FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Solinas, M Yasar, S Goldberg, SR AF Solinas, Marcello Yasar, Sevil Goldberg, Steven R. TI Endocannabinoid system involvement in brain reward processes related to drug abuse SO PHARMACOLOGICAL RESEARCH LA English DT Review DE cannabis; cannabinoid; anandamide; addiction; behavior; self-administration; place preference; brain; dopamine; opioids; reward ID CANNABINOID CB1 RECEPTOR; CONDITIONED PLACE PREFERENCE; ACID AMIDE HYDROLASE; NUCLEUS-ACCUMBENS SHELL; DOPAMINE D2 RECEPTORS; PREFERRING SP RATS; ETHANOL-SEEKING BEHAVIOR; KAPPA-OPIOID RECEPTORS; KNOCKOUT MICE; SQUIRREL-MONKEYS AB Cannabis is the most commonly abused illegal drug in the world and its main psychoactive ingredient, delta-9-tetrahydrocannabinol (THC), produces rewarding effects in humans and non-human primates. Over the last several decades, an endogenous system comprised of cannabinoid receptors, endogenous ligands for these receptors and enzymes responsible for the synthesis and degradation of these endogenous cannabinoid ligands has been discovered and partly characterized. Experimental findings strongly suggest a major involvement of the endocannabinoid system in general brain reward functions and drug abuse. First, natural and synthetic cannabinoids and endocannabinoi,ds can produce rewarding effects in humans and laboratory animals. Second, activation or blockade of the endogenous cannabinoid system has been shown to modulate the rewarding effects of non-cannabinoid psychoactive drugs. Third, most abused drugs alter brain levels of endocannabinoids in the brain. In addition to reward functions, the endocannabinoid cannabinoid system appears to be involved in the ability of drugs and drug-related cues to reinstate drug-seeking behavior in animal models of relapse. Altogether, evidence points to the endocarnnadinoid system as a promising target for the development of medications for the treatment of drug abuse. (c) 2007 Elsevier Ltd. All rights reserved. C1 Univ Poitiers, CNRS, UMR 6187, Inst Physiol & Biol Cellularies, F-86022 Poitiers, France. Johns Hopkins Univ, Sch Med, Div Geriatr Med & Gerontol, Baltimore, MD 21224 USA. Natl Inst Drug Abuse, Preclin Pharmacol Sect, Behav Neurosci Res Branch, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Solinas, M (reprint author), Univ Poitiers, CNRS, UMR 6187, Inst Physiol & Biol Cellularies, 40 Ave Recteur Pineau, F-86022 Poitiers, France. EM marcello.solinas@univ-poitiers.fr RI Solinas, Marcello/M-3500-2016 OI Solinas, Marcello/0000-0002-0664-5964 FU Intramural NIH HHS [Z01 DA000001-23, Z01 DA000003-22] NR 197 TC 47 Z9 50 U1 2 U2 10 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD NOV PY 2007 VL 56 IS 5 BP 393 EP 405 DI 10.1016/j.phrs.2007.09.005 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 239BL UT WOS:000251492700005 PM 17936009 ER PT J AU Tanda, G AF Tanda, Glanluigi TI Modulation of the endocannabinoid system: Therapeutic potential against cocaine dependence SO PHARMACOLOGICAL RESEARCH LA English DT Review DE cannabinoids; cocaine; addiction; behavior ID CONDITIONED PLACE PREFERENCE; CANNABINOID CB1 RECEPTOR; ACID AMIDE HYDROLASE; MESOLIMBIC DOPAMINE TRANSMISSION; BRAIN-STIMULATION REWARD; LONG-TERM POTENTIATION; AGONIST WIN 55,212-2; NUCLEUS-ACCUMBENS; BEHAVIORAL SENSITIZATION; DRUG-USE AB Dependence on cocaine is still a main unresolved medical and social concern, and in spite of research efforts, no pharmacological therapy against cocaine dependence is yet available. Recent studies have shown that the endocannabinoid system participates in specific stages and aspects of drug dependence in general, and some of this evidence suggests an involvement of the cannabinoid system in cocaine effects. For example, cocaine administration has been shown to alter brain endocannabinoid levels, and the endocannabinoid system has been involved in long-term modifications of brain processes that might play a role in neuro/behavioral effects of psychostimulant drugs like cocaine. Human studies show that marijuana dependence is frequently associated with cocaine dependence, and that the cannabinoid receptor CNR1 gene polymorphism might be related to cocaine addiction. This article will review the main papers in the field showing how a modulation of different components of the cannabinoid system might interact with some of the neurobiological/behavioral effects of cocaine related to its reinforcing effects, evaluated in preclinical models or in clinical settings. The goal of this review will be to provide insights into the complex picture of cocaine abuse and addiction, and to extrapolate from such endocannabinoid-cocaine interactions useful information to test the therapeutic potential of cannabinoid ligands and endocannabinoid-level enhancers against cocaine dependence for future preclinical/clinical trials. Published by Elsevier Ltd. C1 Natl Inst Drug Abuse, Psychobiol Sect, Medicat Discovery Res Branch, Natl Inst Hlth,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Tanda, G (reprint author), Natl Inst Drug Abuse, Psychobiol Sect, Medicat Discovery Res Branch, Natl Inst Hlth,Dept Hlth & Human Serv, Bldg C Room 321,5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM gtanda@intra.nida.nih.gov RI Tanda, Gianluigi/B-3318-2009 OI Tanda, Gianluigi/0000-0001-9526-9878 FU Intramural NIH HHS [Z99 DA999999] NR 170 TC 11 Z9 11 U1 4 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-6618 J9 PHARMACOL RES JI Pharmacol. Res. PD NOV PY 2007 VL 56 IS 5 BP 406 EP 417 DI 10.1016/j.phrs.2007.09.001 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 239BL UT WOS:000251492700006 PM 17945506 ER PT J AU Shippenberg, TS Zapata, A Chefer, VI AF Shippenberg, T. S. Zapata, A. Chefer, V. I. TI Dynorphin and the pathophysiology of drug addiction SO PHARMACOLOGY & THERAPEUTICS LA English DT Review DE dynorphin; kappa-opioid receptor; glutamate; dopamine; drug and alcohol addiction ID KAPPA-OPIOID-RECEPTOR; RAT NUCLEUS-ACCUMBENS; COCAINE-SEEKING BEHAVIOR; VENTRAL TEGMENTAL AREA; MEDIAL PREFRONTAL CORTEX; MESSENGER-RNA EXPRESSION; IN-SITU HYBRIDIZATION; INTRACRANIAL SELF-STIMULATION; CONDITIONED PLACE PREFERENCE; PRODYNORPHIN SYSTEM ACTIVITY AB Drug addiction is a chronic relapsing disease in which drug administration becomes the primary stimulus that drives behavior regardless of the adverse consequence that may ensue. As drug use becomes more compulsive, motivation for natural rewards that normally drive behavior decreases. The discontinuation of drug use is associated with somatic signs of withdrawal, dysphoria, anxiety, and anhedonia. These consequences of drug use are thought to contribute to the maintenance of drug use and to the reinstatement of compulsive drug use that occurs during the early phase of abstinence. Even, however, after prolonged periods of abstinence, 80-90% of human addicts relapse to addiction, suggesting that repeated drug use produces enduring changes in brain circuits that subserve incentive motivation and stimulus-response (habit) learning. A major goal of addiction research is the identification of the neural mechanisms by which drugs of abuse produce these effects. This article will review data showing that the dynorphin/kappa-opioid receptor (KOPr) system serves an essential function in opposing alterations in behavior and brain neurochemistry that occur as a consequence of repeated drug use and that aberrant activity of this system may not only contribute to the dysregulation of behavior that characterizes addiction but to individual differences in vulnerability to the pharmacological actions of cocaine and alcohol. We will provide evidence that the repeated administration of cocaine and alcohol up-regulates the dynorphin/KOPr system and that pharmacological treatments that target this system may prove effective in the treatment of drug addiction. Published by Elsevier Inc. C1 NIDA, Integrat Neurosci Sect, NIH, Intramural Res Program, Baltimore, MD 21224 USA. RP Shippenberg, TS (reprint author), NIDA, Integrat Neurosci Sect, NIH, Intramural Res Program, 333 Cassell Dr, Baltimore, MD 21224 USA. EM tshippen@intra.nida.nih.gov FU Intramural NIH HHS [Z01 DA000504-01] NR 220 TC 196 Z9 207 U1 3 U2 20 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 NOV PY 2007 VL 116 IS 2 BP 306 EP 321 DI 10.1016/j.pharmthera.2007.06.011 PG 16 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 227LT UT WOS:000250658900008 PM 17868902 ER PT J AU Shukla, NN Sen, A Prasad, R AF Shukla, Nitya Nath Sen, A. Prasad, R. TI Quantum well states in Fe/Nb(001) multilayers: First principles study SO PHYSICAL REVIEW B LA English DT Article ID NONMAGNETIC METALLIC LAYER; MAGNETIC MULTILAYERS; FERMI-SURFACE; ELECTRON-GAS; EXCHANGE; OSCILLATIONS; SUPERLATTICES; ENERGY; FILMS; FE AB We present a first-principles study to understand the phenomena of interlayer exchange coupling in Fe/Nb multilayers using the linearized-muffin-tin-orbitals method within the generalized gradient approximation. We find that the exchange coupling oscillates with both short and long periodicities, which have been examined in terms of the Ruderman-Kittel-Kasuya-Yosida (RKKY) model as well as the quantum well (QW) model. We have investigated the behavior of the exchange coupling by artificially varying moments of Fe atoms in ferromagnetic layers. For a small moment of Fe, the coupling shows bilinearity in the magnetic moments, implying its RKKY character. However, at higher moments close to that of bulk Fe, the saturation of long-period oscillations is in accordance with the QW model. Quantum well dispersions around the Fermi level demonstrate that the majority-spin bands contribute largely to the formation of quantum well states, which we analyze quantitatively by making use of the phase accumulation model. Our analysis indicates that the quantum well model gives a better description of the oscillatory behavior of the exchange coupling in Fe/Nb multilayers. C1 Indian Inst Technol, Dept Phys, Kanpur 208016, Uttar Pradesh, India. RP Shukla, NN (reprint author), NCI, Elect Res Adm, 6705 Rockledge Dr, Bethesda, MD 20892 USA. EM rprasad@iitk.ac.in NR 55 TC 1 Z9 1 U1 2 U2 3 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 1098-0121 J9 PHYS REV B JI Phys. Rev. B PD NOV PY 2007 VL 76 IS 17 AR 174417 DI 10.1103/PhysRevB.76.174417 PG 9 WC Physics, Condensed Matter SC Physics GA 236TP UT WOS:000251326600079 ER PT J AU Yee, NS Gong, W Huang, Y Lorent, K Dolan, AC Maraia, RJ Pack, M AF Yee, Nelson S. Gong, Weilong Huang, Ying Lorent, Kristin Dolan, Amy C. Maraia, Richard J. Pack, Michael TI Mutation of RNA pol III subunit rpc2/polr3b leads to deficiency of subunit Rpc11 and disrupts zebrafish digestive development SO PLOS BIOLOGY LA English DT Article ID POLYMERASE-III; TRANSCRIPTION TERMINATION; SACCHAROMYCES-CEREVISIAE; BILIARY DEVELOPMENT; CLEAVAGE ACTIVITY; STRUCTURAL BASIS; FISSION YEAST; GENE; REPRESSION; GROWTH AB The role of RNA polymerase III (Pol III) in developing vertebrates has not been examined. Here, we identify a causative mutation of the second largest Pol III subunit, polr3b, that disrupts digestive organ development in zebrafish slim jim (slj) mutants. The slj mutation is a splice-site substitution that causes deletion of a conserved tract of 41 amino acids in the Polr3b protein. Structural considerations predict that the slj Pol3rb deletion might impair its interaction with Polr3k, the ortholog of an essential yeast Pol III subunit, Rpc11, which promotes RNA cleavage and Pol III recycling. We engineered Schizosaccharomyces pombe to carry an Rpc2 deletion comparable to the slj mutation and found that the Pol III recovered from this rpc2-Delta yeast had markedly reduced levels of Rpc11p. Remarkably, overexpression of cDNA encoding the zebrafish rpc11 ortholog, polr3k, rescued the exocrine defects in slj mutants, indicating that the slj phenotype is due to deficiency of Rpc11. These data show that functional interactions between Pol III subunits have been conserved during eukaryotic evolution and support the utility of zebrafish as a model vertebrate for analysis of Pol III function. C1 [Yee, Nelson S.; Gong, Weilong; Lorent, Kristin; Dolan, Amy C.; Pack, Michael] Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. [Huang, Ying; Maraia, Richard J.] NICHHD, NIH, Bethesda, MD 20892 USA. [Pack, Michael] Univ Penn, Sch Med, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. RP Pack, M (reprint author), Univ Penn, Sch Med, Dept Med, Philadelphia, PA 19104 USA. EM mpack@mail.med.upenn.edu FU Intramural NIH HHS; NIDDK NIH HHS [K08 DK060529, K08-DK60529, R01 DK054942, R01 DK061142, R01-DK54942, R01-DK61142] NR 50 TC 30 Z9 31 U1 0 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD NOV PY 2007 VL 5 IS 11 BP 2484 EP 2492 AR e312 DI 10.1371/journal.pbio.0050312 PG 9 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 244OH UT WOS:000251874700008 PM 18044988 ER PT J AU Li, S Sanna, S Maschio, A Busonero, F Usala, G Mulas, A Lai, S Dei, M Orru, M Albai, G Bandinelli, S Schlessinger, D Lakatta, E Scuteri, A Najjar, SS Guralnik, J Naitza, S Crisponi, L Cao, A Abecasis, G Ferrucci, L Uda, M Chen, WM Nagaraja, R AF Li, Siguang Sanna, Serena Maschio, Andrea Busonero, Fabio Usala, Gianluca Mulas, Antonella Lai, Sandra Dei, Mariano Orru, Marco Albai, Giuseppe Bandinelli, Stefania Schlessinger, David Lakatta, Edward Scuteri, Angelo Najjar, Samer S. Guralnik, Jack Naitza, Silvia Crisponi, Laura Cao, Antonio Abecasis, Goncalo Ferrucci, Luigi Uda, Manuela Chen, Wei-Min Nagaraja, Ramaiah TI The GLUT9 gene is associated with serum uric acid levels in Sardinia and chianti cohorts SO PLOS GENETICS LA English DT Article ID URATE-ANION EXCHANGER; ESSENTIAL-HYPERTENSION; RENAL-DISEASE; HUMAN GENOME; IDENTIFICATION; INCHIANTI; VARIANTS AB High serum uric acid levels elevate pro-inflammatory-state gout crystal arthropathy and place individuals at high risk for cardiovascular morbidity and mortality. Genome-wide scans in the genetically isolated Sardinian population identified variants associated with serum uric acid levels as a quantitative trait. They mapped within GLUT9, a Chromosome 4 glucose transporter gene predominantly expressed in liver and kidney. SNP rs6855911 showed the strongest association (p = 1.84 x 10(-16)), along with eight others (p = 7.75 x 10 (-16) to 6.05 x 10(-11)). Individuals homozygous for the rare allele of rs6855911 (minor allele frequency 0.26) had 0.6 mg/dl less uric acid than those homozygous for the common allele; the results were replicated in an unrelated cohort from Tuscany. Our results suggest that polymorphisms in GLUT9 could affect glucose metabolism and uric acid synthesis and/or renal reabsorption, influencing serum uric acid levels over a wide range of values. C1 NIA, Genet Lab, Baltimore, MD 21224 USA. CNR, Ist Neurogenet & Neurofarmacol, Cagliari, Italy. Azienda Sanitaria Firenze, Geriatr Rehabil Unit, Florence, Italy. NIA, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. Ist Nazl Ricovero & Cura Anziani, Unit Operat Geriatr, Rome, Italy. NIA, Lab Epidemiol Demog & Biomet, Bethesda, MD 20892 USA. Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. NIA, Clin Res Branch, Baltimore, MD 21224 USA. RP Nagaraja, R (reprint author), NIA, Genet Lab, Baltimore, MD 21224 USA. EM nagarajar@mail.nih.gov RI Chen, Wei-Min/A-8469-2009; Abecasis, Goncalo/B-7840-2010; Naitza, Silvia/D-5620-2017; OI Mulas, Antonella/0000-0002-6856-1483; sanna, serena/0000-0002-3768-1749; Abecasis, Goncalo/0000-0003-1509-1825 FU Intramural NIH HHS [Z99 AG999999]; NHGRI NIH HHS [HG02651, R01 HG002651]; NIA NIH HHS [N01-AG-1-2109, N01-AG-821336, N01-AG-916413]; NIMHD NIH HHS [263 MD 821336, 263 MD 9164 13, R01 MD009164]; PHS HHS [263-MA-410953] NR 26 TC 135 Z9 149 U1 2 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD NOV PY 2007 VL 3 IS 11 BP 2156 EP 2162 AR e194 DI 10.1371/journal.pgen.0030194 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 236NR UT WOS:000251310200010 PM 17997608 ER PT J AU Crawford, NPS Qian, X Ziogas, A Papageorge, AG Boersma, BJ Walker, RC Lukes, L Rowe, WL Zhang, J Ambs, S Lowy, DR Anton-Culver, H Hunter, KW AF Crawford, Nigel P. S. Qian, Xiaolan Ziogas, Argyrios Papageorge, Alex G. Boersma, Brenda J. Walker, Renard C. Lukes, Luanne Rowe, William L. Zhang, Jinghui Ambs, Stefan Lowy, Douglas R. Anton-Culver, Hoda Hunter, Kent W. TI Rrp1b, a new candidate susceptibility gene for breast cancer progression and metastasis SO PLOS GENETICS LA English DT Article ID GTPASE-ACTIVATING PROTEIN; TRANSGENIC MOUSE MODEL; COMPLEX TRAIT ANALYSIS; MAMMARY-TUMOR; EXPRESSION PROFILES; CELL-ADHESION; SIGNATURE; MULTIPLE; DISEASE; RAP1 AB A novel candidate metastasis modifier, ribosomal RNA processing 1 homolog B (Rrp1b), was identified through two independent approaches. First, yeast two-hybrid, immunoprecipitation, and functional assays demonstrated a physical and functional interaction between Rrp1b and the previous identified metastasis modifier Sipa1. In parallel, using mouse and human metastasis gene expression data it was observed that extracellular matrix (ECM) genes are common components of metastasis predictive signatures, suggesting that ECM genes are either important markers or causal factors in metastasis. To investigate the relationship between ECM genes and poor prognosis in breast cancer, expression quantitative trait locus analysis of polyoma middle-T transgene-induced mammary tumor was performed. ECM gene expression was found to be consistently associated with Rrp1b expression. In vitro expression of Rrp1b significantly altered ECM gene expression, tumor growth, and dissemination in metastasis assays. Furthermore, a gene signature induced by ectopic expression of Rrp1b in tumor cells predicted survival in a human breast cancer gene expression dataset. Finally, constitutional polymorphism within RRP1B was found to be significantly associated with tumor progression in two independent breast cancer cohorts. These data suggest that RRP1B may be a novel susceptibility gene for breast cancer progression and metastasis. C1 NIH, Lab Populat Genet, Bethesda, MD 20892 USA. NCI, NIH, Cellular Oncol Lab, Bethesda, MD 20892 USA. NCI, NIH, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. Univ Calif Irvine, Dept Med, Div Epidemiol, Irvine, CA 92717 USA. RP Hunter, KW (reprint author), NIH, Lab Populat Genet, Bldg 10, Bethesda, MD 20892 USA. EM hunterk@mail.nih.gov RI Boersma, Brenda/A-9270-2009 OI Boersma, Brenda/0000-0002-8992-2735 FU Intramural NIH HHS; NCI NIH HHS [CA58860, CA 58860-09, R01 CA058860, U01 CA058860] NR 42 TC 62 Z9 62 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD NOV PY 2007 VL 3 IS 11 BP 2296 EP 2311 AR e214 DI 10.1371/journal.pgen.0030214 PG 16 WC Genetics & Heredity SC Genetics & Heredity GA 236NR UT WOS:000251310200022 PM 18081427 ER PT J AU Zahn, JM Poosala, S Owen, AB Ingram, DK Lustig, A Carter, A Weeraratna, AT Taub, DD Gorospe, M Mazan-Mamczarz, K Lakatta, EG Boheler, KR Xu, X Mattson, MP Falco, G Ko, MSH Schlessinger, D Firman, J Kummerfeld, SK Ill, WHW Zonderman, AB Kim, SK Becker, KG AF Zahn, Jacob M. Poosala, Suresh Owen, Art B. Ingram, Donald K. Lustig, Ana Carter, Arnell Weeraratna, Ashani T. Taub, Dennis D. Gorospe, Myriam Mazan-Mamczarz, Krystyna Lakatta, Edward G. Boheler, Kenneth R. Xu, Xiangru Mattson, Mark P. Falco, Geppino Ko, Minoru S. H. Schlessinger, David Firman, Jeffrey Kummerfeld, Sarah K. Ill, William H. Wood Zonderman, Alan B. Kim, Stuart K. Becker, Kevin G. TI AGEMAP: A gene expression database for aging in mice SO PLOS GENETICS LA English DT Article ID CALORIC RESTRICTION; TRANSCRIPTIONAL PROFILE; HUMAN KIDNEY; BRAIN; MICROARRAY; P16(INK4A); SENESCENCE; BIOMARKERS; RESPONSES; PATTERNS AB We present the AGEMAP (Atlas of Gene Expression in Mouse Aging Project) gene expression database, which is a resource that catalogs changes in gene expression as a function of age in mice. The AGEMAP database includes expression changes for 8,932 genes in 16 tissues as a function of age. We found great heterogeneity in the amount of transcriptional changes with age in different tissues. Some tissues displayed large transcriptional differences in old mice, suggesting that these tissues may contribute strongly to organismal decline. Other tissues showed few or no changes in expression with age, indicating strong levels of homeostasis throughout life. Based on the pattern of age-related transcriptional changes, we found that tissues could be classified into one of three aging processes: (1) a pattern common to neural tissues, (2) a pattern for vascular tissues, and (3) a pattern for steroid-responsive tissues. We observed that different tissues age in a coordinated fashion in individual mice, such that certain mice exhibit rapid aging, whereas others exhibit slow aging for multiple tissues. Finally, we compared the transcriptional profiles for aging in mice to those from humans, flies, and worms. We found that genes involved in the electron transport chain show common age regulation in all four species, indicating that these genes may be exceptionally good markers of aging. However, we saw no overall correlation of age regulation between mice and humans, suggesting that aging processes in mice and humans may be fundamentally different. C1 Stanford Univ, Dept Dev Biol, Med Ctr, Stanford, CA 94305 USA. NIA, NIH, Baltimore, MD 21224 USA. Stanford Univ, Dept Stat, Stanford, CA 94305 USA. Stanford Univ, Med Ctr, Dept Genet, Stanford, CA 94305 USA. RP Kim, SK (reprint author), Stanford Univ, Dept Dev Biol, Med Ctr, Stanford, CA 94305 USA. EM kim@cmgm.stanford.edu; beckerk@mail.nih.gov RI Mattson, Mark/F-6038-2012; Ko, Minoru/B-7969-2009; OI Ko, Minoru/0000-0002-3530-3015; Becker, Kevin/0000-0002-6794-6656; Zonderman, Alan B/0000-0002-6523-4778 FU Intramural NIH HHS; NIA NIH HHS [R01 AG025941] NR 37 TC 162 Z9 167 U1 1 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-7390 J9 PLOS GENET JI PLoS Genet. PD NOV PY 2007 VL 3 IS 11 BP 2326 EP 2337 AR e201 DI 10.1371/journal.pgen.0030201 PG 12 WC Genetics & Heredity SC Genetics & Heredity GA 236NR UT WOS:000251310200024 PM 18081424 ER PT J AU Henderson, GE Churchill, LR Davis, AM Easter, MM Grady, C Joffe, S Kass, N King, NMP Lidz, CW Miller, FG Nelson, DK Peppercorn, J Rothschild, BB Sankar, P Wilfond, BS Zimmer, CR AF Henderson, Gail E. Churchill, Larry R. Davis, Arlene M. Easter, Michele M. Grady, Christine Joffe, Steven Kass, Nancy King, Nancy M. P. Lidz, Charles W. Miller, Franklin G. Nelson, Daniel K. Peppercorn, Jeffrey Rothschild, Barbra Bluestone Sankar, Pamela Wilfond, Benjamin S. Zimmer, Catherine R. TI Clinical trials and medical care: Defining the therapeutic misconception SO PLOS MEDICINE LA English DT Editorial Material ID GENE-TRANSFER TRIALS; INFORMED-CONSENT; BENEFIT; LANGUAGE; QUALITY; ETHICS; IMPACT; VIEWS C1 [Henderson, Gail E.; Davis, Arlene M.; Easter, Michele M.; Nelson, Daniel K.; Peppercorn, Jeffrey; Rothschild, Barbra Bluestone; Zimmer, Catherine R.] Univ N Carolina, Chapel Hill, NC USA. [Churchill, Larry R.] Vanderbilt Univ, Nashville, TN USA. [Grady, Christine; Miller, Franklin G.] NIH, Ctr Clin, Dept Clin Bioeth, Bethesda, MD 20892 USA. [Joffe, Steven] Harvard Univ, Boston, MA 02115 USA. [Kass, Nancy] Johns Hopkins Univ, Baltimore, MD USA. [King, Nancy M. P.] Wake Forest Univ, Winston Salem, NC 27109 USA. [Lidz, Charles W.] Univ Massachusetts, Worcester, MA USA. [Sankar, Pamela] Univ Penn, Philadelphia, PA 19104 USA. [Wilfond, Benjamin S.] Univ Washington, Seattle, WA 98195 USA. RP Henderson, GE (reprint author), Univ N Carolina, Chapel Hill, NC USA. EM ghenders@med.unc.edu OI Joffe, Steven/0000-0002-0667-7384; Davis, Arlene/0000-0001-6486-0446 FU NHGRI NIH HHS [P20 HG 03387, P20 HG003387, R01 HG 02087, R01 HG002087] NR 44 TC 141 Z9 141 U1 1 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1549-1277 J9 PLOS MED JI PLos Med. PD NOV PY 2007 VL 4 IS 11 BP 1735 EP 1738 AR e324 DI 10.1371/journal.pmed.0040324 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 244OE UT WOS:000251874400010 PM 18044980 ER PT J AU de Moura, TR Oliveira, F Novais, FO Miranda, JC Clarencio, J Follador, I Carvalho, EM Valenzuela, JG Barral, M Barral, A Brodskyn, C de Oliveira, CI AF de Moura, Tatiana R. Oliveira, Fabiano Novais, Fernanda O. Miranda, Jose Carlos Clarencio, Jorge Follador, Ivonise Carvalho, Edgar M. Valenzuela, Jesus G. Barral-Netto, Manoel Barral, Aldina Brodskyn, Claudia de Oliveira, Camila I. TI Enhanced Leishmania braziliensis Infection Following Pre-Exposure to Sandfly Saliva SO PLOS NEGLECTED TROPICAL DISEASES LA English DT Article ID DELAYED-TYPE HYPERSENSITIVITY; LUTZOMYIA-LONGIPALPIS; CUTANEOUS LEISHMANIASIS; PHLEBOTOMINE SANDFLIES; MAJOR INFECTION; MOUSE MODEL; FLY SALIVA; VECTOR; MICE; ANTIGENS AB Background: Sand fly saliva has an array of pharmacological and immunomodulatory components, and immunity to saliva protects against Leishmania infection. In the present study, we have studied the immune response against Lutzomyia intermedia saliva, the main vector of Leishmania braziliensis in Brazil, and the effects of saliva pre-exposure on L. braziliensis infection employing an intradermal experimental model. Methodology/principal findings: BALB/c mice immunized with L. intermedia salivary gland sonicate (SGS) developed a saliva-specific antibody response and a cellular immune response with presence of both IFN-gamma and IL-4. The inflammatory infiltrate observed in SGS-immunized mice was comprised of numerous polymorphonuclear and few mononuclear cells. Mice challenged with live L. braziliensis in the presence of saliva were not protected although lesion development was delayed. The inoculation site and draining lymph node showed continuous parasite replication and low IFN-gamma to IL-4 ratio, indicating that pre-exposure to L. intermedia saliva leads to modulation of the immune response. Furthermore, in an endemic area of cutaneous leishmaniasis, patients with active lesions displayed higher levels of anti-L. intermedia saliva antibodies when compared to individuals with a positive skin test result for Leishmania. Conclusion: These results show that pre-exposure to sand fly saliva plays an important role in the outcome of cutaneous leishmaniasis, in both mice and humans. They emphasize possible hurdles in the development of vaccines based on sand fly saliva and the need to identify and select the individual salivary candidates instead of using whole salivary mixture that may favor a non-protective response. C1 [de Moura, Tatiana R.; Oliveira, Fabiano; Novais, Fernanda O.; Miranda, Jose Carlos; Clarencio, Jorge; Barral-Netto, Manoel; Barral, Aldina; Brodskyn, Claudia; de Oliveira, Camila I.] Fdn Oswaldo Cruz FIOCRUZ, Ctr Pesquisas Goncalo Moniz, Salvador, BA, Brazil. [Oliveira, Fabiano; Valenzuela, Jesus G.] NIAID, Vector Mol Biol Unit, NIH, Rockville, MD USA. [Follador, Ivonise; Carvalho, Edgar M.; Barral-Netto, Manoel; Barral, Aldina; Brodskyn, Claudia] Univ Fed Bahia, Salvador, BA, Brazil. [Barral-Netto, Manoel; Barral, Aldina; Brodskyn, Claudia] Inst Invest & Imunol, Salvador, BA, Brazil. RP de Moura, TR (reprint author), Fdn Oswaldo Cruz FIOCRUZ, Ctr Pesquisas Goncalo Moniz, Salvador, BA, Brazil. EM camila@bahia.fiocruz.br RI Barral Netto, Manoel/B-3904-2009; DE MOURA, TATIANA/L-4556-2016; de Oliveira, Camila/B-4358-2009; Brodskyn, Claudia/A-9970-2010; Oliveira, Fabiano/B-4251-2009; Clarencio, Jorge/H-3940-2012 OI Barral Netto, Manoel/0000-0002-5823-7903; DE MOURA, TATIANA/0000-0002-7442-4434; de Oliveira, Camila/0000-0002-7868-5164; Oliveira, Fabiano/0000-0002-7924-8038; FU FAPESB; PAPES/FIOCRUZ; CNPq; EMC; MBN; AB; CB; CIO FX This work was supported by grants from FAPESB, PAPES/FIOCRUZ and CNPq. TRM was supported by a CNPq fellowship; FON was supported by FAPESB fellowship. EMC, MBN, AB, CB and CIO are senior investigators from CNPq. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. NR 35 TC 53 Z9 53 U1 0 U2 7 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1935-2735 J9 PLOS NEGLECT TROP D JI Plos Neglect. Trop. Dis. PD NOV PY 2007 VL 1 IS 2 AR e84 DI 10.1371/journal.pntd.0000084 PG 10 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 383XI UT WOS:000261707300006 PM 18060088 ER PT J AU Monteiro, AC Schmitz, V Morrot, A de Arruda, LB Nagajyothi, F Granato, A Pesquero, JB Muller-Esterl, W Tanowitz, HB Scharfstein, J AF Monteiro, Ana Carolina Schmitz, Veronica Morrot, Alexandre de Arruda, Luciana Barros Nagajyothi, Fnu Granato, Alessandra Pesquero, Joao B. Mueller-Esterl, Werner Tanowitz, Herbert B. Scharfstein, Julio TI Bradykinin B-2 receptors of dendritic cells, acting as sensors of Kinins proteolytically released by Trypanosoma cruzi, are critical for the development of protective type-1 responses SO PLOS PATHOGENS LA English DT Article ID CHAGAS HEART-DISEASE; CD8(+) T-CELLS; NITRIC-OXIDE PRODUCTION; TOLL-LIKE RECEPTOR-2; CUTTING EDGE; DANGER SIGNAL; INFECTION; MICE; RESISTANCE; ACTIVATION AB Although the concept that dendritic cells (DCs) recognize pathogens through the engagement of Toll-like receptors is widely accepted, we recently suggested that immature DCs might sense kinin-releasing strains of Trypanosoma cruzi through the triggering of G-protein-coupled bradykinin B-2 receptors (B2R). Here we report that C57BL/6.B2R-/- mice infected intraperitoneally with T. cruzi display higher parasitemia and mortality rates as compared to B2R(+/+) mice. qRT-PCR revealed a 5-fold increase in T. cruzi DNA (14 d post-infection [p.i.])in B2R(-/-) heart, while spleen parasitism was negligible in both mice strains. Analysis of recall responses (14 d p.i.) showed high and comparable frequencies of IFN-gamma-producing CD4(+) and CD8(+) T cells in the spleen of B2R-/- and wild-type mice. However, production of IFN-gamma by effector T cells isolated from B2R-/- heart was significantly reduced as compared with wild- type mice. As the infection continued, wild- type mice presented IFN-gamma-producing (CD4(+)CD44(+)and CD8(+)CD44(+)) T cells both in the spleen and heart while B2R-/- mice showed negligible frequencies of such activated T cells. Furthermore, the collapse of type-1 immune responses in B2R(-/-) mice was linked to upregulated secretion of IL-17 and TNF-alpha by antigen- responsive CD4(+) T cells. In vitro analysis of tissue culture trypomastigote interaction with splenic CD11c(+) DCs indicated that DC maturation (IL-12, CD40, and CD86) is controlled by the kinin/B2R pathway. Further, systemic injection of trypomastigotes induced IL- 12 production by CD11c(+) DCs isolated from B2R+/+ spleen, but not by DCs from B2R(-/-) mice. Notably, adoptive transfer of B2R(+-/+-) CD11c(+) DCs (intravenously) into B2R-/- mice rendered them resistant to acute challenge, rescued development of type-1 immunity, and repressed T(H)17 responses. Collectively, our results demonstrate that activation of B2R, a DC sensor of endogenous maturation signals, is critically required for development of acquired resistance to T. cruzi infection. C1 Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, BR-21941 Rio De Janeiro, Brazil. NIAID, Intracellular Parasite Biol Sect, Parasit Dis Lab, Bethesda, MD 20892 USA. Univ Fed Rio de Janeiro, Inst Microbiol Paulo de Goes, Rio De Janeiro, Brazil. Albert Einstein Coll Med, Bronx, NY 10467 USA. Univ Sao Paulo, Dept Biofis, Sao Paulo, Brazil. Goethe Univ Frankfurt, Sch Med, Inst Biochem 2, Frankfurt, Germany. RP Scharfstein, J (reprint author), Univ Fed Rio de Janeiro, Inst Biofis Carlos Chagas Filho, BR-21941 Rio De Janeiro, Brazil. EM scharf@biof.ufrj.br RI Pesquero, Joao/C-1470-2012; Arruda, Luciana/B-5806-2014; Schmitz, Veronica/D-2458-2013; OI Pesquero, Joao/0000-0002-4507-632X; Schmitz, Veronica/0000-0002-0865-133X; Morrot, Alexandre/0000-0001-9432-9701 FU NIAID NIH HHS [AI 052739, R01 AI052739] NR 54 TC 36 Z9 37 U1 0 U2 2 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 NOV PY 2007 VL 3 IS 11 BP 1730 EP 1744 AR e185 DI 10.1371/journal.ppat.0030185 PG 15 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 236NS UT WOS:000251310300017 PM 18052532 ER PT J AU Prinz, WA AF Prinz, William A. TI Non-vesicular sterol transport in cells SO PROGRESS IN LIPID RESEARCH LA English DT Review DE cholestrol; transport; non-vesicular; membranes; lipid transport proteins ID HIGH-DENSITY-LIPOPROTEIN; OXYSTEROL-BINDING-PROTEIN; ACUTE REGULATORY PROTEIN; PICK C1 PROTEIN; INTRACELLULAR CHOLESTEROL TRANSPORT; SCAVENGER RECEPTOR BI; YEAST SACCHAROMYCES-CEREVISIAE; OXIDOSQUALENE CYCLASE ERG7P; SELECTIVE LIPID UPTAKE; PLASMA-MEMBRANE AB Sterols such as cholesterol are important components of cellular membranes. They are not uniformly distributed among organelles and maintaining the proper distribution of sterols is critical for many cellular functions. Both vesicular and non-vesicular pathways move sterols between membranes and into and out of cells. There is growing evidence that a number of non-vesicular transport pathways operate in cells and, in the past few years, a number of proteins have been proposed to facilitate this transfer. Some are soluble sterol transfer proteins that may move sterol between membranes. Others are integral membranes proteins that mediate sterol efflux, uptake from cells, and perhaps intracellular sterol transfer as well. In most cases, the mechanisms and regulation of these proteins remains poorly understood. This review summarizes our current knowledge of these proteins and how they could contribute to intracellular sterol trafficking and distribution. Published by Elsevier Ltd. C1 NIDDKD, Lab Cell Biochem & Biol, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Prinz, WA (reprint author), NIDDKD, Lab Cell Biochem & Biol, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM wprinz@helix.nih.gov FU Intramural NIH HHS [Z01 DK060004-06] NR 183 TC 55 Z9 55 U1 1 U2 8 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0163-7827 J9 PROG LIPID RES JI Prog. Lipid Res. PD NOV PY 2007 VL 46 IS 6 BP 297 EP 314 DI 10.1016/j.plipres.2007.06.002 PG 18 WC Biochemistry & Molecular Biology; Nutrition & Dietetics SC Biochemistry & Molecular Biology; Nutrition & Dietetics GA 232JT UT WOS:000251016100002 PM 17709145 ER PT J AU Calderon, F Kim, HY AF Calderon, Frances Kim, Hee-Yong TI Role of RXR in neurite outgrowth induced by docosahexaenoic acid SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article; Proceedings Paper CT 8th Workshop on Fatty Acids and Cell Signaling CY 2007 CL Quebec City, CANADA ID RETINOID-X-RECEPTOR; FATTY-ACIDS; LIGAND; ALPHA; GROWTH; BRAIN AB We have previously demonstrated that docosahexaenoic acid (DHA) at low micromolar concentrations has a remarkable effect on morphological differentiation of hippocampal neurons by increasing the population of neurons with more branches and longer neurites. In this study, possible involvement of the retinoid X receptor (RXR) in the DHA-induced hippocampal neurite outgrowth was evaluated as DHA is an endogenous ligand for RXR. Immunocytochemical examination revealed that all RXR isoforms, RXR-alpha, -beta(1), -beta(2), and -gamma, are expressed exclusively in neurons with distinctive intracellular distribution. The cell-based dual luciferase reporter assay indicated that DHA activates RXR-alpha at or above 10 mu M but not at 1.5 mu M where DHA induces neurite outgrowth. Arachidonic acid also activated RXR-alpha in a similar concentration range but with lower efficacy. Our results suggest that DHA-induced neurite outgrowth may not be mediated by direct activation of RXR-alpha, although involvement of other isoforms or DHA metabolites cannot be excluded. Published by Elsevier Ltd. C1 [Calderon, Frances; Kim, Hee-Yong] NIAAA, Mol Signalling Lab, NIH, Bethesda, MD 20892 USA. RP Kim, HY (reprint author), NIAAA, Mol Signalling Lab, NIH, 5625 Fishers Lane,3N-07, Bethesda, MD 20892 USA. EM hykim@mail.nih.gov FU Intramural NIH HHS [Z01 AA000284-18] NR 12 TC 26 Z9 30 U1 0 U2 2 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD NOV-DEC PY 2007 VL 77 IS 5-6 BP 227 EP 232 DI 10.1016/j.plefa.2007.10.026 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 257ZT UT WOS:000252838900002 PM 18036800 ER PT J AU Lae, HJ Rao, JS Rapoport, SI Bazinet, RP AF Lae, Ho-Joo Rao, Jagadeesh S. Rapoport, Stanley I. Bazinet, Richard P. TI Antimanic therapies target brain arachidonic acid signaling: Lessons learned about the regulation of brain fatty acid metabolism SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article; Proceedings Paper CT 8th Workshop on Fatty Acids and Cell Signaling CY 2007 CL Quebec City, CANADA ID ACYL-COA SYNTHETASE; CYTOSOLIC PHOSPHOLIPASE A(2); DNA-BINDING ACTIVITY; PLACEBO-CONTROLLED TRIAL; CENTRAL-NERVOUS-SYSTEM; RAT FRONTAL-CORTEX; BIPOLAR DISORDER; DOCOSAHEXAENOIC ACID; CHRONIC LITHIUM; UNANESTHETIZED RAT AB Bipolar disorder is a major medical, social and economic burden worldwide. However, the biochemical basis of the disorder and the mechanisms of action of effective antibipolar disorder drugs remain elusive. In this paper, we review how combining a kinetic approach to studying the turnover of fatty acids within brain phospholipids of unanesthetized rats along with chronic administration of antimanic drugs (lithium, valproate and carbamazepine) at therapeutically relevant doses, shows that the brain arachidonic acid cascade is a common target of these drugs. The overlapping effects of the three drugs are decreased turnover of arachidonic acid but not of docosahexaenoic acid in rat brain phospholipids, and decreased brain cyclooxygenase-2 and prostaglandin E-2. Whereas lithium and carbamazepine target the transcription of the arachidonic acid-selective calcium-dependent cytosolic phospholipase A(2), valproate is a non-competitive inhibitor of an arachidonic acid-selective acyl-CoA synthetase. Two potential models of bipolar disorder, chronic N-methyl-D-aspartate and n-3 polyunsaturated fatty acid deprivation, opposite to the antimanic drugs, increase the turnover and markers of the arachidonic acid cascade in rat brain. These observations support the hypothesis proposed by Rapoport and colleagues that the arachidonic acid cascade is a common target of mood stabilizers and that by targeting substrate-specific enzymes the turnover of individual fatty acids can be regulated within the brain. Published by Elsevier Ltd. C1 [Bazinet, Richard P.] Univ Toronto, Fac Med, Dept Nutr Sci, Toronto, ON M5S 3E2, Canada. [Lae, Ho-Joo; Rao, Jagadeesh S.; Rapoport, Stanley I.] NIA, NIH, Brain Physiol & Metab Sect, Bethesda, MD 20892 USA. RP Bazinet, RP (reprint author), Univ Toronto, Fac Med, Dept Nutr Sci, Toronto, ON M5S 3E2, Canada. EM richard.bazinet@utoronto.ca RI Rao, Jagadeesh/C-1250-2009 NR 97 TC 0 Z9 0 U1 0 U2 3 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD NOV-DEC PY 2007 VL 77 IS 5-6 BP 239 EP 246 DI 10.1016/j.plefa.2007.10.018 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 257ZT UT WOS:000252838900004 ER PT J AU Rapoport, SI Rao, JS Igarashi, M AF Rapoport, Stanley I. Rao, Jagadeesh S. Igarashi, Miki TI Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article; Proceedings Paper CT 8th Workshop on Fatty Acids and Cell Signaling CY 2007 CL Quebec City, CANADA ID ALPHA-LINOLENIC ACID; POSITRON-EMISSION-TOMOGRAPHY; CYTOSOLIC PHOSPHOLIPASE A(2); N-3 PUFA DEPRIVATION; H-3 ARACHIDONIC-ACID; DOCOSAHEXAENOIC ACID; RAT-BRAIN; SIGNAL-TRANSDUCTION; IN-VIVO; UNANESTHETIZED RATS AB Plasma alpha-linolenic acid (alpha-LNA, 18:3n-3) and linoleic acid (LA, 18:2n-6) do not contribute significantly to the brain content of docosahexaenoic acid (DHA, 22:6n-3) or arachidonic acid (AA, 20:4n-6), respectively, and neither DHA nor AA can be synthesized de novo in vertebrate tissue. Therefore, measured rates of incorporation of circulating DHA and AA into brain exactly represent their rates of consumption by brain. Positron emission tomography (PET) has been used to show, based on this information, that the adult human brain consumes AA and DHA at rates of 17.8 and 4.6 mg/day, respectively, and that AA consumption does not change significantly with age. In unanesthetized adult rats fed an n-3 PUFA "adequate" diet containing 4.6% alpha-LNA (of total fatty acids) as its only n-3 PUFA, the rate of liver synthesis of DHA was more than sufficient to maintain brain DHA, whereas the brain's rate of DHA synthesis is very low and unable to do so. Reducing dietary alpha-LNA in the DHA-free diet led to upregulation of liver but not brain coefficients of alpha-LNA conversion to DHA and of liver expression of elongases and desaturases that catalyze this conversion. Concurrently, brain DHA loss slowed due to downregulation of several of its DHA-metabolizing enzymes. Dietary alpha-LNA deficiency also promoted accumulation of brain docosapentaenoic acid (22:5n-6), and upregulated expression of AA-metabolizing enzymes, including cytosolic and secretory phospholipases A(2) and cyclooxygenase-2. These changes, plus reduced levels of brain derived neurotrophic factor (BDNF) and cAMP response element-binding protein (CREB) in n-3 PUFA diet deficient rats, likely render their brain more vulnerable to neuropathological insults. Published by Elsevier Ltd. C1 [Rapoport, Stanley I.; Rao, Jagadeesh S.; Igarashi, Miki] NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. RP Rapoport, SI (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 9,Room 1S128,9000 Rockville Pike, Bethesda, MD 20892 USA. EM sir@helix.nih.gov RI Rao, Jagadeesh/C-1250-2009; Wilkinson, Stuart/C-2802-2013 FU Intramural NIH HHS [Z99 AG999999] NR 71 TC 141 Z9 161 U1 1 U2 9 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0952-3278 EI 1532-2823 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD NOV-DEC PY 2007 VL 77 IS 5-6 BP 251 EP 261 DI 10.1016/j.plefa.2007.10.023 PG 11 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 257ZT UT WOS:000252838900006 PM 18060754 ER PT J AU Fedorova, I Hussein, N Di Martino, C Moriguchi, T Hoshiba, J Majchrzak, S Salem, N AF Fedorova, Irina Hussein, Nahed Di Martino, Carmine Moriguchi, Toru Hoshiba, Junji Majchrzak, Sharon Salem, Norman, Jr. TI An n-3 fatty acid deficient diet affects mouse spatial learning in the Barnes circular maze SO PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS LA English DT Article; Proceedings Paper CT 8th Workshop on Fatty Acids and Cell Signaling CY 2007 CL Quebec City, CANADA ID DOCOSAHEXAENOIC ACID; DOCOSAPENTAENOIC ACID; TASK-PERFORMANCE; ARACHIDONIC-ACID; BRAIN; RATS; LEADS; LINOLEATE; ABILITY; RETINA AB Deficiency in n-3 fatty acids has been accomplished through the use of an artificial rearing method in which ICR mouse pups were hand fed a deficient diet starting from the 2nd day of life. There was a 51% loss of total brain DHA in mice with an n-3 fatty acid-deficient diet relative to those with a diet sufficient in n-3 fatty acids. n-3 fatty acid adequate and deficient mice did not differ in terms of locomotor activity in the open field test or in anxiety-related behavior in the elevated plus maze. The n-3 fatty acid-deficient mice demonstrated impaired learning in the reference-memory version of the Barnes circular maze as they spent more time and made more errors in search of an escape tunnel. No difference in performance between all dietary groups in the cued and working memory version of the Barnes maze was observed. This indicated that motivational, motor and sensory factors did not contribute to the reference memory impairment. Published by Elsevier Ltd. C1 [Fedorova, Irina; Hussein, Nahed; Di Martino, Carmine; Moriguchi, Toru; Majchrzak, Sharon; Salem, Norman, Jr.] NIAAA, Lab Membrane Biochem & Biophys, NIH, Bethesda, MD 20892 USA. [Hoshiba, Junji] Okayama Univ, Adv Sci Res Ctr, Dept Anim Resources, Okayama, Japan. RP Salem, N (reprint author), NIAAA, Lab Membrane Biochem & Biophys, NIH, 5625 Fishers Lane,Room 3N-07,MSC 9410, Bethesda, MD 20892 USA. EM nsalem@niaaa.nih.gov RI Majchrzak, Sharon/F-1830-2013 OI Majchrzak, Sharon/0000-0001-8934-7294 FU Intramural NIH HHS [Z01 AA000235-25] NR 28 TC 54 Z9 54 U1 1 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0952-3278 J9 PROSTAG LEUKOTR ESS JI Prostaglandins Leukot. Essent. Fatty Acids PD NOV-DEC PY 2007 VL 77 IS 5-6 BP 269 EP 277 DI 10.1016/j.plefa.2007.10.013 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Cell Biology; Endocrinology & Metabolism GA 257ZT UT WOS:000252838900008 PM 18037280 ER PT J AU Lin, JA Watanabe, J Rozengurt, N Narasimha, A Martin, MG Wang, J Braun, J Langenbach, R Reddy, ST AF Lin, James A. Watanabe, Junji Rozengurt, Nora Narasimha, Ajay Martin, Martin G. Wang, Jenny Braun, Jonathan Langenbach, Robert Reddy, Srinivasa T. TI Atherogenic diet causes lethal ileo-ceco-colitis in cyclooxygenase-2 deficient mice SO PROSTAGLANDINS & OTHER LIPID MEDIATORS LA English DT Article DE COX-2; bile acids; Crohn's disease; inflammatory bowel disease; intestinal inflammation ID INFLAMMATORY-BOWEL-DISEASE; COLON-CANCER CELLS; INDUCIBLE CYCLOOXYGENASE; CARDIOVASCULAR EVENTS; DEOXYCHOLIC-ACID; CARCINOMA CELLS; BLOOD-PRESSURE; STROMAL CELLS; INHIBITION; COX-2 AB Cyclooxygenases (COX) regulate a variety of inflammatory diseases, including inflammatory bowel disease (IBD). While the pathological effects of COX-1 inhibition by NSAIDs on intestinal ulceration are well established, the role of COX-2 on intestinal inflammation remains under investigation. In this paper, we report a protective role for COX-2 against diet-mediated intestinal inflammation in mice. COX-2(-/-) mice fed an atherogenic diet or diet containing cholate, but not chow or fat alone, had a high mortality whereas COX-1(-/-) mice and wild-type mice were unaffected by the dietary changes. Histological analysis identified the cause of death in COX-2(-/-) mice due to severe intestinal inflammation that was surprisingly limited to the ileo-ceco-colic junction. COX-2 expression is induced in the cecum of wild-type mice fed an atherogenic diet. Our findings show that COX-2 plays an anti-inflammatory role at the ileo-ceco-colic junction in mice, and the pathology of diet-mediated intestinal inflammation in COX-2(-/-) mice offers an excellent model system to elucidate the molecular mechanisms of intestinal inflammation. (c) 2007 Elsevier Inc. All tights reserved. C1 Univ Calif Los Angeles, Dept Med Cardiol, Inst Mol Biol, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Pediat, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Med, Div Cardiol, Atherosclerosis Res Inst, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA 90095 USA. Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Res Triangle Pk, NC USA. RP Reddy, ST (reprint author), Univ Calif Los Angeles, Dept Med Cardiol, Inst Mol Biol, A8-131 CHS,650 Charles E Young Dr S, Los Angeles, CA 90095 USA. EM sreddy@mednet.ucla.edu RI Lin, James/E-4796-2010 FU NCI NIH HHS [P30 CA016042]; NHLBI NIH HHS [R01 HL071776-01, 1R01HL71776, R01 HL071776, R01 HL082823, R01 HL082823-01A2]; NIAID NIH HHS [P30 AI028697]; NIDDK NIH HHS [5R33DK070328, R33 DK070328] NR 47 TC 6 Z9 6 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1098-8823 J9 PROSTAG OTH LIPID M JI Prostaglandins Other Lipid Mediat. PD NOV PY 2007 VL 84 IS 3-4 BP 98 EP 107 DI 10.1016/j.prostaglandins.2007.04.004 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 239CY UT WOS:000251497300002 PM 17991612 ER PT J AU Wu, CK Gousset, K Hughes, SH AF Wu, Chia-Kuei Gousset, Karine Hughes, Stephen H. TI Targeting to the endoplasmic reticulum improves the folding of recombinant human telomerase reverse transcriptase SO PROTEIN EXPRESSION AND PURIFICATION LA English DT Article DE human telomerase reverse transcriptase; protein folding; chaperone; endoplasmic reticulum; co-translational ID BREAST-CANCER CELLS; TERMINAL TRANSFERASE; IMMORTAL CELLS; INSECT CELLS; PROTEIN; SUBUNIT; TETRAHYMENA; EXPRESSION; COMPONENT; RNA AB Telomerase is a specialized reverse transcriptase that catalyzes the addition of telomeric repeats, TTAGGG in all vertebrates, to the ends of chromosomes. The lack of recombinant purified human telomerase reverse transcriptase (hTERT) has hampered biochemical and structural studies. The primary problem in generating active recombinant hTERT appears to be protein folding, which may be due to the fact that telomerase is a multi-component ribonucleoprotein complex. When expressed in most heterologous systems, recombinant hTERT is largely insoluble. Here we describe a protein expression system using a baculovirus vector that can be used to prepare properly folded, enzymatically active, hTERT. In this system, the recombinant hTERT is directed to the endoplasmic reticulum (ER), which is rich in chaperones. This increases the expression of soluble recombinant hTERT, promoting proper folding using intrinsic ER chaperone proteins. Published by Elsevier Inc. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, POB B,Bldg 539,Room 130A, Frederick, MD 21702 USA. EM hughes@ncifcrf.gov OI Gousset, Karine/0000-0002-0988-2332 FU Intramural NIH HHS [Z01 BC010481-05] NR 35 TC 4 Z9 4 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1046-5928 J9 PROTEIN EXPRES PURIF JI Protein Expr. Purif. PD NOV PY 2007 VL 56 IS 1 BP 8 EP 19 DI 10.1016/j.pep.2007.05.016 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 227ED UT WOS:000250639100002 PM 17658270 ER PT J AU Sun, P Austin, BP Schubot, FD Waugh, DS AF Sun, Ping Austin, Brian P. Schubot, Florian D. Waugh, David S. TI New protein fold revealed by a 1.65 angstrom resolution crystal structure of Francisella tularensis pathogenicity island protein IglC SO PROTEIN SCIENCE LA English DT Article DE Francisella tularensis; IglC; crystal structure; bioterrorism ID CYTOPLASM; CRYSTALLOGRAPHY; MACROPHAGES; ESCAPE AB Francisella tularensis is a highly infectious Gram- negative intracellular pathogen that causes the fulminating disease tularemia and is considered to be a potential bioweapon. F. tularensis pathogenicity island proteins play a key role in modulating phagosome biogenesis and subsequent bacterial escape into the cytoplasm of macrophages. The 23 kDa pathogenicity island protein IglC is essential for the survival and proliferation of F. tularensis in macrophages. Seeking to gain some insight into its function, we determined the crystal structure of IglC at 1.65 angstrom resolution. IglC adopts a beta-sandwich conformation that exhibits no similarity with any known protein structure. C1 Natl Canc Inst Frederick, Canc Res Ctr, Macromol Crystallog Inst, Frederick, MD 21702 USA. RP Waugh, DS (reprint author), Natl Canc Inst Frederick, Canc Res Ctr, Macromol Crystallog Inst, POB B, Frederick, MD 21702 USA. EM waughd@ncifcrf.gov NR 23 TC 8 Z9 8 U1 0 U2 0 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD NOV PY 2007 VL 16 IS 11 BP 2560 EP 2563 DI 10.1110/ps.073177307 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 224JX UT WOS:000250444400023 PM 17905833 ER PT J AU Liu, CW Shea, N Rucker, S Harvey, L Russo, P Saul, R Lopez, MF Mikulskis, A Kuzdzal, S Golenko, E Fishman, D Vonderheid, E Booher, S Cowen, EW Hwang, ST Whiteley, GR AF Liu, Chenwei Shea, Nancy Rucker, Sally Harvey, Linda Russo, Paul Saul, Richard Lopez, Mary F. Mikulskis, Alvydas Kuzdzal, Scott Golenko, Eva Fishman, David Vonderheid, Eric Booher, Susan Cowen, Edward W. Hwang, Sam T. Whiteley, Gordon R. TI Proteomic patterns for classification of ovarian cancer and CTCL serum samples utilizing peak pairs indicative of post-translational modifications SO PROTEOMICS LA English DT Article DE bioinformatics; post-translational modifications; proteomic patterns ID DIAGNOSIS; IDENTIFICATION; BIOMARKERS; DISCOVERY AB Proteomic patterns as a potential diagnostic technology has been well established for several cancer conditions and other diseases. The use of machine learning techniques such as decision trees, neural networks, genetic algorithms, and other methods has been the basis for pattern determination. Cancer is known to involve signaling pathways that are regulated through PTM of proteins. These modifications are also detectable with high confidence using high-resolution MS. We generated data using a prOTOF (TM) mass spectrometer on two sets of patient samples: ovarian cancer and cutaneous t-cell lymphoma (CTCL) with matched normal samples for each disease. Using the knowledge of mass shifts caused by common modifications, we built models using peak pairs and compared this to a conventional technique using individual peaks. The results for each disease showed that a small number of peak pairs gave classification equal to or better than the conventional technique that used multiple individual peaks. This simple peak picking technique could be used to guide identification of important peak pairs involved in the disease process. C1 Clin Proteom Reference Lab, Gaithersburg, MD USA. PerkinElmer Life & Analyt Sci, Wellesley, MA USA. NYU, Sch Med, Div Obstet & Gynecol, New York, NY USA. Johns Hopkins Sch Med, Dept Dermatol, Baltimore, MD USA. NCI, Dermatol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Whiteley, GR (reprint author), SAIC Frederick Inc, NCI Frederick, POB B, Frederick, MD 21702 USA. EM whiteleyg@ncifcrf.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 21 TC 13 Z9 13 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD NOV PY 2007 VL 7 IS 22 BP 4045 EP 4052 DI 10.1002/pmic.200601044 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 236HG UT WOS:000251293000003 PM 17952875 ER PT J AU Winters, M Dabir, B Yu, MS Kohn, EC AF Winters, Mary Dabir, Bhavana Yu, Minshu Kohn, Elise C. TI Constitution and quantity of lysis buffer alters outcome of reverse phase protein microarrays SO PROTEOMICS LA English DT Article DE ovarian cancer; protein extraction buffer; reverse phase protein microarray ID WESTERN-BLOT-ANALYSIS; OVARIAN-CANCER; BETA-ACTIN; TISSUE; EXPRESSION; SPECIMENS; PATHWAYS AB Application of novel technology to clinical samples requires optimization of procedures. Reverse phase protein lysate arrays use femtomolar quantities of tissue lysate from clinical samples with which to profile biochemical events happening in the tumor. We analyzed the effects of different tissue solubilization buffers on frozen ovarian tumor samples in order to identify the system with the best signal intensity dynamic range, reproducibility, tissue solubility, and signal consistency. A modified RIPA-like buffer supplemented with DTT and SDS was deemed optimal. C1 NCI, Med Oncol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Pathol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. RP Kohn, EC (reprint author), NCI, Med Oncol Branch, Canc Res Ctr, 10 Ctr Dr,MSC1500, Bethesda, MD 20892 USA. EM kohne@mail.nih.gov FU Intramural NIH HHS NR 15 TC 15 Z9 16 U1 0 U2 0 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1615-9853 J9 PROTEOMICS JI Proteomics PD NOV PY 2007 VL 7 IS 22 BP 4066 EP 4068 DI 10.1002/pmic.200700484 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 236HG UT WOS:000251293000005 PM 17952872 ER PT J AU McBee, JK Yu, LR Kinoshita, Y Uo, T Beyer, RP Veenstra, TD Morrison, RS AF McBee, Joshua K. Yu, Li-Rong Kinoshita, Yoshito Uo, Takuma Beyer, Richard P. Veenstra, Timothy D. Morrison, Richard S. TI Proteomic analysis of protein expression changes in a model of gliomagenesis SO PROTEOMICS CLINICAL APPLICATIONS LA English DT Review DE astrocytoma; brain tumor; mass spectrometry; MCM proteins; p53 ID TREATED CORTICAL-NEURONS; PROSTATE-CANCER CELLS; TUMOR-SUPPRESSOR GENE; HUMAN OVARIAN-CANCER; CODED AFFINITY TAGS; P53-DEFICIENT MICE; BREAST-TUMORS; GROWTH-FACTOR; HUMAN GLIOMAS; LUNG-CANCER AB Loss of p53 function is a common event in a variety of human cancers including tumors of glial origin. Using an in vitro mouse model of malignant astrocyte transformation, three cleavable isotope coded affinity tag (cICAT) experiments were performed comparing cultured wild-type astrocytes and two p53(-/-) astrocyte cultures before and after malignant transformation. We identified and quantitated an average of 1366 proteins per experiment and demonstrated that the protein quantitation ratios in each individual cICAT experiment correlated well to ratios determined in the other two studies. These data were further supported by microarray analysis which also correlated to changes in protein expression. The results showed significant changes in protein expression in association with malignant transformation. Proteins overexpressed in malignant astrocytes were typically involved in ribosome biogenesis/protein synthesis and DNA replication, while underexpressed proteins were generally associated with the regulation of cell cycle checkpoint control, tumor suppression, and apoptosis. Among the significantly up-regulated proteins and transcripts in malignant mouse astrocytes were members of the minichromosome maintenance (MCM) family. Western blot analysis verified increased expression of MCM proteins in malignant human astrocytoma cell lines, which had not previously been described. These results demonstrate the usefulness of the cICAT approach for comparing differences in protein expression profiles between normal and malignant cells. C1 Univ Washington, Sch Med, Dept Neurol Surg, Seattle, WA 98195 USA. Inst Syst Biol, Seattle, WA USA. SAIC Frederick Inc, Natl Canc Inst, Lab Proteom & Analyt Technol, Frederick, MD USA. Univ Washington, Ctr Ecogenet & Environm Hlth, Sch Med, Seattle, WA 98195 USA. RP Morrison, RS (reprint author), Univ Washington, Sch Med, Dept Neurol Surg, Box 356470, Seattle, WA 98195 USA. EM yael@u.washington.edu NR 106 TC 0 Z9 0 U1 0 U2 1 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA POSTFACH 101161, 69451 WEINHEIM, GERMANY SN 1862-8346 EI 1862-8354 J9 PROTEOM CLIN APPL JI Proteom. Clin. Appl. PD NOV PY 2007 VL 1 IS 11 BP 1485 EP 1498 DI 10.1002/prca.200700292 PG 14 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 232MA UT WOS:000251022600014 PM 21136645 ER PT J AU Wang, PS Gruber, MJ Powers, RE Schoenbaum, M Speier, AH Wells, KB Kessler, RC AF Wang, Philip S. Gruber, Michael J. Powers, Richard E. Schoenbaum, Michael Speier, Anthony H. Wells, Kenneth B. Kessler, Ronald C. TI Mental health service use among Hurricane Katrina survivors in the eight months after the disaster SO PSYCHIATRIC SERVICES LA English DT Article ID POSTTRAUMATIC-STRESS-DISORDER; NEW-YORK-CITY; PRIMARY-CARE PATIENTS; SELF-REPORTED USE; GENERAL-POPULATION; TERRORIST ATTACKS; ADMINISTRATIVE RECORDS; COMPETING DEMANDS; UNITED-STATES; NEW-ORLEANS AB Objective: This study examined use of mental health services among adult survivors of Hurricane Katrina in order to improve understanding of the impact of disasters on persons with mental disorders. Methods: A geographically representative telephone survey was conducted between January 19 and March 31, 2006, with 1,043 displaced and nondisplaced English-speaking Katrina survivors aged 18 and older. Survivors who reported serious and mild-moderate mood and anxiety disorders in the past 30 days and those with no such disorders were identified by using the K6 scale of nonspecific psychological distress. Use of services, system sectors, and treatments and reasons for not seeking treatment or dropping out were recorded. Correlates of using services and dropping out were examined. Results: An estimated 31% of respondents (N= 319) had evidence of a mood or anxiety disorder at the time of the interview. Among these only 32% had used any mental health services since the disaster, including 46% of those with serious disorders. Of those who used services, 60% had stopped using them. The general medical sector and pharmacotherapy were most commonly used, although the mental health specialty sector and psychotherapy played important roles, especially for respondents with serious disorders. Many treatments were of low intensity and frequency. Undertreatment was greatest among respondents who were younger, older, never married, members of racial or ethnic minority groups, uninsured, and of moderate means. Structural, financial, and attitudinal barriers were frequent reasons for not obtaining care. Conclusions: Few Katrina survivors with mental disorders received adequate care; future disaster responses will require timely provision of services to address the barriers faced by survivors. C1 [Kessler, Ronald C.] Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. [Wang, Philip S.; Schoenbaum, Michael] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Powers, Richard E.] Univ Alabama, Birmingham, AL USA. [Speier, Anthony H.] Off Mental Hlth, Baton Rouge, LA USA. [Powers, Richard E.] Alabama Dept Mental Hlth & Mental Retardat, Baton Rouge, LA USA. [Wells, Kenneth B.] Univ Calif Los Angeles, David Geffen Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90095 USA. [Wells, Kenneth B.] RAND Corp, Santa Monica, CA USA. RP Kessler, RC (reprint author), Harvard Univ, Sch Med, Dept Hlth Care Policy, 180 Longwood Ave, Boston, MA 02115 USA. EM kessler@hcp.med.harvard.edu FU NIMH NIH HHS [R01 MH070884, R01 MH070884-01A2, R01-MH-070884-01A2] NR 54 TC 62 Z9 62 U1 2 U2 10 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD NOV PY 2007 VL 58 IS 11 BP 1403 EP 1411 DI 10.1176/appi.ps.58.11.1403 PG 9 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 265LQ UT WOS:000253360800004 PM 17978249 ER PT J AU Goldstein, AB Frosch, E Davarya, S Leaf, PJ AF Goldstein, Amy B. Frosch, Emily Davarya, Sarah Leaf, Philip J. TI Factors associated with a six-month return to emergency services among child and adolescent psychiatric patients SO PSYCHIATRIC SERVICES LA English DT Article AB Objectives: This analysis identified factors associated with emergency department recidivism among pediatric psychiatric patients and factors that may differentiate repeat and one-time visits. Methods: The researchers examined six-month recidivism among a sample of 509 patients of ages four to 18 years who made mental health visits to an urban pediatric emergency department in 2004. Results: Patients who made repeat visits were more likely to be involved in mental health and social services than patients who did not return to the emergency department. Repeat visitors were also more likely to be African American, have a history of psychiatric hospitalization, and present with suicidal or disruptive behaviors. Conclusions: These results suggest that the emergency department is being used as part of the continuum of care for patients already in treatment, particularly those displaying disruptive behavior. Additional research is needed to determine whether this recidivism is clinically indicated or reflects a lack of available or appropriate care in community settings. C1 [Goldstein, Amy B.] NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. [Frosch, Emily; Davarya, Sarah] Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. [Leaf, Philip J.] Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. RP Goldstein, AB (reprint author), NIMH, Div Serv & Intervent Res, 6001 Execut Blvd,Room 7144,MSC 9633, Bethesda, MD 20892 USA. EM goldsteinam@mail.nih.gov FU NIMH NIH HHS [5T32-MH019545] NR 4 TC 25 Z9 25 U1 2 U2 4 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 1075-2730 J9 PSYCHIAT SERV JI Psychiatr. Serv. PD NOV PY 2007 VL 58 IS 11 BP 1489 EP 1492 DI 10.1176/appi.ps.58.11.1489 PG 4 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychiatry SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychiatry GA 265LQ UT WOS:000253360800018 PM 17978263 ER PT J AU Huestis, MA Boyd, SJ Heishman, SJ Preston, KL Bonnet, D Le Fur, G Gorelick, DA AF Huestis, Marilyn A. Boyd, Susan J. Heishman, Stephen J. Preston, Kenzie L. Bonnet, Denis Le Fur, Gerard Gorelick, David A. TI Single and multiple doses of rimonabant antagonize acute effects of smoked cannabis in male cannabis users SO PSYCHOPHARMACOLOGY LA English DT Article DE rimonabant; cannabinoids; receptor; antagonist; human; subjective effects; heart rate ID CB1 RECEPTOR ANTAGONIST; MESSENGER-RNA EXPRESSION; RISK-FACTORS; OVERWEIGHT PATIENTS; MARIJUANA SMOKING; FOOD-INTAKE; RATS; SR141716; DELTA(9)-TETRAHYDROCANNABINOL; MEDIATION AB Rationale A single 90- mg dose of the cannabinoid CB1 receptor antagonist rimonabant attenuates effects of smoked cannabis in humans. Objectives The objective of this study is to evaluate whether repeated daily 40- mg doses of rimonabant can attenuate effects of smoked cannabis to the same extent as a single higher ( 90 mg) dose. Materials and methods Forty- two male volunteers received one of three oral drug regimens in a randomized, double blind, parallel group design: ( 1) 40 mg rimonabant daily for 15 days, ( 2) placebo for 14 days, then 90 mg rimonabant on day 15, or ( 3) placebo for 15 days. All participants smoked an active or placebo cannabis cigarette 2 h after medication on days 8 and 15. Subjective effects were measured with visual analog scales and the marijuana- scale of the Addiction Research Center Inventory. Results Cannabis- induced tachycardia was significantly lower for the 40- mg group on day 8 and for the 40 and 90 mg rimonabant groups on day 15 as compared to placebo. The 40- mg dose significantly decreased peak subjective effects on day 8. Neither the 90- mg nor 40- mg doses significantly decreased peak subjective effects on day 15. Rimonabant treatment did not significantly affect Delta(9)- tetrahydrocannabinnol pharmacokinetics. Conclusions Repeated lower daily rimonabant doses ( 40 mg) attenuated the acute physiological effects of smoked cannabis to a similar degree as a single 90- mg dose; repeated 40- mg doses attenuated subjective effects after 8 but not 15 days. C1 Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. NIH, Natl Inst Drug Abuse, Intramural Res Program, Clin Pharmacol & Therapeut Res Branch, Baltimore, MD 21224 USA. Sanofi Aventis Inc, F-34184 Montpellier, France. RP Huestis, MA (reprint author), Univ Maryland, Sch Med, Dept Psychiat, Baltimore, MD 21201 USA. EM mhuestis@intra.nida.nih.gov RI Preston, Kenzie/J-5830-2013 OI Preston, Kenzie/0000-0003-0603-2479 FU Intramural NIH HHS [Z01 DA000415-10] NR 51 TC 60 Z9 65 U1 2 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD NOV PY 2007 VL 194 IS 4 BP 505 EP 515 DI 10.1007/s00213-007-0861-5 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 214JB UT WOS:000249732700008 PM 17619859 ER PT J AU Conklin, SM Manuck, SB Yao, JK Flory, JD Hibbeln, JR Muldoon, MF AF Conklin, Sarah M. Manuck, Stephen B. Yao, Jeffrey K. Flory, Janine D. Hibbeln, Joseph R. Muldoon, Matthew F. TI High omega-6 and low omega-3 fatty acids are associated with depressive symptoms and neuroticism SO PSYCHOSOMATIC MEDICINE LA English DT Article; Proceedings Paper CT Conference on the Futute of Psychiatric Diagnosis - Refining the Research Agenda CT Conference on Somatic Presentations of Mental Disorders CY SEP, 2006 CY SEP, 2006 CL Beijing, PEOPLES R CHINA CL Peking Univ, Dept Psychiat, Beijing, PEOPLES R CHINA SP Amer Psychiat Assoc, Peking Univ, Dept Psychiat SP Amer Psychiat Assoc, WHO, US NIH HO Peking Univ, Dept Psychiat DE neuroticism; depression; negative affect; eicosapentaenoic; docosahexaenoic ID FATTY-ACIDS; PERSONALITY; DISORDERS AB Objective: To examine the concentrations of omega-3 and (omega-6 polyunsaturated fatty acids in serum obtained from nonpatient community volunteers not selected for hypercholesterolemia. Previously we reported that the relative concentrations of omega-3 and omega-6 polyunsaturated fatty acids in serum covary with depressive symptomatology and neuroticism in hypercholesterolemic adults. Methods: A total of 116 adults without current Axis I psychopathology completed the Beck Depression Inventory (BDI) and the NEO Personality Inventory-Revised (NEO-PI-R). Fasting serum phospholipid eicosapentaenoic (EPA), docosahexaenoic (DHA), and arachidonic acid (AA) were determined (% of total pool). Results: Higher AA and AA:EPA ratio, adjusted for age, gender, and race, were associated with greater depressive symptomatology (BDI score of ! 10). Lower EPA, and higher AA, AA:EPA ratio and AA:DHA ratio were associated with greater NEO-PI-R Neuroticism. The six Neuroticism subscales were each associated with two or more fatty acid measurements. Conclusions: In conjunction with other reports, these findings suggest that the (omega-3 and w-6 fatty acids are related to negative affect at both the symptom and trait levels. C1 Allegheny Coll, Dept Psychol, Cardiovasc Behav Med Postdoctoral Training Progra, Meadville, PA 16335 USA. Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. Univ Pittsburgh, VA Pittsburg Healthcare Syst, Pittsburgh, PA USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA USA. Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA USA. CUNY Queens Coll, Dept Psychol, Flushing, NY 11367 USA. NIAAA, Bethesda, MD USA. Univ Pittsburgh, Sch Med, Ctr Clin Pharmacol, Pittsburgh, PA USA. RP Conklin, SM (reprint author), Allegheny Coll, Dept Psychol, Cardiovasc Behav Med Postdoctoral Training Progra, 520 N Main St, Meadville, PA 16335 USA. EM Sarah.Conklin@allegheny.edu FU NHLBI NIH HHS [P01 HL040962, R21 HL081282] NR 17 TC 62 Z9 66 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0033-3174 EI 1534-7796 J9 PSYCHOSOM MED JI Psychosom. Med. PD NOV-DEC PY 2007 VL 69 IS 9 BP 932 EP 934 DI 10.1097/PSY.0b013e31815aaa42 PG 3 WC Psychiatry; Psychology; Psychology, Multidisciplinary SC Psychiatry; Psychology GA 235AC UT WOS:000251204900019 PM 17991818 ER PT J AU Colon-Ramos, U Kabagambe, EK Baylin, A Ascherio, A Campos, H Peterson, KE AF Colon-Ramos, Uriyoan Kabagambe, Edmond K. Baylin, Ana Ascherio, Alberto Campos, Hannia Peterson, Karen E. TI Socio-economic status and health awareness are associated with choice of cooking oil in Costa Rica SO PUBLIC HEALTH NUTRITION LA English DT Article DE cardiovascular disease; Costa Rica; lifestyle; socio-economic factors; palm oil; soybean oil; unsaturated oils ID ACUTE MYOCARDIAL-INFARCTION; CARDIOVASCULAR-DISEASE; HEART-DISEASE; RISK-FACTORS; FATTY-ACIDS; LIFE-STYLE; POPULATION; DIET; LIPOPROTEINS; APOLIPOPROTEINS AB Objective: To examine the socio-economic and lifestyle determinants of cooking oil choice in Costa Rica during the last decade (1994-2004). Design: Cross-sectional study. Subjects (total n = 2274) belonged to the control population of a large case-control study; they were recruited yearly. Data about type of oil used for cooking, dietary intake, socio-economic and demographic characteristics were collected. Setting: A dietitian visited all subjects and conducted the interviews at their homes; all subjects lived in the Costa Rican central valley region. Subjects: Adult, free-living, rural and urban Costa Ricans with no history of myocardial infarction and physical or mental disability. Results: The odds of choosing soybean over palm oil increased significantly each year (P < 0.05) and was determined by high socio-economic status (SES) and variables that suggest health awareness (self-reported history of hypertension, high cholesterol, Multivitamin use and intake of green leafy vegetables). The odds of choosing other unsaturated oils, namely corn and sunflower, over soybean oil also increased yearly (P < 0.05) and was associated with the same two factors (high SES and health awareness). Palm Oil users remained in the lowest SES fertile and were more likely to live in rural areas. Across all SES tertiles, high health awareness determined the odds of choosing other Unsaturated oils over palm oil, and soybean oil (P < 0.05). Conclusion: These data show that, in addition to SES, health awareness is associated with the selection of unsaturated oils over palm oil in a developing country undergoing transition. These data should be considered when targeting nutrition messages and policies that promote better dietary choices. C1 NCI, Bethesda, MD 20892 USA. Univ Alabama, Dept Epidemiol, Birmingham, AL USA. Brown Univ, Dept Community Hlth, Providence, RI 02912 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Colon-Ramos, U (reprint author), NCI, 6130 Execut Blvd, Bethesda, MD 20892 USA. EM colonramosu@mail.nih.gov RI Kabagambe, Edmond/A-3147-2008; OI Kabagambe, Edmond/0000-0002-8993-3186 FU NHLBI NIH HHS [HL071888, HL60692] NR 37 TC 13 Z9 13 U1 0 U2 4 PU CAMBRIDGE UNIV PRESS PI CAMBRIDGE PA EDINBURGH BLDG, SHAFTESBURY RD, CB2 8RU CAMBRIDGE, ENGLAND SN 1368-9800 J9 PUBLIC HEALTH NUTR JI Public Health Nutr. PD NOV PY 2007 VL 10 IS 11 BP 1214 EP 1222 DI 10.1017/S1368980007699571 PG 9 WC Public, Environmental & Occupational Health; Nutrition & Dietetics SC Public, Environmental & Occupational Health; Nutrition & Dietetics GA 235OY UT WOS:000251245400004 PM 17391550 ER PT J AU Choyke, PL AF Choyke, Peter L. TI Is it possible to quantify fluorescence during optical endoscopy? SO RADIOLOGY LA English DT Editorial Material ID CANCER AB Quantitative fluorescence molecular imaging can be performed by compensating for variations in the light intensity caused by a change in the position of the endoscope. By accounting for these differences, quantitation of fluorescence can be used to assess the biologic importance of a lesion that might not otherwise be detected with white light endoscopy. This area of inquiry represents an important new step toward the detection of disease in its earliest phases when it can be treated with minimally invasive surgery or ablation. C1 NCI, Mol Imaging Program, Bethesda, MD 20892 USA. RP Choyke, PL (reprint author), NCI, Mol Imaging Program, 10 Ctr Dr,MSC 1182,Bldg 10,Room 1B40, Bethesda, MD 20892 USA. EM pchoyke@nih.gov NR 4 TC 2 Z9 2 U1 0 U2 0 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 NOV PY 2007 VL 245 IS 2 BP 307 EP 308 DI 10.1148/radiol.2452071020 PG 2 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 223BE UT WOS:000250343800001 PM 17940293 ER PT J AU Makhovskaya, OV Kozlov, S Botos, I Stepnov, AA Andrianova, AG Gushchina, AE Wlodawer, A Mel'nikov, EE Rotanova, TV AF Makhovskaya, O. V. Kozlov, S. Botos, I. Stepnov, A. A. Andrianova, A. G. Gushchina, A. E. Wlodawer, A. Mel'nikov, E. E. Rotanova, T. V. TI Forms of LonB protease from Archaeoglobus fulgidus devoid of the transmembrane domain: The contribution of the quaternary structure to the regulation of enzyme proteolytic activity SO RUSSIAN JOURNAL OF BIOORGANIC CHEMISTRY LA English DT Article DE Archaeoglobus fulgidus; Lon protease; proteolytic activity; subunit interactions; transmembrane domain ID SER-LYS DYAD; ESCHERICHIA-COLI; CLASSIFICATION; PROTEINS; ATPASES; SITES AB Deletion of the transmembrane domain (TM-domain) of Archaeoglobus fulgidus LonB protease (Archaeoglobus fulgidus (AfLon)) was shown to result in uncontrollable activation of the enzyme proteolytic site and in vivo autolysis yielding a stable and functionally inactive fragment consisting of both alpha-helical and proteolytic domains (alpha P). The Delta TM-AfLon-S509A enzyme form, obtained by site-directed mutagenesis of the catalytic Ser residue, is capable of recombination with the alpha P fragment. The mixed oligomers were shown to be proteolytically active, which indicates a crucial role of subunit interactions in the activation of the AfLon proteolytic site. The thermophilic nature of AfLon protease was found to be due to the special features of the enzyme activity regulation, the structure of ATPase domain, and the quaternary structure. C1 Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow 117997, Russia. NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. NIDDK, Mol Biol Lab, Bethesda, MD 20892 USA. RP Rotanova, TV (reprint author), Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Ul Miklukho Malklaya 16-10, Moscow 117997, Russia. EM rotanova@enzyme.siobc.ras.ru NR 12 TC 0 Z9 0 U1 0 U2 0 PU MAIK NAUKA/INTERPERIODICA/SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013-1578 USA SN 1068-1620 J9 RUSS J BIOORG CHEM+ JI Russ. J. Bioorg. Chem. PD NOV PY 2007 VL 33 IS 6 BP 610 EP 613 DI 10.1134/S1068162007060131 PG 4 WC Biochemistry & Molecular Biology; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 236RU UT WOS:000251321900013 ER PT J AU Wang, R Song, L Han, G Wang, J Chen, G Xu, R Yu, M Qian, J Shen, B Li, Y AF Wang, R. Song, L. Han, G. Wang, J. Chen, G. Xu, R. Yu, M. Qian, J. Shen, B. Li, Y. TI Mechanisms of regulatory T-cell induction by antigen-IgG-transduced splenocytes SO SCANDINAVIAN JOURNAL OF IMMUNOLOGY LA English DT Article ID TRANSCRIPTION FACTOR FOXP3; TGF-BETA; IN-VIVO; TOLERANCE; IL-2; SUPPRESSION; RESPONSES; ANTIBODY; DISEASE; MICE AB Our previous studies have demonstrated that splenocytes, transduced with glutamate decarboxylate 65 (GAD) and IgG fusion construct, protect non-obese diabetes (NOD) mice from diabetes. However, the mechanism by which this strategy prevents diabetes is not well understood. Here, we found that CD4(+)Foxp3(+)Treg cells, in vitro induced by GAD-IgG-transduced splenocytes, after transfer, were responsible for prevention of diabetes in NOD mice. Further studies suggested that GAD-IgG-transduced B cells could secrete high level of TGF-beta and stimulated CD4(+)T cells to secrete high level of IFN-gamma. Finally, we found that when TGF-beta and/or IFN-gamma were blocked, CD4(+)Foxp3(-)T cells were not converted into CD4(+)Foxp3(+)Treg cells. The results suggest that GAD-IgG-transduced B cells via TGF-beta and IFN-gamma in vitro induce the CD4(+)Foxp3(+)Treg cells which are responsible for prevention of diabetes in NOD mice by GAD-IgG-gene transfer. C1 Inst Basic Med Sci, Dept Mol Immunol, Beijing 100850, Peoples R China. NCI, NIH, Bethesda, MD 20892 USA. RP Li, Y (reprint author), Inst Basic Med Sci, Dept Mol Immunol, Taiping Rd 27, Beijing 100850, Peoples R China. EM liyan62033@yahoo.com.cn NR 32 TC 6 Z9 6 U1 0 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0300-9475 J9 SCAND J IMMUNOL JI Scand. J. Immunol. PD NOV PY 2007 VL 66 IS 5 BP 515 EP 522 DI 10.1111/j.1365-3083.2007.02004.x PG 8 WC Immunology SC Immunology GA 227QC UT WOS:000250671900004 PM 17883389 ER PT J AU Agodoa, L Eggers, P AF Agodoa, Lawrence Eggers, Paul TI Racial and ethnic disparities in end-stage kidney failure - Survival paradoxes in African-Americans SO SEMINARS IN DIALYSIS LA English DT Article ID NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; CHRONIC RENAL-INSUFFICIENCY; HIV-ASSOCIATED NEPHROPATHY; UNITED-STATES; HEMODIALYSIS-PATIENTS; US POPULATION; AUTOSOMAL-DOMINANT; DIALYSIS PATIENTS; CONTROLLED TRIAL AB The risk of death is nearly 45% lower in African-Americans than Caucasians undergoing chronic hemodialysis. In light of the higher mortality rate in African-Americans in the general US population, this paradox requires explanation and further investigation. Factors that may contribute to this survival advantage include a younger age at which African-Americans arrive at end-stage renal disease (ESRD) and the slightly higher body mass index. On the other hand, factors, such as lower residual renal function, lower mean hemoglobin and hematocrit, increased prevalence of hypertension, a higher prevalence of catheter use for initial dialysis, and generally lower dose of dialysis should put African-Americans on dialysis at a higher risk of death. This survival advantage seems to be completely annulled with a successful renal transplant. Finally, it should be noted that ESRD carries with it a very high mortality rate in all racial and ethnic groups. A successful renal transplant improves but does not restore the expected remaining life times. Therefore, aggressive approach is required in investigating the factors that confer such high mortality risk on ESRD patients. C1 NIDDK, Chron Kidney Dis Program, NIH, Bethesda, MD 20892 USA. NIDDK, End Stage Renal Dis Program, NIH, Bethesda, MD 20892 USA. RP Agodoa, L (reprint author), NIDDK, Chron Kidney Dis Program, NIH, Bethesda, MD 20892 USA. EM agodoal@mail.nih.gov NR 67 TC 44 Z9 45 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0894-0959 J9 SEMIN DIALYSIS JI Semin. Dial. PD NOV-DEC PY 2007 VL 20 IS 6 BP 577 EP 585 DI 10.1111/j.1525-139X.2007.00350.x PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 228WV UT WOS:000250764200018 PM 17991208 ER PT J AU Castle, PE Rodriguez, AC Porras, C Herrero, R Schiffman, M Gonzalez, P Hildesheim, A Burk, RD AF Castle, Philip E. Rodriguez, Ana C. Porras, Carolina Herrero, Rolando Schiffman, Mark Gonzalez, Paula Hildesheim, Allan Burk, Robert D. TI A comparison of cervical and vaginal human papillomavirus SO SEXUALLY TRANSMITTED DISEASES LA English DT Article ID COSTA-RICA; INFECTION; WOMEN; NEOPLASIA; CARCINOGENICITY; GUANACASTE; AGE AB Objectives: We wanted to compare detection of a broad spectrum of human papillomavirus (HPV) types detected in cellular specimens from the vagina and cervix, which could provide information about the potential of each anatomical site for harboring infection. Previous studies have failed to present data on or detect a broad spectrum of HPV genotypes and/or have not carefully sampled the vagina, instead relying on self-collection that is likely contaminated with cervical cells. Study Design: We conducted follow-up study of 353 women who had participated in study of HPV and cervical neoplasia in Costa Rica. We collected paired cervical and vaginal specimens; vaginal specimens were collected from the fornix to minimize cervical contamination. Specimens were tested in a masked fashion for > 40 HPV types using a MY09/MY11 PCR method and type-specific dot blot hybridization. Results: The prevalence for any carcinogenic HPV type in vaginal and cervical specimens was similar (P = 0.3). However, the prevalence for any HPV type in vaginal specimens was greater than in cervical specimens (P = 0.0002), primarily due to a twofold increased vaginal prevalence of HPV types of the alpha 3/alpha 15 phylogenetic species (e.g., HPV61) (P < 0.00005). Conclusions: Carcinogenic HPV types appeared to have a similar affinity for vaginal and cervical epithelium, but noncarcinogenic HPV types of the a3/a15 phylogenetic species may have a tropism for vaginal epithelium. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Proyecto Epidemiol Guanacaste, San Jose, Costa Rica. Albert Einstein Coll Med, Dept Microbiol & Immunol, Albert Einstein Canc Ctr, Bronx, NY 10467 USA. Albert Einstein Coll Med, Dept Pediat, Albert Einstein Canc Ctr, Bronx, NY 10467 USA. Albert Einstein Coll Med, Dept Obstet Gynecol & Womens Hlth, Albert Einstein Canc Ctr, Bronx, NY 10467 USA. Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Albert Einstein Canc Ctr, Bronx, NY 10467 USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room 5004,EPS MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01 CP40542, N01 CP50535, CA78527, N01 CP33061, N01 CP81023, R01 CA078527, N01 CP21081, U01 CA078527] NR 17 TC 49 Z9 49 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0148-5717 J9 SEX TRANSM DIS JI Sex. Transm. Dis. PD NOV PY 2007 VL 34 IS 11 BP 849 EP 855 DI 10.1097/OLQ.0b013e318064c8c5 PG 7 WC Infectious Diseases SC Infectious Diseases GA 224AZ UT WOS:000250418800004 PM 17621246 ER PT J AU Graubard, BI Levy, PS Willis, GB AF Graubard, Barry I. Levy, Paul S. Willis, Gordon B. TI A conversation with Monroe Sirken SO STATISTICAL SCIENCE LA English DT Editorial Material ID MULTIPLICITY AB Born January 11, 1921 in New York City, Monroe Sirken grew up in a suburb of Pasadena, California. He earned B.A. and M.A. degrees in sociology at UCLA in 1946 and 1947, and a Ph.D. in 1950 in sociology with a minor in mathematics at the University of Washington in 1950 where Professor Z. W. Birnbaum was his mentor and thesis advisor. As a Post-Doctoral Fellow of the Social Science Research Council, Monroe spent 1950-1951 at the Statistics Laboratory, University of California at Berkeley and the Office of the Assistant Director for Research, U.S. Bureau of the Census in Suitland, Maryland. Monroe visited the Census Bureau at a time of great change in the use of sampling and survey methods, and decided to remain. He began his government career there in 1951 as a mathematical statistician, and moved to the National Office of Vital Statistics (NOVS) in 1953 where he was an actuarial mathematician and a mathematical statistician. He has held a variety of research and administrative positions at the National Center for Health Statistics (NCHS) and he was the Associate Director, Research and Methodology and the Director, Office of Research and Methodology until 1996 when he became a senior research scientist, the title he currently holds. Aside from administrative responsibilities, Monroe's major professional interests have been conducting and fostering survey and statistical research responsive to the needs of federal statistics. His interest in the design of rare and sensitive population surveys led to the development of network sampling which improves precision by linking multiple selection units to the same observation units. His interest in fostering research on the cognitive aspects of survey methods led to the establishment of permanent questionnaire design research laboratories, first at NCHS and later at other federal statistical agencies here and abroad. Monroe has been active in serving the statistical community. He has served on many committees of the American Statistical Association (ASA) and the Washington Statistical Society (WSS). He is a charter member of the Federal Committee on Statistical Methodology (FCSM) and chairs its research subcommittee that oversees a grants program in statistical and survey research that is funded by a consortium of federal statistical agencies, and administered by the National Science Foundation. He is a Fellow of the American Statistical Association and the American Association for the Advancement of Science, and is an elected member of the International Statistical Institute. He is the recipient of the Public Health Service Superior Service Award, and the ASA WSS Roger Herriot Award for Innovation in Government Statistics. C1 [Graubard, Barry I.] NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. [Levy, Paul S.] RTI Int, Res Triangle Pk, NC 27709 USA. [Willis, Gordon B.] NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Graubard, BI (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM graubarb@mail.nih.gov; levy@rti.org; willisg@mail.nih.gov NR 18 TC 0 Z9 0 U1 2 U2 3 PU INST MATHEMATICAL STATISTICS PI BEACHWOOD PA PO BOX 22718, BEACHWOOD, OH 44122 USA SN 0883-4237 J9 STAT SCI JI Stat. Sci. PD NOV PY 2007 VL 22 IS 4 BP 637 EP 650 DI 10.1214/07-STS245 PG 14 WC Statistics & Probability SC Mathematics GA 295CD UT WOS:000255451700008 ER PT J AU Bratincsak, A Brownstein, MJ Cassiani-Ingoni, R Pastorino, S Szalayova, I Toth, ZE Key, S Nemeth, K Pickel, J Mezey, E AF Bratincsak, Andras Brownstein, Michael J. Cassiani-Ingoni, Riccardo Pastorino, Sandra Szalayova, Ildiko Toth, Zsuzsanna E. Key, Sharon Nemeth, Krisztian Pickel, James Mezey, Eva TI CD45-positive blood cells give rise to uterine epithelial cells in mice SO STEM CELLS LA English DT Article DE adult stem cell; hematopoietic stem cell; endometrium; regeneration ID MARROW-DERIVED CELLS; BONE-MARROW; ESTROUS-CYCLE; STEM-CELLS; MOUSE ENDOMETRIUM; IDENTIFICATION; CD45; IRRADIATION; ENGRAFTMENT; PHENOTYPE AB The uterine endometrium is composed of epithelial and stromal cells, which undergo extensive degeneration and regeneration in every estrous cycle, and dramatic changes occur during pregnancy. The high turnover of cells requires a correspondingly high level of cell division by progenitor cells in the uterus, but the character and source of these cells remain obscure. In the present study, using a novel transgenic mouse, we showed that CD45- positive hematopoietic progenitor cells colonize the uterine epithelium and that in pregnancy more than 80% of the epithelium can derive from these cells. Since we also found green fluorescent protein (GFP)-positive uterine endothelial cells in long-term GFP bone marrow-transplanted mice, we conclude that circulating CD45+ cells play an important role in regenerating the uterine epithelium. C1 NIMH, Bethesda, MD 20892 USA. J Craig Venter Inst, Gaithersburg, MD USA. Natl Inst Neurol Disorders & Stroke, Bethesda, MD USA. Natl Canc Inst, Bethesda, MD USA. Natl Inst Dental & Craniofacial Res, Bethesda, MD USA. Semmelweis Univ, Dept Dermato Venerol & Oncol, Budapest, Hungary. RP Mezey, E (reprint author), 49 Convent Dr,Bldg 49,Room 5A76, Bethesda, MD 20892 USA. EM mezeye@mail.nih.gov FU Intramural NIH HHS NR 36 TC 57 Z9 60 U1 0 U2 1 PU ALPHAMED PRESS PI DURHAM PA 318 BLACKWELL ST, STE 260, DURHAM, NC 27701-2884 USA SN 1066-5099 J9 STEM CELLS JI Stem Cells PD NOV PY 2007 VL 25 IS 11 BP 2820 EP 2826 DI 10.1634/stemcells.2007-0301 PG 7 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 227FI UT WOS:000250642200015 PM 17656643 ER PT J AU Avital, I Moreira, AL Klimstra, DS Leversha, M Papadopoulos, EB Brennan, M Downey, RJ AF Avital, Itzhak Moreira, Andre L. Klimstra, David S. Leversha, Margaret Papadopoulos, Esperanza B. Brennan, Murray Downey, Robert J. TI Donor-derived human bone marrow cells contribute to solid organ cancers developing after bone marrow transplantation SO STEM CELLS LA English DT Article DE cancer stem cells; bone marrow; solid organ cancer; bone marrow transplantation ID EMBEDDED TISSUE-SECTIONS; HEMATOPOIETIC STEM-CELLS; EPITHELIAL CANCERS; MATURATION ARREST; CELLULAR-ORIGIN; Y-CHROMOSOME; CHIMERISM; MICROCHIMERISM; FISH; DIFFERENTIATION AB Bone marrow-derived stem cells have been shown to participate in solid organ repair after tissue injury. Animal models suggest that epithelial malignancies may arise as aberrant stem cell differentiation during tissue repair. We hypothesized that if bone marrow stem cells participate in human neoplasia, then solid organ cancers developing after allogeneic bone marrow transplantation (ABMT) might include malignant cells of donor origin. We identified four male patients who developed solid organ cancers (lung adenocarcinoma, laryngeal squamous cell carcinoma, glioblastoma, and Kaposi sarcoma) after myeloablation, total body irradiation, and ABMT from female donors. Donor-derived malignant cells comprised 2.5%-6% of the tumor cellularity The presence of donor-derived malignant cells in solid organ cancers suggests that human bone marrow-derived stem cells have a role in solid organ cancer's carcinogenesis. However, the nature of this role is yet to be defined. C1 NCI, Surg Branch, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Mol Cytogenet Core Facil, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10021 USA. RP Avital, I (reprint author), NCI, Surg Branch, Bldg 10 Hatfield CRC,Room 3-3940,10 Ctr Dr, Bethesda, MD 20892 USA. EM avitali@mail.nih.gov OI Brennan, Murray/0000-0003-2358-4371 NR 27 TC 58 Z9 61 U1 0 U2 0 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 NOV PY 2007 VL 25 IS 11 BP 2903 EP 2909 DI 10.1634/stemcells.2007-0409 PG 7 WC Cell & Tissue Engineering; Biotechnology & Applied Microbiology; Oncology; Cell Biology; Hematology SC Cell Biology; Biotechnology & Applied Microbiology; Oncology; Hematology GA 227FI UT WOS:000250642200024 PM 17690178 ER PT J AU Merino, JG Latour, LL Todd, JW Luby, M Schellinger, PD Kang, DW Warach, S AF Merino, Jose G. Latour, Lawrence L. Todd, Jason W. Luby, Marie Schellinger, Peter D. Kang, Dong-Wha Warach, Steven TI Lesion volume change after treatment with tissue plasminogen activator can discriminate clinical responders from nonresponders SO STROKE LA English DT Article DE acute stroke; brain imaging; brain infarction; MRI; thrombolysis; thrombolytic RX ID MEAN TRANSIT-TIME; ACUTE STROKE; MRI; DIFFUSION; THROMBOLYSIS; EVOLUTION; DESMOTEPLASE; PERFUSION; TRIAL AB Background and Purpose - A change in acute-to-chronic lesion volume has been proposed as a biomarker for stroke therapies. The objectives of this study were to determine the magnitude of lesion volume change after standard treatment with tissue plasminogen activator and to determine whether specific volume change thresholds can discriminate clinical responders from nonresponders. Methods - We measured lesion volume on diffusion weighted at baseline and on 90-day fluid attenuated inversion recovery MRI and scored 3-month modified Rankin Scale in consecutive patients treated with tissue plasminogen activator. We identified variables associated with excellent (modified Rankin Scale 0 to 1) and independent (modified Rankin Scale 0 to 2) outcomes. Results - We included 53 patients (mean age 69 years, median baseline National Institutes of Health Stroke Scale score 7). The mean acute-to-chronic lesion volume increase was 11.7 (+/-7.7) cm(3). In 23 patients, the chronic lesion was smaller than the baseline lesion. At 3 months, 32 patients had an excellent clinical outcome. Dichotomous volume change variables associated with outcome included decrease in volume >= 30% (P = 0.004) and volume increase >= 5 cm(3) (P = 0.002). Conclusions - In patients given standard tissue plasminogen activator therapy, changes in lesion volume are associated with clinical outcome, and threshold lesion volumes can differentiate excellent and poor outcome, suggesting these as a potential marker of outcome. C1 NINCDS, Sect Stroke Diagnost & Therapeut, NIH, Bethesda, MD 20892 USA. NE Med Ctr, NE Neurol, Concord, NC USA. Univ Klinikum Erlangen, Neurol Klin, Erlangen, Germany. Univ Ulsan, Coll Med, Asan Med Ctr, Dept Neurol, Seoul, South Korea. RP Merino, JG (reprint author), NINCDS, Sect Stroke Diagnost & Therapeut, NIH, 10 Ctr Dr,Room B1D-733,MSC 1063, Bethesda, MD 20892 USA. EM merinoj@ninds.nih.gov OI Merino, Jose/0000-0002-6676-0008 FU Intramural NIH HHS [Z99 NS999999] NR 17 TC 18 Z9 18 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD NOV PY 2007 VL 38 IS 11 BP 2919 EP 2923 DI 10.1161/STROKEAHA.107.485995 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 225LB UT WOS:000250518300009 PM 17901392 ER PT J AU Ay, H Benner, T Arsava, EM Furie, KL Singhal, AB Jensen, MB Ayata, C Towfighi, A Smith, EE Chong, JY Koroshetz, WJ Sorensen, AG AF Ay, Hakan Benner, Thomas Arsava, E. Murat Furie, Karen L. Singhal, Aneesh B. Jensen, Matt B. Ayata, Cenk Towfighi, Amytis Smith, Eric E. Chong, Ji Y. Koroshetz, Walter J. Sorensen, A. Gregory TI A computerized algorithm for etiologic classification of ischemic stroke - The causative classification of stroke system SO STROKE LA English DT Article DE classification cerebral infarct; etiology ID CAROTID-ARTERY STENOSIS; INTEROBSERVER AGREEMENT; CEREBRAL INFARCTION; RELIABILITY; COAGULATION; DIAGNOSIS; REGISTRY; DISEASE; HEALTH; TRIAL AB Background and Purpose - The SSS-TOAST is an evidence-based classification algorithm for acute ischemic stroke designed to determine the most likely etiology in the presence of multiple competing mechanisms. In this article, we present an automated version of the SSS-TOAST, the Causative Classification System (CCS), to facilitate its utility in multicenter settings. Methods - The CCS is a web-based system that consists of questionnaire-style classification scheme for ischemic stroke (http://ccs.martinos.org). Data entry is provided via checkboxes indicating results of clinical and diagnostic evaluations. The automated algorithm reports the stroke subtype and a description of the classification rationale. We evaluated the reliability of the system via assessment of 50 consecutive patients with ischemic stroke by 5 neurologists from 4 academic stroke centers. Results - The kappa value for inter-examiner agreement was 0.86 (95% CI, 0.81 to 0.91) for the 5-item CCS (large artery atherosclerosis, cardio-aortic embolism, small artery occlusion, other causes, and undetermined causes), 0.85 (95% CI, 0.80 to 0.89) with the undetermined group broken into cryptogenic embolism, other cryptogenic, incomplete evaluation, and unclassified groups (8-item CCS), and 0.80 (95% CI, 0.76 to 0.83) for a 16-item breakdown in which diagnoses were stratified by the level of confidence. The intra-examiner reliability was 0.90 (0.75-1.00) for 5-item, 0.87 (0.73-1.00) for 8-item, and 0.86 (0.75-0.97) for 16-item CCS subtypes. Conclusions - The web-based CCS allows rapid analysis of patient data with excellent intra-and inter-examiner reliability, suggesting a potential utility in improving the fidelity of stroke classification in multicenter trials or research databases in which accurate subtyping is critical. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Stroke Serv,Dept Neurol, Boston, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,AA Martinos Ctr Biomed Imaging, Boston, MA 02129 USA. Univ Calif San Diego, Stroke Ctr, San Diego, CA 92103 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Neurol & Stroke, Boston, MA 02129 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Neurovasc Regulat Lab,Dept Radiol, Boston, MA 02129 USA. Univ Calif Los Angeles, Med Ctr, Stroke Ctr, Dept Neurol, Los Angeles, CA 90024 USA. Columbia Univ, Dept Neurol, Div Stroke & Crit Care, New York, NY USA. NINCDS, NIH, Bethesda, MD 20892 USA. RP Ay, H (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Radiol,AA Martinos Ctr Biomed Imaging, 149 13th St,Room 2301, Boston, MA 02129 USA. EM hay@partners.org RI Arsava, Ethem Murat/I-9197-2013; Smith, Eric/C-5443-2012 OI Arsava, Ethem Murat/0000-0002-6527-4139; Smith, Eric/0000-0003-3956-1668 FU AHRQ HHS [R01-HS11392-02]; NCRR NIH HHS [P41-RR14075]; NINDS NIH HHS [R01-NS38477-04] NR 23 TC 155 Z9 160 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD NOV PY 2007 VL 38 IS 11 BP 2979 EP 2984 DI 10.1161/STROKEAHA.107.490896 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 225LB UT WOS:000250518300019 PM 17901381 ER PT J AU Tso, AR Merino, JG Warach, S AF Tso, Amy R. Merino, Jose G. Warach, Steven TI Interleukin-6 - 174G/C polymorphism and ischemic stroke a systematic review SO STROKE LA English DT Review DE acute stroke; genetics; inflammation ID CAROTID-ARTERY ATHEROSCLEROSIS; G/C POLYMORPHISM; GENE PROMOTER; PLASMA-LEVELS; RISK-FACTOR; PROINFLAMMATORY CYTOKINES; CEREBROVASCULAR EVENTS; CARDIOVASCULAR-DISEASE; PRECEDING INFECTION; BRAIN INFARCTION AB Background and Purpose - Interleukin- 6 ( IL- 6) is associated with atherosclerotic disease and is also a key mediator in the inflammatory response to cerebral ischemia. Although the IL- 6 -174G/ C promoter polymorphism has been associated with carotid artery atherosclerosis and coronary heart disease, its relation to ischemic stroke is unclear. This review summarizes the current literature and discusses methodological considerations for future studies. Methods - Electronic searches were conducted in the PubMed MEDLINE, Scopus, and ISI Web of Science databases. Two investigators independently reviewed all abstracts to identify studies examining the association between the IL- 6 - 174G/ C polymorphism and ischemic cerebrovascular events. Results - Twelve relevant publications were identified. Three reported on a subset of patients from a later publication, leaving 9 independent studies. Two studies found an association between ischemic stroke and the G allele or GG genotype, whereas 4 found an association with the C allele or CC genotype. One study found the CC genotype to be significantly less frequent in retinal artery occlusion patients. Two studies found no association between the - 174G/ C polymorphism and stroke. Conclusions - Studies investigating stroke and the - 174G/ C polymorphism report conflicting results, which may reflect the complex physiology of IL- 6 and true differences between stroke subtypes and populations. However, interpretation of published results is hindered by methodological limitations, and greater rigor and consistency in future studies will help unravel the relationship between the - 174G/ C polymorphism and stroke. C1 NINDS, Sect Stroke Diagnost & Therapeut, NIH, Bethesda, MD 20892 USA. RP Warach, S (reprint author), NINDS, Sect Stroke Diagnost & Therapeut, NIH, 10 Ctr Dr,Rm B1D733,MSC 1063, Bethesda, MD 20892 USA. EM warachs@ninds.nih.gov OI Merino, Jose/0000-0002-6676-0008 FU Intramural NIH HHS NR 53 TC 38 Z9 39 U1 1 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD NOV PY 2007 VL 38 IS 11 BP 3070 EP 3075 DI 10.1161/STROKEAHA.107.492231 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 225LB UT WOS:000250518300033 PM 17916761 ER PT J AU Oertel, YC Miyahara-Felipe, L Mendoza, MG Yu, K AF Oertel, Yolanda C. Miyahara-Felipe, Leika Mendoza, Mayo G. Yu, Kai TI Value of repeated fine needle aspirations of the thyroid: An analysis of over ten thousand FNAs SO THYROID LA English DT Article ID TERM-FOLLOW-UP; MANAGEMENT; NODULES; CYTOLOGY; DISEASE; BIOPSY AB Objective: Fine needle aspiration (FNA) has been accepted as the diagnostic method of choice in the initial evaluation of thyroid nodules. However, the value of repeated FNAs in the long-term follow-up of lesions initially diagnosed as benign is being questioned. Do the findings on initial FNA really spare patients thyroidectomy or do they only postpone it? The purpose of the present study is our attempt to answer this question. Design: Retrospective review of cytology reports of patients who underwent thyroidal FNAs at Washington Hospital Center from January 1998 through April 2006. All statistical analyses were done using the statistical package Splus. Main outcome: Patients who had thyroid nodules diagnosed as benign on FNA performed at our institution had a 90% probability of a benign diagnosis (with 95% confidence interval [0.87, 0.92]), when they underwent surgery. When the benign cytologic diagnosis was confirmed on a repeat aspiration, this probability increased to 98% (with 95% confidence interval [0.94, 1.0]). Conclusions: Repeated thyroidal FNAs yielding benign diagnoses are nearly always accurate (98%), and therefore the patients can be followed safely without undergoing surgery, unless an unfavorable clinical change occurs. C1 Washington Hosp Ctr, Dept Pathol C 1219, Washington, DC 20010 USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Oertel, YC (reprint author), Washington Hosp Ctr, Dept Pathol C 1219, 110 Irving St, Washington, DC 20010 USA. EM yolanda.c.oertel@medstar.net NR 23 TC 73 Z9 78 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1050-7256 J9 THYROID JI Thyroid PD NOV PY 2007 VL 17 IS 11 BP 1061 EP 1066 DI 10.1089/thy.2007.0159 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 238KE UT WOS:000251445700006 PM 17910525 ER PT J AU Dunnick, JK Thayer, KA Travlos, GS AF Dunnick, June K. Thayer, Kristina A. Travlos, Gregory S. TI Inclusion of biomarkers for detecting perturbations in the heart and lung and lipid/carbohydrate metabolism in National Toxicology Program studies SO TOXICOLOGICAL SCIENCES LA English DT Editorial Material DE biomarkers; cardiovascular system; lipids ID BRONCHOALVEOLAR LAVAGE; NATRIURETIC PEPTIDE; PULMONARY-EMPHYSEMA; GENE-EXPRESSION; DISEASE; RAT; RESPONSES; MITOCHONDRIAL; HEMOGLOBIN; MECHANISMS AB Environmental factors and exposures may contribute to many serious diseases afflicting humans. Biomarkers are useful to understand disease processes and identify early events leading to disease. The National Toxicology Program (NTP) convened a workshop in September 2006 to help identify biomarkers that could be used in toxicology studies with rodents to predict disease outcome and detect early events in disease processes. Expert scientists reviewed biomarkers for disease/injury related to the heart, lung, and/or changes in lipid/carbohydrate metabolism and made recommendations for those that could be incorporated into NTP studies on a routine or selective basis. Although numerous biomarkers were discussed, only a few were considered amenable for routine use. This article summarizes recommendations for the most promising biomarkers and presents the NTP perspective on those that will be included in the bioassay program on a routine or special study basis. Breakout group reports and additional information on the workshop, including participants, presentations, and background materials, are posted on the NTP Web site http://ntp.niehs.nih.gov/go/20940. C1 NIEHS, Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. RP Dunnick, JK (reprint author), NIEHS, Natl Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. EM dunnickj@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 38 TC 2 Z9 2 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1096-6080 J9 TOXICOL SCI JI Toxicol. Sci. PD NOV PY 2007 VL 100 IS 1 BP 29 EP 35 DI 10.1093/toxsci/kfm113 PG 7 WC Toxicology SC Toxicology GA 227VT UT WOS:000250686600006 PM 17490986 ER PT J AU Athar, M Back, JH Tang, X Kim, KH Kopelovich, L Bickers, DR Kim, AL AF Athar, Mohammad Back, Jung Ho Tang, Xmwel Kim, Kwang Ho Kopelovich, Levy Bickers, David R. Kim, Arianna L. TI Resveratrol: A review of preclinical studies for human cancer prevention SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Review DE resveratrol; human cancer; skin cancer; breast cancer; lung cancer; gastric; colorectal cancer; hepatoma; neuroblastoma; pancreatic cancer; leukemia ID CHEMOPREVENTIVE AGENT RESVERATROL; CELLS IN-VITRO; PACLITAXEL-INDUCED APOPTOSIS; CARCINOMA A431 CELLS; NEUROBLASTOMA SH-SY5Y CELL; BRONCHIAL EPITHELIAL-CELLS; LEUKEMIA HL-60 CELLS; ABERRANT CRYPT FOCI; NF-KAPPA-B; PROSTATE-CANCER AB The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds one of which is resveratrol (trans-3,4',5-trihydroxystilbene), a phytoalexin derived from the skin of grapes and other fruits. Resveratrol is known to have potent anti-inflammatory and antioxidant effects and to inhibit platelet aggregation and the growth of a variety of cancer cells. Its potential chemopreventive and chemotherapeutic activities have been demonstrated in all three stages of carcinogenesis (initiation, promotion, and progression), in both chemically and UVB-induced skin carcinogenesis in mice, as well as in various murine models of human cancers. Evidence from numerous in vitro and in vivo studies has confirmed its ability to modulate various targets and signaling pathways. This review discusses the current preclinical and mechanistic data available and assesses resveratrol's anticancer effects to support its potential as an anticancer agent in human populations. (c) 2007 Elsevier Inc. All rights reserved. C1 Columbia Univ, Coll Phys & Surg, Dept Dermatol, New York, NY 10032 USA. Hallym Univ, Coll Med, Dept Dermatol, Chunchon, South Korea. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Kim, AL (reprint author), Columbia Univ, Coll Phys & Surg, Dept Dermatol, 630 W 168th St VC15-204, New York, NY 10032 USA. EM ak309@columbia.edu FU NCI NIH HHS [R01 CA-097249-01, R01 CA097249, R03 CA125855, R03 CA125855-01A1]; NIAMS NIH HHS [K01 AR048582, K01 AR048582-03, K01 AR048582-05] NR 116 TC 369 Z9 401 U1 8 U2 74 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD NOV 1 PY 2007 VL 224 IS 3 BP 274 EP 283 DI 10.1016/j.taap.2006.12.025 PG 10 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 227EF UT WOS:000250639300010 PM 17306316 ER PT J AU Saporito, RA Donnelly, MA Jain, P Garraffo, HM Spande, TF Daly, JW AF Saporito, Ralph A. Donnelly, Maureen A. Jain, Poonam Garraffo, H. Martin Spande, Thomas F. Daly, John W. TI Spatial and temporal patterns of alkaloid variation in the poison frog Oophaga pumilio in Costa Rica and Panama over 30 years SO TOXICON LA English DT Article DE ants; beetles; chemical defense; decahydroquinolines; dendrobatid frogs; histrionicotoxins; indolizidines; mantellid frogs; mites; pumiliotoxins ID BUFONID TOADS MELANOPHRYNISCUS; DENDROBATES-PUMILIO; SKIN ALKALOIDS; CHEMICAL DEFENSE; DART FROGS; PYRROLIZIDINE ALKALOIDS; CONVERGENT EVOLUTION; DIETARY ALKALOIDS; ARTHROPOD SOURCE; AMPHIBIAN SKIN AB A total of 232 alkaloids, representing 21 structural classes were detected in skin extracts from the dendrobatid poison frog Oophaga pumilio, collected from 53 different populations from over 30 years of research. The highly toxic pumiliotoxins and allopumiliotoxins, along with 5,8-disubstitiuted and 5,6,8-trisubstituted indolizidines, all of which are proposed to be of dietary mite origin, were common constituents in most extracts. One decahydroquinoline (DHQ), previously shown be of ant origin, occurred in many extracts often as a major alkaloid, while other DHQs occurred rather infrequently. Histrionicotoxins, thought to be of ant origin, did not appear to possess a specific pattern of occurrence among the populations, but when present, were usually found as major components. Certain 3,5-disubstituted pyrrolizidines and indolizidines, known to be of ant origin, did occur in extracts, but infrequently. Alkaloid composition differed with regard to geographic location of frog populations, and for populations that were sampled two or more times during the 30-year period significant changes in alkaloid profiles sometimes occurred. The results of this study indicate that chemical defense in a dendrobatid poison frog is dependent on geographic location and habitat type, which presumably controls the abundance and nature of alkaloid-containing arthropods. (c) 2007 Elsevier Ltd. All rights reserved. C1 NIDDKD, NIH, Bioorgan Chem Lab, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Florida Int Univ, Dept Biol Sci, Miami, FL 33199 USA. RP Daly, JW (reprint author), NIDDKD, NIH, Bioorgan Chem Lab, Dept Hlth & Human Serv, Bldg 8,Room 1A-17, Bethesda, MD 20892 USA. EM jdaly@nih.gov NR 84 TC 58 Z9 61 U1 3 U2 18 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0041-0101 J9 TOXICON JI Toxicon PD NOV PY 2007 VL 50 IS 6 BP 757 EP 778 DI 10.1016/j.toxicon.2007.06.022 PG 22 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 225CQ UT WOS:000250495100004 PM 17706737 ER PT J AU Inoue, H Randazzo, PA AF Inoue, Hiroki Randazzo, Paul A. TI Arf GAPs and their interacting proteins SO TRAFFIC LA English DT Review DE actin; Arf1; Arf6; ASAP1; circular dorsal ruffles; cortactin; EGF receptor; focal adhesion; invadopodia; podosome ID GTPASE-ACTIVATING-PROTEIN; EPIDERMAL-GROWTH-FACTOR; CANCER INVASIVE ACTIVITIES; PAXILLIN-BINDING PROTEIN; CELL-MIGRATION; MEMBRANE CURVATURE; ACTIN CYTOSKELETON; ADAPTER PROTEIN; FOCAL ADHESIONS; COPI VESICLES AB Membrane trafficking and remodeling of the actin cytoskeleton are critical activities contributing to cellular events that include cell growth, migration and tumor invasion. ADP-ribosylation factor (Arf)-directed GTPase activating proteins (GAPs) have crucial roles in these processes. The Arf GAPs function in part by regulating hydrolysis of GTP bound to Arf proteins. The Arf GAPs, which have multiple functional domains, also affect the actin cytoskeleton and membranes by specific interactions with lipids and proteins. A description of these interactions provides insights into the molecular mechanisms by which Arf GAPs regulate physiological and pathological cellular events. Here we describe the Arf GAP family and summarize the currently identified protein interactors in the context of known Arf GAP functions. C1 NCI, Cellular & Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Randazzo, PA (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, Bldg 37, Bethesda, MD 20892 USA. EM randazzo@helix.nih.gov FU Intramural NIH HHS NR 96 TC 90 Z9 97 U1 3 U2 12 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1398-9219 J9 TRAFFIC JI Traffic PD NOV PY 2007 VL 8 IS 11 BP 1465 EP 1475 DI 10.1111/j.1600-0854.2007.00624.x PG 11 WC Cell Biology SC Cell Biology GA 223IP UT WOS:000250363800001 PM 17666108 ER PT J AU Gerlitz, G Livnat, I Ziv, C Yarden, O Bustin, M Reiner, O AF Gerlitz, Gabi Livnat, Idit Ziv, Carmit Yarden, Oded Bustin, Michael Reiner, Orly TI Migration cues induce chromatin alterations SO TRAFFIC LA English DT Article DE chromatin; histone H1; histone modifications; migration ID HISTONE H1; CELL-MIGRATION; NUCLEAR-ENVELOPE; LIVING CELLS; IN-VIVO; PROTEINS; BINDING; HETEROCHROMATIN; P27(KIP1); INVASION AB Directed cell migration is a property central to multiple basic biological processes. Here, we show that directed cell migration is associated with global changes in the chromatin fiber. Polarized posttranslational changes in histone H1 along with a transient decrease in H1 mobility were detected in cells facing the scratch in a wound healing assay. In parallel to the changes in H1, the levels of the heterochromatin marker histone H3 lysine 9 tri-methylation were elevated. Interestingly, reduction of the chromatin-binding affinity of H1 altered the cell migration rates. Moreover, migration-associated changes in histone H1 were observed during nuclear motility in the simple multicellular organism Neurospora crassa. Our studies suggest that dynamic reorganization of the chromatin fiber is an early event in the cellular response to migration cues. C1 Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel. NCI, Protein Sect, Lab Metab, US NIH, Bethesda, MD 20892 USA. Hebrew Univ Jerusalem, Fac Agr Food & Environm Qual Sci, Dept Plant Pathol & Microbiol, IL-76100 Rehovot, Israel. RP Bustin, M (reprint author), Weizmann Inst Sci, Dept Mol Genet, IL-76100 Rehovot, Israel. EM bustin@helix.nih.gov; orly.reiner@weizmann.ac.il RI Yarden, Oded/J-5988-2012; Bustin, Michael/G-6155-2015; OI Reiner, Orly/0000-0001-7560-9599 FU Intramural NIH HHS [Z01 BC004496-30] NR 40 TC 23 Z9 23 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1398-9219 J9 TRAFFIC JI Traffic PD NOV PY 2007 VL 8 IS 11 BP 1521 EP 1529 DI 10.1111/j.1600-0854.2007.00638.x PG 9 WC Cell Biology SC Cell Biology GA 223IP UT WOS:000250363800006 PM 17822403 ER PT J AU Bryant, BJ Conry-Cantilena, C Ahlgren, A Felice, A Stroncek, DF Gibble, J Leitman, SF AF Bryant, Barbara J. Conry-Cantilena, Cathy Ahlgren, Alice Felice, Anthony Stroncek, David F. Gibble, Joan Leitman, Susan F. TI Pasteurella multocida bacteremia in asymptomatic plateletpheresis donors: a tale of two cats SO TRANSFUSION LA English DT Article ID BACTERIAL-CONTAMINATION; UNITED-STATES; INFECTED-DOG; EXPERIENCE; SEPTICEMIA; ENDOCARDITIS; APHERESIS; BITES AB Background: Bacterial contamination of platelet (PLT) concentrates occurs in 1 in 1000 to 1 in 3000 components and has been a leading cause of transfusion-associated morbidity and mortality. Two cases of Pasteurella multocida bacteremia in asymptomatic plateletpheresis donors are reported. Clinical outcomes were profoundly different, emphasizing the importance of robust methods to detect bacterial contamination. Case Reports: The first case occurred before the implementation of bacterial testing of PLTs. A plateletpheresis component was collected from a 70-year-old man and transfused to an 88-year-old man, who developed rigors, tachycardia, and hypotension within 15 minutes of the start of the transfusion. Cardiopulmonary arrest ensued and he expired 6 hours after transfusion. Blood cultures collected after transfusion and cultures of the PLT component were positive for the presence of P. multocida. Investigation revealed that a feral cat had bitten the donor 100 minutes before his donation. He had not reported the event to the donor room staff. The second case involved a 74-year-old woman who developed a flulike syndrome 2 days after plateletpheresis donation. P. multocida was isolated in routine bacterial culture of her PLT component. The donor had several feral cats, and although there was no history of bite or scratch, one cat liked to lick her hands, which were chapped from gardening. Conclusion: Occult bacteremia with P. multocida transmitted by feral cats was the source of PLT contamination in two cases over 3 years. Bacterial testing of PLTs is critical in the prevention of transfusion-acquired sepsis and allows the identification and treatment of asymptomatic bacteremic donors. C1 NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. Reston Hosp, Reston, VA USA. Amer Red Cross Blood Serv, Greater Chesapeake & Potomac Res, Baltimore, MD USA. RP Bryant, BJ (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bldg 10,Room 1C711, Bethesda, MD 20892 USA. EM bryantb2@cc.nih.gov NR 31 TC 8 Z9 9 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 NOV PY 2007 VL 47 IS 11 BP 1984 EP 1989 DI 10.1111/j.1537-2995.2007.01421.x PG 6 WC Hematology SC Hematology GA 223IS UT WOS:000250364100007 PM 17958526 ER PT J AU Edgren, G Tran, TN Hjalgrim, H Rostgaard, K Shanwell, A Titlestad, K Wikman, A Norda, R Jersild, C Wideroff, L Gridley, G Adami, J Melbye, M Nyren, O Reilly, M AF Edgren, Gustaf Tran, Trung Nam Hjalgrim, Henrik Rostgaard, Klaus Shanwell, Agneta Titlestad, Kjell Wikman, Agneta Norda, Rut Jersild, Casper Wideroff, Louise Gridley, Gloria Adami, Johanna Melbye, Mads Nyren, Olof Reilly, Marie TI Improving health profile of blood donors as a consequence of transfusion safety efforts SO TRANSFUSION LA English DT Article ID HEPATOCELLULAR-CARCINOMA; MYOCARDIAL-INFARCTION; CANCER INCIDENCE; DONATION; SWEDEN; ASSOCIATION; HEPATITIS; FINLAND; EVENTS; COHORT AB Background: Transfusion safety rests heavily on the health of blood donors. Although they are perceived as being healthier than average, little is known about their long-term disease patterns and to which extent the blood banks' continuous efforts to optimize donor selection has resulted in improvements. Mortality and cancer incidence among blood donors in Sweden and Denmark was investigated. Study Design and Methods: All computerized blood bank databases were compiled into one database, which was linked to national population and health data registers. With a retrospective cohort study design, 1,110,329 blood donors were followed for up to 35 years from first computer-registered blood donation to death, emigration, or December 31, 2002. Standardized mortality and incidence ratios expressed relative risk of death and cancer comparing blood donors to the general population. Results: Blood donors had an overall mortality 30 percent lower (99% confidence interval [CI] 29%-31%) and cancer incidence 4 percent lower (99% CI 2%-5%) than the background population. Mortality rates and cancer incidence were lowest for outcomes that are recognized as being related to lifestyle factors such as smoking or to the selection criteria for blood donation. Blood donors recruited in more recent years exhibited a lower relative mortality than those who started earlier. Conclusion: Blood donors enjoy better than average health. Explicit and informal requirements for blood donation in Scandinavia, although mostly of a simple nature, have successfully refined the selection of a particularly healthy subpopulation. C1 Karolinska Inst, Dept Med Epidemiol & Biostat, S-17177 Stockholm, Sweden. Karolinska Inst, Dept Med, Clin Epidemiol Unit, S-10401 Stockholm, Sweden. State Serum Inst, Dept Epidemiol Res, Copenhagen, Denmark. Karolinska Univ Hosp, Dept Clin Immunol & Transfus Med, Stockholm, Sweden. Odense Univ Hosp, Dept Clin Immunol, DK-5000 Odense, Denmark. Akad Univ Hosp, Dept Immunobiol & Tranfus Med, Uppsala, Sweden. Aarhus Univ Hosp, Dept Clin Immunol, Aarhus, Denmark. Aarhus Univ Hosp, Dept Clin Immunol, Aarhus, Denmark. NCI, Div Canc Epidemiol & Genet, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Nyren, O (reprint author), Karolinska Inst, Dept Med Epidemiol & Biostat, Box 281, S-17177 Stockholm, Sweden. EM olof.nyren@ki.se RI Hernandez, Jessica/G-6527-2011; Edgren, Gustaf/F-4013-2014; OI Edgren, Gustaf/0000-0002-2198-4745; Rostgaard, Klaus/0000-0001-6220-9414 FU NCI NIH HHS [N01-CP-21175] NR 29 TC 30 Z9 30 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 NOV PY 2007 VL 47 IS 11 BP 2017 EP 2024 DI 10.1111/j.1537-2995.2007.01425.x PG 8 WC Hematology SC Hematology GA 223IS UT WOS:000250364100011 PM 17958530 ER PT J AU Hauben, E Roncarolo, MG Draghici, E Nevo, U AF Hauben, Ehud Roncarolo, Maria Grazia Draghici, Elena Nevo, Uri TI The role of tissue adaptation and graft size in immune tolerance SO TRANSPLANT IMMUNOLOGY LA English DT Article DE ecoimmunity; immune-deficient mice; islet transplantation; diabetes; immune tolerance; graft size; tissue adaptation ID T-CELLS; AUTOIMMUNITY; SCHIZOPHRENIA; MAINTENANCE; VACCINATION; REJECTION; ISLETS; SKIN AB Understanding how immune tolerance is induced and maintained is critical for our approach to immune-related diseases. Ecoimmunity is a new theory that views the immune system-tissue interaction as a co-adapting predator-prey system. Ecoimmunity suggests that tissues adapt to the selective immune pressure during ontogeny and throughout life. Therefore, immune tolerance towards 'self' represents a symmetric. balance between the propensity of the immune system to prey on 'self' cells, and the tissue's specific capacity to undergo phenotypic adaptations in order to avoid destructive immune interaction. According to this theory, we hypothesized that tissues of adult immune-deficient mice, which are not exposed to selective immune pressure, will not withstand immune activity and will therefore display higher susceptibility to graft rejection. To test this prediction, C57B1/6 wild type female mice were rendered diabetic by streptozotocin and transplanted with syngeneic pancreatic islets isolated from either immune-deficient C57B1/6 SCID or wild type females. Remarkably, recipients of islet grafts from immune-deficient syngeneic donors displayed significantly impaired glucose homeostasis compared to mice transplanted with islets of wild type donors (p<0.001, two way repeated measures ANOVA). The severity of this impairment was correlated with islet graft size, suggesting a capacity of transplanted islets to gradually acquire a tolerogenic phenotype. These findings support the view of graft survival that is based on 'natural selection' of tissue cells. In addition, we describe a new experimental system for molecular characterization of self-tolerance. (c) 2007 Elsevier B.V. All rights reserved. C1 [Nevo, Uri] NICHHD, Sect Tissue Biophys & Biomimet, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. [Hauben, Ehud; Roncarolo, Maria Grazia; Draghici, Elena] Univ Vita Salute San Raffaele, I-20132 Milan, Italy. RP Nevo, U (reprint author), NICHHD, Sect Tissue Biophys & Biomimet, Lab Integrat & Med Biophys, NIH, 13 S Dr, Bethesda, MD 20892 USA. EM nevouri@mail.nih.gov OI RONCAROLO, Maria Grazia/0000-0002-2193-9186 FU Telethon [TGT06S01] NR 22 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0966-3274 J9 TRANSPL IMMUNOL JI Transpl. Immunol. PD NOV PY 2007 VL 18 IS 2 BP 122 EP 125 DI 10.1016/j.trim.2007.05.006 PG 4 WC Immunology; Transplantation SC Immunology; Transplantation GA 241AP UT WOS:000251629600008 PM 18005855 ER PT J AU Barlic, J Murphy, PM AF Barlic, Jana Murphy, Philip M. TI An oxidized lipid-peroxisome proliferator-activated receptor gamma-chemokine pathway in the regulation of macrophage-vascular smooth muscle cell adhesion SO TRENDS IN CARDIOVASCULAR MEDICINE LA English DT Review ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; LOW-DENSITY-LIPOPROTEIN; IMPROVED INSULIN-SENSITIVITY; PPAR-GAMMA; MYOCARDIAL-INFARCTION; DEFICIENT MICE; ATHEROSCLEROTIC LESIONS; NONDIABETIC PATIENTS; FRACTALKINE CX3CL1; DIABETES-MELLITUS AB Recent genetic studies have implicated pro-inflammatory chemokines and chemokine receptors in atherogenesis. Studies at the molecular and cellular levels have suggested specific atherogenic mechanisms for two chemokine-chemokine receptor pairs, CCL2-CCR2 and CX3CL1-CX3CR1, involving differential receptor regulation by the transcription factor peroxisome proliferator-activated receptor gamma. This pathway is triggered by oxidized proatherogenic lipids, such as oxidized low-density lipoprotein and linoleic acid derivatives, which promote differentiation of CCR2(hi)CX3CRI(lo) human monocytes to CCR2(lo)CX3CR1(hi) macrophages that adhere to coronary artery smooth muscle cells in a CX3CR1- and peroxisome proliferator-activated receptor gamma-dependent manner. Switching CX3CR1 on and CCR2 off in vivo may result in cessation of CCR2-dependent migration and activation of CX3CR1-dependent retention that together may promote foam cell accumulation in the vessel wall. C1 Univ London Imperial Coll Sci & Technol, Fac Med, Natl Heart & Lung Inst, Leukocyte Biol Sect, London SW7 2AZ, England. NIH, NIAID, Immunol Mol Lab, Mol Signaling Sect, Bethesda, MD 20892 USA. RP Murphy, PM (reprint author), NIH, Bldg 10,Rm 11N113, Bethesda, MD 20892 USA. EM pmm@nih.gov FU Intramural NIH HHS [Z01 AI000615-17] NR 69 TC 15 Z9 20 U1 0 U2 3 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1050-1738 J9 TRENDS CARDIOVAS MED JI Trends Cardiovasc. Med. PD NOV PY 2007 VL 17 IS 8 BP 269 EP 274 AR PII S1050-1738(07)00181-8 DI 10.1016/j.tcm.2007.09.004 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 235KX UT WOS:000251234000004 PM 18021937 ER PT J AU Murray, EA AF Murray, Elisabeth A. TI The amygdala, reward and emotion SO TRENDS IN COGNITIVE SCIENCES LA English DT Review ID ORBITAL PREFRONTAL CORTEX; PAVLOVIAN-INSTRUMENTAL TRANSFER; BASOLATERAL AMYGDALA; ORBITOFRONTAL CORTEX; RHESUS-MONKEYS; MACACA-MULATTA; REINFORCER DEVALUATION; PRIMATE AMYGDALA; MACAQUE MONKEYS; LATERAL NUCLEUS AB Recent research provides new insights into amygdala contributions to positive emotion and reward. Studies of neuronal activity in the monkey amygdala and of autonomic responses mediated by the monkey amygdala show that, contrary to a widely held view, the amygdala is just as important for processing positive reward and reinforcement as it is for negative. In addition, neuropsychological studies reveal that the amygdala is essential for only a fraction of what might be considered,stimulus-reward processing', and that the neural substrates for emotion and reward are partially nonoverlapping. Finally, evidence suggests that two systems within the amygdala, operating in parallel, enable reward-predicting cues to influence behavior; one mediates a general, arousing effect of reward and the other links the sensory properties of reward to emotion. C1 NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Murray, EA (reprint author), NIMH, Neuropsychol Lab, NIH, Bldg 49,Room 1B80,49 Convent Dr, Bethesda, MD 20892 USA. EM murraye@mail.nih.gov OI Murray, Elisabeth/0000-0003-1450-1642 NR 82 TC 265 Z9 273 U1 7 U2 62 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 NOV PY 2007 VL 11 IS 11 BP 489 EP 497 DI 10.1016/j.tics.2007.08.013 PG 9 WC Behavioral Sciences; Neurosciences; Psychology, Experimental SC Behavioral Sciences; Neurosciences & Neurology; Psychology GA 250GO UT WOS:000252288200009 PM 17988930 ER PT J AU Wayne, RK Ostrander, EA AF Wayne, Robert K. Ostrander, Elaine A. TI Lessons learned from the dog genome SO TRENDS IN GENETICS LA English DT Review ID QUANTITATIVE TRAIT LOCI; GERMAN-SHEPHERD DOG; DOMESTIC DOG; LINKAGE DISEQUILIBRIUM; CANIS-FAMILIARIS; MITOCHONDRIAL-DNA; GENE-EXPRESSION; CONSERVATION GENETICS; MORPHOLOGICAL CHANGE; CONE DEGENERATION AB Extensive genetic resources and a high-quality genome sequence position the dog as an important model species for understanding genome evolution, population genetics and genes underlying complex phenotypic traits. Newly developed genomic resources have expanded our understanding of canine evolutionary history and dog origins. Domestication involved genetic contributions from multiple populations of gray wolves probably through backcrossing. More recently, the advent of controlled breeding practices has segregated genetic variability into distinct dog breeds that possess specific phenotypic traits. Consequently, genome-wide association and selective sweep scans now allow the discovery of genes underlying breed-specific characteristics. The dog is finally emerging as a novel resource for studying the genetic basis of complex traits, including behavior. C1 Univ Calif Los Angeles, Dept Ecol & Evolut Biol, Los Angeles, CA 91302 USA. NHGRI, Natl Inst Hlth, Canc Genet Branch, Bethesda, MD 20892 USA. RP Wayne, RK (reprint author), Univ Calif Los Angeles, Dept Ecol & Evolut Biol, Los Angeles, CA 91302 USA. EM rwayne@ucla.edu OI Ostrander, Elaine/0000-0001-6075-9738 NR 91 TC 97 Z9 98 U1 9 U2 106 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0168-9525 J9 TRENDS GENET JI Trends Genet. PD NOV PY 2007 VL 23 IS 11 BP 557 EP 567 DI 10.1016/j.tig.2007.08.013 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 239QU UT WOS:000251533600006 PM 17963975 ER PT J AU Terabe, M Berzofsky, JA AF Terabe, Masaki Berzofsky, Jay A. TI NKT cells in immunoregulation of tumor immunity: a new immunoregulatory axis SO TRENDS IN IMMUNOLOGY LA English DT Review ID KILLER-T-CELLS; ANTIGEN-PRESENTING CELLS; GROWTH-FACTOR-BETA; NATURAL-KILLER; ALPHA-GALACTOSYLCERAMIDE; IN-VIVO; ANTITUMOR IMMUNITY; FUNCTIONALLY DISTINCT; REGULATORY-CELLS; IL-12 PRODUCTION AB CD1d-restricted natural killer T (NKT) cells have at least two subsets: type I, semi-invariant TCR alpha chain-expressing (V alpha 14J alpha 18 in mice, V alpha 24J alpha 18 in humans), and type II, variable TCR alpha chain-expressing. The protective role of NKT cells in tumor immunosurveillance and immunity has been well documented but paradoxically, there are also studies ascribing a suppressive role to these cells. Recent studies have resolved this paradox by revealing distinct roles for the two types of NKT cells, whereby type I NKT cells enhance anti-tumor responses and type II NKT cells suppress these responses. The finding of cross-regulation between the two types of NKT cells suggests a new immunoregulatory axis. Consideration of the cross-talk of NKT cells along with the well-defined suppression by regulatory T cells could provide new insights into cancer immunotherapy. C1 [Terabe, Masaki; Berzofsky, Jay A.] NCI, Ctr Canc Res, Vaccine Branch, Bethesda, MD 20814 USA. RP Terabe, M (reprint author), NCI, Ctr Canc Res, Vaccine Branch, Bethesda, MD 20814 USA. EM terabe@mail.nih.gov FU Intramural NIH HHS NR 73 TC 93 Z9 98 U1 0 U2 3 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 NOV PY 2007 VL 28 IS 11 BP 491 EP 496 DI 10.1016/j.it.2007.05.008 PG 6 WC Immunology SC Immunology GA 241MH UT WOS:000251660000005 PM 17964217 ER PT J AU Youm, YH Yang, H Yoon, YD Kim, DY Lee, C Yoo, TK AF Youm, Yun Hee Yang, Hyunwon Yoon, Yong-Dal Kim, Duk-Yoon Lee, Chung Yoo, Tag Keun TI Doxazosin-induced clusterin expression and apoptosis in prostate cancer cells SO UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS LA English DT Article DE apoptosis; clusterin; prostate cancer cells; PC-3 cells ID SULFATED GLYCOPROTEIN-2 CLUSTERIN; NECROSIS-FACTOR-ALPHA; APOLIPOPROTEIN-J; DEATH; RAT; OVEREXPRESSION; INDUCTION; THERAPY; SGP-2; GENE AB The purpose of this study was to correlate temporal expression of clusterin and apoptosis in androgen-independent human prostate cancer cells (PC-3) treated with 25 mu M doxazosin. DNA fragmentation, reverse transcriptase polymerase chain reaction, and terminal transferase-mediated biotinylated 16-desoxy-uridene triphosphate nick-end labeling (TUNEL) assays were used to assess degree of apoptosis and temporal and spatial expression of clusterin mRNA and protein. DNA fragmentation was significant at 48 hours. Clusterin mRNA expression was 3-fold higher than control at 9 hours and was maintained over 48 hours. The TUNEL assay showed increasing percentage of apoptotic cells and presence of clusterin after doxazosin treatment. During doxazosin-induced apoptosis in PC3 cells, clusterin appeared to initially accumulate in the cytoplasm and protect against apoptosis; later, after its transport to the nucleus, clusterin was no longer able to suppress apoptosis. (C) 2007 Elsevier Inc. All rights reserved. C1 Eulji Univ, Sch Med, Inst Life Sci, Seoul, South Korea. NIA, NIH, Gerontol Res Ctr, Immunol Lab, Baltimore, MD 21224 USA. Hanyang Univ, Coll Nat Sci, Dept Life Sci, Seoul, South Korea. Catholic Univ, Dept Urol, Taejon, South Korea. Northwestern Univ, Dept Urol, Chicago, IL 60208 USA. Eulji Univ, Sch Med, Dept Urol, Eulji Med Ctr, Seoul, South Korea. RP Yoo, TK (reprint author), Eulji Univ, Sch Med, Inst Life Sci, Seoul, South Korea. EM ytk5202@eulji.or.kr NR 39 TC 5 Z9 5 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1078-1439 J9 UROL ONCOL-SEMIN ORI JI Urol. Oncol.-Semin. Orig. Investig. PD NOV-DEC PY 2007 VL 25 IS 6 BP 483 EP 488 DI 10.1016/j.urolonc.2007.02.010 PG 6 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 238XV UT WOS:000251482600006 PM 18047956 ER PT J AU Frost, MH Reeve, BB Liepa, AM Stauffer, JW Hays, RD Sloan, JA AF Frost, Marlene H. Reeve, Bryce B. Liepa, Astra M. Stauffer, Joseph W. Hays, Ron D. Sloan, Jeff A. CA Mayo FDA PROCMG TI What is sufficient evidence for the reliability and validity of patient-reported outcome measures? SO VALUE IN HEALTH LA English DT Article; Proceedings Paper CT Meeting on FDA Draft Guidance on Patient-Reported Outcomes CY FEB 23-25, 2006 CL Chantilly, VA DE patient-reported outcomes; psychometric; validation ID ITEM RESPONSE THEORY; FUNCTIONAL STATUS; PERFORMANCE; STANDARD; TESTS; INSTRUMENTS; PRECISE; SCORES; ISSUES; SCALE AB This article focuses on the necessary psychometric properties of a patient-reported outcomes (PROs) measure. Topics include the importance of reliability and validity, psychometric approaches used to provide reliability and validity estimates, the kinds of evidence needed to indicate that a PRO has a sufficient level of reliability and validity, contexts that may affect psychometric properties, methods available to evaluate PRO instruments when the context varies, and types of reliability and validity testing that are appropriate during different phases of clinical trials. Points discussed include the perspective that the psychometric properties of reliability and validity are on a continuum in which the more evidence one has, the greater confidence there is in the value of the PRO data. Construct validity is the type of validity most frequently used with PRO instruments as few "gold standards" exist to allow the use of criterion validity and content validity by itself only provides beginning evidence of validity. Several guidelines are recommended for establishing sufficient evidence of reliability and validity. For clinical trials, a minimum reliability threshold of 0.70 is recommended. Sample sizes for testing should include at least 200 cases and results should be replicated in at least one additional sample. At least one full report on the development of the instrument and one on the use of the instrument are deemed necessary to evaluate the PRO psychometric properties. Psychometric testing ideally occurs before the initiation of Phase III trials. When testing does not occur prior to a Phase III trial, considerable risk is posed in relation to the ability to substantiate the use of the PRO data. Various qualitative (e.g., focus groups, behavioral coding, cognitive interviews) and quantitative approaches (e.g., differential item functioning testing) are useful in evaluating the reliability and validity of PRO instruments. C1 Mayo Clin, Womens Canc Program, Rochester, MN USA. NCI, Div Canc Control & Populat Sci, Outcomes Res Branch, Appl Res Program, Bethesda, MD 20892 USA. Eli Lilly & Co, Global Hlth Outcomes, Indianapolis, IN 46285 USA. Alpharma, Global Med Affairs, Piscataway, NJ USA. Univ Calif Los Angeles, Dept Hlth Sci, Dept Med, UCLA Div Gen Internal Med & Hlth Ser Res, Los Angeles, CA USA. RAND Corp, Santa Monica, CA USA. RP Sloan, JA (reprint author), Care of Jeff A Sloan, Mayo Clin & Mayo Fdn, Dept Hlth Sci Res, 200 1st St SW, Rochester, MN 55905 USA. EM jsloan@mayo.edu RI Hays, Ronald/D-5629-2013 FU NIA NIH HHS [AG-02-004, P01-AG-02-079]; NIMHD NIH HHS [P20-MD00148-01] NR 44 TC 103 Z9 106 U1 3 U2 10 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1098-3015 J9 VALUE HEALTH JI Value Health PD NOV-DEC PY 2007 VL 10 SU 2 BP S94 EP S105 DI 10.1111/j.1524-4733.2007.00272.x PG 12 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 229YN UT WOS:000250842600006 PM 17995479 ER PT J AU Patrick, DL Burke, LB Powers, JH Scott, JA Rock, EP Dawisha, S O'Neill, R Kennedy, DL AF Patrick, Donald L. Burke, Laurie B. Powers, John H. Scott, Jane A. Rock, Edwin P. Dawisha, Sahar O'Neill, Robert Kennedy, Dianne L. TI Patient-reported outcomes to support medical product labeling claims: FDA perspective SO VALUE IN HEALTH LA English DT Article; Proceedings Paper CT Meeting on FDA Draft Guidance on Patient-Reported Outcomes CY FEB 23-25, 2006 CL Chantilly, VA DE clinical trials; FDA; patient-reported outcomes; PRO; QOL; statistical analysis AB This article concerns development and use of patient-reported outcomes (PROs) in clinical trials to evaluate medical products. A PRO is any report coming directly from patients, without interpretation by physicians or others, about how they function or feel in relation to a health condition and its therapy. PRO instruments are used to measure these patient reports. PROs provide a unique perspective on medical therapy, because some effects of a health condition and its therapy are known only to patients. Properly developed and evaluated PRO instruments also have the potential to provide more sensitive and specific measurements of the effects of medical therapies, thereby increasing the efficiency of clinical trials that attempt to measure the meaningful treatment benefits of those therapies. Poorly developed andevaluated instruments may provide misleading conclusions or data that cannot be used to support product labeling claims. We review selected major challenges from Food and Drug Administration's perspective in using PRO instruments, measures, and end points to support treatment benefit claims in product labeling. These challenges highlight the need for sponsors to formulate desired labeling claim(s) prospectively, to acquire and document information needed to support these claim(s), and to identify existing instruments or develop new and more appropriate PRO instruments for evaluating treatment benefit in the defined population in which they will seek claims. C1 Univ Washington, Seattle Qual Life Grp, Special Gov Employee Food & Drug Adm, Seattle, WA 98103 USA. US FDA, Ctr Drug Evaluat & Res, Off New Drugs, Study Endpoionts & Label Dev Team, Silver Spring, MD USA. NIAID, Sci Applicat Int Corp, Natl Inst Hlth, Bethesda, MD 20892 USA. GSK Biol, Collegeville, PA USA. US FDA, Ctr Devices & Radiol Hlth, Div Gen Restorat & Neurol Devices, Rockville, MD 20857 USA. US FDA, Ctr Drug Evaluat & Res, Off Biostat, Silver Spring, MD USA. RP Patrick, DL (reprint author), Univ Washington, Seattle Qual Life Grp, Special Gov Employee Food & Drug Adm, Box 358852, Seattle, WA 98103 USA. EM donald@u.washington.edu NR 19 TC 194 Z9 194 U1 4 U2 16 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1098-3015 J9 VALUE HEALTH JI Value Health PD NOV-DEC PY 2007 VL 10 SU 2 BP S125 EP S137 DI 10.1111/j.1524-4733.2007.00275.x PG 13 WC Economics; Health Care Sciences & Services; Health Policy & Services SC Business & Economics; Health Care Sciences & Services GA 229YN UT WOS:000250842600009 PM 17995471 ER PT J AU Paoloni, MC Khanna, C AF Paoloni, Melissa C. Khanna, Chand TI Comparative oncology today SO VETERINARY CLINICS OF NORTH AMERICA-SMALL ANIMAL PRACTICE LA English DT Article ID MAST-CELL TUMORS; ENCAPSULATED MURAMYL TRIPEPTIDE; SPONTANEOUSLY OCCURRING TUMORS; NATURALLY-OCCURRING CANCERS; COLONY-STIMULATING FACTOR; ANIMAL-MODELS; C-KIT; COMPANION ANIMALS; ADJUVANT THERAPY; CONTROLLED TRIAL AB The value of comparative oncology has been increasingly recognized in the field of cancer research, including the identification of cancer-associated genes; the study of environmental risk factors, tumor biology, and progression; and, perhaps most importantly, the evaluation of novel cancer therapeutics. The fruits of this effort are expected to be the creation of better and more specific drugs to benefit veterinary and human patients who have cancer. The state of the comparative oncology field is outlined in this article, with an emphasis on cancer in dogs. C1 NCI, Comparat Oncol Program, NIH, Bethesda, MD 20892 USA. RP Khanna, C (reprint author), NCI, Comparat Oncol Program, NIH, 37 Convent Dr,Room 2144, Bethesda, MD 20892 USA. EM khannac@mail.nih.gov FU Intramural NIH HHS [Z01 BC010569-03, Z99 CA999999] NR 57 TC 38 Z9 38 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0195-5616 EI 1878-1306 J9 VET CLIN N AM-SMALL JI Vet. Clin. N. Am.