain could be restored by expressing clpP on a plasmid, but not when a catalytically inactive allele of clpP gene was introduced. These observations indicate that the peptidase function of ClpP determines its role in biofilm formation. Experimental data in this work also suggested that clpP influenced initial attachment of bacteria on the plastic surface, the first step of biofilm formation. Furthermore, clpP was found to be regulated by the quorum-sensing agr, suggesting that part of the previously described influence of agr on the initial attachment to plastic surfaces may be mediated by clpP. (C) 2007 Elsevier Masson SAS. All rights reserved. C1 Fudan Univ, Shanghai Med Coll, Key Lab Med Mol Virol, Shanghai 200433, Peoples R China. Fudan Univ, Inst Med Microbiol, Shanghai 200433, Peoples R China. Fudan Univ, Inst Biomed Sci, Shanghai 200433, Peoples R China. NIAID, Rocky Mt Lab, Natl Inst Hlth, Hamilton, MT 59840 USA. RP Gao, Q (reprint author), Fudan Univ, Shanghai Med Coll, Key Lab Med Mol Virol, 138 Yi Xue Yuan Rd, Shanghai 200433, Peoples R China. EM qgao99@yahoo.com OI Otto, Michael/0000-0002-2222-4115 NR 30 TC 42 Z9 45 U1 2 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1286-4579 J9 MICROBES INFECT JI Microbes Infect. PD SEP PY 2007 VL 9 IS 11 BP 1376 EP 1383 DI 10.1016/j.micinf.2007.06.012 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 231LS UT WOS:000250948900017 PM 17890122 ER PT J AU Rasooly, A Sergeev, N Herold, KE AF Rasooly, A. Sergeev, N. Herold, K. E. TI Biosensor technologies for microbial and environmental analysis SO MINERVA BIOTECNOLOGICA LA English DT Article DE biosensing techniques; surface plasmon resonance; resonant crystal ID SURFACE-PLASMON RESONANCE; STAPHYLOCOCCAL-ENTEROTOXIN-B; ESCHERICHIA-COLI O157-H7; PHAGE-DISPLAYED PEPTIDES; OPTIC-BASED BIOSENSOR; ARRAY BIOSENSOR; ELECTROCHEMICAL BIOSENSORS; REAL-TIME; SALMONELLA-TYPHIMURIUM; RAPID IDENTIFICATION AB Microbial and environmental analysis, including the identification and characterization of contaminants, microbial pathogens and their toxins, is critical in many environmental and health-related settings. Biosensors are currently being developed for a wide range of environmental and microbial diagnostic applications. The term "biosensor" is defined by the international Union of Pure and Applied Chemistry (IUFAC) as a "device that uses specific biochemical reactions mediated by isolated enzymes, immunosystems, tissues, organelles or whole cells to detect chemical compounds usually by electrical, thermal or optical signals". In general, biosensors consist of two main components: a biological recognition element and a signal conversion unit (transducer). Numerous types of biosensors have been developed and the design variations are growing, at a rapid rate. Biosensors enable fast detection, portability and versatility for both field and laboratory applications. Biosensors provide several advantages over standard methods of environmental and microbial diagnostics with the primary benefits being assay speed, miniaturization, sensitivity, and low sample volume needed for analysis. The paper describes various biosensors and biosensor applications for microbial and environmental analysis and the expected future trends in the technology. C1 [Rasooly, A.] NCI, Canc Diag Program, DCTD, NIH, Rockville, MD 20852 USA. [Rasooly, A.; Sergeev, N.] US FDA, Ctr Devices & Radiol Hlth, Silver Spring, MD USA. [Herold, K. E.] Univ Maryland, Dept Bioengn, College Pk, MD 20742 USA. RP Rasooly, A (reprint author), NCI, Canc Diag Program, DCTD, NIH, EPN 6035A,6130 Execut Blvd, Rockville, MD 20852 USA. EM rasoolya@mail.nih.gov NR 75 TC 0 Z9 0 U1 1 U2 1 PU EDIZIONI MINERVA MEDICA PI TURIN PA CORSO BRAMANTE 83-85 INT JOURNALS DEPT., 10126 TURIN, ITALY SN 1120-4826 J9 MINERVA BIOTECNOL JI Minerva Biotechnol. PD SEP PY 2007 VL 19 IS 3 BP 105 EP 116 PG 12 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 333JA UT WOS:000258147600004 ER PT J AU Jin, XJ Zhang, JJ Gao, YN Ding, KY Wang, NS Zhou, D Jen, J Cheng, SJ AF Jin, Xiongjie Zhang, Jianjun Gao, Yanning Ding, Keyue Wang, Naishu Zhou, David Jen, Jin Cheng, Shujun TI Relationship between mitochondrial DNA mutations and clinical characteristics in human lung cancer SO MITOCHONDRION LA English DT Article DE mitochondrial DNA; mutation; lung cancer ID PROSTATE-CANCER; MICROSATELLITE INSTABILITY; HEPATOCELLULAR-CARCINOMA; THYROID CARCINOMAS; MTDNA MUTATIONS; BREAST-CANCER; NUCLEAR-DNA; CELL-LINES; GENOME; SEQUENCE AB Mitochondrial DNA (mtDNA) is known for its high frequencies of polymorphisms and mutations, some of which are related to various diseases, including cancers. However, roles of mutations and polymorphisms in some diseases are among heated debate, especially for cancer. To investigate the possible role of mtDNA mutations in lung cancer, we sequenced complete mtDNA of lung cancer tissues, corresponding normal (i.e., non-cancerous) lung tissues, and peripheral blood samples from 55 lung cancer patients and examined the relationship between mtDNA mutations or polymorphisms and clinical parameters. We identified 56 mutations in 33 (60%) of the 55 patients, including 48 point initiations, four single-nucleotide insertions, and four single-nucleotide deletions. Nineteen of these mutations resulted in amino acid substitution. These missense mtDNA mutations were distributed in 9 of 13 mitochondrial DNA coding genes. Three hundred eighty eight polymorphisms were identified among the 55 patients. Seventy-three polymorphisms resulted in amino acid substitution. There was no association of incidence of specific mtDNA mutation or polymorphism with patients' gender, age at diagnosis, smoking history, tumor type or tumor stage (P > 0.05). This study revealed a variety of mtDNA mutations and mtDNA polymorphisms in human lung cancer, some of which might be involved in human lung carcinogenesis. (c) 2007 Elsevier B.V. and Mitochondria Research Society. All rights reserved. C1 Chinese Acad Med Sci, Peking Union Med Coll, Canc Inst Hosp, Dept Etiol & Carcinogen, Beijing 100021, Peoples R China. Chinese Natl Human Genom Ctr, Beijing 100176, Peoples R China. Chinese Acad Med Sci, Peking Union Med Coll, Inst Basic Med Sci, Natl Lab Med Mol Biol, Beijing 100037, Peoples R China. NCI, Canc Res Ctr, Lab Populat Genet, Bethesda, MD 20892 USA. RP Cheng, SJ (reprint author), Chinese Acad Med Sci, Peking Union Med Coll, Canc Inst Hosp, Dept Etiol & Carcinogen, PO Box 2258, Beijing 100021, Peoples R China. EM chengshj@263.net.cn NR 42 TC 26 Z9 30 U1 0 U2 1 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 SEP PY 2007 VL 7 IS 5 BP 347 EP 353 DI 10.1016/j.mito.2007.06.003 PG 7 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 217RG UT WOS:000249964400007 PM 17707697 ER PT J AU Martin-Marcos, P Hinnebusch, AG Tamame, M AF Martin-Marcos, Pilar Hinnebusch, Alan G. Tamame, Mercedes TI Ribosomal protein L33 is required for ribosome biogenesis, subunit joining, and repression of GCN4 translation SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID ACID BIOSYNTHETIC GENES; METHIONYL-TRANSFER-RNA; SACCHAROMYCES-CEREVISIAE; PRE-RIBOSOMES; PEPTIDYLTRANSFERASE ACTIVITY; FUNCTIONAL-CHARACTERIZATION; IN-VIVO; YEAST; IDENTIFICATION; MATURATION AB We identified a mutation in the 60S ribosomal protein L33A (rpl33a-G76R) that elicits derepression of GCN4 translation (Gcd(-) phenotype) by allowing scanning preinitiation complexes to bypass inhibitory upstream open reading frame 4 (uORF4) independently of prior uORF1 translation and reinitiation. At 37 degrees C, rPl33a-G76R confers defects in 60S biogenesis comparable to those produced by the deletion of RPL33A (Delta A). At 28 degrees C, however, the 60S biogenesis defect is less severe in rpl33a-G76R than in Delta A cells, yet rpl33a-G76R confers greater derepression of GCN4 and a larger reduction in general translation. Hence, it appears that rpl33a-G76R has a stronger effect on ribosomal-subunit joining than does a comparable reduction of wild-type 60S levels conferred by Delta A. We suggest that rpl33a-G76R alters the 60S subunit in a way that impedes ribosomal-subunit joining and thereby allows 48S rRNA complexes to abort initiation at uORF4, resume scanning, and initiate downstream at GCN4. Because overexpressing tRNA(i)(Met) suppresses the Gcd(-) phenotype of rpl33a-G76R cells, dissociation of tRNA(i)(MET) from the 40S subunit may be responsible for abortive initiation at uORF4 in this mutant. We further demonstrate that rpl33a-G76R impairs the efficient processing of 35S and 27S pre-rRNAs and reduces the accumulation of all four mature rRNAs, indicating an important role for L33 in the biogenesis of both ribosomal subunits. C1 Univ Salamanca, CSIC, Inst Microbiol Bioquim, Edificio Departamental Biol, Salamanca 37007, Spain. NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. RP Tamame, M (reprint author), Univ Salamanca, CSIC, Inst Microbiol Bioquim, Edificio Departamental Biol, Campus Miguel Unamuno, Salamanca 37007, Spain. EM tamame@usal.es NR 77 TC 32 Z9 32 U1 1 U2 3 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 SEP PY 2007 VL 27 IS 17 BP 5968 EP 5985 DI 10.1128/MCB.00019-07 PG 18 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 203MQ UT WOS:000248979100004 PM 17548477 ER PT J AU Furuya, F Guigon, CJ Zhao, L Lu, C Hanover, JA Cheng, SY AF Furuya, Fumihiko Guigon, Celine J. Zhao, Li Lu, Changxue Hanover, John A. Cheng, Sheue-Yann TI Nuclear receptor corepressor is a novel regulator of phosphatidylinositol 3-kinase signaling SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID THYROID-HORMONE RECEPTOR; BETA-RECEPTOR; MOUSE MODEL; AKT ACTIVATION; KAPPA-B; EXPRESSION; RESISTANCE; GENE; CARCINOMA; CARCINOGENESIS AB The nuclear receptor corepressor (NCoR) regulates the activities of DNA-binding transcription factors. Recent observations of its distribution in the extranuclear compartment raised the possibility that it could have other cellular functions in addition to transcription repression. We previously showed that phosphatidylinositol 3-kinase (PI3K) signaling is aberrantly activated by a mutant thyroid hormone P receptor (TR beta PV, hereafter referred to as PV) via physical interaction with p85 alpha, thus contributing to thyroid carcinogenesis in a mouse model of follicular thyroid carcinoma (TR beta(PV/PV) mouse). Since NCoR is known to modulate the actions of TR beta mutants in vivo and in vitro, we asked whether NCoR regulates PV-activated PI3K signaling. Remarkably, we found that NCoR physically interacted with and competed with PV for binding to the C-terminal SH2 (Src homology 2) domain of p85 alpha, the regulatory subunit of PI3K. Confocal fluorescence microscopy showed that both NCoR and p85 alpha were localized in the nuclear as well as in the cytoplasmic compartments. Overexpression of NCoR in thyroid tumor cells of TR beta(PV/PV) mouse reduced PI3K signaling, as indicated by the decrease in the phosphorylation of its immediate downstream effector, p-AKT. Conversely, lowering cellular NCoR by siRNA knockdown in tumor cells led to overactivated p-AKT and increased cell proliferation and motility. Furthermore, NCoR protein levels were significantly lower in thyroid tumor cells than in wild-type thyrocytes, allowing more effective binding of PV to p85 alpha to activate PI3K signaling and thus contributing to tumor progression. Taken together, these results indicate that NCoR, via protein-protein interaction, is a novel regulator of PI3K signaling and could serve to modulate thyroid tumor progression. C1 NCI, Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. NIDDK, Lab Cellular Biochem & Biol, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, 37 Convent Dr,Room 5128, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov FU Intramural NIH HHS NR 24 TC 24 Z9 25 U1 1 U2 3 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 SEP PY 2007 VL 27 IS 17 BP 6116 EP 6126 DI 10.1128/MCB.00900-07 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 203MQ UT WOS:000248979100015 PM 17606624 ER PT J AU Pullmann, R Kim, HH Abdelmohsen, K Lal, A Martindale, JL Yang, XL Gorospe, M AF Pullmann, Rudolf, Jr. Kim, Hyeon Ho Abdelmohsen, Kotb Lal, Ashish Martindale, Jennifer L. Yang, Xiaoling Gorospe, Myriam TI Analysis of turnover and translation regulatory RNA-Binding protein expression through binding to cognate mRNAs SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID AU-RICH ELEMENT; ACTIVATED T-CELLS; 3'-UNTRANSLATED REGION; TRANSCRIPTION FACTOR; STRESS GRANULES; GENE-EXPRESSION; HUR; TIA-1; PHOSPHORYLATION; DECAY AB RNA-binding proteins (RBPs) that associate with specific mRNA sequences and function as mRNA turnover and translation regulatory (TTR) RBPs are emerging as pivotal posttranscriptional regulators of gene expression. However, little is known about the mechanisms that govern the expression of TTR-RBPs. Here, we employed human cervical carcinoma HeLa cells to test the hypothesis that TTR-RBP expression is influenced posttranscriptionally by TTR-RBPs themselves. Systematic testing of the TTR-RBPs AUF1, HuR, KSRP, NF90, TIA-1, and TIAR led to three key discoveries. First, each TTR-RBP was found to associate with its cognate mRNA and with several other TTR-RBP-encoding mRNAs, as determined by testing both endogenous and biotinylated transcripts. Second, silencing of individual TTR-RBPs influenced the expression of other TTR-RBPs at the mRNA and/or protein level. Third, further analysis of two specific ribonucleoprotein (RNP) complexes revealed that TIA-1 expression was controlled via HuR-enhanced mRNA stabilization and TIAR-repressed translation. Together, our findings underscore the notion that TTR-RBP expression is controlled, at least in part, at the posttranscriptional level through a complex circuitry of self- and cross-regulatory RNP interactions. C1 NIA, Cellular & Mol Biol Lab, Intramural Res Program, NIH, Baltimore, MD 21228 USA. RP Gorospe, M (reprint author), NIA, LCMB, IRP, NIH, Box 12,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov OI abdelmohsen, Kotb/0000-0001-6240-5810 FU Intramural NIH HHS NR 64 TC 123 Z9 124 U1 0 U2 7 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 SEP PY 2007 VL 27 IS 18 BP 6265 EP 6278 DI 10.1128/MCB.00500-07 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 208KW UT WOS:000249319200001 PM 17620417 ER PT J AU Wagenaar-Miller, RA Engelholm, LH Gavard, J Yamada, SS Gutkind, JS Behrendt, N Bugge, TH Holmbeck, K AF Wagenaar-Miller, Rebecca A. Engelholm, Lars H. Gavard, Julie Yamada, Susan S. Gutkind, J. Silvio Behrendt, Niels Bugge, Thomas H. Holmbeck, Kenn TI Complementary roles of intracellular and pericellular collagen degradation pathways in vivo SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID MACROPHAGE MANNOSE RECEPTOR; MATRIX-METALLOPROTEINASE; MT1-MMP-DEFICIENT MICE; EXTRACELLULAR-MATRIX; DEVELOP DWARFISM; CANCER-THERAPY; PHAGOCYTOSIS; FIBROBLASTS; TURNOVER; CARTILAGE AB Collagen degradation is essential for cell migration, proliferation, and differentiation. Two key turnover pathways have been described for collagen: intracellular cathepsin-mediated degradation and pericellular collagenase-mediated degradation. However, the functional relationship between these two pathways is unclear and even controversial. Here we show that intracellular and pericellular collagen turnover pathways have complementary roles in vivo. Individual deficits in intracellular collagen degradation (urokinase plasminogen activator receptor-associated protein/Endo180 ablation) or pericellular collagen degradation (membrane type 1-matrix metalloproteinase ablation) were compatible with development and survival. Their combined deficits, however, synergized to cause postnatal death by severely impairing bone formation. Interestingly, this was mechanistically linked to the proliferative failure and poor survival of cartilage- and bone-forming cells within their collagen-rich microenvironment. These findings have important implications for the use of pharmacological inhibitors of collagenase activity to prevent connective tissue destruction in a variety of diseases. C1 Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. Rigshosp, Finsen Lab, Copenhagen Bioctr, DK-2200 Copenhagen, Denmark. RP Bugge, TH (reprint author), Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Unit, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Room 211, Bethesda, MD 20892 USA. EM kenn.holmbeck@nih.gov RI Gutkind, J. Silvio/A-1053-2009; Gavard, Julie/I-5487-2012; OI Gavard, Julie/0000-0002-7985-9007; Engelholm, Lars/0000-0002-6616-1232 FU Intramural NIH HHS NR 45 TC 51 Z9 53 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 SEP PY 2007 VL 27 IS 18 BP 6309 EP 6322 DI 10.1128/MCB.00291-07 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 208KW UT WOS:000249319200005 PM 17620416 ER PT J AU Wang, L Balas, B Christ-Roberts, CY Kim, RY Ramos, FJ Kikani, CK Li, C Deng, C Reyna, S Musi, N Dong, LQ DeFronzo, RA Liu, F AF Wang, Lixin Balas, Bogdan Christ-Roberts, Christine Y. Kim, Ryang Yeo Ramos, Fresnida J. Kikani, Chintan K. Li, Cuiling Deng, Chuxia Reyna, Sara Musi, Nicolas Dong, Lily Q. DeFronzo, Ralph A. Liu, Feng TI Peripheral disruption of the grb10 gene enhances insulin signaling and sensitivity in vivo SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID GROWTH-FACTOR I; ADAPTER PROTEIN; RESISTANCE; RECEPTOR; EXPRESSION; MEG1/GRB10; MECHANISM; PATHWAY; CLONING; DOMAIN AB Grb10 is a pleckstrin homology and Src homology 2 domain-containing protein that interacts with a number of phosphorylated receptor tyrosine kinases, including the insulin receptor. In mice, Grb10 gene expression is imprinted with maternal expression in all tissues except the brain. While the interaction between Grb10 and the insulin receptor has been extensively investigated in cultured cells, whether this adaptor protein plays a positive or negative role in insulin signaling and action remains controversial. In order to investigate the in vivo role of Grb10 in insulin signaling and action in the periphery, we generated Grb10 knockout mice by the gene trap technique and analyzed mice with maternal inheritance of the knockout allele. Disruption of Grb10 gene expression in peripheral tissues had no significant effect on fasting glucose and insulin levels. On the other hand, peripheral-tissue-specific knockout of Grb10 led to significant overgrowth of the mice, consistent with a role for endogenous Grb10 as a growth suppressor. Loss of Grb10 expression in insulin target tissues, such as skeletal muscle and fat, resulted in enhanced insulin-stimulated Akt and mitogen-activated protein kinase phosphorylation. Hyperinsulinemic-euglycemic clamp studies revealed that disruption of Grb10 gene expression in peripheral tissues led to increased insulin sensitivity. Taken together, our results provide strong evidence that Grb10 is a negative regulator of insulin signaling and action in vivo. C1 UTHSCSA, Dept Pharmacol, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Med, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Biochem, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Cell & Struct Biol, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Barshop Ctr Longev & Aging Studies, San Antonio, TX 78229 USA. NIDDK, Genet Sect, GDDB, NIH, Bethesda, MD 20892 USA. RP Liu, F (reprint author), UTHSCSA, Dept Pharmacol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM liuf@uthsesa.edu RI deng, chuxia/N-6713-2016 FU NIDDK NIH HHS [R01 DK069930, R01 DK052933, R01 DK52933, R01 DK69930] NR 28 TC 77 Z9 81 U1 1 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 SEP PY 2007 VL 27 IS 18 BP 6497 EP 6505 DI 10.1128/MCB.00679-07 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 208KW UT WOS:000249319200020 PM 17620412 ER PT J AU Wong, CM Qiu, HF Hu, C Dong, JS Hinnebusch, AG AF Wong, Chi-Ming Qiu, Hongfang Hu, Cuihua Dong, Jinsheng Hinnebusch, Alan G. TI Yeast cap binding complex impedes recruitment of cleavage factor IA to weak termination sites SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID RNA-POLYMERASE-II; PRE-MESSENGER-RNA; SACCHAROMYCES-CEREVISIAE; IN-VIVO; 3'-END FORMATION; NUCLEAR EXPORT; COMMITMENT COMPLEX; TRANSCRIPTION; PROTEIN; GCN4P AB Nuclear cap binding complex (CBC) is recruited cotranscriptionally and stimulates spliceosome assembly on nascent mRNAs; however, its possible functions in regulating transcription elongation or termination were not well understood. We show that, while CBC appears to be dispensable for normal rates and processivity of elongation by RNA polymerase II (Pol II), it plays a direct role in preventing polyadenylation at weak termination sites. Similarly to Npl3p, with which it interacts, CBC suppresses the weak terminator of the gal10-Delta 56 mutant allele by impeding recruitment of termination factors Pcf11p and Rna15p (subunits of cleavage factor IA [CF IA]) and does so without influencing Npl3p occupancy at the termination site. Importantly, deletion of CBC subunits or NPL3 also increases termination at a naturally occurring weak poly(A) site in the RNA14 coding sequences. We also show that CBC is most likely recruited directly to the cap of nascent transcripts rather than interacting first with transcriptional activators or the phosphorylated C-terminal domain of Pol II. Thus, our findings illuminate the mechanism of CBC recruitment and extend its function in Saccharomyces cerevisiae beyond mRNA splicing and degradation of aberrant nuclear mRNAs to include regulation of CF IA recruitment at poly(A) selection sites. C1 NICHHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Hinnebusch, AG (reprint author), NICHHD, Lab Gene Regulat & Dev, NIH, Bldg 6A Room B1A-13, Bethesda, MD 20892 USA. EM ahinnebusch@nih.gov RI Wong, Chi-Ming/A-7627-2013 OI Wong, Chi-Ming/0000-0002-0025-7135 FU Intramural NIH HHS NR 50 TC 28 Z9 28 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD SEP PY 2007 VL 27 IS 18 BP 6520 EP 6531 DI 10.1128/MCB.00733-07 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 208KW UT WOS:000249319200022 PM 17636014 ER PT J AU Mardones, GA Burgos, PV Brooks, DA Parkinson-Lawrence, E Mattera, R Bonifacino, JS AF Mardones, Gonzalo A. Burgos, Patricia V. Brooks, Doug A. Parkinson-Lawrence, Emma Mattera, Rafael Bonifacino, Juan S. TI The trans-Golgi network accessory protein p56 promotes long-range movement of GGA/clathrin-containing transport carriers and lysosomal enzyme sorting SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID MANNOSE 6-PHOSPHATE RECEPTORS; CLATHRIN-ASSOCIATED PROTEIN; DOMAIN-CONTAINING PROTEIN; ADAPTIN EAR DOMAINS; GAMMA-ADAPTIN; GGA PROTEINS; PLASMA-MEMBRANE; COATED VESICLES; LIVING CELLS; TARGETED DISRUPTION AB The sorting of acid hydrolase precursors at the trans-Golgi network (TGN) is mediated by binding to mannose 6-phosphate receptors (MPRs) and subsequent capture of the hydrolase-MPR complexes into clathrin-coated vesicles or transport carriers (TCs) destined for delivery to endosomes. This capture depends on the function of three monomeric clathrin adaptors named GGAs. The GGAs comprise a C-terminal "ear" domain that binds a specific set of accessory proteins. Herein we show that one of these accessory proteins, p56, colocalizes and physically interacts with the three GGAs at the TGN. Moreover, overexpression of the GGAs enhances the association of p56 with the TGN, and RNA interference (RNAi)-mediated depletion of the GGAs decreases the TGN association and total levels of p56. RNAi-mediated depletion of p56 or the GGAs causes various degrees of missorting of the precursor of the acid hydrolase, cathepsin D. In the case of p56 depletion, this missorting correlates with decreased mobility of GGA-containing TCs. Transfection with an RNAi-resistant p56 construct, but not with a p56 construct lacking the GGA-ear-interacting motif, restores the mobility of the TCs. We conclude that p56 tightly cooperates with the GGAs in the sorting of cathepsin D to lysosomes, probably by enabling the movement of GGA-containing TCs. C1 NIH, NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. Univ S Australia, Sansom Inst, Adelaide, SA 5001, Australia. Children Youth & Womens Hlth Serv, Dept Med Genet, Lysosomal Dis Res Unit, Adelaide, SA 5006, Australia. RP Bonifacino, JS (reprint author), NIH, NICHHD, Cell Biol & Metab Branch, Bldg 10, Bethesda, MD 20892 USA. EM juan@helix.nih.gov RI Brooks, Doug/K-6714-2012; Parkinson-Lawrence, Emma/F-4085-2013; OI Bonifacino, Juan S./0000-0002-5673-6370 FU Intramural NIH HHS NR 69 TC 30 Z9 31 U1 0 U2 2 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 SEP PY 2007 VL 18 IS 9 BP 3486 EP 3501 DI 10.1091/mbc.E07-02-0190 PG 16 WC Cell Biology SC Cell Biology GA 206CT UT WOS:000249162200022 PM 17596511 ER PT J AU Kesavapany, S Patel, V Zheng, YL Pareek, TK Bjelogrlic, M Albers, W Amin, N Jaffe, H Gutkind, JS Strong, MJ Grant, P Pant, HC AF Kesavapany, Sashi Patel, Vyomesh Zheng, Ya-Li Pareek, Tej K. Bjelogrlic, Mia Albers, Wayne Amin, Niranjana Jaffe, Howard Gutkind, J. Silvio Strong, Michael J. Grant, Philip Pant, Harish C. TI Inhibition of pin1 reduces glutamate-induced perikaryal accumulation of phosphorylated neurofilament-H in neurons SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID PROLYL-ISOMERASE PIN1; AMYOTROPHIC-LATERAL-SCLEROSIS; TANDEM MASS-SPECTROMETRY; ROOT GANGLIA NEURONS; ALZHEIMERS-DISEASE; NF-M; NEUROFIBRILLARY TANGLES; TAU-PHOSPHORYLATION; PROTEIN-KINASE; LOLIGO-PEALEI AB Under normal conditions, the proline-directed serine/threonine residues of neurofilament tail-domain repeats are exclusively phosphorylated in axons. In pathological conditions such as amyotrophic lateral sclerosis (ALS), motor neurons contain abnormal perikaryal accumulations of phosphorylated neurofilament proteins. The precise mechanisms for this compartment-specific phosphorylation of neurofilaments are not completely understood. Although localization of kinases and phosphatases is certainly implicated, another possibility involves Pin1 modulation of phosphorylation of the proline-directed serine/threonine residues. Pin1, a prolyl isomerase, selectively binds to phosphorylated proline-directed serine/threonine residues in target proteins and isomerizes cis isomers to more stable trans configurations. In this study we show that Pin1 associates with phosphorylated neurofilament-H (p-NF-H) in neurons and is colocalized in ALS-affected spinal cord neuronal inclusions. To mimic the pathology of neurodegeneration, we studied glutamate-stressed neurons that displayed increased p-NF-H in perikaryal accumulations that colocalized with Pin1 and led to cell death. Both effects were reduced upon inhibition of Pin1 activity by the use of an inhibitor juglone and down-regulating Pin1 levels through the use of Pin1 small interfering RNA. Thus, isomerization of lys-ser-pro repeat residues that are abundant in NF-H tail domains by Pin1 can regulate NF-H phosphorylation, which suggests that Pin1 inhibition may be an attractive therapeutic target to reduce pathological accumulations of p-NF-H. C1 Natl Inst Neurol Disorders & Stroke, NIH, Cytoskeletal Prot Regulat Sect, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, NIH, Cytoskeletal Prot Regulat Sect, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, NIH, Sect Enzyme Chem, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, NIH, Prot & Peptide Facil, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, NIH, Lab Oral & Pharyngeal Canc, Bethesda, MD 20892 USA. Robarts Res Inst, London, ON N6A 5K8, Canada. Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. RP Pant, HC (reprint author), Natl Inst Neurol Disorders & Stroke, NIH, Cytoskeletal Prot Regulat Sect, Bethesda, MD 20892 USA. EM panth@ninds.nih.gov RI Gutkind, J. Silvio/A-1053-2009; Strong, Michael/H-9689-2012; OI Pareek, Tej/0000-0001-5134-1647 FU Intramural NIH HHS; NIMH NIH HHS [MH/NS 31862] NR 62 TC 34 Z9 35 U1 0 U2 4 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 SEP PY 2007 VL 18 IS 9 BP 3645 EP 3655 DI 10.1091/mbc.E07-03-0237 PG 11 WC Cell Biology SC Cell Biology GA 206CT UT WOS:000249162200036 PM 17626162 ER PT J AU Rutkowski, DT Kang, SW Goodman, AG Garrison, JL Taunton, J Katze, MG Kaufman, RJ Hegde, RS AF Rutkowski, D. Thomas Kang, Sang-Wook Goodman, Alan G. Garrison, Jennifer L. Taunton, Jack Katze, Michael G. Kaufman, Randal J. Hegde, Ramanujan S. TI The role of p58(IPK) in protecting the stressed endoplasmic reticulum SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID UNFOLDED PROTEIN RESPONSE; TRANSLATIONAL CONTROL; GLUCOSE-HOMEOSTASIS; SECRETORY PATHWAY; DNAJ HOMOLOG; ER MEMBRANE; TRANSLOCATION; BIP; INHIBITOR; KINASE AB The preemptive quality control (pQC) pathway protects cells from acute endoplasmic reticulum (ER) stress by attenuating translocation of nascent proteins despite their targeting to translocons at the ER membrane. Here, we investigate the hypothesis that the DnaJ protein p58(IPK) plays an essential role in this process via HSP70 recruitment to the cytosolic face of translocons for extraction of translocationally attenuated nascent chains. Our analyses revealed that the heightened stress sensitivity of p58(-/-) cells was not due to an impairment of the pQC pathway or elevated ER substrate burden during acute stress. Instead, the lesion was in the protein processing capacity of the ER lumen, where p58(IPK) was found to normally reside in association with BiP. ER lumenal p58(IPK) could be coimmunoprecipitated with a newly synthesized secretory protein in vitro and stimulated protein maturation upon overexpression in cells. These results identify a previously unanticipated location for p58(IPK) in the ER lumen where its putative function as a cochaperone explains the stress-sensitivity phenotype of knockout cells and mice. C1 Univ Michigan, Med Ctr, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA. Univ Michigan, Med Ctr, Dept Biol Chem & Internal Med, Ann Arbor, MI 48109 USA. NICHHD, NIH, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. Univ Washington, Dept Microbiol, Seattle, WA 98195 USA. Univ Calif San Francisco, Dept Pharmacol, San Francisco, CA 94143 USA. RP Kaufman, RJ (reprint author), Univ Michigan, Med Ctr, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA. EM kaufman@umich.edu; hegder@mail.nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [R01 HL052173, R01 HL-052173]; NIDDK NIH HHS [R01 DK-042394, R01 DK042394] NR 37 TC 111 Z9 113 U1 0 U2 1 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 SEP PY 2007 VL 18 IS 9 BP 3681 EP 3691 DI 10.1091/mbc.E07-03-0272 PG 11 WC Cell Biology SC Cell Biology GA 206CT UT WOS:000249162200039 PM 17567950 ER PT J AU Whibley, CE McPhail, KL Keyzers, RA Maritz, MF Leaner, VD Birrer, MJ Davies-Coleman, MT Hendricks, DT AF Whibley, Catherine E. McPhail, Kerry L. Keyzers, Robert A. Maritz, Michelle F. Leaner, Virna D. Birrer, Michael J. Davies-Coleman, Michael T. Hendricks, Denver T. TI Reactive oxygen species mediated apoptosis of esophageal cancer cells induced by marine triprenyl toluquinones and toluhydroquinones SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID SQUAMOUS CARCINOMA-CELLS; C-JUN; NATURAL-PRODUCTS; ANTICANCER AGENTS; OXIDATIVE STRESS; ACTIVATION; CYTOTOXICITY; RESISTANCE; COMPLEXES; ANTITUMOR AB Marine invertebrates, algae, and microorganisms are prolific producers of novel secondary metabolites. Some of these secondary metabolites have the potential to be developed as chemotherapeutic agents for the treatment of a wide variety of diseases, including cancer. We describe here the mechanism leading to apoptosis of esophageal cancer cell lines in the presence of triprenylated toluquinones and toluhydroquinones originally isolated from the Arminacean nudibranch Leminda millecra. Triprenylated toluquinone-induced and toluhydroquinone-induced cell death is mediated via apoptosis after a cell cycle block. Molecular events include production of reactive oxygen species (ROS), followed by induction and activation of c-Jun (AP1) via c-Jun-NH2-kinase-mediated and extracellular signal-regulated kinase-mediated pathways. Partial resistance to these compounds could be conferred by the ROS scavengers Trolox and butylated hydroxyanisol, a c-Jun-NH2-kinase inhibitor, and inhibition of c-Jun with a dominant negative mutant (TAM67). Interestingly, the levels of ROS produced varied between compounds, but was proportional to the ability of each compound to kill cells. Because cancer cells are often more susceptible to ROS, these compounds present a plausible lead for new antiesophageal cancer treatments and show the potential of the South African marine environment to provide new chemical entities with potential clinical significance. C1 Univ Cape Town, Fac Hlth Sci, Div Med Biochem, Inst Infect Dis & Mol Med, ZA-7935 Cape Town, South Africa. Rhodes Univ, Dept Chem, ZA-6140 Grahamstown, South Africa. Natl Canc Inst, Ctr Canc Res, Cell & Canc Biol Branch, Bethesda, MD USA. RP Hendricks, DT (reprint author), Univ Cape Town, Fac Hlth Sci, Div Med Biochem, Inst Infect Dis & Mol Med, Private Bag X3 Observ, ZA-7935 Cape Town, South Africa. EM Denver.Hendricks@uct.ac.za OI Keyzers, Rob/0000-0002-7658-7421 NR 37 TC 25 Z9 25 U1 0 U2 6 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 SEP PY 2007 VL 6 IS 9 BP 2535 EP 2543 DI 10.1158/1535-7163.MCT-06-0760 PG 9 WC Oncology SC Oncology GA 214DM UT WOS:000249716200018 PM 17876050 ER PT J AU Newbold, RR Jefferson, WN Grissom, SF Padilla-Banks, E Snyder, RJ Lobenhofer, EK AF Newbold, Retha R. Jefferson, Wendy N. Grissom, Sherry F. Padilla-Banks, Elizabeth Snyder, Ryan J. Lobenhofer, Edward K. TI Developmental exposure to diethylstilbestrol alters uterine gene expression that may be associated with uterine neoplasia later in life SO MOLECULAR CARCINOGENESIS LA English DT Article DE early development; estrogen-regulated genes; endocrine disruptors; neonatal imprinting; epigenetics; carcinogenesis; hormonal carcinogenesis ID ENDOMETRIAL EPITHELIAL-CELLS; ADENOSIS-LIKE LESIONS; C-JUN PROTOONCOGENE; MOUSE UTERUS; IN-UTERO; ESTROGEN DIETHYLSTILBESTROL; ENDOCRINE DISRUPTION; REPRODUCTIVE-TRACT; DES EXPOSURE; CD-1 MICE AB Previously, we described a mouse model where the well-known reproductive carcinogen with estrogenic activity, diethylstilbestrol (DES), caused uterine adenocarcinoma following neonatal treatment. Tumor incidence was dose-dependent reaching >90% by 18 mo following neonatal treatment with 1000 mu g/kg/d of DES. These tumors followed the initiation/promotion model of hormonal carcinogenesis with developmental exposure as initiator, and exposure to ovarian hormones at puberty as the promoter. To identify molecular pathways involved in DES-initiation events, uterine gene expression profiles were examined in prepubertal mice exposed to DES (1, 10, or 1000 mu g/kg/d) on days 1-5 and compared to controls. Of more than 20 000 transcripts, approximately 3% were differentially expressed in at least one DES treatment group compared to controls; some transcripts demonstrated dose-responsiveness. Assessment of gene ontology annotation revealed alterations in genes associated with cell growth, differentiation, and adhesion. When expression profiles were compared to published studies of uteri from 5-d-old DES-treated mice, or adult mice treated with 17 beta estradiol, similarities were seen suggesting persistent differential expression of estrogen responsive genes following developmental DES exposure. Moreover, several altered genes were identified in human uterine adenocarcinomas. Four altered genes [lactotransferrin (Ltf), transforming growth factor beta inducible (Tgfb1), cyclin D1 (Ccnd1), and secreted frizzled-related protein 4 (Sfrp4)], selected for real-time RT-PCR analysis, correlated well with the directionality of the microarray data. These data suggested altered gene expression profiles observed 2 wk after treatment ceased, were established at the time of developmental exposure and maybe related to the initiation events resulting in carcinogenesis. (C) 2007 Wiley-Liss, Inc. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Dev Endocrinol & Endocrine Disruptor Sect, Mol Toxicol Lab, Res Triangle Pk, NC USA. NIH, Natl Inst Environm Hlth Sci, Microarray Grp, DHHS, Res Triangle Pk, NC USA. RP Newbold, RR (reprint author), NIEHS, 111 Alexder Dr, S Campus, PO Box 12233, Res Triangle Pk, NC 27709 USA. FU Intramural NIH HHS [Z01 ES070060-34, Z99 ES999999] NR 61 TC 38 Z9 41 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0899-1987 J9 MOL CARCINOGEN JI Mol. Carcinog. PD SEP PY 2007 VL 46 IS 9 BP 783 EP 796 DI 10.1002/mc.20308 PG 14 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 214XT UT WOS:000249772300005 PM 17394237 ER PT J AU Zhen, Y Krausz, KW Chen, C Idle, JR Gonzalez, FJ AF Zhen, Yueying Krausz, Kristopher W. Chen, Chi Idle, Jeffrey R. Gonzalez, Frank J. TI Metabolomic and genetic analysis of biomarkers for peroxisome proliferator-activated receptor alpha expression and activation SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID BENZOIC-ACID; LIQUID-CHROMATOGRAPHY; METABONOMIC APPROACH; MOUSE; RAT; PATHWAY; NMR; IDENTIFICATION; URINE; LIVER AB Peroxisome proliferator-activated receptor alpha ( PPAR alpha) is a nuclear receptor with manifold effects on intermediary metabolism. To define a set of urinary biomarkers that could be used to determine the efficacy of PPAR alpha agonists, a metabolomic investigation was undertaken in wild-type and Ppar alpha- null mice fed for 2 wk either a regular diet or a diet containing the PPAR alpha ligand Wy- 14,643 ([ 4chloro- 6-( 2,3- xylidino)- 2- pyrimidinylthio] acetic acid), and their urine was analyzed by ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry. Principal components analysis of 6393 accurate mass positive ions revealed clustering as a single phenotype of the treated and untreated Ppar alpha (-/-) mice plus two additional discrete phenotypes for the treated and untreated Ppar alpha(+/+) mice. Biomarkers of PPAR alpha activation were identified from their accurate masses and confirmed by tandem mass spectrometry of authentic compounds. Biomarkers were quantitated from raw chromatographic data using appropriate calibration curves. PPAR alpha urinary biomarkers highly statistically significantly elevated by Wy- 14,643 treatment included 11 beta- hydroxy- 3,20dioxopregn-4-en-21-oic acid (> 3700- fold), 11 beta, 20-dihydroxy- 3- oxopregn-4-en-21-oic acid ( 50-fold), nicotinamide (> 2- fold), nicotinamide 1-oxide ( 5-fold), 1-methylnicotinamide ( 1.5-fold), hippuric acid ( 2- fold), and 2,8-dihydroxyquinoline-beta-D-glucuronide ( 3- fold). PPAR alpha urinary biomarkers highly statistically significantly attenuated by Wy- 14,643 treatment included xanthurenic acid ( 1.3-fold), hexanoylglycine ( 20-fold), phenylpropionylglycine ( 4-fold), and cinnamoylglycine ( 9-fold). These biomarkers arise from PPAR alpha effects on tryptophan, corticosterone, and fatty acid metabolism and on glucuronidation. This study underscores the power of mass spectrometry-based metabolomics combined with genetically modified mice in the definition of monogenic metabolic phenotypes. C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Charles Univ Prague, Fac Med 1, Prague 12800 2, Czech Republic. RP Zhen, Y (reprint author), NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RI Chen, Chi/B-4618-2008 FU Intramural NIH HHS [Z01 BC005561-18]; NIAID NIH HHS [U19 AI067773-02] NR 33 TC 46 Z9 48 U1 0 U2 9 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD SEP PY 2007 VL 21 IS 9 BP 2136 EP 2151 DI 10.1210/me.2007-0150 PG 16 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 204CG UT WOS:000249020200008 PM 17550978 ER PT J AU Granot, Z Kobiler, O Melamed-Book, N Eimerl, S Bahat, A Lu, B Braun, S Maurizi, MR Suzuki, CK Oppenheim, AB Orly, J AF Granot, Zvi Kobiler, Oren Melamed-Book, Naomi Eimerl, Sarah Bahat, Assaf Lu, Bin Braun, Sergei Maurizi, Michael R. Suzuki, Carolyn K. Oppenheim, Amos B. Orly, Joseph TI Turnover of mitochondrial steroidogenic acute regulatory (StAR) protein by lon protease: The unexpected effect of proteasome inhibitors SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID ATP-DEPENDENT PROTEASE; SIDE-CHAIN CLEAVAGE; ESCHERICHIA-COLI FTSH; RAT GRANULOSA-CELLS; LEYDIG TUMOR-CELLS; M-AAA PROTEASE; CLP PROTEASE; SPASTIC PARAPLEGIA; HYDROGEN-PEROXIDE; OXIDATIVE STRESS AB Steroidogenic acute regulatory protein ( StAR) is a vital mitochondrial protein promoting transfer of cholesterol into steroid making mitochondria in specialized cells of the adrenal cortex and gonads. Our previous work has demonstrated that StAR is rapidly degraded upon import into the mitochondrial matrix. To identify the protease( s) responsible for this rapid turnover, murine StAR was expressed in wild-type Escherichia coli or in mutant strains lacking one of the four ATP-dependent proteolytic systems, three of which are conserved in mammalian mitochondria -ClpP, FtsH, and Lon. StAR was rapidly degraded in wild-type bacteria and stabilized only in lon (-)mutants; in such cells, StAR turnover was fully restored upon coexpression of human mitochondrial Lon. In mammalian cells, the rate of StAR turnover was proportional to the cell content of Lon protease after expression of a Lon-targeted small interfering RNA, or overexpression of the protein. In vitro assays using purified proteins showed that Lon-mediated degradation of StAR was ATP-dependent and blocked by the proteasome inhibitors MG132 ( IC50 = 20 mu M) and clasto-lactacystin beta-lactone ( cL beta L, IC (50) = 3 mu M); by contrast, epoxomicin, representing a different class of proteasome inhibitors, had no effect. Such inhibition is consistent with results in cultured rat ovarian granulosa cells demonstrating that degradation of StAR in the mitochondrial matrix is blocked by MG132 and cL beta L but not by epoxomicin. Both inhibitors also blocked Lon-mediated cleavage of the model substrate fluorescein isothiocyanate-casein. Taken together, our former studies and the present results suggest that Lon is the primary ATP-dependent protease responsible for StAR turnover in mitochondria of steroidogenic cells. C1 Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, Dept Biol Chem, IL-91904 Jerusalem, Israel. Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Mol Genet & Biotechnol, IL-91010 Jerusalem, Israel. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Biochem & Mol Biol, Newark, NJ 07103 USA. NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Granot, Z (reprint author), Hebrew Univ Jerusalem, Alexander Silberman Inst Life Sci, Dept Biol Chem, IL-91904 Jerusalem, Israel. RI Kobiler, Oren/J-2268-2012 OI Kobiler, Oren/0000-0001-9914-3770 FU Intramural NIH HHS; NIGMS NIH HHS [R01 GM61095-01] NR 79 TC 64 Z9 68 U1 1 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD SEP PY 2007 VL 21 IS 9 BP 2164 EP 2177 DI 10.1210/me.2005-0458 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 204CG UT WOS:000249020200010 PM 17579211 ER PT J AU Rajareddy, S Reddy, P Du, C Liu, L Jagarlamudi, K Tang, W Shen, Y Berthet, C Peng, SL Kaldis, P Liu, K AF Rajareddy, Singareddy Reddy, Pradeep Du, Chun Liu, Lian Jagarlamudi, Krishna Tang, Wenli Shen, Yan Berthet, Cyril Peng, Stanford L. Kaldis, Philipp Liu, Kui TI p27(kip1) (Cyclin-Dependent kinase inhibitor 1B) controls ovarian development by suppressing follicle endowment and activation and promoting follicle atresia in mice SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID TRANSCRIPTION FACTOR FOXO3A; OOCYTE-SPECIFIC EXPRESSION; MAMMALIAN OVARY; GRANULOSA-CELLS; MOUSE OVARY; GERM-CELLS; GROWTH; ADULT; CYSTS; POOL AB In humans, the molecular mechanisms underlying ovarian follicle endowment and activation, which are closely related to the control of female reproduction, occurrence of menopause, and related diseases such as premature ovarian failure, are poorly understood. In the current study, we provide several lines of genetic evidence that the cyclin-dependent kinase ( Cdk) inhibitor 1B ( commonly known as p27(kip1) or p27) controls ovarian development in mice by suppressing follicle endowment and activation, and by promoting follicle death. In p27-deficient ( p27 -/-) mice, postnatal follicle assembly was accelerated, and the number of endowed follicles was doubled as compared with p27 +/+ mice. Moreover, in p27 -/- ovaries the primordial follicle pool was prematurely activated once it was endowed, and at the same time the massive follicular death that occurs before sexual maturity was rescued by loss of p27. In early adulthood, however, the overactivated follicular pool in p27-/- ovaries was largely depleted, causing premature ovarian failure. Furthermore, we have extensively studied the molecular mechanisms underlying the above-mentioned phenotypes seen in p27 -/- ovaries and have found that p27 controls follicular development by several distinct mechanisms at different stages of development of the ovary. For example, p27 controls oocyte growth by suppressing the functions of Cdk2/Cdc2-cyclin A/E1 in oocytes that are arrested at the diplotene stage of meiosis I. This function of p27 is distinct from its well-known role as a suppressor of cell cycle progression. In addition, we have found that p27 activates the caspase-9-caspase-3-caspase7-poly ( ADP- ribose) polymerase apoptotic cascade by inhibiting Cdk2/Cdc2-cyclin A/B1 kinase activities in follicles, thereby inducing follicle atresia. Our results suggest that the p27 gene is important in determining mammalian ovarian development. This study therefore provides insight into ovary-borne genetic aberrations that cause defects in folliculogenesis and infertility in humans. C1 Umea Univ, Dept Med Biochem & Biophys, SE-90187 Umea, Sweden. Shandong Univ, Qilu Hosp, Shandong 250012, Peoples R China. Natl Canc Inst, Mouse Canc Genet Program, Frederick, MD 21702 USA. Autoimmun & Transplantat Res, Dept Inflammat, Palo Alto, CA 94304 USA. RP Rajareddy, S (reprint author), Umea Univ, Dept Med Biochem & Biophys, SE-90187 Umea, Sweden. RI SINGAREDDY, RAJAREDDY/C-8771-2011; Kaldis, Philipp/G-2714-2010; Reddy, Pradeep/G-1770-2014; OI Kaldis, Philipp/0000-0002-7247-7591; Reddy, Pradeep/0000-0002-9173-3845; Liu, Lian/0000-0001-5868-4482 NR 40 TC 58 Z9 62 U1 1 U2 5 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD SEP PY 2007 VL 21 IS 9 BP 2189 EP 2202 DI 10.1210/me.2007-0172 PG 14 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 204CG UT WOS:000249020200012 PM 17565040 ER PT J AU Babady, NE Carelle, N Wells, RD Rouault, TA Hirano, M Lynch, DR Delatycki, MB Wilson, RB Isaya, G Puccio, H AF Babady, Ngolela E. Carelle, Nadege Wells, Robert D. Rouault, Tracey A. Hirano, Michio Lynch, David R. Delatycki, Martin B. Wilson, Robert B. Isaya, Grazia Puccio, Helene TI Advancements in the pathophysiology of Friedreich's Ataxia and new prospects for treatments SO MOLECULAR GENETICS AND METABOLISM LA English DT Review DE Friedreich's Ataxia; frataxin; iron metabolism; mitochondria; drug therapy ID SULFUR CLUSTER BIOGENESIS; MITOCHONDRIAL PROCESSING PEPTIDASE; FRATAXIN HOMOLOG YFH1; YEAST FRATAXIN; IRON-BINDING; TRANSGENIC MICE; REPEAT EXPANSION; OXIDATIVE STRESS; SCAFFOLD PROTEIN; HEME-SYNTHESIS AB On November 9-12, 2006, the Friedreich's Ataxia Research Alliance (FARA) and the National Institutes of Health (NIH) hosted the Third International Friedreich's Ataxia (FRDA) Scientific Conference at the NIH in Bethesda, Maryland, highlighting the exciting research leading now to a variety of clinical trials that show promise of effective treatments for this devastating disorder. Nearly 150 leading FRDA scientists from around the world discussed their new insights and findings. The presence of six pharmaceutical and biotechnology companies underscored the importance of the public-private partnership that has grown in the past years. Some of these companies are already involved in advancing promising drug compounds into clinical trials, while others are eager to help take newer discoveries through drug development and into subsequent clinical trials. National Institute of Neurological Disorders and Stroke (NINDS) Director Dr. Story Landis noted in her opening remarks for the conference that there was a "palpable sense of energy, excitement, and enthusiasm" over the scientific progress made since the FRDA gene was discovered over 10 years ago. (C) 2007 Elsevier Inc. All rights reserved. C1 Mayo Clin, Coll Med, Dept Pediat & Adolescent Med, Rochester, MN 55905 USA. Mayo Clin, Coll Med, Dept Biochem & Mol Biol, Rochester, MN 55905 USA. Univ Strasbourg 1, INSERM, CNRS, Inst Genet & Biol Mol & Cellular, Strasbourg, France. Texas A&M Univ, HSC, Inst Biosci & Technol, Houston, TX 77030 USA. Natl Inst Child Hlth & Human Dev, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. Columbia Univ, Med Ctr, Dept Neurol, New York, NY 10032 USA. Univ Penn, Sch Med, Dept Neurol, Philadelphia, PA 19104 USA. Royal Childrens Hosp, Bruce Lefroy Ctr Genet Hlth Res, Murdoch Childrens Res Inst, Melbourne, Vic, Australia. Univ Penn, Dept Pathol, Lab Med, Philadelphia, PA 19106 USA. RP Puccio, H (reprint author), Mayo Clin, Coll Med, Dept Pediat & Adolescent Med, Rochester, MN 55905 USA. EM isaya@mayo.edu; hpuccio@titus.u-strasbg.fr RI Delatycki, Martin/A-5409-2013; Puccio, Helene/G-1717-2013 OI Puccio, Helene/0000-0003-4711-2248 FU NIA NIH HHS [R01 AG015709] NR 82 TC 38 Z9 38 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 EI 1096-7206 J9 MOL GENET METAB JI Mol. Genet. Metab. PD SEP-OCT PY 2007 VL 92 IS 1-2 BP 23 EP 35 DI 10.1016/j.ymgme.2007.05.009 PG 13 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 218BZ UT WOS:000249992300005 PM 17596984 ER PT J AU Shen, JS Meng, XL Schiffmann, R Brady, RO Kaneski, CR AF Shen, Jin-Song Meng, Xing-Li Schiffmann, Raphael Brady, Roscoe O. Kaneski, Christine R. TI Establishment and characterization of Fabry disease endothelial cells with an extended lifespan SO MOLECULAR GENETICS AND METABOLISM LA English DT Article DE Fabry disease; alpha-galactosidase a deficiency; lysosomal storage disorders; globotriaosylceramide; endothelial cells; hTERT ID NITRIC-OXIDE SYNTHASE; ALPHA-GALACTOSIDASE; HUMAN SKIN; EXPRESSION; FIBROBLASTS; IMMORTALIZATION; SENESCENCE; GENERATION; INVITRO; MODEL AB Fabry disease is an inborn error of glycosphingolipid catabolism resulting from a deficiency of lysosomal enzyme a-galactosidase A. The major clinical manifestations of the disease, such as stroke, cardiac dysfunction, and renal impairment, are thought to be caused by vasculopathy due to progressive accumulation of globotriaosylceramide in vascular endothelial cells. The pathogenesis of the vasculopathy has not been elucidated. Since in vitro studies using primary endothelial cells are hampered by the limited lifespan of these cells, the availability of cultured endothelial cells with an extended lifespan is critical for the study of the vasculopathy of Fabry disease. We therefore generated an endothelial cell line from a Fabry hemizygote by introduction of human telomerase reverse transcriptase gene. The cell line has markedly extended lifespan compared to parental primary cells. The cells stably express many key markers of endothelial cells such as von Willebrand factor, CD31, CD34, and endothelial nitric oxide synthase (eNOS) and retain functional characteristics such as uptake of acetylated low-density lipoprotein, responsiveness to angiogenic growth factors, up-regulation of eNOS production upon extracellular stimuli, and formation of tube-like structures on Matrigel basement membrane matrix. The cells show significantly reduced activity of a-galactosidase A compared with primary endothelial cells from normal individuals and accumulate globotriaosylceramide in lysosomes. This cell line will provide a useful in vitro model of Fabry disease and will facilitate systematic studies to investigate pathogenic mechanisms and explore new therapeutic approaches for Fabry disease. Published by Elsevier Inc. C1 NIH, Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, Bethesda, MD 20892 USA. Natl Inst Child Hlth & Human Dev, NIH, Lab Clin Genom, Bethesda, MD 20892 USA. RP Kaneski, CR (reprint author), NIH, Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, Bldg 10,Rm 3 D04,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kaneskic@ninds.nih.gov OI Kaneski, Christine/0000-0003-1453-2502 FU Intramural NIH HHS [Z99 NS999999] NR 38 TC 16 Z9 16 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 SEP-OCT PY 2007 VL 92 IS 1-2 BP 137 EP 144 DI 10.1016/j.ymgme.2007.06.003 PG 8 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 218BZ UT WOS:000249992300019 PM 17644384 ER PT J AU Lee, HS Remmers, EF Le, JM Kastner, DL Bae, SC Gregersen, PK AF Lee, Hye-Soon Remmers, Elaine F. Le, Julie M. Kastner, Daniel L. Bae, Sang-Cheol Gregersen, Peter K. TI Association of STAM with rheumatoid arthritis in the Korean population SO MOLECULAR MEDICINE LA English DT Article ID CYCLIC CITRULLINATED PEPTIDE; FUNCTIONAL HAPLOTYPE; JAPANESE POPULATION; SHARED EPITOPE; PADI4; GENE; SUSCEPTIBILITY; PTPN22; CELLS; INTERLEUKIN-17 AB A recent study in the North American White population has documented the association of a common STAT4 haplotype (tagged by rs7574865) with risk for rheumatoid arthritis (RA) and systemic lupus erythematosus. To replicate this finding in the Korean population, we performed a case-control association study. We genotyped 67 single nucleotide polymorphisms (SNPs) within the STAT1 and STAT4 regions in 1123 Korean patients with RA and 1008 ethnicity-matched controls. The most significant four risk SNPs (rs] 1889341, rs7574865, rs8179673, and rs10181656 located within the third intron of STAT4) among 67 SNPs are identical with those in the North American study. All four SNPs have modest risk for RA susceptibility (odds ratio 1.21-1.27). A common haplotype defined by these markers (TTCG) carries significant risk for RA in Koreans (34 percent versus 28 percent, P = 0.0027, OR (95 percent CI) = 1.33 (1.10-1.60)). By logistic regression analysis, this haplotype is an independent risk factor in addition to the classical shared epitope alleles at the HLA-DRB1 locus. There were no significant associations with age of disease onset, radiographic progression, or serologic status using either allelic or haplotypic analysis. Unlike several other risk genes for RA such as PTPN22, PAD14, and FCRL3, a haplotype of the STAT4 gene shows consistent association with RA susceptibility across Whites and Asians, suggesting that this risk haplotype predates the divergence of the major racial groups. C1 Hanyang Univ, Med Ctr, Hosp Rheumat Dis, Seoul 133792, South Korea. N Shore Long Isl Jewish Hlth Syst, Feinstein Inst Med Res, Manhasset, NY USA. NIAMSD, Bethesda, MD 20892 USA. RP Bae, SC (reprint author), Hanyang Univ, Med Ctr, Hosp Rheumat Dis, Seoul 133792, South Korea. EM scboe@honyong.ac.kr; peterg@nshs.edu FU Intramural NIH HHS; NIAMS NIH HHS [R01-AR44222] NR 33 TC 120 Z9 125 U1 0 U2 3 PU FEINSTEIN INST MED RES PI MANHASSET PA 350 COMMUNITY DR, MANHASSET, NY 11030 USA SN 1076-1551 J9 MOL MED JI Mol. Med. PD SEP-OCT PY 2007 VL 13 IS 9-10 BP 455 EP 460 DI 10.2119/2007-00072.Lee PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 222FB UT WOS:000250280400001 PM 17932559 ER PT J AU Straub, RE Lipska, BK Egan, MF Goldberg, TE Callicott, JH Mayhew, MB Vakkalanka, RK Kolachana, BS Kleinman, JE Weinberger, DR AF Straub, R. E. Lipska, B. K. Egan, M. F. Goldberg, T. E. Callicott, J. H. Mayhew, M. B. Vakkalanka, R. K. Kolachana, B. S. Kleinman, J. E. Weinberger, D. R. TI Allelic variation in GAD1 (GAD(67)) is associated with schizophrenia and influences cortical function and gene expression SO MOLECULAR PSYCHIATRY LA English DT Review ID GLUTAMIC-ACID DECARBOXYLASE; GAMMA-AMINOBUTYRIC-ACID; CHILDHOOD-ONSET SCHIZOPHRENIA; BIPOLAR AFFECTIVE-DISORDER; MESSENGER-RNA EXPRESSION; POSTMORTEM HUMAN BRAIN; SIB-PAIR FAMILIES; PREFRONTAL CORTEX; TRANSMISSION/DISEQUILIBRIUM TEST; GABAERGIC INTERNEURONS AB Cortical GABAergic dysfunction has been implicated as a key component of the pathophysiology of schizophrenia and decreased expression of the gamma-aminobutyric acid (GABA) synthetic enzyme glutamic acid decarboxylase 67 (GAD67), encoded by GAD1, is found in schizophrenic post-mortem brain. We report evidence of distorted transmission of single-nucleotide polymorphism (SNP) alleles in two independent schizophrenia family-based samples. In both samples, allelic association was dependent on the gender of the affected offspring, and in the Clinical Brain Disorders Branch/National Institute of Mental Health (CBDB/NIMH) sample it was also dependent on catechol-O-methyltransferase (COMT) Val158Met genotype. Quantitative transmission disequilibrium test analyses revealed that variation in GAD1 influenced multiple domains of cognition, including declarative memory, attention and working memory. A 50 flanking SNP affecting cognition in the families was also associated in unrelated healthy individuals with inefficient BOLD functional magnetic resonance imaging activation of dorsal prefrontal cortex (PFC) during a working memory task, a physiologic phenotype associated with schizophrenia and altered cortical inhibition. In addition, a SNP in the 50 untranslated (and predicted promoter) region that also influenced cognition was associated with decreased expression of GAD1 mRNA in the PFC of schizophrenic brain. Finally, we observed evidence of statistical epistasis between two SNPs in COMT and SNPs in GAD1, suggesting a potential biological synergism leading to increased risk. These coincident results implicate GAD1 in the etiology of schizophrenia and suggest that the mechanism involves altered cortical GABA inhibitory activity, perhaps modulated by dopaminergic function. C1 NIMH, Genes Cognit & Psychosis Program, Clin Brain Disorders Branch, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Straub, RE (reprint author), NIMH, Genes Cognit & Psychosis Program, Clin Brain Disorders Branch, NIH,US Dept Hlth & Human Serv, 10 Ctr Dr,Clin Ctr,Bldg 10,Room 4D18,MSC 1385, Bethesda, MD 20892 USA. EM straubr@intra.nimh.nih.gov RI Callicott, Joseph/C-9102-2009; Lipska, Barbara/E-4569-2017 OI Callicott, Joseph/0000-0003-1298-3334; FU Intramural NIH HHS NR 111 TC 151 Z9 152 U1 2 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD SEP PY 2007 VL 12 IS 9 BP 854 EP 869 DI 10.1038/sj.mp.4001988 PG 16 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 205BW UT WOS:000249089100009 PM 17767149 ER PT J AU Brave, A Boberg, A Gudmundsdotter, L Rollman, E Hallermalm, K Ljungberg, K Blomberg, P Stout, R Paulie, S Sandstrom, E Biberfeld, G Earl, P Moss, B Cox, JH Wahren, B AF Brave, Andreas Boberg, Andreas Gudmundsdotter, Lindvi Rollman, Erik Hallermalm, Kristian Ljungberg, Karl Blomberg, Pontus Stout, Richard Paulie, Staffan Sandstrom, Eric Biberfeld, Gunnel Earl, Patricia Moss, Bernard Cox, Josephine H. Wahren, Britta TI A new multi-clade DNA prime/recombinant MVA boost vaccine induces broad and high levels of HIV-1-specific CD8(+) T-cell and humoral responses in mice SO MOLECULAR THERAPY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; IMMUNE-RESPONSES; HIV-1 VACCINE; ANTIBODY-RESPONSES; GENE-TRANSFER; PLASMID DNA; GAG REGION; IMMUNOGENICITY; AIDS; IMMUNIZATION AB The results presented here are from the preclinical evaluation in BALB/c mice of a DNA prime/modified vaccinia virus Ankara ( MVA) boost multi-gene multi-subtype human immunodeficiency virus-1(HIV-1) vaccine intended for use in humans. The plasmid DNA vaccine was delivered intradermally using a Biojector, and the MVA was delivered intramuscularly by needle. This combination of recombinant DNA and MVA proved to induce extraordinarily strong cellular responses, with more than 80% of the CD8(+) T cells specific for HIV-1 antigens. Furthermore, we show that the DNA priming increases the number of T-cell epitopes recognized after the MVA boost. In the prime/boost-immunized animals, a significant proportion of CD8+ T cells were stained positive for both interferon-gamma(IFN-gamma)and interleukin- 2 ( IL-2), a feature that has been associated with control of HIV-1 infection in long-term nonprogressors. The HIV-1-specific antibody levels were moderate after the plasmid DNA immunizations but increased dramatically after the MVA boost. Although the initial injection of MVA induced significant levels of vaccinianeutralizing antibodies, the HIV-specific responses were still significantly boosted by the second MVA immunization. The results from this study demonstrate the potency of this combination of DNA plasmids and MVA construct to induce broad and high levels of immune responses against several HIV-1 proteins of different subtypes. C1 Swedish Inst Infect Dis Control, Dept Virol, S-17182 Solna, Sweden. Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Stockholm, Sweden. Univ Melbourne, Dept Microbiol & Immunol, Melbourne, Vic, Australia. Univ N Carolina, Carolina Vaccine Inst, Chapel Hill, NC USA. Karolinska Univ Hosp, Huddinge, Sweden. Bioject Med Technol, Tualatin, OR USA. Mabtech AB, Nacka, Sweden. Dept Clin Sci & Educ, Stockholm, Sweden. NIAID, NIH, Viral Dis Lab, Bethesda, MD 20892 USA. Walter Reed Army Inst Res, US Mil HIV Res Program, Rockville, MD USA. RP Brave, A (reprint author), Swedish Inst Infect Dis Control, Dept Virol, S-17182 Solna, Sweden. EM andreas.brave@smi.ki.se OI Ljungberg, Karl/0000-0001-7192-6204 NR 42 TC 30 Z9 30 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD SEP PY 2007 VL 15 IS 9 BP 1724 EP 1733 DI 10.1038/sj.mt.6300235 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 205LW UT WOS:000249116400026 PM 17579577 ER PT J AU Manolio, TA Rodriguez, LL Brooks, L Abecasis, G Ballinger, D Daly, M Donnelly, P Faraone, SV Frazer, K Gabriel, S Gejman, P Guttmacher, A Harris, EL Insel, T Kelsoe, JR Lander, E McCowin, N Mailman, MD Nabel, E Ostell, J Pugh, E Sherry, S Sullivan, PF Thompson, JF Warram, J Study, G Wholley, D Milos, PM Collins, FS AF Manolio, Teri A. Rodriguez, Laura Lyman Brooks, Lisa Abecasis, Goncalo Ballinger, Dennis Daly, Mark Donnelly, Peter Faraone, Stephen V. Frazer, Kelly Gabriel, Stacey Gejman, Pablo Guttmacher, Alan Harris, Emily L. Insel, Thomas Kelsoe, John R. Lander, Eric McCowin, Norma Mailman, Matthew D. Nabel, Elizabeth Ostell, James Pugh, Elizabeth Sherry, Stephen Sullivan, Patrick F. Thompson, John F. Warram, James Study, GoKinD Wholley, David Milos, Patrice M. Collins, Francis S. CA Gain Collaborative Res Grp Collaborative Assoc Study Int Multi-Center ADHD Genetics Mol Genetics Schizophrenia Collab Bipolar Genome Study Major Depression Stage 1 Genomewid TI New models of collaboration in genome-wide association studies: the Genetic Association Information Network SO NATURE GENETICS LA English DT Editorial Material ID BREAST-CANCER; SUSCEPTIBILITY; LOCI; VARIANTS; MULTIPLE; LINKAGE; SAMPLE; RISK AB The Genetic Association Information Network ( GAIN) is a public- private partnership established to investigate the genetic basis of common diseases through a series of collaborative genome-wide association studies. GAIN has used new approaches for project selection, data deposition and distribution, collaborative analysis, publication and protection from premature intellectual property claims. These demonstrate a new commitment to shared scientific knowledge that should facilitate rapid advances in understanding the genetics of complex diseases. C1 US NIH, NHGRI, Bethesda, MD 20892 USA. Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. Perlegen Sci, Mountain View, CA 94043 USA. Broad Inst MIT & Harvard, Cambridge, MA 02142 USA. Univ Oxford, Oxford OX1 3TG, England. SUNY Upstate Med Univ, Syracuse, NY 13210 USA. Scripps Res Inst, La Jolla, CA 92037 USA. Evanston NW Healthcare, Evanston, IL 60201 USA. Northwestern Univ, Evanston, IL 60201 USA. NIMH, NIH, Bethesda, MD 20892 USA. Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. Vet Admin San Diego Healthcare Syst, La Jolla, CA 92093 USA. Fdn NIH, Bethesda, MD 20892 USA. Eli Lilly & Co, Lilly Corp Ctr, Indianapolis, IN 46285 USA. Natl Lib Med, NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Ctr Inherited Dis Res, Baltimore, MD 21224 USA. Univ N Carolina, Chapel Hill, NC 27599 USA. Pfizer Inc, Pharmacogenom Pfizer Global Res & Dev, Groton, CT 06340 USA. Joslin Diabet Ctr, Boston, MA 02215 USA. Helicos BioSci Corp, Cambridge, MA 02139 USA. RP Manolio, TA (reprint author), US NIH, NHGRI, 31 Ctr Dr, Bethesda, MD 20892 USA. EM manolio@nih.gov; manolio@nih.gov RI Abecasis, Goncalo/B-7840-2010; OI Abecasis, Goncalo/0000-0003-1509-1825; Thompson, John/0000-0001-8568-3311; Faraone, Stephen/0000-0002-9217-3982 NR 25 TC 200 Z9 207 U1 1 U2 13 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 SEP PY 2007 VL 39 IS 9 BP 1045 EP 1051 DI 10.1038/ng2127 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 205OA UT WOS:000249122400003 ER PT J AU Single, RM Martin, MP Gao, XJ Meyer, DG Yeager, M Kidd, JR Kidd, KK Carrington, M AF Single, Richard M. Martin, Maureen P. Gao, Xiaojiang Meyer, Diogo Yeager, Meredith Kidd, Judith R. Kidd, Kenneth K. Carrington, Mary TI Global diversity and evidence for coevolution of KIR and HLA SO NATURE GENETICS LA English DT Article ID MAJOR HISTOCOMPATIBILITY COMPLEX; NATURAL-SELECTION; RECEPTOR; DISEASE; GENES; SIGNATURES; MOLECULES; EVOLUTION; ALLELES; HISTORY AB The killer immunoglobulin- like receptor ( KIR) gene cluster shows extensive genetic diversity, as do the HLA class I loci, which encode ligands for KIR molecules. We genotyped 1,642 individuals from 30 geographically distinct populations to examine population- level evidence for coevolution of these two functionally related but unlinked gene clusters. We observed strong negative correlations between the presence of activating KIR genes and their corresponding HLA ligand groups across populations, especially KIR3DS1 and its putative HLA- B Bw4-80I ligands ( r=- 0.66, P 0.038). In contrast, we observed weak positive relationships between the various inhibitory KIR genes and their ligands. We observed a negative correlation between distance from East Africa and frequency of activating KIR genes and their corresponding ligands, suggesting a balance between selection on HLA and KIR loci. Most KIR- HLA genetic association studies indicate a primary influence of activating KIR- HLA genotypes in disease risk(1,2); concomitantly, activating receptor- ligand pairs in this study show the strongest signature of coevolution of these two complex genetic systems as compared with inhibitory receptor- ligand pairs. C1 NCI, SAIC Frederick, Lab Genom Divers, Ft Detrick, MD 21702 USA. Univ Vermont, Dept Math & Stat, Burlington, VT 05405 USA. Univ Sao Paulo, Dept Genet & Biol Evolut, BR-05608900 Sao Paulo, SP, Brazil. NCI, SAIC Frederick Inc, Adv Technol Program, Core Genotyping Facil, Ft Detrick, MD 21702 USA. NCI, US Natl Inst Hlth, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Rockville, MD 20852 USA. Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. RP Carrington, M (reprint author), NCI, SAIC Frederick, Lab Genom Divers, Ft Detrick, MD 21702 USA. EM carringt@ncifcrf.gov RI Meyer, Diogo/A-1868-2008 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400]; NIGMS NIH HHS [GM35326] NR 30 TC 132 Z9 140 U1 0 U2 4 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 SEP PY 2007 VL 39 IS 9 BP 1114 EP 1119 DI 10.1038/ng2077 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 205OA UT WOS:000249122400021 PM 17694058 ER PT J AU Brems, H Chmara, M Sahbatou, M Denayer, E Taniguchi, K Kato, R Somers, R Messiaen, L De Schepper, S Fryns, JP Cools, J Marynen, P Thomas, G Yoshimura, A Legius, E AF Brems, Hilde Chmara, Magdalena Sahbatou, Mourad Denayer, Ellen Taniguchi, Koji Kato, Reiko Somers, Riet Messiaen, Ludwine De Schepper, Sofie Fryns, Jean-Pierre Cools, Jan Marynen, Peter Thomas, Gilles Yoshimura, Akihiko Legius, Eric TI Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype SO NATURE GENETICS LA English DT Article ID CAUSE NOONAN-SYNDROME; SPROUTY DOMAIN; GENE; SUPPRESSOR; PTPN11; TYPE-1; IDENTIFICATION; PROTEINS; PATHWAY; DISEASE AB We report germline loss- of- function mutations in SPRED1 in a newly identified autosomal dominant human disorder. SPRED1 is a member of the SPROUTY/ SPRED family(1) of proteins that act as negative regulators of RAS- RAF interaction and mitogen-activated protein kinase ( MAPK) signaling(2). The clinical features of the reported disorder resemble those of neurofibromatosis type 1 and consist of multiple cafe - au- lait spots, axillary freckling and macrocephaly. Melanocytes from a cafe - au- lait spot showed, in addition to the germline SPRED1 mutation, an acquired somatic mutation in the wild- type SPRED1 allele, indicating that complete SPRED1 inactivation is needed to generate a cafe - au- lait spot in this syndrome. This disorder is yet another member of the recently characterized group of phenotypically overlapping syndromes caused by mutations in the genes encoding key components of the RAS- MAPK pathway(3,4). To our knowledge, this is the first report of mutations in the SPRY ( SPROUTY)/ SPRED family of genes in human disease. C1 Catholic Univ Louvain, Dept Human Genet, B-3000 Louvain, Belgium. Med Univ Gdansk, Dept Biol & Genet, Gdansk, Poland. CEPH, Fdn Jean Dausset, F-75010 Paris, France. Kyushu Univ, Med Inst Bioregulat, Div Mol & Cellular Immunol, Fukuoka 8128582, Japan. VIB, Flanders Inst Biotechnol, Dept Mol & Dev Genet, Human Genome Lab, Louvain, Belgium. Univ Alabama Birmingham, Dept Genet, Med Genom Lab, Birmingham, AL USA. Ghent Univ Hosp, Dept Dermatol, Ghent, Belgium. NCI, Dept Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Legius, E (reprint author), Catholic Univ Louvain, Dept Human Genet, B-3000 Louvain, Belgium. EM Eric.Legius@uz.kuleuven.be RI Yoshimura, Akihiko/K-5515-2013; OI Cools, Jan/0000-0001-6626-5843 NR 26 TC 172 Z9 184 U1 1 U2 7 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1061-4036 EI 1546-1718 J9 NAT GENET JI Nature Genet. PD SEP PY 2007 VL 39 IS 9 BP 1120 EP 1126 DI 10.1038/ng2113 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 205OA UT WOS:000249122400022 PM 17704776 ER PT J AU Shukla, V Coumoul, X Wang, RH Kim, HS Deng, CX AF Shukla, Vivek Coumoul, Xavier Wang, Rui-Hong Kim, Hyun-Seok Deng, Chu-Xia TI RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis SO NATURE GENETICS LA English DT Article ID APERT-SYNDROME; MAP KINASE; MUTATIONS; FGFR2; CELLS; DIFFERENTIATION; ACTIVATION; EXPRESSION; RECEPTORS; PATHWAY AB Premature fusion of one or more of the cranial sutures ( craniosynostosis) in humans causes over 100 skeletal diseases, which occur in 1 of approximate to 2,500 live births(1-3). Among them is Apert syndrome, one of the most severe forms of craniosynostosis, primarily caused by missense mutations leading to amino acid changes S252W or P253R in fibroblast growth factor receptor 2 ( FGFR2)(4-6). Here we show that a small hairpin RNA targeting the dominant mutant form of Fgfr2 ( Fgfr2(S252W)) completely prevents Apert- like syndrome in mice. Restoration of normal FGFR2 signaling is manifested by an alteration of the activity of extracellular signal- regulated kinases 1 and 2 ( ERK1/ 2), implicating the gene encoding ERK and the genes downstream of it in disease expressivity. Furthermore, treatment of the mutant mice with U0126, an inhibitor of mitogen- activated protein ( MAP) kinase kinase 1 and 2 ( MEK1/ 2) that blocks phosphorylation and activation of ERK1/ 2, significantly inhibits craniosynostosis. These results illustrate a pathogenic role for ERK activation in craniosynostosis resulting from FGFR2 with the S252W substitution and introduce a new concept of small- molecule inhibitor - mediated prevention and therapy for diseases caused by gain- of- function mutations in the human genome. C1 NIDDKD, US Natl Inst Hlth, Genet Dev & Dis Branch, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDKD, US Natl Inst Hlth, Genet Dev & Dis Branch, 10 Ctr Dr, Bethesda, MD 20892 USA. EM chuxiad@bdg10.niddk.nih.gov RI deng, chuxia/N-6713-2016 FU Intramural NIH HHS NR 30 TC 96 Z9 100 U1 3 U2 8 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD SEP PY 2007 VL 39 IS 9 BP 1145 EP 1150 DI 10.1038/ng2096 PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 205OA UT WOS:000249122400026 PM 17694057 ER PT J AU Brault, AC Huang, CYH Langevin, SA Kinney, RM Bowen, RA Ramey, WN Panella, NA Holmes, EC Powers, AM Miller, BR AF Brault, Aaron C. Huang, Claire Y-H Langevin, Stanley A. Kinney, Richard M. Bowen, Richard A. Ramey, Wanichaya N. Panella, Nicholas A. Holmes, Edward C. Powers, Ann M. Miller, Barry R. TI A single positively selected West Nile viral mutation confers increased virogenesis in American crows SO NATURE GENETICS LA English DT Article ID VIRUS-STRAINS; NEW-YORK; VIRULENCE; BIRDS; TRANSMISSION; DISEASE; EUROPE; HOST; EPIDEMIOLOGY; ENCEPHALITIS AB West Nile virus ( WNV), first recognized in North America in 1999, has been responsible for the largest arboviral epiornitic and epidemic of human encephalitis in recorded history. Despite the well- described epidemiological patterns of WNV in North America, the basis for the emergence of WNV-associated avian pathology, particularly in the American crow ( AMCR) sentinel species, and the large scale of the North American epidemic and epiornitic is uncertain. We report here that the introduction of a T249P amino acid substitution in the NS3 helicase ( found in North American WNV) in a lowvirulence strain was sufficient to generate a phenotype highly virulent to AMCRs. Furthermore, comparative sequence analyses of full- length WNV genomes demonstrated that the same site ( NS3- 249) was subject to adaptive evolution. These phenotypic and evolutionary results provide compelling evidence for the positive selection of a mutation encoding increased viremia potential and virulence in the AMCR sentinel bird species. C1 Univ Calif Davis, Ctr Vector Borne Dis, Sch Vet Med, Davis, CA 95616 USA. Univ Calif Davis, Dept Pathol Microbiol & Immunol, Sch Vet Med, Davis, CA 95616 USA. US Dept HHS, Ctr Dis Control & Prevent, Div Vector Borne Infect Dis, Ft Collins, CO 80522 USA. Colorado State Univ, Dept Biomed Sci, Ft Collins, CO 80523 USA. Penn State Univ, Dept Biol, University Pk, PA 16802 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Brault, AC (reprint author), Univ Calif Davis, Ctr Vector Borne Dis, Sch Vet Med, Davis, CA 95616 USA. EM acbrault@ucdavis.edu OI Holmes, Edward/0000-0001-9596-3552 FU NCPDCID CDC HHS [R01 CI000235, CI000235]; NIAID NIH HHS [AI061822, R01 AI061822, R01 AI061822-01, U54 AI065359, U54 AI065359-010001] NR 28 TC 182 Z9 190 U1 1 U2 22 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD SEP PY 2007 VL 39 IS 9 BP 1162 EP 1166 DI 10.1038/ng2097 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 205OA UT WOS:000249122400029 PM 17694056 ER PT J AU Laurence, A O'Shea, JJ AF Laurence, Arian O'Shea, John J. TI T-H-17 differentiation: of mice and men SO NATURE IMMUNOLOGY LA English DT Editorial Material ID T-CELLS; T(H)17 AB A new subset of interleukin 17-producing CD4(+) helper T cells with diverse functions has now been identified. New work by three groups substantially broadens the understanding of these cells in both mice and humans. C1 NIAMSD, NIH, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. RP O'Shea, JJ (reprint author), NIAMSD, NIH, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. EM osheajo@mail.nih.gov RI Laurence, Arian/A-8770-2009 OI Laurence, Arian/0000-0003-0942-8292 NR 15 TC 102 Z9 113 U1 0 U2 2 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 SEP PY 2007 VL 8 IS 9 BP 903 EP 905 DI 10.1038/ni0907-903 PG 3 WC Immunology SC Immunology GA 202QN UT WOS:000248918200004 PM 17712339 ER PT J AU McFarland, HF Martin, R AF McFarland, Henry F. Martin, Roland TI Multiple sclerosis: a complicated picture of autoimmunity SO NATURE IMMUNOLOGY LA English DT Review ID CD8(+) T-CELLS; CENTRAL-NERVOUS-SYSTEM; MYELIN BASIC-PROTEIN; ANTIMYELIN ANTIBODIES; DEMYELINATING DISEASE; MONOCLONAL-ANTIBODY; INTERFERON BETA-1B; MONONUCLEAR-CELLS; MULTICENTER TRIAL; DENDRITIC CELLS AB Understanding of autoimmune diseases, including multiple sclerosis, has expanded considerably in recent years. New insights have been provided by not only animal models but also studies of patients, often in conjunction with experimental therapies. It is accepted that autoimmune T cells mediate the early steps of new multiple sclerosis lesions, and although uncertainties remain about the specific targets of autoreactive T cells, several studies indicate myelin antigens. Recent findings obtained with both animal models and patients with multiple sclerosis indicate involvement of a T helper cell with a T-H-17 phenotype, in contrast to previous data indicating that T helper type 1 cells are critical. Evidence has also been presented for CD8(+) and regulatory T cell populations, although their involvement remains to be established. Despite evidence supporting the idea that autoreactive T cells are involved in disease induction, cells of myeloid lineage, antibodies and complement as well as processes intrinsic to the central nervous system seem to determine the effector stages of tissue damage. Careful analysis of the alterations in immune processes should further advance knowledge of the relationship between the inflammatory component of this disease and the more diffuse degeneration of progressive multiple sclerosis. C1 NINDS, NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. Univ Med Ctr Eppendorf, Ctr Mol Neurobiol Hamburg, Inst Neuroimmunol, D-20251 Hamburg, Germany. Univ Med Ctr Eppendorf, Ctr Mol Neurobiol Hamburg, Clin Multiple Sclerosis Res, D-20251 Hamburg, Germany. RP McFarland, HF (reprint author), NINDS, NIH, Neuroimmunol Branch, Bethesda, MD 20892 USA. EM mcfarlandh@ninds.nih.gov NR 87 TC 515 Z9 530 U1 7 U2 51 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 SEP PY 2007 VL 8 IS 9 BP 913 EP 919 DI 10.1038/ni1507 PG 7 WC Immunology SC Immunology GA 202QN UT WOS:000248918200014 PM 17712344 ER PT J AU Zhou, LA Ivanov, II Spolski, R Min, R Shenderov, K Egawa, T Levy, DE Leonard, WJ Littman, DR AF Zhou, Liang Ivanov, Ivaylo I. Spolski, Rosanne Min, Roy Shenderov, Kevin Egawa, Takeshi Levy, David E. Leonard, Warren J. Littman, Dan R. TI IL-6 programs TH-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways SO NATURE IMMUNOLOGY LA English DT Article ID INFLAMMATORY-BOWEL-DISEASE; REGULATORY T-CELLS; ROR-GAMMA-T; AUTOIMMUNE INFLAMMATION; TRANSCRIPTION FACTOR; HELPER-CELLS; T-H-17 CELLS; TH2 CELLS; RESPONSES; CYTOKINE AB T helper cells that produce interleukin 17 (IL-17; 'T-H-17 cells') are a distinct subset of proinflammatory cells whose in vivo function requires IL-23 but whose in vitro differentiation requires only IL-6 and transforming growth factor-beta (TGF-beta). We demonstrate here that IL-6 induced expression of IL-21 that amplified an autocrine loop to induce more IL-21 and IL-23 receptor in naive CD4(+) T cells. Both IL-21 and IL-23, along with TGF-beta, induced IL-17 expression independently of IL-6. The effects of IL-6 and IL-21 depended on STAT3, a transcription factor required for the differentiation of T-H-17 cells in vivo. IL-21 and IL-23 induced the orphan nuclear receptor ROR gamma t, which in synergy with STAT3 promoted IL-17 expression. IL-6 therefore orchestrates a series of 'downstream' cytokine-dependent signaling pathways that, in concert with TGF-beta, amplify ROR gamma t-dependent differentiation of TH-17 cells. C1 NYU, Sch Med, Kimmel Ctr Biol & Med, Skirball Inst, New York, NY 10016 USA. NHLBI, Lab Mol Immunol, Bethesda, MD 20892 USA. NYU, Sch Med, Howard Hughes Med Inst, New York, NY 10016 USA. NYU, Sch Med, Dept Pathol, New York, NY 10016 USA. NYU, Sch Med, Dept Microbiol, New York, NY 10016 USA. RP Littman, DR (reprint author), NYU, Sch Med, Kimmel Ctr Biol & Med, Skirball Inst, New York, NY 10016 USA. EM littman@saturn.med.nyu.edu OI Levy, David/0000-0002-7320-7788 FU Intramural NIH HHS NR 50 TC 1116 Z9 1184 U1 5 U2 47 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 SEP PY 2007 VL 8 IS 9 BP 967 EP 974 DI 10.1038/ni1488 PG 8 WC Immunology SC Immunology GA 202QN UT WOS:000248918200020 PM 17581537 ER PT J AU Weinberger, DR AF Weinberger, Daniel R. TI Schizophrenia drug says goodbye to dopamine SO NATURE MEDICINE LA English DT Editorial Material ID EXPRESSION; GLUTAMATE; GENES; BRAIN AB A drug that activates glutamate receptors offers promise for a new class of anti-psychotic therapeutics and sheds light on the pathophysiology of this devastating disease (pages 1102-1107). C1 NIMH, Natl Inst Hlth, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Natl Inst Hlth, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. EM daniel.weinberger@mail.nih.gov NR 12 TC 35 Z9 36 U1 0 U2 1 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 SEP PY 2007 VL 13 IS 9 BP 1018 EP 1019 DI 10.1038/nm0907-1018 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 208XS UT WOS:000249353100013 PM 17828217 ER PT J AU Li, YX Migueles, SA Welcher, B Svehla, K Phogat, A Louder, MK Wu, XL Shaw, GM Connors, M Wyatt, RT Mascola, JR AF Li, Yuxing Migueles, Stephen A. Welcher, Brent Svehla, Krisha Phogat, Adhuna Louder, Mark K. Wu, Xueling Shaw, George M. Connors, Mark Wyatt, Richard T. Mascola, John R. TI Broad HIV-1 neutralization mediated by CD4-binding site antibodies SO NATURE MEDICINE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ENVELOPE GLYCOPROTEINS; GP120; BINDING; SERA AB We have identified several patient sera showing potent and broad HIV-1 neutralization. Using antibody adsorption and elution from selected gp120 variants, the neutralizing specificities of the two most broadly reactive sera were mapped to the primary receptor CD4-binding region of HIV-1 gp120. Novel antibodies to the CD4-binding site are elicited in some HIV-1-infected individuals, and new approaches to present this conserved region of gp120 to the immune system may result in improved vaccine immunogens. C1 Natl Inst Hlth, Vaccine Res Ctr, Bethesda, MD 20892 USA. NIAID, Immunoregulat Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. Univ Alabama, Dept Med & Microbiol, Birmingham, AL 35294 USA. RP Wyatt, RT (reprint author), Natl Inst Hlth, Vaccine Res Ctr, Bethesda, MD 20892 USA. EM richardwyatt@nih.gov FU Intramural NIH HHS; NIAID NIH HHS [U19 AI067854-03, U19 AI067854] NR 15 TC 288 Z9 291 U1 2 U2 11 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 SEP PY 2007 VL 13 IS 9 BP 1032 EP 1034 DI 10.1038/nm1624 PG 3 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 208XS UT WOS:000249353100029 PM 17721546 ER PT J AU Tanno, T Bhanu, NV Oneal, PA Goh, SH Staker, P Lee, YT Moroney, JW Reed, CH Luban, NLC Wang, RH Eling, TE Childs, R Ganz, T Leitman, SF Fucharoen, S Miller, JL AF Tanno, Toshihiko Bhanu, Natarajan V. Oneal, Patricia A. Goh, Sung-Ho Staker, Pamela Lee, Y. Terry Moroney, John W. Reed, Christopher H. Luban, Naomi L. C. Wang, Rui-Hong Eling, Thomas E. Childs, Richard Ganz, Tomas Leitman, Susan F. Fucharoen, Suthat Miller, Jeffery L. TI High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin SO NATURE MEDICINE LA English DT Article ID MACROPHAGE INHIBITORY CYTOKINE-1; BONE MORPHOGENETIC PROTEIN; FACTOR-BETA SUPERFAMILY; SERUM; ERYTHROPOIESIS; METABOLISM; ABSORPTION; ACTIVATION; PREGNANCY AB In thalassemia, deficient globin-chain production during erythropoiesis results in anemia(1-3). Thalassemia may be further complicated by iron overload (frequently exacerbated by blood transfusion), which induces numerous endocrine diseases, hepatic cirrhosis, cardiac failure and even death(4). Accumulation of iron in the absence of blood transfusions may result from inappropriate suppression of the iron-regulating peptide hepcidin by an erythropoietic mechanism(5). To test this hypothesis, we examined erythroblast transcriptome profiles from 15 healthy, nonthalassemic donors. Growth differentiation factor 15 (GDF15), a member of the transforming growth factor-beta superfamily, showed increased expression and secretion during erythroblast maturation. Healthy volunteers had mean GDF15 serum concentrations of 450 +/- 50 pg/ml. In comparison, individuals with beta-thalassemia syndromes had elevated GDF15 serum levels (mean 66,000 +/- 9,600 pg/ml; range 4,800-248,000 pg/ml; P < 0.05) that were positively correlated with the levels of soluble transferrin receptor, erythropoietin and ferritin. Serum from thalassemia patients suppressed hepcidin mRNA expression in primary human hepatocytes, and depletion of GDF15 reversed hepcidin suppression. These results suggest that GDF15 overexpression arising from an expanded erythroid compartment contributes to iron overload in thalassemia syndromes by inhibiting hepcidin expression. C1 NIDDK, Mol Med Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. Natl Naval Med Ctr, Dept Obstet & Gynecol, Bethesda, MD 20889 USA. Childrens Natl Med Ctr, Lab Med Pathol, Washington, DC 20010 USA. NIDDK, Genet Dev & Dis Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Natl Inst Hlth, Res Triangle Pk, NC 27709 USA. NHLBI, Hematol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Dept Pathol & Med, Los Angeles, CA 90095 USA. Natl Inst Hlth, Dept Transfus Med, Bethesda, MD 20892 USA. Mahidol Univ, Inst Sci & Technol Res & Dev, Thalassemia Res Ctr, Phuttamonthon 73170, Nakornpathom, Thailand. RP Miller, JL (reprint author), NIDDK, Mol Med Branch, Natl Inst Hlth, 10 Ctr Dr, Bethesda, MD 20892 USA. EM jm7f@nih.gov FU Intramural NIH HHS NR 30 TC 422 Z9 437 U1 5 U2 24 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD SEP PY 2007 VL 13 IS 9 BP 1096 EP 1101 DI 10.1038/nm1629 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 208XS UT WOS:000249353100037 PM 17721544 ER PT J AU Kapoor, V Subach, FV Kozlov, VG Grudinin, A Verkhusha, VV Telford, WG AF Kapoor, Veena Subach, Fedor V. Kozlov, Vladimir G. Grudinin, Anatoly Verkhusha, Vladislav V. Telford, William G. TI New lasers for flow cytometry: filling the gaps SO NATURE METHODS LA English DT Letter ID FLUORESCENT PROTEINS C1 NIH, Natl Canc Inst, Expt Transplant & Immunol Branch, Bethesda, MD 20892 USA. Fianium Ltd, Southampton SO31 4RA, Hants, England. Albert Einstein Coll Med, Dept Anat & Structural Biol, Bronx, NY 10461 USA. RP Kapoor, V (reprint author), NIH, Natl Canc Inst, Expt Transplant & Immunol Branch, Bethesda, MD 20892 USA. EM telfordw@mail.nih.gov RI Subach, Fedor/K-7080-2014 FU NIGMS NIH HHS [R01 GM070358, R01 GM073913] NR 3 TC 23 Z9 23 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD SEP PY 2007 VL 4 IS 9 BP 678 EP 679 DI 10.1038/nmeth0907-678 PG 3 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 209MG UT WOS:000249392000003 PM 17762872 ER PT J AU Martinowich, K Manji, H Lu, B AF Martinowich, Keri Manji, Husseini Lu, Bai TI New insights into BDNF function in depression and anxiety SO NATURE NEUROSCIENCE LA English DT Article ID LONG-TERM DEPRESSION; NEUROTROPHIC FACTOR TRANSCRIPTS; FAMILY-BASED ASSOCIATION; KNOCKOUT MICE; HIPPOCAMPAL-NEURONS; BIPOLAR DISORDER; GENE-EXPRESSION; MESSENGER-RNA; RAT-BRAIN; ADULT-RAT AB The 'neurotrophin hypothesis of depression' is based largely on correlations between stress or antidepressant treatment and down- or upregulation, respectively, of brain-derived neurotrophic factor ( BDNF). Genetic disruption of the signaling pathways involving BDNF and its receptor, the tyrosine kinase TrkB, does not seem to cause depressive behaviors, but does hamper the effect of antidepressant drugs. Thus, BDNF may be a target of antidepressants, but not the sole mediator of depression or anxiety. Advances in BDNF cell biology, including its transcription through multiple promoters, trafficking and secretion, may provide new insights into its role in mood disorders. Moreover, as the precursor proBDNF and the mature protein mBDNF can elicit opposite effects on cellular functions, the impact of proBDNF and its cleavage on mood should be considered. Opposing influences of mBDNF and proBDNF on long-term potentiation and long-term depression might contribute to the dichotomy of BDNF actions on behaviors mediated by the brain stress and reward systems. C1 NIMH, Mood & Anxiety Program, Bethesda, MD 20892 USA. NICHHD, Sect Neural Dev & Plastic, NIH, Bethesda, MD 20892 USA. RP Martinowich, K (reprint author), NIMH, Mood & Anxiety Program, Bldg 35,Room 1C1004,35 Convent Dr,MSC 3714, Bethesda, MD 20892 USA. EM bailu@mail.nih.gov RI Lu, Bai/A-4018-2012; Martinowich, Keri/F-9841-2012; OI Martinowich, Keri/0000-0002-5237-0789 FU Intramural NIH HHS NR 50 TC 514 Z9 542 U1 12 U2 86 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 SEP PY 2007 VL 10 IS 9 BP 1089 EP 1093 DI 10.1038/nn1971 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 205VZ UT WOS:000249144000006 PM 17726474 ER PT J AU Assisi, C Stopfer, M Laurent, G Bazhenov, M AF Assisi, Collins Stopfer, Mark Laurent, Gilles Bazhenov, Maxim TI Adaptive regulation of sparseness by feedforward inhibition SO NATURE NEUROSCIENCE LA English DT Article ID LOCUST ANTENNAL LOBE; OSCILLATING NEURAL ASSEMBLIES; OLFACTORY NETWORK DYNAMICS; ODOR REPRESENTATIONS; SYSTEM; CELLS; MODEL; SYNCHRONIZATION; INFORMATION; MECHANISMS AB In the mushroom body of insects, odors are represented by very few spikes in a small number of neurons, a highly efficient strategy known as sparse coding. Physiological studies of these neurons have shown that sparseness is maintained across thousand-fold changes in odor concentration. Using a realistic computational model, we propose that sparseness in the olfactory system is regulated by adaptive feedforward inhibition. When odor concentration changes, feedforward inhibition modulates the duration of the temporal window over which the mushroom body neurons may integrate excitatory presynaptic input. This simple adaptive mechanism could maintain the sparseness of sensory representations across wide ranges of stimulus conditions. C1 Salk Inst Biol Studies, La Jolla, CA 92037 USA. NICHHD, US NIH, Bethesda, MD 20892 USA. CALTECH, Pasadena, CA 91125 USA. RP Bazhenov, M (reprint author), Salk Inst Biol Studies, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM bazhenov@salk.edu RI Laurent, Gilles/A-4583-2012; Assisi, Collins/R-7467-2016 OI Assisi, Collins/0000-0003-0108-582X FU Intramural NIH HHS; NIDCD NIH HHS [R01 DC006306-01A1, R01 DC006306] NR 43 TC 65 Z9 65 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 SEP PY 2007 VL 10 IS 9 BP 1176 EP 1184 DI 10.1038/nn1947 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 205VZ UT WOS:000249144000020 PM 17660812 ER PT J AU Dorsam, R Gutkind, JS AF Dorsam, Robert Gutkind, J. Silvio TI Pituitary hormone receptors and tumorigenesis - Reply SO NATURE REVIEWS CANCER LA English DT Letter C1 NCI, Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. RP Gutkind, JS (reprint author), NCI, Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. EM sg39v@nih.gov RI Gutkind, J. Silvio/A-1053-2009 NR 1 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD SEP PY 2007 VL 7 IS 9 DI 10.1038/nrc2069-c2 PG 2 WC Oncology SC Oncology GA 203ZN UT WOS:000249012700020 ER PT J AU Woodcock, J Witter, J Dionne, RA AF Woodcock, Janet Witter, James Dionne, Raymond A. TI Stimulating the development of mechanism-based, individualized pain therapies SO NATURE REVIEWS DRUG DISCOVERY LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; SEROTONIN REUPTAKE INHIBITORS; IMMPACT RECOMMENDATIONS; CLINICAL-TRIALS; GASTROINTESTINAL TOXICITY; POSTOPERATIVE PAIN; NEUROPATHIC PAIN; OUTCOME MEASURES; REMISSION RATES; SEX-DIFFERENCES AB Biomedical science has greatly improved our understanding of pain in recent decades, but few novel molecular entities that address fundamentally new pain mechanisms have entered the clinic, despite dramatically increased pharmaceutical investment. Indeed, virtually all new analgesics approved over the past 25 years are derivatives or reformulations of opioids or aspirin- like drugs, existing drugs given for a new indication or older drugs given by a different route of administration. Here, we discuss factors contributing to this lack of innovation in therapies for pain and advocate public-private partnerships ( PPPs) to translate new knowledge into more efficacious and safer treatments. C1 NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. US FDA, Dept Hlth & Human Serv, Rockville, MD 20857 USA. RP Dionne, RA (reprint author), NIH, Dept Hlth & Human Serv, Bldg 10, Bethesda, MD 20892 USA. EM dionner@mail.nih.gov NR 43 TC 52 Z9 53 U1 1 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD SEP PY 2007 VL 6 IS 9 BP 703 EP 710 DI 10.1038/nrd2335 PG 8 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 207FG UT WOS:000249236400015 PM 17762885 ER PT J AU Wess, J Eglen, RM Gautam, D AF Wess, Juergen Eglen, Richard M. Gautam, Dinesh TI Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development SO NATURE REVIEWS DRUG DISCOVERY LA English DT Review ID CENTRAL-NERVOUS-SYSTEM; ISOLATED RAT SKIN; KNOCK-OUT MICE; SMOOTH-MUSCLE; DEFICIENT MICE; ALZHEIMERS-DISEASE; HIPPOCAMPAL PLASTICITY; N-DESMETHYLCLOZAPINE; INDUCED CONTRACTIONS; TREATMENT STRATEGIES AB Muscarinic acetylcholine receptors ( mAChRs), M-1-M-5, regulate the activity of numerous fundamental central and peripheral functions. The lack of small- molecule ligands that can block or activate specific mAChR subtypes with high selectivity has remained a major obstacle in defining the roles of the individual receptor subtypes and in the development of novel muscarinic drugs. Recently, phenotypic analysis of mutant mouse strains deficient in each of the five mAChR subtypes has led to a wealth of new information regarding the physiological roles of the individual receptor subtypes. Importantly, these studies have identified specific mAChR-regulated pathways as potentially novel targets for the treatment of various important disorders including Alzheimer's disease, schizophrenia, pain, obesity and diabetes. C1 NIDDK, Mol Signalling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. PerkinElmer Life & Analyt Sci, Waltham, MA 02451 USA. RP Wess, J (reprint author), NIDDK, Mol Signalling Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov FU Intramural NIH HHS NR 132 TC 298 Z9 306 U1 3 U2 37 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD SEP PY 2007 VL 6 IS 9 BP 721 EP 733 DI 10.1038/nrd2379 PG 13 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 207FG UT WOS:000249236400017 PM 17762886 ER PT J AU Hayashi, Y Edwards, NA Proescholdt, MA Oldfield, EH Merrill, MJ AF Hayashi, Yasuhiko Edwards, Nancy A. Proescholdt, Martin A. Oldfield, Edward H. Merrill, Marsha J. TI Regulation and function of aquaporin-1 in glioma cells SO NEOPLASIA LA English DT Article DE aquaporin; cathepsin B; glioma; glycolysis; invasion ID HYPERTONICITY-RESPONSIVE ELEMENT; HUMAN BRAIN-TUMORS; WATER CHANNEL; CATHEPSIN-B; CARBONIC-ANHYDRASES; GLIOBLASTOMA-MULTIFORME; MOLECULAR-MECHANISMS; ENDOTHELIAL-CELLS; AQP1 EXPRESSION; RAT AB Glioblastoma multiformes ( GBMs) express increased aquaporin ( AQP) 1 compared to normal brain. AQPs may contribute to edema, cell motility, and shuttling of H2O and H+ from intracellular to extracellular space. We sought to gain insight into AQP1 function in GBM. In cultured 9L gliosarcoma cells, AQP1 expression was induced by dexamethasone, platelet-derived growth factor, NaCl, hypoxia, D-glucose ( but not L-glucose), and fructose. Induction of AQP1 expression correlated with the level of glycolysis, maximized by increasing medium D-glucose or fructose and decreasing O-2, and was quantified by measuring lactate dehydrogenase ( LDH) activity and medium lactate concentration. Upregulation of the protease cathepsin B was also observed in 9L cells cultured under glycolytic conditions. Immunohistochemical staining of human GBM specimens revealed increased coincident expression of AQP1, LDH, and cathepsin B in glioma cells associated with blood vessels at the tumor periphery. GBMs are known to exhibit aerobic glycolysis. Increased glucose metabolism at the tumor periphery may provide a scenario by which upregulation of AQP1, LDH, and cathepsin B contributes to acidification of the extracellular milieu and to invasive potential of glioma cells in perivascular space. The specific upregulation and metabolic consequences of increased AQP1 in gliomas may provide a therapeutic target, both as a cell surface marker and as a functional intervention. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. Kanazawa Univ, Dept Neurosurg, Kanazawa, Ishikawa 9208641, Japan. Univ Regensburg, Dept Neurosurg, D-93053 Regensburg, Germany. RP Merrill, MJ (reprint author), NINDS, Surg Neurol Branch, NIH, Room 5D-37,Bldg 10, Bethesda, MD 20892 USA. EM merrillm@ninds.nih.gov FU Intramural NIH HHS NR 67 TC 50 Z9 62 U1 0 U2 4 PU NEOPLASIA PRESS PI ANN ARBOR PA 1150 W MEDICAL CENTER DR, MSRB III, RM 9303, ANN ARBOR, MI 48109-0648 USA SN 1522-8002 J9 NEOPLASIA JI Neoplasia PD SEP PY 2007 VL 9 IS 9 BP 777 EP 787 DI 10.1593/neo.07454 PG 11 WC Oncology SC Oncology GA 211VT UT WOS:000249552100009 PM 17898873 ER PT J AU Lan, HY Zhang, RX Deng, CX Huang, XR AF Lan, H. Y. Zhang, R. X. Deng, C. X. Huang, X. R. TI ESSENTIAL ROLE OF SMAD3 IN REGULATING TH1 AND TH2 IMMUNE RESPONSE IN ANTI-GBM GLOMERULONEPHRITIS SO NEPHROLOGY LA English DT Meeting Abstract C1 [Lan, H. Y.; Zhang, R. X.; Huang, X. R.] Univ Hong Kong, Dept Med, Hong Kong, Hong Kong, Peoples R China. [Deng, C. X.] NCI, Genet Dev & Dis Branch CD, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1320-5358 J9 NEPHROLOGY JI Nephrology PD SEP PY 2007 VL 12 SU 2 SI SI MA 1137 BP A35 EP A35 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA V28AA UT WOS:000208652500137 ER PT J AU Kuller, LH Arnold, AM Longstreth, WT Manolio, TA O'Leary, DH Burke, GL Fried, LP Newman, AB AF Kuller, Lewis H. Arnold, Alice M. Longstreth, W. T., Jr. Manolio, Teri A. O'Leary, Daniel H. Burke, Gregory L. Fried, Linda P. Newman, Anne B. TI White matter grade and ventricular volume on brain MRI as markers of longevity in the cardiovascular health study SO NEUROBIOLOGY OF AGING LA English DT Article DE MRI; white matter; ventricular size; survival; aging; cardiovascular disease ID PROGRESS PERINDOPRIL PROTECTION; OLDER-ADULTS; ALZHEIMERS-DISEASE; VASCULAR DEMENTIA; COGNITIVE DECLINE; ELDERLY-PEOPLE; RISK-FACTORS; SYSTOLIC HYPERTENSION; HYPERINTENSITY VOLUME; RECURRENT STROKE AB High white mattergrade (WMG) on magnetic resonance imaging (MRI) is a risk factor for dementia, stroke and disability. Higher ventricular Z, size is a marker of brain "atrophy." In the Cardiovascular Health Study (CHS) (it = 3245) mean age 75 years, 50% black and 40% men, we Z, evaluated WM and ventricular grade (VG), total, cardiovascular and noncardiovascular mortality and longevity before and after adjusting C for numerous determinants of longevity over an approximate 10- 12 years of follow-up. A low WMG and VG was a marker for low total, cardiovascular and noncardiovascular mortality and for increased longevity over 10+ years Of follow-up. We estimated that a 75-year-old with WMG below median would have about a 5-6 years greater longevity and for VG about 3 years, than above the median even after adjustment for numerous risk factors. Low WMG and VG on MRI is a powerful determinant of long-term survival among older individuals. (C) 2006 Elsevier Inc. All rights reserved. C1 Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15213 USA. Univ Washington, Dept Biostat, Seattle, WA USA. Univ Washington, Dept Neurol, Seattle, WA USA. Univ Washington, Dept Epidemiol, Seattle, WA USA. Natl Heart Lung & Blood Inst, Div Epidemiol & Clin Applicat, Bethesda, MD USA. Tufts Univ New England Med Ctr, Dept Radiol, Boston, MA USA. Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC USA. Johns Hopkins Univ, Dept Med, Ctr Aging & Hlth, Baltimore, MD USA. Johns Hopkins Univ, Dept Epidemiol, Ctr Aging & Hlth, Baltimore, MD USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA USA. RP Kuller, LH (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, 130 N Bellefield Ave,Rm 550, Pittsburgh, PA 15213 USA. EM kullerl@edc.pitt.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU NHLBI NIH HHS [N01-HC-15103, N01-HC-15129, N01-HC-85086]; PHS HHS [N01-85079] NR 61 TC 41 Z9 41 U1 0 U2 1 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 SEP PY 2007 VL 28 IS 9 BP 1307 EP 1315 DI 10.1016/j.neurobiolaging.2006.06.010 PG 9 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 198DX UT WOS:000248608300002 PM 16857296 ER PT J AU Peila, R Yucesoy, B White, LR Johnson, V Kashon, ML Wu, K Petrovitch, H Luster, M Launer, LJ AF Peila, Rita Yucesoy, Berran White, Lon R. Johnson, Victor Kashon, Michael L. Wu, Kim Petrovitch, Helen Luster, Michael Launer, Lenore J. TI A TGF-beta 1 polymorphism association with dementia and neuropathologies: The HAAS SO NEUROBIOLOGY OF AGING LA English DT Article DE transforming growth factor-beta 1; dementia; cerebral microinfarcts ID TRANSFORMING GROWTH-FACTOR-BETA-1 GENE; JAPANESE-AMERICAN MEN; CEREBRAL AMYLOID ANGIOPATHY; ALZHEIMERS-DISEASE; GROWTH FACTOR-BETA(1); MYOCARDIAL-INFARCTION; BLOOD-PRESSURE; RABBIT MODEL; ISCHEMIA; BRAIN AB The transforming growth factor-beta 1 (TGF-beta 1) is involved in post-ischemic neuronal rescue and in P-amyloid turn-over. We hypothesized that the risk for dementia and related neuropathologies is modified by the TGF-beta 1 functional genetic variants. The association of the TGF-beta 1 + 29T ->) C polymorphism with dementia was examined in a sample of 261 cases and 491 controls from the Honolulu-Asia Aging Study, including 282 subjects with autopsy data. Dementia was assessed in 1991 and 1994 by a multi-step protocol and standardized diagnostic criteria. The analysis was adjusted for demographic and vascular factors. Compared to the TT genotype, the TC and the CC genotypes were associated with a reduced risk for vascular dementia (ORTC = 0.28, 95% confidence interval (CI): 0. 1-0.9; ORcc = 0.28, CI: 0. 1-0.9), microinfarcts (ORCC = 0.3 1, CI: 0. 13-0.7 1) and cerebral amyloid angiopathy (ORCC = 0.48, CI: 0.2-0.9). The CC genotype was associated with an increase risk of neocortical plaques (ORCC =4.34, CI: 1.6-11.8). These preliminary data suggest that the TGF genetic variability may be important in the risk of vascular related dementia. (C) 2006 Published by Elsevier Inc. C1 NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. Pacific Hlth Res Inst, Honolulu, HI 96813 USA. NIOSH, Toxicol & Mol Biol Branch, Morgantown, WV USA. Univ Hawaii Manoa, John A Burns Sch Med, Dept Geriatr Med, Honolulu, HI 96822 USA. NIOSH, Hlth Effects Lab Div, Biostat Branch, Morgantown, WV USA. RP Peila, R (reprint author), NIA, Lab Epidemiol Demog & Biometry, NIH, 7201 Wisconsin Ave Suite 3C-309, Bethesda, MD 20892 USA. EM peilar@mail.nih.gov RI Yucesoy, Berran/B-4497-2009 FU Intramural NIH HHS; NHLBI NIH HHS [N01-HC-0-5102]; NIA NIH HHS [N01-AG-4-2149, R01-AG-0-7155-06A1, UO1-AG-0-9349-03]; NIEHS NIH HHS [Y1-ES-0001] NR 41 TC 20 Z9 21 U1 0 U2 1 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 SEP PY 2007 VL 28 IS 9 BP 1367 EP 1373 DI 10.1016/j.neurobiolaging.2006.06.004 PG 7 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 198DX UT WOS:000248608300008 PM 16904244 ER PT J AU Brynczka, C Merrick, BA AF Brynczka, Christopher Merrick, Bruce Alex TI Nerve growth factor potentiates p53 DNA binding but inhibits nitric oxide-induced apoptosis in neuronal PC12 cells SO NEUROCHEMICAL RESEARCH LA English DT Article DE NO; PC12; mitochondria; differentiation; NGF; p53 ID HUMAN LYMPHOBLASTOID-CELLS; WILD-TYPE P53; PHEOCHROMOCYTOMA CELLS; SYMPATHETIC NEURONS; HEME OXYGENASE-1; MEMBRANE PERMEABILIZATION; NEUROTROPHIC FACTORS; NEURITE OUTGROWTH; SIGNALING PATHWAY; SUBSTANTIA-NIGRA AB NGF is recognized for its role in neuronal differentiation and maintenance. Differentiation of PC12 cells by NGF involves p53, a transcription factor that controls growth arrest and apoptosis. We investigated NGF influence over p53 activity during NO-induced apoptosis by sodium nitroprusside in differentiated and mitotic PC12 cells. NGF-differentiation produced increased p53 levels, nuclear localization and sequence-specific DNA binding. Apoptosis in mitotic cells also produced these events but the accompanying activation of caspases 1-10 and mitochondrial depolarization were inhibited during NGF differentiation and could be reversed in p53-silenced cells. Transcriptional regulation of PUMA and survivin expression were not inhibited by NGF, although NO-induced mitochondrial depolarization was dependent upon de novo gene transcription and only occurred in mitotic cells. We conclude that NGF mediates prosurvival signaling by increasing factors such as Bcl-2 and p21(Waf1/Cip1) without altering p53 transcriptional activity to inhibit mitochondrial depolarization, caspase activation and apoptosis. C1 Natl Inst Environm Hlth Sci, Natl Ctr Toxicogenom, NIH, Res Triangle Pk, NC 27709 USA. N Carolina State Univ, Dept Environm & Mol Toxicol, Raleigh, NC 27606 USA. RP Merrick, BA (reprint author), Natl Inst Environm Hlth Sci, Natl Ctr Toxicogenom, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM merrick@niehs.nih.gov FU Intramural NIH HHS [Z01 ES023012-13] NR 76 TC 10 Z9 11 U1 1 U2 2 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0364-3190 J9 NEUROCHEM RES JI Neurochem. Res. PD SEP PY 2007 VL 32 IS 9 BP 1573 EP 1585 DI 10.1007/s11064-007-9362-5 PG 13 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 192GZ UT WOS:000248190200018 PM 17592775 ER PT J AU Aravamuthan, BR Muthusamy, KA Stein, JF Aziz, TZ Johansen-Berg, H AF Aravamuthan, B. R. Muthusamy, K. A. Stein, J. F. Aziz, T. Z. Johansen-Berg, H. TI Topography of cortical and subcortical connections of the human pedunculopontine and subthalamic nuclei SO NEUROIMAGE LA English DT Article ID DEEP BRAIN-STIMULATION; MESENCEPHALIC LOCOMOTOR REGION; MULTIPLE FIBER ORIENTATIONS; ADVANCED PARKINSONS-DISEASE; BASAL-GANGLIA; TEGMENTAL NUCLEUS; SQUIRREL-MONKEY; DIFFUSION TRACTOGRAPHY; MESOPONTINE TEGMENTUM; MOVEMENT-DISORDERS AB Deep brain stimulation (DBS) ofthe subthalamic nucleus (STN) is the most common surgical therapy for Parkinson' s disease (PD). DBS of the pedunculopontine nucleus (PPN) is emerging as a promising surgical therapy for PD as well. In order to better characterize these nuclei in humans, we determined the anatomical connections of the PPN and STN and the topography of these connections using probabilistic diffusion tractography. Diffusion tractography was carried out in eight healthy adult subjects using diffusion data acquired at 1.5 T MRI (60 directions, b=1000 S/MM2, 2x2x2 MM3 voxels). The major connections that we identified from single seed voxels within STN or PPN were present in at least half the subjects and the topography of these connections within a 36-voxel region surrounding the initial seed voxel was then examined. Both the PPN and STN showed connections with the cortex, basal ganglia, cerebellum, and down the spinal cord, largely matching connections demonstrated in primates. The topography of motor and associative brain areas in the human STN was strikingly similar to that shown in animals. PPN Topography has not been extensively demonstrated in animals, but we showed significant topography of cortical and subcortical connections in the human PPN. In addition to demonstrating the usefulness ofPDT in determining the connections and topography of small grey matter structures in vivo, these results allow for inference of optimal DBS target locations and add to our understanding of the role of these nuclei in PD. (c) 2007 Elsevier Inc. All rights reserved. C1 Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3PT, England. NINDS, Bethesda, MD 20892 USA. Radcliffe Infirm, Dept Neurol Surg, Oxford OX2 6HE, England. John Radcliffe Hosp, Oxford Ctr Funct MRI Brain, Oxford OX3 9DU, England. RP Aravamuthan, BR (reprint author), Univ Oxford, Dept Physiol Anat & Genet, Sherrington Bldg,Parks Rd, Oxford OX1 3PT, England. EM bhooma.aravamuthan@dpag.ox.ac.uk RI BIN ABDULLAH, KAMAL AZRIN/B-8735-2010; OI Johansen-Berg, Heidi/0000-0002-4134-9730 FU Medical Research Council [G0200561]; Wellcome Trust [078204] NR 59 TC 104 Z9 107 U1 0 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 SEP 1 PY 2007 VL 37 IS 3 BP 694 EP 705 DI 10.1016/j.neuroimage.2007.05.050 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 206BZ UT WOS:000249160200002 PM 17644361 ER PT J AU Chen, BS Roche, KW AF Chen, Bo-Shiun Roche, Katherine W. TI Regulation of NMDA receptors by phosphorylation SO NEUROPHARMACOLOGY LA English DT Review DE NMDA receptors; phosphorylation; kinase; glutamate ID D-ASPARTATE RECEPTOR; PROTEIN-KINASE-C; ER RETENTION SIGNAL; NR2B SUBUNIT; NR1 SUBUNIT; TYROSINE PHOSPHORYLATION; SYNAPTIC PLASTICITY; HIPPOCAMPAL-NEURONS; REGIONAL EXPRESSION; SURFACE EXPRESSION AB N-Methyl-D-aspartate (NMDA) receptors are critical for neuronal development and synaptic plasticity. The molecular mechanisms underlying the synaptic localization and functional regulation of NMDA receptors have been the subject of extensive studies. In particular, phosphorylation has emerged as a fundamental mechanism that regulates NMDA receptor trafficking and can alter the channel properties of NMDA receptors. Here we summarize recent advances in the characterization of NMDA receptor phosphorylation, emphasizing subunit-specific phosphorylation, which differentially controls the trafficking and surface expression of NMDA receptors. Published by Elsevier Ltd. C1 NINDS, NIH, Bethesda, MD 20892 USA. RP Chen, BS (reprint author), NINDS, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM chenbos@ninds.nih.gov RI Chen, Bo-Shiun/E-2736-2010; Chen, Bo-Shiun/H-4633-2012; OI Roche, Katherine/0000-0001-7282-6539 FU Intramural NIH HHS [Z01 NS002994-06] NR 87 TC 183 Z9 190 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0028-3908 J9 NEUROPHARMACOLOGY JI Neuropharmacology PD SEP PY 2007 VL 53 IS 3 BP 362 EP 368 DI 10.1016/j.neuropharm.2007.05.018 PG 7 WC Neurosciences; Pharmacology & Pharmacy SC Neurosciences & Neurology; Pharmacology & Pharmacy GA 211GM UT WOS:000249512300002 PM 17644144 ER PT J AU Smith, GS Gunning-Dixon, FM Lotrich, FE Taylor, WD Evans, JD AF Smith, Gwenn S. Gunning-Dixon, Faith M. Lotrich, Francis E. Taylor, Warren D. Evans, Jovier D. TI Translational research in late-life mood disorders: Implications for future intervention and prevention research SO NEUROPSYCHOPHARMACOLOGY LA English DT Review DE geriatric depression; genetics; magnetic resonance imaging; positron emission tomography (PET); neuropsychology; psychopharmacology ID POSITRON-EMISSION-TOMOGRAPHY; RECURRENT MAJOR DEPRESSION; SEROTONIN TRANSPORTER GENE; MRI SIGNAL HYPERINTENSITIES; INDUCED DOPAMINE RELEASE; AGE-RELATED DIFFERENCES; CHRONIC ANTIDEPRESSANT TREATMENT; WHITE-MATTER HYPERINTENSITIES; GLUCOCORTICOID-RECEPTOR GENE; DEFINED VASCULAR DEPRESSION AB Clinical and epidemiological studies have consistently observed the heterogeneous symptomatology and course of geriatric depression. Given the importance of genetic and environmental risk factors, aging processes, neurodegenerative and cerebrovascular disease processes, and medical comorbidity, the integration of basic and clinical neuroscience research approaches is critical for the understanding of the variability in illness course, as well as the development of prevention and intervention strategies that are more effective. These considerations were the impetus for a workshop, sponsored by the Geriatrics Research Branch in the Division of Adult Translational Research and Treatment Development of the National Institute of Mental Health that was held on September 7-8, 2005. The primary goal of the workshop was to bring together investigators in geriatric psychiatry research with researchers in specific topic areas outside of geriatric mental health to identify priority areas to advance translational research in geriatric depression. As described in this report, the workshop focused on a discussion of the development and application of integrative approaches combining genetics and neuroimaging methods to understand such complex issues as treatment response variability, the role of medical comorbidity in depression, and the potential overlap between depression and dementia. Future directions for integrative research were identified. Understanding the nature of geriatric depression requires the application of translational research and interdisciplinary research approaches. Geriatric depression could serve as a model for translational research integrating basic and clinical neuroscience approaches that would have implications for the study of other neuropsychiatric disorders. C1 Univ Toronto, Fac Med, Dept Psychiat, Ctr Addict & Mental Hlth,PET Ctr, Toronto, ON M5T 1R8, Canada. Zucker Hillside Hosp, Dept Psychiat Res, Glen Oaks, NY USA. Cornell Univ, Weil Med Coll, Dept Psychiat, White Plains, NY USA. Univ Pittsburgh, Western Psychiat Inst & Clin, Dept Psychiat, Pittsburgh, PA 15213 USA. Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC USA. NIMH, Geriatr Res Branch, Geriatr Translat Neurosci & Psychopharmacol Inven, Bethesda, MD 20892 USA. RP Smith, GS (reprint author), Univ Toronto, Fac Med, Dept Psychiat, Ctr Addict & Mental Hlth,PET Ctr, 250 Coll St, Toronto, ON M5T 1R8, Canada. EM gwenn_smith@camh.net RI Taylor, Warren/J-3687-2014 FU NIMH NIH HHS [R01 MH 064823, K02 MH 01621, K23 MH 074012, K23 MH 074818, K23 MH 65939] NR 260 TC 30 Z9 30 U1 4 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD SEP PY 2007 VL 32 IS 9 BP 1857 EP 1875 DI 10.1038/sj.npp.1301333 PG 19 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 200US UT WOS:000248788900001 PM 17327888 ER PT J AU Cao, JR Belluzzi, JD Loughlin, SE Keyler, DE Pentel, PR Leslie, FM AF Cao, Junran Belluzzi, James D. Loughlin, Sandra E. Keyler, Daniel E. Pentel, Paul R. Leslie, Frances M. TI Acetaldehyde, a major constituent of tobacco smoke, enhances behavioral, endocrine, and neuronal responses to nicotine in adolescent and adult rats SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE age; anxiety; c-fos; locomotion; paraventricular nucleus; stress ID POSTERIOR PARAVENTRICULAR THALAMUS; CONDITIONED PLACE PREFERENCE; MESSENGER-RNA; PLASMA ACTH; BRAIN; RESPONSIVENESS; STRESS; AGE; VULNERABILITY; MECHANISMS AB We have previously shown that acetaldehyde, a constituent of tobacco smoke, increases nicotine self-administration in adolescent, but not adult, rats. The aim of this study was to determine whether acetaldehyde influences other behavioral, endocrine, or neuronal responses to nicotine at either age. Juvenile ( postnatal day (P) 27) and adult (P90) male Sprague - Dawley rats were treated with saline, acetaldehyde (16 mg/kg/injection x 2, i.v.), nicotine (30 mg/kg/injection x 2, i.v.) or a combination of acetaldehyde and nicotine. Locomotion and center time were evaluated for 30 min in a novel open field, before measurement of plasma corticosterone levels and brain c-fos mRNA. Nicotine increased locomotor activity in juveniles but decreased it in adults; in contrast, center time was increased at both ages. Acetaldehyde potentiated nicotine's locomotor effects, but not center time. Nicotine induced c-fos expression in the bed nucleus of the stria terminalis, the central nucleus of the amygdala (CeA), nucleus accumbens, and the superior colliculus (SC) at both ages, whereas it activated the hypothalamic paraventricular nucleus (PVN) and consequent corticosterone secretion only in adults. Acetaldehyde potentiated nicotine-induced c-fos in CeA and SC, and activation of PVN c-fos expression/plasma corticosterone release; however, this drug interaction was only observed in behaviorally tested animals, not those that were minimally stressed. Thus, acetaldehyde may modulate the interaction of nicotine and stress. Although pharmacokinetic studies showed that acetaldehyde did not change nicotine levels in either brain or serum, nicotine penetration into the brain was slower in juveniles as compared to adults. C1 Natl Inst Drug Abuse, NIH, Behav Neurosci Branch, Intramural Res Program,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. Univ Calif Irvine, Sch Med, Dept Anat & Neurobiol, Irvine, CA 92717 USA. Univ Calif Irvine, Sch Med, Dept Pharmacol, Irvine, CA 92717 USA. Univ Minnesota, Dept Med, Minneapolis, MN 55455 USA. Univ Minnesota, Coll Pharm, Minneapolis, MN 55455 USA. RP Cao, JR (reprint author), Natl Inst Drug Abuse, NIH, Behav Neurosci Branch, Intramural Res Program,Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM caoju@mail.nih.gov RI Cao, Junran/N-9914-2013; Cao, Junran/E-7354-2013 FU NIDA NIH HHS [DA 19138, DA 21267] NR 57 TC 38 Z9 38 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD SEP PY 2007 VL 32 IS 9 BP 2025 EP 2035 DI 10.1038/sj.npp.1301327 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 200US UT WOS:000248788900018 PM 17287824 ER PT J AU Roy, A Hu, XZ Janal, MN Goldman, D AF Roy, Alec Hu, Xian-Zhang Janal, Malvin N. Goldman, David TI Interaction between childhood trauma and serotonin transporter gene variation in suicide SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE suicide attempt; serotonin; transporter; gene; interaction; life-events ID STRESSFUL LIFE EVENTS; CSF MONOAMINE METABOLITE; CEREBROSPINAL-FLUID; MAJOR DEPRESSION; RHESUS-MONKEYS; FOLLOW-UP; INTERINDIVIDUAL DIFFERENCES; 5-HTTLPR POLYMORPHISM; DEPENDENT PATIENTS; RISK-FACTORS AB Although the serotonin transporter promoter polymorphism (5-HTTLPR) contributes to depression and suicidality in a fashion modulated by environmental stress, 5-HTTLPR has been little examined in relation to suicidal behavior in substance dependence. Recently, a third functional allele of 5-HTTLPR was discovered enabling more of the interindividual variation in serotonin transporter expression to be predicted by genotype. We examined whether the 5-HTTLPR gene alone, or interacting with childhood trauma, was predictive of suicidal behavior in substance-dependent patients, a clinical population that is at high risk of suicide, as well as childhood trauma and other stress. We interviewed 306 abstinent male African-American substance-dependent patients about whether they had ever attempted suicide and administered the 34-item Childhood Trauma Questionnaire (CTQ). Patients and 132 male African-American controls were genotyped to determine the S, L-G, and L-A 5-HTTLPR alleles; some analyses grouped the S and L-G alleles on the basis of equivalent function. The distribution of 5-HTTLPR genotypes did not differ between patients and controls, nor between suicide attempters and non-attempters. However, patients with low expression 5-HTTLPR genotypes and above-median CTQ scores were more likely to have attempted suicide. Logistic regression showed increasing risk of a suicide attempt with increasing reports of childhood trauma scores; in addition, this increase was exaggerated among those with low expression forms of the 5-HTTLPR genotype. Childhood trauma interacts with low expressing 5-HTTLPR genotypes to increase the risk of suicidal behavior among patients with substance dependence. C1 NJHCS, Dept Vet Affairs, Psychiat Serv 116A, E Orange, NJ 07018 USA. NIAAA, NIH, Lab Neurogenet, Rockville, MD 20852 USA. Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Psychiat, Newark, NJ 07103 USA. RP Roy, A (reprint author), NJHCS, Dept Vet Affairs, Psychiat Serv 116A, 385 Tremont Ave, E Orange, NJ 07018 USA. EM Alec.Roy@med.va.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 47 TC 97 Z9 99 U1 3 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD SEP PY 2007 VL 32 IS 9 BP 2046 EP 2052 DI 10.1038/sj.npp.1301331 PG 7 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 200US UT WOS:000248788900020 PM 17356577 ER PT J AU Bian, XW Yang, SX Chen, LH Ping, YF Zhou, XD Wang, QL Jiang, XF Gong, WH Xiao, HL Du, LL Chen, ZQ Zhao, W Shi, LQ Wang, JM AF Bian, Xiu-Wu Yang, Shi-Xin Chen, Lian-Hong Ping, Yi-Fang Zhou, Xiang-Dong Wang, Qing-Liang Jiang, Xue-Feng Gong, Wanghua Xiao, Hua-Liang Du, Lin-Lin Chen, Zi-Qiang Zhao, Wen Shi, Ling-Quan Wang, Ji Ming TI Preferential expression of chemokine receptor CXCR4 by highly malignant human gliomas and its association with poor patient survival SO NEUROSURGERY LA English DT Article DE angiogenesis; chemotaxis; CXCR4; glioma; vascular endothelial growth factor ID BREAST-CANCER METASTASIS; MICROVASCULAR ENDOTHELIAL-CELLS; FORMYL-PEPTIDE RECEPTORS; LYMPH-NODE METASTASIS; FORMYLPEPTIDE RECEPTOR; OVARIAN-CANCER; GROWTH-FACTOR; UP-REGULATION; TUMOR-GROWTH; FACTOR-I AB OBJECTIVE: CXCR4 is implicated in the growth, metastasis, and angiogenesis of malignant tumors. We investigated the potential role of CXCR4 in human gliomas. METHODS: The expression of CXCR4 messenger ribonucleic acid and protein by human glioma cell lines was examined by reverse-transcriptase polymerase chain reaction and immunocytochemistry analysis. Tumor cell chemotaxis and production of vascular endothelial growth factor induced by the CXCR4 ligand SDF-1 beta were measured. Xenograft models were used for evaluation of glioma cell tumorigenesis. CXCR4 expression by xenografted tumors and primary human glioma specimens were evaluated for CXCR4 protein expression. The relationship between CXCR4 expression and patient survival was analyzed. A synthetic lipoxygenase inhibitor, Nordy, was tested for its effects on glioma cell expression and function of CXCR4, as well as on glioma cell tumorigenicity. RESULTS: CXCR4 expression correlated directly with the degree of malignancy of the human glioma cell lines and primary tumors. Activation of CXCR4 induced tumor cell chemotaxis and increased production of vascular endothelial growth factor. Glioma cells expressing higher levels of CXCR4 formed more rapidly growing and lethal tumors in nude mice. Primary human glioma specimens expressing CXCR4 contained high-density microvessels. Patients with CXCR4-positive gliomas had poorer prognosis after surgery. The lipoxygenase inhibitor Nordy diminished CXCR4 expression by glioma cell lines in vitro and reduced their tumorigenicity in nude mice. CONCLUSION: The level of CXCR4 expression seems to correlate with the degree of malignancy of human gliomas and may contribute to their rapid growth. C1 Third Mil Med Univ, Southwest Hosp, Inst Pathol, Chongqing 400038, Peoples R China. Third Mil Med Univ, Southwest Hosp, Dept Pharm, Chongqing 400038, Peoples R China. SAIC Frederick Inc, Basic Res Program, Frederick, MD USA. NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, NIH, Frederick, MD 21702 USA. RP Bian, XW (reprint author), Third Mil Med Univ, Southwest Hosp, Inst Pathol, Gaotanyan 30, Chongqing 400038, Peoples R China. EM bianxiuwu@263.net RI Bian, Xiuwu/F-1569-2011; Bian, Xiu-wu/D-4736-2017 OI Bian, Xiu-wu/0000-0003-4383-0197 NR 47 TC 67 Z9 69 U1 1 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-396X J9 NEUROSURGERY JI Neurosurgery PD SEP PY 2007 VL 61 IS 3 BP 570 EP 578 DI 10.1227/01.NEU.0000255478.83376.EF PG 9 WC Clinical Neurology; Surgery SC Neurosciences & Neurology; Surgery GA 214FE UT WOS:000249720600044 PM 17881971 ER PT J AU Mcchetti, I Bachis, A Nosheny, RL Tanda, G AF Mcchetti, Italo Bachis, Alessia Nosheny, Rachel L. Tanda, Gianluigi TI Brain-derived neurotrophic factor expression in the substantia nigra does not change after lesions of Dopaminergic neurons SO NEUROTOXICITY RESEARCH LA English DT Article DE neuronal apoptosis; tyrosine hydroxylase; HIV-associated dementia; BDNF; gp120; MPTP; dopamine ID MPTP MOUSE MODEL; BDNF VAL66MET POLYMORPHISM; PARKINSONS-DISEASE; MESSENGER-RNA; HIV DEMENTIA; CELL-DEATH; IN-VIVO; NEURODEGENERATIVE DISEASES; ROTATIONAL BEHAVIOR; SEROTONERGIC AXONS AB Progressive and irreversible loss of specific neuronal cell populations is commonly seen in chronic neurodegenerative diseases such as Parkinson's disease (PD). Evidence is accumulating that apoptosis is a crucial cellular event responsible for the dysfunction and death of neurons in this disease. Thus, limiting apoptosis may prevent disease pathogenesis. Key to reducing apoptosis is the discovery of neuroprotective compounds that can be given to patients to minimize neuronal damage. In this manuscript, we reviewed the rationale of using an experimental strategy to provide neurotrophic support to injured neurons. Such rationale includes the increase of endogenous production of brain-derived neurotrophic factor (BDNF). BDNF is a potent inhibitor of apoptosis-mediated cell death and neurotoxin-induced degeneration of dopaminergic neurons. However, availability of BDNF may be reduced when dopaminergic neurons degenerate. Therefore, in this work, we have used two well-established neurotoxins for dopaminergic neurons, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and the HIV protein gp120, to examine whether degeneration of nigrostriatal fibers alters BDNF expression. Our data show that these neurotoxins do not decrease the levels of BDNF in the substantia nigra, suggesting that up-regulation of BDNF synthesis by pharmacological means may be a viable therapy to slow down the progress of PD and other neurodegenerative diseases. C1 Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20007 USA. Natl Inst Drug Abuse, DHHS, NIH, Baltimore, MD USA. RP Mcchetti, I (reprint author), Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20007 USA. EM moccheti@georgetown.edu RI Tanda, Gianluigi/B-3318-2009 OI Tanda, Gianluigi/0000-0001-9526-9878 NR 71 TC 1 Z9 1 U1 1 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1029-8428 J9 NEUROTOX RES JI Neurotox. Res. PD SEP PY 2007 VL 12 IS 2 BP 135 EP 143 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 228BL UT WOS:000250701900006 ER PT J AU Chadman, KK Woods, JH Stitzel, J AF Chadman, Kathryn K. Woods, James H. Stitzel, Jerry TI Chlorisondamine inhibits the nicotine-induced stimulation of c-fos in the pigeon brain for up to 2 weeks SO NICOTINE & TOBACCO RESEARCH LA English DT Article ID MOUSE-BRAIN; RAT-BRAIN; RECEPTOR SUBTYPES; ACETYLCHOLINE-RECEPTORS; CHOLINERGIC-RECEPTORS; ALPHA-BUNGAROTOXIN; HIGH-AFFINITY; BINDING; LOCALIZATION; INDUCTION AB Chlorisondamine is a charged molecule that acts as long-acting nicotinic antagonist in many species, including pigeon. Evidence indicates that, despite the charged nature of chlorisondamine, it blocks some central effects of nicotine. The present study examined the time course of chlorisondamine's blockade of nicotine-induced c-fos expression in the pigeon brain. Chlorisondamine's central blockade was examined from I hr to 28 days prior to nicotine administration. Nicotine stimulated increases in c-fos mRNA in the hippocampus, hyperstriatum accessorium, hyperstriatum ventrale, nucleus accumbens, bullbus olfactorius, paleostriatum augmentatum, and stratum griseum et fibrosum superficiale. Nicotinic receptors labeled by [I-125]-epibatidine were not always found in the same regions as nicotine-induced increases in c-fos expression. Acute chlorisondamine increased the level of c-fos mRNA in the cerebellum, hippocampus, hyperstriatum accessorium, locus parolfactorius, nucleus accumbens, tectum opticum, paleostriatum augmentatum, and stratum griseum et fibrosum superficiale but had no effect on its own 24 hr after administration. Chlorisondamine blocked nicotine-induced increases in c-fos RNA for 4 days in the nucleus accumbens, a week in the bulbus olfactorius, and 2 weeks in the stratum griseum et fibrosum superficiale. The time course of chlorisondamine's blockade of nicotine-induced c-fos expression is consistent with the time course of the ability of chlorisondamine to block behavioral and physiological responses to nicotine. C1 NIH, Lab Behav Neurosci, Bethesda, MD 20892 USA. Univ Michigan, Dept Pharmacol, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Psychol, Ann Arbor, MI 48109 USA. Univ Colorado, Inst Behav Genet, Boulder, CO 80309 USA. Univ Colorado, Dept Integrat Physiol, Boulder, CO 80309 USA. RP Chadman, KK (reprint author), NIH, Lab Behav Neurosci, Bldg 35 Room 1C-909,Mailstop 3730, Bethesda, MD 20892 USA. EM chadmank@mail.nih.gov OI STITZEL, JERRY/0000-0001-8161-6525 FU NIDA NIH HHS [DA14369, DA07267, DA00254] NR 43 TC 2 Z9 2 U1 0 U2 0 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 SEP PY 2007 VL 9 IS 9 BP 927 EP 936 DI 10.1080/14622200701540838 PG 10 WC Substance Abuse; Public, Environmental & Occupational Health SC Substance Abuse; Public, Environmental & Occupational Health GA 216CS UT WOS:000249856100004 PM 17763108 ER PT J AU Balaji, S Aravind, L AF Balaji, S. Aravind, L. TI The RAGNYA fold: a novel fold with multiple topological variants found in functionally diverse nucleic acid, nucleotide and peptide-binding proteins SO NUCLEIC ACIDS RESEARCH LA English DT Article ID PSI-BETA-BARRELS; CRYSTAL-STRUCTURE; DNA-POLYMERASE; TRANSFER-RNA; GYF DOMAIN; TRANSCRIPTIONAL REPRESSOR; 3-DIMENSIONAL STRUCTURE; RUDIMENTARY HOMOLOG; SEQUENCE ALIGNMENT; STRUCTURAL BASIS AB Using sensitive structure similarity searches, we identify a shared fold, RAGNYA, principally involved in nucleic acid, nucleotide or peptide interactions in a diverse group of proteins. These include the (R) under bar ibosomal proteins L3 and L1, (A) under bar TP-grasp modules, the (G) under bar YF domain, DNA-recombination proteins of the (N) under bar inB family from caudate bacteriophages, the C-terminal DNA-interacting domain of the (Y) under bar -family DNA polymerases, the uncharacterized enzyme (A) under bar MMECR1, the siRNA silencing repressor of tombusviruses, tRNA Wybutosine biosynthesis enzyme Tyw3p, DNA/RNA ligases and related nucleotidyltransferases and the Enhancer of rudimentary proteins. This fold exhibits three distinct circularly permuted versions and is composed of an internal repeat of a unit with two-strands and a helix. We show that despite considerable structural diversity in the fold, its representatives show a common mode of nucleic acid or nucleotide interaction via the exposed face of the sheet. Using this information and sensitive profile-based sequence searches: (1) we predict the active site, and mode of substrate interaction of the Wybutosine biosynthesis enzyme, Tyw3p, and a potential catalytic role for AMMECR1. (2) We provide insights regarding the mode of nucleic acid interaction of the NinB proteins, and the evolution of the active site of classical ATP-grasp enzymes and DNA/RNA ligases. (3) We also present evidence for a bacterial origin of the GYF domain and propose how this version of the fold might have been utilized in peptide interactions in the context of nucleoprotein complexes. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov FU Intramural NIH HHS NR 79 TC 22 Z9 22 U1 1 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 SEP PY 2007 VL 35 IS 17 BP 5658 EP 5671 DI 10.1093/nar/gkm558 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 227UO UT WOS:000250683500012 PM 17715145 ER PT J AU Kim, A Song, SH Brand, M Dean, A AF Kim, AeRi Song, Sang-hyun Brand, Marjorie Dean, Ann TI Nucleosome and transcription activator antagonism at human beta-globin locus control region DNase I hypersensitive sites SO NUCLEIC ACIDS RESEARCH LA English DT Article ID RNA-POLYMERASE-II; CHROMATIN DOMAIN ACTIVATION; HISTONE ACETYLATION PATTERN; ERYTHROID-CELLS; GENE-EXPRESSION; ENHANCER-BLOCKING; COMPLEX; METHYLTRANSFERASE; DIFFERENTIATION; METHYLATION AB Locus control regions are regulatory elements that activate distant genes and typically consist of several DNase I hypersensitive sites coincident with clusters of transcription activator binding sites. To what extent nucleosomes and activators occupy these sites together or exclusively has not been extensively studied in vivo. We analyzed the chromatin structure of human -globin locus control region hypersensitive sites in erythroid cells expressing embryonic and fetal globin genes. Nucleosomes were variably depleted at hypersensitive sites HS1-HS4 and at HS5 which flanks the 5 of the locus. In lieu of nucleosomes, activators were differentially associated with these sites. Erythroidspecific GATA-1 resided at HS1, HS2 and HS4 but the NF-E2 hetero-dimer was limited to HS2 where nucleosomes were most severely depleted. Histones H3 and H4 were hyperacetylated and H3 was di-methylated at K4 across the LCR, however, the H3 K4 MLL methyltransferase component Ash2L and histone acetyltransferases CBP and p300 occupied essentially only HS2 and the NF-E2 motif in HS2 was required for Ash2L recruitment. Our results indicate that each hypersensitive site in the human beta-globin LCR has distinct structural features and suggest that HS2 plays a pivotal role in LCR organization at embryonic and fetal stages of globin gene expression. C1 Pusan Natl Univ, Coll Nat Sci, Dept Mol Biol, Pusan 609735, South Korea. Ottawa Hlth Res Inst, Sprott Ctr Stem Cell Res, Ottawa, ON K1H 8LC, Canada. NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Kim, A (reprint author), Pusan Natl Univ, Coll Nat Sci, Dept Mol Biol, Pusan 609735, South Korea. EM kimaeri@pusan.ac.kr FU Intramural NIH HHS NR 56 TC 24 Z9 25 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 SEP PY 2007 VL 35 IS 17 BP 5831 EP 5838 DI 10.1093/nar/gkm620 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 227UO UT WOS:000250683500027 PM 17720709 ER PT J AU Hou, EW Prasad, R Asagoshi, K Masaoka, A Wilson, SH AF Hou, Esther W. Prasad, Rajendra Asagoshi, Kenjiro Masaoka, Aya Wilson, Samuel H. TI Comparative assessment of plasmid and oligonucleotide DNA substrates in measurement of in vitro base excision repair activity SO NUCLEIC ACIDS RESEARCH LA English DT Article ID POLYMERASE-BETA; INDUCED CYTOTOXICITY; MAMMALIAN-CELLS; MISMATCH REPAIR; UP-REGULATION; PROTEIN; RECONSTITUTION; EXTRACTS; PATHWAY; SITE AB Mammalian base excision repair (BER) is mediated through at least two subpathways designated single-nucleotide (SN) and long-patch (LP) BER (2-nucleotides long/more repair patch). Two forms of DNA substrate are generally used for in vitro BER assays: oligonucleotide- and plasmid-based. For plasmid-based BER assays, the availability of large quantities of substrate DNA with a specific lesion remains the limiting factor. Using sequence-specific endonucleases that cleave only one strand of DNA on a double-stranded DNA substrate, we prepared large quantities of plasmid DNA with a specific lesion. We compared the kinetic features of BER using plasmid and oligonucleotide substrates containing the same lesion and strategic restriction sites around the lesion. The K-m for plasmid DNA substrate was slightly higher than that for the oligonucleotide substrate, while the V-max of BER product formation for the plasmid and oligonucleotide substrates was similar. The catalytic efficiency of BER with the oligonucleotide substrate was slightly higher than that with the plasmid substrate. We conclude that there were no significant differences in the catalytic efficiency of in vitro BER measured with plasmid and oligonucleotide substrates. Analysis of the ratio of SN BER to LP BER was addressed using cellular extracts and a novel plasmid substrate. C1 Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, 101 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU Intramural NIH HHS NR 37 TC 12 Z9 12 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-1048 J9 NUCLEIC ACIDS RES JI Nucleic Acids Res. PD SEP PY 2007 VL 35 IS 17 AR e112 DI 10.1093/nar/gkm639 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 227UO UT WOS:000250683500005 PM 17720705 ER PT J AU Calzone, K Jenkins, J Badzek, L Debisette, A Feetham, S Hagan, P Hickey, J Kenner, C Krugman, M Lea, D Lewis, J Loud, J Mayor, RM McCloskey, DJ McGuinn, K Messmer, P Prows, C Thornson, E Turner, M Weaver, M Williams, J AF Calzone, Kathleen Jenkins, Jean Badzek, Laurie Debisette, Annette Feetham, Suzanne Hagan, Pamela Hickey, Joanne Kenner, Carole Krugman, Mary Lea, Dale Lewis, Judith Loud, Jennifer Mayor, Rosario-May McCloskey, Donna Jo McGuinn, Kathleen Messmer, Patricia Prows, Cynthia Thornson, Elizabeth Turner, Martha Weaver, Michael Williams, Janet TI Establishing and implementing the essential nursing competencies and curricula guidelines for genetics and genomics SO NURSING & HEALTH SCIENCES LA English DT Meeting Abstract C1 [Calzone, Kathleen] Natl Canc Inst, Bethesda, MD 20857 USA. [Debisette, Annette] US Hlth Resources & Serv Adm, Rockville, MD 20742 USA. [Feetham, Suzanne] Univ Maryland, College Pk, MD USA. [Hickey, Joanne] Amer Nurses Credentialing Ctr, Silver Spring, MD USA. [Kenner, Carole] Council Int Neonatal Nurses, Edmond, OK USA. [Krugman, Mary] Natl Nursing Staff Dev Org, Pensacola, FL USA. [Lewis, Judith] Virginia Commonwealth Univ, Richmond, VA USA. [Loud, Jennifer] Oncol Nursing Soc, Pittsburgh, PA USA. [Mayor, Rosario-May] Natl Coalit Eth Minor Nurses Assoc, Culver City, CA USA. [McCloskey, Donna Jo] Natl Inst Nursing, Bethesda, MD USA. [McGuinn, Kathleen] Amer Assoc Coll Nursing, Washington, DC USA. [Messmer, Patricia] Natl League Nursing Accrediting Commiss, New York, NY USA. [Prows, Cynthia] Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. [Weaver, Michael] Sigma Theta Tau, Indianapolis, IN USA. [Williams, Janet] Univ Iowa, Iowa City, IA USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1441-0745 J9 NURS HEALTH SCI JI Nurs. Health Sci. PD SEP PY 2007 VL 9 IS 3 BP 237 EP 237 PG 1 WC Nursing SC Nursing GA 272GV UT WOS:000253848800023 ER PT J AU Feetham, S Thomson, E AF Feetham, Suzanne Thomson, Elizabeth TI Focus on the family in the era of genetics and genomics SO NURSING & HEALTH SCIENCES LA English DT Meeting Abstract C1 [Feetham, Suzanne] Univ Wisconsin, Milwaukee Coll Nursing, Milwaukee, WI USA. [Thomson, Elizabeth] NHGRI, Natl Inst Hlth, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 2 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1441-0745 J9 NURS HEALTH SCI JI Nurs. Health Sci. PD SEP PY 2007 VL 9 IS 3 BP 240 EP 240 PG 1 WC Nursing SC Nursing GA 272GV UT WOS:000253848800033 ER PT J AU Pratt, CA Lemon, SC Fernandez, ID Goetzel, R Beresford, SA French, SA Stevens, VJ Vogt, TM Webber, LS AF Pratt, Charlotte A. Lemon, Stephenie C. Fernandez, Isabel Diana Goetzel, Ron Beresford, Shirley A. French, Simone A. Stevens, Victor J. Vogt, Thomas M. Webber, Larry S. TI Design characteristics of worksite environmental interventions for obesity prevention SO OBESITY LA English DT Review DE environmental-level interventions; individual-level interventions; physical activity; dietary intake ID HEALTH-PROMOTION PROGRAMS; QUESTIONNAIRE; DIETARY; PERSPECTIVE; VALIDITY; BEHAVIOR; WOMEN AB Objective: This paper describes the design characteristics of the National Heart, Lung, and Blood Institute (NHLBI)-funded studies that are testing innovative environmental interventions for weight control and obesity prevention at worksites. Research Methods and Procedures: Seven separate studies that have a total of 114 worksites (similar to 48,000 employees) across studies are being conducted. The worksite settings include hotels, hospitals, manufacturing facilities, businesses, schools, and bus garages located across the U.S. Each study uses its own conceptual model drawn from the literature and includes the socio-ecological model for health promotion, the epidemiological triad, and those integrating organizational and social contexts. The interventions, which are offered to all employees, include environmental- and individual-level approaches to improve physical activity and promote healthful eating practices. Environmental strategies include reducing portion sizes, modifying cafeteria recipes to lower their fat contents, and increasing the accessibility of fitness equipment at the workplace. Across all seven studies about 48% (N = 23,000) of the population is randomly selected for measurements. The primary outcome measure is change in BMI or body weight after two years of intervention. Secondary measures include waist circumference, objective, and self-report measures of physical activity, dietary intake, changes in vending machines and cafeteria food offerings, work productivity, healthcare use, and return on investment. Discussion: The results of these studies could have important implications for the design and implementation of worksite overweight and obesity control programs. C1 NHLBI, Div Epidemiol & Clin Applicat, Bethesda, MD 20892 USA. Univ Massachusetts, Sch Med, Div Prevent & Behav Med, Worcester, MA USA. Univ Rochester, Sch Med, Dept Community & Prevent Med, Rochester, NY USA. Cornell Univ, Inst Hlth Product Studies, Washington, DC USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Univ Washington, Canc Prevent Program, Seattle, WA 98195 USA. Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. Kaiser Fdn Hosp, Ctr Hlth Res, Honolulu, HI USA. Tulane Univ, Sch Publ Hlth, New Orleans, LA USA. RP Pratt, CA (reprint author), NHLBI, Div Epidemiol & Clin Applicat, 6701 Rockledge Dr, MSC 7936, Rm 10118, Bethesda, MD 20892 USA. EM prattc@nhlbi.nih.gov RI Goetzel, Ron/A-9670-2009 FU NHLBI NIH HHS [R01 HL79491, R01 HL79478, R01 HL79483, R01 HL79505, R01 HL79509, R01 HL79511, R01 HL79546] NR 29 TC 58 Z9 60 U1 5 U2 22 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1930-7381 J9 OBESITY JI Obesity PD SEP PY 2007 VL 15 IS 9 BP 2171 EP 2180 DI 10.1038/oby.2007.258 PG 10 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 219TK UT WOS:000250110900002 PM 17890484 ER PT J AU Saunders, CL Chiodini, BD Sham, P Lewis, CM Abkevich, V Adeyemo, AA de Andrade, M Arya, R Berenson, GS Blangero, J Boehnke, M Borecki, IB Chagnon, YC Chen, W Comuzzie, AG Deng, HW Duggirala, R Feitosa, MF Froguel, P Hanson, RL Hebebrand, J Huezo-Dias, P Kissebah, AH Li, WD Luke, A Martin, LJ Nash, M Ohman, M Palmer, LJ Peltonen, L Perola, M Price, RA Redline, S Srinivasan, SR Stern, MP Stone, S Stringham, H Turner, S Wijmenga, C Collier, DA AF Saunders, Catherine L. Chiodini, Benedetta D. Sham, Pak Lewis, Cathryn M. Abkevich, Victor Adeyemo, Adebowale A. de Andrade, Mariza Arya, Rector Berenson, Gerald S. Blangero, John Boehnke, Michael Borecki, Ingrid B. Chagnon, Yvon C. Chen, Wei Comuzzie, Anthony G. Deng, Hong-Wen Duggirala, Ravindranath Feitosa, Mary F. Froguel, Philippe Hanson, Robert L. Hebebrand, Johannes Huezo-Dias, Patricia Kissebah, Ahmed H. Li, Weidong Luke, Amy Martin, Lisa J. Nash, Matthew Ohman, Muena Palmer, Lyle J. Peltonen, Leena Perola, Markus Price, R. Arlen Redline, Susan Srinivasan, Sathanur R. Stern, Michael P. Stone, Steven Stringham, Heather Turner, Stephen Wijmenga, Cisca Collier, David A. TI Meta-analysis of genome-wide linkage studies in BMI and obesity SO OBESITY LA English DT Article DE diabetes; hypertension; genetics; meta-analysis; adiposity ID BODY-MASS INDEX; QUANTITATIVE-TRAIT LOCI; OBSTRUCTIVE SLEEP-APNEA; SUSCEPTIBILITY LOCUS; SEARCH METAANALYSIS; CHILDHOOD OBESITY; METABOLIC SYNDROME; DIABETES-MELLITUS; SCAN METAANALYSIS; BIPOLAR DISORDER AB Objective: The objective was to provide an overall assessment of genetic linkage data of BMI and BMI-defined obesity using a nonparametric genome scan meta-analysis. Research Methods and Procedures: We identified 37 published studies containing data on over 31,000 individuals from more than >10,000 families and obtained genome-wide logarithm of the odds (LOD) scores, non-parametric linkage (NPL) scores, or maximum likelihood scores (MLS). BMI was analyzed in a pooled set of all studies, as a subgroup of 10 studies that used BMI-defined obesity, and for subgroups ascertained through type 2 diabetes, hypertension, or subjects of European ancestry. Results: Bins at chromosome 13q13.2-q33.1, 12q23-q24.3 achieved suggestive evidence of linkage to BMI in the pooled analysis and samples ascertained for hypertension. Nominal evidence of linkage to these regions and suggestive evidence for 11q13.3-22.3 were also observed for BMI-defined obesity. The FTO obesity gene locus at 16q12.2 also showed nominal evidence for linkage. However, overall distribution of summed rank p values <0.05 is not different from that expected by chance. The strongest evidence was obtained in the families ascertained for hypertension at 9q31.1-qter and 12p11.21-q23 (p < 0.01). Conclusion: Despite having substantial statistical power, we did not unequivocally implicate specific loci for BMI or obesity. This may be because genes influencing adiposity are of very small effect, with substantial genetic heterogeneity and variable dependence on environmental factors. However, the observation that the FTO gene maps to one of the highest ranking bins for obesity is interesting and, while not a validation of this approach, indicates that other potential loci identified in this study should be investigated further. C1 Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, London SE5 8AF, England. Kings Coll London, Guys Kings & St Thomas Sch Med, London WC2R 2LS, England. Kings Coll London, Sch Med, Guys Kings Coll & St Thomas Hosp, Div Med & Mol Genet, London WC2R 2LS, England. Kings Coll London, Inst Psychiat, Div Psychol Med, London WC2R 2LS, England. Mario Negri Inst Pharmacol Res, Dept Cardiovasc Res, Milan, Italy. Myriad Genet Inc, Salt Lake City, UT USA. Howard Univ, Natl Human Genome Ctr, Genet Epidemiol Unit, Washington, DC 20059 USA. Mayo Clin, Div Biostat, Rochester, MN USA. Univ Texas, Hlth Sci Ctr, Dept Med Epidemiol, San Antonio, TX USA. Tulane Univ, Sch Publ Hlth & Trop Med, Ctr Cardiovasc Hlth, Dept Epidemiol, New Orleans, LA USA. Southwest Fdn Biomed Res, Dept Genet, San Antonio, TX USA. Washington Univ, Sch Med, Ctr Genome Sci, Div Stat Genom, St Louis, MO USA. Univ Laval, Res Ctr Robert Giffard, Genom Lab, Quebec City, PQ G1K 7P4, Canada. Creighton Univ, Med Ctr, Osteoporosis Res Ctr, Omaha, NE USA. Xi An Jiao Tong Univ, Sch Life Sci, Inst Genet Mol, Key Lab Biomed Informat Engn Minist Educ, Xian, Peoples R China. Hunan Normal Univ, Coll Life Sci, Lab Mol & Stat Genet, Changsha, Peoples R China. Imperial Coll London, Hammersmith Hosp, London, England. NIH, NIDDK, DECR, Phoenix, AZ USA. Univ Duisburg Essen, Dept Child & Adolescent Psichiat, Essen, Germany. Med Coll Wisconsin, TOPS Ctr Obes & Metal Res, Milwaukee, WI 53226 USA. Univ Penn, Ctr Neurobiol & Behav, Philadelphia, PA 19104 USA. Loyola Univ, Med Ctr, Dept Epidemiol & Prevent Med, Maywood, IL 60153 USA. Univ Cincinnati, Sch Med, Childrens Hosp & Med Ctr, Dept Pediat, Cincinnati, OH USA. Univ Helsinki, Dept Med Genet, Natl Publ Hlth Inst Biomed, Dept Mol Med, Helsinki, Finland. Univ Western Australia, Med Res Ctr, Inst Med Res, Perth, WA 6009, Australia. Harvard Univ, Broad Inst Massachusetts Technol, Cambridge, MA USA. Case Western Reserve Univ, Univ Hosp Cleveland, Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. Mayo Clin, Div Nephrol & Hypertens, Rochester, MN USA. Univ Groningen, Med Ctr, Dept Genet, Groningen, Netherlands. Univ Michigan, Dept Internal Med & Cardiol, Ann Arbor, MI 48109 USA. RP Collier, DA (reprint author), Kings Coll London, Inst Psychiat, Social Genet & Dev Psychiat Ctr, De Crespigny Pk, Denmark Hill, London SE5 8AF, England. EM d.collier@iop.kcl.ac.uk RI Sham, Pak Chung/C-4388-2009; Lewis, Cathryn/A-5225-2010; Wijmenga, Cisca/D-2173-2009; Palmer, Lyle/K-3196-2014; Hanson, Robert/O-3238-2015; Martin, Lisa/E-2425-2016; OI Lewis, Cathryn/0000-0002-8249-8476; Palmer, Lyle/0000-0002-1628-3055; Hanson, Robert/0000-0002-4252-7068; Martin, Lisa/0000-0001-8702-9946; Wijmenga, Cisca/0000-0002-5635-1614; Deng, Hong-Wen/0000-0002-0387-8818 FU NHLBI NIH HHS [HL-38,844, HL45508, HL47910, HL54464, HL54471-3, HL54495-7, HL54509, HL54515, R01 HL 71,917, R01 HL46380, R01 HL51021, U01 HL 67,893-902, U01 HL56563-9, U10 HL54481]; NIA NIH HHS [AG-16,592]; NIDDK NIH HHS [DK42273, DK47482, DK53889, R01 DK54261, R01 DK65598, R01DK44073, R01DK48095, R01DK56210]; PHS HHS [53,353] NR 72 TC 85 Z9 88 U1 0 U2 8 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 SEP PY 2007 VL 15 IS 9 BP 2263 EP 2275 DI 10.1038/oby.2007.269 PG 13 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 219TK UT WOS:000250110900013 PM 17890495 ER PT J AU Barnhart, KT Rosenberg, MJ MacKay, HT Blithe, DL Higgins, J Walsh, T Wan, L Thomas, M Creinin, MD Westhoff, C Schlaff, W Archer, DF Ayers, C Kaunitz, A Das, S Moench, TR AF Barnhart, Kurt T. Rosenberg, Michael J. MacKay, H. Trent Blithe, Diana L. Higgins, Jim Walsh, Terri Wan, Livia Thomas, Michael Creinin, Mitchell D. Westhoff, Carolyn Schlaff, William Archer, David F. Ayers, Charletta Kaunitz, Andrew Das, Sutapa Moench, Thomas R. TI Contraceptive efficacy of a novel spermicidal microbicide used with a diaphragm - A randomized controlled trial SO OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT Microbicides 2006 Conference CY APR 23-26, 2006 CL Cape Town, SOUTH AFRICA ID 1995 NATIONAL-SURVEY; CLINICAL-TRIALS; FAMILY GROWTH; GENITAL-TRACT; UNITED-STATES; MOUSE MODEL; IN-VITRO; NONOXYNOL-9; SAFETY; HIV AB OBJECTIVE: Women need products that protect against both pregnancy and sexually transmitted infections, including human immunodeficiency virus (HIV). The acid buffering gel is a nondetergent spermicide that may provide this dual protection by reinforcing normal vaginal acidity to inactivate both sperm and acid-sensitive sexually transmitted pathogens. The objective of this study was to assess the gel's contraceptive effects, safety, and acceptability. METHODS: We conducted a multicenter, randomized, double-masked, noninferiority study at 11 centers, comparing 621women who used an acid buffering gel plus diaphragm with 300 women who used a nonoxynol-9 spermicide plus diaphragm for 6 months. A double-masked study extension followed 234 women for an additional 6 months of use. RESULTS: The 6-month pregnancy rate per hundred women was 10.1% (95% confidence interval [CI] 7.1-13.1%) for acid buffering gel and 12.3 (95% Cl 7.7-16.9) for nonoxynol-9 spermicide users. The difference in rates was -2.2% with a 95% CI -7.7 to 3.3%. Consistent and correct use 6-month pregnancy rates were 4.7% for acid buffering gel and 6.1% for nonoxynol-9 spermicide users, calculated from those cycles where diary entries indicated such use. Adverse events and acceptability were similar between the two groups. Pregnancy probabilities were similar between groups participating in the 12-month study extension. CONCLUSION: An acid buffering gel used with a diaphragm is a safe, acceptable contraceptive with efficacy comparable to that of a common commercial spermicide with diaphragm. C1 Univ Penn, Med Ctr, Dept Obstet & Gynecol, Philadelphia, PA 19104 USA. Hlth Decis Inc, Chapel Hill, NC USA. NICHHD, Bethesda, MD 20892 USA. Calif Family Hlth Council Los Angelses, Los Angeles, CA USA. NYU, New York, NY USA. Univ Cincinnati, Cincinnati, OH USA. Univ Pittsburgh, Pittsburgh, PA USA. Magee Womens Res Inst, Pittsburgh, PA USA. Columbia Univ, New York, NY USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. Eastern Virginia Med Sch, CONRAD Clin Res Ctr, Norfolk, VA 23501 USA. Univ Med & Dent New Jersey, New Brunswick, NJ USA. Univ Florida, Hlth Sci Ctr, Jacksonville, FL 32209 USA. ReProtect Inc, Baltimore, MD USA. RP Barnhart, KT (reprint author), Univ Penn, Med Ctr, Dept Obstet & Gynecol, 3701 Market St 8th Floor, Philadelphia, PA 19104 USA. EM Kbamhart@obgn.upenn.edu FU NCATS NIH HHS [UL1 TR000005]; NCRR NIH HHS [M01RR000056, M01RR00096]; NICHD NIH HHS [N-01-HD-6-3261] NR 32 TC 38 Z9 39 U1 1 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 SEP PY 2007 VL 110 IS 3 BP 577 EP 586 DI 10.1097/01.AOG.0000278078.45640.13 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 205RQ UT WOS:000249132700007 PM 17766603 ER PT J AU Prater, CE Saleh, AD Wear, MP Miller, PS AF Prater, Chrissy E. Saleh, Anthony D. Wear, Maggie P. Miller, Paul S. TI Allosteric inhibition of the HIV-1 Rev/RRE interaction by a 3 '-methylphosphonate modified antisense Oligo-2 '-O-methylribonucleotide SO OLIGONUCLEOTIDES LA English DT Article ID REV-RESPONSIVE ELEMENT; RNA SECONDARY STRUCTURE; VIRUS TYPE-1 REPLICATION; MESSENGER-RNA; COMPLEX-FORMATION; TARGET SEQUENCE; NUCLEAR EXPORT; ALPHA-HELIX; TAT PROTEIN; BASE-PAIRS AB The HIV-1 Rev response element (RRE), a highly structured RNA sequence consisting of five stemloops, is found in all spliced and partially spliced human immunodeficiency virus (HIV) mRNA transcripts. The RRE interacts with HIV-encoded Rev protein, which facilitates exit of the transcripts from the nucleus to the cytoplasm. Because the Rev/ RRE interaction is critical to virus function, it is considered a potential target for therapeutic drugs. We have investigated the interactions of antisense oligonucleotides with stem- loop II, a region that contains the high- affinity binding site for Rev. Oligo-2'-O-methylribonucleotides terminating in a nuclease resistant 3'- methylphosphonate internucleotide linkage were targeted to the 5'- or 3'- side of stem- loop IIB, which is adjacent to the Rev binding site. Thermal denaturation experiments showed that oligonucleotides of this type form highly stable duplexes with complementary single- stranded RNA. Gel electrophoretic mobility shift assays (EMSA) showed that the oligonucleotides bound with high affinity and specificity at 37 degrees C to RRE stem- loop II RNA with apparent dissociation constants, K-D, in the low nM range. A 16- mer, 21mp, whose K-D is 46 nM, competitively inhibited binding of Rev peptide to RRE stem- loop II RNA as shown by EMSA experiments. When transfected into HEK 293T cells, 2- 1mp inhibited RRE mediated expression of chloramphenicol acetyl transferase ( CAT) by 60% at a concentration of 300 nM oligonucleotide. These results are consistent with a mechanism by which 2- 1mp blocks access of Rev to the RRE/ CAT transcript thus preventing nuclear export and subsequent translation. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, Baltimore, MD 21205 USA. Natl Inst Environm Sci, Lab Resp Biol, Res Triangle Pk, NC USA. RP Miller, PS (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biochem & Mol Biol, 615 N Wolfe St, Baltimore, MD 21205 USA. EM pmiller@jhsph.edu OI Prater, Chrissy/0000-0002-4247-2351 FU NIGMS NIH HHS [GM 057140] NR 43 TC 3 Z9 3 U1 0 U2 4 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1545-4576 J9 OLIGONUCLEOTIDES JI Oligonucleotides PD SEP PY 2007 VL 17 IS 3 BP 275 EP 290 DI 10.1089/oli.2007.0082 PG 16 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 211VW UT WOS:000249552400002 PM 17854268 ER PT J AU Woo, Y Wright, SM Maas, SA Alley, TL Caddle, LB Kamdar, S Affourtit, J Foreman, O Akeson, EC Shaffer, D Bronson, RT Morse, HC Roopenian, D Mills, KD AF Woo, Y. Wright, S. M. Maas, S. A. Alley, T. L. Caddle, L. B. Kamdar, S. Affourtit, J. Foreman, O. Akeson, E. C. Shaffer, D. Bronson, R. T. Morse, H. C., III Roopenian, D. Mills, K. D. TI The nonhomologous end joining factor Artemis suppresses multi-tissue tumor formation and prevents loss of heterozygosity SO ONCOGENE LA English DT Article DE nonhomologous end joining; RS-SCID; Artemis; loss of heterozygosity; p53 ID QUANTITATIVE GENE-EXPRESSION; GENOMIC INSTABILITY; P53-DEFICIENT MICE; DNA BREAKS; TRANSLOCATIONS; P53; IMMUNODEFICIENCY; DEFICIENCY; REPAIR; TUMORIGENESIS AB Nonhomologous end joining ( NHEJ) is a critical DNA repair pathway, with proposed tumor suppression functions in many tissues. Mutations in the NHEJ factor ARTEMIS cause radiation- sensitive severe combined immunodeficiency in humans and may increase susceptibility to lymphoma in some settings. We now report that deficiency for Artemis (encoded by Dclre1c/Art in mouse) accelerates tumorigenesis in several tissues in a Trp53 heterozygous setting, revealing tumor suppression roles for NHEJ in lymphoid and non- lymphoid cells. We also show that B- lineage lymphomas in these mice undergo loss of Trp53 heterozygosity by allele replacement, but arise by mechanisms distinct from those in Art Trp53 double null mice. These findings demonstrate a general tumor suppression function for NHEJ, and reveal that interplay between NHEJ and Trp53 loss of heterozygosity influences the sequence of multi-hit oncogenesis. We present a model where p53 status at the time of tumor initiation is a key determinant of subsequent oncogenic mechanisms. Because Art deficient mice represent a model for radiation-sensitive severe combined immunodeficiency, our findings suggest that these patients maybe at risk for both lymphoid and non- lymphoid cancers. C1 Jackson Lab, Bar Harbor, ME 04609 USA. Univ Maine, Functional Genom PhD Program, Orono, ME USA. Bar Harbor Biotechnol, Trenton, NJ USA. Tufts Univ, Sch Vet Med, Cummings Sch, Dept Biomed Sci, North Grafton, MA 01536 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. NIAID, Immunopathol Lab, Rockville, MD USA. RP Mills, KD (reprint author), Jackson Lab, 600 Main St, Bar Harbor, ME 04609 USA. EM kevin.mills@jax.org OI Morse, Herbert/0000-0002-9331-3705 FU NCI NIH HHS [R01 CA115665]; NICHD NIH HHS [T32 HD07065-27, T32 HD007065] NR 37 TC 16 Z9 16 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD SEP PY 2007 VL 26 IS 41 BP 6010 EP 6020 DI 10.1038/sj.onc.1210430 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 207US UT WOS:000249277200004 PM 17384673 ER PT J AU Lima, EG Bian, L Ng, KW Mauck, RL Byers, BA Tuan, RS Ateshian, GA Hung, CT AF Lima, E. G. Bian, L. Ng, K. W. Mauck, R. L. Byers, B. A. Tuan, R. S. Ateshian, G. A. Hung, C. T. TI The beneficial effect of delayed compressive loading on tissue-engineered cartilage constructs cultured with TGF-beta 3 SO OSTEOARTHRITIS AND CARTILAGE LA English DT Article DE cartilage; functional tissue engineering; TGF-beta 3; dynamic loading; serum-free media; well-defined media; growth factor supplementation ID GROWTH-FACTOR-BETA; BOVINE ARTICULAR-CARTILAGE; SEEDED AGAROSE GELS; CONFINED COMPRESSION; SEEDING DENSITY; REPAIR TISSUE; FACTOR-I; MATRIX; BIOSYNTHESIS; CHONDROCYTES AB Objective: To determine whether the functional properties of tissue-engineered constructs cultured in a chemically-defined medium supplemented briefly with TGF-beta 3 can be enhanced with the application of dynamic deformational loading. Methods: Primary immature bovine cells (2-3 months old) were encapsulated in agarose hydrogel (2%, 30 x 10(6) cells/ml) and cultured in chemically-defined medium supplemented for the first 2 weeks with transforming growth factor beta 3 (TGF-beta 3) (10 mu g/ml). Physiologic deformational loading (1 Hz, 3 h/day, 10% unconfined deformation initially and tapering to 2% peak-to-peak deformation by day 42) was applied either concurrent with or after the period of TGF-03 supplementation. Mechanical and biochemical properties were evaluated up to day 56. Results: Dynamic deformational loading applied concurrently with TGF-beta 3 supplementation yielded significantly lower (-90%) overall mechanical properties when compared to free-swelling controls. In contrast, the same loading protocol applied after the discontinuation of the growth factor resulted in significantly increased (+10%) overall mechanical properties relative to free-swelling controls. Equilibrium modulus values reach 1306 +/- 79 kPa and glycosaminoglycan levels reach 8.7 +/- 1.6% w.w. during this 8-week period and are similar to host cartilage properties (994 +/- 280 kPa, 6.3 +/- 0.9% w.w.). Conclusions: An optimal strategy for the functional tissue engineering of articular cartilage, particularly to accelerate construct development, may incorporate sequential application of different growth factors and applied deformational loading. (C) 2007 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. C1 Columbia Univ, Dept Biomed Engn, New York, NY 10027 USA. Univ Penn, Dept Orthopaed Surg, McKay Orthopaed Res Lab, Philadelphia, PA 19104 USA. NIAMSD, Cartilage Biol & Orthopaed Branch, Bethesda, MD 20892 USA. RP Hung, CT (reprint author), Columbia Univ, Dept Biomed Engn, 351 Engn Terrace MC8904,1210 Amsterdam Ave, New York, NY 10027 USA. EM cth6@columbia.edu RI Bian, Liming/A-7183-2011 OI Bian, Liming/0000-0003-4739-0918 FU NIAMS NIH HHS [AR46532, AR46568, R01 AR046568, R01 AR046568-07] NR 51 TC 156 Z9 159 U1 1 U2 9 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 SEP PY 2007 VL 15 IS 9 BP 1025 EP 1033 DI 10.1016/j.joca.2007.03.008 PG 9 WC Orthopedics; Rheumatology SC Orthopedics; Rheumatology GA 217YM UT WOS:000249983200006 PM 17498976 ER PT J AU Hediger, ML Kiely, JL AF Hediger, Mary L. Kiely, John L. TI Addressing gestational age measurement using birth certificate data - Foreword SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Editorial Material C1 NIH, Div Epidemiol Stat & Prevent Res, NICHHD, Bethesda, MD 20892 USA. RP Hediger, ML (reprint author), NIH, Div Epidemiol Stat & Prevent Res, NICHHD, Bldg 10, Bethesda, MD 20892 USA. NR 2 TC 5 Z9 5 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD SEP PY 2007 VL 21 SU 2 BP 1 EP 3 DI 10.1111/j.1365-3016.2007.00855.x PG 3 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 207IS UT WOS:000249245400001 ER PT J AU Lynch, CD Zhang, J AF Lynch, Courtney D. Zhang, Jun TI The research implications of the selection of a gestational age estimation method SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article; Proceedings Paper CT Workshop on Addressing Gestational Age Measurement Using Birth Certificate Data CY MAR 15, 2005-MAR 16, 2006 CL Atlanta, GA SP US Ctr Dis Control & Prevent DE gestational age; accuracy; post-term; LMP; ultrasound ID LAST MENSTRUAL PERIOD; RANDOMIZED CONTROLLED TRIAL; PRENATAL ULTRASOUND; BIPARIETAL DIAMETER; FETAL AGE; PREGNANCY; OVULATION; PRETERM; PREDICTION; CONCEPTION AB There are three primary methods of gestational age estimation: dating based on last menstrual period (LMP), ultrasound-based dating and neonatal estimates. We review the strengths and limitations of each method as well as their implications for research. Dating based on LMP is a simple, low-cost method of estimating gestational age. Limitations associated with the use of menstrual-based dating include reporting problems such as uncertainty regarding the LMP date, possibly due to bleeding not associated with menses, as well as concerns about the incidence of delayed ovulation, which can result in invalid estimates of gestation, even for women with certain LMP dates. Given that most women in the US have at least one ultrasound during pregnancy, it is becoming increasingly common for clinicians to verify menstrual dates using early ultrasound. To calculate gestational age with the use of ultrasound, fetal measurements are compared with a gestational age-specific reference. The primary limitation of this method is the fact that the gestational age estimates of symmetrically large or small fetuses will be biased. Further, given that ultrasound references were developed using pregnancies that were dated according to reliable LMP dates, they are potentially biased in the same direction as dates calculated according to LMP. Neonatal estimates of gestational age have been shown to be the least precise dating method. To highlight the research implications of the choice of a gestational dating method, we used data from the Routine Antenatal Diagnostic Imaging with Ultrasound Study to identify risk factors for post-term delivery. Risk factors for post-term delivery are shown to vary according to the choice of a gestational dating method, suggesting that some findings are an artefact of the choice of a method rather than evidence of causality. C1 NIH, NICHHD, Epidemiol Branch,Dept Hlth & Human Serv, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. RP Lynch, CD (reprint author), NICHD, NIH, DHHS, Epidemiol Branch,Div Stat & Prevent Res, 6100 Execut Blvd,Room 7B03P, Rockville, MD 20852 USA. EM lynchcd@mail.nih.gov FU Intramural NIH HHS; NICHD NIH HHS [HD19897, HD21017, HD21140] NR 53 TC 100 Z9 100 U1 1 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD SEP PY 2007 VL 21 SU 2 BP 86 EP 96 DI 10.1111/j.1365-3016.2007.00865.x PG 11 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 207IS UT WOS:000249245400011 PM 17803622 ER PT J AU Daniels, JL Rowland, AS Longnecker, MP Crawford, P Golding, J AF Daniels, Julie L. Rowland, Andrew S. Longnecker, Matthew P. Crawford, Peter Golding, Jean CA ALSPAC Study Team TI Maternal dental history, child's birth outcome and early cognitive development SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article DE maternal dental treatment; mercury; X-rays; birthweight; gestation; child development ID NATIONAL-WILMS-TUMOR; MERCURY EXPOSURE; PREGNANT-WOMEN; OCCUPATIONAL EXPOSURE; PERIODONTAL HEALTH; ELEMENTAL MERCURY; ORAL-HEALTH; IN-UTERO; METHYLMERCURY; WEIGHT AB Prenatal exposure to high levels of mercury, radiation and inflammation have been associated with adverse reproductive outcomes such as increases in preterm delivery, low birthweight and delayed neurodevelopment. Few data are available to evaluate the potential effects of prenatal low-level exposure to these factors as may occur during dental care. We evaluated maternal dental history prior to and during pregnancy in relation to birth outcomes and early communicative development among offspring in a large cohort (n = 7375) of British children born in 1991-92. Dental history was assessed by questionnaire. The child's communicative development was assessed using the MacArthur Communicative Development Inventory at 15 months of age. Total mercury was measured in umbilical cord tissue for a subset of the children. Overall, dental care, including amalgam fillings, was not associated with birth outcomes or language development. Having X-rays taken during pregnancy was not associated with birthweight measured continuously (b = 14.7, P = 0.4), but was associated with slightly increased odds of having a term, low-birthweight baby (OR 1.9, [95% confidence interval 1.0, 3.4]). More detailed evaluation of the potential adverse effects of elective dental treatment during pregnancy, particularly dental X-rays, may be warranted. C1 Univ N Carolina, Dept Epidemiol, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Maternal & Child Hlth, Chapel Hill, NC USA. Univ New Mexico, Dept Family & Community Med, MPH Program, Albuquerque, NM 87131 USA. Natl Inst Environm Hlth Sci, Dept Hlth & Human Serv, Res Triangle Pk, NC USA. Univ Bristol, Dept Community Based Med, Bristol, Avon, England. Univ Bristol, Sch Dent, Dept Paediat Dent, Bristol, Avon, England. RP Daniels, JL (reprint author), Univ N Carolina, Dept Epidemiol, CB 7435, Chapel Hill, NC 27599 USA. EM juliedaniels@unc.edu OI Longnecker, Matthew/0000-0001-6073-5322 FU Intramural NIH HHS [Z01 ES049021-12]; Medical Research Council [G9815508]; NIEHS NIH HHS [P30 ES010126, P30 ES10126, P30 ES012072] NR 53 TC 22 Z9 22 U1 0 U2 7 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD SEP PY 2007 VL 21 IS 5 BP 448 EP 457 DI 10.1111/j.1365-3016.2007.00819.x PG 10 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 206PZ UT WOS:000249196700008 PM 17697075 ER PT J AU Jacobs, SS Stork, LC Bostrom, BC Hutchinson, R Holcenberg, J Reaman, GH Erdmann, G Franklin, J Neglia, JP Steinberg, SM Balis, FM Adamson, PC AF Jacobs, Shana S. Stork, Linda C. Bostrom, Bruce C. Hutchinson, Ray Holcenberg, John Reaman, Gregory H. Erdmann, Gary Franklin, Janet Neglia, Joseph P. Steinberg, Seth M. Balis, Frank M. Adamson, Peter C. TI Substitution of oral and intravenous thioguanine for mercaptopurine in a treatment regimen for children with standard risk acute lymphoblastic leukemia: A collaborative children's oncology group/National Cancer Institute Pilot Trial (CCG-1942) SO PEDIATRIC BLOOD & CANCER LA English DT Article DE thioguanine nucleoticles; thiopurines; veno-occlusive disease ID ACUTE MYELOID-LEUKEMIA; THIOPURINE METHYLTRANSFERASE; METABOLITE CONCENTRATIONS; PHASE-I; CHILDHOOD; THERAPY; 6-MERCAPTOPURINE; 6-THIOGUANINE; PHARMACOKINETICS; CHEMOTHERAPY AB Background. Although mercaptopurine (MP) is conventionally used to treat childhood acute lymphoblastic leukemia (ALL), thioguanine (TG) is a more potent thiopurine in vitro and, when administered orally to patients, achieves cytotoxic drug concentrations in the cerebrospinal fluid (CSF). We performed a pilot study incorporating oral and 24-hr continuous IV infusion (CIVI) TG in children with newly diagnosed standard-risk ALL. Procedure. Children with newly diagnosed standard-risk ALL (age 1-10 years, WBC < 50 k) were eligible. Multi-agent chemotherapy was patterned after the Children's Cancer Group (CCG) 105 trial, with the addition of CIVI-TG (480 Mg/m(2)) during consolidation, interim maintenance and maintenance, and substitution of oral TG (60 Mg/m(2)/day) for oral MP during maintenance. Results. Fifty-eight patients (31 female), median age 4.3 years, were enrolled. At 8 years, the relapse-free and overall survival probabilities were 83% and 88%. There were no CNS relapses. Six patients (five males) experienced reversible veno-occlusive disease NOD) while receiving oral TG, and the study was amended to discontinue TG, changing all patients to oral MP. Red cell TG nucleotide concentrations during oral TG averaged 95 ng (570 pmol)/8 x 10(8) RBC, greater than concentrations reported with oral MP. Conclusion. Although the absence of CNS relapses in this pilot study suggests that TG may contribute to the prevention of CNS recurrences, the development of VOD negatively impacts the risk:benefit ratio of substituting TG for MP. C1 NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. Oregon Hlth & Sci Univ, Portland, OR USA. NIH, Biostat & Data Management Sect, CCR, Bethesda, MD 20892 USA. Childrens Hosp Penn, Philadelphia, PA USA. Childrens Hosp & Clin Minnesota, Minneapolis, MN USA. CS Mott Childrens Hosp, Ann Arbor, MI USA. Childrens Hosp & Med Ctr, Seattle, WA 98105 USA. Childrens Oncol Grp, Arcadia, CA USA. PRACS Inst Ltd, Fargo, ND USA. Childrens Hosp Los Angeles, Los Angeles, CA 90027 USA. Univ Minnesota, Ctr Canc, Minneapolis, MN USA. RP Jacobs, SS (reprint author), NCI, Pediat Oncol Branch, NIH, 10 Ctr Dr,Bldg 10,CRC Room 1-3872, Bethesda, MD 20892 USA. EM jacobss@mail.nih.gov FU NCI NIH HHS [U10 CA 13539, U10 CA 98543]; NCRR NIH HHS [M01 RR00069] NR 32 TC 11 Z9 12 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD SEP PY 2007 VL 49 IS 3 BP 250 EP 255 DI 10.1002/pbc.20964 PG 6 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 197EG UT WOS:000248536800006 PM 16856155 ER PT J AU Kontny, U Walsh, TJ Rossler, J Uhl, M Niemeyer, CM AF Kontny, Udo Walsh, Thomas J. Rossler, Jochen Uhl, Markus Niemeyer, Charlotte M. TI Successful treatment of refractory chronic disseminated candidiasis after prolonged administration of caspofungin in a child with acute myeloid leukemia SO PEDIATRIC BLOOD & CANCER LA English DT Article DE AML; infections in immunocompromised hosts; new agents; pediatric oncology ID LIPOSOMAL AMPHOTERICIN-B; HEPATOSPLENIC CANDIDIASIS; INVASIVE CANDIDIASIS; PEDIATRIC-PATIENTS; THERAPY; NEUTROPENIA; RESISTANT; SAFETY AB This report documents the clinical activity of caspofungin in a 13-year-old girl with acute myeloid leukemia (AML) and chronic disseminated candidiasis (CDC), refractory to amphotericin B and fluconazole. Caspofungin was started at 50 mg/d resulting in a temporary response. With no further clinical improvement and radiological progress after 2 months of therapy, the dose of caspofungin was increased to 100 ing/d, leading to a sustained clinical response. Therapy was given for a total of 12 months and had no attributable adverse effects. This approach resulted in successful treatment of refractory CDC with caspofungin. C1 Univ Freiburg, Dept Pediat & Adolescent Med, Div Pediat Hematol & Oncol, D-79106 Freiburg, Germany. NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. Univ Freiburg, Dept Radiol, D-79106 Freiburg, Germany. RP Kontny, U (reprint author), Univ Freiburg, Dept Pediat & Adolescent Med, Div Pediat Hematol & Oncol, Mathildenstr 1, D-79106 Freiburg, Germany. EM kontny@kikli.ukl.uni-freiburg.de NR 22 TC 3 Z9 3 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD SEP PY 2007 VL 49 IS 3 BP 360 EP 362 DI 10.1002/pbc.20751 PG 3 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 197EG UT WOS:000248536800028 PM 16444677 ER PT J AU Cho, M AF Cho, M. TI Fabry disease: What pediatric nephrologists should know? SO PEDIATRIC NEPHROLOGY LA English DT Meeting Abstract C1 NIDDK, Dept Hlth & Human Serv, Kidney Dis Sect, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD SEP PY 2007 VL 22 IS 9 BP 1438 EP 1438 PG 1 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 189GL UT WOS:000247977300137 ER PT J AU Topaloglu, R Tinloy, B Coskun, T Gunay-Aygun, M Jeong, A Bakkaloglu, A Besbas, N Ozen, S Gahl, W Kleta, R AF Topaloglu, R. Tinloy, B. Coskun, T. Gunay-Aygun, M. Jeong, A. Bakkaloglu, A. Besbas, N. Ozen, S. Gahl, W. Kleta, R. TI New molecular findings in Turkish cystinosis patients SO PEDIATRIC NEPHROLOGY LA English DT Meeting Abstract C1 Hacettepe Univ, Fac Med, TR-06100 Ankara, Turkey. NHGRI, NIH, Med Gen Branch, Bethesda, MD 20892 USA. Hacettepe Univ, Fac Med, Dept Metab, TR-06100 Ankara, Turkey. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD SEP PY 2007 VL 22 IS 9 BP 1487 EP 1487 PG 1 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 189GL UT WOS:000247977300330 ER PT J AU Lotan, D Dekel, B Joshua, B Landau, D Kleta, R Anikster, Y AF Lotan, D. Dekel, B. Joshua, B. Landau, D. Kleta, R. Anikster, Y. TI Molecular and clinical findings in autosomal recessive distal renal tubular acidosis and deafness SO PEDIATRIC NEPHROLOGY LA English DT Meeting Abstract C1 Sofra Childrens Hosp, Chaim Sheba Med Ctr, Pediat Nephrol Unit, Tel Hashomer, Israel. Rabin Med Ctr, Petah Tiqwa, Israel. Soroka Hosp, Pediat Nephrol Unit, Beer Sheva, Israel. Sofra Childrens Hosp, Chaim Sheba Med Ctr, Metab Unit, Tel Hashomer, Israel. Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. Natl Human Genome Res Inst, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD SEP PY 2007 VL 22 IS 9 BP 1503 EP 1503 PG 1 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 189GL UT WOS:000247977300396 ER PT J AU Raju, TNK Nelson, KB Ferriero, D Lynch, JK AF Raju, Tonse N. K. Nelson, Karin B. Ferriero, Donna Lynch, John Kylan TI Ischemic perinatal stroke: Summary of a workshop sponsored by the national institute of child health and human development and the national institute of neurological disorders and stroke SO PEDIATRICS LA English DT Article DE cerebral palsy; diseases of pregnancy; focal cerebral infarction; congenital hemiplegia; hypoxic ischemic encephalopathy; intracranial hemorrhage; newborn porencephaly; seizures; thrombotic disorders ID FACTOR-V-LEIDEN; CEREBRAL SINOVENOUS THROMBOSIS; PROTHROMBOTIC RISK-FACTORS; ARTERIAL STROKE; NEONATAL ENCEPHALOPATHY; NEWBORN-INFANTS; TERM INFANTS; INFARCTION; PALSY; IMPAIRMENT AB Ischemic perinatal stroke is a disorder associated with significant long-term neurologic morbidity. With an estimated incidence of 1 in 2300 to 5000 births, stroke is more likely to occur in the perinatal period than at any time in childhood. The incidence of ischemic perinatal stroke ranks second only to that of strokes in the elderly population. Although ischemic perinatal stroke is a well-recognized disorder, many aspects remain to be studied. There is no consensus on its terminology, definition, or classification. Several risk factors have been identified, but their precise roles in causing stroke are not well understood. There are no reliable predictors of ischemic perinatal stroke on which to base prevention or treatment strategies. To review these important issues and propose a research agenda, the National Institute of Child Health and Human Development and the National Institute of Neurological Disorders and Stroke convened a workshop in August 2006. This article provides a summary of the workshop. C1 NICHHD, NIH, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA. RP Raju, TNK (reprint author), 6100 Execut Blvd,Room 4B03, Bethesda, MD 20892 USA. EM rajut@mail.nih.gov RI Kirton, Adam/L-8875-2016 NR 52 TC 143 Z9 152 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 SEP PY 2007 VL 120 IS 3 BP 609 EP 616 DI 10.1542/peds.2007-0336 PG 8 WC Pediatrics SC Pediatrics GA 207DO UT WOS:000249232000020 PM 17766535 ER PT J AU Batista, DL Riar, J Keil, M Stratakis, CA AF Batista, Dalia L. Riar, Jehan Keil, Meg Stratakis, Constantine A. TI Diagnostic tests for children who are referred for the investigation of Cushing syndrome SO PEDIATRICS LA English DT Article DE Cushing syndrome; children; pituitary tumors; adrenal tumors; corticotropin; cortisol ID DEXAMETHASONE-SUPPRESSION TEST; NODULAR ADRENOCORTICAL DISEASE; DIFFERENTIAL-DIAGNOSIS; FREE CORTISOL; PITUITARY; ADOLESCENTS; CHILDHOOD; SECRETION; THERAPY; STATES AB OBJECTIVE. Endogenous Cushing syndrome in children is a rare disorder that is most frequently caused by pituitary or adrenocortical tumors. Diagnostic criteria have generally been derived from studies of adult patients despite significant differences in both the physiology of the hypothalamic-pituitary-adrenal axis and the epidemiology of Cushing syndrome in childhood. The purpose of this study was to identify the tests that most reliably and efficiently diagnose pituitary or adrenal tumors in a large cohort of pediatric patients with Cushing syndrome. METHODS. A retrospective review of clinical data of children who were referred to a tertiary care center for evaluation for Cushing syndrome during the years 1997 to 2005 was conducted. A total of 125 consecutive children were studied retrospectively; 105 were found to have Cushing syndrome, which was confirmed histologically; and 20 children who did not have Cushing syndrome or any other endocrinopathy served as the control group. The following tests were performed in all children: midnight and morning cortisol, corticotropin hormone, urinary free cortisol and 17-hydroxycorticosteroid levels, ovine corticotropin-releasing hormone stimulation test, and overnight high-dosage dexamethasone suppression test. Imaging of the pituitary and adrenal glands was also obtained. The main outcome measure was the sensitivity of these parameters for the diagnosis and differential diagnosis of Cushing syndrome at 100% specificity. RESULTS. A midnight cortisol value of >= 1 4.4 mu g/ dL confirmed the diagnosis of Cushing syndrome in almost all children, with a sensitivity of 99% and a specificity of 100%. Suppression of morning cortisol levels > 20% in response to an overnight, high-dosage dexamethasone test excluded all patients with adrenal tumors and identified almost all patients with pituitary tumors ( sensitivity: 97.5%; specificity: 100%). CONCLUSIONS. Our study suggests that among children who were referred for the evaluation of possible Cushing syndrome, a single cortisol value at midnight followed by overnight high-dosage dexamethasone test led to rapid and accurate confirmation and diagnostic differentiation, respectively, of hypercortisolemia caused by pituitary and adrenal tumors. C1 Natl Inst Hlth, Sect Endocrinol & Genet, Dev Endocrinol Branch, Bethesda, MD USA. NICHHD, Pediat Endocrinol Inter Inst Training Program, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Stratakis, CA (reprint author), NICHD, SEGEN, DEB, NIH, Bldg CRC,Room 1E-3216,10 Ctr Dr,MSC 1862, Bethesda, MD 20892 USA. EM stratakc@mail.nih.gov FU NICHD NIH HHS [201-HD-000642-04] NR 36 TC 57 Z9 62 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 SEP PY 2007 VL 120 IS 3 BP E575 EP E586 DI 10.1542/peds.2006-2402 PG 12 WC Pediatrics SC Pediatrics GA 207DO UT WOS:000249232000062 PM 17698579 ER PT J AU Samal, B Gerdin, MJ Huddleston, D Hsu, CM Elkahloun, AG Stroth, N Hamelink, C Eiden, LE AF Samal, Babru Gerdin, Matthew J. Huddleston, David Hsu, Chang-Mei Elkahloun, Abdel G. Stroth, Nikolas Hamelink, Carol Eiden, Lee E. TI Meta-analysis of microarray-derived data from PACAP-deficient adrenal gland in vivo and PACAP-treated chromaffin cells identifies distinct classes of PACAP-regulated genes SO PEPTIDES LA English DT Article DE adrenal gland; bovine chromaffin cells; Btg2; C/EBP; Ier3; meta-analysis; microarray; middle cerebral artery occlusion; neuroprotection; NF kappa B; PACAP; PC12; Scmh1; secretogranin; Smad; TGT beta; TNF alpha; YWAHZ ID CYCLASE-ACTIVATING POLYPEPTIDE; INTRACELLULAR SIGNALING PATHWAYS; RAT CORTICAL-NEURONS; MESSENGER-RNA LEVELS; ADENYLATE-CYCLASE; PC12 CELLS; SECRETOGRANIN-II; NEUROPEPTIDE-Y; EXPRESSION; DIFFERENTIATION AB Initial PACAP-regulated transcriptomes of PACAP-treated cultured chromaffin cells, and the adrenal gland of wild-type versus PACAP-deficient mice, have been assembled using microarray analysis. These were compared to previously acquired PACAP-regulated transcriptome sets from PC12 cells and mouse central nervous system, using the same microarray platform. The Ingenuity Pathways Knowledge Base was then employed to group regulated transcripts into common first and second messenger regulatory clusters. The purpose of our meta-analysis was to identify sets of genes regulated distinctly or in common by the neurotransmitter/neurotrophin PACAP in specific physiological contexts. Results suggest that PACAP participates in both the basal differentiated expression, and the induction upon physiological stimulation, of distinct sets of transcripts in neuronal and endocrine cells. PACAP in both developmental and acute regulatory paradigms acts on target genes also regulated by either TNF alpha or TGF beta, two first messengers acting on transcription mainly through NF kappa B and Smads, respectively. Published by Elsevier Inc. Published by Elsevier Inc. C1 Lab Cellular & Mol Regulat, Sect Mol Neurosci, Bethesda, MD 20892 USA. NIH, NIMH, IRP Bioinformat Core, Bethesda, MD 20892 USA. NIH, NHGRI, Canc Genet Branch, Bethesda, MD 20892 USA. RP Eiden, LE (reprint author), Lab Cellular & Mol Regulat, Sect Mol Neurosci, 9000 Rockville Pike,Bldg 49,Rm5A-68, Bethesda, MD 20892 USA. EM eidenl@mail.nih.gov RI Samal, Babru/C-5563-2008; OI Eiden, Lee/0000-0001-7524-944X FU Intramural NIH HHS [Z01 MH002386-21, Z99 MH999999] NR 62 TC 9 Z9 10 U1 0 U2 2 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 SEP PY 2007 VL 28 IS 9 BP 1871 EP 1882 DI 10.1016/j.peptides.2007.06.013 PG 12 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 218TQ UT WOS:000250038200033 PM 17651866 ER PT J AU Moody, TW Mantey, SA Fuselier, JA Coy, DH Jensen, RT AF Moody, Terry W. Mantey, Samuel A. Fuselier, Joseph A. Coy, David H. Jensen, Robert T. TI Vasoactive intestinal peptide-camptothecin conjugates inhibit the proliferation of breast cancer cells SO PEPTIDES LA English DT Article DE camptothecin; VIP receptors; cellular proliferation; breast cancer; receptor-mediated cytotoxicity ID HORMONE-RELEASING HORMONE; FUNCTIONAL EXPRESSION; SIGNAL-TRANSDUCTION; VPAC(1) RECEPTORS; HUMAN TUMORS; IN-VITRO; GROWTH; VIP; POLYPEPTIDE; PACAP AB The effects of vasoactive intestinal peptide-camptothecin (VIP-CPT) conjugates were investigated on breast cancer cells and cells transfected with VIP receptors (R). (Ala (2.8,9,19,24.25.27), Nle(17), LyS(28))VIP, (A-NL-K)VIP, was synthesized and LyS(28) was coupled to a linker, N-methylamino-ethyl-glycine, L2, which formed a carbamate bond with CPT. The resulting (A-NL-K)VIP-L2-CPT was cytotoxic for MCF7 breast cancer cells, which have VPAC(1)-R, with IC50 values of 380 and 90 nM using the MTT and clonogenic assays, respectively. (A-NL-K)VIP, (ANL-K)VIP-L2 and (A-NL-K)VIP-L2-CPT inhibited specific binding of I-25-VIP to 3T3 cells transfected with VPAC(1)-R with IC50 values of 1.9, 56 and 126 nM, respectively. In contrast, (A-NL-K)VIP, (A-NL-K)VIP-L2 and (A-NL-K)VIP-L2-CPT inhibited specific binding of I-125-Ro25-1553 to 3T3 cells transfected with VPAC(2)-R with IC50 values of 3.9, 3162 and 2690 nM, respectively. (A-NL-K)VIP, (A-NL-K)VIP-L2 and (A-NL-K)VIP-L2-CPT caused increased cAMP after addition to MCF7 cells. I-125-(A-NL-K)VIP-L2-CPT was internalized by MCF7 cells at 37 degrees C but not 4 degrees C. These results indicate that (A-NL-K)VIP-L2-CPT is a VPAC1-R agonist which is cytotoxic for breast cancer cells. Published by Elsevier Inc. C1 NIH, NCI, Canc Res Ctr, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIH, NIDDKD, Digest Dis Branch, Bethesda, MD 20892 USA. Tulane Univ, Hlth Sci Ctr, Dept Med, Peptide Res Labs, New Orleans, LA 70112 USA. RP Moody, TW (reprint author), NIH, NCI, OD, CCR, Bldg 31,Room 4A48,31 Ctr Dr, Bethesda, MD 20892 USA. EM moodyt@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 48 TC 13 Z9 13 U1 3 U2 4 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 SEP PY 2007 VL 28 IS 9 BP 1883 EP 1890 DI 10.1016/j.peptides.2007.04.017 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 218TQ UT WOS:000250038200034 PM 17580098 ER PT J AU Li, M Maderdrut, JL Lertora, JJL Batuman, V AF Li, Min Maderdrut, Jerome L. Lertora, Juan J. L. Batuman, Vechi TI Intravenous infusion of pituitary adenylate cyclase-activating polypeptide (PACAP) in a patient with multiple myeloma and myeloma kidney: A case study SO PEPTIDES LA English DT Article DE cytokines; inflammation; light-chain immunoglobulins; mitogen-activated protein kinase; myeloma kidney; PACAP; PACAP receptors ID VASOACTIVE-INTESTINAL-PEPTIDE; HORMONE-RELEASING HORMONE; CONVERTASE PC4 PROCESSES; GLUCAGON-LIKE PEPTIDE-1; NECROSIS-FACTOR-ALPHA; FACTOR-KAPPA-B; IN-VIVO; CELL-GROWTH; RECEPTORS; DEGRADATION AB We have recently shown significant renoprotective effects with the administration of pituitary adenylate cyclase-activating polypeptide (PACAP) in models of myeloma kidney. PACAP markedly inhibited the production of proinflammatory cytokines stimulated by immunoglobulin light chains in human renal proximal tubule epithelial cells and in the kidneys of rats infused with myeloma light chains. PACAP was also shown to suppress the proliferation of human kappa and lambda light chain-secreting multiple myeloma-derived cells. In this case study, an 81-year-old male patient with active multiple myeloma and myeloma kidney was infused intravenously with synthetic human PACAP38 at a rate of 4 pmol/kg/min for 120 min. The continuous infusion increased the level of PACAP38 in blood, with a plateau at about 0.2 nM during the infusion. The level of PACAP in the blood rapidly declined after the cessation of administration with a half-life of about 5-10 min. The continuous infusion did not significantly alter the basal glucose level, blood gases or blood pressure. There was a large reduction in free lambda light chains in urine after the start of the treatment with PACAP. These studies show that PACAP can be safely used in humans and suggest that it could be used as a novel therapeutic agent for the treatment of multiple myeloma and myeloma kidney. (C) 2007 Elsevier Inc. All rights reserved. C1 Tulane Univ, Sch Med, Dept Med, New Orleans, LA 70112 USA. RP Li, M (reprint author), NIH, Ctr Clin, Clin Pharmacol Program, Bldg 10, Bethesda, MD 20892 USA. EM minlee@tulane.edu OI Batuman, Vecihi/0000-0002-1800-9009 FU NCRR NIH HHS [2M01RR005096] NR 37 TC 39 Z9 41 U1 0 U2 1 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 SEP PY 2007 VL 28 IS 9 BP 1891 EP 1895 DI 10.1016/j.peptides.2007.05.002 PG 5 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 218TQ UT WOS:000250038200035 PM 17582655 ER PT J AU Skeritzian, CA Milstien, S Spiegel, S AF Skeritzian, Carole A. Milstien, Sheldon Spiegel, Sarah TI Sphingosine-1-phosphate in allergic responses, asthma and anaphylaxis SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE asthma; anaphylaxis; mast cells; immunomodulators; sphingosine-1-phosphate; sphingosine kinase ID NECROSIS-FACTOR-ALPHA; AIRWAY SMOOTH-MUSCLE; FC-EPSILON-RI; MAST-CELL DEGRANULATION; RETRACTED ARTICLE. SEE; SPHINGOSINE 1-PHOSPHATE; LYMPHOCYTE EGRESS; KAPPA-B; CYTOKINE PRODUCTION; BARRIER INTEGRITY AB Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many cellular processes, acting not only as an extracellular ligand to its specific G protein-coupled receptors, but also as a putative intracellular messenger with yet unidentified targets. Mast cells are tissue-dwelling pivotal early effectors of allergic responses, which produce and secrete S1P that can bind to its receptors present on mast cells to influence their activation and functions. In this review, we will first discuss the current knowledge of S1P production by two isozymes of sphingosine kinase (SphK). Mechanisms of SphK activation will be discussed, with an emphasis on experimental approaches developed to study their differential activation and biological roles in the context of mast cells. The relevance of mast cells in the etiology of allergic disorders, asthma and anaphylaxis is well established. In this review, this concept will be revisited, focusing on the contribution of S1P production and secretion to the symptoms associated with dysregulated inflammatory responses. To conclude, counteracting the proinflammatory effects of S1P could be envisioned as a therapeutic strategy to treat allergic disorders, exacerbated airway inflammation, and anaphylactic reactions, and various options will be discussed, such as the development of pharmacological tools to inhibit SphKs, S1P neutralizing monoclonal antibody, and S1P receptor antagonists. (c) 2007 Elsevier Inc. All rights reserved. C1 Virginia Commonwealth Univ, Med Coll Virginia, Sch Med, Dept Biochem & Mol Biol, Richmond, VA 23298 USA. NIMH, NIH, Bethesda, MD 20892 USA. RP Skeritzian, CA (reprint author), Virginia Commonwealth Univ, Med Coll Virginia, Sch Med, Dept Biochem & Mol Biol, 1101 E Marshall St,POB 980614, Richmond, VA 23298 USA. EM coskerit@vcu.edu NR 82 TC 1 Z9 1 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7258 J9 PHARMACOL THERAPEUT JI Pharmacol. Ther. PD SEP PY 2007 VL 115 IS 3 BP 390 EP 399 DI 10.1016/j.pharmthera.2007.05.011 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 218SM UT WOS:000250035200005 ER PT J AU Schmitt, AG Hall, FS Kreutzfeldt, M Perona, MTG Ortega, M Hofmann, M Siemer, M Nietzer, SL Sora, I Uhl, GR Riederer, P Gerlach, M Lesch, KP AF Schmitt, A. G. Hall, F. S. Kreutzfeldt, M. Perona, M. T. G. Ortega, M. Hofmann, M. Siemer, M. Nietzer, S. L. Sora, I Uhl, G. R. Riederer, P. Gerlach, M. Lesch, K. P. TI The effect of methylpheniclate treatment on the expression of synaptic vesicle proteins in a mouse model for attention-deficit/hyperactivity disorder SO PHARMACOPSYCHIATRY LA English DT Meeting Abstract CT 25th Symposium of the Arbeitsgemeinschaft-Neuropsychopharmakologie-und-Pharmakopsychiatrie CY OCT 03-06, 2007 CL Munich, GERMANY SP Arbeitsgemeinsch Neuropsychopharmakolog Pharmakopsychiatri C1 Univ Wurzburg, Dept Psychiat & Psychotherapy, Wurzburg, Germany. NIDA, US Dept HHS, NIH, Bethesda, MD USA. Tohoku Univ, Dept Neurosci, Sendai, Miyagi 980, Japan. Univ Wurzburg, Dept Youth Psychiat, D-97070 Wurzburg, Germany. RI Hall, Frank/C-3036-2013 OI Hall, Frank/0000-0002-0822-4063 NR 0 TC 0 Z9 0 U1 0 U2 0 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0176-3679 J9 PHARMACOPSYCHIATRY JI Pharmacopsychiatry PD SEP PY 2007 VL 40 IS 5 BP 249 EP 249 PG 1 WC Pharmacology & Pharmacy; Psychiatry SC Pharmacology & Pharmacy; Psychiatry GA 216JF UT WOS:000249873600222 ER PT J AU Buice, MA Chow, CC AF Buice, Michael A. Chow, Carson C. TI Correlations, fluctuations, and stability of a finite-size network of coupled oscillators SO PHYSICAL REVIEW E LA English DT Article ID LIMIT-CYCLE OSCILLATORS; KURAMOTO MODEL; SYNCHRONIZATION; ENTRAINMENT; POPULATIONS; SINGULARITIES; DYNAMICS; ONSET; DEATH; ARRAY AB The incoherent state of the Kuramoto model of coupled oscillators exhibits marginal modes in mean field theory. We demonstrate that corrections due to finite size effects render these modes stable in the subcritical case, i.e., when the population is not synchronous. This demonstration is facilitated by the construction of a nonequilibrium statistical field theoretic formulation of a generic model of coupled oscillators. This theory is consistent with previous results. In the all-to-all case, the fluctuations in this theory are due completely to finite size corrections, which can be calculated in an expansion in 1/N, where N is the number of oscillators. The N ->infinity limit of this theory is what is traditionally called mean field theory for the Kuramoto model. C1 NIH, NIDDK, Lab Biol Model, Bethesda, MD 20892 USA. RP Buice, MA (reprint author), NIH, NIDDK, Lab Biol Model, Bldg 10, Bethesda, MD 20892 USA. RI Chow, Carson/A-7970-2009 FU Intramural NIH HHS NR 34 TC 26 Z9 26 U1 0 U2 8 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1539-3755 J9 PHYS REV E JI Phys. Rev. E PD SEP PY 2007 VL 76 IS 3 AR 031118 DI 10.1103/PhysRevE.76.031118 PN 1 PG 25 WC Physics, Fluids & Plasmas; Physics, Mathematical SC Physics GA 215CL UT WOS:000249785800026 PM 