FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Chitkara, P Stojanov, S Kastner, DL AF Chitkara, Puja Stojanov, Silvia Kastner, Daniel L. TI The hereditary autoinflammatory syndromes SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Editorial Material DE recurrent fever; hereditary autoinflammatory syndromes; tumor necrosis factor; periodic fever syndromes ID FAMILIAL MEDITERRANEAN FEVER; HYPERIMMUNOGLOBULINEMIA-D; INFLAMMATORY ATTACKS; PERIODIC SYNDROME; TNF RECEPTOR; MUTATIONS; ETANERCEPT; ANAKINRA; TNFRSF1A; TRAPS C1 NIAMSD, NIH, Bethesda, MD 20892 USA. RP Chitkara, P (reprint author), NIAMSD, NIH, Ctr Dr, Bethesda, MD 20892 USA. NR 15 TC 11 Z9 12 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD APR PY 2007 VL 26 IS 4 BP 353 EP 354 DI 10.1097/01.inf.0000258777.86510.da PG 2 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 151JV UT WOS:000245287200016 PM 17414402 ER PT J AU Santos, RP Sanchez, PJ Mejias, A Benjamin, DK Walsh, TJ Patel, S Jafri, HS AF Santos, Roberto P. Sanchez, Pablo J. Mejias, Asuncion Benjamin, Daniel K., Jr. Walsh, Thomas J. Patel, Sanjay Jafri, Hasan S. TI Successful medical treatment of cutaneous aspergillosis in a premature infant using liposomal amphotericin B, voriconazole and micafungin SO PEDIATRIC INFECTIOUS DISEASE JOURNAL LA English DT Article; Proceedings Paper CT St Jude-Pediatric-Infectious-Diseases-Society Microbial Research Conference CY FEB 24-25, 2006 CL Memphis, TN SP St Jude Pediat Infect Dis Soc DE pharmacokinetic; primary cutaneous aspergillosis; liposomal amphotericin B; voriconazole; micafungin; preterm infant ID INTRAVENOUS VORICONAZOLE; FUNGAL-INFECTIONS; THERAPY; PHARMACOKINETICS; CANDIDIASIS; COMBINATION; CHILDREN; SAFETY AB Treatment options for primary cutaneous aspergillosis in neonates are limited by the lack of pharmacokinetic and safety data of newer antifungal agents that are effective against Aspergillus spp. We report the successful treatment of cutaneous aspergillosis in an extremely low-birth-weight preterm infant with liposomal amphotericin B, voriconazole and micafungin, and provide pharmacokinetic profiles for voriconazole and micafungin. C1 Univ Texas, SW Med Ctr, Dept Pediat, Div Infect Dis, Dallas, TX 75390 USA. Duke Clin Res Inst, Durham, NC USA. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. Odessa Reg Hosp, Odessa, TX USA. RP Santos, RP (reprint author), Univ Texas, SW Med Ctr, Dept Pediat, Div Infect Dis, 5323 Harry Hines Blvd Room F3-202, Dallas, TX 75390 USA. EM roberto.santos@UTSouthwestern.edu RI Mejias, Maria Asuncion/E-3659-2011 FU NICHD NIH HHS [1U10-HD45962-02, HD046000] NR 23 TC 29 Z9 30 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0891-3668 J9 PEDIATR INFECT DIS J JI Pediatr. Infect. Dis. J. PD APR PY 2007 VL 26 IS 4 BP 364 EP 366 DI 10.1097/01.inf.0000258698.98370.89.10 PG 3 WC Immunology; Infectious Diseases; Pediatrics SC Immunology; Infectious Diseases; Pediatrics GA 151JV UT WOS:000245287200022 PM 17414408 ER PT J AU Higgins, RD Bancalari, E Willinger, M Raju, TNK AF Higgins, Rosemary D. Bancalari, Eduardo Willinger, Marian Raju, Tonse N. K. TI Executive summary of the workshop on oxygen in neonatal therapies: Controversies and opportunities for research SO PEDIATRICS LA English DT Editorial Material DE bronchopulmonary dysplasia; intensive care; neonatal resuscitation; oxygen; retinopathy of prematurity; ventilation ID CENTRAL HYPOVENTILATION SYNDROME; TREHALOSE-PHOSPHATE SYNTHASE; NEWBORN RESUSCITATION; ANTIOXIDANT ENZYMES; HEALTHY INFANTS; CHRONIC HYPOXIA; PURE OXYGEN; BRAIN; PREMATURITY; LUNG AB One of the most complex areas in perinatal/neonatal medicine is the use of oxygen in neonatal therapies. To address the knowledge gaps that preclude optimal, evidence-based care in this critical field of perinatal medicine, the National Institute of Child Health and Human Development organized a workshop, Oxygen in Neonatal Therapies: Controversies and Opportunities for Research, in August 2005. The information presented at the workshop included basic and translational oxygen research; a review of completed, ongoing, and planned clinical trials; oxygen administration for neonatal resuscitation; and a review of the collaborative home infant monitoring evaluation study. This article provides a summary of the discussions, focusing on major knowledge gaps, with prioritized suggestions for studies in this area. C1 NICHD, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, NIH, Bethesda, MD 20892 USA. Univ Miami, Coll Med, Dept Pediat, Miami, FL 33152 USA. RP Higgins, RD (reprint author), NICHD, Pregnancy & Perinatol Branch, Ctr Dev Biol & Perinatal Med, NIH, 6100 Exeut Blvd,Room 4B03B,MSC 7510, Bethesda, MD 20892 USA. EM higginsr@mail.nih.gov NR 38 TC 27 Z9 29 U1 0 U2 1 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD APR PY 2007 VL 119 IS 4 BP 790 EP 796 DI 10.1542/peds.2006-2200 PG 7 WC Pediatrics SC Pediatrics GA 153BH UT WOS:000245406200042 PM 17403851 ER PT J AU Flynn, P Havens, P Brady, M Emmanuel, P Read, J Hoyt, L Henry-Reid, L Van Dyke, R Mofenson, L AF Flynn, Patricia Havens, Peter Brady, Michael Emmanuel, Patricia Read, Jennifer Hoyt, Laura Henry-Reid, Lisa Van Dyke, Russell Mofenson, Lynne TI Male circumcision for prevention of HIV and other sexually transmitted diseases SO PEDIATRICS LA English DT Editorial Material ID INFECTION; RISK; TRANSMISSION; METAANALYSIS; COHORT C1 Med Coll Wisconsin, Dept Dis, Div Infect Dis, Milwaukee, WI 53201 USA. St Jude Childrens Res Inst, Dept Infect Dis, Memphis, TN USA. Columbus Childrens Hosp, Dept Pediat, Columbus, OH USA. Univ S Florida, Dept Pediat, Tampa, FL 33620 USA. NICHHD, Pediat Adolescent & Maternal AIDS Branch, Rockville, MD USA. Childrens Hosp & Clin Minnesota, Dept Pediat Infect Dis, St Paul, MN USA. John H Stroger Jr Hosp Cook Cty, Dept Adolescent & Young Adult Med, Chicago, IL USA. Tulane Univ, Sch Med, Dept Pediat, Div Infect Dis, New Orleans, LA 70118 USA. RP Havens, P (reprint author), Med Coll Wisconsin, Dept Dis, Div Infect Dis, Suite C450,POB 1997, Milwaukee, WI 53201 USA. EM phavens@mcw.edu OI Mofenson, Lynne/0000-0002-2818-9808 NR 21 TC 4 Z9 6 U1 2 U2 3 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD APR PY 2007 VL 119 IS 4 BP 821 EP 822 DI 10.1542/peds.2006-3694 PG 2 WC Pediatrics SC Pediatrics GA 153BH UT WOS:000245406200046 PM 17403855 ER PT J AU Kuo, J Usdin, TB AF Kuo, Jonathan Usdin, Ted B. TI Development of a rat parathyroid hormone 2 receptor antagonist SO PEPTIDES LA English DT Article DE peptide antagonist; site-directed mutagenesis; tuberoinfundibular peptide of 39 residues; parathyroid hormone 2 receptor ID HORMONE 2 RECEPTOR; TUBEROINFUNDIBULAR PEPTIDE; 39 RESIDUES; PTH2 RECEPTOR; AGONIST; TIP39; EXPRESSION AB The parathyroid hormone 2 (PTH2) receptor is a Family B G-protein coupled receptor most highly expressed within the brain. Current evidence suggests that tuberoinfundibular pepticle of 39 residues (TIP39) is the PTH2 receptor's endogenous ligand. To facilitate investigation of the physiological function of the PTH2 receptor/TIP39 system, we have developed a novel PTH2 receptor antagonist, by changing several residues within the amino terminal domain of TIP39. Histidine(4), tyrosine(5), tryptophan(6), histidine(7)-TIP39 binds the PTH2 receptor with high affinity, has over 30-fold selectivity for the rat PTH2 receptor over the rat PTH1 receptor and displays no detectable agonist activity. This ligand should be useful for in vivo investigation of PTH2 receptor function. Published by Elsevier Inc. C1 NIMH, Genet Lab, Bethesda, MD 20892 USA. RP Usdin, TB (reprint author), NIMH, Genet Lab, Bldg 35,Room 1B-215,Convent Dr,MSC 3728, Bethesda, MD 20892 USA. EM kuoj@mail.nih.gov; usdint@mail.nih.gov FU Intramural NIH HHS; NIMH NIH HHS [Z01 MH002685-12] NR 21 TC 9 Z9 9 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0196-9781 J9 PEPTIDES JI Peptides PD APR PY 2007 VL 28 IS 4 BP 887 EP 892 DI 10.1016/j.peptides.2006.12.002 PG 6 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Pharmacology & Pharmacy GA 156CP UT WOS:000245625900021 PM 17207559 ER PT J AU Fuselli, S Gilman, RH Chanock, SJ Bonatto, SL De Stefano, G Evans, CA Labuda, D Luiselli, D Salzano, FM Soto, G Vallejo, G Sajantila, A Pettener, D Tarazona-Santos, E AF Fuselli, S. Gilman, R. H. Chanock, S. J. Bonatto, S. L. De Stefano, G. Evans, C. A. Labuda, D. Luiselli, D. Salzano, F. M. Soto, G. Vallejo, G. Sajantila, A. Pettener, D. Tarazona-Santos, E. TI Analysis of nucleotide diversity of NAT2 coding region reveals homogeneity across Native American populations and high intra-population diversity SO PHARMACOGENOMICS JOURNAL LA English DT Article DE acetylator phenotype; Native American; Latin-American populations; drug-metabolizing enzyme; admixture ID N-ACETYLTRANSFERASE GENES; ACETYLATOR PHENOTYPE; SPATIAL AUTOCORRELATION; AMERINDIAN POPULATIONS; INDUCED HEPATOTOXICITY; MOLECULAR-GENETICS; Y-CHROMOSOMES; DNA DIVERSITY; GENOTYPE DATA; HUMAN GENOME AB N-acetyltransferase 2 (NAT2), an important enzyme in clinical pharmacology, metabolizes antibiotics such as isoniazid and sulfamethoxazole, and catalyzes the transformation of aromatic and heterocyclic amines from the environment and diet into carcinogenic intermediates. Polymorphisms in NAT2 account for variability in the acetylator phenotype and the pharmacokinetics of metabolized drugs. Native Americans, settled in rural areas and large cities of Latin America, are under-represented in pharmacogenetics studies; therefore, we sequenced the coding region of NAT2 in 456 chromosomes from 13 populations from the Americas, and two from Siberia, detecting nine substitutions and 11 haplotypes. Variants *4 (37%), *5B (23%) and *7B (24%) showed high frequencies. Average frequencies of fast, intermediate and slow acetylators across Native Americans were 18, 56 and 25%, respectively. NAT2 intra-population genetic diversity for Native Americans is higher than East Asians and similar to the rest of the world, and NAT2 variants are homogeneously distributed across native populations of the continent. C1 Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Biol Geral, BR-31270910 Belo Horizonte, MG, Brazil. Univ Helsinki, Dept Forens Med, SF-00300 Helsinki, Finland. Univ Ferrara, Dept Biol, I-44100 Ferrara, Italy. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Int Hlth, Bethesda, MD USA. NCI, Sect Genom Variat, Pediat Oncol Branch, NIH,Adv Technol Ctr, Bethesda, MD 20892 USA. Pontificia Univ Catolica Rio de Janeiro, Fac Biociencias, Ctr Biol Genom & Mol, Porto Alegre, RS, Brazil. Univ Roma Tor Vergata, Dept Biol, I-00173 Rome, Italy. Assoc Benefica PRISMA, San Miguel, Peru. Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Wellcome Ctr Clin Trop Med, London SW7 2AZ, England. Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Infect Dis & Immun, London SW7 2AZ, England. Hop St Justine, Ctr Rech, Montreal, PQ H3T 1C5, Canada. Univ Bologna, Dipartimento Biol ES, I-40126 Bologna, Italy. Univ Fed Rio Grande do Sul, Inst Biociencias, Dept Genet, BR-90046900 Porto Alegre, RS, Brazil. Univ Tolima, Fac Ciencias, Dept Biol, Ibague, Colombia. RP Tarazona-Santos, E (reprint author), Univ Fed Minas Gerais, Inst Ciencias Biol, Dept Biol Geral, Av Antonio Carlos 6627,Caixa Postal 486, BR-31270910 Belo Horizonte, MG, Brazil. EM edutars@icb.ufmg.br RI Bonatto, Sandro/A-1240-2010; Salzano, Francisco/L-7916-2015; Osborne, Nicholas/N-4915-2015; Pettener, Davide/E-1576-2017; OI Bonatto, Sandro/0000-0002-0064-467X; Osborne, Nicholas/0000-0002-6700-2284; Evans, Carlton/0000-0002-6873-5447 FU Wellcome Trust [, 057434] NR 64 TC 22 Z9 25 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1470-269X J9 PHARMACOGENOMICS J JI Pharmacogenomics J. PD APR PY 2007 VL 7 IS 2 BP 144 EP 152 DI 10.1038/sj.tpj.6500407 PG 9 WC Genetics & Heredity; Pharmacology & Pharmacy SC Genetics & Heredity; Pharmacology & Pharmacy GA 153VZ UT WOS:000245465600007 PM 16847467 ER PT J AU Pritchard, LM Newman, AH McNamara, RK Logue, AD Taylor, B Welge, JA Xu, M Zhang, JH Richtand, NM AF Pritchard, Laurel M. Newman, Amy Hauck McNamara, Robert K. Logue, Aaron D. Taylor, Benjamin Welge, Jeffrey A. Xu, Ming Zhang, Jianhua Richtand, Neil M. TI The doparnine D3 receptor antagonist NGB 2904 increases spontaneous and amphetamine-stimulated locomotion SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE dopamine D3 receptor; knockout mice; amphetamine; NGB 2904; locomotor activity ID DOPAMINE D-3 RECEPTOR; LEVODOPA-INDUCED DYSKINESIA; DRUG-SEEKING BEHAVIOR; IN-VIVO OCCUPANCY; WILD-TYPE MICE; HIGH-AFFINITY; PHARMACOLOGICAL CHARACTERIZATION; INDUCED REINSTATEMENT; INHIBITORY FUNCTION; GENE-EXPRESSION AB The dopamine D3 receptor is believed to play an important role in regulation of rodent locomotor behavior, and has been proposed as a therapeutic target for substance abuse, psychotic disorders, and Parkinson's disease. One model of dopamine D3 receptor function, based on studies utilizing D3 receptor knockout mice and D3 receptor-preferring agonists, proposes that D3 receptor stimulation is inhibitory to psychostimulant-induced locomotion, in opposition to the effects of concurrent dopamine D1 and D2 receptor stimulation. Recent progress in medicinal chemistry has led to the development of highly-selective dopamine D3 receptor antagonists. In order to extend our understanding of D3 dopamine receptor's behavioral functions, we determined the effects of the highly-selective dopamine D3 receptor antagonist NGB 2904 on amphetamine-stimulated and spontaneous locomotion in wild-type and dopamine D3 receptor knockout mice. NGB 2904 (26.0 mu g/kg s.c.) enhanced amphetamine-stimulated locomotion in wild-type mice, but had no measurable effect in dopamine D3 receptor knockout mice. Of a range of doses (0.026 mu g-1.0 mg/kg) given acutely or once daily for seven days, the highest dose of NGB 2904 (1.0 mg/kg) stimulated spontaneous locomotion in wild-type mice, but was without measurable effect in dopamine D3 receptor knockout mice. These behavioral effects of NGB 2904 contrast with those described for other highly D3 receptor-selective antagonists, which have not previously demonstrated an effect on spontaneous locomotor activity. In combination, these data add to the behavioral profile of this novel D3 receptor ligand and provide further support for a role for dopamine D3 receptor inhibitory function in the modulation of rodent locomotion. (c) 2007 Elsevier Inc. All rights reserved. C1 Univ Cincinnati, Coll Med, Dept Psychiat, Cincinnati, OH 45267 USA. NIDA, Intramural Res Program, Med Chem Sect, Baltimore, MD 21131 USA. Univ Cincinnati, Coll Med, Ctr Biostat Serv, Cincinnati, OH 45267 USA. Univ Cincinnati, Coll Med, Dept Canc & Cell Biol, Cincinnati, OH 45267 USA. Univ Chicago, Ctr Med, Dept Anesthesia & Crit Care, Chicago, IL 60637 USA. Cincinnati Vet Affairs Med Ctr, Psychiat Serv, Cincinnati, OH 45220 USA. RP Pritchard, LM (reprint author), Williams Coll, Bronfman Sci Ctr, 18 Hoxsey St, Williamstown, MA 01267 USA. EM Laurel.M.Pritchard@williams.edu RI zhang, jianhua/D-3404-2009; McNamara, Robert/J-4309-2014 FU Intramural NIH HHS; NIDA NIH HHS [DA016778-01, DA14644, DA17323, R01 DA016778] NR 66 TC 25 Z9 25 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD APR PY 2007 VL 86 IS 4 BP 718 EP 726 DI 10.1016/j.pbb.2007.02.019 PG 9 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 184LJ UT WOS:000247642600016 PM 17408730 ER PT J AU Panlilio, LV Thorndike, EB Schindler, CW AF Panlilio, Leigh V. Thorndike, Eric B. Schindler, Charles W. TI Blocking of conditioning to a cocaine-paired stimulus: Testing the hypothesis that cocaine perpetually produces a signal of larger-than-expected reward SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE self-administration; learning; nose-poke response; lever press; rat ID SELECTIVE ATTENTION; AMPHETAMINE; NEURONS; LESIONS AB According to a recent account of addiction, dopaminergic effects of drugs like cocaine mimic the neuronal signal that occurs when a natural reward has a larger value than expected. Consequently, the drug's expected reward value increases with each administration, leading to an over-selection of drug-seeking behavior. One prediction of this hypothesis is that the blocking effect, a cornerstone of contemporary teaming theory, should not occur with drug reinforcers. To test this prediction, two groups of rats were trained to self-administer cocaine with a nose-poking response. For 5 sessions, a tone was paired with each self-administered injection (blocking group), or no stimulus was paired with injection (non-blocking group). Then, in both groups, the tone and a light were both paired with each injection for 5 sessions. In subsequent testing, the light functioned as a conditioned reinforcer for a new response (lever-pressing) in the non-blocking group, but not the blocking group. Thus, contrary to prediction, pre-training with the tone blocked conditioning to the light. Although these results fail to support a potentially powerful explanation of addiction, they are consistent with the fact that most conditioning and teaming phenomena that occur with non-drug reinforcers can also be demonstrated with drug reinforcers. Published by Elsevier Inc. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,DHHS, Baltimore, MD 21224 USA. RP Panlilio, LV (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, Intramural Res Program,NIH,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM lpanlili@intra.nida.nih.gov FU Intramural NIH HHS [Z99 DA999999] NR 25 TC 21 Z9 21 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0091-3057 J9 PHARMACOL BIOCHEM BE JI Pharmacol. Biochem. Behav. PD APR PY 2007 VL 86 IS 4 BP 774 EP 777 DI 10.1016/j.pbb.2007.03.005 PG 4 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 184LJ UT WOS:000247642600022 PM 17445874 ER PT J AU DeCarolis, DD Rice, KL Ho, LB Willenbring, ML Cassaro, S AF DeCarolis, Douglas D. Rice, Kathryn L. Ho, Libin Willenbring, Mark L. Cassaro, Susan TI Symptom-driven lorazepam protocol for treatment of severe alcohol withdrawal delirium in the intensive care unit SO PHARMACOTHERAPY LA English DT Article DE alcohol withdrawal delirium; AWD; alcohol withdrawal syndrome; treatment protocol; benzodiazepine; lorazepam; midazolam; intensive care ID PROPYLENE-GLYCOL TOXICITY; INCREASED OSMOLAR GAP; METABOLIC-ACIDOSIS; PRACTICE GUIDELINE; TREMENS; INFUSION; BENZODIAZEPINE; MANAGEMENT; THERAPY; REQUIREMENTS AB Study Objective. To compare outcomes of treating alcohol withdrawal delirium (AWD) with a symptom-driven benzodiazepine protocol versus nonprotocol benzodiazepine infusions in the intensive care unit (ICU). Design. Retrospective observational study of a quality improvement project. Setting. Medical intensive care unit at a Veterans Affairs medical center. Patients. Thirty-six patients who had 40 ICU admissions for AWD between January 1, 1994, and May 31, 2003. Sixteen episodes (15 patients [historical controls]) occurred before implementation of the symptom-driven protocol in 1998, and 24 episodes (21 patients) occurred after implementation. Measurements and Main Results. Outcomes evaluated were time to reach symptom control, total dose of benzodiazepine, amount of time receiving continuous benzodiazepine infusion, length of ICU and hospital stay, polypharmacy (use of multiple benzodiazepines), and complications of treatment. The historical control group was treated according to physician preference, which consisted of continuous-infusion midazolam without a protocol. The symptom-driven protocol used lorazepam administered initially as intermittent intravenous doses, progressing to a continuous intravenous infusion according to a locally developed symptom scale. The mean +/- SD values for the outcomes in the historical control group versus the protocol group were as follows: time to control symptoms 19.4 +/- 9.7 versus 7.7 +/- 4.9 hours (p=0.002), cumulative benzodiazepine dose in lorazepam equivalents 1677 +/- 937 versus 1044 +/- 534 mg (p=0.014), time receiving benzodiazepine continuous infusion 122.1 +/- 64.4 versus 52.0 +/- 35.1 hours (p=0.001), length of stay in the ICU 7.7 +/- 6.3 versus 5.6 +/- 1.7 days (p=0.21), and length of hospital stay 15.3 +/- 8.9 versus 11.2 +/- 3.4 days (p=0.43). Conclusions. Use of a symptom-driven protocol was associated with significantly decreased time to symptom control, amount of sedative required, and time spent receiving benzodiazepine infusion compared with historical controls. The use of the protocol is effective but requires close monitoring to ensure protocol compliance and to avoid potential propylene glycol toxicity. C1 Vet Affairs Med Ctr, Dept Pharm 119, Minneapolis, MN 55417 USA. Vet Affairs Med Ctr, Dept Med, Minneapolis, MN 55417 USA. Vet Affairs Med Ctr, Dept Nursing, Minneapolis, MN 55417 USA. HelthPartners Med Clin, Dept Internal Med Pediat, Minneapolis, MN USA. HelthPartners Dent Clin, Dept Internal Med Pediat, Minneapolis, MN USA. NIAAA, NIH, Ctr Chron Dis Outcomes Res, Bethesda, MD USA. RP DeCarolis, DD (reprint author), Vet Affairs Med Ctr, Dept Pharm 119, 1 Vet Dr, Minneapolis, MN 55417 USA. NR 43 TC 32 Z9 32 U1 0 U2 5 PU PHARMACOTHERAPY PUBLICATIONS INC PI BOSTON PA NEW ENGLAND MEDICAL CENTER, 806, 750 WASHINGTON ST, BOSTON, MA 02111 USA SN 0277-0008 J9 PHARMACOTHERAPY JI Pharmacotherapy PD APR PY 2007 VL 27 IS 4 BP 510 EP 518 DI 10.1592/phco.27.4.510 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 152QD UT WOS:000245375800004 PM 17381377 ER PT J AU Xia, D Esser, L Yu, L Yu, CA AF Xia, Di Esser, Lothar Yu, Linda Yu, Chang-An TI Structural basis for the mechanism of electron bifurcation at the quinol oxidation site of the cytochrome bc(1) complex SO PHOTOSYNTHESIS RESEARCH LA English DT Review DE crystal structures; cytochrome bc(1) complex; inhibitor binding; conformational changes; electron transfer mechanism ID IRON-SULFUR PROTEIN; YEAST SACCHAROMYCES-CEREVISIAE; C OXIDOREDUCTASE; UBIQUINOL-OXIDATION; DOMAIN MOVEMENT; BOVINE HEART; RHODOBACTER-CAPSULATUS; CRYSTAL-STRUCTURE; B(6)F COMPLEX; BC1 COMPLEX AB At the heart of the Q cycle hypothesis, the cytochrome bc(1) complex (bc(1)) is required to separate the two electrons from a quinol molecule at the quinol oxidation site. Recent studies have brought to light an intricate mechanism for this bifurcated electron transfer. A survey of the protein data bank shows 30 entries for the structures of bc(1) and the homologous b(6)f complex. These structures provide considerable insights into the structural organization of mitochondrial, bacterial, and plant enzymes. Crystallographic binding studies of bc (1) with either quinone reduction (Q(N)) and/or quinol oxidation (Q(P)) site inhibitors offer atomic details on how these compounds interact with residues at their respective sites. Most importantly, the different locations and apparent flexibility observed in crystals for the extrinsic domain of the iron-sulfur protein (ISP) subunit suggest a mechanism for electron bifurcation at the Q(P) site. Analyses of various inhibitor-bound structures revealed two classes of Q(P) site inhibitors: Pm inhibitors that promote ISP mobility and Pf inhibitors that favor the fixation of the ISP conformation. Those analyses also shed light on a possible process by which the ISP motion switch is controlled. The first phase reduction of ISP is shown to be comparable to the reduction of the b(L) heme by pre-steady state kinetic analysis, whereas the second phase reduction of ISP share similar kinetics with the reduction of the b (H) heme. The reduction of cyt c(1) is measured much slower, indicating that the reduced ISP remains bound at the Q(P) site until the reduced heme b(L) is oxidized by the heme b(H) and supporting the existence of a control mechanism for the ISP motion switch. C1 NCI, Cell Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Oklahoma State Univ, Dept Biochem & Mol Biol, Stillwater, OK 74078 USA. RP Xia, D (reprint author), NCI, Cell Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Bldg 37,Room 2122C, Bethesda, MD 20892 USA. EM dixia@helix.nih.gov; cayuq@okstate.edu FU Intramural NIH HHS; NIGMS NIH HHS [GM 30721] NR 60 TC 29 Z9 31 U1 1 U2 11 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0166-8595 J9 PHOTOSYNTH RES JI Photosynth. Res. PD APR PY 2007 VL 92 IS 1 BP 17 EP 34 DI 10.1007/s11120-007-9155-3 PG 18 WC Plant Sciences SC Plant Sciences GA 192UP UT WOS:000248229100005 PM 17457691 ER PT J AU Borello-France, DF Handa, VL Brown, MB Goode, P Kreder, K Scheufele, LL Weber, AM AF Borello-France, Diane F. Handa, Victoria L. Brown, Morton B. Goode, Patricia Kreder, Karl Scheufele, Laura L. Weber, Anne M. CA Pelvic Floor Disorders Network TI Pelvic-floor muscle function in women with pelvic organ prolapse SO PHYSICAL THERAPY LA English DT Article; Proceedings Paper CT 26th Annual Meeting of the American-Urogynecologic-Society CY SEP 15-17, 2005 CL Atlanta, GA SP Amer Urogynecol Soc ID LOWER URINARY-TRACT; CONTINENCE-SOCIETY; SEXUAL FUNCTION; INCONTINENCE; STRENGTH; POPULATION; STANDARDIZATION; TERMINOLOGY; SYMPTOMS AB Background and Purpose The purpose of this study was to determine whether pelvic organ prolapse severity, pelvic symptoms, quality of life, and sexual function differ based on pelvic-floor muscle function in women planning to have prolapse surgery. Subjects and Methods Three hundred seventeen women without urinary stress incontinence who were enrolled in a multicenter surgical trial were examined to determine pelvic-floor muscle function (by Brink scale score). The subjects were 61.6 +/- 10.2 ((X) over bar +/- - SD) years of age. Thirteen percent of the subjects had stage II (to the hymen) pelvic organ prolapse, 68% had stage III (beyond the hymen) prolapse, and 19% had stage IV (complete vaginal eversion) prolapse. Subjects