-Small Anim. Pract. PD NOV PY 2007 VL 37 IS 6 BP 1023 EP + DI 10.1016/i.cvsm.2007.08.003 PG 11 WC Veterinary Sciences SC Veterinary Sciences GA 239KG UT WOS:000251516600003 PM 17950880 ER PT J AU Yates, CC Whaley, D Hancock, WW Lu, B Newsome, J Hebda, PA Bodnar, R Wells, A AF Yates, Cecelia C. Whaley, Diana Hancock, Wayne W. Lu, Bao Newsome, Joseph Hebda, Patricia A. Bodnar, Richard Wells, Alan TI CXCR3-/- mice display a dysfunction in basement membrane remodeling and delay in re-epithelialization during wound healing SO WOUND REPAIR AND REGENERATION LA English DT Meeting Abstract C1 [Yates, Cecelia C.; Whaley, Diana; Hancock, Wayne W.; Lu, Bao; Newsome, Joseph; Hebda, Patricia A.; Bodnar, Richard; Wells, Alan] Univ Pittsburgh, NIH, Natl Inst Gen Med Sci,Pittsburg VAMConflict, Dept Pathol & Otolaryngol, Pittsburgh, PA 15260 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1067-1927 J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD NOV-DEC PY 2007 VL 15 IS 6 BP A123 EP A123 PG 1 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA 232OR UT WOS:000251029500041 ER PT J AU Yates, CC Whaley, D Kulasekaran, P Newsome, J Hebda, P Wells, A AF Yates, Cecelia C. Whaley, Diana Kulasekaran, Priya Newsome, Joseph Hebda, Patricia Wells, Alan TI The ELR-negative CXC chemokine CXCL11 (IP-9 or I-TAC) facilitates dermal and epidermal maturation during wound repair SO WOUND REPAIR AND REGENERATION LA English DT Meeting Abstract C1 [Yates, Cecelia C.; Whaley, Diana; Kulasekaran, Priya; Newsome, Joseph; Hebda, Patricia; Wells, Alan] Univ Pittsburgh, NIH, Natl Inst Gen Med Sci,Pittsburg VAMC Conflict, Dept Pathol & otolaryngol, Pittsburgh, PA 15260 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1067-1927 J9 WOUND REPAIR REGEN JI Wound Repair Regen. PD NOV-DEC PY 2007 VL 15 IS 6 BP A122 EP A122 PG 1 WC Cell Biology; Dermatology; Medicine, Research & Experimental; Surgery SC Cell Biology; Dermatology; Research & Experimental Medicine; Surgery GA 232OR UT WOS:000251029500040 ER PT J AU Meade, KG Gormley, E Doyle, MB Fitzsimons, T O'Farrelly, C Costello, E Keane, J Zhao, YD MacHugh, DE AF Meade, Kieran G. Gormley, Eamonn Doyle, Mairead B. Fitzsimons, Tara O'Farrelly, Cliona Costello, Eamon Keane, Joseph Zhao, Yingdong MacHugh, David E. TI Innate gene repression associated with Mycobacterium bovis infection in cattle: toward a gene signature of disease SO BMC GENOMICS LA English DT Article ID BLOOD MONONUCLEAR-CELLS; AVIUM SUBSP PARATUBERCULOSIS; GAMMA-INTERFERON ASSAY; TOLL-LIKE RECEPTORS; NF-KAPPA-B; IMMUNE-RESPONSES; CDNA MICROARRAY; MONOCYTE CHEMOATTRACTANT; TUBERCULOSIS; EXPRESSION AB Background: Bovine tuberculosis is an enduring disease of cattle that has significant repercussions for human health. The advent of high-throughput functional genomics technologies has facilitated large-scale analyses of the immune response to this disease that may ultimately lead to novel diagnostics and therapeutic targets. Analysis of mRNA abundance in peripheral blood mononuclear cells (PBMC) from six Mycobacterium bovis infected cattle and six non-infected controls was performed. A targeted immunospecific bovine cDNA microarray with duplicated spot features representing 1,391 genes was used to test the hypothesis that a distinct gene expression profile may exist in M. bovis infected animals in vivo. Results: In total, 378 gene features were differentially expressed at the P <= 0.05 level in bovine tuberculosis (BTB)-infected and control animals, of which 244 were expressed at lower levels (65%) in the infected group. Lower relative expression of key innate immune genes, including the Toll-like receptor 2 (TLR2) and TLR4 genes, lack of differential expression of indicator adaptive immune gene transcripts (IFNG, IL2, IL4), and lower BOLA major histocompatibility complex-class I (BOLA) and class II (BOLA-DRA) gene expression was consistent with innate immune gene repression in the BTB-infected animals. Supervised hierarchical cluster analysis and class prediction validation identified a panel of 15 genes predictive of disease status and selected gene transcripts were validated (n = 8 per group) by real time quantitative reverse transcription PCR. Conclusion: These results suggest that large-scale expression profiling can identify gene signatures of disease in peripheral blood that can be used to classify animals on the basis of in vivo infection, in the absence of exogenous antigenic stimulation. C1 [Meade, Kieran G.; O'Farrelly, Cliona; MacHugh, David E.] Univ Coll Dublin, Conway Inst Biomol & Biomed Res, Dublin 4, Ireland. [Meade, Kieran G.; O'Farrelly, Cliona] St Vincents Univ Hosp, Educ & Res Ctr, Dublin 4, Ireland. [Gormley, Eamonn; Doyle, Mairead B.; Fitzsimons, Tara] Univ Coll Dublin, Coll Life Sci, Sch Agr Food Sci & Vet Med, TB Diagnost & Immunol Res Ctr, Dublin 4, Ireland. [Costello, Eamon] Cent Vet Res Lab, Dublin, Ireland. [Keane, Joseph] St James Hosp, Trinity Coll, Sch Med, Dublin 8, Ireland. [Zhao, Yingdong] NCI, Computat Syst Biol Grp, Biometr Res Branch, Rockville, MD USA. [MacHugh, David E.] Univ Coll Dublin, Coll Life Sci, Sch Agr Food Sci & Vet Med, Anim Genom Lab, Dublin 4, Ireland. RP Gormley, E (reprint author), Univ Coll Dublin, Conway Inst Biomol & Biomed Res, Dublin 4, Ireland. EM kieran.meade@ucd.ie; egormley@ucd.ie; mairead.b.doyle@ucd.ie; tara.fitzsimons@ucd.ie; cliona.ofarrelly@ucd.ie; eamonn.costello@agriculture.gov.ie; jkeane@stjames.ie; zhaoy@ctep.nci.nih.gov; david.machugh@ucd.ie RI Meade, Kieran/K-7562-2015; OI Gormley, Eamonn/0000-0003-3900-0393; Keane, Joseph/0000-0001-5313-385X; MacHugh, David/0000-0002-8112-4704 NR 59 TC 42 Z9 45 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD OCT 31 PY 2007 VL 8 AR 400 DI 10.1186/1471-2164-8-400 PG 15 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 257DS UT WOS:000252780000004 PM 17974019 ER PT J AU Driscoll, I Monfils, MH Flynn, C Teskey, GC Kolb, B AF Driscoll, Ira Monfils, Marie-H Flynn, Corey Teskey, G. Campbell Kolb, Bryan TI Neurophysiological properties of cells filling the neonatal medial prefrontal cortex lesion cavity SO BRAIN RESEARCH LA English DT Article DE P10; lesion; unit; recording; regeneration; mPFC1 ID FUNCTIONAL RECOVERY; FRONTAL LESIONS; MOTOR CORTEX; CORTICAL-LESIONS; RATS; DAMAGE; ADULTHOOD; BEHAVIOR; INJURY AB Removal of the medial prefrontal cortex (mPFC) of the rat during the initial 7-12 days of life results in spontaneous filling of lesion cavity that is accompanied by recovery of cognitive and motor functions. To date, it remains uncertain whether tissue filling the lesion cavity is actually supporting the functional improvement. in the present study, we examined whether spontaneous neuronal activity could be recorded in adulthood from the tissue that fills the lesion cavity. We recorded EEG and multiunit activity, in adulthood from the mPFC and the motor cortex of rats that had received neonatal mPFC lesions on post-natal day 10 (P10) or their non-lesioned littermate controls. We found similarities in both the firing pattern and firing rate of cells from the filled-in region compared to that of controls, although the power associated with peak frequencies in the delta, alpha, and beta range in the EEG recorded from the filled-in region was lower compared to controls. Overall, our results suggest that the cells found in the lesion cavity have similar neurophysiological properties to those found in normal tissue and thus should be capable of at least partially supporting the observed recovery of function. (c) 2007 Elsevier B.V. All rights reserved C1 Univ Lethbridge, Canadian Ctr Behavioral Neurosci, Lethbridge, AB T1K 3M4, Canada. Univ Calgary, Behavioral Neurosci Res Grp, Calgary, AB T2N 1N4, Canada. RP Driscoll, I (reprint author), LPC, GRC, NIA, 5600 Nathan Schock Dr, Baltimore, MD 21224 USA. EM driscolli@mail.nih.gov; kolb@uleth.ca RI Monfils, Marie/F-1282-2013; OI Monfils, Marie-H./0000-0001-8971-6651 NR 19 TC 2 Z9 2 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD OCT 31 PY 2007 VL 1178 BP 38 EP 43 DI 10.1016/j.brainres.2007.08.031 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 233VH UT WOS:000251117900005 PM 17915198 ER PT J AU Numachi, Y Ohara, A Yamashita, M Fukushima, S Kobayashi, H Hata, H Watanabe, H Hall, FS Lesch, KP Murphy, DL Uhl, GR Sora, L AF Numachi, Yohtaro Ohara, Arihisa Yamashita, Motoyasu Fukushima, Setsu Kobayashi, Hideaki Hata, Harurmi Watanabe, Hidekazu Hall, F. Scott Lesch, Klaus-Peter Murphy, Dennis L. Uhl, George R. Sora, Lchiro TI Methamphetamine-induced hyperthermia and lethal toxicity: Role of the dopamine and serotonin transporters SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE monoamine; norepmephrine; paradoxical hypothermia; interleukin-1 beta; Transgenic knockout mouse ID TUMOR-NECROSIS-FACTOR; INDUCED NEUROTOXICITY; PLACE PREFERENCE; COCAINE REWARD; KNOCKOUT MICE; AMPHETAMINE; MECHANISMS; MODELS; RATS; TEMPERATURE AB We examined the hyperthermic and lethal toxic effects of methamphetamine in dopamine transporter (DAT) and/or serotonin transporter (SERT) knockout (KO) mice. Methamphetamine (45 mg/kg) caused significant hyperthermia even in the mice with a single DAT gene copy and no SERT copies (DAV(-/-) SERT-/- mice). Mice with no DAT copies and a single SERT gene copy (DAT(-/-) SERT+/- mice) showed significant but reduced hyperthermia when compared to wild-type mice after methamphetamine. Surprisingly, DAT/SERT double KO mice exhibited a paradoxical hypothermia after methamphetamine. These results demonstrate that methamphetamine exerts a hyperthermic effect via DAT, or via SERT, in the absence of DAT. The selective norepinephrine transporter blocker (20 mg/kg nisoxetine) caused hyperthermia in DAT/SERT double KO mice, suggesting that the norepinephrine system is not responsible for methamphetamine-induced paradoxical hypothermia in the double KO mice. DAT gene deletion in mice strikingly increased LD50 of methamphetamine by 1.7-1.8 times that of wild-type mice, suggesting that the lethal toxic effect of methamphetamine is mainly dependent on DAT. Moreover, dissociation between hyperthermic and lethal toxic effects of methamphetamine in DAT single KO mice and DAT/SERT double KO mice suggest that hyperthermia is not a prerequisite for methamphetamine-induced lethality. Methamphetamine (45 mg/kg) significantly increased mRNA of interleukin-1 beta, which is the major endogenous pyrogen, in the hypothalamus of wild-type mice but not in DAT/SERT double KO mice, which provides a partial mechanism of methamphetamine-induced paradoxical hypothermia. These results suggest that DAT and SERT are key molecules for hyperthermic and lethal toxic effects of methamphetamine. (c) 2007 Elsevier B.V. All rights reserved. C1 Tohoku Univ, Grad Sch Med, Dept Biol Psychiat, Sendai, Miyagi 9808574, Japan. Natl Inst Drug Abuse, Div Intramural Res, Mol Neurobiol Branch, Bethesda, MD 20892 USA. Univ Wurzburg, Dept Psychiat, D-97070 Wurzburg, Germany. NIMH, Clin Sci Lab, Div Intramural Res Programs, Bethesda, MD 20892 USA. RP Sora, L (reprint author), Tohoku Univ, Grad Sch Med, Dept Biol Psychiat, 1-1 Seiryo Machi, Sendai, Miyagi 9808574, Japan. EM isora@mail.tains.tohoku.ac.jp RI Kobayashi, Hideaki/C-8617-2009; Lesch, Klaus-Peter/J-4906-2013; Hall, Frank/C-3036-2013 OI Kobayashi, Hideaki/0000-0003-3599-0465; Lesch, Klaus-Peter/0000-0001-8348-153X; Hall, Frank/0000-0002-0822-4063 FU Intramural NIH HHS NR 39 TC 29 Z9 32 U1 1 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 OCT 31 PY 2007 VL 572 IS 2-3 BP 120 EP 128 DI 10.1016/j.ejphar.2007.06.022 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 222IC UT WOS:000250288600005 PM 17673199 ER PT J AU Wu, LG Ryan, TA Lagnado, L AF Wu, Ling-Gang Ryan, Timothy A. Lagnado, Leon TI Modes of vesicle retrieval at ribbon synapses, calyx-type synapses, and small central Synapses SO JOURNAL OF NEUROSCIENCE LA English DT Article DE endocytosis; ribbon synapses; calyx of Held; hippocampal synapses; fusion; kiss-and-run ID RETINAL BIPOLAR CELLS; FROG NEUROMUSCULAR-JUNCTION; CLATHRIN-MEDIATED ENDOCYTOSIS; SINGLE SYNAPTIC VESICLES; HIPPOCAMPAL SYNAPSES; MEMBRANE RETRIEVAL; NERVE-TERMINALS; TRANSMITTER RELEASE; AFFERENT SYNAPSE; TRAPEZOID BODY C1 NINDS, Bethesda, MD 20892 USA. Weill Cornell Med Coll, Dept Biochem, New York, NY 10021 USA. MRC, Mol Biol Lab, Cambridge CB1 0QH, England. RP Wu, LG (reprint author), NINDS, Bethesda, MD 20892 USA. EM wul@ninds.nih.gov OI Ryan, Timothy/0000-0003-2533-9548 FU Medical Research Council [MC_U105178794]; NINDS NIH HHS [R01 NS036942] NR 74 TC 74 Z9 74 U1 0 U2 6 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 OCT 31 PY 2007 VL 27 IS 44 BP 11793 EP 11802 DI 10.1523/JNEUROSCI.3471-07.2007 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 226HB UT WOS:000250577600004 PM 17978015 ER PT J AU Satterlee, JS Barbee, S Jin, P Krichevsky, A Salama, S Schratt, G Wu, DY AF Satterlee, John S. Barbee, Scott Jin, Peng Krichevsky, Anna Salama, Sofie Schratt, Gerhard Wu, Da-Yu TI Noncoding RNAs in the brain SO JOURNAL OF NEUROSCIENCE LA English DT Article DE brain development; CREB; dendritic spine; development; differentiation; epigenetic; human forebrain development; learning and memory; neurogenesis; Purkinje neurons; RNA; synaptic plasticity ID CENTRAL-NERVOUS-SYSTEM; X MENTAL-RETARDATION; P-BODIES; MICRORNAS; PATHWAY; MIR-124; PROTEIN; MECHANISMS; NUCLEAR; MEMORY AB Cells transcribe thousands of RNAs that do not appear to encode proteins. The neuronal functions of these noncoding RNAs(ncRNAs) are for the most part not known, but specific ncRNAs have been shown to regulate dendritic spine development, neuronal fate specification and differentiation, and synaptic protein synthesis. ncRNAs have been implicated in a number of neuronal diseases including Tourette's syndrome and Fragile X syndrome. Future studies will likely identify additional neuronal functions for ncRNAs as well as roles for these molecules in other neuropsychiatric and neurodevelopmental disorders. C1 Natl Inst Drug Abuse, Div Basic Neurosci & Behav Res, Bethesda, MD 20892 USA. Univ Denver, Dept Biol Sci, Denver, CO 80208 USA. Emory Univ, Sch Med, Dept Human Genet, Atlanta, GA 30322 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Neurol Ctr Neurol Dis, Boston, MA 02115 USA. Univ Calif Santa Cruz, Ctr Biomol Engn, Santa Cruz, CA 95064 USA. Univ Heidelberg, Interdisciplinary Ctr Neurosci, D-69120 Heidelberg, Germany. RP Satterlee, JS (reprint author), Natl Inst Drug Abuse, Div Basic Neurosci & Behav Res, 6001 Execut Blvd, Bethesda, MD 20892 USA. EM satterleej@nida.nih.gov RI Jin, Peng/B-5977-2012 NR 42 TC 24 Z9 28 U1 0 U2 5 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 OCT 31 PY 2007 VL 27 IS 44 BP 11856 EP 11859 DI 10.1523/JNEUROSCI.3624-07.2007 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 226HB UT WOS:000250577600013 PM 17978024 ER PT J AU Cookson, MR Dauer, W Dawson, T Fon, EA Guo, M Shen, J AF Cookson, Mark R. Dauer, William Dawson, Ted Fon, Edward A. Guo, Ming Shen, Jie TI The roles of kinases in familial Parkinson's disease SO JOURNAL OF NEUROSCIENCE LA English DT Article DE Parkinson's disease; dopaminergic; genetics; human; knock-out mice; mitochondria; neuron death; phosphorylation; protein kinases; signal transduction ID DEFICIENT MICE; LRRK2 MUTATION; GENE; PINK1; UBIQUITIN; MUTANTS; DROSOPHILA-PINK1; INACTIVATION; PATHOLOGY; PROTEINS AB The purpose of this mini-symposium is to discuss some of the inherited forms of Parkinson's disease (PD) in view of recent data suggesting that some of the proteins affect cellular signaling pathways. As an illustration, we shall focus on two different kinases associated with recessive and dominant forms of PD. Mutations in the mitochondrial kinase PTEN ( phosphatase and tensin homolog)induced kinase 1 (PINK1) are loss-of-function mutations in a normally neuroprotective protein. Loss-of-function mutations in model organisms have variable effects, from dramatic muscle and spermatid defects in Drosophila to more subtle neurophysiological abnormalities in mice. Several lines of evidence relate these to the action of a second gene for familial PD, parkin, an E3 ubiquitin ligase shown recently to have effects on Akt signaling. Mutations in leucine-rich repeat kinase 2 (LRRK2), a cytosolic kinase, are dominant and have the opposite effect of causing neuronal damage. The mechanism(s) involved are uncertain at this time because LRRK2 is a large and complex molecule with several domains. Increased kinase activity accounts for the action of at least some of the mutations, suggesting that hyperactive or misregulated kinase activity may lead to the damaging effects of LRRK2 in neurons. For both PINK1 and LRRK2, the following key question that needs to be answered: what are the physiological substrates that mediate effects in cells? Here, we will discuss some of the recent thinking about physiological and pathological roles for signaling in PD and how these may have therapeutic implications for the future. C1 NIA, Cell Biol & Gene Express Unit, Neurogenet Lab, Bethesda, MD 20892 USA. Columbia Univ, Dept Pharmacol, New York, NY 10032 USA. Columbia Univ, Dept Neurol, New York, NY 10032 USA. Johns Hopkins Univ, Sch Med, Inst Cell Engn, Baltimore, MD 21205 USA. McGill Univ, Montreal Neurol Inst, Ctr Neuronal Survival, Montreal, PQ H3A 2B4, Canada. Univ Calif Los Angeles, Los Angeles Sch Med, Brain Res Inst, Dept Neurol, Los Angeles, CA 90095 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. RP Cookson, MR (reprint author), Bldg 35 Porter Bldg,1a116,35 Convent Dr, Bethesda, MD 20892 USA. EM cookson@mail.nih.gov NR 35 TC 35 Z9 35 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 31 PY 2007 VL 27 IS 44 BP 11865 EP 11868 DI 10.1523/JNEUROSCI.3695-07.2007 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 226HB UT WOS:000250577600015 PM 17978026 ER PT J AU Zhao, M Choi, YS Obrietan, K Dudek, SM AF Zhao, Meilan Choi, Yun-Sik Obrietan, Karl Dudek, Serena M. TI Synaptic plasticity (and the lack thereof) in hippocampal CA2 neurons SO JOURNAL OF NEUROSCIENCE LA English DT Article DE long-term potentiation; long-term depression; TREK-1 channels; STEP; ERK; CREB ID LONG-TERM POTENTIATION; SIGNAL-REGULATED KINASE; TYROSINE PHOSPHATASE STEP; PAIRED-PULSE FACILITATION; NMDA RECEPTOR SUBTYPES; RAT HIPPOCAMPUS; PYRAMIDAL CELLS; NONPYRAMIDAL CELLS; GENE-EXPRESSION; SECTOR CA2 AB The hippocampus is critical for some forms of memory and spatial navigation, but previous research has mostly neglected the CA2, a unique region situated between CA3 and CA1. Here, we show that CA2 pyramidal neurons have distinctive physiological characteristics that include an unprecedented synaptic stability. Although basal synaptic currents in CA1 and CA2 are quite similar, synaptic plasticity including long-term potentiation and long-term depression is absent or less likely to be induced with conventional methods of stimulation in CA2. We also find that CA2 neurons have larger leak currents and more negative resting membrane potentials than CA1 neurons, and consequently, more current is required for action potential generation in CA2 neurons. These data suggest that the molecular "conspiracy against plasticity" in CA2 makes it functionally distinct from the other hippocampal CA regions. This work provides critical insight into hippocampal function and may lead to an understanding of the resistance of CA2 to damage from disease, trauma, and hypoxia. C1 Natl Inst Environm Hlth Sci, NIH, Res Triangle Pk, NC 27709 USA. Ohio State Univ, Dept Neurosci, Columbus, OH 43210 USA. RP Dudek, SM (reprint author), Natl Inst Environm Hlth Sci, NIH, POB 12233,MD F2-04, Res Triangle Pk, NC 27709 USA. EM dudek@niehs.nih.gov OI Dudek, Serena M./0000-0003-4094-8368 FU Intramural NIH HHS [Z01 ES100221-06]; NINDS NIH HHS [NS47176] NR 51 TC 48 Z9 49 U1 0 U2 7 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 OCT 31 PY 2007 VL 27 IS 44 BP 12025 EP 12032 DI 10.1523/JNEUROSCI.4094-07.2007 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 226HB UT WOS:000250577600033 PM 17978044 ER PT J AU Suh, JY Tang, C Clore, GM AF Suh, Jeong-Yong Tang, Chun Clore, G. Marius TI Role of electrostatic interactions in transient encounter complexes in protein-protein association investigated by paramagnetic relaxation enhancement SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID N-TERMINAL DOMAIN; ENZYME-I; PHOSPHOTRANSFERASE SYSTEM; CYTOCHROME-C; NMR; BINDING; DYNAMICS; BARSTAR; BARNASE; HPR AB At equilibrium, the complex between the N-terminal domain of enzyme I (EIN) and HPr consists of a stereospecific complex in rapid exchange with a minor population (<= 10%) of an ensemble of nonspecific encounter complexes. We have investigated the effect of ionic strength on the magnitude of the intermolecular paramagnetic relaxation enhancement (PRE) rates using HPr labeled with EDTA-Mn2+ at two different sites, E5C and E25C. The magnitude of PREs attributable to the stereospecific complex shows only a small dependence on salt concentration and can be accounted for by the dependence of the overall equilibrium dissociation constant on salt concentration, as determined by isothermal titration calorimetry, resulting, under the conditions of the NMR experiments, in a small decrease in the population of bound EIN as the salt concentration is increased from 0 to 0.5 M NaCl. The magnitude of intermolecular PREs originating from the ensemble of nonspecific encounter complexes, however, is much more sensitive to salt concentration, implying that the population of nonspecific encounter complexes is significantly more affected by ionic strength than that of the stereospecific complex. These results demonstrate the importance of electrostatic interactions in the formation of the ensemble of nonspecific encounter complexes and are fully consistent with Debye-Huckel theory since the less compact interfacial packing for the nonspecific encounter complexes relative to the stereospecific complex permits more effective screening of intermolecular electrostatic interactions by ions in solution. C1 NIDDKD, Natl Inst Hlth, Phys Chem Lab, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDKD, Natl Inst Hlth, Phys Chem Lab, Bethesda, MD 20892 USA. RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 NR 18 TC 51 Z9 53 U1 2 U2 23 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD OCT 31 PY 2007 VL 129 IS 43 BP 12954 EP + DI 10.1021/ja0760978 PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 229QK UT WOS:000250818900027 PM 17918946 ER PT J AU Sahu, D Clore, GM Iwahara, J AF Sahu, Debashish Clore, G. Marius Iwahara, Junji TI TROSY-based z-exchange spectroscopy: Application to the determination of the activation energy for intermolecular protein translocation between specific sites on different DNA molecules SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CHEMICAL-EXCHANGE; NMR-SPECTROSCOPY; BIOLOGICAL MACROMOLECULES; HETERONUCLEAR CORRELATION; 2-DIMENSIONAL NMR; RELAXATION; HOMEODOMAIN; N-15; KINETICS; BINDING AB A two-dimensional TROSY-based z-exchange H-1-N-15 correlation experiment for the quantitative analysis of kinetic processes in the slow exchange regime is presented. The pulse scheme converts the product operator terms N-z into 2N(z)H(z) and 2N(z)H(z), into -N-z in the middle of the z-mixing period, thereby suppressing the buildup of spurious semi-TROSY peaks arising from the different relaxation rates for the Nz and 2N(z)H(z) terms and simplifying the behavior of longitudinal magnetization for an exchanging system during the mixing period. Theoretical considerations and experimental data demonstrate that the TROSY-based z-exchange experiment permits quantitative determination of rate constants using the same procedure as that for the conventional non-TROSY N-15(z)-exchange experiment. Line narrowing as a consequence of the use of the TROSY principle makes the method particularly suitable for kinetic studies at low temperature, thereby permitting activation energies to be extracted from data acquired over a wider temperature range. We applied this method to the investigation of the process whereby the HoxD9 homeodomain translocates between specific target sites on different DNA molecules via a direct transfer mechanism without going through the intermediary of free protein. The activation enthalpy for intermolecular translocation was determined to be 17 kcal/mol. C1 Univ Texas, Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA. Univ Texas, Med Branch, Sealy Ctr Struct Biol & Mol Biophys, Galveston, TX 77555 USA. NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Iwahara, J (reprint author), Univ Texas, Med Branch, Dept Biochem & Mol Biol, Galveston, TX 77555 USA. EM j.iwahara@utmb.edu RI Clore, G. Marius/A-3511-2008; OI Clore, G. Marius/0000-0003-3809-1027; Iwahara, Junji/0000-0003-4732-2173 FU Intramural NIH HHS NR 39 TC 33 Z9 33 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD OCT 31 PY 2007 VL 129 IS 43 BP 13232 EP 13237 DI 10.1021/ja074604f PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA 229QK UT WOS:000250818900058 PM 17918842 ER PT J AU Yoo, MH Xu, XM Carlson, BA Patterson, AD Gladyshev, VN Hatfield, DL AF Yoo, Min-Hyuk Xu, Xue-Ming Carlson, Bradley A. Patterson, Andrew D. Gladyshev, Vadim N. Hatfield, Dolph L. TI Targeting Thioredoxin Reductase 1 Reduction in Cancer Cells Inhibits Self-Sufficient Growth and DNA Replication SO PLOS ONE LA English DT Article AB Thioredoxin reductase 1 (TR1) is a major redox regulator in mammalian cells. As an important antioxidant selenoprotein, TR1 is thought to participate in cancer prevention, but is also known to be over-expressed in many cancer cells. Numerous cancer drugs inhibit TR1, and this protein has been proposed as a target for cancer therapy. We previously reported that reduction of TR1 levels in cancer cells reversed many malignant characteristics suggesting that deficiency in TR1 function is antitumorigenic. The molecular basis for TR1's role in cancer development, however, is not understood. Herein, we found that, among selenoproteins, TR1 is uniquely overexpressed in cancer cells and its knockdown in a mouse cancer cell line driven by oncogenic k-ras resulted in morphological changes characteristic of parental (normal) cells, without significant effect on cell growth under normal growth conditions. When grown in serum-deficient medium, TR1 deficient cancer cells lose self-sufficiency of growth, manifest a defective progression in their S phase and a decreased expression of DNA polymerase a, an enzyme important in DNA replication. These observations provide evidence that TR1 is critical for self-sufficiency in growth signals of malignant cells, that TR1 acts largely as a pro-cancer protein and it is indeed a primary target in cancer therapy. C1 [Yoo, Min-Hyuk; Xu, Xue-Ming; Carlson, Bradley A.; Patterson, Andrew D.; Hatfield, Dolph L.] NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. [Gladyshev, Vadim N.] Univ Nebraska, Dept Biochem, Lincoln, NE 68583 USA. RP Hatfield, DL (reprint author), NCI, Mol Biol Selenium Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM hatfield@mail.nih.gov RI Patterson, Andrew/G-3852-2012; Gladyshev, Vadim/A-9894-2013 OI Patterson, Andrew/0000-0003-2073-0070; FU National Institutes of Health [CA080946, GM065204]; National Cancer Institute; Center for Cancer Research; PRAT Fellowship; NIGMS FX This research was supported by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and by NIH grants CA080946 and GM065204 to VNG. ADP was sponsored by the PRAT Fellowship, NIGMS, NIH. NR 26 TC 64 Z9 66 U1 1 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 OCT 31 PY 2007 VL 2 IS 10 AR e1112 DI 10.1371/journal.pone.0001112 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10IW UT WOS:000207458700029 PM 17971875 ER PT J AU Shukla, S Rai, V Saini, P Banerjee, D Menon, AK Prasad, R AF Shukla, Sudhanshu Rai, Versha Saini, Preeti Banerjee, Dibyendu Menon, Anant K. Prasad, Rajendra TI Candida drug resistance protein 1, a major multidrug ATP binding cassette transporter of candida albicans, translocates fluorescent phospholipids in a reconstituted system SO BIOCHEMISTRY LA English DT Article ID AZOLE ANTIFUNGAL AGENTS; MDR2 P-GLYCOPROTEIN; FLIPPASE ACTIVITY; PLASMA-MEMBRANE; LABELED PHOSPHATIDYLCHOLINE; TRANSBILAYER MOVEMENT; LIPID TRANSPORT; CDR1P; VESICLES; EFFLUX AB Candida albicans drug resistance protein 1 (Cdr1p), an ATP-dependent drug efflux pump, contributes to multidrug resistance in Candida-infected immunocompromised patients. Previous cell-based assays suggested that Cdr1p also acts as a phospholipid translocator. To investigate this, we reconstituted purified Cdr1p into sealed membrane vesicles. Comparison of the ATPase activities of sealed and permeabilized proteoliposomes indicated that Cdr1p was asymmetrically reconstituted such that similar to 70% of the molecules had their ATP binding sites accessible to the extravesicular space. Fluorescent glycerophospholipids were incorporated into the outer leaflet of the proteoliposomes, and their transport into the inner leaflet was tracked with a quenching assay using membrane-impermeant dithionite. We observed ATP-dependent transport of the fluorescent lipids into the inner leaflet of the vesicles. With similar to 6 molecules of Cdr similar to p per vesicle on average, the half-time to reach the maximal extent of transport was similar to 15 min. Transport was reduced in vesicles reconstituted with Cdr1p variants with impaired ATPase activity and could be competed out to different levels by a molar excess of drugs such as fluconazole and miconazole that are known to be effluxed by Cdr1p. Transport was not affected by ampicillin, a compound that is not effluxed by Cdr1p. Our results suggest a direct link between the ability of Cdr1p to translocate fluorescent phospholipids and efflux drugs. We note that only a few members of the ABC superfamily of Candida have a well-defined role as drug exporters; thus, lipid translocation mediated by Cdr1p could reflect its cellular function. C1 Jawaharlal Nehru Univ, Sch Life Sci, Membrane Biol Lab, New Delhi 110067, India. Jawaharlal Nehru Univ, Special Ctr Mol Med, New Delhi 110067, India. Weill Cornell Med Coll, Dept Biochem, New York, NY 10021 USA. NICHHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. RP Prasad, R (reprint author), Jawaharlal Nehru Univ, Sch Life Sci, Membrane Biol Lab, New Delhi 110067, India. EM rp47@hotmail.com RI BANERJEE, DIBYENDU/C-6656-2012; OI Shukla, Sudhanshu/0000-0002-7091-7215 FU NIGMS NIH HHS [GM071041, R01 GM071041, R01 GM071041-03] NR 41 TC 17 Z9 20 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 30 PY 2007 VL 46 IS 43 BP 12081 EP 12090 DI 10.1021/bi700453e PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 223OH UT WOS:000250379900010 PM 17924650 ER PT J AU DeRose, EF Clarkson, MW Gilmore, SA Galban, CJ Tripathy, A Havener, JM Mueller, GA Ramsden, DA London, RE Lee, AL AF DeRose, Eugene F. Clarkson, Michael W. Gilmore, Steven A. Galban, Cristina J. Tripathy, Ashutosh Havener, Jody M. Mueller, Geoffrey A. Ramsden, Dale A. London, Robert E. Lee, Andrew L. TI Solution structure of polymerase mu's BRCT domain reveals an element essential for its role in nonhomologous end joining SO BIOCHEMISTRY LA English DT Article ID TORSION ANGLE DYNAMICS; DOUBLE-STRAND BREAKS; DNA-LIGASE III; BACKBONE DYNAMICS; CHEMICAL-SHIFT; C-13/N-15-ENRICHED PROTEINS; PHOSPHOPEPTIDE RECOGNITION; SEQUENTIAL ASSIGNMENT; RESONANCE ASSIGNMENTS; BACH1 PHOSPHOPEPTIDE AB The solution structure and dynamics of the BRCT domain from human DNA polymerase mu, implicated in repair of chromosome breaks by nonhomologous end joining (NHEJ), has been determined using NMR methods. BRCT domains are typically involved in protein-protein interactions between factors required for the cellular response to DNA damage. The pol mu BRCT domain is atypical in that, unlike other reported BRCT structures, the pol mu BRCT is neither part of a tandem grouping, nor does it appear to form stable homodimers. Although the sequence of the pol It BRCT domain has some unique characteristics, particularly the presence of > 10% proline residues, it forms the characteristic alpha beta alpha sandwich, in which three alpha helices are arrayed around a central four-stranded beta-sheet. The structure of helix 0 is characterized by two solvent-exposed hydrophobic residues, F46 and L50, suggesting,that this element may play a role in mediating interactions of pol mu with other proteins. Consistent with this argument, mutation of these residues, as well as the proximal, conserved residue R43, specifically blocked the ability of pol mu to efficiently work together with NHEJ factors Ku and XRCC4-ligase IV to join noncomplementary ends together in vitro. The structural, dynamic, and biochemical evidence reported here identifies a functional surface in the pol mu BRCT domain critical for promoting assembly and activity of the NHEJ machinery. Further, the similarity between the interaction regions of the BRCT domains of pol It and TdT support the conclusion that they participate in NHEJ as alternate polymerases. C1 Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. RP Lee, AL (reprint author), Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Beard Hall CB 7360, Chapel Hill, NC 27599 USA. EM drewlee@unc.edu FU Intramural NIH HHS [Z01 ES050111-19]; NCI NIH HHS [CA097096, R01 CA084442, R01 CA097096, R01 CA097096-02] NR 73 TC 17 Z9 18 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 30 PY 2007 VL 46 IS 43 BP 12100 EP 12110 DI 10.1021/bi7007728 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 223OH UT WOS:000250379900012 PM 17915942 ER PT J AU Lin, J Wilbur, WJ AF Lin, Jimmy Wilbur, W. John TI PubMed related articles: a probabilistic topic-based model for content similarity SO BMC BIOINFORMATICS LA English DT Article AB Background: We present a probabilistic topic-based model for content similarity called pmra that underlies the related article search feature in PubMed. Whether or not a document is about a particular topic is computed from term frequencies, modeled as Poisson distributions. Unlike previous probabilistic retrieval models, we do not attempt to estimate relevance-but rather our focus is "relatedness", the probability that a user would want to examine a particular document given known interest in another. We also describe a novel technique for estimating parameters that does not require human relevance judgments; instead, the process is based on the existence of MeSH (R) in MEDLINE (R). Results: The pmra retrieval model was compared against bm25, a competitive probabilistic model that shares theoretical similarities. Experiments using the test collection from the TREC 2005 genomics track shows a small but statistically significant improvement of pmra over bm25 in terms of precision. Conclusion: Our experiments suggest that the pmra model provides an effective ranking algorithm for related article search. C1 [Lin, Jimmy] Univ Maryland, Coll Informat Studies, College Pk, MD 20742 USA. [Lin, Jimmy; Wilbur, W. John] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Lin, J (reprint author), Univ Maryland, Coll Informat Studies, College Pk, MD 20742 USA. EM jimmylin@umd.edu; wilbur@ncbi.nlm.nih.gov FU Intramural NIH HHS NR 21 TC 62 Z9 62 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD OCT 30 PY 2007 VL 8 AR 423 DI 10.1186/1471-2105-8-423 PG 14 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 253XF UT WOS:000252550200003 PM 17971238 ER PT J AU Ruggiero, C Cherubini, A Najjar, SS Ferrucci, L AF Ruggiero, Carmelinda Cherubini, Antonio Najjar, Samer S. Ferrucci, Luigi TI White cell count, mortality, and metabolic syndrome in the Baltimore longitudinal study of aging - Reply SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Letter ID DIABETES-MELLITUS; RISK C1 NIA, NIA, ASTRA, UNIT, Baltimore, MD 21225 USA. RP Ruggiero, C (reprint author), NIA, NIA, ASTRA, UNIT, 3001 S Hanover St, Baltimore, MD 21225 USA. EM ruggieroc07@hotmail.it NR 9 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 OCT 30 PY 2007 VL 50 IS 18 BP 1810 EP 1811 DI 10.1016/j.jacc.2007.07.048 PG 2 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 226AL UT WOS:000250559400014 ER PT J AU Fujita, K Janz, S AF Fujita, Ken-ichi Janz, Siegfried TI Attenuation of WNT signaling by DKK-1 and -2 regulates BMP2-induced osteoblast differentiation and expression of OPG, RANKL and M-CSF SO MOLECULAR CANCER LA English DT Article ID BONE MORPHOGENETIC PROTEIN-2; RECEPTOR-RELATED PROTEIN-5; SERUM OSTEOPROTEGERIN LEVELS; OSTEOCLASTOGENESIS IN-VITRO; BETA-CATENIN; NEGATIVE REGULATOR; MULTIPLE-MYELOMA; CELLS; GENE; PATHWAY AB Background: Enhanced osteoblast-dependent osteoclastogenesis due to inhibition of Wnt/beta-catenin signaling in bone morphogenic protein (BMP)-driven osteoprogenitors has been repeatedly implicated in the natural history of cancer-associated osteolytic lesions, but the mechanism of this bone loss is poorly understood. Methods: We examined the impact of secreted Wnt inhibitors from the Dickkopf (Dkk) family on pluripotent mesenchymal cells undergoing BMP2-induced osteoblastic differentiation. Results: We found that Dkk1 and -2 restored the Wnt3a-dependent reduction of alkaline phosphatase (ALP), Osterix and p53, indicating that mitigated Wnt/beta-catenin signaling promotes certain aspects of early osteoblastogenesis through the BMP-p53-Osterix-ALP axis. Dkk1 and -2 increased the expression of the osteoclast differentiation factors, receptor activator of NF-kappa B ligand (RANKL) and macrophage-colony stimulating factor (M-CSF), upon stimulation with Wnt3a/1,25-dihydroxyvitamine D(3) and Wnt3a/BMP2, respectively. The decoy receptor of RANKL, osteoprotegerin (OPG), was down regulated under the latter conditions. These findings indicated that Dkk1 and -2 facilitate osteoclastogenesis by enhancing RANKL/RANK and M-CSF/c-Fms interactions. Dkk4 weakly shared activities of Dkk-1 and -2, whereas Dkk3 was ineffective. Conclusion: Our results suggest that inhibited Wnt/beta-catenin signaling in BMP2-induced osteoprogenitors in vivo promotes, on balance, the heightened formation of osteoclasts. Focally increased Dkk1 production by tumor cells in the bone may thus lead to focal bone loss. C1 [Fujita, Ken-ichi; Janz, Siegfried] NCI, Genet Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. [Janz, Siegfried] Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Pathol, Iowa City, IA USA. RP Janz, S (reprint author), NCI, Genet Lab, Ctr Canc Res, NIH, Bldg 37, Bethesda, MD 20892 USA. EM fujitak@mail.nih.gov; siegfried-janz@uiowa.edu FU Intramural NIH HHS NR 52 TC 83 Z9 93 U1 0 U2 11 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1476-4598 J9 MOL CANCER JI Mol. Cancer PD OCT 30 PY 2007 VL 6 AR 71 DI 10.1186/1476-4598-6-71 PG 13 WC Biochemistry & Molecular Biology; Oncology SC Biochemistry & Molecular Biology; Oncology GA 250CI UT WOS:000252277200001 PM 17971207 ER PT J AU Gaillard, WD Berl, MM Moore, EN Ritzl, EK Rosenberger, LR Weinstein, SL Conry, JA Pearl, PL Ritter, FF Sato, S Vezina, LG Vaidya, CJ Wiggs, E Fratalli, C Risse, G Ratner, NB Gioia, G Theodore, WH AF Gaillard, W. D. Berl, M. M. Moore, E. N. Ritzl, E. K. Rosenberger, L. R. Weinstein, S. L. Conry, J. A. Pearl, P. L. Ritter, F. F. Sato, S. Vezina, L. G. Vaidya, C. J. Wiggs, E. Fratalli, C. Risse, G. Ratner, N. B. Gioia, G. Theodore, W. H. TI Atypical language in lesional and nonlesional complex partial epilepsy SO NEUROLOGY LA English DT Article ID TEMPORAL-LOBE EPILEPSY; RIGHT-HEMISPHERIC ORGANIZATION; LATE-ONSET SEIZURES; FUNCTIONAL MRI; VERBAL FLUENCY; YOUNG-CHILDREN; BRAIN-LESIONS; WADA TEST; AUDITORY COMPREHENSION; ACTIVATION PATTERNS AB Objective: We investigated the relationship between partial epilepsy, MRI findings, and atypical language representation. Methods: A total of 102 patients (4 to 55 years) with left hemisphere epileptogenic zones were evaluated using three fMRI language tasks obtained at 1.5 or 3T with EPI BOLD techniques: verbal fluency, reading comprehension, and auditory comprehension. fMRI maps were visually interpreted at a standard threshold and rated as left or atypical language. Results: Atypical language dominance occurred in 30 patients (29%) and varied with MRI type (p < 0.01). Atypical language representation occurred in 36% (13/36) with normal MRI, 21% (6/29) with mesial temporal sclerosis, 14% (4/28) with focal cortical lesions (dysplasia, tumor, vascular malformation), and all (6/6) with a history of stroke. Multivariate logistic regression analysis found handedness, seizure onset, and MRI type accounted for much of the variance in language activation patterns (X-2 = 24.09, p < 0.01). Atypical language was more prevalent in patients with early seizure onset (43.2%, p < 0.05) and atypical handedness (60%, p < 0.01). None of the three clinical factors were correlated with each other (p > 0.40). Patients with atypical language had lower verbal abilities (F = 6.96, p = 0.01) and a trend toward lower nonverbal abilities (F = 3.58, p = 0.06). There were no differences in rates of atypical language across time, age groups, or MRI scanner. Conclusion: Early seizure onset and atypical handedness, as well as the location and nature of pathologic substrate, are important factors in language reorganization. C1 George Washington Univ, Dept Neurosci, Childrens Natl Med Ctr, Sch Med, Washington, DC 20010 USA. George Washington Univ, Sch Med, Dept Radiol, Childrens Natl Med Ctr, Washington, DC USA. NIH, Clin Epilepsy Sect, NINDS, Bethesda, MD 20892 USA. NIH, Ctr Clin, Hearing & Speech Sect, Bethesda, MD 20892 USA. Georgetown Univ, Dept Neurol & Neurosci, Sch Med, Washington, DC 20057 USA. Johns Hopkins Univ Hosp, Dept Neurol, Baltimore, MD 21287 USA. Minnesota Epilepsy Grp, Minneapolis, MN USA. Univ Maryland, Dept Speech & Hearing Sci, College Pk, MD 20742 USA. RP Gaillard, WD (reprint author), George Washington Univ, Dept Neurosci, Childrens Natl Med Ctr, Sch Med, 111 Michigan Ave NW, Washington, DC 20010 USA. EM wgaillar@cnmc.org FU Intramural NIH HHS; NINDS NIH HHS [R01 NS44280] NR 76 TC 67 Z9 68 U1 4 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD OCT 30 PY 2007 VL 69 IS 18 BP 1761 EP 1771 DI 10.1212/01.wnl.0000289650.48830.1a PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 225KZ UT WOS:000250518100006 PM 17967992 ER PT J AU Harden, CL Huff, JS Schwartz, TH Dubinsky, RM Zimmerman, RD Weinstein, S Foltin, JC Theodore, WH AF Harden, C. L. Huff, J. S. Schwartz, T. H. Dubinsky, R. M. Zimmerman, R. D. Weinstein, S. Foltin, J. C. Theodore, W. H. TI Reassessment: Neuroimaging in the emergency patient presenting with seizure (an evidence-based review) - Report of the therapeutics and technology assessment subcommittee of the American academy of neurology SO NEUROLOGY LA English DT Article ID BRAIN COMPUTED-TOMOGRAPHY; NEW-ONSET; GENERALIZED SEIZURE; CHILDREN; PREDICTORS AB Objective: To reassess the value of neuroimaging of the emergency patient presenting with seizure as a screening procedure for providing information that will change acute management, and to reassess clinical and historical features associated with an abnormal neuroimaging study in these patients. Methods: A broad-based panel with topic expertise evaluated the available evidence based on a structured literature review using a Medline search from 1966 until November 2004. Results: The 15 articles meeting criteria were Class II or III evidence since interpretation was not masked to the patient's clinical presentation; most were series including 22 to 875 patients. There is evidence that for adults with first seizure, cranial CT will change acute management in 9 to 17% of patients. CT in the emergency department for children presenting with first seizure will change acute management in approximately 3 to 8%. There is no clear difference between rates of abnormal emergent CT for patients with chronic seizures vs first. Children < 6 months presenting with seizures have clinically relevant abnormalities on CT scans 50% of the time. Persons with AIDS and first seizure have high rates of abnormalities, and CNS toxoplasmosis is frequently found. Abnormal neurologic examination, predisposing history, or focal seizure onset are probably predictive of an abnormal CT study in this context. Conclusions: Immediate noncontrast CT is possibly useful for emergency patients presenting with seizure to guide appropriate acute management especially where there is an abnormal neurologic examination, predisposing history, or focal seizure onset. C1 Weill Cornell Med Coll, Comprehens Epilepsy Ctr, Dept Neurol, New York, NY USA. Weill Cornell Med Coll, Dept Neurosurg, New York, NY USA. Weill Cornell Med Coll, Dept Neuroradiol, New York, NY USA. Univ Virginia Hlth Syst, Charlottesville, VA USA. Univ Kansas, Dept Neurol, Kansas City, KS USA. Childrens Hosp, Washington, DC USA. NYU, Med Ctr, Tisch Hosp, New York, NY 10016 USA. NYU, Sch Med, Dept Pediat, New York, NY USA. NYU, Sch Med, Dept Emergency Med, New York, NY USA. NIH, Clin Epilepsy Sect, Washington, DC USA. RP Harden, CL (reprint author), Amer Acad Neurol, 1080 Montreal Ave, St Paul, MN 55116 USA. EM guidelines@aan.com NR 17 TC 38 Z9 41 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD OCT 30 PY 2007 VL 69 IS 18 BP 1772 EP 1780 DI 10.1212/01.wnl.0000285083.25882.0e PG 9 WC Clinical Neurology SC Neurosciences & Neurology GA 225KZ UT WOS:000250518100007 PM 17967993 ER PT J AU Antinori, A Arendt, G Becker, JT Brew, BJ Byrd, DA Cherner, M Clifford, DB Cinque, P Epstein, LG Goodkin, K Gisslen, M Grant, I Heaton, RK Joseph, J Marder, K Marra, CM McArthur, JC Nunn, M Price, RW Pulliam, L Robertson, KR Sacktor, N Valcour, V Wojna, VE AF Antinori, A. Arendt, G. Becker, J. T. Brew, B. J. Byrd, D. A. Cherner, M. Clifford, D. B. Cinque, P. Epstein, L. G. Goodkin, K. Gisslen, M. Grant, I. Heaton, R. K. Joseph, J. Marder, K. Marra, C. M. McArthur, J. C. Nunn, M. Price, R. W. Pulliam, L. Robertson, K. R. Sacktor, N. Valcour, V. Wojna, V. E. TI Updated research nosology for HIV-associated neurocognitive disorders SO NEUROLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; AIDS DEMENTIA COMPLEX; RAPID SCREENING-TEST; PERFORMANCE; ERA; IMPAIRMENT; INFECTION; DISEASE; SCALE AB In 1991, the AIDS Task Force of the American Academy of Neurology published nomenclature and research case definitions to guide the diagnosis of neurologic manifestations of HIV-1 infection. Now, 16 years later, the National Institute of Mental Health and the National Institute of Neurological Diseases and Stroke have charged a working group to critically review the adequacy and utility of these definitional criteria and to identify aspects that require updating. This report represents a majority view, and unanimity was not reached on all points. It reviews our collective experience with HIV-associated neurocognitive disorders (HAND), particularly since the advent of highly active antiretroviral treatment, and their definitional criteria; discusses the impact of comorbidities; and suggests inclusion of the term asymptomatic neurocognitive impairment to categorize individuals with subclinical impairment. An algorithm is proposed to assist in standardized diagnostic classification of HAND. C1 IRCCS, Natl Inst Infect Dis Lazzaro Spallanzani, Clin Dept, Rome, Italy. Univ Dusseldorf, Dept Neurol, D-4000 Dusseldorf, Germany. Univ Pittsburgh, Dept Neurol, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. Univ New S Wales, Dept Neurol & HIV Med, St Vincents Hosp, Sydney, NSW, Australia. Mt Sinai Med Ctr, Dept Psychiat & Pathol, New York, NY 10029 USA. Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA. Washington Univ, Dept Neurol, St Louis, MO USA. Hosp San Raffaele, Clin Infect Dis, I-20132 Milan, Italy. Childrens Mem Hosp, Dept Neurol, Chicago, IL 60614 USA. Univ Miami, Dept Psychiat, Coral Gables, FL 33124 USA. Univ Miami, Dept Neurol, Coral Gables, FL 33124 USA. Univ Miami, Dept Psychol, Coral Gables, FL 33124 USA. Sahlgrens Univ Hosp, Dept Infect Dis, Gothenburg, Sweden. NIMH, Ctr Menatl Hlth Res AIDS, Bethesda, MD 20892 USA. Columbia Univ, Dept Neurol, New York, NY USA. Univ Washington Seattle, Dept Med Allergy & Infect Dis, Dept Neurol, Seattle, WA 98195 USA. Johns Hopkins Univ, Dept Neurol, Baltimore, MD 21218 USA. Johns Hopkins Univ, Dept Pathol, Baltimore, MD USA. Johns Hopkins Univ, Dept Epidemiol, Baltimore, MD USA. NINDS, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Lab Med & Med, San Francisco, CA 94143 USA. Univ N Carolina, Sch Med, Dept Neurol, Chapel Hill, NC 27515 USA. Univ Hawaii, Hawaii AIDS Clin Res Program, Honolulu, HI 96822 USA. Univ Puerto Rico, NeuroAIDS Program, San Juan, PR 00936 USA. Univ Puerto Rico, Dept Neurol, San Juan, PR 00936 USA. RP McArthur, JC (reprint author), Johns Hopkins Univ Hosp, Meyer Bldg,Room 6-109,600 N Wolfe St, Baltimore, MD 21287 USA. EM jm@jhmi.edu RI Brew, Bruce/J-6513-2012; OI Wojna, Valerie/0000-0002-4014-9921 FU NCRR NIH HHS [P20 RR011126, U54 RR026139]; NIMH NIH HHS [L30 MH072282]; NINDS NIH HHS [S11 NS046278, U54 NS043011] NR 22 TC 936 Z9 974 U1 4 U2 47 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD OCT 30 PY 2007 VL 69 IS 18 BP 1789 EP 1799 DI 10.1212/01.WNL.0000287431.88658.8b PG 11 WC Clinical Neurology SC Neurosciences & Neurology GA 225KZ UT WOS:000250518100009 PM 17914061 ER PT J AU Bong, YS Lee, HS Carim-Todd, L Mood, K Nishanian, TG Tessarollo, L Daar, IO AF Bong, Yong-Sik Lee, Hyun-Shik Carim-Todd, Laura Mood, Kathleen Nishanian, Tagvor G. Tessarollo, Lino Daar, Ira O. TI EphrinB1 signals from the cell surface to the nucleus by recruitment of STAT3 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE FGF receptor; eph receptor; neuroepithelial cells; tyrosine phosphorylation; jak2 ID EPIDERMAL-GROWTH-FACTOR; NEURAL PRECURSOR CELLS; TYROSINE PHOSPHORYLATION; TRANSCRIPTION FACTOR; EPH RECEPTORS; TRANSMEMBRANE LIGANDS; XENOPUS EMBRYOS; SH2 DOMAIN; ACTIVATION; PROTEIN AB The Eph (erythropoietin-producing hepatoma) family of receptor tyrosine kinases and their membrane-bound ligands, the ephrins, have been implicated in regulating cell adhesion and migration during development by mediating cell-to-cell signaling events. The transmembrane ephrinB (Eph receptor interactor B) protein is a bidirectional signaling molecule that sends a forward signal through the activation of its cognate receptor tyrosine kinase, residing on another cell. A reverse signal can be transduced into the ephrinB expressing cell via tyrosine phosphorylation of its conserved C-terminal cytoplasmic domain. Although some insight has been gained regarding how ephrinB may send signals affecting cytoskeletal components, little is known about how ephrinBl reverse signaling affects transcriptional processes. Here we report that signal transducer and activator of transcription 3 (STAT3) can interact with ephrinB1 in a phosphorylation-dependent manner that leads to enhanced activation of STAT3 transcriptional activity. This activity depends on the tyrosine kinase Jak2, and two tyrosines within the intracellular domain of ephrinB1 are critical for the association with STAT3 and its activation. The recruitment of STAT3 to ephrinBl, and its resulting Jak2-dependent activation and transcription of reporter targets, reveals a signaling pathway from ephrinBl to the nucleus. C1 Natl Canc Inst, Lab Cell & Dev Signaling, Frederick, MD 21702 USA. Natl Canc Inst, Mouse Canc Genet Program, Frederick, MD 21702 USA. RP Daar, IO (reprint author), Natl Canc Inst, Lab Cell & Dev Signaling, Bldg 560, Frederick, MD 21702 USA. EM daar@ncifcrf.gov RI Lee, Hyun-Shik/G-3555-2011; OI Daar, Ira/0000-0003-2657-526X FU Intramural NIH HHS NR 48 TC 48 Z9 48 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 OCT 30 PY 2007 VL 104 IS 44 BP 17305 EP 17310 DI 10.1073/pnas.0702337104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 227DW UT WOS:000250638400016 PM 17954917 ER PT J AU Hess, ST Gould, TJ Gudheti, MV Maas, SA Mills, KD Zimmerberg, J AF Hess, Samuel T. Gould, Travis J. Gudheti, Manasa V. Maas, Sarah A. Mills, Kevin D. Zimmerberg, Joshua TI Dynamic clustered distribution of hemagglutinin resolved at 40 nm in living cell membranes discriminates between raft theories SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hemagglutinin; microdomains; fluorescence photoactivation localization microscopy photoactivation; rafts ID PLASMA-MEMBRANE; INFLUENZA HEMAGGLUTININ; ANCHORED PROTEINS; LIPID DOMAINS; VIRUS; MICRODOMAINS; MICROSCOPY; SURFACE; FUSION; ORGANIZATION AB Organization in biological membranes spans many orders of magnitude in length scale, but limited resolution in far-field light microscopy has impeded distinction between numerous biomembrane models. One canonical example of a heterogeneously distributed membrane protein is hemagglutinin (HA) from influenza virus, which is associated with controversial cholesterol-rich lipid rafts. Using fluorescence photoactivation localization microscopy, we are able to image distributions of tens of thousands of HA molecules with subdiffraction resolution (approximate to 40 nm) in live and fixed fibroblasts. HA molecules form irregular clusters on length scales from approximate to 40 nm up to many micrometers, consistent with results from electron microscopy. In live cells, the dynamics of HA molecules within clusters is observed and quantified to determine an effective diffusion coefficient. The results are interpreted in terms of several established models of biological membranes. C1 Univ Maine, Dept Phys & Astron, Orono, ME 04469 USA. Univ Maine, Inst Mol Biophys, Orono, ME 04469 USA. Jackson Lab, Bar Harbor, ME 04609 USA. NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Hess, ST (reprint author), Univ Maine, Dept Phys & Astron, 313 Bennett Hall, Orono, ME 04469 USA. EM sam.hess@umit.maine.edu FU Intramural NIH HHS; NIAID NIH HHS [K25 AI065459, K25AI65459]; NICHD NIH HHS [T32 HD007065] NR 32 TC 236 Z9 238 U1 3 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 OCT 30 PY 2007 VL 104 IS 44 BP 17370 EP 17375 DI 10.1073/pnas.0708066104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 227DW UT WOS:000250638400027 PM 17959773 ER PT J AU Hardy, AW Graham, DR Shearer, GM Herbeuval, JP AF Hardy, Andrew W. Graham, David R. Shearer, Gene M. Herbeuval, Jean-Philippe TI HIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors by Toll-like receptor 7-induced IFN-alpha SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE apoptosis; endocytosis; AT-2 HIV-1; CCR5; CXCR4 ID IMMUNODEFICIENCY-VIRUS TYPE-1; INTERFERON-PRODUCING CELLS; APOPTOSIS-INDUCING LIGAND; CD4(+) T-LYMPHOCYTES; HIV-1-INFECTED PATIENTS; LYMPHOID-TISSUE; DIFFERENTIAL EXPRESSION; GASTROINTESTINAL-TRACT; ADAPTIVE IMMUNITY; VIRAL-INFECTION AB Plasmacytoid dendritic cells (pDC) are key players in viral immunity and produce IFN-alpha after HIV-1 exposure, which in turn regulates TNF-related apoptosis-inducing ligand (TRAIL) expression by CD4(+) T cells. We show here that infectious and noninfectious HIV-1 virions induce activation of pDC into TRAIL-expressing IFN-producing killer pDC (IKpDC). IKpDC expressed high levels of activation markers (HLA-DR, CD80, CD83, and CD86) and the migration marker CCR7. Surprisingly, CXCR4 and CCR5 were down-regulated on IKpDC. We also show that HIV-1-induced IKpDC depended on Toll-like receptor 7 (TLR7) activation. HIV-1 or TLR7 agonist-exposed IKpDC induced apoptosis of the CD4(+) T cell line SupT1 via the TRAIL pathway. Furthermore, IFN-alpha produced after HIV-induced TLR7 stimulation was responsible for TRAIL expression and the down-regulation of both CXCR4 and CCR5 by IKpDC. In contrast, activation and migration markers were not regulated by IFN-alpha. Finally, IFN-alpha increased the survival of IKpDC. We characterized a subset of pDC with a killer activity that is activated by endosomal-associated viral RNA and not by infection. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Mol & Comparat Pathobiol, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Med, Div Cardiol, Baltimore, MD 21224 USA. CNRS, UMR 8147, Fac Med Rene Descartes Paris 5, F-75270 Paris, France. RP Shearer, GM (reprint author), NCI, Expt Immunol Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 5A33, Bethesda, MD 20892 USA. EM shearerg@mail.nih.gov FU Intramural NIH HHS NR 48 TC 111 Z9 119 U1 1 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 30 PY 2007 VL 104 IS 44 BP 17453 EP 17458 DI 10.1073/pnas.0707244104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 227DW UT WOS:000250638400041 PM 17956986 ER PT J AU Enquist, IB Lo Bianco, C Ooka, A Nilsson, E Mansson, JE Ehinger, M Richter, J Brady, RO Kirik, D Karlsson, S AF Enquist, Ida Berglin Lo Bianco, Christophe Ooka, Andreas Nilsson, Eva Mansson, Jan-Eric Ehinger, Mats Richter, Johan Brady, Roscoe O. Kirik, Deniz Karlsson, Stefan TI Murine models of acute neuronopathic Gaucher disease SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE lysosomal storage disorder; glucocerebrosidase deficiency; neurodegeneration; knockout mice; gene therapy ID ACID BETA-GLUCOSIDASE; GLUCOCEREBROSIDASE DEFICIENCY; LATERAL-SCLEROSIS; NERVOUS-SYSTEM; ENZYME THERAPY; MOTOR-NEURONS; MOUSE MODEL; TYPE-2; INFANTILE; MICROGLIA AB Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by mutations in the glucosidase, beta, acid (GBA) gene that encodes the lysosomal enzyme glucosylceramidase (GCase). GCase deficiency leads to characteristic visceral pathology and, in some patients, lethal neurological manifestations. Here, we report the generation of mouse models with the severe neuronopathic form of GD. To circumvent the lethal skin phenotype observed in several of the previous GCase-deficient animals, we genetically engineered a mouse model with strong reduction in GCase activity in all tissues except the skin. These mice exhibit rapid motor dysfunction associated with severe neurodegeneration and apoptotic cell death within the brain, reminiscent of neuronopathic GD. In addition, we have created a second mouse model, in which GCase deficiency is restricted to neural and glial cell progenitors and progeny. These mice develop similar pathology as the first mouse model, but with a delayed onset and slower disease progression, which indicates that GCase deficiency within microglial cells that are of hematopoietic origin is not the primary determinant of the CNS pathology. These findings also demonstrate that normal microglial cells cannot rescue this neurodegenerative disease. These mouse models have significant implications for the development of therapy for patients with neuronopathic GD. C1 Lund Univ, Inst Lab Med, Mol Med & Gen Therapy, S-22184 Lund, Sweden. Lund Univ, Strateg Res Ctr Stem Cell Biol & Cell Therapy, S-22184 Lund, Sweden. Lund Univ, Div Neurobiol, S-22184 Lund, Sweden. Lund Univ, Dept Expt Med Sci, CNS Dis Modeling Unit, Wallenberg Neurosci Ctr, S-22184 Lund, Sweden. Sahlgrens Univ Hosp, Inst Clin Neurosci, S-43180 Molndal, Sweden. Lund Univ, Dept Pathol, S-22100 Lund, Sweden. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Karlsson, S (reprint author), Lund Univ, Inst Lab Med, Mol Med & Gen Therapy, BMC A12, S-22184 Lund, Sweden. EM rb57v@nih.gov RI Kirik, Deniz/E-5156-2011 NR 43 TC 62 Z9 62 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 OCT 30 PY 2007 VL 104 IS 44 BP 17483 EP 17488 DI 10.1073/pnas.0708086104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 227DW UT WOS:000250638400046 PM 17954912 ER PT J AU Oliveira, NM Satija, H Kouwenhoven, IA Eiden, MV AF Oliveira, Nidia M. Satija, Harshita Kouwenhoven, I. Arlette Eiden, Maribeth V. TI Changes in viral protein function that accompany retroviral endogenization SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE adaptation; endogenous retrovirus; koala ID APE LEUKEMIA-VIRUS; ENDOGENOUS KOALA RETROVIRUS; ENVELOPE PROTEIN; GENOME EVOLUTION; MOBILE ELEMENTS; GIBBON; CINEREUS; VECTORS AB Endogenous retroviruses (ERVs) are the remnants of ancient retroviral infections of germ cells and have been maintained in whole or part as heritable genomic elements. The last known endogenization events occurred several million years ago, and therefore stepwise analysis of retroviral endogenization has not been possible. A unique opportunity to study this process became available when a full-length ERV isolated from koalas (KoRV) was shown to have integrated into their germ line within the past 100 years. Even though KoRV shares 78% nucleotide identity with the exogenous and highly infectious gibbon ape leukemia virus (GALV), the infectivity of KoRV, like that of other ERVs, is substantially lower than that of GALV. Differences in the protein coding regions of KoRV that distinguish it from GALV were introduced into the GALV genome, and their functional consequences were assessed. We identified a KoRV gagpol L domain mutation as well as five residues present in the KoRV envelope (env) that, when substituted for the corresponding residues of GALV, resulted in vectors exhibiting substantially reduced titers similar to those observed with KoRV vectors. In addition, KoRV env protein lacks an intact CETTG motif that we have identified as invariant among highly infectious gammaretroviruses. Disruption of this motif in GALV results in vectors with reduced syncytia forming capabilities. Functional assessment of specific sequences that contribute to KoRV's attenuation from a highly infectious GALV-like progenitor virus has allowed the identification of specific modifications in the KoRV genome that correlate with its endogenization. C1 Lab Cellular & Mol Regulat, NIMH, Bethesda, MD 20892 USA. RP Eiden, MV (reprint author), Lab Cellular & Mol Regulat, NIMH, 49 Convent Dr, Bethesda, MD 20892 USA. EM eidenm@mail.nih.gov NR 21 TC 32 Z9 32 U1 2 U2 8 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 OCT 30 PY 2007 VL 104 IS 44 BP 17506 EP 17511 DI 10.1073/pnas.0704313104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 227DW UT WOS:000250638400050 PM 17959780 ER PT J AU Liu, XB Cheng, KT Bandyopadhyay, BC Pani, B Dietrich, A Paria, BC Swaim, WD Beech, D Yildrim, E Singh, BB Birnbaumer, L Ambudkar, IS AF Liu, Xibao Cheng, Kwong Tai Bandyopadhyay, Bidhan C. Pani, Biswaranjan Dietrich, Alexander Paria, Biman C. Swaim, William D. Beech, David Yildrim, Eda Singh, Brij B. Birnbaumer, Lutz Ambudkar, Indu S. TI Attenuation of store-operated Ca2+ current impairs salivary gland fluid secretion in TRPC1(-/-) mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE transient receptor potential; canonical; Ca2+ entry; acinar cells; muscarinic receptor ID CRAC CHANNEL; CALCIUM-ENTRY; PLASMA-MEMBRANE; ORAI PROTEINS; TRPC CHANNELS; ACINAR-CELLS; STIM1; RECEPTOR; INFLUX; DEPLETION AB Agonist-induced Ca2+ entry via store-operated Ca2+ (SOC) channels is suggested to regulate a wide variety of cellular functions, including salivary gland fluid secretion. However, the molecular components of these channels and their physiological function(s) are largely unknown. Here we report that attenuation of SOC current underlies salivary gland dysfunction in mice lacking transient receptor potential 1 (TRPC1). Neurotransmitter-regulated salivary gland fluid secretion in TRPC1-deficient TRPC1(-/-) mice was severely decreased (by 70%). Further, agonist- and thapsigargin-stimulated SOC channel activity was significantly reduced in salivary gland acinar cells isolated from TRPC1(-/-) mice. Deletion of TRPC1 also eliminated sustained Ca2+-dependent potassium channel activity, which depends on Ca2+ entry and is required for fluid secretion. Expression of key proteins involved in fluid secretion and Ca2+ signaling, including STIM1 and other TRPC channels, was not altered. Together, these data demonstrate that reduced SOC entry accounts for the severe loss of salivary gland fluid secretion in TRPC1(-/-) mice. Thus, TRPC1 is a critical component of the SOC channel in salivary gland acinar cells and is essential for neurotransmitter-regulation of fluid secretion. C1 NIH, Natl Inst Environm Hlth Sci, Lab Signal Trasduct, Res Triangle Pk, NC 27709 USA. NIH, Natl Inst Dent & Craniofac Res, Gene Therapy & Therapeut Branch, Sectory Physiol Sect, Bethesda, MD 20892 USA. Univ N Dakota, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, Grand Forks, ND 58202 USA. Philipps Univ, Inst Pharmacol & Toxicol, D-35043 Marburg, Germany. Univ Leeds, Inst Mem & Syst Biol, Leeds LS2 9JT, W Yorkshire, England. RP Liu, XB (reprint author), NIH, Natl Inst Environm Hlth Sci, Lab Signal Trasduct, Res Triangle Pk, NC 27709 USA. EM lutz.birnbaumer@nih.hhs.gov; indu.ambudkar@nih.gov RI Dietrich, Alexander/G-8619-2013; OI Dietrich, Alexander/0000-0002-1168-8707; Singh, Brij/0000-0003-0535-5997 FU Intramural NIH HHS; NCRR NIH HHS [P20 RR017699, P20 RR017699-077011]; NIDCR NIH HHS [DE017102, R01 DE017102, R01 DE017102-01A1, R01 DE017102-02, R01 DE017102-03]; Wellcome Trust [060988] NR 48 TC 123 Z9 124 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 OCT 30 PY 2007 VL 104 IS 44 BP 17542 EP 17547 DI 10.1073/pnas.0701254104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 227DW UT WOS:000250638400056 PM 17956991 ER PT J AU Shu, Y Liu, A Li, Z AF Shu, Y. Liu, A. Li, Z. TI Sequential evaluation of a medical diagnostic test with binary outcomes SO STATISTICS IN MEDICINE LA English DT Article DE diagnostic medicine; interim analysis and early stopping; sensitivity; specificity ID CLINICAL-TRIALS AB in a study evaluating a medical diagnostic test, human samples are valuable and often costly, therefore prime concerns require termination of the study if the test is evidently inefficient (or efficient) in diagnosis of diseases in order to keep the number of samples as low as possible. In this paper, we propose sequential designs to evaluate the sensitivity and specificity of a diagnostic test. One method allows early stopping if the sensitivity and specificity of a new medical test are both within the level of tolerance. Another method terminates the study if either the sensitivity or the specificity is below the minimally acceptable level. The latter method minimizes the expected sample size when the test does not meet expectations on performance, and illustrates substantial advantage of having smaller expected sample sizes in various two-stage designs compared to the sample sizes of single-stage designs when a diagnostic test is not promising. Published in 2007 by John Wiley & Sons, Ltd. C1 George Washington Univ, Biostat Program, Washington, DC 20037 USA. George Washington Univ, Dept Stat, Washington, DC 20037 USA. NICHHD, Biometry & Math Stat Branch, Dept Hlth & Human Serv, Rockville, MD 20852 USA. Natl Canc Inst, Biostat Branch, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Rockville, MD 20852 USA. RP Li, Z (reprint author), George Washington Univ, Biostat Program, 2140 Pennsylvania Ave NW, Washington, DC 20037 USA. EM zli@gwu.edu OI Liu, Aiyi/0000-0002-6618-5082 FU Intramural NIH HHS; NEI NIH HHS [EY014478] NR 11 TC 3 Z9 3 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD OCT 30 PY 2007 VL 26 IS 24 BP 4416 EP 4427 DI 10.1002/sim.2881 PG 12 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 220LL UT WOS:000250158100004 PM 17539044 ER PT J AU Korn, EL Li, MC McShane, LM Simon, R AF Korn, Edward L. Li, Ming-Chung McShane, Lisa M. Simon, Richard TI An investigation of two multivariate permutation methods for controlling the false discovery proportion SO STATISTICS IN MEDICINE LA English DT Article DE false discovery rate; FDP; FDR; microarrays; multiple comparisons ID SMALL MICROARRAY EXPERIMENTS; GENE-EXPRESSION PROFILES; VARIANCE AB Identifying genes that are differentially expressed between classes of samples is an important objective of many microarray experiments. Because of the thousands of genes typically considered, there is a tension between identifying as many of the truly differentially expressed genes as possible, but not too many genes that are not really differentially expressed (false discoveries). Controlling the proportion of identified genes that are false discoveries, the false discovery proportion (FDP), is a goal of interest. In this paper, two multivariate permutation methods are investigated for controlling the FDP. One is based on a multivariate permutation testing (MPT) method that probabilistically controls the number of false discoveries, and the other is based on the Significance Analysis of Microarrays (SAM) procedure that provides an estimate of the FDR Both methods account for the correlations among the genes. We find the ability of the methods to control the proportion of false discoveries varies substantially depending on the implementation characteristics. For example, for both methods one can proceed from the most significant gene to the least significant gene until the estimated FDP is just above the targeted level ('top-down' approach), or from the least significant gene to the most significant gene until the estimated FDP is just below the targeted level ('bottom-up' approach). We find that the top-down MPT-based method probabilistically controls the FDP, whereas our implementation of the top-down SAM-based method does not. Bottom-up MPT-based or SAM-based methods can result in poor control of the FDR Published in 2007 by John Wiley & Sons, Ltd. C1 NCI, Biometr Res Branch, Bethesda, MD 20892 USA. EMMES Corp, Rockville, MD 20850 USA. RP Korn, EL (reprint author), NCI, Biometr Res Branch, EPN-8129, Bethesda, MD 20892 USA. EM korne@ctep.nci.nih.gov NR 22 TC 23 Z9 23 U1 0 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD OCT 30 PY 2007 VL 26 IS 24 BP 4428 EP 4440 DI 10.1002/sim.2865 PG 13 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 220LL UT WOS:000250158100005 PM 17357994 ER PT J AU Yewdell, JW Hickman, HD AF Yewdell, Jonathan W. Hickman, Heather D. TI New lane in the information highway: alternative reading frame peptides elicit T cells with potent antiretrovirus activity SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID I-RESTRICTED EPITOPES; VIRUS-INFECTION; PROTEIN; RESPONSES; CANCER; PATHOGENESIS; TRANSLATION; EXPRESSION; INITIATION AB CD8(+) T cells rapidly recognize virus-infected cells due to the generation of antigenic peptides from defective ribosomal products (DRiPs) that are encoded by standard open reading frames (ORFs). New data now show that alternative reading frame (ARF) DRiPs can also induce robust CD8(+) T cell responses. ARF-specific T cells control retroviral replication and select for viral escape in monkeys, providing the most compelling evidence to date for the biological relevance of ARF immunosurveillance. C1 NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. EM jyewdell@nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012 NR 26 TC 9 Z9 9 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD OCT 29 PY 2007 VL 204 IS 11 BP 2501 EP 2504 DI 10.1084/jem.20071986 PG 4 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 227JE UT WOS:000250652200002 PM 17954574 ER PT J AU Goldszmid, RS Bafica, A Jankovic, D Feng, CG Caspar, P Winkler-Pickett, R Trinchieri, G Sher, A AF Goldszmid, Romina S. Bafica, Andre Jankovic, Dragana Feng, Carl G. Caspar, Pat Winkler-Pickett, Robin Trinchieri, Giorgio Sher, Alan TI TAP-1 indirectly regulates CD4(+) T cell priming in Toxoplasma gondii infection by controlling NK cell IFN-gamma production SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID NATURAL-KILLER-CELLS; CLASS-I MOLECULES; IMMUNE-DEFICIENCY-SYNDROME; DENDRITIC CELLS; PARASITOPHOROUS VACUOLE; ANTIGEN PRESENTATION; INTERFERON-GAMMA; HOST-RESISTANCE; CUTTING EDGE; MICE AB To investigate if transporter associated with antigen processing (TAP)-1 is required for CD8(+) T cell-mediated control of Toxoplasma gondii in vivo, we compared the resistance of TAP-1(-/-), CD8(-/-), and wild-type (WT) mice to infection with the parasite. Unexpectedly, TAP-1(-/-) mice displayed greater susceptibility than CD8(-/-), beta(2)-microglobulin(-/-) (beta(2)m(-/-)), or WT mice to infection with an avirulent parasite strain. The decreased resistance of the TAP-1(-/-) mice correlated with a reduction in the frequency of activated (CD62L(low) CD44(hi)) and interferon (IFN)-gamma-producing CD4(+) T cells. Interestingly, infected TAP-1(-/-) mice also showed reduced numbers of IFN-gamma-producing natural killer (NK) cells relative to WT, CD8(-/-), or beta(2) m(-/-) mice, and after NK cell depletion both CD8(-/-) and WT mice succumbed to infection with the same kinetics as TAP-1(-/-) animals and displayed impaired CD4(+) T cell IFN-gamma responses. Moreover, adoptive transfer of NK cells obtained from IFN-gamma(-/-), but not IFN-gamma(-/-), animals restored the CD4(+) T cell response of infected TAP-1(-/-) mice to normal levels. These results reveal a role for TAP-1 in the induction of IFN-gamma-producing NK cells and demonstrate that NK cell licensing can influence host resistance to infection through its effect on cytokine production in addition to its role in cytotoxicity. C1 NIAID, Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NCI, Canc & Inflammat Program, Canc Res Ctr, NIH, Frederick, MD 21702 USA. Univ Fed Santa Catarina, Dept Microbiol & Parasitol, Div Immunol, BR-88040900 Florianopolis, SC, Brazil. RP Goldszmid, RS (reprint author), NIAID, Immunol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM rgoldszmid@niaid.nih.gov FU Intramural NIH HHS NR 69 TC 36 Z9 36 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD OCT 29 PY 2007 VL 204 IS 11 BP 2591 EP 2602 DI 10.1084/jem.20070634 PG 12 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 227JE UT WOS:000250652200013 PM 17923502 ER PT J AU Kwissa, M Amara, RR Robinson, HL Moss, B Alkan, S Jabbar, A Villinger, F Pulendran, B AF Kwissa, Marcin Amara, Rama R. Robinson, Harriet L. Moss, Bernard Alkan, Sefik Jabbar, Abdul Villinger, Francois Pulendran, Bali TI Adjuvanting a DNA vaccine with a TLR9 ligand plus Flt3 ligand results in enhanced cellular immunity against the simian immunodeficiency virus SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; DENDRITIC CELLS; RHESUS-MONKEYS; IN-VIVO; NONHUMAN-PRIMATES; RECEPTOR AGONISTS; BOOST VACCINATION; HIGH-FREQUENCY; TREATED MICE; GAG PROTEIN AB DNA vaccines offer promising strategies for immunization against infections. However, their clinical use requires improvements in immunogenicity. We explored the efficacy of Toll-like receptor (TLR) ligands (TLR-Ls) on augmenting the immunogenicity of a DNA prime-modified vaccinia virus Ankara (MVA) boost vaccine against SIV. Rhesus macaques were injected with Fms-like tyrosine kinase 3 (Flt3)-ligand (FL) to expand dendritic cells (DCs) and were primed with a DNA vaccine encoding immunodeficiency virus antigens mixed with ligands for TLR9 or TLR7/8. Subsequently, the animals were boosted with DNA and twice with recombinant MVA expressing the same antigens. TLR9-L (CpG DNA) mediated activation of DCs in vivo and enhanced the magnitude of antigen-specific CD8(+) interferon (IFN) gamma(+) T cells and polyfunctional CD8(+) T cells producing IFN-gamma, tumor necrosis factor alpha, and interleukin 2. Although this trial was designed primarily as an immunogenicity study, we challenged the animals with pathogenic SIVmac 251 and observed a reduction in peak viremia and cumulative viral loads in the TLR9-L plus FL-adjuvanted group relative to the unvaccinated group; however, the study design precluded comparisons between the adjuvanted groups and the group vaccinated with DNA/MVA alone. Viral loads were inversely correlated with the magnitude and quality of the immune response. Thus, the immunogenicity of DNA vaccines can be augmented with TLR9-L plus FL. C1 Emory Univ, Vaccine Res Ctr, Atlanta, GA 30329 USA. Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA. Emory Univ, Dept Microbiol & Immunol, Atlanta, GA 30329 USA. Emory Univ, Dept Pathol & Lab Med, Atlanta, GA 30329 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. 3M Pharmaceut, St Paul, MN 55144 USA. RP Pulendran, B (reprint author), Emory Univ, Vaccine Res Ctr, Atlanta, GA 30329 USA. EM bpulend@rmy.emory.edu FU NIAID NIH HHS [R01 AI048638, R21 AI056947] NR 55 TC 56 Z9 56 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD OCT 29 PY 2007 VL 204 IS 11 BP 2733 EP 2746 DI 10.1084/jem.20071211 PG 14 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 227JE UT WOS:000250652200024 PM 17954572 ER PT J AU Karnaukhova, E Ophir, Y Trinh, L Dalal, N Punt, PJ Golding, B Shiloach, J AF Karnaukhova, Elena Ophir, Yakir Trinh, Loc Dalal, Nimish Punt, Peter J. Golding, Basil Shiloach, Joseph TI Expression of human alpha(I)-proteinase inhibitor in Aspergillus niger SO MICROBIAL CELL FACTORIES LA English DT Article ID HETEROLOGOUS PROTEIN-PRODUCTION; FILAMENTOUS FUNGI; FUSION PROTEIN; SECRETION; ALPHA(1)-ANTITRYPSIN; DEFICIENCY; TRYPSIN; GENE AB Background: Human alpha(I)-proteinase inhibitor (alpha(I)-PI), also known as antitrypsin, is the most abundant serine protease inhibitor (serpin) in plasma. Its deficiency is associated with development of progressive, ultimately fatal emphysema. Currently in the United States, alpha(I)-PI is available for replacement therapy as an FDA licensed plasma-derived (pd) product. However, the plasma source itself is limited; moreover, even with efficient viral inactivation steps used in manufacture of plasma products, the risk of contamination from emerging viruses may still exist. Therefore, recombinant alpha(I)-PI (r-alpha(I)-PI) could provide an attractive alternative. Although r-alpha(I)-PI has been produced in several hosts, protein stability in vitro and rapid clearance from the circulation have been major issues, primarily due to absent or altered glycosylation. Results: We have explored the possibility of expressing the gene for human alpha(I)-PI in the filamentous fungus Aspergillus niger (A. niger), a system reported to be capable of providing more "mammalian-like" glycosylation patterns to secretable proteins than commonly used yeast hosts. Our expression strategy was based on fusion of alpha(I)-PI with a strongly expressed, secreted leader protein (glucoamylase G2), separated by dibasic processing site (N-V-I-S-K-R) that provides in vivo cleavage. SDS-PAGE, Western blot, ELISA, and alpha(I)-PI activity assays enabled us to select the transformant(s) secreting a biologically active glycosylated r-alpha(I)-PI with yields of up to 12 mg/L. Matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) analysis further confirmed that molecular mass of the r-alpha(I)-PI was similar to that of the pd-alpha(I)-PI. In vitro stability of the r-alpha(I)-PI from A. niger was tested in comparison with pd-alpha(I)-PI reference and non-glycosylated human r-alpha(I)-PI from E. coli. Conclusion: We examined the suitability of the filamentous fungus A. niger for the expression of the human gene for alpha(I)-PI, a medium size glycoprotein of high therapeutic value. The heterologous expression of the human gene for alpha(I)-PI in A. niger was successfully achieved to produce the secreted mature human r-alpha(I)-PI in A. niger as a biologically active glycosylated protein with improved stability and with yields of up to 12 mg/L in shake-flask growth. C1 [Karnaukhova, Elena; Ophir, Yakir; Golding, Basil] US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. [Trinh, Loc; Dalal, Nimish; Shiloach, Joseph] NIDDK, Bethesda, MD 20892 USA. [Punt, Peter J.] TNO Qual Life, Dept Biol, NL-3704 HE Zeist, Netherlands. RP Karnaukhova, E (reprint author), US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA. EM elena.karnaukhova@fda.hhs.gov; ophiryakir@yahoo.com; loct@intra.niddk.nih.gov; nimish.dalal@bms.com; peter.punt@tno.nl; basil.golding@fda.hhs.gov; ljs@helix.nih.gov NR 34 TC 7 Z9 10 U1 1 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2859 J9 MICROB CELL FACT JI Microb. Cell. Fact. PD OCT 29 PY 2007 VL 6 AR 34 DI 10.1186/1475-2859-6-34 PG 10 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 250CO UT WOS:000252277800001 PM 17967194 ER PT J AU Qu, W Liu, J Fuquay, R Saavedra, JE Keefer, LK Waalkes, MP AF Qu, Wei Liu, Jie Fuquay, Richard Saavedra, Joseph E. Keefer, Larry K. Waalkes, Michael P. TI The nitric oxide prodrug, V-PYRRO/NO, mitigates arsenic-induced liver cell toxicity and apoptosis SO CANCER LETTERS LA English DT Article DE V-PYRRO/NO; arsenic; apoptotic resistance; in uitro; liver cells ID ACUTE PROMYELOCYTIC LEUKEMIA; ACTIVATED PROTEIN-KINASES; INDUCED HEPATOTOXICITY; TRIOXIDE AS2O3; METALLOTHIONEIN; DONOR; MICE; EXPRESSION; INDUCTION; PATHWAY AB Arsenite is an important cancer chemotherapeutic. The liver is a major target tissue of arsenic toxicity and hepatotoxicity may limit its chemotherapeutic efficacy. O-2 -vinyl 1-(pyrrolidin-1-yl)diazen-l-ium-1,2-diolate (V-PYRRO/NO) is a liver-selective nitric oxide (NO)-producing prodrug metabolized by hepatic P450 enzymes to release NO locally. V-PYRRO/NO protects against various organic or inorganic hepatotoxicants but any role in arsenic hepatotoxicity is undefined. Thus, we studied the effects of V-PYRRO/NO (0-1000 mu M) pretreatment on inorganic arsenic-induced toxicity in cultured rat liver (TRL 1215) cells. These cells metabolized the prodrug to release NO, producing extracellular nitrite levels to 41.7-fold above control levels (7.50 +/- 0.38 mu M) after 24 h V-PYRRO/NO (1000 mu M) exposure. The effect of pretreatment with V-PYRRO/NO (24 h) on the cytolethality of arsenic (as NaAsO2,) exposure (24 h) was assessed. Arsenic was markedly less toxic in V-PYRRO/NO pretreated cells (LC50 = 30.3 mu) compared to control (LC50 20.1 mu M) and the increases in LC50 showed a direct relationship to the level of NO produced (measured as nitrite). Consistent with the cytolethality data, V-PYRRO/NO pretreatment markedly reduced arsenic-induced apoptosis as assessed by DNA fragmentation. Activation of the c-Jun N-terminal kinase (JNK) pathway can be critical to apoptosis and pretreatment with VPYRRO/NO suppressed arsenic-induced JNK activation. V-PYRRO/NO pretreatment modestly increased metallothionein (MT), a metal-binding protein, but greatly enhanced arsenic induction of MT. Thus, V-PYRRO/NO pretreatment directly mitigates arsenic toxicity in cultured liver cells, reducing cytolethality, apoptosis and related JNK pathway activation, apparently through generation of NO. The role of NO in reducing the hepatotoxicity of arsenical chemotherapeutics in vivo deserves additional study. Published by Elsevier Ireland Ltd. C1 NCI, Natl Inst Environm Hlth Sci, Comparat Carcinogenesis Lab, Inorgan Carcinogenet Sect, Res Triangle Pk, NC 27709 USA. NCI, SAIC Frederick, Basic Res Program, Frederick, MD 21701 USA. NCI, Comparat Carcinogenesis Lab, Chem Sect, Frederick, MD 21701 USA. RP Waalkes, MP (reprint author), NCI, Natl Inst Environm Hlth Sci, Comparat Carcinogenesis Lab, Inorgan Carcinogenet Sect, POB 12233,Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 FU Intramural NIH HHS [Z01 BC005488-21, Z99 ES999999]; NCI NIH HHS [N01-C0-012400]; PHS HHS [N01-C012400] NR 33 TC 9 Z9 9 U1 0 U2 5 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD OCT 28 PY 2007 VL 256 IS 2 BP 238 EP 245 DI 10.1016/j.canlet.2007.06.009 PG 8 WC Oncology SC Oncology GA 222VZ UT WOS:000250327100009 PM 17658681 ER PT J AU Garantziotis, S Palmer, SM Snyder, LD Ganous, T Chen, BJ Wang, T Cook, DN Schwartz, DA AF Garantziotis, Stavros Palmer, Scott M. Snyder, Laurie D. Ganous, Tonya Chen, Benny J. Wang, Tie Cook, Donald N. Schwartz, David A. TI Alloimmune lung injury induced by local innate immune activation through inhaled lipopolysaccharide SO TRANSPLANTATION LA English DT Article DE bronchiolitis obliterans; allograft rejection; innate immunity; toll-like receptor-4. ID IDIOPATHIC PNEUMONIA SYNDROME; BONE-MARROW-TRANSPLANTATION; STEM-CELL TRANSPLANTATION; AIR-FLOW OBSTRUCTION; ALLOGRAFT-REJECTION; OBLITERATIVE BRONCHIOLITIS; TOLL; RANTES; HYALURONAN; EXPRESSION AB Background. Alloimmune lung injury, characterized by perivascular lymphocytic inflammation, lymphocytic bronchiolitis (LB), and obliterative bronchiolitis (OB), causes substantial morbidity and mortality after lung transplantation and bone marrow transplantation (BMT), but little is known regarding its pathogenesis. We have developed and pursued the hypothesis that local activation of pulmonary innate immunity through toll-like receptor (TLR)-4 is critical to the development of posttransplant alloimmune lung injury. Methods. We developed a fully major histocompatibility complex-mismatched murine BMT model without systemic graft-versus-host disease, and challenged mice with aerosolized lipopolysaccharide (LPS), a prototypic TLR4 agonist, to determine the effect upon pulmonary alloimmune lung injury. Results. LPS-exposed allogeneic BMT recipient mice developed histological and biological features of LB and 013, which were not observed in non-LPS-exposed allogeneic controls or syngeneic LPS-exposed mice. LPS-induced lymphocytic lung inflammation was dependent upon intact TLR4 signaling in donor-derived hematopoietic cells but not recipient structural lung cells, demonstrating a distinct function for TLR4 on hematopoietic cells in mediating alloimmunity. Conclusions. We demonstrate a critical role for localized, environmentally induced innate immune activation in promoting alloimmune lung injury. Local inhibition of TLR4 signaling in pulmonary resident C1 Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. RP Garantziotis, S (reprint author), Natl Inst Environm Hlth Sci, Box 12233,MD E1-03, Res Triangle Pk, NC 27709 USA. EM garantziotis@niehs.nih.gov RI Garantziotis, Stavros/A-6903-2009 OI Garantziotis, Stavros/0000-0003-4007-375X FU Intramural NIH HHS; NHLBI NIH HHS [P50HL-084917, HL69978, K23 HL069978, P50 HL084917] NR 27 TC 28 Z9 30 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD OCT 27 PY 2007 VL 84 IS 8 BP 1012 EP 1019 DI 10.1097/01.tp.0000286040.85007.89 PG 8 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 225CT UT WOS:000250495400011 PM 17989607 ER PT J AU Banerjee, S Sikdar, N Myung, K AF Banerjee, Soma Sikdar, Nilabja Myung, Kyungiae TI Suppression of gross chromosomal rearrangements by a new alternative replication factor C complex SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Review DE genomic instability; DNA replication; ELG1; RFC; PCNA ID SACCHAROMYCES-CEREVISIAE; GENOME STABILITY; DNA-REPLICATION; ASSEMBLY FACTORS; REPAIR PATHWAY; PCNA; MAINTENANCE; CANCER; DAMAGE; FORMS AB Defects in DNA replication fidelity lead to genomic instability. Gross chromosomal rearrangement (GCR), a type of genomic instability, is highly enhanced by various initial mutations affecting DNA replication. Frequent observations of GCRs in many cancers strongly argue the importance of maintaining high fidelity of DNA replication to suppress carcinogenesis. Recent genome wide screens in Saccharomyces cerevisiae identified a new GCR suppressor gene, ELG1, enhanced level of genome instability gene 1. Its physical interaction with proliferating cell nuclear antigen (PCNA) and complex formation with Rfc2-5p proteins suggest that Elg1 functions to load/unload PCNA onto DNA during a certain DNA metabolism. High level of DNA damage accumulation and enhanced phenotypes with mutations in genes involved in cell cycle checkpoints, homologous recombination (HR), or chromatin assembly in the elg1 strain suggest that Elg1p-Rfc2-5p functions in a fundamental DNA metabolism to suppress genomic instability. Published by Elsevier Inc. C1 NCI, NHGRI, Genet & Mol Biol Branch, Genome Instabil Sect, Bethesda, MD 20892 USA. RP Myung, K (reprint author), NCI, NHGRI, Genet & Mol Biol Branch, Genome Instabil Sect, 49 Convent Dr,Rm 4 A22, Bethesda, MD 20892 USA. EM kmyung@nhgri.nih.gov FU Intramural NIH HHS [Z99 HG999999, Z01 HG012003-05] NR 24 TC 12 Z9 12 U1 2 U2 5 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 OCT 26 PY 2007 VL 362 IS 3 BP 546 EP 549 DI 10.1016/j.bbrc.2007.07.126 PG 4 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 212NG UT WOS:000249602700002 PM 17689491 ER PT J AU Nabel, EG AF Nabel, Elizabeth G. TI Shaping the future of research the NHLBI strategic plan SO CIRCULATION RESEARCH LA English DT Editorial Material C1 NHLBI, Bethesda, MD 20892 USA. RP Nabel, EG (reprint author), NHLBI, 31 Ctr Dr,Room 5A48, Bethesda, MD 20892 USA. EM nabele@nih.gov NR 0 TC 2 Z9 2 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 OCT 26 PY 2007 VL 101 IS 9 BP 849 EP 850 DI 10.1161/CIRCRESAHA.107.164582 PG 2 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 226VW UT WOS:000250617600001 PM 17967791 ER PT J AU True, AL Olive, M Boehm, M San, H Westrick, RJ Raghavachari, N Xu, X Lynn, EG Sack, MN Munson, PJ Gladwin, MT Nabel, EG AF True, Andrea L. Olive, Michelle Boehm, Manfred San, Hong Westrick, Randal J. Raghavachari, Nalini Xu, Xiuli Lynn, Edward G. Sack, Michael N. Munson, Peter J. Gladwin, Mark T. Nabel, Elizabeth G. TI Heme oxygenase-1 deficiency accelerates formation of arterial thrombosis through oxidative damage to the endothelium, which is rescued by inhaled carbon monoxide SO CIRCULATION RESEARCH LA English DT Article DE heme oxygenase; thrombosis; endothelium; apoptosis; vascular biology ID PLASMINOGEN-ACTIVATOR INHIBITOR-1; CELL APOPTOSIS; EXPRESSION; STRESS; MICE; ATHEROSCLEROSIS; PROTECTS; DISEASE; GENE; DYSFUNCTION AB Heme oxygenase (HO)-1 (encoded by Hmox1) catalyzes the oxidative degradation of heme to biliverdin and carbon monoxide. HO-1 is induced during inflammation and oxidative stress to protect tissues from oxidative damage. Because intravascular thrombosis forms at sites of tissue inflammation, we hypothesized that HO-1 protects against arterial thrombosis during oxidant stress. To investigate the direct function of HO-1 on thrombosis, we used photochemical-induced vascular injury in Hmox1(-/-) and Hmox1(+/+) mice. Hmox1(-/-) mice developed accelerated, occlusive arterial thrombus compared with Hmox1(+/+) mice, and we detected several mechanisms accounting for this antithrombotic effect. First, endothelial cells in Hmox1(-/-) arteries were more susceptible to apoptosis and denudation, leading to platelet-rich microthrombi in the subendothelium. Second, tissue factor, von Willebrand Factor, and reactive oxygen species were significantly elevated in Hmox1(-/-) mice, consistent with endothelial cell damage and loss. Third, following transplantation of Hmox1(-/-) donor bone marrow into Hmox1(-/-) recipients and subsequent vascular injury, we observed rapid arterial thrombosis compared with Hmox1(+/+) mice receiving Hmox1(+/+) bone marrow. Fourth, inhaled carbon monoxide and biliverdin administration rescued the prothrombotic phenotype in Hmox1(-/-) mice. Fifth, using a transcriptional analysis of arterial tissue, we found that HO-1 determined a transcriptional response to injury, with specific effects on cell cycle regulation, coagulation, thrombosis, and redox homeostasis. These data provide direct genetic evidence for a protective role of HO-1 against thrombosis and reactive oxygen species during vascular damage. Induction of HO-1 may be beneficial in the prevention of thrombosis associated with vascular oxidant stress and inflammation. C1 NHLBI, NIH, Bethesda, MD 20892 USA. NIH, Ctr Informat Technol, Bethesda, MD 20892 USA. Univ Michigan, Med Ctr, Ann Arbor, MI USA. RP Nabel, EG (reprint author), NHLBI, NIH, BLdg 31,Room 5A48,31 Ctr Dr, Bethesda, MD 20892 USA. EM nabele@nhlbi.nih.gov OI Lynn, Edward/0000-0002-8011-5558 FU Intramural NIH HHS NR 38 TC 82 Z9 82 U1 0 U2 4 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 OCT 26 PY 2007 VL 101 IS 9 BP 893 EP 901 DI 10.1161/CIRCRESAHA.107.158998 PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 226VW UT WOS:000250617600010 PM 17885218 ER PT J AU Ashikaga, H Sasano, T Dong, J Zviman, MM Evers, R Hopenfeld, B Castro, V Helm, RH Dickfeld, T Nazarian, S Donahue, JK Berger, RD Calkins, H Abraham, MR Marban, E Lardo, AC McVeigh, ER Halperin, HR AF Ashikaga, Hiroshi Sasano, Tetsuo Dong, Jun Zviman, M. Muz Evers, Robert Hopenfeld, Bruce Castro, Valeria Helm, Robert H. Dickfeld, Timm Nazarian, Saman Donahue, J. Kevin Berger, Ronald D. Calkins, Hugh Abraham, M. Roselle Marban, Eduardo Lardo, Albert C. McVeigh, Elliot R. Halperin, Henry R. TI Magnetic resonance-based anatomical analysis of scar-related ventricular tachycardia - Implications for catheter ablation SO CIRCULATION RESEARCH LA English DT Article DE ventricular tachycardia; catheter ablation; MRI ID CHRONIC MYOCARDIAL-INFARCTION; NONISCHEMIC CARDIOMYOPATHY; CONSCIOUS DOGS; REPERFUSION; LESIONS; TACHYARRHYTHMIAS; OCCLUSION; MODEL; REVASCULARIZATION; STIMULATION AB In catheter ablation of scar-related monomorphic ventricular tachycardia (VT), substrate voltage mapping is used to electrically define the scar during sinus rhythm. However, the electrically defined scar may not accurately reflect the anatomical scar. Magnetic resonance-based visualization of the scar may elucidate the 3D anatomical correlation between the fine structural details of the scar and scar-related VT circuits. We registered VT activation sequence with the 3D scar anatomy derived from high-resolution contrast-enhanced MRI in a swine model of chronic myocardial infarction using epicardial sock electrodes (n=6, epicardial group), which have direct contact with the myocardium where the electrical signal is recorded. In a separate group of animals (n=5, endocardial group), we also assessed the incidence of endocardial reentry in this model using endocardial basket catheters. Ten to 12 weeks after myocardial infarction, sustained monomorphic VT was reproducibly induced in all animals (n=11). In the epicardial group, 21 VT morphologies were induced, of which 4 (19.0%) showed epicardial reentry. The reentry isthmus was characterized by a relatively small volume of viable myocardium bound by the scar tissue at the infarct border zone or over the infarct. In the endocardial group (n=5), 6 VT morphologies were induced, of which 4 (66.7%) showed endocardial reentry. In conclusion, MRI revealed a scar with spatially complex structures, particularly at the isthmus, with substrate for multiple VT morphologies after a single ischemic episode. Magnetic resonance-based visualization of scar morphology would potentially contribute to preprocedural planning for catheter ablation of scar-related, unmappable VT. C1 Johns Hopkins Univ, Sch Med, Div Cardiol, Baltimore, MD 20215 USA. NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. Univ Maryland, Div Cardiol, Baltimore, MD 21201 USA. Case Western Reserve Univ, MetroHealth Hosp, Heart & Vasc Res Ctr, Cleveland, OH 44106 USA. RP Ashikaga, H (reprint author), Johns Hopkins Univ, Sch Med, Div Cardiol, 720 Rutland Ave,Traylor 903, Baltimore, MD 20215 USA. EM ha8000@gmail.com OI Ashikaga, Hiroshi/0000-0003-3689-6892 FU Intramural NIH HHS [Z01 HL004609-04]; NHLBI NIH HHS [P01 HL077180, P01 HL077180-02, P01-HL077180, R01 HL064795, R01 HL064795-08, R01-HL64795, Z01 HL004609, Z01-HL004609] NR 35 TC 91 Z9 92 U1 1 U2 4 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 OCT 26 PY 2007 VL 101 IS 9 BP 939 EP 947 DI 10.1161/CIRCRESAHA.107.158980 PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 226VW UT WOS:000250617600015 PM 17916777 ER PT J AU Gatot, JS Gioia, R Chau, TL Patrascu, F Warnier, M Close, P Chapelle, JP Muraille, E Brown, K Siebenlist, U Piette, J Dejardin, E Chariot, A AF Gatot, Jean-Stephane Gioia, Romain Chau, Tieu-Lan Patrascu, Felicia Warnier, Michael Close, Pierre Chapelle, Jean-Paul Muraille, Eric Brown, Keith Siebenlist, Ulrich Piette, Jacques Dejardin, Emmanuel Chariot, Alain TI Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKK epsilon-dependent lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NF-KAPPA-B; TOLL-LIKE RECEPTORS; UBIQUITIN-CONJUGATING ENZYME; KINASE-RELATED KINASES; IKK-EPSILON; ANTIVIRAL RESPONSE; NEMO/IKK-GAMMA; RIG-I; PATHWAY; TBK1 AB Type I interferon gene induction relies on IKK-related kinase TBK1 and IKK epsilon-mediated phosphorylations of IRF3/7 through the Toll-like receptor-dependent signaling pathways. The scaffold proteins that assemble these kinase complexes are poorly characterized. We show here that TANK/ITRAF is required for the TBK1- and IKK epsilon-mediated IRF3/7 phosphorylations through some Toll-like receptor-dependent pathways and is part of a TRAF3-containing complex. Moreover, TANK is dispensable for the early phase of double-stranded RNA-mediated IRF3 phosphorylation. Interestingly, TANK is heavily phosphorylated by TBK1-IKK epsilon upon lipopolysaccharide stimulation and is also subject to lipopolysaccharide- and TBK1-IKK epsilon-mediated Lys(63)-linked polyubiquitination, a mechanism that does not require TBK1-IKK epsilon kinase activity. Thus, we have identified TANK as a scaffold protein that assembles some but not all IRF3/7-phosphorylating TBK1-IKK epsilon complexes and demonstrated that these kinases possess two functions, namely the phosphorylation of both IRF3/7 and TANK as well as the recruitment of an E3 ligase for Lys63-linked polyubiquitination of their scaffold protein, TANK. C1 Canc Res UK London Res Inst, Clare Hall Labs, S Mimms ENS 3LD, Herts, England. Univ Liege, GIGA Res, Med Chem Unit, B-4000 Liege, Belgium. Univ Liege, Interdisciplinary Cluster Appl Genoproteom, B-4000 Liege, Belgium. Univ Liege, Virol Immunol Units, B-4000 Liege, Belgium. Free Univ Brussels, Parasitol Lab, B-1070 Brussels, Belgium. NIH, NIAID, Immunoregulat Lab, Bethesda, MD 20892 USA. RP Chariot, A (reprint author), Free Univ Brussels, Inst Mol Biol & Med, Dept Appl Genet, B-6041 Gossellies, Belgium. EM Alain.chariot@ulg.ac.be NR 57 TC 44 Z9 47 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 26 PY 2007 VL 282 IS 43 BP 31131 EP 31146 DI 10.1074/jbc.M701690200 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 222PK UT WOS:000250309200003 PM 17823124 ER PT J AU Watanabe, K Bianco, C Strizzi, L Hamada, S Mancino, M Bailly, V Mo, W Wen, D Miatkowski, K Gonzales, M Sanicola, M Seno, M Salomon, DS AF Watanabe, Kazuhide Bianco, Caterina Strizzi, Luigi Hamada, Shin Mancino, Mario Bailly, Veronique Mo, Wenjun Wen, Dingyi Miatkowski, Konrad Gonzales, Monica Sanicola, Michele Seno, Masaharu Salomon, David S. TI Growth factor induction of cripto-1 shedding by glycosylphosphatidylinositol-phospholipase D and enhancement of endothelial cell migration SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NODAL SIGNALING PATHWAY; EGF-CFC FAMILY; ANCHORED PROTEINS; MAMMARY-GLAND; TRANSGENIC MICE; MOUSE EMBRYO; COLON-CANCER; TGF-BETA; RELEASE; ANGIOGENESIS AB Cripto-1 (CR-1) is a glycosylphosphatidylinositol (GPI)-anchored membrane glycoprotein that has been shown to play an important role in embryogenesis and cellular transformation. CR-1 is reported to function as a membrane-bound co-receptor and as a soluble ligand. Although a number of studies implicate the role of CR-1 as a soluble ligand in tumor progression, it is unclear how transition from the membrane-bound to the soluble form is physiologically regulated and whether differences in biological activity exist between these forms. Here, we demonstrate that CR-1 protein is secreted from tumor cells into the conditioned medium after treatment with serum, epidermal growth factor, or lysophosphatidic acid, and this soluble form of CR-1 exhibits the ability to promote endothelial cell migration as a paracrine chemoattractant. On the other hand, membranebound CR-1 can stimulate endothelial cell sprouting through direct cell-cell interaction. Shedding of CR-1 occurs at the GPI-anchorage site by the activity of GPI-phospholipase D (GPIPLD), because CR-1 shedding was suppressed by siRNA knockdown of GPI-PLD and enhanced by overexpression of GPI-PLD. These findings describe a novel molecular mechanism of CR-1 shedding, which may contribute to endothelial cell migration and possibly tumor angiogenesis. C1 NIH, NCI, Canc Res Ctr, Mammary Biol & Tumorgenesis Lab,Tumor Growth FS, Bethesda, MD 20892 USA. Biogen Inc, Cambridge, MA 02142 USA. Okayama Univ, Grad Sch Nat Sci & Technol, Dept Med & Bioengn Sci, Okayama 7008530, Japan. RP Salomon, DS (reprint author), NIH, NCI, Canc Res Ctr, Mammary Biol & Tumorgenesis Lab,Tumor Growth FS, Bethesda, MD 20892 USA. EM salomond@mail.nih.gov RI SENO, Masaharu /B-2092-2011 OI SENO, Masaharu /0000-0001-8547-6259 FU Intramural NIH HHS NR 44 TC 28 Z9 34 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 OCT 26 PY 2007 VL 282 IS 43 BP 31643 EP 31655 DI 10.1074/jbc.M702713200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 222PK UT WOS:000250309200056 PM 17720976 ER PT J AU Devos, JM Tomanicek, SJ Jones, CE Nossal, NG Mueser, TC AF Devos, Juliette M. Tomanicek, Stephen J. Jones, Charles E. Nossal, Nancy G. Mueser, Timothy C. TI Crystal structure of bacteriophage T4 5' nuclease in complex with a branched DNA reveals how flap endonuclease-1 family nucleases bind their substrates SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SINGLE-STRANDED-DNA; REPLICATION PROTEIN-A; T4 RNASE-H; SACCHAROMYCES-CEREVISIAE; POLYMERASE-DELTA; PCNA BINDING; FEN-1; STIMULATION; EXONUCLEASE; CATALYSIS AB Bacteriophage T4 RNase H, a flap endonuclease- 1 family nuclease, removes RNA primers from lagging strand fragments. It has both 5' nuclease and flap endonuclease activities. Our previous structure of native T4 RNase H(PD B code 1TFR) revealed an active site composed of highly conserved Asp residues and two bound hydrated magnesium ions. Here, we report the crystal structure of T4 RNase H in complex with a fork DNA substrate bound in its active site. This is the first structure of a flap endonuclease- 1 family protein with its complete branched substrate. The fork duplex interacts with an extended loop of the helix-hairpin-helix motif class 2. The 5' armcrosses over the active site, extending below the bridge ( helical arch) region. Cleavage assays of this DNA substrate identify a primary cut site 7-bases in from the 5' arm. The scissile phosphate, the first bond in the duplex DNA adjacent to the 5' arm, lies above a magnesium binding site. The less ordered 3' arm reaches toward the C and N termini of the enzyme, which are binding sites for T432 protein and T445 clamp, respectively. In the crystal structure, the scissile bond is located within the double-stranded DNA, between the first two duplex nucleotides next to the 5' arm, and lies above a magnesium binding site. This complex provides important insight into substrate recognition and specificity of the flap endonuclease- 1 enzymes. C1 Univ Toledo, Dept Chem, Toledo, OH 43606 USA. NIDDK, NIH, Mol & Cellular Biol Lab, Bethesda, MD 20892 USA. RP Mueser, TC (reprint author), Univ Toledo, Dept Chem, 2801 W Bancroft St, Toledo, OH 43606 USA. EM timothy.mueser@utoledo.edu FU Intramural NIH HHS NR 55 TC 31 Z9 32 U1 0 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 OCT 26 PY 2007 VL 282 IS 43 BP 31713 EP 31724 DI 10.1074/jbc.M703209200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 222PK UT WOS:000250309200062 PM 17693399 ER PT J AU McGugan, GC Joshi, MB Dwyer, DM AF McGugan, Glen C., Jr. Joshi, Manju B. Dwyer, Dennis M. TI Identification and biochemical characterization of unique secretory nucleases of the human enteric pathogen, Entamoeba histolytica SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NEUTRAL CYSTEINE PROTEINASE; ENDOPLASMIC-RETICULUM; LEISHMANIA-DONOVANI; MEMBRANE-PROTEINS; RHIZOPUS-NIVEUS; GOLGI-APPARATUS; RIBONUCLEASE; GENE; EXPRESSION; SEQUENCE AB The ancient eukaryotic human pathogen, Entamoeba histolytica, is a nucleo-base auxotroph (i.e. lacks the ability to synthesize purines or pyrimidines de novo) and therefore is totally dependent upon its host for the supply of these essential nutrients. In this study, we identified two unique 28- kDa, dithiothreitolsensitive nucleases and showed that they are constitutively released/secreted by parasites during axenic culture. Using several different molecular approaches, we identified and characterized the structure of EhNucI and EhNucII, genes that encode ribonuclease T2 family proteins. Homologous episomal expression of epitope-tagged EhNucI and EhNucII chimeric constructs was used to define the functional and biochemical properties of these released/secreted enzymes. Results of coupled immuno-precipitation-enzyme activity analyses demonstrated that these "secretory" enzymes could hydrolyze a variety of synthetic polynucleotides, as well as the natural nucleic acid substrate RNA. Furthermore, our results demonstrated that sera from acutely infected amebiasis patients recognized and immunoprecipitated these parasite secretory enzymes. Based on these observations, we hypothesize that within its host, these secretory nucleases could function, at a distance away from the parasite, to harness (i.e. hydrolyze/access) host-derived nucleic acids to satisfy the essential purine and pyrimidine requirements of these organisms. Thus, these enzymes might play an important role in facilitating the survival, growth, and development of this important human pathogen. C1 NIAID, Div Intramural Res, Parasit Dis Lab, Cell Biol Sect, Bethesda, MD 20892 USA. RP Dwyer, DM (reprint author), NIAID, Div Intramural Res, Parasit Dis Lab, Cell Biol Sect, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ddwyer@niaid.nih.gov FU Intramural NIH HHS NR 62 TC 8 Z9 9 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 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 26 PY 2007 VL 282 IS 43 BP 31789 EP 31802 DI 10.1074/jbc.M705975200 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 222PK UT WOS:000250309200069 PM 17766245 ER PT J AU Chakrabarti, S Bryant, SH Panchenko, AR AF Chakrabarti, Saikat Bryant, Stephen H. Panchenko, Anna R. TI Functional specificity lies within the properties and evolutionary changes of amino acids SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE functional divergence; subfamily specificity; physico-chemical properties; combined relative entropy; evolutionary rate ID PROTEIN FAMILIES; DIHYDROPTEROATE SYNTHASE; DETERMINING RESIDUES; SECONDARY STRUCTURE; SEQUENCE ALIGNMENT; ACTIVE-SITES; PREDICTION; CONSERVATION; DIVERGENCE; DATABASE AB The rapid increase in the amount of protein sequence data has created a need for automated identification of sites that determine functional specificity among related subfamilies of proteins. A significant fraction of subfamily specific sites are only marginally conserved, which makes it extremely challenging to detect those amino acid changes that lead to functional diversification. To address this critical problem we developed a method named SPEER (specificity prediction using amino acids' properties, entropy and evolution rate) to distinguish specificity determining sites from others. SPEER encodes the conservation patterns of amino acid types using their physico-chemical properties and the heterogeneity of evolutionary changes between and within the subfamilies. To test the method, we compiled a test set containing 13 protein families with known specificity determining sites. Extensive benchmarking by comparing the performance of SPEER with other specificity site prediction algorithms has shown that it performs better in predicting several categories of subfamily specific sites. Published by Elsevier Ltd. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. RP Chakrabarti, S (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Natl Inst Hlth, Bethesda, MD 20894 USA. EM chakraba@ncbi.nlm.nih.gov FU Intramural NIH HHS [Z99 LM999999] NR 58 TC 38 Z9 39 U1 0 U2 3 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 OCT 26 PY 2007 VL 373 IS 3 BP 801 EP 810 DI 10.1016/j.jmb.2007.08.036 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 224IF UT WOS:000250440000024 PM 17868687 ER PT J AU Nowotny, M Gaidamakov, SA Ghirlando, R Cerritelli, SM Crouch, RJ Yang, W AF Nowotny, Marcin Gaidamakov, Sergei A. Ghirlando, Rodolfo Cerritelli, Susana M. Crouch, Robert J. Yang, Wei TI Structure of human RNase h1 complexed with an RNA/DNA hybrid: Insight into HIV reverse transcription SO MOLECULAR CELL LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; MURINE LEUKEMIA-VIRUS; DOUBLE-STRANDED-RNA; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; POLYPURINE TRACT; RIBONUCLEASE-H; SUBSTRATE-SPECIFICITY; ANGSTROM RESOLUTION; DNA-POLYMERASE AB We report here crystal structures of human RNase H1 complexed with an RNA/DNA substrate. Unlike B. halodurans RNase H1, human RNase H1 has a basic protrusion, which forms a DNA binding channel and together with the conserved phosphate-binding pocket confers specif icity for the B form and 2'-deoxy DNA. The RNA strand is recognized by four consecutive 2'-OH groups and cleaved by a two-metal ion mechanism. Although RNase H1 is overall positively charged, the substrate interface is neutral to acidic in character, which likely contributes to the catalytic specificity. Positions of the scissile phosphate and two catalytic metal ions are interdependent and highly coupled. Modeling of HIV reverse transcriptase (RT) with RNA/DNA in its RNase H active site suggests that the substrate cannot simultaneously occupy the polymerase active site and must undergo a conformational change to toggle between the two catalytic centers. The region that accommodates this conformational change offers a target to develop HIV-specific inhibitors. C1 NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM wei.yang@nih.gov RI Ghirlando, Rodolfo/A-8880-2009; Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 FU Intramural NIH HHS NR 53 TC 139 Z9 140 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD OCT 26 PY 2007 VL 28 IS 2 BP 264 EP 276 DI 10.1016/j.molcel.2007.08.015 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 228OR UT WOS:000250739800011 PM 17964265 ER PT J AU Arendash, GW Jensen, MT Salem, N Hussein, N Cracchiolo, J Dickson, A Leighty, R Potter, H AF Arendash, G. W. Jensen, M. T. Salem, N., Jr. Hussein, N. Cracchiolo, J. Dickson, A. Leighty, R. Potter, H. TI A diet high in omega-3 fatty acids does not improve or protect cognitive performance in Alzheimer's transgenic mice SO NEUROSCIENCE LA English DT Article DE DHA; EPA; beta-amyloid; memory ID POLYUNSATURATED FATTY-ACIDS; A-BETA DEPOSITION; DOCOSAHEXAENOIC ACID; LEARNING-ABILITY; BRAIN PHOSPHOLIPIDS; AMYLOID-BETA; MOUSE MODEL; DISEASE; DEMENTIA; IMPAIRMENT AB Although a number of epidemiologic studies reported that higher intake of omega-3 fatty acids (largely associated with fish consumption) is protective against Alzheimer's disease (AD), other human studies reported no such effect. Because retrospective human studies are problematic and controlled longitudinal studies over decades are impractical, the present study utilized Alzheimer's transgenic mice (Tg) in a highly controlled study to determine whether a diet high in omega-3 fatty acid, equivalent to the 13% omega-3 fatty acid diet of Greenland Eskimos, can improve cognitive performance or protect against cognitive impairment. Amyloid precursor protein (APP)-sw+PS1 double transgenic mice, as well as nontransgenic (NT) normal littermates, were given a high omega-3 supplemented diet or a standard diet from 2 through 9 months of age, with a comprehensive behavioral test battery administered during the final 6 weeks. For both Tg and NT mice, long-term n-3 supplementation resulted in cognitive performance that was no better than that of mice fed a standard diet. In NT mice, the high omega-3 diet increased cortical levels of omega-3 fatty acids while decreasing omega-6 levels. However, the high omega-3 diet had no effect on cortical fatty acid levels in Tg mice. Irrespective of diet, no correlations existed between brain omega-3 levels and cognitive performance for individual NT or Tg mice. In contrast, brain levels of omega-6 fatty acids were strongly correlated with cognitive impairment for both genotypes. Thus, elevated brain levels of omega-3 fatty acids were not relevant to cognitive function, whereas high brain levels of omega-6 were associated with impaired cognitive function. In Tg mice, the omega-3 supplemental diet did not induce significant changes in soluble/insoluble A beta within the hippocampus, although strong correlations were evident between hippocampal A beta(1-40) levels and cognitive impairment. While these studies involved a genetically manipulated mouse model of AD, our results suggest that diets high in omega-3 fatty acids, or use of fish oil supplements (DHA+EPA), will not protect against AD, at least in high-risk individuals. However, normal individuals conceivably could derive cognitive benefits from high omega-3 intake if it corrects an elevation in the brain level of n-6 fatty acids as a result. Alternatively, dietary fish may contain nutrients, other than DHA and EPA, that could provide some protection against AD. (C) 2007 IBRO. Published by Elsevier Ltd. All rights reserved. C1 Byrd Alzheimers Inst, Tampa, FL 33613 USA. Florida Alzheimers Dis Res Ctr, Tampa, FL 33613 USA. Univ S Florida, Div Cell Biol Microbiol & Mol Biol, Tampa, FL 33620 USA. NIAAA, Natl Inst Hlth, Bethesda, MD 20892 USA. Univ S Florida, Coll Med, Suncoast Gerontol & Alzheimers Ctr, Tampa, FL 33612 USA. RP Arendash, GW (reprint author), Byrd Alzheimers Inst, 4001 E Fletcher Ave, Tampa, FL 33613 USA. EM arendash@cas.usf.edu FU NIA NIH HHS [P50AG025711] NR 58 TC 62 Z9 63 U1 2 U2 20 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 OCT 26 PY 2007 VL 149 IS 2 BP 286 EP 302 DI 10.1016/j.neuroscience.2007.08.018 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 224VF UT WOS:000250474100005 PM 17904756 ER PT J AU Alves, G Ogurtsov, AY Yu, YK AF Alves, Gelio Ogurtsov, Aleksey Y. Yu, Yi-Kuo TI RAId_DbS: Peptide identification using database searches with realistic statistics SO BIOLOGY DIRECT LA English DT Article ID TANDEM MASS-SPECTROMETRY; PROTEIN IDENTIFICATION; SEQUENCE DATABASES; SPECTRAL DATA; BIOINFORMATICS; ALGORITHM AB Background: The key to mass-spectrometry-based proteomics is peptide identification. A major challenge in peptide identification is to obtain realistic E-values when assigning statistical significance to candidate peptides. Results: Using a simple scoring scheme, we propose a database search method with theoretically characterized statistics. Taking into account possible skewness in the random variable distribution and the effect of finite sampling, we provide a theoretical derivation for the tail of the score distribution. For every experimental spectrum examined, we collect the scores of peptides in the database, and find good agreement between the collected score statistics and our theoretical distribution. Using Student's t-tests, we quantify the degree of agreement between the theoretical distribution and the score statistics collected. The T-tests may be used to measure the reliability of reported statistics. When combined with reported P-value for a peptide hit using a score distribution model, this new measure prevents exaggerated statistics. Another feature of RAId_DbS is its capability of detecting multiple co-eluted peptides. The peptide identification performance and statistical accuracy of RAId_DbS are assessed and compared with several other search tools. The executables and data related to RAId_DbS are freely available upon request. C1 [Alves, Gelio; Ogurtsov, Aleksey Y.; Yu, Yi-Kuo] Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Yu, YK (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM alves@ncbi.nlm.nih.gov; ogurtsov@ncbi.nlm.nih.gov; yyu@ncbi.nlm.nih.gov FU Intramural NIH HHS NR 29 TC 13 Z9 13 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD OCT 25 PY 2007 VL 2 AR 25 DI 10.1186/1745-6150-2-25 PG 20 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 253OS UT WOS:000252528100001 PM 17961253 ER PT J AU Hierro, A Rojas, AL Rojas, R Murthy, N Effantin, G Kajava, AV Steven, AC Bonifacino, JS Hurley, JH AF Hierro, Aitor Rojas, Adriana L. Rojas, Raul Murthy, Namita Effantin, Gregory Kajava, Andrey V. Steven, Alasdair C. Bonifacino, Juan S. Hurley, James H. TI Functional architecture of the retromer cargo-recognition complex SO NATURE LA English DT Article ID MANNOSE 6-PHOSPHATE RECEPTOR; REQUIRES RETROMER; POLYCISTRONIC EXPRESSION; RETROGRADE TRANSPORT; ELECTRON-MICROSCOPY; MAMMALIAN RETROMER; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; PROTEINS; DOMAINS AB The retromer complex(1,2) is required for the sorting of acid hydrolases to lysosomes(3-7), transcytosis of the polymeric immunoglobulin receptor(8), Wnt gradient formation(9,10), iron transporter recycling(11) and processing of the amyloid precursor protein(12). Human retromer consists of two smaller complexes: the cargo recognition VPS26-VPS29-VPS35 heterotrimer and a membrane-targeting heterodimer or homodimer of SNX1 and/or SNX2 (ref. 13). Here we report the crystal structure of a VPS29-VPS35 subcomplex showing how the metallophosphoesterase-fold subunit VPS29 (refs 14, 15) acts as a scaffold for the carboxyterminal half of VPS35. VPS35 forms a horseshoe-shaped, right-handed, alpha-helical solenoid, the concave face of which completely covers the metal-binding site of VPS29, whereas the convex face exposes a series of hydrophobic interhelical grooves. Electron microscopy shows that the intact VPS26-VPS29-VPS35 complex is a stick-shaped, flexible structure, approximately 21 nm long. A hybrid structural model derived from crystal structures, electron microscopy, interaction studies and bioinformatics shows that the alpha-solenoid fold extends the full length of VPS35, and that VPS26 is bound at the opposite end from VPS29. This extended structure presents multiple binding sites for the SNX complex and receptor cargo, and appears capable of flexing to conform to curved vesicular membranes. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. NIAMSD, Struct Biol Lab, NIH, US Dept HHS, Bethesda, MD 20892 USA. Univ Montpellier, CNRS, Ctr Rech Biochim Macromol, F-34293 Montpellier, France. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov RI Hierro, Aitor/F-9998-2011; Rojas, Adriana/G-2403-2011; Kajava, Andrey/E-1107-2014; OI Hierro, Aitor/0000-0002-7721-1581; Rojas, Adriana/0000-0002-7358-3505; Kajava, Andrey/0000-0002-2342-6886; Bonifacino, Juan S./0000-0002-5673-6370 FU Intramural NIH HHS [Z01 DK036118-14] NR 43 TC 120 Z9 123 U1 1 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 25 PY 2007 VL 449 IS 7165 BP 1063 EP U8 DI 10.1038/nature06216 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 223TK UT WOS:000250395000055 PM 17891154 ER PT J AU Tang, C Schwieters, CD Clore, GM AF Tang, Chun Schwieters, Charles D. Clore, G. Marius TI Open-to-closed transition in apo maltose-binding protein observed by paramagnetic NMR SO NATURE LA English DT Article ID DIPOLAR COUPLINGS; ACTIVE-TRANSPORT; MACROMOLECULES; SPECTROSCOPY; DYNAMICS; REFINEMENT; RECEPTOR; DATABASE; DOMAINS; MOTIONS AB Large-scale domain rearrangements in proteins have long been recognized to have a critical function in ligand binding and recognition, catalysis and regulation(1-5). Crystal structures have provided a static picture of the apo (usually open) and holo usually closed) states. The general question arises as to whether the apo state exists as a single species in which the closed state is energetically inaccessible and interdomain rearrangement is induced by ligand or substrate binding, or whether the predominantly open form already coexists in rapid equilibrium with a minor closed species. The maltose-binding protein (MBP), a member of the bacterial periplasmic binding protein family(6), provides a model system for investigating this problem because it has been the subject of extensive studies by crystallography(7,8), NMR9-11 and other biophysical techniques(11-13). Here we show that although paramagnetic relaxation enhancement (PRE) data for the sugar-bound form are consistent with the crystal structure of holo MBP, the PRE data for the apo state are indicative of a rapidly exchanging mixture (ns to mu s regime) of a predominantly (similar to 95%) open form (represented by the apo crystal structure) and a minor (similar to 5%) partially closed species. Using ensemble simulated annealing refinement against the PRE data we are able to determine a [r(-6)] ensemble average structure of the minor apo species and show that it is distinct from the sugar-bound state. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NIH, Div Computat Biosci, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. EM mariusc@intra.niddk.nih.gov RI Clore, G. Marius/A-3511-2008; ID, BioCAT/D-2459-2012 OI Clore, G. Marius/0000-0003-3809-1027; NR 35 TC 241 Z9 244 U1 4 U2 33 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 25 PY 2007 VL 449 IS 7165 BP 1078 EP U12 DI 10.1038/nature06232 PG 7 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 223TK UT WOS:000250395000058 PM 17960247 ER PT J AU Chakrapani, H Showalter, BM Citro, ML Keefer, LK Saavedra, JE AF Chakrapani, Harinath Showalter, Brett M. Citro, Michael L. Keefer, Larry K. Saavedra, Joseph E. TI Nitric oxide prodrugs: Diazeniumdiolate anions of hindered secondary Amines SO ORGANIC LETTERS LA English DT Article ID BIOLOGICAL APPLICATIONS; NITROGEN(II) OXIDE; NOBEL LECTURE; DONOR DRUGS; IN-VITRO; CHEMISTRY; PATHOPHYSIOLOGY; CARCINOGENICITY; NITROSOPROLINE; GLUTATHIONE AB [GRAPHICS] Nitric oxide prodrugs derived from hindered secondary amines were prepared. The decomposition patterns of these prodrugs indicate that alpha-methyl groups around the nitrogen bearing the diazeniumdiolate group prolong their half-life in aqueous buffer. C1 Natl Canc Inst, Comparat Carcinogenesis Lab, Chem Sect, Ft Detrick, MD 21702 USA. Natl Canc Inst, SAIC Frederick, Basic Res Program, Ft Detrick, MD 21702 USA. RP Chakrapani, H (reprint author), Natl Canc Inst, Comparat Carcinogenesis Lab, Chem Sect, Ft Detrick, MD 21702 USA. EM chakrah@ncifcrf.gov; 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 36 TC 11 Z9 11 U1 0 U2 4 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 OCT 25 PY 2007 VL 9 IS 22 BP 4551 EP 4554 DI 10.1021/o17019636 PG 4 WC Chemistry, Organic SC Chemistry GA 222MR UT WOS:000250302000038 PM 17918856 ER PT J AU Boyer, PL Stenbak, CR Hoberman, D Linial, ML Hughes, SH AF Boyer, Paul L. Stenbak, Carolyn R. Hoberman, David Linial, Maxine L. Hughes, Stephen H. TI In vitro fidelity of the prototype primate foamy virus (PFV) RT compared to HIV-1 RT SO VIROLOGY LA English DT Article DE fidelity; reverse transcriptase; spumavirus; HIV-1; lentivirus ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 REVERSE-TRANSCRIPTASE; ANALOG-RESISTANCE MUTATIONS; LONG TERMINAL REPEAT; ACTIVE-SITE; POLYMERASE FIDELITY; ERROR SPECIFICITY; DNA-POLYMERASE; PROCESSIVITY; REPLICATION AB We compared the in vitro fidelity of wild-type human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) and the prototype foamy virus (PFV) RT. Both enzymes had similar error rates for single nucleotide substitutions; however, PFV RT did not appear to make errors at specific hotspots, like HIV-1 RT. In addition, PFV RT made more deletions and insertions than HIV-1 RT. Although the majority of the missense errors made by HIV-1 RT and PFV RT are different, relatively few of the mutations caused by either enzyme can be explained by a misalignment/slippage mechanism. We suggest that the higher polymerase activity of PFV RT could contribute to the ability of the enzyme to jump to the same or a different template. Published by Elsevier Inc. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. Trinity Univ, Dept Biol, San Antonio, TX 78212 USA. Fred Hutchinson Canc Res Ctr, Div Basic Sci A3 015, Seattle, WA 98109 USA. RP Hughes, SH (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. FU Intramural NIH HHS [Z01 BC010481-05]; NCI NIH HHS [CA18282, R01 CA018282] NR 50 TC 15 Z9 15 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 0042-6822 J9 VIROLOGY JI Virology PD OCT 25 PY 2007 VL 367 IS 2 BP 253 EP 264 DI 10.1016/j.virol.2007.05.034 PG 12 WC Virology SC Virology GA 220NH UT WOS:000250162900003 PM 17631930 ER PT J AU Dogan, RI Getoor, L Wilbur, WJ Mount, SM AF Dogan, Rezarta Islamaj Getoor, Lise Wilbur, W. John Mount, Stephen M. TI Features generated for computational splice-site prediction correspond to functional elements SO BMC BIOINFORMATICS LA English DT Article ID SEQUENCE MOTIFS; ENHANCERS; SELECTION; CLASSIFICATION; IDENTIFICATION; DEFINITION; SILENCERS; INTRONS; EXONS; AG AB Background: Accurate selection of splice sites during the splicing of precursors to messenger RNA requires both relatively well-characterized signals at the splice sites and auxiliary signals in the adjacent exons and introns. We previously described a feature generation algorithm (FGA) that is capable of achieving high classification accuracy on human 3' splice sites. In this paper, we extend the splice-site prediction to 5' splice sites and explore the generated features for biologically meaningful splicing signals. Results: We present examples from the observed features that correspond to known signals, both core signals (including the branch site and pyrimidine tract) and auxiliary signals (including GGG triplets and exon splicing enhancers). We present evidence that features identified by FGA include splicing signals not found by other methods. Conclusion: Our generated features capture known biological signals in the expected sequence interval flanking splice sites. The method can be easily applied to other species and to similar classification problems, such as tissue-specific regulatory elements, polyadenylation sites, promoters, etc. C1 [Dogan, Rezarta Islamaj; Getoor, Lise] Univ Maryland, Dept Comp Sci, College Pk, MD 20742 USA. [Dogan, Rezarta Islamaj; Wilbur, W. John] Natl Lib Med, NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. [Mount, Stephen M.] Univ Maryland, Dept Cell Biol & Mol Genet, College Pk, MD 20742 USA. [Mount, Stephen M.] Univ Maryland, Ctr Bioinformat & Computat Biol, College Pk, MD 20742 USA. RP Dogan, RI (reprint author), Univ Maryland, Dept Comp Sci, College Pk, MD 20742 USA. EM rezarta@cs.umd.edu; getoor@cs.umd.edu; wilbur@mail.nih.gov; smount@umd.edu OI Mount, Steve/0000-0003-2748-8205 NR 39 TC 6 Z9 7 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD OCT 24 PY 2007 VL 8 AR 410 DI 10.1186/1471-2105-8-410 PG 16 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 262OV UT WOS:000253158800001 PM 17958908 ER PT J AU Eiss, RB Glass, RI AF Eiss, Robert B. Glass, Roger I. TI Bridging the coverage gap in global health SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID POOR; INTERVENTIONS C1 NIH, Fogarty Int Ctr, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Eiss, RB (reprint author), NIH, Fogarty Int Ctr, Dept Hlth & Human Serv, 31 Ctr Dr,MSC 2220, Bethesda, MD 20892 USA. EM eissr@mail.nih.gov NR 17 TC 2 Z9 2 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 330 N WABASH AVE, STE 39300, CHICAGO, IL 60611-5885 USA SN 0098-7484 EI 1538-3598 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 24 PY 2007 VL 298 IS 16 BP 1940 EP 1942 DI 10.1001/jama.298.16.1940 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 223GC UT WOS:000250356700029 PM 17954548 ER PT J AU Ghitza, UE Nair, SG Golden, SA Gray, SM Uejima, JL Bossert, JM Shaham, Y AF Ghitza, Udi E. Nair, Sunila G. Golden, Sam A. Gray, Sarah M. Uejima, Jamie L. Bossert, Jennifer M. Shaham, Yavin TI Peptide YY3-36 decreases reinstatement of high-fat food seeking during dieting in a rat relapse model SO JOURNAL OF NEUROSCIENCE LA English DT Article DE arcuate nucleus; heroin self-administration; peptide YY; reinstatement; relapse; stress; Y2 receptors; yohimbine ID PRIMING-INDUCED REINSTATEMENT; STRESS-INDUCED REINSTATEMENT; NEUROPEPTIDE YY2 RECEPTOR; VENTRAL TEGMENTAL AREA; BETA-ENDORPHIN LEVELS; NUCLEUS-ACCUMBENS; COCAINE-SEEKING; HEROIN-SEEKING; DRUG-SEEKING; NORADRENERGIC MECHANISMS AB A major problem in treating obesity is high rates of relapse to maladaptive food-taking habits during dieting. This relapse is often provoked by acute re-exposure to palatable food, food-associated cues, or stress. We used a reinstatement model, commonly used to study relapse to abused drugs, to explore the effect of peptide YY3-36 (PYY3-36) on reinstatement of high-fat (35%, 45 mg pellets) food seeking induced by acute exposure to the pellets ( pellet priming), a cue previously associated with pellet delivery ( pellet cue), or yohimbine ( 2 mg/kg, a pharmacological stressor). Rats were placed on a restricted diet ( 16 g of chow per day) and lever-pressed for the pellets for 9-12 sessions (6 h/d, every 48 h); pellet delivery was paired with a tone-light cue. They were then given 10-20 extinction sessions wherein lever presses were not reinforced with the pellets and subsequently tested for reinstatement of food seeking. Systemic PYY3-36 injections (100-200 mu g/kg) decreased pellet priming-and pellet cue-induced reinstatement of food seeking but not yohimbine-induced reinstatement. Arcuate nucleus ( Arc) injections of PYY3-36 ( 0.4 mu g per side) decreased pellet priming-induced reinstatement. The attenuation of pellet priming-induced reinstatement by systemic PYY3-36 was reversed by systemic ( 2 mg/kg) but not Arc ( 0.5 mu g per side) injections of the Y2 receptor antagonist BIIE0246. Arc PYY3-36 injections did not decrease pellet cue-induced reinstatement. Finally, systemic PYY3-36 injections had minimal effects on ongoing food self-administration or heroin priming-or heroin cue-induced reinstatement of heroin seeking. These data identify an effect of systemic PYY3-36 on relapse to food seeking that is independent of Y2 receptor activation in Arc and suggest that PYY3-36 should be considered for the treatment of relapse to maladaptive food-taking habits during dieting. C1 NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Shaham, Y (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM yshaham@intra.nida.nih.gov RI shaham, yavin/G-1306-2014; OI Golden, Sam/0000-0002-2104-2272 FU Intramural NIH HHS [Z01 DA000434-08] NR 88 TC 39 Z9 39 U1 0 U2 6 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 OCT 24 PY 2007 VL 27 IS 43 BP 11522 EP 11532 DI 10.1523/JNEUROSCI.5405-06.2007 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 226HA UT WOS:000250577500010 PM 17959795 ER PT J AU Ho, MTW Pelkey, KA Topolnik, L Petralia, RS Takamiya, K Xia, J Huganir, RL Lacaille, JC McBain, CJ AF Ho, Michelle T. -W. Pelkey, Kenneth A. Topolnik, Lisa Petralia, Ronald S. Takamiya, Kogo Xia, Jun Huganir, Richard L. lacaille, Jean-ClauDe McBain, Chris J. TI Developmental expression of Ca2+-permeable AMPA receptors underlies depolarization-induced long-term depression at mossy fiber-CA3 pyramid Synapses SO JOURNAL OF NEUROSCIENCE LA English DT Article DE LTD; GluR2; mossy fiber; hippocampus; synapse development; calcium ID CALCIUM-PERMEABLE AMPA; SUBUNIT COMPOSITION; SYNAPTIC PLASTICITY; SILENT SYNAPSES; INTRACELLULAR POLYAMINES; NMDA RECEPTORS; IN-VIVO; BIDIRECTIONAL PLASTICITY; STRUCTURAL DETERMINANTS; MOLECULAR-MECHANISMS AB Many central excitatory synapses undergo developmental alterations in the molecular and biophysical characteristics of postsynaptic ionotropic glutamate receptors via changes in subunit composition. Concerning AMPA receptors (AMPARs), glutamate receptor 2 subunit (GluR2)-containing, Ca2+ -impermeable AMPARs (CI-AMPARs) prevail at synapses between mature principal neurons; however, accumulating evidence indicates that GluR2-lacking, Ca2+ permeable AMPARs(CP-AMPARs) contribute at these synapses early in development. Here, we used a combination of imaging and electrophysiological recording techniques to investigate potential roles for CP-AMPARs at developing hippocampal mossy fiber-CA3 pyramidal cell (MF-PYR) synapses. We found that transmission at nascent MF-PYR synapses is mediated by a mixed population of CP- and CI-AMPARs as evidenced by polyamine-dependent inwardly rectifying current-voltage (I-V) relationships, and partial philanthotoxin sensitivity of synaptic events. CP-AMPAR expression at MF-PYR synapses is transient, being limited to the first 3 postnatal weeks. Moreover, the expression of CP- AMPARs is regulated by the PDZ ( postsynaptic density-95/ Discs large/zona occludens-1) domain-containing protein interacting with C kinase 1 (PICK1), because MF-PYR synapses in young PICK1 knock-out mice are philanthotoxin insensitive with linear I-V relationships. Strikingly, MF-PYR transmission via CP- AMPARs is selectively depressed during depolarization-induced long-term depression (DiLTD), a postsynaptic form of MF-PYR plasticity observed only at young MF-PYR synapses. The selective depression of CP- AMPARs during DiLTD was evident as a loss of postsynaptic CP- AMPAR-mediated Ca2+ transients in PYR spines and reduced rectification of MF-PYR synaptic currents. Preferential targeting of CP- AMPARs during DiLTD is further supported by a lack of DiLTD in young PICK1 knock-out mice. Together, these findings indicate that the transient participation of CP- AMPARs at young MF-PYR synapses dictates the developmental window to observe DiLTD. C1 NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. Chinese Univ Hong Kong, Dept Biochem, Hong Kong, Hong Kong, Peoples R China. Univ Montreal, Dept Physiol, Grp Rech Syst Nerveux Cent, Montreal, PQ H3C 3J7, Canada. Johns Hopkins Univ, Dept Neurosci, Baltimore, MD 21205 USA. RP Pelkey, KA (reprint author), NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, Bldg 35,Room 3C705, Bethesda, MD 20892 USA. EM pelkeyk2@mail.nih.gov RI Xia, Jun/C-7234-2009; yu, yan/C-2322-2012; OI Xia, Jun/0000-0001-9308-2188 FU Intramural NIH HHS NR 75 TC 69 Z9 71 U1 2 U2 5 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 OCT 24 PY 2007 VL 27 IS 43 BP 11651 EP 11662 DI 10.1523/JNEUROSCI.2671-07.2007 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 226HA UT WOS:000250577500023 PM 17959808 ER PT J AU Yi, ZH Petralia, RS Fu, ZY Swanwick, CC Wang, YX Prybylowski, K Sans, N Vicini, S Wenthold, RJ AF Yi, Zhaohong Petralia, Ronald S. Fu, Zhanyan Swanwick, Catherine Croft Wang, Ya-Xian Prybylowski, Kate Sans, Nathalie Vicini, Stefano Wenthold, Robert J. TI The role of the PDZ protein GIPC in regulating NMDA receptor trafficking SO JOURNAL OF NEUROSCIENCE LA English DT Article DE NMDA receptor; extrasynaptic receptor; PDZ; GIPC; plasticity; endocytosis ID MEDIATED SYNAPTIC-TRANSMISSION; LONG-TERM POTENTIATION; DOMAIN-CONTAINING PROTEIN; MYOSIN-VI; HIPPOCAMPAL SYNAPSES; GLUTAMATE RECEPTORS; CYTOPLASMIC DOMAIN; AMPA RECEPTORS; C-TERMINUS; ENDOCYTOSIS AB The NMDA receptor is an important component of excitatory synapses in the CNS. In addition to its synaptic localization, the NMDA receptor is also present at extrasynaptic sites where it may have functions distinct from those at the synapse. Little is known about how the number, composition, and localization of extrasynaptic receptors are regulated. We identified a novel NMDA receptor-interacting protein, GIPC (GAIP-interacting protein, C terminus), that associates with surface as well as internalized NMDA receptors when expressed in heterologous cells. In neurons, GIPC colocalizes with a population of NMDA receptors on the cell surface, and changes in GIPC expression alter the number of surface receptors. GIPC is mainly excluded from the synapse, and changes in GIPC expression do not change the total number of synaptic receptors. Our results suggest that GIPC may be preferentially associated with extrasynaptic NMDA receptors and may play a role in the organization and trafficking of this population of receptors. C1 Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bethesda, MD 20892 USA. Georgetown Univ, Med Ctr, Dept Physiol & Biophys, Washington, DC 20007 USA. RP Wenthold, RJ (reprint author), Natl Inst Deafness & Other Commun Disorders, Neurochem Lab, NIH, Bldg 50,Room 4140, Bethesda, MD 20892 USA. EM wenthold@nidcd.nih.gov FU Intramural NIH HHS NR 52 TC 38 Z9 38 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 24 PY 2007 VL 27 IS 43 BP 11663 EP 11675 DI 10.1523/JNEUROSCI.3252-07.2007 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 226HA UT WOS:000250577500024 PM 17959809 ER PT J AU Hume, JCC Tunnicliff, M Ranford-Cartwright, LC Day, KP AF Hume, Jennifer C. C. Tunnicliff, Mark Ranford-Cartwright, Lisa C. Day, Karen P. TI Susceptibility of Anopheles gambiae and Anopheles stephensi to tropical isolates of Plasmodium falciparum SO MALARIA JOURNAL LA English DT Article ID MOSQUITO VECTOR; MALARIA; INFECTION; FARAUTI; HOST AB Background: The susceptibility of anopheline mosquito species to Plasmodium infection is known to be variable with some mosquitoes more permissive to infection than others. Little work, however, has been carried out investigating the susceptibility of major malaria vectors to geographically diverse tropical isolates of Plasmodium falciparum aside from examining the possibility of infection extending its range from tropical regions into more temperate zones. Methods: This study investigates the susceptibility of two major tropical mosquito hosts ( Anopheles gambiae and Anopheles stephensi) to P. falciparum isolates of different tropical geographical origins. Cultured parasite isolates were fed via membrane feeders simultaneously to both mosquito species and the resulting mosquito infections were compared. Results: Infection prevalence was variable with African parasites equally successful in both mosquito species, Thai parasites significantly more successful in An. stephensi, and PNG parasites largely unsuccessful in both species. Conclusion: Infection success of P. falciparum was variable according to geographical origin of both the parasite and the mosquito. Data presented raise the possibility that local adaptation of tropical parasites and mosquitoes has a role to play in limiting gene flow between allopatric parasite populations. C1 [Hume, Jennifer C. C.; Tunnicliff, Mark; Day, Karen P.] Univ Oxford, Peter Medawar Bldg Pathogen Res, Oxford OX1 3SY, England. [Hume, Jennifer C. C.; Tunnicliff, Mark; Day, Karen P.] Univ Oxford, Dept Zool, Oxford OX1 3SY, England. [Ranford-Cartwright, Lisa C.] Univ Glasgow, Glasgow Biomed Res Ctr, Div Infect & Immun, Glasgow G12 8TA, Lanark, Scotland. [Hume, Jennifer C. C.] NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20892 USA. [Day, Karen P.] NYU, Sch Med, Dept Med Parasitol, New York, NY 10010 USA. RP Day, KP (reprint author), Univ Oxford, Peter Medawar Bldg Pathogen Res, S Parks Rd, Oxford OX1 3SY, England. EM humej@niaid.nih.gov; mark.tunnicliff@medawar.oxford.ac.uk; L.C.Ranford-Cartwright@bio.gla.ac.uk; karen.day@med.nyu.edu RI Ranford-Cartwright, Lisa/H-4701-2013; Day, Karen/F-3697-2015 OI Ranford-Cartwright, Lisa/0000-0003-1992-3940; Day, Karen/0000-0002-6115-6135 FU Wellcome Trust NR 24 TC 16 Z9 16 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD OCT 24 PY 2007 VL 6 AR 139 DI 10.1186/1475-2875-6-139 PG 6 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 243SO UT WOS:000251817800002 PM 17958900 ER PT J AU Novozhilov, AS Wolf, YI Koonin, EV AF Novozhilov, Artem S. Wolf, Yuri I. Koonin, Eugene V. TI Evolution of the genetic code: partial optimization of a random code for robustness to translation error in a rugged fitness landscape SO BIOLOGY DIRECT LA English DT Article ID AMINO-ACID CODE; NATURAL-SELECTION; TRANSFER-RNA; ORIGIN; MINIMIZATION; COEVOLUTION; MUTATION; OPTIMALITY; DISTANCES; ACCIDENT AB Background: The standard genetic code table has a distinctly non-random structure, with similar amino acids often encoded by codons series that differ by a single nucleotide substitution, typically, in the third or the first position of the codon. It has been repeatedly argued that this structure of the code results from selective optimization for robustness to translation errors such that translational misreading has the minimal adverse effect. Indeed, it has been shown in several studies that the standard code is more robust than a substantial majority of random codes. However, it remains unclear how much evolution the standard code underwent, what is the level of optimization, and what is the likely starting point. Results: We explored possible evolutionary trajectories of the genetic code within a limited domain of the vast space of possible codes. Only those codes were analyzed for robustness to translation error that possess the same block structure and the same degree of degeneracy as the standard code. This choice of a small part of the vast space of possible codes is based on the notion that the block structure of the standard code is a consequence of the structure of the complex between the cognate tRNA and the codon in mRNA where the third base of the codon plays a minimum role as a specificity determinant. Within this part of the fitness landscape, a simple evolutionary algorithm, with elementary evolutionary steps comprising swaps of four-codon or two-codon series, was employed to investigate the optimization of codes for the maximum attainable robustness. The properties of the standard code were compared to the properties of four sets of codes, namely, purely random codes, random codes that are more robust than the standard code, and two sets of codes that resulted from optimization of the first two sets. The comparison of these sets of codes with the standard code and its locally optimized version showed that, on average, optimization of random codes yielded evolutionary trajectories that converged at the same level of robustness to translation errors as the optimization path of the standard code; however, the standard code required considerably fewer steps to reach that level than an average random code. When evolution starts from random codes whose fitness is comparable to that of the standard code, they typically reach much higher level of optimization than the standard code, i.e., the standard code is much closer to its local minimum (fitness peak) than most of the random codes with similar levels of robustness. Thus, the standard genetic code appears to be a point on an evolutionary trajectory from a random point (code) about half the way to the summit of the local peak. The fitness landscape of code evolution appears to be extremely rugged, containing numerous peaks with a broad distribution of heights, and the standard code is relatively unremarkable, being located on the slope of a moderate-height peak. Conclusion: The standard code appears to be the result of partial optimization of a random code for robustness to errors of translation. The reason the code is not fully optimized could be the trade-off between the beneficial effect of increasing robustness to translation errors and the deleterious effect of codon series reassignment that becomes increasingly severe with growing complexity of the evolving system. Thus, evolution of the code can be represented as a combination of adaptation and frozen accident. Reviewers: This article was reviewed by David Ardell, Allan Drummond ( nominated by Laura Landweber), and Rob Knight. Open Peer Review: This article was reviewed by David Ardell, Allan Drummond ( nominated by Laura Landweber), and Rob Knight. C1 [Novozhilov, Artem S.; Wolf, Yuri I.; Koonin, Eugene V.] Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), Natl Inst Hlth, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM novozhil@ncbi.nlm.nih.gov; wolf@ncbi.nlm.nih.gov; koonin@ncbi.nlm.nih.gov RI Novozhilov, Artem/D-7544-2012; Novozhilov, Artem/C-9248-2013 OI Novozhilov, Artem/0000-0001-5469-2557 FU Intramural NIH HHS NR 61 TC 38 Z9 40 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1745-6150 J9 BIOL DIRECT JI Biol. Direct PD OCT 23 PY 2007 VL 2 AR 24 DI 10.1186/1745-6150-2-24 PG 24 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 253OQ UT WOS:000252527900001 PM 17956616 ER PT J AU Smith, MV Miller, CR Kohn, M Walker, NJ Portier, CJ AF Smith, Marjo V. Miller, Chris R. Kohn, Michael Walker, Nigel J. Portier, Chris J. TI Absolute estimation of initial concentrations of amplicon in a real-time RT-PCR process SO BMC BIOINFORMATICS LA English DT Article ID DNA AMPLIFICATION; QUANTITATIVE PCR; KINETIC PCR; CURVE; MODEL AB Background: Since real time PCR was first developed, several approaches to estimating the initial quantity of template in an RT-PCR reaction have been tried. While initially only the early thermal cycles corresponding to exponential duplication were used, lately there has been an effort to use all of the cycles in a PCR. The efforts have included both fitting empirical sigmoid curves and more elaborate mechanistic models that explore the chemical reactions taking place during each cycle. The more elaborate mechanistic models require many more parameters than can be fit from a single amplification, while the empirical models provide little insight and are difficult to tailor to specific reactants. Results: We directly estimate the initial amount of amplicon using a simplified mechanistic model based on chemical reactions in the annealing step of the PCR. The basic model includes the duplication of DNA with the digestion of Taqman probe and the re-annealing between previously synthesized DNA strands of opposite orientation. By modelling the amount of Taqman probe digested and matching that with the observed fluorescence, the conversion factor between the number of fluorescing dye molecules and observed fluorescent emission can be estimated, along with the absolute initial amount of amplicon and the rate parameter for re-annealing. The model is applied to several PCR reactions with known amounts of amplicon and is shown to work reasonably well. An expanded version of the model allows duplication of amplicon without release of fluorescent dye, by adding 1 more parameter to the model. The additional process is helpful in most cases where the initial primer concentration exceeds the initial probe concentration. Software for applying the algorithm to data may be downloaded at http://www.niehs.nih.gov/research/resources/software/pcranalyzer/ Conclusion: We present proof of the principle that a mechanistically based model can be fit to observations from a single PCR amplification. Initial amounts of amplicon are well estimated without using a standard solution. Using the ratio of the predicted initial amounts of amplicon from 2 PCRs is shown to work well even when the absolute amounts of amplicon are underestimated in the individual PCRs. C1 [Smith, Marjo V.] Constella Grp, Durham, NC USA. [Miller, Chris R.; Kohn, Michael; Walker, Nigel J.; Portier, Chris J.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Smith, MV (reprint author), Constella Grp, Suite 200,2605 Meridian Pky, Durham, NC USA. EM msmith@constellagroup.com; MillerCR@appliedbiosystems.com; kohn@niehs.nih.gov; Walker3@niehs.nih.gov; Portier@niehs.nih.gov RI Portier, Christopher/A-3160-2010; Walker, Nigel/D-6583-2012 OI Portier, Christopher/0000-0002-0954-0279; Walker, Nigel/0000-0002-9111-6855 FU PHS HHS [GS-00F-0003L] NR 12 TC 17 Z9 17 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD OCT 23 PY 2007 VL 8 AR 409 DI 10.1186/1471-2105-8-409 PG 11 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 253WW UT WOS:000252549300001 PM 17956631 ER PT J AU Salajegheh, M Rakocevic, G Raju, R Shatunov, A Goldfarb, LG Dalakas, MC AF Salajegheh, M. Rakocevic, G. Raju, R. Shatunov, A. Goldfarb, L. G. Dalakas, M. C. TI T cell receptor profiling in muscle and blood lymphocytes in sporadic inclusion body myositis SO NEUROLOGY LA English DT Article ID MONOCLONAL-ANTIBODY ANALYSIS; CLONAL EXPANSIONS; BETA-CHAIN; INFILTRATING LYMPHOCYTES; INFLAMMATORY MYOPATHIES; MONONUCLEAR-CELLS; POLYMYOSITIS; REPERTOIRE; EXPRESSION; DERMATOMYOSITIS AB Background: Sporadic IBM ( sIBM) is characterized by invasion of non- necrotic MHC- I class-expressing muscle fibers by clonally expanded CD8+ cells. Whether the endomysial cells expand in situ or are recruited from the circulation is unclear. Methods: We used CDR3 spectratyping of the T cell receptor ( TCR) V beta chains to determine clonal expansion of T cells in simultaneously obtained muscle and peripheral blood lymphocytes ( PBL) from 12 patients with sIBM, and compared the difference between the two compartments. To determine whether the identified clones belonged to autoinvasive T cells, we performed immunohistochemistry on the same muscle specimens. Spectratyping was repeated in four muscle biopsies 1 year after the first. Results: In control PBL, all 24 TCR V beta subfamilies had a polyclonal or Gaussian distribution. In sIBM PBL, 5% of the V beta subfamilies demonstrated a single and 16% up to three peaks. In contrast, in their corresponding muscles, 27% ( p = 0.0003) of the V beta subfamilies demonstrated a single and 71% ( p < 0.0001) up to three peaks. Among the amplified subfamilies, V beta 9, 10, 11, 16, 18, 23, and 24 showed the highest degree of restriction within muscle. Immunohistochemistry demonstrated that the clonally expanded CD8+ cells were autoinvasive. In follow- up biopsies the clonality persisted with an unchanged degree of restriction, but not always of the same subfamilies, suggesting epitope spreading. Conclusion: In sporadic inclusion body myositis, the endomysial T cells are specifically recruited to the muscle or expand in situ. The restriction of multiple V beta subfamilies and their change over time suggests recognition of various local antigens and epitope spreading. C1 NINDS, Neuromuscular Dis Sect, NIH, Bethesda, MD 20892 USA. NINDS, Clin Neurogenet Unit, NIH, Bethesda, MD 20892 USA. RP Dalakas, MC (reprint author), NINDS, Neuromuscular Dis Sect, NIH, Bldg 10,Room 4N248, Bethesda, MD 20892 USA. EM dalakasm@ninds.nih.gov RI Shatunov, Aleksey/E-6946-2011; Raju, Raghavan/E-9219-2011 FU Intramural NIH HHS NR 40 TC 22 Z9 23 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD OCT 23 PY 2007 VL 69 IS 17 BP 1672 EP 1679 DI 10.1212/01.wnl.0000265398.77681.09 PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 222ZZ UT WOS:000250340300007 PM 17954782 ER PT J AU Simon, KC Chen, H Schwarzschild, M Ascherio, A AF Simon, Kelly Claire Chen, Honglei Schwarzschild, Michael Ascherio, Alberto TI Hypertension, hypercholesterolemia, diabetes, and risk of Parkinson disease SO NEUROLOGY LA English DT Article ID CORONARY-HEART-DISEASE; URIC-ACID LEVELS; CARDIOVASCULAR REFLEXES; AUTONOMIC DYSFUNCTION; CHOLESTEROL LEVELS; WOMEN; POPULATION; QUESTIONNAIRE; DIAGNOSIS; ACCURACY AB Objective: To determine whether history of hypertension, hypercholesterolemia, or diabetes is associated with risk of Parkinson disease ( PD). Methods: Prospective study among participants in two large cohorts: the Nurses' Health Study ( 121,046 women) and the Health Professionals Follow- up Study ( 50,833 men). Mean duration of follow- up was 22.9 years in women, aged 30 to 55 years at baseline, and 12.6 years in men, aged 40 to 75 years at baseline. Relative risks ( RRs) of PD were estimated from a Cox proportional hazards model adjusting for potential confounders. Results: We identified a total of 530 incident cases of PD during the follow- up. Risk of PD was not associated with self- reported history of hypertension ( RR = 0.96, 95% CI = 0.80 to 1.15), high cholesterol ( RR = 0.98, 95% CI = 0.82 to 1.19), or diabetes ( RR = 1.04, 95% CI = 0.74 to 1.46), after adjusting for age and smoking in pack- years. Risk of PD decreased modestly with increasing levels of self- reported total cholesterol ( RR for a 50- mg/ dL increase in total cholesterol = 0.86, 95% CI = 0.78 to 0.95, p for trend = 0.02), but use of cholesterol- lowering drugs was not associated with PD risk ( RR comparing users with nonusers = 0.85, 95% CI = 0.59 to 1.23). Among individuals with PD, systolic blood pressure was similar to noncases up to the time of diagnosis but declined afterward. Conclusions: Results of this large prospective study suggest that Parkinson disease risk is not significantly related to history of hypertension, hypercholesterolemia, or diabetes but may modestly decline with increasing blood cholesterol levels. C1 Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Simon, KC (reprint author), Harvard Univ, Sch Publ Hlth, Dept Nutr, 665 Huntington Ave,Bldg 2,Rm 305, Boston, MA 02115 USA. EM ksimon@hsph.harvard.edu OI Chen, Honglei/0000-0003-3446-7779 FU Intramural NIH HHS [Z01 ES101986-02]; NIEHS NIH HHS [T32 ES007069, T32 ES007069-26, T32 ES07069-26]; NINDS NIH HHS [R01 NS048517, R01 NS048517-01A2] NR 36 TC 94 Z9 97 U1 0 U2 8 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD OCT 23 PY 2007 VL 69 IS 17 BP 1688 EP 1695 DI 10.1212/01.wnl.0000271883.45010.8a PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 222ZZ UT WOS:000250340300009 PM 17761552 ER PT J AU Ridnour, LA Windhausen, AN Isenberg, JS Yeung, N Thomas, DD Vitek, MP Roberts, DD Wink, DA AF Ridnour, Lisa A. Windhausen, Alisha N. Isenberg, Jeffrey S. Yeung, Nolan Thomas, Douglas D. Vitek, Michael P. Roberts, David D. Wink, David A. TI Nitric oxide regulates matrix metalloproteinase-9 activity by guanylyl-cyclase-dependent and -independent pathways SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE tissue inhibitor of metalloproteinase-1; thrombospondin-1 ID MATRIX-METALLOPROTEINASE ACTIVITY; CYSTEINE SWITCH; CATALYTIC DOMAIN; CELL RESPONSES; ACTIVATION; MECHANISM; CANCER; THROMBOSPONDIN-1; INFLAMMATION; MYELOPEROXIDASE AB Matrix metalloproteinases (MMPs) are of central importance in the proteolytic remodeling of matrix and the generation of biologically active molecules. MMPs are distinguished by a conserved catalytic domain containing a zinc ion, as well as a prodomain that regulates enzyme activation by modulation of a cysteine residue within that domain. Because nitric oxide (NO) and derived reactive nitrogen species target zinc ions and cysteine thiols, we assessed the ability of NO to regulate MMPs. A dose-dependent, biphasic regulatory effect of NO on the activity of MMPs (MMP-9, -1, and -13) secreted from murine macrophages was observed. Low exogenous NO perturbed MMP/tissue inhibitor of metalloproteinase (TIMP)-1 levels by enhancing MMP activity and suppressing the endogenous inhibitor TIMP-1. This was cGMP-dependent, as confirmed by the cGMP analog 8-bromo-cGMP, as well as by the NO-soluble guanylyl cyclase-cGMP signaling inhibitor thrombospondin-1. Exposure of purified latent MMP-9 to exogenous NO demonstrated a concentration-dependent activation and inactivation of the enzyme, which occurred at higher NO flux. These chemical reactions occurred at concentrations similar to that of activated macrophages. Importantly, these results suggest that NO regulation of MMP-9 secreted from macrophages may occur chemically by reactive nitrogen species-mediated protein modification, biologically through soluble guanylyl-cyclase-dependent modulation of the MMP-9/TIMP-1 balance, or proteolytically through regulation of MMP-1 and -13, which can cleave the prodomain of MMP-9. Furthermore, when applied in a wound model, conditioned media exhibiting peak MMP activity increased vascular cell migration that was MMP-9-dependent, suggesting that MMP-9 is a key physiologic mediator of the effects of NO in this model. C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Div Neurol, Durham, NC 27710 USA. RP Ridnour, LA (reprint author), NCI, Radiat Biol Branch, NIH, Bldg 10,Room B3B35,10 Ctr Dr MSC 1500, Bethesda, MD 20892 USA. EM ridnourl@mail.nih.gov; wink@mail.