17930210 ER PT J AU Thomason, LC Costantino, N Shaw, DV Court, DL AF Thomason, Lynn C. Costantino, Nina Shaw, Dana V. Court, Donald L. TI Multicopy plasmid modification with phage lambda red recombineering SO PLASMID LA English DT Article DE phage lambda red homologous recombination; multicopy plasmid; plasmid multimers; in vivo genetic engineering ID BACTERIAL ARTIFICIAL CHROMOSOMES; ESCHERICHIA-COLI K-12; HOMOLOGOUS RECOMBINATION; BACTERIOPHAGE-LAMBDA; MISMATCH REPAIR; DNA; OLIGONUCLEOTIDES; MULTIMERS; SYSTEM AB Recombineering, in vivo genetic engineering using the bacteriophage lambda Red generalized recombination system, was used to create various modifications of a multicopy plasmid derived from pBR322. All genetic modifications possible on the Escherichia coli chromosome and on bacterial artificial chromosomes (BACs) are also possible on multicopy plasmids and are obtained with similar frequencies to their chromosomal counterparts, including creation of point mutations (5-10% unselected frequency), deletions and substitutions. Parental and recombinant plasmids are nearly always present as a mixture following recombination, and circular multimeric plasmid molecules are often generated during the recombineering. Published by Elsevier Inc. C1 NCI, Gene Regulat & Chromosome Biol Lab, Frederick, MD 21702 USA. Colgate Univ, Hamilton, NY 13346 USA. RP Thomason, LC (reprint author), NCI, Gene Regulat & Chromosome Biol Lab, Bldg 539,Rm 243, Frederick, MD 21702 USA. EM lthomason@ncifcrf.gov FU Intramural NIH HHS [Z99 CA999999] NR 28 TC 36 Z9 38 U1 2 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0147-619X J9 PLASMID JI Plasmid PD SEP PY 2007 VL 58 IS 2 BP 148 EP 158 DI 10.1016/j.plasmid.2007.03.001 PG 11 WC Genetics & Heredity; Microbiology SC Genetics & Heredity; Microbiology GA 208ZF UT WOS:000249357200006 PM 17434584 ER PT J AU Nelson, MI Simonsen, L Viboud, C Miller, MA Holmes, EC AF Nelson, Martha I. Simonsen, Lone Viboud, Cecile Miller, Mark A. Holmes, Edward C. TI Phylogenetic analysis reveals the global migration of seasonal influenza A viruses SO PLOS PATHOGENS LA English DT Article ID UNITED-STATES; EVOLUTION; SPREAD; EPIDEMIOLOGY; MODEL AB The winter seasonality of influenza A virus in temperate climates is one of the most widely recognized, yet least understood, epidemiological patterns in infectious disease. Central to understanding what drives the seasonal emergence of this important human pathogen is determining what becomes of the virus during the non-epidemic summer months. Herein, we take a step towards elucidating the seasonal emergence of influenza virus by determining the evolutionary relationship between populations of influenza A virus sampled from opposite hemispheres. We conducted a phylogenetic analysis of 487 complete genomes of human influenza A/H3N2 viruses collected between 1999 and 2005 from Australia and New Zealand in the southern hemisphere, and a representative sub-sample of viral genome sequences from 413 isolates collected in New York state, United States, representing the northern hemisphere. We show that even in areas as relatively geographically isolated as New Zealand's South Island and Western Australia, global viral migration contributes significantly to the seasonal emergence of influenza A epidemics, and that this migration has no clear directional pattern. These observations run counter to suggestions that local epidemics are triggered by the climate-driven reactivation of influenza viruses that remain latent within hosts between seasons or transmit at low efficiency between seasons. However, a complete understanding of the seasonal movements of influenza A virus will require greatly expanded global surveillance, particularly of tropical regions where the virus circulates year-round, and during non-epidemic periods in temperate climate areas. C1 Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. Penn State Univ, Dept Biol, University Pk, PA 16802 USA. NIH, NIAID, Bethesda, MD 20892 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Holmes, EC (reprint author), Penn State Univ, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. EM ech15@psu.edu OI Simonsen, Lone/0000-0003-1535-8526; Holmes, Edward/0000-0001-9596-3552 FU NIGMS NIH HHS [R01 GM080533, GM080533-01] NR 30 TC 90 Z9 94 U1 1 U2 14 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 SEP PY 2007 VL 3 IS 9 BP 1220 EP 1228 AR e131 DI 10.1371/journal.ppat.0030131 PG 9 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 214WG UT WOS:000249768300005 PM 17941707 ER PT J AU Kim, GB Wang, ZR Liu, YY Stavrou, S Mathias, A Goodwin, KJ Thomas, JM Neville, DM AF Kim, Geun-Bae Wang, Zhirui Liu, Yuan Yi Stavrou, Scott Mathias, Askale Goodwin, K. Jeanine Thomas, Judith M. Neville, David M. TI A fold-back single-chain diabody format enhances the bioactivity of an anti-monkey CD3 recombinant diphtheria toxin-based immunotoxin SO PROTEIN ENGINEERING DESIGN & SELECTION LA English DT Article DE CD3; diabody; FN18; immunotoxin; monkey ID T-CELL DEPLETION; RHESUS-MONKEYS; IN-VIVO; BIVALENT BINDING; TUMOR-CELLS; AFFINITY; TOLERANCE; EFFICACY; SCFV; LYMPHOCYTES AB T-cell depleting anti-CD3 immunotoxins have utility in non-human primate models of transplantation tolerance and autoimmune disease therapy. We recently reported that an affinity matured single-chain (scFv) anti-monkey CD3 antibody, C207, had increased binding to T-cells and increased bioactivity in a diphtheria toxin (DT)-based biscFv immunotoxin compared with the parental antibody, FN18. However, FN18 scFvs and their mutant derivatives such as C207 did not exhibit robust bivalent character in the biscFv format. We now report that C207 in a diabody format exhibits a 7-fold increase in binding to T-cells over scFv (C207) indicating considerable divalent character for the diabody. This construct was formed by reducing the V-L/V-H linker to five residues and was secreted from Pichia pastoris as the non-covalent dimer. An immunotoxin based on this diabody format was secreted as a non-covalent dimer but was devoid of bioactivity and failed to bind T-cells, suggesting steric hindrance from the two large closely positioned truncated DT moieties. We constructed a single-chain diabody immunotoxin by fusing to the truncated DT C-terminus L-1-V-L-L-1-V-H-L-2-V-L-L-1-V-H where L-1 is a five-residue linker and L-2 is the longer (G4S)3 linker permitting interactions between the distal and proximal V-L/V-H domains. This 'fold-back' immunotoxin was secreted predominantly as the monomer and exhibited a 5- to 7-fold increase in bioactivity over DT390biscFv(C207) and depleted monkey T-cells in vivo. C1 NIMH, Mol Biol Lab, Sect Biophys Chem, Bethesda, MD 20892 USA. Univ Alabama, Dept Surg, Sect Transplantat Immunobiol, Birmingham, AL 35294 USA. RP Neville, DM (reprint author), NIMH, Mol Biol Lab, Sect Biophys Chem, Bldg 10,Room 3D46,10 Ctr Dr, Bethesda, MD 20892 USA. EM davidn@mail.nih.gov FU Intramural NIH HHS; NIDDK NIH HHS [5 U19 DK57958-07] NR 24 TC 32 Z9 34 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1741-0126 J9 PROTEIN ENG DES SEL JI Protein Eng. Des. Sel. PD SEP PY 2007 VL 20 IS 9 BP 425 EP 432 DI 10.1093/protein/gzm040 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 227VH UT WOS:000250685400002 PM 17693455 ER PT J AU Spurrier, B Washburn, FL Asin, S Ramalingam, S Nishizuka, S AF Spurrier, Brett Washburn, Frank L. Asin, Samuel Ramalingam, Sundhar Nishizuka, Satoshi TI Antibody screening database for protein kinetic modeling SO PROTEOMICS LA English DT Article DE antibody screening; kinetic models; protein arrays; relational database ID CANCER; MICROARRAYS AB Knowledge-based proteomic studies rely on the availability of quality antibodies. The increasing number of commercially available antibodies covers a wide range of protein networks; however, performance of each antibody can vary, depending on what type of cells, treatments, and time points are studied. Here, we describe an antibody database in which we screened 279 antibodies against multiple cell lysates after various treatments and from different time points. We applied these quality-confirmed antibodies on protein arrays, showing their utility for protein kinetic modeling. C1 NCI, NIH, Mol Therapeut Program, Mol Translat Technol Sect, Bethesda, MD 20892 USA. NCI, SAIC Frederick Inc, Lab Proteom & Analyt Technol, Frederick, MD 21701 USA. Iwate Med Univ, Sch Med, Dept Surg, Morioka, Iwate 020, Japan. RP Nishizuka, S (reprint author), NCI, NIH, Mol Therapeut Program, Mol Translat Technol Sect, Bethesda, MD 20892 USA. EM nishizus@mail.nih.gov FU NCI NIH HHS [N01-CO-12400] NR 12 TC 17 Z9 17 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1615-9853 J9 PROTEOMICS JI Proteomics PD SEP PY 2007 VL 7 IS 18 BP 3259 EP 3263 DI 10.1002/pmic.200700117 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 216UG UT WOS:000249903900003 PM 17708592 ER PT J AU Pollard, HB Srivastava, M Eidelman, O Jozwik, C Rothwell, SW Mueller, GR Jacobowitz, DM Darling, T Guggino, WB Wright, J Zeitlin, PL Paweletz, CP AF Pollard, Harvey B. Srivastava, Meera Eidelman, Ofer Jozwik, Catherine Rothwell, Stephen W. Mueller, Gregory R. Jacobowitz, David M. Darling, Thomas Guggino, William B. Wright, Jerry Zeitlin, Pamela L. Paweletz, Cloud P. TI Protein microarray platforms for clinical proteomics SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Review DE antibody microarrays; bioinformatics; cancer; capture agents; fluorescent dyes ID LUNG EPITHELIAL-CELLS; BREAST-CANCER PATIENTS; REGULATORY T-CELLS; TISSUE MICROARRAY; PROSTATE-CANCER; NONPARAMETRIC METHODS; ANTIBODY SPECIFICITY; FOLLICULAR LYMPHOMA; MULTIPLEX ANALYSIS; ESCHERICHIA-COLI AB Proteomics for clinical applications is presently in a state oftransition. It has become clear that the classical approaches based on 2-DE and/or MS need to be complemented by different kinds of technologies. The well-known problems include sample compleixty, sensitivity, quantitation, reproducibility, and analysis time. We suggest that the new technologies for clinical proteomics can be supported by antibody-centric protein microarray platforms. These platforms presently include antibody microarrays and lysate, or reverse capture/reverse phase protein microarrays. Other forms of these arrays are in less mature developmental stages, including ORF and self assembling protein microarrays. Bioinformatic support for interpreting these arrays is becoming more available as the whole field of systems biology begins to mature. The present set of applications for these platforms is profoundly focused on certain common cancers, immunology, and cystic fibrosis. However, we predict that many more disease entities will become studied as knowledge of the power and availability of these platforms becomes more widely established. We anticipate that these platforms will eventually evolve to accommodate label-free detection technologies, human genome-scale numbers of analytes, and increases in analytic and bioinformatic speeds. C1 Uniformed Serv Univ Hlth Sci, Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Sch Med, Dept Dermatol, Bethesda, MD 20814 USA. Johns Hopkins Univ, Sch Med, Inst Med, Dept Physiol, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Inst Med, Dept Pediat, Baltimore, MD USA. Proteom, Merck & Co Inc, Boston, MA USA. RP Pollard, HB (reprint author), Uniformed Serv Univ Hlth Sci, Sch Med, Dept Anat Physiol & Genet, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM hpollard@usuhs.mil RI Smith, Barry/A-9525-2011; OI Smith, Barry/0000-0003-1384-116X; Darling, Thomas/0000-0002-5161-1974 NR 116 TC 33 Z9 36 U1 1 U2 6 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1862-8346 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD SEP PY 2007 VL 1 IS 9 BP 934 EP 952 DI 10.1002/prca.200700154 PG 19 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 212ZL UT WOS:000249635500003 PM 21136748 ER PT J AU Yu, LR Issaq, HJ Veenstra, TD AF Yu, Li-Rong Issaq, Haleem J. Veenstra, Timothy D. TI Phosphoproteomics for the discovery of kinases as cancer biomarkers and drug targets SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Review DE cancer biomarker; drug target; kinase; mass spectrometry; phosphoproteomics ID TANDEM MASS-SPECTROMETRY; METAL-AFFINITY-CHROMATOGRAPHY; TYROSINE PHOSPHORYLATION SITES; TITANIUM-DIOXIDE MICROCOLUMNS; ELECTRON-CAPTURE DISSOCIATION; CHRONIC MYELOGENOUS LEUKEMIA; LARGE-SCALE ANALYSIS; HUMAN-BREAST-CANCER; POLO-LIKE KINASES; BCR-ABL KINASE AB Early detection and targeted therapy represent a novel regimen of cancer management. The understanding of receptor tyrosine kinases in tumorigenesis at the molecular level has led to the first generation of kinase inhibitors for anticancer therapy that targets a specific kinase or pathway. While the therapeutic advantage is obvious, targeted therapy often relapses and results in drug resistance for advanced cancers. To achieve feasible early detection and better efficacy of therapeutics targeting multiple pathways, significantly more biomarkers and drug targets are in demand, especially for individualized therapy. Recent advances in phosphoprotein enrichment and MS technologies for quantitative phosphoproteome analysis provide great opportunities in the identification and validation of kinases as drug targets. The MS-based phosphoproteomic technologies would be useful tools as well for the identification of phosphosignatures unique to a specific type or subtype of cancer and drug responsive biomarkers. This review summarizes the major kinases acting as cancer biomarkers and drug targets, the advances of MS-based phosphoproteornic technologies, and some potential values and challenges of this emerging phosphoproteomics-based biomarker and drug target discovery field. Strategies for global, targeted, and quantitative phosphoproteomics are discussed, and some recent interesting applications are also evaluated. C1 NCI, SAIC Frederick Inc, Adv TEchnol Program, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. RP Yu, LR (reprint author), NCI, SAIC Frederick Inc, Adv TEchnol Program, Lab Proteom & Analyt Technol, PO Box B,Bldg 434,Rm 5E, Frederick, MD 21702 USA. EM lyu@ncifcrf.gov NR 161 TC 24 Z9 27 U1 2 U2 9 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1862-8346 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD SEP PY 2007 VL 1 IS 9 BP 1042 EP 1057 DI 10.1002/prca.200700102 PG 16 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 212ZL UT WOS:000249635500011 PM 21136756 ER PT J AU Aziz, N AF Aziz, N. TI Post-treatment follow-up care for cancer survivors: Is psychosocial care incorporated within existing models, and if not, why? SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 NCI, Off Canc Survivorship, DCCPS, NIH,DHHS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD SEP PY 2007 VL 16 IS 9 SU S BP S270 EP S271 PG 2 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 213SM UT WOS:000249687400491 ER PT J AU Aziz, N Bellizzi, KM Oeffinger, KC Arora, NK Potosky, A Klabunde, C Hamilton, A AF Aziz, N. Bellizzi, K. M. Oeffinger, K. C. Arora, N. K. Potosky, A. Klabunde, C. Hamilton, A. TI Prevalence of symptoms, medical conditions post diagnosis, physical functioning and communication with doctors among adult non-Hodgkin lymphoma survivors SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Univ So Calif, Los Angeles, CA 90089 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD SEP PY 2007 VL 16 IS 9 SU S BP S54 EP S54 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 213SM UT WOS:000249687400100 ER PT J AU Aziz, N AF Aziz, N. TI International perspectives regarding health and follow-up care needs of cancer survivors SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. NR 0 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 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD SEP PY 2007 VL 16 IS 9 SU S BP S49 EP S49 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 213SM UT WOS:000249687400091 ER PT J AU Bloom, J Maunsell, E Stewart, S Wenzel, L Aziz, N AF Bloom, J. Maunsell, E. Stewart, S. Wenzel, L. Aziz, N. TI Psychological, social, and employment impacts on breast and cervical cancer survivors SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 Univ Laval, Quebec City, PQ G1K 7P4, Canada. NCI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD SEP PY 2007 VL 16 IS 9 SU S BP S39 EP S39 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 213SM UT WOS:000249687400073 ER PT J AU Jeffery, DD Reeve, BB Tzeng, J Weinfurt, KP Flynn, KE Keefe, FJ Porter, LS Hahn, EA Cella, D AF Jeffery, D. D. Reeve, B. B. Tzeng, J. Weinfurt, K. P. Flynn, K. E. Keefe, F. J. Porter, L. S. Hahn, E. A. Cella, D. TI The sexual function domain of the NIHPROMIS: Preliminary report SO PSYCHO-ONCOLOGY LA English DT Meeting Abstract C1 NCI, Div Canc Control & Popoulat Sci, Off Canc Survivorship, Bethesda, MD 20892 USA. NCI, Div Canc Control & Popoulat Sci, Appl Res Program, Bethesda, MD 20892 USA. Duke Univ, Clin Res Inst, Durham, NC 27706 USA. Northwestern Univ, Sch Med, Feinberg Sch Med, Evanston, IL 60208 USA. Northwestern Univ, Sch Med, Evanston NW Healthcare, Evanston, IL 60208 USA. RI Flynn, Kathryn/M-5346-2013 OI Flynn, Kathryn/0000-0002-4427-3583 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 1057-9249 J9 PSYCHO-ONCOL JI Psycho-Oncol. PD SEP PY 2007 VL 16 IS 9 SU S MA P2-107 BP S233 EP S233 PG 1 WC Oncology; Psychology; Psychology, Multidisciplinary; Social Sciences, Biomedical SC Oncology; Psychology; Biomedical Social Sciences GA 213SM UT WOS:000249687400421 ER PT J AU Morsink, LFJ Vogelzangs, N Nicklas, BJ Beekman, ATF Satterfield, S Rubin, SM Yaffe, K Simonsick, E Newman, AB Kritchevsky, SB Penninx, BWJH AF Morsink, Lisette F. J. Vogelzangs, Nicole Nicklas, Barbara J. Beekman, Aartjan T. F. Satterfield, Suzanne Rubin, Susan M. Yaffe, Kristine Simonsick, Eleanor Newman, Anne B. Kritchevsky, Stephen B. Penninx, Brenda W. J. H. CA Hlth ABC Study TI Associations between sex steroid hormone levels and depressive symptoms in elderly men and women: Results from the Health ABC study SO PSYCHONEUROENDOCRINOLOGY LA English DT Article DE depression; sex steroid hormones; older persons; dehydroepiandrosterone-sulfate (DHEAS); free testosterone; total testosterone ID ANDROGEN RECEPTOR POLYMORPHISM; LOW TESTOSTERONE LEVELS; GABA-A RECEPTOR; DEHYDROEPIANDROSTERONE-SULFATE; MAJOR DEPRESSION; OLDER MEN; ENDOGENOUS LEVELS; AFRICAN-AMERICAN; RANCHO-BERNARDO; MOOD AB Introduction: Sex steroid hormone levels decline with age and in some studies this decline has been linked with depressive symptoms. This study investigates the association between total testosterone, free testosterone, and DHEAS levels with depressive symptoms in a well-functioning elderly population. Methods: Data are from 2855 well-functioning elderly men and women, 70-79 years of age, participating in the Health, Aging, and Body Composition study. Depressive symptoms were measured using the Center for Epidemiologic Studies Depression scale. Total testosterone, free testosterone, and DHEAS levels were assessed after an overnight fast. Results: In men and women, DHEAS levels and depressive symptoms were inversely associated after adjustment for covariates (men: beta=-0.059, p = 0.03, women: beta = -0.054, p = 0.05). In addition, free testosterone levels in women, but not in men, were inversely associated with depressive symptoms (adjusted beta=-0.079, p = 0.004). Men, but not women, in the lowest total testosterone quartile reported significantly more depressive symptoms than men in the other total testosterone quartiles (adjusted beta = -0. 166, p = 0. 04). Discussion: Our study is consistent with the idea that testosterone and DHEAS levels may play a role in mechanisms underlying depressive symptoms in old age. (C) 2007 Elsevier Ltd. All rights reserved. C1 [Morsink, Lisette F. J.; Vogelzangs, Nicole; Beekman, Aartjan T. F.; Penninx, Brenda W. J. H.] Vrije Univ Amsterdam Med Ctr, Dept Psychiat, EMGO Inst, NL-1081 HL Amsterdam, Netherlands. [Nicklas, Barbara J.; Kritchevsky, Stephen B.] Wake Forest Univ, Sch Med, Winston Salem, NC 27157 USA. [Satterfield, Suzanne] Univ Tennessee, Memphis, TN 38163 USA. [Rubin, Susan M.; Yaffe, Kristine] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Simonsick, Eleanor] NIA, Baltimore, MD 21224 USA. [Newman, Anne B.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. RP Penninx, BWJH (reprint author), Vrije Univ Amsterdam Med Ctr, Dept Psychiat, EMGO Inst, AJ Ernstsr 887, NL-1081 HL Amsterdam, Netherlands. EM b.penninx@vumc.nl RI Newman, Anne/C-6408-2013; OI Newman, Anne/0000-0002-0106-1150; Kritchevsky, Stephen/0000-0003-3336-6781 FU Intramural NIH HHS; NHLBI NIH HHS [1R01-HL972972]; NIA NIH HHS [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106] NR 36 TC 68 Z9 69 U1 2 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4530 J9 PSYCHONEUROENDOCRINO JI Psychoneuroendocrinology PD SEP-NOV PY 2007 VL 32 IS 8-10 BP 874 EP 883 DI 10.1016/j.psyneuen.2007.06.009 PG 10 WC Endocrinology & Metabolism; Neurosciences; Psychiatry SC Endocrinology & Metabolism; Neurosciences & Neurology; Psychiatry GA 242AY UT WOS:000251698100003 PM 17651906 ER PT J AU Cooper, A Barnea-Ygael, N Levy, D Shaham, Y Zangen, A AF Cooper, Ayelet Barnea-Ygael, Noam Levy, Dino Shaham, Yavin Zangen, Abraham TI A conflict rat model of cue-induced relapse to cocaine seeking SO PSYCHOPHARMACOLOGY LA English DT Article DE animal models; drug cues; cocaine self-administration; reinstatement; relapse ID EXTRACELLULAR DOPAMINE LEVELS; STRESS-INDUCED REINSTATEMENT; SELF-ADMINISTERED COCAINE; TIME-DEPENDENT CHANGES; DRUG-SEEKING; HEROIN-SEEKING; PROLONGED EXTINCTION; SQUIRREL-MONKEYS; ANIMAL-MODELS; BEHAVIOR AB Rationale Relapse to drug use in humans can be induced by exposure to drug-associated cues. The ability of drug cues to provoke 'relapse' has been studied in laboratory animals using a reinstatement model in which resumption of drug seeking is assessed after extinction of drug-reinforced responding. In this model, there are no adverse consequences of drug-seeking behavior. However, in humans, abstinence is often self-imposed, and relapse episodes likely involve making a choice between the desire for the drug and the negative consequences of pursuing it (a conflict situation). In this paper, we describe a conflict model of cue-induced relapse in rats that approximate the human condition. Materials and methods Rats were trained to lever press for cocaine; infusions were paired with a discrete light cue. An 'electric barrier' was then introduced by electrifying the floor area near the levers. Responding decreased over days with increasing shock intensities, until the rats did not approach the levers for 3 days. Subsequently, the effect of intermittent noncontingent light-cue presentations on resumption of lever responding (relapse) was assessed in extinction tests, with the electric barrier remaining activated; during testing, lever presses led to contingent light-cue presentations. Results Noncontingent cue exposure led to resumption of lever presses during the relapse tests in 14 of the 24 rats. Surprisingly, 24 h later, 11 of the 24 rats resumed lever responding in a subsequent post-noncontingent cue test under similar extinction conditions. Large individual differences in responding were observed during both tests. Conclusions At its current stage of development, the conflict relapse model appears particularly suitable for studying individual differences in cue-induced relapse to cocaine seeking or factors that promote this relapse. C1 Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. NIDA, Behav Neurosci Branch, IRP, NIH,DHHS, Baltimore, MD USA. RP Zangen, A (reprint author), Weizmann Inst Sci, Dept Neurobiol, IL-76100 Rehovot, Israel. EM a.zangen@weizmann.ac.il RI shaham, yavin/G-1306-2014 FU Intramural NIH HHS [ZIA DA000434-13] NR 59 TC 36 Z9 36 U1 2 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2007 VL 194 IS 1 BP 117 EP 125 DI 10.1007/s00213-007-0827-7 PG 9 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 201UB UT WOS:000248857000012 PM 17558499 ER PT J AU Lee, HJ Rao, JS Chang, L Rapoport, SI Bazinet, RP AF Lee, Ho-Joo Rao, Jagadeesh S. Chang, Lisa Rapoport, Stanley I. Bazinet, Richard P. TI Chronic lamotrigine does not alter the turnover of arachidonic acid within brain phospholipids of the unanesthetized rat: implications for the treatment of bipolar disorder SO PSYCHOPHARMACOLOGY LA English DT Article DE lamotrigine; brain; arachidonic acid; bipolar disorder; turnover; phospholipids; rat ID LITHIUM MAINTENANCE TREATMENT; CONTROLLED 18-MONTH TRIAL; DNA-BINDING ACTIVITY; DOCOSAHEXAENOIC ACID; FATTY-ACID; FRONTAL-CORTEX; DOUBLE-BLIND; SIGNAL TRANSDUCTION; PROTEIN EXPRESSION; CHRONIC VALPROATE AB Rationale Drugs that are effective in treating the manic phase of bipolar disorder (lithium, carbamazepine, and valproate) upon chronic administration to rats decrease the turnover of arachidonic acid in their brain phospholipids. Lamotrigine may not be effective in the manic phase, but is effective in delaying the depressive phase and for treating rapid cycling bipolar disorder. Thus, lamotrigine provides a pharmacological tool to differentiate if downregulation of arachidonic acid turnover is specific to drugs effective in the manic phase of bipolar disorder. Materials and methods To test this hypothesis, rats were administered lamotrigine (10 mg kg(-1) day(-1)) or vehicle intragastrically once daily for 42 days. In the unanesthetized rat, [1- C-14]arachidonic acid was infused intravenously and arterial blood plasma was sampled until the animal was killed at 5 min, and its microwaved brain was subjected to chemical and radiotracer analysis. Results Using equations from our fatty acid model, we found that chronic lamotrigine compared with vehicle did not alter the net incorporation rate of plasma arachidonic acid into brain phospholipids, nor did it alter the turnover of arachidonic acid within brain phospholipids. Conclusion Chronic lamotrigine, which is effective in the depressive phase or rapid cycling bipolar disorder does not alter brain arachidonic acid turnover in the unanesthetized rat. These results are consistent with the hypothesis that drugs effective in treating the manic phase of bipolar disorder decrease brain arachidonic acid turnover. C1 Univ Toronto, Fac Med, Dept Nutr Sci, Toronto, ON M5S 3E2, Canada. NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Bazinet, RP (reprint author), Univ Toronto, Fac Med, Dept Nutr Sci, FitzGerald Bldg,150 Coll St,Room 306, Toronto, ON M5S 3E2, Canada. EM hojoolee@mail.nih.gov; jrao@mail.nih.gov; lchang@mail.nih.gov; sir@helix.nih.gov; richard.bazinet@utoronto.ca RI Rao, Jagadeesh/C-1250-2009 FU Intramural NIH HHS NR 70 TC 16 Z9 16 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD SEP PY 2007 VL 193 IS 4 BP 467 EP 474 DI 10.1007/s00213-007-0803-2 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 192UR UT WOS:000248229400003 PM 17487474 ER PT J AU Csoka, B Nemeth, ZH Selmeczy, Z Koscso, B Pacher, P Vizi, ES Deitch, EA Hasko, G AF Csoka, Balazs Nemeth, Zoltan H. Selmeczy, Zsolt Koscso, Balazs Pacher, Pal Vizi, E. Sylvester Deitch, Edwin A. Hasko, Gyorgy TI Role of A(2A) adenosine receptors in regulation of opsonized E-coli-induced macrophage function SO PURINERGIC SIGNALLING LA English DT Article DE adenosine; cytokines; inflammation; macrophages; phagocytosis; sepsis ID INFLAMMATORY CYTOKINES; HUMAN MONOCYTES; UNITED-STATES; ORGAN FAILURE; SEVERE SEPSIS; EXPRESSION; HYPOXIA; CELLS; EPIDEMIOLOGY; PHAGOCYTOSIS AB Adenosine is a biologically active molecule that is formed at sites of metabolic stress associated with trauma and inflammation, and its systemic level reaches high concentrations in sepsis. We have recently shown that inactivation of A(2A) adenosine receptors decreases bacterial burden as well as IL-10, IL-6, and MIP-2 production in mice that were made septic by cecal ligation and puncture (CLP). Macrophages are important in both elimination of pathogens and cytokine production in sepsis. Therefore, in the present study, we questioned whether macrophages are responsible for the decreased bacterial load and cytokine production in A(2A) receptor-inactivated septic mice. We showed that A(2A) KO and WT peritoneal macrophages obtained from septic animals were equally effective in phagocytosing opsonized E. coli. IL-10 production induced by opsonized E. coli was decreased in macrophages obtained from septic A(2A) KO mice as compared to WT counterparts. In contrast, the release of IL-6 and MIP-2 induced by opsonized E. coli was higher in septic A(2A) KO macrophages than WT macrophages. These results suggest that peritoneal macrophages are not responsible for the decreased bacterial load and diminished MIP-2 and IL-6 production that are observed in septic A(2A) KO mice. In contrast, peritoneal macrophages may contribute to the suppressive effect of A(2A) receptor inactivation on IL-10 production during sepsis. C1 [Csoka, Balazs; Nemeth, Zoltan H.; Deitch, Edwin A.; Hasko, Gyorgy] Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, Newark, NJ 07103 USA. [Selmeczy, Zsolt; Koscso, Balazs; Vizi, E. Sylvester; Hasko, Gyorgy] Hungarian Acad Sci, Inst Expt Med, Dept Pharmacol, H-1083 Budapest, Hungary. [Pacher, Pal] NIAAA, Bethesda, MD 20892 USA. RP Hasko, G (reprint author), Univ Med & Dent New Jersey, New Jersey Med Sch, Dept Surg, 185 S Orange Ave, Newark, NJ 07103 USA. EM haskoge@umdnj.edu RI Pacher, Pal/B-6378-2008; OI Pacher, Pal/0000-0001-7036-8108; Csoka, Balazs/0000-0002-7562-1130 FU Intramural NIH HHS [Z01 AA000375-02, Z99 AA999999]; NIGMS NIH HHS [R01 GM066189, R56 GM066189] NR 40 TC 10 Z9 10 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 1573-9538 J9 PURINERG SIGNAL JI Purinergic Signal. PD SEP PY 2007 VL 3 IS 4 BP 447 EP 452 DI 10.1007/s11302-007-9075-x PG 6 WC Biochemistry & Molecular Biology; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 341NF UT WOS:000258720500020 PM 18404457 ER PT J AU Thukral, A Thomasson, DM Chow, CK Eulate, R Wedarn, SB Gupta, SN Wise, BJ Steinberg, SM Liewehr, DJ Choyke, PL Swain, SM AF Thukral, Arpi Thomasson, David M. Chow, Catherine K. Eulate, Reyes Wedarn, Suparna B. Gupta, Sandeep N. Wise, Betty J. Steinberg, Seth M. Liewehr, David J. Choyke, Peter L. Swain, Sandra M. TI Inflammatory breast cancer: Dynamic contrast-enhanced MR in patients receiving bevacizumab - Initial experience SO RADIOLOGY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; TUMORS; ANGIOGENESIS; MICROCIRCULATION; REPRODUCIBILITY; PERMEABILITY; TISSUE; BLOOD AB Purpose: To retrospectively compare three dynamic contrast material-enhanced magnetic resonance (MR) imaging (dynamic MR imaging) analytic methods to determine the parameter or combination of parameters most strongly associated with changes in tumor microvasculature during treatment, with bevacizumab alone and bevacizumab plus chemotherapy in patients with inflammatory or locally advanced breast cancer. Materials and Methods: This study was conducted in accordance with the institutional review board of the National Cancer Institute and was compliant with the Privacy Act of 1974. Informed consent was obtained from all patients. Patients with inflammatory or locally advanced breast cancer were treated with one cycle of bevacizumab alone (cycle 1) followed by six cycles of combination bevacizumab and chemotherapy (cycles 2-7). Serial dynamic MR images were obtained, and the kinetic parameters measured by using three dynamic analytic MR methods (heuristic, Brix, and general kinetic models) and two region-of-interest strategies were compared by using two-sided statistical tests. A P value of .01 was required for significance. Results: In 19 patients, with use of a whole-tumor region of interest, the authors observed a significant decrease in the median values of three parameters measured from base-line to cycle 1: forward median values forward transfer rate constant (K-trans) (-34% relative change, P =.003), backflow compartmental rate constant extravascular and extracellular to plasma (K-ep) (-15% relative change, P < .001), and integrated area under the gadolinium concentration curve (IAUGC) at 180 seconds (-23% relative change, P = .009). A trend toward differences in the heuristic slope of the washout curve between responders and nonresponders to therapy was observed after cycle 1 (bevacizumab alone, P = .02). A The median relative change in slope of the wash-in curve from baseline to cycle 4 was significantly different between 4 responders and nonresponders (P = .009). Conclusion: The dynamic contrast-enhanced MR parameters K-trans, K-ep and IAUGC at seconds appear to have the strongest association with early physiologic response to bevacizumab. C1 NIH, Med Oncol Branch, Bethesda, MD 20889 USA. NIH, Mol Imaging Program, Bethesda, MD 20889 USA. NIH, Biostat & Data Management Sect, Bethesda, MD 20889 USA. NCI, NIH, Ctr Canc Res, Bethesda, MD 20889 USA. NIH, Warren G Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20889 USA. GE Healthcare Technol, Hanover, MD USA. RP Swain, SM (reprint author), NIH, Med Oncol Branch, 8901 Wisconsin Ave,Bldg 8,Room 5101, Bethesda, MD 20889 USA. EM Sandra.M.Swain@Medstar.net OI Swain, Sandra/0000-0002-1320-3830 FU Intramural NIH HHS NR 23 TC 47 Z9 52 U1 0 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 SEP PY 2007 VL 244 IS 3 BP 727 EP 735 DI 10.1148/radiol.2443060926 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 203SE UT WOS:000248993500011 PM 17709827 ER PT J AU Badal, A Kyprianou, I Badano, A Sempau, J AF Badal, A. Kyprianou, I. Badano, A. Sempau, J. TI Monte Carlo simulation with penelope and a realistic anthropomorphic phantom described by triangle meshes SO RADIOTHERAPY AND ONCOLOGY LA English DT Meeting Abstract CT 9th Biennial Meeting on Physics and Radiation Technology for Clinical Radiotherapy CY SEP 08-13, 2007 CL Barcelona, SPAIN SP European Soc Therapeut Radiol & Oncol C1 [Badal, A.; Sempau, J.] Univ Politecn Cataluna, Inst Tech Energet, Barcelona, Spain. [Kyprianou, I.; Badano, A.] US FDA, NIIBIB, CDRH, Lab Assessment Med Imaging Syst, Rockville, MD 20857 USA. RI Sempau, Josep/J-7834-2013 OI Sempau, Josep/0000-0002-2754-7685 NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0167-8140 J9 RADIOTHER ONCOL JI Radiother. Oncol. PD SEP PY 2007 VL 84 SU 1 MA 99 BP S46 EP S46 PG 1 WC Oncology; Radiology, Nuclear Medicine & Medical Imaging SC Oncology; Radiology, Nuclear Medicine & Medical Imaging GA 237SU UT WOS:000251397500093 ER PT J AU Ilekis, JV Reddy, UM Roberts, JM AF Ilekis, John V. Reddy, Uma M. Roberts, James M. TI Preeclampsia - A pressing problem: An executive summary of a national institute of child health and human development workshop SO REPRODUCTIVE SCIENCES LA English DT Article; Proceedings Paper CT 2nd Annual International Summit on Topic of Reproductive Medicine CY NOV 07-10, 2007 CL Valencia, SPAIN DE preeclampsia; workshop; research; trials; gaps. ID RECEPTOR AGONISTIC ANTIBODIES; FETAL-GROWTH RESTRICTION; UTERINE ARTERY DOPPLER; ELEVATED LIVER-ENZYMES; LOW PLATELETS SYNDROME; OXIDATIVE STRESS; GESTATIONAL HYPERTENSION; SPIRAL ARTERIES; AT(1) RECEPTOR; PLACENTAL BED AB On September 21 and 22, 2006, the National Institute of Child Health and Human Development of the National Institutes of Health sponsored a 2-day workshop titled "Preeclampsia - A Pressing Problem." The purpose of the workshop was to bring together leaders in the field to present and discuss their diverse research areas, which ranged from basic science to clinical trials and management, and to identify scientific gaps. This article is a summary of the proceedings that workshop. Although much progress is being made in understanding the underpinnings of precclampsia, a number of research gaps are identified that, if filled, would hasten progress in the field. It is the overall consensus that preeclampsia is a multifactorial disease whose pathogenesis is not solely vascular, genetic, immunologic, or environmental but a complex combination of factors. In addition, a number of specific scientific gaps are identified including insufficient multidisciplinary and collaborative research, clinical trials and studies of patient management, and a lack of in-depth mechanistic research. The research community needs to focus on these gaps to better understand the disease, with the ultimate goal of preventing the disorder. C1 NICHHD, Pregnancy & Perinatol Branch, Natl Inst Hlth, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Pittsburgh, Magee Womens Res Inst, Pittsburgh, PA USA. Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. RP Ilekis, JV (reprint author), NICHHD, Pregnancy & Perinatol Branch, Natl Inst Hlth, Dept Hlth & Human Serv, 6100 Execut Blvd,Room 4B03C, Bethesda, MD 20892 USA. EM ilekisj@mail.nih.gov NR 102 TC 69 Z9 75 U1 1 U2 5 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1933-7191 J9 REPROD SCI JI Reprod. Sci. PD SEP PY 2007 VL 14 IS 6 BP 508 EP 523 DI 10.1177/1933719107306232 PG 16 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 227CK UT WOS:000250634600003 PM 17959880 ER PT J AU Ilev, I Waynant, R Gannot, I Gandjbakhche, A AF Ilev, Ilko Waynant, Ronald Gannot, Israel Gandjbakhche, Amir TI Simple fiber-optic confocal microscopy with nanoscale depth resolution beyond the diffraction barrier SO REVIEW OF SCIENTIFIC INSTRUMENTS LA English DT Article ID SCANNING OPTICAL MICROSCOPY AB A novel fiber-optic confocal approach for ultrahigh depth-resolution (<= 2 nm) microscopy beyond the diffraction barrier in the subwavelength nanometric range below 200 nm is presented. The key idea is based on a simple fiber-optic confocal microscope approach that is compatible with a differential confocal microscope technique. To improve the dynamic range of the resolving laser power and to achieve a high resolution in the nanometric range, we have designed a simple apertureless reflection confocal microscope with a highly sensitive single-mode-fiber confocal output. The fiber-optic design is an effective alternative to conventional pinhole-based confocal systems and offers a number of advantages in terms of spatial resolution, flexibility, miniaturization, and scanning potential. Furthermore, the design is compatible with the differential confocal pinhole microscope based on the use of the sharp diffraction-free slope of the axial confocal response curve rather than the area around the maximum of that curve. Combining the advantages of ultrahigh-resolution fiber-optic confocal microscopy, we can work beyond the diffraction barrier in the subwavelength (below 200 nm) nanometric range exploiting confocal nanobioimaging of single cell and intracellular analytes. (c) 2007 American Institute of Physics. C1 US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Div Phys, Silver Spring, MD 20993 USA. George Washington Univ, Sch Engn & Appl Sci, Dept Elect & Comp Engn, Program Biomed Engn, Washington, DC 20052 USA. NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. RP Ilev, I (reprint author), US FDA, Ctr Devices & Radiol Hlth, Off Sci & Engn Labs, Div Phys, 10903 New Hampshire Ave,Bldg 62, Silver Spring, MD 20993 USA. FU Intramural NIH HHS NR 15 TC 10 Z9 10 U1 1 U2 5 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0034-6748 J9 REV SCI INSTRUM JI Rev. Sci. Instrum. PD SEP PY 2007 VL 78 IS 9 AR 093703 DI 10.1063/1.2777173 PG 4 WC Instruments & Instrumentation; Physics, Applied SC Instruments & Instrumentation; Physics GA 215DF UT WOS:000249787800012 PM 17902951 ER PT J AU Stover, E Marder, S Carpenter, W AF Stover, Ellen Marder, Steve Carpenter, William TI Progress on NIMH initiatives (Memorial theme for Wayne Fenton, MD) SO SCHIZOPHRENIA BULLETIN LA English DT Article ID SCHIZOPHRENIA; COGNITION C1 Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. NIMH, Bethesda, MD 20892 USA. RP Carpenter, W (reprint author), Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA. EM wcarpent@mprc.umaryland.edu NR 5 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 EI 1745-1701 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD SEP PY 2007 VL 33 IS 5 BP 1084 EP 1085 DI 10.1093/schbul/sbm091 PG 2 WC Psychiatry SC Psychiatry GA 214HD UT WOS:000249726700007 PM 17641145 ER PT J AU Stover, EL Brady, L Marder, SR AF Stover, Ellen L. Brady, Linda Marder, Stephen R. TI New paradigms for treatment development SO SCHIZOPHRENIA BULLETIN LA English DT Article DE schizophrenia; treatment; pharmacology ID IMPROVE COGNITION; CHRONIC-SCHIZOPHRENIA; ILLNESS AB Wayne Fenton believed that government-particularly National Institute of Mental Health (NIMH)-could play a critical role in addressing important public health problems where the current system of treatment development was inadequate. Earlier experiences in HIV/AIDS convinced him and others that the NIMH can effectively facilitate the rapid development of new research in critical areas. This report will demonstrate how the work of Fenton and others brought together representatives from industry, government, and academia to address issues that included new preclinical approaches to drug development and defining new therapeutic targets in schizophrenia. An initiative to facilitate the development of new pharmacological agents to address the cognitive impairments in schizophrenia-titled Measurement and Treatment Research to Improve Cognition in Schizophreniaor MATRICS-is used as an example of a new paradigm for treatment development. C1 Univ Calif Los Angeles, Semel Inst Neurosci, Los Angeles, CA 90073 USA. Desert Pacific Mental Illness Res Educ & Clin Ctr, Los Angeles, CA 90073 USA. W Los Angeles Vet Affairs Med Ctr, Los Angeles, CA 90073 USA. NIMH, Bethesda, MD 20892 USA. RP Marder, SR (reprint author), Univ Calif Los Angeles, Semel Inst Neurosci, Bldg 210,Room 130,11301 Wilshire Blvd, Los Angeles, CA 90073 USA. EM marder@ucla.edu NR 26 TC 12 Z9 12 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD SEP PY 2007 VL 33 IS 5 BP 1093 EP 1099 DI 10.1093/schbul/sbm085 PG 7 WC Psychiatry SC Psychiatry GA 214HD UT WOS:000249726700009 PM 17673495 ER PT J AU Heinssen, RK AF Heinssen, Robert K. TI Person-centered psychiatric care: A tribute to Wayne S. Fenton, MD SO SCHIZOPHRENIA BULLETIN LA English DT Biographical-Item DE schizophrenia; psychotherapy; recovery AB Wayne S. Fenton, MD, was an accomplished psychiatric researcher, but his colleagues knew him as an equally talented clinician. This memorial recognizes the personal qualities and professional skills that endeared Wayne Fenton to hundreds of mentally ill persons he treated over the course of his professional career. Among these attributes, deep compassion, sincere respect, and tremendous flexibility were hallmarks of an approach that emphasized collaborative, recovery-oriented therapy. Through his actions and writings, Wayne Fenton influenced a generation of mental health professionals who aspire to similar professional excellence in all aspects of clinical care. C1 NIMH, Div Adult Translat Res & Treatment Dev, Bethesda, MD 20892 USA. RP Heinssen, RK (reprint author), NIMH, Div Adult Translat Res & Treatment Dev, Room 7113,MSC 9625, Bethesda, MD 20892 USA. EM rheinsse@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD SEP PY 2007 VL 33 IS 5 BP 1149 EP 1150 DI 10.1093/schbul/sbm075 PG 2 WC Psychiatry SC Psychiatry GA 214HD UT WOS:000249726700014 PM 17615141 ER PT J AU Hyman, SE Insel, TR AF Hyman, Steven E. Insel, Thomas R. TI Commentary: Public health contributions SO SCHIZOPHRENIA BULLETIN LA English DT Editorial Material DE schizophrenia; mental illness; cognition C1 Harvard Univ, Provosts Off, Cambridge, MA 02138 USA. NIMH, Bethesda, MD 20892 USA. RP Hyman, SE (reprint author), Harvard Univ, Provosts Off, Massachussetts Hall, Cambridge, MA 02138 USA. EM seh@harvard.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0586-7614 J9 SCHIZOPHRENIA BULL JI Schizophr. Bull. PD SEP PY 2007 VL 33 IS 5 BP 1151 EP 1152 DI 10.1093/schbul/sbm084 PG 2 WC Psychiatry SC Psychiatry GA 214HD UT WOS:000249726700015 PM 17631617 ER PT J AU Bertolino, A Caforio, G Blasi, G Rampino, A Nardini, M Weinberger, DR Dallapiccola, B Sinibaldi, L Douzgou, S AF Bertolino, Alessandro Caforio, Grazia Blasi, Guseppe Rampino, Antonio Nardini, Marcello Weinberger, Daniel R. Dallapiccola, Bruno Sinibaldi, Lorenzo Douzgou, Sophia TI COMT Val(158) Met polymorphism predicts negative symptoms response to treatment with olanzapine in schizophrenia SO SCHIZOPHRENIA RESEARCH LA English DT Letter ID GENOTYPE C1 Univ Bari, Dept Neurol & Psychiat Sci, Sect Mental Disorders, Psychiat Neurosci Grp, I-70124 Bari, Italy. NIMH, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. IRCCS CSS Mendel, Rome, Italy. Univ Roma La Sapienza, Dept Expt Med & Pathol, Rome, Italy. IRCCS Casa Sollievo Sofferenza, San Giovanni Rotondo, Italy. RP Bertolino, A (reprint author), Univ Bari, Dept Neurol & Psychiat Sci, Sect Mental Disorders, Psychiat Neurosci Grp, Piazza Giulio Cesare 9, I-70124 Bari, Italy. EM a.bertolino@psichiat.uniba.it RI Rampino, Antonio/Q-4465-2016 OI Rampino, Antonio/0000-0002-9654-3266 NR 6 TC 30 Z9 33 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD SEP PY 2007 VL 95 IS 1-3 BP 253 EP 255 DI 10.1016/j.schres.2007.06.014 PG 3 WC Psychiatry SC Psychiatry GA 215VK UT WOS:000249836900035 PM 17644310 ER PT J AU Ozelli, KL Volkow, ND AF Ozelli, Kristin Leutwyler Volkow, Nora D. TI This is your brain on food - Neuroimaging reveals a shared basis for chocoholia and drug addiction SO SCIENTIFIC AMERICAN LA English DT Editorial Material C1 Natl Inst Drug Abuse, Bethesda, MD 20892 USA. SUNY Stony Brook, Sch Med, Stony Brook, NY 11790 USA. Brookhaven Natl Lab, Upton, NY 11973 USA. RP Ozelli, KL (reprint author), Natl Inst Drug Abuse, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 3 PU SCI AMERICAN INC PI NEW YORK PA 415 MADISON AVE, NEW YORK, NY 10017 USA SN 0036-8733 J9 SCI AM JI Sci.Am. PD SEP PY 2007 VL 297 IS 3 BP 84 EP 85 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200OP UT WOS:000248773000032 ER PT J AU Lawrence, EJ Shaw, P Baker, D Patel, M Sierra-Siegert, M Medford, N David, AS AF Lawrence, Emma J. Shaw, Philip Baker, Dawn Patel, Maxine Sierra-Siegert, Mauriclo Medford, Nicholas David, Anthony S. TI Empathy and enduring depersonalization: The role of self-related processes SO SOCIAL NEUROSCIENCE LA English DT Article ID HIGH-FUNCTIONING AUTISM; PERSPECTIVE-TAKING; SPEECH RATE; INTEROCEPTIVE AWARENESS; PSYCHOMETRIC PROPERTIES; SHARED REPRESENTATIONS; AUTONOMIC RESPONSE; ASPERGER-SYNDROME; WOULD FEEL; DISORDER AB Empathy has two key components: affective and cognitive. It relies on "embodied" processes such as the generation, representation and perception of feeling states. People diagnosed with Depersonalization Disorder (DPD) report disturbances in affective experience, such as emotional numbing, alongside aberrations in "body image" such as increased self-focus and feelings of "disembodiment". DPD therefore provides a test bed for the role of such self-related processes in empathy. We tested 16 participants diagnosed with DPD and 48 control volunteers on measures of cognitive and affective empathy. We used self-report measures (EQ; Baron-Cohen & Wheelwright, 2004), an objective measure of cognitive empathy-the "Eyes" task (Baron-Cohen, Wheelwright, Hill, Raste, & Plumb, 2001), and a novel task tapping affective empathy, utilizing speech rate as an implicit measure of physiological arousal. We also measured participants' tendency to use mental representations that relate to the self during the affective empathy task. The DPD group showed intact performance on the cognitive empathy task. However, there was a disruption in the physiological component of affective empathy alongside a more pronounced reliance on mental representations of the self. These findings suggest affective empathy to be reliant on intact emotional experience in the observer. In addition, excessive self-focus may be detrimental to an empathic response. C1 [Lawrence, Emma J.; Baker, Dawn; Patel, Maxine; Sierra-Siegert, Mauriclo; Medford, Nicholas; David, Anthony S.] Kings Coll London, Inst Psychiat, Dept Psychol Med, Sect Cognit Neuropsychiat, London SE5 8AF, England. [Shaw, Philip] NIMH, Bethesda, MD 20892 USA. RP Lawrence, EJ (reprint author), Kings Coll London, Inst Psychiat, Dept Psychol Med, Sect Cognit Neuropsychiat, London SE5 8AF, England. EM e.lawrence@iop.kcl.ac.uk RI X, Simon/F-4678-2011; David, Anthony/C-1315-2011; Patel, Maxine/B-7926-2011 OI David, Anthony/0000-0003-0967-774X; Patel, Maxine/0000-0003-0514-5818 NR 72 TC 8 Z9 8 U1 7 U2 16 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 1747-0919 J9 SOC NEUROSCI JI Soc. Neurosci. PD SEP-DEC PY 2007 VL 2 IS 3-4 BP 292 EP 306 DI 10.1080/17470910701391794 PG 15 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 249RA UT WOS:000252245400009 PM 18633820 ER PT J AU Moll, J de Oliveira-Souza, R Garrido, GJ Bramati, IE Caparelli-Daquer, EMA Paiva, MLMF Zahn, R Grafman, J AF Moll, Jorge de Oliveira-Souza, Ricardo Garrido, Griselda J. Bramati, Ivanei E. Caparelli-Daquer, Egas M. A. Paiva, Mirella L. M. F. Zahn, Roland Grafman, Jordan TI The self as a moral agent: Link-ling the neural bases of social agency and moral sensitivity SO SOCIAL NEUROSCIENCE LA English DT Article ID HUMAN ORBITOFRONTAL CORTEX; MEDIAL PREFRONTAL CORTEX; COGNITIVE NEUROSCIENCE; PERSPECTIVE-TAKING; HEALTHY-SUBJECTS; FUNCTIONAL MRI; ROMANTIC LOVE; BRAIN; REWARD; EMOTION AB The human brain is inherently able to understand the world in moral ways, endowing most of us with an intuitive sense of fairness, concern for others, and observance of cultural norms. We have argued that this moral sensitivity ability depends on a sophisticated integration of cognitive, emotional, and motivational mechanisms, which are modulated by individual experience in different cultural milieus. Different lines of investigation on agency and morality have pointed to overlapping neural systems. Therefore, understanding the relationships between morality and agency may provide key insights into the mechanisms underlying human behavior in several clinical and societal settings. We used functional MRI to investigate the contribution of agency and of specific moral emotions to brain activation using action scripts. Results showed that emotionally neutral agency recruited neural networks previously associated with agency, intentionality and moral cognition, encompassing ventral and subgenual sectors of the medial prefrontal cortex (PFC), insula, anterior temporal cortex and superior temporal sulcus (STS). Compared to emotionally neutral agency, different categories of moral emotions led to distinct activation patterns: (1) prosocial emotions (guilt, embarrassment, compassion) activated the anterior medial PFC and STS, with (2) empathic emotions (guilt and compassion) additionally recruiting the mesolimbic pathway; (3) other-critical emotions (disgust and indignation) were associated with activation of the amygdala-parahippocampal and fusiform areas. These findings indicate that agency related to norm-abiding social behaviors of emotionally neutral scripts share neural substrates both with the "default mode" of brain function and with the moral sensitivity network. Additional activation in specific components of this network is elicited by different classes of moral emotions, in agreement with recent integrative models of moral cognition and emotion. C1 [Moll, Jorge; Grafman, Jordan] NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. [Moll, Jorge; de Oliveira-Souza, Ricardo; Bramati, Ivanei E.; Caparelli-Daquer, Egas M. A.] LABS DOr Hosp Network, Rio De Janeiro, Brazil. [de Oliveira-Souza, Ricardo; Caparelli-Daquer, Egas M. A.] Gaffree & Guinle Univ Hosp, Rio De Janeiro, Brazil. [Garrido, Griselda J.] Inst Israelita Ensino & Pesquisa Albert Einstein, Sao Paulo, Brazil. RP Moll, J (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM mollj@ninds.nih.gov RI Zahn, Roland/C-4665-2008; Moll, Jorge/B-2654-2013 OI Zahn, Roland/0000-0002-8447-1453; NR 76 TC 99 Z9 102 U1 8 U2 37 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 1747-0919 J9 SOC NEUROSCI JI Soc. Neurosci. PD SEP-DEC PY 2007 VL 2 IS 3-4 BP 336 EP 352 DI 10.1080/17470910701392024 PG 17 WC Neurosciences; Psychology SC Neurosciences & Neurology; Psychology GA 249RA UT WOS:000252245400012 PM 18633822 ER PT J AU Aliotta, JM Sanchez-Guijo, FM Dooner, GJ Johnson, KW Dooner, MS Greer, KA Greer, D Pimentel, J Kolankiewicz, LM Puente, N Faradyan, S Ferland, P Bearer, EL Passero, MA Adedi, M Colvin, GA Quesenberry, PJ AF Aliotta, Jason M. Sanchez-Guijo, Fermin M. Dooner, Gerri J. Johnson, Kevin W. Dooner, Mark S. Greer, Kenneth A. Greer, Deborah Pimentel, Jeffrey Kolankiewicz, Lutz M. Puente, Napoleon Faradyan, Sam Ferland, Paulette Bearer, Elaine L. Passero, Michael A. Adedi, Mehrdad Colvin, Geralt A. Quesenberry, Peter J. TI Alteration of marrow cell gene expression, protein production, and engraftment into lung by lung-derived microvesicles: A novel mechanism for phenotype modulation SO STEM CELLS LA English DT Article DE adult bone marrow stein cells; bone marrow transplantation; in vitro differentiation; irradiation; microvesicles ID HEMATOPOIETIC STEM-CELLS; SHED MEMBRANE MICROPARTICLES; BONE-MARROW; IN-VIVO; PLATELET MICROPARTICLES; PROCOAGULANT ACTIVITY; ALVEOLAR EPITHELIUM; HORIZONTAL TRANSFER; MESSENGER-RNA; CONTRIBUTE AB Numerous animal studies have demonstrated that adult marrow-derived cells can contribute to the cellular component of the lung. Lung injury is a major variable in this process; however, the mechanism remains unknown. We hypothesize that injured lung is capable of inducing epigenetic modifications of marrow cells, influencing them to assume phenotypic characteristics of lung cells. We report that under certain conditions, radiation-injured lung induced expression of pulmonary epithelial cell-specific genes and prosurfactant B protein in cocultured whole bone marrow cells separated by a cell-impermeable membrane. Lung-conditioned media had a similar effect on cocultured whole bone marrow cells and was found to contain pulmonary epithelial cell-specific RNA-filled microvesicles that entered whole bone marrow cells in culture. Also, whole bone marrow cells cocultured with lung had a greater propensity to produce type II pneumocytes after transplantation into irradiated mice. These findings demonstrate alterations of marrow cell phenotype by lung-derived microvesicles and suggest a novel mechanism for marrow cell-directed repair of injured tissue. C1 Rhode Isl Hosp, Div Hematol & Oncol, Providence, RI 02903 USA. COBRE, Roger Williams Med Ctr, Providence, RI USA. Brown Univ, Dept Pathol & Lab Med, Providence, RI 02912 USA. RP Aliotta, JM (reprint author), Rhode Isl Hosp, Div Hematol & Oncol, 3rd Floor,George Bldg,593 Eddy St, Providence, RI 02903 USA. EM jason_aliotta@brown.edu RI 2007, Secribsal/A-1556-2012 FU NCRR NIH HHS [P20RR018757-04, P20 RR018757, P20 RR018757-047434]; NHLBI NIH HHS [1K08 HL072332-01, 1R01HL73747-02, K08 HL072332]; NIDDK NIH HHS [1R01DK61858-03, 5K08 DK064980, K08 DK064980, R01 DK061858]; NIGMS NIH HHS [GM47368, R01 GM047368, R01 GM047368-06A2, R01 GM047368-07]; NINDS NIH HHS [R01 NS046810] NR 50 TC 105 Z9 105 U1 1 U2 10 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 SEP PY 2007 VL 25 IS 9 BP 2245 EP 2256 DI 10.1634/stemcells.2007-0128 PG 12 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 206QH UT WOS:000249197500013 PM 17556595 ER PT J AU Chen, HL Pistollato, F Hoeppner, DJ Ni, HT Mckay, RDG Panchision, DM AF Chen, Hui-Ling Pistollato, Francesca Hoeppner, Daniel J. Ni, Hsiao-Tzu Mckay, Ronald D. G. Panchision, David M. TI Oxygen tension regulates survival and fate of mouse central nervous system precursors at multiple levels SO STEM CELLS LA English DT Article DE neural stem cells; oxygen; hypoxia; multipotent; expansion; oligodendrocyte ID NEURAL STEM-CELLS; MAMMALIAN SUBVENTRICULAR ZONE; BRAIN-DEVELOPMENT; DOPAMINERGIC DIFFERENTIATION; OLIGODENDROCYTE DEVELOPMENT; ERYTHROPOIETIN RECEPTOR; CORTICAL NEUROGENESIS; TRANSCRIPTION FACTOR; CEREBRAL-ISCHEMIA; OXIDATIVE STRESS AB Despite evidence that oxygen regulates neural precursor fate, the effects of changing oxygen tensions on distinct stages in precursor differentiation are poorly understood. We found that 5% oxygen permitted clonal and long-term expansion of mouse fetal cortical precursors. In contrast, 20% oxygen caused a rapid decrease in hypoxia-inducible factor la and nucleophosmin, followed by the induction of p53 and apoptosis of cells. This led to a decrease in overall cell number and particularly a loss of astrocytes and oligodendrocytes. Clonal analysis revealed that apoptosis in 20% oxygen was due to a complete loss of CD133(lo)CD24(lo) multipotent precursors, a substantial loss of CD133(hi)CD24(lo) multipotent precursors, and a failure of remaining CD133(hi)CD24(lo) cells to generate glia. In contrast, committed neuronal progenitors were not significantly affected. Switching clones from 5% to 20% oxygen only after mitogen withdrawal led to a decrease in total clone numbers but an even greater decrease in oligodendrocyte-containing clones. During this late exposure to 20% oxygen, bipotent glial (A2B5(+)) and early (platelet-derived growth factor receptor a) oligodendrocyte progenitors appeared and disappeared more quickly, relative to 5% oxygen, and late stage O4(+) oligodendrocyte progenitors never appeared. These results indicate that multipotent cells and oligodendrocyte progenitors are more susceptible to apoptosis at 20% oxygen than committed neuronal progenitors. This has important implications for optimizing ex vivo production methods for cell replacement therapies. C1 Childrens Natl Med Ctr, Ctr Res Neurosci, Washington, DC 20010 USA. Univ Padua, Dept Pediat, Hematooncol Lab, Padua, Italy. Natl Inst Neurol Disorders & Stroke, Mol Biol Lab, Natl Inst Hlth, Bethesda, MD USA. R&D Syst Inc, Minneapolis, MN USA. RP Panchision, DM (reprint author), 5th Floor,Suite 5430,111 Michigan Ave NW, Washington, DC 20010 USA. EM dpanchision@cnmcresearch.org FU Intramural NIH HHS; NICHD NIH HHS [P30HD40677] NR 71 TC 83 Z9 89 U1 1 U2 5 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 SEP PY 2007 VL 25 IS 9 BP 2291 EP 2301 DI 10.1634/stemcells.2006-0609 PG 11 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 206QH UT WOS:000249197500018 PM 17556599 ER PT J AU Howard, G Safford, MM Meschia, JF Moy, CS Howard, VJ Pulley, L Gomez, CR Crowther, M AF Howard, George Safford, Monika M. Meschia, James F. Moy, Claudia S. Howard, Virginia J. Pulley, LeaVonne Gomez, Camilo R. Crowther, Martha TI Stroke symptoms in individuals reporting no prior stroke or transient ischemic attack are associated with a decrease in indices of mental and physical functioning SO STROKE LA English DT Article DE cerebrovascular disorders; cohort studies; health-related quality of life ID RACIAL-DIFFERENCES; RISK-FACTORS; COGNITIVE IMPAIRMENT; GENERAL-POPULATION; SILENT STROKE; DEMENTIA; REASONS; BRAIN; QUESTIONNAIRE; PREVALENCE AB Background and Purpose - Stroke symptoms in the absence of recognized stroke are common, but potential associated dysfunctions have not been described. Methods - We assessed quality-of-life measures using the Physical and Mental Component Summary scores of the Short Form 12 (PCS-12 and MCS-12) in the Reasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. Differences in mean PCS-12 and MCS-12 scores were assessed among participant groups symptoms-free (n = 16 090); history of stroke symptoms but free of stroke/transient ischemic attack (n = 3404); history of stroke (n = 1491); and history of transient ischemic attack (n = 818). Results - Participants with symptoms (but no diagnosis) had average PCS-12 scores 5.5 (95% CI: 5.2 to 5.9) points lower than those without symptoms, a difference similar to transient ischemic attack (6.0; 95% CI: 5.3 to 6.7) and over one half the effect of stroke (8.4; 95% CI: 8.0 to 9.0). MCS-12 scores were 2.7 (95% CI: 2.4 to 3.0) points lower for those ith symptoms, -0.5 for transient ischemic attack (95% CI: 0.0 to -1.1), and -1.6 for stroke (95% CI: -1.2 to -2.0). Differences in demographic and vascular risk factors, health behaviors, physiological measures, and indices of socioeconomic status did not fully explain these differences. Those reporting history of weakness or numbness had larger current decrements in physical functioning, and those reporting history of inability to express themselves or understand language had larger current decrements in mental functioning. Conclusions - Individuals with clinically consistent symptoms but no stroke diagnosis have a lower quality of life than those without symptoms. The difference in physical functioning is substantial with a smaller decline in mental functioning. Apart from so-called "silent stroke," there appear to be many individuals with possibly symptomatic cerebrovascular disease - either stroke or transient ischemic attack - who are not being diagnosed. Furthermore, these symptomatic but undiagnosed strokes may not be benign. C1 Univ Alabama, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA. Univ Alabama, Birmingham VA Med Ctr, Deep S Ctr Effectivenss, Birmingham, AL USA. Univ Alabama, Div Prevent Med, Birmingham, AL USA. Mayo Clin, Jacksonville, FL 32224 USA. NINDS, NIH, Bethesda, MD 20892 USA. Univ Alabama, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. Univ Arkansas Hlth Sci Univ, Dept Hlth Behav, Little Rock, AR 72204 USA. Alabama Neurol Inst, Birmingham, AL USA. Univ Alabama, Sch Publ Hlth, Dept Hlth Behav, Birmingham, AL 35294 USA. RP Howard, G (reprint author), Univ Alabama, Sch Publ Hlth, Dept Biostat, 1665 Univ Blvd, Birmingham, AL 35294 USA. EM ghoward@uab.edu RI crona, malin/B-7085-2012 FU NHLBI NIH HHS [R01 HL080477]; NINDS NIH HHS [NS 041588, R01 NS041588, U01 NS041588] NR 25 TC 22 Z9 22 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD SEP PY 2007 VL 38 IS 9 BP 2446 EP 2452 DI 10.1161/STROKEAHA.106.478032 PG 7 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 204FF UT WOS:000249028400011 PM 17673720 ER PT J AU Hakim, FT Gress, RE AF Hakim, F. T. Gress, R. E. TI Immunosenescence: deficits in adaptive immunity in the elderly SO TISSUE ANTIGENS LA English DT Review DE aging; cytokines; immunosenescence; immunotherapy; thymus ID BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; KERATINOCYTE GROWTH-FACTOR; RECEPTOR EXCISION CIRCLE; THYMIC EPITHELIAL-CELLS; REGULATORY T-CELLS; AGE-RELATED DEFECTS; B-LYMPHOPOIESIS; LYMPH-NODES; IN-VIVO AB Aging is associated clinically with increases in the frequency and severity of infectious diseases and an increased incidence of cancer, chronic inflammatory disorders and autoimmunity. These age-associated immune dysfunctions are the consequence of declines in both the generation of new naive T and B lymphocytes and the functional competence of memory populations. These alterations collectively are termed immunosenescence. C1 NCI, NIH, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. RP Hakim, FT (reprint author), NCI, NIH, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. EM hakimf@mail.nih.gov NR 100 TC 99 Z9 105 U1 0 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD SEP PY 2007 VL 70 IS 3 BP 179 EP 189 DI 10.1111/j.1399-0039.2007.00891.x PG 11 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 200IS UT WOS:000248757700001 PM 17661905 ER PT J AU Fostel, JM Burgoon, L Zwickl, C Lord, P Corton, JC Bushel, PR Cunningham, M Fan, LJ Edwards, SW Hester, S Stevens, J Tong, WD Waters, M Yang, CH Termant, R AF Fostel, Jennifer M. Burgoon, Lyle Zwickl, Craig Lord, Peter Corton, J. Christopher Bushel, Pierre R. Cunningham, Michael Fan, Liju Edwards, Stephen W. Hester, Susan Stevens, James Tong, Weida Waters, Michael Yang, ChiHae Termant, Raymond TI Toward a checklist for exchange and interpretation of data from a toxicology study SO TOXICOLOGICAL SCIENCES LA English DT Article DE toxicogenomics; MIAME; data integration; database ID MICROARRAY DATA; ACETAMINOPHEN TOXICITY; HEPATOTOXICITY; MIAME; MICE; METABOLISM; LIVER; RATS AB Data from toxicology and toxicogenomics studies are valuable, and can be combined for meta-analysis using public data repositories such as Chemical Effects in Biological Systems Knowledgebase, ArrayExpress, and Gene Expression Omnibus. In order to fully utilize the data for secondary analysis, it is necessary to have a description of the study and good annotation of the accompanying data. This study annotation permits sophisticated cross-study comparison and analysis, and allows data from comparable subjects to be identified and fully understood. The Minimal Information About a Microarray Experiment Standard was proposed to permit deposition and sharing of microarray data. We propose the first step toward an analogous standard for a toxicogenomics/toxicology study, by describing a checklist of information that best practices would suggest be included with the study data. When the information in this checklist is deposited together with the study data, the checklist information helps the public explore the study data in context of time, or identify data from similarly treated subjects, and also explore/identify potential sources of experimental variability. The proposed checklist summarizes useful information to include when sharing study data for publication, deposition into a database, or electronic exchange with collaborators. It is not a description of how to carry out an experiment, but a definition of how to describe an experiment. It is anticipated that once a toxicology checklist is accepted and put into use, then toxicology databases can be configured to require and output these fields, making it straightforward to annotate data for interpretation by others. C1 NIEHS, Res Triangle Pk, NC 27709 USA. NIEHS, LMIT ITSS Contract, Res Triangle Pk, NC 27709 USA. Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. Johnson & Johnson PRD, Raritan, NJ 08869 USA. US EPA, Res Triangle Pk, NC 27711 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. Ontology Worshop LLC, Columbia, MD 21045 USA. Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. Integrated Life Sci, Res Triangle Pk, NC 27709 USA. Leadscope, Columbus, OH 43212 USA. RP Fostel, JM (reprint author), NIEHS, POB 12233, 111 Alexander Drive, Res Triangle Pk, NC 27709 USA. EM fostel@niehs.nih.gov OI Burgoon, Lyle/0000-0003-4977-5352 FU Intramural NIH HHS NR 18 TC 12 Z9 13 U1 0 U2 5 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD SEP PY 2007 VL 99 IS 1 BP 26 EP 34 DI 10.1093/toxsci/kfm090 PG 9 WC Toxicology SC Toxicology GA 205XK UT WOS:000249148300004 PM 17442663 ER PT J AU Iida, M Anna, CH Gaskin, ND Walker, NJ Devereux, TR AF Iida, Mari Anna, Colleen H. Gaskin, Nicole D. Walker, Nigel J. Devereux, Theodora R. TI The putative tumor suppressor Tsc-22 is downregulated early in chemically induced hepatocarcinogenesis and may be a suppressor of Gadd45b SO TOXICOLOGICAL SCIENCES LA English DT Article DE non-genotoxic; tumor suppressor gene; SiRNA ID GROWTH-FACTOR-BETA; GLAND CANCER-CELL; STIMULATED CLONE-22; GENE-EXPRESSION; APOPTOSIS; CARCINOGENS; INDUCTION; CLONING; ACID AB Tsc-22 is a novel tumor suppressor gene that represents a new class of transcription factors that has transcriptional repressor activity. We found Tsc-22 downregulation in livers from B6C3F1 mice following treatment for 2 weeks with carcinogenic doses o the antianxiety drug oxazepam (2500 ppm) or the peroxisome proliferator Wyeth-14,643 (500 ppm) but not with two other carcinogens such as o-nitrotoluene or methyleugenol or three noncarcinogens including p-nitrotoluene, eugenol, or acetaminophen. The expression of Tsc-22 was also repressed in B6C3F1 mouse liver tumors that were induced by several chemicals from 2-year carcinogenicity studies as well as in spontaneous liver tumors. To identify potential Tsc-22 target genes in mouse liver, we transfected small interference RNA (SiRNA) designed to inhibit Tsc-22 into murine liver BNL-CL.2 cells. We selected two potential transcriptional targets of Tsc-22, growth arrest and DNA damage-inducible gene 45 0 (Gadd45b) and leucine zipper, putative tumor suppressor 2 (Lzts2) to test based on our previous complementary DNA microarray studies, showing that expression of these cancer-associated genes was increased when Tsc-22 was repressed. SiRNA treatment of BNL-CL.2 cells with Tsc-22 oligonucleotides but not nonspecific oligonucleotides decreased RNA and protein expression of Tsc-22 by 80-90%, while expression of Gadd45b gene, but not Lzts2, was increased over time after an initial decrease. Treatment of these cells with oxazepam for 48 h also resulted in decreased Tsc-22 and increased Gadd45b expression. These data provide evidence that Tsc-22 is a suppressor of Gadd45b expression, which may contribute to an early antiapoptotic response. C1 Biosafety Res Ctr Food Drug & Pesticides, Dept Pathol, Shizuoka 4371213, Japan. Lab Mol Carcinogenes, Res Triangle Pk, NC 27709 USA. Natl Inst Hlth, Natl Inst Environm Hlth Sci, Toxicol Operat Branch, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Iida, M (reprint author), Biosafety Res Ctr Food Drug & Pesticides, Dept Pathol, 582-2 Shioshinden, Iwata-shi, Shizuoka 4371213, Japan. EM kotorogzo@yahoo.co.jp RI Walker, Nigel/D-6583-2012 OI Walker, Nigel/0000-0002-9111-6855 FU Intramural NIH HHS NR 22 TC 7 Z9 8 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD SEP PY 2007 VL 99 IS 1 BP 43 EP 50 DI 10.1093/toxsci/kfm138 PG 8 WC Toxicology SC Toxicology GA 205XK UT WOS:000249148300006 PM 17533171 ER PT J AU Divi, RL Leonard, SL Walker, BL Kuo, MM Shockley, ME St Claire, MC Nagashima, K Harbaugh, SW Harbaugh, JW Poirier, MC AF Divi, Rao L. Leonard, Sarah L. Walker, Brettania L. Kuo, Maryanne M. Shockley, Marie E. St Claire, Marisa C. Nagashima, Kunio Harbaugh, Steven W. Harbaugh, Jeffrey W. Poirier, Miriam C. TI Erythrocebus patas monkey offspring exposed perinatally to NRTIs sustain skeletal muscle mitochondrial compromise at birth and at 1 year of age SO TOXICOLOGICAL SCIENCES LA English DT Article DE zidovudine; lamivudine; stavudine; didanosine; electron microscopy; mitochondrial DNA quantity; oxidative phosphorylation ID REVERSE-TRANSCRIPTASE INHIBITORS; IMMUNODEFICIENCY-VIRUS TYPE-1; HIV-INFECTED WOMEN; IN-UTERO; ANTIRETROVIRAL THERAPY; ZIDOVUDINE TREATMENT; UNINFECTED CHILDREN; CORD BLOOD; INFANTS; TOXICITY AB Antiretroviral nucleoside reverse transcriptase inhibitors (NRTIs), given to human immunodeficiency virus-1-infected pregnant women to prevent vertical viral transmission, have caused mitochondrial dysfunction in some human infants. Here, we examined mitochondrial integrity in skeletal muscle from offspring of pregnant retroviral-free Erythrocebus patas dams administered human-equivalent NRTI doses for the last 10 weeks of gestation or for 10 weeks of gestation and 6 weeks after birth. Exposures included no drug, Zidovudine (AZT), Lamivudine (3TC), AZT/3TC, AZT/ Didanosine (ddI), and Stavudine (d4T)/3TC. Offspring were examined at birth (n = 3 per group) and 1 year (n = 4 per group, not including 3TC alone). Circulating levels of creatine kinase were elevated at I year in the d4T/3TC-exposed group. Measurement of oxidative phosphorylation enzyme activities (complexes 1, 11, and IV) revealed minimal NRTI-induced changes at birth and at I year. Histochemistry for complex IV activity showed abnormal staining with activity depletion at birth and I year in groups exposed to AZT alone and to the 2-NRTI combinations. Electron microscopy of skeletal muscle at birth and 1 year of age showed mild to severe mitochondrial damage in all the NRTI-exposed groups, with 3TC inducing mild damage and the 2-NRTI combinations inducing extensive damage. At birth, mitochondrial DNA (mtDNA) was depleted by similar to 50% in groups exposed to AZT alone and the 2-NRTI combinations. At I year, the mtDNA levels had increased but remained significantly below normal. Therefore, skeletal muscle mitochondrial compromise occurs at birth and persists at I year of age (46 weeks after the last NRTI exposure) in perinatally exposed young monkeys, suggesting that similar events may occur in NRTI-exposed human infants. C1 Bioqual Inc, Rockville, MD 20850 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Cell & Mol Structure, Frederick, MD 21702 USA. RP Divi, RL (reprint author), NCI, NIH, Reg Canc Ctr, 37 Convent Drive, Bethesda, MD 20892 USA. EM divir@exchange.nih.gov FU Intramural NIH HHS NR 36 TC 18 Z9 19 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD SEP PY 2007 VL 99 IS 1 BP 203 EP 213 DI 10.1093/toxsci/kfm143 PG 11 WC Toxicology SC Toxicology GA 205XK UT WOS:000249148300021 PM 17545213 ER PT J AU Bell, DR Clode, S Fan, MQ Fernandes, A Foster, PMD Jiang, T Loizou, G MacNicoll, A Miller, BG Rose, M Tran, L White, S AF Bell, David R. Clode, Sally Fan, Ming Qi Fernandes, Alwyn Foster, Paul M. D. Jiang, Tao Loizou, George MacNicoll, Alan Miller, Brian G. Rose, Martin Tran, Lang White, Shaun TI Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the developing male Wistar(Han) rat. I: No decrease in epididymal sperm count after a single acute dose SO TOXICOLOGICAL SCIENCES LA English DT Article DE dioxin; sperm; developmental; toxicity ID LACTATIONAL EXPOSURE; REPRODUCTIVE-SYSTEM; TISSUE CONCENTRATIONS; ANDROGENIC STATUS; UTERO; TCDD; PROSTATE; INUTERO; MECHANISM; ADULTHOOD AB It has been reported that fetal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes defects in the male reproductive system of the rat. We set out to replicate and extend these effects using a robust experimental design. Groups of 75 (control vehicle) or 55 (50, 200, or 1000 ng of TCDD/kg bodyweight) female Wistar(Han) rats were exposed to TCDD on gestational day (GD)15, then allowed to litter. The high-dose group dams showed no sustained weight loss compared to control, but four animals had total litter loss. Pups in the high-dose group showed reduced body weight up till day 21, and pups in the medium dose group showed reduced body weight in the first week postpartum. Balano-preputial separation was significantly delayed in the high-dose group male offspring. There were no significant effects of treatment when the offspring were subjected to a functional observational battery or mated with females to assess reproductive capability. Twenty-five males per group were killed on postnatal day (PND) 70, and similar to 60 animals per group (similar to 30 for the high-dose group) on PND120 to assess seminology and other end points. At PND120, the two highest dose groups showed a statistically significant elevation of sperm counts, compared to control; however, this effect was small (similar to 30%), within the normal range of sperm counts for this strain of rat, was not reflected in testicular spermatid counts nor PND70 data, and is therefore postulated to have no biological significance. Although there was an increase in the proportion of abnormal sperm at PND70, seminology parameters were otherwise unremarkable. Testis weights in the high-dose group were slightly decreased at PND70 and 120, and at PND120, brain weights were decreased in the high-dose group, liver to body weight ratios were increased for all three dose groups, with an increase in inflammatory cell foci in the epididymis in the high-dose group. These data show that TCDD is a potent developmental toxin after exposure of the developing fetus but that acute developmental exposure to TCDD on GD15 caused no decrease in sperm counts. C1 Covance Lab Ltd, Harrogate HG3 1PY, N Yorkshire, England. NIEHS, Res Triangle Pk, NC 27709 USA. Hlth & Safety Lab, Buxton SK17 9JN, Derbyshire, England. Cent Sci Lab Environm Food & Hlth, York YO41 1LZ, N Yorkshire, England. Inst Occupat Med, Edinburgh EH14 4AP, Midlothian, Scotland. RP Bell, DR (reprint author), Univ Nottingham, Sch Biol, Univ Park, Nottingham NG7 2RD, England. EM david.bell@nottingham.ac.uk OI Rose, Martin/0000-0001-7071-180X NR 43 TC 25 Z9 26 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD SEP PY 2007 VL 99 IS 1 BP 214 EP 223 DI 10.1093/toxsci/kfm140 PG 10 WC Toxicology SC Toxicology GA 205XK UT WOS:000249148300022 PM 17545212 ER PT J AU Bell, DR Clode, S Fan, MQ Fernandes, A Foster, PMD Jiang, T Loizou, G MacNicoll, A Miller, BG Rose, M Tran, L White, S AF Bell, David R. Clode, Sally Fan, Ming Qi Fernandes, Alwyn Foster, Paul M. D. Jiang, Tao Loizou, George MacNicoll, Alan Miller, Brian G. Rose, Martin Tran, Lang White, Shaun TI Toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin in the developing male Wistar(Han) rat. II: Chronic dosing causes developmental delay SO TOXICOLOGICAL SCIENCES LA English DT Article DE dioxin; sperm; developmental toxicity ID LONG-EVANS RATS; DIOXIN-LIKE COMPOUNDS; IN-UTERO EXPOSURE; LACTATIONAL EXPOSURE; TISSUE CONCENTRATIONS; SEX-RATIO; REPRODUCTIVE TOXICITY; ANDROGENIC STATUS; SPERM NUMBERS; TCDD AB We have investigated whether fetal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes defects in the male reproductive system of the rat using chronically exposed rats to ensure continuous exposure of the fetus. Five- to six-week-old rats were exposed to control diet, or diet containing TCDD, to attain an average dose of 2.4, 8, and 46 ng TCDD/kg/day for 12 weeks, whereupon the rats were mated and allowed to litter; rats were switched to control diet after parturition. Male offsprings were allowed to develop until kills on PND70 (25 per group) or PND120 (all remaining animals). Offspring from the high-dose group showed an increase in total litter loss, and the number of animals alive on postnatal day (PND)4 in the high-dose group was similar to 26% less than control. The high and medium dose offsprings showed decreased weights at various ages. Balano-preputial separation (BPS) was significantly delayed in all three dose groups compared to control. There were no significant effects of maternal treatment when the offsprings were subjected to a functional observational battery or learning tests, with the exception that the high-dose group showed a deficit in motor activity. Twenty rats per group were mated to females, and there were no significant effects of maternal treatment on the fertility of these rats or on the F-1 or F-2 sex ratio. Sperm parameters at PND70 and 120 showed no significant effect of maternal treatment, with the exception that there was an increase in the proportion of abnormal sperm in the highdose group at PND70; this is associated with the developmental delay in puberty in this dose group. There were no remarkable findings of maternal treatment on organ weights, with the exception that testis weights were reduced by similar to 10% at PND70 (but not PND120), and although the experiment was sufficiently powered to detect small changes, ventral prostate weight was not reduced. There were no significant effects of maternal treatment upon histopathological comparison of high-dose and control group organs. These data confirm that developmental exposure to TCDD shows no potent effect on adult sperm parameters or accessory sexual organs, but show that delay in BPS occurs after exposure to low doses of TCDD, and this is dependent upon whether TCDD is administered acutely or chronically. C1 Covance Lab Ltd, Harrogate HG3 1PY, N Yorkshire, England. NIEHS, Res Triangle Pk, NC 27709 USA. Hlth & Safety Lab, Buxton SK17 9JN, Derbyshire, England. Cent Sci Lab Environm Food & Hlth, York YO14 1LZ, N Yorkshire, England. Inst Occupat Med, Edinburgh EH14 4AP, Midlothian, Scotland. RP Bell, DR (reprint author), Univ Nottingham, Sch Biol, Nottingham NG7 2RD, England. EM david.bell@nottingham.ac.uk OI Rose, Martin/0000-0001-7071-180X NR 52 TC 29 Z9 30 U1 3 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD SEP PY 2007 VL 99 IS 1 BP 224 EP 233 DI 10.1093/toxsci/kfm141 PG 10 WC Toxicology SC Toxicology GA 205XK UT WOS:000249148300023 PM 17545211 ER PT J AU Beyer, RP Fry, RC Lasarev, MR McConnachie, LA Meira, LB Palmer, VS Powell, CL Ross, PK Bammler, TK Bradford, BU Cranson, AB Cunningham, ML Fannin, RD Higgins, GM Hurban, P Kayton, RJ Kerr, KF Kosyk, O Lobenhofer, EK Sieber, SO Vliet, PA Weis, BK Wolfinger, R Woods, CG Freedman, JH Linney, E Kaufmann, WK Kavanagh, TJ Paules, RS Rusyn, I Samson, LD Spencer, PS Suk, W Tennant, RJ Zarbl, H AF Beyer, Richard P. Fry, Rebecca C. Lasarev, Michael R. McConnachie, Lisa A. Meira, Lisiane B. Palmer, Valerie S. Powell, Christine L. Ross, Pamela K. Bammler, Theo K. Bradford, Blair U. Cranson, Alex B. Cunningham, Michael L. Fannin, Rickie D. Higgins, Gregory M. Hurban, Patrick Kayton, Robert J. Kerr, Kathleen F. Kosyk, Oksana Lobenhofer, Edward K. Sieber, Stella O. Vliet, Portia A. Weis, Brenda K. Wolfinger, Russel Woods, Courtney G. Freedman, Jonathan H. Linney, Elwood Kaufmann, William K. Kavanagh, Terrance J. Paules, Richard S. Rusyn, Ivan Samson, Leona D. Spencer, Peter S. Suk, William Tennant, Raymond J. Zarbl, Helmut CA Toxicogenomics Res Consortium TI Multicenter study of acetaminophen hepatotoxicity reveals the importance of biological endpoints in genomic analyses SO TOXICOLOGICAL SCIENCES LA English DT Article DE liver injury; toxicogenomics; phenotypic anchoring ID GENE-EXPRESSION ANALYSIS; GLUTATHIONE DEPLETION; MICROARRAY DATA; MOUSE-LIVER; RAT-LIVER; IN-VIVO; TOXICOGENOMICS; INHIBITION; PROFILES; STRESS AB Gene expression profiling is a widely used technique with data from the majority of published microarray studies being publicly available. These data are being used for meta-analyses and in silico discovery; however, the comparability of toxicogenomic data generated in multiple laboratories has not been critically evaluated. Using the power of prospective multilaboratory investigations, seven centers individually conducted a common toxicogenomics experiment designed to advance understanding of molecular pathways perturbed in liver by an acute toxic dose of N-acetyl p-aminophenol (APAP) and to uncover reproducible genomic signatures of APAP-induced toxicity. The nonhepatotoxic APAP isomer N-acetyl-m-aminophenol was used to identify gene expression changes unique to APAP Our data show that c-Myc is induced by APAP and that c-Myc-centered interactomes are the most significant networks of proteins associated with liver injury. Furthermore, sources of error and data variability among Centers and methods to accommodate this variability were identified by coupling gene expression with extensive toxicological evaluation of the toxic responses. We show that phenotypic anchoring of gene expression data is required for biologically meaningful analysis of toxicogenomic experiments. C1 Univ N Carolina, Sch Publ Hlth, Dept Environm Sci & Engn, Chapel Hill, NC 27599 USA. Univ Washington, Seattle, WA 98195 USA. MIT, Cambridge, MA 02139 USA. Oregon Hlth & Sci Univ, Portland, OR 97239 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Cogenics, Div Clin Data Inc, Morrisville, NC 27560 USA. SAS Inst Inc, Cary, NC 27513 USA. Duke Univ, Med Ctr, Durham, NC 27710 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. RP Rusyn, I (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Environm Sci & Engn, CB 7431, Chapel Hill, NC 27599 USA. EM iir@unc.edu; iir@unc.edu RI Rusyn, Ivan/S-2426-2016; Kerr, Kathleen/A-2893-2013; OI Meira, Lisiane/0000-0003-4289-2986; Lasarev, Michael R/0000-0002-1896-2705 FU NIEHS NIH HHS [U19-ES011384, N01-ES25497, T32 ES007032, U19-ES011375, U19-ES011387, U19-ES011391, U19-ES011399] NR 51 TC 46 Z9 48 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD SEP PY 2007 VL 99 IS 1 BP 326 EP 337 DI 10.1093/toxsci/kfm150 PG 12 WC Toxicology SC Toxicology GA 205XK UT WOS:000249148300033 PM 17562736 ER PT J AU Kakaya, RM Rios, J Triulzi, DJ Hillyer, CD Kleinman, S Busch, MP Gottschall, JL Carey, PM Schreiber, GB Schlumpf, KS Nemo, G AF Kakaya, R. M. Rios, J. Triulzi, D. J. Hillyer, C. D. Kleinman, S. Busch, M. P. Gottschall, J. L. Carey, P. M. Schreiber, G. B. Schlumpf, K. S. Nemo, G. TI Blood donations from previously transfused or pregnant donors: A multi-center study to determine the frequency of allo-exposure SO TRANSFUSION LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 20-23, 2007 CL Anaheim, CA SP Amer Assoc Blood Banks C1 LifeSource Blood Serv, Glenview, IL 30322 USA. Amer Red Cross, Blood Serv, New England Reg, Dedham, MA USA. Inst Transfus Med, Pittsburgh, PA USA. Emory Univ, So Reg Amer Red Cross Blood Serv, Atlanta, GA USA. Westat Corp, Rockville, MD USA. Blood Ctr Pacific, San Francisco, CA USA. BloodCenter Wisconsin Inc, Milwaukee, WI USA. Hoxworth Blood Ctr, Cincinnati, OH USA. Natl Heart Lung & Blood Inst, Bethesda, MD USA. EM dtriulzi@itxm.org 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2007 VL 47 IS 3 SU S BP 6A EP 6A PG 1 WC Hematology SC Hematology GA 209OJ UT WOS:000249397600016 ER PT J AU Daniel-Johnson, JA AF Daniel-Johnson, J. A. TI Fingerstick Hb varies markedly with changes in body position: Comparison to venous hemoglobin SO TRANSFUSION LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 20-23, 2007 CL Anaheim, CA SP Amer Assoc Blood Banks C1 NIH, Dept Transfus Med, CC, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. EM danieljohnsonj@cc.nih.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2007 VL 47 IS 3 SU S BP 12A EP 12A PG 1 WC Hematology SC Hematology GA 209OJ UT WOS:000249397600033 ER PT J AU Ronquilo, J Yau, Y Stevens, W Cecco, S Matthews, C Byrne, P Alvandi, F Collins, M Wesley, R Rehak, N Leitman, SF Bolan, CD AF Ronquilo, J. Yau, Y. Stevens, W. Cecco, S. Matthews, C. Byrne, P. Alvandi, F. Collins, M. Wesley, R. Rehak, N. Leitman, S. F. Bolan, C. D. TI Acute and sub-acute citrate mediated effects and responses to IV calcium in healthy apheresis donors SO TRANSFUSION LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 20-23, 2007 CL Anaheim, CA SP Amer Assoc Blood Banks C1 VCU, Sch Med, Richmond, VA USA. NIH, CC, Bethesda, MD 20892 USA. Loma Linda Univ, Med Ctr, Loma Linda, CA 92350 USA. NIH, Lab Med, CC, Bethesda, MD 20892 USA. Temple Univ, Philadelphia, PA 19122 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NIH, Off Director, Clin Stat Branch, CC, Bethesda, MD 20892 USA. EM cbolan@mail.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2007 VL 47 IS 3 SU S BP 14A EP 15A PG 2 WC Hematology SC Hematology GA 209OJ UT WOS:000249397600040 ER PT J AU Alter, HJ Busch, MP Schechterly, CA Colvin, CA Lee, TH Drew, WL Mbisa, G Conde-Ortiz, BA Whitby, D Luban, NL AF Alter, H. J. Busch, M. P. Schechterly, C. A. Colvin, C. A. Lee, T. H. Drew, W. L. Mbisa, G. Conde-Ortiz, B. A. Whitby, D. Luban, N. L. TI A prospective study of transfusion-transmitted HIV, HBV, HCV, CMV, HHV-8 (KSHV) and EBV infections SO TRANSFUSION LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 20-23, 2007 CL Anaheim, CA SP Amer Assoc Blood Banks C1 NIH, Dept Transfus Med, Bethesda, MD 20892 USA. Syst Res Inst, San Francisco, CA USA. CNMC, Div Lab Med, Washington, DC USA. Univ Calif San Francisco, Clin Virol Lab, San Francisco, CA 94143 USA. NCI, SAIC Frederick, ATP, Viral Oncol Sect, Frederick, MD 21701 USA. EM nluban@cnmc.org 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2007 VL 47 IS 3 SU S BP 16A EP 17A PG 2 WC Hematology SC Hematology GA 209OJ UT WOS:000249397600045 ER PT J AU Bryant, BJ Khuu, HM Uzel, G Holland, SM Leitman, SF AF Bryant, B. J. Khuu, H. M. Uzel, G. Holland, S. M. Leitman, S. F. TI Topical granulocyte concentrates for chronic wound healing in a patient with leukocyte adhesion deficiency-1 SO TRANSFUSION LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 20-23, 2007 CL Anaheim, CA SP Amer Assoc Blood Banks C1 NIH, Dept Transfus Med, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. EM bryantb2@cc.nih.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2007 VL 47 IS 3 SU S BP 16A EP 16A PG 1 WC Hematology SC Hematology GA 209OJ UT WOS:000249397600043 ER PT J AU Yu, MW Virata-Theimer, ML Geng, Y Schechtetly, CA Colvin, CA Alter, HJ Luban, NL AF Yu, M. W. Virata-Theimer, M. L. Geng, Y. Schechtetly, C. A. Colvin, C. A. Alter, H. J. Luban, N. L. TI Transmission of parvovirus b19 by blood transfusion confirmed by DNA sequencing SO TRANSFUSION LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 20-23, 2007 CL Anaheim, CA SP Amer Assoc Blood Banks C1 US FDA, Div Hematol, OBRR, CBER, Bethesda, MD 20014 USA. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. CNMC, Div Lab Med, Washington, DC USA. NIH, Bethesda, MD 20892 USA. EM marialuisa.virata@fda.hhs.gov NR 0 TC 2 Z9 2 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2007 VL 47 IS 3 SU S BP 16A EP 16A PG 1 WC Hematology SC Hematology GA 209OJ UT WOS:000249397600044 ER PT J AU Busch, MP Murthy, KK Hirschkom, DF Herring, BL Delwart, EL Racanelli, V Rehermann, B Alter, HJ AF Busch, M. P. Murthy, K. K. Hirschkom, D. F. Herring, B. L. Delwart, E. L. Racanelli, V. Rehermann, B. Alter, H. J. TI Infectivity of donations from eclipse and ramp-up stages of HCV infection in chimpanzees SO TRANSFUSION LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 20-23, 2007 CL Anaheim, CA SP Amer Assoc Blood Banks C1 Univ Calif San Francisco, San Francisco, CA 94143 USA. Blood Syst Res Inst, San Francisco, CA USA. SW Fdn Biomed Res, San Antonio, TX 78284 USA. Blood Syst Res INst, San Francisco, CA USA. NIDDK, Bethesda, MD USA. NIH, Bethesda, MD 20892 USA. EM MBusch@bloodsystems.org RI Herring, Belinda/M-7252-2015 NR 0 TC 3 Z9 4 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2007 VL 47 IS 3 SU S BP 17A EP 17A PG 1 WC Hematology SC Hematology GA 209OJ UT WOS:000249397600046 ER PT J AU Ma, M Piatak, M Fritts, L Lu, D Lifson, J Busch, MP Miller, CJ AF Ma, M. Piatak, M. Fritts, L. Lu, D. Lifson, J. Busch, M. P. Miller, C. J. TI Transmission of simian immunodeficiency virus (SIV) by plasma collected prior to detectable viremia, and infectivity of ramp-up versus chronic stages SO TRANSFUSION LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 20-23, 2007 CL Anaheim, CA SP Amer Assoc Blood Banks C1 Univ Calif Davis, Calif Primate Res Ctr, Davis, CA 95616 USA. Univ Calif Davis, Ctr Comparat Med, Davis, CA 95616 USA. SAIC Frederic Inc, AIDS Vaccine Program, Frederick, MD USA. NCI, Frederick, MD 21701 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Blood Syst Res Inst, San Francisco, CA 94143 USA. EM MBusch@bloodsystems.org NR 0 TC 2 Z9 3 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2007 VL 47 IS 3 SU S BP 17A EP 17A PG 1 WC Hematology SC Hematology GA 209OJ UT WOS:000249397600047 ER PT J AU Bryant, BJ Hopkins, JA Leitman, SF AF Bryant, B. J. Hopkins, J. A. Leitman, S. F. TI Evaluation of low red cell mean corpuscular volume in an apheresis donor population SO TRANSFUSION LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 20-23, 2007 CL Anaheim, CA SP Amer Assoc Blood Banks C1 Natl Inst Hlth, Dept Transfus Med, Bethesda, MD USA. EM bryantb2@cc.nih.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2007 VL 47 IS 3 SU S BP 44A EP 44A PG 1 WC Hematology SC Hematology GA 209OJ UT WOS:000249397600123 ER PT J AU Bryant, BJ Leitman, SF AF Bryant, B. J. Leitman, S. F. TI Gravity sedimentation of granulocytapheresis concentrates with hyd roxyethyl starch efficiently removes red cells and retains neutrophils SO TRANSFUSION LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 20-23, 2007 CL Anaheim, CA SP Amer Assoc Blood Banks C1 NIH, Dept Transfus Med, Bethesda, MD USA. EM bryantb2@cc.nih.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2007 VL 47 IS 3 SU S BP 82A EP 83A PG 2 WC Hematology SC Hematology GA 209OJ UT WOS:000249397600237 ER PT J AU Patel, AJ Bryant, BJ Wesley, RA Bolan, CD Leitman, SF AF Patel, A. J. Bryant, B. J. Wesley, R. A. Bolan, C. D. Leitman, S. F. TI Capillary versus venous Hb determination in the eligibility assessment of healthy blood donors SO TRANSFUSION LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 20-23, 2007 CL Anaheim, CA SP Amer Assoc Blood Banks C1 NIH, Dept Transfus Med, Bethesda, MD USA. NIH, Biostat Serv, Bethesda, MD USA. EM bryantb2@cc.nih.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2007 VL 47 IS 3 SU S BP 115A EP 115A PG 1 WC Hematology SC Hematology GA 209OJ UT WOS:000249397600336 ER PT J AU Caruccio, L AF Caruccio, L. TI Expression of adhesion molecules by neurtrophils from patients with chronic myeloproliferative diseases SO TRANSFUSION LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 20-23, 2007 CL Anaheim, CA SP Amer Assoc Blood Banks C1 NIH, Bethesda, MD 20892 USA. EM lcaruccio@mail.cc.nih.