with lowest (3-6) and highest (10-12) Brink scale scores were compared on prolapse severity, pelvic symptoms and bother, quality of life, and sexual function. Results Subjects with the highest Brink scores (n=75) had less advanced prolapse, smaller genital hiatus measurements, and less urinary symptom burden compared with those with the lowest Brink scores (n=56). The results indicated that pelvic-floor muscle function was not associated with condition-specific quality of life or sexual function. Discussion and Conclusion Although modestly clinically significant, better pelvic-floor muscle function was associated with less severe prolapse and urinary symptoms. C1 Duquesne Univ, Dept Phys Therapy, Pittsburgh, PA 15282 USA. Johns Hopkins Univ, Baltimore, MD USA. Univ Michigan, Dept Biostat, Ann Arbor, MI 48109 USA. Univ Alabama, Birmingham, AL USA. Birmingham Vet Affairs Med Ctr, Ctr Geriatr Res Educ & Clin, Clin Program, Birmingham, AL USA. Univ Iowa, Dept Urol, Iowa City, IA 52242 USA. Johns Hopkins Bayview Med Ctr, Baltimore, MD USA. NICHHD, Pelv Floor Disorders Network, NIH, Bethesda, MD 20892 USA. RP Borello-France, DF (reprint author), Duquesne Univ, Dept Phys Therapy, 111 Hlth Sci Bldg, Pittsburgh, PA 15282 USA. EM borellofrance@duq.edu FU NICHD NIH HHS [U10 HD41261, U01 HD41249, U10 HD041261, U10 HD41250, U10 HD41263, U10 HD41267, U10 HD41269, U10 HD41248, U10 HD41268] NR 32 TC 11 Z9 12 U1 0 U2 3 PU AMER PHYSICAL THERAPY ASSOC PI ALEXANDRIA PA 1111 N FAIRFAX ST, ALEXANDRIA, VA 22314 USA SN 0031-9023 J9 PHYS THER JI Phys. Ther. PD APR PY 2007 VL 87 IS 4 BP 399 EP 407 DI 10.2522/ptj.20060160 PG 9 WC Orthopedics; Rehabilitation SC Orthopedics; Rehabilitation GA 150NM UT WOS:000245223500004 PM 17341510 ER PT J AU Ma, J Dey, M Yang, H Poulev, A Pouleva, R Dorn, R Lipsky, PE Kennelly, EJ Raskin, I AF Ma, Jun Dey, Moul Yang, Hui Poulev, Alexander Pouleva, Reneta Dorn, Ruth Lipsky, Peter E. Kennelly, Edward J. Raskin, Ilya TI Anti-inflammatory and immuno suppressive compounds from Tripterygium wilfordii SO PHYTOCHEMISTRY LA English DT Article DE Tripterygium wilfordii; Celastraceae; anti-inflammation; immunosuppression; tetrahydrofuran lignan; cyclooxygenase-2 (COX-2); inducible nitric oxide synthase (iNOS); interleukin-1 beta (IL-1 beta); polymerase chain reaction (PCR); triptolide; tripdiolide ID SESQUITERPENE PYRIDINE ALKALOIDS; ETHYL-ACETATE EXTRACT; HOOK-F; RHEUMATOID-ARTHRITIS; IN-VITRO; LIGNANS AB The extract of Tripterygium wilfordii Hook F. (TwHF), which showed anti-infiammatory and immunosuppressive activities in human clinical trials for rheumatoid arthritis, was subjected to the activity-guided fractionation and spectroscopic characterization of bioactives. A tetrahydrofuran lignan, tripterygiol (1), and eight known compounds, all capable of suppressing pro-inflammatory gene expression were identified. Most of the pharmacological activity of the extract can be attributed to triptolide, its most abundant and active component, with some contribution from tripdiolide. (c) 2007 Elsevier Ltd. All rights reserved. C1 Rutgers State Univ, Cook Coll, Biotech Ctr, New Brunswick, NJ 08901 USA. NIAMSD, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. CUNY Herbert H Lehman Coll, Dept Biol Sci, Bronx, NY 10468 USA. CUNY, Grad Ctr, Bronx, NY 10468 USA. RP Raskin, I (reprint author), Rutgers State Univ, Cook Coll, Biotech Ctr, 59 Dudley Rd, New Brunswick, NJ 08901 USA. EM raskin@aesop.rutgers.edu FU FIC NIH HHS [U01 TW006674]; NCCIH NIH HHS [1-P50 AT002776-01, K99 AT004245] NR 29 TC 61 Z9 78 U1 1 U2 10 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9422 J9 PHYTOCHEMISTRY JI Phytochemistry PD APR PY 2007 VL 68 IS 8 BP 1172 EP 1178 DI 10.1016/j.phytochem.2007.02.021 PG 7 WC Biochemistry & Molecular Biology; Plant Sciences SC Biochemistry & Molecular Biology; Plant Sciences GA 165UR UT WOS:000246331900010 PM 17399748 ER PT J AU Than, NG Paidas, MJ Mizutani, S Sharma, S Padbury, J Barnea, ER AF Than, N. G. Paidas, M. J. Mizutani, S. Sharma, S. Padbury, J. Barnea, E. R. TI Embryo-placento-maternal interaction and biomarkers: from diagnosis to therapy - A workshop report SO PLACENTA LA English DT Article; Proceedings Paper CT 12th Meeting of the International-Federation-of-Placenta-Association/14th Meeting of the Japan-Plancenta-Association/24th Meeting of Japan Trophoblast Disease Study Group CY SEP 06-09, 2006 CL Kobe, JAPAN SP Int Federat Placenta Assoc, Japan Placenta Assoc DE embryonic proteins; placental proteins; biomarkers; fetal-maternal interaction ID SEQUENCE-ANALYSIS; AMINOPEPTIDASE-A; IN-VIVO; EXPRESSION; INTERLEUKIN-8; MECHANISMS; DECIDUA; PROTEIN C1 Hutzel Womens Hosp, NICHD, DHHS, Intramural Div,Perinatol Res Branch,NIH, Detroit, MI 48201 USA. Semmelweis Univ, Dept Obstet & Gynecol 1, H-1085 Budapest, Hungary. Yale Univ, Sch Med, Dept Obstet Gynecol & Reprod Sci, New Haven, CT USA. Nagoya Univ, Sch Med, Dept Med Sci Proteases, Nagoya, Aichi, Japan. Brown Univ, Dept Pediat, Providence, RI 02912 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Camden, NJ 08103 USA. RP Than, NG (reprint author), Hutzel Womens Hosp, NICHD, DHHS, Intramural Div,Perinatol Res Branch,NIH, 3990 John R, Detroit, MI 48201 USA. EM nthan@med.wayne.edu FU NCRR NIH HHS [P20 RR018728, P20 RR018728-01, P20 RR018728-019001]; NHLBI NIH HHS [R01 HL070004, R01 HL070004-04]; NICHD NIH HHS [R01 HD033937-11S1, R01 HD033937, R01 HD033937-11, R01 HD041701, R01 HD041701-01] NR 19 TC 12 Z9 12 U1 0 U2 3 PU W B SAUNDERS CO LTD PI LONDON PA 32 JAMESTOWN RD, LONDON NW1 7BY, ENGLAND SN 0143-4004 J9 PLACENTA JI Placenta PD APR PY 2007 VL 28 SU A BP S107 EP S110 DI 10.1016/j.placenta.2007.01.017 PG 4 WC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology SC Developmental Biology; Obstetrics & Gynecology; Reproductive Biology GA 161EG UT WOS:000245996600019 PM 17382999 ER PT J AU Daly, MJ Gaidamakova, EK Matrosova, VY Vasilenko, A Zhai, M Leapman, RD Lai, B Ravel, B Li, SMW Kemner, KM Fredrickson, JK AF Daly, Michael J. Gaidamakova, Elena K. Matrosova, Vera Y. Vasilenko, Alexander Zhai, Min Leapman, Richard D. Lai, Barry Ravel, Bruce Li, Shu-Mei W. Kemner, Kenneth M. Fredrickson, James K. TI Protein oxidation implicated as the primary determinant of bacterial radioresistance SO PLOS BIOLOGY LA English DT Article ID IONIZING-RADIATION DAMAGE; ABSORPTION FINE-STRUCTURE; DEINOCOCCUS-RADIODURANS; CRYOELECTRON MICROSCOPY; SHEWANELLA-ONEIDENSIS; SUPEROXIDE-DISMUTASE; VITREOUS SECTIONS; HYDROGEN-PEROXIDE; AMINO-ACIDS; RESISTANCE AB In the hierarchy of cellular targets damaged by ionizing radiation (IR), classical models of radiation toxicity place DNA at the top. Yet, many prokaryotes are killed by doses of IR that cause little DNA damage. Here we have probed the nature of Mn-facilitated IR resistance in Deinococcus radiodurans, which together with other extremely IR-resistant bacteria have high intracellular Mn/Fe concentration ratios compared to IR-sensitive bacteria. For in vitro and in vivo irradiation, we demonstrate a mechanistic link between Mn(II) ions and protection of proteins from oxidative modifications that introduce carbonyl groups. Conditions that inhibited Mn accumulation or Mn redox cycling rendered D. radiodurans radiation sensitive and highly susceptible to protein oxidation. X-ray fluorescence microprobe analysis showed that Mn is globally distributed in D. radiodurans, but Fe is sequestered in a region between dividing cells. For a group of phylogenetically diverse IR-resistant and IR-sensitive wild-type bacteria, our findings support the idea that the degree of resistance is determined by the level of oxidative protein damage caused during irradiation. We present the case that protein, rather than DNA, is the principal target of the biological action of IR in sensitive bacteria, and extreme resistance in Mn-accumulating bacteria is based on protein protection. C1 Univ Hlth Sci, Uniformed Serv, Dept Pathol, Bethesda, MD USA. Natl Inst Biomed Imaging & Bioengn, NIH, Bethesda, MD USA. Argonne Natl Lab, Biosci Div & Adv Photon Source, Argonne, IL 60439 USA. Pacific NW Natl Lab, Biol Sci Div, Richland, WA 99352 USA. RP Daly, MJ (reprint author), Univ Hlth Sci, Uniformed Serv, Dept Pathol, Bethesda, MD USA. EM mdaly@usuhs.mil RI ID, MRCAT/G-7586-2011 NR 51 TC 185 Z9 187 U1 2 U2 31 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 APR PY 2007 VL 5 IS 4 BP 769 EP 779 AR e92 DI 10.1371/journal.pbio.0050092 PG 11 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 159XP UT WOS:000245901500010 ER PT J AU Shoemaker, BA Panchenko, AR AF Shoemaker, Benjamin A. Panchenko, Anna R. TI Deciphering protein-protein interactions. Part II. Computational methods to predict protein and domain interaction partners SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID CO-EVOLUTIONARY ANALYSIS; SUPPORT VECTOR MACHINES; INTERACTION NETWORKS; FUNCTIONAL LINKAGES; MICROBIAL GENOMES; INTERACTION SITES; REVEALS INSIGHTS; FUSION EVENTS; COEVOLUTION; CONSERVATION C1 Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, Bethesda, MD 20894 USA. RP Panchenko, AR (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, Computat Biol Branch, Bethesda, MD 20894 USA. EM panch@ncbi.nlm.nih.gov FU Intramural NIH HHS NR 79 TC 180 Z9 184 U1 2 U2 20 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD APR PY 2007 VL 3 IS 4 BP 595 EP 601 AR e43 DI 10.1371/journal.pcbi.0030043 PG 7 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 163VM UT WOS:000246191300002 PM 17465672 ER PT J AU Yang, MQ Koehly, LM Elnitski, L AF Yang, Mary Q. Koehly, Laura M. Elnitski, Laura TI Comprehensive annotation of bidirectional promoters identifies co-regulation among breast and ovarian cancer genes SO PLOS COMPUTATIONAL BIOLOGY LA English DT Article ID DNA METHYLATION PROFILES; HUMAN GENOME; COLORECTAL-CANCER; PROTEINS; MOUSE; CELLS AB A "bidirectional gene pair'' comprises two adjacent genes whose transcription start sites are neighboring and directed away from each other. The intervening regulatory region is called a "bidirectional promoter.'' These promoters are often associated with genes that function in DNA repair, with the potential to participate in the development of cancer. No connection between these gene pairs and cancer has been previously investigated. Using the database of spliced-expressed sequence tags (ESTs), we identified the most complete collection of human transcripts under the control of bidirectional promoters. A rigorous screen of the spliced EST data identified new bidirectional promoters, many of which functioned as alternative promoters or regulated novel transcripts. Additionally, we show a highly significant enrichment of bidirectional promoters in genes implicated in somatic cancer, including a substantial number of genes implicated in breast and ovarian cancers. The repeated use of this promoter structure in the human genome suggests it could regulate co-expression patterns among groups of genes. Using microarray expression data from 79 human tissues, we verify regulatory networks among genes controlled by bidirectional promoters. Subsets of these promoters contain similar combinations of transcription factor binding sites, including evolutionarily conserved ETS factor binding sites in ERBB2, FANCD2, and BRCA2. Interpreting the regulation of genes involved in co-expression networks, especially those involved in cancer, will be an important step toward defining molecular events that may contribute to disease. C1 NHGRI, Genome Technol Branch, NIH, Rockville, MD USA. NHGRI, Social & Behav Res Branch, NIH, Rockville, MD USA. RP Elnitski, L (reprint author), NHGRI, Genome Technol Branch, NIH, Rockville, MD USA. EM Elnitski@mail.nih.gov FU Intramural NIH HHS NR 32 TC 56 Z9 58 U1 1 U2 5 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1553-734X J9 PLOS COMPUT BIOL JI PLoS Comput. Biol. PD APR PY 2007 VL 3 IS 4 BP 733 EP 742 AR e72 DI 10.1371/journal.pcbi.0030072 PG 10 WC Biochemical Research Methods; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Mathematical & Computational Biology GA 163VM UT WOS:000246191300013 PM 17447839 ER PT J AU Lyon, HN Emilsson, V Hinney, A Heid, IM Lasky-Su, J Zhu, XF Thorleifsson, G Gunnarsdottir, S Walters, GB Thorsteinsdottir, U Kong, A Gulcher, J Nguyen, TT Scherag, A Pfeufer, A Meitinger, T Bronner, G Rief, W Soto-Quiros, ME Avila, L Klanderman, B Raby, BA Silverman, EK Weiss, ST Laird, N Ding, X Groop, L Tuomi, T Isomaa, B Bengtsson, K Butler, JL Cooper, RS Fox, CS O'Donnell, CJ Vollmert, C Celedon, JC Wichmann, HE Hebebrand, J Stefansson, K Lange, C Hirschhorn, JN AF Lyon, Helen N. Emilsson, Valur Hinney, Anke Heid, Iris M. Lasky-Su, Jessica Zhu, Xiaofeng Thorleifsson, Gudmar Gunnarsdottir, Steinunn Walters, G. Bragi Thorsteinsdottir, Unnur Kong, Augustine Gulcher, Jeffrey Nguyen, Thuy Trang Scherag, Andre Pfeufer, Arne Meitinger, Thomas Broenner, Guenter Rief, Winfried Soto-Quiros, Manuel E. Avila, Lydiana Klanderman, Barbara Raby, Benjamin A. Silverman, Edwin K. Weiss, Scott T. Laird, Nan Ding, Xiao Groop, Leif Tuomi, Tiinamaija Isomaa, Bo Bengtsson, Kristina Butler, Johannah L. Cooper, Richard S. Fox, Caroline S. O'Donnell, Christopher J. Vollmert, Caren Celedon, Juan C. Wichmann, H. Erich Hebebrand, Johannes Stefansson, Kari Lange, Christoph Hirschhorn, Joel N. TI The association of a SNP upstream of INSIG2 with body mass index is reproduced in several but not all cohorts SO PLOS GENETICS LA English DT Article ID HUMAN OBESITY; GENE; RISK; POLYMORPHISM; PREVALENCE; PHENOTYPES; VARIANTS; PROTEINS; FAMILIES; DISEASE AB A SNP upstream of the INSIG2 gene, rs7566605, was recently found to be associated with obesity as measured by body mass index (BMI) by Herbert and colleagues. The association between increased BMI and homozygosity for the minor allele was first observed in data from a genome-wide association scan of 86,604 SNPs in 923 related individuals from the Framingham Heart Study offspring cohort. The association was reproduced in four additional cohorts, but was not seen in a fifth cohort. To further assess the general reproducibility of this association, we genotyped rs7566605 in nine large cohorts from eight populations across multiple ethnicities (total n = 16,969). We tested this variant for association with BMI in each sample under a recessive model using family-based, population-based, and case-control designs. We observed a significant (p < 0.05) association in five cohorts but saw no association in three other cohorts. There was variability in the strength of association evidence across examination cycles in longitudinal data from unrelated individuals in the Framingham Heart Study Offspring cohort. A combined analysis revealed significant independent validation of this association in both unrelated (p = 0.046) and family-based (p = 0.004) samples. The estimated risk conferred by this allele is small, and could easily be masked by small sample size, population stratification, or other confounders. These validation studies suggest that the original association is less likely to be spurious, but the failure to observe an association in every data set suggests that the effect of SNP rs7566605 on BMI may be heterogeneous across population samples. C1 Childrens Hosp, Program Genom, Div Genet, Boston, MA 02115 USA. Childrens Hosp, Program Genom, Div Endocrinol, Boston, MA 02115 USA. Harvard Univ, Broad Inst, Program Med & Populat Genet, Cambridge, MA 02138 USA. MIT, Cambridge, MA 02139 USA. Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA. deCODE Genet, Reykjavik, Iceland. Univ Duisburg Essen, Rhein Kliniken Essen, Dept Child & Adolescent Psychiat, Essen, Germany. GSF, Inst Epidemiol, Natl Res Ctr Environm & Hlth, Neuherberg, Germany. Univ Munich, Inst Med Informat Biometry & Epidemiol, D-80539 Munich, Germany. Harvard Univ, Brigham & Womens Hosp, Sch Med, Channing Lab, Boston, MA 02115 USA. SUNY Upstate Med Univ, Syracuse, NY USA. Case Western Reserve Univ, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA. Univ Marburg, Inst Med Biometry & Epidemiol, D-35032 Marburg, Germany. Univ Marburg, Dept Clin Psychol & Psychotherapy, D-35032 Marburg, Germany. Tech Univ Munich, Inst Human Genet, D-8000 Munich, Germany. GSF, Natl Res Ctr Environm & Hlth, Genome Anal Ctr, Inst Human Genet, Neuherberg, Germany. Hosp Nacl Ninos Dr Carlos Saenz Herrera, Div Pediat Pulm, San Jose, Costa Rica. Lund Univ, Univ Hosp MAS, Dept Endocrinol, S-22100 Lund, Sweden. Univ Helsinki, Cent Hosp, Dept Med, FIN-00014 Helsinki, Finland. Univ Helsinki, Res Program Mol Med, FIN-00014 Helsinki, Finland. Folkhalsan Res Ctr, Helsinki, Finland. Loyola Univ, Med Ctr, Dept Prevent Med & Epidemiol, Maywood, IL 60153 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Lyon, HN (reprint author), Childrens Hosp, Program Genom, Div Genet, 300 Longwood Ave, Boston, MA 02115 USA. EM helen.lyon@childrens.harvard.edu RI Genetic Epidemiology, Innsbruck Med.Univ./C-2095-2008; Hinney, Anke/D-6953-2011; Pfeufer, Arne/B-6634-2013; Meitinger, Thomas/O-1318-2015; OI Hinney, Anke/0000-0001-5659-0706; Scherag, Andre/0000-0002-9406-4704; Tuomi, Tiinamaija/0000-0002-8306-6202 FU NHLBI NIH HHS [R01 HL074166, HL04370, HL066289, K01 HL004370, N01-HC-25195, N01HC25195, R01 HL066289, R01 HL54485, R37 HL066289, U01 HL054485]; NIDDK NIH HHS [K23 DK067288] NR 38 TC 103 Z9 105 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA SN 1553-7404 J9 PLOS GENET JI PLoS Genet. PD APR PY 2007 VL 3 IS 4 AR e61 DI 10.1371/journal.pgen.0030061 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 161UM UT WOS:000246041700017 PM 17465681 ER PT J AU Maldarelli, F Palmer, S King, MS Wiegand, A Polis, MA Mican, JA Kovacs, JA Davey, RT Rock-Kress, D Dewar, R Liu, SY Metcalf, JA Rehm, C Brun, SC Hanna, GJ Kempf, DJ Coffin, JM Mellors, JW AF Maldarelli, Frank Palmer, Sarah King, Martin S. Wiegand, Ann Polis, Michael A. Mican, JoAnn Kovacs, Joseph A. Davey, Richard T. Rock-Kress, Diane Dewar, Robin Liu, Shuying Metcalf, Julia A. Rehm, Catherine Brun, Scott C. Hanna, George J. Kempf, Dale J. Coffin, John M. Mellors, John W. TI ART suppresses plasma HIV-1 RNA to a stable set point predicted by pretherapy viremia SO PLOS PATHOGENS LA English DT Article ID VIRUS TYPE-1 RNA; ACTIVE ANTIRETROVIRAL THERAPY; CD4(+) T-CELLS; COMBINATION THERAPY; LATENT RESERVOIR; DRUG-RESISTANCE; VIRAL LOAD; NELFINAVIR; INFECTION; REPLICATION AB Current antiretroviral therapy is effective in suppressing but not eliminating HIV-1 infection. Understanding the source of viral persistence is essential for developing strategies to eradicate HIV-1 infection. We therefore investigated the level of plasma HIV-1 RNA in patients with viremia suppressed to less than 50-75 copies/ml on standard protease inhibitor- or non-nucleoside reverse transcriptase inhibitor-containing antiretroviral therapy using a new, real-time PCR-based assay for HIV-1 RNA with a limit of detection of one copy of HIV-1 RNA. Single copy assay results revealed that > 80% of patients on initial antiretroviral therapy for 60 wk had persistent viremia of one copy/ml or more with an overall median of 3.1 copies/ml. The level of viremia correlated with pretherapy plasma HIV-1 RNA but not with the specific treatment regimen. Longitudinal studies revealed no significant decline in the level of viremia between 60 and 110 wk of suppressive antiretroviral therapy. These data suggest that the persistent viremia on current antiretroviral therapy is derived, at least in part, from long-lived cells that are infected prior to initiation of therapy. C1 HIV Drug Resistance Program, NCI, Frederick, MD USA. Abbott Labs, Global Pharmaceut Res & Dev, Abbott Pk, IL USA. Nalt Inst Allergy & Infect Dis, Lab Immunoregulat, NIH, Bethesda, MD USA. Natl Inst Hlth Clin Ctr, Dept Crit Care, NIH, Bethesda, MD USA. SAIC Frederick, Frederick, MD USA. Univ Pittsburgh, Ctr Med, Div Infect Dis, Pittsburgh, PA USA. RP Maldarelli, F (reprint author), HIV Drug Resistance Program, NCI, Frederick, MD USA. EM fmalli@mail.nih.gov OI Polis, Michael/0000-0002-9151-2268 NR 33 TC 180 Z9 181 U1 0 U2 3 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 APR PY 2007 VL 3 IS 4 BP 484 EP 488 AR e46 DI 10.1371/journal.ppat.0030046 PG 5 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 196VP UT WOS:000248510600003 PM 17411338 ER PT J AU Wickner, RB Edskes, HK Shewmaker, F Nakayashiki, T Engel, A McCann, L Kryndushkin, D AF Wickner, Reed B. Edskes, Herman K. Shewmaker, Frank Nakayashiki, Toru Engel, Abbi McCann, Linsay Kryndushkin, Dmitry TI Yeast Prions Evolution of the Prion Concept SO PRION LA English DT Review DE Ure2; Sup35; Rnq1; HETs; PrP; prion; amyloid ID BETA-AMYLOID FIBRILS; SOLID-STATE NMR; UREIDOSUCCINIC ACID UPTAKE; SACCHAROMYCES-CEREVISIAE; SUP35 PROTEIN; TRANSLATION TERMINATION; PODOSPORA-ANSERINA; GENETIC-VARIATION; STRUCTURAL MODEL; POLAR ZIPPERS AB Prions (infectious proteins) analogous to the scrapie agent have been identified in Saccharomyces cerevisiae and Podospora anserina based on their special genetic characteristics. Each is a protein acting as a gene, much like nucleic acids have been shown to act as enzymes. The [URE3], [PSI(+)], [PIN(+)] and [Het-s] prions are self-propagating amyloids of Ure2p, Sup35p, Rnq1p and the HET-s protein, respectively. The [beta] and [C] prions are enzymes whose precursor activation requires their own active form. [URE3] and [PSI(+)] are clearly diseases, while [Het-s] and [beta] carry out normal cell functions. Surprisingly, the prion domains of Ure2p and Sup35p can be randomized without loss of ability to become a prion. Thus amino acid content and not sequence determine these prions. Shuffleability also suggests amyloids with a parallel in-register beta-sheet structure. C1 [Wickner, Reed B.] NIDDK, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Wickner, RB (reprint author), NIDDK, Lab Biochem & Genet, NIH, Bldg 8,Room 207, Bethesda, MD 20892 USA. EM wickner@helix.nih.gov FU NIH; NIDDK FX This research was supported in part by the Intramural Research Program of the NIH, NIDDK. NR 73 TC 20 Z9 23 U1 1 U2 7 PU LANDES BIOSCIENCE PI AUSTIN PA 1002 WEST AVENUE, 2ND FLOOR, AUSTIN, TX 78701 USA SN 1933-6896 J9 PRION JI Prion PD APR-JUN PY 2007 VL 1 IS 2 BP 94 EP 100 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 380MA UT WOS:000261468600003 PM 19164928 ER PT J AU Glinder, JG Beckjord, E Kaiser, CR Compas, BE AF Glinder, Judith G. Beckjord, Ellen Kaiser, Cheryl R. Compas, Bruce E. TI Psychological adjustment to breast cancer: Automatic and controlled responses to stress SO PSYCHOLOGY & HEALTH LA English DT Article DE breast cancer; coping; stress responses; attentional bias ID ATTENTIONAL BIASES; NEGATIVE INFORMATION; STROOP TASK; ANXIETY; DEPRESSION; AWARENESS; THREAT; ADOLESCENCE; DYSPHORIA; RELEVANCE AB This study investigated the role of controlled and automatic responses to stress following a breast cancer diagnosis by combining self-report measures of coping and psychological distress and experimental measures of attention. Within 3 months of receiving a primary diagnosis of breast cancer, 135 women completed questionnaires assessing affect, responses to stress, and responded to a modified probe position task to measure supraliminal (conscious) and subliminal (non-conscious) attentional bias to cancer words and social threat words. Participants selectively attended to supraliminal cancer-related words and avoided subliminal cancer-related words; however, they showed no attentional bias toward or away from social threat words. An attentional bias toward supraliminal cancer-related words was associated with lower self-reported symptoms of emotional distress and higher levels of positive affect and engagement coping. This study demonstrates the utility of combining experimental and self-report methods to understand the full range of responses to stress following a breast cancer diagnosis. C1 Vanderbilt Univ, Peabody Coll 512, Nashville, TN 37203 USA. NCI, Canc Prevent Fellowship Program, NIH, Bethesda, MD 20892 USA. Michigan State Univ, E Lansing, MI 48824 USA. RP Compas, BE (reprint author), Vanderbilt Univ, Peabody Coll 512, 230 Appleton Pl, Nashville, TN 37203 USA. EM bruce.compas@vanderbilt.edu NR 48 TC 12 Z9 12 U1 1 U2 9 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0887-0446 J9 PSYCHOL HEALTH JI Psychol. Health PD APR PY 2007 VL 22 IS 3 BP 337 EP 359 DI 10.1080/14768320600843168 PG 23 WC Public, Environmental & Occupational Health; Psychology, Multidisciplinary SC Public, Environmental & Occupational Health; Psychology GA 141FJ UT WOS:000244563700006 ER PT J AU Hefner, K Holmes, A AF Hefner, Kathryn Holmes, Andrew TI An investigation of the behavioral actions of ethanol across adolescence in mice SO PSYCHOPHARMACOLOGY LA English DT Article DE juvenile; alcohol; mouse; behavior; addiction; metabolism; development; drinking; intoxication ID NMDA RECEPTOR NR2A; ADULT RATS; ALCOHOL-USE; AGE; SENSITIVITY; CONSUMPTION; BRAIN; ONSET; COORDINATION; PREFERENCE AB Rationale The transition from adolescence into adulthood is characterized by rapid maturation of brain systems mediating reward and by increasing experimentation with drugs of abuse including ethanol (EtOH). Previous studies have found marked differences in sensitivity to the behavioral effects of EtOH in adolescent rats as compared to adults, but relatively few studies have been conducted in mice. Objectives The present study examined sensitivity to various behavioral effects of EtOH in C57BL/6J mice at various stages of adolescence/adulthood (4, 6, 8 weeks old). Ages were compared for locomotor stimulant (open field), anxiolytic-like (elevated plus-maze), memory-impairing (Pavlovian fear conditioning) and ataxic (accelerating rotarod) effects of EtOH, and the sedative/hypnotic (sleep time) effects of EtOH and pentobarbital. EtOH