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU Intramural NIH HHS NR 43 TC 88 Z9 93 U1 0 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 23 PY 2007 VL 104 IS 43 BP 16898 EP 16903 DI 10.1073/pnas.0702761104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 224ZT UT WOS:000250487600033 PM 17942699 ER PT J AU Zhang, YJ Xiang, LM Hassan, R Pastan, I AF Zhang, Yujian Xiang, Laiman Hassan, Raffit Pastan, Ira TI Immunotoxin and Taxol synergy results from a decrease in shed mesothelin levels in the extracellular space of tumors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chemotherapy; drug resistance; immunotherapy; mesothelioma; ovarian cancer ID MONOCLONAL-ANTIBODY THERAPY; BINDING-SITE BARRIER; BREAST-CANCER MODEL; SOLID TUMORS; RECOMBINANT IMMUNOTOXIN; TRANSFERRIN RECEPTOR; INTERSTITIAL FLUID; OVARIAN-CARCINOMA; SERUM MESOTHELIN; CELL-LINES AB Recombinant immunotoxins are chimeric proteins composed of the Fv portion of a tumor-specific antibody fused to a toxin. SS1P (CAT-5001) is an immunotoxin composed of an antimesothelin Fv fused to a 38-kDa portion of Pseudomonas exotoxin A. Immunotoxins have been shown to be active in lymphomas and leukemias, but are much less active against solid tumors. We recently reported that Taxol and other chemotherapeutic agents show striking synergistic antitumor activity in mice when immunotoxin SS1P, which targets the mesothelin antigen on solid tumors, is given with Taxol. Using a pair of Taxol-sensitive and Taxol-resistant KB tumors equally sensitive to immunotoxin SS1P, we examined the mechanism of synergy. We show that synergy is only observed with Taxol-sensitive tumors, ruling out an effect of Taxol on endothelial cells. We also show that the KB tumors have high levels of shed mesothelin in their extracellular space; these levels increase with tumor size and, after Taxol treatment, dramatically fall in the drug-sensitive but not the drug-resistant tumors. Because the mesothelin levels in the tumor exceed the levels of SS1P in the tumor, and because shed mesothelin is being continuously released into the circulation at a high rate, we propose that synergy is due to the Taxol-induced fall in shed antigen levels. C1 NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov FU Intramural NIH HHS NR 39 TC 48 Z9 48 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 23 PY 2007 VL 104 IS 43 BP 17099 EP 17104 DI 10.1073/pnas.0708101104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 224ZT UT WOS:000250487600067 PM 17940013 ER PT J AU Ahn, J Schatzkin, A Lacey, JV Albanes, D Ballard-Barbash, R Adams, KF Kipnis, V Mouw, T Hollenbeck, AR Leitzmann, MF AF Ahn, Jiyoung Schatzkin, Arthur Lacey, James V., Jr. Albanes, Demetrius Ballard-Barbash, Rachel Adams, Kenneth F. Kipnis, Victor Mouw, Traci Hollenbeck, Albert R. Leitzmann, Michael F. TI Adiposity, adult weight change, and postmenopausal breast cancer risk SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID BODY-MASS INDEX; REPLACEMENT THERAPY; PROSPECTIVE COHORT; PHYSICAL-ACTIVITY; FAT DISTRIBUTION; RECEPTOR STATUS; WOMENS HEALTH; SEX-HORMONES; SIZE; ESTROGEN AB Background: Obesity is a risk factor for postmenopausal breast cancer, but the role of the timing and amount of adult weight change in breast cancer risk is unclear. Methods: We prospectively examined the relations of adiposity and adult weight change to breast cancer risk among 99 039 postmenopausal women in the National Institutes of Health - AARP Diet and Health Study. Anthropometry was assessed by self- report in 1996. Through 2000, 2111 incident breast cancer cases were ascertained. Results: Current body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared), BMI at ages 50 and 35 years, and waist- hip ratio were associated with increased breast cancer risk, particularly in women not using menopausal hormone therapy (MHT). Weight gained between age 18 years and the current age, between ages 18 and 35 years, between ages 35 and 50 years, and between age 50 years and the current age was consistently associated with increased breast cancer risk in MHT nonusers (relative risk [RR], 2.15; 95% confidence interval [CI], 1.35- 3.42 for a >= 50- kg weight gain between age 18 years and the current age vs stable weight) but not in current MHT users. Risk associated with adult weight change was stronger in women with later vs earlier age at menarche (RR, 4.20; 95% CI, 2.05- 8.64 for >= 15 years vs RR, 1.51; 95% CI, 1.11- 2.06 for 11- 12 years; P=. 007 for interaction). In MHT nonusers, the associations with current BMI and adult weight change were stronger for advanced disease than for nonadvanced disease (=.009 [current BMI] and.21 [weight gain] for heterogeneity) and were stronger for hormone receptor - positive than hormone receptor - negative tumors (P <. 001 for heterogeneity). Conclusion: Weight gain throughout adulthood is associated with increased postmenopausal breast cancer risk in MHT nonusers. C1 NCI, NIH, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet,EPS, Bethesda, MD 20892 USA. NCI, NIH, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, NIH, Div Canc Prevent, Bethesda, MD 20892 USA. AARP, Washington, DC USA. RP Ahn, J (reprint author), NCI, NIH, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet,EPS, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM ahnj@mail.nih.gov RI Albanes, Demetrius/B-9749-2015 FU Intramural NIH HHS NR 43 TC 143 Z9 146 U1 1 U2 13 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD OCT 22 PY 2007 VL 167 IS 19 BP 2091 EP 2102 DI 10.1001/archinte.167.19.2091 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 222VX UT WOS:000250326900013 PM 17954804 ER PT J AU Bansal, S Grenfell, BT Meyers, LA AF Bansal, Shweta Grenfell, Bryan T. Meyers, Lauren Ancel TI When individual behaviour matters: homogeneous and network models in epidemiology SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE epidemic model; compartmental model; homogeneous-mixing; contact network ID COMPLEX HETEROGENEOUS NETWORKS; SMALL-WORLD NETWORKS; SCALE-FREE NETWORKS; TRANSMISSION RATES; INFECTIOUS-DISEASE; MEASLES EPIDEMICS; SOCIAL NETWORKS; DYNAMICS; OUTBREAKS; SPREAD AB Heterogeneity in host contact patterns profoundly shapes population-level disease dynamics. Many epidemiological models make simplifying assumptions about the patterns of disease-causing interactions among hosts. In particular, homogeneous-mixing models assume that all hosts have identical rates of disease-causing contacts. In recent years, several network-based approaches have been developed to explicitly model heterogeneity in host contact patterns. Here, we use a network perspective to quantify the extent to which real populations depart from the homogeneous-mixing assumption, in terms of both the underlying network structure and the resulting epidemiological dynamics. We find that human contact patterns are indeed more heterogeneous than assumed by homogeneous-mixing models, but are not as variable as some have speculated. We then evaluate a variety of methodologies for incorporating contact heterogeneity, including network-based models and several modi. cations to the simple SIR compartmental model. We conclude that the homogeneous-mixing compartmental model is appropriate when host populations are nearly homogeneous, and can be modified effectively for a few classes of non-homogeneous networks. In general, however, network models are more intuitive and accurate for predicting disease spread through heterogeneous host populations. C1 Univ Texas, Inst Computat Engn & Sci, Austin, TX 78712 USA. Penn State Univ, Ctr Infect Dis Dynam, Dept Biol, Mueller Lab 208, University Pk, PA 16802 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. Univ Texas, Inst Mol & Cellular Biol, Sect Integrat Biol, Austin, TX 78712 USA. Santa Fe Inst, Santa Fe, NM 87501 USA. RP Meyers, LA (reprint author), Univ Texas, Sect Integrat Biol, 1 Univ Stn,C0930, Austin, TX 78712 USA. EM laurenmeyers@mail.utexas.edu OI Bansal, Shweta/0000-0002-1740-5421 NR 69 TC 197 Z9 200 U1 1 U2 41 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD OCT 22 PY 2007 VL 4 IS 16 BP 879 EP 891 DI 10.1098/rsif.2007.1100 PG 13 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 209XU UT WOS:000249422100011 PM 17640863 ER PT J AU Fields, RD Fields, KD Fields, MC AF Fields, R. Douglas Fields, Kyle D. Fields, Melanie C. TI Semiconductor gel in shark sense organs? SO NEUROSCIENCE LETTERS LA English DT Article DE ampullae of lorenzini; electroreception; temperature receptors; sharks; rays; chimaeras; thermoelectric semiconduction; sensory reception; lateral line; electrode potential; sensory transduction; ion channels ID SYNAPTIC MORPHOLOGY; ELECTRIC SENSE; ELECTRORECEPTION; TEMPERATURE; LORENZINI; AMPULLAE; HYDROLAGUS AB Sharks can sense bioelectric fields of prey and other animals in seawater using an extraordinary system of sense organs (ampullae of Lorenzini) [R.D. Fields, The shark's electric sense. Sci. Am. 297 (2007) 74-81]. A recent study reported that these sense organs also enable sharks to locate prey-rich thermal fronts using a novel mode of temperature reception without ion channels. The study reported that gel extracted from the organs operates as a thermoelectric semiconductor, generating electricity when it is heated or cooled [B.R. Brown, Neurophysiology: sensing temperature without ion channels, Nature 421 (2003) 495]. Here we report biophysical studies that call into question this mechanism of sensory transduction. Our experiments indicate that the material exhibits no unusual thermoelectric or electromechanical properties, and that the thermoelectric response is an artifact caused by temperature effects on the measurement electrodes. No response is seen when non-metallic electrodes (carbon or salt bridges) are used, and ordinary seawater produces the same effect as shark organ gel when silver wire electrodes are used. These data are consistent with the voltages arising from electrochemical electrode potentials rather generated intrinsically within the sample. This new evidence, together with the anatomy of the organs and behavioral studies in the literature, best support the conclusion that the biological function of these sense organs is to detect electric fields. Published by Elsevier Ireland Ltd. C1 NICHD, NIH, Nervous Syst Dev & Plast Sect, Bethesda, MD 20892 USA. Marine Biol Lab, Woods Hole, MA USA. RP Fields, RD (reprint author), NICHD, NIH, Nervous Syst Dev & Plast Sect, Bldg 35,Rm 2A211, Bethesda, MD 20892 USA. EM fieldsd@mail.nih.gov FU Intramural NIH HHS [Z01 HD000713-13] NR 23 TC 6 Z9 6 U1 5 U2 36 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 EI 1872-7972 J9 NEUROSCI LETT JI Neurosci. Lett. PD OCT 22 PY 2007 VL 426 IS 3 BP 166 EP 170 DI 10.1016/j.neulet.2007.08.064 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 232HL UT WOS:000251009200007 PM 17904741 ER PT J AU Kang, HS Angers, M Beak, JY Wu, X Gimble, JM Wada, T Xie, W Collins, JB Grissom, SF Jetten, AM AF Kang, Hong Soon Angers, Martin Beak, Ju Youn Wu, Xiying Gimble, Jeffrey M. Wada, Taira Xie, Wen Collins, Jennifer B. Grissom, Sherry F. Jetten, Anton M. TI Gene expression profiling reveals a regulatory role for ROR alpha and ROR alpha in phase I and phase II metabolism SO PHYSIOLOGICAL GENOMICS LA English DT Article DE liver; nuclear receptor; metabolism; sulfotransferase; staggerer mice; gene expression analysis; circadian rhythm; retinoid-related orphan receptors ID INDUCED LUNG INFLAMMATION; LIGAND-BINDING DOMAIN; ORPHAN RECEPTOR-BETA; X-RAY-STRUCTURE; NUCLEAR RECEPTOR; TRANSCRIPTIONAL REGULATION; SKELETAL-MUSCLE; RETINOIC ACID; GAMMA; MICE AB Retinoidrelated orphan receptors alpha (ROR alpha) and gamma (ROR gamma) are both expressed in liver; however, their physiological functions in this tissue have not yet been clearly defined. The ROR alpha 1 and ROR gamma 1 isoforms, but not ROR alpha 4, show an oscillatory pattern of expression during circadian rhythm. To obtain insight into the physiological functions of ROR receptors in liver, we analyzed the gene expression profiles of livers from WT, ROR alpha- deficient staggerer (sg) mice (ROR alpha(sg/sg)), ROR gamma(-/-), and ROR alpha(ROR)-R-sg/sg gamma(-/-) double knockout (DKO) mice by microarray analysis. DKO mice were generated to study functional redundancy between ROR gamma(-/-) and ROR gamma(-/-). These analyses demonstrated that ROR alpha and ROR gamma affect the expression of a number of genes. ROR alpha and ROR gamma are particularly important in the regulation of genes encoding several phase I and phase II metabolic enzymes, including several 3 beta-hydroxysteroid dehydrogenases, cytochrome P450 enzymes, and sulfotransferases. In addition, our results indicate that ROR alpha and ROR gamma each affect the expression of a specific set of genes but also exhibit functional redundancy. Our study shows that ROR alpha and ROR gamma receptors influence the regulation of several metabolic pathways, including those involved in the metabolism of steroids, bile acids, and xenobiotics, suggesting that RORs are important in the control of metabolic homeostasis. C1 NIEHS, Cell Biol Sect, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. NIEHS, Microarray Grp, Div Intramural Res, NIH, Res Triangle Pk, NC 27709 USA. Louisiana State Univ Syst, Pennington Biomed Res Ctr, Stem Cell Lab, Baton Rouge, LA USA. Univ Pittsburgh, Ctr Pharmacogenet, Pittsburgh, PA USA. Univ Pittsburgh, Dept Pharmaceut Sci, Pittsburgh, PA USA. RP Kang, HS (reprint author), NIEHS, Cell Biol Sect, Div Intramural Res, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM jetten@niehs.nih.gov RI Xie, Wen/M-1768-2016 FU Intramural NIH HHS; NIDDK NIH HHS [1P30 DK-072476] NR 49 TC 99 Z9 106 U1 1 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD OCT 22 PY 2007 VL 31 IS 2 BP 281 EP 294 DI 10.1152/physiolgenomics.00098.2007 PG 14 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 222ZX UT WOS:000250340100014 PM 17666523 ER PT J AU Auman, JT Boorman, GA Wilson, RE Travlos, GS Paules, RS AF Auman, J. Todd Boorman, Gary A. Wilson, Ralph E. Travlos, Gregory S. Paules, Richard S. TI Heat map visualization of high-density clinical chemistry data SO PHYSIOLOGICAL GENOMICS LA English DT Article DE clinical pathology; hierarchical clustering; rat; hepatotoxicity; toxicogenomics ID TOXICOLOGY; TOXICOGENOMICS; TOXICITY AB Clinical chemistry data are routinely generated as part of preclinical animal toxicity studies and human clinical studies. With large-scale studies involving hundreds or even thousands of samples in multiple treatment groups, it is currently difficult to interpret the resulting complex, high-density clinical chemistry data. Accordingly, we conducted this study to investigate methods for easy visualization of complex, high-density data. Clinical chemistry data were obtained from male rats each treated with one of eight different acute hepatotoxicants from a large-scale toxicogenomics study. The raw data underwent a Z-score transformation comparing each individual animal's clinical chemistry values to that of reference controls from all eight studies and then were visualized in a single graphic using a heat map. The utility of using a heat map to visualize high-density clinical chemistry data was explored by clustering changes in clinical chemistry values for >400 animals. A clear distinction was observed in animals displaying hepatotoxicity from those that did not. Additionally, while animals experiencing hepatotoxicity showed many similarities in the observed clinical chemistry alterations, distinct differences were noted in the heat map profile for the different compounds. Using a heat map to visualize complex, high-density clinical chemistry data in a single graphic facilitates the identification of previously unrecognized trends. This method is simple to implement and maintains the biological integrity of the data. The value of this clinical chemistry data transformation and visualization will manifest itself through integration with other high-density data, such as genomics data, to study physiology at the systems level. C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Paules, RS (reprint author), 111 TW Alexander Dr,POB 12233,Mail Drop D2-03, Res Triangle Pk, NC 27709 USA. EM paules@niehs.nih.gov FU Intramural NIH HHS [Z01 ES023026-09]; NIEHS NIH HHS [N01ES35513] NR 11 TC 6 Z9 6 U1 1 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1094-8341 J9 PHYSIOL GENOMICS JI Physiol. Genomics PD OCT 22 PY 2007 VL 31 IS 2 BP 352 EP 356 DI 10.1152/physiolgenomics.00276.2006 PG 5 WC Cell Biology; Genetics & Heredity; Physiology SC Cell Biology; Genetics & Heredity; Physiology GA 222ZX UT WOS:000250340100020 PM 17652165 ER PT J AU Mittal, J Shen, VK Errington, JR Truskett, TM AF Mittal, Jeetain Shen, Vincent K. Errington, Jeffrey R. Truskett, Thomas M. TI Confinement, entropy, and single-particle dynamics of equilibrium hard-sphere mixtures SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID MATRIX MONTE-CARLO; DENSITY-FUNCTIONAL THEORY; UNIVERSAL SCALING LAW; PHASE-EQUILIBRIA; TRANSITION; BEHAVIOR; LIQUIDS; SYSTEMS; FLUIDS; SUSPENSIONS AB We use discontinuous molecular dynamics and grand-canonical transition-matrix Monte Carlo simulations to explore how confinement between parallel hard walls modifies the relationships between packing fraction, self-diffusivity, partial molar excess entropy, and total excess entropy for binary hard-sphere mixtures. To accomplish this, we introduce an efficient algorithm to calculate partial molar excess entropies from the transition-matrix Monte Carlo simulation data. We find that the species-dependent self-diffusivities of confined fluids are very similar to those of the bulk mixture if compared at the same, appropriately defined, packing fraction up to intermediate values, but then deviate negatively from the bulk behavior at higher packing fractions. On the other hand, the relationships between self-diffusivity and partial molar excess entropy (or total excess entropy) observed in the bulk fluid are preserved under confinement even at relatively high packing fractions and for different mixture compositions. This suggests that the excess entropy, calculable from classical density functional theories of inhomogeneous fluids, can be used to predict some of the nontrivial dynamical behaviors of fluid mixtures in confined environments. (C) 2007 American Institute of Physics. C1 NIDDK, Natl Inst Hlth, Phys Chem Lab, Bethesda, MD 20892 USA. Natl Inst Stand & Technol, Phys & Chem Properties Div, Gaithersburg, MD 20899 USA. SUNY Buffalo, Dept Chem & Biol Engn, Buffalo, NY 14260 USA. Univ Texas, Dept Chem Engn, Inst Theoret Chem, Austin, TX 78712 USA. RP Mittal, J (reprint author), NIDDK, Natl Inst Hlth, Phys Chem Lab, Bethesda, MD 20892 USA. EM jeetain@helix.nih.gov; vincent.shen@nist.gov; jerring@buffalo.edu; truskett@che.utexas.edu RI Truskett, Thomas/D-4624-2009; Errington, Jeffrey/E-8644-2011; Truskett, Thomas/C-4996-2014 OI Truskett, Thomas/0000-0002-6607-6468; Errington, Jeffrey/0000-0003-0365-0271; FU Intramural NIH HHS NR 46 TC 20 Z9 20 U1 1 U2 10 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD OCT 21 PY 2007 VL 127 IS 15 AR 154513 DI 10.1063/1.2795699 PG 8 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 222KS UT WOS:000250295900055 PM 17949179 ER PT J AU Cuadros, M Honrado, E Zajac, M Benitez, J Martinez-Delgado, B Dave, SS Staudt, LM Jaffe, ES Milne, R Alves, J Rodrguez, J AF Cuadros, Marta Honrado, Emiliano Zajac, Magdalena Benitez, Javier Martinez-Delgado, Beatriz Dave, Sandeep S. Staudt, Louis M. Jaffe, Elaine S. Milne, Roger Alves, Javier Rodrguez, Jose TI Gene expression profiling does not identify molecular subgroup among nodal peripheral T-cell lymphomas - In reply SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID SURVIVAL C1 Spanish Natl Canc Ctr, Human Genet Grp, Madrid, Spain. NCI, Lymphoid Malignancies Sect, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. Spanish Natl Canc Ctr, Genotyping Unit, Madrid, Spain. Hosp La Paz, Dept Pathol, Madrid, Spain. Hosp Son Dureta, Dept Oncol, Palma de Mallorca, Spain. RP Cuadros, M (reprint author), Spanish Natl Canc Ctr, Human Genet Grp, Madrid, Spain. RI Alves Ferreira, Francisco Javier/G-4423-2010; Cuadros, Marta/K-1576-2014; Jaffe, Elaine/G-8984-2014; Martinez, Beatriz/B-6833-2013 OI Cuadros, Marta/0000-0002-8329-4854; Jaffe, Elaine/0000-0003-4632-0301; Martinez, Beatriz/0000-0001-6834-350X NR 4 TC 0 Z9 0 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 OCT 20 PY 2007 VL 25 IS 30 BP 4851 EP 4852 DI 10.1200/JCO.2007.13.4858 PG 3 WC Oncology SC Oncology GA 233ET UT WOS:000251073900026 ER PT J AU Nussenzweig, A Nussenzweig, MC AF Nussenzweig, Andre Nussenzweig, Michel C. TI A backup DNA repair pathway moves to the forefront SO CELL LA English DT Editorial Material ID DOUBLE-STRAND BREAKS; CLASS SWITCH RECOMBINATION; GENE AMPLIFICATION; TRANSLOCATIONS; MUTATIONS; CELLS; AID C1 NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. Rockefeller Univ, Lab Mol Immunol, New York, NY 10021 USA. Howard Hughes Med Inst, New York, NY 10021 USA. RP Nussenzweig, MC (reprint author), NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. EM nussenzweig@nih.gov NR 14 TC 114 Z9 114 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 19 PY 2007 VL 131 IS 2 BP 223 EP 225 DI 10.1016/j.cell.2007.10.005 PG 3 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 225HM UT WOS:000250507700009 PM 17956720 ER PT J AU Sacchetti, B Funari, A Michienzi, S Di Cesare, S Piersanti, S Saggio, I Tagliafico, E Ferrari, S Robey, PG Riminucci, M Bianco, P AF Sacchetti, Benedetto Funari, Alessia Michienzi, Stefano Di Cesare, Silvia Piersanti, Stefania Saggio, Isabella Tagliafico, Enrico Ferrari, Stefano Robey, Pamela Gehron Riminucci, Mara Bianco, Paolo TI Self-renewing osteoprogenitors in bone marrow sinusoids can organize a hematopoietic microenvironment SO CELL LA English DT Article ID MESENCHYMAL STEM-CELLS; TYROSINE KINASE GENES; MONOCLONAL-ANTIBODY; PROGENITOR CELLS; STROMAL FIBROBLASTS; ENDOTHELIAL-CELLS; MOLECULAR-CLONING; TIE2 RECEPTOR; GROWTH-FACTOR; IN-VIVO AB The identity of cells that establish the hematopoietic microenvironment (HME) in human bone marrow ( BM), and of clonogenic skeletal progenitors found in BM stroma, has long remained elusive. We show that MCAM/CD146 expressing, subendothelial cells in human BM stroma are capable of transferring, upon transplantation, the HME to heterotopic sites, coincident with the establishment of identical subendothelial cells within a miniature bone organ. Establishment of subendothelial stromal cells in developing heterotopic BM in vivo occurs via specific, dynamic interactions with developing sinusoids. Subendothelial stromal cells residing on the sinusoidal wall are major producers of Angiopoietin-1-(a pivotal molecule of the HSC `` niche'' involved in vascular remodeling). Our data reveal the functional relationships between establishment of the HME in vivo, establishment of skeletal progenitors in BM sinusoids, and angiogenesis. C1 Univ Roma La Sapienza, Dept Expt Med, I-00161 Rome, Italy. Univ Roma La Sapienza, Dept Genet & Mol Biol, I-00161 Rome, Italy. Biomed Sci Pk San Raffaele, I-00128 Rome, Italy. Univ Aquila, Dept Expt Med, I-67100 Laquila, Italy. CNR, Inst Mol Biol & Pathol, Rome, Italy. Univ Modena, Dept Biochem, I-59100 Modena, Italy. Natl Inst Dental & Craniofacial Res, NIH, Craniofacial & Skeletal Dis Branch, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Bianco, P (reprint author), Univ Roma La Sapienza, Dept Expt Med, I-00161 Rome, Italy. EM p.bianco@flashnet.it RI FUNARI, ALESSIA/A-3298-2009; sacchetti, benedetto/A-3314-2009; Tagliafico, Enrico/C-9079-2009; Robey, Pamela/H-1429-2011; OI Tagliafico, Enrico/0000-0003-0981-2542; Robey, Pamela/0000-0002-5316-5576; saggio, isabella/0000-0002-9497-7415 FU Telethon [GGP04263] NR 48 TC 970 Z9 991 U1 7 U2 42 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD OCT 19 PY 2007 VL 131 IS 2 BP 324 EP 336 DI 10.1016/j.cell.2007.08.025 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 225HM UT WOS:000250507700022 PM 17956733 ER PT J AU Franco, R Panayiotidis, MI Cidlowski, JA AF Franco, Rodrigo Panayiotidis, Mihalis I. Cidlowski, John A. TI Glutathione depletion is necessary for apoptosis in lymphoid cells independent of reactive oxygen species formation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FAS-MEDIATED APOPTOSIS; MITOCHONDRIAL PERMEABILITY TRANSITION; JURKAT T-CELLS; INTRACELLULAR GLUTATHIONE; OXIDATIVE STRESS; REDUCED GLUTATHIONE; HYDROGEN-PEROXIDE; NITRIC-OXIDE; MEMBRANE-TRANSPORT; GSH EXTRUSION AB Changes in the intracellular redox environment of cells have been reported to be critical for the activation of apoptotic enzymes and the progression of programmed cell death. Glutathione (GSH) depletion is an early hallmark observed in apoptosis, and we have demonstrated that GSH efflux during death receptor-mediated apoptosis occurs via a GSH transporter. We now evaluate the relationship between GSH depletion, the generation of reactive oxygen species (ROS), and the progression of apoptosis. Simultaneous single cell analysis of changes in GSH content and ROS formation by multiparametric FACS revealed that loss of intracellular GSH was paralleled by the generation of different ROS including hydrogen peroxide, superoxide anion, hydroxyl radical, and lipid peroxides. However, inhibition of ROS formation by a variety of antioxidants showed that GSH loss was independent from the generation of ROS. Furthermore, GSH depletion was observed to be necessary for ROS generation. Interestingly, high extracellular thiol concentration (GSH and N-acetyl-cysteine) inhibited apoptosis, whereas, inhibition of ROS generation by other non-thiol antioxidants was ineffective in preventing cell death. Finally, GSH depletion was shown to be a necessary for the progression of apoptosis activated by both extrinsic and intrinsic signaling pathways. These results document a necessary and critical role for GSH loss in apoptosis and clearly uncouple for the first time GSH depletion from ROS formation. C1 NIEHS, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. RP Cidlowski, JA (reprint author), NIEHS, Lab Signal Transduct, NIH, POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM cidlows1@mail.nih.gov RI Franco, Rodrigo/D-9470-2013; OI Franco, Rodrigo/0000-0003-3241-8615; Panagiotidis, Mihalis/0000-0002-1130-5972 FU Intramural NIH HHS [, NIH0011756287]; PHS HHS [NIH0011756287] NR 98 TC 125 Z9 128 U1 1 U2 10 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 OCT 19 PY 2007 VL 282 IS 42 BP 30452 EP 30465 DI 10.1074/jbc.M703091200 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 220DE UT WOS:000250136300013 PM 17724027 ER PT J AU Choi, JH Williams, J Cho, J Falck, JR Shears, SB AF Choi, Jae H. Williams, Jason Cho, Jaiesoon Falck, J. R. Shears, Stephen B. TI Purification, sequencing, and molecular identification of a mammalian PP-InsP(5) kinase that is activated when cells are exposed to hyperosmotic stress SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BIS-DIPHOSPHOINOSITOL TETRAKISPHOSPHATE; INOSITOL HEXAKISPHOSPHATE KINASE; POLYPHOSPHATE PHOSPHOHYDROLASE; 1,4,5-TRISPHOSPHATE 3-KINASE; SIGNAL-TRANSDUCTION; CRYSTAL-STRUCTURE; TELOMERE LENGTH; PYROPHOSPHATES; FAMILY; PENTAKISPHOSPHATE AB Mammalian cells utilize multiple signaling mechanisms to protect against the osmotic stress that accompanies plasma membrane ion transport, solute uptake, and turnover of protein and carbohydrates (Schliess, F., and Haussinger, D. (2002) Biol. Chem. 383, 577-583). Recently, osmotic stress was found to increase synthesis of bisdiphosphoinositol tetrakisphosphate ((PP)(2)-InsP(4)), a high energy inositol pyrophosphate (Pesesse, X., Choi, K., Zhang, T., and Shears, S. B. (2004) J. Biol. Chem. 279, 43378-43381). Here, we describe the purification from rat brain of a diphosphoinositol pentakisphosphate kinase (PPIP5K) that synthesizes (PP)(2)-InsP(4). Partial amino acid sequence, obtained by mass spectrometry, matched the sequence of a 160-kDa rat protein containing a putative ATP-grasp kinase domain. BLAST searches uncovered two human isoforms (PPIP5K1 (160 kDa) and PPIP5K2 (138 kDa)). Recombinant human PPIP5K1, expressed in Escherichia coli, was found to phosphorylate diphosphoinositol pentakisphosphate (PP-InsP(5)) to (PP)(2)-InsP(4) (V(max) = 8.3 nmol/mg of protein/min; K(m) = 0.34 mu M). Overexpression in human embryonic kidney cells of either PPIP5K1 or PPIP5K2 substantially increased levels of (PP)(2)-InsP(4), whereas overexpression of a catalytically dead PPIP5K1(D332A) mutant had no effect. PPIP5K1 and PPIP5K2 were more active against PP-InsP5 than InsP6, both in vitro and in vivo. Analysis by confocal immunofluorescence showed PPIP5K1 to be distributed throughout the cytoplasm but excluded from the nucleus. Immunopurification of overexpressed PPIP5K1 from osmotically stressed HEK cells (0.2 M sorbitol; 30 min) revealed a persistent, 3.9 +/- 0.4-fold activation when compared with control cells. PPIP5Ks are likely to be important signaling enzymes. C1 NIEHS, Inositide Siganling Grp, Lab Signal Transduct, NIH,DHHS, Res Triangle Pk, NC 27709 USA. NIEHS, Prot Microcharacterizat Core Facil, Struct Biol Lab, NIH,DHHS, Res Triangle Pk, NC 27709 USA. Univ Texas, SW Med Ctr, Dept Biochem, Dallas, TX 75235 USA. Univ Texas, SW Med Ctr, Dept Pharmacol, Dallas, TX 75235 USA. RP Shears, SB (reprint author), NIEHS, Inositide Siganling Grp, Lab Signal Transduct, NIH,DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM shears@niehs.nih.gov OI Falck, John/0000-0002-9219-7845 FU Intramural NIH HHS [Z01 ES080046-19] NR 57 TC 57 Z9 61 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 OCT 19 PY 2007 VL 282 IS 42 BP 30763 EP 30775 DI 10.1074/jbc.M704655200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 220DE UT WOS:000250136300045 PM 17702752 ER PT J AU de Vega, S Iwamoto, T Nakamura, T Hozumi, K McKnight, DA Fisher, LW Fukumoto, S Yamada, Y AF de Vega, Susana Iwamoto, Tsutomu Nakamura, Takashi Hozumi, Kentaro McKnight, Dianalee A. Fisher, Larry W. Fukumoto, Satoshi Yamada, Yoshihiko TI TM14 is a new member of the fibulin family (fibulin-7) that interacts with extracellular matrix molecules and is active for cell binding SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ODONTOBLAST DIFFERENTIATION; TOOTH DEVELOPMENT; TISSUE LOCALIZATION; MEMBRANE-PROTEIN; CARCINOMA CELLS; IN-VIVO; EXPRESSION; FIBRONECTIN; GENE; DOMAINS AB We identified a new extracellular protein, TM14, by differential hybridization using mouse tooth germ cDNA microarrays. TM14 cDNA encodes 440 amino acids containing a signal peptide. The protein contains 3 EGF modules at the center, aC-terminal domain homologous to the fibulin module, and a unique Sushi domain at the N terminus. In situ hybridization revealed that TM14 mRNA was expressed by preodontoblasts and odontoblasts in developing teeth. TM14 mRNA was also expressed in cartilage, hair follicles, and extraembryonic tissues of the placenta. Immunostaining revealed that TM14 was localized at the apical pericellular regions of preodontoblasts. When the dentin matrix was fully formed and dentin mineralization occurred, TM14 was present in the predentin matrix and along the dentinal tubules. We found that the recombinant TM14 protein was glycosylated with N-linked oligosaccharides and interacted with heparin, fibronectin, fibulin-1, and dentin sialophosphoprotein. We also found that TM14 preferentially bound dental mesenchyme cells and odontoblasts but not dental epithelial cells or nondental cells such as HeLa, COS7, or NIH3T3 cells. Heparin, EDTA, and anti-integrin beta 1 antibody inhibited TM14 binding to dental mesenchyme cells, suggesting that both a heparan sulfate-containing cell surface receptor and an integrin are involved in TM14 cell binding. Our findings indicate that TM14 is a cell adhesion molecule that interacts with extracellular matrix molecules in teeth and suggest that TM14 plays important roles in both the differentiation and maintenance of odontoblasts as well as in dentin formation. Because of its protein characteristics, TM14 can be classified as a new member of the fibulin family: fibulin-7. C1 NIDCR, Lab Cell & Dev Biol, NIH, Bethesda, MD 20892 USA. NIDCR, Craniofacial & Skeletal Dis Branch, NIH, Bethesda, MD 20892 USA. Kyushu Univ, Fac Dent Sci, Dept Pediat Dent, Fukuoka 8128582, Japan. RP Yamada, Y (reprint author), NIDCR, Lab Cell & Dev Biol, NIH, Bldg 30,Rm 407,30 Convent Dr MSC 4370, Bethesda, MD 20892 USA. EM yoshi.yamada@nih.gov RI Nakamura, Takashi/P-7796-2016 OI Nakamura, Takashi/0000-0001-9904-1037 FU Intramural NIH HHS NR 55 TC 41 Z9 46 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 19 PY 2007 VL 282 IS 42 BP 30878 EP 30888 DI 10.1074/jbc.M705847200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 220DE UT WOS:000250136300056 PM 17699513 ER PT J AU DellaVecchia, MJ Merrittt, WK Peng, Y Kirby, TW DeRose, EF Mueller, GA Van Houten, B London, RE AF DellaVecchia, Matthew J. Merrittt, W. Keither Peng, Ye Kirby, Thomas W. DeRose, Eugene F. Mueller, Geoffrey A. Van Houten, Bennett London, Robert E. TI NMR analysis of [methyl-C-13]methionine UvrB from Bacillus caldotenax reveals UvrB-domain 4 heterodimer formation in solution SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE UvrB; nucleoticle excision repair (NER); NMR; surface plasmon; resonance [methyl-C-13]methionine UvrB ID NUCLEOTIDE EXCISION-REPAIR; PROBING PROTEIN-STRUCTURE; ESCHERICHIA-COLI; SOLVENT PERTURBATION; CRYSTAL-STRUCTURE; ATPASE ACTIVITY; DNA-REPAIR; SIDE-CHAIN; THERMUS-THERMOPHILUS; COMPLEX AB UvrB is a central DNA damage recognition protein involved in bacterial nucleotide excision repair. Structural information has been limited by the apparent disorder of the C-terminal domain 4 in crystal structures of intact UvrB; in solution, the isolated domain 4 is found to form a helix-loop-helix dimer. In order to gain insight into the behavior of UvrB in solution, we have performed NMR studies on [methyl(-13)C]methionine-labeled UvrB from Bacillus caldotenax(molecular mass=75 kDa). The 13 methyl resonances were assigned on the basis of site-directed mutagenesis and domain deletion. Solvent accessibility was assessed based on the relaxation and chemical shift responses of the probe methyl resonances to the stable nitroxide, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPOL). M632, located at the potential dimer interface of domain 4, provides an ideal probe for UvrB dimerization behavior. The M632 resonance of UvrB is very broad, consistent with some degree of monomer-dimer exchange and/ or conformational instability of the exposed dimer interface. Upon addition of unlabeled domain 4 peptide, the M632 resonance of UvrB sharpens and shifts to a position consistent with a UvrB-domain 4 heterodimer. A dissociation constant (K-D) value of 3.3 mu M for the binding constant of UvrB with the domain 4 peptide was derived from surface plasmon resonance studies. Due to the flexibility of the domain 3-4 linker, inferred from limited proteolysis data and from the relaxation behavior of linker residue M607, the position of domain 4 is constrained not by the stiffness of the linking segment but by direct interactions with domains 1-3 in UvrB. In summary, UvrB homodimerization is disfavored, while domain 4 homodimerization and UvrB-domain 4 heterodimerization are allowed. Published by Elsevier Ltd. C1 NIH, Natl Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. NIH, Natl Inst Environm Hlth Sci, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Van Houten, B (reprint author), NIH, Natl Environm Hlth Sci, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. EM vanhout1@niehs.nih.gov; london@niehs.nih.gov FU Intramural NIH HHS [Z01 ES050111-19, Z01 ES061060-09] NR 40 TC 18 Z9 18 U1 0 U2 3 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 OCT 19 PY 2007 VL 373 IS 2 BP 282 EP 295 DI 10.1016/j.jmb.2007.07.045 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 222MZ UT WOS:000250302900005 PM 17822711 ER PT J AU Yamage, M Joshi, MB Dwyer, DM AF Yamage, Mat Joshi, Manju B. Dwyer, Dennis M. TI Episomally driven antisense mRNA abrogates the hyperinducible expression and function of a unique cell surface class I nuclease in the primitive trypanosomatid parasite, Crithidia lucifiae SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE auxotrophic parasite; class I nuclease; phospho-monoesterase; protozoan; purine salvage ID LEISHMANIA-DONOVANI PROMASTIGOTES; AMASTIGOTE-SPECIFIC PROTEIN; 3'-NUCLEOTIDASE NUCLEASE; PROTOZOAN PARASITE; ACID-PHOSPHATASE; MOLECULAR CHARACTERIZATION; PURINE STARVATION; VIRULENCE FACTOR; MEMBRANE; LUCILIAE AB Here, we show that Crithidia luciliae, a primitive trypanosomatid, purine auxotroph, up-expressed its unique, bi-functional, surface membrane 3'- nucleotidase/nuclease (Cl 3'NT/NU) activity by similar to 1000-fold in response to purine starvation. A second surface membrane phospho-monoesterase, i.e. a tartrate-resistant acid phosphatase (Cl MAcP) was also found to be up-expressed in such purine-starved cells. Here, we used homologous episomal-expression of an antisense construct of the Cl3'NT/NU to dissect the functional expression of these two surface membrane enzymes. In antisense transfected cells, a large excess of the antisense transcript was produced and no trace of any endogenous Cl3'NT/NU sense message was detected. Further, the purine-starvation hyper-induced levels of 3'NT/NU enzyme activity were completely abrogated in these transfected cells versus controls. Moreover, such antisense transcription completely abolished the ability of these transfectants to grow in poly(A)-containing medium demonstrating the essential nature of the 3'NT/NU for the growth/survival of this parasite. In contrast, antisense transcription had no apparent deleterious effects on either endogenous or purine-starvation-induced levels of MAcP enzyme activity, its steady-state mRNA levels, or the constitutive expression of house-keeping genes (e.g. Cl at-tubulin) in these transfectants. Cumulatively, results of our antisense experiments demonstrated that the functional nuclease activity of the surface membrane Cl 3'NT/NU was, in fact, critical/ essential for the growth and development of these primitive parasites. Published by Elsevier Ltd. C1 Natl Inst Hlth, NIAID, Div Intramural Res Programs, Parasit Dis Lab,Cell Biol Sect, Bethesda, MD 20892 USA. RP Dwyer, DM (reprint author), World Org Anim Hlth, Chiyoda Ku, Sanseido Bldg,4F,2-4-10 Kojimachi, Tokyo, Japan. EM DDwyer@niaid.nih.gov OI Yamage, Mat/0000-0002-3051-6732 FU Intramural NIH HHS [Z01 AI000162-31, Z99 AI999999] NR 39 TC 2 Z9 2 U1 0 U2 0 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 OCT 19 PY 2007 VL 373 IS 2 BP 296 EP 307 DI 10.1016/j.jmb.2007.08.014 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 222MZ UT WOS:000250302900006 PM 17850817 ER PT J AU Miller, PJ Pazy, Y Conti, B Riddle, D Appella, E Collins, EJ AF Miller, Peter J. Pazy, Yael Conti, Brian Riddle, David Appella, Ettore Collins, Edward J. TI Single MHC mutation eliminates enthalpy associated with T cell receptor binding SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE MHC; TCR; binding; structure; cytolysis ID MAJOR HISTOCOMPATIBILITY COMPLEX; PEPTIDE-MHC; TCR BINDING; CONFORMATIONAL-CHANGES; V(D)J RECOMBINATION; STRUCTURAL BASIS; RECOGNITION; IDENTIFICATION; MOLECULE; HLA-A2 AB The keystone of the adaptive immune response is T cell receptor (TCR) recognition of peptide presented by major histocompatibility complex (pMHC) molecules. The crystal structure of AHIII TCR bound to MHC, HLA-A2, showed a large interface with an atypical binding orientation. MHC mutations in the interface of the proteins were tested for changes in TCR recognition. From the range of responses observed, three representative HLA-A2 mutants, T163A, W167A, and K66A, were selected for further study. Binding constants and co-crystal structures of the AHIII TCR and the three mutants were determined. K66 in HLA-A2 makes contacts with both peptide and\ TCR, and has been identified as a critical residue for recognition by numerous TCR. The K66A mutation resulted in the lowest AHIII T cell response and the lowest binding affinity; which suggests that the T cell response may correlate with affinity. Importantly, the K66A mutation does not affect the conformation of the peptide. The change in affinity appears to be due to a loss in hydrogen bonds in the interface as a result of a conformational change in the TCR complementarity-determining region 3 (CDR3) loop. Isothermal titration calorimetry confirmed the loss of hydrogen bonding by a large loss in enthalpy. Our findings are inconsistent with the notion that the CDR1 and CDR2 loops of the TCR are responsible for MHC restriction, while the CDR3 loops interact solely with the peptide. Instead, we present here an MHC mutation that does not change the conformation of the peptide, yet results in an altered conformation of a CDR3. (C) 2007 Elsevier Ltd. All rights reserved. C1 Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Microbiol & Immunol, Chapel Hill, NC 27599 USA. NIH, NCI, Cell Biol Lab, Bethesda, MD 20892 USA. RP Collins, EJ (reprint author), Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. EM edward_collins@med.unc.edu FU NCI NIH HHS [R01 CA092368-04, CA92368-02] NR 56 TC 19 Z9 20 U1 0 U2 0 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 OCT 19 PY 2007 VL 373 IS 2 BP 315 EP 327 DI 10.1016/j.jmb.2007.07.028 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 222MZ UT WOS:000250302900008 PM 17825839 ER PT J AU Milac, AL Buchete, NV Fritz, TA Hummer, G Tabak, LA AF Milac, A. L. Buchete, N. V. Fritz, T. A. Hummer, G. Tabak, L. A. TI Substrate-induced conformational changes and dynamics of UDP-N-acetylgalactosamine: Polypeptide N-acetylgalactosaminyltransferase-2 SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE glycosyltransferase; functional conformational changes; substrate recognition; active site hydration; molecular dynamics ID MOLECULAR-DYNAMICS; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; O-GLYCOSYLATION; BLOOD-GROUP; CATALYTIC DOMAIN; ENZYME FUNCTION; GLYCOSYLTRANSFERASES; PROTEIN; SIMULATIONS AB O-Glycan biosynthesis is initiated by the transfer of N-acetylgalactosamine (GalNAc) from a nucleotide sugar donor (UDP-GalNAc) to Ser/Thr residues of an acceptor substrate. The detailed transfer mechanism, catalyzed by the UDP-GalNAc polypeptide:N-acetyl-alpha-galactosaminyl-transferases (ppGalNAcTs), remains unclear despite structural information available for several isoforms in complex with substrates at various stages along the catalytic pathway. We used all-atom molecular dynamics simulations with explicit solvent and counterions to study the conformational dynamics of ppGalNAcT-2 in several enzymatic states along the catalytic pathway. ppGalNAcT-2 is simulated both in the presence and in the absence of substrates and reaction products to examine the role of conformational changes in ligand binding. In multiple 40-ns-long simulations of more than 600 ns total run time, we studied systems ranging from 45,000 to 95,000 atoms. Our simulations accurately identified dynamically active regions of the protein, as previously revealed by the X-ray structures, and permitted a detailed, atomistic description of the conformational changes of loops near the active site and the characterization of the ensemble of structures adopted by the transferase complex on the transition pathway between the ligand-bound and ligand-free states. In particular, the conformational transition of a functional loop adjacent to the active site from closed (active) to open (inactive) is correlated with the rotameric state of the conserved residue W331. Analysis of water dynamics in the active site revealed that internal water molecules have an important role in enhancing the enzyme flexibility. We also found evidence that charged side chains in the active site rearrange during site opening to facilitate ligand binding. Our results are consistent with the single-displacement transfer mechanism previously proposed for ppGalNAcTs based on X-ray structures and mutagenesis data and provide new evidence for possible functional roles of certain amino acids conserved across several isoforms. Published by Elsevier Ltd. C1 NIH, Natl Inst Diabet & Digest & Kidney Dis, Sect Biol Chem, Bethesda, MD 20892 USA. Natl Inst Hlth, Natl Inst Diabet & Digest Kidney Dis, Chem Lab, Bethesda, MD 20892 USA. RP Tabak, LA (reprint author), NIH, Natl Inst Diabet & Digest & Kidney Dis, Sect Biol Chem, Bethesda, MD 20892 USA. EM gerhard.hummer@nih.gov; tabakl@mail.nih.gov RI Milac, Adina/C-1070-2011; Hummer, Gerhard/A-2546-2013; Buchete, Nicolae-Viorel/C-6200-2015 OI Milac, Adina/0000-0003-1845-4281; Hummer, Gerhard/0000-0001-7768-746X; Buchete, Nicolae-Viorel/0000-0001-9861-1157 FU Intramural NIH HHS [Z01 DK029033-08] NR 50 TC 21 Z9 23 U1 0 U2 7 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD OCT 19 PY 2007 VL 373 IS 2 BP 439 EP 451 DI 10.1016/j.jmb.2007.08.028 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 222MZ UT WOS:000250302900017 PM 17850816 ER PT J AU Liu, HJ Finkel, T AF Liu, Hongjun Finkel, Toren TI Of aging mice and men - Response SO SCIENCE LA English DT Letter C1 NHLBI, Cardiol Branch, NIH, Bethesda, MD 20892 USA. RP Liu, HJ (reprint author), NHLBI, Cardiol Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD OCT 19 PY 2007 VL 318 IS 5849 BP 390 EP 390 PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 221LW UT WOS:000250230400014 ER PT J AU Hammarstedt, M Ahlqvist, J Jacobson, S Garoff, H Fogdell-Hahn, A AF Hammarstedt, Maria Ahlqvist, Jenny Jacobson, Steven Garoff, Henrik Fogdell-Hahn, Anna TI Purification of infectious human herpesvirus 6A virions and association of host cell proteins SO VIROLOGY JOURNAL LA English DT Article ID SARCOMA-ASSOCIATED HERPESVIRUS; COMPLEMENT CONTROL PROTEINS; HUMAN CYTOMEGALOVIRUS HCMV; EPSTEIN-BARR-VIRUS; HHV-6 VARIANT-A; VACCINIA VIRUS; CD13-SPECIFIC AUTOIMMUNITY; FATAL ENCEPHALITIS; PLASMA-MEMBRANE; TYPE-1 AB Background: Viruses that are incorporating host cell proteins might trigger autoimmune diseases. It is therefore of interest to identify possible host proteins associated with viruses, especially for enveloped viruses that have been suggested to play a role in autoimmune diseases, like human herpesvirus 6A ( HHV-6A) in multiple sclerosis ( MS). Results: We have established a method for rapid and morphology preserving purification of HHV-6A virions, which in combination with parallel analyses with background control material released from mock-infected cells facilitates qualitative and quantitative investigations of the protein content of HHV-6A virions. In our iodixanol gradient purified preparation, we detected high levels of viral DNA by real-time PCR and viral proteins by metabolic labelling, silver staining and western blots. In contrast, the background level of cellular contamination was low in the purified samples as demonstrated by the silver staining and metabolic labelling analyses. Western blot analyses showed that the cellular complement protein CD46, the receptor for HHV-6A, is associated with the purified and infectious virions. Also, the cellular proteins clathrin, ezrin and Tsg101 are associated with intact HHV-6A virions. Conclusion: Cellular proteins are associated with HHV-6A virions. The relevance of the association in disease and especially in autoimmunity will be further investigated. C1 [Ahlqvist, Jenny; Fogdell-Hahn, Anna] Karolinska Inst, Div Neurol, Dept Clin Neurosci, Stockholm, Sweden. [Hammarstedt, Maria; Garoff, Henrik] Karolinska Inst, Dept Biosci & Nutr Novum, Huddinge, Sweden. [Jacobson, Steven] NINDS, NIH, Bethesda, MD 20892 USA. RP Fogdell-Hahn, A (reprint author), Karolinska Inst, Div Neurol, Dept Clin Neurosci, Stockholm, Sweden. EM hammarstedt@med.lu.se; jenny.ahlqvist2@gmail.com; JacobsonS@ninds.nih.gov; henrik.garoff@cbt.ki.se; Anna.Fogdell-Hahn@ki.se NR 40 TC 2 Z9 2 U1 0 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1743-422X J9 VIROL J JI Virol. J. PD OCT 19 PY 2007 VL 4 AR 101 DI 10.1186/1743-422X-4-101 PG 11 WC Virology SC Virology GA 250AG UT WOS:000252271800001 PM 17949490 ER PT J AU Jaluria, P Betenbaugh, M Konstantopoulos, K Shiloach, J AF Jaluria, Pratik Betenbaugh, Michael Konstantopoulos, Konstantinos Shiloach, Joseph TI Enhancement of cell proliferation in various mammalian cell lines by gene insertion of a cyclin-dependent kinase homolog SO BMC BIOTECHNOLOGY LA English DT Article ID CONSERVED CDC2-RELATED KINASE; HELA-CELLS; PRODUCTION KINETICS; MICROARRAY DATA; VACCINIA VIRUS; LEIGH-SYNDROME; COX15; OXIDASE; HEME; EXPRESSION AB Background: Genomics tools, particularly DNA microarrays, have found application in a number of areas including gene discovery and disease characterization. Despite the vast utility of these tools, little work has been done to explore the basis of distinct cellular properties, especially those important to biotechnology such as growth. And so, with the intent of engineering cell lines by manipulating the expression of these genes, anchorage-independent and anchorage-dependent HeLa cells, displaying markedly different growth characteristics, were analyzed using DNA microarrays. Results: Two genes, cyclin-dependent kinase like 3 (cdk13) and cytochrome c oxidase subunit (cox15), were up-regulated in the faster growing, anchorage-independent (suspension) HeLa cells relative to the slower growing, anchorage-dependent (attached) HeLa cells. Enhanced expression of either gene in the attached HeLa cells resulted in elevated cell proliferation, though insertion of cdk13 had a greater impact than that of cox15. Moreover, flow cytometric analysis indicated that cells with an insert of cdk13 were able to transition from the G0/G1 phases to the S phase faster than control cells. In turn, expression of cox15 was seen to increase the maximum viable cell numbers achieved relative to the control, and to a greater extent than cdk13. Quantitatively similar results were obtained with two Human Embryonic Kidney-293 (HEK-293) cell lines and a Chinese Hamster Ovary (CHO) cell line. Additionally, HEK-293 cells secreting adipocyte complement-related protein of 30 kDa (acrp30) exhibited a slight increase in specific protein production and higher total protein production in response to the insertion of either cdk13 or cox15. Conclusion: These results are consistent with previous studies on the functionalities of cdk13 and cox15. For instance, the effect of cdk13 on cell growth is consistent with its homology to the cdk3 gene which is involved in G1 to S phase transition. Likewise, the increase in cell viability due to cox15 expression is consistent with its role in oxidative phosphorylation as an assembly factor for cytochrome c oxidase and its involvement removing apoptosis-inducing oxygen radicals. Collectively, the present study illustrates the potential of using microarray technology to identify genes influential to specific cellular processes with the possibility of engineering cell lines as desired to meet production needs. C1 [Jaluria, Pratik; Shiloach, Joseph] NIDDKD, NIH, Biotechnol Unit, Bethesda, MD 20892 USA. [Jaluria, Pratik; Betenbaugh, Michael; Konstantopoulos, Konstantinos] Johns Hopkins Univ, Dept Chem & Biomol Engn, Baltimore, MD 21218 USA. RP Shiloach, J (reprint author), NIDDKD, NIH, Biotechnol Unit, Bldg 14A,Room 170, Bethesda, MD 20892 USA. EM pratikj@mail.nih.gov; beten@jhu.edu; kkonstal@jhu.edu; yossi@nih.gov RI Konstantopoulos, Konstantinos/A-7045-2011; Betenbaugh, Michael J./A-3252-2010 OI Betenbaugh, Michael J./0000-0002-6336-4659 FU Intramural NIH HHS; NIAMS NIH HHS [R01 AR053358] NR 44 TC 15 Z9 17 U1 1 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6750 J9 BMC BIOTECHNOL JI BMC Biotechnol. PD OCT 18 PY 2007 VL 7 AR 71 DI 10.1186/1472-6750-7-71 PG 11 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 244ZC UT WOS:000251903000001 PM 17945021 ER PT J AU Javanmard, S Loktionova, NA Fang, Q Pauly, GT Pegg, AE Moschel, RC AF Javanmard, Sahar Loktionova, Natalia A. Fang, Qingming Pauly, Gary T. Pegg, Anthony E. Moschel, Robert C. TI Inactivation of O-6-Alkylguanine-DNA alkyltransferase by folate esters of O-6-Benzyl-2'-deoxyguanosine and of O-6-[4-(Hydroxymethyl)benzyl]guanine SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PHASE-I; O-6-BENZYLGUANINE DERIVATIVES; PLUS O-6-BENZYLGUANINE; FUSION PROTEINS; SOLID TUMORS; TEMOZOLOMIDE; REPAIR; CELLS; COMBINATION; PROTECTION AB O-6-Alkylguanine-DNA alkyltransferase (alkyltransferase) provides an important source of resistance to some cancer chemotherapeutic alkylating agents. Folate ester derivatives of O-6-benzyl-2'-deoxyguanosine and of O-6- [4-(hydroxymethyl)benzyl] guanine were synthesized and tested for their ability to inactivate human alkyltransferase. Inactivation of alkyltransferase by the gamma-folate ester of O-6-[4-(hydroxymethyl)benzyl]guanine was similar to that of the parent base. The gamma-folate esters of O-6-benzyl-2'-deoxyguanosine were more potent alkyltransferase inactivators than the parent nucleoside. The 3'-ester was considerably more potent than the 5'-ester and was more than an order of magnitude more active than O-6-benzylguanine, which is currently in clinical trials to enhance therapy with alkylating agents. They were also able to sensitize human tumor cells to killing by 1,3-bis(2-chloroethyl)-1-nitrosourea, with O-6-benzyl-3'-O-(gamma-folyl)-2'- deoxyguanosine being most active. These compounds provide a new class of highly water-soluble alkyltransferase inactivators and form the basis to construct more tumor-specific and potent compounds targeting this DNA repair protein. C1 Natl Canc Inst, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. Penn State Univ, Coll Med, Dept Cellular & Mol Physiol, Hershey, PA 17033 USA. Penn State Univ, Coll Med, Dept Pharmacol, Hershey, PA 17033 USA. RP Pegg, AE (reprint author), Natl Canc Inst, Comparat Carcinogenesis Lab, Post Off Box B,Bldg 538, Frederick, MD 21702 USA. EM aepl@psu.edu RI Fang, Qingming/B-6839-2008 OI Fang, Qingming/0000-0002-4006-0636 FU Intramural NIH HHS; NCI NIH HHS [CA-071976, CA-018137, R01 CA071976-13, R01 CA018137, R01 CA018137-31, R01 CA071976, R37 CA018137] NR 25 TC 9 Z9 10 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 18 PY 2007 VL 50 IS 21 BP 5193 EP 5201 DI 10.1021/jm0705859 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 219TI UT WOS:000250110700017 PM 17880193 ER PT J AU Oldfield, SP Hall, MD Platts, JA AF Oldfield, Steven P. Hall, Matthew D. Platts, James A. TI Calculation of lipophilicity of a large, diverse dataset of anticancer platinum complexes and the relation to cellular uptake SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ACQUIRED-RESISTANCE; ANTITUMOR-ACTIVITY; MOLECULAR-SURFACE; IN-VITRO; CISPLATIN; HYDROPHOBICITY; REACTIVITY; DRUGS; ACCUMULATION; TOXICITY AB A quantitative structure -property relationship (QPSR) for the octanol-water partition of platinum complexes was constructed using molecular descriptors derived from density functional (DFT) calculations. A dataset of partition data for 64 complexes, consisting of 43 square-planar platinum(II) and 21 octahedral platinum(IV) complexes, was drawn from literature sources. Not only does this dataset include considerable structural diversity of complexes considered but also a variety of techniques for the measurement of partition coefficients. These data were modeled using descriptors drawn from electrostatic potentials and hardness/softness indices projected onto molecular surfaces. This required initial descriptor selection using a genetic algorithm approach, followed by partial least-squares regression against log P-o/w data. In this way, a statistically robust model was constructed, with errors of similar size to the variation in log P,,I, from multiple experimental measurements. Implications of lipophilicity for cellular accumulation of Pt-based drugs, and hence for design of new drugs, are discussed, as is the uptake of metabolites of cisplatin. C1 Cardiff Univ, Sch Chem, Cardiff CF10 3AT, Wales. NCI, NIH, Cell Biol Lab, Bethesda, MD 20892 USA. RP Platts, JA (reprint author), Cardiff Univ, Sch Chem, Cardiff CF10 3AT, Wales. EM plats@cardiff.ac.uk RI Platts, Jamie/A-2310-2011; Hall, Matthew/B-2132-2010 OI Platts, Jamie/0000-0002-1008-6595; NR 45 TC 39 Z9 39 U1 3 U2 15 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 18 PY 2007 VL 50 IS 21 BP 5227 EP 5237 DI 10.1021/jm0708275 PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 219TI UT WOS:000250110700020 PM 17900102 ER PT J AU Oliveira, RV Onorato, JA Siluk, D Walko, CA Lindley, C Wainer, IW AF Oliveira, Regina V. Onorato, Joelle A. Siluk, Danuta Walko, Christine A. Lindley, Celeste Wainer, Irving W. TI Selective liquid chromatography-mass spectrometry assay for the determination of ifosfamide and identification of the N-dechloroethylated metabolites of ifosfamide in human plasma SO JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS LA English DT Article DE chiral separations; cancer chemotherapy; ifosfamide metabolites; chirobiotic T CSP ID ENANTIOSELECTIVE GAS-CHROMATOGRAPHY; 3-N-DECHLOROETHYLATED METABOLITES; CHILDHOOD HEPATOBLASTOMA; S-IFOSFAMIDE; R-IFOSFAMIDE; PHARMACOKINETICS; ENANTIOMERS; SEPARATION; NEUROTOXICITY; EFFICIENCY AB A sensitive and specific liquid chromatography-mass spectrometry (LC-MS) method has been developed and validated for the enantioselective determination of ifosfamide [(R)-IF and (S)-IF] in human plasma and for the detection of the N-dechloroethylated metabolites of IF, 2-N-dechloroethylifosfamide [(R)-2-DCl-IF and (S)-2-DCI-IF] and 3-N-dechloroethylifosfamide [(R)-3-DCl-IF and (S)-3-DCl-IF]. IF, 2-DCl-IF and 3-DCl-IF were extracted from plasma using solid-phase extraction and resolved by liquid chromatography on a column containing a Chirabiotic T chiral stationary phase. The enantioselective separations were achieved using a mobile phase composed of 2-propanol: methanol (60:40, v/v) and a flow rate of 0.5 ml/min. The observed enantioselectivities (a) for IF, 2-DCl-IF and 3-DCl-IF were 1.20, 1.17 and 1.20, respectively. The calibration curve was linear in the concentration range of 37.50-4800 ng/ml for each ifosfamide enantiomer (r(2) > 0.997). The lower limit of detection (LLOD) was 5.00ng/ml. The inter- and intra-day precision ranged from 3.63 to 15.8% relative standard deviation (R.S.D.) and 10.1 to 14.3% R.S.D., respectively, and the accuracy ranged from 89.2 to 101.5% of the nominal values. The method was applied to the analysis of plasma samples obtained from a cancer patient who received 3.75 g/m(2)/day dose of (R,S)-ifosfamide as a 96-h continuous infusion. Published by Elsevier B.V. C1 Univ Fed Sao Carlos, Dept Quim, BR-13565905 Sao Carlos, SP, Brazil. NIA, NIH, Gerontol Res Ctr, Clin Invest Lab, Baltimore, MD 21224 USA. Med Univ Gdansk, Dept Biopharmaceut & Pharmacodynam, Gdansk, Poland. Univ N Carolina, Sch Pharm, Div Pharmacotherapy & Expt Therapeut, Chapel Hill, NC USA. RP Oliveira, RV (reprint author), Univ Fed Sao Carlos, Dept Quim, Rod Washington Luiz,Km 235, BR-13565905 Sao Carlos, SP, Brazil. EM otiveirarv@dq.ufscar.br RI Oliveira, Regina/I-9547-2012 FU Intramural NIH HHS [Z01 AG000297-06]; NCRR NIH HHS [RR00046, M01 RR000046] NR 30 TC 15 Z9 16 U1 1 U2 4 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 OCT 18 PY 2007 VL 45 IS 2 BP 295 EP 303 DI 10.1016/j.jpba.2007.07.026 PG 9 WC Chemistry, Analytical; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 230PP UT WOS:000250888700016 PM 17855037 ER PT J AU Frazer, KA Ballinger, DG Cox, DR Hinds, DA Stuve, LL Gibbs, RA Belmont, JW Boudreau, A Hardenbol, P Leal, SM Pasternak, S Wheeler, DA Willis, TD Yu, FL Yang, HM Zeng, CQ Gao, Y Hu, HR Hu, WT Li, CH Lin, W Liu, SQ Pan, H Tang, XL Wang, J Wang, W Yu, J Zhang, B Zhang, QR Zhao, HB Zhao, H Zhou, J Gabriel, SB Barry, R Blumenstiel, B Camargo, A Defelice, M Faggart, M Goyette, M Gupta, S Moore, J Nguyen, H Onofrio, RC Parkin, M Roy, J Stahl, E Winchester, E Ziaugra, L Altshuler, D Shen, Y Yao, ZJ Huang, W Chu, X He, YG Jin, L Liu, YF Shen, YY Sun, WW Wang, HF Wang, Y Wang, Y Xiong, XY Xu, L Waye, MMY Tsui, SKW Wong, JTF Galver, LM Fan, JB Gunderson, K Murray, SS Oliphant, AR Chee, MS Montpetit, A Chagnon, F Ferretti, V Leboeuf, M Olivier, JF Phillips, MS Roumy, S Sallee, C Verner, A Hudson, TJ Kwok, PY Cai, DM Koboldt, DC Miller, RD Pawlikowska, L Taillon-Miller, P Xiao, M Tsui, LC Mak, W Song, YQ Tam, PKH Nakamura, Y Kawaguchi, T Kitamoto, T Morizono, T Nagashima, A Ohnishi, Y Sekine, A Tanaka, T Tsunoda, T Deloukas, P Bird, CP Delgado, M Dermitzakis, ET Gwilliam, R Hunt, S Morrison, J Powell, D Stranger, BE Whittaker, P Bentley, DR Daly, MJ de Bakker, PIW Barrett, J Chretien, YR Maller, J McCarroll, S Patterson, N Pe'er, I Price, A Purcell, S Richter, DJ Sabeti, P Saxena, R Schaffner, SF Sham, PC Varilly, P Altshuler, D Stein, LD Krishnan, L Smith, AV Tello-Ruiz, MK Thorisson, GA Chakravarti, A Chen, PE Cutler, DJ Kashuk, CS Lin, S Abecasis, GR Guan, WH Li, Y Munro, HM Qin, ZHS Thomas, DJ McVean, G Auton, A Bottolo, L Cardin, N Eyheramendy, S Freeman, C Marchini, J Myers, S Spencer, C Stephens, M Donnelly, P Cardon, LR Clarke, G Evans, DM Morris, AP Weir, BS Tsunoda, T Johnson, TA Mullikin, JC Sherry, ST Feolo, M Skol, A AF Frazer, Kelly A. Ballinger, Dennis G. Cox, David R. Hinds, David A. Stuve, Laura L. Gibbs, Richard A. Belmont, John W. Boudreau, Andrew Hardenbol, Paul Leal, Suzanne M. Pasternak, Shiran Wheeler, David A. Willis, Thomas D. Yu, Fuli Yang, Huanming Zeng, Changqing Gao, Yang Hu, Haoran Hu, Weitao Li, Chaohua Lin, Wei Liu, Siqi Pan, Hao Tang, Xiaoli Wang, Jian Wang, Wei Yu, Jun Zhang, Bo Zhang, Qingrun Zhao, Hongbin Zhao, Hui Zhou, Jun Gabriel, Stacey B. Barry, Rachel Blumenstiel, Brendan Camargo, Amy Defelice, Matthew Faggart, Maura Goyette, Mary Gupta, Supriya Moore, Jamie Nguyen, Huy Onofrio, Robert C. Parkin, Melissa Roy, Jessica Stahl, Erich Winchester, Ellen Ziaugra, Liuda Altshuler, David Shen, Yan Yao, Zhijian Huang, Wei Chu, Xun He, Yungang Jin, Li Liu, Yangfan Shen, Yayun Sun, Weiwei Wang, Haifeng Wang, Yi Wang, Ying Xiong, Xiaoyan Xu, Liang Waye, Mary M. Y. Tsui, Stephen K. W. Wong, J. Tze-Fei Galver, Luana M. Fan, Jian-Bing Gunderson, Kevin Murray, Sarah S. Oliphant, Arnold R. Chee, Mark S. Montpetit, Alexandre Chagnon, Fanny Ferretti, Vincent Leboeuf, Martin Olivier, Jean-Franccois Phillips, Michael S. Roumy, Stephanie Sallee, Clementine Verner, Andrei Hudson, Thomas J. Kwok, Pui-Yan Cai, Dongmei Koboldt, Daniel C. Miller, Raymond D. Pawlikowska, Ludmila Taillon-Miller, Patricia Xiao, Ming Tsui, Lap-Chee Mak, William Song, You Qiang Tam, Paul K. H. Nakamura, Yusuke Kawaguchi, Takahisa Kitamoto, Takuya Morizono, Takashi Nagashima, Atsushi Ohnishi, Yozo Sekine, Akihiro Tanaka, Toshihiro Tsunoda, Tatsuhiko Deloukas, Panos Bird, Christine P. Delgado, Marcos Dermitzakis, Emmanouil T. Gwilliam, Rhian Hunt, Sarah Morrison, Jonathan Powell, Don Stranger, Barbara E. Whittaker, Pamela Bentley, David R. Daly, Mark J. de Bakker, Paul I. W. Barrett, Jeff Chretien, Yves R. Maller, Julian McCarroll, Steve Patterson, Nick Pe'er, Itsik Price, Alkes Purcell, Shaun Richter, Daniel J. Sabeti, Pardis Saxena, Richa Schaffner, Stephen F. Sham, Pak C. Varilly, Patrick Altshuler, David Stein, Lincoln D. Krishnan, Lalitha Smith, Albert Vernon Tello-Ruiz, Marcela K. Thorisson, Gudmundur A. Chakravarti, Aravinda Chen, Peter E. Cutler, David J. Kashuk, Carl S. Lin, Shin Abecasis, Goncalo R. Guan, Weihua Li, Yun Munro, Heather M. Qin, Zhaohui Steve Thomas, Daryl J. McVean, Gilean Auton, Adam Bottolo, Leonardo Cardin, Niall Eyheramendy, Susana Freeman, Colin Marchini, Jonathan Myers, Simon Spencer, Chris Stephens, Matthew Donnelly, Peter Cardon, Lon R. Clarke, Geraldine Evans, David M. Morris, Andrew P. Weir, Bruce S. Tsunoda, Tatsuhiko Johnson, Todd A. Mullikin, James C. Sherry, Stephen T. Feolo, Michael Skol, Andrew CA Int HapMap Consortium TI A second generation human haplotype map of over 3.1 million SNPs SO NATURE LA English DT Article ID GENOME-WIDE ASSOCIATION; LINKAGE DISEQUILIBRIUM; NATURAL-SELECTION; MEIOTIC RECOMBINATION; GENETIC ASSOCIATION; HUMAN-POPULATIONS; RECESSIVE TRAITS; HAPMAP PROJECT; HOT-SPOTS; TAG SNPS AB We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r(2) of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r(2) of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations. C1 Univ Oxford, Dept Stat, Oxford OX1 3TG, England. Scripps Res Inst, La Jolla, CA 92037 USA. Perlegen Sci Inc, Mountain View, CA 94043 USA. Baylor Coll Med, Dept Mol & Human Genet, Human Genome Sequencing Ctr, Houston, TX 77030 USA. Affymetrix Inc, Santa Clara, CA 95051 USA. Pacific Biosci, Menlo Pk, CA 94025 USA. Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. Harvard Univ, Broad Inst, Cambridge, MA 02139 USA. MIT, Cambridge, MA 02139 USA. Chinese Acad Sci, Beijing Genom Inst, Beijing 100300, Peoples R China. Massachusetts Gen Hosp, Boston, MA 02114 USA. Harvard Univ, Sch Med, Simches Res Ctr, Boston, MA 02114 USA. Chinese Natl Human Genome Ctr, Beijing Econ Technol Dev Area, Beijing 100176, Peoples R China. Chinese Natl Human Genome Ctr, Shanghai 201203, Peoples R China. Fudan Univ, Shanghai 201203, Peoples R China. CAS, SIBS, Sch Life Sci, MPG Partner Inst Computat Biol, Shanghai 201203, Peoples R China. Chinese Univ Hong Kong, Dept Biochem, Croucher Lab Human Genet, Shatin, Hong Kong, Peoples R China. Hong Kong Univ Sci & Technol, Dept Biochem, Kowloon, Hong Kong, Peoples R China. Hong Kong Univ Sci & Technol, Appl Genom Ctr, Kowloon, Hong Kong, Peoples R China. Illumina, San Diego, CA 92121 USA. Complete Genom Inc, Sunnyvale, CA 94085 USA. Prognosys Biosci Inc, San Diego, CA 92121 USA. McGill Univ, Montreal, PQ H3A 1A4, Canada. Genome Quebec Innovat Ctr, Montreal, PQ H3A 1A4, Canada. Univ Montreal, Publ Law Res Ctr, Downtown Stn, Montreal, PQ H3C 3J7, Canada. Ontario Inst Canc Res, MaRS Ctr, Toronto, ON M5G 1L7, Canada. Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94143 USA. Washington Univ, Sch Med, Dept Genet, St Louis, MO 63110 USA. Univ Hong Kong, Genome Res Ctr, Hong Kong, Hong Kong, Peoples R China. Univ Tokyo, Inst Med Sci, Minato Ku, Tokyo 1088639, Japan. RIKEN SNP Res Ctr, Tsurumi Ku, Kanagawa 2300045, Japan. Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England. Univ Cambridge, Dept Oncol, Cambridge CB1 8RN, England. Solexa Ltd, Saffron Walden CB10 1XL, Essex, England. Columbia Univ, New York, NY 10027 USA. Univ Leicester, Dept Genet, Leicester LE1 7RH, Leics, England. Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA. Univ Michigan, Dept Biostat, Ctr Stat Genet, Ann Arbor, MI 48109 USA. Int Epidemiol Inst, Rockville, MD 20850 USA. Univ Calif Santa Cruz, Ctr Biomol Sci & Engn, Santa Cruz, CA 95064 USA. Univ Chicago, Dept Stat, Chicago, IL 60637 USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford OX3 7BN, England. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. NHGRI, US NIH, Bethesda, MD 20892 USA. Natl Lib Med, US NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Univ Chicago, Dept Med, Med Genet Sect, Chicago, IL 60637 USA. Beijing Normal Univ, Beijing 100875, Peoples R China. Hlth Sci Univ Hokkaido, Ishikari, Hokkaido 0610293, Japan. Shinshu Univ, Sch Med, Dept Med Genet, Matsumoto, Nagano 3908621, Japan. UNESCO Bangkok, Bangkok 10110, Thailand. Univ Tsukuba, Eubios Eth Inst, Tsukuba, Ibaraki 3058691, Japan. Howard Univ, Natl Human Genome Ctr, Washington, DC 20059 USA. Univ Ibadan, Coll Med, Ibadan, Oyo State, Nigeria. Case Western Reserve Univ, Sch Med, Dept Bioeth, Cleveland, OH 44106 USA. Univ Utah, Dept Human Genet, Eccles Inst Human Genet, Salt Lake City, UT 84112 USA. Chinese Acad Social Sci, Inst Philosophy, Ctr Appl Eth, Beijing 100067, Peoples R China. Genet Interest Grp, London N13 0P, England. Kyoto Univ, Inst Res Humanities, Kyoto 6068501, Japan. Grad Sch Biostudies, Sakyo Ku, Kyoto 6068501, Japan. Nagasaki Univ, Grad Sch Biomed Sci, Dept Human Genet, Nagasaki 8528523, Japan. Univ Oklahoma, Dept Anthropol, Norman, OK 73019 USA. Vanderbilt Univ, Ctr Genet & Hlth Policy, Nashville, TN 37232 USA. Wellcome Trust Res Labs, London NW1 2BE, England. Washington Univ, Sch Med, Genome Sequencing Ctr, St Louis, MO 63108 USA. Chinese Acad Sci, Beijing 100864, Peoples R China. Genome Canada, Ottawa, ON K2P 1P1, Canada. McGill Univ, Off Technol Transfer, Montreal, PQ H3A 2A7, Canada. Genome Quebec, Montreal, PQ H3B 1S6, Canada. Minist Educ Culture Sports Sci & Technol, Chiyoda Ku, Tokyo 1008959, Japan. Minist Sci & Technol, Beijing 100862, Peoples R China. Human Genet Resource Adm China, Beijing 100081, Peoples R China. NHGRI, US NIH, Bethesda, MD 20892 USA. US NIH, Off Behav & Social Sci Res, Bethesda, MD 20892 USA. Novartis Pharmaceut Corp, Biomarker Dev, E Hanover, NJ 07936 USA. US NIH, Off Technol Transfer, Rockville, MD 20852 USA. Univ Maryland, Sch Law, Baltimore, MD 21201 USA. NHGRI, US NIH, Bethesda, MD 20892 USA. RP McVean, G (reprint author), Univ Oxford, Dept Stat, 1 S Parks Rd, Oxford OX1 3TG, England. EM mjdaly@chgr.mgh.harvard.edu; mcvean@stats.ox.ac.uk RI Auton, Adam/B-1159-2009; Jin, Li/C-1468-2009; Schaffner, Stephen/D-1189-2011; Song, You-Qiang/E-5207-2011; Song, You-qiang/C-4401-2009; Sham, Pak Chung/C-4388-2009; Tam, Paul/C-4405-2009; Abecasis, Goncalo/B-7840-2010; Thorisson, Gudmundur/E-7359-2010; Altshuler, David/A-4476-2009; MOE Key Lab at Fudan University, Contemp Anthropology/A-1772-2010; Fudan Anthropology, MOE KeyLab/A-9454-2010; Tsui, Lap-chee/A-1081-2010; Smith, Albert/K-5150-2015; Osborne, Nicholas/N-4915-2015; Qin, Zhaohui/E-8196-2011; 郑, 征/C-8514-2011; Deloukas, Panos/B-2922-2013; Dermitzakis, Emmanouil/B-7687-2013; Varilly, Patrick/C-8118-2013; Evans, David/H-6325-2013; de Bakker, Paul/B-8730-2009; Kwok, Pui-Yan/F-7725-2014; Tsunoda, Tatsuhiko/K-2061-2014; Myers, Simon/A-6792-2015; Waye 韋妙宜教授, Mary Miu Yee /A-9674-2008; Tsui, Stephen Kwok-Wing/E-4385-2015; Tanaka, Toshihiro/J-9310-2014 OI Jin, Li/0000-0002-4546-2415; Thorisson, Gudmundur/0000-0001-5635-1860; Altshuler, David/0000-0002-7250-4107; Abecasis, Goncalo/0000-0003-1509-1825; Johnson, Todd Andrew/0000-0003-3377-6692; Stranger, Barbara/0000-0001-9021-7331; He, Yungang/0000-0002-2931-2871; Evans, David/0000-0003-0663-4621; Adebamowo, Clement/0000-0002-6571-2880; Smith, Albert/0000-0003-1942-5845; Osborne, Nicholas/0000-0002-6700-2284; Clayton, Ellen/0000-0002-0308-4110; Belmont, John/0000-0001-7409-3578; Hudson, Thomas/0000-0002-1376-4849; Maller, Julian/0000-0002-1565-9559; Hunt, Sarah/0000-0002-8350-1235; Qin, Zhaohui/0000-0002-1583-146X; Deloukas, Panos/0000-0001-9251-070X; Varilly, Patrick/0000-0003-4619-8174; de Bakker, Paul/0000-0001-7735-7858; Kwok, Pui-Yan/0000-0002-5087-3059; Myers, Simon/0000-0002-2585-9626; Waye 韋妙宜教授, Mary Miu Yee /0000-0002-2582-4917; Tsui, Stephen Kwok-Wing/0000-0003-0686-4259; Tanaka, Toshihiro/0000-0001-6201-9784 NR 57 TC 2701 Z9 2775 U1 26 U2 267 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 18 PY 2007 VL 449 IS 7164 BP 851 EP U3 DI 10.1038/nature06258 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 221LY UT WOS:000250230600036 ER PT J AU Holland, SM DeLeo, FR Elloumi, HZ Hsu, AP Uzel, G Brodsky, N Freeman, AF Demidowich, A Davis, J Turner, ML Anderson, VL Darnell, DN Welch, PA Kuhns, DB Frucht, DM Malech, HL Gallin, JI Kobayashi, SD Whitney, AR Voyich, JM Musser, JM Woellner, C Schaffer, AA Puck, JM Grimbacher, B AF Holland, Steven M. Deleo, Frank R. Elloumi, Houda Z. Hsu, Amy P. Uzel, Gulbu Brodsky, Nina Freeman, Alexandra F. Demidowich, Andrew Davis, Joie Turner, Maria L. Anderson, Victoria L. Darnell, Dirk N. Welch, Pamela A. Kuhns, Douglas B. Frucht, David M. Malech, Harry L. Gallin, John I. Kobayashi, Scott D. Whitney, Adeline R. Voyich, Jovanka M. Musser, James M. Woellner, Cristina Schaeffer, Alejandro A. Puck, Jennifer M. Grimbacher, Bodo TI STAT3 mutations in the hyper-IgE syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID HYPERIMMUNOGLOBULIN-E SYNDROME; NECROSIS-FACTOR-ALPHA; GENE-EXPRESSION; CYTOKINE SIGNALS; INNATE IMMUNITY; T-CELLS; DISEASE; INTERFERON; DEFICIENCY; ACTIVATION AB Background The hyper-IgE syndrome (or Job's syndrome) is a rare disorder of immunity and connective tissue characterized by dermatitis, boils, cyst-forming pneumonias, elevated serum IgE levels, retained primary dentition, and bone abnormalities. Inheritance is autosomal dominant; sporadic cases are also found. Methods We collected longitudinal clinical data on patients with the hyper-IgE syndrome and their families and assayed the levels of cytokines secreted by stimulated leukocytes and the gene expression in resting and stimulated cells. These data implicated the signal transducer and activator of transcription 3 gene (STAT3) as a candidate gene, which we then sequenced. Results We found increased levels of proinflammatory gene transcripts in unstimulated peripheral-blood neutrophils and mononuclear cells from patients with the hyper-IgE syndrome, as compared with levels in control cells. In vitro cultures of mononuclear cells from patients that were stimulated with lipopolysaccharide, with or without interferon-(gamma), had higher tumor necrosis factor (alpha) levels than did identically treated cells from unaffected persons (P=0.003). In contrast, the cells from patients with the hyper-IgE syndrome generated lower levels of monocyte chemoattractant protein 1 in response to the presence of interleukin-6 (P=0.03), suggesting a defect in interleukin-6 signaling through its downstream mediators, one of which is STAT3. We identified missense mutations and single-codon in-frame deletions in STAT3 in 50 familial and sporadic cases of the hyper-IgE syndrome. Eighteen discrete mutations, five of which were hot spots, were predicted to directly affect the DNA-binding and SRC homology 2 (SH2) domains. Conclusions Mutations in STAT3 underlie sporadic and dominant forms of the hyper-IgE syndrome, an immunodeficiency syndrome involving increased innate immune response, recurrent infections, and complex somatic features. C1 NIAID, NIH, Bethesda, MD 20892 USA. NIAID, Hamilton, MT USA. NHGRI, Bethesda, MD 20892 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Sci Applicat Int Corp, NCI, Frederick, MD USA. US FDA, Ctr Drug Evaluat & Res, Rockville, MD 20857 USA. Royal Free Hosp & UCL, London, England. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Holland, SM (reprint author), NIAID, NIH, CRC B3-4141 MSC 1684, Bethesda, MD 20892 USA. EM smh@nih.gov RI Schaffer, Alejandro/F-2902-2012; OI DeLeo, Frank/0000-0003-3150-2516 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 39 TC 496 Z9 522 U1 4 U2 17 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 OCT 18 PY 2007 VL 357 IS 16 BP 1608 EP 1619 DI 10.1056/NEJMoa073687 PG 12 WC Medicine, General & Internal SC General & Internal Medicine GA 221AY UT WOS:000250200500006 PM 17881745 ER PT J AU Rapisarda, A Melillo, G AF Rapisarda, A. Melillo, G. TI UVC inhibits HIF-1 alpha protein translation by a DNA damage- and topoisomerase I-independent pathway SO ONCOGENE LA English DT Article DE HIF-1; topoisomerase; UVC; translation; DNA damage; cancer therapeutics ID HYPOXIA-INDUCIBLE FACTOR-1; RNA-POLYMERASE-II; XERODERMA-PIGMENTOSUM; ULTRAVIOLET-LIGHT; CANCER-THERAPY; TUMOR-GROWTH; HIF-ALPHA; TRANSCRIPTION; ACTIVATION; ATR AB Hypoxia inducible factor 1 (HIF-1) is a key player in cancer progression and an attractive target for cancer therapy. Several small molecule inhibitors of HIF-1 alpha also induce a DNA damage response. However, whether or not DNA damage is required for or associated with the inhibition of HIF-1 alpha protein accumulation is poorly understood. In this report we investigated the effects of distinct DNA damaging conditions on the hypoxic induction of HIF-1 alpha protein in cancer cell lines. We demonstrate that in addition to topotecan (TPT), a known inhibitor of HIF-1 alpha, UVC, but not other DNA damaging agents (cisplatin, ionizing radiation and doxorubicin), inhibited HIF-1 alpha protein accumulation in a dose-dependent, p53-independent fashion. Low doses UVC decreased HIF-1 alpha translation without affecting global protein synthesis. Inhibition of HIF-1 alpha by UVC required ongoing RNA transcription, but not DNA replication. Moreover, a functional ATR was required for the activation of DNA damage-dependent responses by both UVC and TPT, but was dispensable for the inhibition of HIF-1 alpha protein. Notably, unlike TPT, inhibition of HIF-1 alpha protein by UVC did not require topoisomerase 1, suggesting a similar yet distinct mode of action. Our data reveal that UVC is a novel signal associated with inhibition of HIF-1 alpha protein accumulation, and they uncouple the DNA damage-dependent signaling pathway exerted by UVC and TPT from HIF-1 alpha inhibition. C1 Natl Canc Inst, SAIC Frederick Inc, DTP Tumor Hypoxia Lab, Ft Detrick, MD 21702 USA. RP Melillo, G (reprint author), Natl Canc Inst, SAIC Frederick Inc, DTP Tumor Hypoxia Lab, 1050 Boyles St,Bldg 432,Room 218, Ft Detrick, MD 21702 USA. EM melillog@ncifcff.gov FU NCI NIH HHS [N01-CO-12400] NR 38 TC 10 Z9 10 U1 0 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD OCT 18 PY 2007 VL 26 IS 48 BP 6875 EP 6884 DI 10.1038/sj.onc.1210489 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 220WQ UT WOS:000250188400003 PM 17496931 ER PT J AU Darwiche, N Ryscavage, A Perez-Lorenzo, R Wright, L Bae, DS Hennings, H Yuspa, SH Glick, AB AF Darwiche, N. Ryscavage, A. Perez-Lorenzo, R. Wright, L. Bae, D-S Hennings, H. Yuspa, S. H. Glick, A. B. TI Expression profile of skin papillomas with high cancer risk displays a unique genetic signature that clusters with squamous cell carcinomas and predicts risk for malignant conversion SO ONCOGENE LA English DT Article DE skin carcinogenesis; microarray; squamous cell carcinoma; tumor immunology ID MOUSE SKIN; EPITHELIAL-CELLS; MESSENGER-RNA; IN-VIVO; CARCINOGENESIS; TUMORS; INFLAMMATION; SURVEILLANCE; PROGRESSION; RECEPTORS AB Chemical induction of squamous tumors in the mouse skin induces multiple benign papillomas: high-frequency terminally benign low-risk papillomas and low-frequency high-risk papillomas, the putative precursor lesions to squamous cell carcinoma (SCC). We have compared the gene expression profile of twenty different early low- and high-risk papillomas with normal skin and SCC. Unsupervised clustering of 514 differentially expressed genes (P<0.001) showed that 9/10 high-risk papillomas clustered with SCC, while 1/10 clustered with low-risk papillomas, and this correlated with keratin markers of tumor progression. Prediction analysis for microarrays (PAM) identified 87 genes that distinguished the two papilloma classes, and a majority of these had a similar expression pattern in both high-risk papillomas and SCC. Additional classifier algorithms generated a gene list that correctly classified unknown benign tumors as low- or high-risk concordant with promotion protocol and keratin profiling. Reduced expression of immune function genes characterized the high-risk papillomas and SCC. Immunohistochemistry confirmed reduced T-cell number in high-risk papillomas, suggesting that reduced adaptive immunity defines papillomas that progress to SCC. These results demonstrate that murine premalignant lesions can be segregated into subgroups; by gene expression patterns that correlate with risk for malignant conversion, and suggest a paradigm for generating diagnostic biomarkers for human premalignant lesions with unknown individual risk for malignant conversion. C1 Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, Dept Vet & Biomed Sci, University Pk, PA 16801 USA. Amer Univ Beirut, Dept Biol, Beirut, Lebanon. NCI, Lab Canc Biol & Genet, Bethesda, MD USA. RP Glick, AB (reprint author), Penn State Univ, Ctr Mol Toxicol & Carcinogenesis, Dept Vet & Biomed Sci, University Pk, PA 16801 USA. EM abg11@psu.edu OI Darwiche, Nadine/0000-0002-1862-5426 FU Intramural NIH HHS; NCI NIH HHS [CA117957] NR 38 TC 27 Z9 28 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD OCT 18 PY 2007 VL 26 IS 48 BP 6885 EP 6895 DI 10.1038/sj.onc.1210491 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 220WQ UT WOS:000250188400004 PM 17525749 ER PT J AU Wang, JW Ungar, LH Tseng, H Hannenhalli, S AF Wang, Junwen Ungar, Lyle H. Tseng, Hung Hannenhalli, Sridhar TI MetaProm: a neural network based meta-predictor for alternative human promoter prediction SO BMC GENOMICS LA English DT Article ID RNA-POLYMERASE-II; NONREDUNDANT SEQUENCE DATABASE; TRANSCRIPTION START SITES; HUMAN GENOME; CPG-ISLANDS; GENE MARKERS; HISTONE METHYLATION; IDENTIFICATION; REGIONS; RECOGNITION AB Background: De novo eukaryotic promoter prediction is important for discovering novel genes and understanding gene regulation. In spite of the great advances made in the past decade, recent studies revealed that the overall performances of the current promoter prediction programs (PPPs) are still poor, and predictions made by individual PPPs do not overlap each other. Furthermore, most PPPs are trained and tested on the most-upstream promoters; their performances on alternative promoters have not been assessed. Results: In this paper, we evaluate the performances of current major promoter prediction programs (i.e., PSPA, FirstEF, McPromoter, DragonGSF, DragonPF, and FProm) using 42,536 distinct human gene promoters on a genome-wide scale, and with emphasis on alternative promoters. We describe an artificial neural network ( ANN) based meta-predictor program that integrates predictions from the current PPPs and the predicted promoters' relation to CpG islands. Our specific analysis of recently discovered alternative promoters reveals that although only 41% of the 3' most promoters overlap a CpG island, 74% of 5' most promoters overlap a CpG island. Conclusion: Our assessment of six PPPs on 1.06 x 10(9) bps of human genome sequence reveals the specific strengths and weaknesses of individual PPPs. Our meta-predictor outperforms any individual PPP in sensitivity and specificity. Furthermore, we discovered that the 5' alternative promoters are more likely to be associated with a CpG island. C1 [Wang, Junwen; Ungar, Lyle H.; Hannenhalli, Sridhar] Univ Penn, Ctr Bioinformat, Philadelphia, PA 19104 USA. [Wang, Junwen; Hannenhalli, Sridhar] Univ Penn, Dept Genet, Philadelphia, PA 19104 USA. [Wang, Junwen; Ungar, Lyle H.; Hannenhalli, Sridhar] Univ Penn, Dept Comp & Informat Sci, Philadelphia, PA 19104 USA. [Wang, Junwen] SAIC Frederick, Adv Technol Program, Core Genotyping Facil, Frederick, MD 21702 USA. [Wang, Junwen] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Tseng, Hung] Univ Penn, Dept Dermatol, Philadelphia, PA 19104 USA. [Tseng, Hung] Univ Penn, Ctr Res Reprod & Womens Hlth, Philadelphia, PA 19104 USA. RP Wang, JW (reprint author), Univ Penn, Ctr Bioinformat, Philadelphia, PA 19104 USA. EM junwen2u@gmail.com; ungar@cis.upenn.edu; htsengpe@mail.med.upenn.edu; sridharh@pcbi.upenn.edu RI Wang, Junwen/C-4432-2009; Wang, Junwen/D-3700-2011 OI Wang, Junwen/0000-0002-4432-4707 FU NCI NIH HHS [N01CO12400]; NEI NIH HHS [EY13637, R01 EY013637]; NHGRI NIH HHS [T32-HG00046, T32 HG000046]; NIA NIH HHS [R01 AG014456, AG14456]; NIAID NIH HHS [1R21AI073422-01] NR 45 TC 14 Z9 18 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD OCT 17 PY 2007 VL 8 AR 374 DI 10.1186/1471-2164-8-374 PG 13 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 252IA UT WOS:000252439000001 PM 17941982 ER PT J AU Feero, WG Manolio, TA Guttmacher, AE Collins, FS AF Feero, W. Gregory Manolio, Teri A. Guttmacher, Alan E. Collins, Francis S. TI Validity of reported genetic risk factors for acute coronary syndrome SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID GENOME-WIDE ASSOCIATION; CANCER C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Feero, WG (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM feerow@mail.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 17 PY 2007 VL 298 IS 15 BP 1757 EP 1757 DI 10.1001/jama.298.15.1757-a PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 220WF UT WOS:000250187300011 PM 17940226 ER PT J AU Siman-Tov, T Mendelsohn, A Schonberg, T Avidan, G Podlipsky, I Pessoa, L Gadoth, N Ungerleider, LG Hendler, T AF Siman-Tov, Tali Mendelsohn, Avi Schonberg, Tom Avidan, Galia Podlipsky, Ilana Pessoa, Luiz Gadoth, Natan Ungerleider, Leslie G. Hendler, Talma TI Bihemispheric leftward bias in a Visuospatial attention-related network SO JOURNAL OF NEUROSCIENCE LA English DT Article DE attention; DCM; fMRI; intraparietal sulcus; lateralization; neglect ID DYNAMIC CAUSAL-MODELS; HUMAN PARIETAL CORTEX; SPATIAL ATTENTION; DEFICIT/HYPERACTIVITY DISORDER; NEGLECT; ASYMMETRIES; CHILDREN; BRAIN; TRANSMISSION; MININEGLECT AB Asymmetry of spatial attention has long been described in both disease (hemispatial neglect) and healthy (pseudoneglect) states. Although right-hemisphere specialization for spatial attention has been suggested, the exact neural mechanisms of asymmetry have not been deciphered yet. A recent functional magnetic resonance imaging study from our laboratory serendipitously revealed bihemispheric left-hemifield superiority in activation of a visuospatial attention-related network. Nineteen right-handed healthy adult females participated in two experiments of visual half-field presentation. Either facial expressions (experiment 1) or house images (experiment 2) were presented unilaterally and parafoveally for 150 ms while subjects were engaging a central fixation task. Brain regions previously associated with a visuospatial attention network, in both hemispheres, were found to be more robustly activated by left visual field stimuli. The consistency of this finding with manifestations of attention lateralization is discussed, and a revised model based on neural connectivity asymmetry is proposed. Support for the revised model is given by a dynamic causal modeling analysis. Unraveling the basis for attention asymmetry may lead to better understanding of the pathogenesis of attention disorders, followed by improved diagnosis and treatment. Additionally, the proposed model for asymmetry of visuospatial attention might provide important insights into the mechanisms underlying functional brain lateralization in general. C1 Tel Aviv Sourasky Med Ctr, Wohl Inst Advanced Imag, Funct Brain Imag Unit, IL-64239 Tel Aviv, Israel. Ben Gurion Univ Negev, Dept Behav Sci, IL-84105 Beer Sheva, Israel. NIMH, Lab Brain & Cognition, Bethesda, MD 20892 USA. Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN 47405 USA. Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. Maayanei Ha Yeshua Med Ctr, Dept Neurol, IL-51544 Bnei Braq, Israel. RP Hendler, T (reprint author), Tel Aviv Sourasky Med Ctr, Wohl Inst Advanced Imag, Funct Brain Imag Unit, 6 Weizmann St, IL-64239 Tel Aviv, Israel. EM talma@tasmc.health.gov.il RI hendler, talma/C-7677-2012; Avidan, Galia/B-9347-2011; OI Avidan, Galia/0000-0003-2293-3859; Schonberg, Tom/0000-0002-4485-816X NR 39 TC 65 Z9 72 U1 0 U2 8 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 17 PY 2007 VL 27 IS 42 BP 11271 EP 11278 DI 10.1523/JNEUROSCI.0599-07.2007 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 221JQ UT WOS:000250223700013 PM 17942721 ER PT J AU Rossi, AF Bichot, NP Desimone, R Ungerleider, LG AF Rossi, Andrew F. Bichot, Narcisse P. Desimone, Robert Ungerleider, Leslie G. TI Top-down attentional deficits in macaques with lesions of lateral prefrontal cortex SO JOURNAL OF NEUROSCIENCE LA English DT Article DE switching; primate; bottom-up; pop-out; salience; split brain ID FRONTAL EYE-FIELD; MEDIAL TEMPORAL-LOBE; VISUAL-ATTENTION; NEURAL MECHANISMS; SUPERIOR COLLICULUS; COGNITIVE CONTROL; TARGET SELECTION; WORKING-MEMORY; NEURONAL-ACTIVITY; SEARCH AB Brain imaging, electrical stimulation, and neurophysiological studies have all implicated the prefrontal cortex (PFC) in the top-down control of attention. Specifically, feedback from PFC has been proposed to bias activity in visual cortex in favor of attended stimuli over irrelevant distracters. To identify which attentional functions are critically dependent on PFC, we removed PFC unilaterally in combination with transection of the corpus callosum and anterior commissure in two macaques. In such a preparation, the ipsilesional hemisphere is deprived of top-down feedback from PFC to visual cortex, and the contralesional hemisphere can serve as an intact normal control. Monkeys were trained to fixate a central cue and discriminate the orientation of a colored target grating presented among colored distracter gratings in either the hemifield affected by the PFC lesion or the normal control hemifield. Locations of the targets and distracters were varied, and the color of the central cue specified the color of the target on each trial. The behavioral response was a bar release, and thus attentional impairments could be distinguished from impaired oculomotor control. When the cue was held constant for many trials, task performance in the affected hemifield was nearly normal. However, the monkeys were severely impaired when the cue was switched frequently across trials. The monkeys were unimpaired in a pop-out task with changing targets that did not require top-down attentional control. The PFC thus appears to play a critical role in the ability to flexibly reallocate attention on the basis of changing task demands. C1 NIMH, NIH, Labs Brain & Cognit, Bethesda, MD 20892 USA. NIMH, NIH, Labs Neuropsychol, Bethesda, MD 20892 USA. MIT, McGovern Inst Brain Res, Cambridge, MA 02139 USA. RP Rossi, AF (reprint author), Vanderbilt Univ, Dept Psychol, 111 21st Ave S, Nashville, TN 37203 USA. EM andrew.rossi@vanderbilt.edu FU Intramural NIH HHS; NEI NIH HHS [R01EY017292] NR 83 TC 69 Z9 72 U1 2 U2 13 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 OCT 17 PY 2007 VL 27 IS 42 BP 11306 EP 11314 DI 10.1523/JNEUROSCI.2939-07.2007 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 221JQ UT WOS:000250223700017 PM 17942725 ER PT J AU Mukai, I Kim, D Fukunaga, M Japee, S Marrett, S Ungerleider, LG AF Mukai, Ikuko Kim, David Fukunaga, Masaki Japee, Shruti Marrett, Sean Ungerleider, Leslie G. TI Activations in visual and attention-related areas predict and correlate with the degree of perceptual learning SO JOURNAL OF NEUROSCIENCE LA English DT Article DE perceptual learning; visual; fMRI; attention; human brain; contrast ID SURFACE-BASED ANALYSIS; FUNCTIONAL MRI; DIRECTED ATTENTION; NEURAL MECHANISMS; ORIENTATION DISCRIMINATION; TEXTURE-DISCRIMINATION; VISUOSPATIAL ATTENTION; CORTEX PLASTICITY; STAIRCASE-METHOD; V4 NEURONS AB Repeated experience with a visual stimulus can result in improved perception of the stimulus, i. e., perceptual learning. To understand the underlying neural mechanisms of this process, we used functional magnetic resonance imaging to track brain activations during the course of training on a contrast discrimination task. Based on their ability to improve on the task within a single scan session, subjects were separated into two groups: "learners" and "nonlearners." As learning progressed, learners showed progressively reduced activation in both visual cortex, including Brodmann's areas 18 and 19 and the fusiform gyrus, and several cortical regions associated with the attentional network, namely, the intraparietal sulcus (IPS), frontal eye field (FEF), and supplementary eye field. Among learners, the decrease in brain activations in these regions was highly correlated with the magnitude of performance improvement. Unlike learners, nonlearners showed no changes in brain activations during training. Learners showed stronger activation than nonlearners during the initial period of training in all these brain regions, indicating that one could predict from the initial activation level who would learn and who would not. In addition, over the course of training, the functional connectivity between IPS and FEF in the right hemisphere with early visual areas was stronger for learners than nonlearners. We speculate that sharpened tuning of neuronal representations may cause reduced activation in visual cortex during perceptual learning and that attention may facilitate this process through an interaction of attention-related and visual cortical regions. C1 NIMH, NIH, Lab Brain & Cognit, Bethesda, MD 20892 USA. NIMH, NIH, Funct MRI Facil, Bethesda, MD 20892 USA. NINDS, NIH, Lab Funt & Mol Imaging, Adv MRI, Bethesda, MD 20892 USA. RP Mukai, I (reprint author), NIMH, NIH, Lab Brain & Cognit, Bldg 10,Rm 4C104,10 Ctr Dr, Bethesda, MD 20892 USA. EM mukaii@mail.nih.gov RI Fukunaga, Masaki/F-6441-2013; OI Fukunaga, Masaki/0000-0003-1010-2644; Marrett, Sean/0000-0001-8179-6511 FU Intramural NIH HHS NR 73 TC 90 Z9 96 U1 0 U2 10 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 17 PY 2007 VL 27 IS 42 BP 11401 EP 11411 DI 10.1523/JNEUROSCI.3002-07.2007 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 221JQ UT WOS:000250223700026 PM 17942734 ER PT J AU Savage, SA Greene, MH AF Savage, Sharon A. Greene, Mark H. TI The evidence for prostate cancer risk loci at 8q24 grows stronger SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID GENOME-WIDE ASSOCIATION; CHROMOSOME 8Q24; COLORECTAL-CANCER; VARIANT; SCAN C1 NCI, Div Canc Epidemiol & Genet, Clin Genet Branch, Bethesda, MD 20892 USA. RP Savage, SA (reprint author), NCI, Div Canc Epidemiol & Genet, Clin Genet Branch, 6120 Execut Blvd,EPS-7018, Bethesda, MD 20892 USA. EM savagesh@mail.nih.gov RI Savage, Sharon/B-9747-2015 OI Savage, Sharon/0000-0001-6006-0740 NR 17 TC 7 Z9 7 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 OCT 17 PY 2007 VL 99 IS 20 BP 1499 EP 1501 DI 10.1093/jnci/djm186 PG 3 WC Oncology SC Oncology GA 223RW UT WOS:000250391000002 PM 17925532 ER PT J AU Dicko, A Diemert, DJ Sagara, I Sogoba, M Niambele, MB Assadou, MH Guindo, O Kamate, B Baby, M Sissoko, M Malkin, E Fay, MP Thera, MA Miura, K Dolo, A Diallo, DA Mullen, GE Long, CA Saul, A Doumbo, O Miller, LH AF Dicko, Alassane Diemert, David J. Sagara, Issaka Sogoba, Moussa Niambele, Mohamed B. Assadou, Mahamadoun H. Guindo, Ousmane Kamate, Beh Baby, Mounirou Sissoko, Mady Malkin, Elissa M. Fay, Michael P. Thera, Mahamadou A. Miura, Kazutoyo Dolo, Amagana Diallo, Dapa A. Mullen, Gregory E. Long, Carole A. Saul, Allan Doumbo, Ogobara Miller, Louis H. TI Impact of a Plasmodium falciparum AMA1 vaccine on antibody responses in adult malians SO PLOS CLINICAL TRIALS LA English DT Article ID APICAL MEMBRANE ANTIGEN-1; CANDIDATE MALARIA VACCINE; IN-VITRO; MEROZOITES; INVASION; TRIAL; PROTECTION; INFECTION; CHILDREN; MONKEYS AB Background. Apical Membrane Antigen 1 (AMA1) of Plasmodium falciparum merozoites is a leading blood-stage malaria vaccine candidate. Protection of Aotus monkeys after vaccination with AMA1 correlates with antibody responses. Study Design/Results. A randomized, controlled, double-blind phase 1 clinical trial was conducted in 54 healthy Malian adults living in an area of intense seasonal malaria transmission to assess the safety and immunogenicity of the AMA1-C1 malaria vaccine. AMA1-C1 contains an equal mixture of yeast-expressed recombinant proteins based on sequences from the FVO and 3D7 clones of P. falciparum, adsorbed on Alhydrogel. The control vaccine was the hepatitis B vaccine (Recombivax). Participants were enrolled into 1 of 3 dose cohorts (n=18 per cohort) and randomized 2: 1 to receive either AMA1-C1 or Recombivax. Participants in the first, second, and third cohorts randomized to receive AMA1-C1 were vaccinated with 5, 20 and 80 mu g of AMA1-C1, respectively. Vaccinations were administered on days 0, 28, and 360, and participants were followed until 6 months after the final vaccination. AMA1-C1 was well tolerated; no vaccine-related severe or serious adverse events were observed. AMA1 antibody responses to the 80 mu g dose increased rapidly from baseline levels by days 14 and 28 after the first vaccination and continued to increase after the second vaccination. After a peak 14 days following the second vaccination, antibody levels decreased to baseline levels one year later at the time of the third vaccination that induced little or no increase in antibody levels. Conclusions. Although the AMA1-C1 vaccine candidate was well-tolerated and induced antibody responses to both vaccine and non-vaccine alleles, the antibody response after a third dose given at one year was lower than the response to the initial vaccinations. Additionally, post-vaccination increases in anti-AMA1 antibody levels were not associated with significant changes in in vitro growth inhibition of P. falciparum. Trial Registration. Clinicaltrials.gov NCT00343005. C1 [Diemert, David J.; Malkin, Elissa M.; Miura, Kazutoyo; Mullen, Gregory E.; Long, Carole A.; Saul, Allan; Miller, Louis H.] NIH, NIAID, Malaria Vaccine Dev Branch, Bethesda, MD 20892 USA. [Dicko, Alassane; Sagara, Issaka; Sogoba, Moussa; Niambele, Mohamed B.; Assadou, Mahamadoun H.; Guindo, Ousmane; Kamate, Beh; Baby, Mounirou; Sissoko, Mady; Thera, Mahamadou A.; Dolo, Amagana; Diallo, Dapa A.; Doumbo, Ogobara] Univ Bamako, Malaria Res & Training Ctr, Dept Hematol, Bamako, Mali. [Dicko, Alassane; Sagara, Issaka; Sogoba, Moussa; Niambele, Mohamed B.; Assadou, Mahamadoun H.; Guindo, Ousmane; Kamate, Beh; Baby, Mounirou; Sissoko, Mady; Thera, Mahamadou A.; Dolo, Amagana; Diallo, Dapa A.; Doumbo, Ogobara] Univ Bamako, Malaria Res & Training Ctr, Dept Parasitol, Bamako, Mali. [Diemert, David J.; Malkin, Elissa M.; Miura, Kazutoyo; Mullen, Gregory E.; Miller, Louis H.] NIH, NIAID, Biostat Res Branch, Bethesda, MD 20892 USA. RP Miller, LH (reprint author), NIH, NIAID, Malaria Vaccine Dev Branch, Bldg 10, Bethesda, MD 20892 USA. EM lmiller@niaid.nih.gov NR 28 TC 2 Z9 2 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1555-5887 J9 PLOS CLIN TRIALS JI PLos Clin. Trials PD OCT 17 PY 2007 VL 2 IS 10 AR e1045 DI 10.1371/journal.pone.0001045 PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 248EQ UT WOS:000252135100001 ER PT J AU Dicko, A Diemert, DJ Sagara, I Sogoba, M Niambele, MB Assadou, MH Guindo, O Kamate, B Baby, M Sissoko, M Malkin, EM Fay, MP Thera, MA Miura, K Dolo, A Diallo, DA Mullen, GE Long, CA Saul, A Doumbo, O Miller, LH AF Dicko, Alassane Diemert, David J. Sagara, Issaka Sogoba, Moussa Niambele, Mohamed B. Assadou, Mahamadoun H. Guindo, Ousmane Kamate, Beh Baby, Mounirou Sissoko, Mady Malkin, Elissa M. Fay, Michael P. Thera, Mahamadou A. Miura, Kazutoyo Dolo, Amagana Diallo, Dapa A. Mullen, Gregory E. Long, Carole A. Saul, Allan Doumbo, Ogobara Miller, Louis H. TI Impact of a Plasmodium falciparum AMA1 Vaccine on Antibody Responses in Adult Malians SO PLOS ONE LA English DT Article AB Background. Apical Membrane Antigen 1 (AMA1) of Plasmodium falciparum merozoites is a leading blood-stage malaria vaccine candidate. Protection of Aotus monkeys after vaccination with AMA1 correlates with antibody responses. Study Design/Results. A randomized, controlled, double-blind phase 1 clinical trial was conducted in 54 healthy Malian adults living in an area of intense seasonal malaria transmission to assess the safety and immunogenicity of the AMA1-C1 malaria vaccine. AMA1-C1 contains an equal mixture of yeast-expressed recombinant proteins based on sequences from the FVO and 3D7 clones of P. falciparum, adsorbed on Alhydrogel. The control vaccine was the hepatitis B vaccine (Recombivax). Participants were enrolled into 1 of 3 dose cohorts (n = 18 per cohort) and randomized 2: 1 to receive either AMA1-C1 or Recombivax. Participants in the first, second, and third cohorts randomized to receive AMA1-C1 were vaccinated with 5, 20 and 80 mg of AMA1-C1, respectively. Vaccinations were administered on days 0, 28, and 360, and participants were followed until 6 months after the final vaccination. AMA1-C1 was well tolerated; no vaccine-related severe or serious adverse events were observed. AMA1 antibody responses to the 80 mg dose increased rapidly from baseline levels by days 14 and 28 after the first vaccination and continued to increase after the second vaccination. After a peak 14 days following the second vaccination, antibody levels decreased to baseline levels one year later at the time of the third vaccination that induced little or no increase in antibody levels. Conclusions. Although the AMA1-C1 vaccine candidate was well-tolerated and induced antibody responses to both vaccine and non-vaccine alleles, the antibody response after a third dose given at one year was lower than the response to the initial vaccinations. Additionally, post-vaccination increases in anti-AMA1 antibody levels were not associated with significant changes in in vitro growth inhibition of P. falciparum. Trial Registration. Clinicaltrials.gov NCT00343005 C1 [Diemert, David J.; Malkin, Elissa M.; Miura, Kazutoyo; Mullen, Gregory E.; Long, Carole A.; Saul, Allan; Miller, Louis H.] NIAID, Malaria Vaccine Dev Branch, NIH, Bethesda, MD 20892 USA. [Dicko, Alassane; Sagara, Issaka; Sogoba, Moussa; Niambele, Mohamed B.; Assadou, Mahamadoun H.; Guindo, Ousmane; Kamate, Beh; Baby, Mounirou; Sissoko, Mady; Thera, Mahamadou A.; Dolo, Amagana; Diallo, Dapa A.; Doumbo, Ogobara] Univ Bamako, Dept Hematol, Malaria Res & Training Ctr, Bamako, Mali. [Dicko, Alassane; Sagara, Issaka; Sogoba, Moussa; Niambele, Mohamed B.; Assadou, Mahamadoun H.; Guindo, Ousmane; Kamate, Beh; Baby, Mounirou; Sissoko, Mady; Thera, Mahamadou A.; Dolo, Amagana; Diallo, Dapa A.; Doumbo, Ogobara] Univ Bamako, Dept Parasitol, Malaria Res & Training Ctr, Bamako, Mali. [Fay, Michael P.] NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. RP Miller, LH (reprint author), NIAID, Malaria Vaccine Dev Branch, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM lmiller@niaid.nih.gov RI Saul, Allan/I-6968-2013 OI Saul, Allan/0000-0003-0665-4091 FU National Institute of Allergy and Infectious Diseases, National Institutes of Health FX Site development and the conduct of the trial were directly supported by the Intramural Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. NR 28 TC 4 Z9 4 U1 0 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 17 PY 2007 VL 2 IS 10 AR e1045 DI 10.1371/journal.pone.0001045 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10HW UT WOS:000207456100013 ER PT J AU Nieman, L AF Nieman, Lynnette TI Screening for reversible osteoporosis: Is cortisol a culprit? SO ANNALS OF INTERNAL MEDICINE LA English DT Editorial Material ID SUBCLINICAL CUSHINGS-SYNDROME; PREVALENCE C1 NIH, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. RP Nieman, L (reprint author), NIH, Mark O Hatfield Clin Res Ctr, Bldg 10,1 East,Room 1-3140,10 Ctr Dr,MSC 1109, Bethesda, MD 20892 USA. EM NiemanL@nih.gov NR 15 TC 3 Z9 3 U1 0 U2 0 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD OCT 16 PY 2007 VL 147 IS 8 BP 582 EP 584 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 224HC UT WOS:000250437100009 PM 17938397 ER PT J AU Nagababu, E Ramasamy, S Rifkind, JM AF Nagababu, Enika Ramasamy, Somasundaram Rifkind, Joseph M. TI Intermediates detected by visible Spectroscopy during the reaction of nitrite with deoxyhemoglobin: The effect of nitrite concentration and diphosphoglycerate SO BIOCHEMISTRY LA English DT Article ID BLOOD-FLOW REGULATION; S-NITROSOHEMOGLOBIN; OXYGEN-AFFINITY; RED-CELL; REDUCTIVE NITROSYLATION; HYPOXIC VASODILATION; ALLOSTERIC EFFECTORS; HUMAN METHEMOGLOBIN; HUMAN HEMOGLOBIN; OXIDE AB The reaction of nitrite with deoxyhemoglobin (deoxyHb) results in the reduction of nitrite to NO, which binds unreacted deoxyHb forming Fe(II)-nitrosylhemoglobin (Hb(II)NO). The tight binding of NO to deoxyHb is, however, inconsistent with reports implicating this reaction with hypoxic vasodilation. This dilemma is resolved by the demonstration that metastable intermediates are formed in the course of the reaction of nitrite with deoxyHb. The level of intermediates is quantitated by the excess deoxyHb consumed over the concentrations of the final products formed. The dominant intermediate has a spectrum that does not correspond to that of Hb(III)NO formed when NO reacts with methemoglobin (MetHb), but is similar to metHb resulting in the spectroscopic determinations of elevated levels of metHb. It is a delocalized species involving the heme iron, the NO, and perhaps the beta-93 thiol. The putative role for red cell reacted nitrite on vasodilation is associated with reactions involving the intermediate. (1) The intermediate is less stable with a 10-fold excess of nitrite and is not detected with a 100-fold excess of nitrite. This observation is attributed to the reaction of nitrite with the intermediate producing N2O3. (2) The release of NO quantitated by the formation of Hb(II)NO is regulated by changes in the distal heme pocket as shown by the 4.5-fold decrease in the rate constant in the presence of 2,3-diphosphoglycerate. The regulated release of NO or N2O3 as well as the formation of the S-nitroso derivative of hemoglobin, which has also been reported to be formed from the intermediates generated during nitrite reduction, should be associated with any hypoxic vasodilation attributed to the RBC. C1 NIA, NIH, Mol Dynam Sect, Baltimore, MD 21224 USA. RP Rifkind, JM (reprint author), NIA, NIH, Mol Dynam Sect, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM rifkindj@grc.nia.nih.gov FU Intramural NIH HHS NR 51 TC 28 Z9 28 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD OCT 16 PY 2007 VL 46 IS 41 BP 11650 EP 11659 DI 10.1021/bi700364e PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 218IR UT WOS:000250009700023 PM 17880185 ER PT J AU Hurt, EM Thomas, SB Peng, B Farrar, WL AF Hurt, E. M. Thomas, S. B. Peng, B. Farrar, W. L. TI Molecular consequences of SOD2 expression in epigenetically silenced pancreatic carcinoma cell lines SO BRITISH JOURNAL OF CANCER LA English DT Article DE superoxide dismutase 2; pancreatic neoplasms; proteomics; genomics; epigenetic process ID MANGANESE SUPEROXIDE-DISMUTASE; MULTIPLE-MYELOMA CELLS; PROSTATE-CANCER CELLS; MALIGNANT PHENOTYPE; OXIDATIVE STRESS; OVEREXPRESSION; SUPPRESSION; GROWTH; MNSOD; 2-METHOXYESTRADIOL AB Manganese superoxide dismutase (SOD2) is an enzyme that catalyses the dismutation of superoxide in the mitochondria, leading to reduced levels of reactive oxygen species. Reduced expression levels of SOD2 have been shown to result in increased DNA damage and sod2 heterozygous mice have increased incidences of cancer. It has also been shown that SOD2 expression is lost in pancreatic cell lines, with reintroduction of SOD2 resulting in decreased rate of proliferation. The mechanism of decreased SOD2 expression in pancreatic carcinoma has not been previously determined. We demonstrate, through sodium bisulphite sequencing, that the sod2 locus is methylated in some pancreatic cell lines leading to a corresponding decrease in SOD2 expression. Methylation can be reversed by treatment with zebularine, a methyltransferase inhibitor, resulting in restored SOD2 expression. Furthermore, we demonstrate that sensitivity of pancreatic carcinoma cell lines to 2-methoxyestradiol correlates with SOD2 expression and SOD2 modulation can alter the sensitivity of these cells. Using both genomics and proteomics, we also identify molecular consequences of SOD2 expression in MIA-PaCa2 cells, including dephosphorylation of VEGFR2 and the identification of both SOD2-regulated genes and transcription factors with altered binding activity in response to SOD2 expression. C1 Natl Canc Inst, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Frederick, MD 21702 USA. SAIC Frederick Inc, Basic Res Program, NCI, Frederick, MD 21702 USA. Univ Melbourne, Sch Dent Sci, Melbourne, Vic 3000, Australia. RP Hurt, EM (reprint author), Natl Canc Inst, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res,NIH, 1050 Boykles St,Bldg 560,Room 21-81, Frederick, MD 21702 USA. EM hurte@ncifcrf.gov; farrar@ncifcrf.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 32 TC 35 Z9 38 U1 0 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD OCT 16 PY 2007 VL 97 IS 8 BP 1116 EP 1123 DI 10.1038/sj.bjc.6604000 PG 8 WC Oncology SC Oncology GA 225RZ UT WOS:000250536400015 PM 17895890 ER PT J AU Seth, M Zhang, ZS Mao, L Burch, J Graham, V Rockman, HA Birnbaumer, L Rosenberg, P AF Seth, Malini Zhang, Zhu-Shan Mao, Lan Burch, Jarrett Graham, Victoria Rockman, Howard A. Birnbaumer, Lutz Rosenberg, Paul TI Transient receptor potential channel C1 deficiency protects the murine heart from pressure overload SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Seth, Malini; Zhang, Zhu-Shan; Mao, Lan; Burch, Jarrett; Graham, Victoria; Rockman, Howard A.; Rosenberg, Paul] Duke Univ, Durham, NC USA. [Birnbaumer, Lutz] NIEHS, Res Triangle Pk, NC 27709 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 5 EP 5 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394300022 ER PT J AU Wang, DW Xiao, B Wang, Y Xiong, XJ Zeldin, DC AF Wang, Dao Wen Xiao, Bin Wang, Yong Xiong, Xiaojun Zeldin, Darryl C. TI Overexpression of arachidonic acid cytochrome p450 expoxygenases prevents the development of high blood pressure via enhancing atrial natriuretic peptide in spontaneously hypertensive rats SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Wang, Dao Wen; Xiao, Bin; Wang, Yong; Xiong, Xiaojun] Tongji Hosp, Wuhan, Peoples R China. [Zeldin, Darryl C.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RI Xiao, Bin/E-1875-2015 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 14 EP 14 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394300065 ER PT J AU Schnabel, R Lunetta, KL Larson, MG Dupuis, J Keaney, JF Lipinska, I Govindaraju, DR Hirschhorn, JN Kathiresan, S Meigs, JB Lee, DS O'Donnell, CJ Newton-Cheh, C Chen, MH Zhao, ZM Rong, J Sutherland, P Vasan, RS Benjamin, EJ AF Schnabel, Renate Lunetta, Kathryn L. Larson, Martin G. Dupuis, Josee Keaney, John F. Lipinska, Izabella Govindaraju, Diddahally R. Hirschhorn, Joel N. Kathiresan, Sekar Meigs, James B. Lee, Douglas S. O'Donnell, Christopher J. Newton-Cheh, Christopher Chen, Ming-Huei Zhao, Zhenming Rong, Jian Sutherland, Patrice Vasan, Ramachandran S. Benjamin, Emelia J. TI Association of single nucleotide polymorphisms in inflammatory candidate genes with circulating inflammatory biomarker concentrations: The Framingham Heart Study SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Schnabel, Renate; Govindaraju, Diddahally R.; Newton-Cheh, Christopher; Rong, Jian; Sutherland, Patrice; Vasan, Ramachandran S.; Benjamin, Emelia J.] Boston Univ Framingham Heart Study, Natl Heart Lung & Blood Inst, Boston, MA USA. [Lunetta, Kathryn L.; Dupuis, Josee; Zhao, Zhenming] Boston Univ, Sch Publ Hlth, Boston, MA 02215 USA. [Larson, Martin G.; Chen, Ming-Huei] Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. [Keaney, John F.] Univ Massachusetts, Sch Med, Boston, MA 02125 USA. [Lipinska, Izabella] Boston Univ, Sch Med, Boston, MA 02215 USA. [Hirschhorn, Joel N.; Kathiresan, Sekar] MIT, Broad Inst Harvard, Cambridge, MA 02139 USA. [Meigs, James B.] Harvard Univ, Childrens Hosp, Boston, MA 02115 USA. [Lee, Douglas S.] Univ Toronto, Inst Clin Evaluat Sci, Toronto, ON, Canada. [O'Donnell, Christopher J.] Boston Univ, Div Cardiol, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 39 EP 39 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394300174 ER PT J AU Patel, HH Head, BP Lesnefsky, EJ Jennings, M Pearl, JN Headrick, JP Rothstein, ER Niesman, IR Roth, DM Farquhar, MG Balaban, RS Insel, PA AF Patel, Hernal H. Head, Brian P. Lesnefsky, Edward J. Jennings, Michelle Pearl, Jason N. Headrick, John P. Rothstein, Emily R. Niesman, Ingrid R. Roth, David M. Farquhar, Marilyn G. Balaban, Robert S. Insel, Paul A. TI Caveolae and mitochondria: a subcellular symbiotic relationship that facilitates cardiac myocyte function SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Patel, Hernal H.; Head, Brian P.; Jennings, Michelle; Niesman, Ingrid R.; Roth, David M.; Farquhar, Marilyn G.; Insel, Paul A.] Univ Calif San Diego, La Jolla, CA 92093 USA. [Lesnefsky, Edward J.] Case Western Reserve Univ, Louis Stokes VA Med Ctr, Cleveland, OH 44106 USA. [Pearl, Jason N.; Headrick, John P.] Griffith Univ, Heart Fdn Res Ctr, Brisbane, Qld 4111, Australia. [Rothstein, Emily R.; Balaban, Robert S.] NIH, NHLBI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 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 OCT 16 PY 2007 VL 116 IS 16 SU S BP 40 EP 41 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394300180 ER PT J AU Moens, AL Tocchetti, CG Beep, D Chalir, K Scollick, C Kaminski, P Champion, HC Biswal, SS Wolin, MS Mitchell, JB Kass, D AF Moens, An L. Tocchetti, Carlo G. Beep, Djahida Chalir, Khalid Scollick, Catherine Kaminski, Pawel Champion, Hunter C. Biswal, Shyam S. Wolin, Michael S. Mitchell, Jim B. Kass, David TI Efficacy of targeting enos-generated oxidant stress to reverse cardiac pressure-overload induced hypertrophy SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Moens, An L.; Tocchetti, Carlo G.; Beep, Djahida; Chalir, Khalid; Scollick, Catherine; Champion, Hunter C.; Biswal, Shyam S.; Kass, David] Johns Hopkins Med Inst, Baltimore, MD USA. [Kaminski, Pawel; Wolin, Michael S.] New York Med Coll, Valhalla, NY 10595 USA. [Mitchell, Jim B.] Natl Inst Hlth, Bethesda, MD 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 53 EP 53 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394300234 ER PT J AU Graham, DR Younes, A Lyashkov, A Sheydina, A Volkova, M Mitsak, M Vmogradova, T Ruknudin, A Boheler, K Van Eylk, J Lakatta, E AF Graham, David R. Younes, Antoine Lyashkov, Alexey Sheydina, Anna Volkova, Maria Mitsak, Megan Vmogradova, Tatiana Ruknudin, Abdul Boheler, Kenneth Van Eylk, Jennifer Lakatta, Edward TI Sinoatrial nodal pacemaker cells (SANC) exhibit high basal CA activated adenylyl cyclase (AC) activity and express multiple distinctly localized AC types SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Graham, David R.; Mitsak, Megan; Van Eylk, Jennifer] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Younes, Antoine; Lyashkov, Alexey; Sheydina, Anna; Vmogradova, Tatiana; Ruknudin, Abdul; Boheler, Kenneth; Lakatta, Edward] NIA, Gerontol Res Ctr, NIH, LCS, Bethesda, MD 20892 USA. [Volkova, Maria] Yale Univ, New Haven, CT 06520 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 BP 83 EP 84 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394300371 ER PT J AU Tan, SY Leatherbury, L Rosenthal, J Zhao, XQ Lo, CW AF Tan, Serena Y. Leatherbury, Linda Rosenthal, Julie Zhao, Xiao-Qing Lo, Cecilia W. TI A mouse model of primary ciliary dyskinesia reveals high frequencies of heterotaxy and complex congenital heart defects SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Tan, Serena Y.; Rosenthal, Julie; Zhao, Xiao-Qing; Lo, Cecilia W.] NHLBI, NIH, Bethesda, MD USA. [Leatherbury, Linda] Childrens Natl Med Ctr, Washington, DC 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 BP 83 EP 83 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394300368 ER PT J AU Sirenko, SG Lyashkov, AE Yang, DM Lakatta, EG Vinogradova, TM AF Sirenko, Syevda G. Lyashkov, Alexey E. Yang, Dongmei Lakatta, Edward G. Vinogradova, Tatiana M. TI Differences in sarcoplasmic reticulum Ca2+ loading and spontaneous Ca2+ release in permeabilized sinoatrial nodal and ventricular myocytes: Effect of cAMP SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Sirenko, Syevda G.; Lyashkov, Alexey E.; Yang, Dongmei; Lakatta, Edward G.; Vinogradova, Tatiana M.] NIA, NIH, Gerontol Res Ctr, LCS, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 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 OCT 16 PY 2007 VL 116 IS 16 SU S BP 85 EP 85 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394300377 ER PT J AU Li, Y Sirenko, SG Vinogradova, TM Lyashkov, AE Zhu, WZ Juhaszova, M Ziman, B Wang, S Lakatta, EG AF Li, Yue Sirenko, Syevda G. Vinogradova, Tatiana M. Lyashkov, Alexey E. Zhu, Weizhong Juhaszova, Magdalena Ziman, Bruce Wang, So Lakatta, Edward G. TI High basal Ca2+/calmodulin kinase II activity modulates spontaneous sarcoplasmic reticulum Ca2+ cycling that drives normal automaticity in sinoatrial nodal cells SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Li, Yue; Sirenko, Syevda G.; Vinogradova, Tatiana M.; Lyashkov, Alexey E.; Zhu, Weizhong; Juhaszova, Magdalena; Ziman, Bruce; Wang, So; Lakatta, Edward G.] NIA, NIH, Cardiovasc Sci Lab, Intramural Res Program, Bethesda, MD 20892 USA. NR 0 TC 4 Z9 4 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 86 EP 87 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394300382 ER PT J AU Cimato, TR Beers, J Ding, S Ma, M Tesar, P Mccoy, JP Mckay, R Boehm, M Nalbel, E AF Cimato, Thomas R. Beers, Jeanette Ding, Shunli Ma, Mingchao Tesar, Paul Mccoy, J. Philip Mckay, Ron Boehm, Manfred Nalbel, Elizabeth TI Neuropilin 1 identifies endothelial precursors in murine and human embryonic stem cells prior to CD34 expression SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Cimato, Thomas R.; Beers, Jeanette; Ding, Shunli; Ma, Mingchao; Tesar, Paul; Mccoy, J. Philip; Mckay, Ron; Boehm, Manfred; Nalbel, Elizabeth] Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 135 EP 135 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394300602 ER PT J AU Chopra, N Kannankeril, PJ Yang, T Hlaing, T Holinstat, IA Ettensohn, K Pfeifer, K Akin, B Jones, LR Franzini-Armstrong, C Knollmann, BC AF Chopra, Nagesh Kannankeril, Prince J. Yang, Tao Hlaing, Thinn Holinstat, Izabela A. Ettensohn, Kristen Pfeifer, Karl Akin, Brandy Jones, Larry R. Franzini-Armstrong, Clara Knollmann, Bjorn C. TI Reduction of cardiac calsequestrin increases sarcoplasmic reticulum Ca2+-Leak independent of luminal Ca2+ and triggers ventricular Arrhythmias in mice SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Chopra, Nagesh; Kannankeril, Prince J.; Yang, Tao; Holinstat, Izabela A.; Knollmann, Bjorn C.] Vanderbilt Univ, Sch Med, Nashville, TN 37212 USA. [Hlaing, Thinn] Washington Hosp Ctr, Washington, DC 20010 USA. [Ettensohn, Kristen; Pfeifer, Karl] NIH, NICHD, Bethesda, MD 20892 USA. [Akin, Brandy; Jones, Larry R.] Indiana Univ, Krannert Inst Cardiol, Indianapolis, IN 46204 USA. [Franzini-Armstrong, Clara] Univ Penn, Philadelphia, PA 19104 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 153 EP 153 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394300678 ER PT J AU Das, S Murphy, E Steenbergen, C AF Das, Samarjit Murphy, Elizabeth Steenbergen, Charles TI The cardioprotective effect of glycogen synthase kinase-3 beta (gsk-3 beta) inhibitors involves inhibition of mitochondrial adenine nucleotide transport SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Das, Samarjit; Steenbergen, Charles] Johns Hopkins Univ, Baltimore, MD USA. [Murphy, Elizabeth] NHLBI, Cardiac Physiol Sect, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 165 EP 166 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394300733 ER PT J AU Maltsev, VA Zahanich, I Maltseva, LA Tarasova, YS Li, JL Boheler, KR Stern, MD Lakatta, EG AF Maltsev, Victor A. Zahanich, Ihor Maltseva, Larissa A. Tarasova, Yelena S. Li, Jinliang Boheler, Kenneth R. Stern, Michael D. Lakatta, Edward G. TI L-type Ca2+ current synchronizes local intracellular C-a2+ oscillators which trigger rhythmic action potentials in developing cardiomyocytes SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Maltsev, Victor A.; Zahanich, Ihor; Maltseva, Larissa A.; Tarasova, Yelena S.; Li, Jinliang; Boheler, Kenneth R.; Stern, Michael D.; Lakatta, Edward G.] NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 186 EP 186 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394300825 ER PT J AU Zahanich, I Sirenko, SG Tarasova, YS Li, JL Boheler, KR Stern, MD Lakatta, EG Maltsev, VA AF Zahanich, Ihor Sirenko, Syevda G. Tarasova, Yelena S. Li, Jinliang Boheler, Kenneth R. Stern, Michael D. Lakatta, Edward G. Maltsev, Victor A. TI Local diastolic Ca2+ release and Na+/Ca2+ exchange trigger spontaneous action potentials in developing cardiac cells: a minor role of I-f SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Zahanich, Ihor; Sirenko, Syevda G.; Tarasova, Yelena S.; Li, Jinliang; Boheler, Kenneth R.; Stern, Michael D.; Lakatta, Edward G.; Maltsev, Victor A.] NIA, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 186 EP 186 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394300827 ER PT J AU Melenovsky, V Chantler, PD Majidi, F Ferucci, L Kass, DA Lakatta, EG Najjar, SS AF Melenovsky, Vojtech Chantler, Paul D. Majidi, Farzad Ferucci, Luigi Kass, David A. Lakatta, Edward G. Najjar, Samer S. TI Metabolic syndrome is characterized by ventriculo-arterial mismatch with disproportionate increase of end-systolic ventricular stiffness SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Melenovsky, Vojtech] Inst Clin & Expt Med, IKEM, Prague, Czech Republic. [Chantler, Paul D.; Ferucci, Luigi; Lakatta, Edward G.; Najjar, Samer S.] NIA, NIH, Bethesda, MD 20892 USA. [Majidi, Farzad] Harbor Hosp, Baltimore, MD USA. [Kass, David A.] Johns Hopkins Univ, Baltimore, MD 21218 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 BP 190 EP 190 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394300845 ER PT J AU Adler, E Bystrup, A Saebo, K Mani, V Giovannone, S Young, W Frank, J Weinmann, J Keller, G Fayad, Z AF Adler, Eric Bystrup, Anne Saebo, Karen Mani, Venketesh Giovannone, Steve Young, Wilson Frank, Joseph Weinmann, Joachim Keller, Gordon Fayad, Zahi TI Gadofluorine M-Cy 3, a novel paramegnetic contrast agent for the in vivo and histolgical identification of transplanted cells SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Adler, Eric; Bystrup, Anne; Saebo, Karen; Mani, Venketesh; Young, Wilson; Fayad, Zahi] Mt Sinai, New York, NY USA. [Giovannone, Steve] NYU, Sch Med, New York, NY USA. [Frank, Joseph] Natl Inst Hlth, Bethesda, MD USA. [Weinmann, Joachim] Schering AG, Berlin, Germany. [Keller, Gordon] Univ Toronto, Toronto, ON, Canada. RI Mani, Venkatesh/B-8939-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 MA 1105 BP 221 EP 222 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394301032 ER PT J AU Chavalkis, E Carmona, G Chavakis, T Zeiher, AM Dimmeler, S AF Chavalkis, Emmanouil Carmona, Guillaume Chavakis, Triantafyllos Zeiher, Andreas M., III Dimmeler, Stefanie TI Role of PI3K gamma for integrin-dependent adhesive and migratory functions of progenitor cells in vitro and in vivo SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Chavakis, Triantafyllos] NIH, Natl Canc Inst, Bethesda, MD USA. [Zeiher, Andreas M., III] Univ Frankfurt, Dept Internal Med, Frankfurt, Germany. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 MA 1130 BP 227 EP 227 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394301057 ER PT J AU Larsen, BT Miura, H Myers, CR Campbell, WB Zeldin, DC Gutterman, DD AF Larsen, Brandon T. Miura, Hiroto Myers, Charles R. Campbell, William B. Zeldin, Darryl C. Gutterman, David D. TI Hydrogen peroxide modulates bioavailability of epoxyeicosatrienoic acids in the human coronary microcirculation by directly inhibiting cytochrome p450 epoxygenases SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Larsen, Brandon T.; Miura, Hiroto; Myers, Charles R.; Campbell, William B.; Gutterman, David D.] Med Coll Wisconsin, Milwaukee, WI USA. [Zeldin, Darryl C.] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 1136 BP 229 EP 229 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394301063 ER PT J AU Kurobe, H Urata, M Izawa, Y Fukuhara, Y Kanbara, T Aihara, K Akaike, M Gonzalez, F Matsumoto, T Tamaki, T Kitagawa, T Yoshizumi, M Tomita, S AF Kurobe, Hirotsugu Urata, Masahisa Izawa, Yuki Fukuhara, Yayoi Kanbara, Tamotsu Aihara, Kenichi Akaike, Masashi Gonzalez, Frank Matsumoto, Toshio Tamaki, Toshiaki Kitagawa, Tetsuya Yoshizumi, Masanori Tomita, Shuhei TI Hif-1 alpha in T cells pathway plays a crucial role in the progression of arteriosclerosis and artery intimal thickening SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Kurobe, Hirotsugu; Urata, Masahisa; Izawa, Yuki; Fukuhara, Yayoi; Kanbara, Tamotsu; Aihara, Kenichi; Akaike, Masashi; Matsumoto, Toshio; Tamaki, Toshiaki; Kitagawa, Tetsuya; Yoshizumi, Masanori] Univ Tokushima, Grad Sch, IHBS, Tokushima, Japan. [Gonzalez, Frank] NIH, Bethesda, MD USA. [Tomita, Shuhei] Univ Tokushima, Inst Genom Res, Tokushima, Japan. RI KUROBE, Hirotsugu/E-6982-2011 OI KUROBE, Hirotsugu/0000-0002-5789-5402 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 MA 1211 BP 246 EP 246 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394301138 ER PT J AU Sethi, AA Maureen, S Warnick, R Muniz, N Nordestgaard, BG Tybjaerg-Hansen, A Remaley, AT AF Sethi, Amar A. Maureen, Sampson Warnick, Russel Muniz, Nehemias Nordestgaard, Boerge G. Tybjaerg-Hansen, Anne Remaley, Alan T. TI Composition analysis of high density lipoproteins in patients with extreme HDL-C levels with or without ischemic heart disease SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Sethi, Amar A.; Remaley, Alan T.] VMB, NHLBI, Natl Inst Hlth, Bethesda, MD USA. [Maureen, Sampson] Natl Inst Hlth, Bethesda, MD USA. [Warnick, Russel] Berkeley Heart Lab, Burlingame, CA USA. [Muniz, Nehemias] Quantimetrix, Rodendo Beach, CA USA. [Nordestgaard, Boerge G.] Herlev Univ Hosp, Herlev, Denmark. [Tybjaerg-Hansen, Anne] Copenhagen Univ Hosp, Copenhagen, Denmark. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 1390 BP 285 EP 285 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394301317 ER PT J AU Imig, JD Lee, CR Bradbury, A Graves, JP DeGraff, LM Foley, J Zeldin, DC AF Imig, John D. Lee, Craig R. Bradbury, Alyce Graves, Joan P. DeGraff, Laura M. Foley, Julie Zeldin, Darryl C. TI CYP2J2 endothelial overexpression increases nitric oxide and cyclooxygenase independent renal dilation and attenuates endothelin-1 vasoconstriction SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Imig, John D.] Med Coll Georgia, Augusta, GA USA. [Lee, Craig R.] Univ N Carolina, Chapel Hill, NC USA. [Bradbury, Alyce; Graves, Joan P.; DeGraff, Laura M.; Foley, Julie; Zeldin, Darryl C.] Natl Inst Hlth, Res Triangle Pk, NC 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 1436 BP 295 EP 296 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394301363 ER PT J AU Kohler, JJ Hosseini, S Day, B Saada, A Elpeleg, O Copeland, W Lewis, W AF Kohler, James J. Hosseini, Seyed Day, Brian Saada, Ann Elpeleg, Orly Copeland, William Lewis, William TI Cardiac targeted transgenic models of mutations in TK2 or Pol gamma genes result in ultrastructural changes in mitochondria and cardiac hypertrophy SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Kohler, James J.; Hosseini, Seyed; Lewis, William] Emory Univ, Sch Med, Atlanta, GA 30322 USA. [Day, Brian] Natl Jewish Med Ctr, Denver, CO USA. [Saada, Ann; Elpeleg, Orly] Hadassah Univ, Med Ctr, Jerusalem, Israel. [Copeland, William] Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 1473 BP 303 EP 304 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394301399 ER PT J AU Sun, JH Steenbergen, C Murphy, E AF Sun, Junhui Steenbergen, Charles Murphy, Elizabeth TI Preconditioning with s-nitrosoglutathione (GSNO) results in s-nitrosylation and altered activity of the sarcoplasmic reticulum Ca2+-ATPase (SERCA) and the mitochondrial F1-ATPase SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Sun, Junhui; Murphy, Elizabeth] NHLBI, NIH, Bethesda, MD 20892 USA. [Steenbergen, Charles] Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 1486 BP 306 EP 306 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394301412 ER PT J AU Wong, R Murphy, E AF Wong, Renee Murphy, Elizabeth TI Inhibition of endosomal trafficking alters PC-mediated phosphorylation and expression of ATP synthase, complex I, PDH, and 3-ketoacyl-CoA-thiolase SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Wong, Renee; Murphy, Elizabeth] NIH, 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 1488 BP 307 EP 307 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394301414 ER PT J AU Mukhopadhyay, P Rajesh, M Batkai, S Hasko, G Szabo, C Liaudet, L Pacher, P AF Mukhopadhyay, Partha Rajesh, Mohanraj Batkai, Sandor Hasko, Gyorgy Szabo, Csaba Liaudet, Lucas Pacher, Pal TI Role of superoxide, nitric oxide and peroxynitrite in doxorubicin-induced cell death in vitro and in vivo SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Mukhopadhyay, Partha; Rajesh, Mohanraj; Batkai, Sandor] NIH, Rockville, MD USA. [Hasko, Gyorgy; Szabo, Csaba] Univ Med & Dent New Jersey, New Jersey Med Sch, Newark, NJ 07103 USA. [Liaudet, Lucas] Univ Hosp, Lausanne, Switzerland. [Pacher, Pal] NIH, Rockville, MD USA. RI Batkai, Sandor/G-3889-2010; Batkai, Sandor/H-7983-2014; Liaudet, Lucas/E-1322-2017 OI Liaudet, Lucas/0000-0003-2670-4930 NR 0 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 BP 420 EP 420 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394301867 ER PT J AU Williams, IA Atz, AM Cnota, JF Cohen, MS Colan, SD Gersony, WM Lu, M Margossian, RE Newburger, JW Powell, AJ Sleeper, LA Stephenson, EA Stylianou, M Williams, RV Hsu, DT AF Williams, Ismee A. Atz, Andrew M. Cnota, James F. Cohen, Meryl S. Colan, Steven D. Gersony, Welton M. Lu, Minmin Margossian, Renee E. Newburger, Jane W. Powell, Andrew J. Sleeper, Lynn A. Stephenson, Elizabeth A. Stylianou, Mario Williams, Richard V. Hsu, Daphne T. TI Predictors of functional status following Fontan palliation: Development of a Fontan functional SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Williams, Ismee A.; Gersony, Welton M.; Hsu, Daphne T.] Columbia Univ, Coll Phys & Surg, New York, NY USA. [Atz, Andrew M.] Med Univ S Carolina, Charleston, SC 29425 USA. [Cnota, James F.] Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. [Cohen, Meryl S.] Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. [Colan, Steven D.; Margossian, Renee E.; Newburger, Jane W.; Powell, Andrew J.] Childrens Hosp, Boston, MA 02115 USA. [Lu, Minmin; Sleeper, Lynn A.] New England Res Inst, Watertown, MA 02172 USA. [Stephenson, Elizabeth A.] Hosp Sick Children, Toronto, ON M5G 1X8, Canada. [Stylianou, Mario] NHLBI, Bethesda, MD 20892 USA. [Williams, Richard V.] Primary Childrens Med Ctr, Salt Lake City, UT 84103 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 479 EP 479 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394302208 ER PT J AU Dham, N Sable, C Minnitti, CP Campbell, A Arleta, M Winne, G Rana, S Darbari, D Oneykwere, O Kato, GJ Gladwin, MT Castro, OL Gordeuk, VR Ensing, G AF Dham, Niti Sable, Craig Minnitti, Caterina P. Campbell, Andrew Arleta, Manuel Winne, Glenna Rana, Sohail Darbari, Deepika Oneykwere, Onyinye Kato, Gregory J. Gladwin, Mark T. Castro, Oswaldo L. Gordeuk, Victor R. Ensing, Gregory TI Prospective correlation of Echocardiography findings with hematologic and pulmonary function parameters in children with sickle cell disease SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Dham, Niti; Sable, Craig; Minnitti, Caterina P.; Winne, Glenna; Darbari, Deepika] Childrens Natl Med Ctr, Washington, DC 20010 USA. [Campbell, Andrew; Arleta, Manuel; Ensing, Gregory] Univ Michigan, Ann Arbor, MI 48109 USA. [Rana, Sohail; Oneykwere, Onyinye; Castro, Oswaldo L.; Gordeuk, Victor R.] Howard Univ, Washington, DC 20059 USA. [Gladwin, Mark T.] NIH, Bethesda, MD USA. RI Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 MA 2303 BP 503 EP 503 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394302306 ER PT J AU Merz, CB Olson, M McClure, C Symons, J Sopko, G Kelsey, S Handberg-Thurmond, E Johnson, BD Cooper-DeHoff, R Sharaf, B Rogers, W Pepine, C AF Merz, C. Bailey Olson, Marian McClure, Candace Symons, James Sopko, George Kelsey, Sheryl Handberg-Thurmond, Eileen Johnson, B. Delia Cooper-DeHoff, Rhonda Sharaf, Barry Rogers, Williams Pepine, Carl TI A randomized controlled trial of low dose hormone therapy on myocardial ischemia in postmenopausal women with no obstructive coronary artery disease: Results from the NHLBI-sponsored WISE SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Merz, C. Bailey] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Olson, Marian; McClure, Candace; Johnson, B. Delia] Univ Pittsburgh, Pittsburgh, PA USA. [Symons, James] Med Pharmaceut, Ann Arbor, MI USA. [Sopko, George] NHLBI, Bethesda, MD 20892 USA. [Kelsey, Sheryl] Univ So Calif, Pittsburgh, PA USA. [Handberg-Thurmond, Eileen; Cooper-DeHoff, Rhonda] Univ Florida, Gainesville, FL USA. [Sharaf, Barry] Brown Univ, Providence, RI 02912 USA. [Rogers, Williams] Univ Alabama, Birmingham, AL 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 2450 BP 539 EP 539 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394302452 ER PT J AU George, RT Lardo, AC Kitagawa, K Yousuf, O Chang, HJ Arbab-Zadeh, A Miller, JM Bluernke, DA Lima, JA AF George, Richard T. Lardo, Albert C. Kitagawa, Kakuya Yousuf, Omair Chang, Hyuk-Jae Arbab-Zadeh, Armin Miller, Julie M. Bluernke, David A. Lima, Joao A. TI Combined perfusion and non-invasive coronary angiography in patients with suspected coronary disease using 256 row, 0.5 mm slice thickness non-helical multi-detector computed tomography SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [George, Richard T.; Lardo, Albert C.; Kitagawa, Kakuya; Chang, Hyuk-Jae; Arbab-Zadeh, Armin; Miller, Julie M.; Bluernke, David A.; Lima, Joao A.] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Yousuf, Omair] NIH, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 2589 BP 573 EP 573 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394302591 ER PT J AU Plehn, JF Horton, K Ernst, I DiProspero, NA AF Plehn, Jonathan F. Horton, Ken Ernst, Inez DiProspero, Nicholas A. TI Genomic, proteomic and functional associations with left ventricular mass in a young cohort with Friedreich's ataxia SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Plehn, Jonathan F.; Ernst, Inez] Natl Heart Lung & Blood Inst, Bethesda, MD USA. [Horton, Ken] MedStar Res Inst, Washington, DC USA. [DiProspero, Nicholas A.] Natl Inst Neurol Disorders & Stroke, Bethesda, MD 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 2735 BP 607 EP 607 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394302736 ER PT J AU Lang, I Forman, SA Maggiohi, AP Ruzyllo, W Vozzi, C Renkin, J Steg, PG Hemandez-Gardia, JM Zmudka, K Jimenez-Navarro, M Sopko, G Lamas, GA Hochman, JS AF Lang, Irene Forman, Sandra A. Maggiohi, Aldo P. Ruzyllo, Witold Vozzi, Carlos Renkin, Jean Steg, P. G. Hemandez-Gardia, Jose Maria Zmudka, Krzysztof Jimenez-Navarro, Manuel Sopko, George Lamas, Gervasio A. Hochman, Judith S. TI Causes of death in early MI survivors with persistent vessel occlusion: Results from the occluded artery trial (OAT) SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Lang, Irene] Med Univ Vienna, Vienna, Austria. [Forman, Sandra A.] Maryland Med Res Inst, Baltimore, MD USA. [Maggiohi, Aldo P.] Italina Assoc Hosp Cardiol Res Ctr, Florence, Italy. [Ruzyllo, Witold] Natl Inst Cardiol, Warsaw, Poland. [Vozzi, Carlos] Inst Intervencion Cardiovasc SA, Rosario, Argentina. [Renkin, Jean] Clin Univ St Luc, Brussels, Belgium. [Steg, P. G.] Univ Paris 07, Ctr Hosp Bichat Claude Bernard, Paris, France. [Hemandez-Gardia, Jose Maria; Jimenez-Navarro, Manuel] Univ Virgen Victoria Malaga, Hosp & Clin, Malaga, Spain. [Zmudka, Krzysztof] Jan Pawel 2 Hosp, Int Cardiol Clin, Krakow, Poland. [Sopko, George] NHLBI, Bethesda, MD USA. [Lamas, Gervasio A.] Mt Sinai Med Ctr, Miami Beach, FL USA. [Hochman, Judith S.] NYU, Sch Med, New York, NY USA. RI Winter, Max/E-8456-2011 NR 0 TC 0 Z9 0 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 2813 BP 625 EP 625 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394302812 ER PT J AU Hsia, J Jablonski, KA Rice, MM Sabatine, MS Maggioni, AP Cuddy, TE Domanski, MJ Geller, NL Flaker, G Solomon, S Gersh, BJ Rouleau, JL Braunwald, E Pfeffer, MA AF Hsia, Judith Jablonski, Kathleen A. Rice, Madeline M. Sabatine, Marc S. Maggioni, Aldo P. Cuddy, Thomas E. Domanski, Michael J. Geller, Nancy L. Flaker, Greg Solomon, Scott Gersh, Bernard J. Rouleau, Jean L. Braunwald, Eugene Pfeffer, Marc A. TI Sudden cardiac death in patients with stable coronary disease and preserved left ventricular systolic function SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Hsia, Judith] George Washington Univ, Washington, DC USA. [Jablonski, Kathleen A.; Rice, Madeline M.] George Washington Univ, Rockville, MD USA. [Sabatine, Marc S.; Solomon, Scott; Braunwald, Eugene; Pfeffer, Marc A.] Brigham & Womens Hosp, Harvard Med Sch, Boston, MA 02115 USA. [Sabatine, Marc S.] Univ Texas Hlth Sci Ctr San Antonio, San Antonio, TX USA. [Maggioni, Aldo P.] ANMCO Res Ctr, Florence, Italy. [Cuddy, Thomas E.] Univ Manitoba, Winnipeg, MB, Canada. [Domanski, Michael J.; Geller, Nancy L.] NHLBI, Bethesda, MD 20892 USA. [Flaker, Greg] Univ Missouri, Columbia, MO USA. [Gersh, Bernard J.] Mayo Clin Fdn, Rochester, MN USA. [Rouleau, Jean L.] Univ Montreal, Montreal, PQ, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 2874 BP 640 EP 640 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394302873 ER PT J AU Carson, P White, M Anand, I Plehn, J Gottlieb, S Silver, M Lindenfeld, J O'Connor, C Miller, A Fiuzat, M Liggett, SB Davis, G Robertson, AD Bristow, MR AF Carson, Peter White, Michel Anand, Inder Plehn, Jonathan Gottlieb, Stephen Silver, Marc Lindenfeld, Joann O'Connor, Christopher Miller, Alan Fiuzat, Mona Liggett, Stephen B. Davis, Gordon Robertson, Alastair D. Bristow, Michael R. TI Effect of beta(1) 389 Arg/Gly alpha(2c) 322-325 Wt/Del genotypes on adjudicated hospitalizations in the BEST trial SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Carson, Peter] Washington VAMC, Washington, DC USA. [White, Michel] Montreal Heart Inst, Montreal, PQ H1T 1C8, Canada. [Anand, Inder] Univ Minnesota, Minneapolis, MN USA. [Plehn, Jonathan] NHLBI, Rockville, MD USA. [Gottlieb, Stephen] Univ Maryland, College Pk, MD 20742 USA. [Silver, Marc] Advocate Christ Med Ctr, Oak Lawn, IL USA. [Lindenfeld, Joann; Robertson, Alastair D.; Bristow, Michael R.] Univ Colorado, Hlth Sci Ctr, Denver, CO 80202 USA. [O'Connor, Christopher] Duke Univ, Durham, NC USA. [Miller, Alan] Univ Florida, Hlth Sci Ctr, Jacksonville, FL 32209 USA. [Fiuzat, Mona] ARCA Discovery, Denver, CO USA. [Liggett, Stephen B.] Univ Cincinnati, Cincinnati, OH USA. [Davis, Gordon] ARCA Discovery, Denver, CO USA. RI bristow, michael/G-7850-2011; liggett, stephen/E-7453-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 649 EP 649 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303011 ER PT J AU Agnetti, G Elliott, ST Kane, LA Yung, C Chakir, K Samantapudi, D Guamieri, C Caldarera, CM Kass, DA Van Eyk, JE AF Agnetti, Giulio Elliott, Steven T. Kane, Lesley A. Yung, Christina Chakir, Khalid Samantapudi, Daya Guamieri, Carlo Caldarera, Claudio M. Kass, David A. Van Eyk, Jennifer E. TI Effects of cardiac resynchronization therapy on the mitochondrial proteome in a canine model of heart failure SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Agnetti, Giulio; Elliott, Steven T.; Kane, Lesley A.; Yung, Christina; Van Eyk, Jennifer E.] NHLBI, Hopkins Proteom Ctr, Baltimore, MD USA. [Chakir, Khalid; Samantapudi, Daya; Kass, David A.] Johns Hopkins Univ, Baltimore, MD 21218 USA. [Guamieri, Carlo; Caldarera, Claudio M.] Univ Bologna, I-40126 Bologna, Italy. NR 0 TC 1 Z9 1 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 OCT 16 PY 2007 VL 116 IS 16 SU S MA 2973 BP 664 EP 664 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303072 ER PT J AU Chuang, ML Gona, P Salton, CJ Oyama, N Blease, SJ Levy, D O'Donnell, CJ Manning, WJ AF Chuang, Michael L. Gona, Philimon Salton, Carol J. Oyama, Noriko Blease, Susan J. Levy, Daniel O'Donnell, Christopher J. Manning, Warren J. TI Elevated fasting glucose in non-diabetic persons is associated with increased left ventricular mass and wall thickness in women but not men: The Framingham heart study SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Chuang, Michael L.; Salton, Carol J.; Oyama, Noriko; Manning, Warren J.] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA. [Gona, Philimon] Boston Univ, Boston, MA 02215 USA. [Blease, Susan J.; Levy, Daniel; O'Donnell, Christopher J.] NHLBI Framingham Heart Study, Framingham, MA USA. RI Oyama-Manabe, Noriko/A-5212-2012 NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 670 EP 671 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303096 ER PT J AU Sachdev, V Matura, LA Sidenko, S Ho, V Arai, A Rosing, DR Bondy, C AF Sachdev, Vandana Matura, Lea Ann Sidenko, Stanislav Ho, Vincent Arai, Andrew Rosing, Douglas R. Bondy, Carolyn TI Prevalence of bicuspid aortic valve in Turner syndrome SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Sachdev, Vandana; Matura, Lea Ann; Sidenko, Stanislav; Ho, Vincent; Arai, Andrew; Rosing, Douglas R.; Bondy, Carolyn] NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 3189 BP 717 EP 717 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303286 ER PT J AU Aletras, AH Kellman, P Mohanty, BD Hoyt, RF Arai, AE AF Aletras, Anthony H. Kellman, Peter Mohanty, Bibhu D. Hoyt, Robert F., Jr. Arai, Andrew E. TI Quantitative in vivo T2 measurements differentiate both infarcted and peri-infarct from normal myocardium SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Aletras, Anthony H.; Kellman, Peter; Mohanty, Bibhu D.; Hoyt, Robert F., Jr.; Arai, Andrew E.] Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 MA 3363 BP 758 EP 758 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303458 ER PT J AU Schelbert, EB Mohanty, BD Anderson, SA Hsu, LY Karim, SM Aletras, AH Kellman, P Arai, AE AF Schelbert, Erik B. Mohanty, Bibhu D. Anderson, Stasia A. Hsu, Li-Yueh Karim, Syed M. Aletras, Anthony H. Kellman, Peter Arai, Andrew E. TI MRI delayed enhancement identities cardiac fibrosis after myocardial infarction at the cellular level in ex vivo rat heart SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Schelbert, Erik B.; Mohanty, Bibhu D.; Anderson, Stasia A.; Hsu, Li-Yueh; Karim, Syed M.; Aletras, Anthony H.; Kellman, Peter; Arai, Andrew E.] NHLBI, Bethesda, MD 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 3365 BP 759 EP 759 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303460 ER PT J AU Farasat, SM Morrell, CH Scuteri, A Ting, CT Yin, FC Spurgeon, HA Chen, CH Lakatta, EG Najjar, SS AF Farasat, S. Morteza Morrell, Christopher H. Scuteri, Angelo Ting, Chih-Tai Yin, Frank C. Spurgeon, Harold A. Chen, Chen-Huan Lakatta, Edward G. Najjar, Samer S. TI Pulse pressure is inversely related to aortic root diameter: Implications for the pathogenesis of systolic hypertension SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Farasat, S. Morteza; Morrell, Christopher H.; Spurgeon, Harold A.; Lakatta, Edward G.; Najjar, Samer S.] NIA, NIH, Bethesda, MD 20892 USA. [Scuteri, Angelo] Ist Nazl Ricovero E Cura Anziari, Rome, Italy. [Ting, Chih-Tai; Chen, Chen-Huan] Natl Yang Ming Univ, Taipei, Taiwan. [Yin, Frank C.] Washington Univ, St Louis, MO 63130 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 3431 BP 775 EP 775 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303526 ER PT J AU Koh, KK Quon, MJ Han, SH Chung, WJ AF Koh, Kwang K. Quon, Michael J. Han, Seung H. Chung, Wook-Jin TI Amlodipine improves endothelial function and metabolic parameters in patients with hypertension SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Koh, Kwang K.; Chung, Wook-Jin] Gachon Univ, Inchon, South Korea. [Quon, Michael J.] NIH, Diabet Unit, Bethesda, MD USA. RI Quon, Michael/B-1970-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 3429 BP 775 EP 775 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303524 ER PT J AU Hoffmann, U Massaro, JM Fox, CS Manders, E O'Donnell, CJ AF Hoffmann, Udo Massaro, Joseph M. Fox, Caroline S. Manders, Emily O'Donnell, Christopher J. TI Formal comparison between absolute and relative cut points for coronary artery calcification in at intermediate risk community-based men and women: The Framingham heart study SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Hoffmann, Udo] Massachusetts Gen Hosp, Boston, MA 02114 USA. [Massaro, Joseph M.; Fox, Caroline S.; Manders, Emily; O'Donnell, Christopher J.] NHLBI, Framingham, MA 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 790 EP 790 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303584 ER PT J AU Parikh, NI Hwang, SJ Ingelsson, E Benjamin, EJ Fox, CS Vasan, RS Murabito, JM AF Parikh, Nisha I. Hwang, Shih-Jen Ingelsson, Erik Benjamin, Emelia J. Fox, Caroline S. Vasan, Ramachandran S. Murabito, Joanne M. TI The association of breastfeeding in infancy and adult cardiovascular disease risk factors: The Framingham Third Generation cohort SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Parikh, Nisha I.; Ingelsson, Erik; Murabito, Joanne M.