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2007 VL 47 IS 3 SU S BP 137A EP 137A PG 1 WC Hematology SC Hematology GA 209OJ UT WOS:000249397600402 ER PT J AU Wu, G Tang, Q Shen, W He, B Zhao, T AF Wu, G. Tang, Q. Shen, W. He, B. Zhao, T. TI Characterization of red cell h-deficiency phenotype in a homozygous individual for C658t mutation (h658) of FUT1 gene SO TRANSFUSION LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 20-23, 2007 CL Anaheim, CA SP Amer Assoc Blood Banks C1 Nanning Inst Transfus Med, Nanning, Peoples R China. NIH, Bethesda, MD 20892 USA. EM guangwu@szonline.net 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2007 VL 47 IS 3 SU S BP 144A EP 144A PG 1 WC Hematology SC Hematology GA 209OJ UT WOS:000249397600421 ER PT J AU Lee-Stroka, H Slezak, S Adams, S Martin, J Robbins, F Caruccio, L Byrne, KM Stroncek, DF AF Lee-Stroka, H. Slezak, S. Adams, S. Martin, J. Robbins, F. Caruccio, L. Byrne, K. M. Stroncek, D. F. TI The molecular basis of a KEL1 variant red cell phenotype SO TRANSFUSION LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 20-23, 2007 CL Anaheim, CA SP Amer Assoc Blood Banks C1 NIH, CC, Dept Transfus Med, Bethesda, MD 20892 USA. EM strokaah@cc.nih.gov 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2007 VL 47 IS 3 SU S BP 158A EP 158A PG 1 WC Hematology SC Hematology GA 209OJ UT WOS:000249397600465 ER PT J AU Halverson, GR Tossas, E Velliquette, RW Hue-Roye, K Lobo, C Reid, ME Lee-Stroka, H Castilho, L Credidio, DC Storry, JR AF Halverson, G. R. Tossas, E. Velliquette, R. W. Hue-Roye, K. Lobo, C. Reid, M. E. Lee-Stroka, H. Castilho, L. Credidio, D. C. Storry, J. R. TI Production and characterization of new murine anti-S and anti-U monoclonal antibodies SO TRANSFUSION LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 20-23, 2007 CL Anaheim, CA SP Amer Assoc Blood Banks C1 New York Blood Ctr, New York, NY 10021 USA. NIH, Bethesda, MD 20892 USA. Univ Estadual Campinas, Hemocentro, Campinas, SP, Brazil. Univ Lund Hosp, S-22185 Lund, Sweden. EM ghalverson@nybloodcenter.org NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2007 VL 47 IS 3 SU S BP 161A EP 162A PG 2 WC Hematology SC Hematology GA 209OJ UT WOS:000249397600476 ER PT J AU Bahrami, SH Guiltinan, AM Hirschler, NV Murphy, EL AF Bahrami, S. H. Guiltinan, A. M. Hirschler, N. V. Murphy, E. L., III TI Comparison of two methods of subject recruitment for a blood donor based research study SO TRANSFUSION LA English DT Meeting Abstract CT 60th Annual Meeting of the American-Association-of-Blood-Banks CY OCT 20-23, 2007 CL Anaheim, CA SP Amer Assoc Blood Banks C1 NHLBI, San Francisco, CA USA. Blood Syst Res Inst, San Francisco, CA USA. Blood Ctr Pacific, San Francisco, CA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NHLBI, Bethesda, MD 20892 USA. EM sbahrami@bloodsystems.org 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 0041-1132 J9 TRANSFUSION JI Transfusion PD SEP PY 2007 VL 47 IS 3 SU S BP 267A EP 268A PG 2 WC Hematology SC Hematology GA 209OJ UT WOS:000249397600793 ER PT J AU Blair, RJR AF Blair, R. J. R. TI The amygdala and ventromedial prefrontal cortex in morality and psychopathy SO TRENDS IN COGNITIVE SCIENCES LA English DT Review ID CHILDRENS CONCEPTIONS; RECOGNITION DEFICITS; FEAR-RECOGNITION; DECISION-MAKING; RHESUS-MONKEYS; NEURAL BASIS; BEHAVIOR; DAMAGE; EXPRESSIONS; REWARD AB Recent work has implicated the amygdala and ventromedial prefrontal cortex in morality and, when dysfunctional, psychopathy. This model proposes that the amygdala, through stimulus-reinforcement learning, enables the association of actions that harm others with the aversive reinforcement of the victims' distress. Consequent information on reinforcement expectancy, fed forward to the ventromedial prefrontal cortex, can guide the healthy individual away from moral transgressions. In psychopathy, dysfunction in these structures means that care-based moral reasoning is compromised and the risk that antisocial behavior is used instrumentally to achieve goals is increased. C1 NIMH, Mood & Anxiety Program, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Blair, RJR (reprint author), NIMH, Mood & Anxiety Program, Dept Hlth & Human Serv, 15K North Dr,MSC 2670, Bethesda, MD 20892 USA. EM blairj@intra.nimh.nih.gov FU Intramural NIH HHS NR 70 TC 237 Z9 240 U1 33 U2 139 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1364-6613 J9 TRENDS COGN SCI JI TRENDS COGN. SCI. PD SEP PY 2007 VL 11 IS 9 BP 387 EP 392 DI 10.1016/j.tics.2007.07.003 PG 6 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 214OB UT WOS:000249746800007 PM 17707682 ER PT J AU Nylen, S Sacks, D AF Nylen, Susanne Sacks, David TI Interleukin-10 and the pathogenesis of human visceral leishmaniasis SO TRENDS IN IMMUNOLOGY LA English DT Review ID REGULATORY T-CELLS; TUMOR-NECROSIS-FACTOR; INDIAN KALA-AZAR; CIRCULATING IMMUNE-COMPLEXES; INTERFERON-GAMMA; DONOVANI INFECTION; CUTANEOUS LEISHMANIASIS; CYTOKINE PROFILES; CHAGASI INFECTION; VIRUS-INFECTION AB The mechanisms underlying the failure to control the growth and systemic spread of Leishmania parasites in human visceral leishmaniasis (VL) are not well understood. Although the absence of antigen-specific Th1 responses in the peripheral blood mononuclear cells from VL patients is thought to be causally related to disease progression, the finding that these patients also express elevated interferon-gamma mRNA in lesional tissue, as well as elevated serum levels of proinflammatory cytokines, suggests that their immunological defect cannot be explained simply by immune tolerance or Th2 polarization. As a possible homeostatic mechanism to control persistent infection-induced inflammation, elevated levels of the regulatory cytokine interleukin (IL)-10 have been reported repeatedly in clinical studies of VL. Here, we review the studies with relevance to immune responses in human VL and highlight the central role that IL-10 might have in the pathogenesis of VL and as a target for immune-based therapy. C1 NIAID, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Sacks, D (reprint author), NIAID, Parasit Dis Lab, Bldg 4 RmB1-12,4 Ctr Dr MSC0425, Bethesda, MD 20892 USA. EM dsacks@niaid.nih.gov OI Nylen, Susanne/0000-0002-3875-3353 NR 94 TC 155 Z9 158 U1 3 U2 7 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD SEP PY 2007 VL 28 IS 9 BP 378 EP 384 DI 10.1016/j.it.2007.07.004 PG 7 WC Immunology SC Immunology GA 218QL UT WOS:000250029900003 PM 17689290 ER PT J AU Chavakis, T Preissner, KT Herrmann, M AF Chavakis, Triantafyllos Preissner, Klaus T. Herrmann, Mathias TI The anti-inflammatory activities of Staphylococcus aureus SO TRENDS IN IMMUNOLOGY LA English DT Review ID EXTRACELLULAR ADHERENCE PROTEIN; CHEMOTAXIS INHIBITORY PROTEIN; FIBRINOGEN-BINDING-PROTEIN; FORMYLATED PEPTIDE RECEPTOR; ANTIMICROBIAL PEPTIDES; HOST-DEFENSE; BACTERIAL SUPERANTIGENS; ENDOTHELIAL-CELLS; SURFACE PROTEIN; IMMUNE EVASION AB Staphylococcus aureus is a versatile and harmful pathogen in both hospital- and community-associated infections that range from superficial to systemic infections. S. aureus engages a multitude of mechanisms to subvert the innate immune response of the host, including inhibition of complement activation and neutralization of anti-microbial peptides. In addition, inflammatory cell and phagocyte recruitment is an integral part of the innate defense to staphylococcal infection and comprises a well-coordinated multi-step cascade of adhesive events. Recent and rapidly growing experimental evidence indicates the existence of a machinery of anti-adhesive and antichernotactic moieties of S. aureus that allow the bacterium to interfere with specific adhesive steps of the homing mechanism of leukocytes. Understanding the functions of these S. aureus-derived anti-inflammatory agents could also provide the platform for designing new therapies in several inflammatory and autoimmune diseases. C1 NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. Justus Liebig Univ, Inst Biochem, D-35392 Giessen, Germany. Univ Saarland Hosp, Inst Med Microbiol & Hyg, D-66421 Homburg, Germany. RP Chavakis, T (reprint author), NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. EM chavakist@mail.nih.gov RI Herrmann, Mathias/B-6475-2013 NR 110 TC 56 Z9 59 U1 2 U2 10 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD SEP PY 2007 VL 28 IS 9 BP 408 EP 418 DI 10.1016/j.it.2007.07.002 PG 11 WC Immunology SC Immunology GA 218QL UT WOS:000250029900007 PM 17681885 ER PT J AU Ferre, S Ciruela, F Woods, AS Lluis, C Franco, R AF Ferre, Sergi Ciruela, Francisco Woods, Amina S. Lluis, Carme Franco, Rafael TI Functional relevance of neurotransmitter receptor heteromers in the central nervous system SO TRENDS IN NEUROSCIENCES LA English DT Review ID ADENOSINE A(2A) RECEPTORS; PROTEIN-COUPLED RECEPTORS; METHYL-D-ASPARTATE; DOPAMINE-D-2 RECEPTORS; INTERNATIONAL UNION; SYNAPTIC PLASTICITY; OPIOID RECEPTORS; MGLU5 RECEPTORS; RAT STRIATUM; OLIGOMERIZATION AB The existence of neurotransmitter receptor heteromers is becoming broadly accepted and their functional significance is being revealed. Heteromerization of neurotransmitter receptors produces functional entities that possess different biochemical characteristics with respect to the individual components of the heteromer. Neurotransmitter receptor heteromers can function as processors of computations that modulate cell signaling. Thus, the quantitative or qualitative aspects of the signaling generated by stimulation of any of the individual receptor units in the heteromer are different from those obtained during coactivation. Furthermore, recent studies demonstrate that some neurotransmitter receptor heteromers can exert an effect as processors of computations that directly modulate both pre- and postsynaptic neurotransmission. This is illustrated by the analysis of striatal receptor heteromers that control striatal glutarnatergic neurotransmission. C1 Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, Natl Inst Hlth,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. Univ Barcelona, Fac Biol, Inst Invest Biomed August Pi I Sunyer, E-08028 Barcelona, Spain. Univ Barcelona, Fac Biol, Dept Biochem & Mol Biol, E-08028 Barcelona, Spain. RP Ferre, S (reprint author), Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, Natl Inst Hlth,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. EM sferre@ntra.nida.nih.gov RI Ferre, Sergi/K-6115-2014; Ciruela, Francisco/A-5096-2013; Franco, Rafael/C-3694-2015 OI Ferre, Sergi/0000-0002-1747-1779; Ciruela, Francisco/0000-0003-0832-3739; Franco, Rafael/0000-0003-2549-4919 FU Intramural NIH HHS NR 54 TC 97 Z9 97 U1 1 U2 5 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD SEP PY 2007 VL 30 IS 9 BP 440 EP 446 DI 10.1016/j.tins.2007.07.001 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 220VH UT WOS:000250184900002 PM 17692396 ER PT J AU He, LM Wu, LG AF He, Liming Wu, Ling-Gang TI The debate on the kiss-and-run fusion at synapses SO TRENDS IN NEUROSCIENCES LA English DT Review ID ADRENAL CHROMAFFIN CELLS; FROG NEUROMUSCULAR-JUNCTION; MOTOR-NERVE TERMINALS; CLATHRIN-MEDIATED ENDOCYTOSIS; SINGLE SYNAPTIC VESICLES; RETINAL BIPOLAR CELLS; HIPPOCAMPAL SYNAPSES; TRANSMITTER RELEASE; RAPID ENDOCYTOSIS; NEUROTRANSMITTER RELEASE AB It has long been proposed that following vesicle fusion, a small pore might open and close rapidly without full dilation. Such 'kiss-and-run' vesicle fusion can in principle result in rapid vesicle recycling and influence the size and the kinetics of the resulting synaptic current. However, the existence of kiss-and-run remains highly controversial, as revealed by recent imaging and electrophysiological studies at several synapses, including hippocampal synapses, neuromuscular junctions and retinal bipolar synapses. Only a minor fraction of fusion events has been shown to be kiss-and-run, as determined using cell-attached capacitance recordings in endocrine cells, pituitary nerve terminals and calyx-type synapses. Further work is needed to determine whether kiss-and-run is a major mode of fusion and has a major role in controlling synaptic strength at synapses. C1 NINDS, Bethesda, MD 20892 USA. RP Wu, LG (reprint author), NINDS, 35 Convent Dr,Bldg 35,Rm 2B-1012, Bethesda, MD 20892 USA. EM wul@ninds.nih.gov FU Intramural NIH HHS NR 65 TC 57 Z9 59 U1 2 U2 11 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0166-2236 J9 TRENDS NEUROSCI JI Trends Neurosci. PD SEP PY 2007 VL 30 IS 9 BP 447 EP 455 DI 10.1016/j.tins.2007.06.012 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 220VH UT WOS:000250184900003 PM 17765328 ER PT J AU Scott, I Sparkes, IA Logan, DC AF Scott, Iain Sparkes, Imogen A. Logan, David C. TI The missing link: inter-organellar connections in mitochondria and peroxisomes? SO TRENDS IN PLANT SCIENCE LA English DT Letter ID PLANT-CELLS; ARABIDOPSIS; MORPHOLOGY; DYNAMICS; PROTEIN; GFP C1 Univ St Andrews, Sir Harold Mitchell Bldg, Sch Biol, St Andrews KY16 9TH, Fife, Scotland. NINDS, NIH, Surg Neurol Branch, Biochem Sect, Bethesda, MD 20892 USA. Oxford Brookes Univ, Sch Life Sci, Oxford OX3 0BP, England. RP Logan, DC (reprint author), Univ St Andrews, Sir Harold Mitchell Bldg, Sch Biol, St Andrews KY16 9TH, Fife, Scotland. EM david.logan@st-andrews.ac.uk OI Logan, David/0000-0002-8980-240X NR 15 TC 18 Z9 18 U1 0 U2 2 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1360-1385 J9 TRENDS PLANT SCI JI Trends Plant Sci. PD SEP PY 2007 VL 12 IS 9 BP 380 EP 381 DI 10.1016/j.tplants.2007.08.010 PG 2 WC Plant Sciences SC Plant Sciences GA 215ZM UT WOS:000249847500002 PM 17765598 ER PT J AU Ostacoli, L Costantini, M Beccaro, M Dellai, M Gorzegno, G Picci, RL Sguazzotti, E Berruti, A Torta, R Furlan, PM AF Ostacoli, Luca Costantini, Massimo Beccaro, Monica Dellai, Monica Gorzegno, Gabriella Picci, Rocco Luigi Sguazzotti, Erica Berruti, Alfredo Torta, Riccardo Furlan, Pier Maria TI Development and validation of a patient physician relationship index in the advanced cancer setting SO TUMORI LA English DT Article DE advanced cancer; patient-physician relationship index (PPRI); patient satisfaction; questionnaire ID DOCTOR QUESTIONNAIRE; HOSPITAL ANXIETY; DEPRESSION SCALE; SATISFACTION; CARE; QUALITY; VISIT; LIFE; VALIDITY; ONCOLOGY AB The quality of the relationship between patient and medical staff is crucial in oncological settings. We have developed and validated a short, self-administered questionnaire to measure patients' satisfaction with their relationship with the physician: the Patient-Physician Relationship Index (PPRI). Materials and methods: Content validity was evaluated by a twostage (development and judgment) process. One hundred and nine cancer patients with metastatic disease were assessed during the second cycle of chemotherapy and 59 were reassessed eight weeks later. Quality of life and anxiety and depression were also evaluated. Results: The PPRI is monofactorial. Cronbach's alpha coefficient was 0.81. Sensitivity to change was shown by the correlation with changes in patients' conditions. The PPRI scores were only weakly correlated with the majority of the EORTC and HAD subscale scores. Conclusion: The PPRI is an easy-to-use, self-administered questionnaire, developed in a population of patients with advanced cancer. It has good internal consistency and sensitivity to change. C1 [Ostacoli, Luca; Dellai, Monica; Picci, Rocco Luigi; Sguazzotti, Erica; Furlan, Pier Maria] Univ Turin, S Luigi Gonzaga Hosp, Dept Mental Hlth, Orbassano, TO, Italy. [Costantini, Massimo; Beccaro, Monica] Natl Canc Inst, Clin Epidemiol Unit, Genoa, Italy. [Gorzegno, Gabriella; Berruti, Alfredo] Univ Turin, S Giovanni Battista Hosp, Psychooncol Unit, Genoa, Italy. RP Berruti, A (reprint author), ASO S Luigi Gonzaga, Reg Gonzole 10, I-10043 Orbassano, TO, Italy. EM alfredo.berruti@gmail.com RI costantini, massimo/G-1443-2012; OI costantini, massimo/0000-0002-5293-7079 NR 21 TC 0 Z9 0 U1 3 U2 4 PU PENSIERO SCIENTIFICO EDITOR PI ROME PA VIA BRADANO 3/C, 00199 ROME, ITALY SN 0300-8916 J9 TUMORI JI Tumori PD SEP-OCT PY 2007 VL 93 IS 5 BP 485 EP 490 PG 6 WC Oncology SC Oncology GA 270OO UT WOS:000253730300013 PM 18038882 ER PT J AU Linguraru, MG Vasilyev, NV Del Nido, PJ Howe, RD AF Linguraru, Marius George Vasilyev, Nikolay V. Del Nido, Pedro J. Howe, Robert D. TI Statistical segmentation of surgical instruments in 3-d ultrasound images SO ULTRASOUND IN MEDICINE AND BIOLOGY LA English DT Article ID NEEDLES AB The recent development of real-time 3-D ultrasound (US) enables intracardiac beating-heart procedures, but the distorted appearance of surgical instruments is a major challenge to surgeons. In addition, tissue and instruments have similar gray levels in US images and the interface between instruments and tissue is poorly defined. We present an algorithm that automatically estimates instrument location in intracardiac procedures. Expert-segmented images are used to initialize the statistical distributions of blood, tissue and instruments. Voxels are labeled through an iterative expectation- maximization algorithm using information from the neighboring voxels through a smoothing kernel. Once the three classes of voxels are separated, additional neighboring information is combined with the known shape characteristics of instruments to correct for misclassifications. We analyze the major axis of segmented data through their principal components and refine the results by a watershed transform, which corrects the results at the contact between instrument and tissue. We present results on 3-D in-vitro data from a tank trial and 3-D in-vivo data from cardiac interventions on porcine beating hearts, using instruments of four types of materials. The comparison of algorithm results to expert- annotated images shows the correct segmentation and position of the instrument shaft. (E-mail: lingurarum@mail.nih.gov) (c) 2007 World Federation for Ultrasound in Medicine & Biology. C1 Harvard Univ, Div Engn & Appl Sci, Cambridge, MA 02138 USA. Harvard Univ, Sch Med, Childrens Hosp, Dept Cardiac Surg, Boston, MA USA. RP Linguraru, MG (reprint author), NIH, Dept Diagnost Radiol, Bldg 10, Bethesda, MD 20892 USA. FU NHLBI NIH HHS [R01 HL073647, R01 HL073647-01] NR 22 TC 13 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 0301-5629 EI 1879-291X J9 ULTRASOUND MED BIOL JI Ultrasound Med. Biol. PD SEP PY 2007 VL 33 IS 9 BP 1428 EP 1437 DI 10.1016/j.ultrasmedbio.2007.03.003 PG 10 WC Acoustics; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Radiology, Nuclear Medicine & Medical Imaging GA 208HM UT WOS:000249310400011 PM 17521802 ER PT J AU Gozalo, AS Montali, RJ Claire, MS Barr, B Rejmanek, D Ward, JM AF Gozalo, A. S. Montali, R. J. Claire, M. St. Barr, B. Rejmanek, D. Ward, J. M. TI Chronic polymyositis associated with disseminated Sarcocystosis in a captive-born rhesus macaque SO VETERINARY PATHOLOGY LA English DT Article DE immunohistochemistry; ITS1; light microscopy; macaque; myositis; Sarcocystis spp.; sequence analysis; ultrastructure ID MONKEY MACACA-MULATTA; N-SP; NEURONA; PROTOZOA AB A 2-year-old, captive-born, clinically healthy male, rhesus macaque, was euthanatized as part of an experimental study. At necropsy, diffuse pale streaking of the trunk, lumbar, and limb muscles were noted macroscopically. On histology, numerous elongated cysts that contained crescent-shaped basophilic spores were found in the fibers of skeletal muscles. Scattered affected myofibers were degenerate and accompanied by eosinophilic-to-granulomatous inflammation. Sarcocysts had prominent villus-like projections with the morphology of a type I I sarcocyst wall similar to Sarcocystis neurona but possessing many more villus microtubules than is reported for S. neurona. In addition, bradyzoites were very long, up to approximately 12 pin in length. The protozoa were consistent with a Sarcocystis sp., based on histology and ultrastructure, however, a definitive identification of the species was not possible. Nonspecific immunohistochemical crossreaction with Sarcocystis cruzi antisera was observed. The 18S ribosomal deoxyribonucleic acid sequence showed 91% similarity to Sarcocystis hominis, 90% similarity to Sarcocystis buffalonis, and 89% similarity to Sareocystis hirsuta. Interestingly, the ITS1 sequence showed very little homology to any sequence in GenBank, suggesting that this is possibly a unique Sarcocystis sp. Sarcocystosis is often considered an incidental finding, particularly in wild-caught animals, with little clinical significance. However, as demonstrated in this report and others, disseminated sarcocystosis can occur in captive-born rhesus macaques with or without clinical signs. In some cases interference with research results can occur; including death in fulminant cases. C1 NIAID, NIH, SoBran Inc, Comparat Med Branch, Bethesda, MD 20892 USA. BIOQUAL Inc, Rockville, MD USA. Univ Calif Davis, Calif Anim Hlth & Food Safety Lab, Davis, CA 95616 USA. Univ Calif Davis, Dept Vet Med, Davis, CA 95616 USA. Johns Hopkins Univ, Dept Mol & Comparat Pathobiol, Baltimore, MD USA. RP Gozalo, AS (reprint author), NIAID, NIH, SoBran Inc, Comparat Med Branch, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM gozaloa@niaid.nih.gov FU Intramural NIH HHS NR 13 TC 11 Z9 12 U1 0 U2 1 PU AMER COLL VET PATHOLOGIST PI LAWRENCE PA 810 EAST 10TH STREET, LAWRENCE, KS 66044 USA SN 0300-9858 J9 VET PATHOL JI Vet. Pathol. PD SEP PY 2007 VL 44 IS 5 BP 695 EP 699 DI 10.1354/vp.44-5-695 PG 5 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 219BT UT WOS:000250060400016 PM 17846244 ER PT J AU Mitzel, DN Wolfinbarger, JB Long, RD Masnick, M Best, SM Bloom, ME AF Mitzel, Dana N. Wolfinbarger, James B. Long, R. Daniel Masnick, Max Best, Sonja M. Bloom, Marshall E. TI Tick-borne flavivirus infection in Ixodes scapularis larvae: Development of a novel method for synchronous viral infection of ticks SO VIROLOGY LA English DT Article DE tick; Ixodes scapularis; Langat virus; tick-borne encephalitis; immersion; transmission; virus replication ID ENCEPHALITIS-VIRUS; POWASSAN VIRUS; RHIPICEPHALUS-APPENDICULATUS; AMBLYOMMA-VARIEGATUM; LANGAT VIRUS; WATER-VAPOR; CELL-LINES; RICINUS; IXODIDAE; ACARI AB Following a bite from an infected tick, tick-borne flaviviruses cause encephalitis, meningitis and hemorrhagic fever in humans. Although these viruses spend most of their time in the tick, little is known regarding the virus-vector interactions. We developed a simple method for synchronously infecting Ixodes scapularis larvae with Langat virus (LGTV) by immersion in media containing the vir-us. This technique resulted in approximately 96% of ticks becoming infected. LGTV infection and replication were demonstrated by both viral antigen expression and the accumulation of viral RNA. Furthermore, ticks transmitted LGTV to 100% of the mice and maintained the virus through molting into the next life stage. This technique circumvents limitations present in the current methods by mimicking the natural route of infection and by using attenuated virus strains to infect ticks, thereby making this technique a powerful tool to study both virus and tick determinants of replication, pathogenesis and transmission. Published by Elsevier Inc. C1 NIAID, Rocky Mt Labs, NIH, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. NIAID, Rocky Mt Labs, NIH, Rocky Mt Vet Branch, Hamilton, MT 59840 USA. RP Bloom, ME (reprint author), NIAID, Rocky Mt Labs, NIH, Persistent Viral Dis Lab, Hamilton, MT 59840 USA. EM dmitzel@niaid.nih.gov; mbloom@niaid.nih.gov OI Masnick, Max/0000-0001-6299-6251 FU Intramural NIH HHS [Z99 AI999999, Z01 AI000940-04] NR 33 TC 15 Z9 16 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 1 PY 2007 VL 365 IS 2 BP 410 EP 418 DI 10.1016/j.virol.2007.03.057 PG 9 WC Virology SC Virology GA 203OZ UT WOS:000248985200017 PM 17490700 ER PT J AU Bernardin, F Strainer, SL Rehermann, B Page-Shafer, K Cooper, S Bangsberg, DR Hahn, J Tobler, L Busch, M Delwart, E AF Bernardin, Flavien Strainer, Susan L. Rehermann, Barbara Page-Shafer, Kimberly Cooper, Stewart Bangsberg, David R. Hahn, Judith Tobler, Leslie Busch, Michael Delwart, Eric TI High levels of subgenomic HCV plasma RNA in immunosilent infections SO VIROLOGY LA English DT Article DE HCV; subgenomic; replicon; defective; serosilent ID HEPATITIS-C-VIRUS; DEFECTIVE INTERFERING PARTICLES; FLAVIVIRUS KUNJIN NS3; VIRAL DIARRHEA VIRUS; INJECTION-DRUG USERS; WEST NILE VIRUS; NATURAL-HISTORY; PERSISTENT INFECTION; BLOOD-DONORS; IN-VIVO AB A genetic analysis of hepatitis C virus (HCV) in rare blood donors who remained HCV seronegative despite long-term high-level viremia revealed the chronic presence of HCV genomes with large in frame deletions in their structural genes. Full-length HCV genomes were only detected as minority variants. In one immunodeficiency virus (HIV) co-infected donor the truncated HCV genome transiently decreased in frequency concomitant with delayed seroconversion and re-emerged following partial seroreversion. The long-term production of heavily truncated HCV genomes in vivo suggests that these viruses retained the necessary elements for RNA replication while the deleted structural functions necessary for their spread in vivo was provided in trans by wild-type helper virus in co-infected cells. The absence of immunological pressure and a high viral load may therefore promote the emergence of truncated HCV subgenomic replicons in vivo. (C) 2007 Elsevier Inc. All rights reserved. C1 Blood Syst Res Inst, San Francisco, CA 94118 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Amer Red Cross, Sci Support Off, Rockville, MD 20855 USA. NIH, NIDDK, Liver Dis Branch, Immunol Sect, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Med, Ctr AIDS Prevent Studies, San Francisco, CA 94143 USA. Calif Pacific Med Ctr, San Francisco, CA 94107 USA. Univ Calif San Francisco, San Francisco Gen Hosp, Div Infect Dis, Epidemiol & Prevent Intervent Ctr, San Francisco, CA 94110 USA. RP Delwart, E (reprint author), Blood Syst Res Inst, 270 Mason Ave, San Francisco, CA 94118 USA. EM delwarte@medicine.ucsf.edu OI Page, Kimberly/0000-0002-7120-1673; Delwart, Eric/0000-0002-6296-4484 FU NHLBI NIH HHS [R01 HL076902, R01 HL076902-04, R01-HL-076902]; NIDA NIH HHS [R01 DA031056, 2-R01 DA016017, R01 DA016017, R01 DA016017-02]; NIMH NIH HHS [MH54907, R01 MH054907] NR 72 TC 16 Z9 16 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD SEP 1 PY 2007 VL 365 IS 2 BP 446 EP 456 DI 10.1016/j.virol.2007.04.003 PG 11 WC Virology SC Virology GA 203OZ UT WOS:000248985200020 PM 17493654 ER PT J AU Vitushkina, MV Rogozin, IB Jelkmann, W Koonin, EV Agranovsky, AA AF Vitushkina, Maria V. Rogozin, Igor B. Jelkmann, Wilhelm Koonin, Eugene V. Agranovsky, Alexey A. TI Completion of the mapping of transcription start sites for the five-gene block subgenomic RNAs of Beet yellows Closterovirus and identification of putative subgenomic promoters SO VIRUS RESEARCH LA English DT Article DE Beet yellows Closterovirus; five-gene block; subgenomic RNAs; 5'-end mapping; subgenomic promoter elements ID TO-CELL MOVEMENT; CITRUS-TRISTEZA-VIRUS; CAPSID PROTEIN HOMOLOG; HSP70 HOMOLOG; MESSENGER-RNAS; SEQUENCE; GENOME; ORGANIZATION; EXPRESSION; EVOLUTION AB In the positive-sense RNA genome of Beet yellows Closterovirus (BYV), the 3'-terminal open reading frames (ORFs) 2-8 are expressed as a nested set of subgenomic (sg) RNAs. ORFs 2-6, coding for the structural and movement proteins, form a 'five-gene block' conserved in closteroviruses. We mapped the 5'-end of the ORF 4 sgRNA, which encodes the p64 protein, at adenosine-11169 in the BYV genome. This completes the mapping of the transcription start sites for the five-gene block sgRNAs of BYV. Computer-assisted analysis of the sequences upstream of BYV ORFs 2, 3, 4,5, and 6 revealed two conserved motifs, which might constitute the subgenomic promoter elements. These motifs are conserved in the equivalent positions upstream of three orthologous genes of Citrus tristeza Closterovirus and two orthologous genes of Beet yellow stunt Closterovirus. (C) 2007 Elsevier B.V. All rights reserved. C1 Moscow MV Lomonosov State Univ, Belozersky Inst, Moscow 119992, Russia. Natl Lib Med, Natl Inst Hlth, Natl Ctr Biotechno Informat, Bethesda, MD 20894 USA. Inst Cytol & Genet, Novosibirsk 630090, Russia. BBA, Inst Plant Protect Fruit Crops, D-69221 Dossenheim, Germany. RP Agranovsky, AA (reprint author), Moscow MV Lomonosov State Univ, Belozersky Inst, Moscow 119992, Russia. EM rogozin@ncbl.nlm.nih.gov; wilhelm.jelkmann@urz.uni-heidelberg.de; koonin@ncbi.nlm.nih.gov; aaa@genebee.msu.su FU Intramural NIH HHS NR 25 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-1702 J9 VIRUS RES JI Virus Res. PD SEP PY 2007 VL 128 IS 1-2 BP 153 EP 158 DI 10.1016/j.virusres.2007.04.016 PG 6 WC Virology SC Virology GA 208HP UT WOS:000249310700021 PM 17521763 ER PT J AU Kodaka, Y Sheliga, BM FitzGibbon, EJ Miles, FA AF Kodaka, Y. Sheliga, B. M. FitzGibbon, E. J. Miles, F. A. TI The vergence eye movements induced by radial optic flow: Some fundamental properties of the underlying local-motion detectors SO VISION RESEARCH LA English DT Review DE visual motion; energy-based mechanisms; missing fundamental; spatio-temporal filtering; temporal impulse response; winner-take-all ID LATENCY DISPARITY-VERGENCE; OCULAR FOLLOWING RESPONSES; VISUAL AREA MT; SUPERIOR TEMPORAL AREA; ULTRA-SHORT LATENCIES; TAKE-ALL MECHANISM; MACAQUE MONKEY; APPARENT-MOTION; MST NEURONS; BINOCULAR DISPARITY AB Radial optic flow applied to large random dot patterns is known to elicit horizontal vergence eye movements at short latency, expansion causing convergence and contraction causing divergence: the Radial Flow Vergence Response (RFVR). We elicited RFVRs in human subjects by applying radial motion to concentric circular patterns whose radial luminance modulation was that of a square wave lacking the fundamental: the missing fundamental (mf) stimulus. The radial motion consisted of successive (1)/(4)-wavelength steps, so that the overall pattern and the 4n+1 harmonics (where n = integer) underwent radial expansion (or contraction), whereas the 4n-1 harmonics-including the strongest Fourier component (the 3rd harmonic)-underwent the opposite radial motion. Radial motion commenced only after the subject had fixated the center of the pattern. The initial RFVRs were always in the direction of the 3rd harmonic, e.g., expansion of the mf pattern causing divergence. Thus, the earliest RFVRs were strongly dependent on the motion of the major Fourier component, consistent with early spatio-temporal filtering prior to motion detection, as in the well-known energy model of motion analysis. If the radial mf stimulus was reduced to just two competing harmonics-the 3rd and 5th-the initial RFVRs showed a nonlinear dependence on their relative contrasts: when the two harmonics differed in contrast by more than about an octave then the one with the higher contrast completely dominated the RFVRs and the one with lower contrast lost its influence: winner-take-all. We suggest that these nonlinear interactions result from mutual inhibition between the mechanisms sensing the motion of the different competing harmonics. If single radial-flow steps were used, a brief inter-stimulus interval resulted in reversed RFVRs, consistent with the idea that the motion detectors mediating these responses receive a visual input whose temporal impulse response function is strongly biphasic. Lastly, all of these characteristics of the RFVR, which we attribute to the early cortical processing of visual motion, are known to be shared by the Ocular Following Response (OFR)-a conjugate tracking (version) response elicited at short-latency by linear motion-and even the quantitative details are generally very similar. Thus, although the RFVR and OFR respond to very different patterns of global motion-radial vs. linear-they have very similar local spatiotemporal properties as though mediated by the same low-level, local-motion detectors, which we Suggest are in the striate cortex. (c) 2007 Elsevier Ltd. All rights reserved. C1 NEI, Sensorimotor Res Lab, NIH, Bethesda, MD 20892 USA. Natl Inst AIST, Neurosci Res Inst, Tsukuba, Ibaraki 3058568, Japan. RP Sheliga, BM (reprint author), NEI, Sensorimotor Res Lab, NIH, Bldg 49,Room 2A50,49 Convent Dr, Bethesda, MD 20892 USA. EM bms@lsr.nei.nih.gov FU Intramural NIH HHS [Z01 EY000153-24, Z99 EY999999] NR 118 TC 13 Z9 13 U1 1 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 SEP PY 2007 VL 47 IS 20 BP 2637 EP 2660 DI 10.1016/j.visres.2007.06.013 PG 24 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 221RU UT WOS:000250245800006 PM 17706738 ER PT J AU Alejandro, R Barton, F Appel, M Hering, BJ AF Alejandro, Rodolfo Barton, Franca Appel, Michael Hering, Bernhard J. CA CITR Investigators TI Update from the Collaborative Islet Transplant Registry SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint Meeting of the International-Xenotransplantation-Association/International-Pancrcas-and -Islet-Transplant-Association/Cell-Transplant-Society CY SEP 15-20, 2007 CL Minneapolis, MN SP Int Xenotransplantat Assoc, Int Pancreas & Islet Transplant Assoc, Cell Transplant Soc C1 Univ Miami, Diabet Res Inst, Miami, FL USA. EMMES Corp, Rockville, MD USA. NIDDKD, Bethesda, MD 20892 USA. Univ Minnesota, Diabet Inst Immunol & Transplantat, Minneapolis, MN USA. EM fbarton@emmes.com 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 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP PY 2007 VL 14 IS 5 BP 399 EP 399 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 206RX UT WOS:000249201700074 ER PT J AU Andrades, P Asiedu, CK Goodwin, KJ Deckard, L Wu, J Gansuvd, B He, J Neville, D Bonito, R Papas, K Hering, B Thomas, JM AF Andrades, P. Asiedu, C. K. Goodwin, K. J. Deckard, L. Wu, J. Gansuvd, B. He, J. Neville, D., Jr. Bonito, R. Papas, K. Hering, B. Thomas, J. M. TI Survival of porcine islets transplanted into prefabricated omental pouches in rhesus macaques (RM) SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint Meeting of the International-Xenotransplantation-Association/International-Pancrcas-and -Islet-Transplant-Association/Cell-Transplant-Society CY SEP 15-20, 2007 CL Minneapolis, MN SP Int Xenotransplantat Assoc, Int Pancreas & Islet Transplant Assoc, Cell Transplant Soc C1 Univ Alabama, Birmingham, AL 35233 USA. NIH, Bethesda, MD USA. Univ Minnesota, Minneapolis, MN 55455 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 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP PY 2007 VL 14 IS 5 BP 406 EP 406 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 206RX UT WOS:000249201700098 ER PT J AU Isacson, O AF Isacson, Ole TI Stem cells in the treatment of neural diseases SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint Meeting of the International-Xenotransplantation-Association/International-Pancrcas-and -Islet-Transplant-Association/Cell-Transplant-Society CY SEP 15-20, 2007 CL Minneapolis, MN SP Int Xenotransplantat Assoc, Int Pancreas & Islet Transplant Assoc, Cell Transplant Soc ID DOPAMINERGIC-NEURONS; PARKINSONS-DISEASE; TRANSPLANTATION; MODEL C1 Harvard Med Sch, Belmont, MA USA. McLean Hosp, Harvard Med Sch, Director Ctr Neurogenerat Res, Belmont, MA USA. NINDS, Morris K Udall Parkinsons Dis Res Excellence, Belmont, MA USA. NR 6 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP PY 2007 VL 14 IS 5 BP 412 EP 412 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 206RX UT WOS:000249201700114 ER PT J AU Singh, A Horvath, K Mohiuddin, M AF Singh, Avneesh Horvath, Keith Mohiuddin, Muhammad TI Rapamycin enriches CD4+CD25 hi T regulatory cells in ex-vivo expanded CD4 T cells in baboon SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint Meeting of the International-Xenotransplantation-Association/International-Pancrcas-and -Islet-Transplant-Association/Cell-Transplant-Society CY SEP 15-20, 2007 CL Minneapolis, MN SP Int Xenotransplantat Assoc, Int Pancreas & Islet Transplant Assoc, Cell Transplant Soc C1 NIH, NHLBI, Bethesda, MD USA. RI Mohiuddin, Muhammad/M-4642-2013 OI Mohiuddin, Muhammad/0000-0003-4654-783X 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 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP PY 2007 VL 14 IS 5 BP 422 EP 422 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 206RX UT WOS:000249201700146 ER PT J AU Asiedu, CK Andrades, P Goodwin, KJ Deckard, L Wu, J He, J Ganssuvd, B Bonito, R Papas, K Hering, B Neville, D Thomas, JM AF Asiedu, C. K. Andrades, P. Goodwin, K. J. Deckard, L. Wu, J. He, J. Ganssuvd, B. Bonito, R. Papas, K. Hering, B. Neville, D., Jr. Thomas, J. M. TI Peritransplant therapy with thymoglobulin and Genzyme 29155 delays rejection of intrahepatic porcine islets in nonhuman primates SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint Meeting of the International-Xenotransplantation-Association/International-Pancrcas-and -Islet-Transplant-Association/Cell-Transplant-Society CY SEP 15-20, 2007 CL Minneapolis, MN SP Int Xenotransplantat Assoc, Int Pancreas & Islet Transplant Assoc, Cell Transplant Soc C1 Univ Alabama, Birmingham, AL USA. Univ Minnesota, Minneapolis, MN USA. 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 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP PY 2007 VL 14 IS 5 BP 493 EP 494 PG 2 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 206RX UT WOS:000249201700371 ER PT J AU Elbaz, B Alperovitch, A Sarfaty, CK Gottesman, MM Rahamimoff, H AF Elbaz, Benayahu Alperovitch, Ariella Sarfaty, Chava Kimchi Gottesman, Michael M. Rahamimoff, Hannah TI The effect of Cyclosporin A (CsA) and FK506 on the expression of the Na+-Ca2+ exchangers NCX1, NCX2 and NCX3 SO XENOTRANSPLANTATION LA English DT Meeting Abstract CT Joint Meeting of the International-Xenotransplantation-Association/International-Pancrcas-and -Islet-Transplant-Association/Cell-Transplant-Society CY SEP 15-20, 2007 CL Minneapolis, MN SP Int Xenotransplantat Assoc, Int Pancreas & Islet Transplant Assoc, Cell Transplant Soc C1 Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Biochem, IL-91905 Jerusalem, Israel. Div Hematol, US FDA, Bethesda, MD USA. NCI, NIH, Cell Biol Lab, Bethesda, MD USA. EM Hannah.Rahamimoff@huji.ac.il NR 0 TC 0 Z9 0 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0908-665X J9 XENOTRANSPLANTATION JI Xenotransplantation PD SEP PY 2007 VL 14 IS 5 BP 498 EP 498 PG 1 WC Medicine, Research & Experimental; Transplantation SC Research & Experimental Medicine; Transplantation GA 206RX UT WOS:000249201700385 ER PT J AU Park, ES Shaughnessy, JD Gupta, S Wang, H Lee, JS Woo, HG Zhan, F Owens, JD Potter, M Janz, S Mushinski, JF AF Park, Eun Sung Shaughnessy, John D., Jr. Gupta, Shalu Wang, Hongyang Lee, Ju-Seog Woo, Hyun Goo Zhan, Fenghuang Owens, James D., Jr. Potter, Michael Janz, Siegfried Mushinski, J. Frederic TI Gene expression profiling reveals different pathways related to Abl and other genes that cooperate with c-Myc in a model of plasma cell neoplasia SO BMC GENOMICS LA English DT Article ID MULTIPLE-MYELOMA; B-CELL; V-ABL; PERITONEAL PLASMACYTOMAS; TYROSINE KINASE; BALB/C MICE; INDUCTION; SOCS-1; TRANSLOCATIONS; CLASSIFICATION AB Background: To elucidate the genes involved in the neoplastic transformation of B cells, global gene expression profiles were generated using Affymetrix U74Av2 microarrays, containing 12,488 genes, for four different groups of mouse B- cell lymphomas and six subtypes of pristane- induced mouse plasma cell tumors, three of which developed much earlier than the others. Results: Unsupervised hierarchical cluster analysis exhibited two main sub- clusters of samples: a B- cell lymphoma cluster and a plasma cell tumor cluster with subclusters reflecting mechanism of induction. This report represents the first step in using global gene expression to investigate molecular signatures related to the role of cooperating oncogenes in a model of Myc-induced carcinogenesis. Within a single subgroup, e. g., ABPCs, plasma cell tumors that contained typical T(12; 15) chromosomal translocations did not display gene expression patterns distinct from those with variant T(6; 15) translocations, in which the breakpoint was in the Pvt- 1 locus, 230 kb 3' of cMyc, suggesting that c-Myc activation was the initiating factor in both. When integrated with previously published Affymetrix array data from human multiple myelomas, the IL-6-transgenic subset of mouse plasma cell tumors clustered more closely with MM1 subsets of human myelomas, slow-appearing plasma cell tumors clustered together with MM2, while plasma cell tumors accelerated by v-Abl clustered with the more aggressive MM3-MM4 myeloma subsets. Slow-appearing plasma cell tumors expressed Socs1 and Socs2 but v-Abl-accelerated plasma cell tumors expressed 4-5 times as much. Both v-Abl-accelerated and non-v-Abl- associated tumors exhibited phosphorylated STAT 1 and 3, but only v-Abl-accelerated plasma cell tumors lost viability and STAT 1 and 3 phosphorylation when cultured in the presence of the v-Abl kinase inhibitor, STI- 571. These data suggest that the Jak/Stat pathway was critical in the transformation acceleration by v-Abl and that v- Abl activity remained essential throughout the life of the tumors, not just in their acceleration. A different pathway appears to predominate in the more slowly arising plasma cell tumors. Conclusion: Gene expression profiling differentiates not only B-cell lymphomas from plasma cell tumors but also distinguishes slow from accelerated plasma cell tumors. These data and those obtained from the sensitivity of v-Abl-accelerated plasma cell tumors and their phosphorylated STAT proteins indicate that these similar tumors utilize different signaling pathways but share a common initiating genetic lesion, a c-Myc-activating chromosome translocation. C1 NCI, NIH, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Arkansas Med Sci, Donna & Donald Lambert Lab Myeloma Genet, Myeloma Inst Res & Therapy, Little Rock, AR 72205 USA. NCI, NIH, Expt Carcinogenesis Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Virginia, Dept Med, Charlottesville, VA 22908 USA. Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Pathol, Iowa City, IA 52242 USA. RP Mushinski, JF (reprint author), NCI, NIH, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. EM espark@mdanderson.org; shaughnessyjohn@uams.edu; guptashal@mail.nih.gov; hw4f@virginia.edu; jlee@mdanderson.org; woohy@mail.nih.gov; ZhanFenghuang@uams.edu; jow@helix.nih.gov; potterm@mail.nih.gov; siegfried-janz@uiowa.edu FU Intramural NIH HHS; NCI NIH HHS [CA97513, P01 CA055819, R33 CA097513, R01 CA151354, CA55819] NR 41 TC 7 Z9 8 U1 0 U2 1 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 AUG 31 PY 2007 VL 8 AR 302 DI 10.1186/1471-2164-8-302 PG 16 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 226BM UT WOS:000250562200001 PM 17764563 ER PT J AU Hurst, SA Forde, R Reiter-Theil, S Slowther, AM Perrier, A Pegoraro, R Danis, M AF Hurst, Samia A. Forde, Reidun Reiter-Theil, Stella Slowther, Anne-Marie Perrier, Arnaud Pegoraro, Renzo Danis, Marion TI Physicians' views on resource availability and equity in four European health care systems SO BMC HEALTH SERVICES RESEARCH LA English DT Article ID RESPONSE RATES; MEDICAL-CARE; DOCTORS; ATTITUDES; ACCESS; EXPERIENCES; ALLOCATION; SCARCITY; POLICY; ETHICS AB Background: In response to limited resources, health care systems have adopted diverse cost-containment strategies and give priority to differing types of interventions. The perception of physicians, who witness the effects of these strategies, may provide useful insights regarding the impact of system-wide priority setting on access to care. Methods: We conducted a cross-sectional survey to ascertain generalist physicians' perspectives on resources allocation and its consequences in Norway, Switzerland, Italy and the UK. Results: Survey respondents (N = 656, response rate 43%) ranged in age from 28-82, and averaged 25 years in practice. Most respondents (87.7%) perceived some resources as scarce, with the most restrictive being: access to nursing home, mental health services, referral to a specialist, and rehabilitation for stroke. Respondents attributed adverse outcomes to scarcity, and some respondents had encountered severe adverse events such as death or permanent disability. Despite universal coverage, 45.6% of respondents reported instances of underinsurance. Most respondents (78.7%) also reported some patient groups as more likely than others to be denied beneficial care on the basis of cost. Almost all respondents (97.3%) found at least one cost-containment policy acceptable. The types of policies preferred suggest that respondents are willing to participate in cost-containment, and do not want to be guided by administrative rules (11.2%) or restrictions on hospital beds (10.7%). Conclusion: Physician reports can provide an indication of how organizational factors may affect availability and equity of health care services. Physicians are willing to participate in cost-containment decisions, rather than be guided by administrative rules. Tools should be developed to enable physicians, who are in a unique position to observe unequal access or discrimination in their health care environment, to address these issues in a more targeted way. C1 NIH, Bethesda, MD 20892 USA. Univ Geneva, Sch Med, Inst Biomed Eth, CH-1211 Geneva, Switzerland. Norwegian Med Assoc, Res Inst, Oslo, Norway. Univ Oslo, N-0316 Oslo, Norway. Univ Basel, Inst Appl Eth & Med Eth, CH-4003 Basel, Switzerland. Univ Oxford, Ethox Ctr, Headington, England. Univ Hosp Geneva, Gen Internal Med Serv, Geneva, Switzerland. Fdn Lanza, Padua, Italy. RP Danis, M (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM samia.hurst@medecine.unige.ch; reidun.forde@legeforeningen.no; s.reiter-theil@unibas.ch; anne-marie.slowther@ethox.ox.ac.uk; Arnaud.Perrier@medecine.unige.ch; info@fondazionelanza.it; mdanis@cc.nih.gov RI Hurst, Samia/A-9661-2008 OI Hurst, Samia/0000-0002-1980-5226 NR 41 TC 31 Z9 31 U1 2 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1472-6963 J9 BMC HEALTH SERV RES JI BMC Health Serv. Res. PD AUG 31 PY 2007 VL 7 AR 137 DI 10.1186/1472-6963-7-137 PG 11 WC Health Care Sciences & Services SC Health Care Sciences & Services GA 218ZI UT WOS:000250054100001 PM 17764556 ER PT J AU Gundry, RL Elliott, ST Wollscheid, B Bausch-Fluck, D Boheler, KR Van Eyk, JE AF Gundry, Rebekah L. Elliott, Steven T. Wollscheid, Bernd Bausch-Fluck, Damaris Boheler, Kenneth R. Van Eyk, Jennifer E. TI Use of a novel technology to identify N-linked glycoproteins on the cell surface of cardiac progenitor cells: Discovering markers of differentiation SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT 4th Annual Symposium of the American-Heart-Association-Council on Basic Cardiovascular Sciences CY JUL 30-AUG 02, 2007 CL Keystone, CO SP Amer Heart Assoc Council C1 Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. Swiss Fed Inst Technol, Zurich, Switzerland. NIA, NIH, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RI Wollscheid, Bernd/E-8909-2010 OI Wollscheid, Bernd/0000-0002-3923-1610 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD AUG 31 PY 2007 VL 101 IS 5 BP E58 EP E58 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 205ZZ UT WOS:000249155000040 ER PT J AU Wong, RP Murphy, E AF Wong, Renee P. Murphy, Elizabeth TI Proteomic analysis of mitochondrial proteins in preconditioned mouse myocardium: Effects of endosomal trafficking SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT 4th Annual Symposium of the American-Heart-Association-Council on Basic Cardiovascular Sciences CY JUL 30-AUG 02, 2007 CL Keystone, CO SP Amer Heart Assoc Council C1 NIH, NHLBI, 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 0009-7330 J9 CIRC RES JI Circ.Res. PD AUG 31 PY 2007 VL 101 IS 5 BP E71 EP E71 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 205ZZ UT WOS:000249155000105 ER PT J AU Woo, AY Wang, TB Zhu, WZ Abernethy, D Wainer, I Xiao, RP AF Woo, Anthony Y. Wang, Tian-Bing Zhu, Weizhong Abernethy, Darrell Wainer, Irving Xiao, Rui-Ping TI Enantiomer-specific beta(2)-adrenergic receptor-G-protein coupling in cardiomyocytes SO CIRCULATION RESEARCH LA English DT Meeting Abstract CT 4th Annual Symposium of the American-Heart-Association-Council on Basic Cardiovascular Sciences CY JUL 30-AUG 02, 2007 CL Keystone, CO SP Amer Heart Assoc Council C1 NIA, NIH, Baltimore, MD 21224 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 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 AUG 31 PY 2007 VL 101 IS 5 BP E75 EP E75 PG 1 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 205ZZ UT WOS:000249155000126 ER PT J AU Lassen, N Bateman, JB Estey, T Kuszak, JR Nees, DW Piatigorsky, J Duester, G Day, BJ Huang, J Hines, LM Vasiliou, V AF Lassen, Natalie Bateman, J. Bronwyn Estey, Tia Kuszak, Jer R. Nees, David W. Piatigorsky, Joram Duester, Gregg Day, Brian J. Huang, Jie Hines, Lisa M. Vasiliou, Vasilis TI Multiple and additive functions of ALDH3A1 and ALDH1A1 - Cataract phenotype and ocular oxidative damage in Aldh3a1(-/-)/Aldh1a1(-/-) knock-out mice SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CORNEAL ALDEHYDE DEHYDROGENASE; ULTRAVIOLET-LIGHT; EPITHELIAL-CELLS; STRUCTURAL PROTEIN; OXIDIZED PROTEINS; LENS CRYSTALLINS; RETINOIC ACID; EYE; GLUTATHIONE; ENZYMES AB ALDH3A1 ( aldehyde dehydrogenase 3A1) is abundant in the mouse cornea but undetectable in the lens, and ALDH1A1 is present at lower ( catalytic) levels in the cornea and lens. To test the hypothesis that ALDH3A1 and ALDH1A1 protect the anterior segment of the eye against environmentally induced oxidative damage, Aldh1a1(-/ -)/Aldh3a1( -/ -) double knock-out and Aldh1a1(-/-) and Aldh3a1(-/-) single knock-out mice were evaluated for biochemical changes and cataract formation ( lens opacification). The Aldh1a1/ Aldh3a1- and Aldh3a1- null mice develop cataracts in the anterior and posterior subcapsular regions as well as punctate opacities in the cortex by 1 month of age. The Aldh1a1-null mice also develop cataracts later in life ( 6 - 9 months of age). One-to three-month-old Aldh-null mice exposed to UVB exhibited accelerated anterior lens subcapsular opacification, which was more pronounced in Aldh3a1(-/-) and Aldh3a1(-/-)/ Aldh1a1(-/-) mice compared with Aldh1a1(-/-) and wild type animals. Cataract formation was associated with decreased proteasomal activity, increased protein oxidation, increased GSH levels, and increased levels of 4-hydroxy-2-nonenal- and malondialdehyde-protein adducts. In conclusion, these findings support the hypothesis that corneal ALDH3A1 and lens ALDH1A1 protect the eye against cataract formation via nonenzymatic ( light filtering) and enzymatic ( detoxification) functions. C1 Univ Colorado, Sch Pharm, Dept Pharmaceut Sci,Rocky Mt Lions Eye Inst, Mol Toxicol & Environm Hlth Sci Program,Childrens, Denver, CO 80262 USA. Univ Colorado, Sch Pharm, Childrens Hosp, Rocky Mt Lions Eye Inst,Dept Ophthalmol & Pediat, Denver, CO 80262 USA. Rush Univ, Ctr Med, Dept Ophthalm & Pathol, Chicago, IL 60612 USA. NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Burnham Inst, OncoDev Biol Program, La Jolla, CA 92037 USA. Natl Jewish Med & Res Ctr, Dept Med, Denver, CO 80206 USA. Univ Colorado, Dept Biol, Colorado Springs, CO 80933 USA. RP Vasiliou, V (reprint author), Univ Colorado, Sch Pharm, Dept Pharmaceut Sci,Rocky Mt Lions Eye Inst, Mol Toxicol & Environm Hlth Sci Program,Childrens, Denver, CO 80262 USA. EM vasilis.vasiliou@uchsc.edu FU NEI NIH HHS [R01 EY011490, EY08282, EY11490, EY13969, R01 EY008282, R01 EY013969, R01 EY013969-05A2, R29 EY011490] NR 61 TC 88 Z9 90 U1 2 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 AUG 31 PY 2007 VL 282 IS 35 BP 25668 EP 25676 DI 10.1074/jbc.M702076200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 204AB UT WOS:000249014100054 PM 17567582 ER PT J AU Chen, ZY Asavaritikrai, P Prchal, JT Noguchi, CT AF Chen, Zhi-Yong Asavaritikrai, Pundit Prchal, Josef T. Noguchi, Constance Tom TI Endogenous erythropoietin signaling is required for normal neural progenitor cell proliferation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; STEM-CELLS; RECEPTOR GENE; IN-VITRO; RETINAL DEGENERATION; CEREBRAL-ISCHEMIA; TRANSGENIC MICE; BRAIN; NEURONS; NEUROGENESIS AB Erythropoietin (Epo) and its receptor (EpoR), critical for erythropoiesis, are expressed in the nervous system. Prior to death in utero because of severe anemia EpoR-null mice have fewer neural progenitor cells, and differentiated neurons are markedly sensitive to hypoxia, suggesting that during development Epo stimulates neural cell proliferation and prevents neuron apoptosis by promoting oxygen delivery to brain or by direct interaction with neural cells. Here we present evidence that neural progenitor cells express EpoR at higher levels compared with mature neurons; that Epo stimulates proliferation of embryonic neural progenitor cells; and that endogenous Epo contributes to neural progenitor cell proliferation and maintenance. EpoRnull mice were rescued with selective EpoR expression driven by the endogenous EpoR promoter in hematopoietic tissue but not in brain. Although these mice exhibited normal hematopoiesis and erythrocyte production and survived to adulthood, neural cell proliferation and viability were affected. Embryonic brain exhibited increased neural cell apoptosis, and neural cell proliferation was reduced in the adult hippocampus and subventricular zone. Neural cells from these animals were more sensitive to hypoxia/glutamate neurotoxicity than normal neurons in culture and in vivo. These observations demonstrate that endogenous Epo/EpoR signaling promotes cell survival in embryonic brain and contributes to neural cell proliferation in adult brain in regions associated with neurogenesis. Therefore, Epo exerts extra-hematopoietic function and contributes directly to brain development, maintenance, and repair by promoting cell survival and proliferation independent of insult, injury, or ischemia. C1 NIDDK, Mol Med Branch, NIH, Bethesda, MD 20892 USA. Baylor Coll Med, Dept Med, Div Hematol Oncol, Houston, TX 77030 USA. RP Noguchi, CT (reprint author), NIDDK, Mol Med Branch, NIH, Bldg 10,Rm 9N307,10 Ctr Dr,MSC-1822, Bethesda, MD 20892 USA. EM cnoguchi@helix.nih.gov FU Intramural NIH HHS NR 49 TC 102 Z9 118 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 AUG 31 PY 2007 VL 282 IS 35 BP 25875 EP 25883 DI 10.1074/jbc.M701988200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 204AB UT WOS:000249014100073 PM 17604282 ER PT J AU Fortenberry, NL Sullivan, JF Jordan, PN Knight, DW AF Fortenberry, Norman L. Sullivan, Jacquelyn F. Jordan, Peter N. Knight, Daniel W. TI Engineering education research aids instruction SO SCIENCE LA English DT Editorial Material C1 Natl Acad Engn, Ctr Advancement Scholarship Engn Educ, Washington, DC 20001 USA. Univ Colorado, Integrated Teaching & Learning Program, Coll Engn & Appl Sci, Boulder, CO 80309 USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Fortenberry, NL (reprint author), Natl Acad Engn, Ctr Advancement Scholarship Engn Educ, Washington, DC 20001 USA. EM nfortenb@nae.edu; jacquelyn.sullivan@colorado.edu NR 24 TC 33 Z9 33 U1 0 U2 5 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 AUG 31 PY 2007 VL 317 IS 5842 BP 1175 EP 1176 DI 10.1126/science.1143834 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 205PJ UT WOS:000249126800024 PM 17761868 ER PT J AU Ramalho-Ortigao, M Jochim, RC Anderson, JM Lawyer, PG Pham, VM Kamhawi, S Valenzuela, JG AF Ramalho-Ortigao, Marcelo Jochim, Ryan C. Anderson, Jennifer M. Lawyer, Phillip G. Pham, Van-My Kamhawi, Shaden Valenzuela, Jesus G. TI Exploring the midgut transcriptome of Phlebotomus papatasi: comparative analysis of expression profiles of sugar-fed, blood-fed and Leishmania major-infected sandflies SO BMC GENOMICS LA English DT Article ID PERITROPHIC-MATRIX-PROTEIN; VECTOR LUTZOMYIA-LONGIPALPIS; SALIVARY-GLAND TRANSCRIPTS; AEDES-AEGYPTI; ANOPHELES-GAMBIAE; ANNOTATED CATALOG; SEQUENCE TAGS; SAND FLIES; IDENTIFICATION; MOSQUITO AB Background: In sandflies, the blood meal is responsible for the induction of several physiologic processes that culminate in egg development and maturation. During blood feeding, infected sandflies are also able to transmit the parasite Leishmania to a suitable host. Many blood- induced molecules play significant roles during Leishmania development in the sandfly midgut, including parasite killing within the endoperitrophic space. In this work, we randomly sequenced transcripts from three distinct high quality full-length female Phlebotomus papatasi midgut- specific cDNA libraries from sugar-fed, blood-fed and Leishmania major-infected sandflies. Furthermore, we compared the transcript expression profiles from the three different cDNA libraries by customized bioinformatics analysis and validated these findings by semi-quantitative PCR and real-time PCR. Results: Transcriptome analysis of 4010 cDNA clones resulted in the identification of the most abundant P. papatasi midgut-specific transcripts. The identified molecules included those with putative roles in digestion and peritrophic matrix formation, among others. Moreover, we identified sandfly midgut transcripts that are expressed only after a blood meal, such as microvilli associated-like protein (PpMVP1, PpMVP2 and PpMVP3), a peritrophin (PpPer1), trypsin 4 (PpTryp4), chymotrypsin PpChym2, and two unknown proteins. Of interest, many of these overabundant transcripts such as PpChym2, PpMVP1, PpMVP2, PpPer1 and PpPer2 were of lower abundance when the sandfly was given a blood meal in the presence of L. major. Conclusion: This tissue- specific transcriptome analysis provides a comprehensive look at the repertoire of transcripts present in the midgut of the sandfly P. papatasi. Furthermore, the customized bioinformatic analysis allowed us to compare and identify the overall transcript abundance from sugar-fed, blood- fed and Leishmania-infected sandflies. The suggested upregulation of specific transcripts in a blood-fed cDNA library were validated by real-time PCR, suggesting that this customized bioinformatic analysis is a powerful and accurate tool useful in analysing expression profiles from different cDNA libraries. Additionally, the findings presented in this work suggest that the Leishmania parasite is modulating key enzymes or proteins in the gut of the sandfly that may be beneficial for its establishment and survival. C1 NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. Univ Notre Dame, Ctr Trop Dis Res & Training, Notre Dame, IN USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NIAID, Intracellular Parasites Biol Sect, Parasit Dis Lab, NIH, Rockville, MD USA. RP Valenzuela, JG (reprint author), NIAID, Vector Mol Biol Unit, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. EM m_ortigao@nd.edu; rjochim@niaid.nih.gov; jenanderson@niaid.nih.gov; PhillipL@niaid.nih.gov; vpham@niaid.nih.gov; skamhawi@niaid.nih.gov; jvalenzuela@niaid.nih.gov RI Ramalho-Ortigao, Marcelo/E-8225-2011; Jochim, Ryan/C-6756-2013 FU Intramural NIH HHS NR 37 TC 34 Z9 35 U1 0 U2 8 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 AUG 30 PY 2007 VL 8 AR 300 DI 10.1186/1471-2164-8-300 PG 17 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 226BK UT WOS:000250562000001 PM 17760985 ER PT J AU Frazer, KA Eskin, E Kang, HM Bogue, MA Hinds, DA Beilharz, EJ Gupta, RV Montgomery, J Morenzoni, MM Nilsen, GB Pethiyagoda, CL Stuve, LL Johnson, FM Daly, MJ Wade, CM Cox, DR AF Frazer, Kelly A. Eskin, Eleazar Kang, Hyun Min Bogue, Molly A. Hinds, David A. Beilharz, Erica J. Gupta, Robert V. Montgomery, Julie Morenzoni, Matt M. Nilsen, Geoffrey B. Pethiyagoda, Charit L. Stuve, Laura L. Johnson, Frank M. Daly, Mark J. Wade, Claire M. Cox, David R. TI A sequence-based variation map of 8.27 million SNPs in inbred mouse strains SO NATURE LA English DT Article ID HAPLOTYPE DIVERSITY; GENETIC-VARIATION; PHENOME PROJECT; LABORATORY MICE; GENOME; PATTERNS; DATABASE; REVEALS; SYSTEM AB A dense map of genetic variation in the laboratory mouse genome will provide insights into the evolutionary history of the species(1) and lead to an improved understanding of the relationship between inter-strain genotypic and phenotypic differences. Here we resequence the genomes of four wild-derived and eleven classical strains. We identify 8.27 million high-quality single nucleotide polymorphisms (SNPs) densely distributed across the genome, and determine the locations of the high (divergent subspecies ancestry) and low (common subspecies ancestry) SNP-rate intervals(2-6) for every pairwise combination of classical strains. Using these data, we generate a genome-wide haplotype map containing 40,898 segments, each with an average of three distinct ancestral haplotypes. For the haplotypes in the classical strains that are unequivocally assigned ancestry, the genetic contributions of the Mus musculus subspecies-M. m. domesticus, M. m. musculus, M. m. castaneus and the hybrid M. m. molossinus-are 68%, 6%, 3% and 10%, respectively; the remaining 13% of haplotypes are of unknown ancestral origin. The considerable regional redundancy of the SNP data will facilitate imputation of the majority of these genotypes in less-densely typed classical inbred strains to provide a complete view of variation in additional strains. C1 Perlegen Sci, Mountain View, CA 94043 USA. Univ Calif Los Angeles, Dept Comp Sci, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA. Univ Calif San Diego, Dept Comp Sci & Engn, La Jolla, CA 92093 USA. Jackson Lab, Bar Harbor, ME 04609 USA. NIEHS, Toxicol Operat Branch, Res Triangle Pk, NC 27709 USA. Harvard Univ, Broad Inst, Cambridge, MA 02142 USA. MIT, Cambridge, MA 02142 USA. Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. RP Frazer, KA (reprint author), Perlegen Sci, 2021 Stierlin Court, Mountain View, CA 94043 USA. EM frazer.kelly@scrippshealth.org RI Eskin, Eleazar/J-9187-2012; OI Eskin, Eleazar/0000-0003-1149-4758; Wade, Claire/0000-0003-3413-4771 FU NHLBI NIH HHS [K25 HL080079] NR 26 TC 289 Z9 297 U1 3 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 30 PY 2007 VL 448 IS 7157 BP 1050 EP U8 DI 10.1038/nature06067 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 205EU UT WOS:000249097600038 PM 17660834 ER PT J AU Moolchan, ET Frazier, M Franken, FH Ernst, M AF Moolchan, Eric T. Frazier, Matthew Franken, Frederick H. Ernst, Monique TI Adolescents in smoking cessation treatment: Relationship between externalizing symptoms, smoking history and outcome SO PSYCHIATRY RESEARCH LA English DT Article DE tobacco; externalizing behaviors ID CIGARETTE-SMOKING; PSYCHIATRIC COMORBIDITY; SUBSTANCE USE; PSYCHOPATHOLOGY; PROGRESSION; DEPENDENCE; INITIATION; DISORDERS; CHILDREN; SMOKERS AB Previous research has indicated a potential bi-directional link between youth substance use and externalizing psychiatric comorbidities. We hypothesized that the degree of externalizing symptoms predicts the likelihood of successful smoking cessation (prolonged abstinence) among adolescent smokers participating in a cessation trial. We also explored the association of extemalizing symptoms with age at smoking initiation. Ninety one adolescents (mean +/- S.D.; age 15.1 +/- 1.4 years, cigarettes per day 18.4 +/- 8.1, Fagerstrom Test for Nicotine Dependence 7.1 +/- 1.3) were included. The Child Behavior Checklist/4-18 and Youth Self-Report assessed the degree of externalizing symptoms. Regression analysis indicated that lower CBCL externalizing scores significantly predicted the likelihood of prolonged abstinence. Pearson's correlation analysis indicated a significant association of lower externalizing scores with later onset of smoking initiation. Our findings highlight the importance of addressing externalizing behaviors in adolescent smoking cessation programs. Published by Elsevier Ireland Ltd. C1 TTATRC NIDA IRP NIH DHHS, Baltimore, MD 21224 USA. EDAM NIMH NIH DHHS, Bethesda, MD USA. RP Moolchan, ET (reprint author), TTATRC NIDA IRP NIH DHHS, Baltimore, MD 21224 USA. EM emoolcha@intra.nida.nih.gov FU Intramural NIH HHS NR 25 TC 4 Z9 4 U1 1 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0165-1781 J9 PSYCHIAT RES JI Psychiatry Res. PD AUG 30 PY 2007 VL 152 IS 2-3 BP 281 EP 285 DI 10.1016/j.psychres.2006.05.008 PG 5 WC Psychiatry SC Psychiatry GA 208QH UT WOS:000249333800023 PM 17449109 ER PT J AU Bergen, AW Baccarelli, A McDaniel, TK Kuhn, K Pfeiffer, R Kakol, J Bender, P Jacobs, K Packer, B Chanock, SJ Yeager, M AF Bergen, Andrew W. Baccarelli, Andrea McDaniel, Timothy K. Kuhn, Kenneth Pfeiffer, Ruth Kakol, Jerry Bender, Patrick Jacobs, Kevin Packer, Bernice Chanock, Stephen J. Yeager, Meredith TI cis sequence effects on gene expression SO BMC GENOMICS LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; HUMAN GENOME; ALLELIC VARIATION; ASSAY DEVELOPMENT; HAPLOTYPE TREES; PUBLIC RESOURCE; CANDIDATE GENES; COPY NUMBER; CELL-LINES; ASSOCIATION AB Background: Sequence and transcriptional variability within and between individuals are typically studied independently. The joint analysis of sequence and gene expression variation ( genetical genomics) provides insight into the role of linked sequence variation in the regulation of gene expression. We investigated the role of sequence variation in cis on gene expression ( cis sequence effects) in a group of genes commonly studied in cancer research in lymphoblastoid cell lines. We estimated the proportion of genes exhibiting cis sequence effects and the proportion of gene expression variation explained by cis sequence effects using three different analytical approaches, and compared our results to the literature. Results: We generated gene expression profiling data at N = 697 candidate genes from N = 30 lymphoblastoid cell lines for this study and used available candidate gene resequencing data at N = 552 candidate genes to identify N = 30 candidate genes with sufficient variance in both datasets for the investigation of cis sequence effects. We used two additive models and the haplotype phylogeny scanning approach of Templeton (Tree Scanning) to evaluate association between individual SNPs, all SNPs at a gene, and diplotypes, with log-transformed gene expression. SNPs and diplotypes at eight candidate genes exhibited statistically significant (p < 0.05) association with gene expression. Using the literature as a "gold standard" to compare 14 genes with data from both this study and the literature, we observed 80% and 85% concordance for genes exhibiting and not exhibiting significant cis sequence effects in our study, respectively. Conclusion: Based on analysis of our results and the extant literature, one in four genes exhibits significant cis sequence effects, and for these genes, about 30% of gene expression variation is accounted for by cis sequence variation. Despite diverse experimental approaches, the presence or absence of significant cis sequence effects is largely supported by previously published studies. C1 NIH, Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. SRI Int, Ctr Hlth Sci, Policy Div, Menlo Pk, CA 94025 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Univ Milan, Maggiore Hosp, Mangiagalli & Regina Elena IRCCS Fdn, EPOCA Epidemiol Ctr, Milan, Italy. Illumina, San Diego, CA USA. Coriell Inst Med Res, Camden, NJ USA. Natl Canc Inst, Core Genotyping Facil, Gaithersburg, MD USA. Sci Applicat Int Corp, Natl Canc Inst, NCI, FCRDC, Frederick, MD USA. RP Bergen, AW (reprint author), NIH, Natl Canc Inst, Div Canc Epidemiol & Genet, Bldg 10, Bethesda, MD 20892 USA. EM andrew.bergen@sri.com; abaccare@hsph.harvard.edu; tmcdaniel@illumina.com; kkuhn@illumina.com; pfeiffer@mail.nih.gov; jkakol@illumina.com; pbender@coriell.org; jacobske@mail.nih.gov; packerb@mail.nih.gov; chanocks@mail.nih.gov; yeagerm@mail.nih.gov RI Pfeiffer, Ruth /F-4748-2011; OI Baccarelli, Andrea/0000-0002-3436-0640; Bergen, Andrew/0000-0002-1237-7644 FU Intramural NIH HHS NR 46 TC 5 Z9 5 U1 0 U2 1 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 AUG 29 PY 2007 VL 8 AR 296 DI 10.1186/1471-2164-8-296 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 231CH UT WOS:000250923600001 PM 17727713 ER PT J AU Tong, YX Melara, RD AF Tong, Yunxia Melara, Robert D. TI Behavioral and electrophysiological effects of distractor variation on auditory selective attention SO BRAIN RESEARCH LA English DT Article DE auditory selective attention; target; distractor; distractor variation; ERP ID EVENT-RELATED POTENTIALS; WORKING-MEMORY; INVOLUNTARY ATTENTION; STIMULUS; FREQUENCY; P300; UNCERTAINTY; INFORMATION; SPECIFICITY; DISRUPTION AB Two experiments investigated the effects on auditory selection of varying distractor values in memory. Participants performed a set of control (single distractor) and distractor-variation (multiple distractors) tasks, classifying targets by pitch (Experiments 1A and 2) or loudness (Experiment 1B) while ignoring previously presented (and spatially separate) distractors. When both targets and distractors varied in pitch, the degree of variation among the distractors increasingly disrupted classification accuracy and reaction time to the targets. Physiologically, the degree of distractor variation boosted the N1 response to distractors, the P2 response to both targets and distractors, and the slow-wave response to targets (400-600 ins after stimulus onset). The results suggest that target representations are diminished in distinctiveness as distractors activate a wider range of the task-relevant continuum in working memory. (c) 2007 Elsevier B.V. All rights reserved. C1 NIMH, Gene Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. CUNY City Coll, Dept Psychol, New York, NY 10031 USA. RP Melara, RD (reprint author), NIMH, Gene Cognit & Psychosis Program, NIH, 900 Rockville Pike,Bldg 10,Room 3C101, Bethesda, MD 20892 USA. EM rmelara@ccny.cuny.edu RI Tong, Yunxia/C-1276-2010 NR 52 TC 7 Z9 7 U1 3 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD AUG 29 PY 2007 VL 1166 BP 110 EP 123 DI 10.1016/j.brainres.2007.06.061 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 210NR UT WOS:000249463400012 PM 17669371 ER PT J AU Goila-Gaur, R Khan, MA Miyagi, E Kao, S Strebel, K AF Goila-Gaur, Ritu Khan, Mohammad A. Miyagi, Eri Kao, Sandra Strebel, Klaus TI Targeting APOBEC3A to the viral nucleoprotein complex confers antiviral activity SO RETROVIROLOGY LA English DT Article ID VIRUS TYPE-1 VIF; HEPATITIS-B-VIRUS; EDITING ENZYME APOBEC3G; CYTIDINE DEAMINASE; HIV-1 VIF; POTENT INHIBITORS; STRESS GRANULES; IN-VIVO; PROTEIN; RNA AB Background: APOBEC3 ( A3) proteins constitute a family of cytidine deaminases that provide intracellular resistance to retrovirus replication and to transposition of endogenous retroelements. A3A has significant homology to the C- terminus of A3G but has only a single cytidine deaminase active site ( CDA), unlike A3G, which has a second N- terminal CDA previously found to be important for Vif sensitivity and virus encapsidation. A3A is packaged into HIV-1 virions but, unlike A3G, does not have antiviral properties. Here, we investigated the reason for the lack of A3A antiviral activity. Results: Sequence alignment of A3G and A3A revealed significant homology of A3A to the C-terminal region of A3G. However, while A3G co-purified with detergent- resistant viral nucleoprotein complexes (NPC), virus- associated A3A was highly detergent-sensitive leading us to speculate that the ability to assemble into NPC may be a property conveyed by the A3G N-terminus. To test this model, we constructed an A3G-3A chimeric protein, in which the N-terminal half of A3G was fused to A3A. Interestingly, the A3G-3A chimera was packaged into HIV-1 particles and, unlike A3A, associated with the viral NPC. Furthermore, the A3G-3A chimera displayed strong antiviral activity against HIV-1 and was sensitive to inhibition by HIV-1 Vif. Conclusion: Our results suggest that the A3G N-terminal domain carries determinants important for targeting the protein to viral NPCs. Transfer of this domain to A3A results in A3A targeting to viral NPCs and confers antiviral activity. C1 NIAID, Mol Microbiol Lab, Viral Biochem Sect, NIH, Bethesda, MD 20892 USA. RP Strebel, K (reprint author), NIAID, Mol Microbiol Lab, Viral Biochem Sect, NIH, Bldg 4,Room 310,4 Ctr Dr,MSC 0460, Bethesda, MD 20892 USA. EM rgaur@niaid.nih.gov; mkhan@niaid.nih.gov; emiyagi@niaid.nih.gov; skao@niaid.nih.gov; kstrebel@niaid.nih.gov FU Intramural NIH HHS NR 51 TC 50 Z9 50 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD AUG 29 PY 2007 VL 4 AR 61 DI 10.1186/1742-4690-4-61 PG 10 WC Virology SC Virology GA 224PU UT WOS:000250459700001 PM 17727729 ER PT J AU Hussain, A Das, SR Tanwar, C Jameel, S AF Hussain, Amjad Das, Suman R. Tanwar, Charu Jameel, Shahid TI Oligomerization of the human immunodeficiency virus type 1 (HIV-1) Vpu protein - a genetic, biochemical and biophysical analysis SO VIROLOGY JOURNAL LA English DT Article ID TRANSMEMBRANE DOMAIN; CYTOPLASMIC DOMAIN; MEMBRANE-PROTEIN; PARTICLE RELEASE; MAMMALIAN-CELLS; PLASMA-MEMBRANE; BETA-TRCP; KAPPA-B; F-BOX; CD4 AB Background: The human immunodeficiency virus type 1( HIV- 1) is a complex retrovirus and the causative agent of acquired immunodeficiency syndrome ( AIDS). The HIV- 1 Vpu protein is an oligomeric integral membrane protein essential for particle release, viral load and CD4 degradation. In silico models show Vpu to form pentamers with an ion channel activity. Results: Using Vpu proteins from a primary subtype C and the pNL4-3 subtype B isolates of HIV-1, we show oligomerization of the full- length protein as well as its transmembrane (TM) domain by genetic, biochemical and biophysical methods. We also provide direct evidence of the presence of Vpu pentamers in a stable equilibrium with its monomers in vitro. This was also true for the TM domain of Vpu. Confocal microscopy localized Vpu to the endoplasmic reticulum and Golgi regions of the cell, as well as to post-Golgi vesicles. In fluorescence resonance energy transfer (FRET) experiments in live cells we show that Vpu oligomerizes in what appears to be either the Golgi region or intracellular vesicles, but not in the ER. Conclusion: We provide here direct evidence that the TM domain, is critical for Vpu oligomerization and the most favourable channel assembly is a pentamer. The Vpu oligomerization appears to be either the Golgi region or intracellular vesicles, but not in the ER. C1 Int Ctr Genet Engn & Biotechnol, Virol Grp, New Delhi, India. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Jameel, S (reprint author), Int Ctr Genet Engn & Biotechnol, Virol Grp, New Delhi, India. EM amjadicgeb@yahoo.com; sumanrd@yahoo.com; tanwar_charu@yahoo.co.in; shahid@icgeb.res.in RI Das, Suman/C-8760-2009 FU Wellcome Trust NR 38 TC 16 Z9 17 U1 0 U2 2 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 AUG 29 PY 2007 VL 4 AR 81 DI 10.1186/1743-422X-4-81 PG 11 WC Virology SC Virology GA 224PG UT WOS:000250458300001 PM 17727710 ER PT J AU Yip, VLY Thompson, J Withers, SG AF Yip, Vivian L. Y. Thompson, John Withers, Stephen G. TI Mechanism of GlvA from Bacillus subtilis: A detailed kinetic analysis of a 6-phospho-alpha-glucosidase from glycoside hydrolase family 4 SO BIOCHEMISTRY LA English DT Article ID SEQUENCE-BASED CLASSIFICATION; PHOSPHO-ALPHA-GLUCOSIDASE; FUSOBACTERIUM-MORTIFERUM; THERMOTOGA-MARITIMA; ESCHERICHIA-COLI; HYDROLYSIS; ASSIGNMENT; GLYCOSYLHYDROLASES; PURIFICATION; SUBSTITUTION AB GlvA, a 6-phospho-alpha-glucosidase from Bacillus subtilis assigned to glycoside hydrolase family 4, catalyzes the hydrolysis of maltose 6'-phosphate via a redox-elimination-addition mechanism requiring NAD(+) as cofactor. In contrast to previous reports and consistent with the proposed mechanism, GlvA is only activated in the presence of the nicotinamide cofactor in its oxidized, and not the reduced NADH, form. Significantly, GlvA catalyzes the hydrolysis of both 6-phospho-alpha- and 6-phospho-beta-glucosides containing activated leaving groups such as p-nitrophenol and does so with retention and inversion, respectively, of anomeric configuration. Mechanistic details of the individual bond cleaving and forming steps were probed using a series of 6-phospho-alpha- and 6-phospho-beta-glucosides. Primary deuterium kinetic isotope effects (KIEs) were measured for both classes of substrates in which either the C2 or the C3 protons have been substituted with a deuterium, consistent with C-H bond cleavage at each center being partially rate-limiting. Kinetic parameters were also determined for 1-[H-2]-substituted substrates, and depending on the substrates and the reaction conditions, the measurements of k(cat) and k(cat)/K-M produced either no KIEs or inverse KIEs. In conjunction with results of Bronsted analyses with both aryl 6-phospho-alpha- and beta-glucosides, the kinetic data suggest that GlvA utilizes an E1(cb) mechanism analogous to that proposed for the Thermotoga maritima BglT, a 6-phospho-beta-glucosidase in glycoside hydrolase family 4 (Yip, V.L.Y et al. (2006) Biochemistry 45, 571-580). The pattern of isotope effects measured and the observation of very similar k(cat) values for all substrates, including unactivated and natural substrates, indicate that the oxidation and deprotonation steps are rate-limiting steps in essentially all cases. This mechanism permits the cleavage of both alpha- and beta-glycosides within the same active site motif and, for activated substrates that do not require acid catalysis for cleavage, within the same active site, yielding the product sugar-6-phosphate in the same anomeric form in the two cases. C1 Univ British Columbia, Dept Chem, Vancouver, BC V6T 1Z1, Canada. NIDCR, Oral Infect & Immun Branch, Microbial Biochem & Genet Unit, Bethesda, MD 20892 USA. RP Withers, SG (reprint author), Univ British Columbia, Dept Chem, 2036 Main Mall, Vancouver, BC V6T 1Z1, Canada. EM withers@chem.ubc.ca FU Intramural NIH HHS NR 28 TC 28 Z9 29 U1 1 U2 21 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 28 PY 2007 VL 46 IS 34 BP 9840 EP 9852 DI 10.1021/bi700536p PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 202FD UT WOS:000248886500020 PM 17676871 ER PT J AU Troisi, R Innes, KE Roberts, JM Hoover, RN AF Troisi, R. Innes, K. E. Roberts, J. M. Hoover, R. N. TI Preeclampsia and maternal breast cancer risk by offspring gender: do elevated androgen concentrations play a role? SO BRITISH JOURNAL OF CANCER LA English DT Article DE preeclampsia; androgens; hormones; breast cancer; maternal; offspring gender ID HUMAN CHORIONIC-GONADOTROPIN; PREGNANCY CHARACTERISTICS; SUBSEQUENT RISK; WOMEN; HYPERTENSION; ESTROGEN AB Among older mothers, preeclampsia in the first pregnancy was associated with a reduction in maternal breast cancer risk that was significantly more pronounced in women bearing male than female infants. Androgen concentrations in male, preeclamptic pregnancies were consistent with the hypothesis that elevated pregnancy androgens might mediate this apparent modifying effect of fetal gender. C1 NCI, Div Canc Epidemiol & Genet, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. Dartmouth Coll Sch Med, Dept Community & Family Med, Hanover, NH USA. Univ Virginia Hlth Sci Syst, Ctr Study Complement & Alternat Therapies, Charlottesville, VA USA. Univ Pittsburgh, Magee Womens Hosp, Pittsburgh, PA 15213 USA. RP Troisi, R (reprint author), NCI, Div Canc Epidemiol & Genet, Epidemiol & Biostat Program, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM troisir@mail.nih.gov NR 22 TC 12 Z9 13 U1 0 U2 1 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 AUG 28 PY 2007 VL 97 IS 5 BP 688 EP 690 DI 10.1038/sj.bjc.6603921 PG 3 WC Oncology SC Oncology GA 205OE UT WOS:000249122800017 PM 17687337 ER PT J AU Ingelsson, E Pencina, MJ Tofler, GH Benjamin, EJ Lanier, KJ Jacques, PF Fox, CS Meigs, JB Levy, D Larson, MG Selhub, J D'Agostino, RB Wang, TJ Vasan, RS AF Ingelsson, Erik Pencina, Michael J. Tofler, Geoffrey H. Benjamin, Emelia J. Lanier, Katherine J. Jacques, Paul F. Fox, Caroline S. Meigs, James B. Levy, Daniel Larson, Martin G. Selhub, Jacob D'Agostino, Ralph B., Sr. Wang, Thomas J. Vasan, Ramachandran S. TI Multimarker approach to evaluate the incidence of the metabolic syndrome and longitudinal changes in metabolic risk factors - The framingham offspring study SO CIRCULATION LA English DT Article DE aldosterone; epidemiology; metabolic syndrome X; plasminogen activator inhibitor 1; risk factors ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; C-REACTIVE PROTEIN; INSULIN-RESISTANCE ATHEROSCLEROSIS; ANGIOTENSIN-ALDOSTERONE SYSTEM; NATRIURETIC PEPTIDE LEVELS; TYPE-2 DIABETES-MELLITUS; BLOOD-PRESSURE; CARDIOVASCULAR RISK; MULTIPLE BIOMARKERS; PLASMA-ALDOSTERONE AB Background-The metabolic syndrome (MetS) is associated with increased cardiovascular risk. We evaluated the relative contributions of circulating biomarkers representing distinct biological pathways to the incidence of MetS and to longitudinal changes of its constituent risk factors. Methods and Results-We measured 8 circulating biomarkers reflecting inflammation (C-reactive protein), hemostasis (plasminogen activator inhibitor-1, fibrinogen), neurohormonal activity (aldosterone, renin, B-type natriuretic peptide, N-terminal proatrial natriuretic peptide), and endothelial dysfunction (homocysteine) in 2292 Framingham Offspring Study participants (mean age, 57 years; 56% women). We related the biomarker panel to incidence of MetS on follow-up initially and then related biomarkers associated with incident MetS to longitudinal change in its components. On follow-up ( mean, 2.9 years), 282 participants (of 1473 participants without prevalent MetS at baseline) developed MetS. After adjustment for clinical risk factors, the biomarker panel was associated with incident MetS (P=0.008). On backward elimination, plasminogen activator inhibitor-1 and aldosterone remained associated with incident MetS (multivariable-adjusted odds ratio per 1-SD increment log marker, 1.31 [P=0.004] and 1.21 [P=0.015], respectively). In multivariable analyses evaluating longitudinal change in MetS components (analyzed as continuous variables), plasminogen activator inhibitor-1 was significantly and positively associated with changes in fasting glucose, systolic blood pressure, and triglycerides ( all P < 0.05). Serum aldosterone was associated positively with change in systolic blood pressure (P=0.023) and inversely with change in high-density lipoprotein cholesterol (P=0.001). Conclusions-Higher circulating plasminogen activator inhibitor-1 and aldosterone levels are associated with the development of MetS and with longitudinal change of its components, suggesting that these biomarkers and related pathways play a key role in mediating metabolic risk. C1 Boston Univ, Sch Med, Framingham Heart Study, Framingham, MA 01702 USA. Boston Univ, Sch Med, Dept Math, Boston, MA 02118 USA. Boston Univ, Sch Med, Cardiol Div & Prevent Med, Boston, MA 02118 USA. Royal N Shore Hosp, Sydney, NSW, Australia. Tufts Univ, Jean Mayer US Dept Agr Human Nutr Res Ctr Aging, Boston, MA 02111 USA. Brigham & Womens Hosp, Div Endocrinol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. NHLBI, Bethesda, MD 20892 USA. RP Vasan, RS (reprint author), Boston Univ, Sch Med, Framingham Heart Study, 73 Mt Wayte Ave, Framingham, MA 01702 USA. EM vasan@bu.edu OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K23-HL074077-01, K24-HL-04334, N01-HC-25195] NR 56 TC 104 Z9 108 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 AUG 28 PY 2007 VL 116 IS 9 BP 984 EP 992 DI 10.1161/CIRCULATIONAHA.107.708537 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 204GF UT WOS:000249031100004 PM 17698726 ER PT J AU McDermott, MM Ferrucci, L Guralnik, JM Tian, L Green, D Liu, K Tan, J Liao, Y Pearce, WH Schneider, JR Ridker, P Rifai, N Hoff, F Criqui, MH AF McDermott, Mary M. Ferrucci, Luigi Guralnik, Jack M. Tian, Lu Green, David Liu, Kiang Tan, Jin Liao, Ylhua Pearce, William H. Schneider, Joseph R. Ridker, Paul Rifai, Nader Hoff, Frederick Criqui, Michael H. TI Elevated levels of inflammation, D-dimer, and homocysteine are associated with adverse calf muscle characteristics and reduced calf strength in peripheral arterial disease SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID ANKLE-BRACHIAL INDEX; NECROSIS-FACTOR-ALPHA; SKELETAL-MUSCLE; PHYSICAL-ACTIVITY; FUNCTIONAL DECLINE; PROTEIN BREAKDOWN; ATHEROSCLEROSIS; RATS; QUESTIONNAIRES; CLASSIFICATION AB Objectives This study determined whether increased levels of inflammatory blood markers, D-dimer, and homocysteine were associated with smaller calf skeletal muscle area, increased calf muscle percent fat, reduced calf muscle density, and poorer calf strength in persons with lower extremity peripheral arterial disease (PAD). Background Elevated levels of inflammatory markers and D-dimer are associated with greater functional impairment and functional decline in persons with PAD. Mechanisms of these associations are unknown. Methods Participants were 423 persons with PAD. Calf muscle area, percent fat, and density were measured with computed tomography. Physical activity levels were measured objectively over 7 days with the Caltrac (Muscle Dynamics Fitness Network, Inc., Rocklin, California) vertical accelerometer. Isometric plantarflexion strength was measured. Analyses were adjusted for age, gender, race, comorbidities, the ankle-brachial index, and other potential confounders. Results Higher levels of D-dimer (p = 0.014), C-reactive protein (CRP) (p = 0.002), interleukin (IL)-6 (p < 0.001), and soluble vascular cellular adhesion molecule (sVCAM)-1 (p = 0.008) were associated with smaller calf muscle area. Higher sVCAM-1 (p = 0.004) and IL-6 (p = 0.017) were associated with higher calf muscle percent fat. Higher D-dimer (p < 0.001), sVCAM-1 (p < 0.001), and homocysteine (p = 0.014) were associated with lower calf muscle density. These associations were generally unchanged after additional adjustment for physical activity. Higher sVCAM-1. (p = 0.013) was associated with lower calf strength. Conclusions These data show, for the first time, that higher levels of inflammation, D-dimer, and homocysteine are associated with more adverse calf muscle characteristics in persons with PAD. These associations may contribute to previously established associations between elevated biomarkers and functional impairment and functional decline in 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. NIA, Lab Clin Epidemiol Demography & Biometry, Bethesda, MD 20892 USA. Northwestern Univ, Feinberg Sch Med, Dept Surg, Chicago, IL 60611 USA. NW Hosp, Dept Surg, Div Vasc Surg, Evanston, IL USA. Harvard Univ, Sch Med, Boston, MA USA. Northwestern Univ, Feinberg Sch Med, Dept Radiol, Chicago, IL 60611 USA. RP McDermott, MM (reprint author), 676 N St Clair,Suite 200, Chicago, IL 60611 USA. EM mdm608@northwestern.edu FU Intramural NIH HHS [Z99 AG999999]; NCRR NIH HHS [M01 RR000048]; NHLBI NIH HHS [R01-HL00048, R01 HL064739, R01 HL071223, R01 HL076298, R01-HL58099, R01-HL64739, R01-HL71223] NR 39 TC 37 Z9 37 U1 1 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 AUG 28 PY 2007 VL 50 IS 9 BP 897 EP 905 DI 10.1016/j.jacc.2007.05.017 PG 9 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 203FJ UT WOS:000248960200013 PM 17719478 ER PT J AU Tan, X Mizuuchi, M Mizuuchi, K AF Tan, Xin Mizuuchi, Michiyo Mizuuchi, Kiyoshi TI DNA transposition target immunity and the determinants of the MuB distribution patterns on DNA SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE phage Mu; recombination; DNA-binding protein; biornolecular patterning ID STRAND-TRANSFER; BACTERIOPHAGE-MU; B-PROTEIN; COMPLEX; MECHANISM; INTEGRATION AB MuB, an ATP-dependent DNA-binding protein, is critical for the selection of target sites on the host chromosome during the phage Mu transposition. We developed a multichannel fluidic system to study the MuB-DNA interaction dynamics at the single DNA molecule level by total internal reflection fluorescence microscopy. We analyzed the distribution of MuB along DNA during the assembly and disassembly of MuB polymers on immobilized DNA molecules. The results reveal the absence of a significant correlation of MuB polymer distribution between the assembly and disassembly phases. These observations argue against a model in which MuB polymers on DNA represent a mixture of higher and lower affinity forms, with higher affinity forms being the first to appear and the last to disappear. Instead, assembly and disassembly of MuB polymers involve independent stochastic events. Additionally, we demonstrate that MuB disassembles from the polymer ends at a higher rate than from internal regions of the polymer and MuA stimulates MuB disassembly both at the polymer ends and internally. C1 NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Mizuuchi, K (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM kmizu@helix.nih.gov NR 13 TC 8 Z9 9 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 AUG 28 PY 2007 VL 104 IS 35 BP 13925 EP 13929 DI 10.1073/pnas.0706564104 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 206ML UT WOS:000249187500015 PM 17709741 ER PT J AU Stefanovic, M Markham, NO Parry, EM Garrett-Beal, LJ Cline, AP Gallagher, PG Low, PS Bodine, DM AF Stefanovic, Marko Markham, Nicholas O. Parry, Erin M. Garrett-Beal, Lisa J. Cline, Amanda P. Gallagher, Patrick G. Low, Philip S. Bodine, David M. TI An 11-amino acid beta-hairpin loop in the cytoplasmic domain of band 3 is responsible for ankyrin binding in mouse erythrocytes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cytoskeleton; membrane; transgenic; spherocytosis ID DOMINANT HEREDITARY SPHEROCYTOSIS; HUMAN RED-CELLS; MEMBRANE-SKELETON; HEMOLYTIC-ANEMIA; SPECTRIN DEFICIENCY; TARGETED DISRUPTION; CRYSTAL-STRUCTURE; PROTEIN ANKYRIN; GENE; MICE AB The best-studied cytoskeletal system is the inner surface of the erythrocyte membrane, which provides an erythrocyte with the structural support needed to be stable yet flexible as it passes through the circulation. Current structural models predict that the spectrin-actin-based cytoskeletal network is attached to the plasma membrane through interactions of the protein ankyrin, which binds to both spectrin and the cytoplasmic domain of the transmembrane protein band 3. The crystal structure of the cytoplasmic domain of band 3 predicted that the ankyrin binding site was located on a beta-hairpin loop in the cytoplasmic domain. In vitro, deletion of this loop eliminated ankyrin affinity for band 3 without affecting any other protein-band 3 interaction. To evaluate the importance of the ankyrin-band 3 linkage to membrane properties in vivo, we generated mice with the nucleotides encoding the 11-aa beta-hairpin loop in the mouse Slc4a1 gene replaced with sequence encoding a diglycine bridge. Mice homozygous for the loop deletion were viable with mildly spherocytic and osmotically fragile erythrocytes. in vitro, homozygous Id/Id erythrocytes were incapable of binding ankyrin, but contrary to all previous predictions, abolishing the ankyrin-band 3 linkage destabilized the erythrocyte membrane to a lesser degree than complete deficiencies of either band 3 or ankyrin. Our data indicate that as yet uncharacterized interactions between other membrane proteins must significantly contribute to linkage of the spectrin-actin-based membrane cytoskeleton to the plasma membrane. C1 NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. NHGRI, Embryon Stem Cell & Transgen Mouse Core Facil, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06520 USA. RP Bodine, DM (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, Bldg 49,Room 4A04,49 Convent Dr MSC-4442, Bethesda, MD 20892 USA. EM tedyaz@mail.nih.gov FU Intramural NIH HHS; NIDDK NIH HHS [R01 DK062039, DK62039]; NIGMS NIH HHS [R37 GM024417, R01 GM024417, GM24417-28] NR 41 TC 21 Z9 22 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 AUG 28 PY 2007 VL 104 IS 35 BP 13972 EP 13977 DI 10.1073/pnas.0706266104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 206ML UT WOS:000249187500023 PM 17715300 ER PT J AU Passeron, T Valencia, JC Bertolotto, C Hoashi, T Le Pape, E Takahashi, K Ballotti, R Hearing, VJ AF Passeron, Thierry Valencia, Julio C. Bertolotto, Corine Hoashi, Toshihiko Le Pape, Elodie Takahashi, Kaoruko Ballotti, Robert Hearing, Vincent J. TI SOX9 is a key plaver in ultraviolet B-induced melanocyte differentiation and pigmentation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE microphthalmia-associated transcription factor; tyrosinase; protein kinase A; melanocyte-stimulating hormone; agouti signal protein ID AGOUTI SIGNALING PROTEIN; CHONDROCYTE-SPECIFIC ENHANCER; MICROPHTHALMIA GENE-PRODUCT; AUTOSOMAL SEX REVERSAL; TRANSCRIPTION FACTOR; CYCLIC-AMP; DOPACHROME-TAUTOMERASE; CAMPOMELIC DYSPLASIA; MELANOGENIC GENES; COLLAGEN GENE AB SOX (SRY type HMG box) proteins are transcription factors that are predominantly known for their roles during development. During melanocyte development from the neural crest, SOX10 regulates microphthalmia-associated transcription factor, which controls a set of genes critical for pigment cell development and pigmentation, including dopachrome tautomerase and tyrosinase. We report here that another SOX factor, SOX9, is expressed by melanocytes in neonatal and adult human skin and is up-regulated by UVB exposure. We demonstrate that this regulation is mediated by cAMP and protein kinase. We also show that agouti signal protein, a secreted factor known to decrease pigmentation, down-regulates SOX9 expression. In adult and neonatal melanocytes, SOX9 regulates microphthalmia-associated transcription factor, dopachrome tautomerase, and tyrosinase promoters, leading to an increase in the expression of these key melanogenic proteins and finally to a stimulation of pigmentation. SOX9 completes the complex and tightly regulated process leading to the production of melanin by acting at a very upstream level. This role of SOX9 in pigmentation emphasizes the poorly understood impact of SOX proteins in adult, tissues. C1 NCI, Cell Biol Lab, NIH, Pigment Cell Biol Sect, Bethesda, MD 20814 USA. Univ Nice Sophia Antipolis, Fac Med, Inst Natl Sante & Rech Med, Unite 597, F-06103 Nice, France. RP Hearing, VJ (reprint author), NCI, Cell Biol Lab, NIH, Bldg 37,Room 2132,MSC 4256, Bethesda, MD 20892 USA. EM hearingv@nih.gov RI Bertolotto-Ballotti, Corine/O-2155-2016; BALLOTTI, Robert/F-8825-2013; OI Passeron, Thierry/0000-0002-0797-6570 FU Intramural NIH HHS NR 46 TC 63 Z9 64 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 28 PY 2007 VL 104 IS 35 BP 13984 EP 13989 DI 10.1073/pnas.0705117104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 206ML UT WOS:000249187500025 PM 17702866 ER PT J AU Buchner, DA Su, F Yamaoka, JS Kamei, M Shavit, JA Barthel, LK Mcgee, B Amigo, JD Kim, S Hanosh, AW Jagadeeswaran, P Goldman, D Lawson, ND Raymond, PA Weinstein, BM Ginsburg, D Lyons, SE AF Buchner, David A. Su, Fengyun Yamaoka, Jennifer S. Kamei, Makoto Shavit, Jordan A. Barthel, Linda K. Mcgee, Beth Amigo, Julio D. Kim, Seongcheol Hanosh, Andrew W. Jagadeeswaran, Pudur Goldman, Daniel Lawson, Nathan D. Raymond, Pamela A. Weinstein, Brant M. Ginsburg, David Lyons, Susan E. TI pak2a mutations cause cerebral hemorrhage in redhead zebrafish SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE beta-pix; CNS; endothelial cell; p21-activated kinase; vasculature ID ENDOTHELIAL-CELL MIGRATION; IN-VIVO; CAVERNOUS MALFORMATIONS; P21-ACTIVATED KINASE; VASCULAR DEVELOPMENT; SIGNALING PATHWAY; PROTEIN-KINASE; VEGF; ACTIVATION; PERMEABILITY AB The zebrafish is a powerful model for studying vascular development, demonstrating remarkable conservation of this process with mammals. Here, we identify a zebrafish mutant, redhead (rhd(mi149)), that exhibits embryonic CNS hemorrhage with intact gross development of the vasculature and normal hemostatic function. We show that the rhd phenotype is caused by a hypomorphic mutation in p21-activated kinase 2a (pak2a). PAK2 is a kinase that acts downstream of the Rho-family GTPases CDC42 and RAC and has been implicated in angiogenesis, regulation of cytoskeletal structure, and enclothelial cell migration and contractility among other functions. Correction of the Pak2a-deficient phenotype by Pak2a overexpression depends on kinase activity, implicating Pak2 signaling in the maintenance of vascular integrity. Rescue by an enclothelial-specific transgene further suggests that the hemorrhage seen in Pak2a deficiency is the result of an autonomous enclothelial cell defect. Reduced expression of another PAK2 ortholog, pak2b, in Pak2a-deficient embryos results in a more severe hemorrhagic phenotype, consistent with partially overlapping functions for these two orthologs. These data provide in vivo evidence for a critical function of Pak2 in vascular integrity and demonstrate a severe disease phenotype resulting from loss of Pak2 function. C1 Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA. Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Mol Cellular & Dev Biol, Ann Arbor, MI 48109 USA. Univ Michigan, Ctr Mol & Behav Neurosci, Ann Arbor, MI 48109 USA. Univ Michigan, Dept Biol Chem, Ann Arbor, MI 48109 USA. Univ Michigan, Div Hematol Oncol & cellular Mol Biol Program, Ann Arbor, MI 48109 USA. NIH, Natl Inst Chil Hlth & Human Dev, Mol Genet Lab, Bethesda, MD 20892 USA. Univ N Texas, Dept Biol Sci, Denton, TX 76203 USA. Univ Massachusetts, Sch Med, Program Gene Funct & Express, Worcester, MA 01605 USA. RP Ginsburg, D (reprint author), Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA. EM ginsburg@umich.edu OI Kamei, Makoto/0000-0002-1438-0783; Buchner, David/0000-0003-3920-4871; Raymond, Pamela/0000-0003-1083-5530 FU NCI NIH HHS [K22-CA098024]; NHLBI NIH HHS [F32 HL082213, F32-HL82213-01, P01 HL057346, P01-HL057346, R01 HL077910, R01-HL077910, R37 HL039693, R37-HL039693] NR 40 TC 55 Z9 55 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 AUG 28 PY 2007 VL 104 IS 35 BP 13996 EP 14001 DI 10.1073/pnas.0700947104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 206ML UT WOS:000249187500027 PM 17715297 ER PT J AU Arumugam, TV Tang, SC Lathia, JD Cheng, A Mughal, MR Chigurupati, S Magnus, T Chan, SL Jo, DG Ouyang, X Fairlie, DP Granger, DN Vortmeyer, A Basta, M Mattson, MP AF Arumugam, Thiruma V. Tang, Sung-Chun Lathia, Justin D. Cheng, Aiwu Mughal, Mohamed R. Chigurupati, Srinivasulu Magnus, Tim Chan, Sic L. Jo, Dong-Gyu Ouyang, Xin Fairlie, David P. Granger, Daniel N. Vortmeyer, Alexander Basta, Milan Mattson, Mark P. TI Intravenous immunoglobulin (IVIG) protects the brain against experimental stroke by preventing complement-mediated neuronal cell death SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE C5a; cerebral cortex apoptosis; ischemic stroke; lymphocyte; microglia ID FOCAL CEREBRAL-ISCHEMIA; TISSUE-PLASMINOGEN-ACTIVATOR; HUMAN ALBUMIN; THERAPY; C5A; NEUROPROTECTION; PERFUSION; ADHESION; RECEPTOR; SYSTEM AB Stroke is among the three leading causes of death worldwide and the most frequent cause of permanent disability. Brain ischemia induces an inflammatory response involving activated complement fragments. Here we show that i.v. Ig (IVIG) treatment, which scavenges complement fragments, protects brain cells against the deleterious effects of experimental ischemia and reperfusion (I/R) and prevents I/R-induced mortality in mice. Animals administered IVIG either 30 min before ischemia or after 3 h of reperfusion exhibited a 50-60% reduction of brain infarct size and a 2- to 3-fold improvement of the functional outcome. Even a single low dose of IVIG given after stroke was effective. IVIG was protective in the nonreperfusion model of murine stroke as well and did not exert any peripheral effects. Human IgG as well as intrinsic murine C3 levels were significantly higher in the infarcted brain region compared with the noninjured side, and their physical association was demonstrated by immuno-coprecipitation. C5-deficient mice were significantly protected from I/R injury compared with their wild-type littermates. Exposure of cultured neurons to oxygen/glucose deprivation resulted in increased levels of C3 associated with activation of caspase 3, a marker of apoptosis; both signals were attenuated with IVIG treatment. Our data suggest a major role for complement-mediated cell death in ischemic brain injury and the prospect of using IVIG in relatively low doses as an interventional therapy for stroke. C1 NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. Texas Tech Univ, Hlth Sci Ctr, Dept Pharmaceut Sci, Amarillo, TX 79106 USA. Univ Cent Florida, Biomol Sci Ctr, Orlando, FL 32816 USA. Louisiana State Univ, Hlth Sci Ctr, Dept Cellular & Mol Physiol, Shreveport, LA 71130 USA. Natl Taiwan Univ Hosp, Dept Neurol, Yun Lin Branch, Yunlin 640, Taiwan. Univ Queensland, Inst Mol Biosci, Ctr Drug Design & Dev, Brisbane, Qld 4072, Australia. NINDS, Neuronal Excitabil Sect, NIH, Bethesda, MD 20892 USA. NINDS, Div Neurosurg, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Basta, M (reprint author), Walter Reed Army Inst Res, 503 Robert Grant Ave,Room 1N11, Silver Spring, MD 20910 USA. EM basta.milan@gmaii.com RI Arumugam, Thiruma/C-7969-2009; Arumugam, Thiruma/B-4898-2011; Mattson, Mark/F-6038-2012; Fairlie, David/F-8865-2014; OI Basta, Milan/0000-0001-5958-9241; Tang, Sung-Chun/0000-0003-3731-5973; Fairlie, David/0000-0002-7856-8566 FU NHLBI NIH HHS [HL26441, R01 HL026441] NR 29 TC 100 Z9 104 U1 1 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 28 PY 2007 VL 104 IS 35 BP 14104 EP 14109 DI 10.1073/pnas.0700506104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 206ML UT WOS:000249187500045 PM 17715065 ER PT J AU Izquierdo, A Newman, TK Higley, JD Murray, EA AF Izquierdo, Alicia Newman, Timothy K. Higley, J. Dee Murray, Elisabeth A. TI Genetic modulation of cognitive flexibility and socioemotional behavior in rhesus monkeys SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE aggression; extinction; orbital prefrontal cortex; reversal learning; serotonin ID ORBITAL PREFRONTAL CORTEX; SEROTONIN TRANSPORTER GENE; LINKED POLYMORPHIC REGION; HUMAN AMYGDALA; ORBITOFRONTAL CORTEX; TRYPTOPHAN DEPLETION; EMOTIONAL RESPONSES; DECISION-MAKING; MACAQUE MONKEYS; PROMOTER REGION AB in human and nonhuman primates, structural variants of the gene encoding the serotonin transporter [5-hydroxytryptamine transporter (5-HTT)] affect the transcription and functional efficacy of 5-HTT. Prior work has shown that structural variants differentially affect function of the amygdala and ventromedial prefrontal cortex (VMPFC), regions important for the regulation and expression of emotion. However, relatively little is known about the impact of 5-HTT allelic variants on cognition. To address this question, we tested rhesus monkeys carrying orthologous structural variants of 5-HTT on a battery of tasks that assess cognitive flexibility, reward processing, and emotion. Here we show that rhesus monkeys carrying two copies of the short allele (SS) of the rhesus 5-HTT gene-linked polymorphic region (rh5-HTTLPR) show significantly reduced cognitive flexibility as measured by two tasks in the battery: object discrimination reversal learning and instrumental extinction. Monkeys with the SS genotype also displayed alterations in socioemotional behavior. Genotype variation was not related to visual perceptual abilities, valuation of food rewards, or the ability to express a wide range of defensive responses. Although emotional alterations associated with 5-HTT variation have been described as the primary phenotype, the present study reports differences in at least one type of cognitive flexibility, which has not been described previously. Because behaviors modulated by the 5-HTTLPR are a subset of those dependent on the VMPFC, analysis of structural and functional correlates of gene variation in this region may inform the nature of the genetic modulation of cognition. C1 NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. NIAAA, Lab Clin & Translat Studies, NIH, Poolesville, MD 20837 USA. RP Murray, EA (reprint author), NIMH, Neuropsychol Lab, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. EM murraye@mail.nih.gov OI Murray, Elisabeth/0000-0003-1450-1642 NR 56 TC 48 Z9 48 U1 3 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 AUG 28 PY 2007 VL 104 IS 35 BP 14128 EP 14133 DI 10.1073/pnas.0706583104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 206ML UT WOS:000249187500049 PM 17715054 ER PT J AU Nahin, RL Dahlhamer, JM Taylor, BL Barnes, PM Stussman, BJ Simile, CM Blackman, MR Chesney, MA Jackson, M Miller, H McFann, KK AF Nahin, Richard L. Dahlhamer, James M. Taylor, Beth L. Barnes, Patricia M. Stussman, Barbara J. Simile, Catherine M. Blackman, Marc R. Chesney, Margaret A. Jackson, Morgan Miller, Heather McFann, Kim K. TI Health behaviors and risk factors in those who use complementary and alternative medicine SO BMC PUBLIC HEALTH LA English DT Article ID UNITED-STATES ADULTS; ORTHODOX MEDICINE; LIFE-STYLES; ASSOCIATION; ISSUES AB Background: Surveys have generally found that individuals more likely to use complementary and alternative medicine are female, live in the western United States, are likely to have a health complaint, and have a higher socioeconomic status than do nonusers. What is not known is the extent to which those who use complementary and alternative medicine also engage in positive health behaviors, such as smoking cessation or increased physical activity and/or exhibit fewer health risk factors such as obesity. This has been identified as a key research question in a recent Institute of Medicine report. In the present study we sought to determine whether the use of complementary and alternative medicine is associated with health behaviors or risk factors known to impact on health status. Methods: The current study is a cross-sectional regression analysis using data from the 2002 National Health Interview Survey. Data were collected in-person from 31,044 adults throughout the 50 states and the District of Columbia. Results: After controlling for a range of other factors, we found that engaging in leisure-time physical activity, having consumed alcohol in one's life but not being a current heavy drinker, and being a former smoker are independently associated with the use of CAM. Obese individuals are slightly less likely to use CAM than individuals with a healthy body-mass index. No significant associations were observed between receipt of an influenza vaccine and CAM use. Conclusion: Those engaging in positive health behaviors and exhibiting fewer health risk factors are more likely to use CAM than those who forgo positive health behaviors or exhibit more health risk factors. The fact that users of CAM tend to pursue generally healthy lifestyles suggests that they may be open to additional recommendations toward optimizing their health. C1 Natl Ctr Complementary & Alternat Med, Natl Inst Hlth, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Div Hlth Interview Stat, Hyattsville, MD 20782 USA. Univ Colorado, Denver Hlth Sci Ctr, Barbara Davis Ctr Childhood Diabet, Aurora, CO 80045 USA. RP Nahin, RL (reprint author), Natl Ctr Complementary & Alternat Med, Natl Inst Hlth, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM nahinr@mail.nih.gov; fzd2@cdc.gov; bft8@cdc.gov; plb8@cdc.gov; bjs6@cdc.gov; cus4@cdc.gov; Marc.Blackman@va.gov; chesneym@mail.nih.gov OI Nahin, Richard/0000-0002-3682-4816 NR 28 TC 54 Z9 55 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2458 J9 BMC PUBLIC HEALTH JI BMC Public Health PD AUG 27 PY 2007 VL 7 AR 217 DI 10.1186/1471-2458-7-217 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 225FI UT WOS:000250502100001 PM 17723149 ER PT J AU Liu, Q Pante, N Misteli, T Elsagga, M Crisp, M Hodzic, D Burke, B Roux, KJ AF Liu, Qian Pante, Nelly Misteli, Tom Elsagga, Mohamed Crisp, Melissa Hodzic, Didier Burke, Brian Roux, Kyle J. TI Functional association of Sun1 with nuclear pore complexes SO JOURNAL OF CELL BIOLOGY LA English DT Article ID MEMBRANE-PROTEIN; ACTIN CYTOSKELETON; IN-VIVO; NEUROMUSCULAR-JUNCTION; MAMMALIAN-CELLS; HUMAN-DISEASE; LIVING CELLS; LAMIN-A; ENVELOPE; LOCALIZATION AB Sun1 and 2 are A-type lamin-binding proteins that, in association with nesprins, form a link between the inner nuclear membranes (INMs) and outer nuclear membranes of mammalian nuclear envelopes. Both immunofluorescence and immunoelectron microscopy reveal that Sunl but not Sun2 is intimately associated with nuclear pore complexes (NPCs). Topological analyses indicate that Sunl is a type II integral protein of the INM. Localization of Sun 1 to the INM is defined by at least two discrete regions within its nucleoplasmic domain. However, association with NPCs is dependent on the synergy of both nucleoplasmic and lumenal domains. Cells that are either depleted of Sun1 by RNA interference or that overexpress dominant-negative Sunl fragments exhibit clustering of NPCs. The implication is that Sun 1 represents an important determinant of NPC distribution across the nuclear surface. C1 Univ Florida, Dept Anat & Cell Biol, Gainesville, FL 32610 USA. Univ British Columbia, Dept Zool, Vancouver, BC V6T 1Z4, Canada. NCI, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA. RP Burke, B (reprint author), Univ Florida, Dept Anat & Cell Biol, Gainesville, FL 32610 USA. EM burke@ufl.edu NR 59 TC 101 Z9 103 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD AUG 27 PY 2007 VL 178 IS 5 BP 785 EP 798 DI 10.1083/jcb.200704108 PG 14 WC Cell Biology SC Cell Biology GA 207GY UT WOS:000249240800010 PM 17724119 ER PT J AU Shin, Y Fournier, JH Bruckner, A Madiraju, C Balachandran, R Raccor, BS Edler, MC Hamel, E Sikorski, RP Vogt, A Day, BW Curran, DP AF Shin, Youseung Fournier, Jean-Hugues Bruckner, Arndt Madiraju, Charitha Balachandran, Raghavan Raccor, Brianne S. Edler, Michael C. Hamel, Ernest Sikorski, Rachel P. Vogt, Andreas Day, Billy W. Curran, Dennis P. TI Synthesis and biological evaluation of (-)-dictyostatin and stereoisomers SO TETRAHEDRON LA English DT Article DE microtubule; macrolactone; paclitaxel; discodermolide ID MICROTUBULE-STABILIZING AGENTS; MARINE SPONGE ORIGIN; NATURAL-PRODUCTS; CONFIGURATIONAL ASSIGNMENT; ENANTIOSELECTIVE SYNTHESIS; SIMPLIFIED ANALOGS; SCALE SYNTHESIS; TAXOID SITE; PART 1; TUBULIN AB Total syntheses of (-)-dictyostatin, 6,16-bis-epi-dictyostatin, 6,14,19-tris-epi-dictyostatin, and a number of other isomers and analogs are reported. Three main fragments-top, middle, and bottom-were first assembled and then joined by olefination or anionic addition reactions. After appending the two dienes at either end of the molecule, macrolactonization and deprotection completed the syntheses. The work proves both the relative and absolute configurations of (-)-dictyostatin. The compounds were evaluated by cell-based measurements of increased microtubule mass and antiproliferative activity, and in vitro tubulin polymerization assays as well as competitive assays with paclitaxel for its binding site on microtubules. These assays showed dictyostatin to be the most potent of the agents and further showed that the structural alterations caused from 20-to > 1000-fold decreases in activity. (c) 2007 Elsevier Ltd. All rights reserved. C1 [Shin, Youseung; Fournier, Jean-Hugues; Bruckner, Arndt; Raccor, Brianne S.; Day, Billy W.; Curran, Dennis P.] Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA. [Madiraju, Charitha; Balachandran, Raghavan; Day, Billy W.] Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA 15261 USA. [Sikorski, Rachel P.; Vogt, Andreas] Univ Pittsburgh, Dept Pharmacol, Pittsburgh, PA 15261 USA. [Edler, Michael C.; Hamel, Ernest] NIH, NCI, Div Canc Treatment & Diagnost, Toxicol & Pharmacol Branch,Dev Therapeut Program, Ft Detrick, MD 21702 USA. RP Day, BW (reprint author), Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA. EM bday@pitt.edu; curran@pitt.edu FU NCI NIH HHS [P01 CA078039, P01 CA078039-080005] NR 70 TC 40 Z9 40 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4020 J9 TETRAHEDRON JI Tetrahedron PD AUG 27 PY 2007 VL 63 IS 35 BP 8537 EP 8562 DI 10.1016/j.tet.2007.05.033 PG 26 WC Chemistry, Organic SC Chemistry GA 247PK UT WOS:000252091600020 PM 18728696 ER PT J AU Miguel, V Pezza, RJ Argarana, CE AF Miguel, Virginia Pezza, Roberto J. Argarana, Carlos E. TI The C-terminal region of Escherichia coli MutS and protein oligomerization SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Escherichia coli; mismatch repair; MutS protein; tetramer formation ID DNA MISMATCH REPAIR; TETRAMERIZATION DOMAIN; IN-VIVO; DIMERIZATION; BINDING AB Escherichia coli MutS, an 853 amino acids oligomeric protein, is involved in the postreplicative DNA mismatch repair and avoidance of homeologous recombination. By constructing MutS mutated versions of the C-terminal region, we determined that deletion of the last 7 C-terminal amino acids is enough to abolish tetramer formation and that the K850A substitution destabilize the tetramer structure. It is proposed that the C-terminal extreme alpha helix (residues 839-850) of the protein may play an important role in protein oligomerization. We also show that the C-terminal region or the C-terminal plus the HTH domain of MutS, fused to the monomeric Maltose Binding Protein promote oligomerization of the chimeric protein. However, chemical cross-linking experiments indicate that the HTH domain improves the oligomerization properties of the fused protein. Escherichia coli cells expressing the fused proteins become hypermutator suggesting that the C-terminal region of Mitts plays an important role in vivo. (C) 2007 Elsevier Inc. All rights reserved. C1 Univ Nacl Cordoba, CONICET, Dept Quim Biol, Fac Ciencias Quim,CIQUIBIC, RA-5000 Cordoba, Argentina. NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD 20892 USA. RP Argarana, CE (reprint author), Univ Nacl Cordoba, CONICET, Dept Quim Biol, Fac Ciencias Quim,CIQUIBIC, Ciudad Univ, RA-5000 Cordoba, Argentina. EM carga@mail.fcq.unc.edu.ar NR 17 TC 7 Z9 8 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD AUG 24 PY 2007 VL 360 IS 2 BP 412 EP 417 DI 10.1016/j.bbrc.2007.06.056 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 191VB UT WOS:000248159000019 PM 17599803 ER PT J AU Lee, MY Kim, MA Kim, HJ Bae, YS Park, JI Kwak, JY Chung, JH Yun, J AF Lee, Min-Young Kim, Myoung-Ae Kim, Hyun-Ju Bae, Yoe-Sik Park, Joo-In Kwak, Jong-Young Chung, Jay H. Yun, Jeanho TI Alkylating agent methyl methanesulfonate (MMS) induces a wave of global protein hyperacetylation: Implications in cancer cell death SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE protein acetylation; methyl methanesulfonate; cell death; HDAC inhibitors ID HISTONE ACETYLTRANSFERASE ACTIVITY; DNA-DAMAGE; ACETYLATION; PHOSPHORYLATION; DEACETYLASES; KINASE; PCAF; IDENTIFICATION; BINDING; CBP AB Protein acetylation modification has been implicated in many cellular processes but the direct evidence for the involvement of protein acetylation in signal transduction is very limited. In the present study, we found that an alkylating agent methyl methanesulfonate (MMS) induces a robust and reversible hyperacetylation of both cytoplasmic and nuclear proteins during the early phase of the cellular response to MMS. Notably, the acetylation level upon MMS treatment was strongly correlated with the susceptibility of cancer cells, and the enhancement of MMS-induced acetylation by historic deacetylase (HDAC) inhibitors was shown to increase the cellular susceptibility. These results suggest protein acetylation is important for the cell death signal transduction pathway and indicate that the use of HDAC inhibitors for the treatment of cancer is relevant. (C) 2007 Elsevier Inc. All rights reserved. C1 Dong A Univ, Coll Med, Dept Biochem, Pusan 602714, South Korea. NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP Yun, J (reprint author), Dong A Univ, Coll Med, Dept Biochem, 3-1,Dongdaeshin Dong, Pusan 602714, South Korea. EM yunj@dau.ac.kr NR 23 TC 5 Z9 6 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 AUG 24 PY 2007 VL 360 IS 2 BP 483 EP 489 DI 10.1016/j.bbrc.2007.06.084 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 191VB UT WOS:000248159000032 PM 17603010 ER PT J AU Yamada, KM Cukierman, E AF Yamada, Kenneth M. Cukierman, Edna TI Modeling tissue morphogenesis and cancer in 3D SO CELL LA English DT Review ID EMBRYONIC STEM-CELLS; BRANCHING MORPHOGENESIS; EXTRACELLULAR-MATRIX; BLOOD-VESSELS; BREAST-CANCER; TUMOR-CELLS; IN-VITRO; 3-DIMENSIONAL MATRICES; CULTURE-SYSTEMS; BIOLOGY AB Three-dimensional ( 3D) in vitro models span the gap between two-dimensional cell cultures and whole-animal systems. By mimicking features of the in vivo environment and taking advantage of the same tools used to study cells in traditional cell culture, 3D models provide unique perspectives on the behavior of stem cells, developing tissues and organs, and tumors. These models may help to accelerate translational research in cancer biology and tissue engineering. C1 Natl Inst Hlth, Natl Inst Dental & Craniofacial Res, Lab Cell & Dev Biol, Bethesda, MD 20892 USA. Fox Chase Canc Ctr, Div Basic Sci, Philadelphia, PA 19111 USA. RP Yamada, KM (reprint author), Natl Inst Hlth, Natl Inst Dental & Craniofacial Res, Lab Cell & Dev Biol, Bethesda, MD 20892 USA. EM kenneth.yamada@nih.gov OI Yamada, Kenneth/0000-0003-1512-6805 FU Intramural NIH HHS NR 80 TC 736 Z9 758 U1 29 U2 252 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD AUG 24 PY 2007 VL 130 IS 4 BP 601 EP 610 DI 10.1016/j.cell.2007.08.006 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 208KY UT WOS:000249319400012 PM 17719539 ER PT J AU Chen, FH Herndon, ME Patel, N Hecht, JT Tuan, RS Lawler, J AF Chen, Faye Hui Herndon, Mary E. Patel, Nichlesh Hecht, Jacqueline T. Tuan, Rocky S. Lawler, Jack TI Interaction of cartilage oligomeric matrix protein/thrombospondin 5 with aggrecan SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MULTIPLE EPIPHYSEAL DYSPLASIA; ARTICULAR-CARTILAGE; PSEUDOACHONDROPLASIA; COMP; BINDING; MUTATIONS; AFFINITY; COLLAGEN; CALCIUM; TENDON AB Cartilage oligomeric matrix protein/thrombospondin 5 (COMP/TSP5) is a major component of the extracellular matrix (ECM) of the musculoskeletal system. Its importance is underscored by its association with several growth disorders. In this report, we investigated its interaction with aggrecan, a major component of cartilage ECM. We also tested a COMP/TSP5 mutant, designated MUT3 that accounts for 30% of human pseudoachon-droplasia cases, to determine if the mutation affects function. Using a solid-phase binding assay, we have shown that COMP/TSP5 can bind aggrecan. This binding was decreased with MUT3, or when COMP/TSP5 was treated with EDTA, indicating the presence of a conformation-dependent aggrecan binding site. Soluble glycosaminoglycans (GAGs) partially inhibited binding, suggesting that the interaction was mediated in part through aggrecan GAG side chains. Using affinity co-electrophoresis, we showed that COMP/TSP5, in its calcium-replete conformation, bound to heparin, chondroitin sulfates, and heparan sulfate; this binding was reduced with EDTA treatment of COMP/TSP5. MUT3 showed weaker binding than calcium-repleted COMP/TSP5. Using recombinant COMP/TSP5 fragments, we found that the "signature domain" could bind to aggrecan, suggesting that this domain can mediate the interaction of COMP/TSP5 and aggrecan. In summary, our data indicate that COMP/TSP5 is an aggrecan-binding protein, and this interaction is regulated by the calcium-sensitive conformation of COMP/TSP5; interaction of COMP with aggrecan can be mediated through the GAG side chains on aggrecan and the "signature domain" of COMP/TSP5. Our results suggest that COMP/TSP5 may function to support matrix interactions in cartilage ECM. C1 NIAMS, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. Columbia Univ, Dept Orthopaed Surg, New York, NY 10032 USA. Beth Israel Deaconess Med Ctr, Dept Pathol, Div Tumor Biol & Angiogenesis, Boston, MA 02215 USA. Harvard Univ, Sch Med, Boston, MA 02215 USA. Univ Texas, Sch Med, Dept Pediat, Houston, TX 77225 USA. Shriners Hosp Children, Houston, TX 77225 USA. RP Chen, FH (reprint author), NIAMS, Cartilage Biol & Orthopaed Branch, NIH, Bethesda, MD 20892 USA. EM chenf1@mail.nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [HL49081, R01 HL049081, R01 HL049081-10] NR 40 TC 68 Z9 72 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 AUG 24 PY 2007 VL 282 IS 34 BP 24591 EP 24598 DI 10.1074/jbc.M611390200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 202VU UT WOS:000248933000013 PM 17588949 ER PT J AU Frank, EG Woodgate, R AF Frank, Ekaterina G. Woodgate, Roger TI Increased catalytic activity and altered fidelity of human DNA polymerase iota in the presence of manganese SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID UV-INDUCED LESIONS; IN-VITRO; NUCLEOTIDE INCORPORATION; DEPENDENT REPLICATION; TRANSLESION SYNTHESIS; ESCHERICHIA-COLI; METAL-IONS; POL-IOTA; BYPASS; ETA AB All DNA polymerases require a divalent cation for catalytic activity. It is generally assumed that Mg2+ is the physiological cofactor for replicative DNA polymerases in vivo. However, recent studies suggest that certain repair polymerases, such as pol lambda, may preferentially utilize Mn2+ in vitro. Here we report on the effects of Mn2+ and Mg2+ on the enzymatic properties of human DNA polymerase iota (pol iota). pol iota exhibited the greatest activity in the presence of low levels of Mn2+ (0.05-0.25 mM). Peak activity in the presence of Mg2+ was observed in the range of 0.1-0.5 mM and was significantly reduced at concentrations > 2 mM. Steady-state kinetic analyses revealed that Mn2+ increases the catalytic activity of pol iota by similar to 30-60,000-fold through a dramatic decrease in the Km value for nucleotide incorporation. Interestingly, whereas pol iota preferentially misinserts G opposite T by a factor of similar to 1.4-2.5-fold over the correct base A in the presence of 0.25 and 5 mM Mg2+, respectively, the correct insertion of A is actually favored 2-fold over the misincorporation of G in the presence of 0.075 mM Mn2+. Low levels of Mn2+ also dramatically increased the ability of pol iota to traverse a variety of DNA lesions in vitro. Titration experiments revealed a strong preference of pol iota for Mn2+ even when Mg2+ is present in a > 10-fold excess. Our observations therefore raise the intriguing possibility that the cation utilized by pol iota in vivo may actually be Mn2+ rather than Mg2+, as tacitly assumed. C1 NICHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. RP Woodgate, R (reprint author), NICHD, Lab Genom Integr, NIH, Bldg 6,Rm 1A13,9000 Rockville Pike, Bethesda, MD 20892 USA. EM woodgate@nih.gov FU Intramural NIH HHS NR 48 TC 59 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 AUG 24 PY 2007 VL 282 IS 34 BP 24689 EP 24696 DI 10.1074/jbc.M702159200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 202VU UT WOS:000248933000024 PM 17609217 ER PT J AU Boyer, PL Julias, JG Ambrose, Z Siddiqui, MA MarqueZ, VE Hughes, SH AF Boyer, Paul L. Julias, John G. Ambrose, Zandrea Siddiqui, Maqbool A. MarqueZ, Victor E. Hughes, Stephen H. TI The nucleoside analogs 4 ' C-Methyl thymidine and 4 ' C-Ethyl thymidine block DNA synthesis by wild-type HIV-1 RT and excision proficient NRTI resistant RT variants SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE HIV-1; reverse transcriptase; nucleoside analogs; drug resistance ID IMMUNODEFICIENCY-VIRUS TYPE-1; HERPES-SIMPLEX VIRUS; DOUBLE-STRANDED DNA; REVERSE-TRANSCRIPTASE; MULTIFUNCTIONAL ENZYME; ANGSTROM RESOLUTION; SELECTIVE EXCISION; THYMIDYLATE KINASE; AZTMP AB HIV-1 can become resistant to nucleoside analogs by developing an enhanced ability to excise the analogs after they have been incorporated. Excision requires that the analog be located at the 3' terminus of the primer. We have describe nucleoside analogs that do not block DNA synthesis at the point of incorporation, but only after additional dNTPs have been added to the DNA. These nucleoside analogs are called "delayed chain terminators" and are relatively effective inhibitors of drug-resistant HIV-1 reverse transcriptases (RTs) that are excision proficient. However, the first delayed chain terminator that we characterized was poorly phosphorylated in cultured cells. We have examined other nucleoside analogs to determine whether these compounds also act as delayed chain terminators, but were more efficiently converted to the triphosphate form by cellular kinases. These analogs contain substitutions on the deoxyribose sugar ring at the 4' carbon (4'C-methyl dT and 4'C-ethyl dT). Unlike true delayed chain terminators, which terminate DNA synthesis in a spatial sense (DNA synthesis is halted only after additional dNTPs have been incorporated after the analog), 4'C-methyl dTTP causes a pause in DNA synthesis at the point of incorporation. However, HIV-1 RT can eventually extend the primer blocked by the 4' C-Me dTMP analog. 4'C-methyl dTTP blocks DNA synthesis in a temporal sense, rather than in a spatial sense. A primer blocked by 4'C-ethyl dTMP is not extended by HIV-1 RT, and this compound acts like a conventional chain terminator, despite the presence of a 3'-OH group. These compounds effectively block the replication of an HIV-1-based vector that replicates using wild-type HIV-1 RT, but only in the presence of herpes simplex virus thymidine kinase (HSV TK). These compounds are effective against many NRTI drug-resistant RT variants; however, the M184V mutant is relatively resistant. Published by Elsevier Ltd. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. SAIC Frederick, Frederick, MD 21702 USA. NIH, NCI Frederick, Canc Res Ctr, Med Chem Lab, Frederick, MD 21702 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM hughes@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 20 TC 17 Z9 17 U1 0 U2 1 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD AUG 24 PY 2007 VL 371 IS 4 BP 873 EP 882 DI 10.1016/j.jmb.2007.05.043 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 201CL UT WOS:000248809000003 PM 17597154 ER PT J AU Morningstar, ML Roth, T Farnsworth, DW Smith, MK Watson, K Buckheit, RW Das, K Zhang, WY Arnold, E Julias, JG Hughes, SH Michejda, CJ AF Morningstar, Marshall L. Roth, Thomas Farnsworth, David W. Smith, Marilyn Kroeger Watson, Karen Buckheit, Robert W., Jr. Das, Kalyan Zhang, Wanyi Arnold, Eddy Julias, John G. Hughes, Stephen H. Michejda, Christopher J. TI Synthesis, biological activity, and crystal structure of potent nonnucleoside inhibitors of HIV-1 reverse transcriptase that retain activity against mutant forms of the enzyme SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID POSITIONAL ADAPTABILITY; HIGHLY POTENT; WILD-TYPE; DRUG; THIAZOLOBENZIMIDAZOLE; REPLICATION; DERIVATIVES; DISCOVERY; INVITRO; BINDING AB In an ongoing effort to develop novel and potent nonnucleoside HIV-1 reverse transcriptase (RT) inhibitors that are effective against the wild type (WT) virus and clinically observed mutants, 1,2-bis-substituted benzimidazoles were synthesized and tested. Optimization of the N1 and C2 positions of benzimidazole led to the development of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimidazole (1) (IC50 = 0.2 mu M, EC50 = 0.44 mu M, and TC50 >= 100 against WT). This paper describes how substitution on the benzimidazole ring profoundly affects activity. Substituents at the benzimidazole C4 dramatically enhanced potency, while at C5 or C6 substituents were generally detrimental or neutral to activity, respectively. A 7-methyl analogue did not inhibit HIV-1 RT. Determination of the crystal structure of 1 bound to RT provided the basis for accurate modeling of additional analogues, which were synthesized and tested. Several derivatives were nanomolar inhibitors of wild-type virus and were effective against clinically relevant HIV-1 mutants. C1 NCI, Mol Aspects Drug Design Sect, Frederick, MD 21702 USA. NCI, Retroviral Replicat Lab, Frederick, MD 21702 USA. McDaniel Coll, Westminster, MD 21157 USA. So Res Inst, Frederick Res Ctr, Frederick, MD 21701 USA. Rutgers State Univ, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. Rutgers State Univ, Dept Chem & Chem Biol, Piscataway, NJ 08854 USA. RP Farnsworth, DW (reprint author), NCI, Mol Aspects Drug Design Sect, POB B, Frederick, MD 21702 USA. EM farnswor@ncifcrf.gov FU Intramural NIH HHS; NIAID NIH HHS [AI 27690, R37 AI027690, R37 AI027690-18]; NIGMS NIH HHS [P01 GM 56671, P01 GM066671, P01 GM066671-04] NR 24 TC 60 Z9 63 U1 1 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD AUG 23 PY 2007 VL 50 IS 17 BP 4003 EP 4015 DI 10.1021/jm060103d PG 13 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 200JB UT WOS:000248758600006 PM 17663538 ER PT J AU Grundt, P Prevatt, KM Cao, JJ Taylor, M Floresca, CZ Choi, JK Jenkins, BG Luedtke, RR Newman, AH AF Grundt, Peter Prevatt, Katherine M. Cao, Jianjing Taylor, Michelle Floresca, Christina Z. Choi, Ji-Kyung Jenkins, Bruce G. Luedtke, Robert R. Newman, Amy Hauck TI Heterocyclic analogues of N-(4-(4-(2,3-Dichlorophenyl)piperazin-1-yl)butyl)arylcarboxamides with functionalized linking chains as novel dopamine D3 receptor ligands: Potential substance abuse therapeutic agents SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID D-3 RECEPTOR; PARTIAL AGONISTS; DRUG-ABUSE; ANTAGONISTS; DISCOVERY; BINDING; DESIGN; PET; PERMEABILITY; RADIOTRACER AB Dopamine D3 receptor antagonists and partial agonists have been shown to modulate drug-seeking effects induced by cocaine and other abused substances. Compound 6 [PG01037, (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)-trans-but-2-enyl)-4-pyridine-2-ylbenzamide)] and related analogues are currently being evaluated in animal models of drug addiction. In these studies, a discrepancy between in vitro binding affinity, in vivo occupancy, and behavioral potency has been observed. The purpose of this study was to examine (1) modifications of the 2-pyridylphenyl moiety of 6 and (2) hydroxyl, acetyl, and cyclopropyl substitutions on the butylamide linking chain systematically coupled with 2-fluorenylamide or 2-pyridylphenylamide and 2-methoxy- or 2,3-dichloro-substituted phenylpiperazines to measure the impact on binding affinity, D2/D3 selectivity, lipophilicity, and function. In general, these modifications were well tolerated at the human dopamine D3 (hD3) receptor (K-i = 1-5 nM) as measured in competition binding assays. Several analogues showed > 100-fold selectivity for dopamine D3 over D2 and D4 receptors. In addition, while all the derivatives with an olefinic linker were antagonists, in quinpirole-stimulated mitogenesis at hD3 receptors, several of the hydroxybutyl-linked analogues (16, 17, 21) showed partial agonist activity. Finally, several structural modifications reduced lipophilicities while retaining the desired binding profile. C1 Natl Inst Drug Abuse, Natl Inst Hlth, Intramural Res Program, Med Chem Sect, Baltimore, MD 21224 USA. Univ N Texas, Hlth Sci Ctr, Dept Pharmacol & Neurosci, Ft Worth, TX 76107 USA. Massachusetts Gen Hosp, NMR Ctr, Boston, MA 02129 USA. Harvard Univ, Sch Med, Boston, MA 02129 USA. RP Newman, AH (reprint author), Natl Inst Drug Abuse, Natl Inst Hlth, Intramural Res Program, Med Chem Sect, Baltimore, MD 21224 USA. EM anewman@intra.nida.ni.gov FU Intramural NIH HHS; NIDA NIH HHS [DA13584-01, DA13584-03S1, R01 DA016187] NR 45 TC 66 Z9 67 U1 1 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 AUG 23 PY 2007 VL 50 IS 17 BP 4135 EP 4146 DI 10.1021/jm0704200 PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 200JB UT WOS:000248758600018 PM 17672446 ER PT J AU Welch, JM Lu, J Rodriguiz, RM Trotta, NC Peca, J Ding, JD Feliciano, C Chen, M Adams, JP Luo, JH Dudek, SM Weinberg, RJ Calakos, N Wetsel, WC Feng, GP AF Welch, Jeffrey M. Lu, Jing Rodriguiz, Ramona M. Trotta, Nicholas C. Peca, Joao Ding, Jin-Dong Feliciano, Catia Chen, Meng Adams, J. Paige Luo, Jianhong Dudek, Serena M. Weinberg, Richard J. Calakos, Nicole Wetsel, William C. Feng, Guoping TI Cortico-striatal synaptic defects and OCD-like behaviours in Sapap3-mutant mice SO NATURE LA English DT Article ID OBSESSIVE-COMPULSIVE DISORDER; NMDA-RECEPTORS; HIPPOCAMPAL SYNAPSES; POSTSYNAPTIC DENSITY; SUBUNIT COMPOSITION; NERVOUS-SYSTEM; DISEASE MODELS; MESSENGER-RNA; PROTEINS; TRAFFICKING AB Obsessive-compulsive disorder (OCD) is an anxiety-spectrum disorder characterized by persistent intrusive thoughts (obsessions) and repetitive actions (compulsions). Dysfunction of cortico-striato-thalamo-cortical circuitry is implicated in OCD, although the underlying pathogenic mechanisms are unknown. SAP90/PSD95-associated protein 3 (SAPAP3; also known as DLGAP3) is a postsynaptic scaffolding protein at excitatory synapses that is highly expressed in the striatum. Here we show that mice with genetic deletion of Sapap3 exhibit increased anxiety and compulsive grooming behaviour leading to facial hair loss and skin lesions; both behaviours are alleviated by a selective serotonin reuptake inhibitor. Electrophysiological, structural and biochemical studies of Sapap3-mutant mice reveal defects in cortico-striatal synapses. Furthermore, lentiviral-mediated selective expression of Sapap3 in the striatum rescues the synaptic and behavioural defects of Sapap3-mutant mice. These findings demonstrate a critical role for SAPAP3 at cortico-striatal synapses and emphasize the importance of cortico-striatal circuitry in OCD-like behaviours. C1 Duke Univ, Med Ctr, Dept Neurobiol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Cell Biol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Neurobiol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Mouse Behav & Neuroendocrine Anal Core Facil, Durham, NC 27710 USA. Duke Univ, Med Ctr, Ctr Translat Neurosci, Div Neurol, Durham, NC 27710 USA. Zhejiang Univ, Sch Med, Dept Neurobiol, Hangzhou 310058, Zhejiang, Peoples R China. Univ Coimbra, Ctr Neurosci & Cell Biol, P-3004517 Coimbra, Portugal. Univ N Carolina, Ctr Neurosci, Dept Cell & Dev Biol, Chapel Hill, NC 27599 USA. Gulbenkian Inst Sci, P-2781901 Oeiras, Portugal. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Feng, GP (reprint author), Duke Univ, Med Ctr, Dept Neurobiol, Durham, NC 27710 USA. EM feng@neuro.duke.edu RI Ding, Jindong/B-3324-2008; Peca, Joao/K-7900-2013; OI Ding, Jindong/0000-0003-0427-0369; Peca, Joao/0000-0003-4989-2129; Weinberg, Richard/0000-0001-9689-7278; Feliciano, Catia/0000-0001-7545-6924; Dudek, Serena M./0000-0003-4094-8368 FU Intramural NIH HHS [Z01 ES100221-06]; NIMH NIH HHS [R01 MH081201, R01 MH081201-01]; NINDS NIH HHS [K02 NS054840, K02 NS054840-02, R01 NS039444, R01 NS039444-06] NR 50 TC 295 Z9 305 U1 3 U2 53 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 23 PY 2007 VL 448 IS 7156 BP 894 EP U2 DI 10.1038/nature06104 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 202OM UT WOS:000248912900040 PM 17713528 ER PT J AU Roma, PG Chen, SA Barr, CS Riley, AL AF Roma, Peter G. Chen, Scott A. Barr, Christina S. Riley, Anthony L. TI Dissociation between the aversive and pharmacokinetic effects of ethanol in female Fischer and Lewis rats SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE Fischer; Lewis; alcohol; female; conditioned taste aversion; blood alcohol; sex differences ID CONDITIONED TASTE-AVERSIONS; TRANSPORTER GENE VARIATION; 12-MONTH PREVALENCE; ALCOHOL PREFERENCE; RATTUS-NORVEGICUS; NUCLEUS-ACCUMBENS; SEX-DIFFERENCES; SPRAGUE-DAWLEY; UNITED-STATES; BODY-WEIGHT AB In humans and laboratory animal models, vulnerability to alcohol abuse is influenced by endogenous factors such as genotype. Using the inbred Fischer and Lewis rat strains, we previously reported stronger conditioned taste aversions (CTA) in male Fischer rats that could not be predicted by genotypic differences in alcohol absorption [Roma PG, Flint WW, Higley JD, Riley AL. Assessment of the aversive and rewarding effects of alcohol in Fischer and Lewis rat. Psychopharmacology (Berl) 2006; 189:187-99]. The present study made similar assessments in Fischer and Lewis females via four-trial CTA induced by 1 or 1.5 g/kg intraperitoneal (IP) ethanol (n = 10-12/strain/dose) as well as measures of blood alcohol concentrations (BAC) at 15, 60 and 180 min post-injection with 1.5 g/kg IP ethanol or saline (n = 7-8/strain/dose). Dose-dependent CTAs were produced. but the strains did not differ from each other in these measures, however, BACs in the Lewis females were significantly higher than Fischer at all three time points. As with males of the Fischer and Lewis genotypes, a dissociation between BACs and the aversive effects of alcohol was observed. These data are the first assessments of these particular phenotypes in Fischer and Lewis females, and when considered with the historical data, suggest a Genotype x Sex interaction in the centrally mediated sensitivity to alcohol's aversive effects. (c) 2007 Elsevier B. V. All rights reserved. C1 American Univ, Dept Psychol, Psychopharmacol Lab, Washington, DC 20016 USA. Natl Inst Alcohol Abuse & Alcoholism, Sect Primate Studies, Lab Clin & Translat Studies, Poolesville, MD USA. RP Roma, PG (reprint author), American Univ, Dept Psychol, Psychopharmacol Lab, 4400 Massachusetts Ave,NW, Washington, DC 20016 USA. EM PeteRoma@gmail.com FU Intramural NIH HHS [Z99 HD999999] NR 42 TC 9 Z9 9 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 EI 1872-7549 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD AUG 22 PY 2007 VL 182 IS 1 BP 51 EP 56 DI 10.1016/j.bbr.2007.05.012 PG 6 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 196XX UT WOS:000248517800007 PM 17568694 ER PT J AU Clark, JL Caceres, CF Lescano, AG Konda, KA Leon, SR Jones, FR Kegeles, SM Klausner, JD Coates, TJ AF Clark, Jesse L. Caceres, Carlos F. Lescano, Andres G. Konda, Kelika A. Leon, Segundo R. Jones, Franca R. Kegeles, Susan M. Klausner, Jeffrey D. Coates, Thomas J. CA NIMH STD HIV Collaborative Prevent TI Prevalence of Same-Sex Sexual Behavior and Associated Characteristics among Low-Income Urban Males in Peru SO PLOS ONE LA English DT Article AB Background. Peru has a concentrated HIV epidemic in which men who have sex with men are particularly vulnerable. We describe the lifetime prevalence of same-sex sexual contact and associated risk behaviors of men in Peru's general population, regardless of their sexual identity. Methods and Results. A probability sample of males from low-income households in three Peruvian cities completed an epidemiologic survey addressing their sexual risk behavior, including sex with other men. Serum was tested for HSV-2, HIV, and syphilis. Urine was tested for chlamydia and gonorrhea. A total of 2,271 18-30 year old men and women were contacted, of whom 1,645 (72.4%) agreed to participate in the study. Among the sexually experienced men surveyed, 15.2% (85/558, 95% CI: 12.2%-18.2%) reported a history of sex with other men. Men ever reporting sex with men (MESM) had a lower educational level, had greater numbers of sex partners, and were more likely to engage in risk behaviors including unprotected sex with casual partners, paying for or providing compensated sex, and using illegal drugs. MESM were also more likely to have had previous STI symptoms or a prior STI diagnosis, and had a greater prevalence of HSV-2 seropositivity. Conclusions. Many low-income Peruvian men have engaged in same-sex sexual contact and maintain greater behavioral and biological risk factors for HIV/STI transmission than non-MESM. Improved surveillance strategies for HIV and STIs among MESM are necessary to better understand the epidemiology of HIV in Latin America and to prevent its further spread. C1 [Clark, Jesse L.; Konda, Kelika A.; Coates, Thomas J.] Univ Calif Los Angeles, David Geffen Sch Med, Div Infect Dis, Los Angeles, CA 90095 USA. [Caceres, Carlos F.; Leon, Segundo R.] Univ Peruana Cayetano Heredia, Unidad Salud Sexualidad & Desarrollo Humano, Lima, Peru. [Lescano, Andres G.] USN, Med Ctr Res Detachment, Lima, Peru. [Jones, Franca R.] USN, Med Res Ctr, Biol Def Res Directorate, Silver Spring, MD USA. [Kegeles, Susan M.] Univ Calif San Francisco, Ctr AIDS Prevent Studies, San Francisco, CA 94143 USA. [Klausner, Jeffrey D.] San Francisco Dept Publ Hlth, San Francisco, CA USA. [NIMH STD HIV Collaborative Prevent] NIMH, Multisite Int Grp, Bethesda, MD 20892 USA. RP Clark, JL (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Div Infect Dis, Los Angeles, CA 90095 USA. EM jlclark@mednet.ucla.edu RI Lescano, Andres/B-8479-2008; OI Lescano, Andres/0000-0001-9779-633X; Caceres, Carlos/0000-0002-8101-0790 FU NIH/NIMH [U10 MH61536]; LP-CRADA [NM-04-1787] FX This study was funded by NIH/NIMH grant number U10 MH61536 which is a five-country Cooperative Agreement being conducted in China, India, Peru, Russia, and Zimbabwe. Each site has selected a different venue and population with which to implement the prevention program entitled Community Public Opinion Leader (C-POL) Intervention. This article is based on a pre-baseline study conducted in all the sites to prepare for initiation of the intervention. This study was partially supported by LP-CRADA NM-04-1787. The supporting institutions supervised design and execution of the study, including data collection, and approved the final version of the manuscript. NR 45 TC 18 Z9 18 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 AUG 22 PY 2007 VL 2 IS 8 AR e778 DI 10.1371/journal.pone.0000778 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10HO UT WOS:000207455300026 PM 17712426 ER PT J AU Kamradt, J Jung, V Wahrheit, K Tolosi, L Rahnenfuehrer, J Schilling, M Walker, R Davis, S Stoeckle, M Meltzer, P Wullich, B AF Kamradt, Joern Jung, Volker Wahrheit, Kerstin Tolosi, Laura Rahnenfuehrer, Joerg Schilling, Martin Walker, Robert Davis, Sean Stoeckle, Michael Meltzer, Paul Wullich, Bernd TI Detection of Novel Amplicons in Prostate Cancer by Comprehensive Genomic Profiling of Prostate Cancer Cell Lines Using Oligonucleotide-Based ArrayCGH SO PLOS ONE LA English DT Article AB Background. The purpose of this study was to prove the feasibility of a longmer oligonucleotide microarray platform to profile gene copy number alterations in prostate cancer cell lines and to quickly indicate novel candidate genes, which may play a role in carcinogenesis. Methods/Results and Findings. Genome-wide screening for regions of genetic gains and losses on nine prostate cancer cell lines (PC3, DU145, LNCaP, CWR22, and derived sublines) was carried out using comparative genomic hybridization on a 35,000 feature oligonucleotide microarray (arrayCGH). Compared to conventional chromosomal CGH, more deletions and small regions of gains, particularly in pericentromeric regions and regions next to the telomeres, were detected. As validation of the high-resolution of arrayCGH we further analyzed a small amplicon of 1.7 MB at 9p13.3, which was found in CWR22 and CWR22-Rv1. Increased copy number was confirmed by fluorescence in situ hybridization using the BAC clone RP11-165H19 from the amplified region comprising the two genes interleukin 11 receptor alpha (IL11-RA) and dynactin 3 (DCTN3). Using quantitative real time PCR (qPCR) we could demonstrate that IL11-RA is the gene with the highest copy number gain in the cell lines compared to DCTN3 suggesting IL11-RA to be the amplification target. Screening of 20 primary prostate carcinomas by qPCR revealed an IL11-RA copy number gain in 75% of the tumors analyzed. Gain of DCTN3 was only found in two cases together with a gain of IL11-RA. Conclusions/Significance. ArrayCGH using longmer oligonucleotide microarrays is feasible for high-resolution analysis of chomosomal imbalances. Characterization of a small gained region at 9p13.3 in prostate cancer cell lines and primary prostate cancer samples by fluorescence in situ hybridization and quantitative PCR has revealed interleukin 11 receptor alpha gene as a candidate target of amplification with an amplification frequency of 75% in prostate carcinomas. Frequent amplification of IL11-RA in prostate cancer is a potential mechanism of IL11-RA overexpression in this tumor type. C1 [Kamradt, Joern; Jung, Volker; Wahrheit, Kerstin; Stoeckle, Michael; Wullich, Bernd] Univ Saarland, Dept Urol & Pediat Urol, D-6650 Homburg, Germany. [Tolosi, Laura] Max Planck Inst Informat, Dept Computat Biol & Appl Algorithm, Saarbrucken, Germany. [Rahnenfuehrer, Joerg] Univ Dortmund, Stat Methoden Genet & Chemometrie Fachbereich Sta, Dortmund, Germany. [Schilling, Martin] Univ Saarland, Dept Gen Visceral Vasc & Pediat Surg, D-6650 Homburg, Germany. [Walker, Robert; Davis, Sean; Meltzer, Paul] NCI, Genet Lab, NIH, Bethesda, MD 20892 USA. RP Kamradt, J (reprint author), Univ Saarland, Dept Urol & Pediat Urol, D-6650 Homburg, Germany. EM joern.kamradt@uks.eu OI Davis, Sean/0000-0002-8991-6458 FU Deutsche Forschungsgemeinschaft [KA1793/1-1]; Bundesministerium fur Bildung und Forschung [01GR0453]; BioSapiens Network of Excellence; EU [LSHG-CT-2003-503265] FX Deutsche Forschungsgemeinschaft, grant number KA1793/1-1, Bundesministerium fur Bildung und Forschung, grant number 01GR0453, BioSapiens Network of Excellence, EU contract number LSHG-CT-2003-503265 NR 33 TC 9 Z9 10 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 22 PY 2007 VL 2 IS 8 AR e769 DI 10.1371/journal.pone.0000769 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10HO UT WOS:000207455300017 PM 17712417 ER PT J AU Mirambeau, G Lyonnais, S Coulaud, D Hameau, L Lafosse, S Jeusset, J Borde, I Reboud-Ravaux, M Restle, T Gorelick, RJ Le Cam, E AF Mirambeau, Gilles Lyonnais, Sebastien Coulaud, Dominique Hameau, Laurence Lafosse, Sophie Jeusset, Josette Borde, Isabelle Reboud-Ravaux, Michele Restle, Tobias Gorelick, Robert J. Le Cam, Eric TI HIV-1 Protease and Reverse Transcriptase Control the Architecture of Their Nucleocapsid Partner SO PLOS ONE LA English DT Article AB The HIV-1 nucleocapsid is formed during protease (PR)-directed viral maturation, and is transformed into pre-integration complexes following reverse transcription in the cytoplasm of the infected cell. Here, we report a detailed transmission electron microscopy analysis of the impact of HIV-1 PR and reverse transcriptase (RT) on nucleocapsid plasticity, using in vitro reconstitutions. After binding to nucleic acids, NCp15, a proteolytic intermediate of nucleocapsid protein (NC), was processed at its C-terminus by PR, yielding premature NC (NCp9) followed by mature NC (NCp7), through the consecutive removal of p6 and p1. This allowed NC co-aggregation with its single-stranded nucleic-acid substrate. Examination of these co-aggregates for the ability of RT to catalyse reverse transcription showed an effective synthesis of double-stranded DNA that, remarkably, escaped from the aggregates more efficiently with NCp7 than with NCp9. These data offer a compelling explanation for results from previous virological studies that focused on i) Gag processing leading to nucleocapsid condensation, and ii) the disappearance of NCp7 from the HIV-1 pre-integration complexes. We propose that HIV-1 PR and RT, by controlling the nucleocapsid architecture during the steps of condensation and dismantling, engage in a successive nucleoprotein-remodelling process that spatiotemporally coordinates the pre-integration steps of HIV-1. Finally we suggest that nucleoprotein remodelling mechanisms are common features developed by mobile genetic elements to ensure successful replication. C1 [Mirambeau, Gilles; Lyonnais, Sebastien; Coulaud, Dominique; Hameau, Laurence; Lafosse, Sophie; Jeusset, Josette; Le Cam, Eric] Univ Paris 11, Inst Cancerol Gustave Roussy, CNRS, UMR Interact Mol & Canc 8126,Lab Microscopie Mol, Villejuif, France. [Mirambeau, Gilles] Univ Paris 06, Div Biochim, UFR Sci Vie, Paris, France. [Borde, Isabelle] Univ Paris 06, Lab Biol & Multimedia, Paris, France. [Reboud-Ravaux, Michele] Univ Paris 06, CNRS, Inst Jacques Monod, Lab Enzymol Mol & Fonct,FRE 2852, Paris, France. [Restle, Tobias] Univ Klinikum Schleswig Holstein, Inst Mol Med, D-23538 Lubeck, Germany. [Restle, Tobias] ZMSB, Lubeck, Germany. [Gorelick, Robert J.] NCI, AIDS Vaccine Program, Basic Res Program, Sci Applicat Int Corp Frederick, Frederick, MD 21701 USA. RP Mirambeau, G (reprint author), Univ Paris 11, Inst Cancerol Gustave Roussy, CNRS, UMR Interact Mol & Canc 8126,Lab Microscopie Mol, Villejuif, France. EM gilles.mirambeau@free.fr; elecam@igr.fr OI Lyonnais, Sebastien/0000-0002-3154-8568 FU ANRS; EC [LSHG-CT-2003-503480]; National Cancer Institute, National Institutes of Health [N01-CO-12400] FX SL and LH were supported by fellowships from Agence Nationale de Recherches sur le SIDA (ANRS). This work was supported by grants from ANRS (GM and EL), by EC-grant LSHG-CT-2003-503480 (TR) and with federal funds from the National Cancer Institute, National Institutes of Health, under contract N01-CO-12400 (RG). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government. NR 67 TC 33 Z9 33 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD AUG 22 PY 2007 VL 2 IS 8 AR e669 DI 10.1371/journal.pone.0000669 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10HO UT WOS:000207455300001 PM 17712401 ER PT J AU Gahl, WA Balog, JZ Kleta, R AF Gahl, William A. Balog, Joan Z. Kleta, Robert TI Nephropathic cystinosis in adults: Natural history and effects of oral cysteamine therapy SO ANNALS OF INTERNAL MEDICINE LA English DT Article ID LEUKOCYTE GRANULAR FRACTIONS; SWALLOWING DYSFUNCTION; CORNEAL CRYSTALS; PUBERTAL CHANGES; CTNS MUTATIONS; TRANSPORT; GENE; MANIFESTATIONS; INSUFFICIENCY; HYPERTENSION AB Background: The full burden of nephropathic cystinosis in adulthood and the effects of long-term oral cysteamine therapy on its nonrenal complications have not been elucidated. Objective: To assess the severity of cystinosis in adults receiving and not receiving oral cysteamine therapy. Design: Case series. Setting: National Institutes of Health Clinical Center. Patients: 100 persons (58 men and 42 women) age 18 to 45 years with nephropathic cystinosis examined between January 1985 and May 2006. Measurements: Historical data were collected on renal transplantation, administration of oral cysteamine, and time and cause of death. Patients were evaluated for height and weight; thyroid, pulmonary, and swallowing function; muscle atrophy; hypogonadism (in men); retinopathy; vascular and cerebral calcifications; diabetes mellitus; and homozygosity for the common 57-kb deletion in CTNS. Laboratory studies were also performed. Results: Of 100 adults with nephropathic cystinosis, 92 had received a renal allograft and 33 had died. At least half of the patients had hypothyroidism, hypergonadotropic hypogonadism (in men), pulmonary insufficiency, swallowing abnormalities, or myopathy. One third of the patients had retinopathy or vascular calcifications, and 24% had diabetes. Homozygosity for the 57-kb CTNS deletion was associated with an increased risk for death and morbidity. The 39 patients who received long-term ( >= 8 years) oral cysteamine therapy were taller and heavier, had a renal allograft later in life, had lower cholesterol levels, and experienced fewer complications and deaths than patients who received cysteamine for fewer than 8 years. The frequency of diabetes mellitus, myopathy, pulmonary dysfunction, hypothyroidism, and death increased as time off cysteamine treatment increased, and it decreased as time on cysteamine therapy increased. Limitations: The study was retrospective and not randomized. The criteria used to measure adequacy of treatment were arbitrary. Conclusions: Untreated nephropathic cystinosis causes extensive morbidity and death in adulthood. Long-term oral cysteamine therapy mitigates these effects. C1 NHGRI, NIH, Intramural Off Rare Dis, Bethesda, MD 20892 USA. RP Gahl, WA (reprint author), NHGRI, NIH, Intramural Off Rare Dis, 10 Ctr Dr,Bldg 10,Room 10C-103, Bethesda, MD 20892 USA. EM bgahl@helix.nih.gov FU Intramural NIH HHS NR 47 TC 81 Z9 82 U1 0 U2 6 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 AUG 21 PY 2007 VL 147 IS 4 BP 242 EP 250 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 201AP UT WOS:000248804200004 PM 17709758 ER PT J AU Mukhamedova, N Fu, Y Bukrinsky, M Remaley, AT Sviridov, D AF Mukhamedova, Nigora Fu, Ying Bukrinsky, Michael Remaley, Alan T. Sviridov, Dmitri TI The role of different regions of ATP-Binding cassette transporter A1 in cholesterol efflux SO BIOCHEMISTRY LA English DT Article ID CELLULAR CHOLESTEROL; DENSITY-LIPOPROTEIN; PLASMA-MEMBRANE; LIPID EFFLUX; APOA-I; ABCA1 TRANSPORTER; TANGIER-DISEASE; APOLIPOPROTEIN; CELLS; MUTATIONS AB ABCA1 is a key element of cholesterol efflux, but the mechanism of ABCA1-dependent cholesterol efflux is still unclear. Monoclonal antibodies against ABCA1 were used to map functional domains of ABCA1. Two antibodies were directed against a fragment of the first extracellular loop of ABCA1, and the third antibody was directed against a fragment of the fourth extracellular loop. One antibody against the first loop inhibited cholesterol efflux from human macrophages without inhibiting apolipoprotein A-I (apoA-I) binding and internalization. Another antibody against the first loop inhibited apoA-I binding and internalization without inhibiting cholesterol efflux. The antibody against the fourth loop inhibited apoA-I binding to ABCA1 but enhanced cholesterol efflux from macrophages and reduced intracellular cholesterol content. This antibody also increased cholesterol efflux from HeLa cells transfected with ABCA1 but not from cells with Delta PEST-ABCA1. The mechanism of the stimulating effect of this antibody on cholesterol efflux was found to be stabilization of ABCA1 leading to the increase in abundance of cell surface ABCA1. We conclude that a site on the first extracellular loop is required for cholesterol efflux, whereas a site on the fourth extracellular loop may be responsible for ABCA1 stability. C1 Baker Heart Res Inst, Melbourne, Vic 8008, Australia. George Washington Univ, Washington, DC USA. NIH, Dept Lab Med, Bethesda, MD USA. RP Sviridov, D (reprint author), Baker Heart Res Inst, POB 6492,St,Kilda Rd Central, Melbourne, Vic 8008, Australia. EM Dmitri.Sviridov@Baker.edu.au RI Sviridov, Dmitri/E-7943-2010 NR 37 TC 17 Z9 22 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 21 PY 2007 VL 46 IS 33 BP 9388 EP 9398 DI 10.1021/bi700473t PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 199JP UT WOS:000248692400004 PM 17655203 ER PT J AU Paterson, JK Shukla, S Black, CM Tachiwada, T Garfield, S Wincovitch, S Ernst, DN Agadir, A Li, X Ambudkar, SV Szakacs, G Akiyama, SI Gottesman, MM AF Paterson, Jill K. Shukla, Suneet Black, Chelsea M. Tachiwada, Tokushi Garfield, Susan Wincovitch, Stephen Ernst, David N. Agadir, Anissa Li, Xuelin Ambudkar, Suresh V. Szakacs, Gergely Akiyama, Shin-ichi Gottesman, Michael M. TI Human ABCB6 localizes to both the outer mitochondrial membrane and the plasma membrane SO BIOCHEMISTRY LA English DT Article ID LINKED SIDEROBLASTIC ANEMIA; ATP-BINDING; CELL-LINES; ERYTHROPOIETIC PROTOPORPHYRIA; MULTIDRUG-RESISTANCE; MASS-SPECTROMETRY; IRON HOMEOSTASIS; DRUG-RESISTANCE; PROTEIN IMPORT; INNER MEMBRANE AB Expression of the ATP-binding cassette transporter ABCB6 has been associated with multiple cellular functions, including resistance to several cytotoxic agents, iron homeostasis, and porphyrin transport. To further elucidate its physiological function and/or role in drug resistance, we determined the subcellular location of ABCB6. Using three novel ABCB6-specific antibodies, Western blot analysis of cells expressing cDNA-derived or endogenous ABCB6 revealed two distinct molecular weight forms. Confocal microscopy indicates that the protein localizes to both mitochondria and the plasma membrane. Differential centrifugation revealed that the lower molecular weight form predominantly resides in the mitochondria, while the larger protein form is more abundant in the plasma membrane. Preliminary studies indicate that ABCB6 is functionally relevant in the plasma membrane, where its expression prevents the accumulation of specific porphyrins in the cell. Digitonin solubilization of mitochondria demonstrated that ABCB6 is present in the outer mitochondrial membrane, while back-titration assays with the ABCB6-specific antibodies reveal that the nucleotide binding domain of ABCB6 is cytoplasmic. These studies are the first to demonstrate that ABCB6 exists in two molecular weight forms, is localized to both the outer mitochondrial membrane and the plasma membrane, and plays a functional role in the plasma membrane. C1 NCI, NIH, DHHS, Ctr Canc Res,Lab Cell Biol, Bethesda, MD 20892 USA. Kagoshima Univ, Grad Sch Med, Dent Scu, Dept Mol Oncol, Kagoshima 890, Japan. NIH, NCI, Expt Carcinogenesis Lab, Bethesda, MD 20892 USA. BD Biosci Pharm, San Diego, CA 92121 USA. Hungarian Acad Sci, Inst Enzymol, Budapest, Hungary. RP Gottesman, MM (reprint author), NCI, NIH, DHHS, Ctr Canc Res,Lab Cell Biol, Bethesda, MD 20892 USA. EM MGottesman@nih.gov RI Szakacs, Gergely/A-2580-2009; shukla, suneet/B-4626-2012 OI Szakacs, Gergely/0000-0002-9311-7827; FU Intramural NIH HHS NR 71 TC 59 Z9 66 U1 3 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 21 PY 2007 VL 46 IS 33 BP 9443 EP 9452 DI 10.1021/bi700015m PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 199JP UT WOS:000248692400009 PM 17661442 ER PT J AU Gan, JH Wu, Y Prabakaran, P Gu, Y Li, Y Andrykovitch, M Liu, HH Gong, YC Yan, HG Ji, XH AF Gan, Jianhua Wu, Yan Prabakaran, Ponraj Gu, Yijun Li, Yue Andrykovitch, Michelle Liu, Hehua Gong, Yunchen Yan, Honggao Ji, Xinhua TI Structural and biochemical analyses of shikimate dehydrogenase AroE from Aquifex aeolicus: Implications for the catalytic mechanism SO BIOCHEMISTRY LA English DT Article ID LIVER ALCOHOL-DEHYDROGENASE; CRYSTAL-STRUCTURE; MYCOBACTERIUM-TUBERCULOSIS; ESCHERICHIA-COLI; HYDRIDE TRANSFER; PATHWAY; 5-DEHYDROGENASE; ACID; BIOSYNTHESIS; YDIB AB The shikimate biosynthetic pathway is essential to microorganisms, plants, and parasites but absent from mammals. Therefore, shikimate dehydrogenase (SD) and other enzymes in the pathway are attractive targets for developing nontoxic antimicrobial agents, herbicides, and antiparasite drugs. SD catalyzes the fourth reaction in the pathway, the nicotinamide adenine dinucleotide phosphate- (NADP-) dependent reduction of 3-dehydroshikimic acid to shikimic acid (SA), as well as its reverse, by the transfer of a hydride. Previous structural studies reveal that the enzyme exists in two major conformations, an open and a closed form. For the reaction to occur, it is believed that the catalytic complex assumes the closed conformation. Nonetheless, the only structure containing both SA and NADP(+) exhibits an open conformation (PDB entry 2EV9). Here, we present two crystal structures of Aquifex aeolicus SD, including a ternary complex with both SA and NADP(+), which assumes the closed conformation and therefore contains a catalytically competent active site. On the basis of preexisting and novel structural and biochemical data, a catalytic mechanism is proposed. C1 Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. NCI, Ctr Canc Res, Ft Detrick, MD 21702 USA. RP Yan, HG (reprint author), Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. EM yanh@pilot.msu.edu; jix@ncifcrf.gov RI Gu, Yijun/B-6017-2012; Ji, Xinhua/C-9664-2012; Ponraj, Prabakaran/D-6325-2011 OI Ji, Xinhua/0000-0001-6942-1514; FU Intramural NIH HHS; NIGMS NIH HHS [GM51901] NR 43 TC 14 Z9 15 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 21 PY 2007 VL 46 IS 33 BP 9513 EP 9522 DI 10.1021/bi602601e PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 199JP UT WOS:000248692400016 PM 17649975 ER PT J AU Parvin, MN Gerelsaikhan, T Turner, RJ AF Parvin, Most Nahid Gerelsaikhan, Tudevdagva Turner, R. James TI Regions in the cytosolic C-terminus of the secretory Na+-K+-2Cl(-) cotransporter NKCC1 are required for its homodimerization SO BIOCHEMISTRY LA English DT Article ID NA-K-2CL COTRANSPORTER; FUNCTIONAL EXPRESSION; MOLECULAR-CLONING; STRUCTURAL UNIT; MICE LACKING; TOPOLOGY; DOMAINS; NEURONS AB The "secretory" Na+-K+-2Cl(-) cotransporter, NKCC1, is a member of a small gene family of electroneutral cation-chloride cotransporters (CCCs) with 9 homologues in vertebrates. A number of these transporters, including NKCC1 itself, have been shown to exist as homodimers in the membrane, suggesting that this may be a common feature of the CCCs. Here we employ chemical cross-linking studies, a novel co-immunoprecipition assay, and NKCC1/CCC chimeras to further explore the basis and significance of NKCC1 dimerization. An N-terminally truncated NKCC1 (nttNKCC1), in which the first 20 kDa of the 28 kDa cytosolic N-terminus are deleted, forms homodimers as well as heterodimers with full-length NKCC1, indicating that this region of N-terminus is not required for dimerization. On the other hand, replacing the 50 kDa NKCC1 C-terminus with that of several other non-NKCC1 homologues results in chimeric proteins that form homodimers but show little or no heterodimerization with NKCC1, demonstrating that the C-terminus of NKCC1 plays an essential role in dimerization and that NKCC1 dimerization exhibits definite homologue-specificity. Using additional chimeras we find that the residues required for dimer formation lie between amino acids 751 and 998 of (rat) NKCC1. We also show that dramatically overexpressing the nonfunctional truncated protein nttNKCC1 relative to the endogenous NKCC1 in the HEK293 cells results in a modest inhibition of fluxes via the endogenous transporter and a change in its sensitivity to the specific inhibitor bumetanide. These latter results indicate that there is a functional interaction between dimer subunits but that nonfunctional subunits do not necessarily have a dominant negative effect as has been previously proposed. C1 NIH, Bethesda, MD 20892 USA. Natl Inst Hlth, DHHS, Natl Inst Dental Craniofacial Res, Gene Therapy & Therapeut Branch,Membrane Biol Sec, Bethesda, MD 20892 USA. RP Turner, RJ (reprint author), NIH, Bldg 10,Rm 1A01,10 Ctr Dr MSC 1190, Bethesda, MD 20892 USA. EM rjturner@nih.gov FU Intramural NIH HHS NR 31 TC 21 Z9 21 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 21 PY 2007 VL 46 IS 33 BP 9630 EP 9637 DI 10.1021/bi700881a PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 199JP UT WOS:000248692400027 PM 17655331 ER PT J AU Lauer, MS Martino, D Ishwaran, H Blackstone, EH AF Lauer, Michael S. Martino, Derlis Ishwaran, Hemant Blackstone, Eugene H. TI Quantitative measures of electrocardiographic left ventricular mass, conduction, and repolarization, and long-term survival after coronary artery bypass grafting SO CIRCULATION LA English DT Article DE coronary disease; electrocardiography; prognosis; surgery ID CONGESTIVE-HEART-FAILURE; END-POINT REDUCTION; QRS DURATION; LOSARTAN INTERVENTION; PREDICT MORTALITY; HYPERTROPHY; REGRESSION; TIME; VALIDATION; HYPERTENSION AB Background - Quantitative ECG measures of left ventricular mass and repolarization predict outcome in population-based cohorts and patients with hypertension. We assessed the prognostic value of preoperative quantitative electrocardiography in patients who underwent isolated coronary artery bypass grafting. Methods and Results - For 6 years we followed 8166 patients who underwent primary isolated coronary artery bypass grafting between 1990 and 2003, all of whom had routine preoperative ECGs. With use of specialized digital software, quantitative measures were recorded on ventricular rate, P duration, PR interval, QRS duration, QT interval, QRS axis, Sokolow-Lyon and Cornell voltages, and ST-segment depression and slope. There were 1516 deaths. After adjustment for age, gender, clinical characteristics, left ventricular ejection fraction, and other confounders, death was independently predicted by ventricular rate (adjusted hazard ratio [AHR] for 90 versus 60 beats per minute, 1.34; 95% confidence interval [CI], 1.21 to 1.50; P <.0001), PR interval (AHR for 200 versus 150 ms, 1.05; 95% CI, 1.00 to 1.10; P <.0001), QRS duration (AHR for 120 versus 80 ms, 1.24; 95% CI, 1.07 to 1.44; P <.0001), Sokolow-Lyon voltage ( AHR for 3.5 versus 1.5 mV, 1.18; 95% CI, 1.05 to 1.31; P <.0001), and ST-segment slope (AHR for -0.1 versus 0 mV, 1.16; 95% CI, 1.02 to 1.31; P <.0001). We derived a quantitative ECG score and demonstrated that, with the exception of age, it was the most powerful predictor of long-term death. Conclusions - Quantitative ECG measures of left ventricular rate, mass, and repolarization are predictive of mortality among patients who underwent isolated coronary artery bypass grafting. These findings suggest that quantitative electrocardiography may be valuable for risk stratification in patients with severe coronary artery disease. C1 Case Western Reserve Univ, Sch Med, Dept Cardiovasc Med, Cleveland, OH USA. Case Western Reserve Univ, Sch Med, Dept Thorac & Cardiovasc Surg, Cleveland, OH USA. Case Western Reserve Univ, Sch Med, Cleveland Clin Fdn, Dept Quantitst Hlth Sci, Cleveland, OH USA. Case Western Reserve Univ, Sch Med, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. RP Lauer, MS (reprint author), Div Prevent & Populat Sci, NHLBI, 6701 Rockledge Dr,Room 10122, Bethesda, MD 20892 USA. EM lauer@nhlbi.nih.gov RI Lauer, Michael/L-9656-2013 OI Lauer, Michael/0000-0002-9217-8177 FU NHLBI NIH HHS [P50 HL-77107-1, R01 HL-072771-02, R01 HL-66004-2] NR 27 TC 14 Z9 14 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD AUG 21 PY 2007 VL 116 IS 8 BP 888 EP 893 DI 10.1161/CIRCULATIONAHA.107.698019 PG 6 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 202GB UT WOS:000248888900003 PM 17679612 ER PT J AU Zhu, G Wu, CJ Zhao, Y Ashwell, JD AF Zhu, Guozhi Wu, Chuan-Jin Zhao, Yongge Ashwell, Jonathan D. TI Optineurin negatively regulates TNF alpha-induced NF-kappa B activation by competing with NEMO for ubiquitinated RIP SO CURRENT BIOLOGY LA English DT Article ID NECROSIS-FACTOR-ALPHA; OPEN-ANGLE GLAUCOMA; INDUCED APOPTOSIS; NEURODEGENERATIVE DISEASES; IFN-GAMMA; PROTEIN; CELLS; EXPRESSION; RECEPTOR; NEUROPROTECTION AB NF-kappa B essential modulator (NEMO), the regulatory subunit of the I kappa B kinase (IKK) that activates NF-kappa B, is essential for NF-KB activation [1]. NEMO was recently found to contain a region that preferentially binds Lys (K)63-linked but not K48-linked polyubiquitin (polyUb) chains, and the ability of NEMO to bind to K63-linked polyUb RIP (receptor-interacting protein) is necessary for efficient tumor necrosis factor alpha (TNF alpha)-induced NF-kappa B activation [2, 3]. Optineurin is a homolog of NEMO, and mutations in the optineurin gene are found in a subset of patients with glaucoma [4], a neurodegenerative disease involving the loss of retinal ganglion cells [5]. Although optineurin shares considerable homology with NEMO, in resting cells, it is not present in the high-molecular-weight complex containing IKK alpha and IKK beta, and optineurin cannot substitute for NEMO in lipopolysaccharide (LPS)-induced NF-KB activation [6]. On the other hand, the overexpression of optineurin blocks the protective effect of E3-14.7K on cell death caused by the overexpression of TNF alpha receptor 1 (TNFR1) [7]. Here we show that optineurin has a K63-linked polyUb-binding region similar to that of NEMO, and like NEMO, it bound K63- but not K48-linked polyUb. Optineurin competitively antagonized NEMO's binding to polyUb RIP, and its overexpression inhibited TNF alpha-induced NF-KB activation. This competition occurs at physiologic protein levels because microRNA silencing of optineurin resulted in markedly enhanced TNF alpha-induced NF-kappa B activity. These results reveal a physiologic role for optineurin in dampening TNF alpha signaling, and this role might provide an explanation for its association with glaucoma. C1 NCI, NIH, Lab Immune Cell Biol, Bethesda, MD 20892 USA. RP Ashwell, JD (reprint author), NCI, NIH, Lab Immune Cell Biol, Bethesda, MD 20892 USA. EM jda@pop.nci.nih.gov FU Intramural NIH HHS NR 35 TC 128 Z9 132 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD AUG 21 PY 2007 VL 17 IS 16 BP 1438 EP 1443 DI 10.1016/j.cub.2007.07.041 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 203QQ UT WOS:000248989500041 PM 17702576 ER PT J AU Moon, KH Abdelmegeed, MA Song, BJ AF Moon, Kwan-Hoon Abdelmegeed, Mohamed A. Song, Byoung-Joon TI Inactivation of cytosolic aldehyde dehydrogenase via S-nitrosylation in ethanol-exposed rat liver SO FEBS LETTERS LA English DT Article DE cytosolic aldehyde dehydrogenase (ALDH1); ethanol; s-nitrosylation; reversible inhibition; acetaldehyde metabolism ID NITRIC-OXIDE; 10-FORMYLTETRAHYDROFOLATE DEHYDROGENASE; ACETALDEHYDE METABOLISM; ACTIVE-SITE; ALCOHOL; GENE; ACID; MICE; POLYMORPHISMS; INHIBITION AB Aldehyde dehydrogenase (ALDH) isozymes are critically important in the metabolism of acetaldehyde, thus preventing its accumulation after ethanol-exposure. We previously reported that mitochondrial ALDH2 could be inactivated via S-nitrosylation in ethanol-exposed rats. This study was aimed at investigating whether cytosolic ALDH1, with a relatively-low-K-m value (11-18 mu M) for acetaldehyde, could be also inhibited in ethanol-exposed rats. Chronic or binge ethanol-exposure significantly decreased ALDH1 activity, which was restored by addition of dithiothreitol. Immunoblot analysis with the anti-S-nitroso-Cys antibody showed one immunoreactive band in the immunoprecipitated ALDH1 only from ethanol-exposed rats, but not from pair-fed controls, suggesting S-nitrosylation of ALDH1. Therefore inactivation of ALDH1 via S-nitrosylation can result in accumulation of acetaldehyde upon ethanol-exposure. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 NIAAA, NIH, Lab Membrane Biochem & Biophys, Bethesda, MD 20892 USA. RP Song, BJ (reprint author), NIAAA, NIH, Lab Membrane Biochem & Biophys, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM bjs@mail.nih.gov FU Intramural NIH HHS [Z01 AA000036-21, Z99 AA999999] NR 44 TC 30 Z9 32 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD AUG 21 PY 2007 VL 581 IS 21 BP 3967 EP 3972 DI 10.1016/j.febslet.2007.07.037 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 204XS UT WOS:000249077900013 PM 17673211 ER PT J AU Tai, XG Van Laethem, F Sharpe, AH Singer, A AF Tai, Xuguang Van Laethem, Francois Sharpe, Arlene H. Singer, Alfred TI Induction of autoimmune disease in CTLA-4(-/-) mice depends on a specific CD28 motif that is required for in vivo costimulation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE autoimmunity; lymphoproliferation ID T-CELL COSTIMULATION; P56(LCK) TYROSINE KINASE; PHOSPHATIDYLINOSITOL 3-KINASE; CTLA-4-DEFICIENT MICE; CYTOPLASMIC DOMAIN; RECEPTOR CD28; BINDING; PROTEIN; LCK; LYMPHOPROLIFERATION AB CTLA-4-deficient mice develop a lethal autoimmune lymphoproliferative disorder that is strictly dependent on in vivo CD28 costimulation. Nevertheless, it is not known whether there is a specific site on the CD28 molecule that is required for induction of autoimmunity. Using CTLA-4-deficient mice expressing CD28 molecules with various point mutations in the CD28 cytosolic tail, the present study documents that in vivo costimulation for induction of autoimmune disease strictly requires an intact C-terminal proline motif that promotes lymphocyte-specific protein tyrosine kinase (Lck) binding to the CD28 cytosolic tail, because point mutations in C-terminal proline residues (Pro-187 and Pro-190) completely prevented disease induction. In contrast, in vivo costimulation for disease induction did not require either an intact YMNM motif or an intact N-terminal proline motif, which, respectively, promote phosphoinositide 3-kinase and IL2-inducible T cell kinase binding to the CD28 cytosolic tail. Thus, in vivo CD28 costimulation for induction of autoimmune disease is strictly and specifically dependent on an intact C-terminal proline motif that serves as a lymphocyte-specific protein tyrosine (Lck) kinase binding site in the CD28 cytosolic tail. C1 NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. RP Singer, A (reprint author), NCI, Expt Immunol Branch, Bldg 10,Room 4B36, Bethesda, MD 20892 USA. EM singera@mail.nih.gov FU Intramural NIH HHS NR 30 TC 31 Z9 32 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 21 PY 2007 VL 104 IS 34 BP 13756 EP 13761 DI 10.1073/pnas.0706509104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 204SQ UT WOS:000249064700043 PM 17702861 ER PT J AU Tang, SC Arumugam, TV Xu, XR Cheng, AW Mughal, MR Jo, DG Lathia, JD Siler, DA Chigurupati, S Ouyang, X Magnus, T Camandola, S Mattson, MP AF Tang, Sung-Chun Arumugam, Thiruma V. Xu, Xiangru Cheng, Aiwu Mughal, Mohamed R. Jo, Dong Gyu Lathia, Justin D. Siler, Dominic A. Chigurupati, Srinivasulu Ouyang, Xin Magnus, Tim Camandola, Simonetta Mattson, Mark P. TI Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE AP-1; apoptosis; innate immunity; ischemic stroke; microglia ID NF-KAPPA-B; FOCAL CEREBRAL-ISCHEMIA; SIGNALING PATHWAY; IMMUNE-RESPONSES; GENE-EXPRESSION; INNATE IMMUNITY; ACTIVATION; HYALURONAN; APOPTOSIS; MYD88 AB The innate immune system senses the invasion of pathogenic microorganisms and tissue injury through Toll-like receptors (TLR), a mechanism thought to be limited to immune cells. We now report that neurons express several TLRs, and that the levels of TLR2 and -4 are increased in neurons in response to IFN-gamma stimulation and energy deprivation. Neurons from both TLR2 knockout and -4 mutant mice were protected against energy deprivation-induced cell death, which was associated with decreased activation of a proapoptotic signaling cascade involving jun N-terminal kinase and the transcription factor AP-1. TLR2 and -4 expression was increased in cerebral cortical neurons in response to ischemia/reperfusion injury, and the amount of brain damage and neurological deficits caused by a stroke were significantly less in mice deficient in TLR2 or -4 compared with WT control mice. Our findings establish a proapoptotic signaling pathway for TLR2 and -4 in neurons that may render them vulnerable to ischemic death. C1 Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. Natl Inst Aging Intramural Res program, Neurosci Lab, Baltimore, MD 21224 USA. Natl Taiwan Univ Hosp, Dept Neurol, Stroke Ctr, Taipei 100, Taiwan. Texas Tech Univ, Hlth Sci Ctr, Sch Pharm, Dept Pharmaceut Sci, Amarillo, TX 79106 USA. RP Mattson, MP (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. EM mattsonm@grc.nia.nih.gov RI Arumugam, Thiruma/C-7969-2009; Arumugam, Thiruma/B-4898-2011; Mattson, Mark/F-6038-2012; OI Tang, Sung-Chun/0000-0003-3731-5973 FU Intramural NIH HHS NR 36 TC 393 Z9 411 U1 4 U2 35 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 AUG 21 PY 2007 VL 104 IS 34 BP 13798 EP 13803 DI 10.1073/pnas.0702553104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 204SQ UT WOS:000249064700050 PM 17693552 ER PT J AU Nolan, SM Skiadopoulos, MH Bradley, K Kim, OS Bier, S Amaro-Carambot, E Surman, SR Davis, S Claire, MS Elkins, R Collins, PL Murphy, BR Schaap-Nutt, A AF Nolan, Sheila M. Skiadopoulos, Mario H. Bradley, Konrad Kim, Olivia S. Bier, Stacia Amaro-Carambot, Emerito Surman, Sonja R. Davis, Stephanie Claire, Marisa St. Elkins, Randy Collins, Peter L. Murphy, Brian R. Schaap-Nutt, Anne TI Recombinant human parainfluenza virus type 2 vaccine candidates containing a 3 ' genomic promoter mutation and L polymerase mutations are attenuated and protective in non-human primates SO VACCINE LA English DT Article DE human parainfluenza virus; live attenuated vaccine candidates; non-human primate study ID AMINO-ACID SUBSTITUTIONS; PARA-INFLUENZA VIRUSES; SENDAI-VIRUS; RNA-POLYMERASE; REVERSE GENETICS; TYPE-3 VIRUS; V-PROTEINS; HETEROLOGOUS PARAMYXOVIRUSES; HEALTHY INFANTS; INTERFERON-BETA AB Previously, we identified several attenuating mutations in the L polymerase protein of human parainfluenza virus type 2 (HPIV2) and genetically stabilized those mutations using reverse genetics [Nolan SM, Surman S, Amaro-CarambotE, Collins PL, Murphy BR, Skiadopoulos MH. Live-attenuated intranasal parainfluenza virus type 2 vaccine candidates developed by reverse genetics containing L polymerase protein mutations imported from heterologous paramyxoviruses. Vaccine 2005;39(23):4765-74]. Here we describe the discovery of an attenuating mutation at nucleotide 15 (15 (T -> C)) in the 3' genomic promoter that was also present in the previously characterized mutants. We evaluated the properties of this promoter mutation alone and in various combinations with the L polymerase mutations. Amino acid substitutions at L protein positions 460 (460A or 460P) or 948 (948L), or deletion of amino acids 1724 and 1725 (A 1724), each conferred a temperature sensitivity (ts) phenotype whereas the 15 (T -> C) Mutation did not. The 460A and 948L mutations each contributed to restricted replication in the lower respiratory tract of African green monkeys, but the A 1724 mutation increased attenuation only in certain combinations with other mutations. We constructed two highly attenuated viruses, rV94(15C)/46OA/948L and rV94(15C)/948L/Delta 1724, that were immunogenic and protective against challenge with wild-type HPTV2 in African green monkeys and, therefore, appear to be suitable for evaluation in humans. (c) 2007 Elsevier Ltd. All rights reserved. C1 NIAID, Infect Dis Lab, Resp Viruses Sect, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Schaap-Nutt, A (reprint author), NIAID, Infect Dis Lab, Resp Viruses Sect, NIH,Dept Hlth & Human Serv, 50 S Dr,Bldg 50,Room 6509,MSC 8007, Bethesda, MD 20892 USA. EM schaapa@niaid.nih.gov RI Nutt, Anne/A-4137-2008 FU Intramural NIH HHS [Z01 AI000327-26] NR 51 TC 16 Z9 16 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 AUG 21 PY 2007 VL 25 IS 34 BP 6409 EP 6422 DI 10.1016/j.vaccine.2007.06.028 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 203DJ UT WOS:000248955000017 PM 17658669 ER PT J AU Koonin, EV AF Koonin, Eugene V. TI The Biological Big Bang model for the major transitions in evolution SO BIOLOGY DIRECT LA English DT Review ID HORIZONTAL GENE-TRANSFER; CAMBRIAN EXPLOSION; INFLATIONARY UNIVERSE; GENOME EVOLUTION; PROTEIN FOLDS; PHYLOGENETIC CLASSIFICATION; TRANSLATION MACHINERIES; BACTERIAL PHYLOGENY; MOLECULAR CLOCK; COMMON ORIGIN AB Background: Major transitions in biological evolution show the same pattern of sudden emergence of diverse forms at a new level of complexity. The relationships between major groups within an emergent new class of biological entities are hard to decipher and do not seem to fit the tree pattern that, following Darwin's original proposal, remains the dominant description of biological evolution. The cases in point include the origin of complex RNA molecules and protein folds; major groups of viruses; archaea and bacteria, and the principal lineages within each of these prokaryotic domains; eukaryotic supergroups; and animal phyla. In each of these pivotal nexuses in life's history, the principal "types" seem to appear rapidly and fully equipped with the signature features of the respective new level of biological organization. No intermediate "grades" or intermediate forms between different types are detectable. Usually, this pattern is attributed to cladogenesis compressed in time, combined with the inevitable erosion of the phylogenetic signal. Hypothesis: I propose that most or all major evolutionary transitions that show the "explosive" pattern of emergence of new types of biological entities correspond to a boundary between two qualitatively distinct evolutionary phases. The first, inflationary phase is characterized by extremely rapid evolution driven by various processes of genetic information exchange, such as horizontal gene transfer, recombination, fusion, fission, and spread of mobile elements. These processes give rise to a vast diversity of forms from which the main classes of entities at the new level of complexity emerge independently, through a sampling process. In the second phase, evolution dramatically slows down, the respective process of genetic information exchange tapers off, and multiple lineages of the new type of entities emerge, each of them evolving in a tree-like fashion from that point on. This biphasic model of evolution incorporates the previously developed concepts of the emergence of protein folds by recombination of small structural units and origin of viruses and cells from a pre-cellular compartmentalized pool of recombining genetic elements. The model is extended to encompass other major transitions. It is proposed that bacterial and archaeal phyla emerged independently from two distinct populations of primordial cells that, originally, possessed leaky membranes, which made the cells prone to rampant gene exchange; and that the eukaryotic supergroups emerged through distinct, secondary endosymbiotic events (as opposed to the primary, mitochondrial endosymbiosis). This biphasic model of evolution is substantially analogous to the scenario of the origin of universes in the eternal inflation version of modern cosmology. Under this model, universes like ours emerge in the infinite multiverse when the eternal process of exponential expansion, known as inflation, ceases in a particular region as a result of false vacuum decay, a first order phase transition process. The result is the nucleation of a new universe, which is traditionally denoted Big Bang, although this scenario is radically different from the Big Bang of the traditional model of an expanding universe. Hence I denote the phase transitions at the end of each inflationary epoch in the history of life Biological Big Bangs (BBB). Conclusion: A Biological Big Bang (BBB) model is proposed for the major transitions in life's evolution. According to this model, each transition is a BBB such that new classes of biological entities emerge at the end of a rapid phase of evolution (inflation) that is characterized by extensive exchange of genetic information which takes distinct forms for different BBBs. The major types of new forms emerge independently, via a sampling process, from the pool of recombining entities of the preceding generation. This process is envisaged as being qualitatively different from treepattern cladogenesis. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM koonin@ncbi.nlm.nih.gov FU Intramural NIH HHS NR 117 TC 51 Z9 54 U1 4 U2 34 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD AUG 20 PY 2007 VL 2 AR 21 DI 10.1186/1745-6150-2-21 PG 17 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 209PA UT WOS:000249399300001 PM 17708768 ER PT J AU Lee, JC Stiles, D Lu, J Cam, MC AF Lee, Joseph C. Stiles, David Lu, Jun Cam, Margaret C. TI A detailed transcript-level probe annotation reveals alternative splicing based microarray platform differences SO BMC GENOMICS LA English DT Article ID GENE-EXPRESSION MEASUREMENTS; OLIGONUCLEOTIDE MICROARRAYS; QUALITY-CONTROL; REPRODUCIBILITY; CDNA; REDEFINITION; ACEVIEW; NOISE; SETS AB Background: Microarrays are a popular tool used in experiments to measure gene expression levels. Improving the reproducibility of microarray results produced by different chips from various manufacturers is important to create comparable and combinable experimental results. Alternative splicing has been cited as a possible cause of differences in expression measurements across platforms, though no study to this point has been conducted to show its influence in cross-platform differences. Results: Using probe sequence data, a new microarray probe/transcript annotation was created based on the AceView Aug05 release that allowed for the categorization of genes based on their expression measurements' susceptibility to alternative splicing differences across microarray platforms. Examining gene expression data from multiple platforms in light of the new categorization, genes unsusceptible to alternative splicing differences showed higher signal agreement than those genes most susceptible to alternative splicing differences. The analysis gave rise to a different probe-level visualization method that can highlight probe differences according to transcript specificity. Conclusion: The results highlight the need for detailed probe annotation at the transcriptome level. The presence of alternative splicing within a given sample can affect gene expression measurements and is a contributing factor to overall technical differences across platforms. C1 NIH, NIDDK, Genom Core Lab, Bethesda, MD 20892 USA. NIH, Natl Ctr Biotechnol Informat, Off Director, Bethesda, MD 20894 USA. RP Cam, MC (reprint author), NIH, NIDDK, Genom Core Lab, Bldg 10, Bethesda, MD 20892 USA. EM jclee8@gmail.com; davidst@nei.nih.gov; lujun@mail.nih.gov; maggie.cam@nih.gov FU Intramural NIH HHS NR 28 TC 7 Z9 7 U1 0 U2 0 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 AUG 20 PY 2007 VL 8 AR 284 DI 10.1186/1471-2164-8-284 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 218ZT UT WOS:000250055200001 PM 17708771 ER PT J AU Tummala, MK McGuire, WP AF Tummala, Mohan K. McGuire, William P. TI Ovarian cancer, CA-125 addiction, and informed confusion: Much ado about less SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Editorial Material ID PROGRESSION; PACLITAXEL; TRIAL C1 Univ Maryland, Greenebaum Canc Ctr, Natl Inst Hlth, Clin Res Branch, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Square Hosp, Weinberg Canc Inst, Baltimore, MD 21201 USA. RP Tummala, MK (reprint author), Univ Maryland, Greenebaum Canc Ctr, Natl Inst Hlth, Clin Res Branch, Baltimore, MD 21201 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 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 AUG 20 PY 2007 VL 25 IS 24 BP 3570 EP 3571 DI 10.1200/JCO.2007.11.9735 PG 2 WC Oncology SC Oncology GA 209VK UT WOS:000249415900004 PM 17704402 ER PT J AU Berndt, SI Carter, HB Schoenberg, MP Newschaffer, CJ AF Berndt, Sonja I. Carter, H. Ballentine Schoenberg, Mark P. Newschaffer, Craig J. TI Disparities in treatment and outcome for renal cell cancer among older black and white patients SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID CLINICAL COMORBIDITY INDEX; MEDICARE MANAGED CARE; STAGE LUNG-CANCER; RACIAL-DIFFERENCES; COLORECTAL-CANCER; UNITED-STATES; CAROTID-ENDARTERECTOMY; ADMINISTRATIVE DATA; CARCINOMA; RACE AB Purpose Black patients with renal cell cancer have shorter survival compared with their white counterparts, but the causes for this disparity are unclear. To elucidate reasons for this inequality, we examined differences in treatment and survival between black and white patients. Patients and Methods A retrospective cohort study was conducted using data from the linked Surveillance, Epidemiology and End Results ( SEER) cancer registry and Medicare databases. Participants included 964 black and 10,482 white patients age >= 65 years who were enrolled into Medicare and diagnosed with renal cell cancer between 1986 and 1999. Information on surgical treatment was ascertained from both databases, whereas data regarding coexisting illness and survival was obtained from the Medicare database. Results The percentage of black patients receiving nephrectomy treatment was significantly lower compared with whites ( 61.2% v 70.4%; P < .0001). After adjustment for age, sex, median income, cancer stage, tumor size, and comorbidity index, blacks were less likely to undergo nephrectomy treatment compared with whites ( risk ratio = 0.93; 95% CI, 0.90 to 0.96). Overall survival was worse for blacks than whites even after adjustment for demographic and cancer prognostic factors ( hazard ratio [ HR] = 1.16; 95% CI, 1.07 to 1.25); however, additional adjustment for comorbidity index and nephrectomy treatment reduced the disparity substantially ( HR = 1.00; 95% CI, 0.93 to 1.09). Conclusion This study indicates that the lower survival rate among blacks compared with whites with renal cell cancer can be explained largely by the increased number of comorbid health conditions and the lower rate of surgical treatment among black patients. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. James Buchanan Brady Urol Inst, Dept Urol, Baltimore, MD USA. Johns Hopkins Sch Med, Baltimore, MD USA. RP Berndt, SI (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Executive Blvd,EPS 8012 MSC 7240, Bethesda, MD 20892 USA. EM berndts@mail.nih.gov FU Intramural NIH HHS NR 46 TC 45 Z9 45 U1 2 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 AUG 20 PY 2007 VL 25 IS 24 BP 3589 EP 3595 DI 10.1200/JCO.2006.10.0156 PG 7 WC Oncology SC Oncology GA 209VK UT WOS:000249415900008 PM 17704406 ER PT J AU Hampson, LA Joffe, S Fowler, R Verter, J Emanuel, EJ AF Hampson, Lindsay A. Joffe, Steven Fowler, Robert Verter, Joel Emanuel, Ezekiel J. TI Frequency, type, and monetary value of financial conflicts of interest in cancer clinical research SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID ECONOMIC-ANALYSES; INDUSTRY; TRIALS; QUALITY; DRUGS; ONCOLOGY; FACULTY AB Purpose Using data from American Society of Clinical Oncology ( ASCO) Annual Meetings, we determined the frequency, type, and monetary value of researchers' financial interests. Methods Financial disclosures for the 2004 ( 3,529 abstracts and 25,416 authors) and 2005 ( 3,556 abstracts and 26,181 authors) ASCO Annual Meetings were categorized into four groups: no author with a financial interest, research funding only, employment and leadership positions only, or at least one author with a personal financial interest. Interests were stratified by monetary value and other factors. Results In 2004 and 2005, 23% of abstracts had one or more authors with a personal financial interest. More than 75% of all personal financial interests were valued at less than $ 10,000. More than 90% of financial interests of more than $ 100,000 were employment related. Fewer than 3.5% of authors with personal financial interests had interests valued at more than $ 100,000. Overall, 6.3% ( 2004) and 2.9% ( 2005) of abstracts only had research funding, whereas 7.3% ( 2004) and 6.9% ( 2005) had only commercial employment. In 2005, 60% of plenary sessions compared with 23.1% in general poster sessions and 17.3% for publish-only abstracts reported financial ties. Personal financial interests were more common among US authors compared with non-US authors ( 9.2% v 4.2%). Conclusion About one fourth of abstracts at ASCO Annual Meetings have an author with a personal financial interest. Most personal financial interests are valued at less than $ 10,000 per year, whereas a majority valued at more than $ 100,000 are related to employees of commercial entities. C1 NIH, Ctr Clin, Dept Bioeth, Bethesda, MD 20892 USA. Childrens Hosp, Dana Farber Canc Inst, Dept Pediat Oncol, Dept Med, Boston, MA 02115 USA. RP Emanuel, EJ (reprint author), NIH, Ctr Clin, Dept Bioeth, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM eemanuel@nih.gov OI Hampson, Lindsay/0000-0002-0740-7984; Joffe, Steven/0000-0002-0667-7384 FU Intramural NIH HHS NR 28 TC 16 Z9 18 U1 1 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 2318 MILL ROAD, STE 800, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 20 PY 2007 VL 25 IS 24 BP 3609 EP 3614 DI 10.1200/JCO.2006.09.3633 PG 6 WC Oncology SC Oncology GA 209VK UT WOS:000249415900011 PM 17704409 ER PT J AU Parascandola, M AF Parascandola, Mark TI A turning point for conflicts of interest: The controversy over the national academy of sciences' first conflicts of interest disclosure policy SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID INDUSTRY; DEBATE; NIH; INVESTIGATORS; SCIENTISTS; CANCER AB Conflicts of interest policies have become a part of the fabric of the conduct of biomedical research, yet such concerns are relatively recent history. Until the 1960s, concerns about conflicts of interest were confined to scientists who served as government advisors and contractors. However, in the 1970s, as a range of environmental and consumer safety issues gained public attention, the conclusions of researchers frequently came under attack because of concerns about experts' financial ties to private industry. These debates typically focused on evaluating potential carcinogens in the environment. In response, the National Academy of Sciences ( NAS) developed its first conflict of interest policy, requiring committee members to disclose any '' potential sources of bias '' that '' others might deem prejudicial.'' Scientists universally opposed the policy, however, for a range of reasons - while some argued that all experienced and knowledgeable experts were inherently conflicted, others were offended at the suggestion that any expert could be biased. Despite the controversy, the disclosure policy remained in place and became a model for subsequent professional and institutional policies in the biomedical sciences. However, although disclosure policies have become standard at academic medical centers and for publications in scientific journals, clinical researchers have continued to debate the content of these policies and the need for additional protections beyond disclosure. In the absence of a definitive standard, this historical case study can substantially inform ongoing discussion on conflicts of interest in clinical research. C1 Natl Canc Inst, Bethesda, MD 20892 USA. Natl Canc Inst, Tobacco Control Res Branch, Bethesda, MD USA. RP Parascandola, M (reprint author), Natl Canc Inst, 6130 Execut Blvd,Room 4039, Bethesda, MD 20892 USA. EM paramark@mail.nih.gov NR 60 TC 14 Z9 14 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 AUG 20 PY 2007 VL 25 IS 24 BP 3774 EP 3779 DI 10.1200/JCO.2006.09.2890 PG 6 WC Oncology SC Oncology GA 209VK UT WOS:000249415900035 PM 17704427 ER PT J AU Denduluri, N Walshe, JM Swain, SM AF Denduluri, Neelima Walshe, Janice M. Swain, Sandra M. TI Role of gonadotropin-releasing hormone analog in the management of male metastatic breast cancer is uncertain - In reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID PREMENOPAUSAL WOMEN; ADJUVANT CHEMOTHERAPY; TAMOXIFEN; OVARIAN; THERAPY; CMF C1 Canc Res Ctr, Natl Canc Inst, NIH, Breast Canc Sect,Med Oncol Branch, Bethesda, MD 20814 USA. Adelaide & Meath Hosp Inc, Natl Childrens Hosp, Dublin, Ireland. Washington Hosp Ctr, Inst Canc, Washington, DC 20010 USA. RP Denduluri, N (reprint author), Canc Res Ctr, Natl Canc Inst, NIH, Breast Canc Sect,Med Oncol Branch, Bethesda, MD 20814 USA. NR 10 TC 0 Z9 0 U1 0 U2 0 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 AUG 20 PY 2007 VL 25 IS 24 BP 3788 EP 3789 DI 10.1200/JCO.2007.11.5998 PG 3 WC Oncology SC Oncology GA 209VK UT WOS:000249415900041 ER PT J AU Nikas, SP Thakur, GA Parrish, D Alapafuja, SO Huestis, MA Makriyannis, A AF Nikas, Spyros P. Thakur, Ganesh A. Parrish, Damon Alapafuja, Shakiru O. Huestis, Marilyn A. Makriyannis, Alexandros TI A concise methodology for the synthesis of (-)-Delta(9)-tetrahydrocannabinol and (-)-Delta(9)-tetrahydrocannabivarin metabolites and their regiospecifically deuterated analogs SO TETRAHEDRON LA English DT Article DE (-)-Delta(9)-tetrahydrocannabinol; (-)-Delta(9)-tetrahydrocannabivarin ID CONVENIENT SYNTHESIS; TERPENIC SYNTHON; METHYL-ESTER; CANNABINOIDS; THC; ACID; TETRAHYDROCANNABINOL; CONFIRMATION; DERIVATIVES; OLIVETOL AB The availability of tetrahydrocannabinols (Delta(9)-THC), tetrahydrocannabivarins (Delta(9)-THCV), and their metabolites in both their undeuterated and deuterated forms is critical for the analysis of biological and toxicological samples. We report here a concise methodology for the syntheses of (-)-Delta(9)-THC and (-)-Delta(9)-THCV metabolites in significantly improved overall yields using commercially available starting materials. Our approach allowed us to obtain the key intermediates (6aR,10aR)-9-nor-9-oxo-hexahydrocannabinols in four steps from (+)-(1R)-nopinone. This was followed by an optimized Shapiro reaction to give the (-)-11-nor-9-carboxy-metabolites, which were converted to their respective (-)-11-hydroxy analogs. The synthetic sequence involves a minimum number of steps, avoids undesirable oxidative conditions, and incorporates the costly deuterated resorcinols near the end of the synthetic sequence. This methodology enabled us to synthesize eight regiospecifically deuterated (-)-Delta(9)-THC and (-)-Delta(9)-THCV metabolites in a preparative scale and high optical purity without deuterium scrambling or loss. (c) 2007 Published by Elsevier Ltd. C1 [Nikas, Spyros P.; Thakur, Ganesh A.; Alapafuja, Shakiru O.; Makriyannis, Alexandros] Northeastern Univ, Cent Drug Discovery, Boston, MA 02115 USA. [Parrish, Damon] USN, Res Lab, Washington, DC 20375 USA. [Huestis, Marilyn A.] NIDA, NIH, Intramural Res Program, CPTR Branch,Chem & Drug Metab Sect, Baltimore, MD 21224 USA. RP Nikas, SP (reprint author), Northeastern Univ, Cent Drug Discovery, 116 Mugar Life Sci Bldg,360 Huntington Ave, Boston, MA 02115 USA. EM s.nikas@neu.edu; a.makriyannis@neu.edu NR 53 TC 9 Z9 9 U1 0 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0040-4020 J9 TETRAHEDRON JI Tetrahedron PD AUG 20 PY 2007 VL 63 IS 34 BP 8112 EP 8123 DI 10.1016/j.tet.2007.06.006 PG 12 WC Chemistry, Organic SC Chemistry GA 247ML UT WOS:000252083800007 ER PT J AU Abbondanzieri, EA Liu, SX Bokinsky, GE Zhang, J Le Grice, S Zhuang, XW AF Abbondanzieri, Elio A. Liu, Shixin Bokinsky, Gregory E. Zhang, Jennifer Le Grice, Stuart Zhuang, Xiaowei TI PHYS 292-Discrimination between nucleic acid substrates by HIV reverse transcriptase SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Abbondanzieri, Elio A.; Liu, Shixin; Bokinsky, Gregory E.; Zhang, Jennifer] Harvard Univ, Dept Chem & Biol Chem, Cambridge, MA 02138 USA. [Le Grice, Stuart] NCI, Div Basic Sci, Frederick, MD 21701 USA. [Zhuang, Xiaowei] Harvard Univ, Howard Hughes Med Inst, Cambridge, MA 02138 USA. [Zhuang, Xiaowei] Harvard Univ, Dept Chem & Biol Chem, Cambridge, MA 02138 USA. [Zhuang, Xiaowei] Harvard Univ, Dept Phys, Cambridge, MA 02138 USA. EM abbondan@fas.harvard.edu; sliu@fas.harvard.edu; bokinsky@fas.harvard.edu; zhuang@fas.