self-administration was compared using a two-bottle choice paradigm. Measures of EtOH metabolism were also obtained. Results Early adolescent mice exhibited increased sensitivity to locomotor stimulant (1.5 g/kg), anxiolytic-like (1.5 g/kg) and ataxic (1.5-2.5 g/kg), but not memory impairing (2.0 g/kg), effects of EtOH relative to adults. Early adolescent, and to some extent peri-adolescent, mice were less sensitive than adults to the sedative/hypnotic effects of EtOH (3.5-4.5 g/kg), but not pentobarbital (4050 mg/kg). Early adolescent mice showed lower EtOH preference, but not EtOH consumption, than adults. Blood EtOH concentrations were higher at early time points and lower at later time points after (3.0 g/kg) EtOH injection in early and peri-adolescents relative to adults. Conclusions Present data demonstrate that sensitivity to the acute intoxicating effects of EtOH changes across mouse adolescent development in a behavior-dependent manner. C1 NIMH, NIAAA, Lab Integrat Neurosci, Sect Behav Sci & Genet, Rockville, MD 20852 USA. RP Holmes, A (reprint author), NIMH, NIAAA, Lab Integrat Neurosci, Sect Behav Sci & Genet, 5625 Fishers Lane Rm 2N09, Rockville, MD 20852 USA. EM holmesan@mail.nih.gov OI Hefner, Kathryn/0000-0002-5208-7860 FU Intramural NIH HHS NR 56 TC 58 Z9 58 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD APR PY 2007 VL 191 IS 2 BP 311 EP 322 DI 10.1007/s00213-006-0646-2 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 157WE UT WOS:000245751300013 PM 17206494 ER PT J AU Vrijheid, M Cardis, E Blettner, M Gilbert, E Hakama, M Hill, C Howe, G Kaldor, J Muirhead, CR Schubauer-Berigan, M Yoshimura, T Ahn, YO Ashmore, P Auvinen, A Bae, JM Engels, H Gulis, G Habib, RR Hosoda, Y Kurtinaitis, J Malker, H Moser, M Rodriguez-Artalejo, E Rogel, A Tardy, H Telle-Lamberton, M Turai, I Usel, M Veress, K AF Vrijheid, M. Cardis, E. Blettner, M. Gilbert, E. Hakama, M. Hill, C. Howe, G. Kaldor, J. Muirhead, C. R. Schubauer-Berigan, M. Yoshimura, T. Ahn, Y-O Ashmore, P. Auvinen, A. Bae, J-M. Engels, H. Gulis, G. Habib, R. R. Hosoda, Y. Kurtinaitis, J. Malker, H. Moser, M. Rodriguez-Artalejo, E. Rogel, A. Tardy, H. Telle-Lamberton, M. Turai, I. Usel, M. Veress, K. TI The 15-country collaborative study of cancer risk among radiation workers in the nuclear industry: Design, epidemiological methods and descriptive results SO RADIATION RESEARCH LA English DT Article ID COMPUTERIZED RECORD LINKAGE; NATIONAL DEATH INDEX; LOW-DOSE EXPOSURE; IONIZING-RADIATION; MORTALITY DATA; HANFORD SITE; FOLLOW-UP; COHORT; RATES; COMPARABILITY AB Radiation protection standards are based mainly on risk estimates from studies of atomic bomb survivors in Japan. The validity of extrapolations from the relatively high-dose acute exposures in this population to the low-dose, protracted or fractionated environmental and occupational exposures of primary public health concern has long been the subject of controversy. A collaborative retrospective cohort study was conducted to provide direct estimates of cancer risk after low-dose protracted exposures. The study included nearly 600,000 workers employed in 154 facilities in 15 countries. This paper describes the design, methods and results of descriptive analyses of the study. The main analyses included 407,391 nuclear industry workers employed for at least 1 year in a participating facility who were monitored individually for external radiation exposure and whose doses resulted predominantly from exposure to higher-energy photon radiation. The total duration of follow-up was 5,192,710 person-years. There were 24,158 deaths from all causes, including 6,734 deaths from cancer. The total collective dose was 7,892 Sv. The overall average cumulative recorded dose was 19.4 mSv. A strong healthy worker effect was observed in most countries. This study provides the largest body of direct evidence to date on the effects of low-dose protracted exposures to external photon radiation. (c) 2007 by Radiation Research Society. C1 Int Agcy Res Canc, F-69372 Lyon 08, France. Johannes Gutenberg Univ Mainz, Inst Med Biometrie, D-6500 Mainz, Germany. Natl Canc Inst, Div Epidemiol & Genet, Radiat Epidemiol Branch, Bethesda, MD USA. Univ Tampere, FIN-33101 Tampere, Finland. Inst Gustave Roussy, Villejuif, France. Finnish Canc Registry, Helsinki, Finland. Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY USA. Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW, Australia. Hlth Protect Agcy, Radiat Protect Div, Chilton, England. NIOSH, Cincinnati, OH 45226 USA. Univ Occupat & Environm Hlth, Dept Clin Epidemiol, Inst Ind Ecol Sci, Kitakyushu, Fukuoka 807, Japan. Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. Hlth Canada, Radiat Protect Bur, Ottawa, ON K1A 0L2, Canada. STUK Radiat & Nucl Safety Author, Helsinki, Finland. Jeju Natl Univ, Coll Med, Dept Prevent Med, Chejudo, South Korea. CEN SCK, Nucl Res Ctr, Radiat Protect Div, B-2400 Mol, Belgium. FANC, Brussels, Belgium. Trnava Univ, Dept Hyg & Epidemiol, Fac Hlth Care & Social Work, Trnava, Slovakia. Amer Univ Beirut, Fac Hlth Sci, Beirut, Lebanon. Vilnius State Univ, Inst Oncol, Lithuanian Canc Registry, Vilnius, Lithuania. Sundsvall Hosp, Midsweden Res & Dev Ctr, Sundsvall, Sweden. Fed Off Publ Hlth, Bern, Switzerland. Univ Autonoma Madrid, Sch Med, Dept Prevent Med & Publ Hlth, E-28049 Madrid, Spain. Elect France, Serv Cent Appui Sante Travail, Paris, France. Inst Radioprotect & Surete Nucl, Fontenay Aux Roses, France. Natl Fodor Jozsef Publ Hlth Ctr, Natl Frederic Joliot Curie Res Inst Radiobiol & R, Budapest, Hungary. Semmelweis Univ, Dept Dermatol Venereol & Dermatooncol, H-1085 Budapest, Hungary. RP Vrijheid, M (reprint author), Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon 08, France. EM vrijheid@iarc.fr RI Schubauer-Berigan, Mary/B-3149-2009; Ahn, Yoon-Ok/J-5530-2012; Kaldor, John /D-4545-2011; Gulis, Gabriel/E-4505-2013; Cardis, Elisabeth/C-3904-2017; Vrijheid, M/H-2702-2014 OI Auvinen, Anssi/0000-0003-1125-4818; Schubauer-Berigan, Mary/0000-0002-5175-924X; Vrijheid, M/0000-0002-7090-1758 FU PHS HHS [U50/CCU011778] NR 45 TC 65 Z9 73 U1 0 U2 7 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD APR PY 2007 VL 167 IS 4 BP 361 EP 379 DI 10.1667/RR0554.1 PG 19 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 152AM UT WOS:000245332500001 PM 17388694 ER PT J AU Thierry-Chef, I Marshall, M Fix, JJ Bermann, F Gilbert, ES Hacker, C Heinmiller, B Murray, W Pearce, MS Utterback, D Bernar, K Deboodt, P Eklof, M Griciene, B Holan, K Hyvonen, H Kerekes, A Lee, MC Moser, M Pernicka, F Cardis, E AF Thierry-Chef, I. Marshall, M. Fix, J. J. Bermann, F. Gilbert, E. S. Hacker, C. Heinmiller, B. Murray, W. Pearce, M. S. Utterback, D. Bernar, K. Deboodt, P. Eklof, M. Griciene, B. Holan, K. Hyvonen, H. Kerekes, A. Lee, M-C. Moser, M. Pernicka, F. Cardis, E. TI The 15-country collaborative study of cancer risk among radiation workers in the nuclear industry: Study of errors in dosimetry SO RADIATION RESEARCH LA English DT Article ID IONIZING-RADIATION; EXPOSURE; ENERGY; UNCERTAINTY; MORTALITY; COUNTRIES; POWER AB To provide direct estimates of cancer risk after low-dose protracted exposure to ionizing radiation, a large-scale epidemiological study of nuclear industry workers was conducted in 15 countries. As part of this study, identification and quantification of errors in historical recorded doses was conducted based on a review of dosimetric practices and technologies in participating facilities. The main sources of errors on doses from "high-energy" photons (100-3000 keV) were identified as the response of dosimeters in workplace exposure conditions and historical calibration practices. Errors related to dosimetry technology and radiation fields were quantified to derive period- and facility-specific estimates of bias and uncertainties in recorded doses. This was based on (1) an evaluation of predominant workplace radiation from measurement studies and dosimetry expert assessment and (2) an estimation of the energy and geometry response of dosimeters used historically in study facilities. Coefficients were derived to convert recorded doses to HP(10) and organ dose, taking into account different aspects of the calibration procedures. A parametric, lognormal error structure model was developed to describe errors in doses as a function of facility and time period. Doses from other radiation types, particularly neutrons and radionuclide intake, could not be adequately reconstructed in the framework of the 15-Country Study. Workers with substantial doses from these radiation types were therefore identified and excluded from analyses. Doses from "lower-energy" photons (< 100 keV) and from "higher-energy" photons (> 3 MeV) were estimated to be small. (c) 2007 by Radiation Research Society. C1 Int Agcy Res Canc, F-69372 Lyon, France. Twin Trees, Didcot, Oxon, England. Dade Moeller & Associates, Richland, WA USA. CEA, Paris, France. Natl Canc Inst, Radiat Epidemiol Branch, Div Epidemiol & Genet, Bethesda, MD USA. Australian Nucl Sci & Technol Org, Radiat Protect Serv, Menai, NSW 2234, Australia. Chalk River Labs, AECL Radiat Biol & Hlth Phys Branch, Chalk River, ON, Canada. Oak Ridge Associated Univ, Cincinnati, OH USA. Univ Newcastle Upon Tyne, Sch Clin Med Sci, Paediat & Lifecourse Epidemiol Res Grp, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. NIOSH, Cincinnati, OH 45226 USA. Asoc Espanola Ind Elect UNESA, Madrid, Spain. CEN SCK, Nucl Res Ctr, Radiat Protect Div, B-2400 Mol, Belgium. Statens Vattenfallsverk Forsmark, Osthammer, Sweden. Radiat Protect Ctr, Vilnius, Lithuania. Slovenske Elektrarne AS, Bratislava, Slovakia. STUK Radiat & Nucl Safety Author, Helsinki, Finland. Natl Fodor Jozsef Publ Hlth Ctr, Natl Frederic Joliot Curie Res Inst Radiobiol & R, Budapest, Hungary. Seoul Natl Univ, Coll Med, Dept Nucl Med, Seoul, South Korea. Fed Off Publ Hlth, Bern, Switzerland. IAEA, A-1400 Vienna, Austria. RP Cardis, E (reprint author), 150 Cours Albert Thomas, F-69372 Lyon 08, France. EM cardis@iarc.fr RI Cardis, Elisabeth/C-3904-2017 FU PHS HHS [U50/CCU011778] NR 49 TC 35 Z9 36 U1 0 U2 7 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD APR PY 2007 VL 167 IS 4 BP 380 EP 395 DI 10.1667/RR0552.1 PG 16 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 152AM UT WOS:000245332500002 PM 17388692 ER PT J AU Cardis, E Vrijheid, M Blettner, M Gilbert, E Hakama, M Hill, C Howe, G Kaldor, J Muirhead, CR Schubauer-Berigan, M Yoshimura, T Bermann, F Cowper, G Fix, J Hacker, C Heinmiller, B Marshall, M Thierry-Chef, I Utterback, D Ahn, YO Amoros, E Ashmore, P Auvinen, A Bae, JM Bernar, J Biau, A Combalot, E Deboodt, P Sacristan, AD Eklof, M Engels, H Engholm, G Gulis, G Habib, RR Holan, K Hyvonen, H Kerekes, A Kurtinaitis, J Malker, H Martuzzi, M Mastauskas, A Monnet, A Moser, M Pearce, MS Richardson, DB Rodriguez-Artalejo, F Rogel, A Tardy, H Telle-Lamberton, M Turai, I Usel, M Veress, K AF Cardis, E. Vrijheid, M. Blettner, M. Gilbert, E. Hakama, M. Hill, C. Howe, G. Kaldor, J. Muirhead, C. R. Schubauer-Berigan, M. Yoshimura, T. Bermann, F. Cowper, G. Fix, J. Hacker, C. Heinmiller, B. Marshall, M. Thierry-Chef, I. Utterback, D. Ahn, Y-O Amoros, E. Ashmore, P. Auvinen, A. Bae, J-M. Bernar, J. Biau, A. Combalot, E. Deboodt, P. Sacristan, A. Diez Eklof, M. Engels, H. Engholm, G. Gulis, G. Habib, R. R. Holan, K. Hyvonen, H. Kerekes, A. Kurtinaitis, J. Malker, H. Martuzzi, M. Mastauskas, A. Monnet, A. Moser, M. Pearce, M. S. Richardson, D. B. Rodriguez-Artalejo, F. Rogel, A. Tardy, H. Telle-Lamberton, M. Turai, I. Usel, M. Veress, K. TI The 15-country collaborative study of cancer risk among radiation workers in the nuclear industry: Estimates of radiation-related cancer risks SO RADIATION RESEARCH LA English DT Article ID NATIONAL DOSE REGISTRY; EXTERNAL IONIZING-RADIATION; CAUSE-SPECIFIC MORTALITY; HANFORD SITE; OCCUPATIONAL-EXPOSURE; LUNG-CANCER; FOLLOW-UP; PLUTONIUM; COUNTRIES; CANADA AB A 15-Country collaborative cohort study was conducted to provide direct estimates of cancer risk following protracted low doses of ionizing radiation. Analyses included 407,391 nuclear industry workers monitored individually for external radiation and 5.2 million person-years of follow-up. A significant association was seen between radiation dose and all-cause mortality [excess relative risk (ERR) 0.42 per Sv, 90% CI 0.07, 0.79; 18,993 deaths]. This was mainly attributable to a dose-related increase in all cancer mortality (ERR/Sv 0.97, 90% CI 0.28, 1.77; 5233 deaths). Among 31 specific types of malignancies studied, a significant association was found for lung cancer (ERR/Sv 1.86, 90% CI 0.49, 3.63; 1457 deaths) and a borderline significant (P = 0.06) association for multiple myeloma (ERR/Sv 6.15, 90% CI < 0, 20.6; 83 deaths) and ill-defined and secondary cancers (ERR/Sv 1.96, 90% CI -0.26, 5.90; 328 deaths). Stratification on duration of employment had a large effect on the ERR/Sv, reflecting a strong healthy worker survivor effect in these cohorts. This is the largest analytical epidemiological study of the effects of low-dose protracted exposures to ionizing radiation to date. Further studies will be important to better assess the role of tobacco and other occupational exposures in our risk estimates. (c) 2007 by Radiation Research Society. C1 Int Agcy Res Canc, F-69372 Lyon 08, France. Johannes Gutenberg Univ Mainz, Inst Med Biometrie, D-6500 Mainz, Germany. NCI, Radiat Epidemiol Branch, Div Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Tampere, FIN-33101 Tampere, Finland. Finnish Canc Registry, FIN-00170 Helsinki, Finland. Inst Gustave Roussy, Villejuif, France. Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY USA. Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW, Australia. Hlth Protect Agcy, Radiat Protect Div, Didcot, Oxon, England. NIOSH, Cincinnati, OH 45226 USA. Univ Occupat & Environm Hlth, Dept Clin Epidemiol, Inst Ind Ecol Sci, Kitakyushu, Fukuoka 807, Japan. CEA, Conseiller Med, Paris, France. Atom Energy Commiss Canada, Deep River, ON, Canada. Dade Moeller & Associates, Richland, WA USA. Australian Nucl Sci & Technol Org, Radiat Protect Serv, Menai, NSW 2234, Australia. ACEL Radiat Biol & Hlth Phys Branch, Chalk River, ON, Canada. Twin Trees, Didcot, Oxon, England. Seoul Natl Univ, Coll Med, Dept Prevent Med, Seoul, South Korea. Hlth Canada, Radiat Protect Bur, Ottawa, ON K1A 0L2, Canada. STUK Radiat & Nucl Safety Author, Helsinki, Finland. Jeju Natl Univ, Coll Med, Dept Prevent Med, Chejudo, South Korea. UNESA, Madrid, Spain. DEAS, DESTQ, Inst Radioprotect & Surete Nucl, Le Vesinet, France. CEN SCK, Nucl Res Ctr, Radiat Protect Div, B-2400 Mol, Belgium. Consejo Seguridad Nucl, Madrid, Spain. Statens Vattenfallsverk Forsmark, Osthammer, Sweden. FANC, Brussels, Belgium. Natl Board Hlth & Welf, Stockholm, Sweden. Trnava Univ, Dept Hyg & Epidemiol, Fac Hlth Care & Social Work, Trnava, Slovakia. Amer Univ Beirut, Fac Hlth Sci, Beirut, Lebanon. Slovenske Elektrarne AS, Bratislava, Slovakia. Natl Fodor Jozsef Publ Hlth Cre, Natl Frederic Joliot Curie, Res Inst Radiobiol & Radiohyg, Budapest, Hungary. Vilnius State Univ, Lithuanian Canc Registry, Inst Oncol, Vilnius, Lithuania. Sundsvall Hosp, Midsweden Res & Dev Ctr, Sundsvall, Sweden. WHO, European Ctr Environm & Hlth, Rome, Italy. Radiat Protect Ctr, Vilnius, Lithuania. Serono Int SA, Geneva, Switzerland. Fed Off Publ Hlth, Bern, Switzerland. Newcastle Univ, Paediat & Lifecourse Epidemiol Res Grp, Sch Clin Med Sci, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Univ Autonoma Madrid, Dept Prevent Med & Publ Hlth, Sch Med, Madrid, Spain. Elect France, Serv Cent Appui Sante Travail, Paris, France. Inst Radioprotect & Surete Nucl, Fontenay Aux Roses, France. Med Inspectorate Factories, Geneva, Switzerland. Semmelweis Univ, Dept Dermatol Venerol & Dermatooncol, H-1085 Budapest, Hungary. RP Cardis, E (reprint author), Int Agcy Res Canc, 150 Cours Albert Thomas, F-69372 Lyon 08, France. EM cardis@iarc.fr RI Cardis, Elisabeth/C-3904-2017; Vrijheid, M/H-2702-2014; Schubauer-Berigan, Mary/B-3149-2009; Ahn, Yoon-Ok/J-5530-2012; Kaldor, John /D-4545-2011; Gulis, Gabriel/E-4505-2013; Amoros, Emmanuelle/G-4334-2013 OI Vrijheid, M/0000-0002-7090-1758; Auvinen, Anssi/0000-0003-1125-4818; Schubauer-Berigan, Mary/0000-0002-5175-924X; FU PHS HHS [U50/CCU011778] NR 50 TC 332 Z9 354 U1 4 U2 24 PU RADIATION RESEARCH SOC PI LAWRENCE PA 810 E TENTH STREET, LAWRENCE, KS 66044 USA SN 0033-7587 J9 RADIAT RES JI Radiat. Res. PD APR PY 2007 VL 167 IS 4 BP 396 EP 416 DI 10.1667/RR0553.1 PG 21 WC Biology; Biophysics; Radiology, Nuclear Medicine & Medical Imaging SC Life Sciences & Biomedicine - Other Topics; Biophysics; Radiology, Nuclear Medicine & Medical Imaging GA 152AM UT WOS:000245332500003 PM 17388693 ER PT J AU Hricak, H Choyke, PL Eberhardt, SC Leibel, SA Scardino, PT AF Hricak, Hedvig Choyke, Peter L. Eberhardt, Steven C. Leibel, Steven A. Scardino, Peter T. TI Imaging prostate cancer: A multidisciplinary perspective SO RADIOLOGY LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; LYMPH-NODE METASTASES; RADICAL RETROPUBIC PROSTATECTOMY; INTENSITY-MODULATED RADIOTHERAPY; DOMINANT INTRAPROSTATIC LESIONS; SEMINAL-VESICLE INVASION; RADIONUCLIDE BONE-SCAN; CELL LUNG-CANCER; EXTRACAPSULAR EXTENSION; LOCAL RECURRENCE AB The major goal for prostate cancer imaging in the next decade is more accurate disease characterization through the synthesis of anatomic, functional, and molecular imaging information. No consensus exists regarding the use of imaging for evaluating primary prostate cancers. Ultrasonography is mainly used for biopsy guidance and brachytherapy seed placement. Endorectal magnetic resonance ( MR) imaging is helpful for evaluating local tumor extent, and MR spectroscopic imaging can improve this evaluation while providing information about tumor aggressiveness. MR imaging with superparamagnetic nanoparticles has high sensitivity and specificity in depicting lymph node metastases, but guidelines have not yet been developed for its use, which remains restricted to the research setting. Computed tomography (CT) is reserved for the evaluation of advanced disease. The use of combined positron emission tomography/ CT is limited in the assessment of primary disease but is gaining acceptance in prostate cancer treatment follow-up. Evidence-based guidelines for the use of imaging in assessing the risk of distant spread of prostate cancer are available. Radionuclide bone scanning and CT supplement clinical and biochemical evaluation (prostate-specific antigen [PSA], prostatic acid phosphate) for suspected metastasis to bones and lymph nodes. Guidelines for the use of bone scanning (in patients with PSA level > 10 ng/mL) and CT (in patients with PSA level > 20 ng/mL) have been published and are in clinical use. Nevertheless, changes in practice patterns have been slow. This review presents a multidisciplinary perspective on the optimal role of modern imaging in prostate cancer detection, staging, treatment planning, and follow-up. C1 Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Urol, New York, NY 10021 USA. NCI, Mol Imaging Program, Canc Res Ctr, Bethesda, MD 20892 USA. Univ New Mexico, Dept Radiol, Sch Med, Albuquerque, NM 87131 USA. Stanford Univ, Dept Radiat Oncol, Stanford, CA 94305 USA. RP Hricak, H (reprint author), Mem Sloan Kettering Canc Ctr, Dept Radiol, 1275 York Ave,C-278, New York, NY 10021 USA. EM hricakh@mskcc.org OI Hricak, Hedvig/0000-0003-2240-9694 NR 169 TC 295 Z9 304 U1 3 U2 26 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 APR PY 2007 VL 243 IS 1 BP 28 EP 53 DI 10.1148/radiol.2431030580 PG 26 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 151TA UT WOS:000245312500006 PM 17392247 ER PT J AU Heindel, JJ AF Heindel, Jerrold J. TI Role of exposure to environmental chemicals in the developmental basis of disease and dysfunction SO REPRODUCTIVE TOXICOLOGY LA English DT Editorial Material C1 NIEHS, Div Extramural Res & Training, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Heindel, JJ (reprint author), NIEHS, Div Extramural Res & Training, Dept Hlth & Human Serv, 79 TW Alexander Dr,Bldg 4401,3rd Floor,Mail Drop, Res Triangle Pk, NC 27709 USA. EM heindelj@niehs.nih.gov FU Intramural NIH HHS [NIH0010152617]; PHS HHS [NIH0010152617] NR 10 TC 30 Z9 31 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD APR-MAY PY 2007 VL 23 IS 3 BP 257 EP 259 DI 10.1016/j.reprotox.2007.01.006 PG 3 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 170FB UT WOS:000246646800001 PM 17331698 ER PT J AU Newbold, RR Padilla-Banks, E Snyder, RJ Phillips, TM Jefferson, WN AF Newbold, Retha R. Padilla-Banks, Elizabeth Snyder, Ryan J. Phillips, Terry M. Jefferson, Wendy N. TI Developmental exposure to endocrine disruptors and the obesity epidemic SO REPRODUCTIVE TOXICOLOGY LA English DT Review DE fetal exposure; neonatal exposure; overweight; obese; adipocytes; obesogens; diabetes; cardiovascular disease; epigenetic; DOHaD ID BODY-FAT DISTRIBUTION; FETAL ORIGINS; MOUSE UTERUS; DIETHYLSTILBESTROL; DISEASE; CHEMICALS; TRACT AB Xenobiotic and dietary compounds with hormone-like activity can disrupt endocrine signaling pathways that play important roles during perinatal differentiation and result in alterations that are not apparent until later in life. Evidence implicates developmental exposure to environmental hormone-mimics with a growing list of health problems. Obesity is currently receiving needed attention since it has potential to overwhelm health systems worldwide with associated illnesses such as diabetes and cardiovascular disease. Here, we review the literature that proposes an association of exposure to environmental endocrine disrupting chemicals with the development of obesity. We describe an animal model of developmental exposure to diethylstilbestrol (DES), a potent perinatal endocrine disruptor with estrogenic activity, to study mechanisms involved in programming an organism for obesity. This experimental animal model provides an example of the growing scientific field termed "the developmental origins of adult disease" and suggests new targets of abnormal programming by endocrine disrupting chemicals. Published by Elsevier Inc. C1 NIEHS, Dev Endocrinol & Endocrine Disruptor Sect, Sect Lab Mol Toxicol, NIH,DHHS, Res Triangle Pk, NC 27709 USA. DHHS, Div Bioengn & Phys Sci, Off Res Serv, Off Director,NIH, Bethesda, MD 20892 USA. RP Newbold, RR (reprint author), NIEHS, Dev Endocrinol & Endocrine Disruptor Sect, Sect Lab Mol Toxicol, NIH,DHHS, Mail Drop E4-02, Res Triangle Pk, NC 27709 USA. EM newbold1@niehs.nih.gov FU Intramural NIH HHS [Z01 ES070060-32] NR 31 TC 131 Z9 134 U1 3 U2 25 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD APR-MAY PY 2007 VL 23 IS 3 BP 290 EP 296 DI 10.1016/j.reprotox.2006.12.010 PG 7 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 170FB UT WOS:000246646800005 PM 17321108 ER PT J AU Jefferson, WN Padilla-Banks, E Newbold, RR AF Jefferson, Wendy N. Padilla-Banks, Elizabeth Newbold, Retha R. TI Disruption of the female reproductive system by the phytoestrogen genistein SO REPRODUCTIVE TOXICOLOGY LA English DT Article DE ovary; development; ovulation; ovarian differentiation; transgenerational effects ID SPRAGUE-DAWLEY RATS; SOY-BASED FORMULA; NEONATAL EXPOSURE; POLYOVULAR FOLLICLES; UDP-GLUCURONOSYLTRANSFERASE; DEVELOPMENTAL EXPOSURE; DIETHYLSTILBESTROL DES; UTERINE ADENOCARCINOMA; MAMMARY TUMORIGENESIS; POSTNATAL-DEVELOPMENT AB Studies in our laboratory have shown that developmental exposure to genistin causes deleterious effects on the reproductive system. Oral exposure to genistin (25 mg/kg) increases uterine weight at 5 days of age similar to subcutaneous injection of genistein (20 mg/kg) suggesting that subcutaneous injection of genisten is a suitable model for oral exposure to genistin. Mice treated neonatally by subcutaneous injection of genistin (0.5-50 mg/kg) exhibit altered ovarian differentiation leading to multi-oocyte follicles (MOFs). Ovarian function and estrous cyclicity were disrupted in genistin treated mice with increasing severity over time. Reduced fertility was observed in mice treated with genistein (0.5, 5, or 25 mg/kg) and infertility was observed at 50 mg/kg. Females generated from genistin 25 mg/kg females bred to control males have increased MOFs suggesting these effects can be transmitted to subsequent generations. Thus, neonatal treatment with genistin at environmentally relevant doses caused adverse consequences on reproduction in adulthood. (C) 2007 Published by Elsevier Inc. C1 NIEHS, NIH, Dev Endocrinol & Endocrine Disruptor Sect, Lab Mol Toxicol,DHHS, Res Triangle Pk, NC 27709 USA. RP Jefferson, WN (reprint author), NIEHS, NIH, Dev Endocrinol & Endocrine Disruptor Sect, Lab Mol Toxicol,DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM jeffers1@niehs.nih.gov FU Intramural NIH HHS NR 70 TC 74 Z9 80 U1 2 U2 14 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0890-6238 J9 REPROD TOXICOL JI Reprod. Toxicol. PD APR-MAY PY 2007 VL 23 IS 3 BP 308 EP 316 DI 10.1016/j.reprotox.2006.11.012 PG 9 WC Reproductive Biology; Toxicology SC Reproductive Biology; Toxicology GA 170FB UT WOS:000246646800007 PM 17250991 ER PT J AU Shankaran, S Lester, BM Das, A Bauer, CR Bada, HS Lagasse, L Higgins, R AF Shankaran, Seetha Lester, Barry M. Das, Abhik Bauer, Charles R. Bada, Henrietta S. Lagasse, Linda Higgins, Rosemary TI Impact of maternal substance use during pregnancy on childhood outcome SO SEMINARS IN FETAL & NEONATAL MEDICINE LA English DT Article DE alcohol; child medicine; cocaine; neonatal; neurobehavioral outcome; polydrug use; tobacco ID PRENATAL COCAINE EXPOSURE; NEUROLOGICAL SOFT SIGNS; LIFE-STYLE; IN-UTERO; INTRAUTERINE GROWTH; DRUG EXPOSURE; INFANTS; CHILDREN; AGE; BIRTH AB The impact of maternal substance abuse is reflected in the 2002-2003 National Survey on Drug Use and Health. Among pregnant women in the 15-44 age group, 4.3%, 18% and 9.8% used illicit drugs, tobacco and alcohol, respectively. Maternal pregnancy complications following substance use include increases in sexually transmitted disorders, placental abruption and HIV-positive status. Effects on the neonate include a decrease in growth parameters and increases in central nervous system and autonomic nervous system signs and in referrals to child protective agencies. In childhood, behavioral and cognitive effects are seen after prenatal cocaine exposure; tobacco and alcohol have separate and specific effects. The ongoing use of alcohol and tobacco by the caretaker affects childhood behavior. Therefore, efforts should be made to prevent and treat behavioral problems as well as to limit the onset of drug use by adolescent children born to women who use drugs during pregnancy. (c) 2007 Elsevier Ltd. All rights reserved. C1 Wayne State Univ, Sch Med, Detroit, MI USA. Childrens Hosp Michigan, Div Neonatol, Detroit, MI 48201 USA. Hutzel Womens Hosp, Detroit, MI USA. Brown Univ, Sch Med, Women & Infants Hosp Rhode Isl, Providence, RI 02912 USA. Res Triangle Inst, Rockville, MD USA. Univ Miami, Sch Med, Dept Pediat, Miami, FL 33152 USA. Univ Kentucky, Lexington, KY USA. Brown Univ, Sch Med, Dept Pediat, Providence, RI 02912 USA. NICHD, Ctr Dev Biol & Perinatal Med, NIH, Bethesda, MD USA. RP Shankaran, S (reprint author), Childrens Hosp Michigan, Div Neonatol, 3901 Beaubien, Detroit, MI 48201 USA. EM sshankar@med.wayner.edu FU NICHD NIH HHS [U10 HD021385] NR 42 TC 52 Z9 52 U1 3 U2 20 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1744-165X J9 SEMIN FETAL NEONAT M JI Semin. Fetal Neonatal Med. PD APR PY 2007 VL 12 IS 2 BP 143 EP 150 DI 10.1016/j.siny.2007.01.002 PG 8 WC Pediatrics SC Pediatrics GA 155ZR UT WOS:000245618100008 PM 17317350 ER PT J AU Schmidt, AC AF Schmidt, Alexander C. TI Progress in respiratory virus vaccine development SO SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Review DE vaccine; influenza virus; parainfluenza virus; metapneumovirus; respiratory syncytial virus; clinical trial ID HUMAN METAPNEUMOVIRUS LACKING; L-POLYMERASE PROTEIN; ATTENUATION IN-VIVO; SYNCYTIAL VIRUS; PANDEMIC INFLUENZA; REVERSE GENETICS; HETEROLOGOUS PARAMYXOVIRUSES; PARENTERAL IMMUNIZATION; TYPE-3 VACCINE; H5N1 VACCINE AB Viral respiratory infections continue to cause significant morbidity and mortality in infants and young children as well as in at-risk adults and the elderly. Although many viral pathogens are capable of causing acute respiratory disease, vaccine development has to focus on a limited number of pathogens (i.e., agents that commonly cause serious lower respiratory disease). Inactivated and, more recently, live attenuated influenza virus vaccines are the mainstay of interpandemic influenza prevention, but vaccines are not available yet for other important viruses such as respiratory syncytial virus, metapneumovirus, the parainfluenza viruses, and avian influenza viruses with pandemic potential. Reverse genetics systems that allow rational vaccine development are now widely used, and considerable progress has been made in preclinical and clinical development of novel respiratory virus vaccines. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Schmidt, AC (reprint author), NIAID, Infect Dis Lab, NIH, 50 S Dr,Rm 6511, Bethesda, MD 20892 USA. EM schmidta@niaid.nih.gov FU Intramural NIH HHS NR 73 TC 9 Z9 9 U1 0 U2 0 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 1069-3424 J9 SEMIN RESP CRIT CARE JI Semin. Respir. Crit. Care Med. PD APR PY 2007 VL 28 IS 2 BP 243 EP 252 DI 10.1055/s-2007-976495 PG 10 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 160ZF UT WOS:000245983400010 PM 17458777 ER PT J AU Calhoun, FJ AF Calhoun, Faye J. TI Developmental research on alcohol and spirituality: What we know and what we don't know SO SOUTHERN MEDICAL JOURNAL LA English DT Article C1 NIAAA, NIH, Bethesda, MD USA. RP Calhoun, FJ (reprint author), 510 Holloway St, Durham, NC 27701 USA. EM fbroadwater@verizon.net 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 0038-4348 J9 SOUTH MED J JI South.Med.J. PD APR PY 2007 VL 100 IS 4 BP 427 EP 429 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 172AX UT WOS:000246777600034 PM 17458416 ER PT J AU Dunson, DB AF Dunson, David B. TI Empirical bayes density regression SO STATISTICA SINICA LA English DT Article DE conditional density estimation; Dirichlet process; EM algorithm; Gaussian mixture sieve; Gibbs sampling; nonlinear regression; nonparametric Bayes; smoothing ID MAXIMUM-LIKELIHOOD-ESTIMATION; HIERARCHICAL MIXTURES; CONDITIONAL DENSITIES; DIRICHLET PROCESSES; EM ALGORITHM; MODELS; DISTRIBUTIONS; CONVERGENCE; INFERENCE; SELECTION AB In Bayesian hierarchical modeling, it is often appealing to allow the conditional density of an (observable or unobservable) random variable Y to change flexibly with categorical and continuous predictors X. A mixture of regression models is proposed, with the mixture distribution varying with X. Treating the smoothing parameters and number of mixture components as unknown, the MLE does not exist, motivating an empirical Bayes approach. The proposed method shrinks the spatially-adaptive mixture distributions to a common baseline, while penalizing rapid changes and large numbers of components. The discrete form of the mixture distribution facilitates flexible classification of subjects. A Gibbs sampling algorithm is developed, which embeds a Monte Carlo EM-type stage to estimate smoothing and hyper-parameters. The method is applied to simulated examples and data from an epidemiologic study. C1 NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Dunson, DB (reprint author), NIEHS, Biostat Branch, MD A3-03,POB 12233, Res Triangle Pk, NC 27709 USA. EM dunson1@niehs.nih.gov NR 45 TC 3 Z9 4 U1 0 U2 1 PU STATISTICA SINICA PI TAIPEI PA C/O DR H C HO, INST STATISTICAL SCIENCE, ACADEMIA SINICA, TAIPEI 115, TAIWAN SN 1017-0405 J9 STAT SINICA JI Stat. Sin. PD APR PY 2007 VL 17 IS 2 BP 481 EP 504 PG 24 WC Statistics & Probability SC Mathematics GA 208GG UT WOS:000249307200007 ER PT J AU Wadley, VG McClure, LA Howard, VJ Unverzagt, FW Go, RC Moy, CS Crowther, MR Gomez, CR Howard, G AF Wadley, Virginia G. McClure, Leslie A. Howard, Virginia J. Unverzagt, Frederick W. Go, Rodney C. Moy, Claudia S. Crowther, Martha R. Gomez, Camilo R. Howard, George TI Cognitive status, stroke symptom reports, and modifiable risk factors among individuals with no diagnosis of stroke or transient ischemic attack in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study SO STROKE LA English DT Article DE cardiovascular disease; cognition; depression; risk factors; stroke ID OLDER-ADULTS; POPULATION; HYPERTENSION; ASSOCIATION; PREVALENCE; ATTENTION; DEMENTIA; MEMORY AB Background and Purpose-Vascular disorders that increase risk for stroke may be accompanied by decrements in cognitive functioning and by stroke symptoms in the absence of diagnosed stroke or transient ischemic attack. This study evaluates relationships among cognitive status, stroke symptom reports, and cardiovascular and behavioral factors. Methods-REasons for Geographic and Racial Differences in Stroke (REGARDS), a prospective population study of stroke incidence, assesses stroke risk with telephone interviews and in-home physicals. Excluding subjects with a history of stroke or transient ischemic attack, this analysis includes 14 566 black and white men and women >= 45 years of age. Incremental logistic models examine baseline relationships among cognitive status (Six-item Screener scores), stroke symptom reports, demographics, health behaviors, cardiovascular indices, and depressive symptoms. Results-A history of stroke symptoms was related to impaired cognitive status after adjusting for age, gender, race, and education but not after adjusting for poor health behaviors, vascular risk factors, and depressive symptoms. Odds of experiencing a stroke symptom increased 35% with each of five modifiable factors (hypertension, diabetes, smoking, lack of exercise, depressive symptoms), and odds of cognitive impairment increased an additional 12% with each modifiable factor. Lifelong abstinence from alcohol, lack of exercise, and depressive symptoms were independently related to impaired cognitive status. Conclusions-The increased likelihood of cognitive impairment among subjects reporting stroke symptoms in the absence of a diagnosed stroke or transient ischemic attack suggests that such symptoms are not benign and may warrant clinical evaluation that includes a cognitive assessment. Future studies that include brain imaging may clarify the etiology of these symptoms. C1 Univ Alabama, Div Gerontol & Geriat Med, Dept Med, Birmingham, AL 35294 USA. Univ Alabama, Dept Biostat, Birmingham, AL 35294 USA. Univ Alabama, Dept Epidemiol, Birmingham, AL 35294 USA. Univ Alabama, Dept Hlth Behav, Birmingham, AL 35294 USA. Indiana Univ, Sch Med, Dept Psychiat, Indianapolis, IN 46202 USA. NINDS, NIH, Bethesda, MD 20892 USA. Alabama Neurol Inst, Birmingham, AL USA. RP Wadley, VG (reprint author), Univ Alabama, Div Gerontol & Geriat Med, Dept Med, CH19 218T,1530 3rd Ave S, Birmingham, AL 35294 USA. EM vwadley@uab.edu RI McClure, Leslie/P-2929-2015 FU NINDS NIH HHS [U01 NS041588, R01 NS041588] NR 21 TC 39 Z9 41 U1 2 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2007 VL 38 IS 4 BP 1143 EP 1147 DI 10.1161/01.STR.0000259676.75552.38 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 150JD UT WOS:000245211400011 PM 17322077 ER PT J AU Worrall, BB Brott, TG Brown, RD Brown, WM Rich, SS Arepalli, S Wavrant-De Vrieze, F Duckworth, J Singleton, AB Meschia, JF AF Worrall, Bradford B. Brott, Thomas G. Brown, Robert D., Jr. Brown, W. Mark Rich, Stephen S. Arepalli, Sampath Wavrant-De Vrieze, Fabienne Duckworth, Jaime Singleton, Andrew B. Meschia, James F. CA SWISS, ISGS, MSGD Investigators TI IL1RN VNTR polymorphism in ischemic stroke analysis in 3 populations SO STROKE LA English DT Article; Proceedings Paper CT 30th International Stroke Conference CY FEB 02-04, 2005 CL New Orleans, LA DE atherosclerosis; genetics; IL-1 receptor antagonist; ischemia; stroke ID INTERLEUKIN-1 RECEPTOR ANTAGONIST; CORONARY-ARTERY-DISEASE; HUMAN ENDOTHELIAL-CELLS; GENE POLYMORPHISMS; CAROTID ATHEROSCLEROSIS; INJURY; INFLAMMATION; ASSOCIATION; EXPRESSION; GENOTYPE AB Background and Purpose-Genetic factors influence risk for ischemic stroke and likely do so at multiple steps in the pathogenic process. Variants in genes related to inflammation contribute to risk of stroke. The purpose of this study was to confirm our earlier finding of an association between allele 2 of a variable number tandem repeat of the IL-1 receptor antagonist gene (IL1RN) and cerebrovascular disease. Methods-An association study of the variable number tandem repeat genotype with ischemic stroke and stroke subtypes was performed on samples from a North American study of affected sibling pairs concordant for ischemic stroke and 2 North American cohorts of prospectively ascertained ischemic stroke cases and unrelated controls. DNA analysis was performed on cases and controls, stratified by race. Results-After adjustment for age, sex, and stroke risk factors, the odds ratio for association of allele 2 and ischemic stroke was 2.80 (95% confidence interval, 1.29 to 6.11; P = 0.03) for the white participants. The effect of allele 2 of IL1RN on stroke risk most closely fits a recessive genetic model (P = 0.009). For the smaller sample of nonwhite participants, the results were not significant. Conclusions-Allele 2 of IL1RN, present in nearly one-quarter of stroke patients, may contribute to genetic risk for ischemic stroke and confirm the previously identified association with cerebrovascular disease. These results are driven by the association in the white participants. Further exploration in a larger nonwhite sample is warranted. C1 Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. Univ Virginia Hlth Syst, Dept Neurol, Charlottesville, VA USA. Univ Virginia Hlth Syst, Dept Publ Hlth Sci, Charlottesville, VA USA. Mayo Clin, Dept Neurol, Rochester, MN USA. Wake Forest Univ, Dept Publ Hlth Sci, Winston Salem, NC 27109 USA. NIA, Neurogenet Lab, Bethesda, MD 20892 USA. RP Meschia, JF (reprint author), Mayo Clin, Dept Neurol, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM meschia.james@mayo.edu RI Singleton, Andrew/C-3010-2009 FU Medical Research Council [G0701075]; NIDDK NIH HHS [P50DK0636091]; NINDS NIH HHS [K08 NS045802, K08 NS045802-03, K08-NS45802, R01 NS039987, R01 NS042733, R01 NS39987, R01 NS42733] NR 30 TC 19 Z9 22 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD APR PY 2007 VL 38 IS 4 BP 1189 EP 1196 DI 10.1161/01.STR.0000260099.42744.b0 PG 8 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 150JD UT WOS:000245211400019 PM 17332449 ER PT J AU Yasuno, F Sanabria, SM Burns, D Hargreaves, RJ Ghose, S Ichise, M Chin, FT Morse, CL Pike, VW Innis, RB AF Yasuno, Fumihiko Sanabria, Sandra M. Burns, Donald Hargreaves, Richard J. Ghose, Subroto Ichise, Masanori Chin, Frederick T. Morse, Cheryl L. Pike, Victor W. Innis, Robert B. TI PET imaging of neurokinin-1 receptors with [F-18]SPA-RQ in human subjects: Assessment of reference tissue models and their test-retest reproducibility SO SYNAPSE LA English DT Article DE positron emission tomography; noninvasive quantification; parametric image ID POSITRON-EMISSION-TOMOGRAPHY; SUBSTANCE-P RECEPTORS; HUMAN BRAIN; NK1 RECEPTORS; MICE LACKING; BINDING; ANTAGONIST; TACHYKININ; IMAGES AB [F-18]SPA-RQ (substance P antagonist receptor quantifier) labels the substance P-preferring (NK1) receptor in human brain. A prior study showed that [18F]SPA-RQ brain uptake can be quantified with a reference tissue method and thereby avoid invasive blood sampling. The purposes of this study were to compare three different reference tissue methods and to assess test-retest reproducibility. Eight healthy subjects underwent two [F-18]SPA-RQ scans. We calculated the binding potential (BP), which is proportional to receptor density, from both regional volume of interest and voxel-wise data. We compared three reference tissue methods: simplified reference tissue model, multilinear reference tissue model (MRTM), and its two-parameter version (MRTM2). The three methods generated equivalent values of regional BP, but MRTM2 was the most resistant to noise. Temporally stable values of BP were obtained with 240 min of imaging data. MRTM2 had excellent test-retest reproducibility, with high reliability (intraclass correlation > 0.9) and low variability (< 10%). In addition to regional volume of interest analysis, we also created parametric images of BP, variability, and reliability based on voxel-wise time-activity data. The reproducibility of parametric BP was also good, with variability < 20% and reliability > 0.7 in gray matter regions. In conclusion, a two-parameter reference tissue method (MRTM2) provided reproducible and reliable measurements of [F-18]SPA-RQ brain uptake using 240 min of both regional and voxelwise data. C1 NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. Merck Res Labs, West Point, PA USA. Univ Texas, SW Med Ctr, Dept Psychiat, Dallas, TX 75230 USA. Columbia Univ, Dept Radiol, New York, NY 10027 USA. RP Yasuno, F (reprint author), NIMH, Mol Imaging Branch, Bldg 1,Room B3-10,1 Ctr Dr, Bethesda, MD 20892 USA. EM yasunof@mail.nih.gov RI Ghose, Subroto/J-6732-2016 FU Intramural NIH HHS [ZIA MH002795-11]; NIMH NIH HHS [Z01 MH002852, Z01-MH-002852-01] NR 30 TC 12 Z9 12 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0887-4476 J9 SYNAPSE JI Synapse PD APR PY 2007 VL 61 IS 4 BP 242 EP 251 DI 10.1002/syn.20361 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 134TB UT WOS:000244105900006 PM 17230546 ER PT J AU Gourraud, PA Cambon-Thomsen, A Dauber, EM Feolo, M Hansen, J Mickelson, E Single, RM Thomsen, M Mayr, WR AF Gourraud, P. A. Cambon-Thomsen, A. Dauber, E. M. Feolo, M. Hansen, J. Mickelson, E. Single, R. M. Thomsen, M. Mayr, W. R. TI Nomenclature for HLA microsatellites SO TISSUE ANTIGENS LA English DT Article; Proceedings Paper CT 35th Annual Scientific Meeting of the Australasian-Society-for-Immunology/14th International HLA and Immunogenetics Workshops CY NOV 29-DEC 02, 2005 CL Melbourne, AUSTRALIA SP Australasian Soc Immunol DE HLA; major histocompatibility complex; microsatellite; nomenclature; short tandem repeat; standardization; variable number of tandem repeat AB A proposal for a standardized nomenclature for human leukocyte antigen (HLA) microsatellites is presented. It provides recommendations for Microsatellites as regards to locus name, primer names, and denominations for alleles. C1 Med Univ Wien, Klin Abt Blutgrp Serol, Div Blood Grp Serol, A-1090 Vienna, Austria. Fac Med Toulouse, INSERM, U558, Dept Epidemiol & Publ Hlth, F-31073 Toulouse, France. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. Univ Washington, Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98195 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. Univ Vermont, Dept Math & Stat, Burlington, VT 05405 USA. RP Mayr, WR (reprint author), Med Univ Wien, Klin Abt Blutgrp Serol, Div Blood Grp Serol, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. EM wolfgang.mayr@meduniwien.ac.at RI Thomsen, Mogens/B-7651-2011; Gourraud, Pierre-Antoine/O-3024-2015 OI Thomsen, Mogens/0000-0002-4546-0129; NR 7 TC 4 Z9 5 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0001-2815 J9 TISSUE ANTIGENS JI Tissue Antigens PD APR PY 2007 VL 69 SU 1 BP 210 EP 213 DI 10.1111/j.1399-0039.2006.00771.x PG 4 WC Cell Biology; Immunology; Pathology SC Cell Biology; Immunology; Pathology GA 157XI UT WOS:000245754300055 PM 17445203 ER PT J AU Wei, C Larsen, M Hoffman, MP Yamada, KM AF Wei, Cindy Larsen, Melinda Hoffman, Matthew P. Yamada, Kenneth M. TI Self-organization and branching morphogenesis of primary salivary epithelial cells SO TISSUE ENGINEERING LA English DT Article ID HEPATOCYTE GROWTH-FACTOR; BASEMENT-MEMBRANE MATRIX; INTERCALATED DUCT CELLS; SUBMANDIBULAR-GLAND; MAMMARY-GLAND; IN-VITRO; ALVEOLAR MORPHOGENESIS; GENE-EXPRESSION; PRIMARY CULTURE; ESSENTIAL ROLES AB Embryonic tissues may provide clues about mechanisms required for tissue reassembly and regeneration, but few studies have utilized primary embryonic tissue to study tissue assembly. To test the capacity of tissue fragments to regenerate, we cultured fragments of embryonic day 13 (E13) mouse submandibular gland (SMG) epithelium and found that fragments as small as a quarter-bud retain the ability to branch. Further, we found that completely dissociated SMG epithelial cells self-organize into structures that undergo significant branching. Investigation into the mechanisms involved in tissue self-assembly demonstrated that inhibition of beta(1) integrin prevents cell aggregation, while inhibition of E-cadherin hinders aggregate compaction. Immunostaining showed that the cellular architecture and expression patterns of E-cadherin, beta-catenin, and actin in the reassembled aggregates mirror those seen in intact glands. Adding SMG mesenchymal cells to the epithelial cell cultures facilitates branching and morphological differentiation. Quantitative real-time RT-PCR indicated that the aggregates express the differentiation markers aquaporin-5 (AQP5), prolactin-inducible protein (PIP), and SMG protein C (SMGC). Together, these data show that dissociated SMG epithelial cells self-organize and undergo branching morphogenesis to form tissues with structural features and differentiation markers characteristic of the intact gland. These findings provide insights into self-assembly and branching that will facilitate future regeneration strategies in the salivary gland and other organs. C1 NIDCR, CDBRB, NIH, Lab Cell & Dev Biol, Bethesda, MD 20892 USA. NIH, Howard Hughes Med Inst, Res Scholars Program, Bethesda, MD 20892 USA. Washington Univ, Sch Med, St Louis, MO USA. SUNY Albany, Dept Biol Sci, Albany, NY 12222 USA. RP Yamada, KM (reprint author), NIDCR, CDBRB, NIH, Lab Cell & Dev Biol, Bldg 30,Room 426,30 Convent Dr,MSC 4370, Bethesda, MD 20892 USA. EM mlarsen@albany.edu; kyamada@mail.nih.gov OI Yamada, Kenneth/0000-0003-1512-6805; Larsen, Melinda/0000-0002-5026-2012 FU Intramural NIH HHS NR 62 TC 57 Z9 60 U1 1 U2 12 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1076-3279 J9 TISSUE ENG JI Tissue Eng. PD APR PY 2007 VL 13 IS 4 BP 721 EP 735 DI 10.1089/ten.2006.0123 PG 15 WC Cell & Tissue Engineering SC Cell Biology GA 156WP UT WOS:000245680900008 PM 17341161 ER PT J AU Messer, K Pierce, JP Zhu, SH Hartman, AM Al-Delaimy, WK Trinidad, DR Gilpin, EA AF Messer, Karen Pierce, John P. Zhu, Shu-Hong Hartman, Anne M. Al-Delaimy, Wael K. Trinidad, Dennis R. Gilpin, Elizabeth A. TI The California tobacco control program's effect on adult smokers: (1) smoking cessation SO TOBACCO CONTROL LA English DT Article ID WORKPLACE SMOKING; UNITED-STATES; POPULATION; SELF; RESTRICTIONS; INFORMATION; CONSUMPTION; PREVALENCE; INITIATION; HOUSEHOLD AB Objectives: To estimate national population trends in long-term smoking cessation by age group and to compare cessation rates in California (CA) with those of two comparison groups of states. Setting: Retrospective smoking history of a population sample from the US: from CA, with a comprehensive tobacco-control programme since 1989 with the goal of denormalising tobacco use; from New York and New Jersey (NY & NJ), with similar high cigarette prices but no comprehensive programme; and from the tobacco-growing states (TGS), with low cigarette prices, no tobacco-control programme and social norms relatively supportive of tobacco use. Participants: Respondents to the Current Population Survey-Tobacco Use Supplements (1992 - 2002; n = 57 918 non-Hispanic white ever-smokers). Main outcome measures: The proportion of recent ever-smokers attaining long-term abstinence (quit >= 1 year) and the successful-quit ratio (the proportion of all ever-smokers abstinent >= 1 year). Results: Nationally, long-term cessation rates increased by 25% from the 1980s to the 1990s, averaging 3.4% per year in the 1990s. Cessation increased for all age groups, and by > 40% (p < 0.001) among smokers aged 20 - 34 years. For smokers aged,50 years, higher cigarette prices were associated with higher quitting rates. For smokers aged,35 years, quitting rates in CA were higher than in either comparison group (p < 0.05). Half of the ever-smokers had quit smoking by age 44 years in CA, 47 years in NY & NJ, and by age 54 years in TGS. Conclusion: Successful smoking cessation increased by 25% during the 1990s in the US. Comprehensive tobacco-control programmes were associated with greater cessation success than were with high cigarette prices alone, although both effects were limited to younger adults. C1 Univ Calif San Diego, Canc Prevent & Control Program, Moores UCSD Canc Ctr, La Jolla, CA 92093 USA. NCI, Div Canc Control & Populat Sci, Rockville, MD USA. RP Pierce, JP (reprint author), Univ Calif San Diego, Canc Prevent & Control Program, Moores UCSD Canc Ctr, 3855 Hlth Sci Dr,0901, La Jolla, CA 92093 USA. EM jppierce@ucsd.edu NR 50 TC 69 Z9 71 U1 0 U2 7 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0964-4563 J9 TOB CONTROL JI Tob. Control PD APR PY 2007 VL 16 IS 2 BP 85 EP 90 DI 10.1136/tc.2006.016873 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 152GR UT WOS:000245350100011 PM 17400944 ER PT J AU Golomb, E Schneider, A Houminer, E Dunnick, J Kissling, G Borman, JB Nyska, A Schwalb, H AF Golomb, Eliahu Schneider, Aviva Houminer, Esther Dunnick, June Kissling, Grace Borman, Joseph B. Nyska, Abraham Schwalb, Herzl TI Occult cardiotoxicity: Subtoxic dosage of bis(2-chloroethoxy)methane impairs cardiac response to simulated ischemic injury SO TOXICOLOGIC PATHOLOGY LA English DT Article DE bis(2-chloroethoxy)methane (CEM); cardiotoxicity; 3-(4,5)-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT); energy metabolism ID HUMAN MYOCARDIUM; MITOCHONDRIAL DYSFUNCTION; IN-VITRO; EARLY INDICATOR; CARDIOMYOCYTES; PROTECTION; EXPRESSION; APOPTOSIS; DAMAGE; HEART AB The effect of Bis(2-chloroethoxy)methane (CEM) on myocardial response to ischemia was tested in rats. CEM was dermally applied for 3 days to F344/N male rats, at 0, 100, 400, or 600 mg/kg/d. Subsequently, left ventricular sections were prepared from each rat heart. Part of the sections from each heart were exposed to 90 minutes of simulated ischemia, followed by 90 minutes of reoxygenation. The rest of the sections were continuously oxygenated. Mitochondrial activity was assessed in the sections by the MTT colorimetric assay, reflecting dehydrogenases redox activity. Myocardial toxicity occurred in response to 400 and 600 mg/kg, characterized by myofiber vacuoles, necrosis, and mononuclear infiltrates. The latter dose was lethal. In sections from rats treated with 400 mg/kg CEM, redox activity was decreased by 21% (p < 0.01) in oxygenated conditions and by 45% (p < 0.01) in ischemia-reoxygenation, compared to controls. Hearts of rats treated with 100 mg/kg/d CEM showed normal histology. Their mitochondrial activity did not differ from that of untreated rat hearts in oxygenated conditions. However, in ischemia-reoxygenation, their redox activity was significantly lower (by 46%, p < 0.01) than that of untreated rat hearts. These results demonstrate that subtoxic dosage of a cardiotoxic agent may cause occult cardiotoxicity, reflected by impaired response to ischemia. C1 Hadassah Hebrew Univ, Med Ctr, Joseph Lunenfeld Cardiac Surg Res Ctr, IL-91120 Jerusalem, Israel. Shaare Zedek Med Ctr, Dept Pathol, IL-91031 Jerusalem, Israel. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. Tel Aviv Univ, Sackler Med Sch, IL-23840 Tel Aviv, Israel. RP Schwalb, H (reprint author), Hadassah Hebrew Univ, Med Ctr, Joseph Lunenfeld Cardiac Surg Res Ctr, POB 12000, IL-91120 Jerusalem, Israel. EM schwalb@hadassah.org.il FU NIMH NIH HHS [273-MH-501726] NR 18 TC 8 Z9 8 U1 1 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 0192-6233 J9 TOXICOL PATHOL JI Toxicol. Pathol. PD APR PY 2007 VL 35 IS 3 BP 383 EP 387 DI 10.1080/01926230701230338 PG 5 WC Pathology; Toxicology SC Pathology; Toxicology GA 149AA UT WOS:000245117300007 PM 17455086 ER PT J AU Stroncek, DF Klein, HG AF Stroncek, David F. Klein, Harvey G. TI Heavy breathing in the blood bank: is it transfusion-related acute lung injury, our anxiety, or both? SO TRANSFUSION LA English DT Editorial Material ID RANDOMIZED CONTROLLED TRIAL; HLA ANTIBODIES; DONOR PLASMA; ANTIGEN; TRALI; PLATELETS; MODEL; NEUTROPHILS; TRANSPLANT; SPECTRUM C1 NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. EM dstroncek@cc.nih.gov NR 36 TC 7 Z9 7 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 APR PY 2007 VL 47 IS 4 BP 559 EP 562 DI 10.1111/j.1537-2995.2007.01183.x PG 4 WC Hematology SC Hematology GA 154ZC UT WOS:000245546300003 PM 17381610 ER PT J AU Luban, NLC Colvin, CA Mohan, P Alter, HJ AF Luban, Naomi L. C. Colvin, Camilla A. Mohan, Parvathi Alter, Harvey J. TI The epidemiology of transfusion-associated hepatitis C in a children's hospital SO TRANSFUSION LA English DT Article ID VIRUS-INFECTION; NATURAL-HISTORY; HCV INFECTION; UNITED-STATES; LIVER-DISEASE; BLOOD; RECIPIENTS; TRANSMISSION; NOTIFICATION; PREVALENCE AB BACKGROUND: Children transfused with blood and blood products before 1992 are at risk for chronic hepatitis C virus (HCV) infection. To determine the prevalence of HCV infection and risks associated with acquisition of HCV, a single-institution lookback study was performed. STUDY DESIGN AND METHODS: A total of 5473 infants and children who received transfusions between 1982 and 1992 were identified. A control population of 600 age-, sex-, race- and zip code-matched children who did not receive transfusions with the same exclusions provided background seroprevalence data. Patients were tested for antibodies to HCV, confirmed with second generation recombinant immunoblot assay (RIBA) and when appropriate quantitative and qualitative HCV RNA by reverse transcription polymerase chain reaction (PCR). Viral persistence was assessed by serial PCR determinations for HCV RNA. RESULTS: Of the 5473 eligible patients, 4726 were locatable and 2758 were tested. Forty-three children (1.6%) were persistently anti-HCV enzyme immunoassay (EIA)-positive, confirmed by RIBA; 39 were positive for the presence of HCV RNA. Four cleared their virus as assessed by two negative HCV PCRs 6 months apart. There was a borderline higher number of children with HCV who received fresh whole blood than those who tested HCV-negative. CONCLUSION: Because HCV infection is generally asymptomatic, children are not identified unless they are specifically tested. We identified, enrolled, tested, and confirmed a new diagnosis of HCV infection in 43 patients. As HCV treatments become increasingly effective, it is important to identify silently infected individuals, particularly when the infection was iatrogenically induced. C1 Childrens Natl Med Ctr, Div Lab Med & Pathol, Washington, DC 20010 USA. Childrens Natl Med Ctr, Div Gastroenterol & Nutr, Washington, DC 20010 USA. George Washington Univ, Sch Med, Washington, DC 20052 USA. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. RP Luban, NLC (reprint author), Childrens Natl Med Ctr, Div Lab Med & Pathol, 111 Michigan Ave NW, Washington, DC 20010 USA. EM nluban@cnmc.org FU NHLBI NIH HHS [R01 HL 56060] NR 35 TC 9 Z9 9 U1 1 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0041-1132 J9 TRANSFUSION JI Transfusion PD APR PY 2007 VL 47 IS 4 BP 615 EP 620 DI 10.1111/j.1537-2995.2007.01162.x PG 6 WC Hematology SC Hematology GA 154ZC UT WOS:000245546300012 PM 17381619 ER PT J AU Harris, JR AF Harris, Jennifer R. TI Genetics, social behaviors, social environments and aging SO TWIN RESEARCH AND HUMAN GENETICS LA English DT Editorial Material ID STRESSFUL LIFE EVENTS; SEROTONIN TRANSPORTER; INDIVIDUAL-DIFFERENCES; MALTREATED CHILDREN; MATERNAL-BEHAVIOR; WILLIAMS-SYNDROME; MAJOR DEPRESSION; OLDER-ADULTS; HEALTH; POLYMORPHISM C1 Norwegian Inst Publ Hlth, Div Epidemiol, Dept Genes & Environm, N-0403 Oslo, Norway. NIA, Behav & Social Res Program, NIH, Bethesda, MD 20892 USA. RP Harris, JR (reprint author), Norwegian Inst Publ Hlth, Div Epidemiol, Dept Genes & Environm, Post Box 4404 Nydalen, N-0403 Oslo, Norway. EM Jennifer.harris@fhi.no NR 51 TC 1 Z9 1 U1 6 U2 8 PU AUSTRALIAN ACAD PRESS PI BOWEN HILLS PA 32 JEAYS ST, BOWEN HILLS, QLD 4006, AUSTRALIA SN 1832-4274 J9 TWIN RES HUM GENET JI Twin Res. Hum. Genet. PD APR PY 2007 VL 10 IS 2 BP 235 EP 240 DI 10.1375/twin.10.2.235 PG 6 WC Genetics & Heredity; Obstetrics & Gynecology SC Genetics & Heredity; Obstetrics & Gynecology GA 159NA UT WOS:000245871600001 PM 17564513 ER PT J AU Ganiban, JM Spotts, EL Lichtenstein, P Khera, GS Reiss, D Neiderhiser, JM AF Ganiban, Jody M. Spotts, Erica L. Lichtenstein, Paul Khera, Gagan S. Reiss, David Neiderhiser, Jenae M. TI Can genetic factors explain the spillover of warmth and negativity across family relationships? SO TWIN RESEARCH AND HUMAN GENETICS LA English DT Article ID ENVIRONMENTAL-INFLUENCES; PERSONALITY; ADJUSTMENT; CONFLICT; TWIN; TRANSMISSION; TENSIONS; SWEDISH; MEMORY; DYADS AB Previous studies indicate that the emotional quality of marital relationships is mirrored in parent-child relationships. We explored the degree to which these associations are explained by genetic and environmental factors. Participants were drawn from the Twin and Offspring Study in Sweden (TOSS), and included 544 female twin pairs (258 monozygotic [MZ], 286 dizygotic [DZ]), and 311 male twin pairs (128 MZ, 183 DZ). The spouses and one adolescent child of each twin also participated in this study. The twins completed self-report measures that assessed their marital quality and their warmth and negativity towards their children. Observational ratings of marital warmth and negativity, and of maternal warmth and negativity were obtained for a subset of female twin pairs (150 MZ, 176 DZ). Self-reported marital satisfaction was associated with self-reported parental warmth and negativity for mothers (rs = .25, -.36) and fathers (rs = .25, -.44). For the observational measures, marital warmth was associated with maternal warmth (r = .42), while marital negativity was associated with maternal negativity (r = .34). On average genetic factors explained nearly half of the covariance between self-reported marital satisfaction and parenting for mothers (48%) and fathers (47%). Genetic factors explained 21% of the covariance between observed marital and maternal warmth, but did not contribute to associations between marital and maternal negativity. These findings indicate that parents' genetically influenced characteristics help shape the emotional climate of the family. C1 George Washington Univ, Dept Psychol, Washington, DC 20052 USA. George Washington Univ, Ctr Family Res, Dept Psychiat & Behav Sci, Washington, DC 20052 USA. NIA, Behav & Social Res Program, Bethesda, MD 20892 USA. Karolinska Inst, Dept Med Epidemiol & Biostat, Stockholm, Sweden. RP Ganiban, JM (reprint author), George Washington Univ, Dept Psychol, 2125 G St NW, Washington, DC 20052 USA. EM ganiban@gwu.edu FU NIMH NIH HHS [R01 MH54601] NR 44 TC 13 Z9 14 U1 1 U2 1 PU AUSTRALIAN ACAD PRESS PI BOWEN HILLS PA 32 JEAYS ST, BOWEN HILLS, QLD 4006, AUSTRALIA SN 1832-4274 J9 TWIN RES HUM GENET JI Twin Res. Hum. Genet. PD APR PY 2007 VL 10 IS 2 BP 299 EP 313 DI 10.1375/twin.10.2.299 PG 15 WC Genetics & Heredity; Obstetrics & Gynecology SC Genetics & Heredity; Obstetrics & Gynecology GA 159NA UT WOS:000245871600007 PM 17564519 ER PT J AU Jeanty, C Nien, JK Espinoza, J Kusanovic, JP Goncalves, LF Qureshi, F Jacques, S Lee, W Romero, R AF Jeanty, C. Nien, J. K. Espinoza, J. Kusanovic, J. P. Goncalves, L. F. Qureshi, F. Jacques, S. Lee, W. Romero, R. TI Pleural and pericardial effusion: a potential ultrasonographic marker for the prenatal differential diagnosis between congenital diaphragmatic eventration and congenital diaphragmatic hernia SO ULTRASOUND IN OBSTETRICS & GYNECOLOGY LA English DT Review DE congenital diaphragmatic hernia; diaphragmatic eventration; pericardial effusion; pleural effusion ID FETAL LUNG-VOLUME; SONOGRAPHIC DIAGNOSIS; ANTENATAL DETECTION; HIATAL-HERNIA; PULMONARY SEQUESTRATION; ULTRASOUND DIAGNOSIS; NUCHAL TRANSLUCENCY; CT AMNIOGRAPHY; ABDOMINAL-WALL; EXPERIENCE AB Objectives To determine whether or not the presence of pleural and/or pericardial effusion can be used prenatally as an ultrasonographic marker for the differential diagnosis between diaphragmatic eventration and diaphragmatic hernia. Methods We present two case reports of non-isolated diaphragmatic eventration associated with pleural and/or pericardial effusion. Additionally, we reviewed the literature for all cases of congenital diaphragmatic hernia (CDH) and diaphragmatic eventration that met the following criteria: (1) prenatal diagnosis of a diaphragmatic defect and (2) definitive diagnosis by autopsy or surgery. The frequencies of pleural effusion, pericardial effusion and hydrops were compared between the two conditions using Fisher's exact test. A subanalysis was conducted of cases with isolated diaphragmatic defects (i.e. diaphragmatic defects not associated with hydrops and other major structural or chromosomal anomalies). Results A higher proportion of fetuses with diaphragmatic eventration had associated pleural and pericardial effusions compared with fetuses with diaphragmatic hernia,(58% (7/12) vs. 3.7% (14/382), respectively, P < 0.001). This observation remained true when only cases of diaphragmatic defects not associated with hydrops and other major structural or chromosomal anomalies were compared (29% (2/7) with eventration vs. 2.2% (4/178) with CDH, P < 0.02). Conclusions The presence of pleural and/or pericardial effusion in patients with diaphragmatic defects should raise the possibility of a congenital diaphragmatic eventration. This information is clinically important for management and counseling because the prognosis and treatment for CDH and congenital diaphragmatic eventration are different. Copyright (c) 2007 ISUOG. Published by John Wiley & Sons, Ltd. C1 Wayne State Univ, Hutzel Womens Hosp, NIH, NICHD,Perinatol Res Branch,DHHS, Detroit, MI 48201 USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48202 USA. Wayne State Univ, Dept Pathol, Detroit, MI 48202 USA. Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48202 USA. William Beaumont Hosp, Div Fetal Imaging, Royal Oak, MI 48072 USA. RP Romero, R (reprint author), Wayne State Univ, Hutzel Womens Hosp, NIH, NICHD,Perinatol Res Branch,DHHS, 3990 John R,Box 4, Detroit, MI 48201 USA. EM warfiela@mail.nih.gov FU Intramural NIH HHS [Z99 HD999999, Z01 HD002401-15] NR 103 TC 13 Z9 13 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0960-7692 J9 ULTRASOUND OBST GYN JI Ultrasound Obstet. Gynecol. PD APR PY 2007 VL 29 IS 4 BP 378 EP 387 DI 10.1002/uog.3958 PG 10 WC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging SC Acoustics; Obstetrics & Gynecology; Radiology, Nuclear Medicine & Medical Imaging GA 159YI UT WOS:000245903400004 PM 17366518 ER PT J AU Gallaher, KT Mura, M Todd, WA Harris, TL Kenyon, E Harris, T Johnson, KC Satterfield, S Kritchevsky, SB Iannaccone, A AF Gallaher, Kevin T. Mura, Marco Todd, Wm. Andrew Harris, Tarsha L. Kenyon, Emily Harris, Tamara Johnson, Karen C. Satterfield, Suzanne Kritchevsky, Stephen B. Iannaccone, Alessandro CA Hlth ABC Study TI Estimation of macular pigment optical density in the elderly: Test-retest variability and effect of optical blur in pseudophakic subjects SO VISION RESEARCH LA English DT Article DE macular pigment optical density; heterochromatic flicker photometry; reliability; optical blur; aging ID HETEROCHROMATIC FLICKER PHOTOMETRY; LUTEIN SUPPLEMENTATION; OLDER SUBJECTS; UNITED-STATES; HUMAN-EYE; PRESBYOPIA; ACCOMMODATION; DEGENERATION; CAROTENOIDS; POPULATION AB The reproducibility of macular pigment optical density (MPOD) estimates in the elderly was assessed in 40 subjects (age: 79.1 +/- 3.5). Test-retest variability was good (Pearson's r coefficient: 0.734), with an average coefficient of variation (CV) of 18.4% and an intraclass correlation coefficient (ICC) of 0.96. The effect of optical blur on MPOD estimates was investigated in 22 elderly pseudophakic subjects (age: 79.9 +/- 3.6) by comparing the baseline MPOD, obtained with an optimal correction, with MPODs obtained with a +/- 1.00-diopter optical blur. This optical blur did not cause differences in the MPOD estimates, its accuracy, or test duration. (c) 2007 Elsevier Ltd. All rights reserved. C1 Univ Tennessee, Ctr Hlth Sci, Hamilton Eye Inst, Dept Ophthalmol, Memphis, TN 38163 USA. Univ Cagliari, Dept Ophthalmol, I-09124 Cagliari, Italy. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. NIA, NIH, Bethesda, MD 20892 USA. Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27109 USA. RP Iannaccone, A (reprint author), Univ Tennessee, Ctr Hlth Sci, Hamilton Eye Inst, Dept Ophthalmol, 930 Madison Ave,Suite 731, Memphis, TN 38163 USA. EM iannacca@utmem.edu OI Mura, Marco/0000-0001-5283-5366; Kritchevsky, Stephen/0000-0003-3336-6781 FU Intramural NIH HHS; NEI NIH HHS [K23 EY000409, K23 EY000409-05]; NIA NIH HHS [N01 AG62101, N01 AG062101, N01 AG062103, N01 AG062106, N01 AG62103, N01 AG62106]; NIDDK NIH HHS [T35 DK007405, T35 DK07405] NR 37 TC 18 Z9 19 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0042-6989 J9 VISION RES JI Vision Res. PD APR PY 2007 VL 47 IS 9 BP 1253 EP 1259 DI 10.1016/j.visres.2007.01.013 PG 7 WC Neurosciences; Ophthalmology SC Neurosciences & Neurology; Ophthalmology GA 162OR UT WOS:000246097800013 PM 17376502 ER PT J AU Hamada, S Watanabe, K Hirota, M Bianco, C Strizzi, L Mancino, M Gonzales, M Salomon, DS AF Hamada, Shin Watanabe, Kazuhide Hirota, Morihisa Bianco, Caterina Strizzi, Luigi Mancino, Mario Gonzales, Monica Salomon, David S. TI beta-catenin/TCF/LEF regulate expression of the short form human Cripto-1 SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE Wnt; Cripto-1; beta-catenin ID MAMMARY-GLAND; TRANSGENIC MICE; COLON-CANCER; CATENIN; MOUSE; GENE; DIFFERENTIATION; OVEREXPRESSION; TRANSCRIPTION; RECEPTOR AB The human gene Teratocarcinorna-derived growth factor 1 (TDGF1)/Cripto-1/CR-1 which is expressed in a wide variety of human carcinomas is a member of the EGF-cripto FRL1 cryptic (EGF-CFC) gene family. A majority of human colorectal tumors and hepatomas are known to possess a constitutively active canonical Wnt/beta-catenin/TCF signaling pathway, also express CR-1. Expression of a short form of CR-1 mRNA in colon carcinoma and hepatoma cell lines suggests that there may be differential regulation of CR-1 expression by the canonical Wnt signaling pathway in colon cancer as well as hepatoma cell lines. The present study demonstrates a direct transcriptional regulation of the short form CR-1 expression by the canonical Wnt signaling pathway through an intronic-exonic enhancer element, containing three tandem TCF/LEF binding sites within the CR-1 gene. (c) 2007 Elsevier Inc. All rights reserved. C1 NCI, Mammary Biol & Tumorigenesis Lab, CCR, Bethesda, MD 20892 USA. Tohoku Univ, Grad Sch Med, Dept Gastroenterol, Aoba Ku, Sendai, Miyagi 9808574, Japan. RP Salomon, DS (reprint author), NCI, Mammary Biol & Tumorigenesis Lab, CCR, 37 Convent Dr,Bldg 37, Bethesda, MD 20892 USA. EM salomond@mail.nih.gov FU Intramural NIH HHS [Z99 CA999999] NR 17 TC 25 Z9 26 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 30 PY 2007 VL 355 IS 1 BP 240 EP 244 DI 10.1016/j.bbrc.2007.01.143 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 142HX UT WOS:000244641200040 PM 17291450 ER PT J AU Zheng, J Kohler, ME Chen, QR Weber, J Khan, J Johnson, BD Orentas, RJ AF Zheng, Jin Kohler, M. Eric Chen, Qingrong Weber, James Khan, Javed Johnson, Bryon D. Orentas, Rimas J. TI Serum from mice immunized in the context of Treg inhibition identifies DEK as a neuroblastoma tumor antigen SO BMC IMMUNOLOGY LA English DT Article ID REGULATORY T-CELLS; MINOR HISTOCOMPATIBILITY ANTIGEN; CHROMATIN PROTEIN DEK; GENE-TRANSFER; TRANSPLANTATION; EXPRESSION; RESPONSES; TUMORIGENICITY; LEUKEMIA; CANCER AB Background: We have developed a cell-based vaccine that features the expression of both CD80 and CD86 on the surface of a murine neuroblastoma cell line. The cellular immunity induced by this vaccine is enhanced by treatment with antibody that interferes with T-regulatory cell (Treg) function and we report here that immunization combined with interfering with Treg function also produces a profound serological effect. Serum from mice immunized with our cell-based vaccine in the context of Treg blockade was used to screen a cDNA expression library constructed from the parental neuroblastoma tumor cell line, AGN2a. Results: Serum from mice vaccinated in the context of Treg blockade identified a number of potentially oncogenic transcripts that may serve as important immune targets in a tumor-derived cDNA library screen. This novel approach identified far more candidates than could be seen with serum derived from vaccine-treated only, Treg-depleted only, or tumor-bearing mice. The most commonly identified tumor-associated antigen, using serum from immunized and Treg-depleted mice, was the DEK oncogene. Altered expression of the DEK oncogene has been implicated in a number of human cancers. Importantly, we were able to demonstrate that the DEK oncogene also induces a T cell response. Conclusion: The use of post-vaccine immune serum in this report differs from previous approaches where serum collected at the time of cancer onset or diagnosis and was used for tumor antigen identification. We hypothesize that the use of diagnostic serum samples may be inadequate for the clinical translation of this approach, and that identification of protective immunogenic tumor antigens may require the use of serum from post-treatment or vaccinated subjects. The identification of DEK as a tumor-associated antigen capable of eliciting a T cell response validates our experimental approach and argues for the antigens we have identified here to be evaluated as targets of effector immunity and as vaccine candidates. C1 Med Coll Wisconsin, Dept Pediat, Milwaukee, WI 53226 USA. Childrens Hosp Wisconsin, Childrens Res Inst, Milwaukee, WI 53226 USA. Ctr Adv Technol, US Natl Inst Hlth, Natl Canc Inst, Pediat Oncol Branch, Gaithersburg, MD 20877 USA. RP Orentas, RJ (reprint author), Med Coll Wisconsin, Dept Pediat, 8701 Watertown Plank RD, Milwaukee, WI 53226 USA. EM jzheng@mcw.edu; mkohler@MCW.EDU; chenqi@mail.nih.gov; jweber@mcw.edu; khanjav@mail.nih.gov; bjohnson@mcw.edu; rorentas@mcw.edu RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 NR 43 TC 7 Z9 7 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2172 J9 BMC IMMUNOL JI BMC Immunol. PD MAR 30 PY 2007 VL 8 AR 4 DI 10.1186/1471-2172-8-4 PG 15 WC Immunology SC Immunology GA 157YH UT WOS:000245757000001 PM 17397536 ER PT J AU Thompson, M Lauderdale, S Webster, MJ Chong, VZ McClintock, B Saunders, R Weickert, CS AF Thompson, Mia Lauderdale, Simone Webster, Maree J. Chong, Victor Z. McClintock, Benjamin Saunders, Richard Weickert, Cynthia Shannon TI Widespread expression of ErbB2, ErbB3 and ErbB4 in non-human primate brain SO BRAIN RESEARCH LA English DT Article DE neuroanatomy; forebrain; growth factor; NRG-1; neuregulin receptor ID PREFRONTAL WHITE-MATTER; CENTRAL-NERVOUS-SYSTEM; TYROSINE KINASE; SUBVENTRICULAR ZONE; ADULT-RAT; NEUREGULIN; RECEPTORS; CELLS; SCHIZOPHRENIA; LOCALIZATION AB Neuregulin (NRG) signaling proteins interact with ErbB receptors leading to the proliferation, differentiation and migration of neurons and glia in the developing brain. NRG-1/ErbB4 are susceptibility genes for schizophrenia, yet little is known about the neuroanatomical expression of ErbB receptors specifically in primates. We find widespread expression of ErbB2, ErbB3 and ErbB4 receptor mRNAs throughout the telencephalon of juvenile and adult monkeys with in situ hybridization, with ErbB2 and ErbB4 mRNA more abundant than ErbB3 mRNA. ErbB2 and ErbB4 mRNA are expressed at higher levels in grey matter compared to white matter, whereas ErbB3 mRNA is expressed at low levels in both grey and white matter. We also characterized ErbB protein expression with immunoblotting and immunohistochemistry. In frontal cortex, ErbB2, ErbB3 and ErbB4 antibodies immunostained neuronal soma and nuclei. The ErbB2 antibody also immunostained glia at the pial surface. Within white matter, ErbB3 and ErbB4 proteins were localized to putative interstitial white matter neurons while ErbB2 protein was found in glia. Western blotting revealed immunopositive bands at similar to 180-200 kDa for each ErbB, which is consistent with the size of full-length ErbBs. Smaller immunopositive bands were also identified for each ErbB receptor in whole brain homogenates and separate cytoplasmic and nuclear extracts suggesting nuclear ErbB-back-signaling capacity in the brain. The ubiquitous expression of ErbB receptors indicates that many cell populations throughout the brain of juvenile and adult primates have the potential to respond to NRG-1 in a variety of ways. (c) 2006 Elsevier B.V. All rights reserved. C1 NIMH, MiNDS Unit, Clin Brain Disorders Branch, IRP,NIH, Bethesda, MD 20892 USA. USUHS, Dept Psychiat, Stanley Lab Brain Res, Bethesda, MD 20892 USA. NIMH, Neuropsychol Lab, IRP, NIH, Bethesda, MD 20892 USA. Howard Univ, Coll Med, Dept Anat, Washington, DC 20059 USA. RP Weickert, CS (reprint author), NIMH, MiNDS Unit, Clin Brain Disorders Branch, IRP,NIH, Mail Stop 1385,Bldg 10 Room 4D18, Bethesda, MD 20892 USA. EM shannonwc@mail.nih.gov RI Shannon Weickert, Cynthia/G-3171-2011 NR 40 TC 39 Z9 39 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAR 30 PY 2007 VL 1139 BP 95 EP 109 DI 10.1016/j.brainres.2006.11.047 PG 15 WC Neurosciences SC Neurosciences & Neurology GA 148YW UT WOS:000245114300011 PM 17280647 ER PT J AU Rocha-Sanchez, SMS Morris, KA Kachar, B Nichols, D Fritzsch, B Beisel, KW AF Rocha-Sanchez, Sonia M. S. Morris, Kenneth A. Kachar, Bechara Nichols, David Fritzsch, Bernd Beisel, Kirk W. TI Developmental expression of Kcnq4 in vestibular neurons and neurosensory epithelia SO BRAIN RESEARCH LA English DT Article DE vestibular hair cell; ion channel; Kcnq4; alternative splice variant; immunohistochemistry; immunofluorescence; in situ hybridization; RT-PCR ID OUTER HAIR-CELLS; PERIPHERAL INNERVATION PATTERNS; INNER-EAR INNERVATION; SEMICIRCULAR CANALS; DOMINANT DEAFNESS; COMPARATIVE MORPHOLOGY; NEUROTROPHIC FACTOR; CRISTAE AMPULLARES; SENSORY EPITHELIA; HEARING-LOSS AB Sensory signal transduction of the inner ear afferent neurons and hair cells (HCS) requires numerous ionic conductances. The KCNQ4 voltage-gated M-type potassium channel is thought to set the resting membrane potential in cochlear HCs. Here we describe the spatiotemporal expression patterns of Kcnq4 and the associated alternative splice forms in the HCs of vestibular labyrinth. Whole mount immunodetection, qualitative and quantitative RT-PCR were performed to characterize the expression patterns of Kcnq4 transcripts and proteins. A topographical expression and upregulation of Kcnq4 during development was observed and indicated that Kcnq4 is not restricted to either a specific vestibular structure or cell type, but is present in afferent calyxes, vestibular ganglion neurons, and both type I and type II HCs. Of the four alternative splice variants, Kcnq4_vl transcripts were the predominant form in the HCs, while Kcnq4_u3 was the major variant in the vestibular neurons. Differential quantitative expression of Kcnq4_ul and Kcnq4_v3 were respectively detected in the striolar and extra-striolar regions of the utricle and saccule. Analysis of gerbils and rats yielded results similar to those obtained in mice, suggesting that the spatiotemporal expression pattern of Kcnq4 in the vestibular system is conserved among rodents. Analyses of vestibular HCs of Bdnf conditional mutant mice, which are devoid of any innervation, demonstrate that regulation of Kcnq4 expression in vestibular HCs is independent of innervation. (c) 2007 Elsevier B.V. All rights reserved. C1 Creighton Univ, Sch Dent, Dept Oral Biol, Omaha, NE 68178 USA. Creighton Univ, Dept Biomed Sci, Omaha, NE 68178 USA. NICD, Struct Cell Biol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Rocha-Sanchez, SMS (reprint author), Creighton Univ, Sch Dent, Dept Oral Biol, 2500 Calif Plaza, Omaha, NE 68178 USA. EM ssanchez@creighton.edu OI Fritzsch, Bernd/0000-0002-4882-8398 FU NIDCD NIH HHS [R01 DC004279, R01 DC005009, R01 DC005590, R01 DC007592]; PHS HHS [R01 DG005590, R01 DG04279, R01 DG05009, R01 DG07592] NR 52 TC 18 Z9 21 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD MAR 30 PY 2007 VL 1139 BP 117 EP 125 DI 10.1016/j.brainres.2006.12.087 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 148YW UT WOS:000245114300013 PM 17292869 ER PT J AU Doerries, C Grote, K Hilfiker-Kleiner, D Luchtefeld, M Schaefer, A Holland, SM Sorrentino, S Manes, C Schieffer, B Drexler, H Landmesser, U AF Doerries, Carola Grote, Karsten Hilfiker-Kleiner, Denise Luchtefeld, Maren Schaefer, Arnd Holland, Steven M. Sorrentino, Sajoscha Manes, Costantina Schieffer, Bernhard Drexler, Helmut Landmesser, Ulf TI Critical role of the NAD(P)H