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Hwang, Shih-Jen; Fox, Caroline S.] NHLBI, Framingham Heart Sutdy, Framingham, MA USA. [Benjamin, Emelia J.; Vasan, Ramachandran S.] Boston Univ, Sch Med, Framingham Heart Study, Framingham, MA USA. NR 0 TC 1 Z9 1 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 792 EP 792 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303592 ER PT J AU Nagarajarao, H Taylor, HA Benjamin, EJ Taylor, JK Sarpong, D Akyllbekova, EL Steffes, M Salahudeen, AK Wilson, JG Fox, C Fox, ER AF Nagarajarao, Harsha Taylor, Herman A. Benjamin, Emelia J. Taylor, Jason K. Sarpong, Daniel Akyllbekova, Ermeg L. Steffes, Michael Salahudeen, Abdullah K. Wilson, James G. Fox, Caroline Fox, Ervin R. TI The relation of C-reactive protein to chronic kidney disease in African Americans: The Jackson heart study SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Nagarajarao, Harsha; Taylor, Herman A.; Taylor, Jason K.; Akyllbekova, Ermeg L.; Fox, Ervin R.] Univ Mississippi, Sch Med, Jackson, MS 39216 USA. Boston Univ, Sch Med, Boston, MA USA. [Sarpong, Daniel] Jackson State Univ, Jackson, MS USA. [Steffes, Michael] Univ Minnesota, Minneapolis, MN USA. [Salahudeen, Abdullah K.] MD Anderson Canc Ctr, Houston, TX USA. [Wilson, James G.] GV Sonny Montegomery Vet Adm, Med Ctr, Jackson, MS USA. [Fox, Caroline] 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 3534 BP 800 EP 800 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303626 ER PT J AU Herrera-Galeano, JE Wilson, AF Faraday, N Yanek, LR Moy, TF Becker, DM Becker, LC AF Herrera-Galeano, J. Enrique Wilson, Alexander F. Faraday, Nauder Yanek, Lisa R. Moy, Taryn F. Becker, Diane M. Becker, Lewis C. TI Genetic contribution to collagen-induced platelet aggregation following low-dose aspirin in families with premature coronary artery disease SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Herrera-Galeano, J. Enrique; Faraday, Nauder; Yanek, Lisa R.; Moy, Taryn F.; Becker, Diane M.; Becker, Lewis C.] Johns Hopkins Med Inst, Baltimore, MD 21205 USA. [Wilson, Alexander F.] NIH, NHGRI, Baltimore, MD 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 BP 807 EP 808 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303661 ER PT J AU Tsao, CW Gona, P Salton, CJ Danias, PG Blease, S Albert, MG Levy, D O'Donnell, CJ Manning, WJ Yeon, SB AF Tsao, Connie W. Gona, Philimon Salton, Carol J. Danias, Peter G. Blease, Susan Albert, Mark G. Levy, Daniel O'Donnell, Christopher J. Manning, Warren J. Yeon, Susan B. TI Unsuspected left ventricular wall motion abnormalities identified by cardiovascular magnetic resonance in a free-living population: Lessons from the framingham heart study SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Tsao, Connie W.; Salton, Carol J.; Manning, Warren J.; Yeon, Susan B.] Beth Israel Deaconess Med Ctr, Harvard Med Sch, Boston, MA 02215 USA. [Gona, Philimon] Boston Univ, NHLBI, Dept Math & Stat, Framingham Heart Study, Boston, MA 02215 USA. [Danias, Peter G.] Tufts Univ, Sch Med, Boston, MA 02111 USA. [Blease, Susan; Levy, Daniel; O'Donnell, Christopher J.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Albert, Mark G.] Michigan State Univ, Coll Human Med, E Lansing, MI 48824 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 BP 809 EP 809 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303666 ER PT J AU Waldstein, SR Rice, SC Thayer, JF Najjar, SS Scuteri, A Zonderman, AB AF Waldstein, Shari R. Rice, S. Carrington Thayer, Julian F. Najjar, Samer S. Scuteri, Angelo Zonderman, Alan B. TI Arterial stiffness is an independent predictor of cognitive decline in the Baltimore longitudinal study of aging SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Waldstein, Shari R.; Rice, S. Carrington] Univ Maryland Baltimore Cty, Baltimore, MD 21228 USA. [Thayer, Julian F.] Ohio State Univ, Columbus, OH 43210 USA. [Najjar, Samer S.; Scuteri, Angelo; Zonderman, Alan B.] NIA, Baltimore, MD 21224 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 810 EP 810 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303672 ER PT J AU Hankinson, A Lloyd-Jones, D Jacobs, D Carnethon, M Lewis, CE Loria, C Sidney, S Liu, K AF Hankinson, Arlene Lloyd-Jones, Donald Jacobs, David Carnethon, Mercedes Lewis, Cora E. Loria, Catherine Sidney, Stephen Liu, Kiang TI Long-term relation of physical activity with maintenance of a stable body mass index over 20 years: the CARDIA study SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Hankinson, Arlene; Lloyd-Jones, Donald; Carnethon, Mercedes; Liu, Kiang] Northwestern Univ, Chicago, IL 60611 USA. [Jacobs, David] Univ Minnesota, Minneapolis, MN USA. [Lewis, Cora E.] Univ Alabama, Birmingham, AL USA. [Loria, Catherine] Natl Heart Lung & Blood Inst, Bethesda, MD USA. [Sidney, Stephen] Kaiser Permanente, Oakland, CA USA. RI Lloyd-Jones, Donald/C-5899-2009 NR 0 TC 0 Z9 0 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 3599 BP 815 EP 815 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303691 ER PT J AU Bahrami, H Kronmal, R Bluemke, DA Olson, J Shea, S Liu, K Burke, GL Lima, JA AF Bahrami, Hossein Kronmal, Richard Bluemke, David A. Olson, Jean Shea, Steven Liu, Kiang Burke, Gregory L. Lima, Joao A. TI Differences in the incidence and predictors of heart failure by racial/ethnic group: Multi-ethnic study of atherosclerosis SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Bahrami, Hossein; Bluemke, David A.; Lima, Joao A.] Johns Hopkins Univ, Baltimore, MD USA. [Kronmal, Richard] Univ Washington, Seattle, WA 98195 USA. [Olson, Jean] Natl Inst Hlth, Bethesda, MD USA. [Shea, Steven] Columbia Univ, New York, NY 10027 USA. [Liu, Kiang] Northwestern Univ, Chicago, IL USA. [Burke, Gregory L.] Wake Forest Univ, Winston Salem, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 828 EP 828 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303742 ER PT J AU Johnson, BD Merz, CNB Azziz, R Braunstein, GD Shaw, LJ Pepine, CJ Sopko, G Kelsey, SF AF Johnson, B. Delia Merz, C. Noel Bairey Azziz, Ricardo Braunstein, Glenn D. Shaw, Leslee J. Pepine, Carl J. Sopko, George Kelsey, Sheryl F. TI Menstrual cycling and mechanisms of cardiovascular disease events in post-menopausal women: Results from the NIH-NHLBI-Sponsored Women's Ischernia Syndrome Evaluation (WISE) SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Johnson, B. Delia; Kelsey, Sheryl F.] Univ Pittsburgh, Pittsburgh, PA 15260 USA. [Merz, C. Noel Bairey; Azziz, Ricardo; Braunstein, Glenn D.] Cedars Sinai Med Ctr, Los Angeles, CA USA. [Shaw, Leslee J.] Emory Univ, Atlanta, GA 30322 USA. [Pepine, Carl J.] Univ Florida, Gainesville, FL USA. [Sopko, George] NIH, Bethesda, MD 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 828 EP 828 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303741 ER PT J AU Oyama, N Gona, P Chuang, ML Jhaveri, RR Salton, CJ Blease, SJ Levy, D Manning, AR O'Donnell, CJ Manning, WJ AF Oyama, Noriko Gona, Philimon Chuang, Michael L. Jhaveri, Rahul R. Salton, Carol J. Blease, Susan J. Levy, Daniel Manning, Anya R. O'Donnell, Christopher J. Manning, Warren J. TI Clinical cardiovascular disease in women is associated with increased epicardial, but not subcutaneous fat thickness SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Oyama, Noriko; Chuang, Michael L.; Jhaveri, Rahul R.; Salton, Carol J.; Manning, Anya R.; Manning, Warren J.] Beth Israel Deaconess Med Ctr, Boston, MA USA. [Gona, Philimon; Blease, Susan J.] Boston Univ, Boston, MA USA. [Levy, Daniel; O'Donnell, Christopher J.] Framingham Heart Dis Epidemiol Study, NHLBI, Framingham, MA USA. RI Oyama-Manabe, Noriko/A-5212-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 828 EP 828 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303740 ER PT J AU Klesges, RC Obarzanek, E Klesges, LM Beech, BM Kumanyika, S McClanahan, B Lanctot, J Relyea, G Murray, D Slawson, D Sherrill-Mittleman, D AF Klesges, Robert C. Obarzanek, Eva Klesges, Lisa M. Beech, Bettina M. Kumanyika, Shiriki. McClanahan, Barbara Lanctot, Jennifer Relyea, George Murray, David Slawson, Debbi Sherrill-Mittleman, Deborah TI The Memphis girls health enrichment multisite studies (GEMS): An evaluation of the long term efficacy of a weight gain prevention intervention in African American girls SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Klesges, Robert C.; Klesges, Lisa M.; Lanctot, Jennifer; Sherrill-Mittleman, Deborah] St Jude Childrens Hosp, Memphis, TN USA. [Obarzanek, Eva] NHLBI, Bethesda, MD USA. [Beech, Bettina M.] Vanderbilt Univ, Nashville, TN USA. [Kumanyika, Shiriki.] Univ Penn, Philadelphia, PA 19104 USA. [McClanahan, Barbara; Lanctot, Jennifer; Relyea, George] Univ Memphis, Memphis, TN 38152 USA. [Murray, David] Ohio State Univ, Columbus, OH USA. [Slawson, Debbi] E Tennessee State Univ, Johnson City, TN USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 843 EP 843 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303800 ER PT J AU Robinson, TN Matheson, DM Kraemer, HC Obarzanek, E Wilson, DM Haskell, WL Pruitt, LA Thompson, NS Haydel, KF Fujimoto, M Varady, A Killen, JD AF Robinson, Thomas N. Matheson, Donna M. Kraemer, Helena C. Obarzanek, Eva Wilson, Darrell M. Haskell, William L. Pruitt, Leslie A. Thompson, Nikko S. Haydel, K. Farish Fujimoto, Michelle Varady, Ann Killen, Joel D. TI Stanford GEMS (Girls health enrichment multisite studies): Long-term efficacy of after-school dance and screen time reduction in low-income African-American girls SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Robinson, Thomas N.; Matheson, Donna M.; Kraemer, Helena C.; Wilson, Darrell M.; Haskell, William L.; Pruitt, Leslie A.; Thompson, Nikko S.; Haydel, K. Farish; Fujimoto, Michelle; Varady, Ann; Killen, Joel D.] Stanford Univ, Stanford, CA 94305 USA. [Obarzanek, Eva] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S BP 843 EP 843 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303801 ER PT J AU Solomon, SD Lin, J Solomon, CG Jablonski, K Rice, MM Steffes, M Domanski, M Hsia, J Gersh, BJ Arnold, JMO Rouleau, J Pfeffer, MA AF Solomon, Scott D. Lin, Julie Solomon, Caren G. Jablonski, Kathleen Rice, Madeline Murguia Steffes, Michael Domanski, Michael Hsia, Judith Gersh, Bernard J. Arnold, J. Malcolm O. Rouleau, Jean Pfeffer, Marc A. TI The influence of albuminuria on mortality in patients with stable coronary artery disease SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Solomon, Scott D.; Lin, Julie; Solomon, Caren G.; Pfeffer, Marc A.] Brigham & Womens Hosp, Harvard Med Sch, Boston, MA USA. [Jablonski, Kathleen; Rice, Madeline Murguia] George Washington Univ, Ctr Biostat, Rockville, MD USA. [Steffes, Michael] Univ Minnesota, Sch Med, Minneapolis, MN USA. [Domanski, Michael] NIH, Bethesda, MD USA. [Hsia, Judith] George Washington Univ, Med Ctr, Washington, DC USA. [Gersh, Bernard J.] Mayo Clin, Rochester, MN USA. [Arnold, J. Malcolm O.] London Hlth Serv Ctr, London, ON, Canada. [Rouleau, Jean] Toronto Gen Hosp, Toronto, ON, Canada. RI Solomon, Scott/I-5789-2013 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 MA 3739 BP 850 EP 850 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303830 ER PT J AU Lovely, RS Massaro, JF D'Agostino, RB Benjamin, EJ Kazmierczak, SC O'Donnell, CJ Farrell, DH AF Lovely, Rehana S. Massaro, Joseph F. D'Agostino, Ralph B., Sr. Benjamin, Emelia J. Kazmierczak, Steven C. O'Donnell, Christopher J. Farrell, David H. TI Association of gamma' fibrinogen with risk factors and prevalent cardiovascular disease in the Framingham Heart Study SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Lovely, Rehana S.; Kazmierczak, Steven C.; Farrell, David H.] Oregon Hlth & Sci Univ, Portland, OR USA. [Massaro, Joseph F.; Benjamin, Emelia J.] Boston Univ, Sch Med, Boston, MA 02118 USA. [D'Agostino, Ralph B., Sr.] Boston Univ, Boston, MA 02215 USA. [O'Donnell, Christopher J.] NHLBI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 3746 BP 852 EP 852 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303837 ER PT J AU Levitzky, YS Massaro, J Fox, CS Manders, E Hoffman, U O'Donnell, CJ AF Levitzky, Yamini S. Massaro, Joe Fox, Caroline S. Manders, Emily Hoffman, Udo O'Donnell, Christopher J. TI Distribution of subclinical aortic atherosclerosis detected as abdominal aortic calcification in the Framingham Heart Study SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Levitzky, Yamini S.] Case Western Reserve Univ, NHLBI, Heart & Vasc Ctr, Framingham Heart Study, Cleveland, OH 44106 USA. [Massaro, Joe] Boston Univ, Dept Math, Boston, MA 02215 USA. [Fox, Caroline S.] Brigham & Womens Hosp, Harvard Med Sch, Dept Med, Div Endocrinol Metab & Diabet,NHLBI, Boston, MA USA. [Manders, Emily] NHLBI, Framingham Heart Study, Framingham, MA USA. [Hoffman, Udo] Massachusetts Gen Hosp, Dept Radiol, Cardiac MR PET CT Program, Boston, MA 02114 USA. [O'Donnell, Christopher J.] Massachusetts Gen Hosp, Harvard Med Sch, NHLBI, Dept Med,Cardiol Div,Framingham Heart Study, Boston, MA 02114 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 3754 BP 853 EP 854 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303845 ER PT J AU Parikh, N Hwang, SJ Larson, MG Hoffmann, U Levy, D O'Donnell, CJ Fox, CS AF Parikh, Nisha Hwang, Shih-Jen Larson, Martin G. Hoffmann, Udo Levy, Daniel O'Donnell, Christopher J. Fox, Caroline S. TI The association of indices of kidney function with coronary artery and abdominal aortic calcification: The Framingham Offspring study SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Parikh, Nisha] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Hwang, Shih-Jen; O'Donnell, Christopher J.; Fox, Caroline S.] NHLBI, Framingham Heart Study, Framingham, MA USA. [Larson, Martin G.] Framingham Heart Dis Epidemiol Study, Framingham, MA USA. [Hoffmann, Udo] Massachusetts Gen Hosp, Boston, MA 02114 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 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 MA 3755 BP 854 EP 854 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303846 ER PT J AU Johnson, BD Merz, CNB Berga, SL Braunstein, GD Reis, SE Bittner, V Hodgson, TK Pepine, CJ Sharaf, BL Sopko, G Kelsey, SF AF Johnson, B. Delia Merz, C. Noel Bairey Berga, Sarah L. Braunstein, Glenn D. Reis, Steven E. Bittner, Vera Hodgson, T. Keta Pepine, Carl J. Sharaf, Barry L. Sopko, George Kelsey, Sheryl F. TI Type of menopause, hormone therapy and coronary artery disease in women: New insights from the NHLBI-sponsored women's ischemia syndrome evaluation (WISE) SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Johnson, B. Delia; Reis, Steven E.; Kelsey, Sheryl F.] Univ Pittsburgh, Pittsburgh, PA USA. [Merz, C. Noel Bairey; Braunstein, Glenn D.; Hodgson, T. Keta] Cedars Sinai Med Ctr, Los Angeles, CA 90048 USA. [Berga, Sarah L.] Emory Univ, Atlanta, GA 30322 USA. [Bittner, Vera] Univ Alabama, Birmingham, AL USA. [Pepine, Carl J.] Univ Florida, Gainesville, FL USA. [Sharaf, Barry L.] Rhode Isl Hosp, Providence, RI USA. [Sopko, George] NIH, Bethesda, MD 20892 USA. RI Reis, Steven/J-3957-2014 NR 0 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 3771 BP 857 EP 857 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303861 ER PT J AU Dezfulian, C Alekseyenko, A Jeffries, KR Gladwin, MT AF Dezfulian, Cameron Alekseyenko, Aleksey Jeffries, Kenneth R. Gladwin, Mark T. TI Systemic nitrite (NO2-) levels are depleted in a mouse model of asystolic cardiac arrest and therapeutic repletion improves, survival and functional neurological recovery SO CIRCULATION LA English DT Meeting Abstract CT 80th Annual Scientific Session of the American-Heart-Association CY NOV 04-07, 2007 CL Orlando, FL SP Amer Heart Assoc C1 [Dezfulian, Cameron; Alekseyenko, Aleksey] Natl Inst Hlth, Bethesda, MD USA. [Jeffries, Kenneth R.; Gladwin, Mark T.] NHLBI, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 SU S MA 22 BP 927 EP 928 PG 2 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223TD UT WOS:000250394303909 ER PT J AU Dejam, A Hunter, CJ Tremonti, C Pluta, RM Hon, YY Grimes, G Partovi, K Pelletier, MM Oldfield, EH Cannon, RO Schechter, AN Gladwin, MT AF Dejam, Andre Hunter, Christian J. Tremonti, Carole Pluta, Ryszard M. Hon, Yuen Yi Grimes, George Partovi, Kristine Pelletier, Mildred M. Oldfield, Edward H. Cannon, Richard O., III Schechter, Alan N. Gladwin, Mark T. TI Nitrite infusion in humans and nonhuman primates - Endocrine effects, pharmacokinetics, and tolerance formation SO CIRCULATION LA English DT Article DE endothelium-derived factors; free radicals; hemoglobin; nitroglycerin; nitric oxide ID ISCHEMIA-REPERFUSION INJURY; DIRECTLY ACTING VASODILATOR; OXIDE SYNTHASE ACTIVITY; REGIONAL BLOOD-FLOW; IN-VIVO; PLASMA NITRITE; CIRCULATING NITRITE; SODIUM-NITRITE; SIGNALING MOLECULE; EMERGING BIOLOGY AB Background - The recent discovery that nitrite is an intrinsic vasodilator and signaling molecule at near-physiological concentrations has raised the possibility that nitrite contributes to hypoxic vasodilation and to the bioactivity of nitroglycerin and mediates the cardiovascular protective effects of nitrate in the Mediterranean diet. However, important questions of potency, kinetics, rnechanism of action, and possible induction of tolerance remain unanswered. Methods and Results - In the present study, we performed biochemical, physiological, and pharmacological studies using nitrite infusion protocols in 20 normal human volunteers and in nonhuman primates to answer these questions, and we specifically tested 3 proposed mechanisms of bioactivation: reduction to nitric oxide by xanthine oxidoreductase, nonenzymatic disproportionation, and reduction by deoxyhemoglobin. We found that (1) nitrite is a relatively potent and fast vasodilator at near-physiological concentrations; (2) nitrite functions as an endocrine reservoir of nitric oxide, producing remote vasodilation during first-pass perfusion of the opposite limb; (3) nitrite is reduced to nitric oxide by intravascular reactions with hemoglobin and with intravascular reductants (ie, ascorbate); (4) inhibition of xanthine o xidoreductase with oxypurinol does not inhibit nitrite-dependent vasodilation but potentiates it; and (5) nitrite does not induce tolerance as observed with the organic nitrates. Conclusions - We propose that nitrite functions as a physiological regulator of vascular function and endocrine nitric oxide homeostasis and suggest that it is an active metabolite of the organic nitrates that can be used therapeutically to bypass enzymatic tolerance. C1 NIDDK, NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Cardiol Branch, Clin Cardiol Sect, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA USA. NIH, Ctr Clin, Dept Crit Care Med, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. NINDS, NIH, Surg Neurol Branch, Bethesda, MD 20892 USA. RP Gladwin, MT (reprint author), NIH, CRC, Bldg 10,Room 5-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM mgladwin@mail.nih.gov RI Hunter, Christian/G-4344-2010; OI Schechter, Alan N/0000-0002-5235-9408 FU Intramural NIH HHS NR 74 TC 182 Z9 188 U1 3 U2 12 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 16 PY 2007 VL 116 IS 16 BP 1821 EP 1831 DI 10.1161/CIRCULATIONAHA.107.712133 PG 11 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 223PW UT WOS:000250385800010 PM 17893272 ER PT J AU Hosseinpour, F Timsit, Y Koike, C Matsui, K Yamamoto, Y Moore, R Negishi, M AF Hosseinpour, Fardin Timsit, Yoav Koike, Chika Matsui, Kenji Yamamoto, Yukio Moore, Rick Negishi, Masahiko TI Overexpression of the Rho-guanine nucleotide exchange factor ECT2 inhibits nuclear translocation of nuclear receptor CAR in the mouse liver SO FEBS LETTERS LA English DT Article DE nuclear receptor CAR; phenobarbital; ECT2; drug metabolism; liver; nuclear translocation ID CONSTITUTIVE ACTIVE/ANDROSTANE RECEPTOR; HOMOLOGY DOMAIN; X-RECEPTOR; CYP2B GENE; CROSS-TALK; TRANSFORMATION; LOCALIZATION; REGULATOR; CYTOKINESIS; METABOLISM AB Various drugs such as phenobarbital (PB) trigger translocation of constitutive active/adrostane receptor (CAR) from the cytoplasm into the nucleus of mouse liver cells without directly binding to the receptor. We have now characterized the guanine nucleotide exchange factor epithelial cell-transforming gene 2 (ECT2) as a PB-inducible factor as well as a cellular signal that represses PB-triggered nuclear translocation of CAR. When CFP-tagged ECT2 was co-expressed with YFP-tagged CAR in the liver of Car(-/-) mice, ECT2 repressed CAR nuclear translocation. Coexpression of various deletion mutants delineated this repressive activity to the tandem Dbl homology/pleckstrin homology domains of ECT2 and to their cytosolic expression. CAR directly bound to the PH domain. Thus, ECT2 may comprise a part of the PB response signal regulating the intracellular trafficking of CAR. (c) Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 [Hosseinpour, Fardin; Timsit, Yoav; Koike, Chika; Matsui, Kenji; Yamamoto, Yukio; Moore, Rick; Negishi, Masahiko] NIEHS, Reprod & Dev Toxicol Lab, Pharmacogenet Sect, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, Reprod & Dev Toxicol Lab, Pharmacogenet Sect, NIH, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 26 TC 7 Z9 9 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 EI 1873-3468 J9 FEBS LETT JI FEBS Lett. PD OCT 16 PY 2007 VL 581 IS 25 BP 4937 EP 4942 DI 10.1016/j.febslet.2007.09.024 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 226TE UT WOS:000250610600023 PM 17904126 ER PT J AU Jun, HO Kim, Y Kwon, YW Hong, SS Kim, KW Shin, J Kim, TY AF Jun, Hyoung-Oh Kim, Younghwa Kwon, Yoo-Wook Hong, Soon-Sun Kim, Kyu-Won Shin, Jongheon Kim, Tae-Yoon TI Wondonin, a novel compound, inhibits hypoxia-induced angiogenesis through hypoxia-inducible factor 1 alpha SO FEBS LETTERS LA English DT Article DE wondonin; HIF-1 alpha; VEGF; anti-angiogenic activity; angiogenesis ID ENDOTHELIAL GROWTH-FACTOR; TUMOR-SUPPRESSOR PROTEIN; CANCER-THERAPY; EXPRESSION; MECHANISMS; OXYGEN; CELLS; TUMORIGENESIS; HIF-1-ALPHA; HIF-1 AB Hypoxia regulates a variety of transcription factors including HIT-1, which has been considered a target for anti-angiogenic therapy. While searching for a novel anti-angiogenic agent that would inhibit HIF-1 activity, we identified wondonin, a new his imidazole purified from an association of the sponges Poecillastra wondoenis Wondonin significantly decreased hypoxia-induced HIF-1 alpha protein and VEGF expression and inhibited angiogenesis in vitro and in vivo. Furthermore, wondonin down-regulated HIF-1 alpha protein through the increased interaction with the pVHL in immortalized human keratinocyte cell line. Wondonin also decreased the immunoreactivities of CD31 and VEGF in epidermal hyperplasia in mice. Taken together, these results suggested that wondonin had the potential to become the anti-angiogenic therapeutic agent to target HIF-1 alpha. (c) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 Seoul Natl Univ, Coll Pharm, Inst Nat Prod Res, Seoul 110460, South Korea. Seoul Natl Univ, Coll Pharm, Res Inst Pharmaceut Sci, Seoul 151742, South Korea. Catholic Univ, Kangnam St Marys Hosp, Coll Med, Catholic Res Inst Med Sci,Lab Dermato Immunol, Seoul 137701, South Korea. NIAID, Immunopathol Lab, Rockville, MD 20852 USA. RP Kim, TY (reprint author), Seoul Natl Univ, Coll Pharm, Inst Nat Prod Res, 28 Yungun, Seoul 110460, South Korea. EM shinj@snu.ac.kr; tykimder@catholic.ac.kr NR 33 TC 11 Z9 11 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD OCT 16 PY 2007 VL 581 IS 25 BP 4977 EP 4982 DI 10.1016/j.febslet.2007.09.034 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 226TE UT WOS:000250610600030 PM 17919602 ER PT J AU Goldstein, DS Imrich, R Peckham, E Holmes, C Lopez, G Crews, C Hardy, J Singleton, A Hallett, M AF Goldstein, D. S. Imrich, R. Peckham, E. Holmes, C. Lopez, G. Crews, C. Hardy, J. Singleton, A. Hallett, M. TI Neurocirculatory and nigrostriatal abnormalities in Parkinson disease from LRRK2 mutation SO NEUROLOGY LA English DT Article ID CARDIAC SYMPATHETIC DENERVATION; LEWY BODY DISEASE; DIHYDROXYPHENYLACETIC ACID; AUTONOMIC FAILURE; CATECHOLS; HUMANS; MIBG AB Background: Patients with Parkinson disease (PD) often have cardiac sympathetic denervation and failure of neurocirculatory regulation by baroreflexes. Familial PD caused by mutation of the gene encoding alpha-synuclein or by alpha-synuclein gene triplication also features cardiac sympathetic denervation and baroreflex failure. Methods: Here we report results of cardiac sympathetic neuroimaging by 6-[F-18] fluorodopamine PET, baroreflex testing based on beat-to-beat hemodynamic responses to the Valsalva maneuver, and nigrostriatal neuroimaging using 6-[F-18] fluorodopa PET in a proband with mutation of the gene encoding leucine-rich repeat kinase 2(LRRK2), the most common genetic abnormality identified so far in familial PD. Results: The patient had no detectable 6-[F-18] fluorodopamine-derived radioactivity in the left ventricular myocardium, a progressive fall in blood pressure during the Valsalva maneuver and no pressure overshoot after release of the maneuver, and decreased 6-[F-18] fluorodopa-derived radioactivity bilaterally in the putamen and substantia nigra. Conclusion: This patient with Parkinson disease (PD) caused by LRRK2 mutation had evidence of cardiac sympathetic denervation, baroreflex-sympathoneural and baroreflex-cardiovagal failure, and nigrostriatal dopamine deficiency, a pattern resembling that in the sporadic disease. The results fit with the concept that in LRRK2 PD, parkinsonism, cardiac sympathetic denervation, and baroreflex failure can result from a common pathogenetic process. C1 NIH, Natl Inst Neurol Disorders & Stroke, Clin Neurocardiol Sect, Bethesda, MD USA. NIH, Natl Inst Neurol Disorders & Stroke, Med Neurol Branch, Bethesda, MD USA. NIH, NHGRI, Genet Dis Res Branch, Bethesda, MD USA. NIH, NIA, Neurogenet Lab, Bethesda, MD USA. RP Goldstein, DS (reprint author), NINDS, NIH, 10 Ctr Dr MSC-1620,Bldg 10,Rm 6N252, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov RI Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009 FU Intramural NIH HHS; Medical Research Council [G0701075] NR 31 TC 18 Z9 18 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD OCT 16 PY 2007 VL 69 IS 16 BP 1580 EP 1584 DI 10.1212/01.wnl.0000268696.57912.64 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 221AM UT WOS:000250198800005 PM 17625107 ER PT J AU Kelley, MW AF Kelley, Matthew W. TI Has hair cell loss MET its match? SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID MOUSE INNER-EAR; STEM-CELLS; IN-VITRO; GROWTH; DIFFERENTIATION; PROLIFERATION; EPITHELIA; PROGENITORS; MATURATION; COCHLEA C1 Natl Inst Deafness & Other Commun Disorders, NIH, Porter Neurosci Res Ctr, Bethesda, MD 20892 USA. RP Kelley, MW (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, Porter Neurosci Res Ctr, 35 Convent Dr, Bethesda, MD 20892 USA. EM kelleymt@nidcd.nih.gov NR 23 TC 1 Z9 1 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 OCT 16 PY 2007 VL 104 IS 42 BP 16400 EP 16401 DI 10.1073/pnas.0708154104 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 223MA UT WOS:000250373400005 PM 17925436 ER PT J AU Wright, PF Karron, RA Belshe, RB Shi, JR Randolph, VB Collins, PL O'Shea, AF Gruber, WC Murphy, BR AF Wright, Peter F. Karron, Ruth A. Belshe, Robert B. Shi, Jian R. Randolph, Valerie B. Collins, Peter L. O'Shea, Alice F. Gruber, William C. Murphy, Brian R. TI The absence of enhanced disease with wild type respiratory syncytial virus infection occurring after receipt of live, attenuated, respiratory syncytial virus vaccines SO VACCINE LA English DT Article DE respiratory syncytial virus; vaccines; safety ID L GENE; CANDIDATE; INFANTS; TRIVALENT; CHILDREN; IMMUNIZATION; CHIMPANZEES; MUTATION; NS2 AB Early in the development of respiratory syncytial virus (RSV) vaccines severe disease occurred in children after receipt of fornualinin-activated RSV vaccine. Continuing efforts to develop an appropriately attenuated and immunogenic live RSV vaccine have given opportunities to assure that live vaccines are safe through surveillance of children after vaccination. In the present study, the rate of RSV-associated upper respiratory tract illness in 388 children was lower in RSV vaccinated children than in controls (14% versus 20% in a 6-24 month old group and 16% versus 25% in infants). Additionally, there was no evidence that vaccination predisposed to more severe lower respiratory tract illness. Thus infection with a series of live attenuated RSV vaccines did not result in enhanced disease upon infection with wild type RSV. The impact of RSV during this surveillance will inform the design of future efficacy studies with RSV vaccines. (c) 2007 Elsevier Ltd. All rights reserved. C1 Vanderbilt Univ, Nashville, TN 37232 USA. Johns Hopkins Univ, Sch Publ Hlth, Baltimore, MD USA. St Louis Univ, St Louis, MO 63103 USA. Wyeth Vaccines Res, Pearl River, NY USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Wright, PF (reprint author), Vanderbilt Univ, Nashville, TN 37232 USA. EM peter.wright@vanderbilt.edu FU Intramural NIH HHS; NIAID NIH HHS [N01 AI015444, N01 AI15444, N01AI15444] NR 21 TC 66 Z9 72 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 OCT 16 PY 2007 VL 25 IS 42 BP 7372 EP 7378 DI 10.1016/j.vaccine.2007.08.014 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 227JV UT WOS:000250653900013 PM 17868959 ER PT J AU Higgins, JPT Little, J Ioannidis, JPA Bray, MS Manolio, TA Smeeth, L Sterne, JA Anagnostelis, B Butterworth, AS Danesh, J Dezateux, C Gallacher, JE Gwinn, M Lewis, SJ Minelli, C Pharoah, PD Salanti, G Sanderson, S Smith, LA Taioli, E Thompson, JR Thompson, SG Walker, N Zimmern, RL Khoury, MJ AF Higgins, Julian P. T. Little, Julian Ioannidis, John P. A. Bray, Molly S. Manolio, Teri A. Smeeth, Liam Sterne, Jonathan A. Anagnostelis, Betsy Butterworth, Adam S. Danesh, John Dezateux, Carol Gallacher, John E. Gwinn, Marta Lewis, Sarah J. Minelli, Cosetta Pharoah, Paul D. Salanti, Georgia Sanderson, Simon Smith, Lesley A. Taioli, Emanuela Thompson, John R. Thompson, Simon G. Walker, Neil Zimmern, Ron L. Khoury, Muin J. TI Turning the pump handle: Evolving methods for integrating the evidence on gene-disease association SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material ID GENOME-WIDE ASSOCIATION; EPIDEMIOLOGY; REPLICATION; SUSCEPTIBILITY; METAANALYSIS; NETWORK; LOCI C1 MRC, Biostat Unit, Inst Publ Hlth, Cambridge CB2 OSR, England. Univ Ottawa, Dept Epidemiol & Community Med, Ottawa, ON, Canada. Univ Ioannina, Sch Med, Dept Hyg & Epidemiol, GR-45110 Ioannina, Greece. Univ Texas, Inst Mol Med, Ctr Human Genet, Houston, TX USA. Univ Texas, Sch Publ Hlth, Houston, TX USA. Tufts Univ, Sch Med, Dept Med, Boston, MA 02111 USA. NHGRI, NIH, Bethesda, MD 20892 USA. London Sch Hyg & Trop Med, Dept Epidemiol & Publ Hlth, London WC1, England. Univ Bristol, Dept Social Med, Bristol, Avon, England. UCL, Royal Free Hosp, Med Lib, London, England. Univ Cambridge, Dept Publ Hlth & Primary Care, Cambridge, England. UCL, Inst Child Hlth, Ctr Paediat Epidemiol & Biostat, London, England. Cardiff Univ, Dept Epidemiol, Cardiff, Wales. Ctr Dis Control & Prevent, Natl Off Publ Hlth, Atlanta, GA USA. Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London, England. Univ Cambridge, UK Human Canc Genet Grp, Canc Res, Cambridge, England. Oxford Brookes Univ, Sch Hlth & Social Care, Oxford OX3 0BP, England. Univ Pittsburgh, Med Ctr, Pittsburgh, PA USA. Univ Leicester, Dept Hlth Sci, Leicester, Leics, England. Univ Cambridge, Cambridge Inst Med Res, Wellcome Trust Diabet & Inflammat Lab, Juvenile Diabet Res Fdn, Cambridge, England. PHG Fdn, Cambridge, England. RP Higgins, JPT (reprint author), MRC, Biostat Unit, Inst Publ Hlth, Robinson way, Cambridge CB2 OSR, England. EM julian.higgins@mrc-bsu.cam.ac.uk RI Anagnostelis, Betsy/C-5271-2008; Dezateux, Carol/A-3416-2009; Ioannidis, John/G-9836-2011; Higgins, Julian/H-4008-2011; OI Higgins, Julian/0000-0002-8323-2514; Lewis, Sarah/0000-0003-4311-6890 FU Wellcome Trust [082178] NR 29 TC 20 Z9 20 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 OCT 15 PY 2007 VL 166 IS 8 BP 863 EP 866 DI 10.1093/aje/kwm248 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 220FS UT WOS:000250143200001 PM 17804859 ER PT J AU Flegal, KM Graubard, BI Williamson, DF Gail, MH AF Flegal, Katherine M. Graubard, Barry I. Williamson, David F. Gail, Mitchell H. TI Impact of smoking and preexisting illness on estimates of the fractions of deaths associated with underweight, overweight, and obesity in the US population SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE body mass index; body weight; confounding factors (epidemiology); epidemiologic methods; health surveys; mortality; overweight; thinness ID BODY-MASS INDEX; EXCESS DEATHS; FOLLOW-UP; MORTALITY; WEIGHT; DISEASE; COHORT; WOMEN; MEN AB Studies of body weight and mortality sometimes exclude participants who have ever smoked or who may have had preexisting illness at baseline. This exclusionary approach was applied to data from the National Health and Nutrition Examination Surveys to investigate the potential effects of smoking and preexisting illness on estimates of the attributable fractions of US deaths in 2000 that were associated with different levels of body mass index (BMI; weight (kg)/height (m)(2)). Synthetic estimates were calculated by using postexclusion relative risks for BMI categories in place of BMI relative risks from the full sample, holding the relative risks for all other covariates constant. When the postexclusion relative risks were used, the attributable fractions of deaths associated with underweight and with higher levels of obesity increased slightly and the attributable fractions of deaths associated with overweight and with grade 1 obesity decreased slightly. The relative risks for BMI categories did not show large or systematic changes after simultaneous exclusion of ever smokers, persons with a history of cancer or cardiovascular disease, and persons who died early in the follow-up period or had their heights and weights measured at older ages. These analyses suggest that residual confounding by smoking or preexisting illness had little effect on previous estimates of attributable fractions from nationally representative data with measured heights and weights. C1 Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, Hyattsville, MD 20782 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD USA. Ctr Dis Control & Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Div Diabet Translat, Atlanta, GA USA. RP Flegal, KM (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Stat, 3311 Toledo Rd, Hyattsville, MD 20782 USA. EM kflegal@cdc.gov RI Flegal, Katherine/A-4608-2013; OI Flegal, Katherine/0000-0002-0838-469X NR 28 TC 50 Z9 50 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 OCT 15 PY 2007 VL 166 IS 8 BP 975 EP 982 DI 10.1093/aje/kwm152 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 220FS UT WOS:000250143200014 PM 17670912 ER PT J AU Zhou, M Meng, Z Jobson, AG Pommier, Y Veenstra, TD AF Zhou, Ming Meng, Zhaojing Jobson, Andrew G. Pommier, Yves Veenstra, Timothy D. TI Detection of in vitro kinase generated protein phosphorylation sites using gamma[O-18(4)]-ATP and mass Spectrometry SO ANALYTICAL CHEMISTRY LA English DT Article ID PROTEOMICS; PHOSPHOPEPTIDES; P34CDC2; GENOME; FAMILY; CHK2 AB A novel stable-isotope labeling approach for identification of phosphopeptides that utilizes adenosine triphosphate, in which four oxygen-16 atoms attached to the terminal phosphate group are substituted with oxygen-18 [gamma(O-18(4))-ATP], has been developed. The ability to use gamma(O-18(4))-ATP to monitor phosphorylation modification within various proteins was conducted by performing in vitro kinase reactions in the presence of a 1: 1 Mixture of gamma(O-18(4))-ATP and normal isotopic abundance ATP (ATP). After tryptic digestion, the peptides were analyzed using mass spectrometry (MS). Phosphorylated peptides are easily recognized within the MS spectrum owing to the presence of doublets separated by 6.01 Da; representing versions of the peptide modified by ATP and gamma(O-18(4))-ATP. Standard peptides phosphorylated using gamma(O-18(4))-ATP via in vitro kinase reactions showed no exchange loss of O-18 with O-16. The identity of these doublets as phosphorylated peptides could be readily confirmed using tandem MS. The method described here provides the first direct stable-isotope labeling method to definitely detect phosphorylation sites within proteins. C1 SAIC Frederick Inc, Natl Canc Inst, Frederick, MD 21702 USA. NCI, Mol Pharmacol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Veenstra, TD (reprint author), SAIC Frederick Inc, Natl Canc Inst, Frederick, MD 21702 USA. EM veenstra@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 24 TC 14 Z9 15 U1 0 U2 5 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 OCT 15 PY 2007 VL 79 IS 20 BP 7603 EP 7610 DI 10.1021/ac071584r PG 8 WC Chemistry, Analytical SC Chemistry GA 220QW UT WOS:000250173200003 PM 17877366 ER PT J AU Xu, X Roman, JM Issaq, HJ Keefer, LK Veenstra, TD Zieger, RG AF Xu, Xia Roman, John M. Issaq, Haleem J. Keefer, Larry K. Veenstra, Timothy D. Zieger, Regina G. TI Quantitative measurement of endogenous estrogens and estrogen metabolites in human serum by liquid chromatography-tandem mass spectrometry SO ANALYTICAL CHEMISTRY LA English DT Article ID ELECTROSPRAY-IONIZATION; BREAST-CANCER; HUMAN-PLASMA; DANSYL CHLORIDE; ESTRADIOL; URINE; ASSAY; 2-HYDROXYESTRONE; DERIVATIZATION; MECHANISMS AB Endogenous estrogen plays a key role in the development of human breast cancer, yet the contribution of specific estrogen metabolites and patterns of estrogen metabolism remains unclear. To determine their individual and joint roles in breast carcinogenesis, it is necessary to be able to measure quantitatively each estrogen metabolite in epidemiologic and clinical biospecimens. In this report, we detail a sensitive, specific, accurate, and precise high-performance liquid chromatography-tandem mass spectrometry method utilizing selected reaction monitoring for measuring the absolute quantities of free (unconjugated) and total (conjugated + unconjugated) endogenous estrogens and estrogen metabolites in human serum from premenopausal and postmenopausal women. The method requires a simple sample preparation and only 0.5 mL of serum, yet is capable of quantifying simultaneously 15 estrogens and estrogen metabolites (EM): estrone and its 2-, 4-, and 16 alpha-hydroxy and 2- and 4-methoxy derivatives; 2-hydroxyestrone-3-methyl ether; 17 beta-estradiol and its 2-hydroxy and 2- and 4-methoxy derivatives; and estriol, 17-epiestriol, 16-ketoestradiol, and 16-epiestriol. The lower limit of quantitation for each EM was 0.4 pg on-column, equivalent to 8 pg/mL (26.5-29.6 fmol/mL) in the original serum sample. Calibration curves were linear over a 10(3)-fold concentration range. For a stripped serum sample containing 8 pg/mL of each EM, accuracy (percent recovery of a known added amount) ranged from 91 to 113%. Intrabatch precision (including hydrolysis, extraction, and derivatization steps) ranged from 7 to 30% relative standard deviation (RSD), and interbatch precision ranged from 8 to 29% RSD. Since distinct roles have been proposed for many of these estrogen metabolites, an accurate, precise, sensitive, and specific method for measuring their levels in circulation should suggest new approaches to breast cancer prevention, screening, and treatment. C1 SAIC Frederick Inc, NCI Frederick, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. SAIC Frederick Inc, NCI Frederick, Lab Comparat Carcinogenesis, Ctr Canc Res, Frederick, MD 21702 USA. NCI, Div Canc Epidemol & Genet, Epidemiol & Biostat Program, Bethesda, MD 20892 USA. RP Veenstra, TD (reprint author), SAIC Frederick Inc, NCI Frederick, Lab Proteom & Analyt Technol, POB B, Frederick, MD 21702 USA. EM veenstrat@mail.nih.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 29 TC 148 Z9 150 U1 6 U2 41 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 OCT 15 PY 2007 VL 79 IS 20 BP 7813 EP 7821 DI 10.1021/ac070494j PG 9 WC Chemistry, Analytical SC Chemistry GA 220QW UT WOS:000250173200029 PM 17848096 ER PT J AU Spiller, K Ashby, CR Callahan, PM Tehim, A Xi, ZX Gardner, EL AF Spiller, Krista Ashby, Charles R., Jr. Callahan, Patrick M. Tehim, Ashok Xi, Zheng-Xiong Gardner, Eliot L. TI The partial alpha 4 beta 2 and full alpha 7 nicotinic receptor agonist, varenicline, enhances brain stimulation reward in rats SO BIOCHEMICAL PHARMACOLOGY LA English DT Meeting Abstract CT Symposium on Nicotinic Acetylcholine Receptors as Therapeutic Targets CY OCT 31-NOV 02, 2007 CL San Diego, CA SP Abbott Neurosci, AstraZenerca, Roche, Tobacco Rlelatd dis Red Program, CoMentis, GlaxoSmithKline, Lilly, NeuroSearch, Mem Pharmaceut, Sanofi Aventis, Wyeth C1 Natl Inst Drug Abuse, Intramural Res Program, Baltimore, MD 21224 USA. St Johns Univ, Dept Pharmaceut Sci, Jamaica, NY 11439 USA. Memory Pharmaceut, Montvale, NJ 07645 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 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 OCT 15 PY 2007 VL 74 IS 8 BP SMA45 EP SMA45 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 220WV UT WOS:000250188900099 ER PT J AU Iyer, LM Anantharaman, V Aravind, L AF Iyer, Lakshminarayan M. Anantharaman, Vivek Aravind, L. TI The DOMON domains are involved in heme and sugar recognition SO BIOINFORMATICS LA English DT Article ID CELLOBIOSE DEHYDROGENASE; CYTOCHROMES AB We expand the functionally uncharacterized DOMON domain superfamily to identify several novel families, including the first prokaryotic representatives. Using several computational tools we show that it is involved in ligand binding - either as heme- or sugar-binding domains. We present evidence that the DOMON domain along with the DM13 domain comprises a novel electron-transfer system potentially involved in oxidative modification of animal cell- surface proteins. Other novel versions might function as sugar sensors of histidine kinases of bacterial two component systems. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. NIH, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov OI Anantharaman, Vivek/0000-0001-8395-0009 FU Intramural NIH HHS NR 9 TC 28 Z9 29 U1 2 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD OCT 15 PY 2007 VL 23 IS 20 BP 2660 EP 2664 DI 10.1093/bioinformatics/btm411 PG 5 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 227QW UT WOS:000250673900002 PM 17878204 ER PT J AU Cannon, DM Ichise, M Rollis, D Klaver, JM Gandhi, SK Charney, DS Manji, HK Drevets, WC AF Cannon, Dara M. Ichise, Masanori Rollis, Denise Klaver, Jacqueline M. Gandhi, Shilpa K. Charney, Dennis S. Manji, Husseini K. Drevets, Wayne C. TI Elevated serotonin transporter binding in major depressive disorder assessed using positron emission tomography and [C-11]DASB; Comparison with bipolar disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE major depressive disorder; positron emission tomography; serotonin transporter; [C-11]DASB ID IN-VITRO BINDING; HUMAN BRAIN; MESSENGER-RNA; MONOAMINE TRANSPORTERS; OLFACTORY BULBECTOMY; NONHUMAN-PRIMATES; SUICIDE VICTIMS; MOOD DISORDERS; HEALTHY HUMANS; FRONTAL-CORTEX AB Background: Altered serotonergic function is thought to play a role in the pathophysiology of major depressive episodes based upon evidence from neuroirnaging, pharmacological, postmortem and genetic studies. It remains unclear, however, whether depressed samples that differ with respect to having shown a unipolar versus a bipolar illness course also would show distinct patterns of abnormalities within the serotonergic system. The current study compared serotonin transporter (5-HTT) binding between unipolar-clepressives (MDD), bipolar-depressives (BID) and healthy-controls (HC) to assess whether the abnormalities in 5-HTT binding recently found in depressed subjects with BID extend to depressed subjects with MDD. Methods: The 5-HTT binding-potential (BP) measured using positron emission tomography (PET) and [C-11]DASB was compared between unmedicated, depressed subjects with MDD (n = 18) or BD (n = 18) and HC (n = 34). Results: Relative to the healthy group both MDD and BD groups showed significantly increased 5-HTT BP in the thalamus (24%, 14%, respectively), insula (15%) and striatum (12%). The unipolar-depressives had elevated 5-HTT BP relative to both BID and HC groups in the vicinity of the periaqueductal gray (PAG, 20%, 22%, respectively). The bipolar-depressives had reduced 5-HTT BP relative to both HC and MDD groups in the vicinity of the pontine raphe nuclei. Depression-severity correlated negatively with 5-HTT BP in the thalamus in MDD-subjects. Conclusions: The depressed phases of MDD and BD both were associated with elevated 5-HTT binding in the insula, thalamus and striatum, but showed distinct abnormalities in the brainstem. The latter findings conceivably could underlie differences in the patterns of illness symptoms and pharmacological sensitivity observed between MDD and BID. C1 NIMH, Mol Imaging Branch, Mood & Anxietu Disorders Program, NIH, Bethesda, MD USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Nucl Med, Boston, MA USA. Mt Sinai Sch Med, Dept Psychiat, New York, NY USA. RP Cannon, DM (reprint author), Natl Univ Ireland, Inst Clin Sci, Dept Psychiat, Comerford Bldg,Room 201, Galway, Ireland. EM dara.cannon@nuigalway.ie RI Cannon, Dara/C-1323-2009 OI Cannon, Dara/0000-0001-7378-3411 FU Intramural NIH HHS NR 74 TC 123 Z9 127 U1 0 U2 13 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 OCT 15 PY 2007 VL 62 IS 8 BP 870 EP 877 DI 10.1016/j.biopsych.2007.03.016 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 221JD UT WOS:000250222300008 PM 17678634 ER PT J AU Tavares, JVT Clark, L Cannon, DM Erickson, K Drevets, WC Sahakian, BJ AF Tavares, Joana V. Taylor Clark, Luke Cannon, Dara M. Erickson, Kristine Drevets, Wayne C. Sahakian, Barbara J. TI Distinct profiles of neurocognitive function in unmedicated unipolar depression and bipolar II depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE bipolar II disorder; major depressive disorder; neuropsychological tests; sensitivity to loss; spatial working memory; unmedicated ID DECISION-MAKING COGNITION; PSYCHOMOTOR RETARDATION; PREFRONTAL CORTEX; DISORDER; MEMORY; IMPAIRMENT; MOOD; DEFICITS; MANIA; SCALE AB Background: Studies have demonstrated neuropsychological deficits across a variety of cognitive domains in depression. Few studies have directly compared depressed subjects with major depressive disorder (MDD) and bipolar disorder (BID), and many are confounded by medication status across Subjects. In this study, we compared the performance of unmedicated currently depressed MDD and BD groups on a battery of neuropsychological tests that included measures of risk taking and reflection impulsivity. Methods: Twenty-two MDD, seventeen BDII, and 25 healthy control subjects (HC), matched for age and IQ, were assessed on a battery of neuropsychological tests. Results: The depressed groups showed comparable ratings of depression severity and age of illness onset. The MDD group was impaired on tests of spatial working memory and attentional shifting, sampled less information on a test of reflection impulsivity, and was oversensitive to loss trials on a decision-making test. The BDII subjects were generally intact and did not differ significantly from control subjects on any test. Conclusions: These data indicate differing profiles of cognitive impairment in unmedicated depressed MDD versus BDII subjects. Moderately depressed BDII subjects displayed relatively intact cognitive function, whereas MDD subjects demonstrated a broader range of executive impairments. These cognitive deficits in depression were not attributable to current medication status. C1 Univ Cambridge, Addenbrookes Hosp, Wolfson Brain Imaging Ctr, Cambridge CB2 2QQ, England. NIMH, NIH, Bethesda, MD USA. Univ Cambridge, Dept Expt Psychol, Cambridge CB2 1TN, England. RP Tavares, JVT (reprint author), Univ Cambridge, Addenbrookes Hosp, Wolfson Brain Imaging Ctr, Box 65, Cambridge CB2 2QQ, England. EM jvt21@cam.ac.uk RI Cannon, Dara/C-1323-2009 OI Cannon, Dara/0000-0001-7378-3411 NR 48 TC 91 Z9 93 U1 3 U2 17 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 OCT 15 PY 2007 VL 62 IS 8 BP 917 EP 924 DI 10.1016/j.biopsych.2007.05.034 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 221JD UT WOS:000250222300014 ER PT J AU Huo, L Straub, RE Roca, C Schmidt, PJ Shi, K Vakkalanka, R Weinberger, DR Rubinow, DR AF Huo, Liang Straub, Richard E. Roca, Catherine Schmidt, Peter J. Shi, Kai Vakkalanka, Radhakrishna Weinberger, Daniel R. Rubinow, David R. TI Risk for premenstrual dysphoric disorder is associated with genetic variation in ESR1, the estrogen receptor alpha gene SO BIOLOGICAL PSYCHIATRY LA English DT Article DE ESR1; estrogen receptor alpha gene; PMDD; premenstrual dysphoric disorder ID CATECHOL-O-METHYLTRANSFERASE; SEROTONIN TRANSPORTER GENE; POPULATION-BASED TWIN; FORCED SWIM TEST; BREAST-CANCER; MAJOR DEPRESSION; GONADAL-STEROIDS; PROSTATE-CANCER; DOWN-REGULATION; MESSENGER-RNA AB Background: Premenstrual dysphoric disorder (PMDD) is a heritable mood disorder that is triggered by gonadal steroids during the luteal phase in susceptible women. Methods: We performed haplotype analyses of estrogen receptors alpha and beta (ESR1 and ESR2) in 91 women with prospectively confirmed PMDD and 56 control subjects to investigate possible sources of the genetic susceptibility to affective dysregulation induced by normal levels of gonadal steroids. We also examined associations with the valine (Val)158methionine (Met) single nucleoticle polymorphism (SNP) of the gene for catechol-O-methyltransferase (COMT), an enzyme involved in estrogen metabolism and prefrontal cortical activation. Results: Four SNPs in intron 4 of ESR1 showed significantly different genotype and allele distributions between patients and control subjects. Significant case-control differences wereseen in sliding-window analyses of two-,three-,and four-marker haplotypes but only in those haplotypes containing SNPs in intron 4 that were positive in the single-locus analysis. No significant associations were observed with ESR2 or with the COMT Val158Met polymorphism, although the significant associations with ESR1 were observed only in those with the Val/Val genotype. Conclusions: These are the first positive (albeit preliminary) genetic findings in this reproductive endocrine-related mood disorder and involve the receptor for a hormone that is pathogenically relevant. C1 NIMH, Womens Program, Bethesda, MD USA. NIMH, Behav Endocrinol Branch, Bethesda, MD USA. NIMH, Program Genes Cognit & Psychosis, Bethesda, MD USA. NIMH, NIH, Bethesda, MD USA. RP Weinberger, DR (reprint author), Univ N Carolina, Sch Med, 1st Floor,Neurosci Hosp 7160, Chapel Hill, NC 27599 USA. EM drubinow@med.unc.edu FU Intramural NIH HHS [Z01 MH002865-02] NR 62 TC 56 Z9 59 U1 5 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD OCT 15 PY 2007 VL 62 IS 8 BP 925 EP 933 DI 10.1016/j.biopsych.2006.12.019 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 221JD UT WOS:000250222300015 PM 17599809 ER PT J AU Basselin, M Villacreses, NE Chen, M Bell, JM Rapoport, SI AF Basselin, Mireille Villacreses, Nelly E. Chen, Mei Bell, Jane M. Rapoport, Stanley I. TI Chronic carbamazepine administration reduces N-methyl-D-aspartate receptor-initiated signaling via arachidonic acid in rat brain SO BIOLOGICAL PSYCHIATRY LA English DT Article DE arachidonic acid; bipolar disorder; carbamazepine; NMDA; phospholipase A(2); prostaglandin E-2 ID EXCITATORY AMINO-ACIDS; BIPOLAR AFFECTIVE-DISORDER; LONG-TERM LITHIUM; PHOSPHOLIPASE A(2); ANTIEPILEPTIC DRUGS; MOOD-STABILIZERS; UNANESTHETIZED RATS; NMDA RECEPTORS; CYCLOOXYGENASE-1 AND-2; DOCOSAHEXAENOIC ACID AB Background: Lithium and carbamazepine (CBZ) are used to treat mania in bipolar disorder. When given chronically to rats, both agents reduce arachidonic acid (AA) turnover in brain phospholipids and downstream AA metabolism. Lithium in rats also attenuates brain N-methyl-D-aspartic acid receptor (NMDAR) signaling via AA. We hypothesized that, like chronic lithium, chronic CBZ administration to rats would reduce NMDAR-mediated signaling via AA. Methods: We used our fatty acid method with quantitative autoradiography to image the regional brain incorporation coefficient k* of AA, a marker of AA signaling, in unanesthetized rats that had been given 25 mg/kg/day IP CBZ or vehicle for 30 days, then injected with NMIDA (25 mg/kg IP) or saline. We also measured brain concentrations of two AA metabolites, prostaglandin E-2 (PGE(2)) and thromboxane B-2 (TXB2). Results: In chronic vehicle-treated rats, NMDA compared with saline increased k* significantly in 69 of 82 brain regions examined, but did not change k* significantly in any region in CBZ-treated rats. In vehicle- but not CBZ-treated rats, NMDA also increased brain concentrations of PGE(2) and TXB2. Conclusions: Chronic CBZ administration to rats blocks increments in the AA signal k*, and in PGE(2) and TXB2 Concentrations that are produced by NMDA in vehicle-treated rats. The clinical action of antimanic drugs might involve inhibition of brain NMDAR-mediated signaling involving AA and its metabolites. C1 Natl Inst Aging, Brain Physiol & Metab Sec, NIH, Bethesda, MD 20892 USA. RP Basselin, M (reprint author), Natl Inst Aging, Brain Physiol & Metab Sec, NIH, Bldg 9,Room 1S126,MSC 0947,9 Mem Dr, Bethesda, MD 20892 USA. EM mirvasln@mail.nih.gov FU Intramural NIH HHS [Z99 AG999999] NR 99 TC 26 Z9 26 U1 0 U2 1 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 OCT 15 PY 2007 VL 62 IS 8 BP 934 EP 943 DI 10.1016/j.biopsych.2007.04.021 PG 10 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 221JD UT WOS:000250222300016 PM 17628508 ER PT J AU Bodine, DM AF Bodine, David M. TI Dendritic cells reach out in different directions SO BLOOD LA English DT Editorial Material C1 Natl Human Genome Res Inst, Bethesda, MD 20892 USA. RP Bodine, DM (reprint author), Natl Human Genome Res Inst, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 15 PY 2007 VL 110 IS 8 BP 2783 EP 2783 DI 10.1182/blood-2007-07-099770 PG 1 WC Hematology SC Hematology GA 224DQ UT WOS:000250426700003 ER PT J AU Aerbajinai, WL Zhu, JQ Gao, ZG Chin, K Rodgers, GP AF Aerbajinai, Wulin Zhu, Jianqiong Gao, Zhigang Chin, Kyung Rodgers, Griffin P. TI Thalidomide induces gamma-globin gene expression through increased reactive oxygen species-mediated p38 MAPK signaling and histone H4 acetylation in adult erythropoiesis SO BLOOD LA English DT Article ID FETAL-HEMOGLOBIN INDUCTION; INDUCED ERYTHROID-DIFFERENTIATION; SICKLE-CELL-ANEMIA; DEACETYLASE INHIBITORS; MYELODYSPLASTIC SYNDROMES; MULTIPLE-MYELOMA; OXIDATIVE STRESS; ACTIVATION; MECHANISM; PATHWAYS AB Although thalidomide has been shown to improve anemia in some patients with myelodysplastic syndromes and stimulates erythropoietin in patients with multiple myeloma, thaildomide's specific effects on gamma-globin gene expression during erythroid differentiation have not been studied. Here, we investigated the effects of thalidomide on gamma-globin gene expression and the involved signaling pathway using an ex vivo culture system of primary human CD34(+) cells. We found that thalidomide induced gamma-globin mRNA expression in a dose-dependent manner, but had no effect on beta-globin expression. We also demonstrated that intracellular reactive oxygen species (ROS) levels were increased by treatment with thalidomide for 48 hours (from day 3 to day 5). Western blot analysis demonstrated that thalidomide activated the p38 mitogen-activated protein kinase (MAPK) signaling pathway in a time- and dose-dependent manner and increased histone H4 acetylation. Pretreatment of cells with the antioxidant enzyme catalase and the intracellular hydroxyl scavenger dimethylthiourea (DMTU) abrogated the thaildomide-induced p38 MAPK activation and histone H4 acetylation. Moreover, pretreatment with catalase and DMTU diminished thalidomide-induced gamma-globin gene expression. These data indicate that thalidomide induces increased expression of the gamma-globin gene via ROS-dependent activation of the p38 MAPK signaling pathway and histone H4 acetylation. C1 NIDDK, NIH, Mol & Clin Hematol Branch, Bethesda, MD 20892 USA. RP Rodgers, GP (reprint author), NIDDK, NIH, Mol & Clin Hematol Branch, Bldg 10,Rm 9N-119, Bethesda, MD 20892 USA. EM gr5n@nih.gov NR 42 TC 44 Z9 46 U1 1 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 15 PY 2007 VL 110 IS 8 BP 2864 EP 2871 DI 10.1182/blood-2007-01-065201 PG 8 WC Hematology SC Hematology GA 224DQ UT WOS:000250426700023 PM 17620452 ER PT J AU Tran, DQ Ramsey, H Shevach, EM AF Tran, Dat Q. Ramsey, Heather Shevach, Ethan M. TI Induction of FOXP3 expression in naive human CD4(+)FOXP3(-) T cells by T-cell receptor stimulation is transforming growth factor-beta-dependent but does not confer a regulatory phenotype SO BLOOD LA English DT Article ID DEFECTIVE SUPPRESSOR FUNCTION; TRANSCRIPTION FACTOR FOXP3; MULTIPLE-SCLEROSIS; SELF-TOLERANCE; CUTTING EDGE; EFFECTOR; ANTIGEN; PROLIFERATION; ENTEROPATHY; GENERATION AB Thymic-derived natural T-regulatory cells (nTregs) are important for the induction of self-tolerance and the control of autoimmunity. Murine CD4(+)CD25(-)Foxp3(-) cells can be induced to express Foxp3 after T-cell receptor (TCR) activation in the presence of transforming growth factor R (TGF beta) and are phenotypically similar to nTregs. Some studies have suggested that TCR stimulation of human CD4(+)CD25(-) cells results in the induction of transient expression of FOXP3, but that the induced cells lack a regulatory phenotype. We demonstrate here that TCR stimulation alone was insufficient to induce FOXP3 expression in the absence of TGF beta, whereas high levels of FOXIP3 expression could be induced in the presence of TGF beta. Although FOXP3 expression was stable, the TGF beta-induced FOXP3(+) T cells were neither anergic nor suppressive and produced high levels of effector cytokines. These results suggest that even high levels of FOXP3 expression are insufficient to define a human CD4(+) T cell as a T-regulatory cell. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Shevach, EM (reprint author), NIAID, Immunol Lab, NIH, 10 Ctr Dr,Bldg 10,Rm 11N315, Bethesda, MD 20892 USA. EM eshevach@niaid.nih.gov RI Osborne, Nicholas/N-4915-2015 OI Osborne, Nicholas/0000-0002-6700-2284 FU Intramural NIH HHS NR 40 TC 480 Z9 494 U1 0 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 15 PY 2007 VL 110 IS 8 BP 2983 EP 2990 DI 10.1182/blood-2007-06-094656 PG 8 WC Hematology SC Hematology GA 224DQ UT WOS:000250426700037 PM 17644734 ER PT J AU Pan, D Schomber, T Kalberer, CP Terracciano, LM Hafen, K Krenger, W Hao-Shen, H Deng, C Skoda, RC AF Pan, Dejing Schomber, Tibor Kalberer, Christian P. Terracciano, Luigi M. Hafen, Katrin Krenger, Werner Hao-Shen, Hui Deng, Chuxia Skoda, Radek C. TI Normal. erythropoiesis but severe polyposis and bleeding anemia in Smad4-deficient mice SO BLOOD LA English DT Article ID HEMATOPOIETIC STEM-CELLS; JUVENILE POLYPOSIS; KNOCKOUT MICE; SELF-RENEWAL; IN-VIVO; IRON-METABOLISM; GENE-EXPRESSION; DEFICIENT MICE; MUTANT MICE; DPC4 GENE AB The tumor suppressor Smad4 mediates signaling by the transforming growth factor beta (TGF-beta) superfamily of ligands. Previous studies showed that several TGF-beta family members exert important functions in hematopoiesis. Here, we studied the role of Smad4 in adult murine hematopoiesis using the inducible Mx-Cre/loxP system. Mice with homozygous Smad4 deletion (Smad4(Delta/Delta)) developed severe anemia 6 to 8 weeks after induction (mean hemoglobin level 70 g/L). The anemia was not transplantable, as wild-type mice reconstituted with Smad4(Delta/Delta) bone marrow cells had normal peripheral blood counts. These mice did not develop an inflammatory disease typical for mice deficient in TGF-beta receptors I and II, suggesting that the suppression of inflammation by TGF-beta is Smad4 independent. The same results were obtained when Smad4 alleles were deleted selectively in hematopoietic cells using the VavCre transgenic mice. In contrast, lethally irradiated Smad4(Delta/Delta) mice that received wild-type bone marrow cells developed anemia similar to Smad4(Delta/Delta) mice that did not receive a transplant. Liver iron stores were decreased and blood was present in stool, indicating that the anemia was due to blood loss. Multiple polyps in stomach and colon represent a likely source of the bleeding. We conclude that Smad4 is not required for adult erythropoiesis and that anemia is solely the consequence of blood loss. C1 Univ Basel Hosp, Dept Res Expt Hematol, CH-4031 Basel, Switzerland. Univ Basel Hosp, Dept Pathol, CH-4031 Basel, Switzerland. Univ Molise, Dept Hlth Sci, Campobasso, Italy. Univ Basel, Childrens Hosp, Basel, Switzerland. Univ Basel, Dept Clin Biol Sci, Lab Pediat Immunol, Basel, Switzerland. NIDDK, Mammalian Genet Sect, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. RP Skoda, RC (reprint author), Univ Basel Hosp, Dept Res Expt Hematol, Hebelstr 20, CH-4031 Basel, Switzerland. EM radek.skoda@unibas.ch RI deng, chuxia/N-6713-2016 NR 46 TC 7 Z9 7 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 15 PY 2007 VL 110 IS 8 BP 3049 EP 3055 DI 10.1182/blood-2007-02-074393 PG 7 WC Hematology SC Hematology GA 224DQ UT WOS:000250426700045 PM 17638848 ER PT J AU Alvarez, Y Cederlund, ML Cottell, DC Bill, BR Ekker, SC Torres-Vazquez, J Weinstein, BM Hyde, DR Vihtelic, TS Kennedy, BN AF Alvarez, Yolanda Cederlund, Maria L. Cottell, David C. Bill, Brent R. Ekker, Stephen C. Torres-Vazquez, Jesus Weinstein, Brant M. Hyde, David R. Vihtelic, Thomas S. Kennedy, Breandan N. TI Genetic determinants of hyaloid and retinal vasculature in zebrafish SO BMC DEVELOPMENTAL BIOLOGY LA English DT Article ID HEPARAN-SULFATE PROTEOGLYCANS; ENDOTHELIAL GROWTH-FACTOR; DIABETIC-RETINOPATHY; RAT RETINA; EYE; ANGIOGENESIS; LENS; PHENOTYPES; DISEASE; CELLS AB Background: The retinal vasculature is a capillary network of blood vessels that nourishes the inner retina of most mammals. Developmental abnormalities or microvascular complications in the retinal vasculature result in severe human eye diseases that lead to blindness. To exploit the advantages of zebrafish for genetic, developmental and pharmacological studies of retinal vasculature, we characterised the intraocular vasculature in zebrafish. Results: We show a detailed morphological and developmental analysis of the retinal blood supply in zebrafish. Similar to the transient hyaloid vasculature in mammalian embryos, vessels are first found attached to the zebrafish lens at 2.5 days post fertilisation. These vessels progressively lose contact with the lens and by 30 days post fertilisation adhere to the inner limiting membrane of the juvenile retina. Ultrastructure analysis shows these vessels to exhibit distinctive hallmarks of mammalian retinal vasculature. For example, smooth muscle actin-expressing pericytes are ensheathed by the basal lamina of the blood vessel, and vesicle vacuolar organelles (VVO), subcellular mediators of vessel-retinal nourishment, are present. Finally, we identify 9 genes with cell membrane, extracellular matrix and unknown identity that are necessary for zebrafish hyaloid and retinal vasculature development. Conclusion: Zebrafish have a retinal blood supply with a characteristic developmental and adult morphology. Abnormalities of these intraocular vessels are easily observed, enabling application of genetic and chemical approaches in zebrafish to identify molecular regulators of hyaloid and retinal vasculature in development and disease. C1 [Alvarez, Yolanda; Cederlund, Maria L.; Kennedy, Breandan N.] Natl Univ Ireland Univ Coll Dublin, UCD Sch Biomol, Dublin 4, Ireland. [Cottell, David C.] Natl Univ Ireland Univ Coll Dublin, UCD Conway Inst, Dublin 4, Ireland. [Bill, Brent R.; Ekker, Stephen C.] Univ Minnesota, Ctr Transposon Res, Dept Genet Cell Biol & Dev, Minneapolis, MN 55455 USA. [Torres-Vazquez, Jesus] NYU, Sch Med, Skirball Inst Biomol Med, New York, NY 10016 USA. [Weinstein, Brant M.] NICHD, NIH, Mol Genet Lab, Bethesda, MD 20892 USA. [Hyde, David R.; Vihtelic, Thomas S.] Univ Notre Dame, Dept Biol Sci, Notre Dame, IN 46556 USA. RP Alvarez, Y (reprint author), Natl Univ Ireland Univ Coll Dublin, UCD Sch Biomol, Dublin 4, Ireland. EM yolanda.alvarez@ucd.ie; maria.cederlund@ucd.ie; david.c.cottell@ucd.ie; bill0115@tc.umn.edu; ekker001@mail.med.umn.edu; torres@saturn.med.nyu.edu; bw96w@nih.gov; dhyde@nd.edu; vihtelic.3@nd.edu; brendan.kennedy@ucd.ie OI Kennedy, Breandan/0000-0001-7991-4689 FU NHLBI NIH HHS [R01 HL092263]; NIGMS NIH HHS [R01 GM063904, R01 GM063904-01] NR 66 TC 67 Z9 69 U1 1 U2 10 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-213X J9 BMC DEV BIOL JI BMC Dev. Biol. PD OCT 15 PY 2007 VL 7 AR 114 DI 10.1186/1471-213X-7-114 PG 17 WC Developmental Biology SC Developmental Biology GA 246WS UT WOS:000252039500001 PM 17937808 ER PT J AU Chandler, RJ Sloan, J Fu, H Tsai, M Stabler, S Allen, R Kaestner, KH Kazazian, HH Venditti, CP AF Chandler, Randy J. Sloan, Jennifer Fu, Hong Tsai, Matthew Stabler, Sally Allen, Robert Kaestner, Klaus H. Kazazian, Haig H. Venditti, Charles P. TI Metabolic phenotype of methylmalonic acidemia in mice and humans: the role of skeletal muscle SO BMC MEDICAL GENETICS LA English DT Article ID LIVER-KIDNEY TRANSPLANTATION; COA MUTASE DEFICIENCY; CHAIN AMINO-ACIDS; PROPIONATE METABOLISM; INBORN-ERRORS; ORGANIC ACIDEMIAS; FATTY-ACIDS; ACIDURIA; IDENTIFICATION; MANAGEMENT AB Background: Mutations in methylmalonyl-CoA mutase cause methylmalonic acidemia, a common organic aciduria. Current treatment regimens rely on dietary management and, in severely affected patients, liver or combined liver-kidney transplantation. For undetermined reasons, transplantation does not correct the biochemical phenotype. Methods: To study the metabolic disturbances seen in this disorder, we have created a murine model with a null allele at the methylmalonyl-CoA mutase locus and correlated the results observed in the knock-out mice to patient data. To gain insight into the origin and magnitude of methylmalonic acid (MMA) production in humans with methylmalonyl-CoA mutase deficiency, we evaluated two methylmalonic acidemia patients who had received different variants of combined liver-kidney transplants, one with a complete liver replacement-kidney transplant and the other with an auxiliary liver graft-kidney transplant, and compared their metabolite production to four untransplanted patients with intact renal function. Results: Enzymatic, Western and Northern analyses demonstrated that the targeted allele was null and correctable by lentiviral complementation. Metabolite studies defined the magnitude and tempo of plasma MMA concentrations in the mice. Before a fatal metabolic crisis developed in the first 24-48 hours, the methylmalonic acid content per gram wet-weight was massively elevated in the skeletal muscle as well as the kidneys, liver and brain. Near the end of life, extreme elevations in tissue MMA were present primarily in the liver. The transplant patients studied when well and on dietary therapy, displayed massive elevations of MMA in the plasma and urine, comparable to the levels seen in the untransplanted patients with similar enzymatic phenotypes and dietary regimens. Conclusion: The combined observations from the murine metabolite studies and patient investigations indicate that during homeostasis, a large portion of circulating MMA has an extra-heptorenal origin and likely derives from the skeletal muscle. Our studies suggest that modulating skeletal muscle metabolism may represent a strategy to increase metabolic capacity in methylmalonic acidemia as well as other organic acidurias. This mouse model will be useful for further investigations exploring disease mechanisms and therapeutic interventions in methylmalonic acidemia, a devastating disorder of intermediary metabolism. C1 [Chandler, Randy J.; Sloan, Jennifer; Tsai, Matthew; Venditti, Charles P.] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. [Fu, Hong; Kaestner, Klaus H.; Kazazian, Haig H.] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19114 USA. [Stabler, Sally; Allen, Robert] Univ Colorado, Sch Med, Dept Med, Denver, CO 80206 USA. RP Venditti, CP (reprint author), NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. EM rchandler@mail.nih.gov; jsloan@mail.nih.gov; kaestner@mail.med.upenn.edu; matt.tsai@gmail.com; sally.Stabler@UCHSC.edu; robert.allen@uchsc.edu; kaestner@mail.med.upenn.edu; kazazian@mail.med.upenn.edu; venditti@mail.nih.gov FU Intramural NIH HHS [Z01 HG200318-04, Z01 HG200318-05, Z99 HG999999]; NIDDK NIH HHS [DK049210, P01 DK049210] NR 57 TC 20 Z9 20 U1 2 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD OCT 15 PY 2007 VL 8 AR 64 DI 10.1186/1471-2350-8-64 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 242ZT UT WOS:000251765400001 PM 17937813 ER PT J AU Compton, C AF Compton, Carolyn TI Getting to personalized cancer medicine - Taking out the garbage SO CANCER LA English DT Editorial Material C1 NCI, Off Biorepositories & Biospecimen Res, Bethesda, MD 20892 USA. NCI, Off Technol & Ind Relat, Bethesda, MD 20892 USA. RP Compton, C (reprint author), NCI, Off Biorepositories & Biospecimen Res, Room 10A31,31 Ctr Dr, Bethesda, MD 20892 USA. EM comptcar@mail.nih.gov RI Crozier, Laura/A-7950-2013 NR 1 TC 38 Z9 39 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD OCT 15 PY 2007 VL 110 IS 8 BP 1641 EP 1643 DI 10.1002/cncr.22966 PG 3 WC Oncology SC Oncology GA 218RT UT WOS:000250033300001 PM 17763370 ER PT J AU Mudduluru, G Medved, F Grobhoz, R Jost, C Gruber, A Leupold, JH Post, S Jansen, A Colburn, NH Allgayer, H AF Mudduluru, Giridhar Medved, Fabian Grobhoz, Rainer Jost, Camela Gruber, Anette Leupold, Joerg H. Post, Stefan Jansen, Aaron Colburn, Nancy H. Allgayer, Heike TI Loss of programmed cell death 4 expression marks adenoma-carcinoma transition, correlates inversely with phosphorylated protein kinase B, and is an independent prognostic factor in resected colorectal cancer SO CANCER LA English DT Article DE colorectal cancer; programmed cell death 4; adenoma; protein kinase B; prognosis ID TRANSFORMATION SUPPRESSOR PDCD4; INITIATION-FACTOR 4A; RECEPTOR U-PAR; TOPOISOMERASE INHIBITORS; TUMOR PROGRESSION; GENE; UROKINASE; TRANSLATION; PROMOTER; INVASION AB BACKGROUND. Programmed cell death 4 (Pdcd4) inhibits malignant transformation, and initial studies of Pdcd4 suggested the regulation of Pdcd4 localization by protein kinase B (Akt). However, supporting patient tissue data are missing, and the diagnostic/prognostic potential of Pdcd4 rarely has been studied. The objectives of the current were 1) to determine Pdcd4 as a diagnostic marker in the adenoma-carcinoma sequence, 2) to support phosphorylated Akt (pAkt)-mediated Pdcd4 regulation in vivo, and 3) to obtain the first prognostic evidence of Pdcd4 in colorectal cancer. METHODS. Tumor samples and normal tissues from 71 patients with colorectal cancer who were followed prospectively (median follow-up, 36 months) and 42 adenomas were analyzed for Pdcd4, Akt, and pAkt in immunohistochemical and Western blot analyses. RESULTS. A significant reduction in Pdcd4 was observed between normal mucosa and adenomas and between adenomas and tumor samples (P < .01 and P < .01, respectively). Normal mucosa demonstrated strong nuclear Pdcd4, which was reduced significantly in adenomas (P < .01) and almost was lost in tumors (P < .01). pAkt was correlated inversely with Pdcd4 and with the transition of Pdcd4 from nucleus to cytoplasm (P < .01). Kaplan-Meier analysis (using the Mantel-Cox log-rank test) indicated a significant correlation between the loss of total and nuclear Pdcd4 in tumors and overall survival (P < .05 and P < .02, respectively) and disease-specific survival (P < .01 and P < .01, respectively). In multivariate analysis, loss of total or nuclear Pdcd4 was an independent predictor of disease-specific or overall survival. CONCLUSIONS. To the authors' knowledge, this is the first study to demonstrate an independent prognostic impact of Pdcd4 and its expression pattern in colorectal cancer. Data from this study support the regulation of Pdcd4 locatization by pAkt in vivo. Pdcd4 immunohistochemistry may be useful as a supportive diagnostic tool for the transition between normal, adenoma, and tumor tissues. C1 Univ Heidelberg, Dept Expt Surg mol Oncol Solid Tumors, Mannheim Med Fac,German Canc Res Ctr, Collaborat Unit,Deutsch Krebforsch Zentrum Heidel, D-68167 Mannheim, Germany. Univ Homburg, Dept Pathol, Saar, Germany. Univ Heidelberg, Mannheim Fac, Dept Surg, D-6800 Mannheim, Germany. Natl Canc Inst, Gene Regulat Sect, Bethesda, MD USA. RP Allgayer, H (reprint author), Univ Heidelberg, Dept Expt Surg mol Oncol Solid Tumors, Mannheim Med Fac,German Canc Res Ctr, Collaborat Unit,Deutsch Krebforsch Zentrum Heidel, D-68167 Mannheim, Germany. EM heike.allgayer@chir.ma.uni-heidelberg.de NR 30 TC 127 Z9 136 U1 1 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD OCT 15 PY 2007 VL 110 IS 8 BP 1697 EP 1707 DI 10.1002/cncr.22983 PG 11 WC Oncology SC Oncology GA 218RT UT WOS:000250033300009 PM 17849461 ER PT J AU Sauna, ZE Kimchi-Sarfaty, C Ambudkar, SV Gottesman, MM AF Sauna, Zuben E. Kimchi-Sarfaty, Chava Ambudkar, Suresh V. Gottesman, Michael M. TI Silent Polymorphisms speak: How they affect pharmacogenomics and the treatment of cancer SO CANCER RESEARCH LA English DT Review ID ALZHEIMERS-DISEASE; RATIO TEST; MDR1 GENE; PROTEIN; ASSOCIATION; REGIONS AB Polymorphisms in the human genome contribute to wide variations in how individuals respond to medications, either by changing the pharmacokinetics of drugs or by altering the cellular response to therapeutic agents. The goal of the emerging discipline of pharmacogenomics is to personalize therapy based on an individual's genotype. Due to the relatively large frequency of single-nucleotide polymorphisms (SNP) in the human genome, synonymous SNPs are often disregarded in many pharmacogenomic studies based on the assumption that these are silent. We have shown recently that synonymous SNPs in ABCB1 (P-glycoprotein), which is implicated both in determining drug pharmacoldnetics and multidrug resistance in human cancer cells, can affect protein conformation and function. We discuss the importance of polymorphisms in drug metabolizing enzymes and transporters in anticancer therapy and suggest that synonymous polymorphisms may play a more significant role than is currently assumed. C1 NCI, Cell Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. US FDA, Ctr Biol Evaluat & Res, Bethesda, MD USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, Canc Res Ctr, NIH, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. EM mgottesman@nih.gov FU Intramural NIH HHS NR 29 TC 153 Z9 158 U1 1 U2 21 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 OCT 15 PY 2007 VL 67 IS 20 BP 9609 EP 9612 DI 10.1158/0008-5472.CAN-07-2377 PG 4 WC Oncology SC Oncology GA 222HG UT WOS:000250286300002 PM 17942888 ER PT J AU Takami, T Kaposi-Novak, P Uchida, K Gomez-Quiroz, LE Conner, EA Factor, VM Thorgeirsson, SS AF Takami, Taro Kaposi-Novak, Pal Uchida, Koichi Gomez-Quiroz, Luis E. Conner, Elizabeth A. Factor, Valentina M. Thorgeirsson, Snorri S. TI Loss of hepatocyte growth factor/c-Met signaling pathway accelerates early stages of N-nitrosodiethylamine-induced hepatocarcinogenesis SO CANCER RESEARCH LA English DT Article ID TRANSGENIC MOUSE MODEL; HEPATOCELLULAR-CARCINOMA CELLS; RECEPTOR C-MET; LIVER-REGENERATION; CRE RECOMBINASE; DNA-DAMAGE; RAT-LIVER; OXIDATIVE STRESS; MAMMALIAN-CELLS; FACTOR-ALPHA AB Hepatocyte growth factor (HGF) has been reported to have both positive and negative effects on carcinogenesis. Here, we show that the loss of c-Met signaling in hepatocytes enhanced rather than suppressed the early stages of chemical hepatocarcinogenesis. c-Met conditional knockout mice (c-metfl/fl, AlbCre(+/-); MetLivKO) treated with N-nitrosodiethylamine developed Significantly more and bigger tumors and with a shorter latency compared with control (w/w, AlbCre+/-; Cre-Ctrl) mice. Accelerated tumor development was associated with increased rate of cell proliferation and prolonged activation of epidermal growth factor receptor (EGFR) signaling. MetLivKO livers treated with N-nitrosodiethylamine also displayed elevated lipid peroxidation, decreased ratio of reduced glutathione to oxidized glutathione, and up-regulation of superoxide dismutase I and heat shock protein 70, all consistent with increased oxidative stress. Likewise, gene expression profiling done at 3 and 5 months after N-nitrosodiethylamine treatment revealed up-regulation of genes associated with cell proliferation and stress responses in c-Met mutant livers. The negative effects of c-Met deficiency were reversed by chronic p.o. administration of antioxidant N-acetyl-L-eysteine. N-acetyl-L-cysteine blocked the EGFR activation and reduced the N-nitrosodiethylamineinitiated hepatocarcinogenesis to the levels of Cre-Ctrl mice, These results argue that intact HGF/c-Met signaling is essential for maintaining normal redox homeostasis in the liver and has tumor suppressor effect(s) during the early stages of Nnitrosodiethylamine-induced hepatocarcinogenesis. C1 NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Thorgeirsson, SS (reprint author), NCI, Expt Carcinogenesis Lab, Ctr Canc Res, NIH, Bldg 37,Room 4146A, Bethesda, MD 20892 USA. EM snorri_s_thorgeirsson@nih.gov RI Gomez-Quiroz, Luis/L-8415-2013; OI Gomez-Quiroz, Luis Enrique/0000-0002-5704-5985 FU Intramural NIH HHS NR 53 TC 67 Z9 71 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2007 VL 67 IS 20 BP 9844 EP 9851 DI 10.1158/0008-5472.CAN-07-1905 PG 8 WC Oncology SC Oncology GA 222HG UT WOS:000250286300029 PM 17942915 ER PT J AU Jin, W Yun, C Kim, HS Kim, SJ AF Jin, Wook Yun, Chohee Kim, Hae-Suk Kim, Seong-Jin TI TrkC binds to the bone morphogenetic protein type II receptor to suppress bone morphogenetic protein signaling SO CANCER RESEARCH LA English DT Article ID NERVE GROWTH-FACTOR; PROSTATE-CANCER CELLS; JUVENILE POLYPOSIS; NEUROTROPHIN RECEPTORS; PERINEURAL INVASION; GERMLINE MUTATIONS; NEURAL DEVELOPMENT; KINASE RECEPTOR; EXPRESSION; MOUSE AB TrkC, a member of the tropomyosin-related kinase (Trk) family of neurotrophin receptors, is implicated in the growth and survival of human cancer tissues. TrkC is also a potent oncoprotein expressed in tumors derived from multiple cell lineages, and functions as an active protein tyrosine kinase by neurotrophin-3 (NT-3). We previously reported that TrkC plays an essential role in tumor growth and metastasis in a murine cancer cell line. Here, we report that expression of TrkC suppresses bone morphogenetic protein 2 (BMP-2)induced Smad1 phosphorylation and transcriptional activation. In the highly metastatic CT26 murine colon cancer cell line, which expresses endogenous TrkC, silencing TrkC expression by small interfering RNA significantly enhanced BMP-2-induced Smad1 phosphorylation and restored BMP-2 growth inhibitory activity. In contrast, expression of TrkC in RIE-1 cells, in which TrkC is not expressed, completely suppressed BMP-2 transcriptional activation. Furthermore, we showed that TrkC directly binds to the BMP type II receptor (BMPRII), thereby preventing it from interacting with the BMPRI. This activity requires a functional TrkC protein tyrosine kinase, and the BMPRII seems to be a direct target of TrkC. Our findings provide evidence for a previously unknown mechanism by which TrkC, a neuronal receptor, can block BNIP tumor-suppressor activity. C1 Gachon Univ Med & Sci, Lab Cell Regulat & Carcinogenesis, Lee Gil Ya Canc & Diabet Inst, Inchon 406840, South Korea. NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Kim, SJ (reprint author), Gachon Univ Med & Sci, Lab Cell Regulat & Carcinogenesis, Lee Gil Ya Canc & Diabet Inst, 7-45 Songdo Dong, Inchon 406840, South Korea. EM jasonsjkim@gachon.ac.kr FU Intramural NIH HHS NR 50 TC 17 Z9 19 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2007 VL 67 IS 20 BP 9869 EP 9877 DI 10.1158/0008-5472.CAN-07-0436 PG 9 WC Oncology SC Oncology GA 222HG UT WOS:000250286300032 PM 17942918 ER PT J AU Shimamura, T Royal, RE Kioi, M Nakajima, A Husain, SR Puri, RK AF Shimamura, Takeshi Royal, Richard E. Kioi, Mitomu Nakajima, Atsushi Husain, Syed R. Puri, Raj K. TI Interleukin-4 cytotoxin therapy synergizes with gemcitabine in a mouse model of pancreatic ductal adenocarcinoma SO CANCER RESEARCH LA English DT Article ID RECEPTOR-DIRECTED CYTOTOXIN; RECOMBINANT HUMAN INTERLEUKIN-4; RECURRENT MALIGNANT GLIOMA; PHASE-I TRIAL; PSEUDOMONAS EXOTOXIN; ENDOTHELIAL-CELLS; ORTHOTOPIC MODEL; CANCER THERAPY; IL-4 RECEPTOR; CARCINOMA AB Targeting cell surface receptors with cytotoxins or immunotoxins provides a unique opportunity for tumor therapy. Here, we show the efficacy of the combination therapy of gemcitabine with an interleukin-4 (IL-4) cytotoxin composed of IL-4 and truncated Pseudomonas exotoxin in animal models of pancreatic ductal adenocarcinoma (PDA). We have observed that 42 of 70 (60%) tumor samples from patients with PDA express moderate- to high-density surface IL-4 receptor (11,411), whereas normal pancreatic samples express no or low-density IL-4R. IL-4 cytotoxin was specifically and highly cytotoxic [50% protein synthesis inhibition (IC50) ranging from >0.1 to 13 ng/mL] to six of eight pancreatic cancer cell lines, whereas no cytotoxicity (IC50 >1,000 ng/mL) was observed in normal human pancreatic duct epithelium cells, fibroblasts, and human umbilical vein endothelial cells (HUVEC). We also showed that IL-4 cytotoxin in combination with gemcitabine exhibited synergistic antitumor activity in vitro. To confirm synergistic antitumor activity in vivo and monitor precise real-time disease progression, we used a novel metastatic and orthotopic mouse model using green fluorescent protein-transfected cancer cells and whole-body imaging system. The combination of both agents caused complete eradication of tumors in 40% of nude mice with small established PDA tumors. In addition, combined treatment significantly prolonged the survival of nude mice bearing day 14 advanced distant metastatic PDA tumors. Similar results were observed in mice xenografted with PDA obtained from a patient undergoing surgical resection. These results indicate that IL-4 cytotoxin combined with gemcitabine may provide effective therapy for the treatment of patients with PDA. C1 US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Tumor Vaccines & Biotechnol Branch, Rockville, MD 20857 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. Yokohama City Univ, Grad Sch Med, Div Gastroenterol, Yokohama, Kanagawa 232, Japan. RP Puri, RK (reprint author), NIH Bldg 29B,Room 2NN0,HFM 735,29 Lincoln Dr, Bethesda, MD 20892 USA. EM raj.puri@fda.hhs.gov OI Kioi, Mitomu/0000-0002-7981-3340 NR 50 TC 24 Z9 25 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2007 VL 67 IS 20 BP 9903 EP 9912 DI 10.1158/0008-5472.CAN-06-4558 PG 10 WC Oncology SC Oncology GA 222HG UT WOS:000250286300036 PM 17942922 ER PT J AU Rao, VA Agama, K Holbeck, S Pommier, Y AF Rao, V. Ashutosh Agama, Keli Holbeck, Susan Pommier, Yves TI Batracylin (NSC 320846), a dual inhibitor of DNA Topoisomerases I and II induces histone gamma-H2AX as a biomarker of DNA damage SO CANCER RESEARCH LA English DT Article ID DOUBLE-STRAND BREAKS; TUMOR-CELL-LINES; ANTITUMOR-ACTIVITY; CLEAVAGE COMPLEXES; MAMMALIAN-CELLS; FILTER ELUTION; ACTIVATION; DRUGS; PHOSPHORYLATION; H2AX AB Batracylin (8-aminoisoindolo [1,2-b]quinazolin-10(12H)-one; NSC320846) is an investigational clinical anticancer agent. Previous animal studies showed activity against solid tumors and Adriamycin-resistant leukemia. We initially sought to test the proposed Top2-mediated DNA cleavage activity of batracylin and identify potential biomarkers for activity. COMPARE analysis in the NCI-60 cell lines showed batracylin activity to be most closely related to the class of Top2 inhibitors. The 50% growth inhibition (GI(50)) value for batracylin in HT29 colon carcinoma cells was 10 [mu mol/L. DNA-protein cross-links, consistent with Top2 targeting, were measured by alkaline elution. DNA single-strand breaks were also detected and found to be protein associated. However, only a weak induction of DNA double-strand breaks was observed. Because batracylin induced almost exclusively DNA single-strand breaks, we tested batracylin as a Top1. inhibitor. Batracylin exhibited both Top1- and Top2 alpha/beta-mediated DNA cleavage in vitro and in cells. The phosphorylation of histone (gamma-H2AX) was tested to measure the extent of DNA damage. Kinetics of gamma-H2AX "foci" showed early activation with low [mu mol/L concentrations, thus presenting a useful early biomarker of DNA damage. The halflife of gamma-H2AX signal reversal after drug removal was consistent with reversal of DNA-protein cross-links. The persistence of the DNA-protein complexes induced by batracylin was markedly longer than by etoposide or camptothecin. The phosphorylated DNA damage-responsive kinase, ataxia telangiectasia mutated, was also found activated at sites of gamma-H2AX. The cell cycle checkpoint kinase, Chk2, was only weakly phosphorylated. Thus, batracylin is a dual Top1 and Top2 inhibitor and gamma-H2AX could be considered a biomarker in the ongoing clinical trials. C1 NCI, Mol Pharmacol Lab, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. NCI, Dev Therapeut Program, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Dept Hlth & Human Serv, NIH, 37 Convent Dr,37-5068, Bethesda, MD 20892 USA. EM pommier@nih.gov FU Intramural NIH HHS NR 50 TC 46 Z9 46 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2007 VL 67 IS 20 BP 9971 EP 9979 DI 10.1158/0008-5472.CAN-07-0804 PG 9 WC Oncology SC Oncology GA 222HG UT WOS:000250286300044 PM 17942930 ER PT J AU Zhang, Q Yu, YA Wang, E Chen, N Dannel, RL Munson, PJ Marincola, FM Szalay, AA AF Zhang, Qian Yu, Yong A. Wang, Ena Chen, Nanhai Dannel, Robert L. Munson, Peter J. Marincola, Francesco M. Szalay, Aladar A. TI Eradication of solid human breast tumors in nude mice with an intravenously injected light-emitting oncolytic vaccinia virus SO CANCER RESEARCH LA English DT Article ID HERPES-SIMPLEX-VIRUS; SYSTEMIC DELIVERY; INNATE IMMUNITY; IMMUNODEFICIENT MICE; ANTITUMOR-ACTIVITY; THYMIDINE KINASE; THERAPY; CANCER; GENE; XENOGRAFTS AB Previously, we reported that a recombinant vaccinia virus (VACV) carrying a light-emitting fusion gene enters, replicates in, and reveals the locations of tumors in mice. A new recombinant VACV, GLV-1h68, as a simultaneous diagnostic and therapeutic agent, was constructed by inserting three expression cassettes (encoding Renilla luciferase-Aequorea green fluorescent protein fusion, beta-galactosidase, and beta-glucuronidase) into the F14.5L, J2R (encoding thymidine kinase) and A56R (encoding hemagglutinin) loci of the viral genome, respectively. I.v. injections of GLV-1h68 (I X 107 plaqueforming unit per mouse) into nude mice with established (similar to 300-500 mm(3)) s.c. GI-101A human breast tumors were used to evaluate its toxicity, tumor targeting specificity, and oncolytic efficacy. GLV-1h68 showed an enhanced tumor targeting specificity and much reduced toxicity compared with its parental LIVP strains. The tumors colonized by GLV1h68 exhibited growth, inhibition, and regression phases followed by tumor eradication within 130 days in 95% of the mice tested. Tumor regression in live animals was monitored in real time based on decreasing light emission, hence demonstrating the concept of a combined oncolyticvirusmediated tumor diagnosis and therapy system. Transcriptional profiling of regressing tumors based on a mouse-specific platform revealed gene expression signatures consistent with immune defense activation, inclusive of IFN-stimulated genes (STAT-1 and IRF-7), cytokines, chemokines, and innate immune effector function. These findings suggest that immune activation may combine with viral oncolysis to induce tumor eradication in this model, providing a novel perspective for the design of oncolytic viral therapies for human cancers. [Cancer Res 2007;67(20):10038-46] C1 Genelux Corp, San Diego Sci Ctr, San Diego, CA 92109 USA. Ctr Clin, Dept Crit Care Med, Funct Genom & Proteom Fac, Bethesda, MD USA. NIH, Ctr Informat Technol, Div Computat Biosci, Math & Stat Comp Lab, Bethesda, MD 20892 USA. Univ Wurzburg Hubland, Inst Biochem, Virchow Ctr Expt Biomed, Wurzburg, Germany. Univ Wurzburg Hubland, Inst Mol Infect Biol, Wurzburg, Germany. RP Szalay, AA (reprint author), Genelux Corp, San Diego Sci Ctr, 3030 Bunker Hill St, San Diego, CA 92109 USA. EM aaszalay@genelux.com NR 37 TC 122 Z9 127 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 15 PY 2007 VL 67 IS 20 BP 10038 EP 10046 DI 10.1158/0008-5472.CAN-07-0146 PG 9 WC Oncology SC Oncology GA 222HG UT WOS:000250286300052 PM 17942938 ER PT J AU Aravind, L Iyer, LM Wu, C AF Aravind, L. Iyer, Lakshminarayan M. Wu, Carl TI Domain architectures of the Scm3p protein provide insights into centromere function and evolution SO CELL CYCLE LA English DT Article DE centromere diversity; rapid evolution; zinc fingers; kinetochore; Ndc10p; Hot1p; transposon; transposase ID DNA; SEQUENCE; KINETOCHORE; HISTONE; MOTIFS; FUNGI; CSE4 AB Recently, Scm3p has been shown to be a nonhistone component of centromeric chromatin that binds stoichiometrically to CenH3-H4 histones, and to be required for the assembly of kinetochores in Saccharomyces cerevisiae. Scm3p is conserved across fungi, and displays a remarkable variation in protein size, ranging from similar to 200 amino acids in S. cerevisiae to similar to 1300 amino acids in Neurospora crassa. This is primarily due a variable C-terminal segment that is linked to a conserved N-terminal, CenH3-interacting domain. We have discovered that the extended C-terminal region of Scm3p is strikingly characterized by lineage-specific fusions of single or multiple predicted DNA-binding domains different versions of the MYB and C2H2 zinc finger domains, AT-hooks, and a novel cysteine-rich metal-chelating cluster that are absent from the small versions of Scm3. Instead, S. cerevisiae point centromeres are recognized by components of the CBF3 DNA binding complex, which are conserved amongst close relatives of budding yeast, but are correspondingly absent from more distant fungi that possess regional centromeres. Hence, the C-terminal DNA binding motifs found in large Scm3p proteins may, along with CenH3, serve as a key epigenetic signal by recognizing and accommodating the lineage-specific diversity of centromere DNA in course of evolution. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD USA. NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20894 USA. RP Aravind, L (reprint author), NCI, Lab Biochem & Mol Biol, NIH, Bethesda, MD 20894 USA. EM aravind@ncbi.nlm.nih.gov FU Intramural NIH HHS [Z01 LM594244-01, Z99 LM999999] NR 19 TC 18 Z9 18 U1 1 U2 2 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD OCT 15 PY 2007 VL 6 IS 20 BP 2511 EP 2515 PG 5 WC Cell Biology SC Cell Biology GA 233IY UT WOS:000251085800013 PM 17704645 ER PT J AU Chaturvedi, AK Wilson, M Sanders-Lewis, KA Katki, HA Urquhart, N Walters, MA Miley, W Cranston, B Hanchard, B Hisada, M AF Chaturvedi, Anil K. Wilson, Marianna Sanders-Lewis, Kolby A. Katki, Hormuzd A. Urquhart, Nicole Walters, Michael A. Miley, Wendell Cranston, Beverly Hanchard, Barrie Hisada, Michie TI Hematologic and biochemical changes associated with human T lymphotropic virus type 1 infection in Jamaica: A report from the population-based blood donors study SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID CELL LEUKEMIA LYMPHOMA; HTLV-I; STRONGYLOIDES-STERCORALIS; ABNORMAL LYMPHOCYTES; MIYAZAKI COHORT; IMMUNE-RESPONSE; CARRIERS; JAPAN; MORTALITY; MARKERS AB Objective. We investigated changes in hematologic and biochemical parameters associated with human T lymphotropic virus type 1 (HTLV-1) infection, antibody titer, and provirus load. Additionally, on a subset of participants, we assessed the epidemiologic relationship of HTLV-1 with Strongyloides stercoralis. Methods. Among volunteer blood donors in Jamaica, HTLV-1 carriers (n = 482) were frequency matched with HTLV-1 negative subjects (n = 355) by age (+/-5 years), sex, and date of blood donation (+/-3 months). HTLV-1 antibody titer, provirus load, S. stercoralis IgG antibodies, complete blood cell count, blood chemistry, and urinalysis parameters were measured. Results. HTLV-1 carriers, compared with HTLV-1-negative individuals, had elevated levels of cleaved lymphocytes (24.5% vs. 16.4%), any lymphocyte abnormalities (atypical, cleaved, and reactive lymphocytes combined, 45.7% vs. 35.4%), and gamma-glutamyl transferase levels (21.2 vs. 19.6 IU/L), as well as lower eosinophil count (2.6% vs. 3.1%). Among carriers, HTLV-1 antibody titer (n = 482) was inversely correlated with mean corpuscular volume (r = -0.10) and positively correlated with levels of total protein (r = 0.16), phosphorus (r = 0.12), and lactate dehydrogenase (r = 0.24). HTLV-1-provirus load (n = 326) was higher among carriers with cleaved lymphocytes and any lymphocyte abnormalities. Provirus load was inversely correlated with hemoglobin (r = -0.11), mean corpuscular volume (r = -0.15), neutrophil (r = -0.12), and eosinophil (r = -0.19) levels and was positively correlated with lactate dehydrogenase levels (r = 0.12). Provirus load was significantly higher among male than female subjects. S. stercoralis antibodies were detected in 35 (12.1%) of 288 participants but were not associated with HTLV-1 status, antibody titer, or provirus load. Conclusions. Markers of HTLV-1 infection (infection status, antibody titer, and provirus load) are associated with hematologic and biochemical alterations, such as lymphocyte abnormalities, anemia, decreased eosinophils, and elevated lactate dehydrogenase levels. C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. NCI, Viral Epidemiol Sect, Sci Applicat Int Corp, Frederick, MD 21701 USA. Ctr Dis Control & Prevent, Div Parasit Dis, Natl Ctr Infect Dis, Atlanta, GA USA. Univ W Indies, Dept Pathol, Kingston 7, Jamaica. RP Chaturvedi, AK (reprint author), Viral Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 7072, Rockville, MD 20852 USA. EM chaturva@mail.nih.gov RI Katki, Hormuzd/B-4003-2015; Chaturvedi, Anil/J-2024-2015 OI Chaturvedi, Anil/0000-0003-2696-8899 FU Intramural NIH HHS NR 33 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 OCT 15 PY 2007 VL 45 IS 8 BP 975 EP 982 DI 10.1086/521932 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 211YT UT WOS:000249560900009 PM 17879911 ER PT J AU Alkhatib, G Berger, EA AF Alkhatib, Ghalib Berger, Edward A. TI HIV coreceptors: From discovery and designation to new paradigms and promise SO EUROPEAN JOURNAL OF MEDICAL RESEARCH LA English DT Article DE HIV; AIDS; coreceptor; CCR5; CXCR4; receptor; CD4; chemokine; GPCR; tropism; transmission; pathogenesis; fusion; entry; antibody; resistance; nomenclature; treatment; vaccine; microbicide; maraviroc ID IMMUNODEFICIENCY-VIRUS TYPE-1; GP120 ENVELOPE GLYCOPROTEIN; MOLECULE CCR5 INHIBITOR; CHEMOKINE RECEPTOR GENE; CD8(+) T-CELLS; FUNCTIONAL EXPRESSION; CD4-MEDIATED FUSION; SUPPRESSIVE FACTORS; PRIMARY MACROPHAGES; MEMBRANE-FUSION AB Just over a decade ago, the specific chemokine receptors CXCR4 and CCR5 were identified as the essential coreceptors that function along with CD4 to enable human immunodeficiency virus (HIV) entry into target cells. The coreceptor discoveries immediately provided a molecular explanation for the distinct tropisms of different HIV-1 isolates for different CD4-positive target cell types, and revealed fundamentally new insights into host and viral factors influencing HIV transmission and disease. The sequential 2-step mechanism by which the HIV envelope glycoprotein (Env) interacts first with CD4, then with coreceptor, revealed a major mechanism by which conserved Env epitopes are protected from antibody-mediated neutralization. The Env-coreceptor interaction has become a major target for the development of novel antiviral strategies to treat and prevent HIV infection. C1 Indiana Univ, Sch Med, Walther Canc Inst, Dept Microbiol & Immunol, Indianapolis, IN 46204 USA. NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. RP Alkhatib, G (reprint author), Indiana Univ, Sch Med, Walther Canc Inst, Dept Microbiol & Immunol, Indianapolis, IN 46204 USA. EM galkhati@iupui.edu FU Intramural NIH HHS; NIAID NIH HHS [R01 AI052019] NR 95 TC 26 Z9 27 U1 1 U2 2 PU I HOLZAPFEL VERLAG GMBH PI MUNICH PA HARTHAUSER STR 105, 81545 MUNICH, GERMANY SN 0949-2321 J9 EUR J MED RES JI Eur. J. Med. Res. PD OCT 15 PY 2007 VL 12 IS 9 BP 375 EP 384 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 224YC UT WOS:000250483300003 PM 17933717 ER PT J AU Berger, EA Alkhatib, G AF Berger, Edward A. Alkhatib, Ghalib TI HIV gp120 interactions with coreceptors: Insights from studies with CCR5-based peptides SO EUROPEAN JOURNAL OF MEDICAL RESEARCH LA English DT Article DE HIV; AIDS; coreceptor; CCR5; CXCR4; chemokine receptor; CD4; GPCR; peptides; fusion; entry ID IMMUNODEFICIENCY-VIRUS TYPE-1; PROTEIN-COUPLED RECEPTOR; AMINO-TERMINAL DOMAIN; ENVELOPE GLYCOPROTEIN; CCR5 CORECEPTOR; ADAPTIVE MUTATIONS; CRYSTAL-STRUCTURE; ATOMIC-STRUCTURE; SOLUBLE CD4; N-TERMINUS AB Human immunodeficiency virus enters cells by a direct fusion mechanism triggered by sequential binding of the gp120 subunit of the envelope glycoprotein, first to CD4, then to the coreceptor CCR5 or CXCR4. The coreceptors are chemokine receptors, members of the superfamily of G protein-coupled receptors that are characterized by 7 transmembrane domains. gp120 is presumed to interact with the extracellular portion, which consists of the N-terminal segment and three extracellular loops. Synthetic peptides based on these regions have proven to be valuable probes for elucidating the molecular details of the complex gp120-coreceptor interactions. C1 NIAID, NIH, Viral Dis Lab, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA. RP Alkhatib, G (reprint author), NIAID, NIH, Viral Dis Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM galkhati@iupui.edu FU NIAID NIH HHS [R01 AI052019] NR 37 TC 3 Z9 3 U1 2 U2 2 PU I HOLZAPFEL VERLAG GMBH PI MUNICH PA RAUCHSTR 8, D-81679 MUNICH, GERMANY SN 0949-2321 J9 EUR J MED RES JI Eur. J. Med. Res. PD OCT 15 PY 2007 VL 12 IS 9 BP 403 EP 407 PG 5 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 224YC UT WOS:000250483300007 PM 17933721 ER PT J AU Romanowska, M Maciag, A Smith, AL Fields, JR Fornwald, LW Kikawa, KD Kasprzak, KS Anderson, LM AF Romanowska, Malgorzata Maciag, Anna Smith, Andrew L. Fields, Janet R. Fornwald, Laura W. Kikawa, Keith D. Kasprzak, Kazimierz S. Anderson, Lucy M. TI DNA damage, superoxide, and mutant K-ras in human lung adenocarcinoma cells SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE human lung adenocarcinoma; DNA damage; single-strand breaks; comet assay; K-ras; reactive oxygen species; superoxide; OGG1; manganese superoxide dismutase ID GENETIC INSTABILITY; HA-RAS; DIFFERENTIAL EXPRESSION; OXIDATIVE DAMAGE; EPITHELIAL-CELLS; CANCER PATIENTS; RISK; REPAIR; POLYMORPHISMS; ACTIVATION AB DNA single-strand breaks (quantitative comet assay) were assessed to indicate ongoing genetic instability in a panel of human lung adenocarcinoma cell lines. Of these, 19/20 showed more DNA damage than a nontransformed cell line from human peripheral lung epithelium, HPL1D. DNA damage was significantly greater in those derived from pleural effusates vs those from lymph node metastases. DNA strand breaks correlated positively with superoxide (nitroblue tetrazolium reduction assay), and negatively with amount of OGG1, a repair enzyme for oxidative DNA damage. Levels of CuZn superoxide dismutase varied moderately among the lines and did not correlate with other parameters. A role for mutant K-ras through generation of reactive oxygen species was examined. Cells with mutant K-ras had significantly lower amounts of manganese superoxide dismutase (MnSOD) vs those with wild-type K-ras, but MnSOD protein correlated positively with superoxide levels. In a subset of cell lines with similar levels of MnSOD, comparable to those in HPL1D cells, K-ras activity correlated positively with levels of both superoxide and DNA strand breaks. These results suggest that persistent DNA damage in some lung adenocarcinoma cells may be caused by superoxide resulting from mutant K-ras activity, and that OGG1 is important for prevention of this damage. (c) 2007 Elsevier Inc. All rights reserved. C1 NCI, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. SAIC Frederick Inc, Frederick, MD 21702 USA. RP Maciag, A (reprint author), NCI, Comparat Carcinogenesis Lab, Bldg 538-206, Frederick, MD 21702 USA. EM amaciag@ncifcr.gov FU Intramural NIH HHS NR 53 TC 17 Z9 21 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD OCT 15 PY 2007 VL 43 IS 8 BP 1145 EP 1155 DI 10.1016/j.freeradbiomed.2007.07.004 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 215LB UT WOS:000249808800006 PM 17854710 ER PT J AU Jiang, JJ Corbett, J Hogg, N Mason, RP AF Jiang, JinJie Corbett, Jean Hogg, Neil Mason, Ronald P. TI An electron paramagnetic resonance investigation of the oxygen dependence of the arterial-venous gradient of nitrosyl hemoglobin in blood circulation SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE nitric oxide; hemoglobin; EPR; oxygen saturation; free radicals ID NITRIC-OXIDE; S-NITROSOHEMOGLOBIN; EPR SPECTROSCOPY; TREATED RATS; IN-VIVO; BIOCHEMICAL-CHARACTERIZATION; NITROSOTHIOL FORMATION; BIOLOGICAL-ACTIVITY; QUANTITATIVE EPR; FLOW REGULATION AB Whether there is a nitrosyl hemoglobin (HbNO) gradient between the venous and the arterial parts of the circulatory system is a very controversial issue in nitric oxide research. We have carefully evaluated the measurement of HbNO concentration in blood using EPR generated in vivo by the NO donor DEANO under various oxygen tensions. We found that the absolute concentrations of HbNO in venous and arterial blood were the same within experimental error, independent of hemoglobin saturation; only the ratios of 5-coordinate and 6-coordinate HbNO differed. The HbNO concentration increased when the oxygen concentration breathed by the rats decreased in a manner that was linear in hemoglobin saturation. These results do not support the existence of an arterial-venous gradient of HbNO under our experimental conditions. (c) 2007 Elsevier Inc. All rights reserved. C1 NIEHS, NIH, Chem Pharmacol Lab, Res Triangle Pk, NC 27709 USA. Med Coll Wisconsin, Dept Biophys, Milwaukee, WI 53226 USA. Med Coll Wisconsin, Free Rad Res Ctr, Milwaukee, WI 53226 USA. RP Jiang, JJ (reprint author), NIEHS, NIH, Chem Pharmacol Lab, Res Triangle Ph, Res Triangle Pk, NC 27709 USA. EM jiang1@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999, Z01 ES050117-17] NR 42 TC 6 Z9 8 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD OCT 15 PY 2007 VL 43 IS 8 BP 1208 EP 1215 DI 10.1016/j.freeradbiomed.2007.06.024 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 215LB UT WOS:000249808800012 PM 17854716 ER PT J AU Schymick, JC Talbot, K Traynor, BJ AF Schymick, J. C. Talbot, K. Traynor, B. J. TI Genetics of sporadic amyotrophic lateral sclerosis SO HUMAN MOLECULAR GENETICS LA English DT Review ID MOTOR-NEURON DISEASE; GENOME-WIDE ASSOCIATION; SPINAL MUSCULAR-ATROPHY; FRONTOTEMPORAL LOBAR DEGENERATION; HEAVY NEUROFILAMENT SUBUNIT; SUPEROXIDE-DISMUTASE GENE; HYPOXIA-RESPONSE ELEMENT; ALZHEIMERS-DISEASE; DUTCH POPULATION; HFE MUTATIONS AB Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized clinically by rapidly progressive paralysis leading ultimately to death from respiratory failure. There is substantial evidence suggesting that ALS is a heritable disease, and a number of genes have been identified as being causative in familial ALS. In contrast, the genetics of the much commoner sporadic form of the disease is poorly understood and no single gene has been definitively shown to increase the risk of developing ALS. In this review, we discuss the genetic evidence for each candidate gene that has been putatively associated with increased risk of sporadic ALS. We also review whole genome association studies of ALS and discuss the potential of this methodology for identifying genes relevant to motor neuron degeneration. C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. NIA, Neurogenet Lab, Bethesda, MD 20892 USA. Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England. Univ Oxford, John Radcliffe Hosp, Dept Clin Neurol, Oxford OX3 9DU, England. Johns Hopkins Univ Hosp, Dept Neurol, Baltimore, MD 21287 USA. RP Traynor, BJ (reprint author), NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. EM traynorb@mail.nih.gov RI Talbot, Kevin /F-7361-2011; Traynor, Bryan/G-5690-2010 FU Intramural NIH HHS NR 85 TC 103 Z9 105 U1 0 U2 9 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 EI 1460-2083 J9 HUM MOL GENET JI Hum. Mol. Genet. PD OCT 15 PY 2007 VL 16 SI 2 BP R233 EP R242 DI 10.1093/hmg/ddm215 PG 10 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 234LL UT WOS:000251165500015 PM 17911166 ER PT J AU Mahajan, R Blair, A Coble, J Lynch, CF Hoppin, JA Sandler, DP Alavanja, MCR AF Mahajan, Rajeev Blair, Aaron Coble, Joseph Lynch, Charles F. Hoppin, Jane A. Sandler, Dale P. Alavanja, Michael C. R. TI Carbaryl exposure and incident cancer in the Agricultural Health Study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE agriculture; carbamates; carbaryl; insecticides; neoplasms; occupational exposure ID NON-HODGKINS-LYMPHOMA; ENDOCRINE DISRUPTING CHEMICALS; CHINESE-HAMSTER CELLS; PESTICIDE APPLICATORS; CHROMATID EXCHANGES; NITROSO-COMPOUNDS; GENE-EXPRESSION; RISK-FACTORS; AH RECEPTOR; COSTA-RICA AB Carbaryl is a carbamate insecticide with a broad spectrum of uses in agricultural, commercial and household settings. It has previously been linked with non-Hodgkin lymphoma (NHL) but studies of cancer risk in humans are limited. We examined occupational carbaryl use and risk of all cancers in the Agricultural Health Study, a prospective study of a cohort of pesticide applicators in North Carolina and Iowa. This analysis included 21,416 subjects (1,291 cases) enrolled from 1993-1997 and followed for cancer incidence through 2003. Pesticide exposure and other data were collected using self-administered questionnaires. Poisson regression was used to calculate rate ratios (RRs) and 95% confidence intervals (Cls) while controlling for potential confounders. Carbaryl was not associated with cancer risk overall. Relative to subjects who never used carbaryl, melanoma risk was elevated with >175 lifetime exposure-days (RR = 4.11; 95%CI, 1.33-12.75; p-trend = 0.07), >10 years of use (RR 3.19; 95%CI, 1.28-7.92; p-trend = 0.04), or >10 days of use per year (RR = 5.50; 95%CI, 2.19-13.84; p-trend < 0.001). Risk remained after adjusting for sunlight exposure. Although not significant, there appeared to be a trend of decreasing prostate cancer risk with increasing level of exposure. A small increase in NHL risk was observed using some, but not all, exposure measures. No associations were observed with other examined cancer sites. Because the observed results were not hypothesized a priori and because of limited study of their biological plausibility, they should be interpreted with caution. (C) 2007 Wiley-Liss, Inc. C1 Natl Canc Inst, Natl Inst Hlth, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, Rockville, MD USA. Univ Iowa, Dept Epidemiol, Iowa City, IA USA. Natl Inst Hlth, Natl Inst Environm Hlth Sci, Dept Hlth & Human Serv, Epidemiol Branch, Res Triangle Pk, NC USA. RP Alavanja, MCR (reprint author), 6120 Executive Blvd, EPS 8000, MSC, Rockville, MD 20852 USA. EM alavanjm@mail.nih.gov OI Sandler, Dale/0000-0002-6776-0018 FU Intramural NIH HHS NR 45 TC 27 Z9 33 U1 2 U2 7 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 OCT 15 PY 2007 VL 121 IS 8 BP 1799 EP 1805 DI 10.1002/ijc.22836 PG 7 WC Oncology SC Oncology GA 211EX UT WOS:000249508200022 PM 17534892 ER PT J AU Chi, YH Jeang, KT AF Chi, Ya-Hui Jeang, Kuan-Teh TI Aneuploidy and cancer SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE aneuploidy; cancer; spindle assembly checkpoint; mitosis; cytokinesis; centrosome ID T-CELL LEUKEMIA; MITOTIC-SPINDLE CHECKPOINT; ABNORMAL CENTROSOME AMPLIFICATION; ONCOPROTEIN TAX TARGETS; EPSTEIN-BARR-VIRUS; CHROMOSOME INSTABILITY; GENOMIC INSTABILITY; ASSEMBLY CHECKPOINT; TUMOR-DEVELOPMENT; CYCLE ARREST AB The cell's euploid status is influenced by, amongst other mechanisms, an intact spindle assembly checkpoint (SAC), an accurate centrosome cycle, and proper cytokinesis. Studies in mammalian cells suggest that dysregulated SAC function, centrosome cycle, and cytokinesis can all contribute significantly to aneuploidy. Of interest, human cancers are frequently aneuploid and show altered expression in SAC genes. The SAC is a multi-protein complex that monitors against mis-segregation of sister chromatids. Several recent experimental mouse models have suggested a link between weakened SAC and in vivo tumorigenesis. Here, we review in brief some mechanisms which contribute to cellular aneuploicly and offer a perspective on the relationship between aneuploidy and human cancers. C1 NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), Bldg 4,Room 306,9000 Rockville Pike, Bethesda, MD 20892 USA. EM kj7e@nih.gov RI Jeang, Kuan-Teh/A-2424-2008; Chi, Ya-Hui/B-1080-2010 FU Intramural NIH HHS NR 60 TC 43 Z9 44 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD OCT 15 PY 2007 VL 102 IS 3 BP 531 EP 538 DI 10.1002/jcb.21484 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 219QQ UT WOS:000250100100001 PM 17661351 ER PT J AU Chen, X Gardner, ER Gutierrez, M Kummar, S Figg, WD AF Chen, Xiaohong Gardner, Erin R. Gutierrez, Martin Kummar, Shivaani Figg, William D. TI Determination of 17-dimethylaminoethylamino-17-demethoxygeldanamycin in human plasma by liquid chromatography with mass-spectrometric detection SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE 17-dmag; lc/ms AB An analytical method was developed and validated for the quantitative determination of 17-dimethylaminoethylamino-17-demethoxy- Geldanamycin (17-DMAG, NSC707545), a novel heat shock 90 inhibitor, in human plasma. Calibration curves were linear in the concentration range of 1-500 ng/mL. Sample pretreatment involved a liquid-liquid extraction of 0.2 mL aliquots of plasma with ethyl acetate. 17-DMAG and the internal standard, beclomethasone, were separated on a Zorbax SB C 18 column (75 mm x 2.1 mm, 3.5 mu m), using a mobile phase composed of methanol and 0.2% formic acid (55:45, v/v). The column effluent was monitored by mass spectrometry with electrospray ionization. For the quality control samples at four different concentrations that were analyzed in quintuplicate, on four separate occasions, the accuracy and precision ranged from 93.8% to 99.5% and 1.4% to 3.3%, respectively. The assay modifications significantly improve upon our original, validated method. The developed method was subsequently applied to study the pharmacokinetics of 17-DMAG in a group of 23 patients. (C) 2007 Elsevier B.V. All rights reserved. C1 NCI, Clin Pharmacol Program, Ctr Canc Res, Bethesda, MD 20892 USA. NCI Frederick, Clin Pharmacol Program, SAIC Frederick Inc, Frederick, MD 21702 USA. NCI, Med Oncol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Clin Pharmacol Program, 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 FU Intramural NIH HHS [Z01 SC006536-06, NIH0011335962]; NCI NIH HHS [N01CO12400] NR 8 TC 3 Z9 3 U1 0 U2 0 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 OCT 15 PY 2007 VL 858 IS 1-2 BP 302 EP 306 DI 10.1016/j.jchromb.2007.08.022 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 226SG UT WOS:000250608200041 PM 17851142 ER PT J AU Ambrosino, E Terabe, M Halder, RC Peng, J Takaku, S Miyake, S Yamamura, T Kumar, V Berzofsky, JA AF Ambrosino, Elena Terabe, Masaki Halder, Ramesh C. Peng, Judy Takaku, Shun Miyake, Sachiko Yamamura, Takashi Kumar, Vipin Berzofsky, Jay A. TI Cross-regulation between type I and type IINKT cells in regulating tumor immunity: A new immunoregulatory axis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID KILLER-T-CELLS; V(ALPHA)14 NKT CELLS; GROWTH-FACTOR-BETA; ALPHA-GALACTOSYLCERAMIDE; MYELOID CELLS; IMMUNOSURVEILLANCE; CANCER; ACTIVATION; PREVENTION; IL-13 AB Negative immunoregulation is a major barrier to successful cancer immunotherapy. The NKT cell is known to be one such regulator. In this study we explored the roles of and interaction between the classical type I NKT cell and the poorly understood type II NKT cell in the regulation of tumor immunity. Selective stimulation of type II NKT cells suppressed immunosurveillance, whereas stimulation of type I NKT cells protected against tumor growth even when responses were relatively skewed toward Th2 cytokines. When both were stimulated simultaneously, type II NKT cells appeared to suppress the activation in vitro and protective effect in vivo of type I NKT cells. In the absence of type I, suppression by type II NKT cells increased, suggesting that type I cells reduce the suppressive effect of type II NKT cells. Thus, in tumor immunity type I and type II NKT cells have opposite and counteractive roles and define a new immunoregulatory axis. Alteration of the balance between the protective type I and the suppressive type II NKT cell may be exploited for therapeutic intervention in cancer. C1 NCI, NIH, Vaccine Branch, Bethesda, MD 20892 USA. Torrey Pines Inst Mol Studies, San Diego, CA 92121 USA. Natl Inst Neurosci, Tokyo, Japan. RP Terabe, M (reprint author), NCI, NIH, Vaccine Branch, Bldg 10,Room 6B-12,10 Ctr Dr, Bethesda, MD 20892 USA. EM terabe@mail.nih.gov FU Intramural NIH HHS NR 49 TC 118 Z9 125 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 OCT 15 PY 2007 VL 179 IS 8 BP 5126 EP 5136 PG 11 WC Immunology SC Immunology GA 219QJ UT WOS:000250099400020 PM 17911598 ER PT J AU Silver, PB Agarwal, RK Su, SB Suffia, I Grajewski, RS Luger, D Chan, CC Mahdi, RM Nickerson, JM Caspi, RR AF Silver, Phyllis B. Agarwal, Rajeev K. Su, Shao-Bo Suffia, Isabelle Grajewski, Rafael S. Luger, Dror Chan, Chi-Chao Mahdi, Rashid M. Nickerson, John M. Caspi, Rachel R. TI Hydrodynamic vaccination with DNA encoding an immunologically privileged retinal antigen protects from autoimmunity through induction of regulatory T cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; GLUTAMIC-ACID DECARBOXYLASE-65; NONOBESE DIABETIC MICE; EFFECTOR FUNCTION; DENDRITIC CELLS; CUTTING EDGE; PLASMID DNA; FUNCTIONAL-ROLE; SELF-PEPTIDE; TGF-BETA AB The eye is an immunologically privileged organ whose Ags serve as targets for experimental autoimmune uveitis (EAU), a model for human uveitis. We used a hydrodynamic i.v. injection of naked DNA to express the uveitogenic retinal Ag interphotoreceptor retinoid-binding protein (IRBP) in the periphery, thus revoking its immune-privileged status. IRBP was expressed in the liver within hours of administration of as little as 10 mu g of IRBP-DNA. Vaccinated mice were highly protected from EAU induced by immunization with IRBP for at least 10 wk after vaccination. Protection was partial in a reversal protocol. Mechanistic studies revealed specific hyporesponsiveness to IRBP without immune deviation, no evidence for apoptosis either by the Fas- or Bel-2-regulated (mitochondrial) pathway and apparent lack of dependence on CD8(+) cells, IL-10, or TGF-beta. In contrast, depletion of CD25(+) cells after vaccination and before challenge markedly abrogated protection. IRBP-specific CD4(+)CD25(high) T cells could be cultured from vaccinated mice and transferred protection to unvaccinated, EAU-challenged recipients. In vitro characterization of these cells revealed that they are Ag specific, anergic, express FoxP3, CTLA-4, and glucocorticoid-induced TNFR, and suppress by contact. Thus, expression of IRBP in the periphery by DNA vaccination results in tolerance that acts at least in part through induction of IRBP-specific, FoxP3(+)CD4(+)CD25(+) regulatory T cells. DNA vaccination may offer a new approach to Ag-specific therapy of uveitis. C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. Emory Univ, Dept Ophthalmol, Atlanta, GA 30332 USA. RP Caspi, RR (reprint author), NEI, Immunol Lab, NIH, 10 Ctr Dr,10-10N222, Bethesda, MD 20892 USA. EM rcaspi@helix.nih.gov FU Intramural NIH HHS [Z01 EY000184-25]; NEI NIH HHS [P30 EY006360, R01 EY016470] NR 61 TC 25 Z9 27 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD OCT 15 PY 2007 VL 179 IS 8 BP 5146 EP 5158 PG 13 WC Immunology SC Immunology GA 219QJ UT WOS:000250099400022 PM 17911600 ER PT J AU Arechiga, AF Bell, BD Leverrier, S Weist, BM Porter, M Wu, Z Kanno, Y Ramos, SJ Ong, ST Siegel, R Walsh, CM AF Arechiga, Adrian F. Bell, Bryan D. Leverrier, Sabrina Weist, Brian M. Porter, Melissa Wu, Zhengqi Kanno, Yuka Ramos, Stephanie J. Ong, S. Tiong Siegel, Richard Walsh, Craig M. TI A fas-associated death domain protein/caspase-8-signaling axis promotes S-phase entry and maintains S6 kinase activity in T cells responding to IL-2 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID KAPPA-B ACTIVATION; DOMINANT INTERFERING MUTANT; RIBOSOMAL-PROTEIN S6; PHOSPHATIDYLINOSITOL 3-KINASE; ANTIGEN RECEPTOR; INHIBITS PROLIFERATION; SIGNAL-TRANSDUCTION; CYCLE PROGRESSION; EFFECTOR DOMAIN; CUTTING EDGE AB Fas-associated death domain protein (FADD) constitutes an essential component of TNFR-induced apoptotic signaling. Paradoxically, FADD has also been shown to be crucial for lymphocyte development and activation. In this study, we report that FADD is necessary for long-term maintenance of S6 kinase (S6K) activity. S6 phosphorylation at serines 240 and 244 was only observed after long-term stimulation of wild-type cells, roughly corresponding to the time before S-phase entry, and was poorly induced in T cells expressing a dominantly interfering form of FADD (FADDdd), viral FLIP, or possessing a deficiency in caspase-8. Defects in S6K1 phosphorylation were also observed. However, defective S6K1 phosphorylation was not a consequence of a wholesale defect in mammalian target of rapamycin function, because 4E-BP1 phosphorylation following T cell activation was unaffected by FADDdd expression. Although cyclin D3 up-regulation and retinoblastoma hypophosphorylation occurred normally in FADDdd T cells, cyclin E expression and cyclin-dependent kinase 2 activation were markedly impaired in FADDdd T cells. These results demonstrate that a FADD/caspase-8-signaling axis promotes T cell cycle progression and sustained S6K activity. C1 Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. Univ Calif Irvine, Ctr Immunol, Irvine, CA 92697 USA. NIAMSD, Immunoregulat Unit, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. NIAMS, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. Univ Calif Irvine, Coll Med, Dept Med, Div Hematol Oncol, Irvine, CA 92697 USA. RP Walsh, CM (reprint author), Univ Calif Irvine, Dept Mol Biol & Biochem, Irvine, CA 92697 USA. EM cwalsh@uci.edu RI Siegel, Richard/C-7592-2009; Kanno, Yuka/B-5802-2013 OI Siegel, Richard/0000-0001-5953-9893; FU NCI NIH HHS [T32CA09054]; NIAID NIH HHS [AI050606, T32AI060573]; NIGMS NIH HHS [T32GM007311] NR 69 TC 23 Z9 23 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 OCT 15 PY 2007 VL 179 IS 8 BP 5291 EP 5300 PG 10 WC Immunology SC Immunology GA 219QJ UT WOS:000250099400037 PM 17911615 ER PT J AU Bafica, A Feng, CG Santiago, HC Aliberti, J Cheever, A Thomas, KE Taylor, GA Vogel, SN Sher, A AF Bafica, Andre Feng, Carl G. Santiago, Helton C. Aliberti, Julio Cheever, Allen Thomas, Karen E. Taylor, Gregory A. Vogel, Stefanie N. Sher, Alan TI The IFN-inducible GTPase LRG47 (Irgm1) negatively regulates TLR4-triggered proinflammatory cytokine production and prevents endotoxemia SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; NF-KAPPA-B; PHOSPHATIDYLINOSITOL 3-KINASE-AKT PATHWAY; TNF-ALPHA; MYCOBACTERIUM-TUBERCULOSIS; SIGNALING PATHWAYS; IMMUNE-RESPONSES; INTERFERON-GAMMA; GENE-EXPRESSION; MICE DEFICIENT AB LRG47/Irgm1, a 47-kDa IFN-inducible GTPase, plays a major role in regulating host resistance as well as the hemopoietic response to intracellular pathogens. LRG47 expression in macrophages has been shown previously to be stimulated in vitro by bacterial LPS, a TLR4 ligand. In this study, we demonstrate that induction of LRG47 by LPS is not dependent on MyD88 signaling, but rather, requires STAT-1 and IFN-beta. In addition, LRG47-deficient mice are highly susceptible to LPS, but not TLR2 ligand-induced shock, an outcome that correlates with enhanced proinflammatory cytokine production in vitro and in vivo. Further analysis revealed that LPS-stimulated LRG47-deficient macrophages display enhanced phosphorylation of p38, a downstream response associated with TLR4/MyD88 rather than IFN-beta/STAT-1 signaling. In contrast, LPS-induced phosphorylation of IFN regulatory factor-3 and expression of IFN-beta or the type I IFN-regulated genes, CCL5 and CCL10, were unaltered in LRG47(-/-) cells. Together, these observations indicate that in LPS-stimulated murine macrophages LRG47 is induced by IFN-beta and negatively regulates TLR4 signaling to prevent excess proinflammatory cytokine production and shock. Thus, our findings reveal a new host-protective function for this GTPase in the response to pathogenic encounter. C1 NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Fed Santa Catarina, Dept Microbiol & Parasitol, Div Immunol, Florianopolis, SC, Brazil. Univ Fed Minas Gerais, Belo Horizonte, MG, Brazil. Childrens Hosp, Med Ctr, Div Mol Immunol, Cincinnati, OH 45229 USA. Univ Maryland, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. Duke Univ, Ctr Geriatr Res Educ & Clin, VA Med Ctr, Durham, NC 27710 USA. Duke Univ, Dept Med Immunol, Durham, NC 27710 USA. Duke Univ, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. Duke Univ, Ctr Study Aging, Durham, NC 27710 USA. RP Bafica, A (reprint author), NIAID, Immunobiol Sect, Parasit Dis Lab, NIH, 50 NIH S Dr,Room 6146, Bethesda, MD 20892 USA. EM abafica@niaid.nih.gov RI Santiago, Helton/F-8704-2012; Aliberti, Julio/G-4565-2012; Aliberti, Julio/I-7354-2013 OI Santiago, Helton/0000-0002-5695-8256; Aliberti, Julio/0000-0003-3420-8478 FU Intramural NIH HHS; NIAID NIH HHS [AI-18797, R01 AI057831] NR 61 TC 29 Z9 30 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 OCT 15 PY 2007 VL 179 IS 8 BP 5514 EP 5522 PG 9 WC Immunology SC Immunology GA 219QJ UT WOS:000250099400060 PM 17911638 ER PT J AU Jeronimo, SMB Duggal, P Ettinger, NA Nascimento, ET Monteiro, GR Cabral, AP Pontes, NN Lacerda, HG Queiroz, PV Gomes, CEM Pearson, RD Blackwell, JM Beaty, TH Wilson, ME AF Jeronimo, Selma M. B. Duggal, Priya Ettinger, Nicholas A. Nascimento, Eliana T. Monteiro, Gloria R. Cabral, Angela P. Pontes, Nubia N. Lacerda, Henio G. Queiroz, Paula V. Gomes, Carlos E. M. Pearson, Richard D. Blackwell, Jenefer M. Beaty, Terri H. Wilson, Mary E. TI Genetic predisposition to self-curing infection with the protozoan Leishmania chagasi: A genomewide scan SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID AMERICAN VISCERAL LEISHMANIASIS; NORTHEAST BRAZIL; NATURAL-HISTORY; URBAN OUTBREAK; FOLLOW-UP; LINKAGE; CHROMOSOME; ANTIGEN; LOCUS AB The protozoan Leishmania chagasi can cause disseminated, fatal visceral leishmaniasis (VL) or asymptomatic infection in humans. We hypothesized that host genetic factors contribute to this variable response to infection. A family study was performed in neighborhoods of endemicity for L. chagasi near Natal in northeastern Brazil. Study subjects were assessed for the presence of VL or asymptomatic infection, which was defined by a positive delayed-type hypersensitivity (DTH) skin test response to Leishmania antigen without disease symptoms. A genomewide panel of 385 autosomal microsatellite markers in 1254 subjects from 191 families was analyzed to identify regions of linkage. Regions with potential linkage to the DTH response on chromosomes 15 and 19, as well as a novel region on chromosome 9 with potential linkage to VL, were identified. Understanding the genetic factors that determine whether an individual will develop symptomatic or asymptomatic infection with L. chagasi may identify proteins essential for immune protection against this parasitic disease and reveal strategies for immunotherapy or prevention. C1 Univ Iowa, Dept Internal Med, Mol & Cellular Biol Program, Iowa City, IA 52242 USA. Univ Iowa, Dept Microbiol & Epidemiol, Iowa City, IA 52242 USA. Vet Affairs Med Ctr, Iowa City, IA 52242 USA. Univ Virginia, Sch Med, Div Infect Dis & Int Hlth, Charlottesville, VA USA. Univ Virginia, Sch Med, Dept Internal Med & Pathol, Charlottesville, VA USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. NHGRI, Inherited Dis Res Branch, NIH, Baltimore, MD USA. Univ Cambridge, Addenbrookes Hosp, Sch Clin Med, Cambridge Inst Med Res, Cambridge CB2 2QQ, England. Univ Fed Rio Grande do Norte, Dept Biochem, BR-59072970 Natal, RN, Brazil. Univ Fed Rio Grande do Norte, Dept Infect Dis, BR-59072970 Natal, RN, Brazil. Univ Fed Rio Grande do Norte, Hlth Postgrad Program, BR-59072970 Natal, RN, Brazil. RP Wilson, ME (reprint author), Univ Iowa, Dept Internal Med, Mol & Cellular Biol Program, SW34-GH,200 Hawkins Dr, Iowa City, IA 52242 USA. EM mary-wilson@uiowa.edu RI Jeronimo, Selma/M-8672-2014; Blackwell, Jenefer/H-3015-2015 FU FIC NIH HHS [R03 TW001369]; Intramural NIH HHS; NIAID NIH HHS [AI048822, AI30639, AI45540, P50 AI030639, R01 AI045540, R01 AI048822]; NIDDK NIH HHS [R03 DK052550]; NIGMS NIH HHS [T32 GM007337]; Wellcome Trust [074196] NR 29 TC 35 Z9 36 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD OCT 15 PY 2007 VL 196 IS 8 BP 1261 EP 1269 DI 10.1086/521682 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 212KR UT WOS:000249595700020 PM 17955446 ER PT J AU Lee, PS Foss-Feig, J Henderson, JG Kenworthy, LE Gilotty, L Gaillard, WD Vaidya, CJ AF Lee, Philip S. Foss-Feig, Jennifer Henderson, Joshua G. Kenworthy, Lauren E. Gilotty, Lisa Gaillard, William D. Vaidya, Chandan J. TI Atypical neural substrates of embedded figures task performance in children with autism spectrum disorder SO NEUROIMAGE LA English DT Article ID ANTERIOR CINGULATE CORTEX; PARIETAL CORTEX; FUNCTIONAL MRI; GROUND SEGREGATION; VISUAL-ATTENTION; WORKING-MEMORY; BRAIN; STIMULI; FMRI; ADOLESCENTS AB Superior performance on the Embedded Figures Task (EFT) has been attributed to weak central coherence in perceptual processing in Autism Spectrum Disorder (ASD). The present study used functional magnetic resonance imaging to examine the neural basis of EFT performance in 7- to 12-year-old ASD children and age- and IQ-matched controls. ASD children activated only a subset of the distributed network of regions activated in controls. In frontal cortex, control children activated left dorsolateral, medial and dorsal premotor regions whereas ASD children only activated the dorsal premotor region. In parietal and occipital cortices, activation was bilateral in control children but unilateral (left superior parietal and right occipital) in ASD children. Further, extensive bilateral ventral temporal activation was observed in control, but not ASD children. ASD children performed the EFT at the same level as controls but with reduced cortical involvement, suggesting that disembedded visual processing is accomplished parsimoniously by ASD relative to typically developing brains. (c) 2007 Elsevier Inc. All rights reserved. C1 Georgetown Univ, Dept Psychol, Washington, DC 20057 USA. Childrens Natl Med Ctr, Ctr Autism Spectrum Disorders, Washington, DC 20010 USA. NIMH, Div Pediat Translat Res & Treatment Dev, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. Childrens Natl Med Ctr, Childrens Res Inst, Washington, DC 20010 USA. RP Vaidya, CJ (reprint author), Georgetown Univ, Dept Psychol, 306 White Gravenor Hall, Washington, DC 20057 USA. EM cjv2@georgetown.edu FU NCRR NIH HHS [M01 RR020359, M01 RR020359-03]; NIMH NIH HHS [R01 MH065395-01A2, R01 MH065395] NR 42 TC 48 Z9 49 U1 2 U2 9 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 OCT 15 PY 2007 VL 38 IS 1 BP 184 EP 193 DI 10.1016/j.neuroimage.2007.07.013 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 218CF UT WOS:000249992900018 PM 17707658 ER PT J AU Adamson, PC Matthay, KK O'Brien, M Reaman, GH Sato, JK Balis, FM AF Adamson, Peter C. Matthay, Katherine K. O'Brien, Michelle Reaman, Gregory H. Sato, Judith K. Balis, Frank M. TI A phase 2 trial of all-trans-retinoic acid in combination with interferon-alpha 2A in children with recurrent neuroblastoma or Wilms tumor: A pediatric oncology branch, NCI and children's oncology group study SO PEDIATRIC BLOOD & CANCER LA English DT Article DE interferon; neuroblastoma; phase 2; retinoic acid; Wilms tumor ID HUMAN NEURO-BLASTOMA; CELL LUNG-CANCER; REFRACTORY PROSTATE-CANCER; HIGH-RISK NEUROBLASTOMA; 13-CIS-RETINOIC ACID; II TRIAL; INTERMITTENT SCHEDULE; ALPHA-INTERFERON; GENE-EXPRESSION; CLINICAL-TRIAL AB Background The combination of the anti proliferative and differentiation-inducing effects of retinoids together with the anti-proliferative, immunostimulatory, and differentiation-potentiating effects of interferon-a (IFN-alpha) were the basis for the development of this combination in pediatric patients with refractory neuroblastoma or Wilms tumor. Procedure. A phase 2 trial of all-trans-retinoic acid (ATRA), administered orally at a dose of 90 mg/m(2)/day in three divided doses for 3 consecutive days per week, and IFN-alpha 2a, administered subcutaneously daily at a dose of 3 x 10(6) U/m(2)/day for 5 consecutive days per week, in 4 week cycles was performed. A two-stage design was used for each disease stratum. Results. Seventeen patients 0 6 evaluable) with neuroblastoma, median age 9 years, and 15 patients (14 evaluable) with Wilms tumor, median age 6 years, were enrolled. Overall, the combination was well tolerated, with headache being the most common toxicity observed. There were no complete or partial responses. The median number of cycles administered was 1 (range 1-9). Four patients with neuroblastoma had stable disease for 12 or more weeks. Conclusions. The combination of ATRA and IFN-alpha 2a was inactive in children with relapsed or refractory neuroblastoma and Wilms tumor. The lack of activity with this combination in children with refractory neuroblastoma is similar to the disappointing phase 2 results of single agent 13-cis-retinoic-acid (13cRA) and does not support further development of ATRA for children with relapsed neuroblastoma. C1 Childrens Hosp Philadelphia, Div Clin Pharmacol & Therapeut, Philadelphia, PA 19104 USA. Univ Calif San Francisco, Sch Med, San Francisco, CA 94143 USA. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. Childrens Natl Med Ctr, Washington, DC 20010 USA. City Hope Natl Med Ctr, Duarte, CA 91010 USA. RP Adamson, PC (reprint author), Childrens Hosp Philadelphia, Div Clin Pharmacol & Therapeut, ARC 916,3615 Civ Ctr Blvd, Philadelphia, PA 19104 USA. EM adamsonp@mail.med.upenn.edu NR 52 TC 17 Z9 17 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1545-5009 J9 PEDIATR BLOOD CANCER JI Pediatr. Blood Cancer PD OCT 15 PY 2007 VL 49 IS 5 BP 661 EP 665 DI 10.1002/pbc.21011 PG 5 WC Oncology; Hematology; Pediatrics SC Oncology; Hematology; Pediatrics GA 205AO UT WOS:000249085300011 PM 16900483 ER PT J AU Yeung, ML Benkirane, M Jeang, KT AF Yeung, Man Lung Benkirane, Monsef Jeang, Kuan-Teh TI Small non-coding RNAs, mammalian cells, and viruses: regulatory interactions? SO RETROVIROLOGY LA English DT Editorial Material ID HUMAN-IMMUNODEFICIENCY-VIRUS; TAR RNA; ANTIVIRAL IMMUNITY; HIV-1 TAT; ANTISENSE TRANSCRIPTS; BINDING PROTEIN; MICRORNA; INTERFERENCE; GENOME; DICER AB Recent findings suggest that mammalian cells can use small non-coding RNAs (ncRNA) to regulate physiological viral infections. Here, we comment on several lines of evidence that support this concept. We discuss how viruses may in turn protect, suppress, evade, modulate, or adapt to the host cell's ncRNA regulatory schema. C1 [Yeung, Man Lung; Jeang, Kuan-Teh] NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. [Benkirane, Monsef] Inst Human Genet, Montpellier, France. RP Jeang, KT (reprint author), NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM yeungm@mail.nih.gov; Monsef.BenKirane@igh.cnrs.fr; KJEANG@niaid.nih.gov RI Jeang, Kuan-Teh/A-2424-2008 NR 59 TC 36 Z9 38 U1 0 U2 4 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 OCT 15 PY 2007 VL 4 AR 74 DI 10.1186/1742-4690-4-74 PG 6 WC Virology SC Virology GA 250AY UT WOS:000252273600001 PM 17937800 ER PT J AU Kim, JY Kim, HJ Hurt, EM Chen, X Howard, OMZ Farrar, WL AF Kim, Joon-Young Kim, Han-Jong Hurt, Elaine M. Chen, Xin Howard, O. M. Zack Farrar, William L. TI Functional and genomic analyses of FOXP3-transduced Jurkat-T cells as regulatory T (Treg)-like cells SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE FOXP3; treg; transcluction; jurkat-T cells ID FOXP3; SUPPRESSION; TRANSCRIPTION; LYMPHOCYTE; EXPRESSION; MUTATIONS; TOLERANCE; SCURFIN AB FOXP3, a forkhead transcription factor is essential for the development and function of CD4(+)CD25(+) regulatory T cells (Tregs). In contrast to conversion of murine naive T cells to Tregs by transduction of Foxp3, it is controversial whether ectopic expression of FOXP3 in human CD4(+) T cells is sufficient for acquisition of suppressive activity. Here, we show that retroviral transduction of FOXP3 induces a Treg phenotype in human leukemic CD4(+) Jurkat-T cells, evidenced by increased expression of Treg-associated cell surface markers as well as inhibition of cytokine production. Furthermore, FOXP3-transduced Jurkat-T cells suppress the proliferation of human CD4(+)CD25(-) T cells. Additionally, DNA microarray analysis identifies Treg-related genes regulated by FOXP3. Our study demonstrates that enforced expression of FOXP3 confers Treg-like properties on Jurkat-T cells, which can be a convenient and efficient Treglike cell model for further study to identify Treg cell surface markers and target genes regulated by FOXP3. (c) 2007 Elsevier Inc. All rights reserved. C1 NCI, Canc Stem Cell Sect, Lab Canc Prevent, Frederick, MD 21702 USA. SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. Canc Res Ctr, Natl Canc Inst, Lab Mol Immunoregulat, Frederick, MD 21702 USA. RP Farrar, WL (reprint author), NCI, Canc Stem Cell Sect, Lab Canc Prevent, 1050 Boyles St, Frederick, MD 21702 USA. EM jykim@ncifcrf.gov; farrar@mail.ncifcrf.gov RI Howard, O M Zack/B-6117-2012; Chen, Xin/I-6601-2015 OI Howard, O M Zack/0000-0002-0505-7052; Chen, Xin/0000-0002-2628-4027 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 28 TC 11 Z9 15 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD OCT 12 PY 2007 VL 362 IS 1 BP 44 EP 50 DI 10.1016/j.bbrc.2007.07.187 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 208ZK UT WOS:000249357700008 PM 17706604 ER PT J AU Yan, J Yang, XP Kim, YS Joo, JH Jetten, AM AF Yan, Jun Yang, Xiao-Ping Kim, Yong-Sik Joo, Joung Hyuck Jetten, Anton M. TI RAP80 interacts with the SUMO-conjugating enzyme UBC9 and is a novel target for sumoylation SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE RAP80; UBC9; SUMO-1; sumoylation ID DNA-DAMAGE RESPONSE; KAPPA-B ACTIVATION; TRANSCRIPTION FACTOR; UBIQUITIN; PROTEIN; REPAIR; BRCA1; RECEPTOR; COMPLEX; ALPHA AB RAP80, a nuclear protein with two functional ubiquitin-interaction motifs (UlMs) at its N-terminus, plays a critical role in the regulation of estrogen receptor alpha and DNA damage response signaling. A yeast two-hybrid screen identified the SUMO-conjugating enzyme UBC9 as a protein interacting with RAP80. The interaction of RAP80 with UBC9 was confirmed by co-immunoprecipitation and GST pull-down analyses. The region between aa 122-204 was critical for the interaction of RAP80 with UBC9. In addition, we demonstrate that RAP80 is a target for SUMO-I modification in intact cells. Expression of UBC9 enhanced RAP80 mono-sumoylation and also induced multi-sumoylation of RAP80. In addition to SUMO-1, RAP80 was efficiently conjugated to SUMO-3 but was only a weak substrate for SUMO-2 conjugation. These findings suggest that sumoylation plays a role in the regulation of RAP80 functions. Published by Elsevier Inc. C1 Natl Inst Environm Hlth Sci, NIH, Cell Biol Sect, Div Intramural Res, Res Triangle Pk, NC 27709 USA. RP Jetten, AM (reprint author), Natl Inst Environm Hlth Sci, NIH, Cell Biol Sect, Div Intramural Res, Res Triangle Pk, NC 27709 USA. EM jetten@nichs.nih.gov OI Jetten, Anton/0000-0003-0954-4445 FU Intramural NIH HHS [Z01 ES100485-06] NR 32 TC 20 Z9 24 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD OCT 12 PY 2007 VL 362 IS 1 BP 132 EP 138 DI 10.1016/j.bbrc.2007.07.158 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 208ZK UT WOS:000249357700022 PM 17698038 ER PT J AU Garner, AL Chen, G Chen, N Sridhara, V Kolb, JF Swanson, RJ Beebe, SJ Joshi, RP Schoenbach, KH AF Garner, Allen L. Chen, George Chen, Nianyong Sridhara, Viswanadham Kolb, Juergen F. Swanson, R. James Beebe, Stephen J. Joshi, Ravindra P. Schoenbach, Karl H. TI Ultrashort electric pulse induced changes in cellular dielectric properties SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE dielectric spectroscopy; nanosecond pulsed electric fields; Electroporation; permeabilization; plasma membrane; time domain; intracellular manipulation; ultrashort pulses ID HUMAN T-LYMPHOCYTES; HIGH-INTENSITY; NUCLEAR-ENVELOPE; HUMAN-CELLS; SPECTROSCOPY; NANOSECOND; MEMBRANE; FIELDS; ELECTROPORATION; ELECTROPERMEABILIZATION AB The interaction of nanosecond duration pulsed electric fields (nsPEFs) with biological cells, and the models describing this behavior, depend critically on the electrical properties of the cells being pulsed. Here, we used time domain dielectric spectroscopy to measure the dielectric properties of Jurkat cells, a malignant human T-cell line, before and after exposure to five 10 ns, 150 kV/cm electrical pulses. The cytoplasm and nucleoplasm conductivities decreased dramatically following pulsing, corresponding to previously observed rises in cell suspension conductivity. This suggests that electropermeabilization occurred, resulting in ion transport from the cell's interior to the exterior. A delayed decrease in cell membrane conductivity after the nsPEFs possibly suggests long-term ion channel damage or use dependence due to repeated membrane charging and discharging. This data could be used in models describing the phenomena at work. (c) 2007 Elsevier Inc. All rights reserved. C1 GE Global Res Ctr, Niskayuna, NY 12309 USA. Univ Virginia, Sch Med, Dept Med Pulm & Crit Care, Dep Med, Charlottesville, VA 22908 USA. Natl Ctr Biotechnol Informat, Natl Lib Med, NIH, Bethesda, MD 20892 USA. Univ Michigan, Dept Nucl Engn & Radiol Sci, Bioelectromagnetism Lab, Ann Arbor, MI 48109 USA. Old Dominion Univ, Frank Reidy Res Ctr Bioelect, Norfolk, VA 23510 USA. Univ Southampton, Sch Elect & Comp Sci, Southampton, Hants, England. Old Dominion Univ, Dept Elect & Comp Engn, Norfolk, VA 23529 USA. Old Dominion Univ, Dept Biol Sci, Norfolk, VA 23529 USA. Eastern Virginia Med Sch, Dept Physiol Sci, Norfolk, VA 23510 USA. RP Garner, AL (reprint author), GE Global Res Ctr, Niskayuna, NY 12309 USA. EM garner@ge.com; kschoenb@odu.edu RI Kolb, Juergen/A-5515-2016 OI Kolb, Juergen/0000-0002-0434-5001 NR 32 TC 39 Z9 40 U1 1 U2 12 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 OCT 12 PY 2007 VL 362 IS 1 BP 139 EP 144 DI 10.1016/j.bbrc.2007.07.159 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 208ZK UT WOS:000249357700023 PM 17706595 ER PT J AU Hempel, LU Oliver, B AF Hempel, Leonie U. Oliver, Brian TI Sex-specific Doublesex(M) expression in subsets of Drosophila somatic gonad cells SO BMC DEVELOPMENTAL BIOLOGY LA English DT Article ID GENITAL IMAGINAL DISC; GERM-LINE; MELANOGASTER; GENE; DIFFERENTIATION; MUTATIONS; MORPHOGENESIS; PROTEINS; MESODERM; PATTERNS AB Background: In Drosophila melanogaster, a pre-mRNA splicing hierarchy controls sexual identity and ultimately leads to sex-specific Doublesex (DSX) transcription factor isoforms. The male-specific DSX(M) represses genes involved in female development and activates genes involved in male development. Spatial and temporal control of dsx during embryogenesis is not well documented. Results: Here we show that DSXM is specifically expressed in subsets of male somatic gonad cells during embryogenesis. Following testis formation, germ cells remain in contact with DSX(M)-expressing cells, including hub cells and premeiotic somatic cyst cells that surround germ cells during spermatogenesis in larval and adult testes. Conclusion: We show that dsx is transcriptionally regulated in addition to being regulated at the pre-mRNA splicing level by the sex determination hierarchy. The dsx locus is spatially controlled by somatic gonad identity. The continuous expression of DSXM in cells contacting the germline suggests an ongoing short-range influence of the somatic sex determination pathway on germ cell development. C1 [Hempel, Leonie U.; Oliver, Brian] NIH, NIDDK, Cellular & Dev Biol Lab, Bethesda, MD 20892 USA. RP Hempel, LU (reprint author), NIH, NIDDK, Cellular & Dev Biol Lab, 50 S Dr, Bethesda, MD 20892 USA. EM hempell@niddk.nih.gov; oliver@helix.nih.gov FU Intramural NIH HHS [Z01 DK015600-12] NR 54 TC 44 Z9 44 U1 2 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-213X J9 BMC DEV BIOL JI BMC Dev. Biol. PD OCT 12 PY 2007 VL 7 AR 113 DI 10.1186/1471-213X-7-113 PG 15 WC Developmental Biology SC Developmental Biology GA 244ZN UT WOS:000251904100001 PM 17935627 ER PT J AU Carmel, L Rogozin, IB Wolf, YI Koonin, EV AF Carmel, Liran Rogozin, Igor B. Wolf, Yuri I. Koonin, Eugene V. TI Patterns of intron gain and conservation in eukaryotic genes SO BMC EVOLUTIONARY BIOLOGY LA English DT Article ID MAXIMUM-LIKELIHOOD; SPLICEOSOMAL INTRONS; PHYLOGENETIC ESTIMATION; GIARDIA-LAMBLIA; DNA-SEQUENCES; EVOLUTION; ORIGIN; POSITIONS; SITES; MODEL AB Background: The presence of introns in protein-coding genes is a universal feature of eukaryotic genome organization, and the genes of multicellular eukaryotes, typically, contain multiple introns, a substantial fraction of which share position in distant taxa, such as plants and animals. Depending on the methods and data sets used, researchers have reached opposite conclusions on the causes of the high fraction of shared introns in orthologous genes from distant eukaryotes. Some studies conclude that shared intron positions reflect, almost entirely, a remarkable evolutionary conservation, whereas others attribute it to parallel gain of introns. To resolve these contradictions, it is crucial to analyze the evolution of introns by using a model that minimally relies on arbitrary assumptions. Results: We developed a probabilistic model of evolution that allows for variability of intron gain and loss rates over branches of the phylogenetic tree, individual genes, and individual sites. Applying this model to an extended set of conserved eukaryotic genes, we find that parallel gain, on average, accounts for only similar to 8% of the shared intron positions. However, the distribution of parallel gains over the phylogenetic tree of eukaryotes is highly non-uniform. There are, practically, no parallel gains in closely related lineages, whereas for distant lineages, such as animals and plants, parallel gains appear to contribute up to 20% of the shared intron positions. In accord with these findings, we estimated that ancestral introns have a high probability to be retained in extant genomes, and conversely, that a substantial fraction of extant introns have retained their positions since the early stages of eukaryotic evolution. In addition, the density of sites that are available for intron insertion is estimated to be, approximately, one in seven basepairs. Conclusion: We obtained robust estimates of the contribution of parallel gain to the observed sharing of intron positions between eukaryotic species separated by different evolutionary distances. The results indicate that, although the contribution of parallel gains varies across the phylogenetic tree, the high level of intron position sharing is due, primarily, to evolutionary conservation. Accordingly, numerous introns appear to persist in the same position over hundreds of millions of years of evolution. This is compatible with recent observations of a negative correlation between the rate of intron gain and coding sequence evolution rate of a gene, suggesting that at least some of the introns are functionally relevant. C1 [Carmel, Liran; Rogozin, Igor B.; Wolf, Yuri I.; Koonin, Eugene V.] NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Koonin, EV (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM carmel@ncbi.nlm.nih.gov; rogozin@ncbi.nlm.nih.gov; wolf@ncbi.nlm.nih.gov; koonin@ncbi.nlm.nih.gov RI Carmel, Liran/A-9681-2008 NR 49 TC 51 Z9 53 U1 0 U2 5 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD OCT 12 PY 2007 VL 7 AR 192 DI 10.1186/1471-2148-7-192 PG 16 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 244ZR UT WOS:000251904500002 PM 17935625 ER PT J AU Krueger, F Fischer, R Heinecke, A Hagendorf, H AF Krueger, Frank Fischer, Rico Heinecke, Armin Hagendorf, Herbert TI An MRI investigation into the neural mechanisms of spatial attentional selection in a location-based negative priming task SO BRAIN RESEARCH LA English DT Article DE negative selection bias; selective attention; parietal cortex; dorsolateral prefrontal cortex ID POSTERIOR PARIETAL CORTEX; EVENT-RELATED FMRI; PREFRONTAL CORTEX; VISUAL-ATTENTION; INHIBITORY MECHANISMS; RESPONSE SELECTION; MEMORY RETRIEVAL; PERCEPTUAL LOAD; STROOP TASK; BRAIN AB Selective attention enables us to respond to objects and events that are relevant to our goals for adaptive interactions with the environment. Despite evidence from research addressing the selection of a target location, little is known about the neural mechanisms of attentional selection in situations in which the selection is biased in favor of the information in the irrelevant location. In this study, we combined event-related fMRI and a location-based negative priming paradigm with a prime-probe-trial design to investigate the neural mechanisms of spatial attentional selection. Participants were instructed to respond to the location of a prespecified target while ignoring a distractor at an irrelevant location. The goal of this study was twofold. First, we identified brain regions that are linked to conflict resolution situations, in which the selection bias puts the irrelevant information in the probe trial on a selection advantage over the target. Second, we determined the mechanism of conflict resolution when the encoding conditions of stimuli are manipulated by presenting stimuli either abruptly (onset) or masked (no-onset). The results showed that the bottom-up-induced competition among stimuli in the target selection is stronger for onset than no-onset stimuli. The superior parietal lobule was sensitive to those changes in bottom-up-induced competition. Furthermore, the dorsolateral prefrontal cortex and inferior parietal lobe were activated to resolve the additional processing effort necessary to select the negatively biased target. In conclusion, the present study identified dissociable neural components needed to resolve the negative selection bias, which attentional modulation can be addressed in future studies by examining changes in the functional connectivity. Published by Elsevier B.V. C1 Natl Inst Neurol Disorders & Stroke, Natl Inst Hlth, Cognit Neurosci Sect, Bethesda, MD 20892 USA. Tech Univ Dresden, Dept Psychol, D-8027 Dresden, Germany. Brain Innovat BV, Maastricht, Netherlands. Humboldt Univ, Dept Cognit Psychol, Berlin, Germany. RP Krueger, F (reprint author), Natl Inst Neurol Disorders & Stroke, Natl Inst Hlth, Cognit Neurosci Sect, Bldg 10,Room 7D43,MSC 1440, Bethesda, MD 20892 USA. EM KrugerF@ninds.nih.gov NR 71 TC 15 Z9 15 U1 4 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD OCT 12 PY 2007 VL 1174 BP 110 EP 119 DI 10.1016/j.brainres.2007.08.016 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 226TU UT WOS:000250612200012 PM 17803973 ER PT J AU Xu, YC Zhou, YL Gonzalez, FJ Snead, ML AF Xu, Yucheng Zhou, Yan Larry Gonzalez, Frank J. Snead, Malcolm L. TI CCAAT/Enhancer-binding protein delta(C/EBP delta) maintains amelogenin expression in the absence of C/EBP alpha in vivo SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-ALPHA; GENE-EXPRESSION; ADIPOSE-TISSUE; NF-Y; TRANSCRIPTION; DIFFERENTIATION; MORPHOGENESIS; DISRUPTION; LOCUS; LIVER AB C/ EBP alpha is implicated to regulate mouse amelogenin gene expression during tooth enamel formation in vitro. Because enamel formation occurs during postnatal development and C/ EBP alpha- deficient mice die at birth, we used the Cre/ loxP recombination system to characterize amelogenin expression in C/ EBP alpha conditional knock- out mice. Mice carrying the Cre transgene under the control of the human keratin- 14 promoter show robust Cre expression in the ameloblast cell lineage. Mating between mice bearing the floxed C/ EBP alpha allele with keratin14- Cre mice generate C/ EBP alpha conditional knock- out mice. Real- time PCR analysis shows that removal of one C/EBP alpha allele from the molar enamel epithelial organ of 3- day postnatal mice results in dramatic decrease in endogenous C/EBP alpha mRNAlevels and coordinately altered amelogeninm RNA abundance. Conditional deletion of both C/ EBP alpha alleles further diminishes C/ EBP alpha mRNAlevels; however, rather than ablating amelogenin expression, we observe wild- type amelogenin mRNA abundance levels. We examined C/ EBP beta and nuclear factor YA expression, two transcription factors that had previously been shown to modestly participate in amelogenin expression, in vitro but found no significant changes in either of their mRNA abundance levels comparing conditional knock- out mice with wild- type counterparts. Although the abundance of C/ EBP delta is also unchanged in C/ EBP alpha\ conditional knock- out mice, in vitro we find that C/ EBP delta activates the mouse amelogenin promoter and synergistically cooperates with nuclear factor Y, suggesting that C/ EBP delta can functionally substitute for C/ EBP alpha to produce an enamel matrix competent to direct biomineralization. C1 Univ So Calif, Ctr Craniofacial Mol Biol, Los Angeles, CA 90033 USA. NCI, NIH, Lab Metab, Bethesda, MD 20892 USA. RP Snead, ML (reprint author), Univ So Calif, Ctr Craniofacial Mol Biol, CSA 142,2250 Alcazar St, Los Angeles, CA 90033 USA. EM mlsnead@usc.edu FU NIDCR NIH HHS [R01 DE006988, DE-06988] NR 22 TC 15 Z9 16 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 12 PY 2007 VL 282 IS 41 BP 29882 EP 29889 DI 10.1074/jbc.M702097200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 217XS UT WOS:000249981200017 PM 17704518 ER PT J AU Tanaka, T Suh, KS Lo, AM De Luca, LM AF Tanaka, Takemi Suh, Kwang S. Lo, Angela M. De Luca, Luigi M. TI P21(WAF1/CIP1) is a common transcriptional target of retinoid receptors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CYCLIN-DEPENDENT KINASES; X-RECEPTOR; BREAST-CANCER; RESPONSE ELEMENT; 9-CIS-RETINOIC ACID; HORMONE-RECEPTORS; OVARIAN-CARCINOMA; PROSTATE-CANCER; MOUSE SKIN; VITAMIN-A AB The divergent response and the molecular mechanisms underlying the anti-cancer effects of retinoid X receptor (RXR) ligand (rexinoid) therapy are poorly understood. This study demonstrates that ligand-activated RXR homodimer facilitated G(1) arrest by up-regulation of p21 in vitro and in vivo but failed to induce G1 arrest when p21 expression was blocked by p21 small interfering RNA. RXR ligand-dependent p21 up-regulation was transcriptionally controlled through the direct binding of RXR homodimers to two consecutive retinoid X response elements in the p21 promoter. Structural overlap of a retinoic acid response element with these retinoid X response elements led to a high affinity binding of retinoic acid receptor/RXR heterodimer to the retinoic acid response element, resulting in the prevention of RXR ligand-mediated p21 transactivation. These data show that p21 is a potential and novel molecular target for RXR ligand-mediated anti-cancer therapy and that the expression level of retinoic acid receptor and RXR in tumors may be crucial to induce p21-mediated cell growth arrest in RXR ligand therapy. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Tanaka, T (reprint author), Univ Texas, Hlth Sci Ctr, Inst Mol Med, 1825 Herman Pressler,Rm 537C, Houston, TX 77030 USA. EM Takemi.Tanaka@uth.tmc.edu FU Intramural NIH HHS NR 43 TC 38 Z9 46 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 OCT 12 PY 2007 VL 282 IS 41 BP 29987 EP 29997 DI 10.1074/jbc.M701700200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 217XS UT WOS:000249981200028 PM 17656367 ER PT J AU Collins, QF Liu, HY Pi, JB Liu, ZQ Quon, MJ Cao, WH AF Collins, Qu Fan Liu, Hui-Yu Pi, Jingbo Liu, Zhenqi Quon, Michael J. Cao, Wenhong TI Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, suppresses hepatic gluconeogenesis through 5 '-AMP-activated protein kinase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RECEPTOR TYROSINE KINASES; MAP KINASE; CATECHIN-POLYPHENOLS; CELL-SURVIVAL; NITRIC-OXIDE; GALLATE; ACTIVATION; MECHANISMS; ADIPOCYTES; CANCER AB Epigallocatechin-3-gallate (EGCG), a main catechin of green tea, has been suggested to inhibit hepatic gluconeogenesis. However, the exact role and related mechanism have not been established. In this study, we examined the role of EGCG in hepatic gluconeogenesis at concentrations that are reachable by ingestion of pure EGCG or green tea, and are not toxic to hepatocytes. Our results show in isolated hepatocytes that EGCG at relatively low concentrations (<= 1 mu M) inhibited glucose production via gluconeogenesis and expression of key gluconeogenic genes. EGCG was not toxic at these concentrations while demonstrating significant cytotoxicity at 10 mu M and higher concentrations. EGCG at 1 mu M or lower concentrations effective in suppressing hepatic gluconeogenesis did not activate the insulin signaling pathway, but activated 5 '-AMP-activated protein kinase (AMPK). The EGCG suppression of hepatic gluconeogenesis was prevented by blockade of AMPK activity. In defining the mechanism by which EGCG activates AMPK, we found that the EGCG activation of AMPK was mediated by the Ca2+/calmodulin-dependent protein kinase kinase ( CaMKK). Furthermore, our results show that the EGCG activation of AMPK and EGCG suppression of hepatic gluconeogenesis were both dependent on production of reactive oxygen species (ROS), which was a known activator of CaMKK. Together, our results demonstrate an inhibitory role for EGCG in hepatic gluconeogenesis and shed new light on the mechanism by which EGCG suppresses gluconeogenesis. C1 Hamner Inst Hlth Sci, Res Triangle Pk, NC 27709 USA. Univ Virginia, Hlth Sci Ctr, Dept Internal Med, Div Endocrinol, Charlottesville, VA 22908 USA. NIH, Diabet Unit, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Internal Med, Div Endocrinol, Durham, NC 27710 USA. RP Cao, WH (reprint author), Hamner Inst Hlth Sci, 6 Davis Dr,POB 12137, Res Triangle Pk, NC 27709 USA. EM wcao@thehamner.org RI Quon, Michael/B-1970-2008; OI Quon, Michael/0000-0002-9601-9915; Quon , Michael /0000-0002-5289-3707 FU NIDDK NIH HHS [R01DK076039, R01 DK076039, R01 DK076039-01A2] NR 52 TC 162 Z9 174 U1 2 U2 16 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 OCT 12 PY 2007 VL 282 IS 41 BP 30143 EP 30149 DI 10.1074/jbc.M702390200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 217XS UT WOS:000249981200044 PM 17724029 ER PT J AU Dong, XY Patino-Lopez, G Candotti, F Shaw, S AF Dong, Xiaoyun Patino-Lopez, Genaro Candotti, Fabio Shaw, Stephen TI Structure-function analysis of the WIP role in T cell receptor-stimulated NFAT activation - Evidence that WIP-WASP dissociation is not required and that the WIPNH2 terminus is inhibitory SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID WISKOTT-ALDRICH-SYNDROME; SYNDROME PROTEIN WASP; ACTIN POLYMERIZATION; INTERACTING PROTEIN; NUCLEAR TRANSLOCATION; MOLECULAR-BASIS; EVH1 DOMAIN; N-WASP; GENE; COMPLEX AB WASP and its binding partner WIP play important roles in T cells both in actin polymerization and in interleukin-2 transcription. Aberrations thereof contribute to the pathology of Wiskott-Aldrich syndrome ( WAS). To directly evaluate the cooperativity of WIP and WASP in interleukin-2 transcription, we investigated how the WIP-WASP complex regulates NF-AT-mediated gene transcription. We developed an improved model system for analysis, using WIP and WASP cotransfection into Jurkat cells, in which strong induction of NFAT reporter activation is observed with anti-T cell receptor (TCR) antibody without the phorbol 12-myristate 13-acetate usually used previously. Using this system, our findings contradict a prevailing conceptual model of TCR-induced WIP-WASP dissociation by showing in three ways that the WIP-WASP complex mediates TCR-induced NFAT activation without dissociation. First, phosphorylation of WIP Ser(488) does not cause dissociation of the WIP-WASP complex. Second, WIP-WASP complexes do not dissociate demonstrably after TCR stimulation. Third, a fusion protein of WIP to WASP efficiently mediates NFAT activation. Next, our studies clarify that WIP stabilization of WASP explains otherwise unexpected results in TCR-induced NFAT activation. Finally, we find that the NH2 terminus of WIP is a highly inhibitory region for TCR-mediated transcriptional activation in which at least two elements contribute: the NH2-terminal polyproline and the NH2-terminal actin-binding WH2 domain. This suggests that WIP, like WASP, is subject to autoinhibition. Our data indicate that the WIP-WASP complex plays an important role in WASP stabilization and NFAT activation. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. RP Shaw, S (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Rm 4B36,10 Ctr Dr,MSC 1360, Bethesda, MD 20892 USA. EM sshaw@nih.gov OI Patino-Lopez, Genaro/0000-0002-8716-722X FU Intramural NIH HHS [Z01 BC009257-31, Z99 CA999999] NR 33 TC 17 Z9 17 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD OCT 12 PY 2007 VL 282 IS 41 BP 30303 EP 30310 DI 10.1074/jbc.M704972200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 217XS UT WOS:000249981200061 PM 17711847 ER PT J AU Szklarczyk, A Conant, K Owens, DF Ravin, R Mckay, RD Gerfen, C AF Szklarczyk, A. Conant, K. Owens, D. F. Ravin, R. Mckay, R. D. Gerfen, C. TI Matrix metalloproteinase-7 modulates synaptic vesicle recycling and induces atrophy of neuronal synapses SO NEUROSCIENCE LA English DT Article DE sNAP-25; proteolysis; synapse disassembly; strength; neurotransmission ID LONG-TERM POTENTIATION; HIPPOCAMPAL-NEURONS; MULTIPLE-SCLEROSIS; ALZHEIMERS-DISEASE; NERVOUS-SYSTEM; PLASMINOGEN-ACTIVATOR; EXCITATORY SYNAPSES; EXPRESSION PROFILE; BETA-CATENIN; MUTANT MICE AB Matrix metalloproteinase-7 (MMP-7) belongs to a family of zinc dependent endopeptidases that are expressed in a variety of tissues including the brain. MMPs are known to be potent mediators of pericellular proteolysis and likely mediators of dynamic remodelling of neuronal connections. While an association between proteases and the neuronal synapse is emerging, a full understanding of this relationship is lacking. Here, we show that MMP-7 alters the structure and function of presynaptic terminals without affecting neuronal survival. Bath application of recombinant MMP-7 to cultured rat neurons induced long-lasting inhibition of vesicular recycling as measured by synaptotagmin 1 antibody uptake assays and FM4-64 optical imaging. MMP-7 application resulted in reduced abundance of vesicular and active zone proteins locally within synaptic terminals although their general levels remained unaltered. Finally, chronic application of the protease resulted in synaptic atrophy, including smaller terminals and fewer synaptic vesicles, as determined by electron microscopy. Together these results suggest that MMP-7 is a potent modulator of synaptic vesicle recycling and synaptic ultrastructure and that elevated levels of the enzyme, as may occur with brain inflammation, may adversely influence neurotransmission. (c) 2007 IBRO. Published by Elsevier Ltd. All rights reserved. C1 Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21205 USA. NIH, NIMH, Lab Syst Neurosci, Bethesda, MD 20892 USA. NIH, NINDS, Mol Biol Lab, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21218 USA. RP Szklarczyk, A (reprint author), Johns Hopkins Univ, Sch Med, Dept Neurol, 600 N Wolfe St, Baltimore, MD 21205 USA. EM aszklar1@jhmi.edu; gerfenc@mail.nih.gov NR 78 TC 12 Z9 12 U1 0 U2 1 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 OCT 12 PY 2007 VL 149 IS 1 BP 87 EP 98 DI 10.1016/j.neuroscience.2007.07.032 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 220AB UT WOS:000250128200007 PM 17826919 ER PT J AU Chen, PS Wang, CC Bortner, CD Peng, GS Wu, X Pang, H Lu, RB Gean, PW Chuang, DM Hong, JS AF Chen, P. S. Wang, C.-C. Bortner, C. D. Peng, G.-S. Wu, X. Pang, H. Lu, R.-B. Gean, P.-W. Chuang, D.-M. Hong, J.-S. TI Valproic acid and other histone deacetylase inhibitors induce microglial apoptosis and attenuate lipopolysaccharide-induced dopaminergic neurotoxicity SO NEUROSCIENCE LA English DT Article DE HDAC inhibitors; microglial apoptosis; neuroprotection ID TRANSGENIC MOUSE MODEL; SODIUM-BUTYRATE; INFLAMMATORY RESPONSE; HUNTINGTONS-DISEASE; MOOD STABILIZER; DOWN-REGULATION; NITRIC-OXIDE; CELLS; PHAGOCYTOSIS; ACTIVATION AB Valproic acid (VPA), a widely prescribed drug for seizures and bipolar disorder, has been shown to be an inhibitor of histone deacetylase (HDAC). Our previous study has demonstrated that VPA pretreatment reduces lipopolysaccharide (LPS)-induced dopaminergic (DA) neurotoxicity through the inhibition of microglia over-activation. The aim of this study was to determine the mechanism underlying VPA-induced attenuation of microglia over-activation using rodent primary neuron/glia or enriched glia cultures. Other histone deacetylase inhibitors (HDACIs) were compared with VPA for their effects on microglial activity. We found that VPA induced apoptosis of microglia cells in a time- and concentration-dependent manner. VPA-treated microglial cells showed typical apoptotic hallmarks including phosphatidylserine externalization, chromatin condensation and DNA fragmentation. Further studies revealed that trichostatin A (TSA) and sodium butyrate (SB), two structurally dissimilar HDACIs, also induced microglial apoptosis. The apoptosis of microglia was accompanied by the disruption of mitochondrial membrane potential and the enhancement of acetylation levels of the histone H3 protein. Moreover, pretreatment with SB or TSA caused a robust decrease in LPS-induced pro-inflammatory responses and protected DA neurons from damage in mesencephalic neuron-glia cultures. Taken together, our results shed light on a novel mechanism whereby HDACIs induce neuroprotection and underscore the potential utility of HDACIs in preventing inflammation-related neurodegenerative disorders such as Parkinson's disease. Published by Elsevier Ltd on behalf of IBRO. C1 NIH, NIEHS, Chem Pharmacol Lab, Res Triangle Pk, NC 27709 USA. NIH, NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. Natl Cheng Kung Univ, Coll Med, Inst Basic Med Sci, Tainan 70101, Taiwan. RP Hong, JS (reprint author), NIH, NIEHS, Chem Pharmacol Lab, Res Triangle Pk, NC 27709 USA. EM hong3@niehs.nih.gov FU Intramural NIH HHS [Z01 ES090082-11] NR 41 TC 142 Z9 149 U1 2 U2 8 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 OCT 12 PY 2007 VL 149 IS 1 BP 203 EP 212 DI 10.1016/j.neuroscience.2007.06.053 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 220AB UT WOS:000250128200017 PM 17850978 ER PT J AU Zhang, YC Blattner, M Yu, YK AF Zhang, Yi-Cheng Blattner, Marcel Yu, Yi-Kuo TI Heat conduction process on community networks as a recommendation model SO PHYSICAL REVIEW LETTERS LA English DT Article ID RESISTOR NETWORKS; SYSTEMS AB Using heat conduction mechanism on a social network we develop a systematic method to predict missing values as recommendations. This method can treat very large matrices that are typical of internet communities. In particular, with an innovative, exact formulation that accommodates arbitrary boundary condition, our method is easy to use in real applications. The performance is assessed by comparing with traditional recommendation methods using real data. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Renmin Univ, Dept Phys, Beijing, Peoples R China. Univ Fribourg, Dept Phys, CH-1700 Fribourg, Switzerland. RP Zhang, YC (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM yi-cheng.zhang@unifr.ch; yyu@ncbi.nlm.nih.gov RI 石, 源/D-5929-2012; ruc, phy/E-4170-2012 FU Intramural NIH HHS NR 16 TC 115 Z9 137 U1 3 U2 13 PU AMER PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD OCT 12 PY 2007 VL 99 IS 15 AR 154301 DI 10.1103/PhysRevLett.99.154301 PG 4 WC Physics, Multidisciplinary SC Physics GA 220EV UT WOS:000250140600029 PM 17995171 ER PT J AU Cox-Foster, DL Conlan, S Holmes, EC Palacios, G Evans, JD Moran, NA Quan, PL Briese, T Hornig, M Geiser, DM Martinson, V vanEngelsdorp, D Kalkstein, AL Drysdale, A Hui, J Zhai, JH Cui, LW Hutchison, SK Simons, JF Egholm, M Pettis, JS Lipkin, WI AF Cox-Foster, Diana L. Conlan, Sean Holmes, Edward C. Palacios, Gustavo Evans, Jay D. Moran, Nancy A. Quan, Phenix-Lan Briese, Thomas Hornig, Mady Geiser, David M. Martinson, Vince vanEngelsdorp, Dennis Kalkstein, Abby L. Drysdale, Andrew Hui, Jeffrey Zhai, Junhui Cui, Liwang Hutchison, Stephen K. Simons, Jan Fredrik Egholm, Michael Pettis, Jeffery S. Lipkin, W. Ian TI A metagenomic survey of microbes in honey bee colony collapse disorder SO SCIENCE LA English DT Article ID RIBOSOMAL-RNA; INSECT TRYPANOSOMATIDS; APIS-MELLIFERA; DIVERSITY AB In colony collapse disorder (CCD), honey bee colonies inexplicably lose their workers. CCD has resulted in a loss of 50 to 90% of colonies in beekeeping operations across the United States. The observation that irradiated combs from affected colonies can be repopulated with naive bees suggests that infection may contribute to CCD. We used an unbiased metagenomic approach to survey microflora in CCD hives, normal hives, and imported royal jelly. Candidate pathogens were screened for significance of association with CCD by the examination of samples collected from several sites over a period of 3 years. One organism, Israeli acute paralysis virus of bees, was strongly correlated with CCD. C1 Columbia Univ, Mailman Sch Publ Hlth, Ctr Infect & Immun, New York, NY 10032 USA. Penn State Univ, Dept Entomol, University Pk, PA 16802 USA. Penn State Univ, Dept Biol, Mueller Lab, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. USDA ARS, Bee Res Lab, Beltsville, MD 20705 USA. Univ Arizona, Dept Ecol & Evolutionary Biol, Tucson, AZ 85721 USA. Penn State Univ, Dept Plant Pathol, University Pk, PA 16802 USA. Univ Arizona, Ctr Insect Sci, Tucson, AZ 85721 USA. Penn Dept Hlth, Bur Plant Ind Apiculture, Harrisburg, PA 17110 USA. RP Lipkin, WI (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Ctr Infect & Immun, New York, NY 10032 USA. EM wil2001@columbia.edu RI Moran, Nancy/G-1591-2010; Evans, Jay/C-8408-2012; Geiser, David/J-9950-2013; Cox-Foster, Diana/L-1538-2013; vanEngelsdorp, Dennis/E-7934-2010; Palacios, Gustavo/I-7773-2015; Conlan, Sean/B-4401-2008 OI Holmes, Edward/0000-0001-9596-3552; Evans, Jay/0000-0002-0036-4651; Palacios, Gustavo/0000-0001-5062-1938; Conlan, Sean/0000-0001-6848-3465 FU NIAID NIH HHS [U01AI070411, U54AI57158] NR 21 TC 793 Z9 841 U1 43 U2 492 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 OCT 12 PY 2007 VL 318 IS 5848 BP 283 EP 287 DI 10.1126/science.1146498 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 219LG UT WOS:000250086100050 PM 17823314 ER PT J AU Steeg, PS AF Steeg, Patricia S. TI Cancer - Micromanagement of metastasis SO NATURE LA English DT Editorial Material ID TUMOR-METASTASIS; MICRORNAS; RHOC C1 NCI, Bethesda, MD 20892 USA. RP Steeg, PS (reprint author), NCI, Bldg 37,Room 1122,37 Convent Dr, Bethesda, MD 20892 USA. EM steegp@mail.nih.gov NR 10 TC 18 Z9 22 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD OCT 11 PY 2007 VL 449 IS 7163 BP 671 EP + DI 10.1038/449671a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 218VV UT WOS:000250045000031 PM 17928850 ER PT J AU Domanski, MJ AF Domanski, Michael J. TI Primary prevention of coronary artery disease SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID HEART-DISEASE; CHOLESTEROL CONCENTRATIONS; ATHEROSCLEROSIS RISK; CONTROLLED-TRIAL; ALASKAN NATIVES; MEN; PROTECTION; AVERAGE; EVENTS C1 NHLBI, Atherothrombosis & Coronary Artery Dis Branch, Bethesda, MD 20892 USA. RP Domanski, MJ (reprint author), NHLBI, Atherothrombosis & Coronary Artery Dis Branch, Bldg 10, Bethesda, MD 20892 USA. NR 15 TC 14 Z9 14 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD OCT 11 PY 2007 VL 357 IS 15 BP 1543 EP 1545 DI 10.1056/NEJMe078183 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 218TE UT WOS:000250037000014 PM 17928603 ER PT J AU Migliaccio, A Varricchio, L De Falco, A Castoria, G Arra, C Yamaguchi, H Ciociola, A Lombardi, M Di Stasio, R Barbieri, A Baldi, A Barone, MV Appella, E Auricchio, F AF Migliaccio, A. Varricchio, L. De Falco, A. Castoria, G. Arra, C. Yamaguchi, H. Ciociola, A. Lombardi, M. Di Stasio, R. Barbieri, A. Baldi, A. Barone, M. V. Appella, E. Auricchio, F. TI Inhibition of the SH3 domain-mediated binding of Src to the androgen receptor and its effect on tumor growth SO ONCOGENE LA English DT Article DE androgen receptor; estrogen receptor; receptor antagonist; Src; xenografts ID PROSTATE-CANCER CELLS; ESTROGEN-RECEPTOR; ESTRADIOL-RECEPTOR; PATHWAY ACTIVATION; DNA-SYNTHESIS; MCF-7 CELLS; FACTOR-I; PROTEIN; KINASE; BREAST AB In human mammary and prostate cancer cells, steroid hormones or epidermal growth factor ( EGF) trigger association of the androgen receptor ( AR)- estradiol receptor ( ER) (alpha or beta) complex with Src. This interaction activates Src and affects the G1 to S cell cycle progression. In this report, we identify the sequence responsible for the AR/ Src interaction and describe a 10 amino- acid peptide that inhibits this interaction. Treatment of the human prostate or mammary cancer cells ( LNCaP or MCF- 7, respectively) with nanomolar concentrations of this peptide inhibits the androgen- or estradiol- induced association between the AR or the ER and Src the Src/ Erk pathway activation, cyclin D1 expression and DNA synthesis, without interfering in the receptor- dependent transcriptional activity. Similarly, the peptide prevents the S phase entry of LNCaP and MCF- 7 cells treated with EGF as well as mouse embryo fibroblasts stimulated with androgen or EGF. Interestingly, the peptide does not inhibit the S phase entry and cytoskeletal changes induced by EGF or serum treatment of AR- negative prostate cancer cell lines. The peptide is the first example of a specific inhibitor of steroid receptor-dependent signal transducing activity. The importance of these results is highlighted by the finding that the peptide strongly inhibits the growth of LNCaP xenografts established in nude mice. C1 Univ Naples 2, Fac Med & Chirurg, Dipartimento Patol Gen, I-80138 Naples, Italy. NCI, NIH, Cell Biol Lab, Bethesda, MD 20892 USA. Inst Cura Tumori Fdn, Naples, Italy. Univ Naples 2, Sez Anat Patol, Dipartimento Biochim & Biofis, Naples, Italy. Univ Naples Federico 2, Fac Med, Dipartimento Pediat, Naples, Italy. RP Auricchio, F (reprint author), Univ Naples 2, Fac Med & Chirurg, Dipartimento Patol Gen, Via L Crecchio 7, I-80138 Naples, Italy. EM ferdinando.auricchio@unina2.it OI Baldi, Alfonso/0000-0002-8693-3842; BARONE, Maria Vittoria/0000-0001-6190-4917; Castoria, Gabriella/0000-0002-0576-4494; Arra, Claudio/0000-0003-3162-2091; Migliaccio, Antimo/0000-0002-4197-2055; Barbieri, Antonio/0000-0002-7788-6167 FU Intramural NIH HHS NR 30 TC 47 Z9 47 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD OCT 11 PY 2007 VL 26 IS 46 BP 6619 EP 6629 DI 10.1038/sj.onc.1210487 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 219JT UT WOS:000250081500004 PM 17486077 ER PT J AU Willenbring, ML AF Willenbring, Mark L. TI Medications to treat alcohol dependence - Adding to the continuum of care SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID RANDOMIZED CONTROLLED-TRIAL; NATIONAL EPIDEMIOLOGIC SURVEY; UNITED-STATES; PREVALENCE; EFFICACY C1 NIAAA, NIH, Bethesda, MD 20892 USA. RP Willenbring, ML (reprint author), NIAAA, NIH, 5635 Fishers Ln,Rm 2047, Bethesda, MD 20892 USA. EM mlw@niaaa.nih.gov NR 14 TC 9 Z9 9 U1 1 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 10 PY 2007 VL 298 IS 14 BP 1691 EP 1692 DI 10.1001/jama.298.14.1691 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 218IO UT WOS:000250009400027 PM 17925523 ER PT J AU Saltz, LB Lenz, HJ Kindler, HL Hochster, HS Wadler, S Hoff, PM Kemeny, NE Hollywood, EM Gonen, M Quinones, M Morse, M Chen, HX AF Saltz, Leonard B. Lenz, Heinz-Josef Kindler, Hedy L. Hochster, Howard S. Wadler, Scott Hoff, Paulo M. Kemeny, Nancy E. Hollywood, Ellen M. Gonen, Mithat Quinones, Marcus Morse, Meroe Chen, Helen X. TI Randomized phase II trial of cetuximab, bevacizumab, and irinotecan compared with cetuximab and bevacizumab alone in irinotecan-refractory colorectal cancer: The BOND-2 study SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR; PLUS IRINOTECAN; ANGIOGENESIS AB Purpose We evaluated the safety and efficacy of concurrent administration of two monoclonal antibodies, cetuximab and bevacizumab, in patients with metastatic colorectal cancer. Patients and Methods This was a randomized phase II study in patients with irinotecan-refractory colorectal cancer. All patients were naive to both bevacizumab and cetuximab. Patients in arm A received irinotecan at the same dose and schedule as last received before study entry, plus cetuximab 400 mg/m(2) loading dose, then weekly cetuximab 250 mg/m(2), plus bevacizumab 5 mg/kg administered every other week. Patients in arm B received the same cetuximab and bevacizumab as those in arm A but without irinotecan. Results Forty-three patients received cetuximab, bevacizumab, and irinotecan (CBI) and 40 patients received cetuximab and bevacizumab alone (CB). Toxicities were as would have been expected from the single agents. For the CBI arm, time to tumor progression (TTP) was 7.3 months and the response rate was 37%; for the CB arm, TTP was 4.9 months and the response rate was 20%. The overall survival for the CBI arm was 14.5 months and the overall survival for the CB-alone arm was 11.4 months. Conclusion Cetuximab and bevacizumab can be administered concurrently, with a toxicity pattern that seems to be similar to that which would be expected from the two agents alone. This combination plus irinotecan also seems to be feasible. The activity seen with the addition of bevacizumab to cetuximab, or to cetuximab plus irinotecan, seems to be favorable when compared with historical controls of cetuximab or cetuximab/irinotecan in patients who are naive to bevacizumab. C1 Mem Sloan Kettering Canc Ctr, Dept Med, Div Solid Tumor Oncol, Dept Biostat,Gastrointestinal Oncol Serv, New York, NY 10021 USA. NYU, Dept Med, New York, NY 10016 USA. Cornell Univ, Weill Med Coll, Dept Med, Ithaca, NY 14853 USA. Univ So Calif, Norris Ctr Comprehens Canc, Div Med Oncol, Los Angeles, CA USA. Univ Texas, MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX 77030 USA. NCI, Div Canc Treatment, Chemotherapy Evaluat Program, Bethesda, MD 20892 USA. RP Saltz, LB (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, Div Solid Tumor Oncol, Dept Biostat,Gastrointestinal Oncol Serv, 1275 York Ave,Room H-917, New York, NY 10021 USA. EM saltzl@MSKCC.ORG RI Gonen, Mithat/E-4826-2012; OI Saltz, Leonard/0000-0001-8353-4670 FU NCI NIH HHS [N01-CM17105, N01-CM-07003-CM74S, N01-CM-17003, N01-CM-17102, N01-CM17101] NR 12 TC 258 Z9 271 U1 0 U2 10 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 OCT 10 PY 2007 VL 25 IS 29 BP 4557 EP 4561 DI 10.1200/JCO.2007.12.0949 PG 5 WC Oncology SC Oncology GA 233EQ UT WOS:000251073600011 PM 17876013 ER PT J AU O'Neill, SC Brewer, NT Lillie, SE Morrill, EF Dees, EC Carey, LA Rimer, BK AF O'Neill, Suzanne C. Brewer, Noel T. Lillie, Sarah E. Morrill, Edward F. Dees, E. Claire Carey, Lisa A. Rimer, Barbara K. TI Women's interest in gene expression analysis for breast cancer recurrence risk SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID DECISION-MAKING; ADJUVANT CHEMOTHERAPY; PATIENTS PREFERENCES; SUSCEPTIBILITY; THERAPY; ATTITUDES; SURVIVAL; IMPACT; EXPECTATIONS; INFORMATION AB Purpose Genomic and other technologies are improving the accuracy with which clinicians can estimate risk for recurrence (RFR) of breast cancer and make judgments about potential benefits of chemotherapy. Little is known of how patients will respond to genomic RFR testing or interact with their physicians to make informed decisions regarding treatment. We assessed interest in genomic RFR testing and patient preferences for incorporating results into treatment decision making. Patients and Methods One hundred thirty-nine women previously treated for early-stage breast cancer completed surveys that presented hypothetical scenarios reflecting different test outcomes and potential decisions. We assessed women's attitudes toward RFR testing, how results would affect their choices about adjuvant treatment, and potential concerns about and perceived benefits of testing. Results The majority of participants said they would "definitely" want to be tested (76%), receive their results (87%), and discuss these results with their physicians. They were willing to pay, on average, $997 for testing. Those who expressed more concerns about testing were less interested in testing and in incorporating results into treatment decision making. Participants were more likely to want chemotherapy when presented with high-risk results and would worry more about those results. They were least likely to trust and most likely to express potential anticipated regret in response to intermediate RFR results. Conclusion Participants expressed strong interest in testing. Although these decisions were sensitive to RFR, participants' complex reactions to intermediate RFR suggest care is needed when communicating such results. C1 Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27515 USA. Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC 27515 USA. Univ N Carolina, Dept Psychol, Chapel Hill, NC 27515 USA. RP O'Neill, SC (reprint author), NHGRI, Social & Behav Res Branch, NIH, Bldg 31,B1B36B, Bethesda, MD 20892 USA. EM oneills@mail.nih.gov RI Brewer, Noel/C-4375-2008; OI Lillie, Sarah/0000-0001-9854-7191 FU NCI NIH HHS [R25 CA57726] NR 46 TC 27 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 OCT 10 PY 2007 VL 25 IS 29 BP 4628 EP 4634 DI 10.1200/JCO.2006.09.6255 PG 7 WC Oncology SC Oncology GA 233EQ UT WOS:000251073600022 PM 17925559 ER PT J AU Makareeva, E Leikin, S AF Makareeva, Elena Leikin, Sergey TI Procollagen Triple Helix Assembly: An Unconventional Chaperone-Assisted Folding Paradigm SO PLOS ONE LA English DT Article AB Fibers composed of type I collagen triple helices form the organic scaffold of bone and many other tissues, yet the energetically preferred conformation of type I collagen at body temperature is a random coil. In fibers, the triple helix is stabilized by neighbors, but how does it fold? The observations reported here reveal surprising features that may represent a new paradigm for folding of marginally stable proteins. We find that human procollagen triple helix spontaneously folds into its native conformation at 30-34 degrees C but not at higher temperatures, even in an environment emulating Endoplasmic Reticulum (ER). ER-like molecular crowding by nonspecific proteins does not affect triple helix folding or aggregation of unfolded chains. Common ER chaperones may prevent aggregation and misfolding of procollagen C-propeptide in their traditional role of binding unfolded polypeptide chains. However, such binding only further destabilizes the triple helix. We argue that folding of the triple helix requires stabilization by preferential binding of chaperones to its folded, native conformation. Based on the triple helix folding temperature measured here and published binding constants, we deduce that HSP47 is likely to do just that. It takes over 20 HSP47 molecules to stabilize a single triple helix at body temperature. The required 50-200 mu M concentration of free HSP47 is not unusual for heat-shock chaperones in ER, but it is 100 times higher than used in reported in vitro experiments, which did not reveal such stabilization. C1 [Makareeva, Elena; Leikin, Sergey] NICHHD, Sect Phys Biochem, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Leikin, S (reprint author), NICHHD, Sect Phys Biochem, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. EM leikins@mail.nih.gov RI Makareeva, Elena/F-5183-2011; Leikin, Sergey/A-5518-2008 OI Leikin, Sergey/0000-0001-7095-0739 NR 56 TC 26 Z9 26 U1 0 U2 8 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 10 PY 2007 VL 2 IS 10 AR e1029 DI 10.1371/journal.pone.0001029 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10HV UT WOS:000207456000028 PM 17925877 ER PT J AU Romano, CM de Melo, FL Corsini, MAB Holmes, EC Zanotto, PMDA AF Romano, Camila M. de Melo, Fernando L. Corsini, Marco Aurelio B. Holmes, Edward C. Zanotto, Paolo M. de A. TI Demographic Histories of ERV-K in Humans, Chimpanzees and Rhesus Monkeys SO PLOS ONE LA English DT Article AB We detected 19 complete endogenous retroviruses of the K family in the genome of rhesus monkey (Macaca mulatta; RhERV-K) and 12 full length elements in the genome of the common chimpanzee (Pan troglodytes; CERV-K). These sequences were compared with 55 human HERV-K and 20 CERV-K reported previously, producing a total data set of 106 full-length ERV-K genomes. Overall, 61% of the human elements compared to 21% of the chimpanzee and 47% of rhesus elements had estimated integration times less than 4.5 million years before present (MYBP), with an average integration times of 7.8 MYBP, 13.4 MYBP and 10.3 MYBP for HERV-K, CERV-K and RhERV-K, respectively. By excluding those ERV-K sequences generated by chromosomal duplication, we used 63 of the 106 elements to compare the population dynamics of ERV-K among species. This analysis indicated that both HERV-K and RhERV-K had similar demographic histories, including markedly smaller effective population sizes, compared to CERV-K. We propose that these differing ERV-K dynamics reflect underlying differences in the evolutionary ecology of the host species, such that host ecology and demography represent important determinants of ERV-K dynamics. C1 [Romano, Camila M.; de Melo, Fernando L.; Corsini, Marco Aurelio B.; Zanotto, Paolo M. de A.] Univ Sao Paulo, Biomed Sci Inst ICBII, Dept Microbiol, Lab Mol Evolut & Bioinformat, BR-05508 Sao Paulo, Brazil. [Holmes, Edward C.] Penn State Univ, Dept Biol, Mueller Lab, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. [Holmes, Edward C.] NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Zanotto, PMDA (reprint author), Univ Sao Paulo, Biomed Sci Inst ICBII, Dept Microbiol, Lab Mol Evolut & Bioinformat, BR-05508 Sao Paulo, Brazil. EM pzanotto@usp.br RI Romano, Camila/C-8185-2013; OI Holmes, Edward/0000-0001-9596-3552 FU VGDN [00/04205-6]; CAPES; CNPq FX Funding: This research was funded by VGDN program FAPESP (00/04205-6). CMR and FLM hold a CAPES doctorate fellowship (DO) and PMAZ holds a CNPq PQ Research Scholarship. NR 39 TC 10 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 OCT 10 PY 2007 VL 2 IS 10 AR e1026 DI 10.1371/journal.pone.0001026 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10HV UT WOS:000207456000025 PM 17925874 ER PT J AU Yu, XK Qiao, M Atanasov, I Hu, ZY Kato, T Liang, TJ Zhou, ZH AF Yu, Xuekui Qiao, Ming Atanasov, Ito Hu, Zongyi Kato, Takanobu Liang, T. Jake Zhou, Z. Hong TI Cryo-electron microscopy and three-dimensional reconstructions of hepatitis C virus particles SO VIROLOGY LA English DT Article DE assembly; envelope protein; nucleocapsid; neutralizing antibodies; viral infection ID TICK-BORNE ENCEPHALITIS; WEST-NILE-VIRUS; DENGUE VIRUS; ENVELOPE GLYCOPROTEIN; CORE PROTEIN; IN-VITRO; BINDING; VISUALIZATION; MODEL; LOCALIZATION AB The structural details of hepatitis C virus (HCV) have been elusive because of the lack of a robust tissue culture system for producing an adequate amount of virions from infectious sources for in-depth three-dimensional (3D) structural analysis. Using both negative-stain and cryo-electron microscopy (cryoEM), we show that HCV virions isolated from cell culture have a rather uniform size of 500 A in diameter and that recombinantly expressed HCV-like particles (HCV-LPs) have similar morphologic, biophysical and antigenic features in spite of the varying sizes of the particles. 3D reconstructions were obtained from HCV-LPs with the same size as the HCV virions in the presence and absence of monoclonal antibodies bound to the El glycoprotein. The 31) reconstruction of HCV-LP reveals a multilayered architecture, with smooth outerlayer densities arranged in a 'fishbone' configuration. Reconstruction of the particles in complex with anti-EI antibodies shows that sites of the El epitope are exposed and surround the 5-, 3- and 2-fold axes. The binding pattern of the anti-E1 antibody and the fitting of the structure of the dengue virus E glycoprotein into our 3D reconstructions further suggest that the HCV-LP E1 and E2 proteins form a tetramer (or dimer of heterodimers) that corresponds morphologically and functionally to the flavivirus E homodimer. This first 31) structural analysis of HCV particles offers important insights into the elusive mechanisms of HCV assembly and maturation. (C) 2007 Published by Elsevier Inc. C1 NIDDK, NIH, Liver Dis Branch, Bethesda, MD 20892 USA. Univ Texas, Sch Med, Dept Pathol & Lab Med, Houston, TX 77030 USA. RP Liang, TJ (reprint author), NIDDK, NIH, Liver Dis Branch, Bethesda, MD 20892 USA. EM jfang@nih.gov FU Intramural NIH HHS NR 37 TC 34 Z9 37 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD OCT 10 PY 2007 VL 367 IS 1 BP 126 EP 134 DI 10.1016/j.virol.2007.05.038 PG 9 WC Virology SC Virology GA 216TS UT WOS:000249902500013 PM 17618667 ER PT J AU Seaman, MS LeBlanc, DF Grandpre, LE Bartman, MT Montefiori, DC Letvin, NL Mascola, JR AF Seaman, Michael S. LeBlanc, Daniel F. Grandpre, Lauren E. Bartman, Melissa T. Montefiori, David C. Letvin, Norman L. Mascola, John R. TI Standardized assessment of NAb responses elicited in rhesus monkeys immunized with single- or multi-clade HIV-1 envelope immunogens SO VIROLOGY LA English DT Article DE HIV vaccine; envelope glycoprotein; neutralizing antibody; rhesus monkey; SHIV-89.6P ID HUMAN-IMMUNODEFICIENCY-VIRUS; NEUTRALIZING ANTIBODY-RESPONSE; HUMAN MONOCLONAL-ANTIBODY; SUBTYPE-B; TYPE-1 ISOLATE; ENV CLONES; GP120; MACAQUES; DNA; GLYCOPROTEIN AB The genetic diversity of HIV-1 envelope glycoproteins (Env) remains a major obstacle to the development of an antibody-based AIDS vaccine. The present studies examine the breadth and magnitude of neutralizing antibody (NAb) responses in rhesus monkeys after immunization with DNA prime-recombinant adenovirus (rAd) boost vaccines encoding either single or multiple genetically distant Env immunogens, and subsequently challenged with a pathogenic simian-human immunodeficiency virus (SHIV-89.6P). Using a standardized multi-tier panel of reference Env pseudoviruses for NAb assessment, we show that monkeys immunized with a mixture of Env immunogens (clades A, B, and C) exhibited a greater breadth of NAb activity against neutralization-sensitive Tier 1 viruses following both vaccination and challenge compared to monkeys immunized with a single Env immunogen (clade B or C). However, all groups of Env-vaccinated monkeys demonstrated only limited neutralizing activity against Tier 2 pseudoviruses, which are more characteristic of the neutralization sensitivity of circulating HIV-1. Notably, the development of a post-challenge NAb response against SHIV-89.6P was similar in monkeys receiving either clade B, clade C, or clade A+B+C Env immunogens, suggesting cross-clade priming of NAb responses. In addition, vaccines encoding Env immunogens heterologous to SHIV-89.6P primed for a rapid anamnestic NAb response following infection compared to vaccines lacking an Env component. These results show that DNA/rAd immunization with multiple diverse Env immunogens is a viable approach for enhancing the breadth of NAb responses against HIV-1, and suggest that Env immunogens cart prime for anamnestic NAb responses against a heterologous challenge virus. (C) 2007 Elsevier Inc. All rights reserved. C1 Beth Israel Deaconess Med Ctr, Div Vis Pathogenesis, Boston, MA 02215 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. NIAID, NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Seaman, MS (reprint author), Beth Israel Deaconess Med Ctr, Div Vis Pathogenesis, 330 Brookline Ave RE-204, Boston, MA 02215 USA. EM mseaman@bidmc.harvard.edu FU Intramural NIH HHS [Z99 AI999999]; NIAID NIH HHS [N01AI30033] NR 43 TC 29 Z9 30 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 OCT 10 PY 2007 VL 367 IS 1 BP 175 EP 186 DI 10.1016/j.virol.2007.05.024 PG 12 WC Virology SC Virology GA 216TS UT WOS:000249902500018 PM 17599382 ER PT J AU Shulman-Peleg, A Shatsky, M Nussinov, R Wolfson, HJ AF Shulman-Peleg, Alexandra Shatsky, Maxim Nussinov, Ruth Wolfson, Haim J. TI Spatial chemical conservation of hot spot interactions in protein-protein complexes SO BMC BIOLOGY LA English DT Article ID STRUCTURAL CLASSIFICATION; BINDING INTERFACES; RECOGNITION SITES; DATA SET; RESIDUES; MUTATIONS; ALIGNMENT; SEQUENCE; DATABASE; ENERGY AB Background: Conservation of the spatial binding organizations at the level of physico-chemical interactions is important for the formation and stability of protein-protein complexes as well as protein and drug design. Due to the lack of computational tools for recognition of spatial patterns of interactions shared by a set of protein-protein complexes, the conservation of such interactions has not been addressed previously. Results: We performed extensive spatial comparisons of physico-chemical interactions common to different types of protein-protein complexes. We observed that 80% of these interactions correspond to known hot spots. Moreover, we show that spatially conserved interactions allow prediction of hot spots with a success rate higher than obtained by methods based on sequence or backbone similarity. Detection of spatially conserved interaction patterns was performed by our novel MAPPIS algorithm. MAPPIS performs multiple alignments of the physico-chemical interactions and the binding properties in three dimensional space. It is independent of the overall similarity in the protein sequences, folds or amino acid identities. We present examples of interactions shared between complexes of colicins with immunity proteins, serine proteases with inhibitors and T-cell receptors with superantigens. We unravel previously overlooked similarities, such as the interactions shared by the structurally different RNase-inhibitor families. Conclusion: The key contribution of MAPPIS is in discovering the 3D patterns of physicochemical interactions. The detected patterns describe the conserved binding organizations that involve energetically important hot spot residues and are crucial for the protein-protein associations. C1 [Wolfson, Haim J.] Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Comp Sci, IL-69978 Tel Aviv, Israel. [Nussinov, Ruth] Berkeley Natl Lab, Phys Biosci Div, Berkeley, CA USA. [Nussinov, Ruth] NCI, SAIC Frederick Inc, Ctr Canc Ctr Nanobiol Program, Basic Res Program, Frederick, MD 21701 USA. [Shatsky, Maxim] Tel Aviv Univ, Sackler Fac Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Shulman-Peleg, A (reprint author), Tel Aviv Univ, Raymond & Beverly Sackler Fac Exact Sci, Sch Comp Sci, IL-69978 Tel Aviv, Israel. EM shulmana@tau.ac.il; maxshats@tau.ac.il; ruthn@ncifcrf.gov; wolfson@tau.ac.il RI Wolfson, Haim/A-1837-2011 FU Intramural NIH HHS; NCI NIH HHS [N01CO12400]; NIAID NIH HHS [1UC1AI067231, UC1 AI067231] NR 64 TC 42 Z9 42 U1 0 U2 6 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1741-7007 J9 BMC BIOL JI BMC Biol. PD OCT 9 PY 2007 VL 5 AR 43 DI 10.1186/1741-7007-5-43 PG 11 WC Biology SC Life Sciences & Biomedicine - Other Topics GA 259WN UT WOS:000252971700001 PM 17925020 ER PT J AU Srivastava, S Li, Z Yang, X Yedwabnick, M Shaw, S Chan, C AF Srivastava, Shireesh Li, Zheng Yang, Xuerui Yedwabnick, Matthew Shaw, Stephen Chan, Christina TI Identification of genes that regulate multiple cellular processes/responses in the context of lipotoxicity to hepatoma cells SO BMC GENOMICS LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; POLYUNSATURATED FATTY-ACIDS; BIOCHEMICAL SYSTEMS-THEORY; ACTIVATED PROTEIN-KINASE; STEAROYL-COA DESATURASE; NECROSIS-FACTOR-ALPHA; GOAT MAMMARY-GLAND; RED-BLOOD-CELLS; TRIACYLGLYCEROL SYNTHESIS; TRIGLYCERIDE ACCUMULATION AB Background: In order to devise efficient treatments for complex, multi-factorial diseases, it is important to identify the genes which regulate multiple cellular processes. Exposure to elevated levels of free fatty acids (FFAs) and tumor necrosis factor alpha (TNF-alpha) alters multiple cellular processes, causing lipotoxicity. Intracellular lipid accumulation has been shown to reduce the lipotoxicity of saturated FFA. We hypothesized that the genes which simultaneously regulate lipid accumulation as well as cytotoxicity may provide better targets to counter lipotoxicity of saturated FFA. Results: As a model system to test this hypothesis, human hepatoblastoma cells (HepG2) were exposed to elevated physiological levels of FFAs and TNF-alpha. Triglyceride (TG) accumulation, toxicity and the genomic responses to the treatments were measured. Here, we present a framework to identify such genes in the context of lipotoxicity. The aim of the current study is to identify the genes that could be altered to treat or ameliorate the cellular responses affected by a complex disease rather than to identify the causal genes. Genes that regulate the TG accumulation, cytotoxicity or both were identified by a modified genetic algorithm partial least squares (GA/PLS) analysis. The analyses identified NADH dehydrogenase and mitogen activated protein kinases (MAPKs) as important regulators of both cytotoxicity and lipid accumulation in response to FFA and TNF-alpha exposure. In agreement with the predictions, inhibiting NADH dehydrogenase and c-Jun N-terminal kinase (JNK) reduced cytotoxicity significantly and increased intracellular TG accumulation. Inhibiting another MAPK pathway, the extracellular signal regulated kinase (ERK), on the other hand, improved the cytotoxicity without changing TG accumulation. Much greater reduction in the toxicity was observed upon inhibiting the NADH dehydrogenase and MAPK ( which were identified by the dual-response analysis), than for the stearoyl-CoA desaturase (SCD) activation ( which was identified for the TG-alone analysis). Conclusion: These results demonstrate the applicability of GA/PLS in identifying the genes that regulate multiple cellular responses of interest and that genes regulating multiple cellular responses may be better candidates for countering complex diseases. C1 [Srivastava, Shireesh; Li, Zheng; Yang, Xuerui; Yedwabnick, Matthew; Shaw, Stephen; Chan, Christina] Michigan State Univ, Dept Chem Engn & Mat Sci, E Lansing, MI 48824 USA. [Chan, Christina] Michigan State Univ, Dept Biochem & Mol Biol, E Lansing, MI 48824 USA. [Chan, Christina] Michigan State Univ, Dept Comp Sci & Engn, E Lansing, MI 48824 USA. [Srivastava, Shireesh] NIAAA, NIH, Rockville, MD 20851 USA. [Li, Zheng] Boston Univ, Dept Biomed Engn, Boston, MA 02215 USA. RP Srivastava, S (reprint author), Michigan State Univ, Dept Chem Engn & Mat Sci, E Lansing, MI 48824 USA. EM srivas14@egr.msu.edu; lizheng1@msu.edu; yangxuer@egr.msu.edu; krischan@egr.msu.edu; krischan@egr.msu.edu; krischan@egr.msu.edu FU NCI NIH HHS [R21 CA126136, 1R21CA126136-01]; NIGMS NIH HHS [1R01GM079688-01, R01 GM079688] NR 53 TC 10 Z9 10 U1 0 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2164 J9 BMC GENOMICS JI BMC Genomics PD OCT 9 PY 2007 VL 8 AR 364 DI 10.1186/1471-2164-8-364 PG 16 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 240DC UT WOS:000251566300001 PM 17925029 ER PT J AU Matura, LA Ho, VB Rosing, DR Bondy, CA AF Matura, Lea Ann Ho, Vincent B. Rosing, Douglas R. Bondy, Carolyn A. TI Aortic dilatation and dissection in Turner syndrome SO CIRCULATION LA English DT Article DE aneurysm; aorta; magnetic resonance imaging; sex chromosomes ID CARDIOVASCULAR MALFORMATIONS; MARFANS-SYNDROME; SHORT STATURE; ANOMALIES; ANEURYSM; RUPTURE; DISEASE; PREVALENCE; HOMEOBOX; DILATION AB Background - The risk for aortic dissection is increased among relatively young women with Turner syndrome ( TS). It is unknown whether aortic dilatation precedes acute aortic dissection in TS and, if so, what specific diameter predicts impending deterioration. Methods and Results - Study subjects included 166 adult volunteers with TS ( average age, 36.2 years) who were not selected for cardiovascular disease and 26 healthy female control subjects. Ascending and descending aortic diameters were measured by magnetic resonance imaging at the right pulmonary artery. TS women were on average 20 cm shorter, yet average aortic diameters were identical in the 2 groups. Ascending aortic diameters normalized to body surface area ( aortic size index) were significantly greater in TS, and approximate to 32% of TS women had values greater than the 95th percentile of 2.0 cm/m(2). Ascending diameter/ descending diameter ratios also were significantly greater in the TS group. During approximate to 3 years of follow- up, aortic dissections occurred in 3 women with TS, for an annualized rate of 618 cases/ 100 000 woman- years. These 3 subjects had ascending aortic diameters of 3.7 to 4.8 cm and aortic size indices >2.5 cm/ m(2). Conclusions - The risk for aortic dissection is greatly increased in young women with TS. Because of their small stature, ascending aortic diameters of < 5 cm may represent significant dilatation; thus, the use of aortic size index is preferred. Individuals with a dilated ascending aorta defined as aortic size index > 2.0 cm/m(2) require close cardiovascular surveillance. Those with aortic size index >= 2.5 cm/ m(2) are at highest risk for aortic dissection. C1 NICHHD, NIH, Dev Endocrinol Branch, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Radiol & Radiol Sci, Bethesda, MD 20814 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Bondy, CA (reprint author), NICHHD, NIH, Dev Endocrinol Branch, CRC 1-330,10 Ctr Dr, Bethesda, MD 20892 USA. EM bondyc@mail.nih.gov FU Intramural NIH HHS NR 40 TC 137 Z9 142 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD OCT 9 PY 2007 VL 116 IS 15 BP 1663 EP 1670 DI 10.1161/CIRCULATIONAHA.106.685487 PG 8 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 218HX UT WOS:000250007700004 PM 17875973 ER PT J AU Jiang, G Charoenvit, Y Moreno, A Baraceros, MF Banania, G Richie, N Abot, S Ganeshan, H Fallarme, V Patterson, NB Geall, A Weiss, WR Strobert, E Caro-Aquilar, I Lanar, DE Saul, A Martin, LB Gowda, K Morrissette, CR Kaslow, DC Carucci, DJ Galinski, MR Doolan, DL AF Jiang, George Charoenvit, Yupin Moreno, Alberto Baraceros, Maria F. Banania, Glenna Richie, Nancy Abot, Steve Ganeshan, Harini Fallarme, Victoria Patterson, Noelle B. Geall, Andrew Weiss, Walter R. Strobert, Elizabeth Caro-Aquilar, Ivette Lanar, David E. Saul, Allan Martin, Laura B. Gowda, Kalpana Morrissette, Craig R. Kaslow, David C. Carucci, Daniel J. Galinski, Mary R. Doolan, Denise L. TI Induction of multi-antigen multi-stage immune responses against Plasmodium falciparum in rhesus monkeys, in the absence of antigen interference, with heterologous DNA prime/poxvirus boost immunization SO MALARIA JOURNAL LA English DT Article ID MALARIA VACCINE DEVELOPMENT; APICAL MEMBRANE ANTIGEN-1; NONIONIC BLOCK-COPOLYMER; CYTOTOXIC T-LYMPHOCYTES; GENE-BASED VACCINES; PROTECTIVE IMMUNITY; PLASMID DNA; CIRCUMSPOROZOITE PROTEIN; ANTIBODY-RESPONSES; NONHUMAN-PRIMATES AB The present study has evaluated the immunogenicity of single or multiple Plasmodium falciparum (Pf) antigens administered in a DNA prime/poxvirus boost regimen with or without the poloxamer CRLI005 in rhesus monkeys. Animals were primed with PfCSP plasmid DNA or a mixture of PfCSP, PfSSP2/TRAP, PfLSAI, PfAMAI and PfMSPI-42 (CSLAM) DNA vaccines in PBS or formulated with CRLI005, and subsequently boosted with ALVAC-Pf7, a canarypox virus expressing the CSLAM antigens. Cell-mediated immune responses were evaluated by IFN-gamma ELIspot and intracellular cytokine staining, using recombinant proteins and overlapping synthetic peptides. Antigen- specific and parasite-specific antibody responses were evaluated by ELISA and IFAT, respectively. Immune responses to all components of the multi-antigen mixture were demonstrated following immunization with either DNA/PBS or DNA/CRL1005, and no antigen interference was observed in animals receiving CSLAM as compared to PfCSP alone. These data support the down-selection of the CSLAM antigen combination. CRLI005 formulation had no apparent effect on vaccine-induced T cell or antibody responses, either before or after viral boost. In high responder monkeys, CD4+IL-2+ responses were more predominant than CD8+ T cell responses. Furthermore, CD8+ IFN-responses were detected only in the presence of detectable CD4+ T cell responses. Overall, this study demonstrates the potential for multivalent Pf vaccines based on rational antigen selection and combination, and suggests that further formulation development to increase the immunogenicity of DNA encoded antigens is warranted. C1 [Jiang, George; Charoenvit, Yupin; Baraceros, Maria F.; Banania, Glenna; Richie, Nancy; Abot, Steve; Ganeshan, Harini; Fallarme, Victoria; Patterson, Noelle B.; Geall, Andrew; Weiss, Walter R.; Gowda, Kalpana; Carucci, Daniel J.; Doolan, Denise L.] Naval Med Res Ctr, Malaria Program, Silver Spring, MD 20910 USA. [Jiang, George; Baraceros, Maria F.; Banania, Glenna; Richie, Nancy; Abot, Steve; Ganeshan, Harini; Fallarme, Victoria; Patterson, Noelle B.] Henry M Jackson Fdn, Rockville, MD 20852 USA. [Moreno, Alberto; Galinski, Mary R.] Emory Univ, Yerkes Natl Primate Res Ctr, Emory Vaccine Ctr, Atlanta, GA 30329 USA. [Moreno, Alberto; Strobert, Elizabeth; Caro-Aquilar, Ivette; Galinski, Mary R.] Emory Univ, Sch Med, Dept Med, Div Infect Dis, Atlanta, GA 30329 USA. [Geall, Andrew; Kaslow, David C.] Vical Inc, San Diego, CA 92121 USA. [Lanar, David E.; Morrissette, Craig R.] Walter Reed Army Inst Res, Silver Spring, MD 20910 USA. [Saul, Allan; Martin, Laura B.] NIAID, Malaria Vaccine Dev Branch, NIH, Rockville, MD 20852 USA. [Doolan, Denise L.] Johns Hopkins Univ, Sch Hyg & Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA. [Doolan, Denise L.] Bancroft Ctr, Queensland Inst Med Res, Brisbane, Qld 4029, Australia. RP Doolan, DL (reprint author), Naval Med Res Ctr, Malaria Program, Silver Spring, MD 20910 USA. EM jiang_george@bah.com; charoenvity@nmrc.navy.mil; amoreno@rmy.emory.edu; sjs1973maria@yahoo.com; bananiag@nmrc.navy.mil; Nancy.Richie@amedd.army.mil; abots@nmrc.navy.mil; ganeshanh@nmrc.navy.mil; fallarmev@nmrc.navy.mil; pattersonn@nmrc.navy.mil; andrew.geall@novartis.com; weissw@nmrc.navy.mil; estrobert@rmy.emory.edu; icaroaquilar@rmy.emory.edu; david.lanar@us.army.mil; asaul@niaid.nih.gov; lmartin@niaid.nih.gov; gowdak@nmrc.navy.mil; craig.morrissette@us.army.mil; David_Kaslow@merck.com; dcarucci@fnih.org; Galinski@rmy.emory.edu; Denise.Doolan@qimr.edu.au RI Lanar, David/B-3560-2011; Saul, Allan/I-6968-2013; Martin, Laura/N-1789-2013; Doolan, Denise/F-1969-2015 OI Saul, Allan/0000-0003-0665-4091; Martin, Laura/0000-0002-4431-4381; NR 81 TC 21 Z9 22 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD OCT 9 PY 2007 VL 6 AR 135 DI 10.1186/1475-2875-6-135 PG 17 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 243SN UT WOS:000251817700001 PM 17925026 ER PT J AU Gironella, M Seux, M Xie, MJ Cano, C Tomasini, R Gommeaux, J Garcia, S Nowak, J Yeung, ML Jeang, KT Chaix, A Fazli, L Motoo, Y Wang, Q Rocchi, P Russo, A Gleave, M Dagorn, JC Iovanna, JL Carrier, A Pebusque, MJ Dusetti, NJ AF Gironella, Meritxell Seux, Mylene Xie, Min-Jue Cano, Carla Tomasini, Richard Gommeaux, Julien Garcia, Stephane Nowak, Jonathan Yeung, Man Lung Jeang, Kuan-Teh Chaix, Amandine Fazli, Ladan Motoo, Yoshiharu Wang, Qing Rocchi, Palma Russo, Antonio Gleave, Martin Dagorn, Jean-Charles Iovanna, Juan L. Carrier, Alice Pebusque, Marie-Josephe Dusetti, Nelson J. TI Tumor protein 53-induced nuclear protein 1 expression is repressed by miR-155, and its restoration inhibits pancreatic tumor development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE apoptosis; pancreatic cancer; ponasterone A; tumor suppressor; micro RNA ID INDUCED PROTEIN SIP; B-CELL LYMPHOMAS; INTRAEPITHELIAL NEOPLASIA; MICRORNA SIGNATURE; CANCER; GENE; MICROARRAY; LESIONS; P53; ADENOCARCINOMA AB Pancreatic cancer is a disease with an extremely poor prognosis. Tumorprotein 53-induced nuclearprotein 1 (TP53INP1) is a proapoptotic stress-induced p53 target gene. In this article, we show by immunohistochemical analysis that TP53INP1 expression is dramatically reduced in pancreatic ductal adenocarcinorna (PDAC) and this decrease occurs early during pancreatic cancer development. TP53INP1 reexpression in the pancreatic cancer-derived cell line MiaPaCa2 strongly reduced its capacity to form s.c., i.p., and intrapancreatic tumors in nude mice. This anti-tumoral capacity is, at least in part, due to the induction of caspase 3-mediated apoptosis. In addition, TP53INP1(-/-) mouse embryonic fibroblasts (MEFs) transformed with a retrovirus expressing E1A/ras(V12) oncoproteins developed bigger tumors than TP53INP1(+/+) transformed MEFs or TP53INP1(-/-) transformed MEFs with restored TP53INP1 expression. Finally, TP53INP1 expression is repressed by the oncogenic micro RNA miR-155, which is overexpressed in PDAC cells. TP53INP1 is a previously unknown miR-155 target presenting anti-tumoral activity. C1 INSERM, U624, F-13288 Marseille, France. Univ Aix Marseille, F-13000 Marseille, France. NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. Vancouver Gen Hosp, Prostae Ctr, Vancouver, BC V6H 3Z6, Canada. Kanazawa Med Univ, Dept Med Oncol, Ishikari, Hokkaido 9200293, Japan. Ctr Leon Berard, Unite Oncol Mol, F-69008 Lyon, France. Ctr Leon Berard, INSERM, U590, F-69008 Lyon, France. Univ Palermo, Interdept Ctr Clin Oncol, I-90127 Palermo, Italy. RP Dusetti, NJ (reprint author), INSERM, U624, F-13288 Marseille, France. EM dusetti@marseille.inserm.fr RI Jeang, Kuan-Teh/A-2424-2008; Rocchi, Palma/P-5455-2014; tomasini, richard/F-1130-2017 OI Rocchi, Palma/0000-0002-4383-4684; NR 38 TC 309 Z9 347 U1 4 U2 16 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 OCT 9 PY 2007 VL 104 IS 41 BP 16170 EP 16175 DI 10.1073/pnas.0703942104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 220AH UT WOS:000250128800037 PM 17911264 ER PT J AU Nam, JS Hirohashi, S Wakefield, LM AF Nam, Jeong-Seok Hirohashi, Setsuo Wakefield, Lalage M. TI Dysadherin: A new, player in cancer progression SO CANCER LETTERS LA English DT Review DE dysadherin; E-cadherin; chemokine (C-C motif) ligand 2; metastasis; breast cancer ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; SQUAMOUS-CELL CARCINOMA; HUMAN BREAST-CANCER; LINK NA+/K+-ATPASE; PROGNOSTIC-SIGNIFICANCE; E-CADHERIN; IMMUNOHISTOCHEMICAL ANALYSIS; CLINICAL-SIGNIFICANCE; ADHESION SYSTEM; K-ATPASE AB Dysadherin is a cancer-associated cell membrane glycoprotein that promotes experimental cancer metastasis. Here we review recent work that has provided insights into possible mechanisms of action of this newly recognized player in the cancer progression process. Dysadheyin modulates cell phenotype in a number of ways, including down-regulation of E-cadherin-mediated cell adhesion, and up-regulation of chemokine production. In this way, expression of dysadherin in a tumor can influence both the tumor cell itself and the stromal compartment, so as to create conditions that are more permissive for metastatic spread. Dysadherin expression is also an independent prognostic indicator of metastasis and survival for many different types of human cancer. Thus, dysadherin may represent a new molecular target for the visualization, prevention or treatment of advanced cancer. Published by Elsevier Ireland Ltd. C1 NCI, Cell Reg & Carcinogenesis Lab, Bethesda, MD 20892 USA. Natl Canc Ctr, Res Inst, Div Pathol, Tokyo 104, Japan. RP Nam, JS (reprint author), Gachon Univ Med & Sci, Canc & Diabetes Res Inst, 745 Song-Dong, Inchon, South Korea. EM namje@mail.nih.gov; wakefiel@dce41.nci.nih.gov FU Intramural NIH HHS [Z01 BC005785-12] NR 39 TC 38 Z9 42 U1 2 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD OCT 8 PY 2007 VL 255 IS 2 BP 161 EP 169 DI 10.1016/j.canlet.2007.02.018 PG 9 WC Oncology SC Oncology GA 213OJ UT WOS:000249676700001 PM 17442482 ER PT J AU Goldstein, RB Compton, WM Pulay, AJ Ruan, WJ Pickering, RP Stinson, FS Grant, BF AF Goldstein, Rise B. Compton, Wilson M. Pulay, Attila J. Ruan, W. June Pickering, Roger P. Stinson, Frederick S. Grant, Bridget F. TI Antisocial behavioral syndromes and DSM-IV drug use disorders in the United States: Results from the national epidemiologic survey on alcohol and related conditions SO DRUG AND ALCOHOL DEPENDENCE LA English DT Review DE antisocial personality disorder; conduct disorder; drug use disorders ID SUBSTANCE USE DISORDERS; HIV RISK BEHAVIORS; INTERVIEW SCHEDULE AUDADIS; COCAINE-DEPENDENT PATIENTS; GENERAL-POPULATION SAMPLE; PERSONALITY-DISORDER; CONDUCT PROBLEMS; PSYCHIATRIC-DISORDERS; ANXIETY DISORDERS; LATE-ONSET AB Background: Antisocial behavioral syndromes, including antisocial personality disorder (ASPD), syndromal adult antisocial behavior (AABS) without conduct disorder (CD) before age 15, and CD without progression to ASPD ("CD only") are highly comorbid with drug use disorders (DUDs). Among patients in DUD treatment, antisocial syndromes are associated with greater severity and poorer outcomes. Comparative data concerning associations of antisocial syndromes with clinical characteristics of DUDs among general population adults have not previously been available. This study describes associations of antisocial syndromes with clinical characteristics of lifetime Diagnostic and Statistical Manual-Version IV DUDs in the general U.S. adult population. Methods: This report is based on the 2001-2002 National Epidermologic Survey on Alcohol and Related Conditions (n = 43,093, response rate = 81%). Respondents (n = 4068) with lifetime DUDs were classified according to whether they met criteria for ASPD, AABS, "CD only," or no antisocial syndrome. Associations of antisocial syndromes with clinical characteristics of DUDs were examined using logistic regression. Results: Antisocial syndromes were significantly associated with the phenomenology of DUDs, particularly ASPD with the most severe clinical presentations. Associations with AABS were similar to those with ASPD; those with "CD only" were weak, inconsistent, and not statistically significant. Patterns of associations differed little between men and women. Conclusions: Both ASPD and AABS, but not "CD only," appear to identify greater clinical severity of DUDs among adults in the general U.S. population. (C) 2007 Elsevier Ireland Ltd. All rights reserved. C1 NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, Natl Inst Hlth,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Natl Inst Drug Abuse, Div Epidemiol Serv & Prevent Res, Natl Inst Hlth, Dept Hlth & Human Serv, Bethesda, MD USA. RP Goldstein, RB (reprint author), NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, Natl Inst Hlth,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM goldster@mail.nih.gov RI Pulay, Attila/B-6155-2011; OI Goldstein, Rise/0000-0002-9603-9473 FU Intramural NIH HHS [Z01 AA000449-04, Z99 AA999999] NR 103 TC 46 Z9 47 U1 4 U2 8 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD OCT 8 PY 2007 VL 90 IS 2-3 BP 145 EP 158 DI 10.1016/j.drugalcdep.2007.02.023 PG 14 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 213GD UT WOS:000249653600005 PM 17433571 ER PT J AU Galynker, II Eisenberg, D Matochik, JA Gertmenian-King, E Cohen, L Kimes, AS Contoreggi, C Kurian, V Ernst, M Rosenthal, RN Prosser, J London, ED AF Galynker, Igor I. Eisenberg, Daniel Matochik, John A. Gertmenian-King, Enid Cohen, Lisa Kimes, Alane S. Contoreggi, Carlo Kurian, Varughese Ernst, Monique Rosenthal, Richard N. Prosser, James London, Edythe D. TI Cerebral metabolism and mood in remitted opiate dependence SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE methadone; heroin; abstinence; depression; mood; positron emission tomography ID POSITRON EMISSION TOMOGRAPHY; BLOOD-FLOW; METHADONE-MAINTENANCE; PROTRACTED WITHDRAWAL; OPIOID ADDICTION; BRAIN ACTIVITY; DEPRESSION; ABNORMALITIES; SPECT; ABUSERS AB Background: Opiate-dependent individuals are prone to dysphoria that may contribute to treatment failure. Methadone-maintenance therapy (MMT) may mitigate this vulnerability, but controversy surrounds its long-term use. Little is known about the neurobiology of mood dysregulation in individuals receiving or removed from MMT. Methods: Fifteen opiate-abstinent and 12 methadone-maintained, opiate-dependent subjects, who lacked other Axis I pathology, and 13 control subjects were compared on the Cornell Dysthymia Rating Scale (CDRS) and regional cerebral glucose metabolism (rCMRglc) using [F-18]fluorodeoxyglucose positron emission tomography. Results: CDRS scores showed no group differences. Opiate-abstinent subjects had lower rCMRglc than control subjects in the bilateral perigenual anterior cingulate cortex (ACC), left mid-cingulate cortex, left insula and right superior frontal cortex. Methadone-maintained subjects exhibited lower rCMRglc than control subjects in the left insula and thalamus. In opiate-abstinent subjects, rCMRglc in the left perigenual ACC and mid-cingulate cortex correlated positively with CDRS scores. Conclusions: In remitted heroin dependence, opiate-abstinence is associated with more widespread patterns of abnormal cortical activity than MMT. Aberrant mood processing in the left perigenual ACC and mid-cingulate cortex, seen in opiate-abstinent individuals, is absent in those receiving MMT, suggesting that methadone may improve mood regulation in this population. (C) 2007 Elsevier Ireland Ltd. All rights reserved. C1 Albert Einstein Coll Med, Beth Israel Med Ctr, Dept Psychiat & Behav Sci, New York, NY 10003 USA. Natl Inst Drug Abuse, Intramural Res Program, Natl Inst Hlth, DHHS, Baltimore, MD USA. NIMH, Intramural Res Program, Natl Inst Hlth, DHHS, Baltimore, MD USA. Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, David Geffen Sch Med, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Mol & Med Pharmacol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, David Geffen Sch Med, Brain Res Inst, Los Angeles, CA USA. Columbia Univ, Coll Phys & Surg, St Lukes Roosevelt Med Ctr, Dept Psychiat, New York, NY USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. RP Galynker, II (reprint author), Albert Einstein Coll Med, Beth Israel Med Ctr, Dept Psychiat & Behav Sci, 1st Ave 16th St, New York, NY 10003 USA. EM igalynker@bethisraelny.org RI Eisenberg, Daniel/C-7432-2014; Eisenberg, Daniel/S-4342-2016 FU Intramural NIH HHS; NIDA NIH HHS [R01 DA 12273, R01 DA012273-02, R01 DA012273-03, R01 DA012273-04] NR 41 TC 16 Z9 17 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD OCT 8 PY 2007 VL 90 IS 2-3 BP 166 EP 174 DI 10.1016/j.drugalcdep.2007.03.015 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 213GD UT WOS:000249653600007 PM 17521829 ER PT J AU Blanco, C Alderson, D Ogburn, E Grant, BE Nunes, EV Hatzenbuehler, ML Hasin, DS AF Blanco, Carlos Alderson, Donald Ogburn, Elizabeth Grant, Bridget E. Nunes, Edward V. Hatzenbuehler, Mark L. Hasin, Deborah S. TI Changes in the prevalence of non-medical prescription drug use and drug use disorders in the United States: 1991-1992 and 2001-2002 SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE prescription drug abuse; epidemiology. prevalence trends; NESARC ID ALCOHOL-USE DISORDER; DSM-IV ALCOHOL; NATIONAL EPIDEMIOLOGIC SURVEY; INTERVIEW SCHEDULE AUDADIS; GENERAL-POPULATION SAMPLE; BENZODIAZEPINE USE; ANXIETY DISORDERS; TREATMENT CONTACT; ABUSE; RELIABILITY AB Objective: To examine changes in the prevalence of non-medical prescription drug use and DSM-IV non-medical prescription abuse and dependence in the United States between 1991-1992 and 2001-2002. Method: Comparison of the prevalence of past-year non-medical prescription drug use and drug use disorders in the total sample and among lifetime non-medical users in two large national surveys conducted 10 years apart. Results: From 1991-1992 to 2001-2002, the prevalence of DSM-IV non-medical prescription drug use increased by 53%, from 1.5% to 2.3% (p < 0.001), and the prevalence of drug use disorders increased by 67% from 0.3% to 0.5% (p < 0.001). The conditional prevalence of a disorder among users increased numerically from 19.9% to 23.6%, but this increase was not statistically significant (p = 0.15). Conclusions: There have been substantial increases in the prevalence of prescription drug non-medical use and prescription drug use disorders in the United States. Given the clinical utility of prescription drugs, urgent action is needed to find approaches that balance the need for access to these medications among those who need them, against their potential for abuse and dependence in subgroups of vulnerable individuals. (C) 2007 Published by Elsevier Ireland Ltd. C1 Columbia Univ, Dept Epidemiol & Psychiat, New York, NY 10032 USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. NIAAA, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res, Natl Inst Hlth, Rockville, MD 20852 USA. RP Grant, BE (reprint author), Columbia Univ, Dept Epidemiol & Psychiat, New York, NY 10032 USA. EM bgrant@willco.niaaa.nih.gov RI Blanco, Carlos/I-4906-2013 OI Blanco, Carlos/0000-0001-6187-3057 FU Intramural NIH HHS; NIAAA NIH HHS [K05 AA 014223]; NIDA NIH HHS [K23 DA00482, R01 DA019606, R01 DA020783] NR 39 TC 111 Z9 112 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD OCT 8 PY 2007 VL 90 IS 2-3 BP 252 EP 260 DI 10.1016/j.drugalcdep.2007.04.005 PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 213GD UT WOS:000249653600017 PM 17513069 ER PT J AU Zolnik, BS Burgess, DJ AF Zolnik, Banu S. Burgess, Diane J. TI Effect of acidic pH on PLGA microsphere degradation and release SO JOURNAL OF CONTROLLED RELEASE LA English DT Article; Proceedings Paper CT 13th International Symposium on Recent Advances in Drug Delivery CY FEB 26-28, 2007 CL Salt Lake City, UT SP NCI, Samyang Corp DE biodegradable polymers; dexamethasone; USP 4 apparatus ID DRUG-RELEASE; MICROCLIMATE PH; POLY(LACTIDE-CO-GLYCOLIDE); MICROPARTICLES; EROSION; MEDIA AB Polymer degradation and drug release kinetics from PLGA microspheres were investigated under neutral and acidic pH conditions. Two different Mw formulations (Mw: 25,000 and 70,000) were investigated and both exhibited a triphasic release profile at pH 7.4 as well as at pH 2.4. The initial burst and lag phases were similar for both pH values, while the secondary apparent-zero-order phase was substantially accelerated at pH 2.4. The polymer molecular weight change with time for the microspheres followed first order degradation kinetics for both pH values. A linear relationship was established between % drug release (post burst release) and Ln (Mw) for both pH conditions. Most significantly, morphological studies showed that the mechanism of polymer degradation changed from "inside-out" degradation at pH 7.4 to "outside-in" at pH 2.4. At pH 7.4, the microspheres followed the usual morphological changes such as surface pitting and pore formation. Whereas, at pH 2.4 the microspheres maintained smooth surfaces throughout the degradation process and were susceptible to fracturing. The fracturing of the microspheres was attributed to crystallization of oligomeric degradation products as a consequence of their low solubility at this pH. It also appeared that degradation occurred in a more homogeneous pattern at pH 2.4 than is typical of PLGA microspheres at pH 7.4. This may be a result of the entire microspheres experiencing a close-to-uniform pH at 2.4. However, at pH 7.4, the local micro-environmental pH within the microspheres has been reported to vary considerably due to a build up of acid oligomers. This heterogeneous degradation results in the random fort-nation of channels within microspheres degraded at pH 7.4 which was not observed in those degraded at pH 2.4. This is the first time that morphological changes during PLGA microsphere degradation have been compared for low and neutral pH and the data shows a change in the mechanism of degradation at the low pH. (C) 2007 Elsevier B.V. All tights reserved. C1 Univ Connecticut, Dept Pharmaceut Sci, Storrs, CT 06269 USA. RP Burgess, DJ (reprint author), SAIC Frederick Inc, NCI, Nanotechnol Characterizat Lab, Ft Detrick, MD 21702 USA. EM d.burgess@uconn.edu NR 29 TC 152 Z9 162 U1 5 U2 73 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0168-3659 J9 J CONTROL RELEASE JI J. Control. Release PD OCT 8 PY 2007 VL 122 IS 3 SI SI BP 338 EP 344 DI 10.1016/j.jconrel.2007.05.034 PG 7 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 222SZ UT WOS:000250318800017 PM 17644208 ER PT J AU Michel, J Duarte, RE Bolton, JL Huang, Y Caceres, A Veliz, M Soejarto, DD Mahady, GB AF Michel, Joanna Duarte, Reinel Eduardo Bolton, Judy L. Huang, Yue Caceres, Armando Veliz, Mario Soejarto, Djaja Doel Mahady, Gail B. TI Medical potential of plants used by the Q'eqchi Maya of Livingston, Guatemala for the treatment of women's health complaints SO JOURNAL OF ETHNOPHARMACOLOGY LA English DT Article DE Guatemala; women's health; medicinal plants; serotonin receptor assay; estrogen receptor assay; q'eqchi maya ID HIBISCUS-ROSA-SINENSIS; MEDICINAL-PLANTS; POSTMENOPAUSAL WOMEN; SEROTONIN RECEPTOR; NICARAGUA; BINDING; BELIZE; TRIAL AB Investigation on the medical ethnobotany of the Q'eqchi Maya of Livingston, Izabal, Guatemala, was undertaken in order to explore Q'eqchi perceptions, attitudes, and treatment choices related to women's health. Through participant observation and interviews a total of 48 medicinal plants used to treat conditions related to pregnancy, childbirth, menstruation, and menopause were collected and identified followed by the evaluation of 20 species in bioassays relevant to women's health. Results of field interviews indicate that Q'eqchi cultural perceptions affect women's health experiences while laboratory results (estrogen receptor and serotonin receptor binding assays) provide a scientific correlation between empirical medicinal plant use among the Q'eqchi and the pharmacological basis for their administration. These data can contribute to Guatemala's national effort to promote a complementary relationship between traditional Maya medicine and public health services and can serve as a basis for further pharmacology and phytochemistry on Q'eqchi medicinal plants for the treatment of women's health conditions. (C) 2007 Elsevier Ireland Ltd. All rights reserved. C1 Univ Illinois, Coll Pharm, Dept Pharm Practice, Chicago, IL 60607 USA. Univ Illinois, Coll Pharm, Ctr Bot Dietary Supplements Res, NIH,UIC, Chicago, IL USA. Rural Univ Guatemala, Dept Environm Engn, Guatemala City, Guatemala. Univ San Carlos, Fac Chem Sci & Pharm, Herbarium Sch Biol, Guatemala City, Guatemala. Univ San Carlos, Fac Chem Sci & Pharm, Sch Biol Chem, Guatemala City, Guatemala. RP Michel, J (reprint author), Univ Illinois, Coll Pharm, Dept Pharm Practice, Chicago, IL 60607 USA. EM joannamichel@yahoo.com FU NCCIH NIH HHS [R21 AT002381-01, P50 AT00155, R21 AT002381, AT002381, P50 AT000155, R21 AT002381-02] NR 53 TC 25 Z9 27 U1 1 U2 9 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-8741 J9 J ETHNOPHARMACOL JI J. Ethnopharmacol. PD OCT 8 PY 2007 VL 114 IS 1 BP 92 EP 101 DI 10.1016/j.jep.2007.07.033 PG 10 WC Plant Sciences; Chemistry, Medicinal; Integrative & Complementary Medicine; Pharmacology & Pharmacy SC Plant Sciences; Pharmacology & Pharmacy; Integrative & Complementary Medicine GA 224OI UT WOS:000250455900011 PM 17826926 ER PT J AU Bell, D Fan, M Fernandes, A Foster, P Jiang, T Loizou, G MacNicoll, A Miller, B Rose, M Tran, L White, S AF Bell, David Fan, MingQi Fernandes, Alwyn Foster, Paul Jiang, Tao Loizou, George MacNicoll, Alan Miller, Brian Rose, Martin Tran, Lang White, Shaun TI TCDD is a potent developmental toxin, but fails to affect spermatogenesis in offspring of chronically treated CRL : WI(Han) rats SO TOXICOLOGY LETTERS LA English DT Meeting Abstract C1 Univ Nottingham, Nottingham NG7 2RD, England. Cent Sci Lab, York, N Yorkshire, England. NIEHS, Bethesda, MD 20892 USA. HSL, Buxton, England. IOM, Edinburgh, Midlothian, Scotland. NR 2 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD OCT 7 PY 2007 VL 172 BP S178 EP S178 DI 10.1016/j.toxlet.2007.05.454 PG 1 WC Toxicology SC Toxicology GA 222CM UT WOS:000250273700404 ER PT J AU Crowell, J McCormick, D Cwik, M Kapetanovic, I AF Crowell, James McCormick, David Cwik, Michael Kapetanovic, Izet TI Toxicokinetics of resveratrol in dogs SO TOXICOLOGY LETTERS LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. IITRI Res Inst, Chicago, IL USA. NR 0 TC 0 Z9 0 U1 1 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD OCT 7 PY 2007 VL 172 BP S102 EP S102 DI 10.1016/j.toxlet.2007.05.278 PG 1 WC Toxicology SC Toxicology GA 222CM UT WOS:000250273700233 ER PT J AU Crowell, J McCormick, D Cwik, M Kapetanovic, I AF Crowell, James McCormick, David Cwik, Michael Kapetanovic, Izet TI Pharmacokinetics of resveratrol in monkeys SO TOXICOLOGY LETTERS LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. IITRI Res Inst, Chicago, IL USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD OCT 7 PY 2007 VL 172 BP S102 EP S102 DI 10.1016/j.toxlet.2007.05.277 PG 1 WC Toxicology SC Toxicology GA 222CM UT WOS:000250273700232 ER PT J AU Goshorn, J Chang, F Hudson, V Sun, Y Hazard, G Moore, D AF Goshorn, Jeanne Chang, Florence Hudson, Vera Sun, Ying Hazard, George Moore, Dorothy TI Access to product-based dietary supplement information SO TOXICOLOGY LETTERS LA English DT Meeting Abstract C1 Natl Lib Med, NIH, HHS, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD OCT 7 PY 2007 VL 172 BP S194 EP S195 DI 10.1016/j.toxlet.2007.05.492 PG 2 WC Toxicology SC Toxicology GA 222CM UT WOS:000250273700439 ER PT J AU Kapetanovic, IM Jong, L Green, CE Shankar, G Swezey, R Bakke, J Crowell, JA AF Kapetanovic, Izet M. Jong, Ling Green, Carol E. Shankar, Gita Swezey, Robert Bakke, James Crowell, James A. TI Preclinical toxicology and development of SR13668, a novel new candidate cancer chemopreventive agent SO TOXICOLOGY LETTERS LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. SRI Int, Menlo Pk, CA 94025 USA. NR 0 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0378-4274 J9 TOXICOL LETT JI Toxicol. Lett. PD OCT 7 PY 2007 VL 172 BP S104 EP S105 DI 10.1016/j.toxlet.2007.05.283 PG 2 WC Toxicology SC Toxicology GA 222CM UT WOS:000250273700238 ER PT J AU Hollingworth, P Hamshere, ML Holmans, PA O'Donovan, MC Sims, R Powell, J Lovestone, S Myers, A DeVrieze, FW Hardy, J Goate, A Owen, M Williams, J AF Hollingworth, P. Hamshere, M. L. Holmans, P. A. O'Donovan, M. C. Sims, Rebecca Powell, J. Lovestone, S. Myers, A. DeVrieze, F. W. Hardy, J. Goate, A. Owen, M. Williams, J. TI Increased familial risk and genomewide significant linkage for Alzheimer's disease with psychosis SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE Alzheimer's disease; psychosis; familiality; linkage; covariate; dementia; logistic regression; family based; genome screen; genetics ID SUSCEPTIBILITY LOCUS; BIPOLAR-DISORDER; NEUROPSYCHIATRIC SYMPTOMS; BEHAVIORAL SYMPTOMS; COMPLEX TRAITS; SEMAPHORIN 3A; CHROMOSOME 6Q; PAIR LINKAGE; ONSET; GENE AB Psychotic symptoms are common in Alzheimer's disease (AD) and are associated with increased cognitive impairment and earlier institutionalization. One study has suggested that they are genetically modified and two genome screens have been performed to search for susceptibility loci for AD with psychosis (AD + P). The aim of this study was to further investigate the familial aggregation of AD + P and perform a genome screen for AD, conditioning on the presence or absence of psychotic symptoms. Samples from the UK and US were combined, providing data from 374 families in which at least two members met criteria for AD and had complete data regarding psychotic symptoms. Generalized estimating equations (GEE) were used to assess the relationship of psychotic symptoms between siblings. A total of 321 affected relative pairs (ARPs) were genotyped for linkage. There was a significant association between proband psychosis status and the occurrence of AD + P in siblings in the UK (OR = 4.17, P = 0.002) and US (OR = 3.2, P < 0.001) samples. Chromosomewide and genomewide significant linkage peaks were observed on chromosomes 7 (LOD= 2.84) and 15 (LOD= 3.16), respectively, with the strongest evidence coming from pairs concordant for AD without psychosis. A LOD score of 2.98 was observed close to a previously reported AD + P linkage region on chromosome 6, however the increase in LOD attributable to psychosis was not significant. These findings support the hypothesis that psychotic symptoms in AD are genetically modified and that a gene/s implicated in their aetiology may be located on chromosome 7 and 15. (c) 2007 Wiley-Liss,Inc. C1 Cardiff Univ, Sch Med, Dept Psychol Med, Cardiff CF14 4XN, S Glam, Wales. Cardiff Univ, Sch Med, Biostat & Bioinformat Unit, Cardiff CF14 4XN, S Glam, Wales. Inst Psychiat, London SE5, England. Miller Sch Med, Miami, FL USA. NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63130 USA. RP Hollingworth, P (reprint author), Cardiff Univ, Sch Med, Dept Psychol Med, Heath Pk, Cardiff CF14 4XN, S Glam, Wales. EM hollingworthp@cardiff.ac.uk RI Lovestone, Simon/E-8725-2010; Myers, Amanda/B-1796-2010; turton, miranda/F-4682-2011; Powell, John/G-4412-2011; Hardy, John/C-2451-2009; Holmans, Peter/F-4518-2015; OI Myers, Amanda/0000-0002-3100-9396; Powell, John/0000-0001-6124-439X; Holmans, Peter/0000-0003-0870-9412; O'Donovan, Michael/0000-0001-7073-2379 FU Medical Research Council [G0300429, G0701075]; NIA NIH HHS [AG 16208, AG 5681]; NIMH NIH HHS [U01 MH 46281, U01 MH 46290, U01 MH 46373] NR 56 TC 23 Z9 23 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD OCT 5 PY 2007 VL 144B IS 7 BP 841 EP 848 DI 10.1002/ajmg.b.30515 PG 8 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 215SU UT WOS:000249830100001 PM 17492769 ER PT J AU Krumpe, LR Schumacher, KM McMahon, JB Makowski, L Mori, T AF Krumpe, Lauren Rh Schumacher, Kathryn M. McMahon, James B. Makowski, Lee Mori, Toshiyuki TI Trinucleotide cassettes increase diversity of T7 phage-displayed peptide library SO BMC BIOTECHNOLOGY LA English DT Article ID SEQUENCE; PROTEIN; PHOSPHORAMIDITES AB Background: Amino acid sequence diversity is introduced into a phage-displayed peptide library by randomizing library oligonucleotide DNA. We recently evaluated the diversity of peptide libraries displayed on T7 lytic phage and M13 filamentous phage and showed that T7 phage can display a more diverse amino acid sequence repertoire due to differing processes of viral morphogenesis. Methods: In this study, we evaluated and compared the diversity of a 12-mer T7 phage-displayed peptide library randomized using codon-corrected trinucleotide cassettes with a T7 and an M13 12-mer phage-displayed peptide library constructed using the degenerate codon randomization method. Conclusion: The combination of T7 phage display and trinucleotide cassette randomization resulted in a novel resource for the potential isolation of binding peptides for new and previously studied molecular targets. C1 [Krumpe, Lauren Rh; Schumacher, Kathryn M.; McMahon, James B.; Mori, Toshiyuki] NCI, Canc Res Ctr, Mol Targets Dev Program, Frederick, MD 21702 USA. [Krumpe, Lauren Rh] NCI, SAIC Frederick Inc, Frederick, MD 21702 USA. [Schumacher, Kathryn M.] NCI, Werner H Kirsten Student Internship Program, Frederick, MD 21702 USA. [Makowski, Lee] Argonne Natl Lab, Biosci Div, Argonne, IL 60439 USA. RP Mori, T (reprint author), NCI, Canc Res Ctr, Mol Targets Dev Program, Frederick, MD 21702 USA. EM lhaugh@ncifcrf.gov; kschu@mit.edu; mcmahon@ncifcrf.gov; imakowski@anl.gov; Mori_Toshiyuki2@takeda.co.jp FU NCI NIH HHS [N01CO12400, N01-CO-12400] NR 17 TC 17 Z9 17 U1 0 U2 7 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1472-6750 J9 BMC BIOTECHNOL JI BMC Biotechnol. PD OCT 5 PY 2007 VL 7 AR 65 DI 10.1186/1472-6750-7-65 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 252LR UT WOS:000252448500001 PM 17919322 ER PT J AU Sum, CS Tikhonova, IG Neumann, S Engel, S Raaka, BM Costanzi, S Gershengorn, MC AF Sum, Chi Shing Tikhonova, Irina G. Neumann, Susanne Engel, Stanislav Raaka, Bruce M. Costanzi, Stefano Gershengorn, Marvin C. TI Identification of residues important for agonist recognition and activation in GPR40 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; PANCREATIC BETA-CELLS; INSULIN-SECRETION; FATTY-ACIDS; CRYSTAL-STRUCTURE; BINDING; MOLECULES; RHODOPSIN AB GPR40 was formerly an orphan G protein-coupled receptor whose endogenous ligands have recently been identified as free fatty acids (FFAs). The receptor, now named FFA receptor 1, has been implicated in the pathophysiology of type 2 diabetes and is a drug target because of its role in FFA-mediated enhancement of glucose-stimulated insulin release. Guided by molecular modeling, we investigated the molecular determinants contributing to binding of linoleic acid, a C18 polyunsaturated FFA, and GW9508, a synthetic small molecule agonist. Twelve residues within the putative GPR40-binding pocket including hydrophilic/positively charged, aromatic, and hydrophobic residues were identified and were subjected to site-directed mutagenesis. Our results suggest that linoleic acid and GW9508 are anchored on their carboxylate groups by Arg183, Asn244, and Arg258. Moreover, His86, Tyr91, and His137 may contribute to aromatic and/or hydrophobic interactions with GW9508 that are not present, or relatively weak, with linoleic acid. The anchor residues, as well as the residues Tyr12, Tyr91, His137, and Leu186, appear to be important for receptor activation also. Interestingly, His137 and particularly His86 may interact with GW9508 in a manner dependent on its protonation status. The greater number of putative interactions between GPR40 and GW9508 compared with linoleic acid may explain the higher potency of GW9508. C1 NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Lab Biol Modelling, NIH, Bethesda, MD 20892 USA. RP Gershengorn, MC (reprint author), 50 South Dr,Rm 4134, Bethesda, MD 20892 USA. EM marving@intra.niddk.nih.gov RI Engel, Stanislav/G-2799-2013; Costanzi, Stefano/G-8990-2013; OI Costanzi, Stefano/0000-0003-3183-7332 FU Intramural NIH HHS NR 29 TC 69 Z9 71 U1 2 U2 13 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 OCT 5 PY 2007 VL 282 IS 40 BP 29248 EP 29255 DI 10.1074/jbc.M705077200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 215DH UT WOS:000249788000021 PM 17699519 ER PT J AU Kotsyfakis, M Karim, S Andersen, JF Mather, TN Ribeiro, JMC AF Kotsyfakis, Michalis Karim, Shahid Andersen, John F. Mather, Thomas N. Ribeiro, Jose M. C. TI Selective cysteine protease inhibition contributes to blood-feeding success of the tick Ixodes scapularis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PATHOGEN TRANSMISSION; CATHEPSIN-S; CYSTATIN; PROTEINASES; IMMUNITY; DISRUPTION; SIALOME AB Ixodes scapularis is the main vector of Lyme disease in the eastern and central United States. Tick salivary secretion has been shown as important for both blood-meal completion and pathogen transmission. Here we report a duplication event of cystatin genes in its genome that results in a transcription-regulated boost of saliva inhibitory activity against a conserved and relatively limited number of vertebrate papain-like cysteine proteases during blood feeding. We further show that the polypeptide products of the two genes differ in their binding affinity for some enzyme targets, and they display different antigenicity. Moreover, our reverse genetic approach employing RNA interference uncovered a crucial mediation in tick-feeding success. Given the role of the targeted enzymes in vertebrate immunity, we also show that host immunomodulation is implicated in the deleterious phenotype of silenced ticks making I. scapularis cystatins attractive targets for development of antitick vaccines. C1 NIAID, Vector Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. Univ Rhode Isl, Ctr Vector Borne Dis, Kingston, RI 02881 USA. RP Ribeiro, JMC (reprint author), NIAID, Vector Biol Sect, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. EM jribeiro@niaid.nih.gov RI Kotsyfakis, Michail/G-9525-2014; OI Kotsyfakis, Michail/0000-0002-7526-1876; Ribeiro, Jose/0000-0002-9107-0818 FU Intramural NIH HHS; NIAID NIH HHS [5R01AI037230] NR 28 TC 56 Z9 58 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 OCT 5 PY 2007 VL 282 IS 40 BP 29256 EP 29263 DI 10.1074/jbc.M703143200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 215DH UT WOS:000249788000022 PM 17698852 ER PT J AU Varnai, P Toth, B Toth, DJ Hunyady, L Balla, T AF Varnai, Peter Toth, Balazs Toth, Daniel J. Hunyady, Laszlo Balla, Tamas TI Visualization and manipulation of plasma membrane-endoplasmic reticulum contact sites indicates the presence of additional molecular components within the STIM1-Orai1 complex SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID STROMAL INTERACTION MOLECULE-1; CA2+ STORE DEPLETION; CHANNEL FUNCTION; CRAC CHANNEL; CALCIUM-ENTRY; ORAI PROTEINS; STIM1; SENSOR; IDENTIFICATION; TRANSLOCATION AB STIM1, a recently identified endoplasmic reticulum (ER) protein, rapidly translocates to a plasma membrane-adjacent ER compartment upon depletion of the ER Ca2+ stores. Here we use a novel means, namely a chemically inducible bridge formation between the plasma and ER membranes, to highlight the plasma membrane-adjacent ER compartment and show that this is the site where STIM1 and its Ca2+ channel partner, Orai1, form a productive interaction upon store depletion. By changing the length of the linkers connecting the plasma and ER membranes, we show that Orai1 requires a larger space than STIM1 between the two membranes. This finding suggests that Orai1 is part of a larger macromolecular cluster with an estimated 11-14-nm protrusion to the cytoplasm, whereas the cytoplasmic domain of STIM1 fits in a space calculated to be less than 6 nm. We finally show that agonist-induced translocation of STIM1 is rapidly reversible and only partially affects STIM1 in the juxtanuclear ER compartment. These studies are the first to detect juxtaposed areas between the ER and the plasma membrane in live cells, revealing novel details of STIM1-Orai1 interactions. C1 NIH, Sect Mol Signal Transduct, NICHD, Bethesda, MD 20892 USA. Semmelweis Univ, Sch Med, Dept Physiol, H-1086 Budapest, Hungary. RP Balla, T (reprint author), NIH, Sect Mol Signal Transduct, NICHD, Bldg 49,Rm 6A35,49 Convent Dr, Bethesda, MD 20892 USA. EM ballat@mail.nih.gov RI Toth, Balazs/B-4252-2012; OI Balla, Tamas/0000-0002-9077-3335; Toth, Daniel/0000-0001-6670-3348 FU Intramural NIH HHS NR 33 TC 143 Z9 144 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 OCT 5 PY 2007 VL 282 IS 40 BP 29678 EP 29690 DI 10.1074/jbc.M704339200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 215DH UT WOS:000249788000064 PM 17684017 ER PT J AU Borbulevych, OY Insaidoo, FK Baxter, TK Powell, DJ Johnson, LA Restifo, NP Baker, BM AF Borbulevych, Oleg Y. Insaidoo, Francis K. Baxter, Tiffany K. Powell, Daniel J., Jr. Johnson, Laura A. Restifo, Nicholas P. Baker, Brian M. TI Structures of MART-1(26/27-35) peptide/HLA-A2 complexes reveal a remarkable disconnect between antigen structural homology and T cell recognition SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE peptide/MHC; crystal structure; cross-reactivity; specificity; Melan-A/MART-1 ID TUMOR-INFILTRATING LYMPHOCYTES; SELF-PEPTIDE; REACTIVE CTL; RECEPTOR RECOGNITION; MELANOMA PATIENTS; INCREASED IMMUNOGENICITY; IMMUNODOMINANT PEPTIDE; CONFORMATIONAL ENTROPY; CRYSTAL-STRUCTURES; PERIPHERAL-BLOOD AB Small structural changes in peptides presented by major histocompatibility complex (MHC) molecules often result in large changes in immunogenicity, supporting the notion that T cell receptors are exquisitely sensitive to antigen structure. Yet there are striking examples of TCR recognition of structurally dissimilar ligands. The resulting unpredictability of how T cells will respond to different or modified antigens impacts both our understanding of well as efforts to engineer peptides epitopes and variants derived from the MART-1/Melan-A protein are widely used as clinical vaccines. Two overlapping epitopes spanning amino acid residues 26 through 35 are of particular interest: numerous clinical although only the 27-35 nonamer has been found on the surface of targeted melanoma cells. Here, we show that the 26-35 and 27-35 peptides adopt strikingly different conformations when bound to HLA-A2. Nevertheless, clonally distinct MART-1(26/27-35)-reactive T cells show broad cross-reactivity towards these ligands. Simultaneously, however, many of the cross-reactive T cells remain unable to recognize anchor-modified variants with very subtle structural differences. These dichotomous observations challenge our thinking about how structural information on unligated peptide/MHC complexes should be best used when addressing questions of TCR specificity. Our findings also indicate that caution is warranted in the design of immunotherapeutics based on the MART-1 26/27-35 epitopes, as neither cross-reactivity nor selectivity is predictable based on the analysis of the structures alone. (c) 2007 Elsevier Ltd. All rights reserved. C1 Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA. Univ Notre Dame, Walther Canc Res Ctr, Notre Dame, IN 46530 USA. NCI, NIH, Bethesda, MD 20892 USA. RP Baker, BM (reprint author), Univ Notre Dame, Dept Chem & Biochem, 251 Nieuwland Sci Hall, Notre Dame, IN 46556 USA. EM bbaker2@nd.edu RI Baker, Brian/B-4584-2009; Restifo, Nicholas/A-5713-2008; Johnson, Laura/H-4861-2013; OI Baker, Brian/0000-0002-0864-0964; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999]; NCI NIH HHS [Y1-CO-1020]; NIGMS NIH HHS [Y1-GM-1104] NR 57 TC 45 Z9 45 U1 1 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD OCT 5 PY 2007 VL 372 IS 5 BP 1123 EP 1136 DI 10.1016/j.jmb.2007.07.025 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 215NY UT WOS:000249817500001 PM 17719062 ER PT J AU Larson, RG AF Larson, Ronald G. TI Testing hypotheses about autism SO SCIENCE LA English DT Editorial Material ID RELEVANT; MICE; PHENOTYPES; DISORDERS; BEHAVIOR; MODELS C1 NIMH, Intramural Res Program, Bethesda, MD 20892 USA. RP Larson, RG (reprint author), NIMH, Intramural Res Program, Bethesda, MD 20892 USA. EM rlarson@umich.edu NR 21 TC 0 Z9 0 U1 0 U2 1 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 OCT 5 PY 2007 VL 318 IS 5847 BP 56 EP 57 DI 10.1126/science.1149801 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 216YR UT WOS:000249915400032 ER PT J AU Pereira, LHM Pineda, MA Rowe, WH Fonseca, LR Greene, MH Offit, K Ellis, NA Zhang, J Collins, A Struewing, JP AF Pereira, Lutecia H. Mateus Pineda, Marbin A. Rowe, William H. Fonseca, Libia R. Greene, Mark H. Offit, Kenneth Ellis, Nathan A. Zhang, Jinghui Collins, Andrew Struewing, Jeffery P. TI The BRCA1 Ashkenazi founder mutations occur on common haplotypes and are not highly correlated with anonymous single nucleotide polymorphisms likely to be used in genome-wide case-control association studies SO BMC GENETICS LA English DT Article ID BREAST-CANCER SUSCEPTIBILITY; LINKAGE DISEQUILIBRIUM; ATTRIBUTABLE RISKS; GENE; FAMILY; FREQUENCY; DISEASES; PENETRANCE; BLOCKS; SWEDEN AB Background: We studied linkage disequilibrium (LD) patterns at the BRCAI. locus, a susceptibility gene for breast and ovarian cancer, using a dense set of 114 single nucleotide polymorphisms in 5 population groups. We focused on Ashkenazi Jews in whom there are known founder mutations, to address the question of whether we would have been able to identify the 185delAG mutation in a case-control association study (should one have been done) using anonymous genetic markers. This mutation is present in approximately 1% of the general Ashkenazi population and 4% of Ashkenazi breast cancer cases. We evaluated LD using pairwise and haplotype-based methods, and assessed correlation of SNPs with the founder mutations using Pearson's correlation coefficient. Results: BRCAI is characterized by very high linkage disequilibrium in all populations spanning several hundred kilobases. Overall, haplotype blocks and pair-wise LD bins were highly correlated, with lower LD in African versus non-African populations. The 185delAG and 5382insC founder mutations occur on the two most common haplotypes among Ashkenazim. Because these mutations are rare, even though they are in strong LD with many other SNPs in the region as measured by D-prime, there were no strong associations when assessed by Pearson's correlation coefficient, r (maximum of 0.04 for the 185delAG). Conclusion: Since the required sample size is related to the inverse of r, this suggests that it would have been difficult to map BRCAI in an Ashkenazi case-unrelated control association study using anonymous markers that were linked to the founder mutations. C1 NCI, Lab Populat Genet, Bethesda, MD 20892 USA. Florida Int Univ, Dept Biol Sci, Miami, FL 33199 USA. NCI, Clin Genet Branch, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, Clin Genet Serv, Dept Med, New York, NY 10021 USA. Univ Chicago, Dept Med, Gastroenterol Sect, Chicago, IL 60637 USA. Univ Southampton, Southampton Gen Hosp, Div Human Genet, Southampton SO16 6YD, Hants, England. RP Struewing, JP (reprint author), NCI, Lab Populat Genet, Bethesda, MD 20892 USA. EM luteciap@hotmail.com; pinedama@mail.nih.gov; rowew@mail.nih.gov; lcaba003@fiu.edu; greenem@mail.nih.gov; offitk@mskcc.org; naellis@uchicago.edu; jinghuiz@mail.nih.gov; A.R.Collins@soton.ac.uk; struewij@mail.nih.gov RI Collins, Andrew/A-6595-2010; Struewing, Jeffery/I-7502-2013 OI Collins, Andrew/0000-0001-7108-0771; Struewing, Jeffery/0000-0002-4848-3334 FU Intramural NIH HHS NR 41 TC 4 Z9 4 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2156 J9 BMC GENET JI BMC Genet. PD OCT 4 PY 2007 VL 8 AR 68 DI 10.1186/1471-2156-8-68 PG 15 WC Genetics & Heredity SC Genetics & Heredity GA 234NN UT WOS:000251170900002 PM 17916242 ER PT J AU Jaquish, CE AF Jaquish, Cashell E. TI The Framingham Heart Study, on its way to becoming the gold standard for cardiovascular genetic epidemiology? SO BMC MEDICAL GENETICS LA English DT Editorial Material ID GENOME-WIDE ASSOCIATION; STUDY 100K PROJECT; FOLLOW-UP EXPERIENCE; DISEASE; TRAITS; RISK AB The Framingham Heart Study, founded in 1948 to examine the epidemiology of cardiovascular disease in a small town outside of Boston, has become the worldwide standard for cardiovascular epidemiology. It is among the longest running, most comprehensively characterized multigenerational studies in the world. Such seminal findings as the effects of smoking and high cholesterol on heart disease came from the Framingham Heart Study. At the time of publication these were novel cardiovascular disease (CVD) risk factors, now they are the basis of treatment and prevention in the US. Is the Framingham study now on it's way to becoming the gold standard for genetic epidemiology of CVD? Will the novel genetic findings of today become the health care standards of tomorrow? The accompanying articles summarizing the results of genome-wide association studies (GWAS) give the reader a first glimpse into the possibilities. C1 NHLBI, Div Prevent & Populat Sci, NIH, Bethesda, MD 20892 USA. RP Jaquish, CE (reprint author), NHLBI, Div Prevent & Populat Sci, NIH, 6701 Rockledge Dr,MSC 7963 Suite 10018, Bethesda, MD 20892 USA. EM jaquishc@nhlbi.nih.gov NR 19 TC 16 Z9 17 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD OCT 4 PY 2007 VL 8 AR 63 DI 10.1186/1471-2350-8-63 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 251XE UT WOS:000252408600001 PM 17916250 ER PT J AU Xie, H Ng, D Savinov, SN Dey, B Kwong, PD Wyatt, R Smith, AB Hendrickson, WA AF Xie, Hui Ng, Danny Savinov, Sergey N. Dey, Barna Kwong, Peter D. Wyatt, Richard Smith, Amos B., III Hendrickson, Wayne A. TI Structure-activity relationships in the binding of chemically derivatized CD4 to gp120 from human immunodeficiency virus SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PROTEIN-PROTEIN INTERACTIONS; ENVELOPE GLYCOPROTEIN; HIV-1 GP120; NEUTRALIZATION EPITOPES; CONFORMATIONAL-CHANGES; ENTRY INHIBITORS; RECEPTOR-BINDING; CD4-BOUND STATE; TYPE-1; RETROVIRUS AB The first step in HIV infection is the binding of the envelope glycoprotein gp120 to the host cell receptor CD4. An interfacial "Phe43 cavity" in gp120, adjacent to residue Phe43 of gp120-bound CD4, has been suggested as a potential target for therapeutic intervention. We designed a CD4 mutant (D1D2F43C) for site-specific coupling of compounds for screening against the cavity. Altogether, 81 cysteine-reactive compounds were designed, synthesized, and tested. Eight derivatives exceeded the affinity of native D1D2 for gp 120. Structure-activity relationships (SAR) for derivatized CD4 binding to gp 120 revealed significant plasticity of the Phe43 cavity and a narrow entrance. The primary contacts for compound recognition inside the cavity were found to be van der Waals interactions, whereas hydrophilic interactions were detected in the entrance. This first SAR on ligand binding to an interior cavity of gp 120 may provide a starting point for structure-based assembly of small molecules targeting gp120-CD4 interaction. C1 Columbia Univ, Dept Biochem & Mol Biophys, New York, NY 10032 USA. Columbia Univ, Dept Pharmacol, New York, NY 10032 USA. Univ Penn, Dept Chem, Philadelphia, PA 19104 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Howard Hughes Med Inst, Chevy Chase, MD 20815 USA. RP Hendrickson, WA (reprint author), Columbia Univ, Dept Biochem & Mol Biophys, 630 W 168th St, New York, NY 10032 USA. EM wayne@convex.hhmi.columbia.edu FU Intramural NIH HHS [Z99 AI999999]; NIGMS NIH HHS [P01 GM056550, P01-GM 056550] NR 53 TC 38 Z9 38 U1 2 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD OCT 4 PY 2007 VL 50 IS 20 BP 4898 EP 4908 DI 10.1021/jm070564e PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 216II UT WOS:000249871300010 PM 17803292 ER PT J AU Biertumpfel, C Yang, W Suck, D AF Biertuempfel, Christian Yang, Wei Suck, Dietrich TI Crystal structure of T4 endonuclease VII resolving a Holliday junction SO NATURE LA English DT Article ID FAST SEDIMENTING DNA; NUCLEIC-ACIDS; ESCHERICHIA-COLI; DIFFRACTION DATA; ACTIVE-SITE; CLEAVAGE; BINDING; RESOLUTION; BACTERIOPHAGE-T4; CRYSTALLOGRAPHY AB Holliday proposed a four-way DNA junction as an intermediate in homologous recombination(1), and such Holliday junctions have since been identified as a central component in DNA recombination and repair(2). Phage T4 endonuclease VII (endo VII) was the first enzyme shown to resolve Holliday junctions into duplex DNAs by introducing symmetrical nicks in equivalent strands(3). Several Holliday junction resolvases have since been characterized(4), but an atomic structure of a resolvase complex with a Holliday junction remained elusive. Here we report the crystal structure of an inactive T4 endo VII(N62D) complexed with an immobile four-way junction with alternating arm lengths of 10 and 14 base pairs. The junction is a hybrid of the conventional square-planar and stacked-X conformation. Endo VII protrudes into the junction point from the minor groove side, opening it to a 14 angstrom x 32 angstrom parallelogram. This interaction interrupts the coaxial stacking, yet every base pair surrounding the junction remains intact. Additional interactions involve the positively charged protein and DNA phosphate backbones. Each scissile phosphate that is two base pairs from the crossover interacts with a Mg2+ ion in the active site. The similar overall shape and surface charge potential of the Holliday junction resolvases endo VII, RuvC, Ydc2, Hjc and RecU, despite having different folds, active site composition and DNA sequence preference, suggest a conserved binding mode for Holliday junctions. C1 NIDDKD, Mol Biol Lab, Bethesda, MD 20892 USA. European Mol Biol Lab, Struct & Computat Biol Programme, D-69117 Heidelberg, Germany. RP Yang, W (reprint author), NIDDKD, Mol Biol Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM wei.yang@nih.gov; suck@embl.de RI Yang, Wei/D-4926-2011; OI Yang, Wei/0000-0002-3591-2195; Biertumpfel, Christian/0000-0002-7528-6547 FU Intramural NIH HHS NR 39 TC 58 Z9 59 U1 1 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 OCT 4 PY 2007 VL 449 IS 7162 BP 616 EP U14 DI 10.1038/nature06152 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 216QG UT WOS:000249893500049 PM 17873859 ER PT J AU Birn, RM AF Birn, Rasmus M. TI The Behavioral significance of spontaneous fluctuations in brain activity SO NEURON LA English DT Editorial Material ID CORTEX; MODES; FMRI AB Low-frequency fluctuations in fMRI data are believed to reflect synchronous and spontaneous fluctuations in neuronal networks. A study by Fox et al. in this issue of Neuron shows that these spontaneous fluctuations in the motor cortex can account for significant trial-to-trial variations in both the fMRI response and behavior. C1 NIMH, NIH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Birn, RM (reprint author), NIMH, NIH, Lab Brain & Cognit, Bethesda, MD 20892 USA. EM rbirn@mail.nih.gov NR 11 TC 14 Z9 14 U1 1 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD OCT 4 PY 2007 VL 56 IS 1 BP 8 EP 9 DI 10.1016/j.neuron.2007.09.021 PG 2 WC Neurosciences SC Neurosciences & Neurology GA 222IN UT WOS:000250289800004 PM 17920009 ER PT J AU Rister, J Pauls, D Schnell, B Ting, CY Lee, CH Sinakevitch, I Morante, J Strausfeld, NJ Ito, K Heisenberg, M AF Rister, Jens Pauls, Dennis Schnell, Bettina Ting, Chun-Yuan Lee, Chi-Hon Sinakevitch, Irina Morante, Javier Strausfeld, Nicholas J. Ito, Kei Heisenberg, Martin TI Dissection of the peripheral motion channel in the visual system of Drosophila melanogaster SO NEURON LA English DT Article ID LARGE MONOPOLAR CELLS; MUSCA-DOMESTICA; LAMINA GANGLIONARIS; WILD-TYPE; SYNAPTIC TRANSMISSION; ORIENTATION BEHAVIOR; COURTSHIP BEHAVIOR; COMPOUND EYE; OPTIC LOBE; FLY MUSCA AB In the eye, visual information is segregated into modalities such as color and motion, these being transferred to the central brain through separate channels. Here, we genetically dissect the achromatic motion channel in the fly Drosophila melanogaster at the level of the first relay station in the brain, the lamina, where it is split into four parallel pathways (L1-L3, amc/T1). The functional relevance of this divergence is little understood. We now show that the two most prominent pathways, L1 and L2, together are necessary and largely sufficient for motion-dependent behavior. At high pattern contrast, the two pathways are redundant. At intermediate contrast, they mediate motion stimuli of opposite polarity, L2 front-to-back, L1 back-to-front motion. At low contrast, L1 and L2 depend upon each other for motion processing. Of the two minor pathways, amc/T1 specifically enhances the L1 pathway at intermediate contrast. L3 appears not to contribute to motion but to orientation behavior. C1 Univ Wurzburg, Lehrstuhl Genet & Neurobiol, D-97074 Wurzburg, Germany. NICHD, Lab Gene Regulat & Dev, Bethesda, MD 20892 USA. Univ Arizona, Div Neurobiol, Tucson, AZ 85721 USA. NYU, Dept Biol, New York, NY 10003 USA. Univ Tokyo, Inst Mol & Cellular Biosci, Bunkyo Ku, Tokyo 1130032, Japan. RP Heisenberg, M (reprint author), Univ Wurzburg, Lehrstuhl Genet & Neurobiol, D-97074 Wurzburg, Germany. EM heisenberg@biozentrum.uni-wuerzburg.de RI Lee, Chi-Hon/G-9190-2012; Ting, chun-yuan/F-6448-2013; Morante, Javier/E-3292-2014; OI Morante, Javier/0000-0002-5594-0644; Pauls, Dennis/0000-0001-8330-8120 FU NCRR NIH HHS [R01 RR08688]; NICHD NIH HHS [HD008748-03] NR 63 TC 130 Z9 130 U1 2 U2 18 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD OCT 4 PY 2007 VL 56 IS 1 BP 155 EP 170 DI 10.1016/j.neuron.2007.09.014 PG 16 WC Neurosciences SC Neurosciences & Neurology GA 222IN UT WOS:000250289800017 PM 17920022 ER PT J AU Muntasell, A Berger, AC Roche, PA AF Muntasell, Aura Berger, Adam C. Roche, Paul A. TI T cell-induced secretion of MHC class II-peptide complexes on B cell exosomes SO EMBO JOURNAL LA English DT Article DE antigen presentation; B cell; exosomes; MHC class II ID MATURE DENDRITIC CELLS; ANTIGEN PRESENTATION; MULTIVESICULAR BODIES; PROLIFERATIVE CAPACITY; SURFACE EXPRESSION; IMMUNE-RESPONSES; MOLECULES; RECEPTOR; PATHWAY; COMPARTMENTS AB Antigen-specific interactions between B cells and T cells are essential for the generation of an efficient immune response. Since this requires peptide -MHC class II complexes (pMHC-II) on the B cell to interact with TCR on antigen-specific T cells, we have examined the mechanisms regulating the persistence, loss, and secretion of specific pMHC-II complexes on activated B cells. Using a mAb that recognizes specific pMHC-II, we found that activated B cells degrade approximately 50% of pMHC-II every day and release 12% of these pMHC-II from the cell on small membrane vesicles termed exosomes. These exosomes directly stimulate primed, but not naive, CD4 T cells. Interestingly, engagement of antigen-loaded B cells with specific CD4 T cells stimulates exosome release in a manner that can be mimicked by pMHC-II crosslinking. Biochemical studies revealed that the pMHC-II released on exosomes was previously expressed on the plasma membrane of the B cells, suggesting that regulated exosome release from activated B cells is a mechanism to allow pMHC-II to escape intracellular degradation and decorate secondary lymphoid organs with membrane-associated pMHC-II complexes. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Roche, PA (reprint author), NCI, Expt Immunol Branch, NIH, 9000 Rockville Pike,Bldg 10,Room 4B36, Bethesda, MD 20892 USA. EM paul.roche@nih.gov RI Muntasell, Aura/F-7869-2014 OI Muntasell, Aura/0000-0003-2894-0486 FU Intramural NIH HHS NR 52 TC 77 Z9 79 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD OCT 3 PY 2007 VL 26 IS 19 BP 4263 EP 4272 DI 10.1038/sj.emboj.7601842 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 224SN UT WOS:000250466800008 PM 17805347 ER PT J AU Zarin, DA Ide, NC Tse, T Harlan, WR Lindberg, DAB AF Zarin, Deborah A. Ide, Nicholas C. Tse, Tony Harlan, William R. Lindberg, Donald A. B. TI Clinical trial registries - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIH, Natl Lib Med, Bethesda, MD 20892 USA. RP Zarin, DA (reprint author), NIH, Natl Lib Med, Bldg 10, Bethesda, MD 20892 USA. EM dzarin@mail.nih.gov NR 2 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD OCT 3 PY 2007 VL 298 IS 13 BP 1515 EP 1515 DI 10.1001/jama.298.13.1515-a PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 216EE UT WOS:000249860500017 ER PT J AU Koushik, A Hunter, DJ Spiegelman, D Beeson, WL van den Brandt, PA Buring, JE Calle, EE Cho, E Fraser, GE Freudenheim, JL Fuchs, CS Giovannucci, EL Goldbohm, RA Harnack, L Jacobs, DR Kato, I Krogh, V Larsson, SC Leitzmann, MF Marshall, JR McCullough, ML Miller, AB Pietinen, P Rohan, TE Schatzkin, A Sieri, S Virtanen, MJ Wolk, A Zeleniuch-Jacquotte, A Zhang, SM Smith-Warner, SA AF Koushik, Anita Hunter, David J. Spiegelman, Donna Beeson, W. Lawrence van den Brandt, Piet A. Buring, Julie E. Calle, Eugenia E. Cho, Eunyoung Fraser, Gary E. Freudenheim, Jo L. Fuchs, Charles S. Giovannucci, Edward L. Goldbohm, R. Alexandra Harnack, Lisa Jacobs, David R., Jr. Kato, Ikuko Krogh, Vittorio Larsson, Susanna C. Leitzmann, Michael F. Marshall, James R. McCullough, Marjorie L. Miller, Anthony B. Pietinen, Pirjo Rohan, Thomas E. Schatzkin, Arthur Sieri, Sabina Virtanen, Mikko J. Wolk, Alicja Zeleniuch-Jacquotte, Anne Zhang, Shumin M. Smith-Warner, Stephanie A. TI Fruits, vegetables, and colon cancer risk in a pooled analysis of 14 cohort studies SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID FOOD-FREQUENCY QUESTIONNAIRE; COLORECTAL-CANCER; UNITED-STATES; RECTAL CANCERS; WOMENS HEALTH; PLANT FOODS; DIET; CONSUMPTION; PREVENTION; FIBER AB Background Fruit and vegetable intakes have been associated with a reduced risk of colon cancer; however, in more recent studies associations have been less consistent. Statistical power to examine associations by colon site has been limited in previous studies. Methods Fruit and vegetable intakes in relation to colon cancer risk were examined in the Pooling Project of Prospective Studies of Diet and Cancer. Relative risks (RRs) and 95% confidence intervals (Cis) were estimated separately in 14 studies using Cox proportional hazards model and then pooled using a randomeffects model. Intakes of total fruits and vegetables, total fruits, and total vegetables were categorized according to quintiles and absolute cutpoints. Analyses were conducted for colon cancer overall and for proximal and distal colon cancer separately. All statistical tests were two-sided. Results Among 756217 men and women followed for up to 6 to 20 years, depending on the study, 5838 were diagnosed with colon cancer. The pooled multivariable RRs (95% Cis) of colon cancer for the highest versus lowest quintiles of intake were 0.91 (0.82 to 1-01 1 P-trend =.19) for total fruits and vegetables, 0.93 (0.85 to 1.02, P-trend =.28) for total fruits, and 0.94 (0.86 to 1.02, P-trend =.17) for total vegetables. Similar results were observed when intakes were categorized by identical absolute cut points across studies (pooled multivariable FIR = 0.90, 95% CI = 0.77 to 1.05 for 800 or more versus <200 g/day of total fruits and vegetables, P-trend =.06). The age-standardized incidence rates of colon cancer for these two intake categories were 54 and 61 per 100000 person-years, respectively. When analyzed by colon site, the pooled multivariable RRs (95% Cis) comparing total fruit and vegetable intakes of 800 or more versus less than 200 g/day were 0.74 (0.57 to 0.95, P-trend =.02) for distal colon cancers and 1.02 (0.82 to 1.27, P-trend =.57) for proximal colon cancers. Similar site-specific associations were observed for total fruits and total vegetables. Conclusion Fruit and vegetable intakes were not strongly associated with colon cancer risk overall but may be associated with a lower risk of distal colon cancer. C1 Univ Montreal, CHUM, Ctr Rech, Dept Social & Prevent Med, Montreal, PQ H2W 1V1, Canada. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Loma Linda Univ, Ctr Hlth Res, Loma Linda, CA 92350 USA. Maastricht Univ, Dept Epidemiol, Maastricht, Netherlands. Amer Canc Soc, Atlanta, GA 30329 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Div Prevent Med, Boston, MA 02115 USA. Brigham & Womens Hosp, Channing Lab, Boston, MA 02115 USA. Univ Buffalo State Univ New York, Dept Social & Prevent Med, Buffalo, NY 14222 USA. Roswell Pk Canc Inst, Dept Canc Prevent & Populat Sci, Buffalo, NY 14263 USA. Dana Farber Canc Inst, Dept Adult Oncol, Boston, MA USA. TNO, Dept Food & Chem Risk Anal, Zeist, Netherlands. Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN USA. Wayne State Univ, Sch Med, Dept Pathol, Karmanos Canc Inst, Detroit, MI 48201 USA. Natl Canc Inst, Nutr Epidemiol Unit, I-20133 Milan, Italy. Karolinska Inst, Natl Inst Environm Med, Div Nutr Epidemiol, Stockholm, Sweden. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Toronto, Fac Med, Dept Publ Hlth Sci, Toronto, ON, Canada. Natl Publ Hlth Inst, Dept Epidemiol & Hlth Promot, Helsinki, Finland. Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA. AZJ, Div Epidemiol, Dept Environm Med, New York, NY USA. RP Koushik, A (reprint author), Univ Montreal, CHUM, Ctr Rech, Dept Social & Prevent Med, 3875 Rue St Urbain,3rd Floor, Montreal, PQ H2W 1V1, Canada. EM anita.koushik@umontreal.ca; pooling@hsphsun2.harvard.edu RI Larsson, Susanna/F-6065-2015; Krogh, Vittorio/K-2628-2016; Sieri, Sabina/K-4667-2016; OI Larsson, Susanna/0000-0003-0118-0341; Krogh, Vittorio/0000-0003-0122-8624; Sieri, Sabina/0000-0001-5201-172X; Zeleniuch-Jacquotte, Anne/0000-0001-9350-1303 FU NCI NIH HHS [CA55075] NR 57 TC 122 Z9 127 U1 1 U2 17 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 EI 1460-2105 J9 JNCI-J NATL CANCER I JI JNCI-J. Natl. Cancer Inst. PD OCT 3 PY 2007 VL 99 IS 19 BP 1471 EP 1483 DI 10.1093/jnci/djm155 PG 13 WC Oncology SC Oncology GA 219SO UT WOS:000250105300012 PM 17895473 ER PT J AU Hoe, HS Cooper, MJ Burns, MP Lewis, PA van der Brug, M Chakraborty, G Cartagena, CM Pak, DTS Cookson, MR Rebeck, GW AF Hoe, Hyang-Sook Cooper, Matthew J. Burns, Mark P. Lewis, Patrick A. van der Brug, Marcel Chakraborty, Geetanjali Cartagena, Casandra M. Pak, Daniel T. S. Cookson, Mark R. Rebeck, G. William TI The metalloprotease inhibitor TIMP-3 regulates amyloid precursor protein and apolipoprotein E receptor proteolysis SO JOURNAL OF NEUROSCIENCE LA English DT Article DE Alzheimer's disease; secretase; LXR; apolipoprotein; amyloid; neurodegeneration ID MESSENGER-RNA EXPRESSION; ORPHAN NUCLEAR RECEPTORS; ALZHEIMERS-DISEASE; F-SPONDIN; A-BETA; HIPPOCAMPAL-NEURONS; CONVERTING-ENZYME; TISSUE INHIBITOR; IN-VITRO; ALPHA AB Cellular cholesterol levels alter the processing of the amyloid precursor protein ( APP) to produce A beta. Activation of liver X receptors ( LXRs), one cellular mechanism to regulate cholesterol homeostasis, has been found to alter A beta levels in vitro and in vivo. To identify genes regulated by LXR, we treated human neuroblastoma cells with an LXR agonist ( TO-901317) and examined gene expression by microarray. As expected, TO-901317 upregulated several cholesterol metabolism genes, but it also decreased expression of a metalloprotease inhibitor, TIMP-3. We confirmed this finding using real-time PCR and by measuring TIMP-3 protein in glia, SY5Y cells, and COS7 cells. TIMP-3 is a member of a family of metalloproteinase inhibitors and blocks A disintegrin and metalloproteinase-10 ( ADAM-10) and ADAM-17, two APP alpha-secretases. We found that TIMP-3 inhibited alpha-secretase cleavage of APP and an apolipoprotein E ( apoE) receptor, ApoER2. TIMP-3 decreased surface levels of ADAM-10, APP, and ApoER2. These changes were accompanied by increased APP beta-C-terminal fragment and A beta production. These data suggest that TIMP-3 preferentially routes APP and ApoER2 away from the cell surface and alpha-secretase cleavage and encourages endocytosis and beta-secretase cleavage. In vivo, TO-901317 decreased brain TIMP-3 levels. TIMP-3 protein levels were increased in human Alzheimer's disease ( AD) brain and in APP transgenic mice, suggesting that increased levels of TIMP-3 in AD may contribute to higher levels of A beta. C1 Georgetown Univ, Med Ctr, Dept Neurosci, Washington, DC 20057 USA. Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20057 USA. NIA, Neurogenet Lab, Bethesda, MD 20892 USA. RP Rebeck, GW (reprint author), Georgetown Univ, Med Ctr, Dept Neurosci, 3970 Reservoir Rd NW, Washington, DC 20057 USA. EM gwr2@georgetown.edu RI Lewis , Patrick/C-3674-2009; OI Lewis, Patrick/0000-0003-4537-0489 FU NIA NIH HHS [AG14473]; NINDS NIH HHS [R01 NS048085-02, R01 NS048085] NR 51 TC 32 Z9 33 U1 0 U2 4 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD OCT 3 PY 2007 VL 27 IS 40 BP 10895 EP 10905 DI 10.1523/JNEUROSCI.3135-07.2007 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 217XU UT WOS:000249981400027 PM 17913923 ER PT J AU Rubinstein, LV Dancey, JE Korn, EL Smith, MA Wright, JJ AF Rubinstein, Larry V. Dancey, Janet E. Korn, Edward L. Smith, Malcolm A. Wright, John J. TI Early average change in tumor size in a phase 2 trial: Efficient endpoint or false promise? SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material C1 NCI, NIH, Biometr Res Branch, Bethesda, MD 20892 USA. NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Rubinstein, LV (reprint author), NCI, NIH, Biometr Res Branch, Execut Pl N,Rm 8130,MSC 7434, Bethesda, MD 20892 USA. EM rubinsteint@ctep.nci.nih.gov NR 6 TC 9 Z9 9 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 OCT 3 PY 2007 VL 99 IS 19 BP 1422 EP 1423 DI 10.1093/jnci/djm167 PG 2 WC Oncology SC Oncology GA 219SO UT WOS:000250105300001 PM 17895470 ER PT J AU Lawson, KA Wright, ME Mouw, T Hollenbeck, A Schatzken, A Leitzmann, MF AF Lawson, Karla A. Wright, Margaret E. Mouw, Traci Hollenbeck, Albert Schatzken, Arthur Leitzmann, Michael F. TI Re: Multivitamin use and risk of prostate cancer in the national institutes of Health-AARP diet and health study - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 Dell Childerns Med Ctr, Trauma Serv Dept, Austin, TX USA. NCI, NIH, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Illinois, Coll Med, Dept Pathol, Chicago, IL 60612 USA. AARP, AARP Res Grp, Washington, DC USA. RP Leitzmann, MF (reprint author), 6120 Execut Blvd,EPS Ste 320, Rockville, MD 20852 USA. EM leitzmann@mail.nih.gov NR 3 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD OCT 3 PY 2007 VL 99 IS 19 BP 1492 EP 1493 DI 10.1093/jnci/dim139 PG 2 WC Oncology SC Oncology GA 219SO UT WOS:000250105300017 ER PT J AU Azuma, M Embree, LJ Sabaawy, H Hickstein, DD AF Azuma, Mizuki Embree, Lisa J. Sabaawy, Hatem Hickstein, Dennis D. TI Ewing Sarcoma Protein Ewsr1 Maintains Mitotic Integrity and Proneural Cell Survival in the Zebrafish Embryo SO PLOS ONE LA English DT Article AB Background. The Ewing sarcoma breakpoint region 1 gene (EWSR1), also known as EWS, is fused to a number of different partner genes as a result of chromosomal translocation in diverse sarcomas. Despite the involvement of EWSR1 in these diverse sarcomas, the in vivo function of wild type EWSR1 remains unclear. Principal Findings. We identified two zebrafish EWSR1 orthologues, ewsr1a and ewsr1b, and demonstrate that both genes are expressed maternally, and are expressed ubiquitously throughout zebrafish embryonic development. Morpholino induced knockdown of both zebrafish ewsr1 genes led to mitotic defects with multipolar or otherwise abnormal mitotic spindles starting from the bud stage (10 hour post-fertilization (hpf)). The abnormalities in mitotic spindles were followed by p53-mediated apoptosis in the developing central nervous system (CNS) leading to a reduction in the number of proneural cells, disorganization of neuronal networks, and embryonic lethality by 5 days post-fertilization. siRNA silencing of EWSR1 in Hela cells resulted in mitotic defects accompanied by apoptotic cell death, indicating that the role of EWSR1 is conserved between zebrafish and human. Conclusions. Ewsr1 maintains mitotic integrity and proneural cell survival in early zebrafish development. C1 [Azuma, Mizuki; Embree, Lisa J.; Sabaawy, Hatem; Hickstein, Dennis D.] NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Azuma, M (reprint author), NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM azumam@mail.nih.gov FU NIH, National Cancer Institute, Center for Cancer Research FX The Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research NR 31 TC 33 Z9 34 U1 1 U2 1 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD OCT 3 PY 2007 VL 2 IS 10 AR e979 DI 10.1371/journal.pone.0000979 PG 10 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10HU UT WOS:000207455900015 PM 17912356 ER PT J AU Yang, W Woodgate, R AF Yang, Wei Woodgate, Roger TI What a difference a decade makes: Insights into translesion DNA synthesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Review DE catalysis; regulation; ubiquitylation; y-family polymerases ID CELL NUCLEAR ANTIGEN; REV1 PROTEIN INTERACTS; ESCHERICHIA-COLI DINB; THYMINE DIMER BYPASS; Y-FAMILY POLYMERASES; SACCHAROMYCES-CEREVISIAE; SULFOLOBUS-SOLFATARICUS; LESION-BYPASS; ERROR-PRONE; POL-KAPPA AB Living organisms are continually under attack from a vast array of DNA-damaging agents that imperils their genomic integrity. As a consequence, cells posses an army of enzymes to repair their damaged chromosomes. However, DNA lesions often persist and pose a considerable threat to survival, because they can block the cell's replicase and its ability to complete genome duplication. It has been clear for many years that cells must possess a mechanism whereby the DNA lesion could be tolerated and physically bypassed. Yet it was only within the past decade that specialized DNA polymerases for "translesion DNA synthesis" or "TLS" were identified and characterized. Many of the TLS enzymes belong to the recently described "Y-family" of DNA polymerases. By possessing a spacious preformed active site, these enzymes can physically accommodate a variety of DNA lesions and facilitate their bypass. Flexible DNA-binding domains and a variable binding pocket for the replicating base pair further allow these TLS polymerases to select specific lesions to bypass and favor distinct non-Watson-Crick base pairs. Consequently, TLS polymerases tend to exhibit much lower fidelity than the cell's replicase when copying normal DNA, which results in a dramatic increase in mutagenesis. Occasionally this can be beneficial, but it often speeds the onset of cancer in humans. Cells use both transcriptional and posttranslational regulation to keep these low-fidelity polymerases under strict control and limit their access to a replication fork. Our perspective focuses on the mechanistic insights into TLS by the Y-family polymerases, how they are regulated, and their effects on genomic (in)stability that have been described in the past decade. C1 NIDDK, NICHHD, NIH, Mol Biol Lab, Bethesda, MD 20892 USA. NICHHD, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDK, NICHHD, NIH, Mol Biol Lab, Bethesda, MD 20892 USA. EM wei.yang@nih.gov RI Yang, Wei/D-4926-2011 OI Yang, Wei/0000-0002-3591-2195 FU Intramural NIH HHS NR 155 TC 218 Z9 222 U1 0 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 2 PY 2007 VL 104 IS 40 BP 15591 EP 15598 DI 10.1073/pnas.0704219104 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 217IX UT WOS:000249942700003 PM 17898175 ER PT J AU Tu, D Li, W Ye, Y Brunger, AT AF Tu, Daqi Li, Wei Ye, Yihong Brunger, Axel T. TI Structure and function of the yeast U-box-containing ubiquitin ligase Ufd2p SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE E4 elongation factor; endoplasmic reticulum-associated degradation; cdc48p/p97; polyubiquitination; armadillo repeats ID POLYUBIQUITIN CHAINS; PROTEIN LIGASES; QUALITY-CONTROL; SUBSTRATE; COMPLEX; BINDING; RECOGNITION; DEGRADATION; REGULATOR; ALIGNMENT AB Proteins conjugated by Lys-48-linked polyubiquitin chains are preferred substrates of the eukaryotic proteasome. Polyubiquitination requires an activating enzyme (Ell), a conjugating enzyme (E2), and a ligase (E3). Occasionally, these enzymes only assemble short ubiquitin oligomers, and their extension to full length involves a ubiquitin elongating factor termed E4. Ufd2p, as the first E4 identified to date, is involved in the degradation of misfolded proteins of the encloplasmic reticulum and of a ubiquitin-beta-GAL fusion substrate in Saccharomyces cerevisiae. The mechanism of action of Ufd2p is unknown. Here we describe the crystal structure of the full-length yeast Ufd2p protein. Ufd2p has an elongated shape consisting of several irregular Armadillo-like repeats with two helical hairpins protruding from it and a U-box domain flexibly attached to its C terminus. The U-box of Ufd2p has a fold similar to that of the RING (Really Interesting New Gene) domain that is present in certain ubiquitin ligases. Accordingly, Ufd2p has all of the hallmarks of a RING finger-containing ubiquitin ligase: it associates with its cognate E2 Ubc4p via its U-box domain and catalyzes the transfer of ubiquitin from the E2 active site to Ufd2p itself or to an acceptor ubiquitin molecule to form unanchored diubiquitin oligomers. Thus, Ufd2p can function as a bona fide E3 ubiquitin ligase to promote ubiquitin chain elongation on a substrate. C1 Stanford Univ, Dept Cellular & Mol Physiol, Stanford, CA 94305 USA. Stanford Univ, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. Stanford Univ, Dept Biol Struct, Stanford, CA 94305 USA. Stanford Univ, Dept Photon Sci, Stanford, CA 94305 USA. Stanford Univ, Howard Hughes Med Inst, Stanford, CA 94305 USA. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Brunger, AT (reprint author), Stanford Univ, Dept Cellular & Mol Physiol, 318 Campus Dr,Room E300C, Stanford, CA 94305 USA. EM brunger@stanford.edu OI Brunger, Axel/0000-0001-5121-2036 FU Intramural NIH HHS NR 33 TC 34 Z9 35 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD OCT 2 PY 2007 VL 104 IS 40 BP 15599 EP 15606 DI 10.1073/pnas.0701369104 PG 8 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 217IX UT WOS:000249942700004 PM 17890322 ER PT J AU Pearson, NJ Chesney, MA AF Pearson, Nancy J. Chesney, Margaret A. TI The CAM education program of the national center for complementary and alternative medicine: An overview SO ACADEMIC MEDICINE LA English DT Article ID INTEGRATIVE MEDICINE; UNITED-STATES AB The authors provide a historical context and overview of the experience of education projects at 14 health professions schools in the United States and the American Medical Students Association that were funded by the National Center for Complementary and Alternative Medicine at the National Institutes of Health in cohorts of five per year in 2000, 2001, and 2002-2003. These 15 projects were designed to incorporate CAM information into the curricula of conventional health professions schools. A longer-term goal was to accelerate the integration of CAM and conventional medicine. The overall program started in 2000 at a time when discussions about the definition, goals, and value of integrative medicine were already well underway. The efforts specific to each project, as well as the shared challenges, accomplishments, and collaborative efforts of all 15 projects, can provide guidance for the education of conventional health care providers about CAM in an integrative medicine environment. Challenging issues that must be faced include (1) the need to develop successful strategies to incorporate information about CAM into already dense health professions school curricula, (2) the need for conventional health professionals to have authoritative resources to provide their patients information about risks and benefits of CAM practices, and (3) the need to identify appropriate roles for CAM practitioners in educating conventional health professionals about CAM therapies. The authors discuss these issues and others and present some recommendations. C1 US Dept HHS, NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20982 USA. RP Pearson, NJ (reprint author), US Dept HHS, NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20982 USA. EM pearsonn@mail.nih.gov NR 23 TC 52 Z9 54 U1 3 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD OCT PY 2007 VL 82 IS 10 BP 921 EP 926 PG 6 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 219EL UT WOS:000250067400003 PM 17895649 ER PT J AU Pearson, NJ Chesney, MA AF Pearson, Nancy J. Chesney, Margaret A. TI The national center for complementary and alternative medicine SO ACADEMIC MEDICINE LA English DT Editorial Material C1 NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Chesney, MA (reprint author), NIH, Natl Ctr Complementary & Alternat Med, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 4 Z9 4 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1040-2446 J9 ACAD MED JI Acad. Med. PD OCT PY 2007 VL 82 IS 10 BP 967 EP 967 PG 1 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 219EL UT WOS:000250067400011 PM 17895659 ER PT J AU Pletneva, N Pletnev, V Tikhonova, T Pakhomov, AA Popov, V Martynov, VI Wlodawer, A Dauter, Z Pletnev, S AF Pletneva, Nadezhda Pletnev, Vladimir Tikhonova, Tamara Pakhomov, Alexey A. Popov, Vladimir Martynov, Vladimir I. Wlodawer, Alexander Dauter, Zbigniew Pletnev, Sergei TI Refined crystal structures of red and green fluorescent proteins from the button polyp Zoanthus SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Article ID RESONANCE ENERGY-TRANSFER; GFP-LIKE PROTEINS; GALACTOSE-OXIDASE; ANEMONIA-SULCATA; RADIATION-DAMAGE; MONOMERIC RED; IN-VIVO; CHROMOPHORE; CHROMOPROTEIN; CONVERSION AB The three-dimensional structures of the wild-type red (zRFP574) and green (zGFP506) fluorescent proteins (FP) from the button polyp Zoanthus have been determined at 1.51 and 2.2 angstrom resolution, respectively. In addition, the crystal structures of a zGFP506 variant (zGFP506_N66D) with replacement of the first chromophore-forming residue (Asn66 to Asp) have been determined in the transitional 'green' and mature 'red' states at 2.4 and 2.2 A, respectively. The monomers of these proteins adopt the typical fold of the green fluorescent protein (GFP) family, consisting of an 11-stranded beta-barrel with a chromophore embedded in the middle of an internal alpha-helix directed along the beta-barrel axis. Post-translational modification of the chromophore-forming sequence Asn66-Tyr67-Gly68 within zGFP506 results in a typical GFP-like coplanar two-ring structure consisting of a five-membered imidazolinone heterocycle with the phenolic ring of Tyr67 in a cis orientation to the C-alpha-N(67) bond. A novel post-translational modification of the chromophore-forming sequence Asp66-Tyr67-Gly68 in zRFP574 expands the protein maturation beyond the green-emitting form and results in decarboxylation of the Asp66 side chain. It is suggested that electrostatic conflict between the closely spaced negatively charged side chains of the chromophore Asp66 and the proximal catalytic Glu221 is most likely to be the trigger for the chain of reactions resulting in the observed decarboxylation. The chromophore structures of wild-type zGFP506 and of its mutant zGFP506_N66D in the 'green' and 'red' states support this suggestion. The beta-barrel frames of zRFP574 and zGFP506 reveal the presence of a water-filled pore leading to the chromophore Tyr67, similar to that observed previously in TurboGFP. An analysis of the residue composition at two inter-monomer interfaces in the tetrameric biological unit of zRFP574 and zGFP506, as well as of zYFP538 from the same species, has revealed a group of highly conserved residues that are apparently responsible for oligomerization. These residues present initial useful targets for rational mutagenesis aimed at designing monomeric forms of the fluorescent proteins, which are more suitable for practical applications. C1 Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow, Russia. Russian Acad Sci, Bakh Inst Biochem, Moscow, Russia. Natl Canc Inst, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. Natl Canc Inst, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, Argonne, IL 60439 USA. RP Pletnev, S (reprint author), Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow, Russia. EM svp@ncifcrf.gov RI Pakhomov, Alexey/D-7199-2012; Pletneva, Nadya/F-7839-2014; Pletnev, Vladimir/Q-6151-2016; Martynov, Vladimir/S-3483-2016 OI Martynov, Vladimir/0000-0003-4923-6842 FU Intramural NIH HHS NR 68 TC 22 Z9 25 U1 0 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0907-4449 J9 ACTA CRYSTALLOGR D JI Acta Crystallogr. Sect. D-Biol. Crystallogr. PD OCT PY 2007 VL 63 BP 1082 EP 1093 DI 10.1107/S0907444907042461 PN 10 PG 12 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 211XS UT WOS:000249557600007 PM 17881826 ER PT J AU Hossmann, KA Spatz, M AF Hossmann, Konstantin-A. Spatz, Maria TI In memoriam: Igor Klatzo (1916-2007) SO ACTA NEUROPATHOLOGICA LA English DT Biographical-Item C1 Max Planck Inst Neurol Res, D-50931 Cologne, Germany. NINDS, NIH, Bethesda, MD 20892 USA. RP Hossmann, KA (reprint author), Max Planck Inst Neurol Res, Glueler Str 50, D-50931 Cologne, Germany. EM hossmann@nf.mpg.de 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 0001-6322 J9 ACTA NEUROPATHOL JI Acta Neuropathol. PD OCT PY 2007 VL 114 IS 4 BP 439 EP 440 DI 10.1007/s00401-007-0273-y PG 2 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 214ZE UT WOS:000249776100015 ER PT J AU Strunk, T Curtis, S Richmond, P Currie, AJ Simmer, K Levy, O Otto, M Burgner, D AF Strunk, T. Curtis, S. Richmond, P. Currie, A. J. Simmer, K. Levy, O. Otto, M. Burgner, D. TI Innate immune responses of preterm infants to neonatal bacterial pathogens and toll-like receptor agonists SO ACTA PAEDIATRICA LA English DT Meeting Abstract C1 [Strunk, T.; Curtis, S.; Richmond, P.; Simmer, K.; Burgner, D.] Univ Western Australia, Sch Paediat & Child Hlth, Nedlands, WA 6009, Australia. [Currie, A. J.] Univ Western Australia, Sch Med & Pharmacol, Nedlands, WA 6009, Australia. [Simmer, K.] Univ Western Australia, Sch Womens & Infants Hlth, Perth, WA 6009, Australia. [Levy, O.] Childrens Hosp, Harvard Med Sch, Dept Med, Div Infect Dis, Boston, MA 02115 USA. [Otto, M.] NIH, Natl Inst Allergy & Infect Dis, Hamilton, MT USA. RI Richmond, Peter/G-3379-2012; Simmer, Karen/H-5834-2014; Currie, Andrew/C-2778-2015 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 0803-5253 J9 ACTA PAEDIATR JI Acta Paediatr. PD OCT PY 2007 VL 96 SU 456 BP 154 EP 155 PG 2 WC Pediatrics SC Pediatrics GA 245AR UT WOS:000251907200399 ER PT J AU Michels, II Fang, YX Zhao, D Zhao, LY Lu, L AF Ingo Ilja Michels Yu-Xia Fang Dong Zhao Li-Yan Zhao Lin Lu TI Comparison of drug abuse in Germany and China SO ACTA PHARMACOLOGICA SINICA LA English DT Review DE drug abuse; methadone maintenance treatment; heroin; HIV; AIDS; harm reduction; comparison; Germany; China ID HIGH-PREVALENCE AREAS; USE PATTERNS; METHADONE-MAINTENANCE; RISK BEHAVIORS; OPIATE ADDICTS; HIV-INFECTION; RECENT TRENDS; HEPATITIS-C; USERS; TRANSMISSION AB Drug abuse has a long, but also different history in Germany and China. The Opium War largely influenced the history of China in 19th century; however, China was once recognized as a drug-free nation for 3 decades from the 1950s to the 1980s. Drug abuse has spread quickly since re-emerging as a national problem in China in the late 1980s. The number of registered drug abusers increased from 70 000 in 1990 to more than 1 million by the end of 2005. In past decades, illicit drug trafficking and production have swept most provinces in China, and drug abuse has caused many problems for both abusers and the community. One major drug-related problem is the spread of HIV, which has caused major social and economic damage in China. Germany, the largest developed European country, also faces the drug and addiction problem. Germany has about 150 000 heroin addicts, for whom HIV/AIDS has become a serious threat since the mid 1980s. To control the drug problem, the German Government adopted the "Action Plan on Drugs and Addiction" in 2003; the China Central Government approved a similar regulation in the antidrug campaign in 2005. Germany has experience in reducing drug-related harm. The methadone maintenance treatment (MMT) program has run for more than 20 years and the public has become more tolerant of addicts. In 2003, China began the MMT program for controlling the spread of HIV/AIDS. It is necessary for China to learn from developed countries to acquire success in its antidrug campaign. In this review, we will go over the differences and similarities in drug abuse between Germany and China. The differences are related to history, population and economics, drug policy context, drug laws, HIV/hepatitis C virus infection, the MMT program and so on. These 2 nations have drug abuse problems with different histories and currently use different approaches to handle illicit drug marketing and use. The legal penalties for illicit drug offences reflect the social differences of these 2 nations with respect to the seriousness of particular types of crimes. The characteristics of the MMT program may also influence patterns of drug abuse in these 2 nations and China should improve the MMT program based on the successful model in Europe, the USA, and Australia. We recommend more dialogue and collaboration between Germany and China. C1 Peking Univ, Natl Inst Drug Dependence, Beijing 100083, Peoples R China. Fed Minst Hlth, Off Fed Drug, D-10117 Berlin, Germany. Natl Inst Drug Abuse, Clin Pharmacol & Therapeut Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Lu, L (reprint author), Peking Univ, Natl Inst Drug Dependence, Beijing 100083, Peoples R China. EM linlu@bjmu.edu.cn FU Intramural NIH HHS NR 84 TC 9 Z9 10 U1 4 U2 10 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1671-4083 J9 ACTA PHARMACOL SIN JI Acta Pharmacol. Sin. PD OCT PY 2007 VL 28 IS 10 BP 1505 EP 1518 DI 10.1111/j.1745-7254.2007.00633.x PG 14 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 213XC UT WOS:000249699600001 PM 17883935 ER PT J AU Hansen, PB Friis, UG Uhrenholt, TR Briggs, J Schnermann, J AF Hansen, P. B. Friis, U. G. Uhrenholt, T. R. Briggs, J. Schnermann, J. TI Intracellular signalling pathways in the vasoconstrictor response of mouse afferent arterioles to adenosine SO ACTA PHYSIOLOGICA LA English DT Article DE adenosine; muscle smooth; renal circulation ID SMOOTH-MUSCLE CELLS; TUBULOGLOMERULAR FEEDBACK; ANGIOTENSIN-II; RENAL VASOCONSTRICTION; RECEPTORS; MECHANISM; A(1); ACTIVATION; EXPRESSION; CHANNELS AB Aims: Adenosine causes vasoconstriction of afferent arterioles of the mouse kidney through activation of adenosine A(1) receptors and Gi-mediated stimulation of phospholipase C. In the present study, we further explored the signalling pathways by which adenosine causes arteriolar vasoconstriction. Methods and results: Adenosine (10(-7) m) significantly increased the intracellular calcium concentration in mouse isolated afferent arterioles measured by fura-2 fluorescence. Pre-treatment with thapsigargin (2 mu m) blocked the vasoconstrictor action of adenosine (10(-7) m) indicating that release of calcium from the sarcoplasmic reticulum (SR), stimulated presumably by IP3, is involved in the adenosine contraction mechanism of the afferent arteriole. In agreement with this notion is the observation that 2 aminoethoxydiphenyl borate (100 mu m) blocked the adenosine-induced constriction whereas the protein kinase C inhibitor calphostin C had no effect. The calcium-activated chloride channel inhibitor IAA-94 (30 mu m) inhibited the adenosine-mediated constriction. Patch clamp experiments showed that adenosine treatment induced a depolarizing current in preglomerular smooth muscle cells which was abolished by IAA-94. Furthermore, the vasoconstriction caused by adenosine was significantly inhibited by 5 mu m nifedipine (control 8.3 +/- 0.2 mu m, ado 3.6 +/- 0.6 mu m, ado + nifedipine 6.8 +/- 0.2 mu m) suggesting involvement of voltage-dependent calcium channels. Conclusion: We conclude that adenosine mediates vasoconstriction of afferent arterioles through an increase in intracellular calcium concentration resulting from release of calcium from the SR followed by activation of Ca2+-activated chloride channels leading to depolarization and influx of calcium through voltage-dependent calcium channels. C1 Univ So Denmark, Dept Physiol & Pharmacol, DK-5000 Odense, Denmark. NIDDK, NIH, Bethesda, MD USA. RP Hansen, PB (reprint author), Univ So Denmark, Dept Physiol & Pharmacol, Winsloewparken 21, DK-5000 Odense, Denmark. EM pbhansen@health.sdu.dk RI Briggs, Josephine/B-9394-2009 OI Briggs, Josephine/0000-0003-0798-1190 FU Intramural NIH HHS NR 31 TC 18 Z9 18 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1748-1708 J9 ACTA PHYSIOL JI Acta Physiol. PD OCT PY 2007 VL 191 IS 2 BP 89 EP 97 DI 10.1111/j.1748-1716.2007.01724.x PG 9 WC Physiology SC Physiology GA 209GK UT WOS:000249376800001 PM 17565566 ER PT J AU Fagan, P Moolchan, ET Lawrence, D Fernander, A Ponder, PK AF Fagan, Pebbles Moolchan, Eric T. Lawrence, Deirdre Fernander, Anita Ponder, Paris K. TI Identifying health disparities across the tobacco continuum SO ADDICTION LA English DT Review DE disparities; education; poverty; race/ethnicity; tobacco ID MENTHOLATED CIGARETTE-SMOKING; NUTRITION EXAMINATION SURVEY; LUNG-CANCER SUSCEPTIBILITY; CAUSE-SPECIFIC MORTALITY; 3RD NATIONAL-HEALTH; UNITED-STATES; ETHNIC-DIFFERENCES; AFRICAN-AMERICANS; NICOTINE METABOLISM; MINORITY POPULATIONS AB Aims Few frameworks have addressed work-force diversity, inequities and inequalities as part of a comprehensive approach to eliminating tobacco-related health disparities. This paper summarizes the literature and describes the known disparities that exist along the tobacco disease continuum for minority racial and ethnic groups, those living in poverty, those with low education and blue-collar and service workers. The paper also discusses how work-force diversity, inequities in research practice and knowledge allocation and inequalities in access to and quality of health care are fundamental to addressing disparities in health. Methods We examined the available scientific literature and existing public health reports to identify disparities across the tobacco disease continuum by minority racial/ethnic group, poverty status, education level and occupation. Findings Results indicate that differences in risk indicators along the tobacco disease continuum do not explain fully tobacco-related cancer consequences among some minority racial/ethnic groups, particularly among the aggregate groups, blacks/African Americans and American Indians/Alaska Natives. The lack of within-race/ethnic group data and its interactions with socio-economic factors across the life-span contribute to the inconsistency we observe in the disease causal paradigm. Conclusions More comprehensive models are needed to understand the relationships among disparities, social context, diversity, inequalities and inequities. A systematic approach will also help researchers, practitioners, advocates and policy makers determine critical points for interventions, the types of studies and programs needed and integrative approaches needed to eliminate tobacco-related disparities. C1 NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NIDA, Baltimore, MD 21224 USA. Univ Kentucky, Lexington, KY 40506 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. RP Fagan, P (reprint author), NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Execut Pl N,Room 4042,6130 Execut Blvd,MSC 7337, Bethesda, MD 20892 USA. EM faganp@mail.nih.gov NR 179 TC 111 Z9 112 U1 6 U2 30 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD OCT PY 2007 VL 102 SU 2 BP 5 EP 29 DI 10.1111/j.1360-0443.2007.01952.x PG 25 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 209WL UT WOS:000249418600002 PM 17850611 ER PT J AU Moolchan, ET Fagan, P Fernander, AF Velicer, WF Hayward, MD King, G Clayton, RR AF Moolchan, Eric T. Fagan, Pebbles Fernander, Anita F. Velicer, Wayne F. Hayward, Mark D. King, Gary Clayton, Richard R. TI Addressing tobacco-related health disparities SO ADDICTION LA English DT Review DE addiction; conceptual framework; ethnicity; health disparities; life cycle; multidisciplinary approach; tobacco; treatment ID NICOTINE REPLACEMENT THERAPY; OVER-THE-COUNTER; SMOKING-CESSATION TREATMENT; CIGARETTE-SMOKING; AFRICAN-AMERICANS; FAGERSTROM TEST; ETHNIC-DIFFERENCES; PRIMARY-CARE; ADOLESCENT SMOKING; RACIAL-DIFFERENCES AB Aims The aim of this review is to outline a transdisciplinary research framework for identifying, explaining and intervening to address tobacco-related health disparities (TRHD). We will show the importance of an approach that integrates the human life-cycle (developmental) and tobacco addiction cycle (behavioral) for interventions that address group-specific vulnerabilities. Methods The existing empirical knowledge base on tobacco-related health disparities is mapped onto a conceptual framework built around life-cycle and addiction cycle trajectories for disparate population groups. Findings Current knowledge about developmental trajectories of tobacco use is based on general population studies with minimal information on group differences. At the national level, early onset of tobacco use is associated with a high level of tobacco dependence, low number of quit attempts, long-term smoking history and tobacco-related health harm. These relationships cannot be assumed for all population groups: African Americans and Asian Americans typically have a later age of tobacco use onset compared to European Americans, yet health consequences of smoking are higher among African Americans but not Asian Americans. Even less is known about group differences in the temporal progression from smoking onset to daily smoking. Determining the time-frame from initial to regular smoking seems crucial for targeted secondary prevention, before the establishment of addictive tobacco use patterns. Group-specific data characterizing the duration from daily tobacco use to a quit attempt or request for cessation treatment are also scant. Conclusions A comprehensive, integrated, transdisciplinary framework is needed to guide efforts to understand tobacco-related health disparities and to increase the effectiveness of evidence-based interventions delivered in culturally appropriate and economically practicable ways, while optimizing the balance between demand for and access to services. C1 NIDA, Addict Treatment Res Clin, Intramural Res Program, Baltimore, MD 21224 USA. NCI, Bethesda, MD 20892 USA. Univ Kentucky, Lexington, KY 40506 USA. Univ Rhode Isl, Kingston, RI 02881 USA. Univ Texas, Austin, TX 78712 USA. Penn State Univ, State Coll, PA 16804 USA. RP Moolchan, ET (reprint author), NIDA, Addict Treatment Res Clin, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM emoolcha@mail.nih.gov FU Intramural NIH HHS NR 99 TC 57 Z9 57 U1 5 U2 14 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD OCT PY 2007 VL 102 SU 2 BP 30 EP 42 DI 10.1111/j.1360-0443.2007.01953.x PG 13 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 209WL UT WOS:000249418600003 PM 17850612 ER PT J AU Fernander, AF Shavers, VL Hammons, GJ AF Fernander, Anita F. Shavers, Vickie L. Hammons, George J. TI A biopsychosocial approach to examining tobacco-related health disparities among racially classified social groups SO ADDICTION LA English DT Review DE biopsychosocial; health disparities; racially classified social groups; tobacco ID CORONARY-HEART-DISEASE; NATURAL-KILLER-CELLS; TRANS-FATTY-ACIDS; BODY-MASS INDEX; CIGARETTE-SMOKING; LUNG-CANCER; DNA METHYLATION; NICOTINE DEPENDENCE; BREAST-CANCER; CARDIOVASCULAR-DISEASE AB Aims To articulate a broader, multi-causal model that incorporates psychosocial and environmental factors that can differ systematically across racially classified social groups (RCSGs) and impact biological pathways related to the development of tobacco-related diseases. Mehods This paper is built upon a review of the existing scientific literature on selected biopsychosocial factors (diet/nutrition, obesity, alcoholic intake, psychosocial stress, occupational/environmental exposures and exposure to other diseases and illnesses) and tobacco use in examining the biological contributions to differences in tobacco-related health outcomes among RCSGs. Findings Recent work has focused on RCSG genetic variations as a possible explanation for differences in tobacco-related health disparities. It is argued in this paper that, given the genetic heterogeneity 'within' RCSGs, it is unlikely that across RCSG genetic variations are likely to be the major source of differences impacting biological pathways in tobacco-related health outcomes. The evidence shows that results, even at the level of within-population genetic variations, have been limited and often inconsistent. A conceptual framework is proposed to account for biological pathways related to the development of tobacco-related diseases. Conclusions Determinants of tobacco-related health disparities are not understood clearly. The contribution of biological factors may be important. Current efforts to determine biological differences in tobacco use and related diseases among RCSGs have focused primarily on genetic variations. However, this approach has limitations. An alternative biopsychosocial framework that examines the potential biological mechanisms through which life experiences and behavior might affect tobacco use and health outcomes in these population groups is needed, including those of life-style (e.g. diet/nutrition, obesity, physical exercise, alcohol consumption), psychosocial (e.g. stress and coping), occupational/environmental exposures and the presence of other diseases/illnesses. C1 Philander Smith Coll, Dept Chem, Little Rock, AR 72202 USA. Univ Kentucky, Coll Med, Dept Behav Sci, Lexington, KY 40536 USA. NCI, Div Canc Control & Populat Sci, Appl Res Program, Bethesda, MD 20892 USA. RP Hammons, GJ (reprint author), Philander Smith Coll, Dept Chem, 812 W 13th St, Little Rock, AR 72202 USA. EM ghammons@philander.edu NR 212 TC 15 Z9 16 U1 6 U2 9 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD OCT PY 2007 VL 102 SU 2 BP 43 EP 57 DI 10.1111/j.1360-0443.2007.01954.x PG 15 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 209WL UT WOS:000249418600004 PM 17850613 ER PT J AU Li, TK Hewitt, BG Grant, BF AF Li, Ting-Kai Hewitt, Brenda G. Grant, Bridget F. TI The alcohol dependence syndrome, 30 years later: a commentary - The 2006 H. David Archibald lecture SO ADDICTION LA English DT Article DE alcohol abuse; alcohol addiction; alcohol dependence; alcohol use disorders; alcohol use problems; alcoholism ID NATIONAL EPIDEMIOLOGIC SURVEY; SUBSTANCE USE DISORDERS; ITEM RESPONSE THEORY; DSM-IV; DIAGNOSTIC-CRITERIA; UNITED-STATES; INTERNATIONAL-CLASSIFICATION; MENTAL-DISORDERS; DRUG-USE; DRINKING AB Aims Major classification systems for alcohol use disorders (DSM-IV and ICD-10) contain elements of the 1976 Edwards and Gross formulation of the Alcohol Dependence Syndrome (ADS). However, issues remain about the criteria that identify Alcohol Dependence (AD) as distinct from Alcohol Abuse (AA) in DSM-IV and Harmful Use in ICD-10. These issues, in part, have their roots in changing historical perceptions of alcohol use and its problems. We discuss current diagnostic criteria for AA and AD, collectively called Alcohol Use Disorders (AUDs), in the context of their historical evolution; research progress in understanding alcohol problems, including alcohol dependence; new findings on the severity of AUDs as classified by DSM-IV; and the role of alcohol consumption patterns in future classifications of AUDs. Methods This paper is based largely on the 2006 H. David Archibald Lecture. Parts of the original lecture have been modified to reflect more recent findings from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) of the US National Institute on Alcohol Abuse and Alcoholism (NIAAA). Results The original Edwards and Gross ADS construct is supported by advances in biological and behavioral science over the past 30 years. New findings indicate that DSM-IV AA and AD are not diagnostically distinct entities, but represent a continuum of severity of AUDs. The ADS criteria may best represent one quantifiable dimension of alcohol use problems and this scale can be related to that of the frequency of harmful patterns of drinking. Conclusion The Edwards and Gross ADS criteria can be used as the basis for beginning the development of scalable multi-dimensional criteria for diagnosing AUDs in new initiatives to revise DSM-IV and ICD-10. C1 NIAAA, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Hewitt, BG (reprint author), NIAAA, NIH, US Dept Hlth & Human Serv, 5635 Fishers Lane, Bethesda, MD 20892 USA. EM bhewitt@mail.nih.gov NR 52 TC 73 Z9 73 U1 1 U2 3 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0965-2140 J9 ADDICTION JI Addiction PD OCT PY 2007 VL 102 IS 10 BP 1522 EP 1530 DI 10.1111/j.1360-0443.2007.01911.x PG 9 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 209GJ UT WOS:000249376700003 PM 17680851 ER PT J AU Li, TK Hewitt, BG Grant, BF AF Li, Ting-Kai Hewitt, Brenda G. Grant, Bridget F. TI The alcohol dependence syndrome, 30 years later-a response to the commentaries SO ADDICTION LA English DT Editorial Material ID USE DISORDERS; FUTURE C1 NIAAA, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Li, TK (reprint author), NIAAA, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM bhewitt@mail.nih.gov NR 12 TC 2 Z9 2 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0965-2140 J9 ADDICTION JI Addiction PD OCT PY 2007 VL 102 IS 10 BP 1537 EP 1538 DI 10.1111/j.1360-0443.2007.02005.x PG 3 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 209GJ UT WOS:000249376700009 ER PT J AU Lee, DC Myers, CS Taylor, RC Moolchan, ET Berlin, I Heishman, SJ AF Lee, Dustin C. Myers, Carol S. Taylor, Richard C. Moolchan, Eric T. Berlin, Ivan Heishman, Stephen J. TI Consistency of subjective responses to imagery-induced tobacco craving over multiple sessions SO ADDICTIVE BEHAVIORS LA English DT Article DE craving; tobacco; smoking; imagery; reliability; humans ID MENSTRUAL-CYCLE PHASE; CUE-REACTIVITY; SMOKING CESSATION; NEGATIVE AFFECT; QUESTIONNAIRE; RELIABILITY; NICOTINE; RELAPSE; IMPACT; ABSTINENCE AB Although studies have demonstrated the validity of imagery procedures to elicit tobacco craving responses in single sessions, few studies have examined the consistency of responding in the same individuals over multiple experimental sessions. In this study, nondeprived smokers were presented with a randomized series of imagery scripts that varied in the intensity of smoking-urge content. At each of five sessions spaced over several weeks, participants were exposed to six imagery trials (two each of no-, low-, and high-intensity imagery scripts). After each trial, participants completed subjective measures of tobacco craving and mood. Ratings of craving and negative mood significantly increased as a function of smoking-urge intensity, which was consistent across the five sessions. Further, significant intraclass correlations indicated that craving and mood responses were highly reliable over the five sessions, as well as across two, three, and four sessions. These results have practical implications for examining individual differences in sensitivity to smoking cues and for studies involving repeated measurement of elicited craving over time. Published by Elsevier Ltd. C1 Natl Inst Drug Abuse, Intramural Res Program, NIH, Clin Pharmacol & Therapeut Branch, Baltimore, MD 21224 USA. Grp Hosp Univ Pitie Salpetriere, Serv Pharmacol, F-75013 Paris, France. RP Heishman, SJ (reprint author), Natl Inst Drug Abuse, Intramural Res Program, NIH, Clin Pharmacol & Therapeut Branch, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM heishman@nih.gov OI Lee, Dustin/0000-0002-4818-9733 FU Intramural NIH HHS [Z01 DA000483-03] NR 28 TC 10 Z9 10 U1 2 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4603 J9 ADDICT BEHAV JI Addict. Behav. PD OCT PY 2007 VL 32 IS 10 BP 2130 EP 2139 DI 10.1016/j.addbeh.2007.01.029 PG 10 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 207VK UT WOS:000249279000012 PM 17335983 ER PT J AU Margolis, DM Mukherjee, AL Fletcher, CV Hogg, E Ogata-Arakaki, D Petersen, T Rusin, D Martinez, A Mellors, JW AF Margolis, David M. Mukherjee, A. Lisa Fletcher, Courtney V. Hogg, Evelyn Ogata-Arakaki, Debra Petersen, Tianna Rusin, David Martinez, Ana Mellors, John W. CA ACTG 5165 Team TI The use of beta-D-2,6-diaminopurine dioxolane with or without mycophenolate mofetil in drug-resistant HIV infection SO AIDS LA English DT Article ID INOSINE MONOPHOSPHATE DEHYDROGENASE; REVERSE-TRANSCRIPTASE; IN-VITRO; ANTIRETROVIRAL DRUGS; THERAPY; INHIBITOR; GUANOSINE; ABACAVIR; ACID; TRIPHOSPHATE AB Objective: We evaluated the safety, tolerability and antiretroviral activity of beta-D-2,6-diaminopurine dioxolane (DAPD; amdoxovir) with or without mycophenolate mofetil (MMF) in HIV-1 infection following extensive antiretroviral therapy (ART). Methods: Oral DAPD 500 mg twice daily with placebo or MMF 500 mg twice daily was added to failing ART. HIV-1 RNA viral load (VL) decline to week 2 was analyzed by intent-to-treat, using rank-based tests. Patients with VL decline> 0.5 log(10) copies/ml at week 2 (virologic response, VR) optimized ART and continued therapy for up to 96 weeks. Results: Forty adults with median VL 4.5 log(10) copies/ml, median 184 CD4+ cells/mu l, and a median of 6 nucleoside reverse transcriptase inhibitor (NRTI) mutations (range, 1-8) were randomized. Median VL reduction at week 2 was -0.26 log(10) copies/ml (P < 0.0001). Response to DAPD/placebo (median -0.37 log(10) copies/ml) was unexpectedly greater than to DAPD/MMF (median -0.23 log(10) copies/ml), although this difference was not statistically significant (P= 0.59). MMF appeared to lower concentrations of DAPD and its metabolite dioxolane guanosine. Of 10 patients with VR (DAPD 7, DAPD/MMF 3), four persisted beyond week 24. VR was more frequent with < 5 baseline NRTI mutations (P= 0.12) or < 4 thymidine-associated mutations (TAMs) without E44D or V1 181 (P = 0.08). Twenty-three patients received extended DAPD +/- MMF; five beyond week 24. Few adverse events were related to study medications. Conclusions: The addition of DAPD +/- MMF to failing therapy appears safe and well tolerated. DAPD had significant activity at week 2 (mean -0.35 log(10)) in heavily pretreated patients that was not augmented by MMF. C1 Univ N Carolina, Chapel Hill, NC 27599 USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO 80202 USA. Social & Sci Syst, Silver Spring, MD USA. Univ Hawaii Manoa, Honolulu, HI 96822 USA. SW Texas State Univ, Dallas, TX USA. Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. NIAID, NIH, Bethesda, MD USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. RP Margolis, DM (reprint author), Univ N Carolina, 3302 Michael Hooker Res Ctr,CB7435, Chapel Hill, NC 27599 USA. EM dmargo@med.unc.edu OI Margolis, David/0000-0001-5714-0002 FU NCRR NIH HHS [RR 00051]; NIAID NIH HHS [5P30 AI 50409, AI 027666, AI 032783, AI 045008, AI 046376, AI 25879, AI 25903, AI 27661, AI 27664, AI 32770, AI 34853, AI 38855, AI 38858] NR 21 TC 12 Z9 14 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD OCT 1 PY 2007 VL 21 IS 15 BP 2025 EP 2032 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 217OL UT WOS:000249957100004 PM 17885292 ER PT J AU Hicks, PL Mulvey, KP Chander, G Fleishman, JA Josephs, JS Korthuis, PT Hellinger, J Gaist, P Gebo, KA AF Hicks, P. L. Mulvey, K. P. Chander, G. Fleishman, J. A. Josephs, J. S. Korthuis, P. T. Hellinger, J. Gaist, P. Gebo, K. A. CA Hiv Research Network TI The impact of illicit drug use and substance abuse treatment on adherence to HAART SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; SELF-REPORTED ADHERENCE; CLINICAL-TRIALS; HIV-INFECTION; UNITED-STATES; OUTCOMES; MEDICATIONS; DRINKING; ALCOHOL; PEOPLE AB High levels of adherence to highly active antiretroviral therapy (HAART) are essential for virologic suppression and longer survival in patients with HIV. We examined the effects of substance abuse treatment, current versus former substance use, and hazardous/binge drinking on adherence to HAART. During 2003, 659 HIV patients on HAART in primary care were interviewed. Adherence was defined as >= 95% adherence to all antiretroviral medications. Current substance users used illicit drugs and/or hazardous/binge drinking within the past six months, while former users had not used substances for at least six months. Logistic regression analyses of adherence to HAART included demographic, clinical and substance abuse variables. Sixty-seven percent of the sample reported 95% adherence or greater. However, current users (60%) were significantly less likely to be adherent than former (68%) or never users (77%). In multivariate analysis, former users in substance abuse treatment were as adherent to HAART as never users (Adjusted Odds Ratio (AOR) = 0.82; p > 0.5). In contrast, former users who had not received recent substance abuse treatment were significantly less adherent than never users (AOR = 0.61; p = 0.05). Current substance users were significantly less adherent than never users, regardless of substance abuse treatment (p < 0.01). Substance abuse treatment interacts with current versus former drug use status to affect adherence to HAART. Substance abuse treatment may improve HAART adherence for former substance users. C1 [Hicks, P. L.; Chander, G.; Josephs, J. S.; Gebo, K. A.] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21287 USA. [Mulvey, K. P.] Substance Abuse & Mental Hlth Serv Adm, Ctr Substances Abuse Prevent, Rockville, MD USA. [Fleishman, J. A.] Agcy Healthcare Res & Qual, Rockville, MD USA. [Korthuis, P. T.] Oregon Hlth & Sci Univ, Dept Med, Portland, OR 97201 USA. [Hellinger, J.] Commun Med Alliance, Boston, MA USA. [Gaist, P.] Natl Inst Hlth, Off AIDS Res, Bethesda, MD USA. RP Gebo, KA (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, 1830 E Monument St,Room 442, Baltimore, MD 21287 USA. EM kgebo@jhmi.edu RI Gebo, Kelly/B-9223-2009 FU NIAAA NIH HHS [K23 AA015313, K23 AA015313-04]; NIDA NIH HHS [K23-DA00523, K23 DA000523]; PHS HHS [290-01-0012] NR 23 TC 42 Z9 43 U1 1 U2 2 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PD OCT PY 2007 VL 19 IS 9 BP 1134 EP 1140 DI 10.1080/09540120701351888 PG 7 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA 251TN UT WOS:000252398200009 PM 18058397 ER PT J AU Flynn, PM Rudy, BJ Lindsey, JC Douglas, SD Lathey, J Spector, SA Martinez, J Silio, M Belzer, M Friedman, L D'Angelo, L Smith, E Hodge, J Hughes, MD AF Flynn, Patricia M. Rudy, Bret J. Lindsey, Jane C. Douglas, Steven D. Lathey, Janet Spector, Stephen A. Martinez, Jaime Silio, Margarita Belzer, Marvin Friedman, Lawrence D'Angelo, Lawrence Smith, Elizabeth Hodge, Janice Hughes, Michael D. CA PACTG 381 Study Team TI Long-term observation of adolescents initiating HAART therapy: Three-year follow-up SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; IMMUNODEFICIENCY-VIRUS TYPE-1; REVERSE-TRANSCRIPTASE INHIBITORS; IMMUNOLOGICAL OUTCOMES; PROTEASE INHIBITOR; HIV-1 INFECTION; T-LYMPHOCYTES; NELFINAVIR; LAMIVUDINE; EFAVIRENZ AB The PACTG 381 cohort included 120 adolescents infected via high-risk behaviors and treated with at least two NRTIs plus either a protease inhibitor or an efavirenz-containing HAART regimen. After 24 weeks of therapy, only 69 of 118 (59%) evaluable subjects had undetectable viral loads. We now present findings of the study after 3 years of follow-up. Virologic, immunologic, and treatment information were collected from subjects every 12 weeks beyond the first 24 weeks of therapy through 156 weeks. Of the 120 subjects starting HAART, 44 (37%) stayed on study treatment for the 3 years of observation. Twenty-nine (24%) subjects reached and maintained undetectable viral loads. Poorer adherence (p = 0.016), higher baseline viral load (p = 0.010), and CD8 naive counts (p = 0.034) predicted virologic failure. Immunologic measurements improved from entry to the end of follow-up in the subjects with undetectable viral loads. CD4 counts at the end of study were not significantly different from HIV-uninfected youth, but CD4%, CD8 counts and percent, and CD8 activation markers remained significantly different. Adolescents infected with HIV via highrisk behaviors have less than optimal responses to HAART therapy with only 24% achieving and maintaining undetectable viral loads over 3 years. Immunologic improvement was demonstrated and CD4 counts in subjects with virologic control reached levels in HIV-uninfected adolescents. Interventions, especially those focused on adherence, are necessary to improve HAART outcomes in adolescents. C1 St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38105 USA. Univ Tennessee, Hlth Sci Ctr, Dept Pediat, Memphis, TN 38105 USA. Univ Tennessee, Hlth Sci Ctr, Dept Prevent Med, Memphis, TN 38105 USA. Univ Penn, Sch Med, Dept Pediat, Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Harvard Univ, Sch Med, Dept Biostat, Boston, MA 02115 USA. SeraCare Bioserv, Gaithersburg, MD 20877 USA. Univ Calif San Diego, Dept Pediat, La Jolla, CA 92037 USA. CORE Ctr, Stroger Hosp Cook Cty, Dept Pediat, Chicago, IL 60612 USA. Tulane Univ, Sch Med, Dept Pediat, New Orleans, LA 70112 USA. Univ So Calif, Dept Pediat, Los Angeles, CA 90033 USA. Univ Miami, Sch Med, Dept Pediat, Miami, FL 33136 USA. Childrens Hosp, Natl Med Ctr, Washington, DC 20010 USA. NIAID, Rockville, MD 20857 USA. Frontier Sci & Technol Res Fdn Inc, Amherst, NY 14226 USA. RP Flynn, PM (reprint author), St Jude Childrens Res Hosp, Dept Infect Dis, 332 N Lauderdale, Memphis, TN 38105 USA. EM pat.flynn@stjude.org NR 18 TC 37 Z9 38 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD OCT PY 2007 VL 23 IS 10 BP 1208 EP 1214 DI 10.1089/aid.2006.0290 PG 7 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 228HO UT WOS:000250720900008 PM 17961106 ER PT J AU Huebner, RB Tonigan, JS AF Huebner, Robert B. Tonigan, Jeffery Scott TI The search for mechanisms of behavior change in evidence-based behavioral treatments for alcohol use disorders: Overview SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article ID THERAPY; MEDIATORS AB Background: Over the past three decades, the main question of interest to alcohol treatment researchers has concerned the main effects of a particular behavioral intervention or what works. Increasingly, alcohol treatment researchers are turning their attention to the underlying psychological, social, and even neurophysiologic processes or "active ingredients" that are driving therapeutic change. Method: The articles contained in this supplement to Alcoholism: Clinical and Experimental Research grew out of invited presentations given at a one-day satellite session immediately preceding the 28th Annual Meeting of the Research Society on Alcoholism (RSA). The conference was a collaborative effort of the Center on Alcoholism, Substance Abuse, and Addiction at the University of New Mexico, the Center on Addiction and Substance Abuse at Columbia University, Brown University, and the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health. Results: The conference featured a mix of full-length presentations on conceptual and methodological issues, reports of original research findings, and lively discussion among speakers and conference participants. Understanding mechanisms of behavior change will benefit the field by identifying the key aspects of therapy that must be present for maximum effect, irrespective of the specific technique being applied; provide a new way to approach patient-treatment interactions; and lay the groundwork for understanding how change is affected by social and other extratreatment factors. Conclusion: Although not a new topic to the field, understanding mechanisms of behavior change has begun to capture the interest of an increasing number of alcohol treatment researchers. Understanding behavior change is an exceedingly complex enterprise and innovative thinking and creative research designs will be required to advance the field. C1 NIAAA, Div Treatment & Recovery Res, NIH, Bethesda, MD 20892 USA. Univ New Mexico, Albuquerque, NM 87131 USA. RP Huebner, RB (reprint author), NIAAA, Div Treatment & Recovery Res, NIH, 5635 Fishery Lane,MSC 9304,Room 2049, Bethesda, MD 20892 USA. EM bhuebner@niaaa.nih.gov RI Reis, Aline/G-9573-2012 NR 16 TC 14 Z9 14 U1 4 U2 7 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD OCT PY 2007 VL 31 IS 10 SU S BP 1S EP 3S DI 10.1111/j.1530-0277.2007.00487.x PG 3 WC Substance Abuse SC Substance Abuse GA 212LT UT WOS:000249598600001 PM 17880340 ER PT J AU Willenbring, ML AF Willenbring, Mark L. TI A broader view of change in drinking behavior SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE alcoholism; treatment; addiction; behavior change; mechanisms of change ID ALCOHOL TREATMENT TRIAL; THERAPEUTIC ALLIANCE; UNITED-STATES; DEPENDENCE; RECOVERY; ABUSE; REMISSION; OUTCOMES AB Most research concerning change in drinking behavior has taken place within the context of specialized treatment for a help-seeking population. However, treatment approaches with different purported mechanisms of action yield very similar results, suggesting that common elements, rather than specific mechanisms, may be responsible for the bulk of the individual change process. Mechanisms of change have not been explicitly examined. Other factors such as social pressure may be more important mediators of change, which may occur prior to treatment entry. Also, most change occurs outside the context of specific treatment. A broader perspective focusing on mechanisms of change will need to account for change occurring both with and without professional treatment. Future research must be interdisciplinary in nature, seeking to relate social, behavioral, and neurophysiologic correlates of behavior change. C1 NIAAA, NIH, Bethesda, MD 20892 USA. RP Willenbring, ML (reprint author), NIAAA, NIH, 5635 Fishers Lane Room 2047, Bethesda, MD 20892 USA. EM mlw@niaaa.nih.gov NR 21 TC 13 Z9 13 U1 3 U2 11 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD OCT PY 2007 VL 31 IS 10 SU S BP 84S EP 86S DI 10.1111/j.1530-0277.2007.00501.x PG 3 WC Substance Abuse SC Substance Abuse GA 212LT UT WOS:000249598600015 PM 17880354 ER PT J AU Lacro, RV Dietz, HC Wruck, LM Bradley, TJ Colan, SD Devereux, RB Klein, GL Li, JS Minich, LL Paridon, SM Pearson, GD Printz, BF Pyeritz, RE Radojewski, E Roman, MJ Saul, JP Stylianou, MP Mahony, L AF Lacro, Ronald V. Dietz, Harry C. Wruck, Lisa M. Bradley, Timothy J. Colan, Steven D. Devereux, Richard B. Klein, Gloria L. Li, Jennifer S. Minich, L. LuAnn Paridon, Stephen M. Pearson, Gail D. Printz, Beth F. Pyeritz, Reed E. Radojewski, Elizabeth Roman, Mary J. Saul, J. Philip Stylianou, Mario P. Mahony, Lynn CA Pediat Heart Network Investigators TI Rationale and design of a randomized clinical trial of beta-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome SO AMERICAN HEART JOURNAL LA English DT Article ID GROWTH-FACTOR-BETA; THORACIC AORTIC-ANEURYSMS; MOUSE MODEL; FIBRILLIN; DILATION; ROOT; SIZE; MICROFIBRILS; PATHOGENESIS; DILATATION AB Background Cardiovascular disease, including aortic root dilation, dissection, and rupture, is the leading cause of mortality in patients with Marfan syndrome (MFS). The maximal aortic root diameter at the sinuses of Valsalva is considered the best predictor of adverse cardiovascular outcome. Although advances in therapy have improved life expectancy, affected individuals continue to suffer cardiovascular morbidity and mortality. Recent studies in an FBN 1-targeted mouse model of MFS with aortic disease similar to that seen in humans showed that treatment with losartan normalized aortic root growth and aortic wall architecture. Methods The Pediatric Heart Network designed a randomized clinical trial to compare aortic root growth and other short-term cardiovascular outcomes in subjects with MFS receiving atenolol or losartan. Individuals 6 months to 25 years of age with a body surface area-adjusted aortic root z score >3.0 will be eligible for inclusion. The primary aim is to compare the effect of atenolol therapy with that of losartan therapy on the rate of aortic root growth over 3 years. Secondary end points include progression of aortic regurgitation; incidence of aortic dissection, aortic root surgery, and death; progression of mitral regurgitation; left ventricular size and function; echocardiographically derived measures of central aortic stiffness; skeletal and somatic growth; and incidence of adverse drug reactions. Conclusion This randomized trial should make a substantial contribution to the management of individuals with MFS and expand our understanding of the mechanisms responsible for the aortic manifestations of this disorder. C1 Childrens Hosp, Dept Cardiol, Boston, MA 02115 USA. Harvard Univ, Sch Med, Childrens Hosp, Boston, MA USA. Johns Hopkins Univ, Baltimore, MD USA. New England Res Inst, Watertown, MA USA. Hosp Sick Children, Toronto, ON M5G 1X8, Canada. Cornell Univ, Weill Med Coll, New York, NY USA. Duke Univ, Med Ctr, Durham, NC USA. Primary Childrens Med Ctr, Salt Lake City, UT 84103 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. NHLBI, Bethesda, MD 20892 USA. Columbia Univ, Med Ctr, New York, NY USA. Univ Penn, Philadelphia, PA 19104 USA. Med Univ S Carolina, Charleston, SC 29425 USA. Univ Texas, SW Med Ctr, Dallas, TX 75230 USA. RP Lacro, RV (reprint author), Childrens Hosp, Dept Cardiol, 300 Longwood Ave, Boston, MA 02115 USA. EM ron.lacro@cardio.chboston.org FU NHLBI NIH HHS [U01 HL068292, U01 HL068269, U01 HL068269-01, U01 HL068270, U01 HL068270-01, U01 HL068279, U01 HL068279-01, U01 HL068281, U01 HL068281-01, U01 HL068285, U01 HL068285-01, U01 HL068288, U01 HL068288-01, U01 HL068290, U01 HL068290-01, U01 HL068292-01] NR 35 TC 131 Z9 133 U1 3 U2 11 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD OCT PY 2007 VL 154 IS 4 BP 624 EP 631 DI 10.1016/j.ahj.2007.06.024 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 217KR UT WOS:000249947300007 PM 17892982 ER PT J AU de Jonge, L Redman, LM Nguyen, T Ravussin, E Delany, JP Hadley, EC AF de Jonge, Lilian Redman, Leanne M. Nguyen, Tuong Ravussin, Eric Delany, James P. Hadley, Evan C. TI Validation of energy intake during calorie restriction with the doubly labeled water method and changes in body composition - L Bowman and AB Loucks SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Letter C1 Pennington Biomed Res Ctr, Baton Rouge, LA 70808 USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA 15213 USA. NIA, Bethesda, MD 20892 USA. RP de Jonge, L (reprint author), Pennington Biomed Res Ctr, 6400 Perkins Rd, Baton Rouge, LA 70808 USA. EM dejongeh@pbrc.edu NR 1 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD OCT PY 2007 VL 86 IS 4 BP 1252 EP 1253 PG 2 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 220CN UT WOS:000250134600055 ER PT J AU Wise, LA Titus-Ernstoff, L Palmer, JR Hoover, RN Hatch, EE Perez, KM Strohsnitter, WC Kaufman, R Anderson, D Trosi, R AF Wise, Lauren A. Titus-Ernstoff, Linda Palmer, Julie R. Hoover, Robert N. Hatch, Elizabeth E. Perez, Kimberly M. Strohsnitter, William C. Kaufman, Raymond Anderson, Diane Trosi, Rebecca TI Time to pregnancy and secondary sex ratio in men exposed prenatally to diethylstilbestrol SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE diethylstilbestrol; estrogens; fertility; males; reproduction; sex ratio ID DELAYED CONCEPTION; FOLLOW-UP; POLYCHLORINATED-BIPHENYLS; REPRODUCTIVE-PERFORMANCE; PATERNAL-AGE; CHILDREN; DIOXIN; BIRTH; INUTERO; MOTHERS AB Little is known about the influence of prenatal diethylstilbestrol (DES) exposure on time to pregnancy or secondary sex ratio in men. The authors evaluated these associations among men participating in the DES Combined Cohort Follow-up Study for whom exposure status was confirmed by medical record. In 2001, men provided data on their reproductive histories. Demographic, behavioral, and medical data were collected in 1994, 1997, and 2001. Cox's proportional hazards models with frailty were used to estimate fecundability ratios for time to pregnancy in relation to DES. Generalized estimating equations were used to estimate odds ratios for fathering a male birth in relation to DES. Models included potential confounders and accounted for multiple pregnancies contributed by each man. Overall, DES was not associated with a delay in time to pregnancy (fecundability ratio = 0.95, 95% confidence interval: 0.86, 1.06). The odds ratio for fathering a male birth was 0.92 (95% confidence interval: 0.80, 1.04) comparing the exposed with the unexposed. In conclusion, prenatal DES exposure was not associated with a significant decrease in either fecundability or secondary sex ratio. C1 Boston Univ, Sch Publ Hlth, Slone Epidemiol Ctr, Boston, MA 02215 USA. Boston Univ, Slone Epidemiol Ctr, Boston, MA 02215 USA. Dartmouth Coll Sch Med, Dept Commun, Family Med & Pediat, Lebanon, NH USA. Dartmouth Hitchcock Med Ctr, Hood Ctr Children & Families, Lebanon, NH 03766 USA. Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. Boston Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA USA. Boston Univ, Sch Publ Hlth, Dept Int Hlth, Boston, MA USA. Tufts Univ New England Med Ctr, Dept Obstet & Gynecol, Boston, MA USA. Baylor Coll Med, Dept Obstet & Gynecol, Houston, TX 77030 USA. Univ Chicago, Dept Obstet & Gynecol, Chicago, IL 60637 USA. RP Wise, LA (reprint author), Boston Univ, Sch Publ Hlth, Slone Epidemiol Ctr, 1010 Commonwealth Ave, Boston, MA 02215 USA. EM lwise@bu.edu OI Palmer, Julie/0000-0002-6534-335X; Hatch, Elizabeth/0000-0001-7901-3928; Wise, Lauren/0000-0003-2138-3752 FU NCI NIH HHS [N01-CP-01290, N01-CP-11289, N01-CP-21168, N01-CP-51017] NR 73 TC 6 Z9 6 U1 1 U2 5 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 OCT 1 PY 2007 VL 166 IS 7 BP 765 EP 774 DI 10.1093/aje/kwm136 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 212PW UT WOS:000249610300004 PM 17596265 ER PT J AU Chen, HL Richard, M Sandier, DP Umbach, DM Kamel, F AF Chen, Honglei Richard, Marie Sandier, Dale P. Umbach, David M. Kamel, Freya TI Head injury and amyotrophic lateral sclerosis SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE amyotrophic lateral sclerosis; craniocerebral trauma; head injuries; closed; head injuries; penetrating ID MOTOR-NEURON-DISEASE; RISK-FACTORS; CIGARETTE-SMOKING; BRAIN-INJURY; TRAUMA; ASSOCIATION; PLAYERS; HISTORY; SOCCER; ALS AB Recent data showed that soccer players in Italy had an unusually high risk of amyotrophic lateral sclerosis (ALS) and that repeated head trauma might have contributed to this increase. The authors examined whether head injury was related to ALS risk in a case-control study of 109 New England ALS cases diagnosed in 1993-1996 and 255 matched controls. They also conducted a meta-analysis of the published literature. Overall, ever having experienced a head injury was nonsignificantly associated with a higher ALS risk. When compared with persons without a head injury, a statistically significant ALS risk elevation was found for participants with more than one head injury (odds ratio (OR) = 3.1, 95 percent confidence interval (Cl): 1.2, 8.1) and patients who had had a head injury during the past 10 years (OR = 3.2, 95 percent Cl: 1.0, 10.2). For participants who had had multiple head injuries with the latest occurring in the past 10 years, risk was elevated more than 11-fold. The meta-analysis also indicated a moderately elevated risk of ALS among persons with previous head injuries (OR = 1.7, 95 percent Cl: 1.3, 2.2). In this study population, physical injuries to other body parts, including the trunk, arms, or legs, were not related to ALS risk. These data support the notion that head injury may increase the risk of ALS. C1 Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Nat Inst Environm Hlth Sci, Natl Inst Hlth, Epidemiol Branch, Res Triangle Pk, NC USA. Westat Corp, Durham, NC USA. Nat Inst Environm Hlth Sci, Natl Inst Hlth, Biostat Branch, Res Triangle Pk, NC USA. RP Chen, HL (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, 111 TW Alexander Dr,PO Box 12233, Res Triangle Pk, NC 27709 USA. EM chenh2@niehs.nih.gov OI Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018; Chen, Honglei/0000-0003-3446-7779 FU Intramural NIH HHS [Z01 ES049005-16] NR 29 TC 96 Z9 97 U1 2 U2 8 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 OCT 1 PY 2007 VL 166 IS 7 BP 810 EP 816 DI 10.1093/aje/kwm153 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 212PW UT WOS:000249610300009 PM 17641152 ER PT J AU Schuz, J Svendsen, AL Linet, MS McBride, ML Roman, E Feychting, M Kheifets, L Lightfoot, T Mezei, G Simpson, J Ahlbom, A AF Schuz, Joachim Svendsen, Anne Louise Linet, Martha S. McBride, Mary L. Roman, Eve Feychting, Maria Kheifets, Leeka Lightfoot, Tracy Mezei, Gabor Simpson, Jill Ahlbom, Anders TI Re - "Nighttime exposure to electromagnetic fields and childhood leukemia: An extended pooled analysis" - Reply SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter ID MAGNETIC-FIELDS C1 Inst Canc Epidemiol & Genet, Danish Canc Soc, DK-2100 Copenhagen, Denmark. Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD 20890 USA. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Dept Hlth Sci, Epidemiol & Genet Unit, York YO10 5DD, N Yorkshire, England. Karolinska Inst, Inst Environm Med, S-10401 Stockholm, Sweden. Univ Calif Los Angeles, Sch Publ Hlth, Dept Epidemiol, Los Angeles, CA 90095 USA. Elect Power Res Inst, Palo Alto, CA 94304 USA. RP Schuz, J (reprint author), Inst Canc Epidemiol & Genet, Danish Canc Soc, DK-2100 Copenhagen, Denmark. EM joachim@cancer.dk NR 7 TC 0 Z9 0 U1 1 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 1 PY 2007 VL 166 IS 7 BP 859 EP 860 DI 10.1093/aje/kwm227 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 212PW UT WOS:000249610300016 ER PT J AU Freedman, DM Tarone, RE AF Freedman, D. Michal Tarone, Robert E. TI Re: "From menarche to menopause: Trends among us women born from 1912 to 1969" SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Letter C1 NIH, Natl Canc Inst, US Dept HHS, Bethesda, MD 20892 USA. Int Epidemiol Inst, Rockville, MD 20850 USA. Vanderbilt Univ, Med Ctr, Dept Med Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. RP Freedman, DM (reprint author), NIH, Natl Canc Inst, US Dept HHS, Bethesda, MD 20892 USA. EM bob@iei.ws NR 2 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD OCT 1 PY 2007 VL 166 IS 7 BP 860 EP 861 DI 10.1093/aje/kwm228 PG 2 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 212PW UT WOS:000249610300017 PM 17698972 ER PT J AU Ashktorab, H Daremipouran, M Wilson, M Siddiqi, S Lee, EL Rakhshani, N Malekzadeh, R Johnson, AC Hewitt, SM Smoot, DT AF Ashktorab, Hassan Daremipouran, Mohammad Wilson, Melissa Siddiqi, Serwat Lee, Edward L. Rakhshani, Nasser Malekzadeh, Reza Johnson, Alfred C. Hewitt, Stephen M. Smoot, Duane T. TI Transactivation of the EGFR by AP-1 is induced by Helicobacter pylori in gastric cancer SO AMERICAN JOURNAL OF GASTROENTEROLOGY LA English DT Article ID EPIDERMAL-GROWTH-FACTOR; FACTOR-KAPPA-B; FACTOR RECEPTOR; EPITHELIAL-CELLS; CYCLOOXYGENASE-2 EXPRESSION; SIGNAL-TRANSDUCTION; KINASE-ACTIVITY; FACTOR-I; INFECTION; ACTIVATION AB BACKGROUND: Helicobacter pylori infection of the gastric mucosa is strongly associated with gastritis, peptic ulcer disease, and gastric cancer. However, the mechanisms by which H. pylori causes cancer are currently unknown. Binding of epidermal growth factor (EGF) to its receptor (EGFR) may be important in the development of gastric cancer. This interaction accelerates cell proliferation and migration, and triggers epithelial cell signaling. In this study, we investigated the effects of H. pylori on EGFR- and AP-1-mediated signal transduction pathways in the AGS gastric epithelial cell line and gastric tissue from humans. METHODS: Cells were treated with H. pylori and cell death was examined at a variety of time points using cell viability and trypan blue exclusion dye assay. To investigate the effects on EGFR regulation, AGS cells were transfected with a full-length and truncated EGFR luciferase (luc) reporter. Tissue microarray containing 44 samples of gastric biopsies from H. pylori-positive patients was analyzed for protein expression level of EGFR by immunohistochemistry. RESULTS: EGFR promoter activity was increased (twofold) 3 h after treatment with H. pylori commenced. Using a series of EGFR promoter deletion mutants, we identified a region that was crucial for transactivation of the EGFR by H. pylori. To determine whether AP-1 binding was altered, we transfected AGS cells with an AP-1 luciferase construct and then treated them with H. pylori for up to 6 h. We found that AP-1 activity was induced by H. pylori in gastric cells, while electrophoretic mobility shift assays confirmed that binding of AP-1 to the EGFR promoter site was increased following H. pylori treatment. Binding of c-Jun and c-Fos to the EGFR promoter region -1,062/-900 was induced eight- and six fold, respectively, using ChIP assay. Active EGFR staining was markedly increased in gastric mucosa from infected persons, compared to uninfected controls. CONCLUSIONS: We conclude that exposure of gastric cells to H. pylori induces increased production of EGFR through various signal transduction pathways, including those mediated by the EGFR and AP-1. Distinct effects on EGFR activation may specify the subset of AP-1 target genes that are selected, including those involved in proliferation and apoptosis. This is consistent with EGFR activation that was found in the gastric mucosa of humans infected with H. pylori. Hence, the balance between apoptosis and proliferation in these cells may be altered in response to injury caused by H. pylori infection, leading to an increased risk of cancer. C1 Howard Univ, Coll Med, Ctr Canc, Dept Pathol, Washington, DC 20060 USA. Howard Univ, Coll Med, Dept Med, Washington, DC 20060 USA. NCI, Tissue Array Res Program, Pathol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Tehran Med Sci, Shariati Hosp, Digest Dis Res Ctr, Tehran, Iran. RP Ashktorab, H (reprint author), Howard Univ, Coll Med, Ctr Canc, Dept Pathol, 2041 Georgia Ave,NW, Washington, DC 20060 USA. OI Hewitt, Stephen/0000-0001-8283-1788; Malekzadeh, Reza/0000-0003-1043-3814; Wilson, Melissa/0000-0002-5391-7838 FU Intramural NIH HHS; NIDDK NIH HHS [DK53713, DK56664, R01 DK053713] NR 46 TC 23 Z9 25 U1 1 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0002-9270 J9 AM J GASTROENTEROL JI Am. J. Gastroenterol. PD OCT PY 2007 VL 102 IS 10 BP 2135 EP 2146 DI 10.1111/j.1572-0241.2007.01400.x PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 215QN UT WOS:000249824200005 PM 17617207 ER PT J AU McLaren, CE Barton, JC Gordeuk, VR Wu, L Adams, PC Reboussin, DM Speechley, M Chang, H Acton, RT Harris, EL Ruggiero, AM Castro, O AF McLaren, Christine E. Barton, James C. Gordeuk, Victor R. Wu, Lu Adams, Paul C. Reboussin, David M. Speechley, Mark Chang, Henry Acton, Ronald T. Harris, Emily L. Ruggiero, Andrea M. Castro, Oswaldo CA Hemochromatosis Iron Overload Scre TI Determinants and characteristics of mean corpuscular volume and hemoglobin concentration in white HFE C282Y homozygotes in the Hemochromatosis and Iron Overload Screening Study SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID SERUM FERRITIN; AFRICAN-AMERICANS; STORAGE DISEASE; DEFICIENCY; PHLEBOTOMY; STORES; HEIRS; MACROCYTOSIS; ANCESTRY; MUTATION AB Elevated mean corpuscular volume (MCV) is common in persons with hemochromatosis associated with HFE C282Y homozygosity. We evaluated data from the subset of non-Hispanic white participants in the Hemochromatosis and Iron Overload Screening Study to determine if elevated MCV in C282Y homozygotes is related to this genotype or to serum iron measures. Regression analysis was used to model MCV and Hb from transferrin saturation (TfSat), serum ferritin (SF), mean corpuscular hemoglobin concentration, red blood cell count, age, HFE genotype, Field Center, and presence of liver-related abnormalities in C282Y homozygotes and control subjects without HFE mutations (wt/wt genotype). Mean MCV was higher in C282Y homozygotes than in HFE wt/wt controls (94.4 vs. 89.7 fL in women; 95.3 vs. 91.2 fL in men; P < 0.0001 for both). These differences were largely associated with increased mean TfSat and SF in C282Y homozygotes. Adjusted mean MCV was 92.0 fL (95% confidence interval, 91.1, 92.9) in female C282Y homozygotes and 90.9 fL (90.3, 91.5) in controls. Among women with SF in the reference range 20-200 mu g/L, adjusted mean MCV was 92.9 fL, (91.7, 94.2) in C282Y homozygotes, 1.8 fL higher than in controls (P = 0.013). The adjusted mean MCV of male C282Y homozygotes and controls was similar (P = 0.30). Adjusted mean Hb was 0.2 g/dL higher in women with C282Y/C282Y than in controls. Greater mean MCV in C282Y homozygosity reflects increased mean TfSat and mean SF in men and women; an additional effect of genotype on MCV and Hb was detected in women. C1 Univ Calif Irvine, Dept Epidemiol, Irvine, CA 92697 USA. So Iron Disorders Ctr, Birmingham, W Midlands, England. Howard Univ, Dept Med, Washington, DC 20059 USA. Chao Family Comprehens Canc Ctr, Orange, CA USA. London Hlth Sci Ctr, Dept Med, London, ON, Canada. Wake Forest Univ, Sch Med, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. Univ Western Ontario, Dept Epidemiol & Biostat, London, ON, Canada. NHLBI, Div Blood Dis & Resources, Bethesda, MD 20892 USA. Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. Univ Alabama, Dept Med, Birmingham, AL 35294 USA. Univ Alabama, Dept Epidemiol & Int Hlth, Birmingham, AL 35294 USA. Kaiser Permanente Ctr Hlth Res, Portland, OR USA. RP McLaren, CE (reprint author), Univ Calif Irvine, Dept Epidemiol, 224 Irvine Hall, Irvine, CA 92697 USA. EM cmclaren@uci.edu FU NCRR NIH HHS [M01-RR10284, M01-RR00827, M01-RR00032]; NHLBI NIH HHS [N01-HC-05191, N01-HC-05190, N01-HC-05185, N01-HC-05188, N01-HC-05186, HL03679-05, N01-HC-05189, N01-HC-05192] NR 38 TC 14 Z9 14 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD OCT PY 2007 VL 82 IS 10 BP 898 EP 905 DI 10.1002/ajh.20937 PG 8 WC Hematology SC Hematology GA 215FU UT WOS:000249794500008 PM 17597476 ER PT J AU Ratner, L Grant, C Zimmerman, B Fritz, J Well, G Denes, A Suresh, R Campbell, N Jacobson, S Lairmore, M AF Ratner, Lee Grant, Christian Zimmerman, Bevin Fritz, Joseph Well, Gary Denes, Alex Suresh, Rama Campbell, Nancy Jacobson, Steve Lairmore, Michael TI Effect of treatment of Strongyloides infection on HTLV-1 expression in a patient with adult T-cell leukemia SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article ID MYELOPATHY/TROPICAL SPASTIC PARAPARESIS; LEUKEMIA/LYMPHOMA VIRUS TYPE-1; COMBINATION CHEMOTHERAPY; I INFECTION; STERCORALIS; LYMPHOMA; CARRIERS; LOAD; EXPANSION AB Human T-cell leukemia virus type 1 (HTLV-1) is associated with adult T-cell leukemia-lymphoma (ATLL) in about 5% of infected individuals. Coinfection by Strongyloides stercoralis has been suggested to be a cofactor for development of ATLL. We describe a patient who presented with HTLV-1-associated chronic ATLL and Strongyloides infection. Studies of this patient's viral RNA levels demonstrated stimulation of HTLV-1 replication by Strongyloides, which resolved with anti-helminthic therapy. This case provides support for the hypothesis that Strongyloides is a cofactor for ATLL via T-cell stimulation. C1 Washington Univ, Div Oncol, St Louis, MO 63110 USA. NIH, Viral Immunol Sect, Neuroimmunol Branch, NINDS, Bethesda, MD 20892 USA. Ohio State Univ, Coll Vet Med, Ctr Retrovirus Res, Columbus, OH 43210 USA. Ohio State Univ, Coll Vet Med, Dept Vet Biosci, Columbus, OH 43210 USA. Washington Univ, Div Infect Dis, St Louis, MO 63110 USA. Ohio State Univ, Comprehens Canc Hosp, Columbus, OH 43210 USA. Ohio State Univ, Solove Res Inst, Columbus, OH 43210 USA. RP Ratner, L (reprint author), Washington Univ, Div Oncol, Box 8069,660 S Euclid Ave, St Louis, MO 63110 USA. EM lratner@im.wustl.edu FU NCI NIH HHS [CA105218, CA10073, CA63417, P01 CA100730-05, P01 CA100730-069003, R01 CA063417, R01 CA105218] NR 23 TC 5 Z9 5 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD OCT PY 2007 VL 82 IS 10 BP 929 EP 931 DI 10.1002/ajh.20929 PG 3 WC Hematology SC Hematology GA 215FU UT WOS:000249794500014 PM 17617788 ER PT J AU Rice, G Patrick, T Parmar, R Taylor, CF Aeby, A Aicardi, J Artuch, R Montalto, SA Bacino, CA Barroso, B Baxter, P Benko, WS Bergmann, C Bertini, E Biancheri, R Blair, EM Blau, N Bonthron, DT Briggs, T Brueton, LA Brunner, HG Burke, CJ Carr, IM Carvalho, DR Chandler, KE Christen, HJ Corry, PC Cowan, FM Cox, H D'Arrigo, S Dean, J De Laet, C De Praeter, C Dery, C Ferrie, CD Flintoff, K Frints, SGM Garcia-Cazorla, A Gener, B Goizet, C Goutieres, F Green, AJ Guet, A Hamel, BCJ Hayward, BE Heiberg, A Hennekam, RC Husson, M Jackson, AP Jayatunga, R Jiang, YH Kant, SG Kao, A King, MD Kingston, HM Klepper, J van der Knaap, MS Kornberg, AJ Kotzot, D Kratzer, W Lacombe, D Lagae, L Landrieu, PG Lanzi, G Leitch, A Lim, MJ Livingston, JH Lourenco, CM Lyall, EGH Lynch, SA Lyons, MJ Marom, D McClure, JP McWilliam, R Melancon, SB Mewasingh, LD Moutard, ML Nischal, KK Ostergaard, JR Prendiville, J Rasmussen, M Rogers, RC Roland, D Rosser, EM Rostasy, K Roubertie, A Sanchis, A Schiffmann, R Scholl-Burgi, S Seal, S Shalev, SA Corcoles, CS Sinha, GP Soler, D Spiegel, R Stephenson, JBP Tacke, U Tan, TY Till, M Tolmie, JL Tomlin, P Vagnarelli, F Valente, EM Van Coster, RNA Van der Aa, N Vanderver, A Vles, JSH Voit, T Wassmer, E Weschke, B Whiteford, ML Willemsen, MAA Zankl, A Zuberi, SM Orcesi, S Fazzi, E Lebon, P Crow, YJ AF Rice, Gillian Patrick, Teresa Parmar, Rekha Taylor, Claire F. Aeby, Alec Aicardi, Jean Artuch, Rafael Montalto, Simon Attard Bacino, Carlos A. Barroso, Bruno Baxter, Peter Benko, Willam S. Bergmann, Carsten Bertini, Enrico Biancheri, Roberta Blair, Edward M. Blau, Nenad Bonthron, David T. Briggs, Tracy Brueton, Louise A. Brunner, Han G. Burke, Christopher J. Carr, Ian M. Carvalho, Daniel R. Chandler, Kate E. Christen, Hans-Juergen Corry, Peter C. Cowan, Frances M. Cox, Helen D'Arrigo, Stefano Dean, John De laet, Corinne De Praeter, Claudine Dery, Catherine Ferrie, Colin D. Flintoff, Kim Frints, Suzanna G. M. Garcia-Cazorla, Angels Gener, Blanca Goizet, Cyril Goutieres, Francoise Green, Andrew J. Gueet, Agnes Hamel, Ben C. J. Hayward, Bruce E. Heiberg, Arvid Hennekam, Raoul C. Husson, Marie Jackson, Andrew P. Jayatunga, Rasieka Jiang, Yong-Hui Kant, Sarina G. Kao, Amy King, Mary D. Kingston, Helen M. Klepper, Joerg van der Knaap, Marjo S. Kornberg, Andrew J. Kotzot, Dieter Kratzer, Wilfried Lacombe, Didier Lagae, Lieven Landrieu, Pierre Georges Lanzi, Giovanni Leitch, Andrea Lim, Ming J. Livingston, John H. Lourenco, Charles M. Lyall, E. G. Hermione Lynch, Sally A. Lyons, Michael J. Marom, Daphna McClure, John P. McWilliam, Robert Melancon, Serge B. Mewasingh, Leena D. Moutard, Marie-Laure Nischal, Ken K. Ostergaard, John R. Prendiville, Julie Rasmussen, Magnhild Rogers, R. Curtis Roland, Dominique Rosser, Elisabeth M. Rostasy, Kevin Roubertie, Agathe Sanchis, Amparo Schiffmann, Raphael Scholl-Buergi, Sabine Seal, Sunita Shalev, Stavit A. Corcoles, C. Sierra Sinha, Gyan P. Soler, Doriette Spiegel, Ronen Stephenson, John B. P. Tacke, Uta Tan, Tiong Yang Till, Marianne Tolmie, John L. Tomlin, Pam Vagnarelli, Federica Valente, Enza Maria Van Coster, Rudy N. A. Van der Aa, Nathalie Vanderver, Adeline Vles, Johannes S. H. Voit, Thomas Wassmer, Evangeline Weschke, Bernhard Whiteford, Margo L. Willemsen, Michel A. A. Zankl, Andreas Zuberi, Sameer M. Orcesi, Simona Fazzi, Elisa Lebon, Pierre Crow, Yanick J. TI Clinical and molecular phenotype of Aicardi-Goutieres syndrome SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; INFECTION-LIKE SYNDROME; PROGRESSIVE FAMILIAL ENCEPHALOPATHY; CEREBROSPINAL-FLUID LYMPHOCYTOSIS; INTERFERON-ALPHA; INTRAUTERINE INFECTION; INTRACRANIAL CALCIFICATION; BASAL GANGLIA; 2 BROTHERS; MUTATIONS AB Aicardi-Goutieres syndrome (AGS) is a genetic encephalopathy whose clinical features mimic those of acquired in utero viral infection. AGS exhibits locus heterogeneity, with mutations identified in genes encoding the 3'-> 5' exonuclease TREX1 and the three subunits of the RNASEH2 endonuclease complex. To define the molecular spectrum of AGS, we performed mutation screening in patients, from 127 pedigrees, with a clinical diagnosis of the disease. Biallelic mutations in TREX1, RNASEH2A, RNASEH2B, and RNASEH2C were observed in 31, 3, 47, and 18 families, respectively. In five families, we identified an RNASEH2A or RNASEH2B mutation on one allele only. In one child, the disease occurred because of a de novo heterozygous TREX1 mutation. In 22 families, no mutations were found. Null mutations were common in TREX1, although a specific missense mutation was observed frequently in patients from northern Europe. Almost all mutations in RNASEH2A, RNASEH2B, and RNASEH2C were missense. We identified an RNASEH2C founder mutation in 13 Pakistani families. We also collected clinical data from 123 mutation-positive patients. Two clinical presentations could be delineated: an early-onset neonatal form, highly reminiscent of congenital infection seen particularly with TREX1 mutations, and a later- onset presentation, sometimes occurring after several months of normal development and occasionally associated with remarkably preserved neurological function, most frequently due to RNASEH2B mutations. Mortality was correlated with genotype; 34.3% of patients with TREX1, RNASEH2A, and RNASEH2C mutations versus 8.0% RNASEH2B mutation-positive patients were known to have died (P = .001). Our analysis defines the phenotypic spectrum of AGS and suggests a coherent mutation- screening strategy in this heterogeneous disorder. Additionally, our data indicate that at least one further AGS- causing gene remains to be identified. C1 St James Univ Hosp, Leeds Inst Mol Med, Leeds LS9 7TF, W Yorkshire, England. St James Univ Hosp, Dept Clin Genet, DNA Lab, Leeds LS9 7TF, W Yorkshire, England. Canc Res UK, Mutat Detect Facil, Leeds, W Yorkshire, England. Leeds Gen Infirm, Dept Paediat Neurol, Leeds, W Yorkshire, England. Erasme Univ Hosp, Dept Paediat Neurol, Brussels, Belgium. Childrens Hosp Queen Fabiola, Brussels, Belgium. Hop Trousseau, Serv Neuropediat, F-75571 Paris, France. Hop Trousseau, Dept Paediat Neurol, F-75571 Paris, France. Hop Bicetre, Paediat Neurol Dept, Paris, France. Grp Hosp Pitie Salpetriere, Inst Myol, F-75634 Paris, France. Hop Cochin St Vincent de Paul, Serv Virol, Paris, France. Hosp St Joan Deu Ciberer, Dept Clin Biochem, Barcelona, Spain. Hosp St Joan Deu Ciberer, Dept Barcelona Pediat Neurol, Barcelona, Spain. St Lukes Hosp, Dept Paediat, Guardamangia, Malta. Baylor Coll Med, Dept Human Mol Genet, Houston, TX 77030 USA. Ctr Hosp, Ser Neurol, Pau, France. Sheffield Childrens Hosp, Dept Paediat, Sheffield S10 2TH, S Yorkshire, England. Natl Inst Neurol Disorders & Stroke, Dev & Metab Neurol Branch, Natl Inst Hlth, Bethesda, MD USA. Univ Aachen, Rhein Westfal TH Aachen, Dept Human Genet, D-5100 Aachen, Germany. Bambino Gesu Childrens Res Hosp, Mol Med Unit, Rome, Italy. Mendel Inst Med Genet & Twin Res, IRCCS, Rome, Italy. G Gaslini Inst Children, Muscular & Neurodegeberat Dis Unit, Genoa, Italy. Churchill Hosp, Dept Clin Genet, Oxford OX3 7LJ, England. Univ Childrens Hosp, Div Clin Chem & Biochem, Zurich, Switzerland. Birmingham Womens Hosp, Clin Genet Unit, Birmingham, W Midlands, England. Sandwell & W Birmingham NHS Trust, Dept Paediat, Birmingham, W Midlands, England. Birmingham Childrens Hosp, Dept Neurol, Birmingham, W Midlands, England. Radboud Univ Nijmegen, Dept Human Genet, Nijmegen, Netherlands. Radboud Univ Nijmegen, Dept Pediat Neurol, Nijmegen, Netherlands. Royal Childrens Hosp, Dept Pediat Neurol, Brisbane, Qld, Australia. Royal Childrens Hosp, Genet Hlth Queensland, Brisbane, Qld, Australia. Univ Estadual Sao Paulo, Serv Aconselhamento Genet, Botucatu, SP, Brazil. St Marys Hosp, Acad Unit Med Genet, Manchester M13 0JH, Lancs, England. Kinderkrankenhaus Bult, Hannover, Germany. Bradford Natl Hlth Serv NHS Trust, Dept Paediat, Bradford, W Yorkshire, England. Fdn Ist Neurol C Besta, Dev Neurol Dept, Milan, Italy. Grampian Clin Genet Ctr, Aberdeen, Scotland. State Univ Ghent Hosp, Dept Neonatol, Ghent, Belgium. State Univ Ghent Hosp, Dept Pediat, Ghent, Belgium. Maastricht Univ Hosp, Dept Clin Genet, Maastricht, Netherlands. Maastricht Univ Hosp, Dept Neurol, Maastricht, Netherlands. Great Ormond St Hosp Sick Children, Imperial Coll, Dept Paediat & Imaging Sci, London, England. Great Ormond St Hosp Sick Children, St Marys NHS Trust, London, England. Great Ormond St Hosp Sick Children, Dept Ophthalmol, London, England. Great Ormond St Hosp Sick Children, NE Thames Reg Genet Serv, London, England. Evelina Childrens Hosp, London, England. St Thomas NHS Trust, London, England. Univ Laval, Sch Med, Dept Paediat, Quebec City, PQ, Canada. Hosp Cruces, Clin Genet Unit, Baracaldo, Spain. CHU Pellegrin Enfants, Gen Med Serv, Bordeaux, France. CHU Pellegrin Enfants, Unite Neurol Enfant & Adolescent, Bordeaux, France. Our Ladys Hosp Sick Children, Natl Ctr Med Genet, Dublin, Ireland. Childrens Univ Hosp, Dept Paediat Neurol, Dublin, Ireland. Univ Oslo, Rikshosp, Radiumhosp, Dept Med Genet, N-0027 Oslo, Norway. Univ Oslo, Rikshosp, Radiumhosp, Dept Paediat, N-0027 Oslo, Norway. Vrije Univ Amsterdam, Ctr Med, Dept Child Neurol, Amsterdam, Netherlands. Western Gen Hosp, MRC, Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland. Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands. Oregon Hlth & Sci Univ, Div Pediat Neurol, Portland, OR 97201 USA. Klinikum Aschaffenburg, Aschaffenburg, Germany. Royal Childrens Hosp, Dept Neurol, Parkville, Vic 3052, Australia. Med Univ Innsbruck, Dept Med Genet, Div Clin Genet, Innsbruck, Austria. Childrens Hosp Innsbruck, Dept Pediat, Div Pediat Neurol & Inborn Errors Metab, Innsbruck, Austria. Klin Kinder & Jugendliche, Constance, Germany. Univ Hosp Gasthuisberg, B-3000 Louvain, Belgium. IRCCS Casmiro Mondino Inst Neurol, Dept Child Neurol & Psychiat, Pavia, Italy. Univ Sao Paulo, Dept Neurogenet, Ribeirao Preto, Brazil. Greenwood Genet Ctr, Greenwood, SC 29646 USA. Rabin Med Ctr, Raphael Racanati Genet Inst, Petah Tiqwa, Israel. Crosshouse Hosp, Dept Paediat, Ayr, Scotland. Royal Hosp Sick Children, Fraser Allander Neurosci Unit, Glasgow G3 8SJ, Lanark, Scotland. Royal Hosp Sick Children, Duncan Guthrie Inst Med Genet, Glasgow G3 8SJ, Lanark, Scotland. Montreal Childrens Hosp, Div Med Genet, Montreal, PQ H3H 1P3, Canada. Univ Hosp Leicester NHS Trust, Dept Paediat Neurol, Leicester, Leics, England. Aarhus Univ Hosp, DK-8000 Aarhus, Denmark. British Columbia Childrens Hosp, Div Pediat Dermatol, Vancouver, BC, Canada. Inst Pathol & Genet, Gosselies, Belgium. Gui Chauliac Hosp, Pediat Neurol Dept, Montpellier, France. Hosp Univ Doctor Peset, Serv Pediat, Valencia, Spain. Technion Israel Inst Technol, Rappaport Fac Med, Haifa, Israel. Haemek Med Ctr, Inst Genet, Afula, Israel. Complejo Hosp Jean, Neuropediat Unit, Jean, Spain. Manor Hosp, Dept Paediat, Walsall, W Midlands, England. Univ Hosp, Div Neuropediat, Freiburg, Germany. Royal Childrens Hosp, Genet Hlth Serv Victoria, Brisbane, Qld, Australia. Hop Debrousse, Lyon, France. Lancashire Teaching Hosp Trust, Preston, Lancs, England. Arcispedale Santa Maria Nuova, Neonatal Intens Care Unit, Reggio Emilia, Italy. Ctr Genet Med, Antwerp, Belgium. Childrens Natl Med Ctr, Dept Neurol, Washington, DC 20010 USA. Humboldt Univ, Dept Neuropediat, Berlin, Germany. RP Crow, YJ (reprint author), St James Univ Hosp, Leeds Inst Mol Med, Level 9,Wellcome Trust Brenner Bldg, Leeds LS9 7TF, W Yorkshire, England. EM Yanickcrow@mac.com RI Jackson, Andrew/D-3442-2009; Zankl, Andreas/F-2044-2010; Kant, Sarina/F-8596-2010; Gener, Blanca/E-4310-2012; Brunner, Han/C-9928-2013; Lourenco, Charles/O-2731-2013; Crow, Yanick/N-6120-2014; Rice, Gillian/G-3128-2015; RICE, GREGORY/F-2412-2010; Fazzi, Elisa/J-6076-2016; OI Crow, Yanick/0000-0001-7211-7564; Bertini, Enrico/0000-0001-9276-4590; JACKSON, ALAN/0000-0002-1623-0383; Jackson, Andrew/0000-0002-8739-2646; Zankl, Andreas/0000-0001-8612-1062; Rice, Gillian/0000-0002-4223-0571; RICE, GREGORY/0000-0001-7177-0246; Fazzi, Elisa/0000-0003-4805-7906; Bonthron, David/0000-0001-8132-8179 FU Medical Research Council [MC_U127580972]; NINDS NIH HHS [K08 NS060695] NR 31 TC 166 Z9 173 U1 1 U2 22 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD OCT PY 2007 VL 81 IS 4 BP 713 EP 725 DI 10.1086/521373 PG 13 WC Genetics & Heredity SC Genetics & Heredity GA 208GK UT WOS:000249307600013 PM 17846997 ER PT J AU Luby, M Warach, S AF Luby, M. Warach, S. TI Reliability of MR perfusion-weighted and diffusion-weighted imaging mismatch measurement methods SO AMERICAN JOURNAL OF NEURORADIOLOGY LA English DT Article ID TISSUE-PLASMINOGEN ACTIVATOR; ACUTE STROKE; DESMOTEPLASE AB BACKGROUND AND PURPOSE: We investigated 2 methods of measuring MR imaging perfusion-diffusion mismatch to determine whether reliability is improved by direct measurement on a single, blended map. MATERIALS AND METHODS: Image software was used for measurement of lesion volumes from diffusion-weighted images (DWI) and mean transit time (MTT) calculated from perfusion-weighted (PWI) images on 64 patients with acute stroke. For the first method, the DWI and MITT lesions were measured separately. For the second method, the mismatch volume was measured directly on the blended images created from the registered DWI and MTT images. RESULTS: Test-retest agreement was 100% and 97% for the separate and blended methods using mismatch cutoffs of 20% or more versus less than 20%. There were no significant differences in the mismatch statistics between the methods. CONCLUSIONS: Mismatch volumes by a single reader can provide highly reliable and consistent results even when separately measuring DWI and MTT lesions. Propagation of measurement error was not demonstrated, and the methods were statistically comparable. C1 NINDS, NIH, Bethesda, MD 20892 USA. RP Luby, M (reprint author), NINDS, NIH, 10 Ctr Dr,Rm B1D733, Bethesda, MD 20892 USA. EM lubym@ninds.nih.gov FU Intramural NIH HHS [Z99 NS999999] NR 10 TC 9 Z9 10 U1 0 U2 0 PU AMER SOC NEURORADIOLOGY PI OAK BROOK PA 2210 MIDWEST RD, OAK BROOK, IL 60521 USA SN 0195-6108 J9 AM J NEURORADIOL JI Am. J. Neuroradiol. PD OCT PY 2007 VL 28 IS 9 BP 1674 EP 1678 DI 10.3174/ajnr.A0643 PG 5 WC Clinical Neurology; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 222QO UT WOS:000250312200014 PM 17885243 ER PT J AU Wright, TC Massad, LS Dunton, CJ Spitzer, M Wilkinson, EJ Solomon, D AF Wright, Thomas C., Jr. Massad, L. Stewart Dunton, Charles J. Spitzer, Mark Wilkinson, Edward J. Solomon, Diane CA 2006 Amer Soc Colposcopy Cervical Pathol TI 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Review DE adenocarcinomas in situ of the cervix; cervical intraepithelial neoplasia; cryotherapy; loop electrosurgical excision procedure; treatment ID OF-THE-LITERATURE; HUMAN-PAPILLOMAVIRUS; RANDOMIZED-TRIAL; FOLLOW-UP; CYTOLOGY INTERPRETATIONS; CONSERVATIVE TREATMENT; PRETERM DELIVERY; LOOP EXCISION; LESIONS; CANCER AB A group of 146 experts representing 29 organizations and professional societies met Sept. 18- 19, 2006, in Bethesda, MD, to develop revised evidence- based, consensus guidelines for managing women with abnormal cervical cancer screening tests. The management of low- grade cervical intraepithelial neoplasia ( CIN) grade 1 has been modified significantly. Previously, management depended on whether colposcopy was satisfactory and treatment using ablative or excisional was acceptable for all women with CIN 1. In the new guidelines, cytological follow- up is the only recommended management option for women with CIN 1 who have low- grade referral cervical cytology, regardless of whether the colposcopic examination is satisfactory. Treatment is particularly discouraged in adolescents. The basic management of women in the general population with CIN 2,3 underwent only minor modifications, but options for the conservative management of adolescents with CIN 2,3 have been expanded. Moreover, management recommendations for women with biopsy- confirmed adenocarcinoma in situ are now included. C1 Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA. Washington Univ, Sch Med, Dept Obstet & Gynecol, St Louis, MO 63110 USA. Lankenau Hosp, Dept Obstet & Gynecol, Wynnewood, PA USA. Brookdale Univ Hosp & Med Ctr, Dept Obstet & Gynecol, Brooklyn, NY USA. Univ Florida, Coll Med, Dept Pathol, Gainesville, FL USA. NCI, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. RP Wright, TC (reprint author), Columbia Univ, Coll Phys & Surg, Dept Pathol, Room 16-404,P&S Bldg,630 W 168th st, New York, NY 10032 USA. EM tcw1@columbia.edu NR 55 TC 209 Z9 239 U1 0 U2 12 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD OCT PY 2007 VL 197 IS 4 BP 340 EP 345 DI 10.1016/j.ajog.2007.07.050 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 219PO UT WOS:000250097300003 PM 17904956 ER PT J AU Wright, TC Massad, S Dunton, CJ Spitzer, M Wilkinson, EJ Solomon, D AF Wright, Thomas C., Jr. Massad, Stewart Dunton, Charles J. Spitzer, Mark Wilkinson, Edward J. Solomon, Diane CA 2006 Amer Soc Colposcopy Cervical Pathol TI 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Review DE atypical squamous cells of undetermined significance; cervical cancer screening; cervical cytology; high-grade squamous intraepithelial lesion; human papillomavirus testing; low-grade squamous intraepithelial lesion ID ATYPICAL SQUAMOUS-CELLS; HUMAN-PAPILLOMAVIRUS DNA; INTRAEPITHELIAL LESION TRIAGE; LIQUID-BASED CYTOLOGY; HYBRID CAPTURE-II; UNDETERMINED SIGNIFICANCE; GLANDULAR CELLS; COST-EFFECTIVENESS; RANDOMIZED-TRIAL; FOLLOW-UP AB A group of 146 experts representing 29 organizations and professional societies met September 18- 19, 2006, in Bethesda, MD, to develop revised evidence- based, consensus guidelines for managing women with abnormal cervical cancer screening tests. Recommendations for managing atypical squamous cells of undetermined significance and low- grade squamous intraepithelial lesion ( LSIL) are essentially unchanged. Changes were made for managing these conditions in adolescents for whom cytological follow- up for 2 years was approved. Recommendations for managing high- grade squamous intraepithelial lesion ( HSIL) and atypical glandular cells ( AGC) also underwent only minor modifications. More emphasis is placed on immediate screen- and- treat approaches for HSIL. Human papillomavirus ( HPV) testing is incorporated into the management of AGC after their initial evaluation with colposcopy and endometrial sampling. The 2004 Interim Guidance for HPV testing as an adjunct to cervical cytology for screening in women 30 years of age and older was formally adopted with only very minor modifications. C1 Columbia Univ, Coll Phys & Surg, Dept Pathol, New York, NY 10032 USA. Washington Univ, Sch Med, Dept Obstet & Gynecol, St Louis, MO 63110 USA. Lankenau Hosp, Dept Obstet & Gynecol, Wynnewood, PA USA. Brookdale Univ Hosp & Med Ctr, Dept Obstet & Gynecol, Brooklyn, NY USA. Univ Florida, Coll Med, Dept Pathol, Gainesville, FL USA. NCI, Bethesda, MD 20892 USA. NIH, Bethesda, MD 20892 USA. RP Wright, TC (reprint author), Columbia Univ, Coll Phys & Surg, Dept Pathol, Room 16-404,P&S Bldg,630 W,168th St, New York, NY 10032 USA. EM tcw1@columbia.edu NR 81 TC 487 Z9 515 U1 4 U2 34 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD OCT PY 2007 VL 197 IS 4 BP 346 EP 355 DI 10.1016/j.ajog.2007.07.047 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 219PO UT WOS:000250097300004 PM 17904957 ER PT J AU Wapner, R Thom, E Spong, C AF Wapner, Ronald Thom, Elizabeth Spong, Catherine TI Repeated antenatal steroid trial methodology SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Letter C1 Columbia Univ, Med Ctr, Dept Obstet & Gynecol, New York, NY 10032 USA. George Washington Univ, Ctr Biostat, Rockville, MD 20852 USA. NICHHD, Bethesda, MD 20892 USA. RP Wapner, R (reprint author), Columbia Univ, Med Ctr, Dept Obstet & Gynecol, New York, NY 10032 USA. EM rw2191@columbia.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD OCT PY 2007 VL 197 IS 4 BP 438 EP 438 DI 10.1016/j.ajog.2007.06.081 PG 1 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 219PO UT WOS:000250097300045 ER PT J AU Castle, PE Sideri, M Jeronimo, J Solomon, D Schiffman, M AF Castle, Philip E. Sideri, Mario Jeronimo, Jose Solomon, Diane Schiffman, Mark TI Risk assessment to guide the prevention of cervical cancer SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE biopsy; carcinogenic human papillomavirus; cervical cancer; cervical cytology; cervical precancer; colposcopy; human papillomavirus vaccination; loop electrosurgical excision procedure; Papanicolaou smears; risk ID INTRAEPITHELIAL NEOPLASIA GRADE-2; HUMAN-PAPILLOMAVIRUS DNA; ATYPICAL SQUAMOUS-CELLS; ASCUS-LSIL TRIAGE; FOLLOW-UP; ABSOLUTE RISK; UNDETERMINED SIGNIFICANCE; MANAGEMENT STRATEGIES; RANDOMIZED-TRIAL; WOMEN AB Advances in screening and diagnosis make it increasingly possible to prevent cervical cancer. However, if misused or poorly understood, these new tools will only increase costs and potentially harm patients without benefit. As a framework for standardized care that maximizes patient safety and well- being, we propose that a risk model be adopted to guide clinical management now and in the future. The model would use thresholds of increasing risk for cervical precancer and treatable cancer to guide clinical decision making for screening intensity, diagnostic evaluation, or treatment. Experts would decide on these risk thresholds and stratum based on the patient risk to benefit, independent of current ( eg, cytology, carcinogenic HPV testing, and colposcopy) and future methods of measuring risk. A risk management model for cervical cancer prevention, based on appropriate clinical actions that correspond to risk stratum, can result in better allocation of resources to and increased safety for women at the greatest risk and increased well- being for women at the lowest risk. C1 NCI, NIH, Dept Hlth, Div Canc Epidemiol & Genet,Human Serv, Bethesda, MD 20892 USA. NCI, NIH, Dept Hlth & Human Serv, Div Canc Prevent, Bethesda, MD 20892 USA. NCI, NIH, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. European Inst Oncol, Prevent Gynecol Unit, Milan, Italy. RP Castle, PE (reprint author), NCI, NIH, Dept Hlth, Div Canc Epidemiol & Genet,Human Serv, 6120 Execut Blvd,Room 5004,MSC 7234, Bethesda, MD 20892 USA. EM castlep@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 30 TC 18 Z9 21 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD OCT PY 2007 VL 197 IS 4 AR 356.e1 DI 10.1016/j.ajog.2007.07.049 PG 6 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 219PO UT WOS:000250097300005 PM 17904958 ER PT J AU Habli, M Levine, RJ Qian, C Sibai, B AF Habli, Mounira Levine, Richard J. Qian, Cong Sibai, Baha TI Neonatal outcomes in pregnancies with preeclampsia or gestational hypertension and in normotensive pregnancies that delivered at 35, 36, or 37 weeks of gestation SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 27th Annual Meeting of the Society-of-Maternal-Fetal-Medicine CY FEB 05-10, 2007 CL San Francisco, CA SP Soc Maternal Fetal Med DE labor induction; late preterm birth; neonatal outcome; preeclampsia ID UNITED-STATES; DISORDERS; PRETERM; BIRTH; AGE; CALCIUM; TRIAL; WOMEN AB OBJECTIVE: The purpose of this study was to compare neonatal outcomes of pregnancies with preeclampsia or gestational hypertension with those of normotensive pregnancies that delivered at 35, 36, or 37 weeks of gestation separately. STUDY DESIGN: Secondary analysis of neonatal outcomes by week of delivery between 35 and 37 weeks 6 days of gestation to 4293 nulliparous women who were enrolled in a multicenter National Institute for Child Health and Human Development study. Outcomes included the percentage of neonatal intensive care unit admission, duration of neonatal hospitalization, and neonatal complications. RESULTS: As compared with normotensive pregnancies, hypertensive pregnancies that delivered at 35 and 36 weeks of gestation had higher rates of small for gestational age births ( 17.9% vs 1.7% [ P <.05] and 33.3% vs 12.2% [ P <.01], respectively) and neonatal intensive care unit admission ( 57.1% vs 34.5% [ P <.05] and 33.3% vs 10.7% [ P <.001]). The rate of neonatal intensive care unit admission ( 25.6% vs 8.7%; P <.001) and duration of neonatal stay ( 3.9 vs 2.0 days; P <.001) were greater in hypertensive pregnancies that delivered at 37 weeks of gestation. These differences were observed largely in women whose condition required labor induction, regardless of the severity of the hypertensive disease. CONCLUSION: Pregnancies with preeclampsia or gestational hypertension that delivered between 35 and 37 weeks of gestation had higher rates of neonatal intensive care unit admission, small for gestational age, and longer neonatal stay than normotensive pregnancies, regardless of the severity of the hypertensive disease. C1 Univ Cincinnati, Dept Obstet & Gynecol, Cincinnati, OH 45267 USA. NICHHD, Div Epidemiol Stat & Prevent Res, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RP Habli, M (reprint author), Univ Cincinnati, Dept Obstet & Gynecol, Cincinnati, OH 45267 USA. FU NCATS NIH HHS [UL1 TR001425]; NICHD NIH HHS [N01-HD-1-3121, N01-HD-1-3122, N01-HD-1-3123, N01-HD-1-3124, N01-HD-1-3125, N01-HD-1-3126, N01-HD-3154, N01-HD-5-3246] NR 18 TC 10 Z9 14 U1 1 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD OCT PY 2007 VL 197 IS 4 AR 406.e1 DI 10.1016/j.ajog.2007.06.059 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 219PO UT WOS:000250097300028 PM 17904980 ER PT J AU Nussenblatt, RB Ferris, F AF Nussenblatt, Robert B. Ferris, Frederick, III TI Age-related macular degeneration and the immune response: Implications for therapy SO AMERICAN JOURNAL OF OPHTHALMOLOGY LA English DT Editorial Material ID COMPLEMENT FACTOR-H; RETINAL-PIGMENT EPITHELIUM; CHOROIDAL NEOVASCULARIZATION; MACROPHAGE HETEROGENEITY; INFLAMMATORY DISEASE; LIGAND EXPRESSION; FACTOR-B; CELLS; POLYMORPHISM; ACTIVATION AB PURPOSE: To review the available information concerning the immune mediation of age-related macular degeneration (AMD) and to speculate on proposed mechanisms and immunotherapy. DESIGN: Interpretative essay. METHODS: Literature review and interpretation. RESULTS: An ever-growing body of evidence is gathering concerning the role of the immune system in AMD. Evidence to date suggests that the underlying mechanism leading to AMD is the decline of the ocular downregulatory immune environment. The subsequent activation of the immune system would lead to T-cell sensitization. When combined with local antiangiogenic therapy, several existing immunotherapies may be used to downregulate the immune response, potentially leading to a more efficient inhibition of choroidal neovascularization. CONCLUSIONS: The loss of the downregulatory immune environment is central to the development of AMD, permitting activation of the immune system. If so, immunotherapy could positively alter the course of the disease. C1 NEI, Lab Immunol, NIH, Bethesda, MD 20892 USA. NEI, Div Epidemiol & Clin Res, NIH, Bethesda, MD 20892 USA. RP Nussenblatt, RB (reprint author), NEI, Lab Immunol, NIH, Bldg 10, Bethesda, MD 20892 USA. EM DrBob@nci.nih.gov FU Intramural NIH HHS [Z99 EY999999] NR 87 TC 75 Z9 80 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9394 J9 AM J OPHTHALMOL JI Am. J. Ophthalmol. PD OCT PY 2007 VL 144 IS 4 BP 618 EP 626 DI 10.1016/j.ajo.2007.06.025 PG 9 WC Ophthalmology SC Ophthalmology GA 217GW UT WOS:000249937400023 PM 17698021 ER PT J AU Klement, H Croix, BS Milsom, C May, L Guo, Q Yu, JL Klement, P Rak, J AF Klement, Halka Croix, Brad St. Milsom, Chloe May, Linda Guo, Qing Yu, Joanne L. Klement, Petr Rak, Janusz TI Atherosclerosis and vascular aging as modifiers of tumor progression, angiogenesis, and responsiveness to therapy SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID ENDOTHELIAL-CELLS; BREAST-CANCER; TISSUE FACTOR; AGE; EXPRESSION; DISEASE; GROWTH; MOUSE; MICE; HYPERCHOLESTEROLEMIA AB It is rarely considered that age-related common vascular co-morbidities may affect therapeutic outcomes of antiangiogenic therapy in cancer. indeed, the accepted model of human disease consists of 4- to 8-week-old (young) tumor-bearing, but otherwise healthy, experimental mice, yet human cancers are diagnosed and treated in later decades of life when atherosclerosis and vascular diseases are highly prevalent. Here we present evidence that tumor growth and angiogenesis are profoundly altered in mice affected by natural aging and with genetically induced atherosclerosis (in ApoE(-/-) mice). Thus, transplantable tumors (Lewis lung carcinoma and 1316171) grew at higher rates in young (4 to 8 weeks old) ApoE(+/+) and ApoE(-/-) nonatherosclerotic syngeneic recipients than in their old (12 to 18 months old) or atherosclerotic (old/ApoE(-/-)) counterparts. These age-related changes were paralleled by reduced tumor vascularity, lower expression of tumor endothelial marker 1, increased acute tumor hypoxia, depletion of circulating CD45(-)/VEGFR(+) cells, and impaired endothelial sprouting ex vivo. Exposure of tumor-bearing mice to metronomic therapy with cyclophosphamide exerted antimitotic effects on tumors in young hosts, but this effect was reduced in atherosclerotic mice. Collectively, our results suggest that vascular aging and disease may affect tumor progression, angiogenesis, and responses to therapy. C1 McGill Univ, Montreal Childrens Hosp, Res Inst, Montreal, PQ H3Z 2Z3, Canada. McMaster Univ, Henderson Res Ctr, Hamilton, ON, Canada. McMaster Univ, Populat Hlth Inst, Hamilton, ON, Canada. Univ Vet & Pharmaceut Sci, Brno, Czech Republic. Natl Canc Inst, Frederick, MD USA. RP Rak, J (reprint author), McGill Univ, Montreal Childrens Hosp, Res Inst, 4060 Ste Catherine St, Montreal, PQ H3Z 2Z3, Canada. EM janusz.rak@mcgill.ca NR 41 TC 21 Z9 22 U1 0 U2 0 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD OCT PY 2007 VL 171 IS 4 BP 1342 EP 1351 DI 10.2353/ajpath.2007.070298 PG 10 WC Pathology SC Pathology GA 217TJ UT WOS:000249969900025 PM 17823292 ER PT J AU Radaeva, S Wang, L Radaev, S Jeong, WI Park, O Gao, B AF Radaeva, Svetlana Wang, Lei Radaev, Sergei Jeong, Won-Il Park, Ogyi Gao, Bin TI Retinoic acid signaling sensitizes hepatic stellate cells to NK cell killing via upregulation of NK cell activating ligand RAE1 SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE retinoic acid; stellate cells; NK cells; RAE-1; liver fibrosis ID LIVER FIBROSIS; ALDEHYDE DEHYDROGENASE; SYNTHETIC RETINOIDS; IN-VIVO; METABOLISM; APOPTOSIS; RECEPTOR; IDENTIFICATION; PROLIFERATION; DISULFIRAM AB Retinoic acid signaling sensitizes hepatic stellate cells to NK cell killing via upregulation of NK cell activating ligand RAE1. Am J Physiol Gastrointest Liver Physiol 293: G809-G816, 2007. First published August 2, 2007; doi:10.1152/ajpgi.00212.2007.-Hepatic stellate cells (HSCs) store 75% of the body's supply of vitamin A (retinol) and play a key role in liver fibrogenesis. During liver injury, HSCs become activated and susceptible to natural killer (NK) cell killing due to increased expression of the NK cell activating ligand retinoic acid early inducible gene 1 (RAE-1). To study the mechanism by which RAE-1 is upregulated in HSCs during activation, an in vitro model of cultured mouse HSCs was employed. RAE-1 was detected at low levels in quiescent HSCs but upregulated in 4- and 7-day cultured HSCs (early activated HSCs), whereas 21-day cultured HSCs (fully activated HSCs) lost RAE-1 expression. High levels of RAE-1 in 4- and 7-day cultured HSCs correlated with their susceptibility to NK cell killing, which was diminished by treatment with RAE-1 neutralizing antibody. Furthermore, retinoic acid (RA) and retinal dehydrogenase (Raldh) levels were upregulated in early activated HSCs compared with quiescent or fully activated HSCs. Blocking RA synthesis by the Raldh inhibitor or blocking RA signaling by the retinoic acid receptor antagonist abolished upregulation of RAE-1 whereas treatment with RA induced RAE-1 expression in HSCs. In conclusion, during activation, HSCs lose retinol, which is either secreted out or oxidized into RA; the latter stimulates RAE-1 expression and sensitizes early activated HSCs to NK cell killing. In contrast, fully activated HSCs become resistant to NK cell killing because of lack of RAE1 expression, leading to chronic liver fibrosis and disease. C1 NIAAA, NIH, Sect Liver Biol, Bethesda, MD 20892 USA. NIAAA, Lab Physiol Studies, Sect Liver Biol, Bethesda, MD USA. NIH, NIAID, Struct Immunol Sect, Bethesda, MD USA. RP Radaeva, S (reprint author), NIAAA, NIH, Sect Liver Biol, 5625 Fishers Lane,Rm 2s-33, Bethesda, MD 20892 USA. EM sradaeva@mail.nih.gov; bgao@mail.nih.gov RI JEONG, WON IL/B-6615-2011 FU Intramural NIH HHS NR 38 TC 45 Z9 49 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD OCT PY 2007 VL 293 IS 4 BP G809 EP G816 DI 10.1152/ajpgi.00212.2007 PG 8 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 218DC UT WOS:000249995200019 PM 17673545 ER PT J AU Bubolz, AH Wu, QP Larsen, BT Gutterman, DD Liu, YP AF Bubolz, Aaron H. Wu, Qingping Larsen, Brandon T. Gutterman, David D. Liu, Yanping TI Ebselen reduces nitration and restores voltage-gated potassium channel function in small coronary arteries of diabetic rats SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE peroxynitrite; oxidative stress; coronary circulation ID SMOOTH-MUSCLE-CELLS; CA2+-SENSITIVE K+ CHANNELS; CAMP-MEDIATED DILATION; OXIDATIVE STRESS; VASCULAR COMPLICATIONS; INCREASED EXPRESSION; HYPERTENSIVE-RATS; ELEVATED GLUCOSE; PEROXYNITRITE; PATHOPHYSIOLOGY AB Small coronary arteries (SCA) from diabetic rats exhibit enhanced peroxynitrite (ONOO-) formation and concurrent impairment of voltage-dependent potassium (K-v) channel function. However, it is unclear whether ONOO- plays a causative role in this impairment. We hypothesized that functional loss of K-v channels in coronary smooth muscle cells (SMC) in diabetes is due to ONOO- with subsequent tyrosine nitration of K-v channel proteins. Diabetic rats and nondiabetic controls were treated with or without ebselen (Eb) for 4 wk. SCA were prepared for immunohistochemistry (IHC), immunoprecipitation (IP) followed by Western blot (WB), videomicroscopy, and patch-clamp analysis. IHC revealed excess ONOO- in SCA from diabetic rats. IP and WB revealed elevated nitration of the K(v)1.2 alpha-subunit and reduced K(v)1.2 protein expression in diabetic rats. Each of these changes was improved in Eb-treated rats. Protein nitration and K(v)1.5 expression were unchanged in SCA from diabetic rats. Forskolin, a direct cAMP activator that induces K(v)1 channel activity, dilated SCA from nondiabetic rats in a correolide (Cor; a selective K(v)1 channel blocker)-sensitive fashion. Cor did not alter the reduced dilation to forskolin in diabetic rats; however, Eb partially restored the Cor-sensitive component of dilation. Basal K-v current density and response to forskolin were improved in smooth muscle cells from Eb-treated DM rats. We conclude that enhanced nitrosative stress in diabetes mellitus contributes to K(v)1 channel dysfunction in the coronary microcirculation. Eb may be beneficial for the therapeutic treatment of vascular complications in diabetes mellitus. C1 Natl Ctr Res Resources, NIH, Bethesda, MD 20892 USA. Med Coll Wisconsin, Dept Med, Milwaukee, WI 53226 USA. Med Coll Wisconsin, Ctr Cardiovasc, Milwaukee, WI 53226 USA. Vet Adm Med Ctr, Milwaukee, WI 53295 USA. RP Liu, YP (reprint author), Natl Ctr Res Resources, NIH, 6701 Democracy Blvd, Bethesda, MD 20892 USA. EM liuyanp@mail.nih.gov FU NHLBI NIH HHS [P01 HL-68769] NR 39 TC 16 Z9 16 U1 1 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD OCT PY 2007 VL 293 IS 4 BP H2231 EP H2237 DI 10.1152/ajpheart.00717.2007 PG 7 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 219AZ UT WOS:000250058400026 PM 17675568 ER PT J AU Isbell, TS Gladwin, MT Patel, RP AF Isbell, T. Scott Gladwin, Mark T. Patel, Rakesh P. TI Hemoglobin oxygen fractional saturation regulates nitrite-dependent vasodilation of aortic ring bioassays SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE nitric oxide; hypoxia; blood flow ID ISCHEMIA-REPERFUSION INJURY; REGIONAL BLOOD-FLOW; IN-VIVO; S-NITROSOHEMOGLOBIN; HYPOXIC VASODILATION; SODIUM-NITRITE; RAT-KIDNEY; OXIDE; NO; REDUCTASE AB This reaction has been proposed to contribute to nitrite-dependent vasodilation in vivo and potentially regulate physiological hypoxic vasodilation. Paradoxically, while deoxyhemoglobin can generate NO via nitrite reduction, both oxyhemoglobin and deoxyhemoglobin potently scavenge NO. Furthermore, at the very low O-2 tensions required to deoxygenate cell-free hemoglobin solutions in aortic ring bioassays, surprisingly low doses of nitrite can be reduced to NO directly by the blood vessel, independent of the presence of hemoglobin; this makes assessments of the role of hemoglobin in the bioactivation of nitrite difficult to characterize in these systems. Therefore, to study the O-2 dependence and ability of deoxhemoglobin to generate vasodilatory NO from nitrite, we performed full factorial experiments of oxyhemoglobin, deoxyhemoglobin, and nitrite and found a highly significant interaction between hemoglobin deoxygenation and nitrite-dependent vasodilation (P <= 0.0002). Furthermore, we compared the effect of hemoglobin oxygenation on authentic NO-dependent vasodilation using a NONOate NO donor and found that there was no such interaction, i.e., both oxyhemoglobin and deoxyhemoglobin inhibited NO-mediated vasodilation. Finally, we showed that another NO scavenger, 2-carboxyphenyl-4,4 -5,5-tetramethylimidazoline-1-oxyl-3-oxide, inhibits nitrite-dependent vasodilation under normoxia and hypoxia, illustrating the uniqueness of the interaction of nitrite with deoxyhemoglobin. While both oxyhemoglobin and deoxyhemoglobin potently inhibit NO, deoxyhemoglobin exhibits unique functional duality as an NO scavenger and nitrite-dependent NO generator, suggesting a model in which intravascular NO homeostasis is regulated by a balance between NO scavenging and NO generation that is dynamically regulated by hemoglobin's O-2 fractional saturation and allosteric nitrite reductase activity. C1 Univ Alabama, Dept Pathol, Birmingham, AL 35296 USA. Univ Alabama, Ctr Free Rad Biol, Birmingham, AL USA. NHLBI, Vasc Med Branch, Crit Care Med Dept, NIH, Bethesda, MD 20892 USA. RP Patel, RP (reprint author), Univ Alabama, Dept Pathol, 901 19th St S,BMR 2,Rm 302, Birmingham, AL 35296 USA. EM rakeshp@uab.edu OI Patel, Rakesh/0000-0002-1526-4303 NR 45 TC 51 Z9 52 U1 0 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD OCT PY 2007 VL 293 IS 4 BP H2565 EP H2572 DI 10.1152/ajpheart.00759.2007 PG 8 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 219AZ UT WOS:000250058400066 PM 17766472 ER PT J AU Minneci, PC Deans, KJ Hansen, B Parent, C Romines, C Gonzales, DA Ying, SX Munson, P Suffredini, AF Feng, J Solomon, MA Banks, SM Kern, SJ Danner, RL Eichacker, PQ Natanson, C Solomon, SB AF Minneci, Peter C. Deans, Katherine J. Hansen, Bernie Parent, Chantal Romines, Chris Gonzales, Denise A. Ying, Sai-Xia Munson, Peter Suffredini, Anthony F. Feng, Jing Solomon, Michael A. Banks, Steven M. Kern, Steven J. Danner, Robert L. Eichacker, Peter Q. Natanson, Charles Solomon, Steven B. TI A canine model of septic shock: balancing animal welfare and scientific relevance SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE sepsis; dog; Staphylococcus aureus ID NITRIC-OXIDE SYNTHASE; TUMOR-NECROSIS-FACTOR; CONTINUOUS ARTERIOVENOUS HEMOFILTRATION; ESCHERICHIA-COLI PNEUMONIA; CARDIOVASCULAR DYSFUNCTION; MONOCLONAL-ANTIBODIES; MYOCARDIAL DEPRESSION; IMPROVES SURVIVAL; FACTOR CHALLENGES; INTENSIVE-CARE AB A shock canine pneumonia model that permitted relief of discomfort with the use of objective criteria was developed and validated. After intrabronchial Staphylococcus aureus challenge, mechanical ventilation, antibiotics, fluids, vasopressors, sedatives, and analgesics were titrated based on algorithms for 96 h. Increasing S. aureus (1 to 8 x 10(9) colony-forming units/kg) produced decreasing survival rates (P = 0.04). From 4 to 96 h, changes in arterial-alveolar oxygen gradients, mean pulmonary artery pressure, IL-1, serum sodium levels, mechanical ventilation, and vasopressor support were ordered based on survival time [acute nonsurvivors (<= 24 h until death, n = 8) >= subacute nonsurvivors (> 24 to 96 h until death, n = 8) >= survivors (>= 96 h until death, n = 22) (all P < 0.05)]. In the first 12 h, increases in lactate and renal abnormalities were greatest in acute nonsurvivors (all P < 0.05). Compared with survivors, subacute nonsurvivors had greater rises in cytokines and liver enzymes and greater falls in platelets, white cell counts, pH, and urine output from 24 to 96 h (all P < 0.05). Importantly, these changes were not attributable to dosages of sedation, which decreased in nonsurvivors [survivors vs. nonsurvivors: 5.0 +/- 1.0 vs. 3.8 +/- 0.7 ml center dot h(-1)center dot(fentanyl/midazolam/ medetomidine)(-1); P = 0.02]. In this model, the pain control regimen did not mask changes in metabolic function and lung injury or the need for more hemodynamic and pulmonary support related to increasing severity of sepsis. The integration into this model of both specific and supportive titrated therapies routinely used in septic patients may provide a more realistic setting to evaluate therapies for sepsis. C1 NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. N Carolina State Univ, Raleigh, NC 27695 USA. NIH, Ctr Informat Technol, Math & Stat Comp Lab, Bethesda, MD 20892 USA. Childrens Hosp, Dept Surg, Philadelphia, PA 19104 USA. RP Solomon, SB (reprint author), NIH, Dept Crit Care Med, Bldg 10,Rm 2C145, Bethesda, MD 20892 USA. EM ssolomon@cc.nih.gov FU Intramural NIH HHS NR 56 TC 15 Z9 15 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD OCT PY 2007 VL 293 IS 4 BP H2487 EP H2500 DI 10.1152/ajpheart.00589.2007 PG 14 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 219AZ UT WOS:000250058400056 PM 17644570 ER PT J AU Rajesh, M Mukhopadhyay, P Batkai, S Hasko, G Liaudet, L Huffman, JW Csiszar, A Ungvari, Z Mackie, K Chatterjee, S Pacher, P AF Rajesh, Mohanraj Mukhopadhyay, Partha Batkai, Sandor Hasko, Gyoergy Liaudet, Lucas Huffman, John W. Csiszar, Anna Ungvari, Zoltan Mackie, Ken Chatterjee, Subroto Pacher, Pal TI CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE endothelial activation; inflammation; RhoA; adhesion molecules ID NECROSIS-FACTOR-ALPHA; CB2 RECEPTOR ACTIVATION; C-REACTIVE PROTEIN; CANNABINOID RECEPTORS; MOLECULE EXPRESSION; THERAPEUTIC TARGETS; POTENTIAL ROLE; KNOCKOUT MICE; NITRIC-OXIDE; ATHEROSCLEROSIS AB Targeting cannabinoid-2 (CB2) receptors with selective agonists may represent a novel therapeutic avenue in various inflammatory diseases, but the mechanisms by which CB2 activation exerts its anti-inflammatory effects and the cellular targets are elusive. Here, we investigated the effects of CB2-receptor activation on TNF-alpha-induced signal transduction in human coronary artery endothelial cells in vitro and on endotoxin-induced vascular inflammatory response in vivo. TNF-alpha-induced NF-kappa B and RhoA activation and upregulation of adhesion molecules ICAM-1 and VCAM-1, increased expression of monocyte chemoattractant protein, enhanced transendothelial migration of monocytes, and augmented monocyte-endothelial adhesion. Remarkably, all of the above-mentioned effects of TNF-alpha were attenuated by CB2 agonists. CB2 agonists also decreased the TNF-alpha- and/or endotoxin-induced ICAM-1 and VCAM-1 expression in isolated aortas and the adhesion of monocytes to aortic vascular endothelium. CB1 and CB2 receptors were detectable in human coronary artery endothelial cells by Western blotting, RT-PCR, real-time PCR, and immunofluorescence staining. Because the above-mentioned TNF-alpha-induced phenotypic changes are critical in the initiation and progression of atherosclerosis and restenosis, our findings suggest that targeting CB2 receptors on endothelial cells may offer a novel approach in the treatment of these pathologies. C1 NIAAA, NIH, Lab Physiol Studies, Sect Oxidat Stress Tissue Injury, Bethesda, MD 20892 USA. Univ Med & Dent New Jersey, Dept Surg, New Jersey Med Sch, Newark, NJ 07103 USA. Univ Lausanne Hosp, Dept Intens Care Med, Lausanne, Switzerland. Clemson Univ, Howard L Hunter Chem Lab, Clemson, SC 29631 USA. New York Med Coll, Dept Physiol, Valhalla, NY 10595 USA. Indiana Univ, Dept Psychol & Brain Sci, Bloomington, IN USA. Johns Hopkins Univ, Dept Pediat, Baltimore, MD 21218 USA. RP Pacher, P (reprint author), NIAAA, NIH, Lab Physiol Studies, Sect Oxidat Stress Tissue Injury, 5625 Fishers Lane,MSC-9413, Bethesda, MD 20892 USA. EM pacher@mail.nih.gov RI Mackie, Kenneth/B-7358-2011; Batkai, Sandor/G-3889-2010; MUKHOPADHYAY, PARTHA/G-3890-2010; Pacher, Pal/B-6378-2008; Mackie, Ken/E-3715-2013; Batkai, Sandor/H-7983-2014; Liaudet, Lucas/E-1322-2017 OI MUKHOPADHYAY, PARTHA/0000-0002-1178-1274; Pacher, Pal/0000-0001-7036-8108; Mackie, Ken/0000-0001-8501-6199; Liaudet, Lucas/0000-0003-2670-4930 FU Intramural NIH HHS [Z01 AA000375-02]; NIDA NIH HHS [R01 DA011322, DA-03590, DA-11322, R01 DA003590] NR 52 TC 129 Z9 133 U1 0 U2 8 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD OCT PY 2007 VL 293 IS 4 BP H2210 EP H2218 DI 10.1152/ajpheart.00688.2007 PG 9 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 219AZ UT WOS:000250058400024 PM 17660390 ER PT J AU Lo, CM Zhang, DM Pearson, K Ma, LY Sun, W Sakai, RR Davidson, WS Liu, M Raybould, HE Woods, SC Tso, P AF Lo, Chun Min Zhang, Dian Ming Pearson, Kevin Ma, Liyun Sun, William Sakai, Randall R. Davidson, W. Sean Liu, Min Raybould, Helen E. Woods, Stephen C. Tso, Patrick TI Interaction of apolipoprotein AIV with cholecystokinin on the control of food intake SO AMERICAN JOURNAL OF PHYSIOLOGY-REGULATORY INTEGRATIVE AND COMPARATIVE PHYSIOLOGY LA English DT Article DE intraperitoneal injection; inhibition; satiation effect ID A-IV; PERIPHERAL INJECTION; GASTRIC-MOTILITY; FOS EXPRESSION; RATS; CCK; SATIETY; INHIBITION; SECRETION; SUPPRESSION AB Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are peptides that act both peripherally and centrally to reduce food intake by decreasing meal size. The present study examined the effects of intraperitoneally administered bolus doses of recombinant apo AIV, CCK-8, and a combination of subthreshold doses of apo AIV and CCK on 4-h food intake in rats that were fasted overnight. Apo AIV at 100 mu g/kg reduced food intake significantly relative to the saline control for 1 h, as did doses of CCK-8 at or above 0.125 mu g/kg. Doses of apo AIV (50 mu g/kg) or CCK (0.06 mu g/kg) alone had no effect on food intake. However, when these subthreshold doses of apo AIV and CCK were administered together, the combination produced a significant inhibition of food intake relative to saline controls (P < 0.001), and the duration of the effect was longer than that caused by the administration of either apo AIV or CCK alone. The satiation effect produced by CCK-8 + apo AIV was attenuated by lorglumide, a CCK1 receptor antagonist. We conclude that, whereas the intraperitoneal administration of doses of either recombinant apo AIV or CCK at or above threshold levels reduces food intake, the coadministration of subthreshold doses of the two peptides is highly satiating and works via CCK1 receptor. C1 Univ Cincinnati, Dept Pathol & Lab Med, Cincinnati, OH 45237 USA. Univ Cincinnati, Dept Psychiat, Cincinnati, OH USA. Univ Calif Davis, Sch Vet Med, Dept Anat Physiol & Cell Biol, Davis, CA 95616 USA. NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA. RP Tso, P (reprint author), Univ Cincinnati, Dept Pathol & Lab Med, 2120 E Galbraith Rd, Cincinnati, OH 45237 USA. EM tsopp@email.uc.edu FU NHLBI NIH HHS [HL-82734]; NIDDK NIH HHS [DK-63907, DK-76928, DK-17844, DK-56910, DK-38180]; NIEHS NIH HHS [ES-14464] NR 41 TC 28 Z9 28 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6119 J9 AM J PHYSIOL-REG I JI Am. J. Physiol.-Regul. Integr. Comp. Physiol. PD OCT PY 2007 VL 293 IS 4 BP R1490 EP R1494 DI 10.1152/ajpregu.00329.2007 PG 5 WC Physiology SC Physiology GA 219LZ UT WOS:000250088000004 PM 17634201 ER PT J AU Ideura, H Hiromura, K Hiramatsu, N Shigehara, T Takeuchi, S Tomioka, M Sakairi, T Yamashita, S Maeshima, A Kaneko, Y Kuroiwa, T Kopp, JB Nojima, Y AF Ideura, Hiroshi Hiromura, Keiju Hiramatsu, Noriyuki Shigehara, Tetsuya Takeuchi, Shigeru Tomioka, Mai Sakairi, Toru Yamashita, Shin Maeshima, Akito Kaneko, Yoriaki Kuroiwa, Takashi Kopp, Jeffrey B. Nojima, Yoshihisa TI Angiotensin II provokes podocyte injury in murine model of HIV-associated nephropathy SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE human immunodeficiency virus-associated nephropathy; proteinuria; glomerulosclerosis; angiotensin II type 1 receptor blocker; conditional transgenic mice ID SEGMENTAL GLOMERULOSCLEROSIS; RENAL SURVIVAL; EARLY PHASE; INFECTION; KIDNEY; EXPRESSION; RAT; GLOMERULONEPHRITIS; PROGRESSION; ARTERIOLES AB Conditional transgenic mice that express one of the human immunodeficiency virus (HIV)-1 accessory genes, vpr, selectively in podocytes using a podocin promoter and a tetracycline-inducible system develop renal injuries similar to those of patients with HIV-associated nephropathy (HIVAN). We have shown that a heminephrectomy accelerates podocyte injury, which is alleviated by angiotensin II (ANG II) type 1 receptor blocker (ARB). The current study further explores the role of ANG II in the genesis of HIVAN in this murine model. With ANG II infusion, heavy proteinuria was observed at 1 wk after the initiation of doxycycline administration to induce vpr expression in podocytes. Severe morphological and phenotypical changes in the podocytes were observed at 2 wk, together with extensive glomerulosclerosis. Norepinephrine infusion, instead of ANG II, increased the systemic blood pressure to the same level as that achieved using ANG II. However, albuminuria and glomerular injury were modest in norepinephrine-infused mice. Treatment with an ARB, olmesartan, almost completely inhibited glomerular injury. In contrast, lowering the blood pressure with a vasodilator, hydralazine, partially decreased albuminuria but did not produce any histological changes. ANG II infusion alone without doxycycline resulted in a lower level of albuminuria and minimal histological changes. These data demonstrate that excessive ANG II accelerates vpr-induced podocyte injury in a mouse model of HIVAN. C1 Gunma Univ, Grad Sch Med, Dept Med & CLin Sci, Gunma, Japan. NIDDK, Kidney Dis Sect, Kidney Dis Branch, Bethesda, MD USA. RP Hiromura, K (reprint author), 3-39-22 Showa, Gunma 3718511, Japan. EM hiromura@med.gunma-u.ac.jp OI Kopp, Jeffrey/0000-0001-9052-186X NR 37 TC 21 Z9 22 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD OCT PY 2007 VL 293 IS 4 BP F1214 EP F1221 DI 10.1152/ajprenal.00162.2007 PG 8 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 221BE UT WOS:000250201200029 PM 17652372 ER PT J AU Kim, YH Pech, V Spencer, KB Beierwaltes, WH Everett, LA Green, ED Shin, W Verlander, JW Sutliff, RL Wall, SM AF Kim, Young Hee Pech, Vladimir Spencer, Kathryn B. Beierwaltes, William H. Everett, Lorraine A. Green, Eric D. Shin, Wonkyong Verlander, Jill W. Sutliff, Roy L. Wall, Susan M. TI Reduced ENaC protein abundance contributes to the lower blood pressure observed in pendrin-null mice SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE intercalated cell; Slc26a4; apical Cl(-)/HCO(3)(-) exchanger; epithelial sodium channel; aldosterone ID EPITHELIAL NA+ CHANNEL; CORTICAL COLLECTING DUCT; SURFACE LIQUID VOLUME; LONG-TERM REGULATION; RAT-KIDNEY; PLASMA-MEMBRANE; GAMMA-SUBUNIT; INTERCALATED CELLS; CYSTIC-FIBROSIS; SODIUM-CHANNEL AB Pendrin ( encoded by Pds, Slc26a4) is a Cl(-)/HCO(3)(-) exchanger expressed in the apical regions of type B and non-A, non-B intercalated cells of kidney and mediates renal Cl(-) absorption, particularly when upregulated. Aldosterone increases blood pressure by increasing absorption of both Na(+) and Cl(-) through increased protein abundance and function of Na(+) transporters, such as the epithelial Na(+) channel ( ENaC) and the Na(+)-Cl(-) cotransporter (NCC), as well as Cl(-) transporters, such as pendrin. Because aldosterone analogs do not increase blood pressure in Slc26a4(-/-) mice, we asked whether Na(+) excretion and Na(+) transporter protein abundance are altered in kidneys from these mutant mice. Thus wild-type and Slc26a4-null mice were given a NaCl-replete, a NaCl-restricted, or NaCl-replete diet and aldosterone or aldosterone analogs. Abundance of the major renal Na(+) transporters was examined with immunoblots and immunohistochemistry. Slc26a4-null mice showed an impaired ability to conserve Na(+) during dietary NaCl restriction. Under treatment conditions in which circulating aldosterone is increased, alpha-, beta-, and 85-kDa gamma-ENaC subunit protein abundances were reduced 15-35%, whereas abundance of the 70-kDa fragment of gamma-ENaC was reduced similar to 70% in Slc26a4-null relative to wild-type mice. Moreover, ENaC-dependent changes in transepithelial voltage were much lower in cortical collecting ducts from Slc26a4-null than from wild-type mice. Thus, in kidney, ENaC protein abundance and function are modulated by pendrin or through a pendrin-dependent downstream event. The reduced ENaC protein abundance and function observed in Slc26a4-null mice contribute to their lower blood pressure and reduced ability to conserve Na(+) during NaCl restriction. C1 Emory Univ, Sch Med, Dept Med, Div Renal, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Physiol, Div Renal, Atlanta, GA 30322 USA. Wayne State Univ, Sch Med, Detroit, MI USA. Henry Ford Hosp, Hypertens & Vasc Res Div, Detroit, MI 48202 USA. Wellcome Trust Sanger Inst, Cambridge, England. NHGRI, NIH, Genome Technol Branch, Bethesda, MD 20892 USA. Univ Florida, Dept Med, Gainesville, FL USA. Vet Affairs Med Ctr, Atlanta, GA 30033 USA. RP Wall, SM (reprint author), Emory Univ, Sch Med, Dept Med, Div Renal, WMB Rm 338,1639 Pierce Dr NE, Atlanta, GA 30322 USA. EM smwall@emory.edu RI Verlander, Jill/I-5991-2015; OI Pech, Vladimir/0000-0002-1994-4277 FU PHS HHS [P01 061521] NR 47 TC 60 Z9 60 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD OCT PY 2007 VL 293 IS 4 BP F1314 EP F1324 DI 10.1152/ajprenal.00155.2007 PG 11 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 221BE UT WOS:000250201200041 PM 17686956 ER PT J AU Norman, GJ Zabinski, MF Adams, MA Rosenberg, DE Yaroch, AL Atienza, AA AF Norman, Gregory J. Zabinski, Marion F. Adams, Marc A. Rosenberg, Dori E. Yaroch, Amy L. Atienza, Audie A. TI A review of eHealth interventions for physical activity and dietary behavior change SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; DIABETES SELF-MANAGEMENT; WEIGHT-LOSS PROGRAM; PRIMARY-CARE; E-MAIL; INTERACTIVE MULTIMEDIA; MULTICOMPONENT PROGRAM; DECREASE CONSUMPTION; INCREASE CONSUMPTION; NUTRITION BEHAVIOR AB Objective: To review eHealth intervention studies for adults and children that targeted behavior change for physical activity, healthy eating, or both behaviors. Data Sources: Systematic literature searches were performed using five databases: MEDLINE, PsychInfo, CINAHL, ERIC, and the Cochrane Library to retrieve articles. Study Inclusion and Exclusion Criteria: Articles published in scientific journals were included if they evaluated an intervention for physical activity and/or dietary behaviors, or focused on weight loss, used randomized or quasi-experimental designs, measured outcomes at baseline and a follow-up period, and included an intervention where participants interacted with some type of electronic technology either as the main intervention or an adjunct component. All studies were published between 2000 and 2005. Results: Eighty-six publications were initially identified, of which 49 met the inclusion criteria (13 physical activity publications, 16 dietary behaviors publications, and 20 weight loss or both physical activity and diet publications), and represented 47 different studies. Studies were described on multiple dimensions, including sample characteristics, design, intervention, measures, and results. eHealth interventions were superior to comparison groups for 21 of 41 (51%) studies (3 physical activity, 7 diet, 11 weight loss/physical activity and diet). Twenty-four studies had indeterminate results, and in four studies the comparison conditions outperformed eHealth interventions. Conclusions: Published studies of eHealth interventions for physical activity and dietary behavior change are in their infancy. Results indicated mixed findings related to the effectiveness of eHealth interventions. Interventions that feature interactive technologies need to be refined and more rigorously evaluated to fully determine their potential as tools to facilitate health behavior change. C1 Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. Univ Calif San Diego, Joint Doctoral Program Clin Psychol, San Diego, CA 92103 USA. San Diego State Univ, San Diego, CA 92182 USA. Joint Doctoral Program Publ Hlth, San Diego, CA USA. NCI, Bethesda, MD 20892 USA. RP Norman, GJ (reprint author), Univ Calif San Diego, Dept Family & Prevent Med, La Jolla, CA 92093 USA. EM gnorman@paceproject.org RI Adams, Marc/A-2547-2009; Adams, Marc/C-3513-2013 OI Adams, Marc/0000-0001-6310-1472 FU NCI NIH HHS [R01 CA113828-02, R01 CA113828] NR 72 TC 231 Z9 231 U1 14 U2 77 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD OCT PY 2007 VL 33 IS 4 BP 336 EP 345 DI 10.1016/j.amepre.2007.05.007 PG 10 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 217RQ UT WOS:000249965400009 PM 17888860 ER PT J AU Masse, LC Frosh, MM Chriqui, JF Yaroch, AL Agurs-Collins, T Blanck, HM Atienza, AA McKenna, ML Igoe, JF AF Masse, Louise C. Frosh, Marcy M. Chriqui, Jamie F. Yaroch, Amy L. Agurs-Collins, Tanya Blanck, Heidi M. Atienza, Audie A. McKenna, Mary L. Igoe, James F. TI Development of a school nutrition-environment state policy classification system (SNESPCS) SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID INDOOR AIR LAWS; PRICING STRATEGY; RATING SYSTEM; UNITED-STATES; YOUTH-ACCESS; HEALTH; FOOD; CHILDREN; PROGRAMS; CONSUMPTION AB Background: As policy strategies are rapidly being developed to address childhood overweight, a system was developed to systematically and reliably classify state policies related to the school nutrition environment. This study describes the development process, the inter-rater reliability to code state policies enacted as of December 2003, and the variability in state policies related to the school nutrition environment. Methods: The development of the School Nutrition Environment State Policy Classification System (SNESPCS) included a comprehensive review of published literature, reports from government and nongovernmental sources, input from an expert panel, and select experts. Baseline statutes and regulations for each of the 50 states and the District of Columbia were retrieved from Westlaw (data retrieved in 2005-2006 and analyzed in 2006) and pilot testing of the system was conducted. Results: SNESPCS included 11 policy areas that relate to a range of environmental and surveillance domains. At baseline, states had no (advertising/promotion and preferential pricing) or modest (school meal environment, reimbursable school meals, coordinating or advisory councils, body mass index screening) activities in many of the policy areas. As of 2003, 60% of the states had policies related to the sale of foods in school that compete with the school meal program. Conclusions: Evaluation of policies that affect the school-nutrition environment is in its earliest stage. SNESPCS provides a mechanism for assessing variation in state policies that can be incorporated in an evaluation framework aimed at elucidating the impact of state policies on the school environment, social norms, and children's dietary behaviors in schools. C1 Univ British Columbia, Ctr Community Child Hlth Res, Vancouver, BC V5Z 1M9, Canada. MayaTech Corp, Ctr Hlth Policy & Legislat Anal, Silver Spring, MD USA. Natl Canc Inst, Hlth Promot Res Branch, Bethesda, MD USA. Ctr Dis Control & Prevent, Div Nutr & Phys Act, Atlanta, GA USA. Univ New Brunswick, Fac Kinesiol, Fredericton, NB, Canada. RP Masse, LC (reprint author), Univ British Columbia, Ctr Community Child Hlth Res, Dept Pediat, L408-4480 Oak St, Vancouver, BC V6H 3V4, Canada. EM lmasse@cw.bc.ca FU NCI NIH HHS [N02-PC-444006]; PHS HHS [263-MQ-515012] NR 65 TC 33 Z9 33 U1 1 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD OCT PY 2007 VL 33 IS 4 SU S BP S277 EP S291 DI 10.1016/j.amepre.2007.07.017 PG 15 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 220ZW UT WOS:000250197100018 PM 17884576 ER PT J AU Masse, LC Chriqui, JF Igoe, JF Atienza, AA Kruger, J Kohl, HW Frosh, MM Yaroch, AL AF Masse, Louise C. Chriqui, Jamie F. Igoe, James F. Atienza, Audie A. Kruger, Judy Kohl, Harold W., III Frosh, Marcy M. Yaroch, Amy L. TI Development of a physical education-related state policy classification system (PERSPCS) SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Article ID RATING SYSTEM; UNITED-STATES; OVERWEIGHT; PROGRAM; OBESITY; FITNESS; SCHOOLS; SPARK; LAWS AB Background: As policy-based approaches are increasingly proposed to address childhood obesity, this paper seeks to: (1) present the development of a system to systematically and reliably assess the nature and extent of state physical education (PE) and recess-related policies; (2) determine the inter-rater agreement in using the system; and (3) report on the variability in state policies using a December 31, 2003 baseline. Methods: The PE and Recess State Policy Classification System (PERSPCS) was developed from a conceptual framework and was informed by reviewing the scientific and gray literatures and through consultations with an expert panel and key experts. Statutes and regulations enacted as of December 31, 2003 were retrieved from Westlaw (data retrieved and analyzed in 2004-2005). Results: PERSPCS addresses five areas: PE time requirements, staffing requirements for PE, curriculum standards for PE, assessment of health-related fitness, and recess time (elementary schools only). The inter-rater agreement ranged from 0.876 (PE staffing requirements) to perfect agreement (recess time). Staffing requirements had more restrictive policies, followed in decreasing order by time requirements, curriculum standards, assessment, and recess time. Overall, state policies met minimal requirements across areas and grade levels as of December 2003. Conclusions: Extending PERSPCS to address other aspects of childhood obesity is a critical first step in understanding the range of state policy approaches in this area and their impact. PERSPCS should be examined in conjunction with school district-level policies to determine the overall effects of policies on school environmental and behavioral outcomes. PERSPCS is not designed to set policy guidelines. C1 Univ British Columbia, Ctr Community Child Hlth Res, Vancouver, BC, Canada. MayaTech Corp, Ctr Hlth Policy & Legislative Anal, Silver Spring, MD USA. Natl Canc Inst, Hlth Promot Res Branch, Bethesda, MD USA. Ctr Dis Control & Prevent, Div Nutr & Phys Act, Atlanta, GA USA. RP Masse, LC (reprint author), Univ British Columbia, Ctr Community Child Hlth Res, Dept Pediat, L408-4480 Oak St, Vancouver, BC V6H 3V4, Canada. EM lmasse@cw.bc.ca FU PHS HHS [282-98-0014, 263-MQ-515012] NR 43 TC 26 Z9 26 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD OCT PY 2007 VL 33 IS 4 SU S BP S264 EP S276 DI 10.1016/j.amepre.2007.07.019 PG 13 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 220ZW UT WOS:000250197100017 PM 17884575 ER PT J AU Springer, DA Baker, KC AF Springer, Danielle A. Baker, Kate C. TI Effect of ketamine anesthesia on daily food intake in Macaca mulatta and Cercopithecus aethiops SO AMERICAN JOURNAL OF PRIMATOLOGY LA English DT Article DE rhesus macaque; African green monkey; anorexia; stress; non-human primate; research variables; food intake ID PEDIATRIC EMERGENCY-DEPARTMENT; URINARY CORTISOL RESPONSES; LOW-DOSE KETAMINE; RHESUS-MONKEYS; VERVET MONKEYS; LONGTAILED MACAQUES; PROCEDURAL SEDATION; ROOM CHANGE; CAGE SIZES; CHILDREN AB Ketamine hydrochloride is frequently administered to non-human primates as a means of chemical restraint. This procedure can be a frequent source of stress to monkeys at research facilities, impacting animal health, well-being and research quality. This study was designed to measure ketamine's effect on daily food intake, a parameter that reflects and influences animal well-being and directly impacts research studies. On five occasions, baseline daily food intake was compared to daily food intake occurring 24, 48, 72, 96, and 120 h after an intramuscular injection of 10 mg/kg ketamine in male African green monkeys (AGMs) (Cercopithecus aethiops) and male and female rhesus macaques (Macaca mulatta). AGMs and female rhesus macaques had significantly reduced daily food intake during the first 4 days after receiving ketamine. The AGMs continued to display significantly reduced daily food intake on the fifth day after ketamine. The male rhesus macagues showed a trend toward reduced daily food intake, greatest during the first 2 days and remaining less than baseline intake through the fifth day following ketamine. The degree of observed food intake reduction was most severe at the 24 h (mean percent intake reduction: AGMs: 57%; rhesus males: 48%; rhesus females: 40%) and 48 h time points (AGMs: 24%; rhesus males: 14%; rhesus females: 13%). A subset of the AGMs that did not receive ketamine, but observed other animals in the room receive ketamine, showed reduced food intake at 24 and 48 h after ketamine, though not to the degree associated with ketamine administration. These results indicate that ketamine anesthesia is associated with a prolonged reduction in daily food intake in AGMs and rhesus macaques. Frequent use of ketamine in non-human primates may have a significant impact on animal health and well-being, and alternatives to its use warrant consideration. C1 NHLBI, NIH, Bethesda, MD 20892 USA. Tulane Natl Primate Res Ctr, Covington, LA USA. RP Springer, DA (reprint author), NHLBI, NIH, 9000 Rockville Pike,Bldg 14E,Rm 107A,14 Serv Rd W, Bethesda, MD 20892 USA. EM ds628k@nih.gov FU NCRR NIH HHS [5P51-RR00164, G20 RR05169, G20 RR016930, G20 RR019628, G20 RR018397, G20 RR013466, 1C06 RR012112] NR 44 TC 13 Z9 13 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0275-2565 J9 AM J PRIMATOL JI Am. J. Primatol. PD OCT PY 2007 VL 69 IS 10 BP 1080 EP 1092 DI 10.1002/ajp.20421 PG 13 WC Zoology SC Zoology GA 211GO UT WOS:000249512500002 PM 17330308 ER PT J AU Laje, G Paddock, S Manji, H Rush, AJ Wilson, AF Charney, D McMahon, FJ AF Laje, Gonzalo Paddock, Silvia Manji, Husseini Rush, A. John Wilson, Alexander F. Charney, Dennis McMahon, Francis J. TI Genetic markers of suicidal ideation emerging during citalopram treatment of major depression SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 14th World Congress on Psychiatric Genetics CY OCT 28-NOV 01, 2006 CL Cagliari, ITALY SP Int Soc Psychiat Genet ID STAR-ASTERISK-D; SEQUENCED TREATMENT ALTERNATIVES; REPORT QIDS-SR; ANTIDEPRESSANT TREATMENT; QUICK INVENTORY; PSYCHOMETRIC EVALUATION; RATING-SCALE; ASSOCIATION; SYMPTOMATOLOGY; POLYMORPHISMS AB Objective: Suicidal ideation is an uncommon symptom than can emerge during antidepressant treatment. The biological basis of treatment-emergent suicidal ideation is unknown. Genetic markers may shed light on the causes of treatment-emergent suicidal ideation and help identify individuals at high risk who may benefit from closer monitoring, alternative treatments, or specialty care. Method: A clinically representative cohort of outpatients with major depressive disorder who enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial were treated with citalopram under a standard protocol for up to 14 weeks. DNA samples from 1,915 participants were genotyped for 768 single-nucleotide polymorphisms in 68 candidate genes. Allele and genotype frequencies were compared between the 120 participants who developed treatment-emergent suicidal ideation and those who did not. Results: Two markers were significantly associated with treatment-emergent suicidal ideation in this sample (marker rs4825476, p = 0.0000784, odds ratio = 1.94; permutation p = 0.01; marker rs2518224, p = 0.0000243, odds ratio = 8.23; permutation p = 0.003). These markers reside within the genes GRIA3 and GRIK2, respectively, both of which encode ionotropic glutamate receptors. Conclusions: Markers within GRIK2 and GRIA3 were associated with treatment-emergent suicidal ideation during citalopram therapy. if replicated, these findings may shed light on the biological basis of this potentially dangerous adverse event and help identify patients at increased risk. C1 NIMH, Genet Basis Mood & Anxiety Disorders Unit, Bethesda, MD 20892 USA. NIMH, Mol Pathophysiol Lab, Mood & Anxiety Program, Bethesda, MD 20892 USA. Univ Texas, SW Med Ctr, Dept Clin Sci, Dallas, TX 75230 USA. Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX 75230 USA. NHGRI, Inherited Dis Res Branch, Genometr Sect, NIH, Baltimore, MD USA. Mt Sinai Sch Med, New York, NY USA. RP Laje, G (reprint author), NIMH, Genet Basis Mood & Anxiety Disorders Unit, 35 Convent Dr,Rm 1A207, Bethesda, MD 20892 USA. EM gonzalo.laje@nih.gov RI Laje, Gonzalo/L-2654-2014; McMahon, Francis/A-7290-2009; Wilson, Alexander/C-2320-2009; OI Laje, Gonzalo/0000-0003-2763-3329; Rush, Augustus/0000-0003-2004-2382; McMahon, Francis/0000-0002-9469-305X FU Intramural NIH HHS; NIMH NIH HHS [N01MH90003] NR 38 TC 136 Z9 140 U1 1 U2 3 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD OCT PY 2007 VL 164 IS 10 BP 1530 EP 1538 DI 10.1176/appi.ajp.2007.06122018 PG 9 WC Psychiatry SC Psychiatry GA 218XP UT WOS:000250049600017 PM 17898344 ER PT J AU Rosas, IO Ren, P Avila, NA Chow, CK Franks, TJ Travis, WD McCoy, JP May, RM Wu, HP Nguyen, DM Arcos-Burgos, M MacDonald, SD Gochuico, BR AF Rosas, Ivan O. Ren, Ping Avila, Nilo A. Chow, Catherine K. Franks, Teri J. Travis, William D. McCoy, J. Philip, Jr. May, Rose M. Wu, Hai-Ping Nguyen, Dao M. Arcos-Burgos, Mauricio MacDonald, Sandra D. Gochuico, Bernadette R. TI Early interstitial lung disease in familial pulmonary fibrosis SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE idiopathic pulmonary fibrosis; interstitial lung disease; high-resolution computed tomography; bronchoalveolar lavage; asymptomatic interstitial lung disease ID HERMANSKY-PUDLAK-SYNDROME; BRONCHOALVEOLAR LAVAGE; T-CELLS; SURVIVAL; THERAPY; GENE; ALVEOLITIS; PNEUMONIA; FEATURES; FLUID AB Rationale:Identification of early, asymptomatic interstitial lung disease (ILD) in populations at risk of developing idiopathic pulmonary fibrosis (IPF) may improve the understanding of the natural history of IPF. Objectives: To determine clinical, radiographic, physiologic, and pathologic features of asymptomatic ILD in family members of patients with familial IPF. Methods: One hundred sixty-four subjects from 18 kindreds affected with familial IPF were evaluated for ILD. Bronchoalveolar lavage fluid cells were analyzed using flow cytometry. Lung biopsies were performed in six subjects with asymptomatic ILD. Measurements and Main Results: High-resolution computed tomography abnormalities suggesting ILD were identified in 31 (22%) of 143 asymptomatic subjects. Subjects with asymptomatic ILD were significantly younger than subjects with known familial IPF (P < 0.001) and significantly older than related subjects without lung disease (P < 0.001). A history of smoking was identified in 45% of subjects with asymptomatic ILD and in 67% of subjects with familial IPF; these percentages were significantly higher than that of related subjects without lung disease (23%) (P = 0.02 and P < 0.001, respectively). Percentages of activated CD4(+) lymphocytes were significantly higher in bronchoalveolar lavage fluid cells from subjects with asymptomatic ILD compared with related subjects without lung disease (P < 0.001). Lung biopsies performed in subjects with asymptomatic ILD revealed diverse histologic subtypes. Conclusions: Asymptomatic ILID in individuals at risk of developing familial IPF can be identified using high-resolution computed tomography scan of the chest, especially in those with a history of smoking. Lung biopsies from individuals in this cohort with early asymptomatic lung disease demonstrate various histologic subtypes of ILD. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. NIH, Diagnost Radiol Dept, Ctr Clin, Bethesda, MD 20892 USA. Armed Forces Inst Pathol, Dept Pulm & Mediastinal Pathol, Washington, DC 20306 USA. NHLBI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. NCI, Surg Branch, NIH, Bethesda, MD 20892 USA. Natl Human Genome Res Inst, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Gochuico, BR (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. EM gochuicb@mail.nih.gov FU Intramural NIH HHS NR 31 TC 66 Z9 72 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 25 BROADWAY, 18 FL, NEW YORK, NY 10004 USA SN 1073-449X EI 1535-4970 J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD OCT 1 PY 2007 VL 176 IS 7 BP 698 EP 705 DI 10.1164/rccm.200702-254OC PG 8 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 215SP UT WOS:000249829600012 PM 17641157 ER PT J AU Ocak, I Bernardo, M Metzger, G Barrett, T Pinto, P Albert, PS Choyke, PL AF Ocak, Iclal Bernardo, Marcelino Metzger, Greg Barrett, Tristan Pinto, Peter Albert, Paul S. Choyke, Peter L. TI Dynamic contrast-enhanced MRI of prostate cancer at 3 T: A study of pharmacokinetic parameters SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE dynamic contrast-enhanced MRI; genitourinary imaging; MRI; pharmacokinetics; prostate cancer ID ENDORECTAL MR; TUMOR VOLUME; 3 TESLA; LOCALIZATION; CARCINOMA; BIOPSY; GLAND; DISCRIMINATION; EXPERIENCE; SPECIMENS AB OBJECTIVE. The objectives of our study were to determine whether dynamic contrast-enhanced MRI performed at 3 T and analyzed using a pharmacokinetic model improves the diagnostic performance of MRI for the detection of prostate cancer compared with conventional T2-weighted imaging, and to determine which pharmacokinetic parameters are useful in diagnosing prostate cancer. SUBJECTS AND METHODS. This prospective study included 50 consecutive patients with biopsy-proven prostate cancer who underwent imaging of the prostate on a 3-T scanner with a combination of a sensitivity-encoding (SENSE) cardiac coil and an endorectal coil. Scans were obtained at least 5 weeks after biopsy. T2-weighted turbo spin-echo images were obtained in three planes, and dynamic contrast-enhanced images were acquired during a single-dose bolus injection of gadopentetate dimeglumine (0.1 mmol/kg). Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were estimated for T2-weighted and dynamic contrast-enhanced MRI. The following pharmacokinetic modeling parameters were determined and compared for cancer, inflammation, and healthy peripheral zone: K-trans (forward volume transfer constant), k(ep) (reverse reflux rate constant between extracellular space and plasma), v, (the fractional volume of extracellular space per unit volume of tissue), and the area under the gadolinium concentration curve (AUGC) in the first 90 seconds after injection. RESULTS. Pathologically confirmed cancers in the peripheral zone of the prostate were characterized by their low signal intensity on T2-weighted scans and by their early enhancement, early washout, or both on dynamic contrast-enhanced MR images. The overall sensitivity, specificity, PPV, and NPV of T2-weighted imaging were 94%, 37%, 50%, and 89%, respectively. The sensitivity, specificity, PPV, and NPV of dynamic contrast-enhanced MRI were 73%, 88%, 75%, and 75%, respectively. K-trans, k(ep), and AUGC were significantly higher (p < 0.001) in cancer than in normal peripheral zone. The v(e) parameter was not significantly associated with prostate cancer. CONCLUSION. MRI of the prostate performed at 3 T using an endorectal coil produces high-quality T2-weighted images; however, specificity for prostate cancer is improved by also performing dynamic contrast-enhanced MRI and using pharmacokinetic parameters, particularly K-trans and k(ep), for analysis. These results are comparable to published results at 1.5 T. C1 NCI, Mol Imaging Program, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Mol Imaging Program, SAIC Frederick Inc, Frederick, MD 21701 USA. NCI, Res Technol Program, SAIC Frederick Inc, Frederick, MD 21701 USA. Univ Minnesota, Ctr Magnet Resonance Res, Minneapolis, MN USA. NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Ocak, I (reprint author), Univ Pittsburgh, Med Ctr, Dept Radiol, 200 Lothrop St, Pittsburgh, PA 15213 USA. EM ocaki@upmc.edu NR 43 TC 60 Z9 61 U1 1 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD OCT PY 2007 VL 189 IS 4 BP W192 EP W201 DI 10.2214/AJR.06.1329 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 212KS UT WOS:000249595800019 ER PT J AU Merino, MJ Torres-Cabala, C Pinto, P Linehan, WM AF Merino, Maria J. Torres-Cabala, Carlos Pinto, Peter Linehan, William Marston TI The morphologic spectrum of kidney tumors in hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE renal cancer; hereditary renal syndrome; skin and; uterine leiomyomata; fumarate hydratase ID HOGG-DUBE-SYNDROME; COLLECTING DUCT CARCINOMA; CUTANEOUS LEIOMYOMATOSIS; SPONTANEOUS PNEUMOTHORAX; UTERINE LEIOMYOMAS; SOMATIC MUTATIONS; CANCER; GENE; NEOPLASMS; CLASSIFICATION AB Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an autosomal dominant familial syndrome characterized by the development of cutaneous and uterine leiomyomas as well as renal tumors. The mutation of this condition has been identified in the fumarate hydratase (FH, 1q42.3-q43) gene. The histology of the renal cancers has not been well described or illustrated because of the newness of the syndrome. We reviewed 40 renal tumors resected from 38 patients belonging to HLRCC families with proven fumarate hydratase germline mutation. Patients ranged in age from 17 to 75 years of age. Tumors were unilateral in all but 2 cases. The size of the tumors varied between 2.3 and 20 cm and there was no laterality preference. Several different architectural patterns were recognized: papillary (25 cases), tubulo-papillary (8 cases), tubular (2 cases), and solid (I case). Mixed patterns were also present in 4 cases. The most important histologic feature of these neoplasms, which we believe to be the hallmark of the HLRCC tumors, is the presence of a characteristic large nucleus with a very prominent inclusion like orangiophilic or eosinophilic nucleolus, surrounded by a clear halo. Immunohistochemical studies did not provide a specific marker for these tumors, however, loss of heterozygosity at 1q32 and 1q42-44 was frequently found. These tumors are associated with poor prognosis and frequent spread to regional lymph nodes. At the moment, morphology is the best tool to recognize these tumors. Proper diagnosis of this syndrome by the pathologist may assist in early detection of these tumors. C1 NCI, Pathol Lab, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. RP Merino, MJ (reprint author), NCI, Pathol Lab, Bldg 10,Rm 2N212, Bethesda, MD 20892 USA. EM mjmerino@mail.nih.gov NR 29 TC 118 Z9 121 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2007 VL 31 IS 10 BP 1578 EP 1585 PG 8 WC Pathology; Surgery SC Pathology; Surgery GA 217TE UT WOS:000249969400016 PM 17895761 ER PT J AU Mao, ZR Quintanilla-Martinez, L Raffeld, M Richter, M Krugmann, J Burek, C Hartmann, E Rudiger, T Jaffe, ES Muller-Hermelink, HK Ott, G Fend, F Rosenwald, A AF Mao, Zhengrong Quintanilla-Martinez, Leticia Raffeld, Mark Richter, Manfred Krugmann, Jens Burek, Christof Hartmann, Elena Rudiger, Thomas Jaffe, Elaine S. Mueller-Hermelink, Hans Konrad Ott, German Fend, Falko Rosenwald, Andreas TI IgVH mutational status and clonality analysis of Richter's transformation - Diffuse large B-cell lymphoma and Hodgkin lymphoma in association with B-cell chronic lymphocytic leukemia (B-CLL) represent 2 different pathways of disease evolution SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE Richter's transformation; clonality analysis; IgH mutational analysis; B-cell chronic lymphocytic leukemia; Hodgkin lymphoma; microdissection ID EPSTEIN-BARR-VIRUS; HEAVY-CHAIN GENE; V-H GENES; GENOMIC ABERRATIONS; ANTIGEN RECEPTORS; STERNBERG CELLS; TELOMERE LENGTH; CD38 EXPRESSION; ORIGIN; SURVIVAL AB Approximately 5% of B-cell chronic lymphocytic leukemia (B-CLL) patients develop a secondary aggressive lymphoma, usually of diffuse large B-cell type (DLBCL), termed Richter's transformation (RT). Rarely, classic Hodgkin lymphoma (HL) is observed. Published small series suggest that tumor cells in DLBCL and HL can be clonally identical to the B-CLL clone or arise as an independent, secondary lymphoma. We describe the morphology, immunophenotype, and clinical features of 34 classic RT patients with DLBCL, 6 cases of B-CLL with HL, and 8 cases with scattered CD30-positive Hodgkin and Reed-Sternberg (HRS)-like cells. The clonal relationship of the 2 components was analyzed using sequencing analysis of immunoglobulin heavy chain variable region (IgVH) genes. In classic RT, 18/23 B-CLL cases (78%) showed clonal progression to DLBCL with identical IgVH sequences in both lymphoma components, whereas in 5 cases (22%) the DLBCL was clonally unrelated. Among clonally related RT samples, 73% carried unmutated IgVH genes, whereas 4/5 unrelated cases were mutated. Immunophenotypically, most cases of DLBCL irrespective of clonal relatedness showed significant differences in phenotype compared with the B-CLL, with common loss of CD5 and CD23. Using immuno-laser capture microdissection, sequencing of the IgVH CDR3 region of isolated HRS cells showed that 2/2 cases with HL were clonally unrelated, whereas they were clonally identical in 1/2 cases of B-CLL with scattered HRS-like cells. HRS or HRS-like cells in all 3 unrelated cases showed evidence of Epstein-Barr virus infection. Of interest, 5/6 cases of B-CLL with HL, and 5/6 cases of B-CLL with HRS cells showed mutated IgVH genes. C1 GSF, Natl Res Ctr Hlth & Environm, Neuherberg, Germany. Univ Wurzburg, Inst Pathol, D-97070 Wurzburg, Germany. NCI, Pathol Lab, Hematopathol Sect, Bethesda, MD 20892 USA. Univ Innsbruck, Inst Pathol, A-6020 Innsbruck, Austria. RP Mao, ZR (reprint author), Tech Univ Munich, Inst Pathol, Ismaningerstr 22, D-81675 Munich, Germany. EM fend@lrz.tum.de NR 44 TC 73 Z9 75 U1 1 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD OCT PY 2007 VL 31 IS 10 BP 1605 EP 1614 PG 10 WC Pathology; Surgery SC Pathology; Surgery GA 217TE UT WOS:000249969400019 PM 17895764 ER PT J AU Wieacker, P Stratakis, CA Horvath, A Klose, S Nickel, I Muschke, P AF Wieacker, P. Stratakis, C. A. Horvath, A. Klose, S. Nickel, I. Muschke, P. TI Male infertility as a component of Carney complex SO ANDROLOGIA LA English DT Article DE carney complex; infertility AB Carney complex (CNC) is a multiple neoplasia syndrome characterised by endocrine tumours, spotty skin pigmentation, cardiac and other myxomas, psamommatous and pigmented schwannomas, large cell calcifying Sertoli cell tumours, and mammary ductal adenomas and other more rare lesions. CNC is inherited in an autosomal-dominant manner and has been mapped to at least two chromosomal loci. Patients who map to the CNC1 locus located on chromosome 17 carry inactivating mutations of the PRKAR1A gene that encodes the cAMP-dependent protein kinase regulatory subunit type 1-alpha (Kirschner et al., 2000). One gene responsible for type 2 (CNC2) is located on chromosome 2p16. Infertility in CNC can be caused by a number of factors; there is evidence that prkar1a deficiency in mice leads directly to infertility (Burton et al., 2006), but patients with CNC also have Sertoli cell tumours and a number of other reasons to affect fertility. We report on an infertile male with CNC and present evidence that male infertility should be considered as part of the phenotype of CNC. C1 Univ Munster, Inst Human Genet, D-48149 Munster, Germany. Otto Von Guericke Univ, Inst Human Genet, Magdeburg, Germany. NICHD, Dev Endocrinol Branch, Sect Endocrinol & Genet, NIH, Bethesda, MD USA. Otto Von Guericke Univ, Clin Endocrinol, Magdeburg, Germany. Otto Von Guericke Univ, Clin Gynecol Endocrinol & Reprod Med, Magdeburg, Germany. RP Wieacker, P (reprint author), Univ Munster, Inst Human Genet, Vesaliusweg 12-14, D-48149 Munster, Germany. EM wieacker@uni-muenster.de FU Intramural NIH HHS NR 5 TC 9 Z9 10 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0303-4569 J9 ANDROLOGIA JI Andrologia PD OCT PY 2007 VL 39 IS 5 BP 196 EP 197 DI 10.1111/j.1439-0272.2007.00784.x PG 2 WC Andrology SC Endocrinology & Metabolism GA 200JX UT WOS:000248760800006 PM 17714219 ER PT J AU Hopenfeld, B Ashikaga, H McVeigh, ER AF Hopenfeld, Bruce Ashikaga, Hiroshi McVeigh, Elliot R. TI Geodesic based registration of sensor data and anatomical surface image data SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE registration; geodesics; spherical harmonics ID HEART; BRAIN AB This paper presents two related methods for registering an image of an anatomical object with data from sensors arranged on the object. One method is described with reference to a test case involving a rectangular electrode plaque disposed on a heart surface, which is imaged with MRI. Data from the electrodes is fused with the MRI image at the appropriate locations. The registration scheme involves four parts. First, selected landmarks on a data surface (e.g., electrode plaque) are registered to known locations on a target anatomical surface image. Second, the anatomical surface is represented numerically with a spherical harmonic expansion. Third, given the registration of the select data surface landmarks, the location of the outer four corners of the rectangular electrode plaque are located on the anatomical surface. Fourth, a quasi-evenly spaced grid within these four corners is formed on the anatomical surface. The third and fourth steps involve calculating geodesics on the anatomical surface, preferably by utilizing the spherical harmonic expansion. According to the second registration method, spherical harmonics and geodesics are used to extract a mesh from the anatomical surface. Laplace's equation is solved on this mesh to generate a mapping from the anatomical surface to the data surface (electrode plaque). C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Hopenfeld, B (reprint author), NHLBI, NIH, 10 Ctr Dr,MSC 1061, Bethesda, MD 20892 USA. EM brhopenfeld@yahoo.com OI Ashikaga, Hiroshi/0000-0003-3689-6892 FU Intramural NIH HHS [Z01 HL004609-04]; NHLBI NIH HHS [Z01 HL004609] NR 10 TC 4 Z9 4 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0090-6964 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD OCT PY 2007 VL 35 IS 10 BP 1771 EP 1781 DI 10.1007/s10439-007-9350-6 PG 11 WC Engineering, Biomedical SC Engineering GA 212RW UT WOS:000249615500012 PM 17616820 ER PT J AU Nguyen, RHN Wilcox, AJ Moen, BE McConnaughey, DR Lie, RT AF Nguyen, Ruby H. N. Wilcox, Allen J. Moen, Bente E. McConnaughey, D. Robert Lie, Rolv T. TI Parent's occupation and isolated orofacial clefts in Norway: A population-based case-control study SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE occupations; cleft lip; cleft palate; abnormalities; parents ID ORAL CLEFTS; BIRTH-DEFECTS; CONGENITAL-MALFORMATIONS; PATERNAL OCCUPATION; RISK-FACTORS; DEVELOPMENTAL TOXICITY; MATERNAL OCCUPATION; EXPOSURE; PREGNANCY; CORTICOSTEROIDS AB PURPOSE: Occupational factors have been associated with risk of orofacial clefts in offspring, although data are limited. We explored associations between parent's occupation and isolated orofacial clefts using a population-based case-control study. METHODS: Cases were restricted to infants born with an isolated orofacial cleft in Norway during the period 1996 to 2001 (314 with cleft lip with or without palate [CLP] and 118 with cleft palate only [CPO]). Controls (n = 763) were chosen randomly from all Norwegian live births. We considered full-time employment during the first 3 months of pregnancy. RESULTS: Several maternal occupations previously associated with clefts showed some evidence of association, including hairdressers (CLP; adjusted odds ratio = 4.8; 95% confidence interval [CI]: 0.99-23). Mothers working in manufacturing and in food production had increased odds for babies with CPO (3.8; 1.3-11, and 7. 1; 1.5-33, respectively). Among fathers' occupations previously associated with clefts, an association was suggested for woodworking both for CLP (1.7; 0.85-3.2) and for CPO (2.0; 0.82-4-7). Fathers working as professional housekeepers showed substantial increased odds of CPO (12; 3.3-46). CONCLUSIONS: Taken together with previous studies, these results suggest that exposures in certain occupations may influence the risk of orofacial clefting in offspring. Specific exposures accompanying these occupations warrant exploration. (C) 2007 Elsevier Inc. All rights reserved. C1 NIEHS, NIH, Durham, NC USA. Westat Corp, Durham, NC USA. Norwegian Inst Publ Hlth, Bergen, Norway. Univ Bergen, Bergen, Norway. Med Birth Registry Norway, Bergen, Norway. RP Nguyen, RHN (reprint author), 111 TW Alexander Dr,POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM nguyen5@niehs.nih.gov OI Wilcox, Allen/0000-0002-3376-1311 FU Intramural NIH HHS NR 37 TC 16 Z9 16 U1 1 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD OCT PY 2007 VL 17 IS 10 BP 763 EP 771 DI 10.1016/j.annepidem.2007.04.008 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 219EJ UT WOS:000250067200002 PM 17664071 ER PT J AU Colantonio, I Russi, E Numico, G Vigna-Taglianti, R Di Costanzo, G Vigo, V Bacigalupo, A Vitiello, R Benasso, M Merlano, M AF Colantonio, Ida Russi, Elvio Numico, Gianmauro Vigna-Taglianti, Riccardo Di Costanzo, Gianna Vigo, V. Bacigalupo, A. Vitiello, R. Benasso, M. Merlano, M. TI Cetuximab (C-MAB) and chemo-radiation for loco-regional advanced squamous cell carcinoma of the head and neck (HNC). A phase II study SO ANNALS OF ONCOLOGY LA English DT Meeting Abstract CT 9th National Congress of Medical Oncology CY OCT 12-15, 2007 CL Palermo, ITALY C1 [Vigo, V.; Bacigalupo, A.; Benasso, M.] Natl Canc Inst, Genoa, Italy. [Colantonio, Ida; Russi, Elvio; Numico, Gianmauro; Vigna-Taglianti, Riccardo; Di Costanzo, Gianna; Merlano, M.] S Croce Gen Hosp, Cuneo, Italy. [Vitiello, R.] SS Annunziata Gen Hosp, Savigliano, Italy. NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0923-7534 J9 ANN ONCOL JI Ann. Oncol. PD OCT PY 2007 VL 18 SU 11 BP 83 EP 83 PG 1 WC Oncology SC Oncology GA 264WX UT WOS:000253322200348 ER PT J AU Rowley, AK Resman-Targoff, BH Marra, CA Pucino, F AF Rowley, Ayana K. Resman-Targoff, Beth H. Marra, Carlo A. Pucino, Frank TI Evolution of clinical pharmacy in the practice of rheumatology SO ANNALS OF PHARMACOTHERAPY LA English DT Article ID DRUG-RELATED PROBLEMS; TOPHACEOUS GOUT; ARTHRITIS; RASBURICASE C1 NIH, Ctr Clin, Dept Pharm, Bethesda, MD 20892 USA. Univ Oklahoma, Hlth Sci Ctr, Coll Pharm, Dept Pharm Clin & Adm Sci, Oklahoma City, OK 73190 USA. Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC V5Z 1M9, Canada. RP Rowley, AK (reprint author), NIH, Ctr Clin, Dept Pharm, Bldg 10,Room 1N257,10 Ctr Dr, Bethesda, MD 20892 USA. EM rowleya@mail.nih.gov NR 22 TC 1 Z9 1 U1 1 U2 2 PU HARVEY WHITNEY BOOKS CO PI CINCINNATI PA PO BOX 42696, CINCINNATI, OH 45242 USA SN 1060-0280 J9 ANN PHARMACOTHER JI Ann. Pharmacother. PD OCT PY 2007 VL 41 IS 10 BP 1705 EP 1707 DI 10.1345/aph.1K275 PG 3 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 215EA UT WOS:000249789900018 PM 17848418 ER PT J AU Flynn, PM Rodman, J Lindsey, JC Robbins, B Capparelli, E Knapp, KM Rodriguez, JF McNamara, J Serchuck, L Heckman, B Martinez, J AF Flynn, Patricia M. Rodman, John Lindsey, Jane C. Robbins, Brian Capparelli, Edmund Knapp, Katherine M. Rodriguez, Jose F. McNamara, James Serchuck, Leslie Heckman, Barbara Martinez, Jaime CA PACTG P1012 Team TI Intracellular pharmacokinetics of once versus twice daily zidovudine and lamivudine in adolescents SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; STEADY-STATE PHARMACOKINETICS; BLOOD MONONUCLEAR-CELLS; CUBIC MILLIMETER; HIV-INFECTION; CARTRIDGE RADIOIMMUNOASSAY; THERAPY; PHOSPHORYLATION; TRIPHOSPHATE; MODEL AB Zidovudine (ZDV) and lamivudine (3TC) metabolism to triphosphates (TP) is necessary for antiviral activity. The aims of this study were to compare ZDV-TP and 3TC-TP concentrations in adolescents receiving twice daily (BID) and once daily (QD) regimens and to determine the metabolite concentrations of ZDV and 3TC during chronic therapy on a QD regimen. Human immunodeficiency virus-infected patients (12 to 24 years) taking ZDV (600 mg/day) and 3TC (300 mg/day) as part of a highly active antiretroviral therapy regimen received QD and BID regimens of ZDV and 3TC for 7 to 14 days in a crossover design. Serial blood samples were obtained over 24 h on the QD regimen. Intracellular mono-, di-, and triphosphates for ZDV and 3TC were measured. The median ratio of BID/QD for ZDV-TP predose concentrations was 1.28 (95% confidence interval [CI] = 1.00 to 2.45) and for 3TC-TP was 1.12 (95% CI = 0.81 to 1.96). The typical population estimated half-lives (+/- the standard error of the mean) were 9.1 +/- 0.859 h for ZDV-TP and 17.7 +/- 2.8 h for 3TC-TP. Most patients had detectable levels of the TP of ZDV (24 of 27) and 3TC (24 of 25) 24 h after dosing, and half-lives on a QD regimen were similar to previously reported values when the drugs were given BID. Lower, but not significantly different, concentrations of ZDV-TP were demonstrated in the QD regimen compared to the BID regimen (P = 0.056). Although findings were similar between the BID and QD groups, the lower concentrations of ZDV and the number of patients below the level of detection after 24 h suggests that ZDV should continue to be administered BID. C1 St Jude Childrens Hosp, Dept Infect Dis, Memphis, TN 38105 USA. Univ Tennessee, Ctr Hlth Sci, Dept Pediat, Memphis, TN 38163 USA. St Jude Childrens Hosp, Dept Pharmaceut Sci, Memphis, TN 38105 USA. Harvard Sch Pub Hlth, Stat & Data Anal Ctr, Boston, MA USA. Univ Calif San Diego, Pediat Pharmacol Res Unit, La Jolla, CA 92093 USA. Univ Puerto Rico, Dept Biochem, San Juan, PR 00936 USA. Puerto Rico Forens Sci Inst, San Juan, PR 00936 USA. NIH, NIAID, Bethesda, MD 20892 USA. NIH, NICHD, Bethesda, MD 20892 USA. Frontier Sci & Technol Res Fdn Inc, Amherst, NY USA. John H Stroger Jr Hosp Cook Cty, CORE Ctr, Chicago, IL USA. RP Flynn, PM (reprint author), St Jude Childrens Hosp, Dept Infect Dis, 332 N Lauderdale, Memphis, TN 38105 USA. EM pat.flynn@stjude.org FU NIAID NIH HHS [U01 AI041089, U01 AI41089]; NIBIB NIH HHS [P41 EB001978] NR 28 TC 14 Z9 15 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD OCT PY 2007 VL 51 IS 10 BP 3516 EP 3522 DI 10.1128/AAC.01626-06 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 215FX UT WOS:000249794800007 PM 17664328 ER PT J AU Hope, WW Seibel, NL Schwartz, CL Arrieta, A Flynn, P Shad, A Albano, E Keirns, JJ Buell, DN Gumbo, T Drusano, GL Walsh, TJ AF Hope, William W. Seibel, Nita L. Schwartz, Cindy L. Arrieta, Antonio Flynn, Patricia Shad, Aziza Albano, Edythe Keirns, James J. Buell, Donald N. Gumbo, Tawanda Drusano, George L. Walsh, Thomas J. TI Population pharmacokinetics of micafungin in pediatric patients and implications for antifungal dosing SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID INVASIVE FUNGAL-INFECTIONS; CHILDREN; SAFETY; TOLERABILITY; ECHINOCANDIN; CANDIDEMIA; INFANTS; SIZE; RISK AB The echinocandins potentially have an important role in treatment of infections caused by Candida spp. and Aspergillus spp. in inummocompromised children. However, there are no population pharmacokinetic models of the echinocandins for pediatric patients. The safety and descriptive pharmacokinetics of micafungin in children were recently reported. However, a population pharmacokinetic model in children is needed in order to accurately determine the dosage of micafungin that produces an equivalent magnitude of drug exposure to that observed in adults. In order to explore the effect of weight on micafungin pharmacokinetics, a standard two-compartment pharmacokinetic model, a linear model, and an allometric power model were developed. For all three models, the fit to the data was excellent, with comparable measures of precision and bias. However, the superior log-likelihood value of the allometric power model suggested that it best reflected the data and was therefore chosen for a more detailed analysis of the magnitude and pattern of drug exposure which develop following the administration of micafungin. The allometric power model suggested that clearance in smaller children is higher than that predicted on the basis of weight alone. Consequently, a degree of dosage increase is required in smaller children to ensure comparable levels of drug exposure to those observed in larger children and adults. The allometric power model developed in this study enables identification of pediatric dosage regimens of micafungin which, based upon Monte Carlo simulations, result in equivalent drug exposures to those observed in adults, for which antifungal efficacy has been established. C1 NCI, NIH, Pediat Oncol Branch, Bethesda, MD 20892 USA. Ordway Res Inst, Emerging Pathogen Sect, Albany, NY 12208 USA. George Washington Univ, Sch Med & Publ Hlth, Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA. Childrens Hosp Orange Cty, Orange, CA 92868 USA. Brown Univ, Warren Albert Med Sch, Providence, RI 02903 USA. St Jude Childrens Res Hosp, Dept Infect Dis, Memphis, TN 38105 USA. Georgetown Univ, Med Ctr, Div Pediat Hematol Oncol, Dept Pediat, Washington, DC 20007 USA. Childrens Hosp, Denver, CO 80218 USA. Astellas Pharma US, Deerfield, IL USA. RP Walsh, TJ (reprint author), NCI, NIH, Pediat Oncol Branch, CRC Room 1-5750,10 Ctr Dr, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov OI Gumbo, Tawanda/0000-0001-7592-8012; Hope, William/0000-0001-6187-878X FU Intramural NIH HHS NR 19 TC 67 Z9 67 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 EI 1098-6596 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD OCT PY 2007 VL 51 IS 10 BP 3714 EP 3719 DI 10.1128/AAC.00398-07 PG 6 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 215FX UT WOS:000249794800032 PM 17638696 ER PT J AU Hope, WW Warn, PA Sharp, A Reed, P Keevil, B Louie, A Walsh, TJ Denning, DW Drusano, GL AF Hope, William W. Warn, Peter A. Sharp, Andrew Reed, Paul Keevil, Brian Louie, Arnold Walsh, Thomas J. Denning, David W. Drusano, George L. TI Optimization of the dosage of flucytosine in combination with amphotericin B for disseminated candidiasis: a pharmacodynamic rationale for reduced dosing SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID INVASIVE PULMONARY ASPERGILLOSIS; ANTIFUNGAL THERAPY; MODEL; 5-FLUOROCYTOSINE; PHARMACOKINETICS; DEOXYCHOLATE AB Amphotericin B and flucytosine (5FC) have an additive effect when used for disseminated candidiasis. Here, we bridge the results of an experimental pharmacodynamic study to humans and demonstrate that a 5FC dosage of 25 mg/kg of body weight/day in four divided doses in combination with amphotericin B produces near-maximal effect. C1 Univ Manchester, Dept Med, Manchester M13 9PL, Lancs, England. Ordway Res Inst, Albany, NY 12208 USA. NIH, Natl Canc Inst, Pediat Oncol Branch, Immunocompromised Host Sect, Bethesda, MD 20892 USA. Hope Hosp, Dept Biochem, Salford M6 8HD, Lancs, England. Wythenshawe Hosp, Dept Biochem, Manchester M23 9LT, Lancs, England. RP Hope, WW (reprint author), Univ Manchester, Dept Med, 1800 Stopford Bldg,Oxford Rd, Manchester M13 9PL, Lancs, England. EM william.hope@manchester.ac.uk OI Denning, David/0000-0001-5626-2251; Hope, William/0000-0001-6187-878X NR 14 TC 7 Z9 7 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD OCT PY 2007 VL 51 IS 10 BP 3760 EP 3762 DI 10.1128/AAC.00488-07 PG 3 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 215FX UT WOS:000249794800043 PM 17682101 ER PT J AU Hama, Y Matsumoto, KI Murugesan, R Subramanian, S Devasahayam, N Koscielniak, JW Hyodo, F Cook, JA Mitchell, JB Krishna, MC AF Hama, Yukihiro Matsumoto, Ken-Ichiro Murugesan, Ramachandran Subramanian, Sankaran Devasahayam, Nallathamby Koscielniak, Janusz W. Hyodo, Fuminori Cook, John A. Mitchell, James B. Krishna, Murali C. TI Continuous wave EPR oximetric imaging at 300 MHz using Radiofrequency power saturation effects SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Article ID ELECTRON-PARAMAGNETIC-RESONANCE; IN-VIVO OXYMETRY; MAGNETIC-RESONANCE; BOLD MRI; TUMOR; OXYGEN; RADICALS; HYPOXIA; HETEROGENEITY; MEMBRANES AB A novel continuous wave (CW), radiofrequency (RF), electron paramagnetic resonance (EPR) oximetric imaging technique is proposed, based on the influence of oxygen concentration on the RF power saturation of the EPR resonance. A linear relationship is demonstrated between the partial oxygen pressure (PO2) and the normalized signal intensity (I-N), defined as, I-N = (I-HP - I-LP)/I-LP, where I-LP and I-HP refer to signal intensities at low (P-L) and high (P-H) RF power levels, respectively. A formula for the determination Of PO2, derived on the basis of the experimental results, reliably estimated various oxygen concentrations in a five-tube phantom. This new technique was time-efficient and also avoided the missing angle problem associated with conventional spectral-spatial CW EPR oximetric imaging. In vivo power saturation oximetric imaging in a tumor bearing mouse clearly depicted the hypoxic foci within the tumor. C1 NCI, Ctr Canc Res, Radiat Biol Branch, Bethesda, MD 20892 USA. Natl Inst Radiol Sci, Heavy Ion Radiobiol Res Grp, Res Ctr Charged Particle Therapy, Chiba 260, Japan. Madurai Kamaraj Univ, Sch Chem, Madurai 625021, Tamil Nadu, India. NCI, Ctr Canc Res, Lab Proteom & Anal Technol, Frederick, MD 21701 USA. RP Krishna, MC (reprint author), NCI, Ctr Canc Res, Radiat Biol Branch, Bethesda, MD 20892 USA. EM murali@helix.nih.gov FU Intramural NIH HHS NR 35 TC 7 Z9 7 U1 1 U2 5 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD OCT PY 2007 VL 9 IS 10 BP 1709 EP 1716 DI 10.1089/ars.2007.1720 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 211KB UT WOS:000249521600013 PM 17696765 ER PT J AU Soule, BP Hyodo, F Matsumoto, KI Simone, NL Cook, JA Krishna, MC Mitchell, JB AF Soule, Benjamin P. Hyodo, Fuminori Matsumoto, Ken-Ichiro Simone, Nicole L. Cook, John A. Krishna, Murali C. Mitchell, James B. TI Therapeutic and clinical applications of nitroxide compounds SO ANTIOXIDANTS & REDOX SIGNALING LA English DT Review ID PERMEABLE RADICAL SCAVENGER; ELECTRON-PARAMAGNETIC-RESONANCE; SUPEROXIDE-DISMUTASE MIMICS; NUCLEAR MAGNETIC-RESONANCE; LENS EPITHELIAL-CELLS; PARKINSONS-DISEASE; OXIDATIVE DAMAGE; CONTRAST AGENTS; REDOX STATUS; CANCER CHEMOPREVENTION AB Nitroxide compounds have been used for many years as biophysical tools, but only during the past 15-20 years have the many interesting biochemical interactions been discovered and harnessed for therapeutic applications. By modifying oxidative stress and altering the redox status of tissues, nitroxides have the ability to interact with and alter many metabolic processes. This interaction can be exploited for therapeutic and research use, including protection against ionizing radiation, as probes in functional magnetic resonance imaging, cancer prevention and treatment, control of hypertension and weight, and protection from damage resulting from ischemia/reperfusion injury. Although much remains to be done, many applications have been well studied, and some are presently being tested in clinical trials. The therapeutic and research uses of nitroxides are reviewed here, with a focus on the progress from initial development to modern, state-of-the art trials. C1 NCI, Rad Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Soule, BP (reprint author), NCI, Rad Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. EM souleb@mail.nih.gov FU Intramural NIH HHS NR 101 TC 61 Z9 61 U1 0 U2 10 PU MARY ANN LIEBERT, INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1523-0864 EI 1557-7716 J9 ANTIOXID REDOX SIGN JI Antioxid. Redox Signal. PD OCT PY 2007 VL 9 IS 10 BP 1731 EP 1743 DI 10.1089/ars.2007.1722 PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 211KB UT WOS:000249521600015 PM 17665971 ER PT J AU Revaz, V Zurbriggen, R Moser, C Schiller, JT Ponci, F Bobst, M Nardelli-Haefliger, D AF Revaz, Veronique Zurbriggen, Rinaldo Moser, Christian Schiller, John T. Ponci, Franqoise Bobst, Martine Nardelli-Haefliger, Denise TI Humoral and cellular immune responses to airway immunization of mice with human papillomavirus type 16 virus-like particles and mucosal adjuvants SO ANTIVIRAL RESEARCH LA English DT Article DE human papillomavirus type 16; virus-like particles; HLT; CpG ODN; mucosal immunization; antibody and cell-mediated immune responses ID RANDOMIZED CONTROLLED-TRIAL; CYTOTOXIC T-LYMPHOCYTES; HEAT-LABILE ENTEROTOXIN; CPG-DNA; NEUTRALIZING ANTIBODIES; INTRANASAL IMMUNIZATION; CERVICAL-CANCER; DENDRITIC CELLS; CHOLERA-TOXIN; NASAL IMMUNIZATION AB Cervical cancer results from cervical infection by human papillomaviruses (HPV), especially HPV 16. Intramuscular administrations of HPV 16 virus-like particle (VLP) vaccines have been shown to induce strong neutralizing antibody responses and protect women against genital HPV16 infection and associated lesions. However, an alternative route of administration that avoids parenteral injection might facilitate vaccine implementation, particularly in developing countries which account for the majority of the worldwide cases of cervical cancer. In addition, inducing mucosal immunity could partially overcome the substantial variation in HPV16 antibodies at the cervix seen in ovulating women. Aerosol vaccination with HPV16 VLPs was previously shown to be immunogenic in mice and in women. Here, we examine whether exposure to other respiratory viral antigens may interfere with the HPV16 VLP-specific humoral response and whether two known mucosal adjuvants, CpG oligodeoxynucleotides and a natural non-toxic Escherichia coli heat-labile enterotoxin (HLT), can enhance the immunogenicity of airway immunization (nasal or aerosollike) of mice with HPV16 VLPs. Our data show that HLT can significantly improve anti-VLP humoral responses in serum and mucosal secretions, as well as VLP-specific proliferative responses and IFN-gamma production by CD8 T cells, and that recent exposure to influenza surface antigens can diminish mucosal, but not systemic, antibody responses to the VLPs. (c) 2007 Elsevier B.V. All rights reserved. C1 CHU Vaudois, Inst Microbiol, CH-1011 Lausanne, Switzerland. Berna Biotech Ltd, CH-3018 Bern, Switzerland. NCCR Mol Oncol, CH-1066 Epalinges, Switzerland. NCI, Ctr Canc Res, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Nardelli-Haefliger, D (reprint author), CHU Vaudois, Inst Microbiol, Bugnon 48, CH-1011 Lausanne, Switzerland. EM DNARDELL@hospvd.ch OI nardelli-haefliger, denise/0000-0003-1812-9905 NR 56 TC 18 Z9 18 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-3542 J9 ANTIVIR RES JI Antiviral Res. PD OCT PY 2007 VL 76 IS 1 BP 75 EP 85 DI 10.1016/j.antiviral.2007.05.005 PG 11 WC Pharmacology & Pharmacy; Virology SC Pharmacology & Pharmacy; Virology GA 207JD UT WOS:000249246500009 PM 17617476 ER PT J AU Saito, K Drgon, T Krupatkina, DN Drgonova, J Terlizzi, DE Mercer, N Vasta, GR AF Saito, Keiko Drgon, Tomas Krupatkina, Danara N. Drgonova, Jana Terlizzi, Daniel E. Mercer, Natalia Vasta, Gerardo R. TI Effect of biotic and abiotic factors on in vitro proliferation, encystment, and excystment of Pfiesteria piscicida SO APPLIED AND ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID DINOFLAGELLATE HETEROCAPSA-CIRCULARISQUAMA; PHOSPHORUS-LIMITED CULTURES; TOXIC DINOFLAGELLATE; GONYAULAX-TAMARENSIS; CYST GERMINATION; GROWTH-RATES; LIFE-CYCLE; ENVIRONMENTAL EXPOSURE; FORMING DINOFLAGELLATE; ICHTHYOCIDAL ACTIVITY AB Pfiesteria spp. are mixotrophic armored dinoflagellates populating the Atlantic coastal waters of the United States. They have been a focus of intense research due to their reported association with several fish mortality events. We have now used a clonal culture of Pfiesteria piscicida and several new environmental isolates to describe growth characteristics, feeding, and factors contributing to the encystment and germination of the organism in both laboratory and environmental samples. We also discuss applied methods of detection of the different morphological forms of Pfiesteria in environmental samples. In summary, Pfiesteria, when grown with its algal prey, Rhodomonas sp., presents a typical growth curve with lag, exponential, and stationary phases, followed by encystment. The doubling time in exponential phase is about 12. h. The profiles of proliferation under a standard light cycle and in the dark were similar, although the peak cell densities were markedly lower when cells were grown in the dark. The addition of urea, chicken manure, and soil extracts did not enhance Pfiesteria proliferation, but crude unfiltered spent aquarium water did. Under conditions of food deprivation or cold (4 degrees C), Pfiesteria readily formed harvestable cysts that were further analyzed by PCR and scanning electron microscopy. The germination of Pfiesteria cysts in environmental sediment was enhanced by the presence of live fish: dinospores could be detected 13 to 15 days earlier and reached 5- to 10-times-higher peak cell densities with live fish than with artificial seawater or f/2 medium alone. The addition of ammonia, urea, nitrate, phosphate, or surprisingly, spent fish aquarium water had no effect. C1 Univ Maryland, Ctr Marine Biotechnol, Inst Biotechnol, Baltimore, MD 21202 USA. NIH, Natl Inst Drug Abuse, Baltimore, MD 21224 USA. Univ Nacl La Plata, Fac Ciencias Exactas, Catedra Inmunol, La Plata, Argentina. RP Vasta, GR (reprint author), Univ Maryland, Ctr Marine Biotechnol, Inst Biotechnol, 701 E Pratt St, Baltimore, MD 21202 USA. EM vasta@umbi.umd.edu RI Drgonova, Jana/B-2903-2008; OI Drgonova, Jana/0000-0002-4623-8466 NR 68 TC 4 Z9 5 U1 0 U2 8 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0099-2240 J9 APPL ENVIRON MICROB JI Appl. Environ. Microbiol. PD OCT PY 2007 VL 73 IS 20 BP 6410 EP 6420 DI 10.1128/AEM.01229-07 PG 11 WC Biotechnology & Applied Microbiology; Microbiology SC Biotechnology & Applied Microbiology; Microbiology GA 221SU UT WOS:000250248400011 PM 17704277 ER PT J AU Brotman, LM Gouley, KK Huang, KY Kamboukos, D Fratto, C Pine, DS AF Brotman, Laurie Miller Gouley, Kathleen Kiely Huang, Keng-Yen Kamboukos, Dimitra Fratto, Carolyn Pine, Daniel S. TI Effects of a psychosocial family-based preventive intervention on cortisol response to a social challenge in preschoolers at high risk for antisocial behavior SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID SALIVARY CORTISOL; CONDUCT PROBLEMS; INDIVIDUAL-DIFFERENCES; MATERNAL-CARE; ADRENOCORTICAL ACTIVITY; NEUROENDOCRINE ACTIVITY; DISRUPTIVE BEHAVIOR; STRESS REACTIVITY; HEAD-START; CHILD-CARE AB Context: Salivary cortisol levels during social challenge relate to adaptive functioning in children and adults. Low cortisol levels have been related to conduct problems and antisocial behavior. Although studies in rodents implicate early- life social experience in cortisol regulation, no studies with humans have examined the effects of an experimentally manipulated early- life social experience on cortisol regulation. Objective: To examine the effects of experimental manipulations of social experience on cortisol response to a social challenge in preschoolers at risk for antisocial behavior. Design: Randomized controlled trial. Setting: Department of Child and Adolescent Psychiatry, New York University School of Medicine. Participants: Ninety- two preschool- age siblings of youths adjudicated for delinquent acts. Intervention: Family- based intervention included 22 weekly group sessions for parents and preschoolers and 10 biweekly home visits conducted during a 6- to 8- month period. Main Outcome Measures: Salivary cortisol levels before and after a social challenge ( entry into an unfamiliar peer group). Results: Relative to controls, children in the intervention condition had increased cortisol levels in anticipation of the peer social challenge. Increases were relative to both preintervention cortisol levels during the challenge and cortisol levels in the home, which were not altered by the intervention. Conclusions: A family- based preventive intervention for children at high risk for antisocial behavior alters stress response in anticipation of a peer social challenge. The experimentally induced change in cortisol levels parallels patterns found in normally developing, low- risk children. C1 NYU, Sch Med, Ctr Child Study, Dept Child & Adolescent Psychiat, New York, NY 10016 USA. NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20892 USA. RP Brotman, LM (reprint author), NYU, Sch Med, Ctr Child Study, Dept Child & Adolescent Psychiat, 215 Lexington Ave, New York, NY 10016 USA. EM Laurie.Brotman@nyumc.org OI Brotman, Laurie/0000-0002-3384-3886 FU NIMH NIH HHS [R01 MH 55188] NR 50 TC 58 Z9 58 U1 5 U2 14 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD OCT PY 2007 VL 64 IS 10 BP 1172 EP 1179 DI 10.1001/archpsyc.64.10.1172 PG 8 WC Psychiatry SC Psychiatry GA 215YI UT WOS:000249844500008 PM 17909129 ER PT J AU Merikangas, KR Ames, M Cui, L Stang, PE Ustun, TB Von Korff, M Kessler, RC AF Merikangas, Kathleen R. Ames, Minnie Cui, Lihong Stang, Paul E. Ustun, T. Bedirhan Von Korff, Michael Kessler, Ronald C. TI The impact of comorbidity of mental and physical conditions on role disability in the US adult household population SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID WORLD-HEALTH-ORGANIZATION; CHRONIC MEDICAL CONDITIONS; QUALITY-OF-LIFE; PERFORMANCE QUESTIONNAIRE HPQ; REPLICATION NCS-R; COST-EFFECTIVENESS; ECONOMIC BURDEN; PRODUCTIVITY; DEPRESSION; DISORDERS AB Context: There is limited information that accounts for comorbidity on the impact of role disability associated with a wide range of mental and physical disorders in population- based samples. Objective: To estimate the comparative effects of common mental and physical conditions on role disability in the general population using a novel method that accounts for comorbidity. Design: Direct interviews about physical and mental conditions during the past year. Setting: The National Comorbidity Survey Replication, a nationally representative series of face- to- face interviews. Patients: A nationally representative sample of adults living in households ( N= 5962 respondents, 18 years and older). Main Outcome Measure: Disability in major life roles was assessed with the World Health Organization Disability Assessment Schedule. Simulations that allow for complex interactions among conditions were used to estimate the conditions' effects on disability days, when respondents were completely unable to carry out their usual daily activities because of problems with mental or physical health, in the past 12 months. Results: An estimated 53.4% of US adults have 1 or more of the mental or physical conditions assessed in the survey. These respondents report an average 32.1 more roledisability days in the past year than demographically matched controls, equivalent to nearly 3.6 billion days of role disability in the population. Musculoskeletal disorders and major depression had the greatest effects on disability days. Mental conditions accounted for more than half as many disability days as all physical conditions at the population level. Associations of specific conditions with disability decreased substantially after controlling for comorbidity, suggesting that prior studies, which generally did not control for comorbidity, overestimated disea-sespecific effects. Conclusion: The staggering amount of health- related disability associated with mental and physical conditions should be considered in establishing priorities for the allocation of health care and research resources. C1 NIMH, Sect Dev Genet Epidemiol, Intramural Res Program, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. W Chester Univ, Dept Epidemiol, W Chester, PA 19380 USA. Galt Assoc, Blue Bell, PA USA. WHO, Assessment Classificat & Evaluat Grp, CH-1211 Geneva, Switzerland. Grp Hlth Cooperat Puget Sound, Seattle, WA USA. RP Merikangas, KR (reprint author), NIMH, Sect Dev Genet Epidemiol, Intramural Res Program, Dept Hlth & Human Serv, 35 Convent Dr,1A201,MSC 3720, Bethesda, MD 20892 USA. EM kathleen.merikangas@nih.gov FU FIC NIH HHS [R01 TW 006481, R03 TW006481, R03 TW006481-03]; NIDA NIH HHS [R01 DA 016558, R01 DA016558, R01 DA016558-04]; NIMH NIH HHS [R01 MH069864, R01 MH 069864, R01 MH 070884, R01 MH069864-04, R01 MH070884, R01 MH070884-02, R13 MH 066849, R13 MH066849, R13 MH066849-05, U01 MH 60220, U01 MH060220, U01 MH060220-06A1, U13 MH066849] NR 55 TC 206 Z9 207 U1 1 U2 16 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD OCT PY 2007 VL 64 IS 10 BP 1180 EP 1188 DI 10.1001/archpsyc.64.10.1180 PG 9 WC Psychiatry SC Psychiatry GA 215YI UT WOS:000249844500009 PM 17909130 ER PT J AU Druss, BG Wang, PS Sampson, NA Olfson, M Pincus, HA Wells, KB Kessler, RC AF Druss, Benjamin G. Wang, Philip S. Sampson, Nancy A. Olfson, Mark Pincus, Harold A. Wells, Kenneth B. Kessler, Ronald C. TI Understanding mental health treatment in persons without mental diagnoses - Results from the National Comorbidity Survey replication SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID UNITED-STATES; NCS-R; MINOR DEPRESSION; CARE QUALITY; DISORDERS; PREVALENCE; SERVICES; ORGANIZATION; PATTERNS; THERAPY AB Context: Epidemiologic surveys have consistently found that approximately half of respondents who obtained treatment for mental or substance use disorders in the year before interview did not meet the criteria for any of the disorders assessed in the survey. Concerns have been raised that this pattern might represent evidence of misallocation of treatment resources. Objective: To examine patterns and correlates of 12-month treatment of mental health or substance use problems among people who do not have a 12- month DSM- IV disorder. Design and Setting: Data are from the National Comorbidity Survey Replication, a nationally representative face- to- face US household survey performed between February 5, 2001, and April 7, 2003, that assessed DSM- IV disorders using a fully structured diagnostic interview, the World Health Organization Composite International Diagnostic Interview ( CIDI). Participants: A total of 5692 English- speaking respondents 18 years and older. Main Outcome Measures: Patterns of 12- month service use among respondents without any 12- month DSM- IV CIDI disorders. Results: Of respondents who used 12- monthservices, 61.2% had a 12- month DSM- IV CIDI diagnosis, 21.1% had a life-time but not a 12-month diagnosis, and 9.7% had some other indicator of possible need for treatment ( subthreshold 12-month disorder, serious 12- month stressor, or lifetime hospitalization). The remaining 8.0% of service users accounted for only 5.6% of all services and even lower proportions of specialty( 1.9%- 2.4%) and general medical( 3.7%) visits compared with higher proportions of human services ( 18.9%) and complementary and alternative medicine ( 7.6%) visits. Only 26.5% of the services provided to the 8.0% of presumably low- need patients were delivered in the mental health specialty or general medical sectors. Conclusions: Most services provided for emotional or substance use problems in the United States go to people with a 12- month diagnosis or other indicators of need. Patients who lack these indicators of need receive care largely outside the formal health care system. C1 Emory Univ, Rollins Sch Publ Hlth, Dept Hlth Policy & Management, Atlanta, GA 30322 USA. NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Hlth Care Policy, Boston, MA 02115 USA. Columbia Univ, Dept Psychiat, New York, NY USA. Univ Calif Los Angeles, Dept Psychiat & Behav Sci, Los Angeles, CA 90024 USA. RP Druss, BG (reprint author), Emory Univ, Rollins Sch Publ Hlth, Dept Hlth Policy & Management, 1518 Clifton Rd NE,Room 606, Atlanta, GA 30322 USA. EM bdruss@emory.edu FU FIC NIH HHS [R03 TW 006481, R03 TW006481, R03 TW006481-03]; NIDA NIH HHS [R01 DA 016558, R01 DA016558, R01 DA016558-04]; NIMH NIH HHS [U13 MH066849, 1K24 MH 075867-01A1, K24 MH075867, R01 MH 069864, R01 MH 070884, R01 MH069864, R01 MH069864-04, R01 MH070884, R01 MH070884-03, R13 MH 066849, R13 MH066849, R13 MH066849-05, U01 MH 60220, U01 MH060220, U01 MH060220-06A1] NR 47 TC 70 Z9 71 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD OCT PY 2007 VL 64 IS 10 BP 1196 EP 1203 DI 10.1001/archpsyc.64.10.1196 PG 8 WC Psychiatry SC Psychiatry GA 215YI UT WOS:000249844500011 PM 17909132 ER PT J AU Marquez-Gutierrez, MA Benitez-Hess, ML DiPaolo, JA Alvarez-Salas, LM AF Marquez-Gutierrez, Miguel A. Benitez-Hess, Maria L. DiPaolo, Joseph A. Alvarez-Salas, Luis M. TI Effect of combined antisense oligodeoxynucleotides directed against the human papillomavirus type 16 on cervical carcinoma cells SO ARCHIVES OF MEDICAL RESEARCH LA English DT Article DE papillomavirus; antisense; oligodeoxynucleotides; cervical carcinoma; gene therapy ID SEQUENCE VARIANTS; NUCLEIC-ACIDS; E6 GENE; CANCER; INHIBITION; OLIGONUCLEOTIDES; L1; IMMORTALIZATION; KERATINOCYTES; TRANSLATION AB Background. Cervical cancer is highly associated with human papillomavirus (HPV) E6 and E7 gene expression. We have previously reported two antisense oligodeoxynucleotides (AS-ODNs) directed against adjacent targets within the HPV-16 E6/E7 mRNA (419 and 434), each able to downregulate HPV-16 E6/E7 mRNA in vitro and in vivo and to specifically inhibit tumor cell growth in culture and animal models. Methods. Towards potential clinical application and improved in vivo performance, we analyzed the effect of the combined treatment of 419-434 AS-ODNs on the anchorage independent growth (AIG) of HPV- 16-positive cervical carcinoma cell lines. Results. We found similar responses between combined 419-434 and individual AS-ODNs treatments in RNaseH assays, cell uptake, and in vivo degradation of HPV-16 E6/E7 transcripts. Moreover, the combined use of 419-434 AS-ODNs resulted in additive AIG inhibition of CaSki and SiHa cells, similar to that obtained with equivalent doses of the individual AS-ODNs. Conclusions. By using a combined treatment, it may be possible to overcome the potential mutations frequently reported within HPV-16 genome, thus improving the potential application of 419 and 434 AS-ODNs as a therapeutic alternative for cervical cancer. (c) 2007 IMSS. Published by Elsevier Inc. C1 CINVESTAV, Dept Genet & Biol Mol, Lab Terapia Genet, Mexico City 07360, DF, Mexico. NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Alvarez-Salas, LM (reprint author), CINVESTAV, Dept Genet & Biol Mol, Lab Terapia Genet, Av Inst Politecn Nacl 2508,Col San Pedro Zacatenc, Mexico City 07360, DF, Mexico. EM lalvarez@cinvestav.mx NR 45 TC 11 Z9 11 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0188-4409 J9 ARCH MED RES JI Arch. Med. Res. PD OCT PY 2007 VL 38 IS 7 BP 730 EP 738 DI 10.1016/j.arcmed.2007.04.011 PG 9 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 215DR UT WOS:000249789000003 PM 17845891 ER PT J AU Shilo, K Dracheva, T Mani, H Fukuoka, J Sesterhenn, IA Chu, WS Shih, JH Jen, J Travis, WD Franks, TJ AF Shilo, Konstantin Dracheva, Tatiana Mani, Haresh Fukuoka, Junya Sesterhenn, Isabell A. Chu, Wei-Sing Shih, Joanna H. Jen, Jin Travis, William D. Franks, Teri J. TI alpha-methylacyl CoA racemase in pulmonary adenocarcinoma, squamous cell carcinoma, and neuroendocrine tumors - Expression and survival analysis SO ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE LA English DT Article ID COENZYME-A-RACEMASE; PROSTATE-CANCER; LUNG-CANCER; PROTEIN EXPRESSION; MOLECULAR MARKER; P504S; DIFFERENTIATION; BIOMARKER; ANTIBODY AB Context.-alpha-Methylacyl CoA racemase (AMACR) is an oxidative enzyme involved in isomeric transformation of fatty acids entering the beta-oxidation pathway. AMACR serves as a useful marker in establishing a diagnosis of prostatic malignancy; however, limited information is available in regard to its presence in pulmonary neoplasms. Objective.-To investigate AMACR expression within a spectrum of lung carcinomas and its correlation with patients' survival. Design.-Four hundred seventy-seven pulmonary carcinomas, including 150 squamous cell carcinomas, 150 adenocarcinomas, 46 typical carcinoids, 31 atypical carcinoids, 28 large cell neuroendocrine carcinomas, and 72 small cell carcinomas, were studied immunohistochemically using tissue microarray-based samples. Results.-Overall, pulmonary tumors were positive for AMACR in a significant percentage (47%) of cases. Among tumor types, 22% of squamous cell carcinoma, 56% of adenocarcinoma, 72% of typical carcinoid, 52% of atypical carcinoid, 70% of large cell neuroendocrine carcinoma, and 51% of small cell lung carcinoma were positive for AMACR. Furthermore, the Kaplan-Meier analysis revealed that the patients with AMACR-positive small cell carcinoma had better survival (19% vs 5% after 5 years, P=.04) than patients with AMACR-negative tumors. Such survival advantage was seen for patients with stage I-II (P=.01) but not stage III-IV small cell carcinomas (P=.58). Conclusions.-These results indicate that, similar to prostate cancer, the overexpression of AMACR frequently occurs in pulmonary carcinomas. Additionally, its positive correlation with outcome of stage I-II small cell lung carcinoma warrants further investigation of the AMACR role in the prognosis of this tumor. C1 Armed Forces Inst Pathol, Dept Pulm & Mediastinal Pathol, Washington, DC 20306 USA. Armed Forces Inst Pathol, Dept Genitourinary Pathol, Washington, DC 20306 USA. Armed Forces Inst Pathol, Sci Labs, Washington, DC 20306 USA. NIH, Lab Populat Genet, Bethesda, MD 20892 USA. NIH, Biometr Res Branch, Bethesda, MD 20892 USA. Toyama Univ Hosp, Pathol Lab, Toyama, Japan. Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. RP Shilo, K (reprint author), Armed Forces Inst Pathol, Dept Pulm & Mediastinal Pathol, Washington, DC 20306 USA. EM shilok@afip.osd.mil RI Shilo, Konstantin/E-4084-2011 NR 21 TC 20 Z9 20 U1 0 U2 1 PU COLLEGE AMER PATHOLOGISTS PI NORTHFIELD PA C/O KIMBERLY GACKI, 325 WAUKEGAN RD, NORTHFIELD, IL 60093-2750 USA SN 0003-9985 J9 ARCH PATHOL LAB MED JI Arch. Pathol. Lab. Med. PD OCT PY 2007 VL 131 IS 10 BP 1555 EP 1560 PG 6 WC Medical Laboratory Technology; Medicine, Research & Experimental; Pathology SC Medical Laboratory Technology; Research & Experimental Medicine; Pathology GA 219DS UT WOS:000250065500017 PM 17922592 ER PT J AU Picciano, MF Dwyer, JT Radimer, KL Wilson, DH Fisher, KD Thomas, PR Yetley, EA Moshfegh, AJ Levy, PS Nielsen, SJ Marriott, BM AF Picciano, Mary Frances Dwyer, Johanna T. Radimer, Kathy L. Wilson, David H. Fisher, Kenneth D. Thomas, Paul R. Yetley, Elizabeth A. Moshfegh, Alanna J. Levy, Paul S. Nielsen, Samara Joy Marriott, Bernadette M. TI Dietary supplement use among infants, children, and adolescents in the united states, 1999-2002 SO ARCHIVES OF PEDIATRICS & ADOLESCENT MEDICINE LA English DT Article ID NUTRITIONAL RICKETS; MINERAL SUPPLEMENTS; NATIONAL-HEALTH; IRON STATUS; VITAMIN; TRENDS; NONUSERS; FORTIFICATION; ASSOCIATION; NUTRIENTS AB Objective: To describe dietary supplement use among US children. Design: Analysis of nationally representative data from the 1999-2002 National Health and Nutrition Examination Survey ( NHANES). Setting: Home interviews and a mobile examination center. Participants: Children from birth through 18 years who participated in NHANES (N = 10 136). Main Exposure: Frequency of use of any dietary supplement product. Outcome Measure: Prevalence of use and intake of key nutrients from supplements among children. Results: In 1999-2002, 31.8% of children used dietary supplements, with the lowest use reported among infants younger than 1 year (11.9%) and teenagers 14 to 18 years old (25.7%) and highest use among 4- to 8-year-old children (48.5%). Use was highest among non-Hispanic white (38.1%) and Mexican American (22.4%) participants, lowest among non-Hispanic black participants (18.8%), and was not found to differ by sex. The type of supplement most commonly used was multivitamins and multiminerals (18.3%). Ascorbic acid (28.6%), retinol (25.8%), vitamin D(25.6%), calcium (21.1%), and iron (19.3%) were the primary supplemental nutrients consumed. Supplement use was associated with families with higher incomes; a smoke-free environment; not being certified by the US Department of Agriculture Special Supplemental Nutrition Program for Women, Infants and Children in the last 12 months; lower child body mass index; and less daily recreational screen time (television, video games, computers, etc) (P < .005). The highest prevalence of supplement use (P < .005) was in children who were underweight or at risk for underweight (P < .005). Conclusions: More than 30% of children in the United States take dietary supplements regularly, most often multivitamins and multiminerals. Given such extensive use, nutrient intakes from dietary supplements must be included to obtain accurate estimates of overall nutrient intake in children. C1 NIH, Off Dietary Supplements, Bethesda, MD 20892 USA. Natl Ctr Hlth Stat, Div Hlth Examinat Stat, Natl Hlth & Nutr Examinat Survey, Hyattsville, MD 20782 USA. RTI Int, Res Triangle Pk, NC USA. USDA, Beltsville Human Nutr Res Ctr, Beltsville, MD 20705 USA. ABT Associates Inc, Cambridge, MA 02138 USA. RP Picciano, MF (reprint author), NIH, Off Dietary Supplements, 6100 Execut Blvd,3B01, Bethesda, MD 20892 USA. EM piccianm@od.nih.gov OI Nielsen, Samara Joy/0000-0002-5777-6542; Dwyer, Johanna/0000-0002-0783-1769 NR 48 TC 78 Z9 85 U1 5 U2 14 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 1072-4710 J9 ARCH PEDIAT ADOL MED JI Arch. Pediatr. Adolesc. Med. PD OCT PY 2007 VL 161 IS 10 BP 978 EP 985 DI 10.1001/archpedi.161.10.978 PG 8 WC Pediatrics SC Pediatrics GA 215YH UT WOS:000249844400009 PM 17909142 ER PT J AU Bjorkdahl, A Heilig, M Palmstierna, T Hansebo, G AF Bjorkdahl, Anna Heilig, Markus Palmstierna, Tom Hansebo, Gorel TI Changes in the occurrences of coercive interventions and staff injuries on a psychiatric intensive care unit SO ARCHIVES OF PSYCHIATRIC NURSING LA English DT Article ID PATIENT AGGRESSION; VIOLENCE; NURSES; WARDS; RESTRAINT; MANAGEMENT AB The purpose of this study was to compare the occurrences of coercive interventions and violence-related staff injuries before and after a 2-year violence prevention intervention on a psychiatric intensive care unit. The intervention aimed to improve nursing care by addressing patient violence from multiple perspectives. During the study, the unit was reorganized toward a higher concentration of severely disturbed patients. The results showed an increased proportion of coercive interventions without a corresponding increase in staff injuries. Use of coercive interventions is discussed in relation to a safe environment for both patients and staff. (c) 2007 Elsevier Inc. All rights reserved. C1 Stockholms Lans Sjukvardsomrade, RMN, SE-11895 Stockholm, Sweden. Karolinska Inst, Div Psychiat, Dept Clin Neurosci, Stockholm, Sweden. NIAAA, NIH, Bethesda, MD USA. Norwegian Univ Sci & Technol, St Olavs Hosp, Forens Dept, N-7034 Trondheim, Norway. Norwegian Univ Sci & Technol, St Olavs Hosp, Res Ctr, Reg Secure Unit Broset, N-7034 Trondheim, Norway. Ersta Skondal Univ Coll, Dept Hlth Care Sci, Stockholm, Sweden. RP Bjorkdahl, A (reprint author), Stockholms Lans Sjukvardsomrade, RMN, Folkungagatan 44,Box 17914, SE-11895 Stockholm, Sweden. EM anna.bjorkdahl@sll.se NR 45 TC 8 Z9 8 U1 0 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0883-9417 J9 ARCH PSYCHIAT NURS JI Arch. Psychiatr. Nurs. PD OCT PY 2007 VL 21 IS 5 BP 270 EP 277 DI 10.1016/j.apnu.2007.06.007 PG 8 WC Nursing; Psychiatry SC Nursing; Psychiatry GA 222AJ UT WOS:000250268200005 PM 17904484 ER PT J AU Runstadler, JA Happ, GM Slemons, RD Sheng, ZM Gundlach, N Petrula, M Senne, D Nolting, J Evers, DL Modrell, A Huson, H Hills, S Rothe, T Marr, T Taubenberger, JK AF Runstadler, J. A. Happ, G. M. Slemons, R. D. Sheng, Z.-M. Gundlach, N. Petrula, M. Senne, D. Nolting, J. Evers, D. L. Modrell, A. Huson, H. Hills, S. Rothe, T. Marr, T. Taubenberger, J. K. TI Using RRT-PCR analysis and virus isolation to determine the prevalence of avian influenza virus infections in ducks at Minto Flats State Game Refuge, Alaska, during August 2005 SO ARCHIVES OF VIROLOGY LA English DT Article ID A VIRUSES; H5N1 INFLUENZA; STABLE-ISOTOPE; YELLOW WARBLER; NORTH-AMERICA; DENDROICA-PETECHIA; CATCHMENT AREAS; BIRDS; WILD; POPULATIONS AB This study describes surveillance for avian influenza viruses (AIV) in the Minto Flats State Game Refuge, high-density waterfowl breeding grounds in Alaska. Five hundred paired cloacal samples from dabbling ducks (Northern Pintail, Mallard, Green Wing Teal, and Widgeon) were placed into ethanol and viral transport medium (VTM). Additional ethanol-preserved samples were taken. Of the ethanol-preserved samples, 25.6% were AIV RNA-positive by real-time RT-PCR. The hemagglutinin (HA) and neuraminidase (NA) subtypes were determined for 38 of the first-passage isolates, and four first-passage isolates could not be definitively subtyped. Five influenza A virus HA-NA combinations were identified: H3N6, H3N8, H4N6, H8N4, and H12N5. Differences in the prevalence of AIV infections by sex and by age classes of Northern Pintail and Mallard ducks were detected, but the significance of these differences is undefined. In the 500 paired samples, molecular screening detected positive birds at a higher rate than viral isolation (chi(2) = 8.35, p = 0.0035, df = 1); however, 20 AIV isolates were recovered from PCR-negative ducks. Further research is warranted to compare the two screening protocols' potential for estimating true prevalence in wild birds. Our success during 2005 indicates Minto Flats will be a valuable study site for a longitudinal research project designed to gain further insight into the natural history, evolution, and ecology of AIV in wild birds. C1 Univ Alaska Fairbanks, Inst Arctic Biol, Fairbanks, AK 99775 USA. Ohio State Univ, Dept Vet Prevent Med, Columbus, OH 43210 USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Alaska Dept Fish & Game, Div Wildlife Conservat, Anchorage, AK 99518 USA. USDA, Natl Vet Serv Lab, Anim & Plant Hlth Inspect Serv, Ames, IA USA. RP Runstadler, JA (reprint author), Univ Alaska Fairbanks, Inst Arctic Biol, 902 N Koyukuk Dr, Fairbanks, AK 99775 USA. EM j.runstadler@uaf.edu RI Nolting, Jacqueline/C-4464-2015 FU Intramural NIH HHS [Z01 AI000996-01]; NCRR NIH HHS [2 P20 RR016466, P20 RR016466] NR 41 TC 62 Z9 65 U1 3 U2 6 PU SPRINGER WIEN PI WIEN PA SACHSENPLATZ 4-6, PO BOX 89, A-1201 WIEN, AUSTRIA SN 0304-8608 J9 ARCH VIROL JI Arch. Virol. PD OCT PY 2007 VL 152 IS 10 BP 1901 EP 1910 DI 10.1007/s00705-007-0994-1 PG 10 WC Virology SC Virology GA 215MQ UT WOS:000249813300012 PM 17541700 ER PT J AU Gold, LS Ward, MH Dosemeci, M De Roos, AJ AF Gold, L. S. Ward, M. H. Dosemeci, M. De Roos, A. J. TI Systemic autoimmune disease mortality and occupational exposures SO ARTHRITIS AND RHEUMATISM LA English DT Article ID EPSTEIN-BARR-VIRUS; RHEUMATOID-ARTHRITIS; LUPUS-ERYTHEMATOSUS; RISK-FACTORS; SILICA EXPOSURE; UNITED-STATES; DEATH CERTIFICATES; POPULATION; SCLEROSIS; EPIDEMIOLOGY AB Objective. To generate hypotheses regarding occupational exposures that may cause systemic autoimmune diseases. Methods. Based on examination of US death certificates, we identified deaths in 26 states for which a cause was listed as rheumatoid arthritis (RA) (n = 36,178), systemic lupus erythematosus (SLE) (n = 7,241), systemic sclerosis (n = 5,642), or other systemic autoimmune disease (n = 4,270). Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated to estimate associations between occupation and death from any systemic autoimmune' disease, and from RA, SLE, and systemic sclerosis, specifically. Additionally, we estimated risks associated with occupational exposures, which were assigned using job-exposure matrices. Results. A broad array of occupations was associated with death from systemic autoimmune diseases, including several of a priori interest. Farming occupation was associated with death from any systemic autoimmune disease (OR 1.3 [95% CI 1.2-1.4]), and increased risk was also seen with occupational exposure to animals and pesticides. Several industrial occupations were associated with death from any systemic autoimmune disease, including mining machine operators (OR 1.3 [95% CI 1.1-1.5]), miscellaneous textile machine operators (OR 1.2 [95% CI 1.0-1.4]), and hand painting, coating, and decorating occupations (OR 1.8 [95% CI 1.0-2.9]). These occupations were also significantly associated with death from the specific autoimmune diseases examined. Certain occupations entailing exposure to the public, such as teachers, were associated with systemic autoimmune disease-related death, whereas others, such as waiters and waitresses, were not. Conclusion. Our results suggest that death from systemic autoimmune diseases may be associated with occupational exposures encountered in farming and industry. The hypotheses generated in this study provide leads for future research on determinants of these diseases. C1 Fred Hutchinson Canc Res Ctr, Seattle, WA 98109 USA. Univ Washington, Seattle, WA 98195 USA. NCI, Bethesda, MD 20892 USA. RP Gold, LS (reprint author), Fred Hutchinson Canc Res Ctr, 1100 Fairview Ave N,PO Box 19024, Seattle, WA 98109 USA. EM lgold@fhcrc.org FU Intramural NIH HHS; NIEHS NIH HHS [T32-ES-07262] NR 49 TC 34 Z9 35 U1 0 U2 10 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD OCT PY 2007 VL 56 IS 10 BP 3189 EP 3201 DI 10.1002/art.22880 PG 15 WC Rheumatology SC Rheumatology GA 221ZB UT WOS:000250264800005 PM 17907164 ER PT J AU Glaser, V AF Glaser, Vicki TI An interview with Bryan Roth SO ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES LA English DT Editorial Material ID VALVULAR HEART-DISEASE; ANTIPSYCHOTIC-DRUG; DOPAMINE AGONISTS; WEIGHT-GAIN C1 Univ N Carolina, Sch Pharm, Dept Pharmacol, Div Med Chem & Nat Prod, Chapel Hill, NC 27515 USA. Univ N Carolina, Sch Med, NIMH, Psyhoact Drug Screening Program, Chapel Hill, NC 27515 USA. RP Glaser, V (reprint author), Univ N Carolina, Sch Pharm, Dept Pharmacol, Div Med Chem & Nat Prod, Chapel Hill, NC 27515 USA. NR 9 TC 0 Z9 0 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-658X J9 ASSAY DRUG DEV TECHN JI ASSAY DRUG DEV. TECHNOL. PD OCT PY 2007 VL 5 IS 5 BP 593 EP 598 DI 10.1089/adt.2007.9987 PG 6 WC Biochemical Research Methods; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 231QD UT WOS:000250963200001 ER PT J AU Shaw, P AF Shaw, Philip TI Intelligence and the developing human brain SO BIOESSAYS LA English DT Review ID CATECHOL-O-METHYLTRANSFERASE; POSITRON EMISSION TOMOGRAPHY; VOXEL-BASED MORPHOMETRY; HUMAN CEREBRAL-CORTEX; CORTICAL THICKNESS; FLUID INTELLIGENCE; APOLIPOPROTEIN-E; INDIVIDUAL-DIFFERENCES; GENERAL INTELLIGENCE; PREFRONTAL CORTEX AB Determining the brain properties that make people 'brainier' has moved well beyond early demonstrations that increasing intelligence correlates with increasing grey and white matter volumes. Both structural and functional in vivo neuroimaging techniques delineate a distributed network of brain regions, perhaps with a focus in the lateral prefrontal cortex, which varies in extent and connectivity with individual differences in intelligence. Longitudinal studies further show that the neuroanatomic correlates of intelligence are dynamic, changing most rapidly in early childhood. Several promising candidate genes affecting neuronal development and neurotransmission have been proposed that might begin to explain the marked genetic overlap between cortical morphology and intelligence. A majorfuture challenge is to determine the cellular events that underpin the neuroanatomic differences correlated with intelligence. C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Shaw, P (reprint author), NIMH, Child Psychiat Branch, Bldg 10, Bethesda, MD 20892 USA. EM shawp@mail.nih.gov RI Shaw, Philip/A-1129-2008 NR 88 TC 21 Z9 22 U1 9 U2 36 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0265-9247 J9 BIOESSAYS JI Bioessays PD OCT PY 2007 VL 29 IS 10 BP 962 EP 973 DI 10.1002/bies.20641 PG 12 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 221TL UT WOS:000250250100004 PM 17876781 ER PT J AU Beaulieu, LM Whitley, BR Wiesner, ITF Rehault, SM Palmieri, D Elkahloun, AG Church, FC AF Beaulieu, Lea M. Whitley, Brand R. Wiesner, I. Theodore F. Rehault, Sophie M. Palmieri, Diane Elkahloun, Abdel G. Church, Frank C. TI Breast cancer and metabolic syndrome linked through the plasminogen activator inhibitor-1 cycle SO BIOESSAYS LA English DT Article ID RECEPTOR-RELATED PROTEIN; ADENOVIRAL GENE-TRANSFER; UROKINASE RECEPTOR; CELL-MIGRATION; ENDOTHELIAL-CELLS; TUMOR-GROWTH; INSULIN-RESISTANCE; IN-VITRO; VITRONECTIN BINDING; ACTIN CYTOSKELETON AB Plasminogen activator inhibitor-1 (PAI-1) is a physiological inhibitor of urokinase (uPA), a serine protease known to promote cell migration and invasion. Intuitively, increased levels of PAI-1 should be beneficial in downregulating uPA activity, particularly in cancer. By contrast, in vivo, increased levels of PAI-1 are associated with a poor prognosis in breast cancer. This phenomenon is termed the "PAI-1 paradox". Many factors are responsible for the upregulation of PAI-1 in the tumor microenvironment. We hypothesize that there is a breast cancer predisposition to a more aggressive stage when PAI-1 is upregulated as a consequence of Metabolic Syndrome (MetS). MetS exerts a detrimental effect on the breast tumor microenvironment that supports cancer invasion. People with MetS have an increased risk of coronary heart disease, stroke, peripheral vascular disease and hyperinsulinemia. Recently, MetS has also been identified as a risk factor for breast cancer. We hypothesize the existence of the "PAI-1 cycle". Sustained by MetS, adipocytokines alter PAI-1 expression to promote anglogenesis, tumor-cell migration and procoagulant microparticle formation from endothelial cells, which generates thrombin and further propagates PAI-1 synthesis. All of these factors culminate in a chemotherapy-resistant breast tumor microenvironment. The PAI-1 cycle may partly explain the PAI-1 paradox. In this hypothesis paper, we will discuss further how MetS upregulates PAI-1 and how an increased level of PAI-1 can be linked to a poor prognosis. C1 Univ N Carolina, Div Hematol & Oncol, Dept Med, Chapel Hill, NC 27599 USA. Cato Res Inc, Durham, NC 27713 USA. INRA, UR83 Rec Avicoles, F-37380 Nouzilly, France. Natl Canc Inst, Womens Canc Sect, Mol Pharmacol Lab, Bethesda, MD USA. Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA. Natl Inst Hlth, NHGRI, Gen Technol Branch, Bethesda, MD 20892 USA. RP Church, FC (reprint author), Univ N Carolina, Div Hematol & Oncol, Dept Med, 932 Mary Ellen Jones Bldg,Campus Box 7035, Chapel Hill, NC 27599 USA. EM fchurch@email.unc.edu RI Palmieri, Diane/B-4258-2015 FU NHLBI NIH HHS [T32 HL069768, T32 HL69768]; NIEHS NIH HHS [5T32-ES-07017]; NINDS NIH HHS [F31 NS054590] NR 99 TC 20 Z9 21 U1 1 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0265-9247 J9 BIOESSAYS JI Bioessays PD OCT PY 2007 VL 29 IS 10 BP 1029 EP 1038 DI 10.1002/bies.20640 PG 10 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 221TL UT WOS:000250250100010 PM 17876797 ER PT J AU Tseng, KY Lewis, BL Lipska, BK O'Donnell, P AF Tseng, Kuei-Yuan Lewis, Barbara L. Lipska, Barbara K. O'Donnell, Patricio TI Post-pubertal disruption of medial prefrontal cortical dopamine-glutamate interactions in a developmental animal model of schizophrenia SO BIOLOGICAL PSYCHIATRY LA English DT Article DE adolescence; dopamine receptors; electrophysiology; GABA transmission; neonatal ventral hippocampal lesion; NMDA; puberty ID EXCITOTOXIC HIPPOCAMPAL DAMAGE; WORKING-MEMORY PERFORMANCE; FAST-SPIKING INTERNEURONS; PYRAMIDAL NEURONS; GENE-EXPRESSION; CORTEX; RAT; RECEPTORS; EXCITABILITY; DYSFUNCTION AB Background: A neonatal ventral hippocampal lesion (NVHL) induces behavioral and physiological anomalies mimicking pathophysiological changes of schizophrenia. Because prefrontal cortical (PFC) pyramidal neurons recorded from adult NVHL rats exhibit abnormal responses to activation of the mesocortical dopaminergic (DA) system, we explored whether these changes are due to an altered DA modulation of pyramidal neurons. Methods: Whole-cell recordings were used to examine the effects of DA and glutamate agonists on cell excitability in brain slices obtained from pre- (postnatal day [PD] 28-35) and post-pubertal (PD > 61) sham and NVHL animals. Results: N-methyl d-aspartate (NMDA),(alpha-amino-3-hydroxy-5-methylisoxazole propionate (AMPA), and the D-1 agonist SKF38393 increased excitability of deep layer pyramidal neurons in a concentration-dependent manner. The opposite effect was observed with the D-2 agonist quinpirole. The effects of NMDA (but not AMPA) and SKF38393 on cell excitability were significantly higher in slices from NVHL animals, whereas quinpirole decrease of cell excitability was reduced. These differences were not observed in slices from pre-pubertal rats, suggesting that PFC DA and glutamatergic systems become altered after puberty in NVHL rats. Conclusions: A disruption of PFC dopamine-glutamate interactions might emerge after puberty in brains with an early postnatal deficit in hippocampal inputs, and this disruption could contribute to the manifestation of schizophrenia-like symptoms. C1 Univ Maryland, Sch Med, Dept Anat & Neurobiol, Baltimore, MD 21201 USA. Albany Med Coll, Ctr Neuropharmacol & Neurosci, Albany, NY 12208 USA. Rosalind Franklin Univ Med & Sci, Chicago Med Sch, Dept Cell & Mol Pharmacol, N Chicago, IL USA. NIMH, Clin Brain Disorders Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP O'Donnell, P (reprint author), Univ Maryland, Sch Med, Dept Anat & Neurobiol, 20 Penn St, Baltimore, MD 21201 USA. EM podon002@umaryland.edu RI Sia, Michelle/A-1756-2010; Lipska, Barbara/E-4569-2017; OI O'Donnell, Patricio/0000-0001-7788-624X FU NIMH NIH HHS [MH57683, R01 MH057683, R01 MH057683-10, R56 MH057683] NR 42 TC 73 Z9 73 U1 2 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 OCT 1 PY 2007 VL 62 IS 7 BP 730 EP 738 DI 10.1016/j.biopsych.2006.10.012 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 211GE UT WOS:000249511500004 PM 17207473 ER PT J AU Savani, BN Mielke, S Rezvani, K Montero, A Yong, AS Wish, L Superata, J Kurlander, R Singh, A Childs, R Barrett, AJ AF Savani, Bipin N. Mielke, Stephan Rezvani, Katayoun Montero, Aldemar Yong, Agnes S. Wish, Laura Superata, Jeannine Kurlander, Roger Singh, Anurag Childs, Richard Barrett, A. John TI Absolute lymphocyte count on day 30 is a surrogate for robust hematopoietic recovery and strongly predicts outcome after T cell-depleted allogeneic stem cell transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE AML; ALL; CML; day 30 lymphocyte count; allogeneic stem cell transplantation ID BONE-MARROW-TRANSPLANTATION; VERSUS-HOST-DISEASE; RECONSTITUTION; GRAFT; LEUKEMIA; CHEMOTHERAPY; IMPACT; GVHD AB Several studies have shown that a higher lymphocyte count 3-4 weeks after allogeneic stem cell transplantation (SCT) is associated with better transplant outcome. However, the factors determining early lymphocyte recovery are not defined. To further explore the relationship between lymphocyte recovery and outcome we analyzed lymphocyte counts and other engraftment parameters in 157 patients with leukemia (48 acute myelogenous leukemia, 80 chronic myelogenous leukemia, and 29 acute lymphoblastic leukemia [ALL]) receiving T cell-depleted mycloablative SCT from an HLA-identical sibling. In multivariate analysis the day 30 absolute lymphocyte count (LC30) above the median of 450/mu L was associated with improved survival (71% +/- 5% versus 38% +/- 6%, P < .0001), less relapse (21% +/- 5% versus 44% +/- 7%, P = .009), less nonrelapse mortality (NRM; 9 +/- 3 versus 36% +/- 6%, P < .0001) and less acute graft-versus-host disease (aGVHD) (34% +/- 5% versus 51% +/- 6%, P = .025). The beneficial effect of a higher LC30 influenced outcome in patients with both standard and high-risk disease but did not affect survival and relapse in ALL. We found that a higher LC30 correlated with higher lymphocyte counts at all time points between 30 and 90 days post-SCT and also with more rapid neutrophil and platelet engraftment. These results indicate that LC30 is a surrogate for robust engraftment and identifies an "at-risk" population of patients after T cell-depleted SCT. (C) 2007 American Society fir Blood and Marrow Transplantation. C1 NHLBI, Stem Cell Allogene Transplantat Sect, Hematol Branch, NIH,Hatield CRC, Bethesda, MD 20892 USA. NCI, NIH Clin Ctr, Dept Lab Med, NIH, Bethesda, MD 20892 USA. NCI, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Savani, BN (reprint author), NHLBI, Stem Cell Allogene Transplantat Sect, Hematol Branch, NIH,Hatield CRC, Bldg 10,Room 3-5320,10 Ctr Dr MSC 1202, Bethesda, MD 20892 USA. EM barrettj@nhlbi.nih.gov FU Intramural NIH HHS [ZIA HL006105-01] NR 19 TC 55 Z9 58 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD OCT PY 2007 VL 13 IS 10 BP 1216 EP 1223 DI 10.1016/j.bbmt.2007.07.005 PG 8 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 219RX UT WOS:000250103400012 PM 17889359 ER PT J AU Randazzo, PA Inoue, H Bharti, S AF Randazzo, Paul A. Inoue, Hiroki Bharti, Sanita TI Arf GAPs as regulators of the actin cytoskeleton SO BIOLOGY OF THE CELL LA English DT Review DE actin; ADP-ribosylation factor (Art); ASAP1; focal adhesion; GTPase-activating protein; invadopodia ID GTPASE-ACTIVATING-PROTEIN; ADP-RIBOSYLATION-FACTOR; PAXILLIN KINASE LINKER; PHOSPHATIDYLINOSITOL 4-PHOSPHATE 5-KINASE; GROWTH-FACTOR RECEPTOR; FOCAL ADHESION KINASE; ROUS-SARCOMA VIRUS; CANCER INVASIVE ACTIVITIES; STRESS FIBER FORMATION; SRC FAMILY KINASES AB The Arf (ADP-ribosylation factor) GAPs (GTPase-activating proteins) are a family of proteins with a common catalytic domain that induces hydrolysis of GTP bound to Arf GTP-binding proteins. At least three groups of multiclomain Arf GAPs affect the actin cytoskeleton and cellular activities, such as migration and movement, that depend on the cytoskeleton. One role of the Arf GAPs is to regulate membrane remodelling that accompanies actin polymerization. Regulation of membrane remodelling is mediated in part by the regulation of Arf proteins. However, Arf GAPs also regulate actin independently of effects on membranes or Arf. These functions include acting as upstream regulators of Rho family proteins and providing a scaffold for Rho effectors and exchange factors. With multiple functional elements, the Arf GAPs could integrate signals and biochemical activities that result in co-ordinated changes in actin and membranes necessary for a wide range of cellular functions. C1 NCI, Cellular & Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. RP Randazzo, PA (reprint author), NCI, Cellular & Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM randazzo@helix.nih.gov FU Intramural NIH HHS NR 181 TC 57 Z9 58 U1 0 U2 4 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0248-4900 J9 BIOL CELL JI Biol. Cell PD OCT PY 2007 VL 99 IS 10 BP 583 EP 600 DI 10.1042/BC20070034 PG 18 WC Cell Biology SC Cell Biology GA 223HR UT WOS:000250361300005 PM 17868031 ER PT J AU Zanuy, D Rodriguez-Ropero, F Haspel, N Zheng, J Nussinov, R Aleman, C AF Zanuy, David Rodriguez-Ropero, Francisco Haspel, Nurit Zheng, Jie Nussinov, Ruth Aleman, Carlos TI Stability of tubular structures based on beta-helical proteins: Self-assembled versus polymerized nanoconstructs and wild-type versus mutated sequences SO BIOMACROMOLECULES LA English DT Article ID MOLECULAR-DYNAMICS; AMINO-ACIDS; BUILDING-BLOCKS; REPEAT PROTEINS; PEPTIDES; ORGANIZATION; DESIGN; RESIDUES; ACETYLTRANSFERASE; NANOSTRUCTURES AB In this work we used atomistic molecular dynamics simulations to examine different aspects of tubular nanostructures constructed using protein building blocks with a beta-helical conformation. Initially, we considered two different natural protein building blocks, which were extracted from the protein data base, to compare the relative stabilities of the nanotubes obtained made of self-assembled and covalently linked repeats. Results show nanotubes constructed by linking building blocks through covalent bonds are very stable suggesting that the basic principles of polymer physics are valid when the repeating units are made of large fragments of proteins. In contrast, the stability of self-assembled nanostructures strongly depends on the attractive nonbonding interactions associated to building blocks aligned in a complementary manner. On the other hand, we investigated the ability of a conformationally constrained synthetic amino acid to enhance the stability of both self-assembled and polymerized nanotubes when it is used to substitute natural residues. Specifically, we considered 1-aminocyclopentane-1-caboxylic acid, which involves strong stereochemical constraints produced by the cyclopentane side chain. We found that the incorporation of this amino acid within the more flexible regions of the P-helical building blocks is an excellent strategy to enhance the stability of the nanotubes. Thus, when a single mutation is performed in the loop region of the P-helix, the bend architecture of the whole loop is stabilized since the conformational mobility is reduced not only at the mutated position but also at the adjacent positions. C1 Univ Politecn Cataluna, Dept Engn Quim, ETS Engn Ind Barcelona, E-08028 Barcelona, Spain. Rice Univ, Houston, TX 77251 USA. SAIC Frederick Inc, Basic Res Program, Canc Res Ctr, Nanobiol Program,NCI FCRDC, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Zanuy, D (reprint author), Univ Politecn Cataluna, Dept Engn Quim, ETS Engn Ind Barcelona, Diagonal 647, E-08028 Barcelona, Spain. EM david.zanuy@upc.es; carlos.aleman@upe.edu RI Rodriguez-Ropero, Francisco/F-2458-2011; Zheng, Jie/B-5057-2013; Zanuy, David/G-3930-2014; Haspel, Nurit/D-1961-2017 OI Rodriguez-Ropero, Francisco/0000-0001-7435-8986; Zheng, Jie/0000-0003-1547-3612; Zanuy, David/0000-0001-7704-2178; FU NCI NIH HHS [N01 CO12400] NR 49 TC 9 Z9 9 U1 1 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1525-7797 J9 BIOMACROMOLECULES JI Biomacromolecules PD OCT PY 2007 VL 8 IS 10 BP 3135 EP 3146 DI 10.1021/bm700561t PG 12 WC Biochemistry & Molecular Biology; Chemistry, Organic; Polymer Science SC Biochemistry & Molecular Biology; Chemistry; Polymer Science GA 218IT UT WOS:000250009900022 PM 17854222 ER PT J AU Jiang, LL Zhang, YH Song, GX Chen, GH Chen, BH Zhao, NQ Kan, HD AF Jiang, Li-Li Zhang, Yun-Hui Song, Gui-Xiang Chen, Guo-Hai Chen, Bing-Heng Zhao, Nai-Qing Kan, Hai-Dong TI A time series analysis of outdoor air pollution and preterm birth in Shanghai, China SO BIOMEDICAL AND ENVIRONMENTAL SCIENCES LA English DT Article DE air pollution; preterm birth; time series ID PREGNANCY OUTCOMES; ACUTE PYELONEPHRITIS; WEIGHT; EXPOSURE; HEALTH; ABC; EPIDEMIOLOGY; ASSOCIATION; MORTALITY; PREMATURITY AB Objective To investigate the relation between air pollution exposure and preterm birth in Shangha China. Methods We examined the effect of ambient air pollution on preterm birth using time-series approach in Shanghai in 2004. This method can eliminate potential confounding by individual risk factors that do not change over a short period of time. Daily numbers of preterm births were obtained from the live birth database maintained by Shanghai Municipal Center of Disease Control and Prevention. We used the generalized additive model (GAM) with penalized splines to analyze the relation between preterm birth, air pollution, and covariates. Results We observed a significant effect of outdoor air pollution only with 8-week exposure before preterm births. An increase of 10 mu g/m(3) of 8-week average PM10, SO2, NO2, and 03 corresponded to 4.42% (95%CI 1.60%, 7.25%), 11.89% (95%CI 6.69%, 17.09%), 5.43% (95%CI 1.78%, 9.08%), and 4.63% (95%CI 0.35%, 8.91%) increase of preterm birth. We did not find any significant acute effect of outdoor air pollution on preterm birth in the week before birth. Conclusion Ambient air pollution may contribute to the risk of preterm birth in Shanghai. Our analyses also strengthen the rationale for further limiting air pollution level in the city. C1 Shanghai Municipal Ctr Dis Control & Prevent, Shanghai 200336, Peoples R China. Fudan Univ, Sch Publ Hlth, Dept Environm Hlth, Shanghai 200032, Peoples R China. Shanghai Environm Monitoring Ctr, Shanghai 200030, Peoples R China. Fudan Univ, Sch Publ Hlth, Dept Hlth Stat, Shanghai 200032, Peoples R China. RP Kan, HD (reprint author), NIEHS, Epidemiol Branch, POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM haidongkan@gmail.com NR 46 TC 18 Z9 26 U1 1 U2 8 PU CHINESE ACAD PREVENTIVE MEDICINE PI ORLANDO PA C/O ACADEMIC PRESS INC, 6277 SEA HARBOR DR, ORLANDO, FL 32887-4900 USA SN 0895-3988 J9 BIOMED ENVIRON SCI JI Biomed. Environ. Sci. PD OCT PY 2007 VL 20 IS 5 BP 426 EP 431 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 226UC UT WOS:000250613000014 PM 18188997 ER PT J AU Liao, CZ Karki, RG Marchand, C Pommier, Y Nicklaus, MC AF Liao, Chenzhong Karki, Rajeshri G. Marchand, Christophe Pommier, Yves Nicklaus, Marc C. TI Virtual screening application of a model of full-length HIV-1 integrase complexed with viral DNA SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE HIV-1 integrase strand transfer inhibitors; computer-aided drug design; virtual screening; drug discovery ID VIRUS TYPE-1 INTEGRASE; INHIBITORS; DESIGN; DOCKING; DOMAINS; PROTEIN AB To address the absence of experimental data on the full-length structure of HTV-1 integrase and the way it binds to viral and human DNA, we had previously [Karki, R. G.; Tang, Y.; Burke, T. R., Jr.; Nicklaus, M. C. J. Comput. Aided Mol. Des. 2004, 18, 739] constructed models of full-length HIV-1 integrase complexed with models of viral and human DNA. Here we describe the discovery of novel HIV-1 integrase strand transfer inhibitors based on one of these models. Virtual screening methods including docking and filtering by predicted ADME/Tox properties yielded several mu M level inhibitors of the strand transfer reaction catalyzed by wild-type HIV-1 integrase. (C) 2007 Published by Elsevier Ltd. C1 NCI, Med Chem Lab, Ctr Canc Res, NIH,DHHS, Frederick, MD 21702 USA. NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH,DHHS, Bethesda, MD 20892 USA. RP Nicklaus, MC (reprint author), NCI, Med Chem Lab, Ctr Canc Res, NIH,DHHS, Frederick, MD 21702 USA. EM mnl@helix.nih.gov RI Nicklaus, Marc/N-4183-2014; Marchand, Christophe/D-8559-2016; OI Nicklaus, Marc/0000-0002-4775-7030 FU Intramural NIH HHS NR 31 TC 20 Z9 23 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD OCT 1 PY 2007 VL 17 IS 19 BP 5361 EP 5365 DI 10.1016/j.bmcl.2007.08.011 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 218UU UT WOS:000250041400014 PM 17719223 ER PT J AU Zheng, W Brooks, BR Thirumalai, D AF Zheng, Wenjun Brooks, Bernard R. Thirumalai, D. TI Allosteric transitions in the chaperonin GroEL are captured by a dominant normal mode that is most robust to sequence variations SO BIOPHYSICAL JOURNAL LA English DT Article ID ELASTIC-NETWORK MODEL; CONFORMATIONAL-CHANGES; CRYSTAL-STRUCTURE; MECHANISM; MOTIONS; ATP; SUBSTRATE; PROTEINS; RESIDUES; BINDING AB The Escherichia coli chaperonin GroEL, which helps proteins to fold, consists of two heptameric rings stacked back-to-back. During the reaction cycle GroEL undergoes a series of allosteric transitions triggered by ligand ( substrate protein, ATP, and the cochaperonin GroES) binding. Based on an elastic network model of the bullet-shaped double-ring chaperonin GroEL-(ADP)(7)- GroES structure (R" T state), we perform a normal mode analysis to explore the energetically favorable collective motions encoded in the R" T structure. By comparing each normal mode with the observed conformational changes in the R" T -> TR" transition, a single dominant normal mode provides a simple description of this highly intricate allosteric transition. A detailed analysis of this relatively high-frequency mode describes the structural and dynamic changes that underlie the positive intra-ring and negative inter-ring cooperativity. The dynamics embedded in the dominant mode entails highly concerted structural motions with approximate preservation of sevenfold symmetry within each ring and negatively correlated ones between the two rings. The dominant normal mode ( in comparison with the other modes) is robust to parametric perturbations caused by sequence variations, which validates its functional importance. Response of the dominant mode to local changes that mimic mutations using the structural perturbation method technique leads to a wiring diagram that identifies a network of key residues that regulate the allosteric transitions. Many of these residues are located in intersubunit interfaces, and may therefore play a critical role in transmitting allosteric signals between subunits. C1 NHLBI, NIH, Lab Computat Biol, Bethesda, MD 20892 USA. Univ Maryland, Inst Phys Sci & Technol, Biophys Program, College Pk, MD 20742 USA. RP Zheng, W (reprint author), SUNY Buffalo, Dept Phys, 239 Fronczak Hall, Buffalo, NY 14260 USA. EM zhengwj@helix.nih.gov; thirum@glue.umd.edu OI Zheng, Wenjun/0000-0002-6236-9765 FU Intramural NIH HHS; NIGMS NIH HHS [1R01GM067851-01, R01 GM067851] NR 42 TC 77 Z9 77 U1 0 U2 7 PU BIOPHYSICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD OCT PY 2007 VL 93 IS 7 BP 2289 EP 2299 DI 10.1529/biophysj.107.105270 PG 11 WC Biophysics SC Biophysics GA 207UK UT WOS:000249276400002 PM 17557788 ER PT J AU Lee, JSH Hale, CM Panorchan, P Khatau, SB George, JP Tseng, Y Stewart, CL Hodzic, D Wirtz, D AF Lee, Jerry S. H. Hale, Christopher M. Panorchan, Porntula Khatau, Shyam B. George, Jerry P. Tseng, Yiider Stewart, Colin L. Hodzic, Didier Wirtz, Denis TI Nuclear lamin A/C deficiency induces defects in cell mechanics, polarization, and migration SO BIOPHYSICAL JOURNAL LA English DT Article ID PARTICLE-TRACKING MICRORHEOLOGY; A-TYPE LAMINS; DIFFUSING WAVE SPECTROSCOPY; GILFORD-PROGERIA-SYNDROME; ACTIN-FILAMENT NETWORKS; DILATED CARDIOMYOPATHY; MUSCULAR-DYSTROPHY; ENDOTHELIAL-CELLS; SHEAR-STRESS; ENVELOPE AB Lamin A/C is a major constituent of the nuclear lamina, a thin. lamentous protein layer that lies beneath the nuclear envelope. Here we show that lamin A/C deficiency in mouse embryonic. broblasts (Lmna(-/)-MEFs) diminishes the ability of these cells to polarize at the edge of a wound and significantly reduces cell migration speed into the wound. Moreover, lamin A/C de. ciency induces significant separation of the microtubule organizing center (MTOC) from the nuclear envelope. Investigations using ballistic intracellular nanorheology reveal that lamin A/C de. ciency also dramatically affects the micromechanical properties of the cytoplasm. Both the elasticity (stretchiness) and the viscosity (propensity of a material to flow) of the cytoplasm in Lmna(-/-) MEFs are significantly reduced. Disassembly of either the actin. lament or microtubule networks in Lmna(+/+) MEFs results in decrease of cytoplasmic elasticity and viscosity down to levels found in Lmna(-/)-MEFs. Together these results show that both the mechanical properties of the cytoskeleton and cytoskeleton-based processes, including cell motility, coupled MTOC and nucleus dynamics, and cell polarization, depend critically on the integrity of the nuclear lamina, which suggest the existence of a functional mechanical connection between the nucleus and the cytoskeleton. These results also suggest that cell polarization during cell migration requires tight mechanical coupling between MTOC and nucleus, which is mediated by lamin A/C. C1 Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA. Johns Hopkins Univ, Grad Training Program, Dept Chem & Biomol Engn, Baltimore, MD USA. Johns Hopkins Univ, Grad Training Program, Inst NanoBioTechnol, Baltimore, MD USA. Johns Hopkins Univ, Howard Hughes Med Inst, Grad Training Program, Baltimore, MD USA. NCI, Canc & Dev Biol, Frederick, MD 21701 USA. Univ Florida, Dept Chem Engn, Gainesville, FL 32611 USA. RP Hodzic, D (reprint author), Washington Univ, Sch Med, Dept Cell Biol & Physiol, 660 S Euclid Ave, St Louis, MO 63110 USA. RI Lee, Jerry/A-3189-2008; Wirtz, Denis/A-3257-2010; Khatau, Shyam/D-6985-2011; Hale, Christopher/A-6633-2009; Lee, Jerry/K-4553-2014 OI Lee, Jerry/0000-0003-1515-0952; Hale, Christopher/0000-0002-2360-7759; FU NIGMS NIH HHS [R01 GM075305, R01 GM075305-01] NR 58 TC 150 Z9 154 U1 1 U2 29 PU BIOPHYSICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD OCT PY 2007 VL 93 IS 7 BP 2542 EP 2552 DI 10.1529/biophysj.106.102426 PG 11 WC Biophysics SC Biophysics GA 207UK UT WOS:000249276400027 PM 17631533 ER PT J AU Damjanovic, A Schlessman, JL Fitch, CA Garcia, AE Garcia-Moreno, B AF Damjanovic, Ana Schlessman, Jamie L. Fitch, Carolyn A. Garcia, Angel E. Garcia-Moreno, Bertrand TI Role of flexibility and polarity as determinants of the hydration of internal cavities and pockets in proteins SO BIOPHYSICAL JOURNAL LA English DT Article ID ACID-BINDING PROTEIN; MOLECULAR-DYNAMICS; WATER PENETRATION; STAPHYLOCOCCAL NUCLEASE; DIELECTRIC-CONSTANTS; GLOBULAR-PROTEINS; FUNCTIONAL WATER; BURIED WATER; CHANNEL; INTERIOR AB Molecular dynamics simulations of Staphylococcal nuclease and of 10 variants with internal polar or ionizable groups were performed to investigate systematically the molecular determinants of hydration of internal cavities and pockets in proteins. In contrast to apolar cavities in rigid carbon structures, such as nanotubes or buckeyballs, internal cavities in proteins that are large enough to house a few water molecules will most likely be dehydrated unless they contain a source of polarity. The water content in the protein interior can be modulated by the flexibility of protein elements that interact with water, which can impart positional disorder to water molecules, or bias the pattern of internal hydration that is stabilized. This might explain differences in the patterns of hydration observed in crystal structures obtained at cryogenic and room temperature conditions. The ability of molecular dynamics simulations to determine the most likely sites of water binding in internal pockets and cavities depends on its efficiency in sampling the hydration of internal sites and alternative protein and water conformations. This can be enhanced significantly by performing multiple molecular dynamics simulations as well as simulations started from different initial hydration states. C1 Johns Hopkins Univ, Sch Med, Dept Biophys, Baltimore, MD 21205 USA. USN Acad, Dept Chem, Annapolis, MD 21402 USA. Rensselaer Polytech Inst, Dept Phys Appl Phys & Astron, Troy, NY USA. Ctr Biotechnol & Interdisciplinary Studies, Troy, NY USA. NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP Garcia-Moreno, B (reprint author), Johns Hopkins Univ, Sch Med, Dept Biophys, Baltimore, MD 21205 USA. EM bertrand@jhu.edu FU NIGMS NIH HHS [R01 GM061597] NR 61 TC 31 Z9 32 U1 1 U2 17 PU BIOPHYSICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD OCT PY 2007 VL 93 IS 8 BP 2791 EP 2804 DI 10.1529/biophysj.107.104182 PG 14 WC Biophysics SC Biophysics GA 212YF UT WOS:000249632300020 PM 17604315 ER PT J AU Mager, DE Kobrinsky, E Masoudieh, A Maltsev, A Abernethy, DR Soldatovy, NM AF Mager, Donald E. Kobrinsky, Evgeny Masoudieh, Amirali Maltsev, Anna Abernethy, Darrell R. Soldatovy, Nikolai M. TI Analysis of functional signaling domains from fluorescence imaging and the two-dimensional continuous wavelet transform SO BIOPHYSICAL JOURNAL LA English DT Article ID PROTEIN-KINASE-C; CAVEOLAE; PHOSPHORYLATION; MICRODOMAINS; MICROSCOPY; BIOLOGY AB A technique that utilizes the one-dimensional (1D) continuous wavelet transform (CWT) of linearized fluorescence resonance energy transfer (FRET) microscopic images has been extended to identify signaling macro- and micro-domains in cell plasma membranes by incorporating the two-dimensional (2D) CWT of time-lapse fluorescence and/ or FRET images. Signaling domains were identified from differences in wavelet coefficient matrices, and there was good agreement between the 1D and 2D methods on examining a), static fluorescent images of COS1 cells expressing calmodulin kinase II fused with enhanced yellow fluorescent protein, and b), time lapse FRET images of reporters of protein kinase C (PKC) ( PKC activity reporter) and adenylyl cyclase dynamics (cAMP) activity within COS1 plasma membrane confines after stimulation by phorbol-12,13-dibutyrate or forskolin, respectively. The proposed 2D wavelet-based image analysis effectively detected phosphorylation/dephosphorylation signaling microdomains (PKC) as well as those reflective of cAMP without the limitation of requiring linearized signals imposed by the 1D approach. Illustrating successful application to the analysis of intracellular compartments, the 2D CWT was further used to identify signaling domains of cAMP response element-binding (CREB)-induced transcriptional activation in the nuclei of COS1 cells, which could not be achieved with the 1D approach. This technique may be eventually used to characterize complex cellular signaling and protein-protein interactions within localized cytoplasmic domains. C1 NIA, NIH, Baltimore, MD 21224 USA. SUNY Buffalo, Dept Pharmaceut Sci, Buffalo, NY 14260 USA. RP Soldatovy, NM (reprint author), NIA, NIH, Baltimore, MD 21224 USA. EM soldatovn@grc.nia.nih.gov FU Intramural NIH HHS NR 20 TC 5 Z9 5 U1 0 U2 3 PU BIOPHYSICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD OCT PY 2007 VL 93 IS 8 BP 2900 EP 2910 DI 10.1529/biophysj.106.102582 PG 11 WC Biophysics SC Biophysics GA 212YF UT WOS:000249632300031 PM 17586569 ER PT J AU Pennell, ML Dunson, DB AF Pennell, Michael L. Dunson, David B. TI Fitting semiparametric random effects models to large data sets SO BIOSTATISTICS LA English DT Article DE cluster analysis; Dirichlet process; latent variables; longitudinal data; mixed effects model; prior elicitation ID GENERALIZED LINEAR-MODELS; MIXED-EFFECTS MODEL; DISTRIBUTIONS; MIXTURES AB For large data sets, it can be difficult or impossible to fit models with random effects using standard algorithms due to memory limitations or high computational burdens. In addition, it would be advantageous to use the abundant information to relax assumptions, such as normality of random effects. Motivated by data from an epidemiologic study of childhood growth, we propose a 2-stage method for fitting semiparametric random effects models to longitudinal data with many subjects. In the first stage, we use a multivariate clustering method to identify G << N groups of subjects whose data have no scientifically important differences, as defined by subject matter experts. Then, in stage 2, group-specific random effects are assumed to come from an unknown distribution, which is assigned a Dirichlet process prior, further clustering the groups from stage 1. We use our approach to model the effects of maternal smoking during pregnancy on growth in 17 518 girls. C1 Ohio State Univ, Coll Publ Hlth, Div Biostat, Columbus, OH 43210 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Pennell, ML (reprint author), Ohio State Univ, Coll Publ Hlth, Div Biostat, B-115Starling Loving Hall,320 W 10th Ave, Columbus, OH 43210 USA. EM mpennell@cph.osu.edu FU Intramural NIH HHS NR 33 TC 6 Z9 6 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1465-4644 J9 BIOSTATISTICS JI Biostatistics PD OCT PY 2007 VL 8 IS 4 BP 821 EP 834 DI 10.1093/biostatistics/kxm008 PG 14 WC Mathematical & Computational Biology; Statistics & Probability SC Mathematical & Computational Biology; Mathematics GA 227QX UT WOS:000250674000012 PM 17429104 ER PT J AU Barrett, AJ AF Barrett, A. John TI Fingernail transplants? SO BLOOD LA English DT Editorial Material C1 NHLBI, Bethesda, MD 20892 USA. RP Barrett, AJ (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2007 VL 110 IS 7 BP 2221 EP 2221 DI 10.1182/blood-2007-06-096669 PG 1 WC Hematology SC Hematology GA 215ID UT WOS:000249800900005 ER PT J AU Tisdale, JF AF Tisdale, John F. TI Tortoise and hare win for SCD SO BLOOD LA English DT Editorial Material ID SICKLE-CELL-DISEASE; TRANSPLANTATION; THALASSEMIA C1 NIH, Bethesda, MD USA. RP Tisdale, JF (reprint author), NIH, Bethesda, MD USA. NR 4 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2007 VL 110 IS 7 BP 2223 EP 2224 DI 10.1182/blood-2007-07-101006 PG 2 WC Hematology SC Hematology GA 215ID UT WOS:000249800900008 ER PT J AU Sierra, MDLL Gasperini, P McCormick, PJ Zhu, JF Tosato, G AF Sierra, Maria De La Luz Gasperini, Paola McCormick, Peter J. Zhu, Jinfang Tosato, Giovanna TI Transcription factor Gfi-1 induced by G-CSF is a negative regulator of CXCR4 in myeloid cells SO BLOOD LA English DT Article ID COLONY-STIMULATING FACTOR; CHEMOKINE RECEPTOR CXCR4; SEVERE CONGENITAL NEUTROPENIA; HEMATOPOIETIC STEM-CELLS; BONE-MARROW; FACTOR-I; CD34(+) CELLS; GRANULOCYTIC DIFFERENTIATION; PROGENITOR CELLS; REPRESSOR GFI1 AB The mechanisms underlying granulocyte-colony stimulating factor (G-CSF)induced mobilization of granulocytic lineage cells from the bone marrow to the peripheral blood remain elusive. We provide evidence that the transcriptional repressor growth factor independence-1 (Gfi-1) is involved in G-CSF-induced mobilization of granulocytic lineage cells from the bone marrow to the peripheral blood. We show that in vitro and in vivo G-CSF promotes expression of Gfi-1 and down-regulates expression of CXCR4, a chemokine receptor essential for the retention of hematopoietic stem cells and granulocytic cells in the bone marrow. Gfi-1 binds to DNA sequences upstream of the CXCR4 gene and represses CXCR4 expression in myeloid lineage cells. As a consequence, myeloid cell responses to the CXCR4 unique ligand SDF-1 are reduced. Thus, Gfi-1 not only regulates hematopoietic stem cell function and myeloid cell development but also probably promotes the release of granulocytic lineage cells from the bone marrow to the peripheral blood by reducing CXCR4 expression and function. C1 NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Tosato, G (reprint author), NCI, Cellular Oncol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM tosatog@mail.nih.gov RI Zhu, Jinfang/B-7574-2012; McCormick, Peter/E-7387-2012 OI McCormick, Peter/0000-0002-2225-5181 NR 55 TC 26 Z9 26 U1 1 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2007 VL 110 IS 7 BP 2276 EP 2285 DI 10.1182/blood-2007-03-081448 PG 10 WC Hematology SC Hematology GA 215ID UT WOS:000249800900021 ER PT J AU Akin, C Scott, LM Kocabas, CN Kushnir-Sukhov, N Brittain, E Noel, P Metcalfe, DD AF Akin, Cem Scott, Linda M. Kocabas, Can N. Kushnir-Sukhov, Nataliya Brittain, Erica Noel, Pierre Metcalfe, Dean D. TI Demonstration of an aberrant mast-cell population with clonal markers in a subset of patients with "idiopathic" anaphylaxis SO BLOOD LA English DT Article ID SYSTEMIC MASTOCYTOSIS; KIT MUTATION; C-KIT; DISORDERS; DIAGNOSIS; TRYPTASE; IGE; CLASSIFICATION; DEGRANULATION; PATHOLOGY AB Idiopathic anaphylaxis remains a perplexing disorder in which existing prophylactic therapy is inadequate. In this prospective study, we sought to determine whether patients with idiopathic anaphylaxis might have evidence for a clonal disorder of mast cells related to mastocytosis and for which novel targeted therapies might be considered. We report 12 patients with "Idiopathic" anaphylaxis who did not exhibit either urticaria pigmentosa or the characteristic bone marrow biopsy finding of multifocal mast-cell aggregates observed in systemic mastocytosis. Of these 12 patients, 5 had evidence of 1 or more minor criteria for mastocytosis. C-KITmutational analysis was positive for the 816D > V activating mutation in 3 of 3 patients in CD25(+) bone marrow cells where the analysis was performed. These results demonstrate the presence of an aberrant mast-cell population carrying clonal markers in a subset of patients diagnosed with "idiopathic" anaphylaxis, who may respond to inhibitors targeting mutated C-KIT. This intramural clinical trial was conducted in 2003 and 2004 and was registered at http:// clinicalcenter.nih.gov with a study number 03-1-0010. C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD USA. NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. RP Akin, C (reprint author), Univ Michigan, 5520-B MSRB-1,Box 0600,1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. EM cemakin@umich.edu OI Akin, Cem/0000-0001-6301-4520 FU Intramural NIH HHS NR 21 TC 110 Z9 111 U1 0 U2 2 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2007 VL 110 IS 7 BP 2331 EP 2333 DI 10.1182/blood-2006-06-028100 PG 3 WC Hematology SC Hematology GA 215ID UT WOS:000249800900028 PM 17638853 ER PT J AU Gupta, R Sharma, S Sommers, JA Kenny, MK Cantor, SB Brosh, RM AF Gupta, Rigu Sharma, Sudha Sommers, Joshua A. Kenny, Mark K. Cantor, Sharon B. Brosh, Robert M., Jr. TI FANCJ (BACH1) helicase forms DNA damage inducible foci with replication protein A and interacts physically and functionally with the single-stranded DNA-binding protein SO BLOOD LA English DT Article ID WERNER-SYNDROME PROTEIN; CROSS-LINK REPAIR; ESCHERICHIA-COLI; ANEMIA PATHWAY; BREAST-CANCER; HOMOLOGOUS RECOMBINATION; BLOOM-SYNDROME; WRN HELICASE; BRCA1; RECOGNITION AB The BRCA1 associated C-terminal helicase (BACH1, designated FANCJ) is implicated in the chromosomal instability genetic disorder Fanconi anemia (FA) and hereditary breast cancer. A critical role of FANCJ helicase may be to restart replication as a component of downstream events that occur during the repair of DNA cross-links or double-strand breaks. We investigated the potential interaction of FANCJ with replication protein A (RPA), a single-stranded DNA-binding protein implicated in both DNA replication and repair. FANCJ and RPA were shown to coimmunoprecipitate most likely through a direct interaction of FANCJ and the RPA70 subunit. Moreover, dependent on the presence of BRCA1, FANCJ colocalizes with RPA in nuclear foci after DNA damage. Our data are consistent with a model in which FANCJ associates with RPA in a DNA damage-inducible manner and through the protein interaction RPA stimulates FANCJ helicase to better unwind duplex DNA substrates. These findings identify RPA as the first regulatory partner of FANCJ. The FANCJ-RPA interaction is likely to be important for the role of the helicase to more efficiently unwind DNA repair intermediates to maintain genomic stability. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Montefiore Med Ctr, Albert Einstein Coll Med, Dept Emergency Med, Bronx, NY 10467 USA. Univ Massachusetts, Sch Med, Dept Canc Biol, Worcester, MA USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM BroshR@grc.nia.nih.gov OI Sharma, Sudha/0000-0003-2765-2482 FU Intramural NIH HHS NR 44 TC 60 Z9 60 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2007 VL 110 IS 7 BP 2390 EP 2398 DI 10.1182/blood-2006-11-057273 PG 9 WC Hematology SC Hematology GA 215ID UT WOS:000249800900035 PM 17596542 ER PT J AU Fasseu, M Aplan, PD Chopin, M Boissel, N Bories, JC Soulier, J von Boehmer, H Sigaux, F Regnault, A AF Fasseu, Magali Aplan, Peter D. Chopin, Martine Boissel, Nicolas Bories, Jean-Christophe Soulier, Jean von Boehmer, Harald Sigaux, Francois Regnault, Armelle TI p(16INK4A) tumor suppressor gene expression and CD3(epsilon) deficiency but not pre-TCR deficiency inhibit TAL1-linked T-lineage leukemogenesis SO BLOOD LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; DOUBLE-TRANSGENIC MICE; CELL LEUKEMIA; THYMOCYTE DIFFERENTIATION; RECOMBINASE ACTIVITY; MOLECULAR-GENETICS; ACTIVATED LCK; MUTANT MICE; ALPHA-CHAIN; NOTCH1 AB Inactivation of the CDKN2 genes that encode the p16(INK4A) and p14(ARF) proteins occurs in the majority of human T-cell acute lymphoblastic leukemias (T-ALLs). Ectopic expression of TAL1 and LMO1 genes is linked to the development of T-ALL in humans. In TAL1xLMO1 mice, leukemia develops in 100% of mice at 5 months. To identify the molecular events crucial to leukemic transformation, we produced several mouse models. We report here that expression of P16(INK4A) in developing TAL1xLMO1 thymocytes blocks leukemogenesis in the majority of the mice, and the leukemias that eventually develop show P16(INK4A) loss of expression. Events related to the T-cell receptor 0 selection process are thought to be important for leukemic transformation. We show here that the absence of the pT alpha. chain only slightly delays the appearance of TAL1xLMO1-induced T-ALL, which indicates a minor role of the pT alpha chain. We also show that the CD3 epsilon-mediated signal transduction pathway is essential for this transformation process, since the TAL1xLMO1xCD3 epsilon-deficient mice do not develop T-ALL for up to 1 year. C1 Hop St Louis, Inst Hematol, INSERM U462, F-75010 Paris, France. NCI, Ctr Canc Res, Genet Branch, NIH, Bethesda, MD USA. Hop St Louis, Inst Hematopl, INSERM, U662, Paris, France. Hop St Louis, Inst Hematol, EA 3963, INSERM, Paris, France. Dana Farber Canc Inst, Boston, MA USA. RP Regnault, A (reprint author), Hop St Louis, Inst Hematol, INSERM U462, 1 Ave Claude Vellefaux, F-75010 Paris, France. EM armelle.regnault@wanadoo.fr RI REGNAULT, Armelle/G-4142-2011; Aplan, Peter/K-9064-2016 OI REGNAULT, Armelle/0000-0001-7286-9491; FU Intramural NIH HHS NR 62 TC 9 Z9 9 U1 0 U2 4 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2007 VL 110 IS 7 BP 2610 EP 2619 DI 10.1182/blood-2007-01-066209 PG 10 WC Hematology SC Hematology GA 215ID UT WOS:000249800900062 PM 17507663 ER PT J AU Csoka, B Nemeth, ZH Virag, L Gergely, P Leibovich, SJ Pacher, P Sun, CX Blackburn, MR Vizi, ES Deitch, EA Hasko, G AF Csoka, Balazs Nemeth, Zoltan H. Virag, Laszlo Gergely, Pal Leibovich, S. Joseph Pacher, Pal Sun, Chun-Xiao Blackburn, Michael R. Vizi, E. Sylvester Deitch, Edwin A. Hasko, Gyorgy TI A(2A) adenosine receptors and C/EBP beta are crucially required for IL-10 production by macrophages exposed to Escherichia coli SO BLOOD LA English DT Article ID TOLL-LIKE RECEPTORS; ADENOSINE A(2A) RECEPTORS; NITRIC-OXIDE PRODUCTION; ACUTE-PHASE RESPONSE; GENE-EXPRESSION; TRANSCRIPTION FACTORS; IMMUNE-RESPONSE; DENDRITIC CELLS; CUTTING EDGE; TNF-ALPHA AB We recently showed that A(2A) adenosine receptor activation by endogenous adenosine contributes to interieukin-10 (IL-10) production in polymicrobial sepsis. Here 14 we investigated the molecular mechanisms underpinning this interaction between adenosine receptor signaling and infection by exposing macrophages to Escherichia coli. We demonstrated using receptor knockout mice that A2A receptor activation is critically required for the stimulatory effect of adenosine on IL-10 production by E coli-challenged macrophages, whereas A(2B) receptors have a minor role. The stimulatory effect of adenosine on E coli-induced IL-10 production did not require toll-like receptor 4 (TLR4) or MyD88, but was blocked by p38 inhibition. Using shRNA we demonstrated that TRAF6 impairs the potentiating effect of adenosine. Measuring IL-10 mRNA abundance and transfection with an IL-10 promoter-luciferase construct indicated that E coli and adenosine synergistically activate IL-10 transcription. Sequential deletion analysis and site-directed mutagenesis of the IL-10 promoter revealed that a region harboring C/EBP binding elements was responsible for the stimulatory effect of adenosine on E coli-induced IL-10 promoter activity. Adenosine augmented E coli-induced nuclear accumulation and DNA binding of C/EBP beta. C/EBP beta-deficient macrophages failed to produce IL-10 in response to adenosine and E coli. Our results suggest that the A(2A) receptor-C/EBP beta axis is critical for IL-10 production after bacterial infection. C1 UMDNJ, Sch Med, Dept Surg, Newark, NJ 07103 USA. Univ Debrecen, Med & Hlth Sci Ctr, Dept Med Chem, Debrecen, Hungary. Univ Med & Dent New Jersey, Dept Cell Biol & Mol Med, Newark, NJ USA. Natl Inst Alcohol Abuse & Alcoholism, Bethesda, MD USA. Univ Texas, Houston Med Sch, Dept Biochem & Mol Biol, Houston, TX USA. Hungarian Acad Sci, Inst Expt Med, Dept Pharmacol, Budapest, Hungary. RP Hasko, G (reprint author), UMDNJ, Sch Med, Dept Surg, 185 S Orange Ave, Newark, NJ 07103 USA. EM haskoge@umdnj.edu RI Gergely, Pal/A-5547-2008; Virag, Laszlo/E-6124-2010; Pacher, Pal/B-6378-2008; OI Pacher, Pal/0000-0001-7036-8108; Blackburn, Michael/0000-0002-1394-9966; Csoka, Balazs/0000-0002-7562-1130 FU Intramural NIH HHS; NIGMS NIH HHS [R01 GM066189, R01 GM66189] NR 72 TC 89 Z9 91 U1 1 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD OCT 1 PY 2007 VL 110 IS 7 BP 2685 EP 2695 DI 10.1182/blood-2007-01-065870 PG 11 WC Hematology SC Hematology GA 215ID UT WOS:000249800900070 PM 17525287 ER PT J AU Sebastiani, P Nolan, VG Baldwin, CT Abad-Grau, MM Wang, L Adewoye, AH McMahon, LC Farrer, LA Taylor, JG Kato, GJ Gladwin, MT Steinberg, MH AF Sebastiani, Paola Nolan, Vikki G. Baldwin, Clinton T. Abad-Grau, Maria M. Wang, Ling Adewoye, Adeboye H. McMahon, Lillian C. Farrer, Lindsay A. Taylor, James G. Kato, Gregory J. Gladwin, Mark T. Steinberg, Martin H. TI A network model to predict the risk of death in sickle cell disease SO BLOOD LA English DT Article ID PULMONARY-HYPERTENSION; NITRIC-OXIDE; RELATIVE HYPERTENSION; CLINICAL SEVERITY; BAYESIAN NETWORK; FREE HEMOGLOBIN; ANEMIA; HEMOLYSIS; CHILDREN; MORTALITY AB Modeling the complexity of sickle cell disease pathophysiology and severity is difficult. Using data from 3380 patients accounting for all common genotypes of sickle cell disease, Bayesian network modeling of 25 clinical events and laboratory tests was used to estimate sickle cell disease severity, which was represented as a score predicting the risk of death within 5 years. The reliability of the model was supported by analysis of 2 independent patient groups. In 1 group, the severity score was related to disease severity based on the opinion of expert clinicians. In the other group, the severity score was related to the presence and severity of pulmonary hypertension and the risk of death. Along with previously known risk factors for mortality, like renal insufficiency and leukocytosis, the network identified laboratory markers of the severity of hemolytic anemia and its associated clinical events as contributing risk factors. This model can be used to compute a personalized disease severity score allowing therapeutic decisions to be made according to the prognosis. The severity score could serve as an estimate of overall disease severity in genotype-phenotype association studies, and the model provides an additional method to study the complex pathophysiology of sickle cell disease. C1 Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. Univ Granada, E-18071 Granada, Spain. Clin Ctr, Natl Heart Lung & Blood Inst, Vasc Med Branch, NIH, Bethesda, MD USA. RP Steinberg, MH (reprint author), Boston Univ, Sch Med, Dept Med, Rm E248,88 E Newton St, Boston, MA 02118 USA. EM mhsteinb@bu.edu RI Abad Grau, Maria del Mar/B-2172-2012; Kato, Gregory/I-7615-2014; OI Abad Grau, Maria del Mar/0000-0001-8470-9719; Kato, Gregory/0000-0003-4465-3217; Steinberg, Martin/0000-0001-8800-8020; Farrer, Lindsay/0000-0001-5533-4225; sebastiani, paola/0000-0001-6419-1545; Taylor, James/0000-0002-4421-1809 FU Intramural NIH HHS [Z99 HL999999, ZIA HL006012-01]; NHLBI NIH HHS [R01 HL068970, R01 HL68970, R21 HL080463, T32 HL007501, U54 HL070819, U54 HL70819] NR 43 TC 66 Z9 67 U1 1 U2 5 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD OCT 1 PY 2007 VL 110 IS 7 BP 2727 EP 2735 DI 10.1182/blood-2007-04-084921 PG 9 WC Hematology SC Hematology GA 215ID UT WOS:000249800900075 PM 17600133 ER PT J AU Lacey, EH Lott, SN Sperling, AJ Snider, SF Friedman, RB AF Lacey, Elizabeth H. Lott, Susan Nitzberg Sperling, Anne J. Snider, Sarah Ferguson Friedman, Rhonda B. TI Multiple oral re-reading treatment for alexia: It works, but why? SO BRAIN AND LANGUAGE LA English DT Meeting Abstract C1 [Lacey, Elizabeth H.; Lott, Susan Nitzberg; Sperling, Anne J.; Snider, Sarah Ferguson; Friedman, Rhonda B.] Georgetown Univ, Med Ctr, Dept Neurol, Cognit Neuropsychol Lab, Washington, DC 20057 USA. [Lacey, Elizabeth H.] Georgetown Univ, Interdisciplinary Program Neurosci, Washington, DC 20057 USA. [Sperling, Anne J.] NIMH, Bethesda, MD 20892 USA. EM ehl4@georgetown.edu NR 5 TC 1 Z9 1 U1 2 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0093-934X J9 BRAIN LANG JI Brain Lang. PD OCT-NOV PY 2007 VL 103 IS 1-2 BP 115 EP 116 DI 10.1016/j.bandl.2007.07.071 PG 2 WC Audiology & Speech-Language Pathology; Linguistics; Neurosciences; Psychology, Experimental SC Audiology & Speech-Language Pathology; Linguistics; Neurosciences & Neurology; Psychology GA 227MF UT WOS:000250660100054 ER PT J AU Postman-Caucheteux, WA Hoffman, S Picchiom, D McArdle, J Birn, R Braun, A AF Postman-Caucheteux, W. A. Hoffman, S. Picchiom, D. McArdle, J. Birn, R. Braun, A. TI Distinct activation patterns for accurate vs. inaccurate naming of actions and objects: An fMRI study with stroke patients with chronic aphasia SO BRAIN AND LANGUAGE LA English DT Meeting Abstract C1 [Postman-Caucheteux, W. A.; Hoffman, S.; McArdle, J.; Braun, A.] Natl Inst Deafness & Commun Disorders, NIH, Bethesda, MD 20892 USA. [Picchiom, D.] Walter Reed Army Inst Res, Div Psychiat & Neurosci, Silver Spring, MD USA. [Birn, R.] NIMH, NIH, Bethesda, MD 20892 USA. EM postmanw@nided.nih.gov NR 6 TC 1 Z9 1 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 0093-934X J9 BRAIN LANG JI Brain Lang. PD OCT-NOV PY 2007 VL 103 IS 1-2 BP 150 EP 151 DI 10.1016/j.bandl.2007.07.090 PG 2 WC Audiology & Speech-Language Pathology; Linguistics; Neurosciences; Psychology, Experimental SC Audiology & Speech-Language Pathology; Linguistics; Neurosciences & Neurology; Psychology GA 227MF UT WOS:000250660100072 ER PT J AU Crawley, JN AF Crawley, Jacqueline N. TI Mouse behavioral assays relevant to the symptoms of autism SO BRAIN PATHOLOGY LA English DT Review ID FRAGILE-X-SYNDROME; ANXIETY-LIKE BEHAVIOR; OVEREXPRESSING TRANSGENIC MICE; SENSORIMOTOR GATING ABNORMALITIES; SOCIAL APPROACH BEHAVIORS; QUANTITATIVE TRAIT LOCUS; GENETIC ANIMAL-MODELS; LEMLI-OPITZ-SYNDROME; ELEVATED PLUS-MAZE; KNOCKOUT MICE AB While the cause of autism remains unknown, the high concordance between monozygotic twins supports a strong genetic component. The importance of genetic factors in autism encourages the development of mutant mouse models, to advance our understanding of biological mechanisms underlying autistic behaviors. Mouse models of human neuropsychiatric diseases are designed to optimize (i) face validity (resemblance to the human symptoms) (ii) construct validity (similarity to the underlying causes of the disease) and (iii) predictive validity (expected responses to treatments that are effective in the human disease). There is a growing need for mouse behavioral tasks with all three types of validity, to define robust phenotypes in mouse models of autism. Ideal mouse models will incorporate analogies to the three diagnostic symptoms of autism: abnormal social interactions, deficits in communication and high levels of repetitive behaviors. Social approach is tested in an automated three chambered apparatus that offers the subject a choice between spending time with another mouse, with a novel object, or remaining in an empty familiar environment. Reciprocal social interaction is scored from videotapes of interactions between pairs of unfamiliar mice. Communication is evaluated by measuring emission and responses to vocalizations and olfactory cues. Repetitive behaviors are scored for measures of grooming, jumping, or stereotyped sniffing of one location or object. Insistence on sameness is modeled by scoring a change in habit, for example, reversal of the spatial location of a reinforcer in the Morris water maze or T-maze. Associated features of autism, for example, mouse phenotypes relevant to anxiety, seizures, sleep disturbances and sensory hypersensitivity, may be useful to include in a mouse model that meets some of the core diagnostic criteria. Applications of these assays include (i) behavioral phenotyping of transgenic and knockout mice with mutations in genes relevant to autism; (ii) characterization of inbred strains of mice; (iii) evaluation of environmental toxins; (iv) comparison of behavioral phenotypes with genetic factors, such as unusual expression patterns of genes or unusual single nucleotide polymorphisms; and (v) evaluation of proposed therapeutics for the treatment of autism. C1 NIMH, Lab Behav Neurosci, Intramural Res Program, Bethesda, MD 20892 USA. Univ N Carolina, Neurodev Disorders Res Ctr, Chapel Hill, NC USA. RP Crawley, JN (reprint author), NIMH, Lab Behav Neurosci, Intramural Res Program, Bldg 35 Rm 1c903, Bethesda, MD 20892 USA. EM crawleyj@intra.nimh.nih.gov FU Intramural NIH HHS; NIMH NIH HHS [MH66418]; PHS HHS [NICHD P30] NR 203 TC 235 Z9 240 U1 8 U2 31 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1015-6305 J9 BRAIN PATHOL JI Brain Pathol. PD OCT PY 2007 VL 17 IS 4 BP 448 EP 459 DI 10.1111/j.1750-3639.2007.00096.x PG 12 WC Clinical Neurology; Neurosciences; Pathology SC Neurosciences & Neurology; Pathology GA 217NC UT WOS:000249953600013 PM 17919130 ER PT J AU Lugassy, C Kleinman, HK Vernon, SE Welch, DR Barnhill, RL AF Lugassy, C. Kleinman, H. K. Vernon, S. E. Welch, D. R. Barnhill, R. L. TI C16 laminin peptide increases angiotropic extravascular migration of human melanoma cells in a shell-less chick chorioallantoic membrane assay SO BRITISH JOURNAL OF DERMATOLOGY LA English DT Article DE angiotropism; C16 laminin peptide; extravascular migratory metastasis; green fluorescent protein; human melanoma cells; shell-less chick chorioallantoic membrane ID IMMUNOHISTOCHEMICAL OBSERVATIONS; MALIGNANT-MELANOMA; METASTASIS; IDENTIFICATION; MATRIX; CHAIN AB Background As distinct from intravascular dissemination, extravascular migratory metastasis (EVMM) has been described as a potential additional mechanism of melanoma spread in which tumour cells migrate along the external surfaces of vessels. Recent experimental studies strongly suggest a correlation of angiotropism of melanoma cells with EVMM. Angiotropic melanoma cells are linked to the endothelium by an amorphous matrix confirmed to contain laminin. Objectives To investigate whether laminin plays a role in this extravascular mechanism of tumour spread. Methods We tested the effect of the C16 laminin peptide on melanoma spread in a shell-less chick chorioallantoic membrane model. Results After 3 days, green fluorescent protein-expressing melanoma cells were observed spreading along or in the immediate proximity of vessels. The C16 laminin peptide significantly lengthened the distance of extravascular, angiotropic migration of melanoma cells. Histopathology confirmed the angiotropism of melanoma cells without intravasation, compatible with that observed with human angiotropic melanoma. Conclusions The results of this study suggest that the C16 laminin gamma 1 chain peptide has angiotropic, extravascular migration-promoting activity on human melanoma cells, and might be a molecular target for preventing melanoma metastasis. C1 Univ Miami, Miller Sch Med JMH, Dept Pathol, Miami, FL 33136 USA. NIH, Natl Inst Dent & Craniofacial Res, Bethesda, MD USA. Univ Alabama, Ctr Comprehens Canc, Dept Pathol, Birmingham, AL USA. Univ Miami, Miller Sch Med JMH, Dept Dermatol, Miami, FL 33136 USA. RP Lugassy, C (reprint author), Univ Miami, Miller Sch Med JMH, Dept Pathol, Miami, FL 33136 USA. EM clugassy@med.miami.edu RI Welch, Danny/B-7310-2009 OI Welch, Danny/0000-0002-1951-4947 NR 14 TC 17 Z9 17 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0007-0963 J9 BRIT J DERMATOL JI Br. J. Dermatol. PD OCT PY 2007 VL 157 IS 4 BP 780 EP 782 DI 10.1111/j.1365-2133.2007.08120.x PG 3 WC Dermatology SC Dermatology GA 209GL UT WOS:000249376900023 PM 17711523 ER PT J AU Amsellem, N Jakubowicz, C Poinsot, R Rizk, T Siri, M Spire, A AF Amsellem, N. Jakubowicz, C. Poinsot, R. Rizk, T. Siri, M. Spire, A. TI On the relation of patients to medical institutions for cancer SO BULLETIN DU CANCER LA French DT Article C1 Natl Canc Inst, Bethesda, MD 20892 USA. RP Amsellem, N (reprint author), Natl Canc Inst, Bethesda, MD 20892 USA. EM namsellem@institutcancer.fr NR 18 TC 1 Z9 1 U1 0 U2 0 PU JOHN LIBBEY EUROTEXT LTD PI MONTROUGE PA 127 AVE DE LA REPUBLIQUE, 92120 MONTROUGE, FRANCE SN 0007-4551 J9 B CANCER JI Bull. Cancer PD OCT PY 2007 VL 94 IS 10 BP 923 EP 926 DI 10.1684/bdc.2007.0453 PG 4 WC Oncology SC Oncology GA 238JP UT WOS:000251444000013 ER PT J AU Levine, KE Essader, AS Weber, FX Perlmutter, JM Milstein, LS Fernando, RA Levine, MA Collins, BJ Adams, JB Grohse, PM AF Levine, K. E. Essader, A. S. Weber, F. X. Perlmutter, J. M. Milstein, L. S. Fernando, R. A. Levine, M. A. Collins, B. J. Adams, J. B. Grohse, P. M. TI Determination of iodine in low mass human hair samples by inductively coupled plasma mass spectrometry SO BULLETIN OF ENVIRONMENTAL CONTAMINATION AND TOXICOLOGY LA English DT Article ID NUTRITION; ELEMENTS C1 RTI Int, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. Arizona State Univ, Tempe, AZ 85287 USA. RP Levine, KE (reprint author), RTI Int, 3040 Conrwallis Rd,PO Box 12194, Res Triangle Pk, NC 27709 USA. EM levine@rti.org FU NIEHS NIH HHS [N01-ES-05455, N01-ES-65554] NR 15 TC 0 Z9 0 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0007-4861 J9 B ENVIRON CONTAM TOX JI Bull. Environ. Contam. Toxicol. PD OCT PY 2007 VL 79 IS 4 BP 401 EP 404 DI 10.1007/s00128-007-9264-x PG 4 WC Environmental Sciences; Toxicology SC Environmental Sciences & Ecology; Toxicology GA 219VH UT WOS:000250115800009 PM 17721731 ER PT J AU Deininger, MWN Cortes, J Paquette, R Park, B Hochhaus, A Baccarani, M Stone, R Fischer, T Kantarjian, H Niederwieser, D Gambacorti-Passerini, C So, C Gathmann, I Goldman, JM Smith, D Druker, BJ Guilhot, F AF Deininger, Michael W. N. Cortes, Jorge Paquette, Ron Park, Byung Hochhaus, Andreas Baccarani, Michele Stone, Richard Fischer, Thomas Kantarjian, Hagop Niederwieser, Dietger Gambacorti-Passerini, Carlo So, Charlene Gathmann, Insa Goldman, John M. Smith, Douglas Druker, Brian J. Guilhot, Francois TI The prognosis for patients with chronic myeloid leukemia who have clonal cytogenetic abnormalities in Philadelphia chromosome-negative cells SO CANCER LA English DT Article DE chronic myeloid leukemia; cytogenetic abnormalities; Philadelphia chromosome; BCR-ABL; imatinib ID CHRONIC MYELOGENOUS LEUKEMIA; IMATINIB MESYLATE THERAPY; INTERFERON-ALPHA; CHRONIC-PHASE; CML PATIENTS; FOLLOW-UP; PH-CELLS; EMERGENCE; HEMATOPOIESIS; ABERRATIONS AB BACKGROUND. Clonal cytogenetic abnormalities (CCA) were detected in Philadelphia chromosome (Ph)-negative cells in some patients with chronic myeloid leukemia (CML) who attained a cytogenetic response to imatinib mesylate. In some patients, CCA/Ph-negative status was associated with myelodysplasia or acute myeloid leukemia. The objective of the current study was to determine the prognostic impact of CCA/Ph-negative cells. METHODS. The authors compared the pretherapeutic risk factors (Kruskall-Wallis test), exposure to cytotoxic drugs (chi-square test), and overall and progression-free survival (Kaplan-Meyer and logistic regression analysis, respectively) of 515 patients with mostly chronic-phase CML who were treated with imatinib mesylate after failure of interferon-alpha according to whether they attained a major cytogenetic response (MCR) (n = 324 patients), an MCR with CCA/Ph-negative status (n = 30 patients), or no MCR (n = 161 patients). RESULTS. CCA/Ph-negative status most frequently involved chromosomes Y, 8, and 7. No significant differences in pretherapeutic risk factors were detected between patients who attained an MCR with and without CCA/Ph-negative cells, except that exposure to alkylating agents was more frequent in patients with CCA/Ph-negative cells, and overall and progression-free survival were identical. With a median follow-up of 51 months, only 2 patients developed myelodysplastic syndromes (MDS). CONCLUSIONS. The overall prognosis for patients who had CML with CCA/Ph-negative status was good and was driven by the CML response to imatinib mesylate. Isolated CCA/Ph-negative cells in the absence of morphologic evidence of MDS do not justify a change in therapy. C1 Oregon Hlth & Sci Univ, Inst Canc, Div Hematol & Med Oncol, Portland, OR 97239 USA. Univ Texas, MD Anderson Canc Ctr, Dept Leukemia, Houston, TX 77030 USA. Univ Calif Los Angeles, Div Hematol Oncol, Los Angeles, CA USA. Univ Heidelberg, Fac Med, D-6800 Mannheim, Germany. Univ Bologna, S Orsola M Malpighi Hosp, Dept Hematol & Oncol L & A Seragnoli, Bologna, Italy. Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA. Univ Mainz, Dept Med 3, D-6500 Mainz, Germany. Univ Leipzig, Dept Hematol & Oncol, D-7010 Leipzig, Germany. Univ Milan, Dept Internal Med, Monza, Italy. McGill Univ, Dept Hematol, Montreal, PQ, Canada. Novartis Pharmaceut, Dept Biostat, Basel, Switzerland. NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Kimmel Comprehens Canc Ctr, Div Hematol Malignancies, Baltimore, MD USA. Howard Hughes Med Inst, Chevy Chase, MD USA. Univ Miletrie Hosp, Clin Res Ctr, Dept Oncol Hematol & Cell Therapy, Poitiers, France. Novartis Pharmaceut, Clin Dev, Basel, Switzerland. RP Deininger, MWN (reprint author), Oregon Hlth & Sci Univ, Inst Canc, Div Hematol & Med Oncol, L592,3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM deininge@ohsu.edu OI GAMBACORTI PASSERINI, CARLO/0000-0001-6058-515X; Hochhaus, Andreas/0000-0003-0626-0834; /0000-0003-3516-7516 NR 27 TC 69 Z9 70 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD OCT 1 PY 2007 VL 110 IS 7 BP 1509 EP 1519 DI 10.1002/cncr.22936 PG 11 WC Oncology SC Oncology GA 211HG UT WOS:000249514300013 PM 17702093 ER PT J AU Freedman, ND Abnet, CC Leitzmann, MF Hollenbeck, AR Schatzkin, A AF Freedman, Neal D. Abnet, Christian C. Leitzmann, Michael F. Hollenbeck, Albert R. Schatzkin, Arthur TI Prospective investigation of the cigarette smoking-head and neck cancer association by sex SO CANCER LA English DT Article DE head and neck neoplasms; smoking; cohort study; men; women ID LUNG-CANCER; GENDER DIFFERENCES; SMOKELESS TOBACCO; ATTRIBUTABLE RISK; LARYNGEAL-CANCER; CHEWING TOBACCO; FEMALE SMOKERS; UNITED-STATES; ORAL-CANCER; MORTALITY AB BACKGROUND. Men are approximately 3 times more likely to develop squamous cancers of the head and neck (oral cavity, pharynx, and larynx) than women. Very few prospective studies have examined the association between cigarette smoking and cancers of the head and neck in women, even though the rates of smoking in women are increasing rapidly worldwide. METHODS. The association between cigarette smoking and head and neck cancer was investigated in 476,211 participants, aged 50-71 years, of the National Institutes of Health/American Association of Retired Persons (NIH-AARP) diet and health study by using age-standardized incidence rates and hazard ratios from Cox models adjusted for other risk factors for these cancers. RESULTS. Over the course of follow-up (1995 through 2000), 584 Dien and 175 women were diagnosed with head and neck cancer. Nonsmoking (24.4), former smoking (36.9), and current smoking (147.3) men had higher rates of incident head and neck cancer per 100,000 person-years of follow-up than women did in each equivalent category of cigarette use (non: 4.8; former: 17.2; current: 75.7). The hazard ratios associated with smoking were significantly larger in women (12.96; 95% confidence interval [CI], 7.81-21.52) than in men (5.45, 95% CI, 4.22-7.05; P for interaction: <.001) for head and neck cancer overall and also for the 3 subsites (oral cavity, oro-hypopharynx, and larynx) examined in stratified analyses. Ever-smoking accounted for 45% of head and neck cancers in men and 75% in women, assuming causality. CONCLUSIONS. Cigarette smoking is a strong risk factor for head and neck cancer in both men and women. Incidence rates of head and neck cancer were higher in male smokers than female smokers, but smoking may explain a higher proportion of head and neck cancer in women than in men. C1 NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. NCI, Div Canc Prevent, Rockville, MD 20852 USA. AARP, Washington, DC USA. RP Abnet, CC (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS-320,MSC 7232, Rockville, MD 20852 USA. EM abnetc@mail.nih.gov RI Abnet, Christian/C-4111-2015; Freedman, Neal/B-9741-2015 OI Abnet, Christian/0000-0002-3008-7843; Freedman, Neal/0000-0003-0074-1098 FU Intramural NIH HHS NR 43 TC 55 Z9 56 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD OCT 1 PY 2007 VL 110 IS 7 BP 1593 EP 1601 DI 10.1002/cncr.22957 PG 9 WC Oncology SC Oncology GA 211HG UT WOS:000249514300023 PM 17724671 ER PT J AU Buchanan, DR O'Mara, AM Kelaghan, JW Sgambati, M McCaskill-Stevens, W Minasian, L AF Buchanan, David R. O'Mara, Ann M. Kelaghan, Joseph W. Sgambati, Maria McCaskill-Stevens, Worta Minasian, Lori TI Challenges and recommendations for advancing the state-of-the-science of quality of life assessment in symptom management trials SO CANCER LA English DT Article DE health-related quality of life; HRQOL; symptom management; cancer ID RANDOMIZED CONTROLLED-TRIAL; ITEM RESPONSE THEORY; CLINICAL-SIGNIFICANCE; OUTCOMES; SINGLE; ONCOLOGY; COMMUNICATION; COMBINATION; INDICATORS; VARIABLES AB Major findings are presented from a workshop on Quality of Life Assessment in Cancer Symptom Management Trials, sponsored by the National Cancer Institute. Data-driven research reports focused on 3 topics, 1) the rationale and utility of health-related quality of life (HRQOL) assessment, 2) conceptual models, and 3) measurement and design issues. Recommendations for including HRQOL assessment cited the potential value of. capturing additional treatment effects (eg, fatigue + depression); describing the patient experience; predicting patient prognosis; identifying potential adverse effects; observing interactions among symptoms; calculating quality adjusted survival and cost-effectiveness; and generating new hypotheses. Recommendations for developing more fully developed conceptual models focused on maintaining clear distinctions among symptoms, function, summary measures of HRQOL, and global HRQOL assessments; identifying symptom clusters; pursuing hypotheses about whether clustering is better explained as symptom-related or as patient-related (genetic predispositions); and gaining a better understanding of the dynamic and reciprocal influences of symptoms on each other. With respect to measurement and design issues, because different HRQOL measures cover different domains with various degrees of sensitivity, there is a need to select measures that are carefully tailored to the study's hypotheses. Finally, there is a growing appreciation that trials must be powered to test for effects on secondary endpoints. C1 NCI, Bethesda, MD 20892 USA. NIH, NCI, Dept Hlth & Human Serv,Div Canc Prevent, Commun Oncol & Prevent Trials Res Grp, Bethesda, MD USA. RP Buchanan, DR (reprint author), NCI, 6130 Execut Plaza,Rm 2149, Bethesda, MD 20892 USA. EM buchanad@mail.nih.gov NR 29 TC 17 Z9 17 U1 0 U2 5 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD OCT 1 PY 2007 VL 110 IS 7 BP 1621 EP 1628 DI 10.1002/cncr.22893 PG 8 WC Oncology SC Oncology GA 211HG UT WOS:000249514300026 PM 17868120 ER PT J AU Cozen, W Cerhan, JR Martinez-Maza, O Ward, MH Linet, M Colt, JS Davis, S Severson, RK Hartge, P Bernstein, L AF Cozen, W. Cerhan, J. R. Martinez-Maza, O. Ward, M. H. Linet, M. Colt, J. S. Davis, S. Severson, R. K. Hartge, P. Bernstein, L. TI The effect of atopy, childhood crowding, and other immune-related factors on non-Hodgkin lymphoma risk SO CANCER CAUSES & CONTROL LA English DT Article DE non-Hodgkin lymphoma; sibship size; birth order; allergy; atopy; childhood exposures; immune response ID FRANCISCO BAY AREA; SAN-FRANCISCO; MEDICAL CONDITIONS; FAMILY-STRUCTURE; SIBSHIP SIZE; HAY-FEVER; CANCER; ALLERGY; INFECTION; LEUKEMIA AB Objective Since adult immune responsiveness is influenced by early childhood exposures, we examined the role of family size, history of atopic disease, and other childhood immune-related exposures in a multi-center case-control study of NHL. Methods Interviews were completed with 1,321 cases ascertained from population-based cancer registries in Seattle, Detroit, Los Angeles and Iowa, and with 1,057 frequency-matched controls, selected by random-digit dialing and from the Medicare files database. Multivariable logistic regression was used to estimate risk. Results A history of any allergy (excluding drug allergies), decreased risk of all NHL (Odds Ratio [OR] = 0.7, 95% Confidence Interval [CI] = 0.6-1.0), diffuse large B-cell lymphoma [DLBCL] (OR = 0.6, 95% CI = 0.4-0.9), and follicular NHL (OR = 0.7, 95 CI = 0.5, 1.0). A similar effect was observed for hay fever. A history of eczema was associated with an increased risk of follicular lymphoma (OR = 1.9, 95% CI = 1.1-3.4), but not DLBCL (OR = 1.1, 95% CI = 0.6-2.0). Asthma did not affect risk. Youngest compared to oldest siblings had a 90% increased risk of DLBCL (95% CI = 1.2-3.1; p for trend with increasing birth order = 0.006), but not follicular lymphoma (OR = 1.1, 95% CI = 0.6-1.8). Conclusions We infer that some childhood and immune-related factors may alter NHL risk. C1 Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA 90089 USA. Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90089 USA. Mayo Clin, Coll Med, Dept Hlth Sci Res, Rochester, MN USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, David Geffen Sch Med, Dept Obstet & Gynecol, Los Angeles, CA 90024 USA. NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98195 USA. Wayne State Univ, Karmanos Canc Inst, Dept Family Med, Detroit, MI 48202 USA. RP Cozen, W (reprint author), Univ So Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, 1441 Eastlake Ave,MC 9175, Los Angeles, CA 90089 USA. EM wcozen@usc.edu RI Martinez-Maza, Otoniel/B-2667-2009; OI Martinez-Maza, Otoniel/0000-0003-1364-0675; Cerhan, James/0000-0002-7482-178X FU NCI NIH HHS [N01 PC065064, CA57152, CA73475, N01-PC-35139, N01-PC-67008, N01-PC-67009, N01-PC-71105, P01 CA17054, P30 CA014089]; NIEHS NIH HHS [P30 ES07048]; PHS HHS [U55/CCR921930-02] NR 49 TC 27 Z9 27 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD OCT PY 2007 VL 18 IS 8 BP 821 EP 831 DI 10.1007/s10552-007-9025-5 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 194WS UT WOS:000248375100004 PM 17588155 ER PT J AU Strayer, L Jacobs, DR Schairer, C Schatzkin, A Flood, A AF Strayer, Lori Jacobs, David R., Jr. Schairer, Catherine Schatzkin, Arthur Flood, Andrew TI Dietary carbohydrate, glycemic index, and glycemic load and the risk of colorectal cancer in the BCDDP cohort SO CANCER CAUSES & CONTROL LA English DT Article DE colorectal cancer; glycemic index; glycemic load; dietary carbohydrate; insulin resistance ID GROWTH-FACTOR-I; IGF-BINDING-PROTEINS; FOLLOW-UP COHORT; VITAMIN-D; COLON-CANCER; DIABETES-MELLITUS; C-PEPTIDE; INSULIN-RESISTANCE; CALCIUM INTAKE; FACTOR (IGF)-I AB Background There is considerable support for associations between insulin and IGF-I levels and colorectal cancer. Diet may relate to colorectal cancer through this mechanism, for example, diets high in glycemic index, glycemic load and/or carbohydrate are hypothesized to increase insulin load and the risk of insulin resistance, hyperinsulinemia. Case-control studies support this hypothesis, but prospective cohorts have had mixed results. Methods In the Breast Cancer Detection Demonstration Project (BCDDP) follow-up cohort of 45,561 women, we used Cox proportional hazards regression to assess the distribution of 490 incident cases of colorectal cancer ascertained during 8.5 years of follow-up across quintiles of carbohydrate intake, glycemic index, and glycemic load. We also stratified by combined BMI and physical activity levels. Results We found reductions in colorectal cancer risk for diets high in carbohydrate (RR for Q5 vs. Q1 = 0.70, 95% CI: 0.50-0.97) and glycemic index (0.75, 95% CI: 0.56-1.00), and no significant association for glycemic load (0.91, 95% CI: 0.70-1.20). Inverse associations were weakest in normal weight active persons. The inverse association for glycemic index was strongest for the portion from dairy food. Conclusions These results do not support an association between diets high in carbohydrate, glycemic index or glycemic load and colorectal cancer. C1 Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, Minneapolis, MN 55454 USA. Univ Oslo, Dept Nutr, N-0316 Oslo, Norway. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Strayer, L (reprint author), Univ Minnesota, Sch Publ Hlth, Div Epidemiol & Community Hlth, 1300 S Second St,Suite 300, Minneapolis, MN 55454 USA. EM flood@epi.umn.edu NR 60 TC 16 Z9 18 U1 1 U2 4 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD OCT PY 2007 VL 18 IS 8 BP 853 EP 863 DI 10.1007/s10552-007-9030-8 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 194WS UT WOS:000248375100008 PM 17605083 ER PT J AU Marehbian, J Colt, JS Baris, D Stewart, P Stukel, TA Spencer, SK Karagas, MR AF Marehbian, Josh Colt, Joanne S. Baris, Dalsu Stewart, Patricia Stukel, Therese A. Spencer, Steven K. Karagas, Margaret R. TI Occupation and keratinocyte cancer risk: a population-based case-control study SO CANCER CAUSES & CONTROL LA English DT Article DE keratinocyte cancer; basal cell carcinoma; squamous cell carcinoma ID NONMELANOMA SKIN-CANCER; BASAL-CELL CARCINOMA; POLYCYCLIC AROMATIC-HYDROCARBONS; MALIGNANT-MELANOMA; EXPOSURE; MORTALITY; HISTORY; WORKERS AB Objective The aim of our study was to identify occupations associated with increased risk of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Methods We conducted a population-based case-control study of BCC and SCC in New Hampshire. Cases (n = 599 BCC, n = 290 SCC) and controls (n = 524) completed a self-administered residence and work history questionnaire and personal interview regarding major risk factors for skin cancer. Reported jobs were coded using the Standardized Occupational Classification system (SOC). Odds ratios (ORs) and confidence intervals (CIs) for BCC and SCC were calculated for men and women separately using unconditional logistic regression models taking into account age, education, skin reaction to sun, history of painful sunburns, time spent outdoors, and for SCC, smoking. Results Among men, we observed elevated risks of both BCC and SCC among groundskeepers and gardeners, except farm (SOC 5622). We also found that garage and service station-related occupations (SOCs 873) and to some extent food/beverage preparation/service occupations (SOC 521) were associated with BCC risk among men. Women in health services occupations (SOC 523) had elevated risks for both tumors, especially for BCC. Additionally, administrative support (SOC 46/47) occupations were related to BCC risk among women. Other occupations were associated with excess risks, but without consistent trends by duration of employment. Conclusion We observed several occupations associated with elevated BCC and SCC risk. These results resemble reported findings for cutaneous melanoma and are generally consistent with the few available studies on keratinocyte cancers. C1 Dartmouth Coll, Ctr Environm Hlth Sci, Norris Cotton Canc Ctr, Dept Community & Family Med,Sect Biostat & Epidem, Hannover, Germany. Dartmouth Coll, Dartmouth Med Sch, Ctr Evaluat Clin Sci, Hannover, Germany. NIH, NCI, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Inst Clin Evaluat, Toronto, ON, Canada. Dartmouth Coll Sch Med, Norris Cotton Canc Ctr, Darthmouth Hitchcock Med Ctr, Dermatol Sect, Hanover, NH USA. RP Marehbian, J (reprint author), Dartmouth Coll, Ctr Environm Hlth Sci, Norris Cotton Canc Ctr, Dept Community & Family Med,Sect Biostat & Epidem, Hannover, Germany. EM Margaret.Karagas@Dartmouth.Edu FU NCI NIH HHS [R01CA57494] NR 28 TC 22 Z9 23 U1 1 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD OCT PY 2007 VL 18 IS 8 BP 895 EP 908 DI 10.1007/s10552-007-9034-4 PG 14 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 194WS UT WOS:000248375100011 PM 17638107 ER PT J AU Wakefield, LM Stuelten, C AF Wakefield, Lalage M. Stuelten, Christina TI Keeping order in the neighborhood: New roles for TGFP in maintaining epithelial homeostasis SO CANCER CELL LA English DT Editorial Material ID BETA; CANCER AB TGF beta s are thought to have tumor suppressor activity in many organ systems, but receptor inactivation in mouse models has not previously resulted in increased spontaneous tumorigenesis. A study in this issue of Cancer Cell shows that mice with a targeted knockout of the type 11 TGF beta receptor in stratified epithelia specifically develop spontaneous squamous cell carcinomas in the anogenital region, but not in the skin. Loss of TGF beta signaling appears to destabilize the epithelium such that homeostasis fails in the face of persistent proliferative challenge, a normal feature of the anogenital site, and latent invasive and migratory phenotypes are unmasked. C1 NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Cell & Canc Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Wakefield, LM (reprint author), NCI, Lab Canc Biol & Genet, Ctr Canc Res, Bethesda, MD 20892 USA. EM lw34g@nih.gov NR 8 TC 22 Z9 23 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD OCT PY 2007 VL 12 IS 4 BP 293 EP 295 DI 10.1016/j.ccr.2007.10.002 PG 3 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 223ID UT WOS:000250362600001 PM 17936552 ER PT J AU Meyerhardt, JA Clark, JW Supko, JG Eder, JP Ogino, S Stewart, CF D'Amato, F Dancey, J Enzinger, PC Zhu, AX Ryan, DP Earle, CC Mayer, RJ Michelini, A Kinsella, K Fuchs, CS AF Meyerhardt, Jeffrey A. Clark, Jeffrey W. Supko, Jeffrey G. Eder, Joseph P. Ogino, Shuji Stewart, Clinton F. D'Amato, Ferdinando Dancey, Janet Enzinger, Peter C. Zhu, Andrew X. Ryan, David P. Earle, Craig C. Mayer, Robert J. Michelini, Ann Kinsella, Kate Fuchs, Charles S. TI Phase I study of gefitinib, irinotecan, 5-fluorouracil and leucovorin in patients with metastatic colorectal cancer SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article ID GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITOR; PREVIOUSLY TREATED PATIENTS; CELL LUNG-CANCER; SOLID TUMORS; TRIAL; FLUOROURACIL; IRESSA; THERAPY; MALIGNANCIES AB Purpose To determine the maximum tolerated doses (MTD), toxicities, efficacy, and pharmacokinetics (PK) of gefitinib combined with irinotecan, 5-fluorouracil (5-FU) and leucovorin (IFL) in patients with previously untreated advanced colorectal cancer. Experimental Design Starting doses were gefitinib 250 mg/day orally without interruption, irinotecan 100 mg/m(2) stop as a 90 min intravenous (i.v.) infusion, 5-FU 400 mg/m(2) stop bolus i.v. and leucovorin 20 mg/m(2) stop i.v. on days 1 and 8 of a 21-day cycle. Dose escalations involved increasing gefitinib to 500 mg then increasing irinotecan to 125 mg/m(2) stop and 5-FU to 500 mg/m(2) stop. Results Twenty-four patients received therapy. The starting doses proved to be the MTD, as attempts to increase the dose of either gefitinib or the chemotherapeutic agents resulted in dose-limiting toxicities. Gastrointestinal effects and bone marrow suppression were the principal toxicities; however, only 1/17 (6%) patients treated with the MTD had severe (grades 3-4) diarrhea and severe neutropenia occurred in only two (12%) patients. Partial responses occurred in 10/17 patients receiving the MTD and another five had stable disease. Median progression-free and overall survivals were 12.2 and 26.6 months, respectively. In ten patients treated with the MTD, the steady-state PK of gefitinib was not affected by IFL nor did gefitinib appear to influence the PK of either irinotecan or 5-FU. Conclusions Gefitinib can be safely combined with an intermittent weekly schedule of IFL. Evidence of promising activity should encourage further clinical evaluation of epidermal growth factor receptor tyrosine kinase inhibitors, such as gefitinib, combined with multiagent chemotherapy for metastatic colorectal cancer. C1 Dana Farber Canc Inst, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. St Jude Childrens Hosp, Memphis, TN 38105 USA. NCI, Div Canc Treatment, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA. RP Meyerhardt, JA (reprint author), Dana Farber Canc Inst, Boston, MA 02115 USA. EM jmeyerhardt@partners.org FU NCI NIH HHS [2 P30CA0516, U01 CA62490] NR 52 TC 15 Z9 15 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD OCT PY 2007 VL 60 IS 5 BP 661 EP 670 DI 10.1007/s00280-006-0411-6 PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 201EJ UT WOS:000248814000005 PM 17216531 ER PT J AU Wolff, MS Anderson, HA Britton, JA Rothman, N AF Wolff, Mary S. Anderson, Henry A. Britton, Julie A. Rothman, Nat TI Pharmacokinetic variability and modern epidemiology - The example of dichlorodiphenyltrichloroethane, body mass index, and birth cohort SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material ID POLYCHLORINATED-BIPHENYLS; BREAST-CANCER; SERUM CONCENTRATIONS; ENVIRONMENTAL CONTAMINANTS; CHLORINATED HYDROCARBONS; ORGANOCHLORINE COMPOUNDS; PANCREATIC-CANCER; CHINESE WOMEN; BLOOD-LEVELS; HALF-LIFE C1 Mt Sinai Sch Med, Div Environm & Occupat Med, New York, NY 10029 USA. Wisconsin Div Publ Hlth, Madison, WI USA. Natl Canc Inst, Bethesda, MD USA. Univ London Imperial Coll Sci Technol & Med, London, England. RP Wolff, MS (reprint author), Mt Sinai Sch Med, Div Environm & Occupat Med, Box 1057,1 Gustave L Levy Pl, New York, NY 10029 USA. EM mary.wolff@mssm.edu FU NCI NIH HHS [CA665572, CA93447]; NIEHS NIH HHS [ES0102771, ES012771, ES09584] NR 35 TC 65 Z9 65 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2007 VL 16 IS 10 BP 1925 EP 1930 DI 10.1158/1055-9965.EPI-07-0394 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 222HC UT WOS:000250285900005 PM 17932339 ER PT J AU Chen, YC Kraft, P Bretsky, P Ketkar, S Hunter, DJ Albanes, D Altshuler, D Andriole, G Berg, CD Boeing, H Burtt, N Bueno-De-Mesquita, B Cann, H Canzian, F Chanock, S Dunning, A Feigelson, HS Freedman, M Gaziano, JM Giovannucci, E Sanchez, MJ Haiman, CA Hallmans, G Hayes, RB Henderson, BE Hirschhorn, J Kaaks, R Key, TJ Kolonel, LN LeMarchand, L Ma, J Overvad, K Palli, D Pharaoh, P Pike, M Riboli, E Rodriguez, C Setiawan, VW Stampfer, M Stram, DO Thomas, G Thun, MJ Travis, RC Virtamo, J Trichopouiou, A Wacholder, S Weinstein, SJ AF Chen, Yen-Ching Kraft, Peter Bretsky, Philip Ketkar, Shamika Hunter, David J. Albanes, Demetrius Altshuler, David Andriole, Gerald Berg, Christine D. Boeing, Heiner Burtt, Noel Bueno-de-Mesquita, Bas Cann, Howard Canzian, Federico Chanock, Stephen Dunning, Alison Feigelson, Heather S. Freedman, Matthew Gaziano, J. Michael Giovannucci, Edward Sanchez, Maria-Jose Haiman, Christopher A. Hallmans, Goran Hayes, Richard B. Henderson, Brian E. Hirschhorn, Joel Kaaks, Rudolf Key, Timothy J. Kolonel, Laurence N. LeMarchand, Loic Ma, Jing Overvad, Kim Palli, Domenico Pharaoh, Paul Pike, Malcolm Riboli, Eliot Rodriguez, Carmen Setiawan, V. Wendy Stampfer, Meir Stram, Daniel O. Thomas, Gilles Thun, Michael J. Travis, Ruth C. Virtamo, Jarmo Trichopouiou, Antonia Wacholder, Sholom Weinstein, Stephanie J. TI Sequence variants of estrogen receptor beta and risk of prostate cancer in the national cancer institute breast and prostate cancer cohort consortium SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GROWTH-FACTOR-I; ER-BETA; MULTIETHNIC COHORT; FAMILY-HISTORY; HUMAN GENOME; TAG SNPS; EXPRESSION; GENES; ASSOCIATION; POPULATIONS AB Background: Estrogen receptor beta (ESR2) may play a role in modulating prostate carcirtogenesis through the regulation of genes related to cell proliferation and apoptosis. Methods: We conducted nested case-control studies in the Breast and Prostate Cancer Cohort Consortium (BPC3) that pooled 8,323 prostate cancer cases and 9,412 controls from seven cohorts. Whites were the predominant ethnic group. We characterized genetic variation in ESR2 by resequencing exons in 190 breast and prostate cancer cases and genotyping a dense set of single nucleotide polymorphisms (SNP) spanning the locus in a multiethnic panel of 349 cancer-free subjects. We selected four haplotype-tagging SNPs (htSNP) to capture common ESR2 variation in Whites; these htSNPs were then genotyped in all cohorts. Conditional logistic regression models were used to assess the association between sequence variants of ESR2 and the risk of prostate cancer. We also investigated the effect modification by age, body mass index, and family history, as well as the association between sequence variants of ESR2 and advanced-stage (>= T3b, N-1, or M-1) and high-grade (Gleason sum >= 8) prostate cancer, respectively. Results: The four tag SNPs in ESR2 were not significantly associated with prostate cancer risk, individually. The global test for the influence of any haplotype on the risk of prostate cancer was not significant (P = 0.31). However, we observed that men carrying two copies of one of the variant haplotypes (TACC) had a 1.46-fold increased risk of prostate cancer (99% confidence interval, 1.06-2.01) compared with men carrying zero copies of this variant haplotype. No SNPs or haplotypes were associated with advanced stage or high grade of prostate cancer. Conclusion: In our analysis focused on genetic variation common in Whites, we observed little evidence for any substantial association of inherited variation in ESR2 with risk of prostate cancer. A nominally significant (P < 0.01) association between the TACC haplotype and prostate cancer risk under the recessive model could be a chance finding and, in any event, would seem to contribute only slightly to the overall burden of prostate cancer. C1 Channing Labs, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Div Aging, Boston, MA 02115 USA. Harvard Univ, Sch Med, Program Mol & Genet Epidemiol, Cambridge, MA 02138 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Natl Taiwan Univ, Coll Publ Hlth, Grad Inst Epidemiol, Res Ctr Genes Environm & Human Hlth, Taipei 10764, Taiwan. Cedars Sinai Med Ctr, Dept Internal Med, Los Angeles, CA 90048 USA. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. Washington Univ, St Louis, MO USA. Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD USA. Broad Inst Harvard, Cambridge, MA 02139 USA. MIT, Whitehead Inst Biomed Res, Cambridge, MA USA. Natl Canc Inst, Div Canc Prevent, Bethesda, MD USA. German Inst Human Nutr, Dept Epidemiol, Potsdam, Germany. Natl Inst Publ Hlth & Environm, Ctr Nutr & Hlth, NL-3720 BA Bilthoven, Netherlands. Ctr Etud Polymorphisme Humain, Fdn Jean Dausset, F-75010 Paris, France. Genet Susceptibil Grp, Lyon, France. IARC, Unit Nutr & Canc, Lyon, France. Natl Canc Inst, Core Genotyping Facil, Gaithersburg, MD USA. Univ Cambridge, Dept Oncol, Cambridge, England. Amer Canc Soc, Natl Home Off, Dept Epidemiol & Surveillance Res, Atlanta, GA 30329 USA. Andalusian Sch Publ Hlth, Granada, Spain. Umea Univ, Dept Publ Hlth & Clin Med, Umea, Sweden. German Canc Res Ctr, Div Canc Epidemiol, Heidelberg, Germany. Canc Res, Epidemiol Unit, Oxford, England. Univ Hawaii, Canc Res Ctr, Honolulu, HI 96813 USA. Aarhus Univ Hosp, Aalborg Hosp, Dept Clin Epidemiol, Aalborg, Denmark. CSPO Sci Inst Tuscany, Mol & Nutr Epidemiol Unit, Florence, Italy. Natl Publ Hlth Inst, Canc Prevent Unit, Helsinki, Finland. Univ Athens, Sch Med, Dept Hyg & Epidemiol, GR-11527 Athens, Greece. RP Chen, YC (reprint author), Channing Labs, 181 Longwood Ave, Boston, MA 02115 USA. EM karen.chen@channing.harvard.edu RI Altshuler, David/A-4476-2009; Chen, Yen-Ching/D-1098-2010; SANCHEZ-PEREZ, MARIA JOSE/D-1087-2011; Albanes, Demetrius/B-9749-2015; OI Altshuler, David/0000-0002-7250-4107; Chen, Yen-Ching/0000-0002-8159-7202; SANCHEZ-PEREZ, MARIA JOSE/0000-0003-4817-0757; Dunning, Alison Margaret/0000-0001-6651-7166; Hayes, Richard/0000-0002-0918-661X FU Intramural NIH HHS; NCI NIH HHS [R01 CA097193] NR 40 TC 21 Z9 23 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2007 VL 16 IS 10 BP 1973 EP 1981 DI 10.1158/1055-9965.EPI-07-0431 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 222HC UT WOS:000250285900010 PM 17932344 ER PT J AU Holick, CN Stanford, JL Kwon, EM Ostrander, EA Nejentsev, S Peters, U AF Holick, Crystal N. Stanford, Janet L. Kwon, Erika M. Ostrander, Elaine A. Nejentsev, Sergey Peters, Ulrike TI Comprehensive association analysis of the vitamin D pathway genes, VDR, CYP27B1, and CYP24A1, in prostate cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID D-RECEPTOR GENE; 1,25-DIHYDROXYVITAMIN D-3; SUBSEQUENT DEVELOPMENT; ULTRAVIOLET-RADIATION; 25-HYDROXYVITAMIN D-3; UNITED-STATES; D METABOLITES; RISK; POLYMORPHISMS; CELLS AB Genetic variation in vitamin D-related genes has not been investigated comprehensively and findings are equivocal. We studied the association between polymorphisms across the entire vitamin D receptor (VDR) gene and genes encoding for vitamin D activating enzyme 1-alpha-hydroxylase (CYP27B1) and deactivating enzyme 24-hyroxylase (CYP24A1) and prostate cancer risk among middle-aged men using a population-based case-control study design. DNA samples and survey data were obtained from incident cases (n = 630), 40 to 64 years old, identified through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry from 1993 to 1996 and from random controls (n = 565) of similar age without a history of prostate cancer. We selected and genotyped tag single-nucleotide polymorphisms to predict common variants across VDR (n = 22), CYP27B1 (n = 2), and CYP24A1 (n = 14). Haplotypes of VDR and CYP24A1 were not associated with prostate cancer risk. In the genotype analysis, homozygotes at two VDR loci (rs2107301 and rs2238135) were associated with a 2- to 2.5-fold higher risk of prostate cancer compared with the homozygote common allele [odds ratio, 2.47 (95% confidence interval, 1.52-4.00; P = 0.002) and 1.95 (95% confidence interval, 1.17-3.26; P = 0.007), respectively, P value corrected for multiple comparisons for VDR = 0.002]. We found no evidence that the two associated VDR single-nucleotide polymorphisms were modified by age at diagnosis, prostate cancer aggressiveness, first-degree family history of prostate cancer, or vitamin D intake. Genotypes of CYP27B1 and CYP24A1 were not associated with prostate cancer risk. Our findings suggest that polymorphisms, in the VDR gene may be associated with prostate cancer risk and, therefore, that the vitamin D pathway might have an etiologic role in the development of prostate cancer. C1 Fred Hutchinson Canc Res Ctr, Canc Prevent Program, Waltham, MA 02451 USA. Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. NIH, Natl Ctr Human Genome Res, Canc Genet Branch, Bethesda, MD 20892 USA. Univ Cambridge, Cambridge Inst Med Res, Wellcome Trust Diabet & Inflammat Lab, Juvenile Diabet Res Fdn, Cambridge, England. RP Holick, CN (reprint author), Fred Hutchinson Canc Res Ctr, Canc Prevent Program, i3 Drug Safety 950 Winter St,Suite 3800, Waltham, MA 02451 USA. EM crystal.holick@i3drugsafety.com OI Ostrander, Elaine/0000-0001-6075-9738 FU Intramural NIH HHS; NCI NIH HHS [CA94880, P50 CA97186, R01 CA56678, K22 CA118421] NR 38 TC 60 Z9 63 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2007 VL 16 IS 10 BP 1990 EP 1999 DI 10.1158/1055-9965.EPI-07-0487 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 222HC UT WOS:000250285900012 PM 17932346 ER PT J AU Sigurdson, AJ Bhatti, P Doody, MM Hauptmann, M Bowen, L Simon, SL Weinstock, RM Linet, MS Rosenstein, M Stovall, M Alexander, BH Preston, DL Struewing, JP Rajaraman, P AF Sigurdson, Alice J. Bhatti, Parveen Doody, Michele M. Hauptmann, Michael Bowen, Laura Simon, Steven L. Weinstock, Robert M. Linet, Martha S. Rosenstein, Marvin Stovall, Marilyn Alexander, Bruce H. Preston, Dale L. Struewing, Jeffrey P. Rajaraman, Preetha TI Polymorphisms in apoptosis- and proliferation-related genes, ionizing radiation exposure, and risk of breast cancer among US radiologic technologists SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID ASSOCIATION; VARIANT; CELLS; CASP8 AB Background: Although genes involved in apoptosis pathways and DNA repair pathways are both essential for maintaining genomic integrity, genetic variants in DNA repair have been thought to increase susceptibility to radiation carcinogenesis, but similar hypotheses have not generally been raised about apoptosis genes. For this reason, potential modification of the relationship between ionizing radiation exposure and breast cancer risk by polymorphic apoptosis gene variants have not been investigated among radiation-exposed women. Methods: In a case-control study of 859 cases and 1,083 controls within the U.S. Radiologic Technologists cohort, we assessed breast cancer risk with respect to 16 candidate variants in eight genes involved in apoptosis, inflammation, and proliferation. Using carefully reconstructed cumulative breast dose estimates from occupational and personal diagnostic ionizing radiation, we also investigated the joint effects of these polymorphisms on the risk of breast cancer. Results: In multivariate analyses, we observed a significantly decreased risk of breast cancer associated with the homozygous minor allele of CASP8 D302H [rs1045485, odd.s ratio (OR), 0.3; 95% confidence interval (95% CI), 0.1-0.8]. We found a significantly increased breast cancer risk with increasing minor alleles for ILIA A114S (rs17561); heterozygote OR 1.2 (95% CI, 1.0-1.4) and homozygote OR 1.5 (95% CI, 1.1-2.0), P-trend = 0.008. Assuming a dominant genetic model, ILIA A114S significantly modified the dose-response relationship between cumulative personal diagnostic radiation and breast cancer risk, adjusted for occupational dose (P-interaction = 0.004). Conclusion: The U.S. Radiologic Technologists breast cancer study provided a unique opportunity to examine the joint effects of common genetic variation and ionizing radiation exposure to the breast using detailed occupational and personal diagnostic dose data. We found evidence of effect modification of the radiation and breast cancer dose-response relationship that should be confirmed in studies with more cases and controls and quantified radiation breast doses in the low-to-moderate range. C1 NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Lab Populat Genet, Canc Res Ctr, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Res Triangle Inst, Bethesda, MD USA. Informat Management Syst, Silver Spring, MD USA. Consultant Res Triangle Inst, Silver Spring, MD USA. Univ Texas, MD Anderson Canc Ctr, Dept Radiat Phys, Houston, TX 77030 USA. Univ Minnesota, Minneapolis, MN USA. HiroSoft Int Corp, Seattle, WA USA. RP Sigurdson, AJ (reprint author), NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 7092,MSC 7238, Bethesda, MD 20892 USA. EM sigurdsa@mail.nih.gov RI Struewing, Jeffery/I-7502-2013 OI Struewing, Jeffery/0000-0002-4848-3334 FU Intramural NIH HHS NR 37 TC 29 Z9 29 U1 3 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2007 VL 16 IS 10 BP 2000 EP 2007 DI 10.1158/1055-9965.EPI-07-0282 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 222HC UT WOS:000250285900013 PM 17932347 ER PT J AU Tammemagi, CM Freedman, MT Church, TR Oken, MM Hocking, WG Kvale, PA Hu, P Riley, TL Ragard, LR Prorok, PC Berg, CD AF Tammemagi, C. Martin Freedman, Matthew T. Church, Timothy R. Oken, Martin M. Hocking, William G. Kvale, Paul A. Hu, Ping Riley, Thomas L. Ragard, Lawrence R. Prorok, Philip C. Berg, Christine D. TI Factors associated with human small aggressive non-small cell lung cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ESTROGEN-RECEPTOR-BETA; LYMPH-NODE METASTASIS; DNA ADDUCT LEVELS; SEX-DIFFERENCES; EXPRESSION PROFILES; GENDER-DIFFERENCES; CIGARETTE-SMOKING; SCREENING TRIAL; RISK AB Background: Some non-small cell lung cancers (NSCLC) progress to distant lymph nodes or metastasize while relatively small. Such small aggressive NSCLCs (SA-NSCLC) are no longer resectable with curative intent, carry a grave prognosis, and may involve unique biological pathways. This is a study of factors associated with SA-NSCLC. Methods: A nested case-case study was embedded in the National Cancer Institute's Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. SA-NSCLC cases had stage T-1, N-3, and/or M-1 NSCLC (n = 48) and non-SA-NSCLC cases had T-2 to T-3, No to N-2, and M-0 NSCLC (n = 329). Associations were assessed by multiple logistic regression. Results: SA-NSCLCs were associated with younger age at diagnosis [odds ratio (OR)(>= 65) versus (<65), 0.44; 95% confidence interval (95% CI), 0.22-0.881, female gender, family history of lung cancer, and the interaction gender*family history of lung cancer and were inversely associated with ibuprofen use (ORyes versus no, 0.29; 95% CI, 0.11-0.76). The ORs for associating gender (women versus men) with SA-NSCLC in those with and without a family history of lung cancer were 11.76 (95% CI, 2.00-69.22) and 1.86 (95% CI, 0.88-3.96), respectively. These associations held adjusted for histology and time from screening to diagnosis and when alternative controls were assessed. Conclusion: SA-NSCLC was associated with female gender, especially in those with a family history of lung cancer. If these exploratory findings, which are subject to bias, are validated as causal, elucidation of the genetic and female factors involved may improve understanding of cancer progression and lead to preventions and therapies. Ibuprofen may inhibit lung cancer progression. C1 Brock Univ, Dept Community Hlth Sci, St Catharines, ON L2S 3A1, Canada. Georgetown Univ, Dept Oncol, Washington, DC USA. Univ Minnesota, Dept Environm Hlth Sci, Minneapolis, MN USA. N Memorial Hlth Care, Hubert H Humphrey Ctr, Robbinsdale, MI USA. Marshfield Clin Fdn Med Res & Educ, Dept Hematol Oncol, Marshfield, WI USA. Henry Ford Hlth Syst, Div Pulm & Crit Care, Detroit, MI USA. NIH, NCI, Biometry Res Grp, Bethesda, MD 20892 USA. NIH, NCI, Early Detect Res Grp, Bethesda, MD 20892 USA. NIH, NCI, Div Canc Prevent, St Catharines, ON, Canada. Informat Management Serv Inc, Rockville, MD USA. Westat Corp, Rockville, MD USA. RP Tammemagi, CM (reprint author), Brock Univ, Dept Community Hlth Sci, 500 Glenridge Ave, St Catharines, ON L2S 3A1, Canada. EM martin.tammemagi@brocku.ca OI Hocking, William/0000-0002-0690-3759; Church, Timothy R./0000-0003-3292-5035 NR 50 TC 6 Z9 6 U1 2 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2007 VL 16 IS 10 BP 2082 EP 2089 DI 10.1158/1055-9965.EPI-07-0251 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 222HC UT WOS:000250285900024 PM 17932357 ER PT J AU Schenck, AP Klabunde, CN Warren, JL Peacock, S Davis, WW Hawley, ST Pignone, M Ransohoff, DF AF Schenck, Anna P. Klabunde, Carrie N. Warren, Joan L. Peacock, Sharon Davis, William W. Hawley, Sarah T. Pignone, Michael Ransohoff, David F. TI Data sources for measuring colorectal endoscopy use among medicare enrollees SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SELF-REPORT; CLAIMS DATA; MAMMOGRAPHY USE; ELDERLY-WOMEN; RECORD AUDIT; CANCER; CARE; BENEFICIARIES; CONCORDANCE; GUIDELINES AB Background: Estimates of colorectal cancer test use vary widely by data source. Medicare claims offer one source for monitoring test use, but their utility has not been validated. We compared ascertainment of sigmoidoscopy and colonoscopy between three data sources: self reports, Medicare claims, and medical records. Materials and Methods: The study population included Medicare enrollees residing in North Carolina (n = 561) who had participated in a telephone survey on colorectal cancer tests. Medicare claims were obtained for the 5 years preceding the survey (January 1, 1998 to December 31, 2002). Information about sigmoidoscopy and colonoscopy procedures conducted in physician offices were abstracted from medical records. Sensitivity, specificity, positive predictive value, negative predictive value, agreement, and K statistics were calculated using the medical record as the gold standard. Agreement on specific procedure type and purpose was also assessed. Results: Agreement between claim and medical record regarding whether an endoscopic procedure had been done was high (over 90%). Agreement between self report and medical record and between self report and claim was good (79% and 74%, respectively). All three data sources adequately distinguished the type of procedure done. None of the data sources showed reliable levels of agreement regarding procedure purpose (screening or diagnostic). Conclusion: Medicare claims can provide accurate information on whether a patient has undergone colorectal endoscopy and may be more complete than physician medical records. Medicare claims cannot be used to distinguish screening from diagnostic tests. Recognizing this limitation, researchers who use Medicare claims to assess rates of colorectal testing should include both screening and diagnostic endoscopy procedures in their analyses. C1 Carolinas Ctr Med Excellence, Cary, NC 27511 USA. NCI, Hlth Serv, Bethesda, MD 20892 USA. NCI, Econ Branch, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. NCI, Stat Res & Applicat Branch, Surveillance Res Program, Div Canc Control & Populat Sci, Rockville, MD USA. Univ Michigan, Div Gen Med, Ann Arbor, MI 48109 USA. Univ N Carolina, Dept Med, Chapel Hill, NC USA. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. Univ N Carolina, Ceceil Sheps Ctr Hlth Serv Res, Chapel Hill, NC USA. RP Schenck, AP (reprint author), Carolinas Ctr Med Excellence, 100 Regency Forest,Suite 200, Cary, NC 27511 USA. EM aschenck@ncqio.sdps.org OI Pignone, Michael/0000-0002-6657-7342 FU NCI NIH HHS [Y1-PC-1007] NR 35 TC 53 Z9 53 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2007 VL 16 IS 10 BP 2118 EP 2127 DI 10.1158/1055-9965.EPI-07-0123 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 222HC UT WOS:000250285900029 PM 17932360 ER PT J AU Castano-Vinyals, G Talaska, G Rothman, N Alguacil, J Garcia-Closas, M Dosemeci, M Cantor, KP Malats, N Real, FX Silverman, D Serra, C Carrato, A Tardon, A Garcia-Closas, R Kogevinas, M Vermeulen, R AF Castano-Vinyals, Gemma Talaska, Glenn Rothman, Nathaniel Alguacil, Juan Garcia-Closas, Montserrat Dosemeci, Mustafa Cantor, Kenneth P. Malats, Nuria Real, Francisco X. Silverman, Debra Serra, Consol Carrato, Alfredo Tardon, Adonina Garcia-Closas, Reina Kogevinas, Manolis Vermeulen, Roel TI Bulky DNA adduct formation and risk of bladder cancer SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID POLYCYCLIC AROMATIC-HYDROCARBONS; LUNG; HEALTH; DAMAGE; ENHANCEMENT; OCCUPATION; MORTALITY; EXPOSURE; WORKERS; CELLS AB Exposure to polycyclic aromatic hydrocarbons (PAHs) has been associated with risk of bladder cancer and with increased bulky DNA adduct levels in several studies, mainly in smokers. We investigated the relation between bulky PAH-DNA adducts in peripheral blood mononuclear cells and bladder cancer in nonsmoking subjects from a large hospital-based case-control study in Spain. Additionally, we examined the association between DNA adduct formation and several air pollution proxies. The study comprised 76 nonsmoking cases and 76 individually matched controls by sex, region of residence, age, and smoking status (never, former). To maximize the relevance of the DNA adduct measurement as a proxy of PAH exposure, subjects selected had not changed residence, occupation, and major lifestyle factors during the last 10 years. Bulky DNA adducts were measured using the P-32-postlabeling technique, nuclease P1 treatment. The percentage of detectable adducts was higher in controls (41%) than in cases (32%) with an odds ratio of 0.75 (95% confidence interval, 0.36-1.58). In an analysis limited to controls, a higher percentage of DNA adducts was found among those whose last residence was in a big city (50%) compared with those living in villages (19%; P = 0.04). No consistent associations were found for other markers of air pollution. In this study, among nonsmokers with stable environmental and lifestyle factors, bulky DNA adducts were not associated with bladder cancer risk. Results do not support an association of bladder cancer risk with low-level exposure to PAHs as measured through the formation of bulky DNA adducts in peripheral mononuclear cells. C1 Univ Pompeu Fabra, Ctr Res Environm Epidemiol, Inst Municipal Invest Med, Barcelona 08003, Spain. Univ Pompeu Fabra, Unita Biol Cellular & Mol, Inst Municipal Invest Med, Barcelona 08003, Spain. Univ Pompeu Fabra, Dept Ciencies Expt & Salut, Barcelona 08003, Spain. CIBER Epidemiol & Salud Publ, Barcelona, Spain. Univ Cincinnati, Dept Environm Hlth, Cincinnati, OH USA. NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Huelva, Dept Biol Ambiental & Salud Publ, Area Med Prevent, Huelva, Spain. Consorci Hosp Parc Tauli, Sabadell, Spain. Hosp Gen Elche, Elche, Spain. Univ Oviedo, Oviedo, Spain. Hosp Univ Canarias, Unidad Invest, Tenerife, Spain. Univ Crete, Sch Med, Iraklion, Crete, Greece. Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. RP Castano-Vinyals, G (reprint author), Univ Pompeu Fabra, Ctr Res Environm Epidemiol, Inst Municipal Invest Med, Doctor Aiguader 88, Barcelona 08003, Spain. EM gcastano@imim.es RI Serra, C/E-6879-2014; Vermeulen, Roel/F-8037-2011; Garcia-Closas, Montserrat /F-3871-2015; Kogevinas, Manolis/C-3918-2017; Real, Francisco X/H-5275-2015; OI Serra, C/0000-0001-8337-8356; Vermeulen, Roel/0000-0003-4082-8163; Garcia-Closas, Montserrat /0000-0003-1033-2650; Real, Francisco X/0000-0001-9501-498X; Castano-Vinyals, Gemma/0000-0003-4468-1816; Malats, Nuria/0000-0003-2538-3784 FU Intramural NIH HHS NR 18 TC 10 Z9 10 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD OCT PY 2007 VL 16 IS 10 BP 2155 EP 2159 DI 10.1158/1055-9965.EPI-07-0184 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 222HC UT WOS:000250285900034 PM 17932365 ER PT J AU Hoque, A Parnes, HL Stefanek, ME Heymach, JV Brown, PH Lippman, SM AF Hoque, Ashraful Parnes, Howard L. Stefanek, Michael E. Heymach, John V. Brown, Powel H. Lippman, Scott M. TI Meeting report: Fifth annual AACR frontiers in cancer prevention research SO CANCER RESEARCH LA English DT Article ID PROSTATE-CANCER; HUMAN-PAPILLOMAVIRUS; BREAST-CANCER; RISK; CHEMOPREVENTION; TRIAL; CARCINOGENESIS; MORTALITY; TAMOXIFEN; PROGRESS AB Addressing genetics, risk modeling, molecular targets for chemoprevention, clinical prevention trials, behavioral prevention research, public policy, and more, the Fifth Annual International Conference on Frontiers in Cancer Prevention Research, held in Boston, Massachusetts, in November 2006, added an outstanding new chapter to the landmark AACR Frontiers program for advancing the science and practice of cancer prevention throughout the world. C1 Univ Texas, Dept Thorac Head & Neck Oncol, Unit 432, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Texas, Dept Clin Canc Prevent, Houston, TX 77030 USA. Baylor Coll Med, Breast Canc, Houston, TX USA. Natl Canc Inst, Bethesda, MD USA. Amer Canc Soc, Atlanta, GA USA. RP Lippman, SM (reprint author), Univ Texas, Dept Thorac Head & Neck Oncol, Unit 432, MD Anderson Canc Ctr, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM slippman@mdanderson.org NR 20 TC 2 Z9 2 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 1 PY 2007 VL 67 IS 19 BP 8989 EP 8993 DI 10.1158/0008-5472.CAN-07-3171 PG 5 WC Oncology SC Oncology GA 217NV UT WOS:000249955500004 PM 17895292 ER PT J AU Chen, MJ Dumitrache, LC Wangsa, D Ma, SM Padilla-Nash, H Ried, T Hasty, P AF Chen, Ming-Jiu Dumitrache, Lavinia C. Wangsa, Danny Ma, Sheng-Mei Padilla-Nash, Hesed Ried, Thomas Hasty, Paul TI Cisplatin depletes TREX2 and causes Robertsonian translocations as seen in TREX2 knockout cells SO CANCER RESEARCH LA English DT Article ID INTERSTRAND CROSS-LINKS; EMBRYONIC STEM-CELLS; DOUBLE-STRAND BREAKS; DNA MISMATCH REPAIR; EXONUCLEASE ACTIVITY; CATALYTIC SUBUNIT; MOLECULAR-CLONING; 3' TERMINI; GENE; PROTEIN AB Cisplatin, an anticancer drug, forms DNA interstrand crosslinks (ICL) that interfere with replication, whereas TREX2 is a 3' -> 5' exonuclease that removes 3' mismatched nucleotides and promotes cellular proliferation. Here, we show that TREX2 is depleted in human cells derived from cancer after exposure to cisplatin but not other genotoxins including another cross-linking agent, mitomycin C (MMC), indicating a potential role for TREX2 depletion in cisplatin-induced cytotoxicity. To better understand TREX2 cellular function, we deleted TREX2 in mouse embryonic stem (ES) cells by gene targeting and find these cells exhibit reduced proliferation and gross chromosomal rearrangements including Robertsonian translocations (RbT). Quite interestingly, ES cells exposed to cisplatin also exhibit RbTs. By contrast, RbTs are not observed for ES cells exposed to MMC, indicating that RbTs are not caused by ICLs but instead TREX2 depletion by either cisplatin exposure or mutation. Taken together, our results show that cisplatin depletes TREX2 and causes genomic instability that is similarly observed in TREX2-mutant cells. Thus, cisplatin has two potential cytotoxic activities: (a) the generation of lCLs and (b) the depletion of ;TREX2. C1 Univ Texas, Hlth Sci Ctr, Dept Mol Med, Inst Biotechnol, San Antonio, TX 78245 USA. NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Hasty, P (reprint author), Univ Texas, Hlth Sci Ctr, Dept Mol Med, Inst Biotechnol, 15355 Lambda Dr, San Antonio, TX 78245 USA. EM hastye@uthscsa.edu FU NCI NIH HHS [R01 CA123203-01A1, T32 CA86800-03]; NIEHS NIH HHS [U01 ES11044] NR 42 TC 13 Z9 13 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 1 PY 2007 VL 67 IS 19 BP 9077 EP 9083 DI 10.1158/0008-5472.CAN-07-1146 PG 7 WC Oncology SC Oncology GA 217NV UT WOS:000249955500017 PM 17909011 ER PT J AU Yang, YL Kitagaki, J Dai, RM Tsai, YC Lorick, KL Ludwig, RL Pierre, SA Jensen, JP Davydov, IV Oberoi, P Li, CCH Kenten, JH Beutler, JA Vousden, KH Weissman, AM AF Yang, Yili Kitagaki, Jirouta Dai, Ren-Ming Tsai, Yien Che Lorick, Kevin L. Ludwig, Robert L. Pierre, Shervon A. Jensen, Jane P. Davydov, Ilia V. Oberoi, Pankaj Li, Chou-Chi H. Kenten, John H. Beutler, John A. Vousden, Karen H. Weissman, Allan M. TI Inhibitors of ubiquitin-activating enzyme (E1), a new class of potential cancer therapeutics SO CANCER RESEARCH LA English DT Article ID PROTEASOME SYSTEM; CONJUGATING ENZYMES; LIGASE ACTIVITY; PROTEIN LIGASE; P53 PATHWAY; CELL-CYCLE; MDM2; IDENTIFICATION; DEGRADATION; BORTEZOMIB AB The conjugation of proteins with ubiquitin plays numerous regulatory roles through both proteasomal-dependent and nonproteasomal-dependent functions. Alterations in ubiquitylation are observed in a wide range of pathologic conditions, including numerous malignancies. For this reason, there is great interest in targeting the ubiquitin-proteasome system in cancer. Several classes of proteasome inhibitors, which block degradation of ubiquitylated proteins, are widely used in research, and one, Bortezomib, is now in clinical use. Despite the well-defined and central role of the ubiquitin-activating enzyme (E1), no cell permeable inhibitors of El have been identified. Such inhibitors should, in principle, block all functions of ubiquitylation. We now report 4[4-(5-nitro-furan-2-ylmethylene)-3,5-dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester (PYR-41) as the first such inhibitor. Unexpectedly, in addition to blocking ubiquitylation, PYR-41 increased total sumoylation in cells. The molecular basis for this is unknown; however, increased sumoylation was also observed in cells harboring temperature-sensitive El. Functionally, PYR-41 attenuates cytokine-mediated nuclear factor-kappa B activation. This correlates with inhibition of nonproteasomal (Lys-63) ubiquitylation of TRAF6, which is essential to I kappa B kinase activation. PYR-41 also prevents the downstream ubiquitylation and proteasomal degradation of I kappa B alpha. Furthermore, PYR-41 inhibits degradation of p53 and activates the transcriptional activity of this tumor suppressor. Consistent with this, it differentially kills transformed p53-expressing cells. Thus, PYR-41 and related pyrazones provide proof of principle for the capacity to differentially kill transformed cells, suggesting the potential for E I inhibitors as therapeutics in cancer. These inhibitors can also be valuable tools for studying ubiquitylation. C1 NCI, Lab Prot Dynam & Signalling, NIH, Frederick, MD 21702 USA. NCI, Lab Canc Prevent, NIH, Frederick, MD 21702 USA. NCI, Lab Canc Prevent, NIH, Frederick, MD 21702 USA. NCI, Mol Targets Dev Program, Canc Res Ctr, NIH, Frederick, MD 21702 USA. Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland. Meso Scale Discovery, Gaithersburg, MD USA. RP Weissman, AM (reprint author), NCI, Lab Prot Dynam & Signalling, NIH, Bldg 560,Room 22-103,560 Boyles St, Frederick, MD 21702 USA. EM yangyili@ncifcrf.gov; amw@nih.gov RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 NR 47 TC 202 Z9 206 U1 2 U2 20 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 OCT 1 PY 2007 VL 67 IS 19 BP 9472 EP 9481 DI 10.1158/0008-5472.CAN-07-0568 PG 10 WC Oncology SC Oncology GA 217NV UT WOS:000249955500063 PM 17909057 ER PT J AU Hong, S Lee, C Kim, SJ AF Hong, Suntaek Lee, Chan Kim, Seong-Jin TI Smad7 sensitizes tumor necrosis factor - Induced apoptosis through the inhibition of antiapoptotic gene expression by suppressing activation of the nuclear factor-kappa B pathway SO CANCER RESEARCH LA English DT Article ID GROWTH-FACTOR-BETA; ALPHA-INDUCED APOPTOSIS; TGF-BETA; CANCER-CELLS; SIGNAL-TRANSDUCTION; TNF-ALPHA; NEGATIVE REGULATION; IN-VIVO; INFLAMMATION; TGF-BETA-1 AB Although tumor necrosis factor(TNF) induces apoptosis and cell death in many tumor cells, some cancer cells are still resistant to the TNF-induced death signal. In this report, we showed that Smad7, an inhibitory Smad of transforming growth factor-beta (TGF-beta) signaling, can overcome the TNF resistance in human breast and gastric cancer cells. Overexpression of Smad7 induces the degradation of poly(ADPribose) polymerase and the activation of caspase cascade. Although c-Jun NH2-terminal kinase (JNK) signaling is involved in TNF-induced cell death, the expression of Smad7 does not synergize the activation of JNK. However, the activation of nuclear factor-kappa B (NF-kappa B), the cell survival factor, is markedly decreased in Smad7-stable cells. Furthermore, the expression of antiapoptotic target genes of NF-kappa B is significantly reduced in accordance with the level of Smad7. In addition, Smad7 mediates the inhibitory activity of TGF-beta on TNF-induced NF-kappa B activation and the synergistic activity of TGF-beta on TNF-induced apoptosis. These findings suggest that Smad7 sensitizes the tumor cells to TNF-induced apoptosis through the inhibition of expression of antiapoptotic NF-kappa B target genes. C1 Gachon Univ Med & Sci, Lee Gil Ya Canc & Diabet Inst, Lab Cell Regulat & Carcinogenesis, Inchon 406840, South Korea. NCI, Lab Canc Biol & Genet, Bethesda, MD 20892 USA. RP Kim, SJ (reprint author), Gachon Univ Med & Sci, Lee Gil Ya Canc & Diabet Inst, Lab Cell Regulat & Carcinogenesis, Inchon 406840, South Korea. EM jasonsjkim@gachon.ac.kr FU Intramural NIH HHS NR 50 TC 39 Z9 42 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD OCT 1 PY 2007 VL 67 IS 19 BP 9577 EP 9583 DI 10.1158/0008-5472.CAN-07-1179 PG 7 WC Oncology SC Oncology GA 217NV UT WOS:000249955500075 PM 17909069 ER PT J AU Tsutsumi, S Neckers, L AF Tsutsumi, Shinji Neckers, Len TI Extracellular heat shock protein 90: A role for a molecular chaperone in cell motility and cancer metastasis SO CANCER SCIENCE LA English DT Review ID HEAT-SHOCK-PROTEIN; SURFACE EXPRESSION; STRESS-PROTEINS; TUMOR-CELLS; HSP90; MELANOMA; CALRETICULIN; INDUCTION; ACTIVATION; INHIBITORS AB Heat shock protein 90 (Hsp90) is a molecular chaperone whose association is required for the stability and function of multiple mutated, chimeric and over-expressed signaling proteins that promote the growth and/or survival of cancer cells. Hsp90 client proteins include mutated p53, Bcr-Abl, Raf-1, Akt, HER2/Neu (ErbB2) and HIF-1 alpha. Hsp90 inhibitors, by interacting specifically with a single molecular target, cause the destabilization and eventual degradation of Hsp90 client proteins, and the first-in-class Hsp90 inhibitor, 17-allylamino-17 demethoxygeldanamycin (17AAG), is currently in phase II clinical trials. A fraction of Hsp90 has been identified at the cell surface and its presence has recently been shown to correlate with melanoma progression. Inhibition of cell-surface Hsp90 with antibodies or cell-impermeable Hsp90 inhibitors blocks cell motility and invasion in vitro and cancer metastasis in vivo. Thus, cell-surface Hsp90 may play a unique role in tumor metastasis, distinct from but perhaps overlapping with its intracellular function. In addition, because cell-surface Hsp90 may be the point of contact between some viruses and host cells, this pool of the chaperone may play a distinct role in initiation of infectious disease. C1 NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, 9000 Rockville Pike,Bldg 10-CRC, Bethesda, MD 20892 USA. EM len@helix.nih.gov NR 34 TC 131 Z9 134 U1 2 U2 11 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1347-9032 J9 CANCER SCI JI Cancer Sci. PD OCT PY 2007 VL 98 IS 10 BP 1536 EP 1539 DI 10.1111/j.1349-7006.2007.00561.x PG 4 WC Oncology SC Oncology GA 204JN UT WOS:000249039900005 PM 17645779 ER PT J AU Goldman, R Ressom, HW Abdel-Hamid, M Goldman, L Wang, A Varghese, RS An, Y Loffredo, CA Drake, SK Eissa, SA Gouda, I Ezzat, S Moiseiwitsch, FS AF Goldman, Radoslav Ressom, Habtom W. Abdel-Hamid, Mohamed Goldman, Lenka Wang, Antai Varghese, Rency S. An, Yanming Loffredo, Christopher A. Drake, Steven K. Eissa, Sohair A. Gouda, Iman Ezzat, Sameera Moiseiwitsch, Francoise Seillier TI Candidate markers for the detection of hepatocellular carcinoma in low-molecular weight fraction of serum SO CARCINOGENESIS LA English DT Article ID HEPATITIS-C; UNITED-STATES; CANCER; HCV; PROTEOMICS; PEPTIDOME; MORTALITY; DISCOVERY; BIOMARKER; OPINION AB Hepatocellular carcinoma (HCC) represents an important public health problem in Egypt where up to 90% of HCC cases are attributable to hepatitis C viral (HCV) infection. Serum alpha-fetoprotein is elevated in only similar to 60% of HCC patients. The development of effective markers for the detection of HCC could have an impact on cancer mortality and significant public health implications worldwide. The objective of our study was to assess six candidate markers for detection of HCC identified by mass spectrometric analysis of enriched serum. The study examined 78 HCC cases and 72 age- and gender-matched cancer-free controls recruited from the Egyptian population. Matrix-assisted laser desorption-ionization time-of-flight mass spectrometric analysis of enriched low-molecular weight fraction of serum was used for identification of the candidate markers. Our analyses show that all six candidate markers are associated with HCC after adjustment for important covariates including HCV and hepatitis B viral infections. The marker candidates are independently predictive of HCC with areas under the receiver operating characteristic (AuROC) curve ranging from 63-93%. A combination of the six markers improves prediction accuracy to 100% sensitivity, 91% specificity and 98% AuROC curve in an independent test set of 50 patients. Two of the candidate markers were identified by sequencing as fragments of complement C3 and C4. In conclusion, a set of six peptides distinguished with high prediction accuracy HCC from controls in an Egyptian population with a high rate of chronic HCV infection. Further evaluation of these marker candidates for the diagnosis of HCC is needed. C1 Georgetown Univ, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. Menia Univ, Cairo, Egypt. NHTMRI, Viral Hepatitis Res Lab, Cairo, Egypt. NIH, Dept Lab Med, Clin Chem Serv, Bethesda, MD 20892 USA. Natl Canc Inst, Cairo, Egypt. Menoufiya Univ, Shibin El Kom, Egypt. RP Goldman, R (reprint author), Georgetown Univ, Lombardi Comprehens Canc Ctr, 3970 Reservoir Rd NW, Washington, DC 20057 USA. EM rg26@georgetown.edu RI Varghese, Rency/A-8770-2012 FU NCI NIH HHS [R01 CA115625-01A2, R01CA85888, R01 CA115625, R03 CA119288, R01 CA085888, R03 CA119313, R03 CA119313-01A2] NR 35 TC 27 Z9 28 U1 1 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD OCT PY 2007 VL 28 IS 10 BP 2149 EP 2153 DI 10.1093/carcin/bgm177 PG 5 WC Oncology SC Oncology GA 227RV UT WOS:000250676400013 PM 17724376 ER PT J AU Balansky, R Ganchev, G Iltcheva, M Steele, VE D'Agostini, F De Flora, S AF Balansky, Roumen Ganchev, Gancho Iltcheva, Marietta Steele, Vernon E. D'Agostini, Francesco De Flora, Silvio TI Potent carcinogenicity of cigarette smoke in mice exposed early in life SO CARCINOGENESIS LA English DT Article ID ENVIRONMENTAL TOBACCO-SMOKE; LUNG-TUMOR MODEL; MOUSE LUNG; N-ACETYLCYSTEINE; NEWBORN MICE; A/J MOUSE; CHEMOPREVENTIVE AGENTS; INHALATION EXPOSURE; TRANSGENIC MICE; CANCER RISK AB In spite of the dominant role of cigarette smoke (CS) in cancer epidemiology, all studies performed during the past 60 years have shown that this complex mixture is either negative or weakly tumorigenic in experimental animals. We implemented studies aimed at evaluating whether exposure of mice early in life may enhance susceptibility to CS carcinogenicity. A total of 98 newborn Swiss albino mice were either untreated (controls) or received a subcutaneous injection of benzo( a) pyrene [B(a) P] (positive control) or were exposed whole-body to mainstream cigarette smoke (MCS) for 120 days, starting within 12 h after birth. Complete necropsy and histopathological analyses were performed at periodical intervals. In contrast with the lack of lung tumors in controls, MCS-exposed mice developed microscopically detectable tumors, starting only 75 days after birth and reaching an overall incidence of 78.3% after 181-230 days. The mean lung tumor multiplicities were 6.1 and 13.6 tumors per mouse in males and females, respectively, showing a significant intergender difference. Most tumors were microadenomas or adenomas, but 18.4% of the mice additionally had malignant lung cancer. MCS also induced bronchial and alveolar epithelial hyperplasia, and blood vessel proliferation. Furthermore, malignant tumors, some of which may have a metastatic origin, were detected in the urinary tract and liver of MCS-exposed mice. A somewhat different spectrum of tumors was observed in B(a) P-treated mice. In conclusion, MCS is a potent and broad spectrum carcinogen in mice when exposure starts early in life, covering stages of life corresponding to neonatal, childhood and adolescence periods in humans. This animal model will be useful to explore the mechanisms involved in CS-induced carcinogenesis and to investigate the protective effects of dietary agents and chemopreventive drugs. C1 Univ Genoa, Dept Hlth Sci, I-16132 Genoa, Italy. NCI, Bethesda, MD 20892 USA. Natl Oncol Ctr, Sofia 1756, Bulgaria. RP De Flora, S (reprint author), Univ Genoa, Dept Hlth Sci, Via A Pastore 1, I-16132 Genoa, Italy. EM sdf@unige.it FU NCI NIH HHS [N01-CN53301] NR 71 TC 51 Z9 51 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD OCT PY 2007 VL 28 IS 10 BP 2236 EP 2243 DI 10.1093/carcin/bgm122 PG 8 WC Oncology SC Oncology GA 227RV UT WOS:000250676400024 PM 17522065 ER PT J AU Oh, WJ Rishi, V Pelech, S Vinson, C AF Oh, Won-Jun Rishi, Vikas Pelech, Steven Vinson, Charles TI Histological and proteomic analysis of reversible H-Ras(V12G) expression in transgenic mouse skin SO CARCINOGENESIS LA English DT Article ID PROTEIN-KINASE-C; ENDOTHELIAL GROWTH-FACTOR; K-RAS; DOWN-REGULATION; CELL-DEATH; CONDITIONAL EXPRESSION; KERATINOCYTE APOPTOSIS; LUNG ADENOCARCINOMAS; EPITHELIAL-CELLS; GENE-EXPRESSION AB We have used a two-transgene tetracycline system to reversibly express oncogenic H-Ras(V12G) in mouse skin and primary keratinocytes culture using the bovine keratin 5 promoter. Induction of H-Ras(V12G) expression in skin at 30 days after birth causes epidermal basal cell hyperplasia, an eruption of keratinous cysts and loss of hair follicles by 3 weeks. Subsequent H-Ras(V12G) de-induction for 3 days results in massive apoptosis in the non-H-Ras(V12G)-expressing stroma as well as in the suprabasal cells of the epidermis. Several procaspases such as CASP3, 1 alpha, 5 and 12 disappeared, whereas the pro-apoptotic proteins AIF, Bax and Fas ligand were induced in H-Ras(V12G) de-induction skin. This process is followed by a wave of cell division at 14 days as hair follicles regrew, returning to near normal histology and skin appearance by 30 days. Using Kinetworks (TM) multi-immunoblotting screens, the phosphorylation status of 37 proteins and expression levels of 75 protein kinases in the skin were determined in three samples: (i) wild-type skin, (ii) hyperplastic H-Ras(V12G)-expressing skin and (iii) skin where H-Ras(V12G) expression was suppressed for 7 days. Following H-Ras(V12G) induction, 16 kinases were increased over 2-fold, and 2 kinases were reduced over 50%. This included increased phosphorylation of both known downstream H-Ras(V12G) targets and unknown H-Ras(V12G) targets. After H-Ras(V12G) suppression, many but not all protein changes were reversed. These results from skin and primary keratinocytes are organized to reflect the molecular events that cause the histological changes observed. These proteomic changes identify markers that may mediate the oncogenic addiction paradigm. C1 NCI, NIH, Lab Metab, Canc Res Ctr, Bethesda, MD 20892 USA. Kinexus Bioinformat Corp, Vancouver, BC V6T 1Z3, Canada. Univ British Columbia, Dept Med, Vancouver, BC V6T 1Z3, Canada. RP Vinson, C (reprint author), NCI, NIH, Lab Metab, Canc Res Ctr, Bldg 37,Room 3128, Bethesda, MD 20892 USA. EM vinsonc@dc37a.nci.nih.gov NR 49 TC 4 Z9 4 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD OCT PY 2007 VL 28 IS 10 BP 2244 EP 2252 DI 10.1093/carcin/bgm127 PG 9 WC Oncology SC Oncology GA 227RV UT WOS:000250676400025 PM 17551062 ER PT J AU Elagha, AA Kim, AH Kocaturk, O Lederman, RJ AF Elagha, Abdalla A. Kim, Ann H. Kocaturk, Ozgur Lederman, Robert J. TI Blunt atrial transseptal puncture using excimer laser in swine SO CATHETERIZATION AND CARDIOVASCULAR INTERVENTIONS LA English DT Review DE atrial transseptal puncture; laser angioplasty; catheterization ID LEFT-HEART CATHETERIZATION; EXPERIENCE; PERFORATION; ABLATION; SAFETY AB Objectives: We describe a new approach that may enhance safety of atrial transseptal puncture using a commercially available laser catheter that is capable of perforation only when energized. We test this approach in swine. Background: Despite wide application, conventional needle transseptal puncture continues to risk inadvertent nontarget perforation and its consequences. Methods: We used a commercial excimer laser catheter (0.9-mm Clirpath, Spectranetics). Perforation force was compared in vitro with a conventional Brockenbrough needle. Eight swine underwent laser transseptal puncture under X-ray fluoroscopy steered using a variety of delivery catheters. Results: The 0.9-mm laser catheter traversed in vitro targets with reduced force compared with a Brockenbrough needle. In vitro, the laser catheter created holes that were 25-30% larger than the Brockenbrough needle. Laser puncture of the atrial septum was successful and accurate in all animals, evidenced by oximetry, pressure, angiography, and necropsy. The laser catheter was steered effectively using a modified Mullins introducer sheath and using two different deflectable guiding catheters. The mean procedure time was 15 +/- 6 min, with an average 3.0 +/- 0.8 sec of laser activation. There were no adverse sequelae after prolonged observation. Necropsy revealed discrete 0.9-mm holes in all septae. Conclusion: Laser puncture of the interatrial septum is feasible and safe in swine, using a blunt laser catheter that perforates tissues in a controlled fashion. (C) 2007 Wiley-Liss, Inc. C1 NHLBI, Natl Inst Hlth, Div Intramural Res, Cardiovasc Branch, Bethesda, MD 20892 USA. RP Lederman, RJ (reprint author), NHLBI, Natl Inst Hlth, Div Intramural Res, Cardiovasc Branch, Bldg 10,Room 2c713,MSC1538, Bethesda, MD 20892 USA. EM ledermar@nhlbi.nih.gov OI Elagha, Abdalla/0000-0003-3136-2293; lederman, robert/0000-0003-1202-6673 FU Intramural NIH HHS [Z01 HL005062-05]; NHLBI NIH HHS [Z01 HL005062, 1-Z01-HL005062-04] NR 16 TC 6 Z9 6 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1522-1946 J9 CATHETER CARDIO INTE JI Catheter. Cardiovasc. Interv. PD OCT 1 PY 2007 VL 70 IS 4 BP 585 EP 590 DI 10.1002/ccd.21257 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 219SG UT WOS:000250104300022 PM 17896413 ER PT J AU Nussenzweig, A AF Nussenzweig, Andre TI Causes and consequences of the DNA damage response SO CELL CYCLE LA English DT Article DE chromatin; genomic stability; aging; cancer; ATM; ATR ID HEMATOPOIETIC STEM-CELLS; REPAIR; CHECKPOINTS; ACTIVATION; SENESCENCE; NBS1 AB A prerequisite for maintaining genome stability in all cell types is the accurate repair and efficient signaling of DNA double strand breaks (DSBs). It is believed that DSBs are initially detected by damage sensors that trigger the activation of transducing kinases. These transducers amplify the damage signal, which is then relayed to effector proteins, which regulate the progression of the cell cycle, DNA repair and apoptosis. Errors in the execution of the repair and/or signaling of DSBs can give rise to multi-systemic disorders characterized by tissue degeneration, infertility, immune system dysfunction, age-related pathologies and cancer. This special Spotlight issue of Cell Cycle highlights recent advances in our understanding of the biology and significance of the DNA damage response. A range of issues are addressed including mechanistic ones: What is the aberrant DNA structure that triggers the activation of the checkpoint? How does chromatin structure influence the recruitment of repair and checkpoint proteins? How does chromosomal instability contribute to the evolution of cancer? In addition, questions related to the physiology of the DNA damage response in normal and abnormal cells is explored: What is the in vivo consequence of altering specific amino acids in a DNA damage sensor? Does DNA damage accumulation in stem cells cause aging? How is neurodegeneration linked to deficiencies in specific DNA repair pathways? And finally, what is the biological basis for selection of aberrant DNA damage responses in cancer cells? C1 NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. RP Nussenzweig, A (reprint author), NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. EM andre_nussenzweig@nih.gov NR 12 TC 12 Z9 12 U1 0 U2 1 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD OCT 1 PY 2007 VL 6 IS 19 BP 2339 EP 2340 PG 2 WC Cell Biology SC Cell Biology GA 233IX UT WOS:000251085700005 PM 17914283 ER PT J AU Difilippantonio, S Nussenzweig, A AF Difilippantonio, Simone Nussenzweig, Andre TI The NBS1-ATM connection revisited SO CELL CYCLE LA English DT Article DE genomic instability; DNA damage response; cell cycle checkpoints; apoptosis; DNA repair; cancer ID NIJMEGEN BREAKAGE SYNDROME; DNA-DAMAGE RESPONSE; DOUBLE-STRAND BREAKS; S-PHASE CHECKPOINT; ATM ACTIVATION; MRE11 COMPLEX; ATAXIA-TELANGIECTASIA; IONIZING-RADIATION; HISTONE H2AX; HOMOLOGOUS RECOMBINATION AB Nijmegen Breakage syndrome (NBS) is a rare autosomal recessive disorder characterized by microcephaly, immunodeficiency, and increased predisposition to the development of malignancy. (1,2) Due to the overlap of clinical and cellular features of patients with ataxia telangiectasia (AT), NBS was described as an AT variant syndrome until the underlying gene product mutation was identified. (3-5) Cells from both AT and NBS patients show increased sensitivity to ionizing radiation (IR), genomic instability and cell cycle checkpoint defects following DNA damage, (6,7) suggesting that both gene products participate in the same DNA damage response pathway. Here we highlight recent developments and refinements in our understanding of the interplay between NBS1 and ATM in vivo. C1 NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. RP Difilippantonio, S (reprint author), NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. EM DifilipS@mail.nih.gov FU Intramural NIH HHS NR 67 TC 39 Z9 40 U1 0 U2 2 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD OCT 1 PY 2007 VL 6 IS 19 BP 2366 EP 2370 PG 5 WC Cell Biology SC Cell Biology GA 233IX UT WOS:000251085700011 PM 17881893 ER PT J AU Katsafanas, GC Moss, B AF Katsafanas, George C. Moss, Bernard TI Colocalization of transcription and translation within cytoplasmic poxvirus factories coordinates viral expression and subjugates host functions SO CELL HOST & MICROBE LA English DT Article ID EARLY MESSENGER-RNAS; VACCINIA VIRUS-RNA; GENE-EXPRESSION; DNA-REPLICATION; EUKARYOTIC TRANSLATION; MAMMALIAN-CELLS; D10 PROTEIN; ORGANIZATION; INITIATION; MECHANISM AB Poxviruses are large DNA viruses that include the causal agent of human smallpox and vaccinia virus. Poxviruses replicate in cytoplasmic foci known as DNA factories. Here we show that a virus-encoded transcription factor, viral mRNA, cellular RNA-binding protein heterodimer G3BP/Caprin-1 (p137), translation initiation factors elF4E and elF4G, and ribosomal proteins are concentrated in the same sub-domains of cytoplasmic DNA factories. Furthermore, a cell coinfected with two recombinant vaccinia viruses expressing a virus core protein fused to cyan or yellow fluorescent protein displayed separate cyan and yellow factories, indicating that each factory formed from a single genome and was the site of transcription and translation as well as DNA replication. Hijacking of the host translation apparatus within the factory likely enhances the efficiency of virus replication and contributes to the suppression of host protein synthesis, thereby facilitating poxvirus subjugation of the cell. C1 Natl Inst Hlth, Natl Inst Allergy & Infect Dis, Viral Dis Lab, Bethesda, MD 20892 USA. RP Moss, B (reprint author), Natl Inst Hlth, Natl Inst Allergy & Infect Dis, Viral Dis Lab, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Intramural NIH HHS [Z01 AI000307-26] NR 37 TC 117 Z9 118 U1 2 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD OCT PY 2007 VL 2 IS 4 BP 221 EP 228 DI 10.1016/j.chom.2007.08.005 PG 8 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 223IC UT WOS:000250362500005 PM 18005740 ER PT J AU McAuley, JL Hornung, F Boyd, KL Smith, AM McKeon, R Bennink, J Yewdell, JW McCullers, JA AF McAuley, Julie L. Hornung, Felicita Boyd, Kelli L. Smith, Amber M. McKeon, Raelene Bennink, Jack Yewdell, Jonathan W. McCullers, Jonathan A. TI Expression of the 1918 influenza A virus PB1-F2 enhances the pathogenesis of viral and secondary bacterial pneumonia SO CELL HOST & MICROBE LA English DT Article ID STREPTOCOCCUS-PNEUMONIAE; MITOCHONDRIAL PROTEIN; LETHAL SYNERGISM; UNITED-STATES; CELL-DEATH; MICE; INFECTION; HOSPITALIZATIONS; NEURAMINIDASE; REPLICATION AB Secondary bacterial pneumonia frequently claimed the lives of victims during the devastating 1918 influenza A virus pandemic. Little is known about the viral factors contributing to the lethality of the 1918 pandemic. Here we show that expression of the viral accessory protein PB1-F2 enhances inflammation during primary viral infection of mice and increases both the frequency and severity of secondary bacterial pneumonia. The priming effect of PB1-F2 on bacterial pneumonia could be recapitulated in mice by intranasal delivery of a synthetic peptide derived from the C-terminal portion of the PB1-F2. Relative to its isogenic parent, an influenza virus engineered to express a PB1-F2 with coding changes matching the 1918 pandemic strain was more virulent in mice, induced more pulmonary immunopathology, and led to more severe secondary bacterial pneumonia. These findings help explain both the unparalleled virulence of the 1918 strain and the high incidence of fatal pneumonia during the pandemic. C1 St Jude Childrens Hosp, Dept Infect Dis, Memphis, TN 38105 USA. St Jude Childrens Hosp, Anim Resources Ctr, Memphis, TN 38105 USA. NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. Univ Utah, Dept Math, Salt Lake City, UT 84112 USA. RP McCullers, JA (reprint author), St Jude Childrens Hosp, Dept Infect Dis, 332 N Lauderdale St, Memphis, TN 38105 USA. EM jon.mccullers@stjude.org RI yewdell, jyewdell@nih.gov/A-1702-2012; OI McAuley, Julie/0000-0003-2493-3465 FU Intramural NIH HHS; NIAID NIH HHS [R21 AI054802, AI-54802, AI-66349, R01 AI066349, R01 AI066349-03] NR 36 TC 227 Z9 240 U1 2 U2 20 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1931-3128 J9 CELL HOST MICROBE JI Cell Host Microbe PD OCT PY 2007 VL 2 IS 4 BP 240 EP 249 DI 10.1016/j.chom.2007.09.001 PG 10 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 223IC UT WOS:000250362500007 PM 18005742 ER PT J AU Gudmundsson, L Aspelund, T Thorgeirsson, G Johannsson, M Scher, AI Launer, L Gudnason, V AF Gudmundsson, Larus Aspelund, T. Thorgeirsson, G. Johannsson, M. Scher, A. I. Launer, L. Gudnason, V. TI C-reactive protein levels in migraine patients is similar to that of controls SO CEPHALALGIA LA English DT Meeting Abstract C1 Univ Iceland, Dept Pharmacol Toxicol, IS-101 Reykjavik, Iceland. Univ Iceland, IS-101 Reykjavik, Iceland. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. NIA, Bethesda, MD 20892 USA. RI Aspelund, Thor/C-5983-2008; Aspelund, Thor/F-4826-2011; Gudnason, Vilmundur/K-6885-2015 OI Aspelund, Thor/0000-0002-7998-5433; Gudnason, Vilmundur/0000-0001-5696-0084 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 0333-1024 J9 CEPHALALGIA JI Cephalalgia PD OCT PY 2007 VL 27 IS 10 MA B085 BP 1184 EP 1184 PG 1 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 213IG UT WOS:000249659500026 ER PT J AU Goel, V Tierney, M Sheesley, L Bartolo, A Vartanian, O Grafman, J AF Goel, Vinod Tierney, Michael Sheesley, Laura Bartolo, Angela Vartanian, Oshin Grafman, Jordan TI Hemispheric specialization in human prefrontal cortex for resolving certain and uncertain inferences SO CEREBRAL CORTEX LA English DT Article DE decision making; frontal lobes; indeterminacy; lateralization; lesions; reasoning ID FRONTAL-LOBE DAMAGE; DECISION-MAKING; ORBITOFRONTAL CORTEX; INVOLVEMENT; ACTIVATION; PARIETAL; DISSOCIATION; IMPAIRMENTS; CORTICES; IMAGES AB Uncertainty is a fact of life that must be accommodated in real-world decision making. Although it has been suggested that the right prefrontal cortex (PFC) has a special role to play in decision making under uncertainty, there is very little hard data to support this hypothesis. To better understand the roles of left and right PFCs in reasoning and decision making in situations with complete and incomplete information, we administered simple inference problems to 18 patients with lateralized focal lesions to PFC (9 right hemisphere, 9 left hemisphere) and 22 age- and education-matched normal controls. The stimuli were systematically manipulated for completeness of information regarding the status of the conclusion. Our results demonstrated a 2-way interaction such that patients with left PFC lesions were selectively impaired in trials with complete information, whereas patients with right PFC lesions were selectively impaired in trials with incomplete information. These results provide compelling evidence for hemispheric specialization for reasoning in PFC and suggest that the right PFC has a critical role to play in reasoning about incompletely specified situations. We postulate this role involves the maintenance of ambiguous mental representations that temper premature overinterpretation by the left hemisphere. C1 York Univ, Dept Psychol, Toronto, ON M3J 1P3, Canada. NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. RP Goel, V (reprint author), York Univ, Dept Psychol, Toronto, ON M3J 1P3, Canada. EM vgoel@yorku.ca OI Grafman, Jordan H./0000-0001-8645-4457 NR 44 TC 44 Z9 47 U1 3 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD OCT PY 2007 VL 17 IS 10 BP 2245 EP 2250 DI 10.1093/cercor/bhl132 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 212HP UT WOS:000249587100002 PM 17158186 ER PT J AU Krueger, F Moll, J Zahn, R Heinecke, A Grafman, J AF Krueger, Frank Moll, Jorge Zahn, Roland Heinecke, Armin Grafman, Jordan TI Event frequency modulates the processing of daily life activities in human medial prefrontal cortex SO CEREBRAL CORTEX LA English DT Article DE Brodmann area 10; event sequence knowledge; fMRI; scripts ID FRONTAL-LOBE LESIONS; FUNCTIONAL SPECIALIZATION; AUTOBIOGRAPHICAL MEMORY; BRAIN ACTIVATION; PYRAMIDAL CELLS; WORKING-MEMORY; FMRI; IMPAIRMENTS; KNOWLEDGE; NEOCORTEX AB Event sequence knowledge is necessary to learn, plan, and perform activities of daily life. Clinical observations suggest that the prefrontal cortex (PFC) is crucial for goal-directed behavior such as carrying out plans, controlling a course of actions, or organizing everyday life routines. Functional neuroimaging studies provide further evidence that the PFC is involved in processing event sequence knowledge, with the medial PFC (Brodmann area 10) primarily engaged in mediating predictable event sequences. However, the exact role of the medial PFC in processing event sequence knowledge depending on the frequency of corresponding daily life activities remains obscure. We used event-related functional magnetic resonance imaging while healthy volunteers judged whether event sequences from high- (HF), moderate- (MF), and low-frequency (LF) daily life activities were correctly ordered. The results demonstrated that different medial PFC subregions were activated depending on frequency. The anterior medial Area 10 was differentially activated for LF and the posterior medial Area 10 for HF activities. We conclude that subregions of the medial PFC are differentially engaged in processing event sequence knowledge depending on how often the activity was reportedly performed in daily life. C1 NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD 20892 USA. Brain Innovat BV, NL-6201 BC Maastricht, Netherlands. RP Grafman, J (reprint author), NINDS, Cognit Neurosci Sect, NIH, Bldg 10,Room 5C205,MSC 1440, Bethesda, MD 20892 USA. EM Grafmanj@ninds.nih.gov RI Zahn, Roland/C-4665-2008; Moll, Jorge/B-2654-2013; OI Zahn, Roland/0000-0002-8447-1453; Grafman, Jordan H./0000-0001-8645-4457 FU Intramural NIH HHS NR 51 TC 46 Z9 46 U1 7 U2 12 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 1047-3211 J9 CEREB CORTEX JI Cereb. Cortex PD OCT PY 2007 VL 17 IS 10 BP 2346 EP 2353 DI 10.1093/cercor/bhl143 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 212HP UT WOS:000249587100013 PM 17190970 ER PT J AU Otto, M AF Otto, Michael TI Antibodies to block staph virulence SO CHEMISTRY & BIOLOGY LA English DT Editorial Material ID AUREUS; INTERFERENCE; PHEROMONE; PEPTIDE; SYSTEM; TARGET C1 NIAID, Rocky Mt Labs, Natl Inst Hlth, Hamilton, MT 59840 USA. RP Otto, M (reprint author), NIAID, Rocky Mt Labs, Natl Inst Hlth, 903 S 4th St, Hamilton, MT 59840 USA. EM motto@niaid.nih.gov OI Otto, Michael/0000-0002-2222-4115 NR 14 TC 4 Z9 4 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD OCT PY 2007 VL 14 IS 10 BP 1093 EP 1094 DI 10.1016/j.chembiol.2007.10.001 PG 2 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 226PY UT WOS:000250602200002 PM 17961820 ER PT J AU Cuttica, MJ Anderson, K Barnett, CF Shlobin, OA Ahmad, S Barnett, S Machado, R Gladwin, M Nathan, SD AF Cuttica, Michael J. Anderson, Katrina Barnett, Christopher F. Shlobin, Oksana A. Ahmad, Shahzad Barnett, Scott Machado, Roberto Gladwin, Mark Nathan, Steven D. TI Prevalence and impact of pulmonary hypertension in patients with chronic obstructive pulmonary disease (COPD) listed for lung, transplantation SO CHEST LA English DT Meeting Abstract CT CHEST 2007 Conference CY OCT 20-25, 2007 CL Chicago, IL SP Amer Coll Chest Phys C1 [Cuttica, Michael J.; Anderson, Katrina; Barnett, Christopher F.; Shlobin, Oksana A.; Ahmad, Shahzad; Barnett, Scott; Machado, Roberto; Gladwin, Mark; Nathan, Steven D.] Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD OCT PY 2007 VL 132 IS 4 SU S BP 621S EP 621S PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 222FY UT WOS:000250282700683 ER PT J AU Barnett, CF Cuttica, MJ Janka, J Machado, RF AF Barnett, Christopher F. Cuttica, Michael J. Janka, Jacqueline Machado, Roberto F. TI A case of pulmonary hypertension associated with Poems syndrome SO CHEST LA English DT Meeting Abstract CT CHEST 2007 Conference CY OCT 20-25, 2007 CL Chicago, IL SP Amer Coll Chest Phys C1 [Barnett, Christopher F.; Cuttica, Michael J.; Janka, Jacqueline; Machado, Roberto F.] Natl Inst Hlth, Crit Care Med, Bethesda, MD USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD OCT PY 2007 VL 132 IS 4 SU S BP 728S EP 728S PG 1 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 222FY UT WOS:000250282700976 ER PT J AU Rothman, RB Baumann, MH AF Rothman, Richard B. Baumann, Michael H. TI Methamphetamine and uopathic pulmonary arterial hypertension SO CHEST LA English DT Letter ID FENFLURAMINE; SEROTONIN C1 Natl Inst Drug Abuse, NIH, Baltimore, MD USA. RP Rothman, RB (reprint author), Natl Inst Drug Abuse, NIH, Clin Psychopharmacol Sect, Intramural Res Program, Baltimore, MD 21224 USA. EM rrotham@mail.nih.gov NR 10 TC 8 Z9 8 U1 0 U2 0 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD OCT PY 2007 VL 132 IS 4 BP 1412 EP 1413 DI 10.1378/chest.07-0235 PG 2 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 221UY UT WOS:000250254000060 PM 17934137 ER PT J AU Harashima, SI Harashima, C Nishimura, T Hu, Y Notkins, AL AF Harashima, S.-I. Harashima, C. Nishimura, T. Hu, Y. Notkins, A. L. TI Overexpression of the autoantigen IA-2 puts beta cells into a pre-apoptotic state: autoantigen-induced, but non-autoimmune-mediated, tissue destruction SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE Akt; apoptosis; autoimmunity; IA-2; sorting nexin 19 ID PROTEIN-TYROSINE-PHOSPHATASE; DEPENDENT DIABETES-MELLITUS; INSULIN-SECRETION; MOLECULAR-CLONING; PANCREATIC-ISLETS; SORTING NEXINS; PX DOMAIN; GLUCOSE; TYPE-1; EXPRESSION AB IA-2 is a major autoantigen in type 1 diabetes and autoantibodies to it have become important diagnostic and predictive markers. IA-2 also is an intrinsic transmembrane component of dense core secretory vesicles and knock-out studies showed that IA-2 is a regulator of insulin secretion. Here we show that overexpression of IA-2 puts mouse insulinoma MIN-6 beta cells into a pre-apoptotic state and that exposure to high glucose results in G2/M arrest and apoptosis. Molecular study revealed a decrease in phosphoinositide-dependent kinase (PDK)-1 and Akt/protein kinase B (PKB) phosphorylation. Treatment of IA-2-transfected cells with IA-2 siRNA prevented both G2/M arrest and apoptosis and increased Akt/PKB phosphorylation. A search for IA-2 interacting proteins revealed that IA-2 interacts with sorting nexin (SNX)19 and that SNX19, but not IA-2, inhibits the conversion of PtdIns(4,5)P2 to PtdIns(3,4,5)P3 and thereby suppresses the phosphorylation of proteins in the Akt signalling pathway resulting in apoptosis. We conclude that IA-2 acts through SNX19 to initiate the pre-apoptotic state. Our findings point to the possibility that in autoimmune diseases, tissue destruction may be autoantigen-induced, but not necessarily immunologically mediated. C1 NIH, Natl Inst Dental & Craniofacial Res, Oral Infect & Immun Branch, Expt Med Sect, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Sch Med, Dept Anat Physiol & Genet, Bethesda, MD 20814 USA. RP Notkins, AL (reprint author), NIH, Natl Inst Dental & Craniofacial Res, Oral Infect & Immun Branch, Expt Med Sect, Bethesda, MD 20892 USA. EM anotkins@mail.nih.gov NR 38 TC 5 Z9 5 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD OCT PY 2007 VL 150 IS 1 BP 49 EP 60 DI 10.1111/j.1365-2249.2007.03455.x PG 12 WC Immunology SC Immunology GA 207UB UT WOS:000249275500006 PM 17725654 ER PT J AU Chiu, AW Ehrmantraut, M Richert, ND Ikonomidou, VN Pellegrini, S McFarland, HF Frank, JA Bagnato, F AF Chiu, A. W. Ehrmantraut, M. Richert, N. D. Ikonomidou, V. N. Pellegrini, S. McFarland, H. F. Frank, J. A. Bagnato, F. TI A case study on the effect of neutralizing antibodies to interferon beta 1b in multiple sclerosis patients followed for 3 years with monthly imaging SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE IFN-beta; magnetic resonance imaging; multiple sclerosis; neutralizing antibodies ID SECONDARY PROGRESSIVE MS; IFN-BETA; IFN-BETA-1B; GUIDELINES; BIOASSAY; TRIAL AB Interferon beta (IFN-beta) is among the first-line treatment options for patients with multiple sclerosis (MS). A potential caveat of therapy, however, is the development of neutralizing antibodies (NAb) and/or neutralizing activity (NA) non-antibody mediated, although debate is still ongoing as to whether NAb significantly hampers the efficacy of the drug or rather represents an immunologically irrelevant epiphenomenon. In the present study, we describe the effect of NAb on IFN-beta-1b through clinical and magnetic resonance imaging (MRI) outcome measures of five relapsing-remitting multiple sclerosis (RRMS) patients who were treated with 250 mu g of subcutaneously administered IFN-beta-1b every other day and developed NAb at varying titres and times during the course of therapy. Despite the small number of NAb(+) patients, heterogeneity in MRI/clinical response to IFN-beta-1b was identified. Response to IFN-beta-1b therapy was observed in the absence or presence of NAb. Also observed was failure to IFN-beta-1b coincident with high and sustained NAb titres, but also before NAb development or in the presence of low NAb titres. Multiple MRI and NAb measurements performed within the same individual allow for a better description of the complex heterogeneous response to IFN-beta-1b with respect to NAb occurrence. C1 NIH, NINDS, NIB, Bethesda, MD 20892 USA. NIH, NINDS, Lab Diag Radiol & Res, Bethesda, MD 20892 USA. NIH, NINDS, Neuroimmunol Branch, Bethesda, MD USA. RP Bagnato, F (reprint author), NIH, NINDS, NIB, Bldg 10,Room 5B16,10 Ctr Dr, Bethesda, MD 20892 USA. EM bagnatof@ninds.nih.gov FU Intramural NIH HHS NR 22 TC 6 Z9 7 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD OCT PY 2007 VL 150 IS 1 BP 61 EP 67 DI 10.1111/j.1365-2249.2007.03467.x PG 7 WC Immunology SC Immunology GA 207UB UT WOS:000249275500007 PM 17666095 ER PT J AU Breunis, WB Biezeveld, MH Geissler, J Kuipers, IM Lam, J Ottenkamp, J Hutchinson, A Welch, R Chanock, SJ Kuijpers, TW AF Breunis, W. B. Biezeveld, M. H. Geissler, J. Kuipers, I. M. Lam, J. Ottenkamp, J. Hutchinson, A. Welch, R. Chanock, S. J. Kuijpers, T. W. TI Polymorphisms in chemokine receptor genes and susceptibility to Kawasaki disease SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE chemokine receptor; chemokines; Kawasaki disease; single nucleotide polymorphism ID TUMOR-NECROSIS-FACTOR; HAPLOTYPE RECONSTRUCTION; CELL RECRUITMENT; IMMUNE-RESPONSES; HIV-1 INFECTION; HOST-DEFENSE; MICE LACKING; FACTOR-ALPHA; INTERLEUKIN-6; ASSOCIATION AB Kawasaki disease (KD) is an acute vasculitis occurring in young children. Its aetiology is unknown, but an infectious agent is assumed. Increased levels of proinflammatory cytokines and chemokines have been reported in KD. Genetic variation in these genes and the receptors for these genes could influence the regulation of cytokines and chemokines. In a case-control study of 170 Dutch Caucasian KD patients and 300 healthy Dutch Caucasian controls, common genetic variants in chemokine receptor genes CCR3, CCR2, CCR5, CX3CR1, CXCR1 and CXCR2 were analysed. Of the eight studied single nucleotide polymorphisms (SNPs) in the CCR3-CCR2-CCR5 gene cluster, four showed a significant association with susceptibility to KD. Moreover the CCR5-Delta 32 was observed with an allele frequency of 10.7% in the control population compared to 6.5% in the KD patients (P = 0.04). Two haplotypes of the CCR3-CCR2-CCR5 gene-cluster appear to be at risk haplotypes for KD and one a protective haplotype. No association was observed with the studied SNPs in CX3CR1, CXCR1 and CXCR2. In conclusion, in a Dutch cohort of KD patients an association of KD occurrence with common genetic variants in the chemokine receptor gene-cluster CCR3-CCR2-CCR5 was observed. C1 Emma Childrens Hosp Acad Med Ctr, NL-1105 AZ Amsterdam, Netherlands. Sanquim Res, Amsterdam, Netherlands. Univ Amsterdam, Acad Med Ctr, Landsteiner Lab, Amsterdam, Netherlands. LUMC, Dept Pediat Cardiol, Leiden, Netherlands. SAIC Frederick Inc, Natl Canc Inst, CORE Genotyping Fac, Bethesda, MD USA. SAIC Frederick Inc, Natl Canc Inst, Ctr Adv Technol, Bethesda, MD USA. Natl Inst Hlth, Pediat Oncol Branch, Sect Genom Variat, Bethesda, MD USA. RP Breunis, WB (reprint author), Emma Childrens Hosp Acad Med Ctr, F8-240,Meibergdreef 9, NL-1105 AZ Amsterdam, Netherlands. EM w.b.breunis@amc.uva.nl NR 43 TC 26 Z9 28 U1 1 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD OCT PY 2007 VL 150 IS 1 BP 83 EP 90 DI 10.1111/j.1365-2249.2007.03457.x PG 8 WC Immunology SC Immunology GA 207UB UT WOS:000249275500010 PM 17672867 ER PT J AU Sokolowska, M Borowiec, M Ptasinska, A Cieslak, M Shelhamer, JH Kowalski, ML Pawliczak, R AF Sokolowska, M. Borowiec, M. Ptasinska, A. Cieslak, M. Shelhamer, J. H. Kowalski, M. L. Pawliczak, R. TI 85-kDa cytosolic phospholipase A(2) group IV alpha gene promoter polymorphisms in patients with severe asthma: a gene expression and case-control study SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE airway inflammation; cytosolic phospholipase A(2); gene expression; microsatellites; severe asthma ID CYCLOOXYGENASE-2; INTERLEUKIN-8; CELLS AB Cytosolic phospholipase A(2) (cPLA(2)) group IVa is a critical enzyme involved in the liberation of arachidonic acid from cellular membranes. cPLA2 (-/-) mice have reduced allergen- induced bronchoconstriction and bronchial hyperresponsiveness. The goal of this study was to investigate polymorphisms of the (CA)(n) and (T)(n) microsatellites and surrounding regions in the cPLA(2)alpha gene promoter. We analysed the cPLA(2) promoter regions containing (CA) n and (T) (n) repeats in 87 patients with severe asthma and in 48 control subjects by bidirectional sequencing. Functional studies were performed utilizing reporter genes derived from subjects with varying numbers of these repeats, and on constructs with a series of deletions. We found that the (CA) n and (T) (n) regions are polymorphic and that constructs with CA or T repeats or CA and T repeats deleted revealed, respectively, a 41.8 +/- 7%, 22.3 +/- 5% and 100 +/- 20% increase in reporter gene activity. A lower number of CA or T repeats caused higher cPLA(2) promoter luciferase activity. The group of shorter alleles of the (CA) (n) microsatellite region ( n = 12 - 18) (P-cor = 0 . 00006), and the group of shorter alleles of ( T) (n) repeats region ( n = 17 - 38) (P-cor = 0 . 0039) occurred significantly more often in patients with severe asthma. We also found novel SNPs in positions - 292 C > G, - 185 A > C, - 180 T > C and - 165 A > C. Two of them were associated with the severe asthma phenotype: - 180T allele (P-cor = 0 . 03996) and - 185 A allele (P-cor = 0 . 03966). These results demonstrate that (CA)(n) and (T)(n) repeats may have an influence on cPLA(2) transcription which might play a role in severe asthma pathogenesis. C1 Med Univ Lodz, Dept Immunopathol, Chair Immunol, Lodz, Poland. Harvard Univ, Joslin Diabet Ctr, Boston, MA 02115 USA. Natl Inst Hlth, Warren Grant Magnuson Clin Ctr, Dept Crit Care Med, Bethesda, MD USA. Med Univ Lodz, Chair Immunol, Dept Rheumatol Immunol & Allergy, Lodz, Poland. RP Pawliczak, R (reprint author), Med Univ Lodz, Dept Immunopathol, Chair Immunol, Lodz, Poland. EM rafal.pawliczak@csk.umed.lodz.pl RI Borowiec, Maciej/S-9220-2016; Pawliczak, Rafal/S-9649-2016; OI Pawliczak, Rafal/0000-0001-6784-453X NR 21 TC 10 Z9 10 U1 1 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD OCT PY 2007 VL 150 IS 1 BP 124 EP 131 DI 10.1111/j.1365-2249.2007.03459.x PG 8 WC Immunology SC Immunology GA 207UB UT WOS:000249275500015 PM 17672871 ER PT J AU Fraillery, D Baud, D Pang, SYY Schiller, J Bobst, M Zosso, N Ponci, F Nardelli-Haefliger, D AF Fraillery, Dominique Baud, David Pang, Susana Yuk-Ying Schiller, John Bobst, Martine Zosso, Nathalie Ponci, Francoise Nardelli-Haefliger, Denise TI Salmonella enterica serovar Typhi Ty2la expressing human papillomavirus type 16 L1 as a potential live vaccine against cervical cancer and typhoid fever SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID VIRUS-LIKE PARTICLES; HUMAN-PAPILLOMAVIRUS; HELICOBACTER-PYLORI; ESCHERICHIA-COLI; VECTOR VACCINES; NEUTRALIZING ANTIBODIES; IMMUNE-RESPONSES; ADULT VOLUNTEERS; MURINE MODEL; MUCOSAL AB Human papillomavirus (HPV) vaccines based on L1 virus-like particles (VLPs) can prevent HPV-induced genital neoplasias, the precursors of cervical cancer. However, most cervical cancers occur in developing countries, where the implementation of expensive vaccines requiring multiple injections will be difficult. A live Salmonella-based vaccine could be a lower-cost alternative. We previously demonstrated that high HPV type 16 (HPV16) -neutralizing titers are induced after a single oral immunization of mice with attenuated Salmonella enterica serovar Typhimurium strains expressing a codon-optimized version of HPV16 L1 (LIS). To allow the testing of this type of vaccine in women, we constructed a new L1-expressing plasmid, kanL1S, and tested kanL1S recombinants of three Salmonella enterica serovar Typhi vaccine strains shown to be safe in humans, i.e., Ty21a, the actual licensed typhoid vaccine, and two highly immunogenic typhoid vaccine candidates, Ty800 and CVD908-htrA. In an intranasal mouse model of Salmonella serovar Typhi infection, Ty21a kanL1S was unique in inducing HPV16-neutralizing antibodies in serum and genital secretions, while anti-Salmonella responses were similar to those against the parental Ty21a vaccine. Electron microscopy examination of Ty21a kanL1S lysates showed that L1 assembled in capsomers and capsomer aggregates but not well-ordered VLPs. Comparison to the neutralizing antibody response induced by purified HPV16 L1 VLP immunizations in mice suggests that Ty21a kanL1S may be an effective prophylactic HPV vaccine. Ty21a has been widely used against typhoid fever in humans with a remarkable safety record. These finds encourage clinical testing of Ty21a kanL1S as a combined typhoid fever/cervical cancer vaccine with the potential for worldwide application. C1 CHU Vaudois, Inst Microbiol, CH-1011 Lausanne, Switzerland. Univ Lausanne, CH-1011 Lausanne, Switzerland. NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Nardelli-Haefliger, D (reprint author), CHU Vaudois, Inst Microbiol, Bugnon 48, CH-1011 Lausanne, Switzerland. EM dnardell@hospvd.ch NR 52 TC 40 Z9 41 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD OCT PY 2007 VL 14 IS 10 BP 1285 EP 1295 DI 10.1128/CVI.00164-07 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 220OA UT WOS:000250164800006 PM 17687110 ER PT J AU Higgins, J Hill, V Lau, K Simpson, V Roayaei, J Klabansky, R Stevens, RA Metcalf, JA Baselerl, M AF Higgins, Jeanette Hill, Valerie Lau, Karen Simpson, Virginia Roayaei, Jean Klabansky, Rick Stevens, Randy A. Metcalf, Julia A. Baselerl, Michael TI Evaluation of a single-platform technology for lymphocyte immunophenotyping SO CLINICAL AND VACCINE IMMUNOLOGY LA English DT Article ID CD4 AB An accurate and reproducible CD4 count is a fundamental clinical tool for monitoring and treating human immunodeficiency virus infection and its complications. Two methods exist for calculating absolute CD4 counts: dual-platform technology (DPT) and single-platform technology (SPT). Numerous studies have documented the unacceptably wide range of variation in absolute CD4 counts between laboratories. SPT was introduced in 1996 to reduce the interlaboratory variation in absolute CD4 counts. The aim of this study was to compare DPT with the BD Biosciences Trucount method (an SPIT method). Both the percentages of CD4 (r = 0.986; P = 0.0541) and the absolute, CD4 counts (r = 0.960; P = 0.0001) had very good correlation between the two methods. However, poor correlation was observed for the CD8(+) RO- (r = 0.314; P = 0.0002), CD8(+) DR' (r = 0.666; P 0.0138), CD3(+) CD38(+) (r = 0.8000; P = 0.0004), CD3(+) CD25(+) (r = 0.464; P = 0.0082), and CD4(+) CD38(+) = 0.357; P = 0.0127) measurements. C1 NCI Frederick, SAIC Frederick Inc, Clin Serv Program, AIDS Monitoring Lab, Ft Detrick, MD 21702 USA. NCI Frederick, SAIC Frederick Inc, Clin Serv Program, Neutrophil Monitoring Lab, Ft Detrick, MD 21702 USA. NCI Frederick, Data Management Serv Inc, Frederick, MD USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Higgins, J (reprint author), NCI Frederick, SAIC Frederick Inc, Clin Serv Program, AIDS Monitoring Lab, POB B,Bldg 469-3 Room 9, Ft Detrick, MD 21702 USA. EM jhiggins@mail.nih.gov FU NCI NIH HHS [N01CO12400, N01-CO-12400] NR 10 TC 3 Z9 3 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 1556-6811 J9 CLIN VACCINE IMMUNOL JI Clin. Vaccine Immunol. PD OCT PY 2007 VL 14 IS 10 BP 1342 EP 1348 DI 10.1128/CVI.00168-07 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 220OA UT WOS:000250164800014 PM 17761524 ER PT J AU Fojo, T Coley, HM AF Fojo, Tito Coley, Helen M. TI The role of efflux pumps in drug-resistant metastatic breast cancer: New insights and treatment strategies SO CLINICAL BREAST CANCER LA English DT Review DE epothilones; multidrug resistance proteins; P-glycoprotein; nanoparticles ID MICROTUBULE-STABILIZING AGENTS; ACUTE MYELOID-LEUKEMIA; IN-VIVO DETECTION; CELL LUNG-CANCER; PHASE-II TRIAL; MULTIDRUG-RESISTANCE; P-GLYCOPROTEIN; EPOTHILONE-B; FORMULATION VEHICLES; 1ST-LINE TREATMENT AB Chemotherapy plays a vital role in the treatment and management of breast cancer and is associated with significant improvements in survival. Regimens such as CMF (cyclophosphamide/methotrexate/5-fluorouracil) and, more recently, TAC (docetaxel/doxorubicin/cyclophosphamide) have been used with good response rates and complete remissions achieved in approximately 15% of cases. However, a significant proportion of women experience a recurrence of metastatic disease, with an average survival between 1-2 years. The monoclonal antibody trostuzumab is used in the treatment of HER2/neu-positive breast cancer. Although such targeted agents have heralded an exciting new era in cancer therapy, they are limited by the fact that only a subset of patients can benefit from treatment and by the emergence of resistance. Thus, the pursuit of a strategy that modulates resistance to standard chemotherapeutics remains valid. Accumulating evidence indicates that a number of mechanisms known to contribute to clinical drug resistance might be relevant to breast cancer. Tumor cell drug resistance might arise as a result of systemic pharmacologic factors, changes in the tumor microenvironment (eg, pH), cellular pharmacokinetics, drug metabolism and detoxification, drug target modifications, DNA repair, and apoptotic mechanisms. The adenotriphosphate- binding cassette membrane transporter family contributes to clinical drug resistance, especially in breast cancer. The most frequently described of this family is P-glycoprotein, followed by multidrug resistance protein-1. This review describes the factors thought to play a role in clinical breast cancer drug resistance and describes potential methods by which it might be circumvented. C1 NCI, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Surrey, Guildford GU2 5XH, Surrey, England. RP Fojo, T (reprint author), NCI, Ctr Canc Res, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tfojo@helix.nih.gov NR 91 TC 27 Z9 31 U1 2 U2 10 PU CIG MEDIA GROUP, LP PI DALLAS PA 3500 MAPLE AVENUE, STE 750, DALLAS, TX 75219-3931 USA SN 1526-8209 J9 CLIN BREAST CANCER JI Clin. Breast Cancer PD OCT PY 2007 VL 7 IS 10 BP 749 EP 756 DI 10.3816/CBC.2007.n.035 PG 8 WC Oncology SC Oncology GA 227ZG UT WOS:000250696000003 PM 18021475 ER PT J AU Lee, TL Yang, XP Yan, B Friedman, J Duggal, P Bagain, L Dong, G Yeh, NT Wang, J Zhou, J Elkahloun, A Van Waes, C Chen, Z AF Lee, Tin Lap Yang, Xin Ping Yan, Bin Friedman, Jay Duggal, Praveen Bagain, Lorena Dong, Gang Yeh, Ning T. Wang, Jie Zhou, Jian Elkahloun, Abdel Van Waes, Carter Chen, Zhong TI A novel nuclear factor-kappa B gene signature is differentially expressed in head and neck squamous cell carcinomas in association with TP53 status SO CLINICAL CANCER RESEARCH LA English DT Article ID PROINFLAMMATORY CYTOKINE EXPRESSION; INTERCELLULAR-ADHESION MOLECULE-1; LASER-CAPTURE MICRODISSECTION; PROTEASOME INHIBITOR BORTEZOMIB; GROWTH-FACTOR RECEPTOR; ORAL-CANCER DETECTION; ARF TUMOR-SUPPRESSOR; TRANSCRIPTION FACTORS; TARGET GENES; CONSTITUTIVE ACTIVATION AB Purpose: To determine if gene signatures differentially expressed in head and neck squamous cell wcarcinomas (HNSCC) are related to alterations in transcription factors nuclear factor-kappa 13 (NF-kappa B) andTP53 previously associated with decreased cell death, response to therapy, and worse prognosis. Experimental Design: Unique gene signatures expressed by HNSCC lines were identified by cDNA microarray, principal components, and cluster analyses and validated by quantitative reverse transcription- PCR (RT-PCR) and in situ hybridization. Bioinformatic analysis of the promoters and ontogeny of these clustered genes was done. Expression of proteins encoded by genes of a putative NF-kappa B signature, NF-kappa B p65, and TP53 were examined in HNSCC tissue specimens by immunostaining. Predicted promoter binding and modulation of expression of candidate NF-KB genes and cell survival were evaluated by p65 chromatin immunoprecipitation (ChIP) and small interfering RNA (siRNA) knockdown. Results: Two groups of HNSCC exhibiting distinct gene signatures were identified: cluster A enriched for histone genes, with a higher prevalence of TP53 promoter binding motifs; and cluster B enriched for injury response genes with NF-kappa B regulatory motifs. Coexpression of cluster B proteins was observed with strong NF-kappa B phospho-p65 and weak TP53 staining, and NF-kappa B phospho-p65 was inversely associated with TP53 (P = 0.02). Promoter binding of the NF-kappa B signature genes was confirmed by p65 ChIP, and down-modulation of theirexpression and cell death were induced by p65 siRNA. Conclusion: NF-kappa B promotes expression of a novel NF-kappa B -related gene signature and cell survival in HNSCC that weakly express TP53, a subset previously associated with inactivated wild-type TP53, greater resistance to chemoradiotherapy, and worse prognosis. C1 NIH, Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, Bethesda, MD 20892 USA. NIH, Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, Tumor Biol Sect, Bethesda, MD 20892 USA. NIH, Natl Inst Child & Dev, Dev Endocrinol Branch, Bethesda, MD 20892 USA. NIH, NHGRI, Canc Genet Branch, Microarray Unit, Bethesda, MD 20892 USA. RP Chen, Z (reprint author), NIH, Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, Bldg 10, Bethesda, MD 20892 USA. EM chenz@nidcd.nih.gov RI Lee, Tin-Lap/A-7853-2009 OI Lee, Tin-Lap/0000-0002-6654-0988 FU Intramural NIH HHS NR 81 TC 49 Z9 49 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 1 PY 2007 VL 13 IS 19 BP 5680 EP 5691 DI 10.1158/1078-0432.CCR-07-0670 PG 12 WC Oncology SC Oncology GA 218CN UT WOS:000249993700006 PM 17908957 ER PT J AU Freedman, RS Wang, E Voiculescu, S Patenia, R Bassett, RL Cleavers, M Marincola, FM Yang, PY Newman, RA AF Freedman, Ralph S. Wang, Ena Voiculescu, Sonia Patenia, Rebecca Bassett, Roland L., Jr. Cleavers, Michael Marincola, Francesco M. Yang, Peiying Newman, Robert A. TI Comparative analysis of peritoneum and tumor eicosanoids and pathways in advanced ovarian cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID 15-LIPOXYGENASE-2 15-LOX2; COLORECTAL-CANCER; CELL-LINES; EXPRESSION; SYNTHASE; ACID; CYCLOOXYGENASE-1; PROSTAGLANDINS; LIPOXYGENASES; SUPPRESSOR AB Purpose: To describe the eicosanoid profile and differentially expressed eicosanoid and arachiclonic acid pathway genes in tissues from patients with advanced epithelial ovarian cancer (EOC). Experimental Design: We first employed electrospray tandem mass spectrometry to determine tissue-specific concentrations of the eicosanoids prostaglandin E-2 (PGE(2)), the hydroxyeicosatetraenoic acids (12-HETE and 5-HETE), and leukotriene (LTB4), selected for tumor growth potential, and two other bioactive lipids (15-HETE and 13-HODE) with tumor cell proliferation interference potential. The cellular location of eicosanoid activity was identified by immunofluorescence antibody costaining and confocal microscopy. Differential analysis of eicosanoid and arachiclonic pathway genes was done using a previously validated cDNA microarray platform. Tissues used included EOC tumor, tumor-free malignant peritoneum (MP), and benign peritoneum (BP) from patients with benign pelvicclisease. Results: (a) Eicosanoid products were detected in tumor, MP, and EP specimens. PGE2 levels were significantly elevated in tumors in an overall comparison with MP or BP (P < 0.001). Combined levels of PGE2,12-HETE, 5-HETE, and LTB4 increased progressively from low to high concentrations in BP, MP, and tumors (P = 0.012). Neither 15-HETE nor 13-HODE showed a significant opposite trend toward levels found in BP. (b) Tissue specimens representing common EOC histotypes showed strong coexpressions of cyclooxygenases (COX-1) and prostaglandin E synthases (PGES-1) on tumor cells, whereas intratumoral or peritumoral MO/MA coexpressed COX-1 and COX-2 and PGES-1 and PGES-2, respectively. (c) cDNA microarray analysis of Mp, EP, and tumor showed that a number of eicosanoid and arachiclonic acid pathway genes were differentially expressed in MP and BP compared with tumor, except for CYP2J2, which was increased in tumors. Conclusions: Elevated levels of eicosanoid metabolites in tumors and differential expression of eicosanoid and arachiclonic acid pathway genes in the peritoneum support the involvement of bioactive lipids in the inflammatory tumor environment of EOC. C1 Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Quantitat Sci, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA. NIH, Dept Transfus Med, Immunogenet Sect, Bethesda, MD 20892 USA. RP Freedman, RS (reprint author), Univ Texas, MD Anderson Canc Ctr, 1515 Holcombe Blvd, Houston, TX 77030 USA. EM rfreedma@mdanderson.org NR 37 TC 25 Z9 30 U1 0 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 1 PY 2007 VL 13 IS 19 BP 5736 EP 5744 DI 10.1158/1078-0432.CCR-07-0583 PG 9 WC Oncology SC Oncology GA 218CN UT WOS:000249993700012 PM 17908963 ER PT J AU Overmoyer, B Fu, P Hoppel, C Radivoyevitch, T Shenk, R Persons, M Silverman, P Robertson, K Ziats, NP Wasman, JK Abdul-Karim, FW Jesberger, JA Duerk, J Hartman, P Hanks, S Lewin, J Dowlati, A McCrae, K Ivy, P Remick, SC AF Overmoyer, Beth Fu, Pingfu Hoppel, Charles Radivoyevitch, Tomas Shenk, Robert Persons, Marjie Silverman, Paula Robertson, Kelly Ziats, Nicholas P. Wasman, Jay K. Abdul-Karim, Fadi W. Jesberger, John A. Duerk, Jeffrey Hartman, Paul Hanks, Shelli Lewin, Jonathan Dowlati, Afshin McCrae, Keith Ivy, Percy Remick, Scot C. TI Inflammatory breast cancer as a model disease to study tumor angiogenesis: Results of a phase IB trial of combination SU5416 and doxorubicin SO CLINICAL CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; END RESULTS PROGRAM; CARCINOMA INCIDENCE; PHARMACOKINETICS; EPIDEMIOLOGY; SURVEILLANCE; METASTASIS; PACLITAXEL; REGRESSION; INHIBITOR AB Purpose: We used inflammatory breast cancer (IBC) as a model disease to investigate biological changes associated with an antiangiogenesis agent, SU5416, combined with doxorubicin. Experimental Design: Patients with stage 11113 or IV IBC were treated neoadjuvantly with the combination of SU5416 and doxorubicin for induction therapy. The dose of SU5416 (administered on days 1 and 4, every 3 weeks) and doxorubicin (administered on day 1 every 3 weeks) 2 were escalated in cohorts of three patients starting at 110 and 60 mg/m, respectively, for a total of five cycles leading up to mastectomy. Patients underwent serial assessment (pharmacokinetic sampling, biopsy of breast, tumor blood flow dynamic contrast-enhanced magnetic resonance imaging, plasma angiogenesis, and endothelial cell damage markers) prior to treatment, at the end of cycles no. 2 and no. 5, and after mastectomy. Results: Eighteen patients were enrolled; neutropenia was dose-limiting, and overall median survival was not reached (50 months of study follow-up). Four patients (22%) experienced congestive heart failure, which resolved and were likely attributable to a smaller volume of distribution and higher C-max of doxorubicin in combination with SU5416. We did observe a significant decline in tumor blood flow using Kep calculated by Brix (pretreatment versus post-cycle no. 5; P = 0.033), trend for a decline in tumor microvessel density after treatment, and low baseline levels of soluble intracellular adhesion molecule were associated with improved event-free survival. Conclusions: This study showed evidence of an unfavorable cardiac interaction between SU5416 and doxorubicin, which prohibits further investigation of this combination. However, this study supports the importance of using IBC as a model for investigating angiogenesis inhibitors. C1 Connecticut Oncol & Hematol Associates US Oncol, Torrington, CT 06790 USA. Univ Hosp Case Med Ctr, Dev Therapeut Program, Cleveland, OH USA. Univ Hosp Case Med Ctr, Case Comprehens Canc Ctr, Translat Res Core Facil, Cleveland, OH USA. Univ Hosp Case Med Ctr, Dept Biostat, Cleveland, OH USA. Univ Hosp Case Med Ctr, Dept Med, Cleveland, OH USA. Univ Hosp Case Med Ctr, Dept Pharmacol, Cleveland, OH USA. Univ Hosp Case Med Ctr, Dept Surg, Cleveland, OH USA. Univ Hosp Case Med Ctr, Dept Pathol, Cleveland, OH USA. Univ Hosp Case Med Ctr, Dept Radiol, Case Imaging Res Ctr, Cleveland, OH USA. Univ Arizona, Dept Radiat Oncol, Tucson, AZ 85721 USA. Johns Hopkins Univ Hosp, Sch Med, Russell H Morgan Dept Radiol & Radiol Sci, Baltimore, MD 21287 USA. Natl Canc Inst, Canc Therapy Evaluat Program, Investigat Drug Branch, Bethesda, MD USA. RP Overmoyer, B (reprint author), Connecticut Oncol & Hematol Associates US Oncol, 200 Kennedy Dr, Torrington, CT 06790 USA. EM beth.overmoyer@usoncology.com RI Lewin, Jonathan/A-4331-2009; OI Radivoyevitch, Tomas/0000-0002-9701-1851 FU NCI NIH HHS [P30 CA43703, U01 CA62502, K23 CA87725]; NCRR NIH HHS [M01-RR-00080] NR 31 TC 32 Z9 33 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD OCT 1 PY 2007 VL 13 IS 19 BP 5862 EP 5868 DI 10.1158/1078-0432.CCR-07-0688 PG 7 WC Oncology SC Oncology GA 218CN UT WOS:000249993700029 PM 17908980 ER PT J AU Fortuny, J Johnson, CC Bohlke, K Chow, WH Hart, G Kucera, G Mujumdar, U Ownby, D Wells, K Yood, MU Engel, LS AF Fortuny, Joan Johnson, Christine C. Bohlke, Kari Chow, Wong-Ho Hart, Gene Kucera, Gena Mujumdar, Urvi Ownby, Dennis Wells, Karen Yood, Marianne Ulcickas Engel, Lawrence S. TI Use of anti-inflammatory drugs and lower esophageal sphincter-relaxing drugs and risk of esophageal and gastric cancers SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article ID GASTROESOPHAGEAL-REFLUX DISEASE; BODY-MASS INDEX; UNITED-STATES; ADENOCARCINOMAS; CARDIA; ALCOHOL; METAANALYSIS; TOBACCO; ASTHMA AB Background & Aims: The incidence of esophageal and gastric cardia adenocarcinoma has increased in Western countries in recent decades for largely unknown reasons. We investigated whether use of LES-relaxing drugs was related to an increased risk of esophageal and gastric cardia adenocarcinoma, and whether use of NSAIDs was related to a reduced risk of esophageal and gastric cancers. Methods: We examined these associations by using administrative databases in a case-control study in 2 integrated health care delivery systems. Cases were incident esophageal adenocarcinomas (n = 163) and squamous cell carcinomas (n = 114) and gastric cardia (n = 176) and non-cardia adenocarcinomas (n = 320), diagnosed between 1980-2002 in one health system and between 1993-2002 in the other. Matched controls (n = 3996) were selected. Com- plete prescription information was available for the study period. Results: Prescription of corticosteroids was associated with a decreased risk of esophageal adenocarcinoma (odds ratio [OR], 0.6; 95% confidence interval [CI], 0.40.9), esophageal squamous cell carcinoma (OR, 0.4; 95% CI, 0.2-0.6), and gastric non-cardia carcinoma (OR, 0.4, 95% CI, 0.3-0.6). Ever use of pharmacy-purchased aspirin was associated with 30%-60% decreased risks of the studied cancers. As a group, LES-relaxing drugs showed little evidence of association with increased risk of any esophageal or gastric cancer. Conclusions: Corticosteroid and aspirin use were associated with significantly decreased risks of esophageal and gastric cancer. LES-relaxing drugs as a group did not affect these risks, although we had limited power to assess individual drugs. The possibility that corticosteroids and aspirin might reduce esophageal cancer risk warrants further consideration. C1 Mem Sloan Kettering Canc Ctr, Epidemiol Serv, Dept Epidemiol & Biostat, New York, NY 10021 USA. Municipal Inst Med Res, Environm & Resp Res Unit, Barcelona, Catalonia, Spain. Henry Ford Hlth Syst, Detroit, MI USA. Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA 98101 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Med Coll Georgia, Augusta, GA 30912 USA. Yale Univ, Sch Med, New Haven, CT USA. RP Engel, LS (reprint author), Mem Sloan Kettering Canc Ctr, Epidemiol Serv, Dept Epidemiol & Biostat, 307 E 63rd St,3rd Floor, New York, NY 10021 USA. EM engell@mskcc.org OI Ulcickas Yood, Marianne/0000-0003-4204-0871; Johnson, Christine Cole/0000-0002-6864-6604; Engel, Lawrence/0000-0001-9268-4830 FU Intramural NIH HHS [Z99 CA999999]; NCI NIH HHS [U19 CA79689, U19 CA079689, R01 CA140754] NR 28 TC 28 Z9 29 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD OCT PY 2007 VL 5 IS 10 BP 1154 EP 1159 DI 10.1016/j.cgh.2007.05.022 PG 6 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 223IN UT WOS:000250363600009 PM 17644046 ER PT J AU Welzel, TM Graubard, BI El-Serag, HB Shaib, YH Hsing, AW Davila, JA McGlynn, KA AF Welzelt, Tania M. Graubard, Barry I. El-Serag, Hashem B. Shaib, Yasser H. Hsing, Ann W. Davila, Jessica A. McGlynn, Katherine A. TI Risk factors for intrahepatic and extrahepatic Cholangiocarcinoma in the United States: A population-based case-control study SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article ID PRIMARY SCLEROSING CHOLANGITIS; HEPATITIS-C-VIRUS; FATTY LIVER-DISEASE; HEPATOCELLULAR-CARCINOMA; HELICOBACTER-PYLORI; NATURAL-HISTORY; STEM-CELLS; STEATOSIS; HEPATOLITHIASIS; CIRRHOSIS AB Background & Aims: Intrahepatic and extrahepatic cholangiocarcinomas are rare and highly malignant cancers of the bile duct. Although the incidence of extrahepatic cholangiocarcinoma (ECC) has remained constant, the incidence of intrahepatic cholangiocarcinoma (ICC) has increased in the United States. Because the etiology of both tumors is poorly understood, a population-based case-control study was conducted to examine the association of ECC and ICC with preexisting medical conditions. Methods: Medical conditions among 535 ICC patients, 549 ECC patients (diagnosed 1993-1999), and 102,782 cancer-free controls were identified by using the Surveillance, Epidemiology and End Results-Medicare databases. Logistic regression analysis was used to calculate adjusted odds ratios. Results: In addition to established risk factors (choledochal cysts, cholangitis, inflammatory bowel disease), several other conditions were significantly associated with ECC and ICC: biliary cirrhosis (ECC, ICC: P <.001), cholelithiasis (ECC, ICC: P <.001), alcoholic liver disease (ECC, P <.001; ICC, P =.01), nonspecific cirrhosis (ECC, ICC: P <.001), diabetes (ECC, ICC: P <.001), thyrotoxicosis (ECC, P =.006; ICC, P =.04), and chronic pancreatitis (ECC, ICC: P <.001). Conditions only associated with ICC were obesity (ECC, P =.71; ICC, P =.01), chronic nonalcoholic liver disease (ECC, P =.08; ICC, P =.02), HCV infection (ECC, P =.67; ICC, P =.01), and smoking (ECC, P =.07; ICC, P =.04). Conclusions: Several novel associations with ECC and ICC were identified. HCV infection, chronic nonalcoholic liver disease, and obesity, all of which are increasing in incidence, and smoking were associated only with ICC, suggesting that these conditions might explain the divergent incidence trends of the tumors. C1 NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. Michael E Debakey Vet Affairs Med Ctr, Sect Hlth Serv Res, Houston, TX USA. Michael E Debakey Vet Affairs Med Ctr, Gastroenterol Sect, Houston, TX USA. Baylor Coll Med, Houston, TX 77030 USA. RP Welzel, TM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, 6120 Execut Blvd,EPS Suite 550,MSC-7234, Bethesda, MD 20892 USA. EM weizelt@mall.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 53 TC 201 Z9 211 U1 1 U2 16 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD OCT PY 2007 VL 5 IS 10 BP 1221 EP 1228 DI 10.1016/j.cgh.2007.05-020 PG 8 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 223IN UT WOS:000250363600019 PM 17689296 ER PT J AU Levin, JH Kaler, SG AF Levin, J. H. Kaler, S. G. TI Non-random maternal X-chromosome inactivation associated with PHACES SO CLINICAL GENETICS LA English DT Article DE hemangioma; PHACES syndrome; sternal cleft; supraumbilical raphe; X-inactivation ID RIGHT AORTIC-ARCH; INFANTILE HEMANGIOMAS; DYSPLASIA ASSOCIATION; FOSSA MALFORMATIONS; ARTERIAL ANOMALIES; FACIAL HEMANGIOMAS; EYE ABNORMALITIES; CARDIAC DEFECTS; STERNAL CLEFT; RETT-SYNDROME AB The acronym PHACES is used to describe the association of posterior fossa malformations, hemangiomas, arterial anomalies (cardiovascular or cerebrovascular), coarctation of the aorta and cardiac defects, eye abnormalities, and sternal or ventral defects. We report a female patient with an uncommon variant of this neurocutaneous disorder who manifested a sternal cleft; supraumbilical raphe; hemangiomas of the face, chest, and extremities; micrognathia and cerebrovascular anomalies. A literature review of PHACES patients with both sternal cleft and supraumbilical raphe showed a marked female predilection. Taken together with cases of sternal cleft, supraumbilical raphe and facial hemangiomas tabulated by Gorlin et al. (1994), 91% (40/44) of patients are female. One affected male died shortly after birth. We hypothesized that the gender bias in PHACES results from mutation in an X-linked dominant gene often lethal in males, and performed X-inactivation analysis of the polymorphic androgen receptor locus in this family. We documented consistently skewed X-inactivation (80%/20% in two independent analyses) in the unaffected mother and consistently random X-inactivation (47:53 and 61:39 in independent analyses) in the proband. These findings are consistent with favorably skewed X-inactivation producing a normal maternal phenotype, a phenomenon documented in X-linked dominant Rett syndrome. C1 NICHHD, Natl Inst Hlth, Lab Clin Genom, Unit Pediat Genet, Bethesda, MD 20892 USA. RP Kaler, SG (reprint author), NICHHD, Natl Inst Hlth, Lab Clin Genom, Unit Pediat Genet, Bldg 10,Rm 5-2571,10 Ctr Dr MSC 1834, Bethesda, MD 20892 USA. EM kalers@mail.nih.gov FU Intramural NIH HHS NR 29 TC 15 Z9 15 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD OCT PY 2007 VL 72 IS 4 BP 345 EP 350 DI 10.1111/j.1399-0004.2007.00851.x PG 6 WC Genetics & Heredity SC Genetics & Heredity GA 209WT UT WOS:000249419400010 PM 17850631 ER PT J AU Raja, M Azzoni, A Giona, F Regis, S Grossi, S Filocamo, M Sidransky, E AF Raja, M. Azzoni, A. Giona, F. Regis, S. Grossi, S. Filocamo, M. Sidransky, E. TI Movement and mood disorder in two brothers with Gaucher disease SO CLINICAL GENETICS LA English DT Article DE Gaucher disease; glucocerebrosidase; mood disorder; parkinsonism ID GLUCOCEREBROSIDASE GENE; PARKINSONS-DISEASE; MUTATIONS; CHOLELITHIASIS; ASSOCIATION; PSEUDOGENE; ALLELE; PCR AB Gaucher disease (GD) is a lysosomal storage disorder with a wide spectrum of phenotypic presentations. We report the case histories of two adult brothers with GD who developed both parkinsonism and psychiatric symptoms. Direct sequencing and real-time polymerase chain reaction were used to establish that the patients were homozygous for mutation L444P. While parkinsonism has been described previously in GD, these patients had atypical features, including a complicated mood disorder. The comorbidity of GD and a mood disorder is a new finding, as psychiatric manifestations of GD have been described rarely. The etiology of the mental illness could be related to the processes contributing to the development of parkinsonism. C1 NHGRI, Med Genet Branch, Sect Mol Neurogenet, NIH, Bethesda, MD 20892 USA. Osped Santo Spirito, Serv Psichiatr Diagnos Cura, Rome, Italy. Univ Studi La Sapienza, Ist Ematol, Rome, Italy. IRCCS G Gaslini, Lab Diagnosi pre Postnatale Malattie Metab, Genoa, Italy. RP Sidransky, E (reprint author), NHGRI, Med Genet Branch, Sect Mol Neurogenet, NIH, Bldg 35,Rm 1A213,35 Convent Dr,MSC 3708, Bethesda, MD 20892 USA. EM sidranse@mail.nih.gov FU Intramural NIH HHS NR 27 TC 5 Z9 6 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD OCT PY 2007 VL 72 IS 4 BP 357 EP 361 DI 10.1111/j.1399-0004.2007.00863.x PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 209WT UT WOS:000249419400012 PM 17850633 ER PT J AU Sakakura, K Chikamatsu, K Furuya, N Appella, E Whiteside, TL Deleo, AB AF Sakakura, Koichi Chikamatsu, Kazuaki Furuya, Nobuhiko Appella, Ettore Whiteside, Theresa L. Deleo, Albert B. TI Toward the development of multi-epitope p53 cancer vaccines: An in vitro assessment of CD8(+) T cell responses to HLA class I-restricted wild-type sequence p53 peptides SO CLINICAL IMMUNOLOGY LA English DT Article DE p53; CD8(+) T cells; immune response; head and neck cancer; ELISPOT ID DENDRITIC CELLS; NECK-CANCER; PERIPHERAL-CIRCULATION; SPONTANEOUS APOPTOSIS; CLINICAL-SIGNIFICANCE; P53(264-272) PEPTIDE; CARCINOMA; HEAD; LYMPHOCYTES; ANTIGEN AB Wild-type sequence (wt) p53 peptides are attractive candidates for broadly applicable cancer vaccines. Six HLA-A2 or HLA-A24-restricted wt p53 peptides were evaluated for their ex vivo immunogenicity and their potential for use in cancer vaccines. Peripheral blood mononuclear cells (PBMC) obtained from HLA-A*0201(+) and/or HLA-A*2402(+) normal donors and subjects with squamous cell carcinoma of the head and neck (SCCHN) were analyzed for p53 peptide-specific reactivity in ELISPOT IFN-gamma assays. CD8(+) T cells in 7/10 normal donors (HD) and 11/23 subjects with SCCHN responded to at least one of the wt p53 peptides. CD8(+) T cell precursors responsive to wt p53 epitopes were detected in the circulation of most subjects with early disease, and an elevated blood Tc-1/Tc-2 ratio distinguished wt p53 peptide responders from non-responders. The identification of multiple wt p53 peptides able to induce cytolytic T lymphocytes in most subjects with cancer promotes the development of multi-epitope p53 vaccines. (c) 2007 Elsevier Inc. All rights reserved. C1 Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, Sch Med,Dept Pathol, Pittsburgh, PA 15213 USA. Gunma Univ, Grad Sch Med, Dept Otolaryngol Head & Neck Surg, Maebashi, Gumma 371, Japan. NCI, Bethesda, MD 20892 USA. Univ Pittsburgh, Div Basic Res, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Sch Med, Dept Otolaryngol, Pittsburgh, PA 15213 USA. RP Whiteside, TL (reprint author), Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, Sch Med,Dept Pathol, 5117 Ctr Ave,Suite 1-27, Pittsburgh, PA 15213 USA. EM whitesidetl@upmc.edu FU NIDCR NIH HHS [P01 DE012321, P01 DE12321, P01 DE012321-05] NR 40 TC 16 Z9 17 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD OCT PY 2007 VL 125 IS 1 BP 43 EP 51 DI 10.1016/j.clim.2007.05.015 PG 9 WC Immunology SC Immunology GA 212XH UT WOS:000249629800007 PM 17631051 ER PT J AU Durairaj, DC Krishna, MC Murugesan, R AF Durairaj, D. Christopher Krishna, Murah C. Murugesan, Rarnachandran TI A neural network approach for image reconstruction in electron magnetic resonance tomography SO COMPUTERS IN BIOLOGY AND MEDICINE LA English DT Article DE electron magnetic resonance tomography; image reconstruction; artificial neural networks; back propagation; filtered back projection; multiplicative algebraic reconstruction technique ID CLASSIFICATION; SEGMENTATION AB An object-oriented, artificial neural network (ANN) based, application system for reconstruction of two-dimensional spatial images in electron magnetic resonance (EMR) tomography is presented. The standard back propagation algorithm is utilized to train a three-layer sigmoidal feed-forward, supervised, ANN to perform the image reconstruction. The network learns the relationship between the 'ideal' images that are reconstructed using filtered back projection (FBP) technique and the corresponding projection data (sinograms). The input layer of the network is provided with a training set that contains projection data from various phantoms as well as in vivo objects, acquired from an EMR imager. Twenty five different network configurations are investigated to test the ability of the generalization of the network. The trained ANN then reconstructs two-dimensional temporal spatial images that present the distribution of free radicals in biological systems. Image reconstruction by the trained neural network shows better time complexity than the conventional iterative reconstruction algorithms such as multiplicative algebraic reconstruction technique (MART). The network is further explored for image reconstruction from 'noisy' EMR data and the results show better performance than the FBP method. The network is also tested for its ability to reconstruct from limited-angle EMR data set. (c) 2007 Elsevier Ltd. All rights reserved. C1 Madurai Kamaraj Univ, Madurai 625021, Tamil Nadu, India. VHNSN Coll, Dept Comp Sci, Virudunagar, India. NCI, Radiat Biol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. RP Murugesan, R (reprint author), Madurai Kamaraj Univ, Madurai 625021, Tamil Nadu, India. EM rammku@eth.net NR 35 TC 9 Z9 9 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0010-4825 J9 COMPUT BIOL MED JI Comput. Biol. Med. PD OCT PY 2007 VL 37 IS 10 BP 1492 EP 1501 DI 10.1016/j.compbiomed.2007.01.010 PG 10 WC Biology; Computer Science, Interdisciplinary Applications; Engineering, Biomedical; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Computer Science; Engineering; Mathematical & Computational Biology GA 217GZ UT WOS:000249937700017 PM 17362904 ER PT J AU Dear, JW Leelahavanichkul, A Aponte, A Hu, XZ Constant, SL Hewitt, SM Yuen, PST Star, RA AF Dear, James W. Leelahavanichkul, Asada Aponte, Angel Hu, Xuzhen Constant, Stephanie L. Hewitt, Stephen M. Yuen, Peter S. T. Star, Robert A. TI Liver proteomics for therapeutic drug discovery: Inhibition of the cyclophilin receptor CD147 attenuates sepsis-induced acute renal failure SO CRITICAL CARE MEDICINE LA English DT Article DE sepsis; proteins; mice model; multi-organ failure; liver ID S-ADENOSYLMETHIONINE; GEL-ELECTROPHORESIS; AGED MICE; RATS; MODULATION; APOPTOSIS; ENDOTOXIN; METABOLISM; DIFFERENCE; MONOCYTES AB Objective. Sepsis-induced multi-organ failure continues to have a high mortality. The liver is an organ central to the disease pathogenesis. The objective of this study was to identify the liver proteins that change in abundance with sepsis and subsequently identify new drug targets. Design: Proteomic discovery study and drug target validation. For the proteomics study, three biological replicate mice were used per group. Setting: Research institute laboratory. Subjects: Three-month-old C57BL/6 mice. Interventions: We used a mouse model of sepsis based on cecal ligation and puncture, but with fluid and antibiotic resuscitation. Liver proteins that changed in abundance were identified by difference in gel electrophoresis. We compared liver proteins from 6-hr post-cecal ligation and puncture to sham-operated mice ("early proteins") and 24-hr post-cecal ligation and puncture with 6-hr post-cecal ligation and puncture ("late proteins"). Proteins that changed in abundance were identified by tandem mass spectrometry. We then inhibited the receptor for one protein and determined the effect on sepsis-induced organ dysfunction. Results. The liver proteins that changed in abundance after sepsis had a range of functions such as acute phase response, coagulation, endoplasmic reticulum stress, oxidative stress, apoptosis, mitochondrial electron transfer proteins, and nitric oxide metabolism. We found that cyclophilin increased in abundance after cecal ligation and puncture. When the receptor for this protein, CD147, was inhibited, sepsis-induced renal dysfunction was reduced. There was also a significant reduction in serum cytokine production when CD147 was inhibited. Conclusion: By applying proteomics to a clinically relevant mouse model of sepsis, we identified a number of novel proteins that changed in abundance. The inhibition of the receptor for one of these proteins, cyclophilin, attenuated sepsis-induced acute renal failure. The application of proteomics to sepsis research can facilitate the discovery of new therapeutic targets. C1 NIDDKD, Renal Diagnost & Therapeut Unit, NIH, Bethesda, MD 20892 USA. NHLBI, Proteom Core Facil, NIH, Bethesda, MD 20892 USA. NCI, Tissue Array Res Program, Pathol Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. George Washington Univ, Dept Microbiol Immunol & Trop Med, Washington, DC USA. RP Star, RA (reprint author), Univ Edinburgh, Cardiovasc Sci Ctr, Queens Med Res Inst, Edinburgh, Midlothian, Scotland. EM robert_star@nih.gov RI Yuen, Peter/B-1954-2008; OI Yuen, Peter/0000-0001-9557-3909; Hewitt, Stephen/0000-0001-8283-1788 FU Intramural NIH HHS [Z01 DK043403-08, Z01 DK043400-08] NR 36 TC 26 Z9 29 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD OCT PY 2007 VL 35 IS 10 BP 2319 EP 2328 DI 10.1097/01.CCM.0000281858.44387.A2 PG 10 WC Critical Care Medicine SC General & Internal Medicine GA 217HH UT WOS:000249938500013 PM 17944020 ER PT J AU Ghanayem, BI Hoffler, U AF Ghanayem, Burhan I. Hoffler, Undi TI Investigation of xenobiotics metabolism, genotoxicity, and carcinogenicity using Cyp2e1-/-mice SO CURRENT DRUG METABOLISM LA English DT Review ID ETHYL CARBAMATE URETHANE; CYP2E1 KNOCKOUT MICE; CHRONIC ETHANOL-CONSUMPTION; FEMALE B6C3F1 MICE; MOUSE BONE-MARROW; WILD-TYPE MICE; MICROSOMAL EPOXIDE HYDROLASE; CYTOCHROME-P450 2E1 CYP2E1; TANDEM MASS-SPECTROMETRY; CENTRAL-NERVOUS-SYSTEM AB Cytochromes P450 (CYPs) comprise a number of enzyme subfamilies responsible for the oxidative metabolism of a wide range of therapeutic agents, environmental toxicants mutagens, and carcinogens. In particular, cytochrome P450 2E1 (CYP2E1) is implicated in the oxidative bioactivation of a variety of small hydrophobic chemicals including a number of epoxide-forming drugs and environmentally important toxicants including urethane, acrylamide, acrylonitrile, benzene, vinyl chloride, styrene, I-bromopropane, trichloroethylene, dichloroethylene, acetaminophen, and butadiene. Until recently, chemical modulators (inducers and inhibitors) were used in order to characterize the enzymatic basis of xenobiotic metabolism and the relationships between CYP-mediated bioactivation and chemical- induced toxicity/carcinogen icity. With the advent of genetically engineered knockout mice, the ability to evaluate the roles of specific CYPs in the metabolism of xenobiotics has become more attainable. The main focus of the current review is to present studies that characterized the enzymatic, metabolic, and molecular mechanisms of toxicity, genotoxicity, and carcinogenicity of various xenobiotics using Cyp2e1-/- mice. Data presented in this review demonstrated that the most comprehensive studies using Cyp2e1-/- mice, encompassing the entire paradigm of metabolism to toxicity, genotoxicity, and carcinogenicity were possible when a substrate was primarily metabolized via CYP2E1 (e.g. urethane and acrylamide). In contrast, when multiple CYP enzymes were prevalent in the oxidation of a particular substrate (e.g.: trichloroethylene, methacrylonitrile, crotononitrile), investigating the relationships between oxidative metabolism and biological activity became more complicated and required the use of chemical modulators. In conclusion, the current review showed that Cyp2e1-/- mice are a valuable animal model for the investigation of the metabolic and molecular basis of toxicity, genotoxicity, and carcinogenicity of xenobiotics. C1 Natl Inst Environm Hlth Sci, Natl Inst Hlth, Natl Toxicol Program, Lab Pharmacol & Chem,Metab & Exposure Markers, Res Triangle Pk, NC 27709 USA. RP Ghanayem, BI (reprint author), Natl Inst Environm Hlth Sci, Natl Inst Hlth, Natl Toxicol Program, Lab Pharmacol & Chem,Metab & Exposure Markers, Res Triangle Pk, NC 27709 USA. EM Ghanayem@niehs.nih.gov FU Intramural NIH HHS NR 253 TC 28 Z9 38 U1 2 U2 12 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-2002 J9 CURR DRUG METAB JI Curr. Drug Metab. PD OCT PY 2007 VL 8 IS 7 BP 728 EP 749 DI 10.2174/138920007782109760 PG 22 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 216GZ UT WOS:000249867800010 PM 17979661 ER PT J AU Muul, LM Candotti, F AF Muul, Linda Mesler Candotti, Fabio TI Immune responses to gene-modified T cells SO CURRENT GENE THERAPY LA English DT Review ID GREEN FLUORESCENT PROTEIN; GRAFT-VERSUS-LEUKEMIA; BONE-MARROW-TRANSPLANTATION; FETAL CALF SERUM; ADENOSINE-DEAMINASE DEFICIENCY; PERIPHERAL-BLOOD LYMPHOCYTES; SUICIDE-GENE; IN-VIVO; HOST-DISEASE; RETROVIRAL VECTOR AB Gene-modified T cells were the first gene therapy tool used in clinical gene transfer trials. After the first applications in immunodeficiency diseases, T cell gene therapy has been extended to HIV infection and cancer. The primary obstacle to successful T cell gene therapy has proven to be the robust immune responses elicited by the gene-modified T cells even in severely immunosuppressed patients. The potent antibody and cytotoxic immune responses have interfered with the expression and persistence of the therapeutic transgene. In this review we will address each of the components of T cell gene therapy-culture conditions, vector, and transgene-that have elicited these immune responses and the strategies used to minimize them. C1 [Muul, Linda Mesler; Candotti, Fabio] Natl Inst Hlth, NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. RP Muul, LM (reprint author), Natl Inst Hlth, NHGRI, Genet & Mol Biol Branch, 10 Ctr Dr,Bldg 10 CRC,Rm 5-5270, Bethesda, MD 20892 USA. EM muull@mail.nih.gov FU Intramural NIH HHS NR 75 TC 10 Z9 10 U1 1 U2 3 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1566-5232 J9 CURR GENE THER JI Curr. Gene Ther. PD OCT PY 2007 VL 7 IS 5 BP 361 EP 368 DI 10.2174/156652307782151489 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 242OL UT WOS:000251735000008 PM 17979682 ER PT J AU Hodges, MG Keane-Myers, AM AF Hodges, Marcus G. Keane-Myers, Andrea M. TI Classification of ocular allergy SO CURRENT OPINION IN ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Review DE allergic conjunctivitis; classification; conjunctiva; ocular allergy ID EYE DISEASE; T-CELLS; CONJUNCTIVITIS; INFLAMMATION; SUPPRESS; BLEPHAROCONJUNCTIVITIS; MICROSCOPY; PROTEINS; MODEL AB Purpose of review The purpose of this article is to summarize the clinical presentations associated with the classification of ocular allergy. This article also serves to summarize recent findings of pathophysiological mechanisms associated with ocular allergy and to highlight recently improved diagnostic methods for ocular allergic inflammation. Recent findings The term allergic conjunctivitis may not sufficiently describe all forms of allergic eye disease, thus a new classification system is desirable, preferably derived from the varied pathophysiological mechanisms operating in the different forms of ocular allergy. Recent published material has further characterized the roles that inflammatory and structural cells have in ocular allergic inflammation. Improved diagnostic methods have also been developed to assess the underlying causes of ocular allergy. Summary The underlying immune responses of ocular allergies are complex, indicating the critical need to understand the pathophysiology behind these diseases. Extensive research over the past several years has provided valuable insight into understanding the pathophysiology associated with the different forms of allergic conjunctivitis. Further clarification of the mechanisms associated with different forms of ocular allergy is essential for improved methods of classification, diagnosis, and treatment. C1 NIH, Natl Inst Allergy & Infect Dis, Rockville, MD USA. RP Keane-Myers, AM (reprint author), NIH, Natl Inst Allergy & Infect Dis, Rockville, MD USA. EM akeane@niaid.nih.gov NR 35 TC 16 Z9 20 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1528-4050 J9 CURR OPIN ALLERGY CL JI Curr. Opin. Allergy Clin. Immunol. PD OCT PY 2007 VL 7 IS 5 BP 424 EP 428 PG 5 WC Allergy; Immunology SC Allergy; Immunology GA 216XE UT WOS:000249911500010 PM 17873583 ER PT J AU Wallace, JA Felsenfeld, G AF Wallace, Julie A. Felsenfeld, Gary TI We gather together: insulators and genome organization SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Review ID BETA-GLOBIN DOMAIN; RNA-POLYMERASE-II; ENHANCER-BLOCKING; CHROMATIN INSULATOR; PROTEIN CTCF; NUCLEAR-ORGANIZATION; BINDING FACTOR; TRANSCRIPTION; SITES; METHYLATION AB When placed between an enhancer and promoter, certain DNA sequence elements inhibit enhancer-stimulated gene expression. The best characterized of these enhancer-blocking insulators, gypsy in Drosophila and the CTCF-bincling element in vertebrates and flies, stabilize contacts between distant genomic regulatory sites leading to the formation of loop domains. Current results show that CTCF mediates long-range contacts in the mouse P-globin locus and at the Igf2/H19-imprinted locus. Recently described active chromatin hubs and transcription factories also involve long-range interactions; it is likely that CTCF interferes with their formation when acting as an insulator. The properties of CTCF, and its newly described genomic distribution, suggest that it may play an important role in large-scale nuclear architecture, perhaps mediated by the co-factors with which it interacts in vivo. C1 NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Felsenfeld, G (reprint author), NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM gary.felsenfeld@nih.gov FU Intramural NIH HHS [Z01 DK034001-42] NR 46 TC 277 Z9 287 U1 2 U2 24 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD OCT PY 2007 VL 17 IS 5 BP 400 EP 407 DI 10.1016/j.gde.2007.08.005 PG 8 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 237CE UT WOS:000251349600006 PM 17913488 ER PT J AU Soutoglou, E Misteli, T AF Soutoglou, Evi Misteli, Tom TI Mobility and immobility of chromatin in transcription and genome stability SO CURRENT OPINION IN GENETICS & DEVELOPMENT LA English DT Review ID DOUBLE-STRAND BREAKS; INTERPHASE NUCLEI; MAMMALIAN-CELLS; EARLY G1; IN-VIVO; DYNAMICS; ORGANIZATION; COMPLEX; MITOSIS; GENES AB Chromatin is increasingly recognized as a highly dynamic entity. Chromosome sites in lower and higher eukaryotes undergo frequent, rapid, and constrained local motion and occasional slow, long-range movements. Recent observations have revealed some of the functional relevance of chromatin mobility. Paradoxically, both the mobility and immobility of chromatin appear to have functional consequences: Local diffusional motion of chromatin is important in gene regulation, but global chromatin immobility plays a key role in maintenance of genomic stability. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov FU Intramural NIH HHS [Z01 BC010309-08] NR 38 TC 58 Z9 59 U1 0 U2 3 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-437X J9 CURR OPIN GENET DEV JI Curr. Opin. Genet. Dev. PD OCT PY 2007 VL 17 IS 5 BP 435 EP 442 DI 10.1016/j.gde.2007.08.004 PG 8 WC Cell Biology; Genetics & Heredity SC Cell Biology; Genetics & Heredity GA 237CE UT WOS:000251349600011 PM 17905579 ER PT J AU Saul, A AF Saul, Allan TI Mosquito stage, transmission blocking vaccines for malaria SO CURRENT OPINION IN INFECTIOUS DISEASES LA English DT Review DE gamete; malaria; mosquito; ookinete; plasmodium; transmission blocking vaccine ID PARASITE PLASMODIUM-FALCIPARUM; DOMAIN-RELATED PROTEIN; SURFACE PROTEIN; OOKINETE SURFACE; MINIMAL VARIATION; VIVAX MALARIA; SEXUAL-STAGE; MONOCLONAL-ANTIBODY; ANOPHELES-GAMBIAE; TARGET ANTIGENS AB Purpose of review This review highlights progress made in the development of vaccines aimed at the stages of malaria parasites found in mosquitoes that block the transmission of malaria within a community. Recent findings Substantial progress has been made on the production and characterization of the leading candidates P25 and P28 from Plasmodium falciparum and P. vivax. Immunogenicity data have been obtained for P25 in humans that showed significant transmission blocking activity and further advances in formulation should boost this activity, The completion of the malaria genome and ongoing proteomics identified further candidate antigens now entering development. Summary Recent advances increase confidence that a mosquito stage transmission blocking malaria vaccine will be feasible. C1 NIAID, Lab Malaria & Vector Biol, NIH, Rockville, MD 20852 USA. RP Saul, A (reprint author), NIAID, Lab Malaria & Vector Biol, NIH, 12735 Twinbrook Pkwy,Twinbrook 3 Room 1E-04, Rockville, MD 20852 USA. EM ASaul@niaid.nih.gov RI Saul, Allan/I-6968-2013 OI Saul, Allan/0000-0003-0665-4091 FU Intramural NIH HHS NR 70 TC 55 Z9 59 U1 1 U2 13 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7375 J9 CURR OPIN INFECT DIS JI Curr. Opin. Infect. Dis. PD OCT PY 2007 VL 20 IS 5 BP 476 EP 481 DI 10.1097/QCO.0b013e3282a95e12 PG 6 WC Infectious Diseases SC Infectious Diseases GA 217SC UT WOS:000249966600005 PM 17762780 ER PT J AU Luan, H White, BH AF Luan, Haojiang White, Benjamin H. TI Combinatorial methods for refined neuronal gene targeting SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Article ID SITE-SPECIFIC RECOMBINATION; TRANSGENE EXPRESSION; CRE RECOMBINASE; MUSHROOM BODY; IN-VIVO; DROSOPHILA; PROTEIN; SYSTEM; MOUSE; ACTIVATION AB Methods for the selective and reproducible expression of genetically encoded tools in targeted subsets of cells are required to facilitate studies of neuronal development, connectivity, and function in living animals. In the absence of techniques for synthesizing promoters that target defined cell groups, current methods exploit the regulatory elements of endogenous genes to achieve specificity of transgene expression. However, single promoters often have expression patterns too broad to pinpoint the functional roles of specific neurons. In this review, we describe emerging combinatorial techniques that make transgene expression contingent not upon a single promoter, but upon two or more promoters. Although only a few such techniques are currently available, recent developments promise rapid growth in this area in the coming years. C1 [Luan, Haojiang; White, Benjamin H.] NIMH, Mol Biol Lab, Bethesda, MD 20892 USA. RP Luan, H (reprint author), NIMH, Mol Biol Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM luanh@mail.nih.gov; benjaminwhite@mail.nih.gov FU Intramural NIH HHS; NIMH NIH HHS [1Z01MH002800-04] NR 50 TC 23 Z9 23 U1 0 U2 1 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD OCT PY 2007 VL 17 IS 5 BP 572 EP 580 DI 10.1016/j.conb.2007.10.001 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 257YH UT WOS:000252835100011 PM 18024005 ER PT J AU Subramaniam, S Bartesaghi, A Liu, J Bennett, AE Sougrat, R AF Subramaniam, Sriram Bartesaghi, Alberto Liu, Jun Bennett, Adam E. Sougrat, Rachid TI Electron tomography of viruses SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Review ID HERPES-SIMPLEX-VIRUS; CRYOELECTRON TOMOGRAPHY; VACCINIA-VIRUS; 3-DIMENSIONAL STRUCTURE; IN-SITU; PROTEIN; CORE; MICROSCOPY; VISUALIZATION; REVEALS AB Understanding the molecular architectures of enveloped and complex viruses is a challenging frontier in structural biology. In these viruses, the structural and compositional variation from one viral particle to another generally precludes the use of either crystallization or image averaging procedures that have been successfully implemented in the past for highly symmetric viruses. While advances in cryo electron tomography of unstained specimens provide new opportunities for identification and molecular averaging of individual subcomponents such as the surface glycoprotein spikes on purified viruses, electron tomography of stained and plunge-frozen cells is being used to visualize the cellular context of viral entry and replication. Here, we review recent developments in both areas as they relate to our understanding of the biology of heterogeneous and pleiomorphic viruses. C1 NCI, NIH, Ctr Canc Res, Cell Biol Lab, Bethesda, MD 20892 USA. RP Subramaniam, S (reprint author), NCI, NIH, Ctr Canc Res, Cell Biol Lab, Bethesda, MD 20892 USA. EM ssl@nih.gov OI Sougrat, Rachid/0000-0001-6476-1886 FU Intramural NIH HHS [Z01 BC010278-09] NR 36 TC 32 Z9 33 U1 0 U2 8 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD OCT PY 2007 VL 17 IS 5 BP 596 EP 602 DI 10.1016/j.sbi.2007.09.009 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 237BR UT WOS:000251348200015 PM 17964134 ER PT J AU Clore, GM Tang, C Iwahara, J AF Clore, G. Marius Tang, Chun Iwahara, Junji TI Elucidating transient macromolecular interactions using paramagnetic relaxation enhancement SO CURRENT OPINION IN STRUCTURAL BIOLOGY LA English DT Review ID GLOBAL FOLD DETERMINATION; LONG-RANGE STRUCTURE; SITE-DIRECTED SPIN; NMR STRUCTURE; STRUCTURAL-CHARACTERIZATION; STRUCTURE REFINEMENT; ALPHA-SYNUCLEIN; CYTOCHROME-C; PROTEIN; BINDING AB Recent advances in the use of paramagnetic relaxation enhancement (PRE) in structure refinement and in the analysis of transient dynamic processes involved in macromolecular complex formation are presented. In the slow exchange regime, we show, using the SRY/DNA complex as an example, that the PRE provides a powerful tool that can lead to significant increases in the reliability and accuracy of NMR structure determinations. Refinement necessitates the use of an ensemble representation of the paramagnetic center and a model-free extension of the Solomon-Bloembergen equations. In the fast exchange regime, the PRE provides insight into dynamic processes and the existence of transient, low population intermediate species. The PRE allows one to characterize dynamic nonspecific binding of a protein to DNA; to directly demonstrate that the search process whereby a transcription factor locates its specific DNA target site involves both intramolecular (sliding) and intermolecular (hopping and intersegment transfer) translocation; and to detect and visualize the distribution of an ensemble of transient encounter complexes in protein-protein association. C1 NIDDK, NIH, Chem Phys Lab, Bethesda, MD 20892 USA. RP Iwahara, J (reprint author), Univ Texas Med Branch, Sealy Ctr Struct Biol, 301 Univ Blvd, Galveston, TX 77555 USA. EM mariusc@intra.niddk.nih.gov RI Clore, G. Marius/A-3511-2008; OI Clore, G. Marius/0000-0003-3809-1027; Iwahara, Junji/0000-0003-4732-2173 FU Intramural NIH HHS [Z01 DK029023-17] NR 58 TC 126 Z9 128 U1 3 U2 39 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-440X J9 CURR OPIN STRUC BIOL JI Curr. Opin. Struct. Biol. PD OCT PY 2007 VL 17 IS 5 BP 603 EP 616 DI 10.1016/j.sbi.2007.08.013 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 237BR UT WOS:000251348200016 PM 17913493 ER PT J AU Gabriele, L Ozato, K AF Gabriele, Lucia Ozato, Keiko TI The role of the interferon regulatory factor (IRF) family in dendritic cell development and function SO CYTOKINE & GROWTH FACTOR REVIEWS LA English DT Review DE IRF; dendritic cells; innate immunity; host defence; interferon; cytokines ID TOLL-LIKE RECEPTORS; VIRAL-INFECTION; IN-VITRO; DIFFERENTIAL EXPRESSION; TRANSCRIPTION FACTORS; ANTIVIRAL RESPONSE; ADAPTIVE IMMUNITY; ALPHA INDUCTION; GENE INDUCTION; MACROPHAGES AB Dendritic cells (DCs) are powerful sensors of foreign pathogens as well as cancer cells and provide the first line of defence against infection. They also serve as a major link between innate and adaptive immunity. Immature DCs respond to incoming danger signals and undergo maturation to produce high levels of proinflammatory cytokines including type I interferons (IFNs) to establish innate immunity. They then present antigens to T lymphocytes to stimulate lasting specific immune responses. Recent studies point to the importance of DCs in the induction of peripheral tolerance. Transcription factors of the IRF family have emerged as crucial controllers of many aspects of DC activity, playing an essential role in the establishment of early innate immunity. Furthermore, eight of the nine members of the IRF family have been shown to control either the differentiation and/or the functional activities of DCs. In this review, we focus on three aspects of DC properties that are under the control of IRFs: (1) the development and differentiation, (2) maturation in response to toll-like receptor (TLR) signalling and the production of anti-microbial cytokines, and (3) activation and expansion of lymphocytes to generate protective or tolerogenic immune responses. (c) 2007 Elsevier Ltd. All rights reserved. C1 Ist Super Sanita, Dept Cell Biol & Neurosci, I-00161 Rome, Italy. Natl Inst Child Hlth & Human Dev, Natl Inst Hlth, Lab Mol Growth Regulat, Bethesda, MD 20892 USA. RP Gabriele, L (reprint author), Ist Super Sanita, Dept Cell Biol & Neurosci, Viale Regina Elena 299, I-00161 Rome, Italy. EM lucia.gabriele@iss.it; ozatok@nih.gov OI Gabriele, Lucia/0000-0002-1483-866X FU Intramural NIH HHS NR 65 TC 44 Z9 47 U1 0 U2 6 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6101 J9 CYTOKINE GROWTH F R JI Cytokine Growth Factor Rev. PD OCT-DEC PY 2007 VL 18 IS 5-6 BP 503 EP 510 DI 10.1016/j.cytogfr.2007.06.008 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 216GL UT WOS:000249866400020 PM 17702640 ER PT J AU Pei, WH Noushmehr, H Costa, J Ouspenskaia, MV Elkahloun, AG Feldman, B AF Pei, Wuhong Noushmehr, Houtan Costa, Justin Ouspenskaia, Maia V. Elkahloun, Abdel G. Feldman, Benjamin TI An early requirement for maternal FoxH1 during zebrafish gastrulation SO DEVELOPMENTAL BIOLOGY LA English DT Article DE FoxH1; gastrulation; enveloping layer; keratin ID TGF-BETA; VERTEBRATE GASTRULATION; ASYMMETRIC EXPRESSION; MESODERM INDUCERS; GENE; EMBRYOS; MOUSE; EMBRYOGENESIS; SPECIFICATION; SIGNALS AB The Forkhead Box HI (FoxH1) protein is a co-transcription factor recruited by phosphorylated Smad2 downstream of several TGF beta s, including Nodal-related proteins. We have reassessed the function of zebrafish FoxH1 using antisense morpholino oligonucleotides (MOs). MOs targeting translation offoxH1 disrupt embryonic epiboly movements during gastrulation and cause death on the first day of development. The FoxH1 morphant phenotype is much more severe than that of zebrafish carrying foxh1/schmalspur (sur) DNA-binding domain mutations, FoxH1 splice-blocking morphants or other Nodal pathway mutants, and it cannot be altered by concomitant perturbations in Nodal signaling. Apart from disrupting epiboly, FoxH1 MO treatment disrupts convergence and internalization movements. Late gastrula-stage FoxH1 morphants exhibit delayed mesoderm and endoderm marker gene expression and failed patterning of the central nervous system. Probing FoxH1 morphant RNA by microarray, we identified a cohort of five keratin genes - cyt1, cyt2, krt4, krt8 and krt18 - that are normally transcribed in the embryo's enveloping layer (EVL) and which have significantly reduced expression in FoxH1-depleted embryos. Simultaneously disrupting these keratins with a mixture of MOs reproduces the FoxH1 morphant phenotype. Our studies thus point to an essential role for maternal FoxH1 and downstream keratins during gastrulation that is epistatic to Nodal signaling. (C) 2007 Elsevier Inc. All rights reserved. C1 Natl Ctr Human Genome Res, Med Genet Branch, NIH, Bethesda, MD 20892 USA. RP Feldman, B (reprint author), Natl Ctr Human Genome Res, Med Genet Branch, NIH, 9000 Rockville Pike,Bldg 35,Room 1B 205, Bethesda, MD 20892 USA. EM bfeldman@mail.nih.gov RI Noushmehr, Houtan/C-9692-2013; OI Noushmehr, Houtan/0000-0003-4051-8114; Feldman, Benjamin/0000-0003-4838-8641 FU Intramural NIH HHS [Z01 HG200309-05, Z99 HG999999] NR 53 TC 25 Z9 26 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD OCT 1 PY 2007 VL 310 IS 1 BP 10 EP 22 DI 10.1016/j.ydbio.2007.07.011 PG 13 WC Developmental Biology SC Developmental Biology GA 219JF UT WOS:000250080000002 PM 17719025 ER PT J AU Kuzin, A Kundu, M Brody, T Odenwald, WF AF Kuzin, Alexander Kundu, Mukta Brody, Thomas Odenwald, Ward F. TI The Drosophila nerfin-1 mRNA requires multiple microRNAs to regulate its spatial and temporal translation dynamics in the developing nervous system SO DEVELOPMENTAL BIOLOGY LA English DT Article DE MicroRNAs; post-transcriptional regulation; nervous system development ID FINGER TRANSCRIPTION FACTOR; ELEMENT VECTORS; CELL FATE; GENES; IDENTIFICATION; SPECIFICATION; EXPRESSION; PROTEINS; NERFIN-1; ELEGANS AB The mRNA encoding the Drosophila Zn-finger transcription factor Nerfin-1, required for CNS axon pathfinding events, is Subject to post-transcriptional silencing. Although neifin-1 mRNA is expressed in many neural precursor cells including all early delaminating CNS neuroblasts, the encoded Nerfin-1 protein is detected only in the nuclei of neural precursors that divide just once to generate neurons and then only transiently in nascent neurons. Using a nerfin-1 promoter-controlled reporter transgene, replacement of the nerfin-1 3' UTR with the viral SV-40 3' UTR releases the neuroblast translational block and prolongs reporter protein expression in neurons. Comparative genomics analysis reveals that the neifin-1 mRNA 3' UTR contains multiple highly conserved sequence blocks that either harbor and/or overlap 21 predicted binding sites for 18 different microRNAs. To determine the functional significance of these micro RNA-binding sites and less conserved microRNA target sites, we have studied their ability to block or limit the expression ofreporter protein in nerfin-1-expressing cells during embryonic development. Our results indicate that no single microRNA is sufficient to fully inhibit protein expression but rather multiple microRNAs that target different binding sites are required to block ectopic protein expression in neural precursor cells and temporally restrict expression in neurons. Taken together, these results suggest that multiple microRNAs play a cooperative role in the post-transcriptional regulation of neifin-1 mRNA, and the high degree of microRNA-binding site evolutionary conservation indicates that all members of the Drosophila genus employ a similar strategy to regulate the onset and extinction dynamics of Nerfin-1 expression. Published by Elsevier Inc. C1 NINDS, Neural Cell Fate Determinants Sect, NIH, Bethesda, MD 20892 USA. RP Kuzin, A (reprint author), NINDS, Neural Cell Fate Determinants Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. EM Alex.Kuzin@ninds.nih.gov; ward@codon.nih.gov FU Intramural NIH HHS [Z01 NS002820-18] NR 35 TC 16 Z9 16 U1 1 U2 2 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 OCT 1 PY 2007 VL 310 IS 1 BP 35 EP 43 DI 10.1016/j.ydbio.2007.07.012 PG 9 WC Developmental Biology SC Developmental Biology GA 219JF UT WOS:000250080000004 PM 17714701 ER PT J AU Fueger, PT Lee-Young, RS Shearer, J Bracy, DP Heikkinen, S Laakso, M Rottman, JN Wasserman, DH AF Fueger, Patrick T. Lee-Young, Robert S. Shearer, Jane Bracy, Deanna P. Heikkinen, Sami Laakso, Markku Rottman, Jeffrey N. Wasserman, David H. TI Phosphorylation barriers to skeletal and cardiac muscle glucose uptakes in high-fat-fed mice - Studies in mice with a 50% reduction of hexokinase II SO DIABETES LA English DT Article ID CONSCIOUS MOUSE; C57BL/6J MICE; INSULIN; EXERCISE; TRANSPORT; RAT; METABOLISM; CAPACITY; OVEREXPRESSION; TRANSLOCATION AB OBJECTIVE-Muscle glucose uptake (MGU) is regulated by glucose delivery to, transport into, and phosphorylation within muscle. The aim of this study was to determine the role of limitations in glucose phosphorylation in the control of MGU during either physiological insulin stimulation (4 mU center dot kg(-1) center dot min(-1)) or exercise with chow or high-fat feeding. RESEARCH DESIGN AND METHODS-C57BL/6J mice with (HK+/-) and without (WT) a 50% hexokinase (HK) II deletion were fed chow or high-fat diets and studied at 4 months of age during a 120-min insulin clamp or 30 min of treadmill exercise (n = 8-10 mice/group). 2-deoxy [H-3]glucose was used to measure R,, an index of MGU. RESULTS-Body weight and fasting arterial glucose were increased by high-fat feeding and partial HK II knockout (HK+/-). Both high-fat feeding and partial HK II knockout independently created fasting hyperinsulinemia, a response that was increased synergistically with combined high-fat feeding and HK II knockout. Whole-body insulin action was suppressed by similar to 25% with either high-fat feeding or partial HK II knockout alone but by >50% when the two were combined. Insulin-stimulated R-g was modestly impaired by high-fat feeding and partial HK II knockout independently (-15-20%) but markedly reduced by the two together (similar to 40-50%). Exercise-stimulated R-g was reduced by similar to 50% with high-fat feeding and partial HK II knockout alone and was not attenuated further by combining the two. CONCLUSIONS-In summary, impairments in whole-body metabolism and MGU due to high-fat feeding and partial HK II knockout combined during insulin stimulation are additive. In contrast, combining high-fat feeding and partial HK II knockout during exercise causes no greater impairment in MGU than the two manipulations independently. This suggests that MGU is impaired during exercise by high-fat feeding due to, in large part, a limitation in glucose phosphorylation. Together, these studies show that the high-fat-fed mouse is characterized by defects at multiple steps of the MGU system that are precipitated by different physiological conditions. C1 Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27704 USA. Vanderbilt Univ, Sch Med, Dept Mol Physiol & Biophys, Nashville, TN 37212 USA. Vanderbilt Univ, Sch Med, Mouse Metab Phenotyping Ctr, Nashville, TN 37212 USA. Univ Kuopio, AI Virtanen Inst, FIN-70211 Kuopio, Finland. Univ Kuopio, Dept Biochem & Biotechnol, FIN-70211 Kuopio, Finland. Univ Kuopio, Dept Med, SF-70210 Kuopio, Finland. Vanderbilt Univ, Sch Med, Dept Internal Med, Nashville, TN 37212 USA. RP Fueger, PT (reprint author), Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, 4321 Med Pk Dr,Suite 200, Durham, NC 27704 USA. EM patrick.fueger@duke.edu RI Fueger, Patrick/G-8956-2013; Heikkinen, Sami/L-1460-2013 OI Heikkinen, Sami/0000-0002-6083-2402 FU NIDDK NIH HHS [R01 DK-54902, U24 DK-59637] NR 31 TC 22 Z9 22 U1 0 U2 3 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD OCT PY 2007 VL 56 IS 10 BP 2476 EP 2484 DI 10.2337/db07-0532 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 218UQ UT WOS:000250040900009 PM 17639019 ER PT J AU Nansel, TR Iannotti, R Simons-Morton, BG Cox, C Plotnick, LP Clark, LM Zeitzoff, L AF Nansel, Tonja R. Iannotti, Ronaldj. Simons-Morton, Bruce G. Cox, Christopher Plotnick, Leslie P. Clark, Loretta M. Zeitzoff, Linda TI Diabetes personal trainer outcomes - Sthort-term and 1-year outcomes of a diabetes personal trainer intervention among youth with type 1 diabets SO DIABETES CARE LA English DT Article ID SELF-MANAGEMENT; METABOLIC-CONTROL; GLYCEMIC CONTROL; ADOLESCENTS; CHILDREN; ADHERENCE; MELLITUS; EFFICACY; GLUCOSE; CARE AB OBJECTIVE - To assess the social-cognitive, behavioral, and physiological outcomes of a self-management intervention for youth with type I diabetes. RESEARCH DESIGN AND METHODS - A total of 81 youth with type I diabetes aged 11-16 years were randomized to usual care versus a "diabetes personal trainer" intervention, consisting of six self-monitoring, goal-setting, and problem-solving sessions with trained nonprofessionals, Assessments were completed at baseline and multiple follow-up intervals. AIC data were obtained from medical records. ANCOVA adjusting for age and baseline values were conducted for each outcome, RESULTS - At both short-term and 1-year follow-up, there was a trend for an overall intervention effect on AIC (short-term F = 3.71, P = 0.06; 1-year F = 3.79, P = 0.06) and a significant intervention-by-age interaction, indicating a great effect among older than younger youth (short-term F = 4.78, P = 0.03; 1-year F = 4.53, P = 0.04). Subgroup analyses demonstrated no treatment group difference among younger youth but a significant difference among the older youth. No treatment group differences in parent or youth report of adherence were observed. CONCLUSIONS - The diabetes personal trainer intervention demonstrated significant effects in AIC among middle adolescents. C1 Natl Inst Child Hlth & Human Dev, Natl Inst Hlth, Dept Hlth & Human Serv, Div Epidemiol Stat & Prevent Res, Bethesda, MD USA. Johns Hopkins Med Ctr, Dept Pediat Endocrinol, Baltimore, MD USA. Mt Washington Pediat Hosp, Diabet Clin, Baltimore, MD USA. RP Nansel, TR (reprint author), 6100 Executive Blvd,Rm 7B13R, Bethesda, MD 20892 USA. EM nanselt@mail.nih.gov OI Nansel, Tonja/0000-0002-8298-7595; Simons-Morton, Bruce/0000-0003-1099-6617 FU Intramural NIH HHS [Z99 HD999999] NR 37 TC 40 Z9 43 U1 1 U2 13 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD OCT PY 2007 VL 30 IS 10 BP 2471 EP 2477 DI 10.2337/dc06-2621 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 221JN UT WOS:000250223400008 PM 17620445 ER PT J AU Meigs, JB Larson, MG Fox, CS Keaney, JF Vasan, RS Benjamin, EJ AF Meigs, James B. Larson, Martin G. Fox, Caroline S. Keaney, John F., Jr. Vasan, Ramachandran S. Benjamin, Emelia J. TI Association of oxidative stress, insulin resistance, and diabetes risk phenotypes - The framingham offspring study SO DIABETES CARE LA English DT Article ID ACTIVATED SIGNALING PATHWAYS; ENDOTHELIAL DYSFUNCTION; METABOLIC SYNDROME; LIPID-PEROXIDATION; GLUCOSE; MARKERS; OBESITY; MYELOPEROXIDASE; MELLITUS; DISEASE AB OBJECTIVE - Systemic oxidative stress causes insulin resistance in rodents. We tested the hypothesis that oxidative stress and insulin resistance are associated in humans. RESEARCH DESIGN AND METHODS - We used cross-sectional data from 2,002 nondiabetic subjects of the community-based Framingham Offspring Study. We measured insulin resistance with the homeostasis model and defined categorical insulin resistance as oxidative stress using the ratio of urine 8-epi-prostaglandin F-2 alpha (8-epi-PGF(2 alpha)) to creatinine and used age- and sex-adjusted regression models to test the association of oxidative stress with insulin resistance in individuals without diabetes and among subgroups at elevated risk of diabetes. RESULTS - Across 8-epi-PGF(2 alpha)/creatinine tertiles, the prevalence of insulin resistance increased (18.0 and 29.4% for the first, second, and third tertiles, respectively; P < 0.0001), as did mean levels of HOMA-IR (3.28,3.83, and 4.06 units; P < 0.0001). The insulin resistanceoxidative stress association was attenuated by additional adjustment for BMI (P = 0.06 across tertiles for insulin resistance prevalence; P = 0.004 for mean HOMA-IR). Twenty-six percent of participants were obese (BMI :30 kg/m(2)), 39% had metabolic syndrome (according to the Adult Treatment Panel III definition), and 37% had impaired fasting glucose (IFG) (fasting glucose 5.6-6.9 mmol/l). Among 528 obese participants, respectively, insulin resistance prevalence was 41.3, 60.6, and 54.2% across 8-epi-PGF(2 alpha)/creatinine tertiles (P = 0.005); among 781 subjects with metabolic syndrome, insulin resistance prevalence was 41.3, 56.7, and 51.7% (P = 0.0025); and among 749 subjects with IFG, insulin resistance prevalence was 39.6, 47.2, and 51.6% (P = 0.04). CONCLUSIONS - Systemic oxidative stress is associated with insulin resistance in individuals at average or elevated risk of diabetes even after accounting for BMI. C1 Harvard Med Sch, Massachusetts Gen Hosp, Dept Med, Boston, MA USA. Boston Univ, Dept Math & Stat, Boston, MA USA. Natl Heart Lung Blood Inst, Framingham Heart Study, Framingham, MA USA. Harvard Med Sch, Brigham & Womens Hosp, Div Endocrinol Diabet & Hypertens, Boston, MA USA. Univ Massachusetts, Sch Med, Div Cardiovasc Med, Worcester, MA USA. Whitaker Cardiovasc Inst, Evans Dept Med, Boston, MA USA. Boston Univ, Sch Med, Prevent Med Sect, Boston, MA USA. RP Meigs, JB (reprint author), Massachusetts Gen Hosp, Div Gen Med, 50 Staniford St,9th Floor, Boston, MA 02114 USA. EM jmeigs@partners.org OI Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [2K24-HL-04334, HL076784, HL64753, HL71039, N01 HV 28178, N01-HC-25195]; NIA NIH HHS [AG028321] NR 47 TC 96 Z9 117 U1 0 U2 5 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD OCT PY 2007 VL 30 IS 10 BP 2529 EP 2535 DI 10.2337/dc07-0817 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 221JN UT WOS:000250223400022 PM 17586736 ER PT J AU Maahs, DM Snively, BM Bell, RA Dolan, L Hirsch, I Imperatore, G Linder, B Marcovina, SM Mayer-Davis, EJ Pettitt, DJ Rodriguez, BL Dabelea, D AF Maahs, David M. Snively, Beverly M. Bell, Ronny A. Dolan, Lawrence Hirsch, Irl Imperatore, Giuseppina Linder, Barbara Marcovina, Santica M. Mayer-Davis, Elizabeth J. Pettitt, David J. Rodriguez, Beatriz L. Dabelea, Dana TI Higher prevalence of elevated albumin excretion in youth with type 2 than type I diabetes SO DIABETES CARE LA English DT Article ID RISK-FACTORS; INSULIN-RESISTANCE; NATURAL-HISTORY; RENAL-DISEASE; PIMA-INDIANS; MICROALBUMINURIA; ADOLESCENTS; CHILDREN; MELLITUS; YOUNG AB OBJECTIVE - To estimate the prevalence of an elevated albumin-to-creatinine ratio (ACR) (>= 30 mu g/mg) among youth with type 1 or type 2 diabetes and to identify factors associated with elevated ACR and their effect on the relationship between elevated ACR and type of diabetes. RESEARCH DESIGN AND METHODS - Cross-sectional data were analyzed from 259 participants with onset of diabetes at < 20 years of age in the SEARCH for Diabetes in 3, Youth, a multicenter observational study of diabetes in youth. Multiple logistic regression was used to explore determinants of elevated ACR and factors accounting for differences in this prevalence between type 2 and type I diabetes. RESULTS- The prevalence of elevated ACR was 9.2% in type 1 and 22.2% in type 2 diabetes (prevalence ratio 2.4 [95% Cl 1.9-3.0]; P < 0.0001). In multiple logistic regression analysis, female sex, ACR and triglyceride values, hypertension, and type of diabetes (type 2 versus type 1) were significantly associated with elevated ACR. Adjustment for variables related to insulin resistance (obesity, hypertension, dyslipidemia, and inflammation)attenuated,but did not comletely explain, the association of diabetes type wit CONCLUSIONS - Youth with type 2 diabetes have a higher prevalence of elevated ACR than youth with type I diabetes, in an association that apparently does not completely depend on age, duration of diabetes, race/ethnicity, sex, level of glycemic control, or features of insulin resistance. C1 Univ Colorado, Hlth Sci Ctr, Barbara Davis Ctr Childhood Diabet, Aurora, CO 80045 USA. Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. Univ Washington, Sch Med, Seattle, WA USA. Ctr Dis Control & Prevent, Atlanta, GA USA. NIDDK, Bethesda, MD USA. Univ S Carolina, Columbia, SC 29208 USA. Sansum Diabet Res Inst, Santa Barbara, CA USA. Pacific Hlth Res Inst, Honolulu, HI USA. Univ Colorado, Hlth Sci Ctr, Dept Prevent Med & Biometr, Denver, CO 80262 USA. RP Maahs, DM (reprint author), Univ Colorado, Hlth Sci Ctr, Barbara Davis Ctr Childhood Diabet, POB 6511,Mail Stop A140, Aurora, CO 80045 USA. EM david.maahs@uchsc.edu FU NCCDPHP CDC HHS [DP-05-069]; NCRR NIH HHS [M01RR00069, M01RR08084, M01RR00037, M01RR001271, M01RR01070] NR 44 TC 63 Z9 66 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD OCT PY 2007 VL 30 IS 10 BP 2593 EP 2598 DI 10.2337/dc07-0450 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 221JN UT WOS:000250223400036 PM 17630264 ER PT J AU Ribisl, PM Lang, W Jaramillo, SA Jakicic, JM Stewart, KJ Bahnson, J Bright, R Curtis, JF Crow, RS Soberman, JE AF Ribisl, Paul M. Lang, Wei Jaramillo, Sarah A. Jakicic, John M. Stewart, Kerry J. Bahnson, Judy Bright, Renee Curtis, Jeff F. Crow, Richard S. Soberman, Judith E. CA Look AHEAD Res Grp TI Exercise capacity and cardiovascular/metabolic characteristics of overweight and obese individuals with type 2 diabetes - The look AHEAD clinical trial SO DIABETES CARE LA English DT Article; Proceedings Paper CT 25th Annual Meeting of the Rosario-Biology-Society CY DEC 12-14, 2005 CL Rosario, ARGENTINA SP Rosario Biol Soc ID BODY-MASS INDEX; HEART-RATE RECOVERY; ALL-CAUSE MORTALITY; CARDIORESPIRATORY FITNESS; METABOLIC SYNDROME; PHYSICAL-ACTIVITY; AEROBIC EXERCISE; VISCERAL FAT; WEIGHT-LOSS; MEN AB We examined associations of cardiovascular, metabolic, and body composition measures with exercise capacity using baseline data from 5,145 over-weight and/or obese (BMI >= 25.0 kg/m(2)) men and women with type 2 diabetes who were randomized participants for the Look AHEAD (Action for Health in Diabetes) clinical trial. RESEARCH DESIGN AND METHODS - Peak exercise capacity expressed as METs and estimated from treadmill speed and grade was measured during a graded exercise test 2 designed to elicit a maximal effort. Other measures included waist circumference, BMI, type diabetes duration, types of medication used, A1C, history of cardiovascular disease, metabolic syndrome, P-blocker use, and race/ethnicity. RESULTS - Peak exercise capacity was higher for men (8.0 +/- 2.1 METs) than for women (6.7 +/- 1.7 METs) (P < 0.001). Exercise capacity also decreased across each decade of age (P < 0.001) and with increasing BMI and waist circumference levels in both sexes. Older age, increased waist circumference and BMI, a longer duration of diabetes, increased A1C, a history of cardiovascular disease, having metabolic syndrome, P-blocker use, and being African American compared with being Caucasian were associated with a lower peak exercise capacity for both sexes. Hypertension and use of diabetes medications were associated with lower peak exercise capacity in women. CONCLUSIONS - Individuals with diabetes who are overweight or obese have impaired exercise capacity, which is primarily related to age, female sex, and race, as well as poor metabolic control, BMI, and central obesity. C1 Wake Forest Univ, Sch Med, Dept Biostat Sci, Winston Salem, NC 27109 USA. Univ Pittsburgh, Dept Hlth & Phys Act, Pittsburgh, PA USA. Johns Hopkins Univ, Dept Med, Div Cardiol, Baltimore, MD USA. Brown Univ, Brown Med Sch, Miriam Hosp, Providence, RI 02912 USA. NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. Univ Minnesota, Dept Epidemiol & Community Hlth, Minneapolis, MN USA. Univ Tennessee, Ctr Hlth Sci, Dept Med, Div Cardiol, Memphis, TN 38163 USA. RP Ribisl, PM (reprint author), Wake Forest Univ, Sch Med, Dept Biostat Sci, Wake Forest Rd, Winston Salem, NC 27109 USA. EM ribisl@wfu.edu FU NCRR NIH HHS [M01 RR00051, M01 RR000056 44, M01-RR-02719, M01RR00211-40, M01-RR-01066]; NIDDK NIH HHS [DK56990, DK57171, DK57178, DK57002, DK57149, DK57154, DK56992, DK 046204, DK57136, DK57078, DK57177, P30 DK48520, DK57151, DK57135, DK57219, DK57182, DK57131, DK57008] NR 36 TC 40 Z9 41 U1 2 U2 10 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD OCT PY 2007 VL 30 IS 10 BP 2679 EP 2684 DI 10.2337/dc06-2487 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 221JN UT WOS:000250223400054 PM 17644623 ER PT J AU Khil, LY Jun, HS Kwon, H Yoo, JK Kim, S Notkins, AL Yoon, JW AF Khil, L.-Y. Jun, H.-S. Kwon, H. Yoo, J. K. Kim, S. Notkins, A. L. Yoon, J.-W. TI Human chorionic gonadotropin is an immune modulator and can prevent autoimmune diabetes in NOD mice SO DIABETOLOGIA LA English DT Article DE autoimmune disease; cytokines; human chorionic gonadotropin; immune regulation; insulitis; NOD mice; regulatory T cells; T cells; Th1 immune response; type 1 diabetes ID IMMUNOREGULATORY T-CELLS; TUMOR-NECROSIS-FACTOR; IN-VITRO; REGULATORY CELLS; HUMAN-PREGNANCY; TGF-BETA; ACTIVATION; INHIBITION; MECHANISMS; EXPRESSION AB Aims/hypothesis Expression of T helper (Th)1 cytokine mRNA in pregnant women is known to be inversely correlated with serum human chorionic gonadotropin (hCG). Type 1 diabetes is a Th1-mediated autoimmune disease, in which intervention at an early stage of the autoimmune process can prevent disease progression. We hypothesised that immune modulation by treating young NOD mice with hCG may prevent diabetes. Methods Female NOD mice were treated with hCG or recombinant hCG from 3 to 15 weeks of age and the incidence of diabetes and development of insulitis was determined. CD4(+) and CD8(+) T cell populations, T cell proliferation, cytokine production and CD4(+)CD25(+) regulatory T cells were examined and adoptive transfer experiments were performed. Results Both purified and recombinant hCG prevented development of diabetes in NOD mice. hCG decreased the proportion and number of CD4(+) and CD8(+) T cells and inhibited T cell proliferative responses against beta cell antigens. hCG treatment suppressed IFN-gamma production, but increased IL-10 and TGF-beta production in splenocytes stimulated with anti-CD3 antibody. hCG treatment also suppressed TNF-alpha production in splenocytes stimulated with lipopolysaccharide. Furthermore, hCG treatment increased the CD4(+)CD25(+)/CD4(+) T cell ratio in spleen and pancreatic lymph nodes. Depletion of CD4(+)CD25(+) T cells from splenocytes of hCG-treated NOD mice abolished their preventive effect on diabetes transfer. Conclusion/interpretation We conclude that hCG has an immunomodulatory effect by downregulating effector cells, including Th1 cells, CD8(+) T cells and macrophages, and increasing the CD4(+)CD25(+)/CD4(+) T cell ratio, thus preventing autoimmune diabetes in NOD mice. C1 Chicago Med Sch, Rosalind Franklin Comprehens Diabet Ctr, Abbott Pk, IL 60064 USA. Univ Calgary, Fac Med, Dept Microbiol & Infect Dis, Calgary, AB, Canada. NIDCR, NIH, Expt Med Sect, Oral Infect & Immun Branch, Bethesda, MD USA. RP Khil, LY (reprint author), Chicago Med Sch, Rosalind Franklin Comprehens Diabet Ctr, 3333 Green Bay Rd, Abbott Pk, IL 60064 USA. EM hee-sook.jeon@rosalindfranklin.edu NR 39 TC 20 Z9 22 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0012-186X J9 DIABETOLOGIA JI Diabetologia PD OCT PY 2007 VL 50 IS 10 BP 2147 EP 2155 DI 10.1007/s00125-007-0769-y PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 208DI UT WOS:000249299600017 PM 17676307 ER PT J AU Di Nardo, G De Giorgio, R Stanghellini, V Borrelli, O Tempesta, AM Labalestra, V Federici, T Cucchiara, S AF Di Nardo, G. De Giorgio, R. Stanghellini, V. Borrelli, O. Tempesta, A. M. Labalestra, V. Federici, T. Cucchiara, S. TI Congenital intestinal obstruction mimicking chronic idiopathic intestinal pseudo-obstruction: A case report SO DIGESTIVE AND LIVER DISEASE LA English DT Meeting Abstract C1 [Di Nardo, G.; Borrelli, O.; Labalestra, V.; Federici, T.; Cucchiara, S.] Univ Roma La Sapienza, Pediat Gastroenterol Unit, Rome, Italy. [De Giorgio, R.; Stanghellini, V.] Univ Bologna, Dept Internal Med & Gastroenterol, Bologna, Italy. [Tempesta, A. M.] NCI, Endoscopy Unit, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU PACINI EDITORE PI PISA PA VIA DELLA GHERARDESCA-ZONA INDUSTRIALE OSPEDALETTO, 56121 PISA, ITALY SN 1590-8658 J9 DIGEST LIVER DIS JI Dig. Liver Dis. PD OCT PY 2007 VL 39 IS 10 BP A54 EP A54 DI 10.1016/j.dld.2007.07.064 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 230GH UT WOS:000250863800081 ER PT J AU Duncan, B Zhao, K AF Duncan, Beverly Zhao, Keji TI HMGA1 mediates the activation of the CRYAB promoter by BRG1 SO DNA AND CELL BIOLOGY LA English DT Article ID MAMMALIAN SWI/SNF COMPLEXES; B-CRYSTALLIN GENE; SWI-SNF COMPLEX; NUCLEOSOMAL DNA; CHROMOSOMAL-PROTEINS; CHROMATIN-STRUCTURE; BAF COMPLEX; BINDING; TRANSCRIPTION; EXPRESSION AB alpha B-Crystallin (CRYAB) is a small heat-shock protein that is implicated in many cellular processes, such as transcription and differentiation, as well as pathologic process. It is expressed at high levels in vertebrate eye lens and at low levels in a variety of other cell types. We previously identified CRYAB as a target gene of the chromatin-remodeling SWI/SNF-like Brg or hBrm-associated factors (BAF) complexes. In this report, we identify a 30 bp DNA element required for mediating the activation of CRYAB by brahma-related gene 1 (BRG1). This BRG1-response element is located at the edge of a positioned nucleosome immediately upstream of the transcription initiation site. An AT-rich sequence within this region is bound by the high-mobility group AT-hook 1 (HMGA1) proteins in vitro and in vivo. We demonstrate that theHMGA1 target sequences and HMGA1 proteins are required for the maximal activation of the CRYAB promoter by BRG1. Our data indicate that HMGA1 nonhistone chromatin proteins, the SWI/SNF chromatin remodeling complexes, and sequence-specific transcription factors act together to regulate the expression of the CRYAB gene. C1 NHLBI, NIH, Lab Mol Immunol, Bethesda, MD 20892 USA. Howard Univ, Dept Genet & Human Genet, Washington, DC 20059 USA. RP Zhao, K (reprint author), Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. EM zhaok@nhlbi.nih.gov FU Intramural NIH HHS NR 39 TC 15 Z9 15 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1044-5498 J9 DNA CELL BIOL JI DNA Cell Biol. PD OCT PY 2007 VL 26 IS 10 BP 745 EP 752 DI 10.1089/dna.2007.0629 PG 8 WC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity GA 224SH UT WOS:000250466200008 PM 17723105 ER PT J AU Friedberg, EC Hanaoka, F Tanaka, K Wilson, S Yasui, A AF Friedberg, Errol C. Hanaoka, Fumio Tanaka, Kiyoji Wilson, Sam Yasui, Akira TI The 3rd Japan-US DNA repair meeting, Sendai, Japan, May 7-11, 2007 SO DNA REPAIR LA English DT Editorial Material C1 Univ Texas, Southwestern Med Ctr, Dept Pathol, Lab Mol Pathol, Dallas, TX 75390 USA. Osaka Univ, Grad Sch Frontier Biosci, Human Cell Biol Grp, Osaka 5650871, Japan. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. Tohuko Univ, Dept Mol Genet, Sendai, Miyagi 9808575, Japan. RP Friedberg, EC (reprint author), Univ Texas, Southwestern Med Ctr, Dept Pathol, Lab Mol Pathol, Dallas, TX 75390 USA. EM errol.friedberg@utsouthwestern.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD OCT 1 PY 2007 VL 6 IS 10 BP 1545 EP 1555 DI 10.1016/j.dnarep.2007.07.001 PG 11 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 219JH UT WOS:000250080300016 PM 17704011 ER PT J AU Aszalos, A AF Aszalos, Adorjan TI Drug-drug interactions affected by the transporter protein, P-glycoprotein (ABCB1, MDR1). I. Preclinical aspects SO DRUG DISCOVERY TODAY LA English DT Review ID BLOOD-BRAIN-BARRIER; MULTIDRUG-RESISTANCE; CELLS; GENE; VIVO; MODULATION; EXPRESSION; EFFLUX; COMBINATION; INHIBITION AB When certain coadministered drugs interfere with the transport of one another at the P-glycoprotein (Pgp) level, we observe the phenomenon of "drug-drug interactions". We describe here the physical and biochemical ways that drugs react with Pgp, the induction of Pgp by xenobiotics and the polymorphisms of Pgp related to drug-drug interactions. We also describe methods that can be used to detect potential drug-drug interactions. Among the widely used methods are flow cytometry, cell culture with polarized expression of Pgp, liposome and inside-out membrane preparations, ex vivo studies, in silico calculations, cDNA microarrays, in vivo mouse models, positron emission tomography (PET), and nuclear magnetic resonance (NMR) methods with live animals. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Aszalos, A (reprint author), NCI, Cell Biol Lab, NIH, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. EM aszalosa@mail.nih.gov NR 40 TC 25 Z9 27 U1 1 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD OCT PY 2007 VL 12 IS 19-20 BP 833 EP 837 DI 10.1016/j.drudis.2007.07.022 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 227MU UT WOS:000250661600007 PM 17933684 ER PT J AU Aszalos, A AF Aszalos, Adorjan TI Drug-drug interactions affected by the transporter protein, P-glycoprotein (ABCB1, MDR1). II. Clinical aspects SO DRUG DISCOVERY TODAY LA English DT Review ID MULTIDRUG-RESISTANCE PROTEIN; ACUTE MYELOID-LEUKEMIA; HEALTHY-VOLUNTEERS; CREMOPHOR EL; COMBINATION; CELLS; ERYTHROMYCIN; CYCLOSPORINE; INHIBITOR; DIGOXIN AB The simultaneous use of several drugs (polypharmacy) for the treatment of cancer, HIV, and other diseases and for multiple ailments of the elderly is a common practice in modern medicine. Co-administration of drugs may result in unwanted side effects. One reason for these side effects can be the altered function of transport proteins, especially of P-glycoprotein (Pgp), due to its simultaneous interaction with several drugs. We describe here some of the observed, unexpected side effects of polypharmacy in the clinic. We also describe intentional modulation of the function of Pgp that is introduced when facilitation of absorption of a drug through the intestines is needed and in cancer chemotherapy. In addition, we mention some methods of testing and ways by which doctors and patients can be alerted to potential side effects. C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Aszalos, A (reprint author), NCI, Cell Biol Lab, NIH, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. EM aszalosa@mail.nih.gov NR 39 TC 38 Z9 41 U1 1 U2 8 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1359-6446 J9 DRUG DISCOV TODAY JI Drug Discov. Today PD OCT PY 2007 VL 12 IS 19-20 BP 838 EP 843 DI 10.1016/j.drudis.2007.07.021 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 227MU UT WOS:000250661600008 PM 17933685 ER PT J AU Ludlow, CL Sonies, BC Humbert, IA Crujido, L Martin, SB Lowell, SY AF Ludlow, Christy L. Sonies, B. C. Humbert, I. A. Crujido, L. Martin, S. B. Lowell, S. Y. TI Validity and reliability of the swallowing safety scale SO DYSPHAGIA LA English DT Meeting Abstract C1 NIH, NINDS, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0179-051X J9 DYSPHAGIA JI Dysphagia PD OCT PY 2007 VL 22 IS 4 BP 395 EP 395 PG 1 WC Otorhinolaryngology SC Otorhinolaryngology GA 219VN UT WOS:000250116400087 ER EF