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 292-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907423 ER PT J AU Bai, YW AF Bai, Yawen TI Hidden folding intermediates in small proteins: Implications for the folding energy landscape, cooperativity, and evolution of protein structures SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Bai, Yawen] NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM yawen@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 16-BIOT PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593903014 ER PT J AU Becker, A Kohfeld, S Preu, L Pies, T Zaharevitz, DW Kunick, C AF Becker, Anja Kohfeld, Simone Preu, Lutz Pies, Tanja Zaharevitz, Daniel W. Kunick, Conrad TI MEDI 441-Paullones are rearranged to 11H-indolo[3,2-c]quinoline-6-carboxylic acids by a novel ring contraction reaction SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Becker, Anja; Kohfeld, Simone; Preu, Lutz; Kunick, Conrad] Tech Univ Carolo Wilhelmina Braunschweig, Inst Pharmazeut Chem, D-38106 Braunschweig, Germany. [Pies, Tanja] Univ Hamburg, Inst Pharm, D-20146 Hamburg, Germany. [Zaharevitz, Daniel W.] Natl Canc Inst, Informat Technol Branch, Dev Therapeut Program, EPN, Bethesda, MD 20892 USA. EM c.kunick@tu-bs.de; zaharevitz@dtpax2.ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 441-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906812 ER PT J AU Berg, JM AF Berg, Jeremy M. TI Opportunities for chemists through the National Institutes of Health SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Berg, Jeremy M.] Natl Inst Gen Med Sci, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 5-PRES PG 2 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593904821 ER PT J AU Bezrukov, SM AF Bezrukov, Sergey M. TI PHYS 712-Large ion channels: Role of interactions with penetrating molecules SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Bezrukov, Sergey M.] NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. EM bezrukos@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 712-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907537 ER PT J AU Biswas, P AF Biswas, Pradip TI BIOL 85-Solid-liquid multiphase simulation in with simulation in CHARMM with simultaneous use of class-I and class-II force fields: Application to peptide adsorptions on polymer surfaces SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Biswas, Pradip] NIH, Biophys Chem Lab, Bethesda, MD 3309 USA. EM biswasp@nhlbi.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 85-BIOL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593900786 ER PT J AU Brooks, BR Woodcock, HL Zheng, W AF Brooks, Bernard R. Woodcock, H. Lee, III Zheng, Wenjun TI PHYS 300-Techniques for free energies estimation using ab initio QM/MM methods SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Brooks, Bernard R.; Woodcock, H. Lee, III; Zheng, Wenjun] NHLBI, NIH, Lab Computat Biol, Bethesda, MD 20892 USA. EM brb@nih.gov; hlwood@nih.gov; zhengwj@helix.nih.gov RI Woodc, Henry/D-9275-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 300-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907517 ER PT J AU Buchete, NV Hummer, G AF Buchete, Nicolae-Viorel Hummer, Gerhard TI COMP 362-Coarse master equations for peptide folding kinetics from atomistic molecular simulations SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Buchete, Nicolae-Viorel; Hummer, Gerhard] NIDDK, NIH, Chem Phys Lab, Bethesda, MD 20892 USA. EM buchete@nih.gov; Gerhard.Hummer@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 362-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906293 ER PT J AU Cellmer, T Eaton, WA Hofrichter, J AF Cellmer, Troy Eaton, William A. Hofrichter, James TI Ultrafast folding of the villin subdomain SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Cellmer, Troy; Eaton, William A.; Hofrichter, James] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM cellmert@niddk.nih.gov; eaton@helix.nih.gov; jim@sunder.niddk.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 18-BIOT PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593903299 ER PT J AU Chan, ER Nablo, BJ Nguyen, TL Kasianowicz, JJ Stanford, VM AF Chan, Elaine R. Nablo, Brian J. Nguyen, Tam L. Kasianowicz, John J. Stanford, Vincent M. TI PHYS 714-Insights on the structural properties of the anthrax ion channel from electrophysiological measurements and modeling SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Chan, Elaine R.; Nablo, Brian J.; Kasianowicz, John J.] NIST, Div Semicond Elect, Elect & Elect Engn Lab, Gaithersburg, MD 20899 USA. [Nguyen, Tam L.] NCI Frederick, Frederick, MD 21702 USA. [Nguyen, Tam L.] SAIC Frederick, Target Based Drug Discovery Grp, Frederick, MD 21702 USA. [Stanford, Vincent M.] NIST, Informat Access Div, Informat Technol Lab, Gaithersburg, MD 20899 USA. EM elaine.chan@nist.gov; brian.nablo@nist.gov; nguyent@ncifcrf.gov; john.kasianowicz@nist.gov; vincent.stanford@nist.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 714-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907593 ER PT J AU Chandrasekaran, V Lee, CJ Duke, RE Perera, L Pedersen, LG AF Chandrasekaran, Vasu Lee, Chang Jun Duke, Robert E. Perera, Lalith Pedersen, Lee G. TI COMP 120-A proposed structural model for human protein Z and its putative activated form (Za) SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Chandrasekaran, Vasu; Lee, Chang Jun; Duke, Robert E.; Pedersen, Lee G.] Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. [Perera, Lalith] NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. EM vasu@email.unc.edu; pereral2@niehs.nih.gov; pedersen@email.unc.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 120-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906309 ER PT J AU Cheng, KJ Gawrisch, K Rice, KC AF Cheng, Kejun Gawrisch, Klaus Rice, Kenner C. TI MEDI 32-Deuterated and tritiated enantiomers of CP55,940 as novel probes of cannabinoid receptors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Cheng, Kejun; Rice, Kenner C.] Natl Inst Drug Abuse, Natl Inst Hlth, Chem Biol Res Branch, Bethesda, MD 20892 USA. [Gawrisch, Klaus] NIAAA, NIH, Lab Membrane Biochem & Biophys, Bethesda, MD 20892 USA. EM kejunch@niddk.nih.gov; klaus.gawrisch@hhs.gov; kr21f@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 32-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907727 ER PT J AU Choi, WJ Stephen, AG Fisher, RJ Burke, TR AF Choi, Won Jun Stephen, Andrew G. Fisher, Robert J. Burke, Terrence R., Jr. TI MEDI 121-Synthetic efforts toward the development of Shc SH2 domain-binding peptides SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Choi, Won Jun; Burke, Terrence R., Jr.] NCI, Med Chem Lab, CCR, NIH, Frederick, MD 21702 USA. [Stephen, Andrew G.; Fisher, Robert J.] SAIC Frederick, Prot Chem Lab, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 121-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906656 ER PT J AU Cisneros, GA Piquemal, JP Darden, TA AF Cisneros, G. Andres Piquemal, Jean-Philip Darden, Thomas A. TI Generalization of the Gaussian Electrostatic Model: A molecular density based force field SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Cisneros, G. Andres; Darden, Thomas A.] NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. [Piquemal, Jean-Philip] Univ Paris 06, CNRS, Chim Theor Lab, UMR 7616, F-75252 Paris 05, France. EM cisnero1@niehs.nih.gov; jpp@lct.jussieu.fr NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 64-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906081 ER PT J AU Cisneros, GA Piquemal, JP Darden, TA AF Cisneros, G. Andres Piquemal, Jean-Philip Darden, Thomas A. TI AEI 45-Generalization of the Gaussian electrostatic model: A molecular density based force field SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Cisneros, G. Andres; Darden, Thomas A.] NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. [Piquemal, Jean-Philip] Univ Paris 06, CNRS, Chim Theor Lab, UMR 7616, F-75252 Paris 5, France. EM cisnero1@niehs.nih.gov; jpp@lct.jussieu.fr NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 45-AEI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593900018 ER PT J AU Egert, AM Kohfeld, S Totzke, F Schachtele, C Kubbutat, MHG Zaharevitz, DW Kunick, C AF Egert, Anne-Marie Kohfeld, Simone Totzke, Frank Schaechtele, Christoph Kubbutat, Michael H. G. Zaharevitz, Daniel W. Kunick, Conrad TI MEDI 435-Synthesis and profiling of a new multiple kinase inhibitor chemotype SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Egert, Anne-Marie; Kohfeld, Simone; Kunick, Conrad] Tech Univ Carolo Wilhelmina Braunschweig, Inst Pharmaceut Chem, D-38106 Braunschweig, Germany. [Totzke, Frank; Schaechtele, Christoph; Kubbutat, Michael H. G.] ProQinase GmbH, D-79106 Freiburg, Germany. [Zaharevitz, Daniel W.] NCI, Informat Technol Branch, Dev Therapeut Program, Bethesda, MD 20892 USA. EM c.kunick@tu-bs.de; zaharevitz@dtpax2.ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 435-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907730 ER PT J AU El Kazzouli, S Lewin, NE Blumberg, PM Marquez, VE AF El Kazzouli, Said Lewin, Nancy E. Blumberg, Peter M. Marquez, Vicror E. TI MEDI 399-Synthesis of DAG-lactones containing heterocyclic moieties: Small focused libraries in search of C1-specific domain interactions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [El Kazzouli, Said; Marquez, Vicror E.] NCI, Med Chem Lab, Natl Inst Healt, Ctr Canc Res, Frederick, MD 21702 USA. [Lewin, Nancy E.; Blumberg, Peter M.] NCI, Lab Canc Biol & Genet, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. EM elkazzoulis@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 399-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906746 ER PT J AU Fishelovitch, D Hazan, C Shaik, S Wolfson, H Nussinov, R AF Fishelovitch, Dan Hazan, Carina Shaik, Sason Wolfson, Haim Nussinov, Ruth TI MEDI 202-Structural dynamics of the cooperative binding of organic molecules in the human Cytochrome P450 3A4 (CYP3A4) SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Fishelovitch, Dan] Tel Aviv Univ, Dept Human Genet, IL-61390 Tel Aviv, Israel. [Hazan, Carina] Hebrew Univ Jerusalem, Inst Chem, IL-91904 Jerusalem, Israel. [Hazan, Carina] Hebrew Univ Jerusalem, Lise Meitner Minerva Ctr Computat Quantum Chem, IL-91904 Jerusalem, Israel. [Shaik, Sason] Hebrew Univ Jerusalem, Dept Organ Chem, IL-91904 Jerusalem, Israel. [Shaik, Sason] Hebrew Univ Jerusalem, Lise Meitner Minerva Ctr Computat Chem, IL-91904 Jerusalem, Israel. [Nussinov, Ruth] NCI, SAIC Frederick Inc, Basic Res Program Macromol Struct, Frederick, MD 21702 USA. EM danfishl@post.tau.ac.il; sason@yfaat.ch.huji.ac.il; wolfson@tau.ac.il; ruthn@ncisgi.ncifcrf.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 202-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906564 ER PT J AU Guo, T Wang, WJ Lee, CS Zhuang, ZP Weil, R Balgley, BM AF Guo, Tong Wang, Weijie Lee, Cheng S. Zhuang, Zhengping Weil, Robert Balgley, Brian M. TI ANYL 318-Discovery and validation of astrocytoma biomarkers using microdissected tissue specimens coupled with targeted and mass spectrometry-based proteomic studies SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Guo, Tong; Lee, Cheng S.] Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. [Wang, Weijie; Balgley, Brian M.] Calibrant Biosyst, Gaithersburg, MD 20878 USA. [Zhuang, Zhengping] NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. [Weil, Robert] Cleveland Clin Fdn, Brain Tumor & Neurooncol Ctr, Cleveland, OH 44195 USA. EM tguo@umd.edu; weijie.wang@calibrant.com; clee1@umd.edu; Zhuangp@ninds.nih.gov; brian.balgley@calibrant.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 318-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593901109 ER PT J AU He, HJ Pires, R Zhu, TN Zhou, AH Gaigalas, AK Zou, S Wang, LL AF He, Hua-Jun Pires, Richard Zhu, Tie-Nian Zhou, Anhong Gaigalas, Adolfas K. Zou, Sige Wang, Lili TI ANYL 420-Fluorescence resonance energy transfer based method for detection of DNA binding activities of nuclear factor kappa B SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [He, Hua-Jun; Gaigalas, Adolfas K.; Wang, Lili] NIST, Div Biochem Sci, Gaithersburg, MD 20899 USA. [Pires, Richard] Montgomery Coll, Dept Nat Sci, Germantown, MD 20876 USA. [Zhu, Tie-Nian] NIA, NIH, Clin Invest Lab, Baltimore, MD 21224 USA. [Zhou, Anhong] Utah State Univ, Dept Biol & Irrigat Engn, Logan, UT 84322 USA. [Zou, Sige] NIA, NIH, Lab Expt Gerontol, Baltimore, MD 21224 USA. EM hua.he@nist.gov; zhuti@mail.nih.gov; adolfas.gaigalas@nist.gov; zous@grc.nia.nih.gov; lili.wang@nist.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 420-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593901012 ER PT J AU Hoffer, B AF Hoffer, Barry TI MEDI 207-Addiction and brain mechanisms SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Hoffer, Barry] NIDA, NIH, Baltimore, MD 21224 USA. EM BHOFFER@intra.nida.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 207-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907846 ER PT J AU Horkay, F AF Horkay, Ferenc TI Biopolymer gels and ions SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Horkay, Ferenc] NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. EM horkay@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 189-PMSE PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593905327 ER PT J AU Horkay, F Lin, DC Horkayne-Szakaly, I Dimitriadis, EK Silva, C Basser, PJ AF Horkay, Ferenc Lin, David C. Horkayne-Szakaly, Iren Dimitriadis, Emilios K. Silva, Candida Basser, Peter J. TI BIOT 416-Biomechanical properties of tissue engineered cartilage SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Horkay, Ferenc; Lin, David C.; Horkayne-Szakaly, Iren; Silva, Candida; Basser, Peter J.] NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. [Dimitriadis, Emilios K.] NIH, Div Bioengn & Phys Sci, ORS, Bethesda, MD 20892 USA. EM horkay@helix.nih.gov; lindavid@mail.nih.gov; horkayi@mail.nih.gov; dimitre@ors.od.nih.gov; pjbasser@helix.nih.gov RI Basser, Peter/H-5477-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 416-BIOT PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593903195 ER PT J AU Hummer, G Hassan, SA Lee, YS Dellago, C AF Hummer, Gerhard Hassan, Sergio A. Lee, Yong S. Dellago, Christoph TI PHYS 222-Proton transfer along ordered water chains inside carbon nanotubes SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Hummer, Gerhard] NIDDK, NIH, Chem Phys Lab, Bethesda, MD 20892 USA. [Hassan, Sergio A.] NIH, Ctr Mol Modeling, DHHS, Bethesda, MD 20892 USA. [Lee, Yong S.] NIH, Ctr Mol Modeling, Ctr Informat Technol, Bethesda, MD 20892 USA. [Dellago, Christoph] Univ Vienna, Fac Phys, A-1090 Vienna, Austria. EM Gerhard.Hummer@nih.gov; mago@helix.nih.gov; leeys@mail.nih.gov; christoph.dellago@univie.ac.at RI Dellago, Christoph/E-1625-2011; Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 222-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907147 ER PT J AU Hummer, G Rasaiah, JC Yin, H AF Hummer, Gerhard Rasaiah, Jayendran C. Yin, Hao TI Water in nonpolar pores and protein cavities SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Hummer, Gerhard] NIDDK, NIH, Chem Phys Lab, Bethesda, MD 20892 USA. [Rasaiah, Jayendran C.; Yin, Hao] Univ Maine, Orono, ME 04469 USA. EM Gerhard.Hummer@nih.gov; rasaiah@maine.edu RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 215-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906002 ER PT J AU Issaq, HJ Xu, X Roman, JM Abbott, E Veenstra, TD AF Issaq, Haleem J. Xu, X. Roman, J. M. Abbott, E. Veenstra, T. D. TI ANYL 299-Packed column SFC: A fast separation technique for the clinical laboratory SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Issaq, Haleem J.; Xu, X.; Roman, J. M.; Abbott, E.; Veenstra, T. D.] NCI, Lab Prote & Analyt Technol, Frederick, MD 21702 USA. EM issaqh@mail.ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 299-ANYL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593901462 ER PT J AU Jiang, JK Chen, Z O'Shea, JJ Liu, EH Harlan, DM Thomas, CJ Perreira, M AF Jiang, Jian Kang Chen, Zhi O'Shea, John J. Liu, Eric H. Harlan, David M. Thomas, Craig J. Perreira, Melissa TI An expedient route for the enantioselective synthesis of immunosuppressive agent CP-690,550 SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Jiang, Jian Kang] NHGRI, Chem Genom Ctr, NIH, Rockville, MD 20850 USA. [Chen, Zhi; O'Shea, John J.] NIAMS, Natl Inst Hlth, Mol Immunol & Inflammat Branch, Bethesda, MD 20892 USA. [Liu, Eric H.] NIDDK, Natl Inst Hlth, Diabet Branch, Bethesda, MD 20854 USA. [Harlan, David M.] NIDDK, Mark O Hatfield Clin Res Ctr, Natl Inst Hlth, Diabet Branch, Bethesda, MD 20854 USA. [Thomas, Craig J.] NHGRI, Chem Genom Ctr, NIH, Rockville, MD 20850 USA. [Perreira, Melissa] US Patent & Trademark Off, Alexandria, VA USA. EM jiankangj@gmail.com; chenzhi@mail.nih.gov; osheajo@mail.nih.gov; ericliu@mail.nih.gov; davidmh@intra.niddk.nih.gov; craigt@nhgri.nih.gov; perreiramelissa@hotmail.com NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 676-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12JA UT WOS:000207594300724 ER PT J AU Ju, C You, QA Holt, M Cheng, LL Pohl, LR AF Ju, Cynthia You, Qiang Holt, Michael Cheng, Linling Pohl, Lance R. TI Role of the innate immune system in drug-induced liver injury SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Ju, Cynthia; You, Qiang; Holt, Michael; Cheng, Linling] Univ Colorado, Hlth Sci Ctr, Dept Pharmaceut Sci, Denver, CO 80262 USA. [Pohl, Lance R.] NHLBI, Mol & Cellular Toxicol Sect, NIH, Bethesda, MD 20892 USA. EM Cynthia.Ju@UCHSC.edu; pohll@nhlbi.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 33-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593905133 ER PT J AU Keiser, MJ Roth, BL Armburster, BN Ernsberger, P Irwin, JJ Shoichet, BK AF Keiser, M. J. Roth, Bryan L. Armburster, B. N. Ernsberger, P. Irwin, John J. Shoichet, Brian K. TI CINF 7-Relating protein pharmacology by ligand chemistry SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Keiser, M. J.; Irwin, John J.; Shoichet, Brian K.] Univ Calif San Francisco, Dept Pharmaceut Chem, San Francisco, CA 94143 USA. [Roth, Bryan L.; Armburster, B. N.; Ernsberger, P.] Univ N Carolina, Natl Inst Mental Hlth Psychoact Drug Screening Pr, Chapel Hill, NC 27599 USA. [Roth, Bryan L.; Armburster, B. N.; Ernsberger, P.] Univ N Carolina, Dept Pharmacol, Chapel Hill, NC 27599 USA. EM keiser@gmail.com; bryan_roth@med.unc.edu; jji@cgl.ucsf.edu RI Ernsberger, Paul/O-2702-2014 OI Ernsberger, Paul/0000-0003-2372-2500 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 7-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593901713 ER PT J AU Kim, SE Shi, ZD Peach, M Giubellino, A Nicklaus, MC Bottaro, D Burke, TR AF Kim, Sung-Eun Shi, Zhen-Dan Peach, Megan Giubellino, Alessio Nicklaus, Marc C. Bottaro, Donald Burke, Terrence R., Jr. TI MEDI 361-Design and synthesis of c-met kinase inhibitors based on an in silico screen-derived lead SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Kim, Sung-Eun; Shi, Zhen-Dan; Peach, Megan; Nicklaus, Marc C.; Burke, Terrence R., Jr.] NCI, Med Chem Lab, CCR, NIH, Frederick, MD 21702 USA. [Giubellino, Alessio; Bottaro, Donald] NCI, Urol Oncol Branch, CCR, NIH, Bethesda, MD 20892 USA. EM kims@ncifcrf.gov; shizh@nhlbi.nih.gov; mpeach@helix.nih.gov; giubella@mail.nih.gov; mnl@helix.nih.gov; bottarod@mail.nih.gov; tburke@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 361-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907723 ER PT J AU Kim, Y Klutz, AM Hechler, B Gachet, C Jacobson, KA AF Kim, Yoonkyung Klutz, Athena M. Hechler, Beatrice Gachet, Christian Jacobson, Kenneth A. TI Toward multivalent GPCR signaling from poly(amidoamine) dendrimer conjugates SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Kim, Yoonkyung; Klutz, Athena M.; Jacobson, Kenneth A.] NIDDK, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. [Hechler, Beatrice; Gachet, Christian] INSERM, Etab Francais Sang Alsace, U311, Strasbourg, France. EM kimyoonk@niddk.nih.gov RI Hechler, Beatrice/D-4227-2017 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 275-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906797 ER PT J AU Kobayashi, H Hama, Y Gunn, AJ Koyama, Y Urano, Y Choyke, PL AF Kobayashi, Hisataka Hama, Yukihiro Gunn, Andrew J. Koyama, Yoshinori Urano, Yasuteru Choyke, Peter L. TI BIOT 188-D-galactose receptor-targeted in vivo spectral fluorescence molecular imaging of peritoneal metastasis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Kobayashi, Hisataka; Hama, Yukihiro; Gunn, Andrew J.; Koyama, Yoshinori; Choyke, Peter L.] NCI, Mol Imaging Program, CCR, NIH, Bethesda, MD 20892 USA. [Urano, Yasuteru] Univ Tokyo, Grad Sch Pharmaceut Sci, Bunkyo Ku, Tokyo 1130033, Japan. EM Kobayash@mail.nih.gov; hamay@mail.nih.gov; urano@mol.f.u-tokyo.ac.jp RI Urano, Yasuteru/H-1380-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 188-BIOT PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593903077 ER PT J AU Kong, L Saavedra, JE Nagashima, K Zheng, JW Patri, A Keefer, LK AF Kong, Li Saavedra, Joseph E. Nagashima, Kunio Zheng, Jiwen Patri, Anil Keefer, Larry K. TI Nitric oxide-induced deamidation retards and reverses fibril formation by an oligo(glutamine/asparagine) peptide SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Kong, Li; Keefer, Larry K.] NCI, Comparat Carcinogenesis Lab, Chem Sect, Frederick, MD 21702 USA. [Saavedra, Joseph E.] SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. [Nagashima, Kunio] NCI, Res Technol Program, Image Anal Lab, SAIC Frederick, Frederick, MD 21702 USA. [Zheng, Jiwen; Patri, Anil] NCI, Nanotechnol Characterizat Lab, SAIC Frederick, Frederick, MD 21702 USA. EM kongl@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 120-TOXI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593905176 ER PT J AU LeClair, CA Prinz, WA Raychaudhuri, S Thomas, CJ AF LeClair, Christopher A. Prinz, William A. Raychaudhuri, Sumana Thomas, Craig J. TI MEDI 445-Utilizing a diazirine and alkyne containing probe in a proof of principle study to investigate small molecule interactions across the proteome SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [LeClair, Christopher A.; Thomas, Craig J.] NHGRI, NIH Chem Genom Ctr, NIH, Rockville, MD 20850 USA. [Prinz, William A.; Raychaudhuri, Sumana] NIDDKD, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. EM leclairc@mail.nih.gov; wp53m@mail.nih.gov; sr377u@mail.nih.gov; craigt@nhgri.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 445-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907766 ER PT J AU Li, HT Kaur, G Shi, Z Sulima, A Teng, B Vasalatiy, O Wu, H Xu, B Cofiell, S Neale, N Ruddy, B Wilson, C Griffiths, GL AF Li, Haitao Kaur, G. Shi, Z. Sulima, A. Teng, B. Vasalatiy, O. Wu, H. Xu, B. Cofiell, S. Neale, N. Ruddy, B. Wilson, C. Griffiths, G. L. TI The Imaging Probe Development Center: An NIH roadmap initiative to promote molecular imaging applications in interdisciplinary research SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Li, Haitao; Kaur, G.; Shi, Z.; Sulima, A.; Teng, B.; Vasalatiy, O.; Wu, H.; Xu, B.; Cofiell, S.; Neale, N.; Ruddy, B.; Wilson, C.; Griffiths, G. L.] NHLBI, Imaging Probe Dev Ctr, NIH, Rockville, MD 20850 USA. EM lih3@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 78-NUCL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593904567 ER PT J AU Liu, F Worthy, KM Bindu, L Fisher, RJ Burke, TR AF Liu, Fa Worthy, Karen M. Bindu, Lakshman Fisher, Robert J. Burke, Terrence R., Jr. TI MEDI 120-Examination of secondary conformational constraint in the design of macrocyclic Grb2-SH2 domain-binding ligands SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Liu, Fa; Burke, Terrence R., Jr.] NCI, Med Chem Lab, CCR, NIH, Ft Detrick, MD 21702 USA. [Worthy, Karen M.; Bindu, Lakshman; Fisher, Robert J.] SAIC Frederick, Prot Chem Lab, Ft Detrick, MD 21702 USA. EM liuf@ncifcrf.gov; tburke@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 120-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906677 ER PT J AU Liu, J Nussinov, R AF Liu, Jin Nussinov, Ruth TI COMP 203-Molecular dynamics simulations suggest a way to stabilize von Hippel-Lindau tumor suppressor protein and rescue its function SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Liu, Jin] NCI Frederick, Ctr Canc Res, Nanobiol Program, Basic Res Program,SAIC, Ft Detrick, MD 21702 USA. [Nussinov, Ruth] SAIC, NCI FCRDC, Ctr Canc Res Nanobiol Program, Basic Res Program, Ft Detrick, MD 21702 USA. EM jliu@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 203-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906181 ER PT J AU Liu, SX Abbondanzieri, EA Bokinsky, G Le Grice, S Zhuang, XW AF Liu, Shixin Abbondanzieri, Elio A. Bokinsky, Gregory Le Grice, Stuart Zhuang, Xiaowei TI PHYS 594-HIV-1 reverse transcriptase shuttles back and forth during strand displacement synthesis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Liu, Shixin; Abbondanzieri, Elio A.; Bokinsky, Gregory; Zhuang, Xiaowei] Harvard Univ, Dept Chem & Biol Chem, Cambridge, MA 02138 USA. [Le Grice, Stuart] NCI Frederick, Div Basic Sci, Frederick, MD 21701 USA. EM sliu@fas.harvard.edu; abbondan@fas.harvard.edu; zhuang@chemistry.harvard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 594-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907310 ER PT J AU Low, PS Paulos, CM Varghese, B AF Low, Philip S. Paulos, Chrystal M. Varghese, Bindu TI MEDI 227-Folate receptor-targeted therapies for inflammatory and autoimmune diseases SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Low, Philip S.] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA. [Paulos, Chrystal M.] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. EM chrystal_paulos@nih.gov; varghesb@purdue.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 227-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906529 ER PT J AU Ma, BY Levine, AJ AF Ma, Buyong Levine, Arnold J. TI COMP 140-Deducing the multiple binding modes of p53 tetramer - DNA interaction based on full-site palindrome of p53 response elements SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Ma, Buyong] NCI, Ctr Canc Res Nanobiol Program, Basic Res Program, SAIC,FCRDC, Frederick, MD 21702 USA. [Levine, Arnold J.] Inst Adv Study, Princeton, NJ 08540 USA. EM mab@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 140-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906290 ER PT J AU Marquez, VE Ludek, OR AF Marquez, Victor E. Ludek, Olaf R. TI ORGN 148-Carbocyclic analogs of 1,3-diazepin-2-one nucleosides as transition-state inhibitors of cytidine deaminase SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Marquez, Victor E.; Ludek, Olaf R.] NCI, NIH, Med Chem Lab, Frederick, MD 21702 USA. EM marquezv@mail.nih.gov; oludek@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 148-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12JA UT WOS:000207594300572 ER PT J AU Mayer, M AF Mayer, Mark TI PHYS 20-Structural analysis of glutamate receptor function SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Mayer, Mark] NICHD, Lab Cellular & Mol Neurophysiol, Natl Inst Hlth, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. EM mayerm@mail.nih.gov RI Mayer, Mark/H-5500-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 20-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907704 ER PT J AU Musier-Forsyth, K Mitra, M Stewart-Maynard, KM Vo, MN Cruceanu, M Wang, F Gorelick, RJ Williams, MC Rouzina, I AF Musier-Forsyth, Karin Mitra, Mithun Stewart-Maynard, Kristen M. Vo, My-Nuong Cruceanu, Margareta Wang, Fei Gorelick, Robert J. Williams, Mark C. Rouzina, Ioulia TI COMP 220-Mechanistic studies of nucleic acid chaperone activity of retroviral nucleocapsid proteins SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Musier-Forsyth, Karin; Mitra, Mithun] Ohio State Univ, Dept Chem, Columbus, OH 43210 USA. [Stewart-Maynard, Kristen M.; Vo, My-Nuong] Univ Minnesota, Dept Chem, Minneapolis, MN 55455 USA. [Cruceanu, Margareta; Wang, Fei; Williams, Mark C.] Northeastern Univ, Dept Phys, Boston, MA 02115 USA. [Gorelick, Robert J.] SAIC Frederick Inc, NCI Frederick, AIDS Vaccine Program, Frederick, MD 21702 USA. [Rouzina, Ioulia] Univ Minnesota, Dept Biochem Mol Biol & Biophys, Minneapolis, MN 55455 USA. EM musier@chemistry.ohio-state.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 220-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906343 ER PT J AU Nikas, SP Thakur, GA Parish, D Alapafuja, SO Huestis, MA Makriyannis, A AF Nikas, Spyros P. Thakur, Ganesh A. Parish, Damon Alapafuja, Shakiru O. Huestis, Marilyn A. Makriyannis, Alexandros TI Synthesis of (-)-Delta(9)-tetrahydrocannabinol and (-)-Delta(9)-tetrahydrocannabivarin metabolites and their regiospecifically deuterated analogs SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Nikas, Spyros P.; Thakur, Ganesh A.; Alapafuja, Shakiru O.; Makriyannis, Alexandros] Northeastern Univ, Dept Pharmaceut Sci, Ctr Drug Discovery, Boston, MA 02115 USA. [Parish, Damon] USN, Res Lab, Washington, DC 20375 USA. [Huestis, Marilyn A.] NIDA, Chem & Drug Metab Sect, CPTR Branch, Intramural Res Program,NIH, Baltimore, MD USA. EM spyridonnikas@yahoo.com; gathakur@gmail.com; Alapafuja@yahoo.com; a.makriyannis@neu.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 31-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906514 ER PT J AU Nussinov, R Jang, H Zheng, J Ma, BY AF Nussinov, Ruth Jang, Hyunbum Zheng, Jie Ma, Buyong TI PHYS 298-Modeling Alzheimer amyloid conformations and toxicity SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Jang, Hyunbum; Ma, Buyong] NCI, FCRDC, SAIC, Ctr Canc Res Nanobiol Program,Basic Res Program, Frederick, MD 21702 USA. [Nussinov, Ruth; Zheng, Jie] NCI, Frederick Canc Res & Dev Ctr, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. EM ruthn@ncifcrf.gov; jangh@ncifcrf.gov; jzheng@ncifcrf.gov; mab@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 298-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907377 ER PT J AU Phillips, CM Schreiter, ER Guo, YY Drennan, CL AF Phillips, Christine M. Schreiter, Eric R. Guo, Yayi Drennan, Catherine L. TI INOR 148-How binding of different metals affects the structure of nickel regulator protein NikR SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Phillips, Christine M.; Guo, Yayi; Drennan, Catherine L.] MIT, Dept Chem, Cambridge, MA 02139 USA. [Schreiter, Eric R.] Univ Puerto Rico, NIH, Prot Res Ctr, Mayaguez, PR 00681 USA. EM cmp_chem@mit.edu; eric_sch@mit.edu; cdrennan@mit.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 148-INOR PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593909426 ER PT J AU Polozov, IV AF Polozov, Ivan V. TI PHYS 148-Membrane permeabilization by cationic amphipathic peptides SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Polozov, Ivan V.] NICHD, Lab Cell & Mol Biophys, Natl Inst Hlth, Bethesda, MD 20892 USA. EM ipolozov@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 148-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907705 ER PT J AU Qasba, PK Boeggeman, E Ramakrishnan, B AF Qasba, Pradman Krishen Boeggeman, Elizabeth Ramakrishnan, Boopathy TI BIOT 185-Mutant glycosyltransferases assist in linking glycoconjugates via glycan chains: Development of a targeted drug delivery system and contrast agents for MRI SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Boeggeman, Elizabeth; Ramakrishnan, Boopathy] NCI Frederick, Struct Glycobiol Sect, Nanobiol Program, Ctr Canc Res,SAIC Inc,NCI,NIH, Ft Detrick, MD 21702 USA. EM qasba@helix.nih.gov; eeb@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 185-BIOT PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593903059 ER PT J AU Rai, G Thomas, CJ AF Rai, Ganesha Thomas, Craig J. TI MEDI 442-Syntheses of UDP-GlcNYn, UDP-GalNYn and several analogs with utility to analyze sugar-transferase protein substrates SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Rai, Ganesha; Thomas, Craig J.] NHGRI, NIH, Chem Gen Ctr, Rockville, MD 20850 USA. EM bantukallug@mail.nih.gov; craigt@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 442-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907826 ER PT J AU Rasaiah, JC Yin, H Hummer, G AF Rasaiah, Jayendran C. Yin, Hao Hummer, Gerhard TI PHYS 567-Water clusters in the nonpolar cavities of the protein tetrabrachion SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Rasaiah, Jayendran C.; Yin, Hao] Univ Maine, Orono, ME 04469 USA. [Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM rasaiah@maine.edu; Gerhard.Hummer@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 567-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907262 ER PT J AU Rice, KC AF Rice, Kenner C. TI MEDI 211-Medicinal chemistry in drug abuse research SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Rice, Kenner C.] Natl Inst Drug Abuse, Chem Biol Res Branch, NIH, Bethesda, MD 20892 USA. EM kr21f@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 211-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906757 ER PT J AU Roth, BR AF Roth, Bryan R. TI CINF 1-Mining the receptorome: A powerful approach for predicting efficacies and side effects of repositioned medications SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Roth, Bryan R.] Univ N Carolina, Sch Med, Dept Pharmacol, Natl Inst Mental Hlth Psychoact Drug Screening Pr, Chapel Hill, NC 27599 USA. [Roth, Bryan R.] Univ N Carolina, Sch Med, Dept Pharmacol, Dept Biochem, Chapel Hill, NC 27599 USA. EM bryan_roth@med.unc.edu NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 1-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593901733 ER PT J AU Russell, TP Shin, D Molnar, LK Kim, SH Xu, T AF Russell, Thomas P. Shin, Dongseok Molnar, Linda K. Kim, Seung Hyun Xu, Ting TI Incorporation and selective localization of bio-nanoparticles in thin film of water-insoluble block copolymer SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Russell, Thomas P.; Shin, Dongseok] Univ Massachusetts, Dept Polymer Sci & Engn, Amherst, MA 01003 USA. [Molnar, Linda K.] NCI, Off Director, Bethesda, MD 20892 USA. [Kim, Seung Hyun] Inha Univ, Div Nanosyst Engn, Inchon, South Korea. [Xu, Ting] Univ Calif Berkeley, Dept Mat Sci, Berkeley, CA 94720 USA. EM russell@mail.pse.umass.edu NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 159-PMSE PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593905325 ER PT J AU Saneyoshi, H Marquez, VE AF Saneyoshi, Hisao Marquez, Victor E. TI MEDI 339-Study of conformationally biased oligodeoxyribonucleotides designed to induce bending and/or novel secondary structures in DNA SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Saneyoshi, Hisao; Marquez, Victor E.] NCI Frederick, Med Chem Lab, Ctr Canc Res, Ft Detrick, MD 21702 USA. EM saneyoshih@ncifcrf.gov; marquezv@dc37a.nci.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 339-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906748 ER PT J AU Saneyoshi, H Choi, Y Strazewski, P Marquez, VE AF Saneyoshi, Hisao Choi, Yongseok Strazewski, Peter Marquez, Victor E. TI MEDI 439-Synthesis of conformationally locked versions of puromycin as tools to understand the role of furanose conformation in the peptidyl transfer reaction SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Saneyoshi, Hisao; Choi, Yongseok; Marquez, Victor E.] NCI, Med Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. [Strazewski, Peter] Univ Lyon 1, Lab Synth Biomol, F-69622 Villeurbanne, France. EM saneyoshih@ncifcrf.gov; marquezv@dc37a.nci.nih.gov RI Choi, Yongseok/F-8375-2012 OI Choi, Yongseok/0000-0002-3622-3439 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 439-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906754 ER PT J AU Schuck, P AF Schuck, Peter TI Analytical ultracentrifugation for the characterization of proteins and protein assemblies SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Schuck, Peter] Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD 20892 USA. EM pschuck@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 145-PMSE PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593905432 ER PT J AU Sitzmann, M Filippov, IV Ihlenfeldt, WD Nicklaus, MC AF Sitzmann, Markus Filippov, Igor V. Ihlenfeldt, Wolf-Dietrich Nicklaus, Marc C. TI CINF 84-An address book for chemical space: The Chemical Structure Lookup Service (CSLS) SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Sitzmann, Markus; Nicklaus, Marc C.] NCI, Med Chem Lab, Ctr Canc Res, NIH,DHHS, Frederick, MD 21702 USA. [Filippov, Igor V.] NCI, Med Chem Lab, SAIC Frederick Inc, Frederick, MD 21702 USA. [Ihlenfeldt, Wolf-Dietrich] Xemistry GmbH, D-35094 Lahntal, Germany. EM sitzmann@helix.nih.gov; mn1@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 84-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593901700 ER PT J AU Sundgren, A AF Sundgren, Andreas TI MEDI 412-Synthesis of gold nanoparticles bearing tumor antigens as novel anticancer therapeutics SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Sundgren, Andreas] NCI, Med Chem Lab, Frederick, MD 21702 USA. EM sundgrena@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 412-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907748 ER PT J AU Szabo, A Gopich, I AF Szabo, Attila Gopich, Irina TI PHYS 664-Single molecule FRET efficiency distributions of diffusing molecules with conformational dynamics SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Szabo, Attila; Gopich, Irina] NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. EM attilas@nih.gov; gopich@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 664-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907579 ER PT J AU Thomas, JD Hofer, T Rader, C Burke, TR AF Thomas, Joshua D. Hofer, Thomas Rader, Christoph Burke, Terrence R., Jr. TI MEDI 110-Synthesis of a reactive linker for the construction of antibody-drug hybrid molecules SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Thomas, Joshua D.; Burke, Terrence R., Jr.] NCI, Med Chem Lab, CCR, NIH, Frederick, MD 21702 USA. [Hofer, Thomas; Rader, Christoph] NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. EM josthom@ncifcrf.gov; raderc@mail.nih.gov; tburke@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 110-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906723 ER PT J AU Tullius, TD Parker, SCJ Bishop, E Hansen, L Margulies, EH AF Tullius, Thomas D. Parker, Stephen C. J. Bishop, Eric Hansen, Loren Margulies, Elliott H. TI CARB 20-Structure-based identification of functional regions in the human genome SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Tullius, Thomas D.; Parker, Stephen C. J.; Bishop, Eric; Hansen, Loren] Boston Univ, Boston, MA 02215 USA. [Margulies, Elliott H.] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20982 USA. EM tullius@bu.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 20-CARB PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593901547 ER PT J AU Vaiana, S Eaton, WA Ghirlando, R Hofrichter, J AF Vaiana, Sara Eaton, William A. Ghirlando, Rodolfo Hofrichter, James TI BIOT 45-Dynamics of intramolecular contact formation in islet amyloid polypeptide (IAPP) SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Vaiana, Sara] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. [Ghirlando, Rodolfo] NIDDK, Mol Biol Lab, NIH, Bethesda, MD USA. EM sarav@niddk.nih.gov; eaton@helix.nih.gov; RodolfoG@intra.niddk.nih.gov; jim@sunder.niddk.nih.gov NR 0 TC 0 Z9 0 U1 2 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 45-BIOT PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593903396 ER PT J AU Wang, K Golbraikh, A Roth, BR Tropsha, A AF Wang, Kun Golbraikh, Alexander Roth, Bryan R. Tropsha, Alexander TI MEDI 151-Classifcation QSAR modeling of the imbalanced dataset of hERG K plus channel blockers and openers SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Golbraikh, Alexander; Tropsha, Alexander] Univ N Carolina, Sch Pharm, Lab Mol Modeling, Chapel Hill, NC 27599 USA. [Roth, Bryan R.] Univ N Carolina, Natl Inst Mental Hlth Psychoact Drug Screening Pr, Chapel Hill, NC 27599 USA. [Roth, Bryan R.] Univ N Carolina, Dept Biochem, Chapel Hill, NC 27599 USA. [Roth, Bryan R.] Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. EM kunwang@email.unc.edu; golbraik@email.unc.edu; bryan_roth@med.unc.edu; alex_tropsha@unc.edu RI Tropsha, Alexander/G-6245-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 151-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907841 ER PT J AU Washburn, NR Bencherif, SA Srinivasan, A Hollinger, J Horkay, F Matyjaszewski, K AF Washburn, Newell R. Bencherif, Sidi A. Srinivasan, Abiraman Hollinger, Jeffrey Horkay, Ferenc Matyjaszewski, Krzysztof TI POLY 539-Synthesis and characterization of highly crosslinked hyaluronan hydrogels SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Washburn, Newell R.] Carnegie Mellon Univ, Dept Chem, Pittsburgh, PA 15217 USA. [Washburn, Newell R.] Carnegie Mellon Univ, Dept Biomed Engn, Pittsburgh, PA 15217 USA. [Bencherif, Sidi A.; Matyjaszewski, Krzysztof] Carnegie Mellon Univ, Dept Chem, Pittsburgh, PA 15213 USA. [Srinivasan, Abiraman] Carnegie Mellon Univ, Dept Biomed Engn, Pittsburgh, PA 15213 USA. [Hollinger, Jeffrey] Carnegie Mellon Univ, BTEC, Pittsburgh, PA 15213 USA. [Horkay, Ferenc] NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. EM washburn@andrew.cmu.edu; sabenche@andrew.cmu.edu; abiraman@andrew.cmu.edu; horkay@helix.nih.gov; km3b@andrew.cmu.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 539-POLY PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593908278 ER PT J AU Weidlich, IE Dexheimer, T Pommier, Y Merchand, C Nicklaus, MC AF Weidlich, Iwona E. Dexheimer, Thomas Pommier, Yves Merchand, Christophe Nicklaus, Marc C. TI MEDI 176-Virtual screening of the inhibitors into Tyrosyl-DNA Phoshodiesterase (Tdp1) active sites SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Weidlich, Iwona E.; Nicklaus, Marc C.] NCI, Med Chem Lab, Ctr Canc Res, NIH,DHHS, Ft Detrick, MD 21702 USA. [Dexheimer, Thomas; Pommier, Yves; Merchand, Christophe] NCI, Mol Pharmacol Lab, CCR, NIH, Bethesda, MD 20892 USA. EM pommier@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 176-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907800 ER PT J AU Weidlich, IE Marchand, C Pommier, Y Nicklaus, MC AF Weidlich, Iwona E. Marchand, Christophe Pommier, Yves Nicklaus, Marc C. TI MEDI 95-Discovery of novel HIV-1 integrase inhibitors by pharmacophore search SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Weidlich, Iwona E.; Nicklaus, Marc C.] NCI, Med Chem Lab, Ctr Canc Res, NIH,DHHS, Frederick, MD 21702 USA. [Marchand, Christophe; Pommier, Yves] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. EM mn1@helix.nih.gov RI Marchand, Christophe/D-8559-2016 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 95-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593907786 ER PT J AU Weidlich, IE Tarasov, SG Michejda, CJ Nicklaus, MC AF Weidlich, Iwona E. Tarasov, Sergey G. Michejda, Christopher J. Nicklaus, Marc C. TI Nature of stacking interactions between imidazoacridone intercalators and DNA Base Pairs SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Weidlich, Iwona E.; Nicklaus, Marc C.] NCI, Med Chem Lab, Ctr Canc Res, NIH,DHHS, Frederick, MD 21702 USA. [Tarasov, Sergey G.] NCI Frederick, Struct Biophys Lab, Frederick, MD 21702 USA. [Michejda, Christopher J.] NCI Frederick, Struct Biophys Lab, Mol Aspects Drug Design Sect, Frederick, MD 21702 USA. EM iweidlic@helix.nih.gov; tarasovs@ncifcrf.gov; michejda@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 309-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906392 ER PT J AU Woodcock, HL Hodoscek, M Brooks, BR AF Woodcock, H. Lee, III Hodoscek, Milan Brooks, Bernard R. TI COMP 245-Exploring QM/MM paths for mapping reaction mechanisms SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Woodcock, H. Lee, III; Brooks, Bernard R.] NHLBI, NIH, Lab Computat Biol, Bethesda, MD 20892 USA. [Hodoscek, Milan] Natl Inst Chem, Ctr Mol Modeling, SI-1000 Ljubljana, Slovenia. EM hlwood@nih.gov; brb@nih.gov RI Woodc, Henry/D-9275-2011 NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 245-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906299 ER PT J AU Wu, XW Klauda, JB Pastor, RW Brooks, BR AF Wu, Xiongwu Klauda, Jeffery B. Pastor, Richard W. Brooks, Bernard R. TI COMP 12-Simulation of interfacial systems with isotropic periodical sum SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Wu, Xiongwu; Klauda, Jeffery B.; Pastor, Richard W.; Brooks, Bernard R.] NHLBI, Lab Computat Biol, Bethesda, MD 20892 USA. EM WuXW@nhlbi.nih.gov; klauda@helix.nih.gov; pastorr@nhlbi.nih.gov; brb@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 12-COMP PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906111 ER PT J AU Zhao, XZ Semenova, EA Vu, BC Liao, CZ Nicklaus, MC Hughes, SH Pommier, Y Burke, TR AF Zhao, Xue Zhi Semenova, Elena A. Vu, B. Christie Liao, Chenzhong Nicklaus, Marc C. Hughes, Stephen H. Pommier, Yves Burke, Terrence R., Jr. TI MEDI 93-Phthalimide-containing hydrazides and amides as diketo acid-class HIV-1 integrase inhibitors SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Zhao, Xue Zhi; Liao, Chenzhong; Nicklaus, Marc C.; Burke, Terrence R., Jr.] NCI, Med Chem Lab, CCR, NIH, Frederick, MD 21702 USA. [Semenova, Elena A.; Pommier, Yves] NCI, Mol Pharmacol Lab, CCR, NIH, Bethesda, MD 20892 USA. [Vu, B. Christie; Hughes, Stephen H.] NCI, HIV Drug Resistance Program, NIH, Frederick, MD 21702 USA. EM Semenovel@mail.nih.gov; cvu@ncifcrf.gov; czliao@helix.nih.gov; mn1@helix.nih.gov; hughes@ncifcrf.gov; pommier@nih.gov; tburke@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 93-MEDI PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593906662 ER PT J AU Zhu, JW Xie, YQ Vyas, VV Keseling, B Roach, J Mitra, G Creekmore, SP AF Zhu, Jianwei Xie, Yueqing Vyas, Vinay V. Keseling, Beverly Roach, John Mitra, George Creekmore, Stephen P. TI BIOT 224-Rapid development of mammalian cell production process of clinical material for proof of principle of novel therapeutic molecules SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Mitra, George] SAIC Frederick, Biopharmaceut Dev Program, NCI FCRDC, Frederick, MD 21702 USA. [Creekmore, Stephen P.] NCI, DTP, DCTD, Biol Resouces Branch, Bethesda, MD 20892 USA. EM jianweiz@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD AUG 19 PY 2007 VL 234 MA 224-BIOT PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V12IW UT WOS:000207593903425 ER PT J AU Basu, NK Kole, L Basu, M McDonagh, AF Owens, IS AF Basu, Nikhil K. Kole, Labanyamoy Basu, Mousumi McDonagh, Antony F. Owens, Ida S. TI Targeted inhibition of glucuronidation markedly improves drug efficacy in mice - A model SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE UDP-glucuronosyltraiisferase; phosphorylation; proof of principle; immunosupression; mycophenolic acid; CTL assay; curcumin; calphostin-C; PKC; drug efficacy ID PROTEIN-KINASE-C; MYCOPHENOLIC-ACID; ACYL GLUCURONIDE; CURCUMIN; IDENTIFICATION; CANCER; CELL; PHOSPHORYLATION; METABOLISM; MECHANISM AB Finding UDP-glucuronosyltransferases (UGT) require protein kinase C-mediated phosphorylation is important information that allows manipulation of this critical system. UGTs glucuronidate numerous aromatic-like chemicals derived from metabolites, diet, environment and, inadvertently, therapeutics to reduce toxicities. As UGTs are inactivated by downregulating PKCs with reversibly-acting dietary curcumin, we determined the impact of gastro-intestinal glucuronidation on free-drug uptake and efficacy using immunosuppressant, mycophenolic acid (MPA), in mice. Expressed in COS-1 cells, mouse GI-distributed Ugtlal glucuronidates curcumin and MPA and undergoes irreversibly and reversibly dephosphorylation by PKC-specific inhibitor calphostin-C and general-kinase inhibitor curcumin, respectively, with parallel effects on activity. Moreover, oral curcumin-administration to mice reversibly inhibited glucuronidation in GI-tissues. Finally, successive oral administration of curcumin and MPA to antigen-treated mice increased serum free MPA and immunosuppression up to 9-fold. Results indicate targeted inhibition of GI glucuronidation in mice markedly improved free-chemical uptake and efficacy using MPA as a model. (c) Published by Elsevier Inc. C1 NICHHD, Heritable Disorders Branch, NIH, Bethesda, MD 20892 USA. Univ Calif San Francisco, Div Gastroenterol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Ctr Liver, Dept Med, San Francisco, CA 94143 USA. RP Owens, IS (reprint author), NICHHD, Heritable Disorders Branch, NIH, Bldg 10,Room 8D-42, Bethesda, MD 20892 USA. EM basun@mail.nih.gov; owensi@mail.nih.gov FU Intramural NIH HHS [Z01 HD008751-06] NR 22 TC 10 Z9 11 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 AUG 17 PY 2007 VL 360 IS 1 BP 7 EP 13 DI 10.1016/j.bbrc.2007.05.224 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 191NH UT WOS:000248137400002 PM 17586469 ER PT J AU Knollmann, BC Sirenko, S Rong, Q Katchman, AN Casimiro, M Pfeifer, K Ebert, SN AF Knollmann, Bjorn C. Sirenko, Syevda Rong, Qi Katchman, Alexander N. Casimiro, Mathew Pfeifer, Karl Ebert, Steven N. TI Kcnq1 contributes to an adrenergic-sensitive steady-state K+ current in mouse heart SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE potassium channel; transgenic mouse; electrophysiology; adrenergic; heart ID LANGE-NIELSEN-SYNDROME; POTASSIUM CHANNEL; VENTRICULAR MYOCYTES; TARGETED DISRUPTION; RAT-HEART; EXPRESSION; MICE; PROTEINS; SUBUNIT; KVLQT1 AB It has been suggested that Kcnel subunits are required for adrenergic regulation of Kcnq1 potassium channels. However, in adult mouse hearts, which do not express Kcne1, loss of Kcnq1 causes a Long QT phenotype during adrenergic challenge, raising the possibility that native Kcnq1 currents exist and are adrenergically regulated even in absence of Kcnel. Here, we used immunoblotting and immunohistochemical staining to show that Kcnq1 protein is present in adult mouse hearts. Voltage-clamp experiments demonstrated that Kcnq1 contributes to a steady-state outward current (I-SS) in wild-type (Kcnq1+/+) ventricular myocytes during isoproterenol stimulation, resulting in a significant 7.1% increase in Iss density (0.43 +/- 0.16 pA/pF, p < 0.05, n = 15), an effect that was absent in Kcnq1-deficient (Kcnq1(-/-)) myocytes (-0.14 +/- 0.13 pA/pF, n = 17). These results demonstrate for the first time that Kcnq1 protein is expressed in adult mouse hearts where it contributes to a beta-adrenergic-induced component of Iss that does not require co-assembly with Kcnel. (c) 2007 Elsevier Inc. All rights reserved. C1 Vanderbilt Univ, Sch Med, Dept Med, Nashville, TN 37212 USA. Vanderbilt Univ, Sch Med, Dept Pharmacol, Nashville, TN 37212 USA. Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20007 USA. Georgetown Univ, Med Ctr, Dept Med, Washington, DC 20007 USA. NIH, NICHHD, Lab Mammalian Genes & Dev, Bethesda, MD 20892 USA. RP Ebert, SN (reprint author), Univ Cent Florida, Biomol Sci Ctr, Burnett Coll Biomed Sci, BMS Bldg,Room 321-321A, Orlando, FL 32816 USA. EM ebert@mail.ucf.edu OI Knollmann, Bjorn/0000-0003-4956-9735; Pfeifer, Karl/0000-0002-0254-682X FU Intramural NIH HHS; NHLBI NIH HHS [HL78716, R01 HL078716, R01 HL078716-03, HL71670, HL88635, R01 HL071670, R01 HL088635] NR 39 TC 6 Z9 8 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 AUG 17 PY 2007 VL 360 IS 1 BP 212 EP 218 DI 10.1016/j.bbrc.2007.06.038 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 191NH UT WOS:000248137400034 PM 17597584 ER PT J AU Sun, J Liu, YH Chen, H Nguyen, MP Mishina, Y Upperman, JS Ford, HR Shi, W AF Sun, Jianping Liu, Yi-Hsin Chen, Hui Nguyen, Manuel P. Mishina, Yuji Upperman, Jeffrey S. Ford, Henri R. Shi, Wei TI Deficient Alk3-mediated BMP signaling causes prenatal omphalocele-like defect SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE BMP; Alk3; omphalocele; ventral body wall ID ABDOMINAL-WALL DEFECTS; KNOCKOUT MICE; MOUSE; RECEPTOR; REVEALS; CLOSURE; FUSION; SOMITE; PAX3 AB BMP signaling plays important roles in many embryonic developmental processes. Alk3 is one of two BMP type I receptors that transduces BMP signal from the cell surface into cell. Conventional knockout of Alk3 resulted in early embryonic lethality around E7.5-E9.5. In this study, we have generated embryonic mesoderm-specific Alk3 conditional knockout by crossing Dermol-Cre and floxed Alk3 mice. Abrogation of Alk3-mediated BMP signaling in this mouse resulted in severe defect of secondary ventral body wall formation, replicating the omphalocele phenotype in human. Our finding suggests that Alk3 plays an essential role in the formation of embryonic ventral abdominal wall, and abrogation of BMP signaling activity due to gene mutations in its signaling components could be one of the underlying causes of omphalocele at birth. (c) 2007 Elsevier Inc. All rights reserved. C1 Childrens Hosp Los Angeles, Dept Surg, Dev Biol Program, Los Angeles, CA 90027 USA. Univ So Calif, Keck Sch Med, Dept Ophthalmol, Los Angeles, CA 90033 USA. NIH, Reprod & Dev Toxicol Lab, Mol Dev Biol Grp, Res Triangle Pk, NC 27709 USA. RP Shi, W (reprint author), Childrens Hosp Los Angeles, Dept Surg, Dev Biol Program, 4650 Sunset Blvd,MS 35, Los Angeles, CA 90027 USA. EM wshi@chla.usc.edu FU NEI NIH HHS [R01 EY015417, EY015417]; NHLBI NIH HHS [HL68597, R01 HL068597, R01 HL068597-06] NR 32 TC 13 Z9 13 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 AUG 17 PY 2007 VL 360 IS 1 BP 238 EP 243 DI 10.1016/j.bbrc.2007.06.049 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 191NH UT WOS:000248137400038 PM 17588538 ER PT J AU Xu, TH Nie, LP Zhang, Y Mo, JL Feng, WH Wei, DG Petrov, E Calisto, LE Kachar, B Beisel, KW Vazquez, AE Yamoah, EN AF Xu, Tonghui Nie, Liping Zhang, Yi Mo, Jiling Feng, Weihong Wei, Dongguang Petrov, Evgueni Calisto, Lilian E. Kachar, Bechara Beisel, Kirk W. Vazquez, Ana E. Yamoah, Ebenezer N. TI Roles of alternative splicing in the functional properties of inner ear-specific KCNQ4 channels SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID OUTER HAIR-CELLS; GUINEA-PIG COCHLEA; POTASSIUM CHANNEL; K+ CHANNEL; DIFFERENTIAL EXPRESSION; SUBUNIT STOICHIOMETRY; DOMINANT DEAFNESS; AUDITORY PATHWAY; SODIUM-CHANNELS; HEARING-LOSS AB The function of the KCNQ4 channel in the auditory setting is crucial to hearing, underpinned by the finding that mutations of the channel result in an autosomal dominant form of nonsyndromic progressive high frequency hearing loss. The precise function of KCNQ4 in the inner ear has not been established. However, recently we demonstrated that there is differential expression among four splice variants of KCNQ4 ( KCNQ4_v1-v4) along the tonotopic axis of the cochlea. Alternative splicing specifies the outcome of functional channels by modifying the amino acid sequences within the C terminus at a site designated as the membrane proximal region. We show that variations within the C terminus of splice variants produce profound differences in the voltage-dependent phenotype and functional expression of the channel. KCNQ4_v4 lacks exons 9-11, resulting in deletion of 54 amino acid residues adjacent to the S6 domain compared with KCNQ4_v1. Consequently, the voltage-dependent activation of KCNQ4_v4 is shifted leftward by similar to 20 mV, and the number of functional channels is increased severalfold compared with KCNQ4_v1. The properties of KCNQ4_v2 and KCNQ4_v3 fall between KCNQ4_v1 and KCNQ4_v4. Because of variations in the calmodulin binding domains of the splice variants, the channels are differentially modulated by calmodulin. Co-expression of these splice variants yielded current magnitudes suggesting that the channels are composed of heterotetramers. Indeed, a dominant negative mutant of KCNQ4_v1 cripples the currents of the entire KCNQ4 channel family. Furthermore, the dominant negative KCNQ4 mutant stifles the activity of KCNQ2-5, raising the possibility of a global disruption of KCNQ channel activity and the ensuing auditory phenotype. C1 Univ Calif Davis, Dept Otolaryngol, Ctr Neurosci, Davis, CA 95618 USA. Univ Calif Davis, Commun Sci Program, Davis, CA 95618 USA. NIDCD, Gene Struct Cell Biol, NIH, Bethesda, MD 20892 USA. Creighton Univ, Sch Med, Dept Biomed Sci, Omaha, NE 68178 USA. RP Nie, LP (reprint author), Univ Calif Davis, Dept Otolaryngol, Ctr Neurosci, 1544 Newton Ct, Davis, CA 95618 USA. EM lnie@ucdavis.edu; enyamoah@ucdavis.edu OI Petrov, Evgeny/0000-0002-4055-6981 FU NIDCD NIH HHS [DC008649, DC03828, DC04279, DC05009, DC07592, R01 DC004279, R01 DC005009] NR 39 TC 23 Z9 24 U1 0 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 17 PY 2007 VL 282 IS 33 BP 23899 EP 23909 DI 10.1074/jbc.M702108200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 199HK UT WOS:000248686600017 PM 17561493 ER PT J AU Li, YF Poole, S Rasulova, F McVeigh, AL Savarino, SJ Xia, D AF Li, Yong-Fu Poole, Steven Rasulova, Fatima McVeigh, Annette L. Savarino, Stephen J. Xia, Di TI Receptor-binding site as revealed by the crystal structure of CfaE, the colonization factor antigen I fimbrial adhesin of enterotoxigenic Escherichia coli SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FIMH ADHESIN; CS1 PILI; ERYTHROCYTE RECEPTOR; DEVELOPING-COUNTRIES; PROTEIN STRUCTURES; DIARRHEA; CHILDREN; ARCHITECTURE; BIOGENESIS; RESOLUTION AB CfaE is the minor, tip-localized adhesive subunit of colonization factor antigen I fimbriae (CFA/I) of enterotoxigenic Escherichia coli and is thought to be essential for the attachment of enterotoxigenic E. coli to the human small intestine early in diarrhea pathogenesis. The crystal structure of an in cis donor strand complemented CfaE was determined, providing the first atomic view of a fimbrial subunit assembled by the alternate chaperone pathway. The in cis donor strand complemented variant of CfaE structure consists of an N-terminal adhesin domain and a C-terminal pilin domain of similar size, each featuring a variable immunoglobulin-like fold. Extensive interactions exist between the two domains and appear to rigidify the molecule. The upper surface of the adhesin domain distal to the pilin domain reveals a depression consisting of conserved residues including Arg(181), previously shown to be necessary for erythrocyte adhesion. Mutational analysis revealed a cluster of conserved, positively charged residues that are required for CFA/I-mediated hemagglutination, implicating this as the receptor-binding pocket. Mutations in a few subclass-specific residues that surround the cluster displayed differential effects on the two red cell species used in hemagglutination, suggesting that these residues play a role in host or cell specificity. The C-terminal donor strand derived from the major subunit CfaB is folded as a beta-strand and fits into a hydrophobic groove in the pilin domain to complete the immunoglobulin fold. The location of this well ordered donor strand suggests the positioning and orientation of the subjacent major fimbrial subunit CfaB in the native assembly of CFA/I fimbriae. C1 USN, Med Res Ctr, Enter DIs Dept, Infect Dis Directorate, Silver Spring, MD 20910 USA. NCI, Ctr Canc Res, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Pediat, Bethesda, MD 20814 USA. RP Savarino, SJ (reprint author), USN, Med Res Ctr, Enter DIs Dept, Infect Dis Directorate, 503 Robert Grant Ave,Silver Spring, Silver Spring, MD 20910 USA. EM savarinos@nmrc.navy.mil; dixia@helix.nih.gov RI Savarino, Stephen/A-8030-2011 FU Intramural NIH HHS NR 59 TC 31 Z9 33 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 17 PY 2007 VL 282 IS 33 BP 23970 EP 23980 DI 10.1074/jbc.M700921200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 199HK UT WOS:000248686600023 PM 17569668 ER PT J AU McCloskey, N Hunt, J Beavil, RL Jutton, MR Grundy, GJ Girardi, E Fabiane, SM Fear, DJ Conrad, DH Sutton, BJ Gould, HJ AF McCloskey, Natalie Hunt, James Beavil, Rebecca L. Jutton, Mark R. Grundy, Gabrielle J. Girardi, Enrico Fabiane, Stella M. Fear, David J. Conrad, Daniel H. Sutton, Brian J. Gould, Hannah J. TI Soluble CD23 monomers inhibit and oligomers stimulate IGE synthesis in human B cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID LOW-AFFINITY RECEPTOR; IMMUNOGLOBULIN-E; INVITRO SYNTHESIS; HUMAN-LYMPHOCYTES; BINDING FACTORS; MONOCLONAL-ANTIBODIES; ANTIGEN RECEPTOR; HUMAN MONOCYTES; SERUM-LEVELS; FC AB The low affinity IgE receptor, CD23, is implicated in IgE regulation and the pathogenesis of allergic disease. CD23 is a type II integral membrane protein, comprising a lectin " head," N- terminal " stalk," and C- terminal " tail" in the extracellular sequence. Endogenous proteases cleave CD23 in the stalk and the tail to release soluble fragments that either stimulate or inhibit IgE synthesis in human B cells. The molecular basis of these paradoxical activities is not understood. We have characterized three fragments of CD23, monomeric derCD23, monomeric exCD23, and oligomeric lzCD23. We show that the monomers inhibit and the oligomer stimulates IgE synthesis in human B cells after heavy chain switching to IgE. CD23 fragments could be targets for therapeutic intervention in allergic disease. C1 Kings Coll London, Randall Div Cell & Mol Biophys, London SE1 1UL, England. Kings Coll London, MRC, Asthma UK Ctr Allerg Mech, London SE1 1UL, England. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Virginia Commonwealth Univ, Dept Microbiol & Immunol, Richmond, VA 23298 USA. RP McCloskey, N (reprint author), Kings Coll London, Randall Div Cell & Mol Biophys, New Hunta House,Guys Campus,St Thomas St, London SE1 1UL, England. EM natalie.mccloskey@kcl.ac.uk RI Girardi, Enrico/L-4033-2014 OI Girardi, Enrico/0000-0003-3508-2723 FU Medical Research Council [G0200486, G0400106]; Wellcome Trust [076343] NR 51 TC 39 Z9 40 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 17 PY 2007 VL 282 IS 33 BP 24083 EP 24091 DI 10.1074/jbc.M703195200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 199HK UT WOS:000248686600034 PM 17576766 ER PT J AU Tan, W Wang, YH Gold, B Chen, JS Dean, M Harrison, PJ Weinberger, DR Law, AJ AF Tan, Wei Wang, Yanhong Gold, Bert Chen, Jingshan Dean, Michael Harrison, Paul J. Weinberger, Daniel R. Law, Amanda J. TI Molecular cloning of a brain-specific, developmentally regulated neuregulin 1 (NRG1) isoform and identification of a functional promoter variant associated with schizophrenia SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID GENE-EXPRESSION; ALTERNATIVE PROMOTERS; DOMAIN; CELLS; DISORDER; DISEASE; SYSTEM; CANCER AB Neuregulin 1 (NRG1) is essential for the development and function of multiple organ systems, and its dysregulation has been linked to diseases such as cancer and schizophrenia. Recently, altered expression of a novel isoform (type IV) in the brain has been associated with schizophrenia-related genetic variants, especially rs6994992 (SNP8NRG243177). Here we have isolated and characterized full-length NRG1 type IV cDNAs from the adult and fetal human brain and identified novel splice variants of NRG1. Full-length type IV spans 1.8 kb and encodes a putative protein of 590 amino acids with a predicted molecular mass of similar to 66 kDa. The transcript consists of 11 exons with an Ig-like domain, an epidermal growth factor-like (EGF) domain, a beta-stalk, a transmembrane domain, and a cytoplasmic "a-tail," placing it in the beta 1a NRG1 subclass. NRG1 type IV was not detected in any tissues except brain and a putative type IV NRG1 protein of 66 kDa was similarly brain-specific. Type IV transcripts are more abundantly expressed in the fetal brain, where, in addition to the full-length structure, two novel type IV variants were identified. In vitro luciferase-reporter assays demonstrate that the 5' promoter region upstream of type IV is functional, with differential activity associated with genetic variation at rs6994992, and that promoter competition may impact on type IV expression. Our data suggest that type IV is a unique brain- specific NRG1 that is differentially expressed and processed during early development, is translated, and its expression regulated by a schizophrenia risk-associated functional promoter or single nucleotide polymorphism (SNP). C1 Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford OX3 7JX, England. NCI, SAIC Frederick, Frederick, MD 21702 USA. NCI, NIH, Lab Genome Divers, Frederick, MD 21702 USA. NIMH, Intramural Res Program, Clin Brain Disorders Branch, Bethesda, MD 20892 USA. RP Law, AJ (reprint author), Univ Oxford, Warneford Hosp, Dept Psychiat, Oxford OX3 7JX, England. EM amanda.law@psych.ox.ac.uk RI Law, Amanda/G-6372-2012; OI Dean, Michael/0000-0003-2234-0631; Law, Amanda/0000-0002-2574-1564 FU Intramural NIH HHS; Medical Research Council [G120/997]; NCI NIH HHS [N01-CO-12400] NR 36 TC 85 Z9 87 U1 1 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 17 PY 2007 VL 282 IS 33 BP 24343 EP 24351 DI 10.1074/jbc.M702953200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 199HK UT WOS:000248686600060 PM 17565985 ER PT J AU Tolstorukov, MY Colasanti, AV McCandlish, DM Olson, WK Zhurkin, VB AF Tolstorukov, Michael Y. Colasanti, Andrew V. McCandlish, David M. Olson, Wilma K. Zhurkin, Victor B. TI A novel roll-and-slide mechanism of DNA folding in chromatin: Implications for nucleosome positioning SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE base-pair shearing; DNA deformation; knowledge-based potentials; nucleosome positioning; superhelical pitch ID CORE PARTICLE; ANGSTROM RESOLUTION; ANISOTROPIC FLEXIBILITY; CRYSTAL-STRUCTURE; HISTONE OCTAMER; IN-VITRO; B-DNA; SEQUENCE; VISUALIZATION; GEOMETRY AB How eukaryotic genomes encode the folding of DNA into nucleosomes and how this intrinsic organization of chromatin guides biological function are questions of wide interest. The physical basis of nucleosome positioning lies in the sequence-dependent propensity of DNA to adopt the tightly bent configuration imposed by the binding of the histone proteins. Traditionally, only DNA bending and twisting deformations are considered, while the effects of the lateral displacements of adjacent base pairs are neglected. We demonstrate, however, that these displacements have a much more important structural role than ever imagined. Specifically, the lateral Slide deformations observed at sites of local anisotropic bending of DNA define its superhelical trajectory in chromatin. Furthermore, the computed cost of deforming DNA on the nucleosome is sequence-specific: in optimally positioned sequences the most easily deformed base-pair steps (CA:TG and TA) occur at sites of large positive Slide and negative Roll (where the DNA bends into the minor groove). These conclusions rest upon a treatment of DNA that goes beyond the conventional ribbon model, incorporating all essential degrees of freedom of "real" duplexes in the estimation of DNA deformation energies. Indeed, only after lateral Slide displacements are considered are we able to account for the sequence-specific folding of DNA found in nucleosome structures. The close correspondence between the predicted and observed nucleosome locations demonstrates the potential advantage of our "structural" approach in the computer mapping of nucleosome positioning. (c) 2007 Elsevier Ltd. All rights reserved. C1 NCI, Bethesda, MD 20892 USA. V Karazin Kharkov Natl Univ, Dept Biol & Med Phys, UA-61077 Kharkov, Ukraine. Rutgers State Univ, Wright Rieman Labs, Piscataway, NJ 08854 USA. RP Olson, WK (reprint author), NCI, Bethesda, MD 20892 USA. EM wilma.olson@rutgers.edu; zhurkin@nih.gov FU NIGMS NIH HHS [R01 GM020861-32, GM20861, R01 GM020861, T32 GM008319] NR 50 TC 133 Z9 138 U1 3 U2 10 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD AUG 17 PY 2007 VL 371 IS 3 BP 725 EP 738 DI 10.1016/j.jmb.2007.05.048 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 199TY UT WOS:000248719300013 PM 17585938 ER PT J AU Shi, XB Kachirskaia, L Yamaguchi, H West, LE Wen, H Wang, EW Dutta, S Appella, E Gozani, O AF Shi, Xiaobing Kachirskaia, Loulia Yamaguchi, Hiroshi West, Lisandra E. Wen, Hong Wang, Evelyn W. Dutta, Sucharita Appella, Ettore Gozani, Or TI Modulation of p53 function by SET8-mediated methylation at lysine 382 SO MOLECULAR CELL LA English DT Article ID HISTONE H4; POSTTRANSLATIONAL MODIFICATIONS; TRANSCRIPTIONAL REGULATION; METHYLTRANSFERASE; DOMAIN; REPRESSION; APOPTOSIS; PR-SET7; H3; HETEROCHROMATIN AB Reversible covalent methylation of lysine residues on histone proteins constitutes a principal molecular mechanism that links chromatin states to diverse biological outcomes. Recently, lysine methylation has been observed on nonhistone proteins, suggesting broad cellular roles for the enzymes generating and removing methyl moieties. Here we report that the lysine methyltransferase enzyme SET8/PR-Set7 regulates the tumor suppressor protein p53. We find that SET8 specifically monomethylates; p53 at lysine 382 (p53K382me1). This methylation event robustly suppresses p53-mediated transcription activation of highly responsive target genes but has little influence on weak targets. Further, depletion of SET8 augments the proapoptotic and checkpoint activation functions of p53, and accordingly, SET8 expression is downregulated upon DNA damage. Together, our study identifies SET8 as a p53-modifying enzyme, identifies p53K382me1 as a regulatory posttranslational modification of p53, and begins to dissect how methylation may contribute to a dynamic posttranslational code that modulates distinct p53 functions. C1 Stanford Univ, Dept Biol Sci, Stanford, CA 94305 USA. NCI, Cell Biol Lab, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Dept Pathol, Stanford, CA 94305 USA. RP Gozani, O (reprint author), Stanford Univ, Dept Biol Sci, Stanford, CA 94305 USA. EM ogozani@stanford.edu FU Intramural NIH HHS [Z01 BC005599-17]; NIGMS NIH HHS [R01 GM079641, R01 GM079641-02] NR 38 TC 203 Z9 219 U1 2 U2 18 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD AUG 17 PY 2007 VL 27 IS 4 BP 636 EP 646 DI 10.1016/j.molcel.2007.07.012 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 204NE UT WOS:000249050200014 PM 17707234 ER PT J AU Finkel, T Serrano, M Blasco, MA AF Finkel, Toren Serrano, Manuel Blasco, Maria A. TI The common biology of cancer and ageing SO NATURE LA English DT Review ID ONCOGENE-INDUCED SENESCENCE; DNA-DAMAGE RESPONSE; LIFE-SPAN; TELOMERE LENGTH; C-ELEGANS; HUMAN FIBROBLASTS; OXIDATIVE STRESS; HUMAN-CELLS; SUCCINATE-DEHYDROGENASE; GENOMIC INSTABILITY AB At first glance, cancer and ageing would seem to be unlikely bedfellows. Yet the origins for this improbable union can actually be traced back to a sequence of tragic - and some say unethical - events that unfolded more than half a century ago. Here we review the series of key observations that has led to a complex but growing convergence between our understanding of the biology of ageing and the mechanisms that underlie cancer. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. Spanish Natl Canc Res Ctr CNIO, Madrid 28029, Spain. RP Finkel, T (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10,CRC 5-3330,10 Ctr Dr, Bethesda, MD 20892 USA. EM finkelt@nih.gov RI Serrano, Manuel/H-2634-2015; Blasco , Maria A./M-1694-2014 OI Serrano, Manuel/0000-0001-7177-9312; Blasco , Maria A./0000-0002-4211-233X FU Intramural NIH HHS NR 101 TC 438 Z9 467 U1 17 U2 79 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD AUG 16 PY 2007 VL 448 IS 7155 BP 767 EP 774 DI 10.1038/nature05985 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 200HJ UT WOS:000248754200031 PM 17700693 ER PT J AU Koh, SWM Guo, Y Bernstein, SL Waschek, JA Liu, XH Symes, AJ AF Koh, Shay-Whey M. Guo, Yan Bernstein, Steve L. Waschek, James A. Liu, Xiuhuai Symes, Aviva J. TI Vasoactive intestinal peptide induction by ciliary neurotrophic factor in donor human corneal endothelium in situ SO NEUROSCIENCE LETTERS LA English DT Article DE VIP; CNTF; corneal endothelial cells; gene transcription ID CULTURED SYMPATHETIC NEURONS; LEUKEMIA INHIBITORY FACTOR; INDUCED UP-REGULATION; TYROSINE-HYDROXYLASE; OXIDATIVE STRESS; MESSENGER-RNAS; TROPHIC FACTOR; FACTOR CNTF; EXPRESSION; INJURY AB After peripheral nerve axotomy, vasoactive intestinal peptide (VIP) gene expression is upregulated in neurons, whereas ciliary neurotrophic factor (CNTF) accumulates extracellularly at the lesion site. Although CNTF-induced VIP gene expression has been reported in cultured sympathetic neurons and neuroblastoma cells, it still remains to be determined if CNTF and VIP play interrelated roles in nerve injury. The corneal endothelium, like sympathetic neurons, derives from the neural crest. Previously, we demonstrated that a sublethal-level of oxidative stress induces CNTF release from corneal endothelial (CE) cells in situ. Here, we show that human CE cells express the 53 kDa ligand-binding alpha subunit of the CNTF receptor (CNTFR alpha). We further demonstrate that CNTF induces VIP immunoreactivity in human donor corneas. To determine if the increase in VIP immunoreactivity was reflected by an increase in gene expression, donor human corneas were bisected and treated with CNTF or vehicle, and analyzed by real-time RT-qPCR. Two experiments using different sets of bisected corneas indicated that CNTF induced increases in VIP mRNA levels of 6.5 +/- 2.2-fold (N = 7 corneas) and 2.3 +/- 0.6-fold (N = 10 corneas) (mean +/- S.E.M.), respectively. Whereas VIP is produced as a CE autocrine factor against oxidative stress, the present study suggested that oxidative stress-released CNTF plays a role in protecting CE cells against oxidative stress injury by upregulating VIP expression. (c) 2007 Elsevier Ireland Ltd. All rights reserved. C1 Univ Maryland, Dept Ophthalmol & Visual Sci, Baltimore, MD 21201 USA. Univ Calif Los Angeles, Mental Retardat Res Ctr, Dept Psychiat, Los Angeles, CA 90024 USA. NIMH, NIH, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Pharmacol, Bethesda, MD 20814 USA. RP Koh, SWM (reprint author), Univ Maryland, Dept Ophthalmol & Visual Sci, Baltimore, MD 21201 USA. EM skoh@umaryland.edu RI Symes, Aviva/S-7471-2016 OI Symes, Aviva/0000-0003-2557-9939 FU NEI NIH HHS [EY15304, R01 EY011607, R01 EY011607-08, R01 EY015304]; NICHD NIH HHS [HD04612, P30 HD004612, P01 HD006576, HD06576, HD34475, R01 HD034475]; NINDS NIH HHS [R29 NS035839, R29NS35839]; PHS HHS [DY11607] NR 31 TC 8 Z9 8 U1 2 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD AUG 16 PY 2007 VL 423 IS 2 BP 89 EP 94 DI 10.1016/j.neulet.2007.05.067 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 210YJ UT WOS:000249491200001 PM 17692461 ER PT J AU Virk, J Zhang, J Olsen, J AF Virk, Jasveer Zhang, Jun Olsen, Jorn TI Medical abortion and the risk of subsequent adverse pregnancy outcomes SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID MULTIPLE INDUCED ABORTIONS; LOW-BIRTH-WEIGHT; ECTOPIC PREGNANCY; MIFEPRISTONE; MISCARRIAGE; TRIMESTER; FRANCE AB Background: The long-term safety of surgical abortion in the first trimester is well established. Despite the increasing use of medical abortion (abortion by means of medication), limited information is available regarding the effects of this procedure on subsequent pregnancies. Methods: We identified all women living in Denmark who had undergone an abortion for nonmedical reasons between 1999 and 2004 and obtained information regarding subsequent pregnancies from national registries. Risks of ectopic pregnancy, spontaneous abortion, preterm birth (at < 37 weeks of gestation), and low birth weight (< 2500 g) in the first subsequent pregnancy in women who had had a first-trimester medical abortion were compared with risks in women who had had a first-trimester surgical abortion. Results: Among 11,814 pregnancies in women who had had a previous first-trimester medical abortion (2710 women) or surgical abortion (9104 women), there were 274 ectopic pregnancies (respective incidence rates, 2.4% and 2.3%), 1426 spontaneous abortions (12.2% and 12.7%), 552 preterm births (5.4% and 6.7%), and 478 births with low birth weight (4.0% and 5.1%). After adjustment for maternal age, interval between pregnancies, gestational age at abortion, parity, cohabitation status, and urban or nonurban residence, medical abortion was not associated with a significantly increased risk of ectopic pregnancy (relative risk, 1.04; 95% confidence interval [CI], 0.76 to 1.41), spontaneous abortion (relative risk, 0.87; 95% CI, 0.72 to 1.05), preterm birth (relative risk, 0.88; 95% CI, 0.66 to 1.18), or low birth weight (relative risk, 0.82; 95% CI, 0.61 to 1.11). Gestational age at medical abortion was not significantly associated with any of these adverse outcomes. Conclusions: We found no evidence that a previous medical abortion, as compared with a previous surgical abortion, increases the risk of spontaneous abortion, ectopic pregnancy, preterm birth, or low birth weight. C1 NICHHD, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Dept Epidemiol, Los Angeles, CA USA. Aarhus Univ, Inst Publ Hlth, Aarhus, Denmark. RP Zhang, J (reprint author), NICHHD, Epidemiol Branch, NIH, Bldg 6100,Rm 7B03, Bethesda, MD 20892 USA. EM zhangj@mail.nih.gov FU Intramural NIH HHS NR 32 TC 42 Z9 46 U1 2 U2 6 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 AUG 16 PY 2007 VL 357 IS 7 BP 648 EP 653 DI 10.1056/NEJMoa070445 PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 200EF UT WOS:000248746000004 PM 17699814 ER PT J AU Chakrapani, H Showalter, BM Kong, L Keefer, LK Saavedra, JE AF Chakrapani, Harinath Showalter, Brett M. Kong, Li Keefer, Larry K. Saavedra, Joseph E. TI V-PROLI/NO, a prodrug of the nitric oxide donor, PROLI/NO SO ORGANIC LETTERS LA English DT Article ID IN-VITRO; PYRRO/NO; CHEMISTRY; LIVER; APOPTOSIS; TOXICITY; POLYMERS; PROTECTS; RELEASE; IONS AB The sensitivity to decomposition of the nitric oxide (NO) donor ion, 1-[2-(carboxylato)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate (PROLI/NO), complicates direct electrophilic substitution to form useful prodrug derivatives. A modified general synthetic approach involving 1-[2-(hydroxymethyl)pyrrolidin-1-yl]diazen-1-ium-1,2-diolate ion (structure A, above) was used to prepare several PROLI/NO prodrugs including the previously inaccessible O-2-vinyl derivative, V-PROLI/NO. Metabolism of V-PROLI/NO by liver microsomes enriched in human cytochrome P450 isoforms was demonstrated. C1 NCI, Comparat Carcinogenesis Lab, Chem Sect, Frederick, MD 21702 USA. NCI, SAIC Frederick, Basic Res Program, Frederick, MD 21702 USA. RP Saavedra, JE (reprint author), NCI, Comparat Carcinogenesis Lab, Chem Sect, Frederick, MD 21702 USA. EM saavj@ncifcrf.gov RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 24 TC 25 Z9 25 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD AUG 16 PY 2007 VL 9 IS 17 BP 3409 EP 3412 DI 10.1021/ol701419a PG 4 WC Chemistry, Organic SC Chemistry GA 198WS UT WOS:000248658800054 PM 17658755 ER PT J AU Weinberg, CR Shore, DL Umbach, DM Sandler, DP AF Weinberg, Clarice R. Shore, David L. Umbach, David M. Sandler, Dale P. TI Using risk-based sampling to enrich cohorts for endpoints, genes, and exposures SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE cohort studies; disease susceptibility; genes; prospective studies; risk; sampling studies ID BREAST-CANCER RISK; CASE-PARENT TRIADS; LOGISTIC-REGRESSION; DISEASE; DESIGN AB Targeting the first-degree relatives of people with a particular complex disease can offer a powerful approach to building a risk-based cohort for prospective studies of etiologic factors. Such a cohort provides both a sizable increase in the rate of accrual of newly incident cases, enriching for risk factors that are known or even unknown, and a high level of motivation among participants. A nationwide study of breast cancer in the United States and Puerto Rico, the Sister Study, made up of women who are each the sister of a woman with breast cancer, exemplifies this approach. In this paper, the authors provide power calculations to aid in the design of such studies and quantify their benefits for detecting both genetic variants related to risk and interactive effects of genetic and environmental factors. While the risk-based cohort can have markedly increased prevalences of rare causative alleles, most of the power advantages for this design is due to the increased rate of accrual of newly incident cases rather than the increase in any one individual allele. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. WESTAT Corp, Durham, NC USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. RP Weinberg, CR (reprint author), NIEHS, Biostat Branch, POB 12233, Res Triangle Pk, NC 27709 USA. EM weinberg@niehs.nih.gov OI Sandler, Dale/0000-0002-6776-0018 FU Intramural NIH HHS [Z01 ES040006-11] NR 16 TC 31 Z9 31 U1 0 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2007 VL 166 IS 4 BP 447 EP 455 DI 10.1093/aje/kwm097 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197XX UT WOS:000248591700011 PM 17556763 ER PT J AU Lubin, JH Alavanja, MCR Caporaso, N Brown, LM Brownson, RC Field, RW Garcia-Closas, M Hartge, P Hauptmann, M Hayes, RB Kleinerman, R Kogevinas, M Krewski, D Langholz, B Letourneau, EG Lynch, CF Malats, N Sandler, DP Schaffrath-Rosario, A Schoenberg, JB Silverman, DT Wang, ZY Wichmann, HE Wilcox, HB Zielinski, JM AF Lubin, Jay H. Alavanja, Michael C. R. Caporaso, Neil Brown, Linda M. Brownson, Ross C. Field, R. William Garcia-Closas, Montserrat Hartge, Patricia Hauptmann, Michael Hayes, Richard B. Kleinerman, Ruth Kogevinas, Manolis Krewski, Daniel Langholz, Bryan Letourneau, Ernest G. Lynch, Charles F. Malats, Nuria Sandler, Dale P. Schaffrath-Rosario, Angelika Schoenberg, Janet B. Silverman, Debra T. Wang, Zuoyuan Wichmann, H.-Erich Wilcox, Homer B. Zielinski, Jan M. TI Cigarette smoking and cancer risk: Modeling total exposure and intensity SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE case-control studies; epidemiologic methods; models; statistical; neoplasms; risk; smoking ID RESIDENTIAL RADON EXPOSURE; LUNG-CANCER; URANIUM-MINERS; BLADDER-CANCER; COLORADO PLATEAU; CLINICAL-TRIALS; UNITED-STATES; CHINA; TOBACCO; MORTALITY AB A recent analysis showed that the excess odds ratio (EOR) for lung cancer due to smoking can be modeled by a function which is linear in total pack-years and exponential in the logarithm of smoking intensity and its square. Below 15-20 cigarettes per day, the EOR/pack-year increased with intensity (direct exposure rate or enhanced potency effect), suggesting greater risk for a total exposure delivered at higher intensity (for a shorter duration) than for an equivalent exposure delivered at lower intensity. Above 20 cigarettes per day, the EOR/pack-year decreased with increasing intensity (inverse exposure rate or reduced potency effect), suggesting greater risk for a total exposure delivered at lower intensity (for a longer duration) than for an equivalent exposure delivered at higher intensity. The authors applied this model to data from 10 case-control studies of cancer, including cancers of the lung, bladder, oral cavity, pancreas, and esophagus. At lower intensities, there was enhanced potency for several cancer sites, but narrow ranges for pack-years increased uncertainty, precluding definitive conclusions. At higher intensities, there was a consistent reduced potency effect across studies. The intensity effects were statistically homogeneous, indicating that after accounting for risk from total pack-years, intensity patterns were comparable across the diverse cancer sites. C1 NCI, Div Canc Epidemiol & Genet, Biostat Branch, Rockville, MD 20852 USA. NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, Bethesda, MD 20892 USA. St Louis Univ, Sch Publ Hlth, Dept Community Hlth, St Louis, MO 63103 USA. Univ Iowa, Coll Publ Hlth, Dept Epidemiol, Iowa City, IA USA. Univ Iowa, Coll Publ Hlth, Dept Environm & Occupat Hlth, Iowa City, IA USA. NCI, Div Canc Epidemiol & Genet, Hormonal & Reprod Epidemiol Branch, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Radiat Epidemiol Branch, Bethesda, MD 20892 USA. Municipal Inst Med Res IMIM, Ctr Res Environm & Epidemiol, Barcelona, Spain. Univ Crete, Sch Med, Dept Social Med, Iraklion, Greece. Univ Ottawa, Fac Med, McLaughlin Ctr Populat Hlth Risk Assessment, Ottawa, ON, Canada. Univ So Calif, Sch Med, Dept Prevent Med, Los Angeles, CA 90033 USA. Hlth Canada, Hlth Protect Branch, Radiat Protect Bur, Ottawa, ON K1A 0L2, Canada. Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC USA. Robert Koch Inst, Abt Epidemiol & Gesundheitsberichterstattung, D-1000 Berlin, Germany. New Jersey Dept Hlth & Senior Serv, Canc Epidemiol Serv, Trenton, NJ USA. Minist Hlth, Lab Ind Hyg, Beijing, Peoples R China. GSF, Natl Res Ctr Environm & Hlth, Inst Epidemiol, Neuherberg, Germany. Hlth Canada, Healthy Environm & Consumer Safety Branch, Ottawa, ON K1A 0L2, Canada. Univ Ottawa, Fac Med, Dept Epidemiol & Community Med, Ottawa, ON, Canada. RP Lubin, JH (reprint author), NCI, Div Canc Epidemiol & Genet, Biostat Branch, 6120 Execut Blvd, Rockville, MD 20852 USA. EM lubinj@mail.nih.gov RI Garcia-Closas, Montserrat /F-3871-2015; Kogevinas, Manolis/C-3918-2017; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Kleinerman, Ruth/0000-0001-7415-2478; Hayes, Richard/0000-0002-0918-661X; Sandler, Dale/0000-0002-6776-0018; Malats, Nuria/0000-0003-2538-3784 FU Intramural NIH HHS NR 40 TC 45 Z9 46 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD AUG 15 PY 2007 VL 166 IS 4 BP 479 EP 489 DI 10.1093/aje/kwm089 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 197XX UT WOS:000248591700015 PM 17548786 ER PT J AU Krasnewich, D O'Brien, K Sparks, S AF Krasnewich, Donna O'Brien, Kevin Sparks, Susan TI Clinical features in adults with congenital disorders of glycosylation type Ia (CDG-Ia) SO AMERICAN JOURNAL OF MEDICAL GENETICS PART C-SEMINARS IN MEDICAL GENETICS LA English DT Article DE congenital disorders of glycosylation; glycobiology ID DEFICIENT GLYCOPROTEIN SYNDROME; PRESENTATIONS; TRANSFERRIN; SERUM AB Congenital disorders of glycosylation (CDG) are a group of metabolic disorders resulting from defective synthesis of Winked oligosaccharides. CDG-la is the most common of the 21 known types defined by defects in different steps of the synthetic pathway. An increasing number of American adults with CDG-la are being recognized but little is documented on the morbidity and mortality in this population. These adults have moderate mental retardation, ataxia, retinitis pigmentosa, peripheral neuropathy, kyphoscoliosis, and endocrinopathies. Four adults with CDG-la, ages 19-36 years old are presented. All are active, dysarthric conversant adults with moderate cognitive impairment. They are ataxic and wheelchair dependent, however, only the oldest man shows significant muscle atrophy. All have diagnosed peripheral neuropathy. Three of four remain on anticonvulsants with only occasional seizures, none have had stroke-like episodes since their teen years. Their skeletal issues include significant kyposcoliosis, joint contractures, and osteopenia. Retinitis pigmentosa and myopia complicate their functional vision. The women do not menstruate and the men have small testes resulting from 14 hypogonadotropic hypogonadism. Documentation of clinical complications and successful management strategies in adults with CDG will improve their quality of life and allow more informed prognostic discussions with families of younger affected individuals. Published 2007 Wiley-Liss, Inc. C1 NIH, NHGRI, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. RP Krasnewich, D (reprint author), NIH, NHGRI, Bldg 10 CRC,Room 3-2551,10 Ctr Dr, Bethesda, MD 20892 USA. EM dkras@mail.nih.gov NR 15 TC 26 Z9 27 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4868 J9 AM J MED GENET C JI Am. J. Med. Genet. C PD AUG 15 PY 2007 VL 145C IS 3 BP 302 EP 306 DI 10.1002/ajmg.c.30143 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 203UL UT WOS:000248999400012 PM 17639595 ER PT J AU Deterding, LJ Lhattacharjee, S Ramirez, DC Mason, RP Tomer, KB AF Deterding, Leesa J. Lhattacharjee, Suchandra Ramirez, Dario C. Mason, Ronald P. Tomer, Kenneth B. TI Top-down and bottom-up mass spectrometric characterization of human myoglobin-centered free radicals induced by oxidative damage SO ANALYTICAL CHEMISTRY LA English DT Article ID INFRARED MULTIPHOTON DISSOCIATION; ELECTRON-CAPTURE DISSOCIATION; HYDROGEN-PEROXIDE; CYTOCHROME-C; PROTEIN; IDENTIFICATION; RESOLUTION; HEMOGLOBIN; DISEASE; H2O2 AB In an effort to determine the utility of top-down mass spectrometric methodologies for the characterization of protein radical adducts, top-down approaches were investigated and compared to the traditional bottom-up approaches. Specifically, the nature of the radicals on human myoglobin induced by the addition of hydrogen peroxide and captured by the spin trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) was investigated. The most abundant ion observed in the electrospray mass spectrum of this reaction mixture corresponds in mass to the human myoglobin plus one DMPO molecule. In addition, a second ion of lower abundance is observed, which corresponds to a second DMPO molecule being trapped on myoglobin. Top-down analyses using Fourier transform ion cyclotron resonance mass spectrometry can be used to characterize proteins and, thus, were performed on several different charge-state ions of both the native and the mono-DMPO nitrone adduct of human myoglobin. Data produced from the top-down analyses are very complex yet information rich. In the case of DMPO-modified human myoglobin, the top-down data localized the DMPO spin trap to residues 97-110 of the myoglobin. The observation of the y(43)(+5) fragment ion arising from C-terminal cleavage to the cysteine-110 residue in the MS/MS spectrum of DMPO-modified myoglobin and not in the unmodified myoglobin implicates a change to this residue, specifically, DMPO adduction. On the other hand, using the traditional bottom-up approach of peptide mapping and MS sequencing methodologies, two DMPO radical adducts on human myoglobin were identified, Cys-110 and Tyr-103. The bottom-up approach is more proven and robust than the top-down methodologies. Nonetheless, the bottom-up and top-down approaches to protein characterization are complementary rather than competitive approaches with each having its own utility. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. RP Deterding, LJ (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233,MD F0-03, Res Triangle Pk, NC 27709 USA. EM deterdi2@niehs.nih.gov RI Tomer, Kenneth/E-8018-2013; RAMIREZ, DARIO/K-3312-2013 OI RAMIREZ, DARIO/0000-0001-6725-3326 FU Intramural NIH HHS [Z01 ES050171-08] NR 48 TC 23 Z9 23 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD AUG 15 PY 2007 VL 79 IS 16 BP 6236 EP 6248 DI 10.1021/ac070935z PG 13 WC Chemistry, Analytical SC Chemistry GA 203SC UT WOS:000248993300024 PM 17637042 ER PT J AU Lafite, P Dijols, S Zeldin, DC Dansette, PM Mansuy, D AF Lafite, Pierre Dijols, Sylvie Zeldin, Darryl C. Dansette, Patrick M. Mansuy, Daniel TI Selective, competitive and mechanism-based inhibitors of human cytochrome P450 2J2 SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE ebastine; terfenadine; drug metabolism; arachidonic acid epoxidation; vascular P450s; benzo-1,3-dioxole; hydroxylation; monooxygenases; hemeproteins ID POTENTIAL FUNCTIONAL-SIGNIFICANCE; EPOXYEICOSATRIENOIC ACIDS EETS; ARACHIDONIC-ACID; HYPERPOLARIZING FACTOR; CATALYTIC-ACTIVITIES; ENDOTHELIAL-CELLS; CRYSTAL-STRUCTURE; LIVER-MICROSOMES; TIENILIC ACID; HIGH-AFFINITY AB Twenty five derivatives of the drugs terfenadine and ebastine have been designed, synthesized and evaluated as inhibitors of recombinant human CYP2J2. Compound 14, which has an imidazole substituent, is a good non-competitive inhibitor of CYP2.12 (IC50 - 400 nM). It is not selective towards CYP2.12 as it also efficiently inhibits the other main vascular CYPs, such as CYP2B6, 2C8. 