oxidase subunit p47(phox) for left ventricular remodeling/dysfunction and survival after myocardial infarction SO CIRCULATION RESEARCH LA English DT Article DE myocardial infarction; remodeling; heart failure; NAD(P)H oxidase; superoxide anion ID VASCULAR OXIDATIVE STRESS; NECROSIS-FACTOR-ALPHA; RAT CARDIAC MYOCYTES; SMOOTH-MUSCLE CELLS; ANGIOTENSIN-II; NADPH OXIDASE; HEART-FAILURE; SUPEROXIDE-PRODUCTION; XANTHINE OXIDOREDUCTASE; ENDOTHELIAL DYSFUNCTION AB Accumulating evidence suggests a critical role of increased reactive oxygen species production for left ventricular ( LV) remodeling and dysfunction after myocardial infarction ( MI). An increased myocardial activity of the NAD( P) H oxidase, a major oxidant enzyme system, has been observed in human heart failure; however, the role of the NAD( P) H oxidase for LV remodeling and dysfunction after MI remains to be determined. MI was induced in wild-type ( WT) mice ( n = 46) and mice lacking the cytosolic NAD( P) H oxidase component p47(phox) ( p47(phox-/-) mice) ( n = 32). Infarct size was similar among the groups. NAD( P) H oxidase activity was markedly increased in remote LV myocardium of WT mice after MI as compared with sham-operated mice ( 83 +/- 8 versus 16.7 +/- 3.5 nmol of O-2(-.) . mu g(-1).min(-1); P < 0.01) but not in p47(phox-/-) mice after MI ( 13.5 +/- 3.6 versus 15.5 +/- 3.5 nmol of O2(-.) mu g(-1).min(-1)), as assessed by electron-spin resonance spectroscopy using the spin probe CP-H. Furthermore, increased myocardial xanthine oxidase activity was observed in WT, but not in p47(phox-/-) mice after MI, suggesting NAD( P) H oxidase - dependent xanthine oxidase activation. Myocardial reactive oxygen species production was increased in WT mice, but not in p47(phox-/-) mice, after MI. LV cavity dilatation and dysfunction 4 weeks after MI were markedly attenuated in p47(phox-/-) mice as compared with WT mice, as assessed by echocardiography ( LV end-diastolic diameter: 4.5 +/- 0.2 versus 6.3 +/- 0.3 mm, P < 0.01; LV ejection fraction, 35.8 +/- 2.5 versus 22.6 +/- 4.4%, P < 0.05). Furthermore, cardiomyocyte hypertrophy, apoptosis, and interstitial fibrosis were substantially reduced in p47(phox-/-) mice as compared with WT mice. Importantly, the survival rate was markedly higher in p47(phox-/-) mice as compared with WT mice after MI ( 72% versus 48%; P < 0.05). These results suggest a pivotal role of NAD( P) H oxidase activation and its subunit p47(phox) for LV remodeling/ dysfunction and survival after MI. The NAD( P) H oxidase system represents therefore a potential novel therapeutic target to prevent cardiac failure after MI. C1 Hannover Med Sch, Abt Kardiol & Angiol, D-30625 Hannover, Germany. NIH, Lab Clin Infect Dis, Bethesda, MD 20892 USA. RP Landmesser, U (reprint author), Hannover Med Sch, Abt Kardiol & Angiol, Carl Neuberg Str 1, D-30625 Hannover, Germany. EM Landmesser.Ulf@mh-hannover.de NR 51 TC 128 Z9 132 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD MAR 30 PY 2007 VL 100 IS 6 BP 894 EP 903 DI 10.1161/01.RES.0000261657.76299.ff PG 10 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 151TE UT WOS:000245312900021 PM 17332431 ER PT J AU Heffernan, TP Unsal-Kacmaz, K Heinloth, AN Simpson, DA Paules, RS Sancar, A Cordeiro-Stone, M Kaufmann, WK AF Heffernan, Timothy P. Unsal-Kacmaz, Keziban Heinloth, Alexandra N. Simpson, Dennis A. Paules, Richard S. Sancar, Aziz Cordeiro-Stone, Marila Kaufmann, William K. TI Cdc7-dbf4 and the human S checkpoint response to UVC SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA-DAMAGE CHECKPOINT; DIPLOID HUMAN FIBROBLASTS; CELL-CYCLE REGULATION; PHASE CHECKPOINT; PROTEIN-KINASE; DOWNSTREAM EFFECTOR; IONIZING-RADIATION; CDC7P-DBF4P KINASE; ULTRAVIOLET-LIGHT; POLYMERASE ALPHA AB The S checkpoint response to ultraviolet radiation (UVC) that inhibits replicon initiation is dependent on the ATR and Chk1 kinases. Downstream effectors of this response, however, are not well characterized. Data reported here eliminated Cdc25A degradation and inhibition of Cdk2-cyclin E as intrinsic components of the UVC-induced pathway of inhibition of replicon initiation in human cells. A sublethal dose of UVC (1 j/m(2)), which selectively inhibits replicon initiation by 50%, failed to reduce the amount of Cdc25A protein or decrease Cdk2-cyclin E kinase activity. Cdc25A degradation was observed after irradiation with cytotoxic fluences of UVC, suggesting that severe inhibition of DNA chain elongation and activation of the replication checkpoint might be responsible for the UVC-induced degradation of Cdc25A. Another proposed effector of the S checkpoint is the Cdc7-Dbf4 complex. Dbf4 interacted weakly with Chk1 in vivo but was recognized as a substrate for Chk1-dependent phosphorylation in vitro. FLAG-Dbf4 formed complexes with endogenous Cdc7, and this interaction was stable in UVC-irradiated HeLa cells. Overexpression of FLAG- or Myc-tagged Dbf4 abrogated the S checkpoint response to UVC but not ionizing radiation. These findings implicate a Dbf4-dependent kinase as a possible target of the ATR- and Chk1-dependent S checkpoint response to UVC. C1 Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. Univ N Carolina, Dept Biochem & Biophys, Chapel Hill, NC 27599 USA. Univ N Carolina, Ctr Environm Hlth & Susceptibil, Chapel Hill, NC 27599 USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. NIEHS, Growth Control & Canc Grp, NIH, Res Triangle Pk, NC 27709 USA. RP Kaufmann, WK (reprint author), Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27599 USA. EM wkarlk@med.unc.edu FU NCI NIH HHS [P30 CA016086, R01 CA055065, CA055065, P30-CA 16086]; NIEHS NIH HHS [ES11012, ES07017, P30 ES010126, P30-ES10126, R01 ES011012, T32 ES007017] NR 81 TC 39 Z9 40 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 30 PY 2007 VL 282 IS 13 BP 9458 EP 9468 DI 10.1074/jbc.M611292200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 153HA UT WOS:000245421700018 PM 17276990 ER PT J AU Thompson, BD Jin, YZ Wu, KH Colvirl, RA Luster, AD Birnbaumer, L Wu, MX AF Thompson, Brian D. Jin, Yongzhu Wu, Kevin H. Colvirl, Richard A. Luster, Andrew D. Birnbaumer, Lutz Wu, Mei X. TI Inhibition of G alpha(i2) activation by G alpha(i3) in CXCR3-mediated signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; ACUTE ALLOGRAFT-REJECTION; PERTUSSIS-TOXIN; T-CELLS; G-ALPHA-I2(-/-) MICE; MULTIGENE FAMILY; ALPHA-SUBUNIT; BINDING; CXCR3; LYMPHOCYTES AB G protein-coupled receptors (GPCRs) convey extracellular stimulation into dynamic intracellular action, leading to the regulation of cell migration and differentiation. T lymphocytes express G alpha(12), and G alpha(i3), two members of the G alpha(i/o). protein family, but whether these two G alpha(i) proteins have distinguishable roles guiding T cell migration remains largely unknown because of a lack of member-specific inhibitors. This study details distinct G alpha(i2) and G alpha(i3) effects on chemokine receptor CXCR3-mediated signaling. Our data showed that Gai, was indispensable for T cell responses to three CXCR3 ligands, CXCL9, CXCL10, and CXCL11, as the lack of G alpha(i2) abolished CXCR3-stimulated migration and guanosine 5'-3-O-(thio)triphosphate (GTP gamma S) incorporation. In sharp contrast, T cells isolated from G alpha(i3) knock-out mice displayed a significant increase in both GTP gamma S incorporation and migration as compared with wild type T cells when stimulated with CXCR3 agonists. The increased GTP gamma S incorporation was blocked by G alpha(i3) protein in a dose-dependent manner. G alpha(i3)-mediated blockade of Gai, activation did not result from Gai3 activation, but instead resulted from competition or steric hindrance of Gai, interaction with the CXCR3 receptor via the N terminus of the second intracellular loop. A mutation in this domain abrogated not only G alpha(i2) activation induced by a CXCR3 agonist but also the interaction of Gai3 to the CXCR3 receptor. These findings reveal for the first time an interplay of Gai proteins in transmitting G protein-coupled receptor signals. This interplay has heretofore been masked by the use of pertussis toxin, a broad inhibitor of the G alpha(i/o) protein family. C1 Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed,Dept Dermatol, Boston, MA 02114 USA. NIEHS, Transmembrane Signaling Grp, Lab Signal Transduct, NIH, Res Triangle Pk, NC 27709 USA. Massachusetts Gen Hosp, Ctr Immunol & Inflammatory Dis, Div Rheumatol Allergy & Immunol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. RP Wu, MX (reprint author), Harvard Univ, Massachusetts Gen Hosp, Sch Med, Wellman Ctr Photomed,Dept Dermatol, 55 Fruit St,Edwards 222, Boston, MA 02114 USA. EM mwu2@partners.org FU Intramural NIH HHS [Z01 ES101643-05]; NIAID NIH HHS [AI070785, AI050822, R01 AI050822, K02 AI070785]; NIAMS NIH HHS [T32 AR007098, T32 AR07098-31]; NIDDK NIH HHS [R01 DK074449, P30 DK043351, DK074449, DK43351] NR 46 TC 32 Z9 34 U1 1 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 MAR 30 PY 2007 VL 282 IS 13 BP 9547 EP 9555 DI 10.1074/jbc.M610931200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 153HA UT WOS:000245421700027 PM 17289675 ER PT J AU Islam, A Shen, XY Hiroi, T Moss, J Vaughan, M Levine, SJ AF Islam, Aminul Shen, Xiaoyan Hiroi, Toyoko Moss, Joel Vaughan, Martha Levine, Stewart J. TI The brefeldin A-inhibited guanine nucleotide-exchange protein, BIG2, regulates the constitutive release of TNFR1 exosome-like vesicles SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR-NECROSIS-FACTOR; ADP-RIBOSYLATION FACTOR; FACTOR-BINDING-PROTEIN; TRANS-GOLGI NETWORK; FACTOR RECEPTOR; ENDOPLASMIC-RETICULUM; RECYCLING ENDOSOMES; CELL-SURFACE; SOLUBLE FORM; TRAFFICKING AB The type 1, 55-kDa tumor necrosis factor receptor (TNFR1) is released from cells to the extracellular space where it can bind and modulate TNF bioactivity. Extracellular TNFR1 release occurs by two distinct pathways: the inducible proteolytic cleavage of TNFR1 ectodomains and the constitutive release of full-length TNFR1 in exosome-like vesicles. Regulation of both TNFR1 release pathways appears to involve the trafficking of cytoplasmic TNFRI vesicles. Vesicular trafficking is controlled by ADP-ribosylation factors (ARFs), which are active in the GTP-bound state and inactive when bound to GDP. ARF activation is enhanced by guanine nucleotide-exchange factors that catalyze replacement of GDP by GTP. We investigated whether the brefeldin A (BFA)-inhibited guanine nucleotide-exchange proteins, BIG1 and/or BIG2, are required for TNFRI release from human umbilical vein endothelial cells. Effects of specific RNA interference (RNAi) showed that BIG2, but not BIG1, regulated the release of TNFR1 exosome-like vesicles, whereas neither BIG2 nor BIG1 was required for the IL-1 beta-induced proteolytic cleavage of TNFRI ectodomains. BIG2 co-localized with TNFRI in diffusely distributed cytoplasmic vesicles, and the association between BIG2 and TNFRI was disrupted by BFA. Consistent with the preferential activation of class I ARFs by BIG2, ARF1 and ARF3 participated in the extracellular release of TNFR1 exosome-like vesicles in a nonredundant and additive fashion. We conclude that the association between BIG2 and TNFRI selectively regulates the extracellular release of TNFR1 exosome-like vesicles from human vascular endothelial cells via an ARF1- and ARF3-dependent mechanism. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Levine, SJ (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10,Rm 6D03,MSC 1590, Bethesda, MD 20892 USA. EM levines@nhlbi.nih.gov FU Intramural NIH HHS NR 41 TC 35 Z9 38 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 30 PY 2007 VL 282 IS 13 BP 9591 EP 9599 DI 10.1074/jbc.M607122200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 153HA UT WOS:000245421700032 PM 17276987 ER PT J AU Nakamura, K Moore, R Negishi, M Sueyoshi, T AF Nakamura, Kouichi Moore, Rick Negishi, Masahiko Sueyoshi, Tatsuya TI Nuclear pregnane X receptor cross-talk with FoxA2 to mediate drug-induced regulation of lipid metabolism in fasting mouse liver SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MITOCHONDRIAL BETA-OXIDATION; COA DESATURASE 1; GENE-EXPRESSION; XENOBIOTIC RECEPTORS; RESPONSE ELEMENT; ENHANCER MODULE; UGT1A1 GENE; CAR; TRANSCRIPTION; INSULIN AB Upon drug activation, the nuclear pregnane X receptor (PXR) regulates not only hepatic drug but also energy metabolism. Using Pxr(-/-) mice, we have now investigated the PXR-mediated repression of lipid metabolism in the fasting livers. Treatment with PXR activator pregnenolone 16 alpha-carbonitrile (PCN) down-regulated the mRNA levels of carnitine palmitoyltransferase 1A (in beta-oxidation) and mitochondrial 3-hydroxy-3-methylglutarate-CoA synthase 2 (in ketogenesis) in wild-type (Pxr(+/+)) mice only. In contrast, the stearoyl-CoA desaturase 1 (in lipogenesis) mRNA was up-regulated in the PCN-treated Pxr(+/+) mice. Reflecting these up- and down-regulations and consistent with decreased energy metabolism, the levels of hepatic triglycerides and of serum 3-hydroxybutylate were increased and decreased, respectively, in the PCN-treated Pxr(+/+) mice. Using gel shift, glutathione S-transferase pull-down and cell-based reporter assays, we then examined whether PXR could cross-talk with the insulin response forkhead factor FoxA2 to repress the transcription of the Cpt1a and Hmgcs2 genes, because FoxA2 activates these genes in fasting liver. PXR directly bound to FoxA2 and repressed its activation of the Cpt1a and Hmgcs2 promoters. Moreover, ChIP assays showed that PCN treatment attenuated the binding of FoxA2 to these promoters in fasting Pxr(+/+) but not Pxr(-/-) mice. These results are consistent with the conclusion that PCN-activated PXR represses FoxA2-mediated transcription of Ctp1a and Hmgcs2 genes in fasting liver. C1 NIEHS, Pharmacogenet Sect, Lab Reprod & Dev Toxicol, NIH, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, Pharmacogenet Sect, Lab Reprod & Dev Toxicol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov FU Intramural NIH HHS [Z01 ES080040-22] NR 47 TC 95 Z9 104 U1 2 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 30 PY 2007 VL 282 IS 13 BP 9768 EP 9776 DI 10.1074/jbc.M610072200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 153HA UT WOS:000245421700051 PM 17267396 ER PT J AU Chen, KH Liu, S Bankston, LA Liddington, RC Leppla, SH AF Chen, Kuang-Hua Liu, Shihui Bankston, Laurie A. Liddington, Robert C. Leppla, Stephen H. TI Selection of anthrax toxin protective antigen variants that discriminate between the cellular receptors TEM8 and CMG2 and achieve targeting of tumor cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CAPILLARY MORPHOGENESIS PROTEIN-2; CRYSTAL-STRUCTURE; BACILLUS-ANTHRACIS; LETHAL FACTOR; DOMAIN; UROKINASE; BINDING; IDENTIFICATION; ENDOTHELIUM; SPECIFICITY AB Anthrax toxin, a three-component protein toxin secreted by Bacillus anthracis, assembles into toxic complexes at the surface of receptor-bearing eukaryotic cells. The protective antigen (PA) protein binds to receptors, either tumor endothelial cell marker 8 (TEM8) or CMG2 (capillary morphogenesis protein 2), and orchestrates the delivery of the lethal and edema factors into the cytosol. TEM8 is reported to be overexpressed during tumor angiogenesis, whereas CMG2 is more widely expressed in normal tissues. To extend prior work on targeting of tumor with modified anthrax toxins, we used phage display to select PA variants that preferentially bind to TEM8 as compared with CMG2. Substitutions were randomly introduced into residues 605-729 of PA, within the C-terminal domain 4 of PA, which is the principal region that contacts receptor. Candidates were characterized in cellular cytotoxicity assays with Chinese hamster ovary (CHO) cells expressing either TEM8 or CMG2. A PA mutant having the substitutions R659S and M662R had enhanced specificity toward TEM8-overexpressing CHO cells. This PA variant also displayed broad and potent tumoricidal activity to various human tumor cells, especially to HeLa and A549/ATCC cells. By contrast, the substitution N657Q significantly reduced toxicity to TEM8 but not CMG2-overexpressing CHO cells. Our results indicate that certain amino acid substitutions within PA domain 4 create anthrax toxins that selectively kill human tumor cells. The PA R659S/M662R protein may be useful as a therapeutic agent for cancer treatment. C1 NIAID, NIH, Lab Bacterial Dis, Bethesda, MD 20892 USA. Burnham Inst Med Res, Infect & Inflammatory Dis Ctr, La Jolla, CA 92037 USA. RP Leppla, SH (reprint author), NIAID, NIH, Lab Bacterial Dis, Bldg 33,Rm 1W20B, Bethesda, MD 20892 USA. EM sleppla@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000929-05]; NIAID NIH HHS [P01 AI055789, P01 AI055789-040001, AI055789] NR 33 TC 24 Z9 25 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 30 PY 2007 VL 282 IS 13 BP 9834 EP 9845 DI 10.1074/jbc.M611142200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 153HA UT WOS:000245421700058 PM 17251181 ER PT J AU Joshi, MB Dwyer, DM AF Joshi, Manju B. Dwyer, Dennis M. TI Molecular and functional analyses of a novel class I secretory nuclease from the human pathogen, Leishmania donovani SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID POLYACRYLAMIDE-GEL ELECTROPHORESIS; EUKARYOTIC HUMAN PATHOGENS; STRAND-SPECIFIC NUCLEASE; PARASITIC PROTOZOA; GENOME SEQUENCE; NUCLEOSIDE TRANSPORTERS; EXTRACELLULAR NUCLEASE; ENDOPLASMIC-RETICULUM; PENICILLIUM-CITRINUM; ASPERGILLUS-ORYZAE AB The primitive protozoan pathogen of humans, Leishmania donovani, resides and multiplies in highly restricted micro-environments within their hosts (i.e. as promastigotes in the gut lumen of their sandfly vectors and as amastigotes in the phagolysosomal compartments of infected mammalian macrophages). Like other trypanosomatid parasites, they are purine auxotrophs (i.e. lack the ability to synthesize purines de novo) and therefore are totally dependent upon salvaging these essential nutrients from their hosts. In that context, in this study we identified a unique 35-kDa, dithiothreitol-sensitive nuclease and showed that it was constitutively released/secreted by both promastigote and amastigote developmental forms of this parasite. By using several different molecular approaches, we identified and characterized the structure of LdNuc(s), a gene that encodes this new 35-kDa class I nuclease family member in these organisms. Homologous episomal expression of an epitope-tagged LdNuc(s) chimeric construct was used in conjunction with an anti-LdNuc(s) peptide antibody to delineate the functional and biochemical properties of this unique 35-kDa parasite released/secreted enzyme. Results of coupled immunoprecipitation-enzyme activity analyses demonstrated that this "secretory" enzyme could hydrolyze a variety of synthetic polynucleotides as well as several natural nucleic acid substrates, including RNA and single- and double-stranded DNA. Based on these cumulative observations, we hypothesize that within the micro-environments of its host, this leishmanial "secretory" nuclease could function at a distance away from the parasite to harness (i.e. hydrolyze/access) host-derived nucleic acids to satisfy the essential purine requirements of these organisms. Thus, this enzyme might play an important role(s) in facilitating the survival, growth, and development of this important human pathogen. C1 NIAID, Cell Biol Sect, Lab Parasit Dis, Div Intramural Res,NIH, Bethesda, MD 20892 USA. RP Dwyer, DM (reprint author), NIAID, Cell Biol Sect, Lab Parasit Dis, Div Intramural Res,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ddwyer@niaid.nih.gov FU Intramural NIH HHS NR 61 TC 11 Z9 12 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 30 PY 2007 VL 282 IS 13 BP 10079 EP 10095 DI 10.1074/jbc.M610770200 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 153HA UT WOS:000245421700082 PM 17276983 ER PT J AU Miller, SLH Scappini, EL O'Bryan, J AF Miller, Stephanie L. H. Scappini, Erica L. O'Bryan, John TI Ubiquitin-interacting motifs inhibit aggregation of PolyQ-expanded huntingtin SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN; DISEASE; IDENTIFICATION; UBIQUITYLATION; PATHOGENESIS; AGGRESOMES; COMPONENTS; ATAXIN-3; EPS15; EPSIN AB Expansion of polyglutamine (polyQ) tracts within proteins underlies a number of neurodegenerative diseases, such as Huntington disease, Kennedy disease, and spinocerebellar ataxias. The resulting mutant proteins are unstable, forming insoluble aggregates that are associated with components of the ubiquitin system, including ubiquitin, ubiquitin-like proteins, and proteins that bind to ubiquitin. Given the presence of these ubiquitin-binding proteins in the insoluble aggregates, we examined whether heterologous expression of short motifs that bind ubiquitin, termed ubiquitin-interacting motifs (UIMs), altered the aggregation of polyQ-expanded huntingtin (Htt), the protein product of the Huntington disease gene. We found that a subset of UIMs associated with mutant Htt. The ability to interact with ubiquitin was necessary, but not sufficient, for interaction with mutant Htt. Furthermore, we found that expression of single, isolated UIMs inhibited aggregation of mutant Htt. These data suggest that isolated UIMs might serve as potential inhibitors of polyQ-aggregation in vivo. C1 Univ Illinois, Coll Med, Dept Pharmacol, Chicago, IL 60612 USA. NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP O'Bryan, J (reprint author), Univ Illinois, Coll Med, Dept Pharmacol, 835 S Wolcott,Rm E403,M-C 868, Chicago, IL 60612 USA. EM obryanj@uic.edu FU Intramural NIH HHS NR 29 TC 6 Z9 6 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 30 PY 2007 VL 282 IS 13 BP 10096 EP 10103 DI 10.1074/jbc.M611151200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 153HA UT WOS:000245421700083 PM 17276991 ER PT J AU Shimura, T Martin, MM Torres, MJ Gu, C Pluth, JM DiBernardi, MA McDonald, JS Aladjem, MI AF Shimura, Tsutomu Martin, Melvenia M. Torres, Michael J. Gu, Cory Pluth, Janice M. DiBernardi, Maria A. McDonald, Jeffrey S. Aladjem, Mirit I. TI DNA-PK is involved in repairing a transient surge of DNA breaks induced by deceleration of DNA replication SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE DNA-PK; replication arrest; non-homologous end joining; aphidicolin; DNA damage S-phase checkpoint ID DEPENDENT PROTEIN-KINASE; DOUBLE-STRAND BREAKS; S-PHASE CHECKPOINT; SPONTANEOUS HOMOLOGOUS RECOMBINATION; POLYMERASE-ALPHA INHIBITION; CATALYTIC SUBUNIT; MAMMALIAN-CELLS; HISTONE H2AX; GAMMA-H2AX FOCI; DAMAGING AGENTS AB Cells that suffer substantial inhibition of DNA replication halt their cell cycle via a checkpoint response mediated by the P13 kinases ATM and ATR. It is unclear how cells cope with milder replication insults, which are under the threshold for ATM and ATR activation. A third P13 kinase, DNA-dependent protein kinase (DNA-PK), is also activated following replication inhibition, but the role DNA-PK might play in response to perturbed replication is unclear, since this kinase does not activate the signaling cascades involved in the S-phase checkpoint. Here we report that mild, transient drug-induced perturbation of DNA replication rapidly induced DNA breaks that promptly disappeared in cells that contained a functional DNA-PK whereas such breaks persisted in cells that were deficient in DNA-PK activity. After the initial transient burst of DNA breaks, cells with a functional DNA-PK did not halt replication and continued to synthesize DNA at a slow pace in the presence of replication inhibitors. In contrast, DNA-PK deficient cells subject to low levels of replication inhibition halted cell cycle progression via an ATR-mediated S-phase checkpoint. The ATM kinase was dispensable for the induction of the initial DNA breaks. These observations suggest that DNA-PK is involved in setting a high threshold for the ATR-Chk1-mediated S-phase checkpoint by promptly repairing DNA breaks that appear immediately following inhibition of DNA replication. Published by Elsevier Ltd. C1 NCI, Ctr Canc Res, Lab Mol Pharmacol, NIH, Bethesda, MD 20892 USA. Lawrence Berkeley Lab, Life Sci Div, Berkeley, CA 94720 USA. Johns Hopkins Univ, Dept Biol, Shady Grove, MD 20850 USA. BD Imaging, Rockville, MD 20850 USA. RP Aladjem, MI (reprint author), NCI, Ctr Canc Res, Lab Mol Pharmacol, NIH, Bethesda, MD 20892 USA. EM aladjemm@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [Z01 BC010411-06] NR 61 TC 34 Z9 35 U1 0 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAR 30 PY 2007 VL 367 IS 3 BP 665 EP 680 DI 10.1016/j.jmb.2007.01.018 PG 16 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 149CH UT WOS:000245123700006 PM 17280685 ER PT J AU Collins, MD Quillin, ML Hummer, G Matthews, BW Gruner, SM AF Collins, Marcus D. Quillin, Michael L. Hummer, Gerhard Matthews, Brian W. Gruner, Sol M. TI Structural rigidity of a large cavity-containing protein revealed by high-pressure crystallography SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE structural rigidity; protein; high pressure crystallography ID RAY-DIFFRACTION DATA; EGG-WHITE LYSOZYME; T4 LYSOZYME; HYDROSTATIC-PRESSURE; PHAGE-T4 LYSOZYME; CRYSTAL-STRUCTURE; NMR-SPECTROSCOPY; ANALYTICAL SHAPE; LIGAND-BINDING; NOBLE-GASES AB Steric constraints, charged interactions and many other forces important to protein structure and function can be explored by mutagenic experiments. Research of this kind has led to a wealth of knowledge about what stabilizes proteins in their folded states. To gain a more complete picture requires that we perturb these structures in a continuous manner, something mutagenesis cannot achieve. With high pressure crystallographic methods it is now possible to explore the detailed properties of proteins while continuously