2C9 and 3A4: however, it could be an interesting tool to inhibit all these vascular CYPs. Compounds 4, 5 and 13, which have a propyl, allyl and benzo-1,3-dioxole terminal group, respectively, are selective CYP2J2 inhibitors. Compound 4 is a high-affinity, competitive inhibitor and alternative substrate of CYP2J2 (K-i = 160 50 nM). Compounds 5 and 13 are efficient mechanism-based inhibitors of CYP2J2 (k(inact)/K-i values similar to 3000 L mol(-1) s(-1)). Inactivation of CYP2J2 by 13 is due to the formation of a stable iron-carbene bond which occurs upon CYP2J2-catalyzed oxidation of 13 with a partition ratio of 18 +/- 3. These new selective inhibitors should be interesting tools to study the biological roles of CYP2J2. Published by Elsevier Inc. C1 Univ Paris 05, CNRS, Chim & Biochim Pharmacol & Toxicol Lab, UMR 8601, F-75270 Paris 06, France. NIEHS, NIH, Res Triangle Pk, NC 27709 USA. RP Mansuy, D (reprint author), Univ Paris 05, CNRS, Chim & Biochim Pharmacol & Toxicol Lab, UMR 8601, 45 Rue St Peres, F-75270 Paris 06, France. EM daniel.mansuy@univ-paris5.fr RI DANSETTE, Patrick/B-8384-2014; Lafite, Pierre/F-6806-2011 OI Lafite, Pierre/0000-0003-1637-4966 FU Intramural NIH HHS [Z01 ES025034-13] NR 77 TC 30 Z9 31 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD AUG 15 PY 2007 VL 464 IS 2 BP 155 EP 168 DI 10.1016/j.abb.2007.03.028 PG 14 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 201ZB UT WOS:000248870000002 PM 17470359 ER PT J AU Vermeire, K Lisco, A Grivel, JC Scarbrough, E Dey, K Duffy, N Margolis, L Bell, TW Schols, D AF Vermeire, Kurt Lisco, Andrea Grivel, Jean-Charles Scarbrough, Emily Dey, Kaka Duffy, Noah Margolis, Leonid Bell, Thomas W. Schols, Dominique TI Design and cellular kinetics of dansyl-labeled CADA derivatives with anti-HIV and CD4 receptor downmodulating activity SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE CADA; dansyl; anti-HIV; CD4 receptor; reversible Down-modulation; cellular kinetics ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1; REPLICATION; ANTAGONISTS; RETROVIRUS; INFECTION; COFACTOR; ANALOGS; FUSION; ENTRY AB A new class of anti-retrovirals, cyclotriazadisulfonamide (CADA) and its derivatives, specifically down-regulate CD4, the main receptor of HIV, and prevent HIV infection in vitro. In this work, several CADA derivatives, chemically labeled with a fluorescent dansyl group, were evaluated for their biological features and cellular uptake kinetics. We identified a derivative KKD-016 with antiviral and CD4 down-modulating capabilities similar to those of the parental compound CADA. By using flow cytometry, we demonstrated that the dose-dependent cellular uptake of this derivative correlated with CD4 down-modulation. The uptake and activity of the dansyl-labeled compounds were not dependent on the level of expression of CD4 at the cell surface. Removal of the CADA compounds from the cell culture medium resulted in their release from the cells followed by a complete restoration of CD4 expression. The inability of several fluorescent CADA derivatives to down-modulate CD4 was not associated with their lower cellular uptake and was not reversed by facilitating their cell penetration by a surfactant. These results prove the successful integration of the dansyl fluorophore into the chemical structure of a CD4 down-modulating anti-HIV compound, and show the feasibility of tracking a receptor and its down-modulator simultaneously. These fluorescent CADA analogs with reversible CD4 down-regulating potency can now be applied in further studies on receptor modulation, and in the exploration of their potentials as preventive and therapeutic anti-HIV drugs. (C) 2007 Elsevier Inc. All rights reserved. C1 Katholieke Univ Leuven, Dept Microbiol & Immunol, Rega Inst Med Res, BE-3000 Louvain, Belgium. NICHHD, Lab Mol & Cellular Biophys, Bethesda, MD 20892 USA. Univ Nevada, Dept Chem, Reno, NV 89557 USA. RP Vermeire, K (reprint author), Katholieke Univ Leuven, Dept Microbiol & Immunol, Rega Inst Med Res, Minderbroedersstr 10, BE-3000 Louvain, Belgium. EM kurt.vermeire@rega.kuleuven.be NR 30 TC 8 Z9 8 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD AUG 15 PY 2007 VL 74 IS 4 BP 566 EP 578 DI 10.1016/j.bcp.2007.05.018 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 198WJ UT WOS:000248657900004 PM 17603023 ER PT J AU Wang, YH Miao, ZH Pommier, Y Kawasaki, ES Player, A AF Wang, Yonghong Miao, Ze-Hong Pommier, Yves Kawasaki, Ernest S. Player, Audrey TI Characterization of mismatch and high-signal intensity probes associated with Affymetrix genechips SO BIOINFORMATICS LA English DT Article ID MICROARRAY; ARRAY; HYBRIDIZATION; NORMALIZATION AB Motivation: For Affymetrix microarray platforms, gene expression is determined by computing the difference in signal intensities between perfect match ( PM) and mismatch ( MM) probesets. Although the use of PM is not controversial, MM probesets have been associated with variance and ultimately inaccurate gene expression calls. A principal focus of this study was to investigate the nature of the MM signal intensities and demonstrate its contribution to the experimental results. Results: While most MM intensities were likely associated with random noise, a subset of similar to 20% ( 99 485) of the MM probes displayed relatively high signal intensities to the corresponding PM probes (MM > PM) in a non-random fashion; 13 440 of these probes demonstrated exceptionally high 'outlier' intensities. About 15 938 PM probes also demonstrated exceptionally high outlier intensities consistently across all hybridizations. About 92% of the MM > PM probes had either a dThymidine (dT) or a dCytidine (dC) at the 13th position of the probe sequence. MM and PM probes displaying extremely high outlier intensities contained high dC rich nucleotides, and low dA contents at other nucleotides positions along the 25mer probe sequence. Differentially expressed genes generated using Genechip Operating System (GCOS) or modified PM-only methods were also examined. Of those candidate genes identified in the PM-only method, 157 of them were designated by GCOS as absent across all datasets and many others contained probes with MM > PM signal intensities. Our data suggests that MM intensity from PM signal can be a major source of error analysis, leading to fewer potentially biologically important candidate genes. Contact: wangyong@mail.nih.gov Supplementary information: Supplementary data are available at Bioinformatics online. C1 Ctr Canc Res, NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. NCI, NIH, Microarray Core Facil, Bethesda, MD 20892 USA. SAIC Frederick Inc, NCI, Ft Detrick, MD 21702 USA. RP Wang, YH (reprint author), Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China. EM wangyong@mail.nih.gov FU NCI NIH HHS [N01-CO-12400] NR 17 TC 12 Z9 13 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD AUG 15 PY 2007 VL 23 IS 16 BP 2088 EP 2095 DI 10.1093/bioinformatics/btm306 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 215OG UT WOS:000249818300008 PM 17553856 ER PT J AU Kling, MA Alesci, S Csako, G Costello, R Luckenbaugh, DA Bonne, O Duncko, R Drevets, WC Manji, HK Charney, DS Gold, PW Neumeister, A AF Kling, Mitchel A. Alesci, Salvatore Csako, Gyorgy Costello, Rene Luckenbaugh, David A. Bonne, Omer Duncko, Roman Drevets, Wayne C. Manji, Husseini K. Charney, Dennis S. Gold, Philip W. Neumeister, Alexander TI Sustained low-grade pro-inflammatory state in unmedicated, remitted women with major depressive disorder as evidenced by elevated serum levels of the acute phase proteins c-reactive protein and serum amyloid a SO BIOLOGICAL PSYCHIATRY LA English DT Article DE acute phase response; biomarkers; cardiovascular disease; depression; innate immunity; risk factors ID CORONARY-ARTERY-DISEASE; CARDIOVASCULAR-DISEASE; BODY-COMPOSITION; HEART-DISEASE; RISK-FACTOR; MARKERS; INTERLEUKIN-6; MECHANISMS; RESPONSES; OBESITY AB Background: Major depressive disorder (MDD) shows increased coronary artery disease (CAD) risk of unknown mechanism(s). MDD is more common in women than men; CAD diagnosis can be difficult in women. Elevations of the inflammatory markers C-reactive protein (CRP) and serum amyloid A (SAA) predict increased CAD risk in populations; few data on these markers exist in MDD, particularly in remitted patients. Methods: We measured fasting am serum CRP (high sensitivity, CRPhs) and SAA in 18 unmedicated, remitted women with MDD (mean age 41 +/- (SD) 12, body mass index (BMI) 25.2 +/- 4.1 kg/m(2)) and 18 BMI-matched healthy control subjects (age 36 10, BMI 25.3 +/- 3.8 kg/m(2)) on 2 separate occasions, ! 6 days apart. Results: Repeat SAA and CRPhs measurements strongly correlated across study days (SAA: r = .83, p < .001; CRPhs: r = .94, p < .001). Both SAA (5.30 +/- 3.39 vs. 2.84 +/- 1.87 mg/L, p < .005) and CRPhs (3.23 +/- 3.17 vs. 1.12 +/- 1.45 mg/L; p < .01) were significantly elevated in MDD women versus controls. Conclusions: Elevated SAA and CRPhs in remitted, unmedicated women with MDD indicate a pro-inflammatory state unrelated to current depressive symptoms or pharmacotherapy. These findings suggest that inflammatory mechanisms may in part underlie findings of increased CAD risk in MDD. C1 NIMH, Clin Neuroendocrinol Branch, Bethesda, MD 20892 USA. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. NIMH, Div Intramural Res Program, Bethesda, MD 20892 USA. Ctr Clin, Dept Lab Med, Bethesda, MD USA. Mt Sinai Sch Med, Off Dean, New York, NY USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT 06520 USA. W Haven Vet Affairs Med Ctr, Psychiat Serv, New Haven, CT USA. Hebrew Univ Jerusalem, Hadassah Med Ctr, Dept Psychiat, IL-91905 Jerusalem, Israel. RP Kling, MA (reprint author), NIH, Bldg 10 Room 2D-46,10 Ctr Dr,MSC 1284, Bethesda, MD 20892 USA. EM klingm@mail.nih.gov RI Kling, Mitchel/F-4152-2010 OI Kling, Mitchel/0000-0002-2232-1409 FU Intramural NIH HHS [Z01 CL010306-07, Z01 MH002659-13, Z01 MH002817-03] NR 35 TC 58 Z9 60 U1 0 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 AUG 15 PY 2007 VL 62 IS 4 BP 309 EP 313 DI 10.1016/j.biopsych.2006.09.033 PG 5 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 198WL UT WOS:000248658100005 PM 17178112 ER PT J AU Fowler, JS Alia-Klein, N Kriplani, A Logan, J Williams, B Zhu, W Craig, IW Telang, F Goldstein, R Volkow, ND Vaska, P Wang, GJ AF Fowler, Joanna S. Alia-Klein, Nelly Kriplani, Aarti Logan, Jean Williams, Benjamin Zhu, Wei Craig, Ian W. Telang, Frank Goldstein, Rita Volkow, Nora D. Vaska, Paul Wang, Gene-Jack TI Evidence that brain MAO A activity does not correspond to MAO A genotype in healthy male subjects SO BIOLOGICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 52nd Annual Meeting of the Society-of-Nuclear-Medicine CY JUN 18-22, 2005 CL Toronto, CANADA SP Soc Nucl Med DE brain MAO activity; MAO A genotype ID MONOAMINE-OXIDASE-A; FUNCTIONAL POLYMORPHISM; SEROTONIN-TRANSPORTER; AGGRESSIVE-BEHAVIOR; GENE PROMOTER; ASSOCIATION; IMPULSIVITY; INHIBITION; EXPRESSION; VIOLENCE AB Background: A functional polymorphism in the promoter region of the monoamine oxidase A (MAO A) gene has two common alleles that are referred to as the high and low MAO A genotypes. We report the first in vivo human study to determine whether there is an association between MAO A genotype and brain MAO A activity in healthy male subjects. Methods: Brain MAO A activity was measured with positron emission tomography and [C-11]clorgyline in 38 healthy adult male nonsmokers genotyped for MAO A polymorphism. Results: There was no significant difference in brain MAO A activity between the high (n = 26) and low (n = 12) MAO A genotypes. Conclusions: The lack of an association between the high and low MAO A genotype and brain MAO A activity suggests that this polymorphism by itself does not contribute to differences in brain MAO A activity in healthy adult male subjects. C1 Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. Kings Coll London, London WC2R 2LS, England. SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA. SUNY Stony Brook, Dept Biomed Engn, Stony Brook, NY 11794 USA. NIDA, Bethesda, MD 20892 USA. NIAAA, Rockville, MD 20852 USA. RP Fowler, JS (reprint author), Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. EM fowler@bnl.gov OI Craig, Ian/0000-0002-4063-1005; Logan, Jean/0000-0002-6993-9994 FU NCRR NIH HHS [M01 RR010710, M01 RR010710-11, M01 RR10710]; NIBIB NIH HHS [EB002630, R01 EB002630]; NIDA NIH HHS [K05 DA020001, K05 DA020001-03, K05 DA020001-04, K05 DA02001] NR 26 TC 66 Z9 68 U1 4 U2 6 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 AUG 15 PY 2007 VL 62 IS 4 BP 355 EP 358 DI 10.1016/j.biopsych.2006.08.038 PG 4 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 198WL UT WOS:000248658100012 PM 17141746 ER PT J AU Karginov, VA Nestorovich, EM Schmidtmann, F Robinson, TM Yohannes, A Fahmi, NE Bezrukov, SM Hecht, SM AF Karginov, Vladimir A. Nestorovich, Ekaterina M. Schmidtmann, Frank Robinson, Tanisha M. Yohannes, Adiamseged Fahmi, Nour Eddine Bezrukov, Seraev M. Hecht, Sidnev M. TI Inhibition of S-aureus alpha-hemolysin and B-anthracis lethal toxin by beta-cyclodextrin derivatives SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE anthrax toxin; alpha-hemolysin; Staphylococcus aureus; inhibitors; beta-cyclodextrin derivatives ID PROTECTIVE ANTIGEN; CHANNEL; MEMBRANES; PORE AB Many pathogens utilize the formation of transmembrane pores in target cells in the process of infection. A great number of pore-forming proteins, both bacterial and viral, are considered to be important virulence factors, which makes them attractive targets for the discovery of new therapeutic agents. Our research is based on the idea that compounds designed to block the pores can inhibit the action of virulence factors, and that the chances to find high affinity blocking agents increase if they have the same symmetry as the target pore. Recently, we demonstrated that derivatives of beta-cyclodextrin inhibited anthrax lethal toxin (LeTx) action by blocking the transmembrane pore formed by the protective antigen (PA) subunit of the toxin. To test the broader applicability of this approach, we sought beta-cyclodextrin derivatives capable of inhibiting the activity of Staphylococcus aureus alpha-hemolysin (alpha-HL), which is regarded as a major virulence factor playing an important role in staphylococcal infection. We identified several amino acid derivatives of beta-cyclodextrin that inhibited the activity of alpha-HL and LeTx in cell-based assays at low micromolar concentrations. One of the compounds was tested for the ability to block ion conductance through the pores formed by alpha-HL and PA in artificial lipid membranes. We anticipate that this approach can serve as the basis for a structure-directed drug discovery program to find new and effective therapeutics against various pathogens that utilize pore-forming proteins as virulence factors. (c) 2007 Elsevier Ltd. All rights reserved. C1 Innovat Biol Inc, Manassas, VA 20110 USA. NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. Pinnacle Pharmaceut Inc, Emerging Technol Ctr 1, Charlottesville, VA 22911 USA. Univ Virginia, Dept Chem, Charlottesville, VA 22901 USA. Univ Virginia, Dept Biol, Charlottesville, VA 22901 USA. RP Karginov, VA (reprint author), Innovat Biol Inc, 10900 Univ blvd,MSN 1A8, Manassas, VA 20110 USA. EM vak@innovbio.com FU Intramural NIH HHS; NIAID NIH HHS [R44 AI052894, 2R44AI052894-02, R44 AI052894-02, R44 AI052894-03] NR 19 TC 44 Z9 45 U1 0 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD AUG 15 PY 2007 VL 15 IS 16 BP 5424 EP 5431 DI 10.1016/j.bmc.2007.05.058 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 192AI UT WOS:000248172700006 PM 17572091 ER PT J AU Jha, A Mukherjee, C Rolle, AJ De Clercq, E Balzarini, J Stables, JP AF Jha, Amitabh Mukherjee, Chandrani Rolle, Alfred J. De Clercq, Erik Balzarini, Jan Stables, James P. TI Cytostatic activity of novel 4-aminochalcone-based imides SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE chalcone; maleimides; cytostatic activity; thiol-alkylators; QSAR ID TOPOISOMERASE-II; CYCLIC IMIDES; IN-VITRO; INHIBITION; CYTOTOXICITY; CHALCONES; CARCINOGENESIS; PROLIFERATION; DERIVATIVES; GROWTH AB A series of nine 1-(4-((E)-3-arylacryloyl)phenyl)-1H-pyrrole-2,5-diones 3a-i (4 '-aminochalcone-based maleimides)was synthesized as candidate cytotoxic agents. The efficacy of these potential cytotoxics were evaluated against three representative cell lines and more than half of the drug candidates proved to exhibit significant cytostatic activity in vitro. QSAR studies using statistical analyses on several physicochemical parameters and IC(50) values resulted in a few very important correlations which will aid in later the amplification of the project. Representative test compounds were well tolerated by mice in in vivo survival and toxicity studies. (c) 2007 Elsevier Ltd. All rights reserved. C1 Acadia Univ, Dept Chem, Wolfville, NS B4P 2R6, Canada. Katholieke Univ Leuven, Rega Inst Med Res, B-3000 Louvain, Belgium. Natl Inst Neurol Disorders & Stroke, Rockville, MD 20852 USA. RP Jha, A (reprint author), Acadia Univ, Dept Chem, Wolfville, NS B4P 2R6, Canada. EM ajha@j.acadiau.ca RI Jha, Amitabh/B-5452-2010 OI Jha, Amitabh/0000-0002-6305-0721 NR 34 TC 12 Z9 14 U1 0 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD AUG 15 PY 2007 VL 17 IS 16 BP 4545 EP 4550 DI 10.1016/j.bmcl.2007.05.094 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 202BX UT WOS:000248877800028 PM 17566734 ER PT J AU Nabel, EG Shurin, SB AF Nabel, Elizabeth G. Shurin, Susan B. TI Notes from the director, national heart, lung, and blood institute: NHLBI core values and shaping the 2007 budget SO BLOOD LA English DT Editorial Material RP Nabel, EG (reprint author), NHLBI, Natl Inst Hlth, Bldg 10, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2007 VL 110 IS 4 BP 1091 EP 1091 DI 10.1182/blood-2007-05-089607 PG 1 WC Hematology SC Hematology GA 198VJ UT WOS:000248655300008 PM 17675556 ER PT J AU Calado, RT Graf, SA Wilkerson, KL Kajigaya, S Ancliff, PJ Dror, Y Chanock, SJ Lansdorp, PM Young, NS AF Calado, Rodrigo T. Graf, Solomon A. Wilkerson, Keisha L. Kajigaya, Sachiko Ancliff, Philip J. Dror, Yigal Chanock, Stephen J. Lansdorp, Peter M. Young, Neal S. TI Mutations in the SBDS gene in acquired aplastic anemia SO BLOOD LA English DT Article ID SHWACHMAN-DIAMOND-SYNDROME; DYSKERATOSIS-CONGENITA; TELOMERE LENGTH; REVERSE-TRANSCRIPTASE; RNA; PROTEIN; LOCALIZES AB Shwachman-Diamond syndrome (SDS; OMIM 260400), an inherited bone marrow failure syndrome, is caused by mutations in both alleles of the SBDS gene, which encodes a protein of unknown function. Here we report heterozygosity for the 258 + 2 T > C SBDS gene mutation previously identified in SDS patients in 4 of 91 patients with apparently acquired aplastic anemia (AA) but not in 276 ethnically matched controls (Fisher exact test, P < .004). Affected patients were young and had a poor outcome; they had re- duced SBDS expression but no evidence of the pancreatic exocrine failure or skeletal abnormalities typical of SDS. Length of telomeres in granulocytes of SBDS heterozygous patients was short for their age, and in SDS patients with both SBDS alleles affected further analyzed, granulocytes' telomeres were even shorter, correlating in length with SBDS expression. Higher heterogeneity in telomere length also was observed in SDS patients. Telomerase activity of SBDS-deficient patients' lymphocytes was comparable with controls, and no physical interaction between SBDS protein and telomerase complex components (TERT or TERC) was established. We propose that heterozygosity for the 258 + 2 T > C SBDS mutation predisposes to AA by accelerating telomere shortening of leukocytes via a telomerase-independent mechanism. C1 NHLBI, NIH, Hematol Branch, Bethesda, MD 20892 USA. Howard Hughes Med Inst, NIH, Res Scholars Program, Bethesda, MD 20817 USA. Great Ormond St Hosp Sick Children, Camelia Botnar Labs, London WC1N 3JH, England. Univ Toronto, Hosp Sick Children, Cell Biol Program, Toronto, ON M5G 1X8, Canada. Natl Canc Inst, NIH, Pediat Oncol Branch, Bethesda, MD USA. Univ British Columbia, BC Canc Res Ctr, Dept Med, Terry Fox Lab, Vancouver, BC V5Z 1M9, Canada. RP Calado, RT (reprint author), NHLBI, NIH, Hematol Branch, Bldg 10, Bethesda, MD 20892 USA. EM calador@nhlbi.nih.gov RI Calado, Rodrigo/G-2619-2011 FU Intramural NIH HHS NR 29 TC 33 Z9 40 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2007 VL 110 IS 4 BP 1141 EP 1146 DI 10.1182/blood-2007-03-080044 PG 6 WC Hematology SC Hematology GA 198VJ UT WOS:000248655300016 PM 17478638 ER PT J AU Ward, J Bonaparte, M Sacks, J Guterman, J Fogli, M Mavilio, D Barker, E AF Ward, Jeffrey Bonaparte, Matthew Sacks, Jennifer Guterman, Jacqueline Fogli, Manuela Mavilio, Domenico Barker, Edward TI HIV modulates the expression of ligands important in triggering natural killer cell cytotoxic responses on infected primary T-cell blasts SO BLOOD LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; CLASS-I MOLECULES; HUMAN NK CELLS; INHIBITORY RECEPTOR; HLA-E; HERPESVIRUS INFECTIONS; HOMOPHILIC INTERACTION; ACTIVATING RECEPTORS; SURFACE-MOLECULE; DOWN-REGULATION AB The ability of natural killer (NK) cells to kill virus-infected cells depends on the presence of ligands for activation receptors on the target cells. We found the presence of few, if any, NKp30 and NK46 ligands on T cell blasts infected with HIV, although NKp44 ligands were found on infected cells. HIV does induce the NKG2D ligands ULBP-1, -2, and -3. These ligands are involved in triggering NK cells to kill aurtologous HIV-infected cells, because interfering with the interaction between NKG2D, but not NKp46, on NK cells and its ligands on HIV-infected cells drastically reduced the lysis of infected cells. Interfering with the binding of the NK-cell coreceptors NTB-A and 2B4 to their ligands also decreased destruction by NK cells. The coreceptor ligands, NTB-A and CD48, were also found to be down-regulated during the course of HIV infection. Thus, ligands for NK-cell receptors are modulated during the course of HIV infection, which may greatly alter NK cells' ability to kill the infected cells. C1 SUNY Syracuse, Dept Microbiol & Immunol, Syracuse, NY 13210 USA. NIAID, NIH, Immunoregulat Lab, Bethesda, MD 20892 USA. Rush Univ, Med Ctr, Dept Immunol & Microbiol, Chicago, IL 60612 USA. RP Barker, E (reprint author), SUNY Syracuse, Dept Microbiol & Immunol, Syracuse, NY 13210 USA. EM edward_barker@rush.edu OI Mavilio, Domenico/0000-0001-6147-0952 FU NIAID NIH HHS [R03 AI052809, AI16536, AI52809, AI56923, R21 AI056923] NR 59 TC 101 Z9 107 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2007 VL 110 IS 4 BP 1207 EP 1214 DI 10.1182/blood-2006-06-028175 PG 8 WC Hematology SC Hematology GA 198VJ UT WOS:000248655300025 PM 17513617 ER PT J AU Murakami, T Chen, X Hase, K Sakamoto, A Nishigaki, C Ohno, H AF Murakami, Takaya Chen, Xin Hase, Koji Sakamoto, Ayako Nishigaki, Chie Ohno, Hiroshi TI Splenic CD19(-)CD35(+)B220(+) cells function as an inducer of follicular dendritic cell network formation SO BLOOD LA English DT Article ID LYMPHOTOXIN-BETA-RECEPTOR; TUMOR-NECROSIS-FACTOR; BONE-MARROW-CELLS; CENTER B-CELLS; STROMAL CELLS; LYMPHOID FOLLICLES; IMMUNE-COMPLEXES; MARGINAL ZONE; IN-VITRO; LYMPHOCYTES AB Follicular dendritic cells (FDCs) form a reticular FDC network in the lymphoid follicle that is essential for the retention and presentation of native antigens in the form of antigen-antibody immune complexes (ICs) to B cells during secondary immune response. Although the presence of migrating precursors of FDCs has been hypothesized, their entity has not been elucidated. Here we report the identification of murine splenic CD19(-)CD11c(-)CD35(+)B220(+) cells as an inducer of FDC network formation. We demonstrated that CD19(-)CD11c(-)CD35(+)B220(+) cells, together with stromal cells, had the remarkable ability to form lymphold-follicle-like structures that contained B220(+)FDC(-)M1(+) reticular cells originally derived from CD19(-)CD11c(-)CD35(+)B220(+) cells in the CD35(+) reticulum. Our results indicate that CD19(-)CD11c(-)CD35(+)B220(+) cells function as an inducer of FDC network formation and that the interaction between CD19(-)CD11c(-)CD35(+)B220(+) cells and stromal cells is required to initiate lymphoid follicle formation. C1 RIKEN, Res Ctr Allergy & Immunol, Lab Epithelial Immunobiol, Yokohama, Kanagawa, Japan. NCI, SAIC, Lab Mol Immunoregulat, Basic Res Program, Frederick, MD USA. Yokohama City Univ, Int Grad Sch Arts & Sci, Yokohama, Kanagawa 232, Japan. RP Ohno, H (reprint author), RIKEN, Res Ctr Allergy & Immunol, Lab Epithelial Immunobiol, Yokohama, Kanagawa, Japan. EM ohno@rcai.riken.jp RI Ohno, Hiroshi/L-7899-2014; Chen, Xin/I-6601-2015 OI Ohno, Hiroshi/0000-0001-8776-9661; Chen, Xin/0000-0002-2628-4027 FU NCI NIH HHS [N01CO12400, N01-CO12400] NR 47 TC 17 Z9 18 U1 0 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD AUG 15 PY 2007 VL 110 IS 4 BP 1215 EP 1224 DI 10.1182/blood-2007-01-068387 PG 10 WC Hematology SC Hematology GA 198VJ UT WOS:000248655300026 PM 17519390 ER PT J AU Clark-Langone, KM Wu, JY Sangli, C Chen, A Snable, JL Nguyen, A Hackett, JR Baker, J Yothers, G Kim, C Cronin, MT AF Clark-Langone, Kim M. Wu, Jenny Y. Sangli, Chithra Chen, Angela Snable, James L. Nguyen, Anhthu Hackett, James R. Baker, Joffre Yothers, Greg Kim, Chungyeul Cronin, Maureen T. TI Biomarker discovery for colon cancer using a 761 gene RT-PCR assay SO BMC GENOMICS LA English DT Article ID PARAFFIN-EMBEDDED TISSUES; GENE-EXPRESSION PROFILES; BREAST-CANCER; PREDICT RECURRENCE; EPITHELIAL-CELLS; CHEMOTHERAPY; FIBROBLASTS; PROGNOSIS; SIGNATURE; CARCINOMA AB Background: Reverse transcription PCR ( RT- PCR) is widely recognized to be the gold standard method for quantifying gene expression. Studies using RT- PCR technology as a discovery tool have historically been limited to relatively small gene sets compared to other gene expression platforms such as microarrays. We have recently shown that TaqMan (R) RT- PCR can be scaled up to profile expression for 192 genes in fixed paraffin- embedded ( FPE) clinical study tumor specimens. This technology has also been used to develop and commercialize a widely used clinical test for breast cancer prognosis and prediction, the Onco typeDX (TM) assay. A similar need exists in colon cancer for a test that provides information on the likelihood of disease recurrence in colon cancer ( prognosis) and the likelihood of tumor response to standard chemotherapy regimens ( prediction). We have now scaled our RT- PCR assay to efficiently screen 761 biomarkers across hundreds of patient samples and applied this process to biomarker discovery in colon cancer. This screening strategy remains attractive due to the inherent advantages of maintaining platform consistency from discovery through clinical application. Results: RNA was extracted from formalin fixed paraffin embedded ( FPE) tissue, as old as 28 years, from 354 patients enrolled in NSABP C- 01 and C- 02 colon cancer studies. Multiplexed reverse transcription reactions were performed using a gene specific primer pool containing 761 unique primers. PCR was performed as independent TaqMan (R) reactions for each candidate gene. Hierarchal clustering demonstrates that genes expected to co- express form obvious, distinct and in certain cases very tightly correlated clusters, validating the reliability of this technical approach to biomarker discovery. Conclusion: We have developed a high throughput, quantitatively precise multi- analyte gene expression platform for biomarker discovery that approaches low density DNA arrays in numbers of genes analyzed while maintaining the high specificity, sensitivity and reproducibility that are characteristics of RT- PCR. Biomarkers discovered using this approach can be transferred to a clinical reference laboratory setting without having to re-validate the assay on a second technology platform. C1 Genom Hlth Inc, Redwood City, CA 94063 USA. Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA USA. RP Clark-Langone, KM (reprint author), Genom Hlth Inc, Redwood City, CA 94063 USA. EM klangone@genomichealth.com; jenwu22@yahoo.com; csangli@genomichealth.com; achen@genomichealth.com; jsnable@genomichealth.com; anguyen@genomichealth.com; jhackett@genomichealth.com; jbaker@genomichealth.com; yothers@nsabp.pitt.edu; ckim@nsabp.org; mcronin@genomichealth.com OI kim, chungyeul/0000-0002-9636-5228; Yothers, Greg/0000-0002-7965-7333 NR 28 TC 33 Z9 33 U1 0 U2 2 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 AUG 15 PY 2007 VL 8 AR 279 DI 10.1186/1471-2164-8-279 PG 18 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 218ZQ UT WOS:000250054900001 PM 17697383 ER PT J AU Joo, JH Liao, G Collins, JB Grissom, SF Jetten, AM AF Joo, Joung Hyuck Liao, Grace Collins, Jennifer B. Grissom, Sherry F. Jetten, Anton M. TI Farnesol-induced apoptosis in human lung carcinoma cells is coupled to the endoplasmic reticulum stress response SO CANCER RESEARCH LA English DT Article ID UNFOLDED PROTEIN RESPONSE; PHOSPHOCHOLINE CYTIDYLYLTRANSFERASE-ALPHA; ISOPRENOIDS PERILLYL ALCOHOL; MESSENGER-RNA; ER STRESS; PHOSPHATIDYLCHOLINE SYNTHESIS; SACCHAROMYCES-CEREVISIAE; ADENOCARCINOMA CELLS; INDUCED GENERATION; MAP KINASE AB Farnesol (FOH) and other isoprenoid alcohols induce apoptosis in various carcinoma cells and inhibit tumorigenesis in several in vivo models. However, the mechanisms by which they mediate their effects are not yet fully understood. In this study, we show that FOH is an effective inducer of apoptosis in several lung carcinoma cells, including H460. This induction is associated with activation of several caspases and cleavage of poly(ADP-ribose) polymerase (PARP). To obtain insight into the mechanism involved in FOH-induced apoptosis, we compared the gene expression profiles of FOH-treated and control H460 cells by microarray analysis. This analysis revealed that many genes implicated in endoplasmic reticulum (ER) stress signaling, including ATF3, DDIT3, HEKPUD1, HSPA5, XBP1, PDLA4, and PHLDA1, were highly up-regulated within 4 h of FOH treatment, suggesting that FOH-induced apoptosis involves an ER stress response. This was supported by observations showing that treatment with FOH induces splicing of XBP1 mRNA and phosphorylation of eIF2 alpha,. FOH induces activation of several mitogen-activated protein kinase (MAPK) pathways, including p38, MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK, and c-jun NH2-terminal kinase (JNK). Inhibition of NIEKI/2 by U0126 inhibited the induction of ER stress response genes. In addition, knockdown of the MEK1/2 and JNK 1/2 expression by short interfering RNA (siRNA) effectively inhibited the cleavage of caspase-3 and PARP and apoptosis induced by FOH. However, only NIEKI/2 siRNAs inhibited the induction of ER stress-related genes, XBP1 mRNA splicing, and eIF2 alpha phosphorylation. Our results show that FOH-induced apoptosis is coupled to ER stress and that activation of NIEKI/2 is an early upstream event in the FOH-induced ER stress signaling cascade. C1 NIH, Natl Inst Environm Hlth Sci, Div Intramural Res, LRB,Cell Biol lab, Res Triangle Pk, NC 27709 USA. NIH, Natl Inst Environm Hlth Sci, Div Intramural Res, Microarray Grp, Res Triangle Pk, NC USA. RP Jetten, AM (reprint author), NIH, Natl Inst Environm Hlth Sci, Div Intramural Res, LRB,Cell Biol lab, 111 TW Alexander Dr,Res Triangle Pk, Res Triangle Pk, NC 27709 USA. EM jetten@niehs.nih.gov OI Jetten, Anton/0000-0003-0954-4445 FU Intramural NIH HHS NR 50 TC 64 Z9 67 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD AUG 15 PY 2007 VL 67 IS 16 BP 7929 EP 7936 DI 10.1158/0008-5472.CAN-07-0931 PG 8 WC Oncology SC Oncology GA 200XJ UT WOS:000248795800047 PM 17699800 ER PT J AU Rubin, JS Bottaro, DP AF Rubin, Jeffrey S. Bottaro, Donald P. TI Loss of secreted frizzled-related protein-1 expression in renal cell carcinoma reveals a critical tumor suppressor function SO CLINICAL CANCER RESEARCH LA English DT Article ID BETA-CATENIN; COLORECTAL-CANCER; ANTAGONIST; ACTIVATION; PATHWAY; GENES; REIC/DKK-3; PROGNOSIS; MECHANISM; MOTILITY C1 NCI, Urol Oncol Branch, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, NIH, Cellular & Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Bottaro, DP (reprint author), NCI, Urol Oncol Branch, NIH, Ctr Canc Res, Bldg 10 Rm 1-3961,10 Ctr Dr,MSC 1107, Bethesda, MD 20892 USA. EM dbottaro@helix.nih.gov RI Bottaro, Donald/F-8550-2010 OI Bottaro, Donald/0000-0002-5057-5334 FU Intramural NIH HHS NR 25 TC 4 Z9 4 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2007 VL 13 IS 16 BP 4660 EP 4663 DI 10.1158/1078-0432.CCR-07-1077 PG 4 WC Oncology SC Oncology GA 201ND UT WOS:000248837900003 PM 17699841 ER PT J AU Bratslavsky, G Sudarshan, S Neckers, L Linehan, M AF Bratslavsky, Gennady Sudarshan, Sunil Neckers, Len Linehan, W. Marston TI Pseudohypoxic pathways in renal cell carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID LINDAU TUMOR-SUPPRESSOR; ENDOTHELIAL GROWTH-FACTOR; HYPOXIA-INDUCIBLE FACTOR-1-ALPHA; GERMLINE MUTATIONS; HIF-ALPHA; VHL GENE; HEREDITARY LEIOMYOMATOSIS; CUTANEOUS LEIOMYOMATA; FUMARATE-HYDRATASE; UTERINE FIBROIDS AB Mutations of the von Hippel-Lindau (VHL) or fumarate hydratase (FH) genes lead to morphologically different renal cell carcinomas with distinct clinical courses and outcomes. The VHL protein is a part of an ubiquitin ligase complex that targets proteins for proteosomal degradation. FH is one of the mitochondrial enzymes of the Kreb's cycle. Despite two different functionalities and cellular locations, loss of either VHL or FH products has been shown to alter expression levels of hypoxia-inducible factors (HIF-1 alpha and HIF-2 alpha) and their downstream targets. HIF proteins are key regulators of oxygen homeostasis. Tight regulation of HIF allows for cell survival and growth at the time of hypoxic stress. HIF acts via transcriptional regulation of vascular endothelial growth factor, platelet derived growth factor, endothelial growth factor receptor, glucose transporter protein 1, erythropoietin, and transforming growth factor-a. Loss of VHL or FH is thought to result in a pseudohypoxic state so that cellular response pathways mediated by HIF are activated despite normal oxygen conditions, Understanding of these pseudohypoxic pathways has provided a better appreciation of the molecular mechanisms of carcinogenesis in addition to providing a rationale for targeted therapeutic approaches. C1 NCI, Urol Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Linehan, M (reprint author), NCI, Urol Oncol Branch, Ctr Canc Res, Bldg 10,Room 1-5940, Bethesda, MD 20892 USA. EM wml@nih.gov FU Intramural NIH HHS NR 55 TC 37 Z9 37 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2007 VL 13 IS 16 BP 4667 EP 4671 DI 10.1158/1078-0432.CCR-06-2510 PG 5 WC Oncology SC Oncology GA 201ND UT WOS:000248837900005 PM 17699843 ER PT J AU Westermann, F Henrich, KO Wei, JS Lutz, W Fischer, M Konig, R Wiedemeyer, R Ehemann, V Brors, B Ernestus, K Leuschner, I Benner, A Khan, J Schwab, M AF Westermann, Frank Henrich, Kai-Oliver Wei, Jun S. Lutz, Werner Fischer, Matthias Koenig, Rainer Wiedemeyer, Ruprecht Ehemann, Volker Brors, Benedikt Ernestus, Karen Leuschner, Ivo Benner, Axel Khan, Javed Schwab, Manfred TI High Skp2 expression characterizes high-risk neuroblastomas independent of MYCN status SO CLINICAL CANCER RESEARCH LA English DT Article ID ADVANCED-STAGE NEUROBLASTOMA; CELL-CYCLE PROGRESSION; CDK INHIBITOR P27; BOX PROTEIN SKP2; N-MYC; CDNA MICROARRAY; S-PHASE; DEGRADATION; GENES; PATHWAY AB Purpose: Amplified MYCN oncogene defines a subgroup of neuroblastomas with poor outcome. However, a substantial number of MYCN single-copy neuroblastomas exhibits an aggressive phenotype similar to that of MYCN-amplified neuroblastomas even in the absence of high MYCN mRNA and/or protein levels. Experimental Design: To identify shared molecular mechanisms that mediate the aggressive phenotype in MYCN-amplified and single-copy high-risk neuroblastomas, we defined genetic programs evoked by ectopically expressed MYCN in vitro and analyzed them in high-risk versus low-risk neuroblastoma tumors (n = 49) using cDNA microarrays. Candidate gene expression was validated in a separate cohort of 117 patients using quantitative PCR, and protein expression was analyzed in neuroblastoma tumors by immunoblotting and immunohistochemistry. Results: We identified a genetic signature characterized by a subset of MYCN/MYC and E2F targets, including Skp2, encoding the F-box protein of the SCFSkp2 E3-ligase, to be highly expressed in high-risk neuroblastomas independent of amplified MYCN. We validated the findings for Skp2 and analyzed its expression in relation to MYCN and E2F-1 expression in a separate cohort (n = 117) using quantitative PCR. High Skp2 expression proved to be a highly significant marker of dire prognosis independent of both MYCN status and disease stage, on the basis of multivariate analysis of event-free survival (hazard ratio, 3.54; 95% confidence interval, 1.56-8.00; P = 0.002). Skp2 protein expression was inversely correlated with expression of p27, the primary target of the SCF Skp2 E3-ligase, in neuroblastoma tumors. Conclusion: Skp2 may have a key role in the progression of neuroblastomas and should make an attractive target for therapeutic approaches. C1 German Canc Res Ctr, Dept Tumor Genet, D-69221 Heidelberg, BW, Germany. Natl Canc Inst, Ctr Adv Technol, Pediat Oncol Branch, Oncogenom Sect, Gaithersburg, MD USA. Univ Marburg, Inst Mol Biol & Tumor Res, Marburg, Germany. Univ Childrens Hosp Cologne, Dept Pediat Oncol, Cologne, Germany. German Canc Res Ctr, Heidelberg, Germany. Univ Heidelberg, Dept Pathol, D-6900 Heidelberg, Germany. German Canc Res Ctr, Dept Biostat, D-6900 Heidelberg, Germany. Univ Kiel, Dept Pathol, D-2300 Kiel, Germany. RP Westermann, F (reprint author), German Canc Res Ctr, Dept Tumor Genet, Im Neuenheimer Feld 280, D-69221 Heidelberg, BW, Germany. EM f.westermann@dkfz.de RI Leuschner, Ivo/E-9437-2010; Brors, Benedikt/E-5620-2013; Khan, Javed/P-9157-2014 OI Brors, Benedikt/0000-0001-5940-3101; Khan, Javed/0000-0002-5858-0488 NR 43 TC 24 Z9 25 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2007 VL 13 IS 16 BP 4695 EP 4703 DI 10.1158/1078-0432.CCR-06-2818 PG 9 WC Oncology SC Oncology GA 201ND UT WOS:000248837900009 PM 17652624 ER PT J AU Takimoto, CH Graham, MA Lockwood, G Ng, CM Goetz, A Greenslade, D Remick, SC Sharma, S Mani, S Ramanathan, RK Synold, TW Doroshow, JH Hamilton, A Mulkerin, DL Ivy, P Egorin, MJ Grem, JL AF Takimoto, Chris H. Graham, Martin A. Lockwood, Graham Ng, Chee M. Goetz, Andrew Greenslade, Dennis Remick, Scot C. Sharma, Sunil Mani, Sridhar Ramanathan, Ramesh K. Synold, Timothy W. Doroshow, James H. Hamilton, Anne Mulkerin, Daniel L. Ivy, Percy Egorin, Merrill J. Grem, Jean L. TI Oxaliplatin pharmacokinetics and pharmacodynamics in adult cancer patients with impaired renal function SO CLINICAL CANCER RESEARCH LA English DT Article ID CREATININE CLEARANCE; PHASE-I; PERFORMANCE; PREDICTION; PLATINUM AB Purpose: To characterize the pharmacokinetics and pharmacodynamics of oxaliplatin in cancer patients with impaired renal function. Experimental Design: Thirty-four patients were stratified by 24-h urinary creatinine clearance (CrCL) into four renal dysfunction groups: group A (control, CrCL, >= 60 mL/min), B (mild, CrCL, 40-59 mL/min), C (moderate, CrCL, 20-39 mL/min), and D (severe, CrCL, <20 mL/min). Patients were treated with 60 to 130 mg/m(2) oxaliplatin infused over 2 h every 3 weeks. Pharmacokinetic monitoring of platinum in plasma, plasma ultrafiltrates, and urine was done during cycles 1 and 2. Results: Plasma ultrafiltrate platinum clearance strongly correlated with CrCL (r(2) = 0.712). Platinum elimination from plasma was triphasic, and maximal platinum concentrations (C-max) were consistent across all renal impairment groups. However, only the beta-half-life was significantly prolonged by renal impairment, with values of 14.0 +/- 4.3, 20.3 +/- 17.7, 29.2 +/- 29.6, and 68.1 h in groups A, B, C, and D, respectively (P = 0.002). At a dose level of 130 mg/m(2), the area under the concentration time curve increased in with the degree of renal impairment, with values of 16.4 +/- 5.03, 39.7 +/- 11.5, and 44.6 +/- 14.6 mu g.h/mL, in groups A, B, and C, respectively. However, there was no increase in pharmacodynamic drug-related toxicities. Estimated CrCL using the Cockcroft-Gault method approximated the measured 24-h urinary CrCL (mean prediction error, -5.0 mL/min). Conclusions: Oxaliplatin pharmacokinetics are altered in patients with renal impairment, but a corresponding increase in oxaliplatin-related toxicities is not observed. C1 Canc Therapy & Res Ctr S Texas, Inst Drug Dev, San Antonio, TX 78245 USA. NCI, Med Branch Navy, Natl Naval Med Ctr, Bethesda, MD 20892 USA. NCI, Div Canc Treatment & Ctr, Invest Drug Branch, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. Dept Global Metab & Pharmacokinet, Malvern, PA USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. NYU, San Antonio, TX USA. Montefiore Hosp, Albert Einstein Coll Med, Bronx, NY USA. Univ Pittsburgh, Pittsburgh Canc Inst, Pittsburgh, PA USA. City Hope Natl Med Ctr, Duarte, CA 91010 USA. Univ Wisconsin, Madison, WI USA. RP Takimoto, CH (reprint author), Canc Therapy & Res Ctr S Texas, Inst Drug Dev, 14960 Omicron Dr, San Antonio, TX 78245 USA. EM ctakimot@idd.org FU NCI NIH HHS [U01CA062491, U01 CA062491, U01CA062502, U01CA062505, U01CA069853, U01CA069855, U01CA069856, U01CA076642] NR 24 TC 37 Z9 37 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2007 VL 13 IS 16 BP 4832 EP 4839 DI 10.1158/1078-0432,CCR-07-0475 PG 8 WC Oncology SC Oncology GA 201ND UT WOS:000248837900025 PM 17699862 ER PT J AU Duran, I Hotte, SJ Hirte, H Chen, EX MacLean, M Turner, S Duan, L Pond, GR Lathia, C Walsh, S Wright, JJ Dancey, J Siu, LL AF Duran, Ignacio Hotte, Sebastien J. Hirte, Holger Chen, Eric X. MacLean, Martha Turner, Sandra Duan, Lixia Pond, Gregory R. Lathia, Chetan Walsh, Scott Wright, John J. Dancey, Janet Siu, Lillian L. TI Phase I targeted combination trial of sorafenib and erlotinib in patients with advanced solid tumors SO CLINICAL CANCER RESEARCH LA English DT Article ID TYROSINE KINASE INHIBITOR; ENDOTHELIAL GROWTH-FACTOR; RENAL-CELL CARCINOMA; RANDOMIZED DISCONTINUATION TRIAL; FACTOR RECEPTOR INHIBITOR; DAYS ON/7 DAYS; RAF KINASE; LUNG-CANCER; SIGNAL-TRANSDUCTION; ANTICANCER THERAPEUTICS AB Purpose: Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their inhibitory target profile and efficacy as single agents, the combination of these drugs is of considerable interest in solid malignancies. This study aimed to determine the recommended phase II dose of this targeted combination, their toxicity profile, pharmacokinetic interaction, and preliminary clinical activities. Experimental Design: Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously, with every 28 days considered as a cycle. Three dose levels were assessed. Results: Seventeen patients with advanced solid tumors received 75 cycles of treatment. The most frequent adverse events of all grades were constitutional and gastrointestinal in nature followed by electrolytes and dermatologic toxicities. Fatigue was the most common adverse event (17 patients; 100%) followed by diarrhea (15 patients; 88%), hypophosphatemia (13 patients; 76%), and acneiform rash (12 patients; 71%). These adverse events were predominantly mild to moderate. The recommended phase II dose of this combination was determined as 400 mg twice daily sorafenib and 150 mg daily erlotinib. Pharmacokinetic analysis revealed no significant effect of erlotinib on the pharmacokinetic profile of sorafenib. Among 15 evaluable patients, 3 (20%) achieved a confirmed partial response and 9 (60%) had stable disease as best response. Conclusions: Sorafenib and erlotinib are well tolerated and seem to have no pharmacokinetic interactions when administered in combination at their full single-agent recommended doses. This well tolerated combination resulted in promising activity that needs further validation in phase II studies. C1 NCI, Bethesda, MD 20892 USA. Bayer Pharmaceut Corp, West Haven, CT USA. Sunnybrook Hlth Sci Ctr, Div Dermatol, Toronto, ON, Canada. Princess Margaret Hosp Phase II Consortium, Toronto, ON, Canada. RP Siu, LL (reprint author), Univ Hlth Network, Princess Margaret Hosp, Dept Med Oncol & Hematol, 610 Univ Ave,Suite 5-178, Toronto, ON M5G 2M9, Canada. EM lillian.siu@uhn.on.ca FU NCI NIH HHS [N01-CM-17107] NR 48 TC 64 Z9 65 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2007 VL 13 IS 16 BP 4849 EP 4857 DI 10.1158/1078-0432.CCR-07-0382 PG 9 WC Oncology SC Oncology GA 201ND UT WOS:000248837900027 PM 17699864 ER PT J AU Cotrim, AP Hyodo, F Matsumoto, KI Sowers, AL Cook, JA Baum, BJ Krishna, MC Mitchell, JB AF Cotrim, Ana P. Hyodo, Fuminori Matsumoto, Ken-Ichiro Sowers, Anastasia L. Cook, John A. Baum, Bruce J. Krishna, Murali C. Mitchell, James B. TI Differential radiation protection of salivary glands versus tumor by tempol with accompanying tissue assessment of tempol by magnetic resonance Imaging SO CLINICAL CANCER RESEARCH LA English DT Article ID SENSITIVE CONTRAST AGENTS; CANCER STATISTICS; NECK RADIOTHERAPY; NITROXIDE TEMPOL; INDUCED DAMAGE; REDOX STATUS; MOUSE MODEL; HEAD; AMIFOSTINE; IRRADIATION AB Purpose: The nitroxide free radical,Tempol, was evaluated for potential differential radiation protection of salivary glands and tumor using fractionated radiation. Mechanistic information was explored by monitoring the presence and bioreduction of Tempol in both tissues noninvasively by magnetic resonance imaging (MRI). Experimental Design: Female C3H mice were immobilized using custom-made Lucite jigs for localized irradiation (five daily fractions) either to the oral cavity or tumor-bearing leg. Tempol (275 mg/kg) was administered (i.p.) 10 min before each radiation fraction. Salivary gland damage was assessed 8 weeks after radiation by measuring pilocarpine-mediated saliva output. Tumor growth was assessed by standard radiation regrowth methods. Dynamic T-1-weighted magnetic resonance scans were acquired before and after Tempol injection using a 4.7Tanimal MRI instrument. Results: Tempol treatment was found to protect salivary glands significantly against radiation damage ( similar to 60% improvement); whereas no tumor protection was observed. Intracellular reduction of Tempol to the nonradioprotective hydroxylamine as assessed by MRI was 2-fold faster in tumor compared with salivary glands or muscle. Conclusions: Tempol provided salivary gland radioprotection and did not protect tumor, consistent with the hypothesis that differential radioprotection by Tempol resides in faster reduction to the nonradioprotective hydroxylamine in tumor compared with normal tissues. The unique paramagnetic properties of Tempol afforded noninvasive MRI monitoring of dynamic changes of Tempol levels in tissue to support the finding. These data support further development and consideration of Tempol for human clinical trials as a selective protector against radiation- induced salivary gland damage. C1 Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Cotrim, AP (reprint author), Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, Bldg 10,Room 1N113,MSC-1190, Bethesda, MD 20892 USA. EM acotrim@nidcr.nih.gov FU Intramural NIH HHS NR 33 TC 66 Z9 70 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2007 VL 13 IS 16 BP 4928 EP 4933 DI 10.1158/1078-0432.CCR-07-0662 PG 6 WC Oncology SC Oncology GA 201ND UT WOS:000248837900036 PM 17699873 ER PT J AU Arun, B Valero, V Logan, C Broglio, K Rivera, E Brewster, A Yin, GS Green, M Kuerer, H Gong, Y Browne, D Hortobagyi, GN Sneige, N AF Arun, Banu Valero, Vicente Logan, Catherine Broglio, Kristine Rivera, Edgardo Brewster, Abenaa Yin, Guosheng Green, Marjorie Kuerer, Henry Gong, Yun Browne, Doris Hortobagyi, Gabriel N. Sneige, Nour TI Comparison of ductal lavage and random periareolar fine needle aspiration as tissue acquisition methods in early breast cancer prevention trials SO CLINICAL CANCER RESEARCH LA English DT Article ID SURROGATE END-POINTS; HIGH-RISK; NIPPLE ASPIRATION; PHASE-II; WOMEN; ATYPIA; CHEMOPREVENTION; BIOMARKERS; SPECIMENS; TAMOXIFEN AB Purpose: Short-term phase I and phase II breast cancer prevention trials require tissue acquisition at baseline and after intervention to evaluate modulation of potential biomarkers. Currently used tissue acquisition methods include ductal lavage (DL), random periareolar fine needle aspiration (RPFNA), and core needle biopsy. The optimum method to retrieve adequate samples and the most accepted method by study participants is not known. Experimental Design: We compared RPFNA and DL as breast tissue acquisition methods for short-term breast cancer prevention trials by evaluating sample adequacy and tolerability in subjects who participated in two prospective phase II breast cancer prevention trials. Eighty-six women at increased risk for breast cancer were included in this study and underwent baseline DL and RPFNA. High risk was defined as having a 5-year Gail score of > 1.67% or a history of atypical hyperplasia (AH), lobular carcinoma, or breast cancer. Results: Median age was 54.5 years (range, 39-75 years); 75% of the women were postmenopausal. About 51% of the women yielded nipple aspiration fluid, and breast fluid samples via DL were retrieved in 73 % of these subjects. Of these samples, 71 % were adequate samples (greater than 10 epithelial cells). However, when the entire cohort was considered, only 31% of the subjects had adequate samples. RPFNA was also attempted in all subjects, and sample retrieval rate was100%. Out of these, 96% of the subjects had adequate samples. In DI-samples, AH rate was 3.7% was and hyperplasia (H) rate was 11.1%. In RPFNA samples, AH rate was 12.9%, and H rate was 24.7%. Cytology findings in RPFNA samples correlated with age, menopausal status, and breast cancer risk category (previous history of lobular carcinoma in situ). Both procedures were well tolerated, and no complications occurred among participants. Conclusions: Considering that the main end point for short-term prevention trials is the modulation of biomarkers, it is important to optimize adequate sample acquisition; therefore, RPFNA is a more practical option for future phase I and 11 breast cancer prevention trials compared with DIL. C1 Univ Texas, MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Surg, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. NCI, Breast & Gynecol Canc Res Grp, Houston, TX USA. RP Arun, B (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Biostat, 1155 Pressler St CPB5, Houston, TX 77030 USA. EM barun@mdanderson.org NR 28 TC 14 Z9 14 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD AUG 15 PY 2007 VL 13 IS 16 BP 4943 EP 4948 DI 10.1158/1078-0432.CCR-06-2732 PG 6 WC Oncology SC Oncology GA 201ND UT WOS:000248837900038 PM 17699874 ER PT J AU Brunell, P AF Brunell, Philip TI The effectiveness of evaluating mumps vaccine effectiveness SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID FIELD EVALUATION; VIRUS VACCINE; UNITED-STATES; EFFICACY; UPDATE C1 Natl Inst Hlth, Bethesda, MD 20892 USA. RP Brunell, P (reprint author), Natl Inst Hlth, Bldg 10, Rm 11N228 MSC 1888, 10 Ctr Dr, Bethesda, MD 20892 USA. EM pbrunell@niaid.nih.gov NR 12 TC 3 Z9 3 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD AUG 15 PY 2007 VL 45 IS 4 BP 467 EP 469 DI 10.1086/520027 PG 3 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 190SK UT WOS:000248079500010 PM 17638195 ER PT J AU Jacques, BE Montcouquiol, ME Layman, EM Lewandoski, M Kelley, MW AF Jacques, Bonnie E. Montcouquiol, Mireille E. Layman, Erynn M. Lewandoski, Mark Kelley, Matthew W. TI Fgf8 induces pillar cell fate and regulates cellular patterning in the mammalian cochlea SO DEVELOPMENT LA English DT Article DE organ of Corti; hair cell; Fgfr3; mouse ID FIBROBLAST-GROWTH-FACTOR; AUDITORY SENSORY EPITHELIUM; CHICK INNER-EAR; NEURONAL DIFFERENTIATION; STRUCTURAL BASIS; HAIR-CELLS; ORGAN; EXPRESSION; CORTI; GENE AB The mammalian auditory sensory epithelium (the organ of Corti) contains a number of unique cell types that are arranged in ordered rows. Two of these cell types, inner and outer pillar cells (PCs), are arranged in adjacent rows that form a boundary between a single row of inner hair cells and three rows of outer hair cells (OHCs). PCs are required for auditory function, as mice lacking PCs owing to a mutation in Fgfr3 are deaf. Here, using in vitro and in vivo techniques, we demonstrate that an Fgf8 signal arising from the inner hair cells is the key component in an inductive pathway that regulates the number, position and rate of development of PCs. Deletion of Fgf8 or inhibition of binding between Fgf8 and Fgfr3 leads to defects in PC development, whereas overexpression of Fgf8 or exogenous Fgfr3 activation induces ectopic PC formation and inhibits OHC development. These results suggest that Fgf8-Fgfr3 interactions regulate cellular patterning within the organ of Corti through the induction of one cell fate (PC) and simultaneous inhibition of an alternate fate (OHC) in separate progenitor cells. Some of the effects of both inhibition and overactivation of the Fgf8-Fgfr3 signaling pathway are reversible, suggesting that PC differentiation is dependent upon constant activation of Fgfr3 by Fgf8. These results suggest that PCs might exist in a transient state of differentiation that makes them potential targets for regenerative therapies. C1 INSERM, Inst F Magendie Neurosci, Equipe AVENIR 2 Neurosci Dev IFR8, F-33077 Bordeaux, France. Natl Inst Hlth, Natl Inst Deafness & Other Commun Disorders, Porter Neurosci Res Ctr, Sect Dev Neurosci, Bethesda, MD 20892 USA. Univ Maryland, Dept Biol, College Pk, MD USA. Natl Canc Inst, Canc & Dev Biol Lab, Genet Vertebrate Dev Sect, Frederick, MD USA. RP Kelley, MW (reprint author), INSERM, Inst F Magendie Neurosci, Equipe AVENIR 2 Neurosci Dev IFR8, F-33077 Bordeaux, France. EM kelleymt@nidcd.nih.gov OI montcouquiol, mireille/0000-0001-8739-6519 FU Intramural NIH HHS NR 31 TC 78 Z9 80 U1 0 U2 4 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 EI 1477-9129 J9 DEVELOPMENT JI Development PD AUG 15 PY 2007 VL 134 IS 16 BP 3021 EP 3029 DI 10.1242/dev.02874 PG 9 WC Developmental Biology SC Developmental Biology GA 195AN UT WOS:000248385000014 PM 17634195 ER PT J AU Pei, W Williams, PH Clark, MD Stemple, DL Feldman, B AF Pei, Wuhong Williams, P. Huw Clark, Matthew D. Stemple, Derek L. Feldman, Benjamin TI Environmental and genetic modifiers of squint penetrance during zebrafish embryogenesis SO DEVELOPMENTAL BIOLOGY LA English DT Article DE TGF beta signaling; gastrulation; embryogenesis; zebrafish ID LEFT-RIGHT ASYMMETRY; SIGNALING PATHWAY; FISH EMBRYOS; EXPRESSION; INDUCTION; MESODERM; ACTIVIN; IDENTIFICATION; SPECIFICATION; MESENDODERM AB The Nodal-related subgroup of the TGF beta superfamily of secreted cytokines regulates the specification of the mesodermal and endodermal germ layers during gastrulation. Two Nodal-related proteins - Squint (Sqt) and Cyclops (Cyc) - are expressed during germ-layer specification in zebrafish. Genetic sqt mutant phenotypes have defined a variable requirement for zygotic Sqt, but not for maternal Sqt, in midline mesendoderm development. However a comparison of phenotypes arising from oocytes or zygotes injected with Sqt antisense morpholmos has suggested a novel requirement for maternal Sqt in dorsal specification. In this study we examined matemal-zygotic mutants for each of two sqt alleles and we also compared phenotypes of closely related zygotic and matemal-zygotic sqt mutants. Each of these approaches indicated there is no general requirement for maternal Sqt. To better understand the dispensability of maternal and zygotic Sqt, we sought out developmental contexts that more rigorously demand intact Sqt signalling. We found that sqt penctrance is influenced by genetic modifiers, by environmental temperature, by levels of residual Activin-like activity and by Heat-Shock Protein 90 (HSP90) activity. Therefore, Sqt may confer an evolutionary advantage by protecting early-stage embryos against detrimental interacting alleles and environmental challenges. (c) 2007 Elsevier Inc. All dghts reserved. C1 Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. NHGRI, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Stemple, DL (reprint author), Wellcome Trust Sanger Inst, Wellcome Trust Genome Campus, Cambridge CB10 1SA, England. EM ds4@sanger.ac.uk; bfeldman@mail.nih.gov OI Feldman, Benjamin/0000-0003-4838-8641 FU Intramural NIH HHS [Z01 HG200309-05, Z99 HG999999]; Wellcome Trust NR 43 TC 19 Z9 19 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD AUG 15 PY 2007 VL 308 IS 2 BP 368 EP 378 DI 10.1016/j.ydbio.2007.05.026 PG 11 WC Developmental Biology SC Developmental Biology GA 202GT UT WOS:000248890700011 PM 17583692 ER PT J AU Paterson, JK Gottesman, MM AF Paterson, Jill K. Gottesman, Michael M. TI P-Glycoprotein is not present in mitochondrial membranes SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE P-glycoprotein; P-gp; multidrug resistance; mitochondria; cellular localization ID RESISTANT CELL-LINES; MULTIDRUG-RESISTANCE; FUNCTIONAL-CHARACTERIZATION; CANCER-CELLS; MONOCLONAL-ANTIBODIES; EXPRESSION; LOCALIZATION; TISSUES; SENSITIVITY; MECHANISMS AB Recent reports have indicated the presence of P-glycoprotein in crude mitochondrial membrane fractions, leading to the assumption that P-glycoprotein is present in mitochondrial membranes, and may be involved in transport across these membranes. To determine the validity of this claim, two cell lines overexpressing endogenous P-glycoprotein were investigated. Using various centrifugation steps, mitochondria were purified from these cells and analyzed by Western blot reaction with the anti-P-glycoprotein antibody C219 and organelle-specific antibodies. While P-glycoprotein is present in crude mitochondrial fractions, these fractions are contaminated with plasma membranes. Further purification of the mitochondria to remove plasma membranes revealed that P-glycoprotein is not expressed in mitochondria of the KB-V1 (vinblastine-resistant KB-3-1 cells) or MCF-7(ADR) (adriamycin-resistant MCF-7 cells) cell lines. To further substantiate these findings, we used confocal microscopy and the anti-P-glycoprotein antibody 17F9. This demonstrated that in intact cells, P-glycoprotein is not present in mitochondria and is primarily localized to the plasma membrane. These findings are consistent with the role of P-glycoprotein in conferring multidrug resistance by decreasing cellular drug accumulation. Therefore, contrary to previous speculation, P-glycoprotein does not confer cellular protection by residing in mitochondrial membranes. Published by Elsevier Inc. C1 NCI, Ctr Canc Res, Cell Biol Lab, NIH,DHHS, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Ctr Canc Res, Cell Biol Lab, NIH,DHHS, Bethesda, MD 20892 USA. EM MGottesman@nih.gov FU Intramural NIH HHS [Z01 BC005598-17] NR 28 TC 14 Z9 16 U1 1 U2 4 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 EI 1090-2422 J9 EXP CELL RES JI Exp. Cell Res. PD AUG 15 PY 2007 VL 313 IS 14 BP 3100 EP 3105 DI 10.1016/j.yexcr.2007.04.019 PG 6 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 199EU UT WOS:000248679800013 PM 17512524 ER PT J AU Remington, N Stevens, RD Wells, RS Holn, A Dhungana, S Taboy, CH Crumbliss, AL Henkens, R Bonaventura, C AF Remington, Nicole Stevens, Robert D. Wells, Randall S. Holn, Aleta Dhungana, Suraj Taboy, Celine H. Crumbliss, Alvin L. Henkens, Robert Bonaventura, Celia TI Genetic diversity of coastal bottlenose dolphins revealed by structurally and functionally diverse hemoglobins SO GENE LA English DT Article; Proceedings Paper CT 14th International Conference on Dioxygen Binding and Sensing Proteins CY SEP 03-07, 2006 CL Naples, ITALY DE population diversity; alleles; oxygen binding; allostery; redox chemistry ID WEDDELL SEALS; BLOOD-OXYGEN; HEMATOLOGY; MYOGLOBIN; CHEMISTRY; PORPOISES; TURSIOPS; BINDING; ECOLOGY; WHALES AB Studies of structure-function relationships in the respiratory proteins of marine mammals revealed unexpected variations in the number and types of hemoglobins (Hbs) present in coastal bottlenose dolphins, Tursiops truncatus. We obtained blood samples from free-ranging coastal bottlenose dolphins as a component of capture-release studies. We found that the oxygen-binding functions of bottlenose dolphin blood are poised between effector-saturated and unsaturated levels, enabling exercise-dependent shifts in oxygen transfer functions. Isolated bottlenose dolphin Hbs showed elevated pH sensitivities (Bohr effects) and appreciably lower oxygen affinities than adult human Hb in the absence of allosteric effectors. These properties may be an adaptive modification that enhances oxygen delivery during diving episodes when oxygen tensions and effector levels are low. The Hbs of individual dolphins showed similar oxygen affinities, responses to effectors, and expression of heme-heme interaction in oxygen binding, but differed in their redox potentials and rates of autoxidation. The heterogeneity suggested by these functional variations in Hbs of individual dolphins was born out by variations in the molecular weights and numbers of their alpha and beta globin chains. Although coastal bottlenose dolphins were expected to have a single type of Hb, the mass differences observed revealed considerable genetic diversity. There were multiple Hb forms in some individuals and differences in Hb patterns among individuals within the same community. (c) 2007 Elsevier B.V. All rights reserved. C1 Duke Univ, Marine Lab, Nicholas Sch Environm & Earth Sci, Beaufort, NC 28516 USA. Duke Univ, Med Ctr, Sarah W Stedman Nutr & Metab Ctr, Durham, NC 27705 USA. Mote Marine Lab, Chicago Zool Soc, Sarasota, FL 34236 USA. NOAA, Beaufort Lab, SE Fisheries Sci Ctr, Beaufort, NC 28516 USA. Duke Univ, Dept Chem, Durham, NC 27708 USA. NCDWQ, Aquat Toxicol Unit, Raleigh, NC 27607 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Ctr Dis Control, NCHHSTP CCID, Atlanta, GA 30333 USA. RP Bonaventura, C (reprint author), Duke Univ, Marine Lab, Nicholas Sch Environm & Earth Sci, Beaufort, NC 28516 USA. EM bona@duke.edu FU NHLBI NIH HHS [P01 HL071064, R01 HL058248-05, 5P01-HL-071064-04] NR 38 TC 6 Z9 6 U1 2 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD AUG 15 PY 2007 VL 398 IS 1-2 SI SI BP 123 EP 131 DI 10.1016/j.gene.2007.02.050 PG 9 WC Genetics & Heredity SC Genetics & Heredity GA 200SX UT WOS:000248784200015 PM 17604574 ER PT J AU Zhang, W Dallas, S Zhang, D Guo, JP Pang, H Wilson, B Miller, DS Chen, B Zhang, WQ McGeer, PL Hong, JS Zhang, J AF Zhang, Wei Dallas, Shannon Zhang, Dan Guo, Juan-Ping Pang, Hao Wilson, Belinda Miller, David S. Chen, Biao Zhang, Wanqin McGeer, Patrick L. Hong, Jau-Shyong Zhang, Jing TI Microglial PHOX and Mac-1 are essential to the enhanced dopaminergic neurodegeneration elicited by A30P and A53T mutant alpha-synuclein SO GLIA LA English DT Article DE Parkinson's disease; microglia; synuclein ID PARKINSONS-DISEASE; NADPH OXIDASE; ALZHEIMERS-DISEASE; NERVOUS-SYSTEM; PROTEOMIC ANALYSIS; SUBSTANTIA-NIGRA; OXIDATIVE STRESS; RISK-FACTORS; CELL-DEATH; ACTIVATION AB alpha-Synuclein, a gene whose mutations, duplication, and trip lication has been linked to autosomal dominant familial Parkinson's disease (fPD), appears to play a central role in the pathogenesis of sporadic PD (sPD) as well. Enhancement of neurodegeneration induced by mutant alpha-synuclein has been attributed to date largely to faster formation of alpha-synuclein aggregates in neurons. Recently, we reported that microglial activation enhances wild type (WT) alpha-synuclein-elicited dopaminergic neurodegeneration. In the present study, using a primary mesencephalic culture system, we tested whether mutated alpha-synuclein could activate microglia more powerfully than WT alpha-synuclein, thereby contributing to the accelerated neurodegeneration observed in fPD. The results showed that alpha-synuclein with the A30P or A53T mutations caused greater microglial activation than WT alpha-synuclein. Furthermore, the extent of microglial activation paralleled the degree of dopaminergic neurotoxicity induced by WT and mutant alpha-synuclein. Mutant alpha-synuclein also induced greater production of reactive oxygen species than WT alpha-synuclein by NADPH oxidase (PHOX), and PHOX activation was linked to direct activation of macrophage antigen-1 (Mac-1) receptor, rather than alpha-synuclein internalization via scavenger receptors. These results have, for the first time, demonstrated that microglia are also critical in enhanced neurotoxicity induced by mutant alpha-synuclein. (C) 2007 Wiley-Liss, Inc. C1 Univ Washington, Harborview Med Ctr, Sch Med, Div Neuropathol,Dept Pathol, Seattle, WA 98104 USA. Dalian Med Univ, Dept Physiol, Dalian, Peoples R China. Capital Univ Med Sci, Xuanwu Hosp, Dept Neurol, Beijing, Peoples R China. NIEHS, Neuropharmacol Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Capital Med Univ, Beijign Tian Tan Hosp, Dept Neurol, Beijing, Peoples R China. NIEHS, Intracellular Regulat Sect, Lab Pharmacol & Chem, NIH, Res Triangle Pk, NC 27709 USA. Univ British Columbia, Kinsmen Lab Neurol Res, Vancouver, BC V5Z 1M9, Canada. RP Zhang, J (reprint author), Univ Washington, Harborview Med Ctr, Sch Med, Div Neuropathol,Dept Pathol, 325 9Th Ave,Box 359635, Seattle, WA 98104 USA. EM zhangj@u.washington.edu FU Intramural NIH HHS; NIA NIH HHS [R01AG025327]; NIEHS NIH HHS [R01ES012703] NR 62 TC 75 Z9 81 U1 0 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0894-1491 J9 GLIA JI Glia PD AUG 15 PY 2007 VL 55 IS 11 BP 1178 EP 1188 DI 10.1002/glia.20532 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 197RB UT WOS:000248572600008 PM 17600340 ER PT J AU Michienzi, S Cherman, N Holmbeck, K Funari, A Collins, MT Bianco, P Robey, PG Riminucci, M AF Michienzi, Stefano Cherman, Natasha Holmbeck, Kenn Funari, Alessia Collins, Michael T. Bianco, Paolo Robey, Pamela Gehron Riminucci, Mara TI GNAS transcripts in skeletal progenitors: evidence for random asymmetric allelic expression of Gs alpha SO HUMAN MOLECULAR GENETICS LA English DT Article ID MCCUNE-ALBRIGHT-SYNDROME; STIMULATORY G-PROTEIN; PSEUDOHYPOPARATHYROIDISM TYPE IB; SIGNAL-TRANSDUCTION PROTEIN; FIBROUS DYSPLASIA; MESSENGER-RNA; ADENYLYL-CYCLASE; ENDOCRINE TUMORS; PARENTAL ORIGIN; GENE-EXPRESSION AB Activating mutations of the Gs alpha gene, encoded by the guanine nucleotide-binding protein, alpha stimulating (GNAS) locus located on chromosome 20q13, underlie different clinical phenotypes characterized by skeletal lesions [fibrous dysplasia (FD) of bone], extraskeletal diseases (mainly endocrine hyperfunction and skin hyperpigmentation) and variable combinations thereof [the McCune-Albright syndrome (MAS)]. This clinical heterogeneity is commonly assumed to reflect the post-zygotic origin of the mutation. However, the pattern of imprinting of the Gs alpha gene in some human post-natal tissues suggests that parental-dependent epigenetic mechanisms may also play a role in the phenotypic effect of the mutated GNAS genotype. FD lesions are generated by mutated clonogenic osteoprogenitors that reside, along with their normal counterparts, in FD bone marrow stroma. We analyzed the allelic expression pattern of Gs alpha and other GNAS alternative transcripts in the progeny of normal and mutated clonogenic stromal cells isolated in vitro from a series of informative FD/MAS patients. We report here for the first time that the two Gs alpha alleles are unequally expressed in both normal and FD-mutated stromal clones. However, in contrast to imprinting, the ratio of Gs alpha allelic expression is randomly established in different clones from the same patient. This result suggests that a parental-independent modulation of Gs alpha expression occurs in clonogenic osteoprogenitor cells and, at the single cell level, may impact on the severity of an FD lesion. Furthermore, we show that normal and mutated clonogenic stromal cells express GNAS alternative transcripts other than the common Gs alpha, some of which may be relevant to the development of FD. C1 NIH, Natl Inst Dental & Craniofacial Res, Craniofacial & Skeletal Dis Branch, DHHS, Bethesda, MD 20892 USA. Fdn Parco Sci San Raffaele, Rome 00128, Italy. Univ Aquila, Dipartimento Med Sperimentale, I-67100 Laquila, Italy. Univ Roma La Sapienza, Dipartimento Med Sperimentale, I-00161 Rome, Italy. RP Robey, PG (reprint author), NIH, Natl Inst Dental & Craniofacial Res, Craniofacial & Skeletal Dis Branch, DHHS, 30 Convent Dr MSC 4320 Bldg 30,Rm 228, Bethesda, MD 20892 USA. EM probey@dir.nidcr.nih.gov RI FUNARI, ALESSIA/A-3298-2009; Robey, Pamela/H-1429-2011 OI Robey, Pamela/0000-0002-5316-5576 FU Telethon [GGP04263] NR 58 TC 15 Z9 16 U1 1 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 AUG 15 PY 2007 VL 16 IS 16 BP 1921 EP 1930 DI 10.1093/hmg/ddm139 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 219LI UT WOS:000250086300002 PM 17566083 ER PT J AU Goldstein, AM Chaudru, V Ghiorzo, P Badenas, C Malvehy, J Pastorino, L Laud, K Hulley, B Avril, MF Puig-Butille, JA Miniere, A Marti, R Chompret, A Cuellar, F Kolm, I Mila, M Tucker, MA Demenais, F Bianchi-Scarra, G Puig, S de-Paillerets, BB AF Goldstein, Alisa M. Chaudru, Valerie Ghiorzo, Paola Badenas, Celia Malvehy, Josep Pastorino, Lorenza Laud, Karine Hulley, Benjamin Avril, Marie-Francoise Puig-Butille, Joan A. Miniere, Annie Marti, Rosa Chompret, Agnes Cuellar, Francisco Kolm, Isabel Mila, Montserrat Tucker, Margaret A. Demenais, Florence Bianchi-Scarra, Giovanna Puig, Susana de-Paillerets, Brigitte Bressac TI Cutaneous phenotype and MC1R variants as modifying factors for the development of melanoma in CDKN2A G101W mutation carriers from 4 countries SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE melanoma; CDKN2A; MC1R; G101W ID MELANOCORTIN-1 RECEPTOR MC1R; NONMELANOMA SKIN-CANCER; CYCLIN D1 POLYMORPHISM; PRONE FAMILIES; GENE VARIANTS; MALIGNANT-MELANOMA; MEDITERRANEAN POPULATION; COLORECTAL-CANCER; INCREASED RISK; DNA-REPAIR AB The G101W founder mutation is the most common CDKN2A mutation in Italy, Spain, and France. As the background of modifying genes, environmental exposures, and sun behavior vary across countries, studying G101W carriers from distinct countries offers a unique opportunity to evaluate possible modifying factors in melanoma development. We evaluated 76 G101W cases and 59 carrier controls from France, Italy, Spain, and the United States. Hair color and dysplastic nevi distributions differed significantly in cases and controls across the 4 study groups. Cases also varied significantly for eye color, freckling, and nevi. The distribution of MC1R variants in cases differed significantly across study groups because 12% of Italian melanoma patients had >= 2 MC1R variants vs. >50% for the other case groups. Several MC1R covariates showed significant associations with melanoma risk in all groups combined and in the American, French, and Spanish samples; no significant findings were observed in the Italian sample. In multiple-case families, the number and type of MC1R variants varied significantly between multiple-primary-melanoma and single-primary-melanoma patients from the 4 groups; there was also a significant decrease in median age at melanoma diagnosis as the number or type of MC1R variants increased. The variation in the effects of the cutaneous phenotypic and MC1R factors across the study sample suggests that these factors differentially contribute to development of melanoma even on a common genetic background of a germline CDKN2A mutation. Differences in melanoma risk across geographic regions justify the need for individual studies in each country before counseling should be considered. (c) 2007 Wiley-Liss, Inc. C1 NCI, NIH, DHHS, Genet Epidemiol Branch,Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. INSERM, Inst Natl Sante & Rech Med, U794, Evry, France. Univ Evry, Evry, France. Univ Genoa, Dept Oncol Biol & Genet, Genoa, Italy. Hosp Clin Barcelona, IDIBAPS Inst Recerca August Pi Sune, Mol Genet Lab, Barcelona, Spain. Hosp Clin Barcelona, IDIBAPS Inst Recerca August Pi Sune, Dept Dermatol, Barcelona, Spain. Inst Gustave Roussy, Serv Genet, Villejuif, France. Univ Paris 05, Hop Cochin, AP HP, F-75270 Paris 06, France. Univ Lleida, Hosp Arnau Vilanova, Dept Dermatol, Lleida, Spain. RP Goldstein, AM (reprint author), NCI, NIH, DHHS, Genet Epidemiol Branch,Div Canc Epidemiol & Genet, Execut Plaza S,Room 7004,6120 Execut Blvd,MSC 723, Bethesda, MD 20892 USA. EM goldstea@exchange.nih.gov RI Marti, Rosa/A-2256-2010; Bianchi Scarra, Giovanna/G-8933-2014; Demenais, Florence/G-3298-2013; Tucker, Margaret/B-4297-2015; OI Marti, Rosa/0000-0001-6866-6114; Bianchi Scarra, Giovanna/0000-0002-6127-1192; Demenais, Florence/0000-0001-8361-0936; Badenas, Celia/0000-0002-0621-0477; Mila, Montserrat/0000-0002-7906-0916; Puig, Susana/0000-0003-1337-9745 NR 36 TC 33 Z9 33 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD AUG 15 PY 2007 VL 121 IS 4 BP 825 EP 831 DI 10.1002/ijc.22712 PG 7 WC Oncology SC Oncology GA 193OK UT WOS:000248283300017 PM 17397031 ER PT J AU Hsing, AW Bai, Y Andreotti, G Rashid, A Deng, J Chen, JB Goldstein, AM Han, TQ Shen, MC Fraumeni, JF Gao, YT AF Hsing, Ann W. Bai, Yan Andreotti, Gabriella Rashid, Asif Deng, Jie Chen, Jinbo Goldstein, Alisa M. Han, Tian-Quan Shen, Ming-Chang Fraumeni, Joseph F., Jr. Gao, Yu-Tang TI Family history of gallstones and the risk of biliary tract cancer and gallstones: A population-based study in Shanghai, China SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE biliary tract cancer; cholelithiasis; familial aggregation; genetic susceptibility; China ID GALLBLADDER CANCER; PREVALENCE; EPIDEMIOLOGY; DISEASE; STONES AB Cancers of the biliary tract arise from the gallbladder, extrahepatic bile ducts and ampulla of Vater. Although relatively uncommon, the incidence of biliary tract cancer rose more than 100% in Shanghai, China between 1972 and 1994. Gallstones are the predominant risk factor for biliary tract cancers, with over 60% of the cancer cases having gallstones. A familial tendency to gallstones has been reported and may elevate the risk of gallbladder cancer further. As part of a large population-based case-control study of biliary tract cancers in Shanghai, China, we examined the association between a family history of gallstones and biliary tract cancers as well as biliary stones. A total of 627 biliary tract cancers (368 gallbladder, 191 bile duct, 68 ampulla of Vater), 1,037 biliary stone cases (774 gallbladder, 263 bile duct) and 959 healthy subjects randomly selected from the population were included in this study. Information on family history of gallstones among first- degree relatives (i.e., parents, siblings, offspring) was obtained through a self-reported history during in-person interviews. A family history of gallstones was associated with increased risks of biliary stones [odds ratio (OR) = 2.8, 95% confidence interval (CI) = 2.1-3.8], gallbladder cancer (OR = 2.1, 95% CI = 1.4-3.3) and bile duct cancer (OR = 1.5, 95% CI = 0.9-2.5), after adjustment for age, gender, marital status, education, smoking, alcohol drinking and body mass index. For gallbladder cancer, subjects with gallstones but without a family history of gallstones had a 21-fold risk (95% CI 14.8-30.1), while those with both gallstones and a positive family history had a 57-fold risk (95% CI 32.0-110.5). Significant risks for gallbladder cancer persisted after additional adjustment for gallstones, and when the analysis was restricted to subjects with first-degree relatives whose gallstones were treated with cholecystectomy. The significant associations with a family history of gallstones were seen for all first-degree relatives, including parents, siblings and offspring, but not spouses. This large population-based study not only supports the role of gallstones in biliary carcinogenesis but also suggests that the underlying genetic or lifestyle determinants of stones within families contribute to the risk of biliary tract cancer. (c) 2007 Wiley-Liss, Inc. C1 NCI, NIH, DHHS, Div Canc Epidemiol & Genet, Bethesda, MD 20852 USA. Global Pharmacovigilance & Epidemiol, Sanofi Aventis, Bridgewater, NJ USA. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. Med Univ 2, Ruijin Hosp, Dept Surg, Shanghai, Peoples R China. Fudan Univ, Zhongshan Hosp, Dept Surg, Shanghai 200433, Peoples R China. RP Hsing, AW (reprint author), NCI, NIH, DHHS, Div Canc Epidemiol & Genet, EPS 7085,MSC7234,6120 Execut Blvd, Bethesda, MD 20852 USA. EM hsinga@mail.nih.gov FU Intramural NIH HHS [ZIA CP010158-09] NR 32 TC 39 Z9 41 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD AUG 15 PY 2007 VL 121 IS 4 BP 832 EP 838 DI 10.1002/ijc.22756 PG 7 WC Oncology SC Oncology GA 193OK UT WOS:000248283300018 PM 17450525 ER PT J AU Martin, S Wolters, PL Calabrese, SK Toledo-Tamula, MA Wood, LV Roby, G Elliott-DeSorbo, DK AF Martin, Staci Wolters, Pamela L. Calabrese, Sarah K. Toledo-Tamula, Mary Anne Wood, Lauren V. Roby, Gregg Elliott-DeSorbo, Deborah K. TI The antiretroviral regimen complexity index - A novel method of quantifying regimen complexity SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article DE antiretroviral therapy; HIV disease; regimen complexity ID SELF-REPORTED ADHERENCE; MEDICATION ADHERENCE; HIV PATIENTS; THERAPY; DISEASE; COHORT AB Background: Individuals with HIV disease often must adhere to complex medication regimens. To date, regimen complexity has not been examined in the literature using standardized procedures incorporating all important elements of antiretroviral (ARV) regimens. Objective: This article presents a novel method of quantifying regimen complexity using objective criteria addressing the factors that may complicate adherence to ARV regimens. Methods: Part I of this article describes the development of the Antiretroviral Regimen Complexity (ARC) Index scoring system. Based on input from pediatric and adult patients, caregivers of pediatric patients, and health care professionals, this comprehensive system includes the number of medications, dosing schedules, administration methods, special instructions, and required preparations associated with ARV regimens. Weights are applied for each of these factors to produce an overall score representing the regimen's level of complexity. Part 2 of this article presents reliability and validity data for the system. Results: The ARC Index demonstrates excellent test-retest and interrater reliability as well as strong construct and discriminant validity. An on-line version of this system minimizes computation errors. Conclusions: Although modifications may be necessary for patients requiring nonstandard dosing instructions, preliminary evidence Supports the Utility of this measure as a reliable and valid indicator of the complexity of antiretroviral treatment regimens. C1 NIAID, Natl Inst Hlth, Natl Canc Inst, Canc Res Ctr, Bethesda, MD 20892 USA. Med Illness Counseling Ctr, Chevy Chase, MD USA. Natl Inst Hlth, Vaccine Branch, Bethesda, MD USA. NIAID, Natl Inst Hlth, Intramural Clin Management & Operat Branch, Bethesda, MD USA. RP Martin, S (reprint author), NIAID, Natl Inst Hlth, Natl Canc Inst, Canc Res Ctr, 9030 Old Georgetown Rd, Bethesda, MD 20892 USA. EM martins@mail.nih.gov FU Intramural NIH HHS NR 14 TC 16 Z9 17 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD AUG 15 PY 2007 VL 45 IS 5 BP 535 EP 544 DI 10.1097/QAI.0b013e31811ed1f1 PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 198IU UT WOS:000248621200008 PM 17589371 ER PT J AU Hildesheim, A Herrero, R Wacholder, S Rodriguez, AC Solomon, D Bratti, MC Schiller, JT Gonzalez, P Dubin, G Porras, C Jimenez, SE Lowy, DR AF Hildesheim, Allan Herrero, Rolando Wacholder, Sholom Rodriguez, Ana C. Solomon, Diane Bratti, M. Concepcion Schiller, John T. Gonzalez, Paula Dubin, Gary Porras, Carolina Jimenez, Silvia E. Lowy, Douglas R. CA Costa Rican HPV Vaccine Tr TI Effect of human papillomavirus 16/18 L1 viruslike particle vaccine among young women with preexisting infection - A randomized trial SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID HUMAN-PAPILLOMAVIRUS TYPE-16; CELLULAR IMMUNE-RESPONSES; BROAD-SPECTRUM; EFFICACY; PCR; DNA; PREVENTION; NEOPLASIA; LESIONS; CANCER AB Context Viruslike particle human papillomavirus (HPV) vaccines were designed to prevent HPV infection and development of cervical precancers and cancer. Women with oncogenic HPV infections might consider vaccination as therapy. Objective To determine whether vaccination against HPV types 16 and 18 increases the rate of viral clearance in women already infected with HPV. Design and Setting Phase 3, masked, community-based randomized trial conducted in 2 provinces of Costa Rica. Participants A total of 2189 women aged 18 to 25 years who were recruited between June 2004 and December 2005. Participants were positive for HPV DNA at enrollment, had at least 6 months of follow-up, and had follow-up HPV DNA results. Intervention Participants were randomly assigned to receive 3 doses of a bivalent HPV-16/18 L1 protein viruslike particle ASO4 candidate vaccine (n = 1088) or a control hepatitis A vaccine (n = 1101) over 6 months. Main Outcome Measures Presence of HPV DNA was determined in cervical specimins by a molecular hybridization assay using chemiluminescence with HPV RNA probes and by polymerase chain reaction using SPF10 primers and a line probe assay detection system before vaccination and by polymerase chain reaction after vaccination. We compared rates of type-specific viral clearance using generalized estimating equations methods at the 6-month visit (after 2 doses) and 12-month visit (after 3 doses) in the 2 study groups. Results There was no evidence of increased viral clearance at 6 or 12 months in the group who received HPV vaccine compared with the control group. Clearance rates for HPV-16/18 infections at 6 months were 33.4% (82/248) in the HPV vaccine group and 31.6% (95/298) in the control group (vaccine efficacy for viral clearance, 2.5%; 95% confidence interval, -9.8% to 13.5%). Human papillomavirus 16/ 18 clearance rates at 12 months were 48.8% (86/177) in the HPV vaccine group and 49.8% (110/220) in the control group (vaccine efficacy for viral clearance, -2.0%; 95% confidence interval, -24.3% to 16.3%). There was no evidence of a therapeutic effect for other oncogenic or nononcogenic HPV categories, among women receiving all vaccine doses, among women with single infections, or among women stratified by the following entry variables: HPV-16/18 serology, cytologic results, HPV DNA viral load, time since sexual debut, Chlamydia trachomatis or Neisseria gonorrhoeae infection, hormonal contraceptive use, or smoking. Conclusion In women positive for HPV DNA, HPV-16/18 vaccination does not accelerate clearance of the virus and should not be used to treat prevalent infections. C1 NCI, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. RP Herrero, R (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Ste 550, Rockville, MD 20852 USA. EM Rherrero@amnet.co.cr FU NCI NIH HHS [N01-CP-11005] NR 28 TC 316 Z9 332 U1 0 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 AUG 15 PY 2007 VL 298 IS 7 BP 743 EP 753 DI 10.1001/jama.298.7.743 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 199XP UT WOS:000248728800019 PM 17699008 ER PT J AU Stepp, MA Liu, Y Pal-Ghosh, S Jurjus, RA Tadvalkar, G Sekaran, A LoSicco, K Jiang, L Larsen, M Li, L Yuspa, SH AF Stepp, Mary Ann Liu, Yueyuan Pal-Ghosh, Sonali Jurjus, Rosalyn A. Tadvalkar, Gauri Sekaran, Adith LoSicco, Kristen Jiang, Li Larsen, Melinda Li, Luowei Yuspa, Stuart H. TI Reduced migration, altered matrix and enhanced TGF beta 1 signaling are signatures of mouse keratinocytes lacking Sdc1 SO JOURNAL OF CELL SCIENCE LA English DT Article DE syndecan-1; keratinocytes; integrins ID GROWTH-FACTOR-BETA; LEUKOCYTE-ENDOTHELIAL INTERACTIONS; CULTURED EPITHELIAL-CELLS; EXTRACELLULAR-MATRIX; ALPHA-3-BETA-1 INTEGRIN; ALPHA-6-BETA-4 INTEGRIN; SYNDECAN-1; LAMININ-5; EXPRESSION; MICE AB We have reported previously that syndecan-1 ( Sdc1)-null mice show delayed re-epithelialization after skin and corneal wounding. Here, we show that primary keratinocytes obtained from Sdc1-null mice and grown for 3-5 days in culture are more proliferative, more adherent and migrate more slowly than wt keratinocytes. However, the migration rates of Sdc1-null keratinocytes can be restored to wild-type levels by replating Sdc1-null keratinocytes onto tissue culture plates coated with fibronectin and collagen I, laminin (LN)-332 or onto the matrices produced by wild-type cells. Migration rates can also be restored by treating Sdc1-null keratinocytes with antibodies that block alpha 6 or alpha v integrin function, or with TGF beta 1. Antagonizing either beta 1 integrin function using a function-blocking antibody or TGF beta 1 using a neutralizing antibody reduced wild-type keratinocyte migration more than Sdc1- null keratinocyte migration. Cultures of Sdc1-null keratinocytes accumulated less collagen than wild-type cultures but their matrices contained the same amount of LN-332. The Sdc1- null keratinocytes expressed similar total amounts of eight different integrin subunits but showed increased surface expression of alpha v beta 6, alpha v beta 8, and alpha 6 beta 4 integrins compared with wild-type keratinocytes. Whereas wild-type keratinocytes increased their surface expression of alpha 2 beta 1, alpha v beta 6, alpha v beta 8, and alpha 6 beta 4 after treatment with TGF alpha 1, Sdc1-null keratinocytes did not. Additional data from a dual-reporter assay and quantification of phosphorylated Smad2 show that TGF beta 1 signaling is constitutively elevated in Sdc1-null keratinocytes. Thus, our results identify TGF beta 1 signaling and Sdc1 expression as important factors regulating integrin surface expression, activity and migration in keratinocyte and provide new insight into the functions regulated by Sdc1. C1 George Washington Univ, Sch Med, Dept Anat & Cell Biol, Washington, DC 20037 USA. George Washington Univ, Sch Med, Dept Ophthalmol, Washington, DC 20037 USA. George Washington Univ, Sch Engn & Appl Sci, Inst Biomed Engn, Washington, DC 20037 USA. Natl Inst Dental & Craniofacial Res, Cellular & Dev Biol Lab, Bethesda, MD 20892 USA. NCI, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. RP Stepp, MA (reprint author), George Washington Univ, Sch Med, Dept Anat & Cell Biol, Washington, DC 20037 USA. EM mastepp@gwu.edu OI Stepp, Mary Ann/0000-0001-5623-2538 FU Intramural NIH HHS; NEI NIH HHS [R01-EY08512-17, R01-EY13559-05] NR 58 TC 38 Z9 38 U1 0 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD AUG 15 PY 2007 VL 120 IS 16 BP 2851 EP 2863 DI 10.1242/jcs.03480 PG 13 WC Cell Biology SC Cell Biology GA 199KF UT WOS:000248694000010 PM 17666434 ER PT J AU Sonoda, KH Nakamura, T Young, HA Hart, D Carmeliet, P Stein-Streilein, J AF Sonoda, Koh-Hei Nakamura, Takahiko Young, Howard A. Hart, David Carmeliet, Peter Stein-Streilein, Joan TI NKT cell-derived urokinase-type plasminogen activator promotes peripheral tolerance associated with eye SO JOURNAL OF IMMUNOLOGY LA English DT Article ID IMMUNE DEVIATION ACAID; T-REGULATORY CELLS; ANTERIOR-CHAMBER; TOLEROGENIC APC; B-CELLS; AUTOIMMUNE ENCEPHALOMYELITIS; ANTIGEN PRESENTATION; SYSTEMIC TOLERANCE; PRIVILEGED SITE; SOLUBLE-ANTIGEN AB In a model of peripheral tolerance called anterior chamber-associated immune deviation (ACAID), the differentiation of the T regulatory cells depends on NKT cells and occurs in the spleen. In this study, we show that NKT cells that express the invariant (i) TCR and are the CDld-reactive NKT cells (required for development of peripheral tolerance) actually produced urokinase-type plasminogen activator (uPA) during tolerance induction. The RT-PCR and in vitro plasmin assay showed that splenic iNKT cells derived uPA-converted plasminogen to plasmin. Moreover, uPA was required for tolerance induction because uPA knockout (KO) mice did not develop peripheral tolerance or develop CD8(+) T regulatory cells after Ag inoculation into the anterior chamber. In contrast, other aspects of ACAID-induced tolerance, including recruitment of iNKT cells to the spleen and production of IL-10 by iNKT cells, were unchanged in uPA-deficient mice. The adoptive transfer of splenic NKT cells from wild-type mice restored ACAID in J alpha 8 KO mice (iNKT cell deficient), but NKT cells from uPA KO mice did not. We postulate that the mechanism of action of uPA is through its binding to the uPAR receptor, and enzymatic cleavage of plasminogen to plasmin, which in turn activates latent TGF beta. In conclusion, uPA derived from iNKT cells is required to induce peripheral tolerance via the eye. C1 Harvard Univ, Sch Med, Schepens Eye Res Inst, Dept Ophthalmol, Boston, MA 02114 USA. Kyushu Univ, Grad Sch Med Sci, Dept Ophthalmol, Fukuoka, Japan. NCI, Expt Immunol Lab, Ft Detrick, MD 21702 USA. Univ Calgary, Dept Infect Dis & Microbiol, Calgary, AB, Canada. Katholieke Univ Leuven, Ctr Transgene Technol & Gene Therapy, Louvain, Belgium. RP Stein-Streilein, J (reprint author), Harvard Univ, Sch Med, Schepens Eye Res Inst, Dept Ophthalmol, 20 Staniford St, Boston, MA 02114 USA. EM joan.stein@schepens.harvard.edu FU NEI NIH HHS [EY 13306, R01 EY11983] NR 56 TC 13 Z9 14 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD AUG 15 PY 2007 VL 179 IS 4 BP 2215 EP 2222 PG 8 WC Immunology SC Immunology GA 203EZ UT WOS:000248959200024 PM 17675481 ER PT J AU Derre, L Bruyninx, M Baumgaertner, P Devevre, E Corthesy, P Touvrey, C Mahnke, YD Pircher, H Voelter, V Romero, P Speiser, DE Rufer, N AF Derre, Laurent Bruyninx, Marc Baumgaertner, Petra Devevre, Estelle Corthesy, Patricia Touvrey, Cedric Mahnke, Yolanda D. Pircher, Hanspeter Voelter, Verena Romero, Pedro Speiser, Daniel E. Rufer, Nathalie TI In vivo persistence of codominant human CD8(+) T cell clonotypes is not limited by replicative senescence or functional alteration SO JOURNAL OF IMMUNOLOGY LA English DT Article ID RECEPTOR G1; DISEASE PROGRESSION; LYMPHOCYTE CLONES; ANTIGEN NY-ESO-1; VIRUS-INFECTIONS; TCR REPERTOIRES; FLOW-CYTOMETRY; HIV-INFECTION; INFLUENZA-A; MEMORY AB T cell responses to viral epitopes are often composed of a small number of codominant clonotypes. In this study, we show that tumor Ag-specific T cells can behave similarly. In a melanoma patient with a long lasting HLA-A2/NY-ESO-1-specific T cell response, reaching 10% of circulating CD8 T cells, we identified nine codominant clonotypes characterized by individual TCRs. These clonotypes made up almost the entire pool of highly differentiated effector cells, but only a fraction of the small pool of less differentiated "memory" cells, suggesting that the latter serve to maintain effector cells. The different clonotypes displayed full effector function and expressed TCRs with similar functional avidity. Nevertheless, some clonotypes increased, whereas others declined in numbers over the observation period of 6 years. One clonotype disappeared from circulating blood, but without preceding critical telomere shortening. In turn, clonotypes with increasing frequency had accelerated telomere shortening, correlating with strong in vivo proliferation. Interestingly, the final prevalence of the different T cell clonotypes in circulation was anticipated in a metastatic lymph node withdrawn 2 years earlier, suggesting in vivo clonotype selection driven by metastases. Together, these data provide novel insight in long term in vivo persistence of T cell clonotypes associated with continued cell turnover but not replicative senescence or functional alteration. C1 Swiss Inst Expt Canc Res, CH-1066 Epalinges, Switzerland. Univ Lausanne Hosp, Ludwig Inst Canc Res, Div Clin Oncoimmunol, Lausanne, Switzerland. NIAID, NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. Univ Freiburg, Dept Immunol, Inst Med Microbiol & Hyg, Freiburg, Germany. CHUV, Multidisciplinary Oncol Ctr, Lausanne, Switzerland. RP Rufer, N (reprint author), Swiss Inst Expt Canc Res, 155 Ch Boveresses, CH-1066 Epalinges, Switzerland. EM Nathalie.Rufer@isrec.ch RI Speiser, Daniel/F-2173-2013 NR 53 TC 21 Z9 21 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 AUG 15 PY 2007 VL 179 IS 4 BP 2368 EP 2379 PG 12 WC Immunology SC Immunology GA 203EZ UT WOS:000248959200041 PM 17675498 ER PT J AU Nagase, H Jones, KM Anderson, CF Noben-Trauth, N AF Nagase, Hisashi Jones, Kathryn M. Anderson, Charles F. Noben-Trauth, Nancy TI Despite increased CD4(+)Foxp3(+) BALB/c IL-4 receptor-deficient cells within the infection site, mice reveal CD4(+)Foxp3-Negative T cells as a source of IL-10 in Leishmania major susceptibility SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EXPERIMENTAL VISCERAL LEISHMANIASIS; IMMUNOLOGICAL SELF-TOLERANCE; TRANSCRIPTION FACTOR FOXP3; DENDRITIC CELLS; TGF-BETA; DISEASE; AMAZONENSIS; EXPRESSION; RESPONSES; IMMUNITY AB BALB/c IL-4R alpha(-/-) mice,,despite the absence of IL-4/IL-13 signaling and potent Th2 responses, remain highly susceptible to Leishmania major substain LV39 due exclusively to residual levels of IL-10. To address the contribution of CD4(+)CD25(+) T regulatory (Treg) cells to IL-10-mediated susceptibility, we depleted CD4(+)CD25(+) cells in vivo and reconstituted IL-4R alpha X RAG2 recipients with purified CD4(+)CD25(-) T cells. Although anti-CD25 mAb treatment significantly decreased parasite numbers in IL-4R alpha(-/-) mice, treatment with anti-IL-10R mAb virtually eliminated L. major parasites in both footpad and dermal infection sites. In addition, IL-4Ra X RAG2 mice reconstituted with CD4(+) cells depleted of CD25(+) Treg cells remained highly susceptible to infection. Analysis of L. major-infected BALB/c and IL-4R alpha(-/-) inflammatory sites revealed that the majority of IL-10 was secreted by the CD4(+)Foxp3(-) population, with a,fraction of IL-10 coming from CD4(+)Foxp3(+) Treg cells. All T cell IFN-gamma production was also derived from the CD4+Foxp3- population. Nevertheless, the IL-4R alpha(-/-)-infected ear dermis, but not draining lymph nodes, consistently displayed 1.5- to 2-fold greater percentages of CD4(+)CD25(+) and CD4(+)Foxp3(+) Treg cells compared with the BALB/c-infected dermis. Thus, CD4(+)Foxp3(-) T cells are a major source of IL-10 that disrupts IFN-gamma activity in L. major-susceptible BALB/c mice. However, the increase in CD4(+)Foxp3(+) T cells within the IL-4Ra-/- dermis implies a possible IL-10-independent role for Treg cells within the infection site, and may indicate a novel immune escape mechanism used by L. major parasites in the absence of IL-4/IL-13 signaling. C1 George Washington Univ, Ctr Med, Dept Microbiol Immunol & Trop Med, Washington, DC 20037 USA. NIAID, NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Noben-Trauth, N (reprint author), George Washington Univ, Ctr Med, Dept Microbiol Immunol & Trop Med, Ross Hall,Room 407,2300 Eye St NW, Washington, DC 20037 USA. EM nnoben@gwu.edu FU NIAID NIH HHS [AI054717] NR 56 TC 33 Z9 36 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 AUG 15 PY 2007 VL 179 IS 4 BP 2435 EP 2444 PG 10 WC Immunology SC Immunology GA 203EZ UT WOS:000248959200048 PM 17675505 ER PT J AU Babu, S Blauvelt, CP Nutman, TB AF Babu, Subash Blauvelt, Carla P. Nutman, Thomas B. TI Filarial parasites induce NK cell activation, type 1 and type 2 cytokine secretion, and subsequent apoptotic cell death SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NATURAL-KILLER-CELLS; IFN-GAMMA PRODUCTION; BRUGIA-MALAYI; INNATE IMMUNITY; NITRIC-OXIDE; DEPENDENT ACTIVATION; DENDRITIC CELLS; T-CELLS; INFECTION; MACROPHAGES AB Nk cells are an important source of early cytokine production in a variety of intracellular viral, bacterial, and protozoan infections; however, the role of NK cells in extracellular parasitic infections such as filarial infections is not well-defined. To investigate the role of NK cells in filarial infections, we have used an in vitro model system of culturing live infective-stage larvae (L3) or five microfilariae (Mf) of Brugia malayi, a causative agent of human lymphatic filariasis, with PBMC of normal individuals. We found that NK cells undergo early cell activation and produce IFN-gamma and TNF-alpha within 24 h after stimulation with both live L3 and ME Interestingly, NK cells also express IL-4 and IL-5 at this time point in response to live Mf but not L3. This is accompanied by significant alterations in NK cell expression of costimulatory molecules and natural cytotoxicity receptors. This activation is dependent on the presence of monocytes in the culture, IL-12, and direct contact with live parasites. The early activation event is subsequently followed by apoptosis of NK cells involving a caspase-dependent mechanism in response to live L3 but not live ME Thus, the NK cell-parasite interaction is complex, with filarial parasites inducing NK cell activation and cytokine secretion and finally NK cell apoptosis, which may provide an additional mechanism of down-regulating the host immune response. C1 NIAID, NIH, Parasit Dis Lab, Bethesda, MD 20892 USA. RP Babu, S (reprint author), NIAID, NIH, Parasit Dis Lab, 4 Ctr Dr,Room 4-126, Bethesda, MD 20892 USA. EM sbabu@niaid.nih.gov FU Intramural NIH HHS NR 45 TC 25 Z9 26 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 AUG 15 PY 2007 VL 179 IS 4 BP 2445 EP 2456 PG 12 WC Immunology SC Immunology GA 203EZ UT WOS:000248959200049 PM 17675506 ER PT J AU Condack, C Grivel, JC Devaux, P Margolis, L Cattaneo, R AF Condack, Cristian Grivel, Jean-Charles Devaux, Patricia Margolis, Leonid Cattaneo, Roberto TI Measles virus vaccine attenuation: Suboptimal infection of lymphatic tissue and tropism alteration SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID HUMAN LYMPHOID-TISSUE; DENDRITIC CELLS; T-CELLS; IN-VITRO; CXCR4-TROPIC HIV-1; IMMUNE-RESPONSES; PATHOGENESIS; RECEPTOR; REPLICATION; PROTEIN AB The mechanisms of measles virus (MV) vaccine attenuation are insufficiently characterized. Because the Edmonston vaccine strain can enter cells through CD46 in addition to the primary MV receptor signaling lymphocyte activation molecule (SLAM or CD150), we asked whether and how its tropism is altered. In human tonsillar tissue, this vaccine strain infects naive (CD45RA(+)CD62L(+)) T lymphocytes, which express SLAM very infrequently, with much higher efficiency than do wild-type strains. By contrast, it infects B lymphocytes, macrophages, and NK cells with significantly lower efficiencies than those of wild-type strains. Infection levels by wild-type strains correlate with the frequency of SLAM expression and are highest in B cells, which are 40%-55% infected. SLAM-expressing T cells are more readily infected by all MV strains than are SLAM-expressing B cells. Thus, vaccine attenuation may be caused by tropism alteration in combination with suboptimal replication. C1 NICHHD, Lab Mol & Cellular Biophys, Bethesda, MD 20892 USA. Mayo Clin, Coll Med, Virol & Gene Therapy Grad Track, Rochester, MN USA. RP Grivel, JC (reprint author), NIH, Bldg 10,Rm 9D58,10 Ctr Dr, Bethesda, MD 20892 USA. EM grigri@helix.nih.gov FU NCI NIH HHS [R01 CA90636]; NIAID NIH HHS [R01 AI57761] NR 46 TC 40 Z9 40 U1 1 U2 1 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1537-6613 J9 J INFECT DIS JI J. Infect. Dis. PD AUG 15 PY 2007 VL 196 IS 4 BP 541 EP 549 DI 10.1086/519689 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 190DD UT WOS:000248037300009 PM 17624839 ER PT J AU Woodruff, ML Olshevskaya, EV Savchenko, AB Peshenko, IV Barrett, R Bush, RA Sieving, PA Fain, GL Dizhoor, AM AF Woodruff, Michael L. Olshevskaya, Elena V. Savchenko, Andrey B. Peshenko, Igor V. Barrett, Ronald Bush, Ronald A. Sieving, Paul A. Fain, Gordon L. Dizhoor, Alexander M. TI Constitutive excitation by Gly90Asp rhodopsin rescues rods from degeneration caused by elevated production of cGMP in the dark SO JOURNAL OF NEUROSCIENCE LA English DT Article DE rod; retina; degeneration; cGMP; GCAP; guanylyl cyclase; calcium ID CYCLASE-ACTIVATING PROTEINS; PHOTORECEPTOR GUANYLYL CYCLASE; DOMINANT CONE DEGENERATION; CONGENITAL NIGHT BLINDNESS; OUTER SEGMENTS; VERTEBRATE PHOTORECEPTORS; CALCIUM-CONCENTRATION; OPSIN ACTIVATION; SALAMANDER RODS; RETINAL RODS AB Previous experiments indicate that congenital human retinal degeneration caused by genetic mutations that change the Ca2+ sensitivity of retinal guanylyl cyclase (retGC) can result from an increase in concentration of free intracellular cGMP and Ca2+ in the photoreceptors. To rescue degeneration in transgenic mouse models having either the Y99C or E155G mutations of the retGC modulator guanylyl cyclase-activating protein 1 (GCAP-1), which produce elevated cGMP synthesis in the dark, we used the G90D rhodopsin mutation, which produces constitutive stimulation of cGMP hydrolysis. The effects of the G90D transgene were evaluated by measuring retGC activity biochemically, by recording single rod and electroretinogram (ERG) responses, by intracellular free Ca2+ measurement, and by retinal morphological analysis. Although the G90D rhodopsin did not alter the abnormal Ca2+ sensitivity of retGC in the double-mutant animals, the intracellular free cGMP and Ca2+ concentrations returned close to normal levels, consistent with constitutive activation of the phosphodiesterase PDE6 cascade in darkness. G90D decreased the light sensitivity of rods but spared them from severe retinal degeneration in Y99C and E155G GCAP-1 mice. More than half of the photoreceptors remained alive, appeared morphologically normal, and produced electrical responses, at the time when their siblings lacking the G90D rhodopsin transgene lost the entire retinal outer nuclear layer and no longer responded to illumination. These experiments indicate that mutations that lead to increases in cGMP and Ca2+ can trigger photoreceptor degeneration but that constitutive activation of the transduction cascade in these animals can greatly enhance cell survival. C1 Penn Coll Optometry, Hafter Res Labs, Elkins Pk, PA 19027 USA. Univ Calif Los Angeles, Dept Physiol Sci, Los Angeles, CA USA. Wayne State Univ, Dept Anat & Cell Biol, Detroit, MI 48202 USA. Natl Inst Deafness & Other Comm Disorders, NEI, Natl Inst Hlth, Bethesda, MD 20892 USA. Univ Calif Los Angeles, Sch Med, Jules Stein Eye Inst, Los Angeles, CA 90095 USA. RP Dizhoor, AM (reprint author), Penn Coll Optometry, Hafter Res Labs, 8360 Old York Rd, Elkins Pk, PA 19027 USA. EM adizhoor@pco.edu FU NEI NIH HHS [R01 EY011522, EY04068, P30 EY000331, R01 EY001844, R01 EY011522-12, EY11522, EY 00331, EY01844, P30 EY004068, R37 EY001844] NR 57 TC 46 Z9 46 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 AUG 15 PY 2007 VL 27 IS 33 BP 8805 EP 8815 DI 10.1523/JNEUROSCI.2751-07.2007 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 200WY UT WOS:000248794700006 PM 17699662 ER PT J AU Ponzio, TA Yue, C Gainer, H AF Ponzio, Todd A. Yue, Chunmei Gainer, Harold TI An intron-based real-time PCR method for measuring vasopressin gene transcription SO JOURNAL OF NEUROSCIENCE METHODS LA English DT Article DE vasopressin; supraoptic nucleus; quantitative PCR; hyperosmotic stimuli; heteronuclear RNA ID HETERONUCLEAR RNA; HYPOTENSIVE HEMORRHAGE; PLASMA OSMOLALITY; SUPRAOPTIC NUCLEI; RAT HYPOTHALAMUS; EXPRESSION; OXYTOCIN; RELEASE; NEURONS; STIMULATION AB The hypothalamus contains distinct neuronal populations that express distinguishing neuropeptides. The supraoptic nucleus contains magnocellular neurons that predominantly express either vasopressin or oxytocin. Transcriptional activators of vasopressin and other neuropeptides have been the subject of much research. Here we present a method of measuring neuropeptide transcription by tailoring one-step quantitative real-time PCR (qRT-PCR) for the analysis of processed and pre-mRNA (heteronuclear RNA). Using moderate and strong hyperosmotic stimuli to induce transcription, we report an increase in vasopressin transcription (pre-mRNA) of 141% and 406% over control levels in response to a 2% injection of 900 mOsm saline or a 1% body weight i.p. injection of 2 M NaCl, respectively. These results agree with a host of studies employing the more labor-intensive method of in situ hybridization histochemistry by which investigators also measured intron-containing heteronuclear RNAs. Furthermore, these results confirm that qRT-PCR with intron-specific primers can be used to rapidly analyze transcription, and suggest an important further benefit of a real-time PCR analysis, such as the ability of measuring transcription of multiple neuropeptides along with other genes from a single sample. Published by Elsevier B.V. C1 NINDS NIH, Lab Neurochem, Bethesda, MD 20892 USA. RP Gainer, H (reprint author), 9000 Rockville Pike,Bld 49,Rm 5A78,MSC 4479, Bethesda, MD 20892 USA. EM gainerh@ninds.nih.gov FU Intramural NIH HHS [Z01 NS002723-21] NR 29 TC 15 Z9 15 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0270 J9 J NEUROSCI METH JI J. Neurosci. Methods PD AUG 15 PY 2007 VL 164 IS 1 BP 149 EP 154 DI 10.1016/j.jneumeth.2007.03.012 PG 6 WC Biochemical Research Methods; Neurosciences SC Biochemistry & Molecular Biology; Neurosciences & Neurology GA 191ZK UT WOS:000248170300016 PM 17540451 ER PT J AU Luo, YQ Xue, HP Pardo, AC Mattson, MP Rao, MS Maragakis, NJ AF Luo, Yongquan Xue, Haipeng Pardo, Andrea C. Mattson, Mark P. Rao, Mahendra S. Maragakis, Nicholas J. TI Impaired SDF1/CXCR4 signaling in glial progenitors derived from SOD1(G93A) mice SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE neural progenitors; migration; ERK activation; neurodegeneration; chemotaxis ID NEUROEPITHELIAL STEM-CELLS; CHEMOKINE RECEPTOR CXCR4; SPINAL-CORD; MOTOR-NEURONS; SUPEROXIDE-DISMUTASE; GRANULE CELLS; NEURAL STEM; DISEASE; SDF-1; PRECURSORS AB Mutations in the superoxide dismutase 1 (SOD1) gene are associated with familial amyotrophic lateral sclerosis (ALS), and the SOD1(G93A) transgenic mouse has been widely used as one animal model for studies of this neurodegenerative disorder. Recently, several reports have shown that abnormalities in neuronal development in other models of neurodegeneration occur much earlier than previously thought. To study the role of mutant SOD1 in glial progenitor biology, we immortalized glial restricted precursors (GRIPs) derived from mouse E11.5 neural tubes of wild-type and SOD1(G93A) mutant mice. Immunocytochemistry using cell lineage markers shows that these cell lines can be maintained as glial progenitors, because they continue to express A2B5, with very low levels of glial fibrillary acidic protein (astrocyte), beta III-tubulin (neuron), and undetected GaIC (oligodendrocyte) markers. RT-PCR and immunoblot analyses indicate that the chemokine receptor CXCR4 is reduced in SOD1(G93A) GRIPs. Subsequently, SOD1(G93A) GRIPs are unable to respond to SDF1 alpha to activate ERK1/2 enzymes and the transcription factor CREB. This may be one pathway leading to a reduction in SOD1(G93A) cell migration. These data indicate that the abnormalities in SOD1(G93A) glial progenitor expression of CXCR4 and its mediated signaling and function occur during spinal cord development and highlight nonneuronal (glial) abnormalities in this ALS model. (C) 2007 Wiley-Liss, Inc. C1 Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21287 USA. NIA, Intramural Res Program, Neurosci Lab, Baltimore, MD 21224 USA. Invitrogen Corp, Carlsbad, CA USA. RP Maragakis, NJ (reprint author), Johns Hopkins Univ, Dept Neurol, 600 N Wolfe St,Meyer 6-119, Baltimore, MD 21287 USA. EM nmaragak@jhmi.edu RI Mattson, Mark/F-6038-2012; OI Pardo, Andrea/0000-0001-7767-8539 FU Intramural NIH HHS; NINDS NIH HHS [R01NS041680] NR 36 TC 9 Z9 9 U1 0 U2 3 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 AUG 15 PY 2007 VL 85 IS 11 BP 2422 EP 2432 DI 10.1002/jnr.21398 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 203JS UT WOS:000248971500013 PM 17567884 ER PT J AU Siluk, D Oliveira, RV Esther-Rodriguez-Rosas, M Ling, S Bos, A Ferrucci, L Wainer, IW AF Siluk, Danuta Oliveira, Regina V. Esther-Rodriguez-Rosas, Maria Ling, Shari Bos, Angelo Ferrucci, Luigi Wainer, Irving W. TI A validated liquid chromatography method for the determination of vitamins A and E in human simultaneous plasma SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE vitamins; all-trans-retinol; alpha-tocopherol; gamma-tocophero; delta-tocopherol; HPLC; fluorescence detection ID MICELLAR ELECTROKINETIC CHROMATOGRAPHY; ALPHA-TOCOPHEROL; BETA-CAROTENE; HUMAN SERUM; MAJOR CAROTENOIDS; RETINOL; BLOOD; HPLC; EXTRACTION; SEPARATION AB A fast (15 min) and simple HPLC method for determination of all-trans-retinol and alpha-, gamma- and delta-tocopherols inhuman plasma has been developed. The assay utilized 200 mu l of plasma to which 20 mu l of internal standard solution (retinol acetate) was added followed by 200 mu l of water, 400 mu l of ethanol and 800 mu l of hexane. The hexane layer was collected, evaporated, the residue dissolved in 200 mu l of methanol and analyzed on a Zorbax Eclipse XDB-C 18 column using a step gradient with a polar organic mobile phase composed of acetonitrile and methanol and variable wavelength fluorescence detection. The quantification limits for all-trans-retinol and gamma-tocopherol were 20 ng/ml and for alpha- and delta-tocopherols 500 ng/ml and 10 ng/mI, respectively. The procedure was validated and applied to the analysis of plasma samples from the Baltimore Longitudinal Study of Aging. (c) 2007 Elsevier B.V. All rights reserved. C1 NIA, Clin Invest Lab, Ctr Gerontol Res, NIH, Baltimore, MD 21224 USA. Med Univ Gdansk, Dept Biopharmaceut & Pharmacodynam, Gdansk, Poland. NIA, Clin Res Branch, Longitudinal Studies Sect, Harbor Hosp Ctr,NIH, Baltimore, MD 21224 USA. RP Wainer, IW (reprint author), NIA, Clin Invest Lab, Ctr Gerontol Res, NIH, Baltimore, MD 21224 USA. EM wainerir@mail.nih.gov RI Oliveira, Regina/I-9547-2012 FU Intramural NIH HHS [Z01 AG000015-49] NR 43 TC 39 Z9 39 U1 0 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0731-7085 J9 J PHARMACEUT BIOMED JI J. Pharm. Biomed. Anal. PD AUG 15 PY 2007 VL 44 IS 4 BP 1001 EP 1007 DI 10.1016/j.jpba.2007.03.033 PG 7 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 206KK UT WOS:000249182100023 PM 17499473 ER PT J AU Ziegler, RG Lim, U AF Ziegler, Regina G. Lim, Unhee TI One-carbon metabolism, colorectal carcinogenesis, chemoprevention - with caution SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID CANCER RISK; DNA METHYLATION; FOLATE INTAKE; CHOLINE; HOMOCYSTEINE; BETAINE; TRIAL C1 NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Ziegler, RG (reprint author), NCI, Epidemiol & Biostat Program, Div Canc Epidemiol & Genet, Execut Plaza 8098, Bethesda, MD 20892 USA. EM zieglerr@mail.nih.gov FU Intramural NIH HHS NR 16 TC 10 Z9 10 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD AUG 15 PY 2007 VL 99 IS 16 BP 1214 EP 1215 DI 10.1093/jnci/djm105 PG 2 WC Oncology SC Oncology GA 204PD UT WOS:000249055600001 PM 17686821 ER PT J AU Qu, CX Kamangar, F Fan, JH Yu, BB Sun, XD Taylor, PB Chen, BSE Abnet, CC Qiao, YL Mark, SD Dawsey, SM AF Qu, Chen-Xu Kamangar, Farin Fan, Jin-Hu Yu, Binbing Sun, Xiu-Di Taylor, Philip B. Chen, Bingshu E. Abnet, Christian C. Qiao, You-Lin Mark, Steven D. Dawsey, Sanford M. TI Chemoprevention of primary liver cancer: A randomized, double-blind trial in Linxian, China SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID HEPATOCELLULAR-CARCINOMA; LUNG-CANCER; ANTIOXIDANT SUPPLEMENTS; VITAMIN SUPPLEMENTATION; INTERVENTION TRIALS; GENERAL-POPULATION; ESOPHAGEAL CANCER; GASTRIC CANCERS; BETA-CAROTENE; SERUM RETINOL AB Background Primary liver cancer is a common malignancy with a dismal prognosis. New primary prevention strategies are needed to reduce mortality from this disease. We examined the effects of supplementation with four different combinations of vitamins and minerals on primary liver cancer mortality among 29450 initially healthy adults from Linxian, China. Methods Participants were randomly assigned to take either a vitamin-mineral combination ("factor") or a placebo daily for 5.25 years (March 1986-May 1991). Four factors (at doses one to two times the US Recommended Daily Allowance) - retinol and zinc (factor A); riboflavin and niacin (factor B); ascorbic acid and molybdenum (factor C); and beta-carotene, alpha-tocopherol, and selenium (factor D) - were tested in a partial factorial design. The study outcome was primary liver cancer death occurring from 1986 through 2001. Adjusted Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) of liver cancer death with and without each factor. All P values are two-sided. Results A total of 151 liver cancer deaths occurred during the analysis period. No statistically significant differences in liver cancer mortality were found comparing the presence and absence of any of the four intervention factors. However, both factor A and factor B reduced liver cancer mortality in individuals younger than 55 years at randomization (HR = 0.59, 95% CI = 0.34 to 1.00, and HR = 0.54, 95% CI = 0.31 to 0.93, respectively) but not in older individuals (HR = 1.06, 95% CI = 0.71 to 1.59, and HR = 1.12, 95% CI = 0.75 to 1.68, respectively). Factor C reduced liver cancer death, albeit with only borderline statistical significance in males (HR = 0.70, 95% CI = 0.47 to 1.02) but not in females (HR = 1.30, 95% CI = 0.72 to 2.37). Cumulative risks of liver cancer death were 6.0 per 1000 in the placebo arm, 5.4 per 1000 in the arms with two factors, and 2.4 per 1000 in the arm with all four factors. Conclusion None of the factors tested reduced overall liver cancer mortality. However, three factors reduced liver cancer mortality in certain subgroups. C1 Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Chinese Acad Sci, Inst Canc, Beijing, Peoples R China. Informat Management Serv Inc, Silver Spring, MD USA. Univ Colorado, Hlth Sci Ctr, Dept Prevent Med & Biometr, Denver, CO 80262 USA. RP Kamangar, F (reprint author), Natl Canc Inst, Div Canc Epidemiol & Genet, 6120 Execut Bldvd,Rm 3034, Bethesda, MD 20892 USA. EM qiaoy@public.bta.net.cn RI Qiao, You-Lin/B-4139-2012; Abnet, Christian/C-4111-2015 OI Qiao, You-Lin/0000-0001-6380-0871; Abnet, Christian/0000-0002-3008-7843 FU CCR NIH HHS [N01-RC-47701]; Intramural NIH HHS; NCI NIH HHS [N01-SC-91030] NR 39 TC 16 Z9 17 U1 0 U2 4 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 AUG 15 PY 2007 VL 99 IS 16 BP 1240 EP 1247 DI 10.1093/jnci/djm084 PG 8 WC Oncology SC Oncology GA 204PD UT WOS:000249055600008 PM 17686823 ER PT J AU Schairer, C Hisada, M Chen, BSE Brown, LM Howard, R Fossa, SD Gail, M Travis, LB AF Schairer, Catherine Hisada, Michie Chen, Bingshu E. Brown, Linda M. Howard, Regan Fossa, Sophie D. Gail, Mitchell Travis, Lois B. TI Comparative mortality for 621 second cancers in 29356 testicular cancer survivors and 12420 matched first cancers SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CELL LUNG-CANCER; RANDOMIZED-TRIAL; PRIMARY HEAD; SEMINOMA; RADIATION; THERAPY; LEUKEMIA; TESTIS AB Background Testicular cancer survivors, many of whom have undergone radiotherapy, are at substantial risk of second cancers. Treatment for testicular cancer may limit treatment options for second cancers, thereby adversely affecting survival after the second cancer. However, no data on outcomes of testicular cancer survivors with second cancers compared to patients with comparable first cancers exist. Methods Among 29356 white testicular cancer patients reported to the Surveillance, Epidemiology, and End Results (SEER) program (1973-2002), 621 developed a second cancer with known stage and were matched to a random sample of 12420 white male first cancer patients in the SEER program by cancer site, stage, diagnosis year, and age at diagnosis. Mortality was ascertained through 2002. Cancer-specific and all-cause mortality following second cancers were compared with those of matched first cancers, and rate ratios (RRs) were estimated using proportional hazards analysis. Survival functions were calculated using product-limit estimates. Results During the study period, 284 testicular cancer survivors with second cancers died, 191 from their second cancer; 5443 matched first cancer patients died, 3929 from their first cancer. Rate ratios for cancer-specific and all-cause mortality for second cancers compared with matched first cancers were 1.05 (95% confidence interval [CI] = 0.90 to 1.23) and 1.09 (95% CI = 0.96 to 1.23), respectively. However, among testicular cancer patients who were diagnosed during 1973-1979, an era in which radiation therapy was given at high doses and to the chest area, all-cause mortality following second cancers at sites below the diaphragm (79 deaths) and second lung cancers (29 deaths) was statistically significantly higher than that from matched first cancers (RR = 1.44, 95% CI = 1.13 to 1.83, and RR = 1.65, 95% CI = 1.12 to 2.42, respectively). Conclusions Mortality from second cancers following testicular cancer was similar to matched first cancers, except for selected tumors in the radiotherapy field among testicular cancer patients who were diagnosed during 1973-1979, a time when radiotherapy doses for treatment of testicular cancer were high and chest irradiation was an option in standard practice. C1 NCI, Div Canc Epidemiol & Genet, Natl Inst Hlth, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Rikshosp Raduimhosp Med Ctr, Dept Clin Res, Oslo, Norway. RP Schairer, C (reprint author), NCI, Div Canc Epidemiol & Genet, Natl Inst Hlth, Dept Hlth & Human Serv, Execut Plaza S,Rm 8020, Bethesda, MD 20892 USA. EM schairec@exchange.nih.gov FU Intramural NIH HHS NR 35 TC 22 Z9 22 U1 0 U2 8 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 AUG 15 PY 2007 VL 99 IS 16 BP 1248 EP 1256 DI 10.1093/jnci/djm081 PG 9 WC Oncology SC Oncology GA 204PD UT WOS:000249055600009 PM 17686826 ER PT J AU Seike, M Yanaihara, N Bowman, ED Zanetti, KA Budhu, A Kumamoto, K Mechanic, LE Matsumoto, S Yokota, J Shibata, T Sugimura, H Gemma, A Kudoh, S Wang, XW Harris, CC AF Seike, Masahiro Yanaihara, Nozomu Bowman, Elise D. Zanetti, Krista A. Budhu, Anuradha Kumamoto, Kensuke Mechanic, Leah E. Matsumoto, Shingo Yokota, Jun Shibata, Tatsuhiro Sugimura, Haruhiko Gemma, Akihiko Kudoh, Shoji Wang, Xin W. Harris, Curtis C. TI Use of a cytokine gene expression signature in lung adenocarcinoma and the surrounding tissue as a prognostic classifier SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID VINORELBINE PLUS CISPLATIN; POLYMERASE-CHAIN-REACTION; LYMPH-NODE METASTASIS; REGULATORY T-CELLS; CANCER PATIENTS; BREAST-CANCER; ADJUVANT CHEMOTHERAPY; PERIPHERAL-BLOOD; GROWTH-FACTOR; SERUM-LEVELS AB Background A 17-cytokine gene expression signature in noncancerous hepatic tissue from patients with metastatic hepatocellular carcinoma (HCC) was recently found to predict HCC metastasis and recurrence. We examined whether the cytokine gene expression profile of noncancerous lung tissue could predict the metastatic capability of adjacent lung adenocarcinoma. Methods We analyzed a 15-cytokine gene expression profile in noncancerous lung tissue and corresponding lung tumor tissue from 80 US lung adenocarcinorna patients using real-time quantitative reverse transcription-polymerase chain reaction. We then used unsupervised hierarchical clustering and Prediction Analysis of Microarray classification to test the prognostic ability of the 15-cytokine gene profile in the US patients and in an independent validation set comprising 50 Japanese patients with stage I disease. Survival was analyzed by the Kaplan-Meier method using the log-rank test, and univariate and multivariable Cox proportional hazards modeling were used to analyze the association of clinical variables with patient survival. All statistical tests were two-sided. Results A 15-cytokine gene signature in noncancerous lung tissue primarily reflected the lymph node status of 80 long adenocarcinoma patients, whereas the gene signature of the corresponding lung tumor tissue was associated with prognosis independent of lymph node status. Cytokine Lung Adenocarcinoma Survival Signature of 11 genes (CLASS-11), a refined 11-gene signature, accurately classified patients, including those with stage I disease, according to risk of death from adenocarcinoma. CLASS-1 1 prognostic classification was statistically significantly associated with survival and was an independent prognostic factor for stage I patients (hazard ratio for death in the high-risk CLASS-11 group compared with the low-risk CLASS-1 1 reference group = 7.46, 95% confidence interval = 2.14 to 26.05; P = .002). CLASS-11 also classified patients in the validation set according to risk of recurrence. Conclusion CLASS-11, which consists of genes for pro- and anti-inflammatory cytokines, identifies stage I lung adenocarcinoma patients who have a poor prognosis. C1 NCI, Natl Inst Hlth, Canc Prevent Fellowship Program, Div Canc Prevent, Bethesda, MD 20892 USA. Natl Canc Ctr, Div Biol, Tokyo, Japan. Natl Canc Ctr, Canc Genom Project, Tokyo, Japan. Hamamatsu Univ Sch Med, Dept Pathol, Hamamatsu, Shizuoka 43131, Japan. Nippon Med Coll, Dept Pulm Med Infect & Oncol, Tokyo 113, Japan. RP Harris, CC (reprint author), NCI, Natl Inst Hlth, Human Carcinogenesis Lab, Ctr Canc Res, 37 Convent Dr,Bldg 37,Rm 3068, Bethesda, MD 20892 USA. EM curtis_harris@nih.gov RI Wang, Xin/B-6162-2009 FU Intramural NIH HHS NR 53 TC 86 Z9 90 U1 0 U2 4 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 AUG 15 PY 2007 VL 99 IS 16 BP 1257 EP 1269 DI 10.1093/jnci/djm083 PG 13 WC Oncology SC Oncology GA 204PD UT WOS:000249055600010 PM 17686824 ER PT J AU Egger, K Mueller, J Schocke, M Brenneis, C Rinnerthaler, M Seppi, K Trieb, T Wenning, GK Hallett, M Poewe, W AF Egger, Karl Mueller, Joerg Schocke, Michael Brenneis, Christian Rinnerthaler, Martina Seppi, Klaus Trieb, Thomas Wenning, Gregor K. Hallett, Mark Poewe, Werner TI Voxel based morphometry reveals specific gray matter changes in primary dystonia SO MOVEMENT DISORDERS LA English DT Article DE voxel-based morphometry; primary dystonia; globus pallidus internus; orbitofrontal cortex; nucleus; accumbens ID OBSESSIVE-COMPULSIVE DISORDER; IDIOPATHIC FOCAL DYSTONIA; GENERALIZED DYSTONIA; CERVICAL DYSTONIA; SPASMODIC TORTICOLLIS; ABNORMALITIES; BLEPHAROSPASM; PUTAMEN; AREAS AB The present study assessed patterns of brain tissue alterations in different types of primary dystonia using voxel-based morphometry (VBM). Nine patients with primary generalized dystonia (GD), 11 patients with primary cervical dystonia (CD), and 11 patients with primary focal hand dystonia (FHD) as well as 31 age and gender-matched controls were included. When compared with healthy controls, patients with primary dystonia (n = 31) showed gray matter volume increase bilaterally in the globus pallidus internus, nucleus accumbens, prefrontal cortex, as well as unilaterally in the left inferior parietal lobe. This is the first study using VBM in patients with different types of primary dystonia, showing a common pattern of gray matter changes. (c) 2007 Movement Disorder Society. C1 Innsbruck Med Univ, Dept Neurol, A-6020 Innsbruck, Austria. Innsbruck Med Univ, Dept Radiol, A-6020 Innsbruck, Austria. NINDS, Human Motor Control Sect, Med Neurol Branch, Bethesda, MD 20892 USA. RP Mueller, J (reprint author), Innsbruck Med Univ, Dept Neurol, Anichstr 35, A-6020 Innsbruck, Austria. EM joerg.mueller@uibk.ac.at NR 29 TC 58 Z9 58 U1 1 U2 5 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 AUG 15 PY 2007 VL 22 IS 11 BP 1538 EP 1542 DI 10.1002/mds.21619 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 207CI UT WOS:000249228800003 PM 17588241 ER PT J AU Abbott, RD Ross, GW Petrovitch, H Tanner, CM Davis, DG Masaki, KH Launer, LJ Curb, JD White, LR AF Abbott, Robert D. Ross, G. Webster Petrovitch, Helen Tanner, Caroline M. Davis, Daron G. Masaki, Karnal H. Launer, Lenore J. Curb, J. David White, Lon R. TI Bowel movement frequency in late-life and incidental Lewy bodies SO MOVEMENT DISORDERS LA English DT Article DE bowel movement; constipation; lewy body; Parkinson's disease; preclinical ID PARKINSONS-DISEASE; GASTROINTESTINAL DYSFUNCTION; PHYSICAL-ACTIVITY; BRAIN PATHOLOGY; POPULATION; MEN; CONSTIPATION; INCLUSIONS; DEFECATION; STROKE AB It is not known if constipation is associated with the preclinical phase of Parkinson's disease (PD), often characterized by the presence of incidental Lewy bodies (ILB). Such an association could provide evidence that constipation is an early symptom of PD. The purpose of this report is to examine the association between late-life bowel movement frequency and ILB. Bowel movement frequency was assessed from 1991 to 1993 in 245 men aged 71 to 93 years in the Honolulu-Asia Aging Study who later received postmortem examinations. All were without clinical PD and dementia. Brains were examined for ILB in the substantia nigra and locus ceruleus. Among the decedents, 30 men had ILB (12.2%). After age-adjustment, the percent of brains with ILB declined with increasing bowel movement frequency (P = 0.0 13). For men with < 1, 1, and > 1 bowel movement/day, corresponding percents were 24.1, 13.5, and 6.5%. Findings persisted after additional adjustment for time to death, mid-life pack-years of smoking and coffee intake, physical activity, and cognitive function. Infrequent bowel movements are associated with ILB. Findings provide evidence that constipation can predate the extrapyramidal signs of PD. Constipation could be one of the earliest markers of the beginning of PD processes. (c) 2007 Movement Disorder Society. C1 Univ Virginia, Dept Publ Hlth Sci, Div Biostat & Epidemiol, Sch Med, Charlottesville, VA 22908 USA. Shiga Univ Med Sci, Dept Hlth Sci, Otsu, Shiga 52021, Japan. Pacific Hlth Res Inst, Honolulu, HI USA. Vet Affairs Pacific Isl Hlth Care Syst, Honolulu, HI USA. Univ Hawaii, John A Burns Sch Med, Dept Med, Honolulu, HI 96822 USA. Univ Hawaii, John A Burns Sch Med, Dept Geriatr Med, Honolulu, HI 96822 USA. Parkinsons Inst, Sunnyvale, CA USA. Pathol & Cytol Labs, Lexington, KY USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Abbott, RD (reprint author), Univ Virginia, Dept Publ Hlth Sci, Div Biostat & Epidemiol, Sch Med, POB 800717, Charlottesville, VA 22908 USA. EM rda3e@virginia.edu FU NHLBI NIH HHS [N01-HC-05102]; NIA NIH HHS [1-R01-AG17155-01A1, N01-AG-4-2149]; NINDS NIH HHS [1-R01-NS41265-01] NR 37 TC 100 Z9 107 U1 0 U2 4 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 AUG 15 PY 2007 VL 22 IS 11 BP 1581 EP 1586 DI 10.1002/mds.21560 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 207CI UT WOS:000249228800010 PM 17523195 ER PT J AU Huang, X Lee, YZ McKeown, M Gerig, G Gu, H Lin, W Lewis, MM Ford, S Troster, AI Weinberger, DR Styner, M AF Huang, Xuemei Lee, Yueh Z. McKeown, Martin Gerig, Guido Gu, Hongbin Lin, Weili Lewis, Mechelle M. Ford, Sutapa Troester, Alexander I. Weinberger, Daniel R. Styner, Martin TI Asymmetrical ventricular enlargement in Parkinson's disease SO MOVEMENT DISORDERS LA English DT Article DE parkinson's disease; ventricle; volume asymmetry; motor impairment ID ATROPHY; RATES AB Parkinson's disease (PD) typically manifests with asymmetric motor symptom onset. Ventricular enlargement, a nonspecific measure of brain atrophy, has been associated with cognitive decline in PD, but not with motor symptom asymmetry. Asymmetrical ventricular enlargement on magnetic resonance images was explored in a monozygotic twin pair discordant for PD and in nine healthy monozygotic twin pairs. The left-right lateral ventricular volumetric difference of the PD-twin was greater than that of his twin and all other healthy twins, with the larger ventricle observed contralateral to the more symptomatic side. Moreover, the lateral ventricle asymmetry difference between twin pairs was significantly higher for the discordant PD-twin pair than for the healthy twin pairs. This is the first report to suggest the presence of asymmetrical ventricular enlargement in PD, findings that may be worthy of further study. (c) 2007 Movement Disorder Society. C1 Univ N Carolina, Sch Med, Dept Neurol, Chapel Hill, NC 27599 USA. Univ N Carolina, Sch Med, Dept Radiol, Chapel Hill, NC 27599 USA. Univ British Columbia, Dept Med Neurol, Pacific Parkinsons Res Ctr, Univ Hosp, Vancouver, BC V5Z 1M9, Canada. Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Comp Sci, Chapel Hill, NC 27599 USA. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Huang, X (reprint author), Univ N Carolina, Sch Med, Dept Neurol, CB 7025, Chapel Hill, NC 27599 USA. EM xuemei@med.unc.edu OI Lee, Yueh/0000-0003-1846-7680; Styner, Martin/0000-0002-8747-5118; Gerig, Guido/0000-0002-9547-6233 FU NCRR NIH HHS [RR00046]; NIA NIH HHS [AG21491] NR 12 TC 7 Z9 8 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0885-3185 EI 1531-8257 J9 MOVEMENT DISORD JI Mov. Disord. PD AUG 15 PY 2007 VL 22 IS 11 BP 1657 EP 1660 DI 10.1002/mds.21626 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 207CI UT WOS:000249228800025 PM 17588238 ER PT J AU Papapetropoulos, S Friedman, J Blackstone, C Kleiner, GI Bowen, BC Singer, C AF Papapetropoulos, Spiridon Friedman, Jennifer Blackstone, Craig Kleiner, Gary I. Bowen, Brian C. Singer, Carlos TI A progressive, fatal dystonia-parkinsonism syndrome in a patient with primary immunodeficiency receiving chronic IVIG therapy SO MOVEMENT DISORDERS LA English DT Article DE extrapyramidal syndrome; dystonia; IVIG; X-linked agammaglobulinemia ID X-LINKED AGAMMAGLOBULINEMIA; INTRAVENOUS IMMUNOGLOBULIN; BRAIN IRON; GENE; NEURODEGENERATION; PROTEIN AB !fX-linked agammaglobulinemia (XLA) is a primary immunodeficiency disorder caused by a mutation in the Bruton agammaglobulinemia tyrosine kinase gene that results in severe B-cell deficiency. So far, neurological complications of XLA have been primarily related to acute and/or chronic central nervous system enteroviral infections. In the last few years a progressive neurodegenerative syndrome of unknown etiology has been described in XLA patients. We describe and present a video of an XLA patient who developed a fatal dementing, dystonia-Parkinsonism syndrome 14 years into his immune disorder. Physician awareness of this rare syndrome may lead to its better characterization and management. (C) 2007 Movement Disorder Society. C1 Univ Miami, Miller Sch Med, Dept Neurol, Miami, FL 33136 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Rady Childrens Hosp, Dept Neurol, San Diego, CA USA. Natl Inst Neurol Disorders & Stroke, Cellular Neurol Unit, NIH, Bethesda, MD USA. Univ Miami, Miller Sch Med, Dept Pediat, Miami, FL 33152 USA. Univ Miami, Miller Sch Med, Dept Radiol, Miami, FL 33152 USA. RP Papapetropoulos, S (reprint author), Univ Miami, Miller Sch Med, Dept Neurol, 1501 NW 9th Ave NPF,Room 4004, Miami, FL 33136 USA. EM spapapetropoulos@med.miami.edu NR 14 TC 4 Z9 4 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 AUG 15 PY 2007 VL 22 IS 11 BP 1664 EP 1666 DI 10.1002/mds.21631 PG 3 WC Clinical Neurology SC Neurosciences & Neurology GA 207CI UT WOS:000249228800027 PM 17588239 ER PT J AU Shamim, EA AF Shamim, Ejaz A. TI Intramedullary spinal tumor causing "Belly dancer syndrome" SO MOVEMENT DISORDERS LA English DT Letter ID DIAPHRAGMATIC FLUTTER C1 Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, NIH, Bethesda, MD USA. RP Shamim, EA (reprint author), Natl Inst Neurol Disorders & Stroke, Human Motor Control Sect, NIH, Bethesda, MD USA. EM shamime@ninds.nih.gov NR 6 TC 8 Z9 8 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 AUG 15 PY 2007 VL 22 IS 11 BP 1673 EP 1674 DI 10.1002/mds.21280 PG 2 WC Clinical Neurology SC Neurosciences & Neurology GA 207CI UT WOS:000249228800033 PM 17216647 ER PT J AU Simonyan, K Saad, ZS Loucks, TMJ Poletto, CJ Ludlow, CL AF Simonyan, Kristina Saad, Ziad S. Loucks, Torrey M. J. Poletto, Christopher J. Ludlow, Christy L. TI Functional neuroanatomy of human voluntary cough and sniff production SO NEUROIMAGE LA English DT Article DE respiratory control; cerebral cortex; functional MRI ID PRIMARY SOMATOSENSORY CORTEX; HUMAN PARIETAL OPERCULUM; INTERINDIVIDUAL VARIABILITY; OLFACTORY DYSFUNCTION; PARKINSONS-DISEASE; MOTOR PATTERN; AREAS 3A; REFLEX; SYSTEM; SUPPRESSION AB Cough and sniff are both spontaneous respiratory behaviors that can be initiated voluntarily in humans. Disturbances of cough may be life threatening, while inability to sniff impairs the sense of smell in neurological patients. Cortical mechanisms of voluntary cough and sniff production have been predicted to exist; however, the localization and function of supramedullary areas responsible for these behaviors are poorly understood. We used functional magnetic resonance imaging to identify the central control of voluntary cough and sniff compared with breathing. We determined that both voluntary cough and sniff require a widespread pattern of sensorimotor activation along the Sylvian fissure convergent with voluntary breathing. Task-specific activation occurred in a pontomesencephalic region during voluntary coughing and in the hippocampus and piriform cortex during voluntary sniffing. Identification of the localization of cortical activation for cough control in humans may help potential drug development to target these regions in patients with chronic cough. Understanding the sensorimotor sniff control mechanisms may provide a new view on the cerebral functional reorganization of olfactory control in patients with neurological disorders. Published by Elsevier Inc. C1 NIH, NINDS, Med Neurol Branch, Laryngeal & Speech Sect, Bethesda, MD 20814 USA. NIH, NIMH, Sci & Stat Comp Core, Bethesda, MD 20892 USA. RP Simonyan, K (reprint author), NIH, NINDS, Med Neurol Branch, Laryngeal & Speech Sect, Bldg 10,Room 5D38, Bethesda, MD 20814 USA. EM simonyak@ninds.nih.gov OI Simonyan, Kristina/0000-0001-7444-0437; Ludlow, Christy/0000-0002-2015-6171 FU Intramural NIH HHS [NIH0011665477, Z01 NS002980-08] NR 52 TC 41 Z9 44 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 AUG 15 PY 2007 VL 37 IS 2 BP 401 EP 409 DI 10.1016/j.neuroimage.2007.05.021 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 197VU UT WOS:000248585400004 PM 17574873 ER PT J AU Tomasi, D Goldstein, RZ Telang, F Maloney, T Alia-Klein, N Caparelli, EC Volkow, ND AF Tomasi, Dardo Goldstein, Rita Z. Telang, Frank Maloney, Thomas Alia-Klein, Nelly Caparelli, Elisabeth C. Volkow, Nora D. TI Thalamo-cortical dysfunction in cocaine abusers: Implications in attention and perception SO PSYCHIATRY RESEARCH-NEUROIMAGING LA English DT Article DE fMRI; PET; visual attention; dopamine; norepinephrine; addict ID LATERAL GENICULATE-NUCLEUS; ANTERIOR CINGULATE CORTEX; WORKING-MEMORY; PREFRONTAL CORTEX; VISUAL-ATTENTION; PARKINSONS-DISEASE; LOCUS-COERULEUS; HUMAN BRAIN; DOPAMINERGIC MODULATION; COGNITIVE IMPAIRMENT AB Cocaine affects sensory perception and attention, but little is known about the neural substrates underlying these effects in the human brain. We used functional magnetic resonance imaging (fMRI) and a sustained visuospatial attention task to assess if the visual attention network is dysfunctional in cocaine abusers (n = 14) compared to age-, gender-, and education-matched controls (n= 14). Compared with controls, cocaine abusers showed (1) hypo-activation of the thalamus, which may reflect noradrenergic and/or dopaminergic deficits; (2) hyper-activation in occipital and prefrontal cortices, which may reflect increased visual cortical processing to compensate for inefficient visual thalamic processing; and (3) larger deactivation of parietal and frontal regions possibly to support the larger hemodynamic supply to the hyper-activated brain regions. These findings provide evidence of abnormalities in thalamo-cortical responses in cocaine abusers that are likely to contribute to the impairments in sensory processing and in attention. The development of therapies that diminish these thalamo-cortical deficits could improve the treatment of cocaine addiction. Published by Elsevier Ireland Ltd. C1 Brookhaven Natl Lab, Dept Med, Upton, NY 11973 USA. Natl Inst Drug Abuse, Bethesda, MD USA. RP Tomasi, D (reprint author), Brookhaven Natl Lab, Dept Med, Bldg 490,30 Bell Ave, Upton, NY 11973 USA. EM tomasi@bnl.gov RI Tomasi, Dardo/J-2127-2015 FU NCRR NIH HHS [M01 RR010710, M01-RR-10710]; NIDA NIH HHS [R03 DA 017070-01, K23 DA015517, K23 DA15517-01, R03 DA017070, R03 DA017070-01] NR 84 TC 61 Z9 62 U1 4 U2 10 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0925-4927 J9 PSYCHIAT RES-NEUROIM JI Psychiatry Res. Neuroimaging PD AUG 15 PY 2007 VL 155 IS 3 BP 189 EP 201 DI 10.1016/j.pseychresns.2007.03.002 PG 13 WC Clinical Neurology; Neuroimaging; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 203JV UT WOS:000248971800002 PM 17582746 ER PT J AU Fromme, R Katiliene, Z Giomarelli, B Bogani, F Mc Mahon, J Mori, T Fromme, P Ghirlanda, G AF Fromme, Raimund Katiliene, Zivile Giomarelli, Barbara Bogani, Federica Mc Mahon, James Mori, Toshiyuki Fromme, Petra Ghirlanda, Giovanna TI A monovalent mutant of cyanovirin-N provides insight into the role of multiple interactions with gp120 for antiviral activity SO BIOCHEMISTRY LA English DT Article ID HIV-INACTIVATING PROTEIN; DOMAIN-SWAPPED DIMER; CARBOHYDRATE-BINDING; STRUCTURAL BASIS; X-RAY; VIRUS; INHIBITION; FUSION; MODEL; GLYCOPROTEIN AB Cyanovirin-N (CV-N) is a 101 amino acid cyanobacterial lectin with potent antiviral activity against HIV, mediated by high-affinity binding to branched N-linked oligomannosides on the viral surface envelope protein gp 120. The protein contains two carbohydrate-binding domains, A and B, each of which binds short oligomannosides independently in vitro. The interaction to gp120 could involve either a single domain or both domains simultaneously; it is not clear which mode would elicit the antiviral activity. The model is complicated by the formation of a domain-swapped dimer form, in which part of each domain is exchanged between two monomers, which contains four functional carbohydrate-binding domains. To clarify whether multivalent interactions with gp120 are necessary for the antiviral activity, we engineered a novel mutant, P51G-m4-CVN, in which the binding site on domain A has been knocked out; in addition, a [P51G] mutation prevents the formation of domain-swapped dimers under physiological conditions. Here, we present the crystal structures at 1.8 angstrom of the free and of the dimannose-bound forms of P51 Gm4-CVN, revealing a monomeric structure in which only domain B is bound to dimannose. P51G-m4-CVN binds gp120 with an affinity almost 2 orders of magnitude lower than wt CV-N and is completely inactive against HIV. The tight binding to gp120 is recovered in the domain-swapped version of P51Gm4-CVN, prepared under extreme conditions. Our findings show that the presence of at least two olicomannoside-binding sites, either by the presence of intact domains A and B or by formation of domainswapped dimers, is essential for activity. C1 Arizona State Univ, Dept Chem & Biochem, Tempe, AZ 85287 USA. NCI Frederick, Ctr Canc Res, Frederick, MD 21702 USA. RP Ghirlanda, G (reprint author), Arizona State Univ, Dept Chem & Biochem, Tempe, AZ 85287 USA. EM gghirianda@asu.edu RI Fromme, Raimund/C-8885-2012 OI Fromme, Raimund/0000-0003-4835-1080 FU Intramural NIH HHS NR 45 TC 25 Z9 25 U1 2 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD AUG 14 PY 2007 VL 46 IS 32 BP 9199 EP 9207 DI 10.1021/bi700666m PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 199XI UT WOS:000248728100005 PM 17636873 ER PT J AU Ashikaga, H McVeigh, ER Omens, JH AF Ashikaga, Hiroshi McVeigh, Elliot R. Omens, Jeffrey H. TI On the mechanisms of transmural dispersion of myocardial mechanics - Reply SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter ID HETEROGENEITY; CANINE C1 NHLBI, Cardiac Energet Lab, Bethesda, MD 20892 USA. RP Ashikaga, H (reprint author), NHLBI, Cardiac Energet Lab, 10 Ctr Dr,Bldg 10-B1D416, Bethesda, MD 20892 USA. EM ha8000@gmail.com OI Ashikaga, Hiroshi/0000-0003-3689-6892 NR 4 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD AUG 14 PY 2007 VL 50 IS 7 BP 650 EP 650 DI 10.1016/j.jacc.2007.05.013 PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 204MY UT WOS:000249049300015 ER PT J AU Gottwein, JM Bukh, J AF Gottwein, Judith M. Bukh, Jens TI Hepatitis C virus-host cell interactions uncovered SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID SUBGENOMIC REPLICON; MICROARRAY ANALYSIS; PROTEOME ANALYSIS; RNA INTERFERENCE; REPLICATION; INFECTION; LIVER; IDENTIFICATION; MICRORNAS; CULTURE C1 Univ Copenhagen, Hvidovre Hosp, Dept Infect Dis, DK-2650 Hvidovre, Denmark. Univ Copenhagen, Panum Inst, Fac Hlth Sci, Dept Int Hlth Immunol & Microbiol, DK-2200 Copenhagen, Denmark. NIAID, Infect Dis Lab, Hepatitis Viruses Sect, Bethesda, MD 20892 USA. RP Bukh, J (reprint author), Univ Copenhagen, Hvidovre Hosp, Dept Infect Dis, DK-2650 Hvidovre, Denmark. EM jbukh@niaid.nih.gov NR 23 TC 4 Z9 5 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD AUG 14 PY 2007 VL 104 IS 33 BP 13215 EP 13216 DI 10.1073/pnas.0705890104 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 202KE UT WOS:000248899600002 PM 17684095 ER PT J AU Dinglasan, RR Kalume, DE Kanzok, SM Ghosh, AK Muratova, O Pandey, A Jacobs-Lorena, M AF Dinglasan, Rhoel R. Kalume, Dario E. Kanzok, Stefan M. Ghosh, Anil K. Muratova, Olga Pandey, Akhilesh Jacobs-Lorena, Marcelo TI Disruption of Plasmodium falciparum development by antibodies against a conserved mosquito midgut antigen SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE glycan; malaria; mass spectrometry; transmission-blocking vaccine ID AEDES-AEGYPTI MIDGUT; ANOPHELES-STEPHENSI; MALARIA PARASITE; PERITROPHIC MATRIX; MASS-SPECTROMETRY; SALIVARY-GLANDS; TRANSMISSION; GAMBIAE; PROTEIN; IDENTIFICATION AB Malaria parasites must undergo development within mosquitoes to be transmitted to a new host. Antivector transmission-blocking vaccines inhibit parasite development by preventing ookinete interaction with mosquito midgut ligands. Therefore, the discovery of novel midgut antigen targets is paramount. Jacalin (a lectin) inhibits ookinete attachment by masking glycan ligands on midgut epithelial surface glycoproteins. However, the identities of these midgut glycoproteins have remained unknown. Here we report on the molecular characterization of an Anopheles gambiae aminopeptidase N (AgAPN1) as the predominant jacalin target on the mosquito midgut luminal surface and provide evidence for its role in ookinete invasion. alpha-AgAPN1 IgG strongly inhibited both Plasmodium berghei and Plasmodium falciparum development in different mosquito species, implying that AgAPN1 has a conserved role in ookinete invasion of the midgut. Molecules targeting single midgut antigens seldom achieve complete abrogation of parasite development. However, the combined blocking activity of a-AgAPN1 IgG and an unrelated inhibitory peptide, SM1, against A berghei was incomplete. We also found that SM1 can block only A berghei, whereas a-AgAPN1 IgG can block both parasite species significantly. Therefore, we hypothesize that ookinetes can evade inhibition by two potent transmission-blocking molecules, presumably through the use of other ligands, and that this process further partitions murine from human parasite midgut invasion models. These results advance our understanding of malaria parasite-mosquito host interactions and guide in the design of transmission-blocking vaccines. C1 Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Inst Med Genet, Baltimore, MD 21205 USA. NIAID, Malaria Vaccine Dev Unit, NIH, Rockville, MD 20852 USA. RP Dinglasan, RR (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, 615 N Wolfe St, Baltimore, MD 21205 USA. EM rdinglas@jhsph.edu; mlorena@jhsph.edu RI Pandey, Akhilesh/B-4127-2009; OI Pandey, Akhilesh/0000-0001-9943-6127; Dinglasan, Rhoel/0000-0001-5433-8179; Dinglasan, Rhoel/0000-0001-6563-1506 FU NCRR NIH HHS [M01 RR000052, RR00052]; NIAID NIH HHS [5F32AI068212-02, F32 AI068212, R01 AI031478, R01AI031478] NR 38 TC 85 Z9 88 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 AUG 14 PY 2007 VL 104 IS 33 BP 13461 EP 13466 DI 10.1073/pnas.0702239104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 202KE UT WOS:000248899600045 PM 17673553 ER PT J AU Xu, DQ Cisar, JO Osorio, M Wai, TT Kopecko, DJ AF Xu, De Qi Cisar, John O. Osorio, Manuel Wai, Tint T. Kopecko, Dennis J. TI Core-linked LPS expression of Shigella dysenteriae serotype 1 O-antigen in live Salmonella Typhi vaccine vector Ty21a: Preclinical evidence of immunogenicity and protection SO VACCINE LA English DT Article DE bifunctional vaccine; oral vaccine; Typhoid-Shigella vaccine; heterologous LPS expression; Shigella dysenteriae 1; Salmonella Typhi Ty21a; live bacterial vector ID FORM-I ANTIGEN; CHROMOSOMAL GENES; IMMUNE-RESPONSES; BIVALENT VACCINE; LIPOPOLYSACCHARIDE; PLASMID; SHIGELLA-DYSENTERIAE-1; STRAIN; CONSTRUCTION; CLONING AB Shigella dysenteriae serotype 1 (S. dysenteriae 1) causes severe shigellosis that is typically associated with high mortality. Antibodies against Shigella serotype-specific O-polysaccharide (O-Ps) have been shown to be host protective. In this study, the rfb locus and the rfp gene with their cognate promoter regions were PCR-amplified from S. dysenteriae 1, cloned, and sequenced. Deletion analysis showed that eight rfb ORFs plus rfp are necessary for biosynthesis of this O-Ps. A tandemly-linked rfb-rfp gene cassette was cloned into low copy plasmid pGB2 to create pSd1. Avirulent Salmonella enterica serovar Typhi (S. Typhi) Ty21a harboring pSd1 synthesized S. Typhi 9, 12 LPS as well as typical core-linked S. dysenteriae 1 LPS. Animal immunization studies showed that Ty21 a (pSd1) induces protective immunity against high stringency challenge with virulent S. dysentericte 1 strain 1617. These data further demonstrate the utility of S. Typhi Ty21 a as a live, bacterial vaccine delivery system for heterologous O-antigens, supporting the promise of a bifunctional oral vaccine for prevention of shigellosis and typhoid fever. (c) Published by Elsevier Ltd. C1 FDA CBER, Lab Enter & STDs, Bethesda, MD 20892 USA. Natl Inst Dental & Carniofac Res, NIH, Oral Infect & Immun Branch, Bethesda, MD 20892 USA. RP Kopecko, DJ (reprint author), FDA CBER, Lab Enter & STDs, Bldg 29,NIH Campus,HFM440 Rockville Pike, Bethesda, MD 20892 USA. EM dennis.kopecko@fda.hhs.gov FU Intramural NIH HHS NR 45 TC 11 Z9 11 U1 1 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 AUG 14 PY 2007 VL 25 IS 33 BP 6167 EP 6175 DI 10.1016/j.vaccine.2007.06.003 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 202MN UT WOS:000248905900005 PM 17629369 ER PT J AU Drel, VR Pacher, P Vareniuk, I Pavlov, I Llnytska, O Lyzogubov, VV Tibrewala, J Groves, JT Obrosova, IG AF Drel, Viktor R. Pacher, Pal Vareniuk, Igor Pavlov, Ivan Llnytska, Olga Lyzogubov, Valeriy V. Tibrewala, Jyoti Groves, Jolm T. Obrosova, Irina G. TI A peroxynitrite decomposition catalyst counteracts sensory neuropathy in streptozotocin-diabetic mice SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE intraepidermal nerve fiber loss; nitrosative stress; peroxynitrite decomposition catalyst; poly(ADP-ribose) polymerase; tactile allodynia; thermal hypoalgesia ID POLY(ADP-RIBOSE) POLYMERASE ACTIVATION; ALDOSE REDUCTASE INHIBITION; OXIDATIVE-NITROSATIVE STRESS; NERVE CONDUCTION-VELOCITY; ALPHA-LIPOIC ACID; NEUROVASCULAR DEFICITS; VASCULAR REACTIVITY; RADICAL SCAVENGER; BLOOD-FLOW; RATS AB Whereas an important role of free radicals and oxidants in peripheral diabetic neuropathy is well established, the contribution of nitrosative stress and, in particular, of the highly reactive oxidant peroxynitrite, has not been properly explored. Our previous findings implicate peroxynitrite in diabetes-associated motor and sensory nerve conduction deficits and peripheral nerve energy deficiency and poly(ADP-ribose) polymerase activation associated with Type I diabetes. In this study the role of nitrosative stress in diabetic sensory neuropathy is evaluated. The peroxynitrite decomposition catalyst Fe(III) tetrakis-2-(N-triethylene glycol monomethyl ether)pyridyl porphyrin (FP15) was administered to control and streptozotocin (STZ)-diabetic mice at the dose of 5 mg kg(-1) day(-1) (FP 15), for 3 weeks after initial 3 weeks without treatment. Mice with 6-week duration of diabetes developed clearly manifest thermal hypoalgesia (paw withdrawal, tail-flick, and hot plate tests), mechanical hypoalgesia (tail pressure Randall-Sellito test), tactile allodynia (flexible von Frey filament test), and similar to 38% loss of intraepidermal nerve fibers. They also had increased nitrotyrosine and poly(ADP-ribose) irmiumofluorescence in the sciatic nerve, grey matter of spinal cord, and dorsal root ganglion neurons. FP 15 treatment was associated with alleviation of thermal and mechanical hypoalgesia. Tactile response threshold tended to increase in response to peroxynitrite decomposition catalyst treatment, but still remained similar to 59% lower compared with non-diabetic controls. Intraepidermal nerve fiber density was 25% higher in FP15-treated than in untreated diabetic rats, but the difference between two groups did not achieve statistical significance (p = 0.054). Nitrotyrosine and poly(ADP-ribose) immunofluorescence in sciatic nerve, spinal cord, and dorsal root ganglion neurons of peroxynitrite decomposition catalyst-treated diabetic mice were markedly reduced. In conclusion, nitrosative stress plays an important role in sensory neuropathy associated with Type I diabetes. The findings provide rationale for further studies of peroxynitrite decomposition catalysts in a long-term diabetic model. (c) 2007 Elsevier B.V. All rights reserved. C1 Louisiana State Univ, Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. NIAAA, NIH, Lab Physiol Studies, Sect Oxidat Str Tissue Injury, Bethesda, MD USA. Princeton Univ, Dept Chem, Princeton, NJ 08544 USA. RP Obrosova, IG (reprint author), Louisiana State Univ, Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM obrosoig@pbrc.edu RI Pacher, Pal/B-6378-2008; Drel, Viktor/G-8883-2016 OI Pacher, Pal/0000-0001-7036-8108; Drel, Viktor/0000-0003-4542-0132 FU Intramural NIH HHS [Z01 AA000375-02]; NIDDK NIH HHS [DK 071566-01, R21 DK071566, R21 DK071566-01]; NIGMS NIH HHS [R01 GM033881, GM 36298, R01 GM033881-17, R01 GM036298, R37 GM036298] NR 53 TC 61 Z9 64 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD AUG 13 PY 2007 VL 569 IS 1-2 BP 48 EP 58 DI 10.1016/j.ejphar.2007.05.055 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 205AQ UT WOS:000249085500007 PM 17644085 ER PT J AU Murr, R Vaissiere, T Sawan, C Shukla, V Herceg, Z AF Murr, R. Vaissiere, T. Sawan, C. Shukla, V. Herceg, Z. TI Orchestration of chromatin-based processes: mind the TRRAP SO ONCOGENE LA English DT Review DE TRRAP; HATs; histone acetylation; transcription; DNA repair; cancer ID STRAND BREAK REPAIR; HISTONE ACETYLTRANSFERASE COMPLEX; NUCLEAR-RECEPTOR FUNCTION; EARLY EMBRYONIC LETHALITY; CELL-CYCLE PROGRESSION; DNA-DAMAGE RESPONSE; PIK-RELATED KINASES; HAT COFACTOR TRRAP; C-MYC; TRANSCRIPTIONAL ACTIVATION AB Chromatin modi. cations at core histones including acetylation, methylation, phosphorylation and ubiquitination play an important role in diverse biological processes. Acetylation of specific lysine residues within the N terminus tails of core histones is arguably the most studied histone modi. cation; however, its precise roles in different cellular processes and how it is disrupted in human diseases remain poorly understood. In the last decade, a number of histone acetyltransferases ( HATs) enzymes responsible for histone acetylation, has been identified and functional studies have begun to unravel their biological functions. The activity of many HATs is dependent on HAT complexes, the multiprotein assemblies that contain one HAT catalytic subunit, adapter proteins, several other molecules of unknown function and a large protein called TRansformation/tRanscription domain-Associated Protein ( TRRAP). As a common component of many HAT complexes, TRRAP appears to be responsible for the recruitment of these complexes to chromatin during transcription, replication and DNA repair. Recent studies have shed new light on the role of TRRAP in HAT complexes as well as mechanisms by which it mediates diverse cellular processes. Thus, TRRAP appears to be responsible for a concerted and context-dependent recruitment of HATs and coordination of distinct chromatin-based processes, suggesting that its deregulation may contribute to diseases. In this review, we summarize recent developments in our understanding of the function of TRRAP and TRRAP-containing HAT complexes in normal cellular processes and speculate on the mechanism underlying abnormal events that may lead to human diseases such as cancer. C1 Int Agcy Res Canc, Epigenet Team, Mol Carcinogenesis & Biomarkers Grp, F-69008 Lyon, France. NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. RP Herceg, Z (reprint author), Int Agcy Res Canc, Epigenet Team, Mol Carcinogenesis & Biomarkers Grp, 150 Cours Albert Thomas, F-69008 Lyon, France. EM herceg@iarc.fr RI Vaissiere, Thomas/E-1121-2011; OI Murr, Rabih/0000-0002-3346-6590 NR 144 TC 70 Z9 70 U1 2 U2 11 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 EI 1476-5594 J9 ONCOGENE JI Oncogene PD AUG 13 PY 2007 VL 26 IS 37 BP 5358 EP 5372 DI 10.1038/sj.onc.1210605 PG 15 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 199CR UT WOS:000248674300005 PM 17694078 ER PT J AU Denslow, SA Wade, PA AF Denslow, S. A. Wade, P. A. TI The human Mi-2/NuRD complex and gene regulation SO ONCOGENE LA English DT Review DE histone deacetylase; chromatin; transcriptional repression; chromatin remodeling ID ESTROGEN-RECEPTOR-ALPHA; BREAST-CANCER CELLS; HISTONE DEACETYLASE; DNA METHYLATION; TRANSCRIPTIONAL REPRESSION; REMODELING COMPLEX; MI-2 AUTOANTIGEN; BINDING DOMAIN; MECP1 COMPLEX; PROTEINS AB The Mi-2/(nu) under bar cleosome (r) under bar emodeling and (d) under bar eacetylase ( NuRD) complex is an abundant deacetylase complex with a broad cellular and tissue distribution. It is unique in that it couples histone deacetylation and chromatin remodeling ATPase activities in the same complex. A decade of research has uncovered a number of interesting connections between Mi-2/NuRD and gene regulation. The subunit composition of the enzyme appears to vary with cell type and in response to physiologic signals within a tissue. Here, we review the known subunits of the complex, their connections to signaling networks, and their association with cancer. In addition, we propose a working model that integrates the known biochemical properties of the enzyme with emerging models on how chromatin structure and modi. cation relate to gene activity. C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Wade, PA (reprint author), NIEHS, Mol Carcinogenesis Lab, 111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM Wadep2@niehs.nih.gov FU Intramural NIH HHS NR 67 TC 244 Z9 248 U1 2 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 AUG 13 PY 2007 VL 26 IS 37 BP 5433 EP 5438 DI 10.1038/sj.onc.1210611 PG 6 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 199CR UT WOS:000248674300011 PM 17694084 ER PT J AU Shen, T Zheng, M Cao, CM Chen, CL Tang, J Zhang, WR Cheng, HP Chen, KH Xiao, RP AF Shen, Tao Zheng, Ming Cao, Chunmei Chen, Chunlei Tang, Jian Zhang, Wanrui Cheng, Heping Chen, Kuang-Hueih Xiao, Rui-Ping TI Mitofusin-2 is a major determinant of oxidative stress-mediated heart muscle cell apoptosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FAILING HUMAN HEART; MITOCHONDRIAL FUSION; CARDIOMYOCYTE APOPTOSIS; MAMMALIAN HOMOLOGS; SIGNALING PATHWAY; CARDIAC MYOCYTES; DEATH; FAILURE; BAX; MFN2 AB An inexorable loss of terminally differentiated heart muscle cells is a crucial causal factor for heart failure. Here, we have provided several lines of evidence to demonstrate that mitofusin-2 (Mfn-2; also called hyperplasia suppressor gene), a member of the mitofusin family, is a major determinant of oxidative stress-mediated cardiomyocyte apoptosis. First, oxidative stress with H2O2 led to concurrent increases in Mfn-2 expression and apoptosis in cultured neonatal rat cardiomyocytes. Second, overexpression of Mfn-2 to a level similar to that induced by H2O2 was sufficient to trigger myocyte apoptosis, which is associated with profound inhibition of Akt activation without altering ERK1/2 signaling. Third, Mfn-2 silencing inhibited oxidative stress-induced apoptosis in H9C2 cells, a cardiac muscle cell line. Furthermore, Mfn-2-induced myocyte apoptosis was abrogated by inhibition of caspase-9 (but not caspase-8) and by overexpression of Bcl-x(L) or enhanced activation of phosphatidylinositol 3-kinase-Akt, suggesting that inhibition of Akt signaling and activation of the mitochondrial death pathway are essentially involved in Mfn-2-induced heart muscle cell apoptosis. These results indicate that increased cardiac Mfn-2 expression is both necessary and sufficient for oxidative stress-induced heart muscle cell apoptosis, suggesting that Mfn-2 deregulation may be a crucial pathogenic element and a potential therapeutic target for heart failure. C1 NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. Peking Univ, Inst Cardiovasc Sci, Beijing 100083, Peoples R China. Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. RP Chen, KH (reprint author), NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM chenku@grc.nia.nih.gov; Xiaor@grc.nia.nih.gov FU Intramural NIH HHS NR 38 TC 78 Z9 93 U1 4 U2 17 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 AUG 10 PY 2007 VL 282 IS 32 BP 23354 EP 23361 DI 10.1074/jbc.M702657200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 197ST UT WOS:000248577500036 PM 17562700 ER PT J AU Sachs, UJH Andrei-Selmer, CL Maniar, A Weiss, T Paddock, C Orlova, VV Choi, EY Newman, PJ Preissner, KT Chavakis, T Santoso, S AF Sachs, Ulrich J. H. Andrei-Selmer, Cornelia L. Maniar, Amudhan Weiss, Timo Paddock, Cathy Orlova, Valeria V. Choi, Eun Young Newman, Peter J. Preissner, Klaus T. Chavakis, Triantafyllos Santoso, Sentot TI The neutrophil-specific antigen CD177 is a counter-receptor for platelet endothelial cell adhesion molecule-1 (CD31) SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID POLYCYTHEMIA RUBRA VERA; MIGRATION IN-VITRO; TRANSENDOTHELIAL MIGRATION; UROKINASE RECEPTOR; PECAM-1 CD31; SURFACE GLYCOSAMINOGLYCANS; LEUKOCYTE TRANSMIGRATION; INTERCELLULAR-JUNCTIONS; ALPHA-V-BETA-3 INTEGRIN; MONOCLONAL-ANTIBODY AB Human neutrophil-specific CD177 (NB1 and PRV-1) has been reported to be up-regulated in a number of inflammatory settings, including bacterial infection and granulocyte-colonystimulating factor application. Little is known about its function. By flow cytometry and immunoprecipitation studies, we identified platelet endothelial cell adhesion molecule-1 (PECAM-1) as a binding partner of CD177. Real-time protein-protein analysis using surface plasmon resonance confirmed a cation-dependent, specific interaction between CD177 and the heterophilic domains of PECAM-1. Monoclonal antibodies against CD177 and against PECAM-1 domain 6 inhibited adhesion of U937 cells stably expressing CD177 to immobilized PECAM-1. Transendothelial migration of human neutrophils was also inhibited by these antibodies. Our findings provide direct evidence that neutrophil-specific CD177 is a heterophilic binding partner of PECAM-1. This interaction may constitute a new pathway that participates in neutrophil transmigration. C1 Univ Giessen, Inst Clin Immunol & Transfus Med, D-35392 Giessen, Germany. Univ Giessen, Inst Biochem, D-35392 Giessen, Germany. Blood Ctr SE Wisconsin Inc, Blood Res Inst, Milwaukee, WI 53233 USA. NCI, Expt Immunol Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Santoso, S (reprint author), Univ Giessen, Inst Clin Immunol & Transfus Med, Langhansstr 7, D-35392 Giessen, Germany. EM Sentot.santoso@med.uni-giessen.de RI Orlova, Valeria/C-6065-2014 OI Orlova, Valeria/0000-0002-1169-2802 NR 50 TC 93 Z9 93 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 AUG 10 PY 2007 VL 282 IS 32 BP 23603 EP 23612 DI 10.1074/jbc.M701120200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 197ST UT WOS:000248577500062 PM 17580308 ER PT J AU Hernandez-Negrete, I Carretero-Ortega, J Rosenfeldt, H Hernandez-Garcia, R Calderon-Salinas, JV Reyes-Cruz, G Gutkind, JS Vazquez-Prado, J AF Hernandez-Negrete, Ivette Carretero-Ortega, Jorge Rosenfeldt, Hans Hernandez-Garcia, Ricardo Calderon-Salinas, J. Victor Reyes-Cruz, Guadalupe Gutkind, J. Silvio Vazquez-Prado, Jose TI P-Rex1 links mammalian target of rapamycin signaling to Rac activation and cell migration SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEOTIDE EXCHANGE FACTOR; RICTOR-MTOR COMPLEX; SUBSTRATE-SPECIFICITY; ACTIN CYTOSKELETON; BINDING PARTNER; S6 KINASE; PATHWAY; RAPTOR; PHOSPHORYLATION; TOR AB Polarized cell migration results from the transduction of extracellular cues promoting the activation of Rho GTPases with the intervention of multidomain proteins, including guanine exchange factors. P-Rex1 and P-Rex2 are Rac GEFs connecting G beta gamma and phosphatidylinositol 3-kinase signaling to Rac activation. Their complex architecture suggests their regulation by protein-protein interactions. Novel mechanisms of activation of Rho GTPases are associated with mammalian target of rapamycin ( mTOR), a serine/threonine kinase known as a central regulator of cell growth and proliferation. Recently, two independent multiprotein complexes containing mTOR have been described. mTORC1 links to the classical rapamycin-sensitive pathways relevant for protein synthesis; mTORC2 links to the activation of Rho GTPases and cytoskeletal events via undefined mechanisms. Here we demonstrate that P-Rex1 and P-Rex2 establish, through their tandem DEP domains, interactions with mTOR, suggesting their potential as effectors in the signaling of mTOR to Rac activation and cell migration. This possibility was consistent with the effect of dominant-negative constructs and short hairpin RNA-mediated knockdown of P-Rex1, which decreased mTOR-dependent leucine-induced activation of Rac and cell migration. Rapamycin, a widely used inhibitor of mTOR signaling, did not inhibit Rac activity and cell migration induced by leucine, indicating that P-Rex1, which we found associated to both mTOR complexes, is only active when in the mTORC2 complex. mTORC2 has been described as the catalytic complex that phosphorylates AKT/PKB at Ser-473 and elicits activation of Rho GTPases and cytoskeletal reorganization. Thus, P-Rex1 links mTOR signaling to Rac activation and cell migration. C1 Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Dept Pharmacol, Mexico City 07000, DF, Mexico. Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Dept Cell Biol, Mexico City 07000, DF, Mexico. Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Dept Biochem, Mexico City 07000, DF, Mexico. NIDCR, Oral & Pharyngeal Canc Branch, Natl Inst Hlth, Bethesda, MD 20892 USA. RP Vazquez-Prado, J (reprint author), Inst Politecn Nacl, Ctr Invest & Estudios Avanzados, Dept Pharmacol, Apartado Postal 14-740, Mexico City 07000, DF, Mexico. EM jvazquez@cinvestav.mx RI Gutkind, J. Silvio/A-1053-2009; VAZQUEZ-PRADO, JOSE/C-1630-2017; OI Hernandez Negrete, Ivette/0000-0003-1097-0038 FU FIC NIH HHS [R01TW006664] NR 32 TC 87 Z9 90 U1 0 U2 14 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD AUG 10 PY 2007 VL 282 IS 32 BP 23708 EP 23715 DI 10.1074/jbc.M703771200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 197ST UT WOS:000248577500074 PM 17565979 ER PT J AU Dy, GK Krook, JE Green, EM Sargent, DJ Delaunoit, T Morton, RF Fuchs, CS Ramanathan, RK Williamson, SK Findlay, BP Pockaj, BA Sticca, RP Alberts, SR Pitot, HC Goldberg, RM AF Dy, Grace K. Krook, James E. Green, Erin M. Sargent, Daniel J. Delaunoit, Thierry Morton, Roscoe F. Fuchs, Charles S. Ramanathan, Ramesh K. Williamson, Stephen K. Findlay, Brian P. Pockaj, Barbara A. Sticca, Robert P. Alberts, Steven R. Pitot, Henry C. Goldberg, Richard M. TI Impact of complete response to chemotherapy on overall survival in advanced colorectal cancer: Results from intergroup N9741 SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID LIVER METASTASES; RANDOMIZED-TRIAL; PREOPERATIVE CHEMOTHERAPY; FLUOROURACIL FAILURE; CONTINUOUS-INFUSION; 1ST-LINE TREATMENT; PLUS IRINOTECAN; PHASE-III; OXALIPLATIN; LEUCOVORIN AB Purpose To evaluate clinical characteristics and survival outcomes among patients with locally advanced or metastatic colorectal cancer who achieve a complete response (CR) to systemic treatment either alone or with multimodality approach. Patients and Methods Data were collected retrospectively from CRC patients enrolled onto the phase III trial N9741, a National Cancer Institute-funded and Gastrointestinal Cancer Intergroup-sponsored study coordinated by the North Central Cancer Treatment Group. Patients were randomly assigned to combinations of oxaliplatin, fluorouracil (FU)/ leucovorin (LV) and irinotecan. The three treatment arms consist of IFL (irinotecan + FU/ LV), FOLFOX4 (oxaliplatin + FU/ LV), and IROX (irinotecan + oxaliplatin). Median follow-up was 42.6 months. Results Sixty-two (4%) of 1,508 patients had a CR to chemotherapy alone, and an additional 32 (2%) had a CR after multimodality treatment. Factors associated with achieving CR with systemic chemotherapy alone included FOLFOX4 treatment, patients with assessable disease, or a single site of metastasis. Continuing protocol treatment beyond two cycles after documentation of CR was not associated with improved survival. The rate of curative intent resection was significantly higher for patients treated with oxaliplatin- containing regimens (P =.02). Median survival was similar between patients with CR after chemotherapy alone (44.3 months) or after multimodality approach (47.4 months; P =.81). Conclusion FOLFOX4 was more likely to produce a CR than were IFL or IROX. Oxaliplatin regimens were more likely to result in successful surgical resections. Patients who have CR to systemic chemotherapy alone can achieve impressive survival outcomes similar to those seen among patients who attained a CR status after multimodality treatment. C1 Mayo Clin, Rochester, MN 55905 USA. Mayo Fdn, Rochester, MN USA. Duluth CCOOP, Duluth, MN USA. Jolimont Hosp, La Louviere, Belgium. Iowa Oncol Res Assoc CCOP, Moines, IA USA. Dana Farber Canc Ctr Inst, Boston, MA USA. Univ Pittsburgh, Ctr Med, Pittsburgh, PA USA. Univ Pittsburgh, Ctr Canc, Pittsburgh, PA USA. Univ Kansas, Med Ctr, Kansas City, KS 66103 USA. NCI, St Catharines, ON, Canada. Univ N Dakota, Sch Med & Hlth Sci, Grand Forks, ND 58201 USA. Univ N Carolina, Chapel Hill, NC USA. RP Dy, GK (reprint author), Mayo Clin, 200 1st St SW, Rochester, MN 55905 USA. EM dy.grace@mayo.edu RI Goldberg , Richard/M-1311-2013; OI Sargent, Daniel/0000-0002-2684-4741 FU NCI NIH HHS [CA-21115, CA-25224, CA-32102, CA-35101, CA-35195, CA-37404, CA-38926] NR 25 TC 39 Z9 41 U1 0 U2 0 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 AUG 10 PY 2007 VL 25 IS 23 BP 3469 EP 3474 DI 10.1200/JCO.2007.10.7128 PG 6 WC Oncology SC Oncology GA 200DO UT WOS:000248744300015 PM 17687151 ER PT J AU Hammond, C Abrams, JR Syrjala, KL AF Hammond, Camille Abrams, Janet R. Syrjala, Karen L. TI Fertility and risk factors for elevated infertility concern in 10-year hematopoietic cell transplant survivors and case-matched controls SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article; Proceedings Paper CT 62nd Annual Meeting of the American-Society-for-Reproductive-Medicine CY OCT 21-25, 2006 CL New Orleans, LA SP Amer Soc Reprod Med ID BONE-MARROW-TRANSPLANTATION; CANCER; PREGNANCY AB Purpose To describe fertility status and the prevalence of and risk factors for elevated infertility concern in 10-year adult cancer survivors who underwent myeloablative stem cell transplant (SCT). Patients and Methods Perceived fertility status, conception efforts, and infertility concern were reported before transplant and after 10 years by 120 cancer survivors who received myeloablative SCT and their case- matched controls. Results Respondents (including cases and controls) were predominantly white and married. Sex, age, race, ethnicity and education level were case matched. Four survivors (all males) conceived after completing cancer treatment, one with unassisted conception. Twenty- wo percent of survivors compared with 9% of controls reported that they had looked into family-building options because of infertility (P =.009). Fourteen survivors (12%) compared with eight controls ( 7%) indicated that they had tried unsuccessfully to have children in the previous 10 years (P = not significant). One quarter of survivors had moderate to high levels of concern about infertility, compared with 7% of controls. A majority of survivors younger than age 40 years (n = 20; 54%) expressed elevated infertility concern. Survivors without children before transplant had greater risk of elevated concern after 10 years (odds ratio, 3.41; 95% Cl, 1.93 to 11.30; P =.05). Although female controls were more likely to express elevated infertility concern (P =.007), sex did not discriminate concern among survivors. Conclusion The prevalence of infertility and related concerns is higher among long- term SCT survivors than among age-, sex-, and education-matched controls. Younger SCT recipients and those without children have persistent fertility-related needs even 10 years after treatment. C1 Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. Natl Canc Inst, Off Canc Survivorship, Bethesda, MD USA. Univ Washington, Sch Med, Seattle, WA USA. RP Syrjala, KL (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1100 Fairview Ave N,D5-220, Seattle, WA 98109 USA. EM ksyrjala@fhcrc.org FU NCI NIH HHS [CA63030, CA112631, CA78990, R01 CA078990, R01 CA112631] NR 25 TC 41 Z9 41 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD AUG 10 PY 2007 VL 25 IS 23 BP 3511 EP 3517 DI 10.1200/JCO.2007.10.8993 PG 7 WC Oncology SC Oncology GA 200DO UT WOS:000248744300021 PM 17646668 ER PT J AU Marks, WB Burke, RE AF Marks, William B. Burke, Robert E. TI Simulation of motoneuron morphology in three dimensions. I. Building individual dendritic trees SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE spinal cord; dendrite architecture; data analysis; computational models ID IDENTIFIED ALPHA-MOTONEURONS; CAT SPINAL-CORD; COMPUTER-SIMULATION; MORPHOMETRIC ANALYSIS; BRANCHING PATTERN; GROWTH; MODEL; NEURONS; ARCHITECTURE; GENERATION AB We have developed a computational method that accurately reproduces the three-dimensional (3D) morphology of individual dendritic trees of six cat alpha motoneurons. The first step was simulation of trees with straight branches based on the branch lengths and topology of actual trees. A second step introduced the meandering, or wandering, trajectories observed in natural dendritic branches into the straight-branch tree simulations. These two steps each required only two parameters, one extracted from the data on actual motoneuron dendrites and the other adjusted by comparing simulated and observed trees, using measurements that were independent of the model specifications (i.e., emergent properties). The results suggest that: 1) there is a somatofugal "tropism" (a bias introduced by the environment that affects the trajectory of dendritic branches) that tends to constrain the lateral expansion of alpha motoneuron dendrites; and 2) that most of the meandering of natural dendritic branches can be described by assuming that they are fractal objects with an average fractal dimension D of about 1.05. When analyzed in the same way, the dendrites of gamma motoneurons showed no evidence of a similar tropism, although they had the same fractal dimension of branch meandering. (c) 2007 Wiley-Liss, Inc. C1 NINDS, Lab Neural Control, NIH, Bethesda, MD 20892 USA. RP Burke, RE (reprint author), POB 1722, El Prado, NM 87529 USA. EM reburke@taosnet.com FU Intramural NIH HHS NR 59 TC 8 Z9 8 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9967 J9 J COMP NEUROL JI J. Comp. Neurol. PD AUG 10 PY 2007 VL 503 IS 5 BP 685 EP 700 DI 10.1002/cne.21418 PG 16 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 188UE UT WOS:000247944000008 PM 17559104 ER PT J AU Marks, WB Burke, RE AF Marks, William B. Burke, Robert E. TI Simulation of motoneuron morphology in three dimensions. II. Building complete neurons SO JOURNAL OF COMPARATIVE NEUROLOGY LA English DT Article DE spinal cord; neuronal architecture; data analysis; computational models ID ALPHA-MOTONEURONS; DENDRITIC TREES; HIPPOCAMPAL-NEURONS; CULTURE; ARBORS; CELLS; AXONS AB By using dendrogram data from six adult cat alpha motoneurons, we have constructed computer simulations of these cells in three dimensions (3D) by "growing" their dendritic trees from stem branches that were oriented as in the original cells. Individual trees were simulated by using the algorithms and parameters discussed in the companion paper (Marks and Burke [2007] J. Comp. Neurol. 503:685-700). It was not possible to distinguish real from simulated motoneurons by visual inspection of 3D drawings. Simulated cells were compared quantitatively with their actual exemplars by using features that were measured in spherical shells at various radii centered on the soma. These included nearest neighbor distances (NNDs) between branches, the sizes and overlaps between the territories of individual dendrites measured as convex hulls (polygons that enclose all branches passing through a shell), and the sizes of circular zones that contained no branches. We also compared the 3D fractal dimensions and lacunarity (a measure of the 3D dispersion of branches) in actual cells and their simulations. The statistical properties of these quantitative measures were not significantly different, suggesting that the simulation algorithm was quite successful. However, there were three exceptions: 1) there were more NNIDs at distances < 50 mu in simulated than in actual motoneurons; 2) average overlaps between the territories of different dendrites were almost twice as large in simulated compared with actual motoneurons; and 3) estimates of lacunarity were also larger in simulated cells. These exceptions suggest that dendritic branches in actual motoneurons tend to avoid one another. We discuss possible interpretations of these results. (c) 2007 Wiley-Liss, Inc. C1 NINDS, Lab Neural Control, NIH, Bethesda, MD 20892 USA. RP Burke, RE (reprint author), POB 1722, El Prado, NM 87529 USA. EM reburke@taosnet.com FU Intramural NIH HHS NR 37 TC 3 Z9 3 U1 0 U2 2 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0021-9967 EI 1096-9861 J9 J COMP NEUROL JI J. Comp. Neurol. PD AUG 10 PY 2007 VL 503 IS 5 BP 701 EP 716 DI 10.1002/cne.21417 PG 16 WC Neurosciences; Zoology SC Neurosciences & Neurology; Zoology GA 188UE UT WOS:000247944000009 PM 17559105 ER PT J AU Wang, X Baumann, MH Dersch, CM Rothman, RB AF Wang, X. Baumann, M. H. Dersch, C. M. Rothman, R. B. TI Restoration of 3,4-methylenedioxymethamphetamine-induced 5-HT depletion by the administration of L-5-hydroxytryptophan SO NEUROSCIENCE LA English DT Article DE amphetamine; ecstasy; 5-HT transporter; RTI-55; binding ID SEROTONIN TRANSPORTER FUNCTION; RAT-BRAIN; TRYPTOPHAN-HYDROXYLASE; PARTIAL RECOVERY; 52-WEEK PERIOD; MESSENGER-RNA; MDMA; METHYLENEDIOXYMETHAMPHETAMINE; BINDING; NEUROTOXICITY AB Background: 3,4-Methylenedioxymethamphetamine (MDMA) causes persistent decreases in brain 5-HT content and 5-HT transporter (SERT) binding, with no detectable changes in SERT protein. Such data suggest that MDMA impairs 5-HT transmission but leaves 5-HT nerve terminals intact. To further test this hypothesis, we carried out two types of experiments in rats exposed to high-dose MDMA. First, we examined the effects of MDMA on SERT binding and function using different in vitro assay conditions. Next, we treated rats with the 5-HT precursor, L-5-hydroxytryptophan (5-HTP), in an attempt to restore MDMA-induced depletions of 5-HT. Methods: Rats received three i.p. injections of saline or MDMA (7.5 mg/kg), one injection every 2 h. Rats in one group were decapitated, and brain tissue was assayed for SERT binding and [H-3]5-HT uptake under conditions of normal (100 or 126 mM) and low (20 mM) NaCl concentration. Rats from another group received saline or 5-hydroxytryptophan/ benserazide (5-HTP-B), each drug at 50 mg/kg i.p., and were killed 2 h later. Results: MDMA reduced SERT binding to 10% of control when assayed in 100 mM NaCl, but this reduction was only 55% of control in 20 mM NaCl. MDMA decreased immunoreactive 5-HT in caudate and hippocampus to about 35% of control. Administration of 5-HTP-B to MDMA-pretreated rats significantly increased the 5-HT signal toward normal levels in caudate (85% of control) and hippocampus (66% of control). Conclusion: 1) Following high-dose MDMA treatment sufficient to reduce SERT binding by 90%, a significant number of functionally intact 5-HT nerve terminals survive. 2) The degree of MDMA-induced decreases in SERT binding depends on the in vitro assay conditions. 3) 5-HTP-B restores brain 5-HT depleted by MDMA, suggesting that this approach might be clinically useful in abstinent MDMA users. (c) 2007 Published by Elsevier Ltd on behalf of IBRO. C1 NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Rothman, RB (reprint author), NIDA, Clin Psychopharmacol Sect, Intramural Res Program, NIH, POB 5180,5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM rrothman@mail.nih.gov FU Intramural NIH HHS NR 36 TC 12 Z9 12 U1 1 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 AUG 10 PY 2007 VL 148 IS 1 BP 212 EP 220 DI 10.1016/j.neuroscience.2007.05.024 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 206BC UT WOS:000249157900019 PM 17629409 ER PT J AU Insel, TR AF Insel, Thomas R. TI Shining light on depression SO SCIENCE LA English DT Editorial Material ID PREFRONTAL CORTEX; MAJOR DEPRESSION; HIPPOCAMPAL; DISORDERS C1 NIMH, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIMH, Room 8235,6001 Execut Blvd, Bethesda, MD 20892 USA. EM tinsel@mail.nih.gov FU Intramural NIH HHS [Z99 MH999999] NR 15 TC 14 Z9 14 U1 0 U2 7 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 AUG 10 PY 2007 VL 317 IS 5839 BP 757 EP 758 DI 10.1126/science.1147565 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 198JN UT WOS:000248624500023 PM 17690279 ER PT J AU Liu, HJ Fergusson, MM Castilho, RM Liu, J Cao, L Chen, JH Malide, D Rovira, II Schimel, D Kuo, CJ Gutkind, JS Hwang, PM Finkel, T AF Liu, Hongjun Fergusson, Maria M. Castilho, Rogerio M. Liu, Jie Cao, Liu Chen, Jichun Malide, Daniela Rovira, Ilsa I. Schimel, Daniel Kuo, Calvin J. Gutkind, J. Silvio Hwang, Paul M. Finkel, Toren TI Augmented Wnt signaling in a mammalian model of accelerated aging SO SCIENCE LA English DT Article ID HEMATOPOIETIC STEM-CELL; KLOTHO; SKIN; MICE; DIFFERENTIATION; ACTIVATION; REPAIR; LEADS AB The contribution of stem and progenitor cell dysfunction and depletion in normal aging remains incompletely understood. We explored this concept in the Klotho mouse model of accelerated aging. Analysis of various tissues and organs from young Klotho mice revealed a decrease in stem cell number and an increase in progenitor cell senescence. Because klotho is a secreted protein, we postulated that klotho might interact with other soluble mediators of stem cells. We found that klotho bound to various Wnt family members. In a cell culture model, the Wnt-klotho interaction resulted in the suppression of Wnt biological activity. Tissues and organs from klotho-deficient animals showed evidence of increased Wnt signaling, and ectopic expression of klotho antagonized the activity of endogenous and exogenous Wnt. Both in vitro and in vivo, continuous Wnt exposure triggered accelerated cellular senescence. Thus, klotho appears to be a secreted Wnt antagonist and Wnt proteins have an unexpected role in mammalian aging. C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Oral Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Light Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. NIH, Mouse Imaging Facil, Bethesda, MD 20892 USA. Stanford Univ, Sch Med, Div Hematol, Stanford, CA 94305 USA. RP Finkel, T (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM finkelt@nih.gov RI Gutkind, J. Silvio/A-1053-2009; Castilho, Rogerio/E-4987-2010 FU Intramural NIH HHS; NIDDK NIH HHS [1 R01 DK069989-01] NR 22 TC 333 Z9 350 U1 1 U2 25 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 AUG 10 PY 2007 VL 317 IS 5839 BP 803 EP 806 DI 10.1126/science.1143578 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 198JN UT WOS:000248624500040 PM 17690294 ER PT J AU Yang, ZY Wei, CJ Kong, WP Wu, L Xu, L Smith, DF Nabel, GJ AF Yang, Zhi-Yong Wei, Chih-Jen Kong, Wing-Pui Wu, Lan Xu, Ling Smith, David F. Nabel, Gary J. TI Immunization by avian H5 influenza hemagglutinin mutants with altered receptor binding specificity SO SCIENCE LA English DT Article ID VIRUS HEMAGGLUTININ; NEUTRALIZING ANTIBODY; PANDEMIC INFLUENZA; ESCAPE MUTANTS; A VIRUSES; GLYCOPROTEIN; CORONAVIRUS; SITES; ENTRY AB Influenza virus entry is mediated by the receptor binding domain (RBD) of its spike, the hemagglutinin (HA). Adaptation of avian viruses to humans is associated with HA specificity for alpha 2,6- rather than alpha 2,3-linked sialic acid (SA) receptors. Here, we define mutations in influenza A subtype H5N1 (avian) HA that alter its specificity for SA either by decreasing alpha 2,3- or increasing alpha 2,6- SA recognition. RBD mutants were used to develop vaccines and monoclonal antibodies that neutralized new variants. Structure-based modification of HA specificity can guide the development of preemptive vaccines and therapeutic monoclonal antibodies that can be evaluated before the emergence of human-adapted H5N1 strains. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Emory Univ, Sch Med, Atlanta, GA 30322 USA. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, Bldg 40,Room 4502,Mailstop Code MSC-3005,40 Conve, Bethesda, MD 20892 USA. EM gnabel@nih.gov FU Intramural NIH HHS [Z99 AI999999] NR 24 TC 114 Z9 119 U1 1 U2 8 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 AUG 10 PY 2007 VL 317 IS 5839 BP 825 EP 828 DI 10.1126/science.1135165 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 198JN UT WOS:000248624500047 PM 17690300 ER PT J AU Zotenko, E Dogan, RI Wilbur, WJ O'Leary, DP Przytycka, TM AF Zotenko, Elena Dogan, Rezarta Islamaj Wilbur, W. John O'Leary, Dianne P. Przytycka, Teresa M. TI Structural footprinting in protein structure comparison: the impact of structural fragments SO BMC STRUCTURAL BIOLOGY LA English DT Article ID SECONDARY STRUCTURE; CLASSIFICATION; CATH; SUPERFAMILIES; RECOGNITION; DICTIONARY; SIMILARITY; ALIGNMENT; DATABASE; SPACE AB Background: One approach for speeding-up protein structure comparison is the projection approach, where a protein structure is mapped to a high-dimensional vector and structural similarity is approximated by distance between the corresponding vectors. Structural footprinting methods are projection methods that employ the same general technique to produce the mapping: first select a representative set of structural fragments as models and then map a protein structure to a vector in which each dimension corresponds to a particular model and "counts" the number of times the model appears in the structure. The main difference between any two structural footprinting methods is in the set of models they use; in fact a large number of methods can be generated by varying the type of structural fragments used and the amount of detail in their representation. How do these choices affect the ability of the method to detect various types of structural similarity? Results: To answer this question we benchmarked three structural footprinting methods that vary significantly in their selection of models against the CATH database. In the first set of experiments we compared the methods' ability to detect structural similarity characteristic of evolutionarily related structures, i.e., structures within the same CATH superfamily. In the second set of experiments we tested the methods' agreement with the boundaries imposed by classification groups at the Class, Architecture, and Fold levels of the CATH hierarchy. Conclusion: In both experiments we found that the method which uses secondary structure information has the best performance on average, but no one method performs consistently the best across all groups at a given classification level. We also found that combining the methods' outputs significantly improves the performance. Moreover, our new techniques to measure and visualize the methods' agreement with the CATH hierarchy, including the threshholded affinity graph, are useful beyond this work. In particular, they can be used to expose a similar composition of different classification groups in terms of structural fragments used by the method and thus provide an alternative demonstration of the continuous nature of the protein structure universe. C1 NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Univ Maryland, Dept Comp Sci, College Pk, MD 20742 USA. Univ Maryland, Inst Adv Comp Studies, College Pk, MD 20742 USA. RP Przytycka, TM (reprint author), NIH, Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM zotenko@mail.nih.gov; islamaj@mail.nih.gov; wilbur@mail.nih.gov; oleary@cs.umd.edu; przytyck@mail.nih.gov OI Zotenko, Elena/0000-0002-0256-3195; Islamaj Dogan, Rezarta/0000-0001-5651-1860 FU Intramural NIH HHS NR 26 TC 8 Z9 8 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2237 J9 BMC STRUCT BIOL JI BMC Struct. Biol. PD AUG 9 PY 2007 VL 7 AR 53 DI 10.1186/1472-6807-7-53 PG 14 WC Biophysics SC Biophysics GA 234BV UT WOS:000251136600001 PM 17688700 ER PT J AU Hiebel, AC Lee, YS Bilsky, E Giuvelis, D Deschamps, JR Parrish, DA Aceto, MD May, EL Harris, LS Coop, A Dersch, CM Partilla, JS Rothman, RB Cheng, KJ Jacobson, AE Rice, KC AF Hiebel, Anne-Cecile Lee, Yong Sok Bilsky, Edward Giuvelis, Denise Deschamps, Jeffrey R. Parrish, Darnon A. Aceto, Mario D. May, Everette L. Harris, Louis S. Coop, Andrew Dersch, Christina M. Partilla, John S. Rothman, Richard B. Cheng, Kejun Jacobson, Arthur E. Rice, Kenner C. TI Probes for narcotic receptor mediated phenomena. 34. Synthesis and structure-activity relationships of a potent mu-agonist delta-antagonist and an exceedingly potent Antinociceptive in the enantiomeric C9-substituted 5-(3-hydroxyphenyl)-N-phenylethylmorphan series SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID OPIOID PEPTIDE RECEPTOR; PROTON-TRANSFER; SCHIFF-BASE; BACTERIORHODOPSIN; MORPHINE; LIGANDS; ANALOGS; PROTEIN AB Both of the enantiomers of 5-(3-hydroxyphenyl)-N-phenylethylmorphan with C9 alpha-methyl, C9-methylene, C9-keto, and C9 alpha- and C9 beta-hydroxy substituents were synthesized and pharmacologically evaluated. Three of the 10 compounds, (1R,5R,9S)-(-)-9-hydroxy-5-(3-hydroxyphenyl-2-phenylethyl-2-azabicyclo[3.3.1]nonane ((1R,5R,9S)-(-)-10), (1R,5S)-(+)-5-(3-hydroxyphenyl)-9-methylene-2-phenethyl-2-azabicyclo[3.3. I]nonane ((IR,5S)-(+)-14), and (IR,5S,9R)-(-)-5-(3-hydroxyphenyl)-9-methyl-2-phenethyl-2-azabicyclo-[3.3. I]nonane ((lR,5S,9R)-(+)-15) had subnanomolar affinity at mu-opioid receptors (K(i) = 0.19, 0.19, and 0.63 nM, respectively). The (1R,5S)-(+)-14 was found to be a mu-opioid agonist and a mu-, delta-, and kappa-antagonist in [35S]GTP-gamma-S assays and was approximately 50 times more potent than morphine in a number of acute and subchronic pain assays, including thermal and visceral models of nociception. The (I R,5R,9S)-(-)-10 compound with a C9-hydroxy substituent axially oriented to the piperidine ring (C9 beta-hydroxy) was a mu-agonist about 500 times more potent than morphine. In the single-dose suppression assay, it was greater than 1000 times more potent than morphine. It is the most potent known phenylmorphan antinociceptive. The molecular structures of these compounds were energy minimized with density functional theory at the B3LYP/6-31G* level and then overlaid onto (IR,5R,9S)-(-)-10 using the heavy atoms in the morphan moiety as a common docking point. Based on modeling, the spatial arrangement of the protonated nitrogen atom and the 9 beta-OH substituent in (lR,5R,9S)-(-)-10 may facilitate the alignment of a putative water chain enabling proton transfer to a nearby proton acceptor group in the,mu-opioid receptor. C1 Natl Inst Drug Abuse, Chem Biol Res Branch, Drug Design & Synth Sect, Bethesda, MD 20892 USA. NIH, Ctr Mol Modeling, Div Computat Biosci, Ctr Informat Technol,DHHS, Bethesda, MD 20892 USA. Univ New England, Coll Osteopath Med, Biddeford, ME 04005 USA. USN, Res Lab, Struct Matter Lab, Washington, DC 20375 USA. Virginia Commonwealth Univ, Sch Med, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. Univ Maryland, Sch Pharm, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. Natl Inst Drug Abuse, Clin Psychopharmacol Sect, Addict Res Ctr, NIH,DHHS, Baltimore, MD 21224 USA. RP Rice, KC (reprint author), Natl Inst Drug Abuse, Drug Design & Synth Sect, Chem Biol Res Branch, NIH,DHHS, Bethesda, MD 20892 USA. EM kr21f@nih.gov FU Intramural NIH HHS; NIDA NIH HHS [K02 DA 19634, K02 DA019634, K02 DA019634-01] NR 39 TC 22 Z9 23 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 AUG 9 PY 2007 VL 50 IS 16 BP 3765 EP 3776 DI 10.1021/jm061325e PG 12 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 196JK UT WOS:000248477300002 PM 17625813 ER PT J AU Davis, CH Deerfield, D Stafford, DW Pedersen, LG AF Davis, Charles H. Deerfield, David, II Stafford, Darrel W. Pedersen, Lee G. TI Quantum chemical study of the mechanism of action of vitamin K carboxylase (VKC). IV. Intermediates and transition states SO JOURNAL OF PHYSICAL CHEMISTRY A LA English DT Article ID GAMMA-GLUTAMYL CARBOXYLASE; EPOXIDE REDUCTASE; CARBOXYGLUTAMIC ACID; IDENTIFICATION; CRYSTALLIZATION; PROTHROMBIN; DISEASE; BASE AB We studied proposed steps for the enzymatic formation of gamma-carboxyglutamic acid by density functional theory (DFT) quantum chemistry. Our results for one potentially feasible mechanism show that a vitamin K alkoxide intermediate can abstract a proton from glutamic acid at the gamma-carbon to form a carbanion and vitamin K epoxide. The hydrated carbanion can then react with CO2 to form gamma-carboxyglutamic acid. Computations at the B3LYP/6-311G** level were used to determine the intermediates and transition states for the overall process. The activation free energy for the gas-phase path is 22 kcal/mol, with the rate-limiting step for the reaction being the attack of the carbanion on CO2. Additional solvation studies, however, indicate that the formation of the carbanion step can be competitive with the CO2 attack step in high-dielectric systems. We relate these computations to the entire vitamin K cycle in the blood coagulation cascade, which is essential for viability of vertebrates. C1 Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Chem, Chapel Hill, NC 27599 USA. Pittsburgh Supercomp Ctr, Biomed Grp, Pittsburgh, PA 15213 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27009 USA. RP Pedersen, LG (reprint author), Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. RI Pedersen, Lee/E-3405-2013 OI Pedersen, Lee/0000-0003-1262-9861 FU NCRR NIH HHS [RR06009]; NHLBI NIH HHS [HL-06350, HL-48318] NR 28 TC 11 Z9 12 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1089-5639 J9 J PHYS CHEM A JI J. Phys. Chem. A PD AUG 9 PY 2007 VL 111 IS 31 BP 7257 EP 7261 DI 10.1021/jp068564y PG 5 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 196JX UT WOS:000248478700002 PM 17503787 ER PT J AU Amarnath, S Dong, L Li, J Wu, YT Chen, WJ AF Amarnath, Shoba Dong, Li Li, Jun Wu, Yuntao Chen, WanJun TI Endogenous TGF-beta activation by reactive oxygen species is key to Foxp3 induction in TCR-stimulated and HIV-I-infected human CD4(+)CD25(-) T cells SO RETROVIROLOGY LA English DT Article ID TRANSFORMING-GROWTH-FACTOR; TRANSCRIPTION FACTOR FOXP3; REGULATORY CELLS; CUTTING EDGE; APOPTOSIS; EXPRESSION; CD4(+); AUTOIMMUNITY; ACQUISITION; TOLERANCE AB Background: CD4(+)CD25(+) T regulatory cells (Tregs) play an important role in regulating immune responses, and in influencing human immune diseases such as HIV infection. It has been shown that human CD4(+)CD25(+) Tregs can be induced in vitro by TCR stimulation of CD4(+)CD25(-) T cells. However, the mechanism remains elusive, and intriguingly, similar treatment of murine CD4(+)CD25(-) cells did not induce CD4(+)CD25(+)Foxp3(+) Tregs unless exogenous TGF-beta was added during stimulation. Thus, we investigated the possible role of TGF-beta in the induction of human Tregs by TCR engagement. We also explored the effects of TGF-beta on HIV-1 infection mediated induction of human Tregs since recent evidence has suggested that HIV-1 infection may also impact the generation of Tregs in infected patients. Results: We show here that endogenous TGF-beta is key to TCR induction of Foxp3 in human CD4(+)CD25(-) T cells. These events involve, first, the production of TGF-beta by TCR and CD28 stimulation and the activation of latent TGF-beta by reactive oxygen species generated from the activated T cells. Biologically active TGF-beta then engages in the induction of Foxp3. Neutralization of active TGF-beta with anti-TGF-beta antibody or elimination of ROS with MnTBAP abrogated Foxp3 expression. HIV-1 infection enhanced Foxp3 expression in activated CD4(+)CD25(-) T cells; which was also abrogated by blockade of endogenous TGF-beta. Conclusion: Several conclusions can be drawn from this work: (1) TCR and CD28-induced Foxp3 expression is a late event following TCR stimulation; (2) TGF-beta serves as a link in Foxp3 induction in human CD4(+)CD25(-) T cells following TCR stimulation, which induces not only latent, but also active TGF-beta; (3) the activation of TGF-beta requires reactive oxygen species; (4) HIV infection results in an increase in Foxp3 expression in TCR-activated CD25(-) T cells, which is also associated with TGF-beta. Taken together, our findings reinforce a definitive role of TGF-beta not only in the generation of Tregs with respect to normal immune responses, but also is critical in immune diseases such as HIV-1 infection. C1 NIH, NIDCR, Mucosal Immun Unit, OIIB, Bethesda, MD 20895 USA. George Mason Univ, Natl Ctr Biodef & Infect Dis, Dept Mol Microbiol, Manassas, VA USA. RP Chen, WJ (reprint author), NIH, NIDCR, Mucosal Immun Unit, OIIB, Bethesda, MD 20895 USA. EM samamath@mail.nih.gov; ldong@gmu.edu; lijun@nidcr.nih.gov; ywu8@gmu.edu; wchen@mail.nih.gov RI Li, Jun/N-6267-2015 FU Intramural NIH HHS NR 45 TC 43 Z9 43 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD AUG 9 PY 2007 VL 4 AR 57 DI 10.1186/1742-4690-4-57 PG 16 WC Virology SC Virology GA 238MJ UT WOS:000251451600001 PM 17688698 ER EF