varying thermodynamic parameters. Here, we detail the structural response of the cavity-containing mutant L99A of T4 lysozyme, as well as its pseudo wild-type (WT*) counterpart, to hydrostatic pressure. Surprisingly, the cavity has almost no effect on the pressure response: virtually the same changes are observed in WT* as in L99A under pressure. The cavity is most rigid, while other regions deform substantially. This implies that while some residues may increase the thermodynamic stability of a protein, they may also be structurally irrelevant. As recently shown, the cavity fills with water at pressures above 100 MPa while retaining its overall size. The resultant picture of the protein is one in which conformationally fluctuating side groups provide a liquid-like environment, but which also contribute to the rigidity of the peptide backbone. (c) 2006 Elsevier Ltd. All rights reserved. C1 Cornell Univ, Dept Phys, Ithaca, NY 14853 USA. Univ Oregon, Howard Hughes Med Inst, Inst Mol Biol, Eugene, OR 97403 USA. Univ Oregon, Dept Phys, Eugene, OR 97403 USA. Natl Inst Diabet & Digest & Kidney Dis, Lab Chem Phys, NIH, Bethesda, MD 20892 USA. RP Gruner, SM (reprint author), Cornell Univ, Dept Phys, Ithaca, NY 14853 USA. EM smg26@cornell.edu RI Hummer, Gerhard/A-2546-2013; Gruner, Sol/G-2924-2010 OI Hummer, Gerhard/0000-0001-7768-746X; Gruner, Sol/0000-0002-1171-4426 FU Intramural NIH HHS; NCRR NIH HHS [P41 RR001646]; NIGMS NIH HHS [DMR0225180, GM21967, R01 GM021967] NR 45 TC 42 Z9 43 U1 1 U2 7 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAR 30 PY 2007 VL 367 IS 3 BP 752 EP 763 DI 10.1016/j.jmb.2006.12.021 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 149CH UT WOS:000245123700013 PM 17292912 ER PT J AU Kirkland, D Pfuhler, S Tweats, D Aardema, M Corvi, R Darroudi, F Elhajouji, A Glatt, H Hastwell, P Hayashi, M Kasper, P Kirchner, S Lynch, A Marzin, D Maurici, D Meunier, JR Muller, L Nohynek, G Parry, J Parry, E Thybaud, V Tice, R van Benthem, J Vanparys, P White, P AF Kirkland, David Pfuhler, Stefan Tweats, David Aardema, Marilyn Corvi, Raffaella Darroudi, Firouz Elhajouji, Azeddine Glatt, Hansruedi Hastwell, Paul Hayashi, Makoto Kasper, Peter Kirchner, Stephan Lynch, Anthony Marzin, Daniel Maurici, Daniela Meunier, Jean-Roc Mueller, Lutz Nohynek, Gerhard Parry, James Parry, Elizabeth Thybaud, Veronique Tice, Ray van Benthem, Jan Vanparys, Philippe White, Paul TI How to reduce false positive results when undertaking in vitro genotoxicity testing and thus avoid unnecessary follow-up animal tests: Report of an ECVAM Workshop SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE genotoxicity in vitro; false positives; animal tests ID HUMAN CELL-LINE; CHROMOSOME-ABERRATIONS; HYDROGEN-PEROXIDE; CYTOCHROMES P450; GENE-EXPRESSION; HEPG2 CELLS; INDUCTION; HEPATOCYTES; CARCINOGENS; ENZYMES AB Workshop participants agreed that genotoxicity tests in mammalian cells in vitro produce a remarkably high and unacceptable occurrence of irrelevant positive results (e.g. when compared with rodent carcinogenicity). As reported in several recent reviews, the rate of irrelevant positives (i.e. low specificity) for some studies using in vitro methods (when compared to this "gold standard") means that an increased number of test articles are subjected to additional in vivo genotoxicity testing, in many cases before, e.g. the efficacy (in the case of pharmaceuticals) of the compound has been evaluated. If in vitro tests were more predictive for in vivo genotoxicity and carcinogenicity (i.e. fewer false positives) then there would be a significant reduction in the number of animals used. Beyond animal (or human) carcinogenicity as the "gold standard", it is acknowledged that genotoxicity tests provide much information about cellular behaviour, cell division processes and cellular fate to a (geno)toxic insult. Since the disease impact of these effects is seldom known, and a verification of relevant toxicity is normally also the subject of (sub)chronic animal studies, the prediction of in vivo relevant results from in vitro genotoxicity tests is also important for aspects that may not have a direct impact on carcinogenesis as the ultimate endpoint of concern. In order to address the high rate of in vitro false positive results, a 2-day workshop was held at the European Centre for the Validation of Alternative Methods (ECVAM), Ispra, Italy in April 2006. More than 20 genotoxicity experts from academia, government and industry were invited to review data from the currently available cell systems, to discuss whether there exist cells and test systems that have a reduced tendency to false positive results, to review potential modifications to existing protocols and cell systems that might result in improved specificity, and to review the performance of some new test systems that show promise of improved specificity without sacrificing sensitivity. It was concluded that better guidance on the likely mechanisms resulting in positive results that are not biologically relevant for human health, and how to obtain evidence for those mechanisms, is needed both for practitioners and regulatory reviewers. Participants discussed the fact that cell lines commonly used for genotoxicity testing have a number of deficiencies that may contribute to the high false positive rate. These include, amongst others, lack of normal metabolism leading to reliance on exogenous metabolic activation systems (e.g. Aroclor-induced rat S9), impaired p53 function and altered DNA repair capability. The high concentrations of test chemicals (i.e. 10 mM or 5000 mu g/ml, unless precluded by solubility or excessive toxicity) and the high levels of cytotoxicity currently required in mammalian cell genotoxicity tests were discussed as further potential sources of false positive results. Even if the goal is to detect carcinogens with short in vitro tests under more or less acute conditions, it does not seem logical to exceed the capabilities of cellular metabolic turnover, activation and defence processes. The concept of "promiscuous activation" was discussed. For numerous mutagens, the decisive in vivo enzymes are missing in vitro. However, if the substrate concentration is increased sufficiently, some other enzymes (that are unimportant in vivo) may take over the activation-leading to the same or a different active metabolite. Since we often do not use the right enzyme systems for positive controls in vitro, we have to rely on their promiscuous activation, i.e. to use excessive concentrations to get an empirical correlation between genotoxicity and carcinogenicity. A thorough review of published and industry data is urgently needed to determine whether the currently required limit concentration of 10 mM or 5000 mu g/ml, and high levels of cytotoxicity, are necessary for the detection of in vivo genotoxins and DNA-reactive, mutagenic carcinogens. In addition, various measures of cytotoxicity are currently allowable under OECD test guidelines, but there are few comparative data on whether different measures would result in different maximum concentrations for testing. A detailed comparison of cytotoxicity assessment strategies is needed. An assessment of whether test endpoints can be selected that are not intrinsically associated with cytotoxicity, and therefore are less susceptible to artefacts produced by cytotoxicity, should also be undertaken. There was agreement amongst the workshop participants that cell systems which are p53 and DNA-repair proficient, and have defined Phase 1 and Phase 2 metabolism, covering a broad set of enzyme forms, and used within the context of appropriately set limits of concentration and cytotoxicity, offer the best hope for reduced false positives. Whilst there is some evidence that human lymphocytes are less susceptible to false positives than the current rodent cell lines, other cell systems based on HepG2, TK6 and MCL-5 cells, as well as 3D skin models based on primary human keratinocytes also show some promise. Other human cell lines such as HepaRG, and human stem cells (the target for carcinogenicity) have not been used for genotoxicity investigations and should be considered for evaluation. Genetic engineering is also a valuable tool to incorporate missing enzyme systems into target cells. A collaborative research programme is needed to identify, further develop and evaluate new cell systems with appropriate sensitivity but improved specificity. In order to review current data for selection of appropriate top concentrations, measures and levels of cytotoxicity, metabolism, and to be able to improve existing or validate new assay systems, the participants called for the establishment of an expert group to identify the in vivo genotoxins and DNA-reactive, mutagenic carcinogens that we expect our in vitro genotoxicity assays to detect as well as the non-genotoxins and non-carcinogens we expect them not to detect. (c) 2007 Elsevier B.V. All rights reserved. C1 Covance Labs Ltd, Harrogate HG3 1PY, England. Procter & Gamble Cosmital SA, CH-1723 Marly, Switzerland. Univ Coll Swansea, Sch Med, Swansea SA2 8PP, W Glam, Wales. Procter & Gamble Co, Mimai Valley Innovat Ctr, Cincinnati, OH 45239 USA. Commiss European Communities, Joint Res Ctr, ECVAM, IHCP, I-21020 Ispra, Italy. Leiden Univ, Med Ctr, Dept Toxicogenet, NL-2300 RC Leiden, Netherlands. Novartis Pharma AG, CH-4002 Basel, Switzerland. German Inst Human Nutr, D-14558 Nuthetal, Germany. GlaxoSmithKline R&D, Ware SG12 0DP, Herts, England. Natl Inst Hyg Sci, Div Genet & Mutagenesis, Setagaya Ku, Tokyo 1588501, Japan. BfArM, D-53175 Bonn, Germany. F Hoffmann La Roche & Co Ltd, CH-4070 Basel, Switzerland. Inst Pasteur, F-59019 Lille, France. LOreal, F-93600 Aulnay Sous Bois, France. LOreal, Worldwide Safety Dept, F-92600 Asnieres, France. Sanofi Aventis, F-94403 Vitry Sur Seine, France. NIEHS, NICEATM, Res Triangle Pk, NC 27709 USA. Natl Inst Publ Hlth & Environm, NL-3720 BA Bilthoven, Netherlands. Johnson & Johnson Pharmaceut Res & Dev, B-2340 Beerse, Belgium. Hlth Canada, Mutagenesis Sect, Safe Environm Programme, Ottawa, ON K1A O12, Canada. RP Kirkland, D (reprint author), Covance Labs Ltd, Otley Rd, Harrogate HG3 1PY, England. EM david.kirkland@covance.com OI Glatt, Hansruedi/0000-0001-6053-0562; white, paul/0000-0001-5853-4759 NR 40 TC 225 Z9 233 U1 1 U2 21 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1383-5718 J9 MUTAT RES-GEN TOX EN JI Mutat. Res. Genet. Toxicol. Environ. Mutagen. PD MAR 30 PY 2007 VL 628 IS 1 BP 31 EP 55 DI 10.1016/j.mrgentox.2006.11.008 PG 25 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 151WF UT WOS:000245320900004 PM 17293159 ER PT J AU Pianta, RC Belsky, J Houts, R Morrison, F AF Pianta, Robert C. Belsky, Jay Houts, Renate Morrison, Fred CA NICHD Early Child Care Res Network TI Opportunities to learn in America's elementary classrooms SO SCIENCE LA English DT Editorial Material ID TEACHER C1 Univ Virginia, Ctr Adv Study Teaching & Learning, Charlottesville, VA 22903 USA. Birkbeck Univ London, Inst Study Children Family & Soc, London, England. RTI Int, Dept Stat & Epidemiol, Res Triangle Pk, NC 27709 USA. Univ Michigan, Dept Psychol, Ann Arbor, MI 48103 USA. NICHD, NICHD Early Child Care & Youth Dev Res Network, CRMC, Rockville, MD 20852 USA. RP Pianta, RC (reprint author), Univ Virginia, Ctr Adv Study Teaching & Learning, Charlottesville, VA 22903 USA. EM rcp4p@virginia.edu OI Belsky, Jay/0000-0003-2191-2503; Pianta, Robert/0000-0002-6280-8051 FU NICHD NIH HHS [U01 HD033343-13] NR 13 TC 121 Z9 121 U1 3 U2 13 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 MAR 30 PY 2007 VL 315 IS 5820 BP 1795 EP 1796 DI 10.1126/science.1139719 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 151HC UT WOS:000245280100024 PM 17395814 ER PT J AU Fortini, ME AF Fortini, Mark E. TI Medicine - Anticipating trouble from gene transcription SO SCIENCE LA English DT Editorial Material ID REPEAT INSTABILITY; CAG REPEATS; DISEASE; DROSOPHILA; SPERM; MECHANISMS; EXPANSION C1 NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. RP Fortini, ME (reprint author), NCI, Canc & Dev Biol Lab, Frederick, MD 21702 USA. EM fortini@ncifcrf.gov NR 12 TC 1 Z9 1 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 MAR 30 PY 2007 VL 315 IS 5820 BP 1800 EP 1801 DI 10.1126/science.1141279 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 151HC UT WOS:000245280100027 PM 17395816 ER PT J AU Guarda, G Hons, M Martin-Fontecha, A Lanzavecchia, A Sallusto, F Fernandez, SS Stein, J Huang, A Polley, R Germain, R AF Guarda, G. Hons, M. Martin-Fontecha, A. Lanzavecchia, A. Sallusto, F. Fernandez, Soriano S. Stein, J. Huang, A. Polley, R. Germain, R. TI Transient recruitment of effector and effector memory CD8(+) T cells to reactive lymph nodes leads to dendritic cell killing and inhibition of immune responses SO SWISS MEDICAL WEEKLY LA English DT Meeting Abstract C1 Univ Bern, Theodor Kocher Inst, CH-3012 Bern, Switzerland. NIAID, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU E M H SWISS MEDICAL PUBLISHERS LTD PI MUTTENZ PA FARNSBURGERSTR 8, CH-4132 MUTTENZ, SWITZERLAND SN 1424-7860 J9 SWISS MED WKLY JI Swiss Med. Wkly. PD MAR 30 PY 2007 VL 137 SU 157 BP 11S EP 11S PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 152IN UT WOS:000245355800030 ER PT J AU Barthlott, T Jeker, L Keller, M Zuklys, S Boulay, T Hafen, K Peter, A Deng, CX Hollander, G AF Barthlott, T. Jeker, L. Keller, M. Zuklys, S. Boulay, T. Hafen, K. Peter, A. Deng, C. X. Hollaender, G. A. TI A critical role for Smad4 mediated TGF beta family - signaling in thymic epithelial cells to attract T cell precursors into the thymus SO SWISS MEDICAL WEEKLY LA English DT Meeting Abstract C1 Pediat Immunol Ctr Biomed, Dept Clin Biol Sci, Basel, Switzerland. Univ Basel, Childrens Hosp Both Cantons Basel, UKBB, Basel, Switzerland. NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU E M H SWISS MEDICAL PUBLISHERS LTD PI MUTTENZ PA FARNSBURGERSTR 8, CH-4132 MUTTENZ, SWITZERLAND SN 1424-7860 J9 SWISS MED WKLY JI Swiss Med. Wkly. PD MAR 30 PY 2007 VL 137 SU 157 BP 15S EP 15S PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 152IN UT WOS:000245355800043 ER PT J AU Ono, A Waheed, AA Freed, EO AF Ono, Akira Waheed, Abdul A. Freed, Eric O. TI Depletion of cellular cholesterol inhibits membrane binding and higher-order multimerization of human immunodeficiency virus type 1 Gag SO VIROLOGY LA English DT Article DE HIV-1; Gag; retrovirus assembly; cholesterol; lipid raft; myristyl switch; membrane binding ID LIPID RAFTS; PLASMA-MEMBRANE; HIV-1 GAG; MATRIX PROTEIN; PARTICLE-PRODUCTION; INFECTIOUS HIV-1; TERMINAL REGION; I DOMAIN; LOCALIZATION; PR55(GAG) AB Recent studies have suggested that the plasma membrane contains cholesterol-enriched microdomains known as lipid rafts. HIV-1 Gag binds raft-rich regions of the plasma membrane, and cholesterol depiction impairs HIV-1 particle production. In this study, we sought to define the block imposed by cholesterol depletion. We observed that membrane binding and higher-order multimerization of Gag were markedly reduced upon cholesterol depletion. Fusing to Gag a highly efficient, heterologous membrane-binding sequence reversed the defects in Gag-membrane binding and multimerization caused by cholesterol depiction, indicating that the impact of reducing the membrane cholesterol content on Gag-membrane binding and multimerization can be circumvented by increasing the affinity of Gag for membrane. Virus release efficiency of this Gag derivative was minimally affected by cholesterol depletion. Altogether, these results are consistent with the hypothesis that cholesterol-enriched membrane microdomains promote HIV-1 particle production by facilitating both Gag-membrane binding and Gag multimerization. (c) 2006 Elsevier Inc. All rights reserved. C1 Univ Michigan, Sch Med, Dept Microbiol & Immunol, Ann Arbor, MI 48109 USA. Natl Canc Inst, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Ono, A (reprint author), Univ Michigan, Sch Med, Dept Microbiol & Immunol, 5736 Med Sci Bldg 2, Ann Arbor, MI 48109 USA. EM akiraono@umich.edu OI Ono, Akira/0000-0001-7841-851X FU Intramural NIH HHS [Z01 BC010619-03, Z01 BC010776-01, Z99 CA999999] NR 68 TC 62 Z9 64 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 30 PY 2007 VL 360 IS 1 BP 27 EP 35 DI 10.1016/j.virol.2006.10.011 PG 9 WC Virology SC Virology GA 149JB UT WOS:000245142100004 PM 17095032 ER PT J AU Lu, J Lee, JC Salit, ML Cam, MC AF Lu, Jun Lee, Joseph C. Salit, Marc L. Cam, Margaret C. TI Transcript-based redefinition of grouped oligonucleotide probe sets using AceView: High-resolution annotation for microarrays SO BMC BIOINFORMATICS LA English DT Article ID GENE-EXPRESSION MEASUREMENTS; ARRAYS; MODEL; INDEX; INCONSISTENCIES; HYBRIDIZATION; PLATFORMS; RESOURCES; LEVEL AB Background: Extracting biological information from high-density Affymetrix arrays is a multi-step process that begins with the accurate annotation of microarray probes. Shortfalls in the original Affymetrix probe annotation have been described; however, few studies have provided rigorous solutions for routine data analysis. Results: Using AceView, a comprehensive human transcript database, we have reannotated the probes by matching them to RNA transcripts instead of genes. Based on this transcript-level annotation, a new probe set definition was created in which every probe in a probe set maps to a common set of AceView gene transcripts. In addition, using artificial data sets we identified that a minimal probe set size of 4 is necessary for reliable statistical summarization. We further demonstrate that applying the new probe set definition can detect specific transcript variants contributing to differential expression and it also improves cross-platform concordance. Conclusion: We conclude that our transcript-level reannotation and redefinition of probe sets complement the original Affymetrix design. Redefinitions introduce probe sets whose sizes may not support reliable statistical summarization; therefore, we advocate using our transcript-level mapping redefinition in a secondary analysis step rather than as a replacement. Knowing which specific transcripts are differentially expressed is important to properly design probe/primer pairs for validation purposes. For convenience, we have created custom chip-description-files (CDFs) and annotation files for our new probe set definitions that are compatible with Bioconductor, Affymetrix Expression Console or third party software. C1 NIDDK, Genom Core Lab, NIH, Bethesda, MD 20892 USA. Natl Inst Stand & Technol, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. RP Cam, MC (reprint author), NIDDK, Genom Core Lab, NIH, Bethesda, MD 20892 USA. EM lujun@mail.nih.gov; jclee8@gmail.com; salit@nist.gov; maggie.cam@nih.gov FU Intramural NIH HHS NR 38 TC 39 Z9 39 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD MAR 29 PY 2007 VL 8 AR 108 DI 10.1186/1471-2105-8-108 PG 14 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 158PV UT WOS:000245804400002 PM 17394657 ER PT J AU Zanuy, D Jimenez, AI Cativiela, C Nussinov, R Aleman, C AF Zanuy, David Jimenez, Ana I. Cativiela, Carlos Nussinov, Ruth Aleman, Carlos TI Use of constrained synthetic amino acids in beta-helix proteins for conformational control SO JOURNAL OF PHYSICAL CHEMISTRY B LA English DT Article ID MOLECULAR-DYNAMICS; DESIGN; SYSTEMS; DENSITY; FIELD AB A highly constrained amino acid has been introduced in the turn region of a beta-helix to increase the conformational stability of the native fold for nanotechnological purposes. The influence of this specific amino acid replacement in the final organization of beta-helix motifs has been evaluated by combining ab initio first-principles calculations on model systems and molecular dynamics simulations of entire peptide segments. The former methodology, which has been applied to a sequence containing three amino acids, has been used to develop adjusted templates. Calculations indicated that 1-amino-2,2-diphenylcyclopropanecarboxylic acid, a constrained cyclopropane analogue of phenylalanine, exhibits a strong tendency to form and promote folded conformations. On the other hand, molecular dynamics simulations are employed to probe the ability of such a synthetic amino acid to enhance the conformational stability of the beta-helix motif, which is the first requirement for further protein nanoengineering. A highly regular segment from a naturally occurring beta-helix protein was selected as a potential nanoconstruct module. Simulations of wild type and mutated segments revealed that the ability of the phenylalanine analogue to nucleate turn conformations enhances the conformational stability of the beta-helix motif in isolated peptide segments. C1 Univ Politecn Catalunya, ETSEIB, Dept Engn Quim, E-08028 Barcelona, Spain. Univ Zaragoza, Dept Quim Organ, ICMA, CSIC, E-50009 Zaragoza, Spain. NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res,Nanobiol Program, Frederick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, Dept Human Genet, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), Univ Politecn Catalunya, ETSEIB, Dept Engn Quim, Diagonal 647, E-08028 Barcelona, Spain. EM ruthn@ncifcrf.gov; carlos.aleman@upc.edu RI Zanuy, David/G-3930-2014 OI Zanuy, David/0000-0001-7704-2178 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 32 TC 20 Z9 20 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1520-6106 J9 J PHYS CHEM B JI J. Phys. Chem. B PD MAR 29 PY 2007 VL 111 IS 12 BP 3236 EP 3242 DI 10.1021/jp065025k PG 7 WC Chemistry, Physical SC Chemistry GA 148OE UT WOS:000245083700021 PM 17388467 ER PT J AU Bloom, SL Spong, CY Thom, EA AF Bloom, Steven L. Spong, Catherine Y. Thom, Elizabeth A. TI Fetal pulse oximetry and cesarean delivery - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 Univ Texas, SW Med Ctr, Dallas, TX 75390 USA. NICHHD, Bethesda, MD 20892 USA. George Washington Univ, Ctr Biostat, Rockville, MD 20852 USA. RP Bloom, SL (reprint author), Univ Texas, SW Med Ctr, Dallas, TX 75390 USA. EM steven.bloom@utsouthwestern.edu NR 0 TC 0 Z9 0 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 MAR 29 PY 2007 VL 356 IS 13 BP 1377 EP 1378 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 150MN UT WOS:000245221000028 ER PT J AU Kibenge, FSB Xu, HT Kibenge, MJT Qian, B Joseph, T AF Kibenge, Frederick S. B. Xu, Hongtao Kibenge, Molly J. T. Qian, Biao Joseph, Tomy TI Characterization of gene expression on genomic segment 7 of infectious salmon anaemia virus SO VIROLOGY JOURNAL LA English DT Article ID ORTHOMYXO-LIKE VIRUS; ATLANTIC SALMON; SALAR L.; ISAV; PROTEIN; IDENTIFICATION; INFLUENZA; DNA; SEQUENCES; CELLS AB Background: Infectious salmon anaemia (ISA) virus (ISAV), an important pathogen of fish that causes disease accompanied by high mortality in marine-farmed Atlantic salmon, is the only species in the genus Isavirus, one of the five genera of the Orthomyxoviridae family. The Isavirus genome consists of eight single-stranded RNA species, and the virions have two surface glycoproteins; haemagglutinin-esterase (HE) protein encoded on segment 6 and fusion (F) protein encoded on segment 5. Based on the initial demonstration of two 5'-coterminal mRNA transcripts by RT-PCR, ISAV genomic segment 7 was suggested to share a similar coding strategy with segment 7 of influenza A virus, encoding two proteins. However, there appears to be confusion as to the protein sizes predicted from the two open reading frames (ORFs) of ISAV segment 7 which has in turn led to confusion of the predicted protein functions. The primary goal of the present work was to clone and express these two ORFs in order to assess whether the predicted protein sizes match those of the expressed proteins so as to clarify the coding assignments, and thereby identify any additional structural proteins of ISAV. Results: In the present study we show that ISAV segment 7 encodes 3 proteins with estimated molecular masses of 32, 18, and 9.5 kDa. The 18-kDa and 9.5-kDa products are based on removal of an intron each from the primary transcript (7-ORFI) so that the translation continues in the +2 and +3 reading frames, respectively. The segment 7-ORFI/3 product is variably truncated in the sequence of ISAV isolates of the European genotype. All three proteins are recognized by rabbit antiserum against the 32-kDa product of the primary transcript, as they all share the N-terminal 22 amino acids. This antiserum detected a single 35-kDa protein in Western blots of purified virus, and immunoprecipitated a 32-kDa protein in ISAV-infected TO cells. Immunofluorescence staining of infected cells with the same antiserum revealed the protein(s) to be localized in the cytoplasm. Vaccination of farmed Atlantic salmon with the 32-kDa protein resulted in a higher survival rate than what was attainable with the HE protein, albeit a moderate protection against the low ISAV challenge. Conclusion: Collectively, our observations suggest that the product of ISAV segment 7 primary transcript (7ORFI) is a structural protein. The 18-kDa (7-ORFI/2) protein is identified as the putative ISAV nuclear export protein based on the presence of nuclear export signals. The function of the 9.5-kDa (7-ORFI/3) protein is not presently known. C1 Univ Prince Edward Isl, Atlantic Vet Coll, Dept Pathol & Microbiol, Charlottetown, PE C1A 4P3, Canada. Jewish Gen Hosp, McGill AIDS Ctr, Montreal, PQ H3T 1E2, Canada. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Kibenge, FSB (reprint author), Univ Prince Edward Isl, Atlantic Vet Coll, Dept Pathol & Microbiol, 550 Univ Ave, Charlottetown, PE C1A 4P3, Canada. EM kibenge@upei.ca; hongtaoxu_00@yahoo.com; mkibenge@upei.ca; qian@upei.ca; josephto@niaid.nih.gov NR 43 TC 19 Z9 20 U1 1 U2 4 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 MAR 29 PY 2007 VL 4 AR 34 DI 10.1186/1743-422X-4-34 PG 15 WC Virology SC Virology GA 182QT UT WOS:000247519800001 PM 17394643 ER PT J AU Herce, HD Garcia, AE Darden, T AF Herce, Henry David Garcia, Angel Enrique Darden, Thomas TI The electrostatic surface term: (I) Periodic systems SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID PARTICLE MESH EWALD; DYNAMICS COMPUTER-SIMULATION; CHARGING FREE-ENERGIES; BOUNDARY-CONDITIONS; MOLECULAR-DYNAMICS; LATTICE SUMS; WATER; CRYSTALS; SOLVATION; SUMMATION AB The authors propose a new approach to understand the electrostatic surface contributions to the interactions of large but finite periodic distributions of charges. They present a simple method to derive and interpret the surface contribution to any electrostatic field produced by a periodic distribution of charges. They discuss the physical and mathematical interpretations of this term. They present several examples and physical details associated with the calculation of the surface term. Finally, they provide a simple derivation of the surface contribution to the virial. This term does not disappear even if tinfoil boundary conditions are applied. (c) 2007 American Institute of Physics. C1 Rensselaer Polytech Inst, Dept Phys, Troy, NY 12180 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Herce, HD (reprint author), Rensselaer Polytech Inst, Dept Phys, Troy, NY 12180 USA. NR 37 TC 19 Z9 20 U1 0 U2 14 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 MAR 28 PY 2007 VL 126 IS 12 AR 124106 DI 10.1063/1.2714527 PG 13 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 151VB UT WOS:000245317800008 PM 17411107 ER PT J AU Hahn, B Ross, TJ Yang, YH Kim, I Huestis, MA Stein, EA AF Hahn, Britta Ross, Thomas J. Yang, Yihong Kim, Insook Huestis, Marilyn A. Stein, Elliot A. TI Nicotine enhances visuospatial attention by deactivating areas of the resting brain default network SO JOURNAL OF NEUROSCIENCE LA English DT Article DE nicotine; attention; fMRI; default network; alerting; ASL ID CEREBRAL BLOOD OXYGENATION; MEDIAL PREFRONTAL CORTEX; REACTION-TIME-TASK; CIGARETTE-SMOKING; VISUAL-ATTENTION; WORKING-MEMORY; COGNITIVE PERFORMANCE; TRANSDERMAL NICOTINE; PROCESSING SPEED; PARIETAL CORTEX AB Nicotine-induced attentional enhancement is of potential therapeutic value. To investigate the precise attentional function(s) affected and their neuronal mechanisms, the current functional magnetic resonance imaging (fMRI) study used an attention task in which subjects responded to stimuli of high (INThigh) or low intensity presented randomly in one of four peripheral locations. Central cues of varying precision predicted the target location. In some trials, the cue was not followed by a target, allowing separate analysis of blood oxygenation level-dependent (BOLD) responses to cue. Minimally deprived smokers underwent fast event-related fMRI twice: once with a nicotine patch (21 mg) and once with a placebo patch. Matched nonsmokers were scanned twice without a patch. Behaviorally, nicotine reduced omission errors and reaction time (RT) of valid and invalid cue trials and intra-individual variability of RT and did so preferentially in trials with INThigh. The BOLD signal related to cue-only trials, regardless of cue precision, demonstrated nicotine-induced deactivation in anterior and posterior cingulate, angular gyrus, middle frontal gyrus, and cuneus. These regions overlapped with the so-called "default network," which activates during rest and deactivates with attention-demanding activities. Partial correlations controlling for nicotine plasma levels indicated associations of deactivation by nicotine in posterior cingulate and angular gyrus with performance improvements under INThigh. Performance and regional activity in the absence of nicotine never differed between smokers and nonsmokers, ruling out a simple reversal of a deprivation-induced state. These findings suggest that nicotine improved attentional performance by downregulating resting brain function in response to task-related cues. Together with the selectivity of effects for INThigh, this suggests a nicotine-induced potentiation of the alerting properties of external stimuli. C1 NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NIDA, Chem & Drug Metab Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Hahn, B (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM bhahn@intra.nida.nih.gov RI Ross, Thomas/B-7469-2008; Stein, Elliot/C-7349-2008; Hahn, Britta/G-4593-2012 OI Ross, Thomas/0000-0002-7745-3572; FU Intramural NIH HHS [Z01 DA000413-10, Z99 DA999999] NR 62 TC 101 Z9 102 U1 3 U2 9 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 MAR 28 PY 2007 VL 27 IS 13 BP 3477 EP 3489 DI 10.1523/JNEUROSCI.5129-06.2007 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 153WT UT WOS:000245468200015 PM 17392464 ER PT J AU Wang, J Carnicella, S Phamluong, K Jeanblanc, J Ronesi, JA Chaudhri, N Janak, PH Lovinger, DM Ron, D AF Wang, Jun Carnicella, Sebastien Phamluong, Khanhky Jeanblanc, Jerome Ronesi, Jennifer A. Chaudhri, Nadia Janak, Patricia H. Lovinger, David M. Ron, Dorit TI Ethanol induces long-term facilitation of NR2B-NMDA receptor activity in the dorsal striatum: Implications for alcohol drinking Behavior SO JOURNAL OF NEUROSCIENCE LA English DT Article DE accumbens; addiction; drinking; Fyn; NMDA receptors; self-administration; striatum; synaptic plasticity ID ASPARTATE GLUTAMATE RECEPTORS; SYNAPTIC PLASTICITY; NMDA RECEPTORS; SPRAGUE-DAWLEY; BASAL GANGLIA; HOMEOSTATIC PATHWAY; HIPPOCAMPAL-NEURONS; NEUROTROPHIC FACTOR; TYROSINE KINASES; COCAINE-SEEKING AB Addiction is characterized by compulsive alcohol or drug taking and seeking, and the dorsal striatum has been implicated in such maladaptive persistent habits. The NMDA receptor (NMDAR), which is a major target of alcohol, is implicated in striatal-based habit learning. We found that, in the dorsal striatum, alcohol (ethanol) exposure produced an increase in the phosphorylation of the NR2B subunit of the NMDAR, and a corresponding increase in the activity of Fyn kinase, which phosphorylates NR2B. We further observed an ethanol-mediated long-term facilitation (LTF) of the activity of NR2B-containing NMDARs(NR2B-NMDARs) in the dorsal striatum. This LTF is Fyn kinase dependent, because it was observed in Fyn wild-type but not in Fyn knock-out mice. Importantly, none of these biochemical and physiological changes was observed in the ventral striatum. Finally, dorsal but not ventral striatum infusion of a Fyn or NR2B-NMDAR inhibitor reduced rat operant self-administration of ethanol. Our results suggest that the Fyn-mediated phosphorylation and LTF of NR2B-NMDAR activity in the dorsal striatum after exposure to ethanol may underlie aberrant plasticity that contributes to mechanisms underlying alcohol drinking behavior. C1 Univ Calif San Francisco, Ernest Gallo Res Ctr, Emeryville, CA 94608 USA. Univ Calif San Francisco, Dept Neurol, Emeryville, CA 94608 USA. NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. RP Ron, D (reprint author), Univ Calif San Francisco, Ernest Gallo Res Ctr, 588 Horton St,Suite 200, Emeryville, CA 94608 USA. EM dorit.ron@ucsf.edu RI Wang, Jun/N-8472-2015; Wang, Jun/M-2337-2016; OI Wang, Jun/0000-0002-0085-4722; Wang, Jun/0000-0002-0085-4722; Janak, Patricia/0000-0002-3333-9049 FU Intramural NIH HHS; NIAAA NIH HHS [R01AA/MH13438-01A1] NR 63 TC 87 Z9 93 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 MAR 28 PY 2007 VL 27 IS 13 BP 3593 EP 3602 DI 10.1523/JNEUROSCI.4749-06.2007 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 153WT UT WOS:000245468200026 PM 17392475 ER PT J AU Woodcock, HL Moran, D Brooks, BR Schleyer, PV Schaefer, HF AF Woodcock, H. Lee Moran, Damian Brooks, Bernard R. Schleyer, Paul v. R. Schaefer, Henry F., III TI Carbene stabilization by aryl substituents. Is bigger better? SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ELECTRON-PARAMAGNETIC RESONANCE; DENSITY-FUNCTIONAL THEORY; NUCLEAR DOUBLE-RESONANCE; LASER FLASH-PHOTOLYSIS; CHEMICAL-SHIFTS NICS; TRIPLET GROUND STATE; ENERGY DIFFERENCES; PICOSECOND LASER; QUANTUM-CHEMISTRY; SOLVENT POLARITY AB The geometries and relative stabilities of the singlet and triplet states of phenyl- (C-s), diphenyl- (C-2), 1-naphthyl- (C-s), di(1-naphthyl)- (C-2), and 9-anthryl-substituted (C-s) carbenes were investigated at the B3LYP/6-311+G(d,p) + ZPVE level of density functional theory. The singlet-triplet energy separations (Delta E-ST), 2.7, 2.9, 3.4, 3.7, and 5.7 kcal/mol, respectively, after including an empirical correction (2.8 kcal/mol) based on the error in the computed singlet-triplet gap for methylene versus experiment, are in good agreement with available experimental values. Consistent with literature reports, triplet di(9-anthryl)carbene has a linear, D-2d symmetrical, allene structure with 1.336 A CC bond lengths and considerable biradical character. B3LYP favors such cumulene biradical structures and triplet spin states and predicts a large (> 15 kcal/mol) "di(9-anthryl)carbene" singlet-triplet (biradical) energy gap. The resonance stabilization of both singlet and triplet carbenes increases modestly with the size of the arene substituent and overall, (di)arylcarbenes, both singlet and triplet, are better stabilized by bigger substituents. For example, methylene is stabilized more by a naphthyl than a phenyl group (singlets, 26.6 versus 24.4; and triplets, 20.9 versus 18.1 kcal/mol, respectively). The carbene geometries are affected by both steric effects and arene-carbene orbital interactions (sigma-p and p-pi). For instance, the central angles at the carbene are widened by a second arene group, which leads to increased s-character and shorter carbene bond lengths (i.e., -C, -H). In general, the aromaticity of the substituted rings in triplet carbenes is most affected by the presence of the unpaired electrons. C1 Univ Georgia, Ctr Computat Chem, Athens, GA 30602 USA. NHLBI, Computat Biophys Sect, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. Univ Sydney, Sch Chem, Sydney, NSW 2006, Australia. RP Woodcock, HL (reprint author), Univ Georgia, Ctr Computat Chem, Athens, GA 30602 USA. EM hlwood@nih.gov; dmoran@chem.usyd.edu.au; schleyer@chem.uga.edu RI Woodc, Henry/D-9275-2011; OI Moran, Damian/0000-0002-8316-8823; Woodcock, Henry/0000-0003-3539-273X FU Intramural NIH HHS NR 85 TC 32 Z9 32 U1 0 U2 14 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 MAR 28 PY 2007 VL 129 IS 12 BP 3763 EP 3770 DI 10.1021/ja068899t PG 8 WC Chemistry, Multidisciplinary SC Chemistry GA 147YI UT WOS:000245041300062 PM 17326641 ER PT J AU Slezak, SL Bettinotti, M Selleri, S Adams, S Marincola, FM Stroncek, DF AF Slezak, Stefanie L. Bettinotti, Maria Selleri, Silvia Adams, Sharon Marincola, Francesco M. Stroncek, David F. TI CMV pp65 and IE-1 T cell epitopes recognized by healthy subjects SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID MATRIX PROTEIN PP65; HUMAN CYTOMEGALOVIRUS; FLOW-CYTOMETRY; PEPTIDE; IDENTIFICATION; FREQUENCY; VIRUS; PHOSPHOPROTEIN-65; INDIVIDUALS; LYMPHOCYTES AB Background: Adoptive immune and vaccine therapies have been used to prevent cytomegalovirus ( CMV) disease in recipients of hematopoietic progenitor cell transplants, but the nature of T cell responses to CMV have not been completely characterized. Methods: Peptide pools and individual peptides derived from the immune-dominant CMV proteins pp65 and IE-I and antigen-specific, cytokine flow cytometry were used to characterize the prevalence and frequency of CD4+ and CD8+ memory T cells in 20 healthy CMV-seropositive subjects. Results: CD8+ T cell responses to pp65 were detected in 35% of subjects and to IE-I in 40% of subjects. CD4+ T cell responses to pp65 were detected in 50% of subjects, but none were detected to IE-I. Several new IE-I HLA class I epitopes were identified, including 4 restricted to HLA-C antigens. One region of IE-I spanning amino acids 300 to 327 was rich in class I epitopes. The HLA class I restrictions of IE-1 peptides were more promiscuous than those of pp65 peptides. Conclusion: Since naturally occurring CD4+ and CD8+ T cell responses to pp65 were detectable in many subjects, but only CD8+ T cell responses to IE-I were detected, pp65 may be better than IE-I for use in vaccine and adoptive immune therapies. C1 NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. RP Stroncek, DF (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. EM sslezak@cc.nih.gov; maria.p.bettinotti@questdiagnostics.com; selleris@cc.nih.gov; sadams1@cc.nih.gov; fmarincola@cc.nih.gov; dstroncek@cc.nih.gov NR 30 TC 30 Z9 30 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD MAR 28 PY 2007 VL 5 AR 17 DI 10.1186/1479-5876-5-17 PG 16 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 157LP UT WOS:000245721500001 PM 17391521 ER PT J AU Xu, Q Guo, HB Wlodawer, A Nakayama, T Guo, H AF Xu, Qin Guo, Hao-Bo Wlodawer, Alexander Nakayama, Toru Guo, Hong TI The QM/MM molecular dynamics and free energy simulations of the acylation reaction catalyzed by the serine-carboxyl peptidase kumamolisin-As SO BIOCHEMISTRY LA English DT Article ID SUBSTRATE-ASSISTED CATALYSIS; NEURONAL CEROID-LIPOFUSCINOSIS; SCC-DFTB METHOD; ACTIVE-SITE; TETRAHEDRAL ADDUCT; PROTEINASE; MECHANISM; SPECIFICITY; FAMILY; PURIFICATION AB Quantum mechanical/molecular mechanical molecular dynamics and free energy simulations are performed to study the acylation reaction catalyzed by kumamolisin-As, a serine-carboxyl peptidase, and to elucidate the catalytic mechanism and the origin of substrate specificity. It is demonstrated that the nucleophilic attack by the serine residue on the substrate may not be the rate-limiting step for the acylation of the GPH*FF substrate. The present study also confirms the earlier suggestions that Asp164 acts as a general acid during the catalysis and that the electrostatic oxyanion hole interactions may not be sufficient to lead a stable tetrahedral intermediate along the reaction pathway. Moreover, Asp164 is found to act as a general base during the formation of the acyl-enzyme from the tetrahedral intermediate. The role of dynamic substrate assisted catalysis (DSAC) involving His at the P-1 site of the substrate is examined for the acylation reaction. It is demonstrated that the bond-breaking and -making events at each stage of the reaction trigger a change of the position for the His side chain and lead to the formation of the alternative hydrogen bonds. The back and forth movements of the His side chain between the CO group of Pro at P-2 and O-delta 2 of Asp164 in a ping-pong-like mechanism and the formation of the alternative hydrogen bonds effectively lower the free energy barriers for both the nucleophilic attack and the acyl-enzyme formation and may therefore contribute to the relatively high activity of kumamolisin-As toward the substrates with His at the P-1 site. C1 Univ Tennessee, Dept Biochem, Knoxville, TN 37996 USA. Univ Tennessee, Dept Mol & Cellular Biol, Knoxville, TN 37996 USA. NCI, Struct Sect, Macromol Crystallog Lab, Ft Detrick, MD 21702 USA. Tohoku Univ, Grad Sch Engn, Dept Biomol Engn, Sendai, Miyagi 9808579, Japan. RP Guo, H (reprint author), Univ Tennessee, Dept Biochem, Knoxville, TN 37996 USA. EM hguo1@utk.edu RI Guo, Hao-Bo/B-7486-2009; Guo, Hong/E-6357-2010; Xu, Qin/O-7310-2015 OI Guo, Hao-Bo/0000-0003-1321-1758; Xu, Qin/0000-0002-8346-9431 FU Intramural NIH HHS [Z01 BC010348-08] NR 38 TC 18 Z9 19 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 27 PY 2007 VL 46 IS 12 BP 3784 EP 3792 DI 10.1021/bi061737p PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 147OT UT WOS:000245013000020 PM 17326662 ER PT J AU Sabatine, MS Morrow, DA Jablonski, KA Rice, MM Warnica, JW Domanski, MJ Hsia, J Gersh, BJ Rifai, N Ridker, PM Pfeffer, MA Braunwald, E AF Sabatine, Marc S. Morrow, David A. Jablonski, Kathleen A. Rice, Madeline Murguia Warnica, J. Wayne Domanski, Michael J. Hsia, Judith Gersh, Bernard J. Rifai, Nader Ridker, Paul M. Pfeffer, Marc A. Braunwald, Eugene CA PEACE Investigators TI Prognostic significance of the Centers for Disease Control/American Heart Association high-sensitivity C-reactive protein cut points for cardiovascular and other outcomes in patients with stable coronary artery disease SO CIRCULATION LA English DT Article DE coronary disease; C-reactive protein; inflammation; risk factors ID DENSITY-LIPOPROTEIN CHOLESTEROL; CONVERTING-ENZYME-INHIBITION; ACUTE MYOCARDIAL-INFARCTION; TYPE-2 DIABETES-MELLITUS; LONG-TERM MORTALITY; STATIN THERAPY; PRIMARY PREVENTION; UNSTABLE ANGINA; RISK; INFLAMMATION AB Background-Data supporting the prognostic significance of high-sensitivity C-reactive protein (hs-CRP) are derived largely from individuals with no overt coronary artery disease or from patients with acute coronary syndromes. In contrast, the ability of hs-CRP to predict outcomes in patients with stable coronary artery disease and the prognostic significance of the Centers for Disease Control/American Heart Association hs-CRP cut points in such a population remain relatively unexplored. Methods and Results-We measured hs-CRP in 3771 patients with stable coronary artery disease from the Prevention of Events With Angiotensin-Converting Enzyme Inhibition (PEACE) trial, a randomized placebo-controlled trial of the angiotensin-converting enzyme inhibitor trandolapril. Patients were followed up for a median of 4.8 years for cardiovascular death, myocardial infarction, or stroke, as well as new heart failure and diabetes. After adjustment for baseline characteristics and treatments, higher hs-CRP levels, even > 1 mg/L, were associated with a significantly greater risk of cardiovascular death, myocardial infarction, or stroke (hs-CRP 1 to 3 mg/L: adjusted hazard ratio, 1.39; 95% CI, 1.06 to 1.81; P = 0.016; hs-CRP > 3 mg/L: adjusted hazard ratio, 1.52; 95% CI, 1.15 to 2.02; P = 0.003). Similarly, elevated hs-CRP levels were an independent predictor of new heart failure (adjusted P < 0.001 for trend) and new diabetes (adjusted P < 0.001 for trend). There were no significant interactions between hs-CRP levels and the effects of trandolapril on any of the above outcomes. Conclusions-In stable coronary artery disease, an elevated hs-CRP level, even > 1 mg/L, is a significant predictor of adverse cardiovascular events independently of baseline characteristics and treatments. An elevated hs-CRP does not appear to identify patients with stable coronary artery disease and preserved ejection fraction who derive particular benefit from angiotensin-converting enzyme inhibition. C1 Brigham & Womens Hosp, Div Cardiovasc, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. George Washington Univ, Rockville, MD USA. George Washington Univ, Washington, DC 20052 USA. Univ Calgary, Dept Cardiac Sci, Calgary, AB T2N 1N4, Canada. NHLBI, Bethesda, MD 20892 USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. Childrens Hosp, Dept Lab Med & Pathol, Boston, MA 02115 USA. RP Sabatine, MS (reprint author), Brigham & Womens Hosp, Div Cardiovasc, 75 Francis St, Boston, MA 02115 USA. EM msabatine@partners.org FU NHLBI NIH HHS [N01 HC065149, N01 HC65149] NR 39 TC 174 Z9 181 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 27 PY 2007 VL 115 IS 12 BP 1528 EP 1536 DI 10.1161/CIRCULATIONAHA.106.649939 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 150JC UT WOS:000245211300005 PM 17372173 ER PT J AU Fox, CS Coady, S Sorlie, PD D'Agostino, RB Pencina, MJ Vasan, RS Meigs, JB Levy, D Savage, PJ AF Fox, Caroline S. Coady, Sean Sorlie, Paul D. D'Agostino, Ralph B. Pencina, Michael J. Vasan, Ramachandran S. Meigs, James B. Levy, Daniel Savage, Peter J. TI Increasing cardiovascular disease burden due to diabetes mellitus - The Framingham Heart Study SO CIRCULATION LA English DT Article DE diabetes mellitus; cardiovascular diseases; epidemiology; risk factors ID ACUTE MYOCARDIAL-INFARCTION; US ADULTS; NATIONAL-HEALTH; TEMPORAL TRENDS; ELUTING STENTS; RISK-FACTORS; MORTALITY; PREVALENCE; IMPACT; CHOLESTEROL AB Background-Marked reductions in cardiovascular disease (CVD) morbidity and mortality have occurred in the United States over the last 50 years. We tested the hypothesis that the relative burden of CVD attributable to diabetes mellitus (DM) has increased over the past 5 decades. Methods and Results-Participants aged 45 to 64 years from the Framingham Heart Study, who attended examinations in an "early" time period (1952 to 1974), were compared with those who attended examinations in a later time period (1975 to 1998). The risk of CVD events (n = 133 among those with and 1093 among those without DM) attributable to DM in the 2 time periods was assessed with Cox proportional hazards models; population attributable risk of DM as a CVD risk factor was calculated for each time period. The age-and sex-adjusted hazard ratio for DM as a CVD risk factor was 3.0 (95% CI, 2.3 to 3.9) in the earlier time period and 2.5 (95% CI, 1.9 to 3.2) in the later time period. The population attributable risk for DM as a CVD risk factor increased from 5.4% (95% CI, 3.8% to 6.9%) in the earlier time period to 8.7% (95% CI, 5.9% to 11.4%) in the later time period (P for attributable risk ratio = 0.04), although multivariable adjustment resulted in attenuation of these findings (P = 0.12); most of these observations were found among men. Conclusions-The proportion of CVD attributable to DM has increased over the past 50 years in Framingham. These findings emphasize the need for increased efforts to prevent DM and to aggressively treat and control CVD risk factors among those with DM. C1 Framingham Heart Dis Epidemiol Study, NHLBI, Framingham, MA 01702 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Diabet Endocrinol & Hypertens, Boston, MA 02115 USA. Massachusetts Gen Hosp, Dept Med, Div Gen Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. Boston Univ, Sch Med, Boston, MA 02118 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Fox, CS (reprint author), Framingham Heart Dis Epidemiol Study, NHLBI, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM foxca@nhlbi.nih.gov OI Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [N01-HC-25195]; PHS HHS [5K24H004334] NR 38 TC 276 Z9 285 U1 1 U2 17 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 27 PY 2007 VL 115 IS 12 BP 1544 EP 1550 DI 10.1161/CIRCULATIONAHA.106.658948 PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 150JC UT WOS:000245211300007 PM 17353438 ER PT J AU Raghavachari, N Xu, XL Harris, A Villagra, J Logun, C Barb, J Solomon, MA Suffredini, AF Danner, RL Kato, G Munson, PJ Morris, SM Gladwin, MT AF Raghavachari, Nalini Xu, Xiuli Harris, Amy Villagra, Jose Logun, Carolea Barb, Jennifer Solomon, Michael A. Suffredini, Anthony F. Danner, Robert L. Kato, Gregory Munson, Peter J. Morris, Sidney M., Jr. Gladwin, Mark T. TI Amplified expression profiling of platelet transcriptome reveals changes in arginine metabolic pathways in patients with sickle cell disease SO CIRCULATION LA English DT Article DE platelets; genes; enzymes; metabolism; thrombolysis; polymerase chain reaction; signal transduction ID PULMONARY-HYPERTENSION; NITRIC-OXIDE; GENE-EXPRESSION; ENDOTHELIAL-CELLS; ARGINASE-II; ACTIVATION; PATHOGENESIS; POLYAMINES; INHIBITION; PROTEOMICS AB Background-In sickle cell disease, ischemia-reperfusion injury and intravascular hemolysis produce endothelial dysfunction and vasculopathy characterized by reduced nitric oxide and arginine bioavailability. Recent functional studies of platelets in patients with sickle cell disease reveal a basally activated state, which suggests that pathological platelet activation may contribute to sickle cell disease vasculopathy. Methods and Results-Studies were therefore undertaken to examine transcriptional signaling pathways in platelets that may be dysregulated in sickle cell disease. We demonstrate and validate in the present study the feasibility of comparative platelet transcriptome studies on clinical samples from single donors by the application of RNA amplification followed by microarray-based analysis of 54 000 probe sets. Data mining an existing microarray database, we identified 220 highly abundant genes in platelets and a subset of 72 relatively platelet-specific genes, defined by > 10-fold increased expression compared with the median of other cell types in the database with amplified transcripts. The highly abundant platelet transcripts found in the present study included 82% or 70% of platelet-abundant genes identified in 2 previous gene expression studies on nonamplified mRNA from pooled or apheresis samples, respectively. On comparing the platelet gene expression profiles in 18 patients with sickle cell disease in steady state to those of 12 black control subjects, at a 3-fold cutoff and 5% false-discovery rate, we identified approximate to 100 differentially expressed genes, including multiple genes involved in arginine metabolism and redox homeostasis. Further characterization of these pathways with real-time polymerase chain reaction and biochemical assays revealed increased arginase II expression and activity and decreased platelet polyamine levels. Conclusions-The present studies suggest a potential pathogenic role for platelet arginase and altered arginine and polyamine metabolism in sickle cell disease and provide a novel framework for the study of disease-specific platelet biology. C1 NHLBI, Vasc Med Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Cardiovasc Branch, Bethesda, MD 20892 USA. NHLBI, Genom Core Facil, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Crit Care Med, Funct Genom & Proteom Facil, Bethesda, MD 20892 USA. NIH, Math & Stat Comp Lab, Div Biosci, Ctr Informat Technol, Bethesda, MD USA. Univ Pittsburgh, Sch Med, Dept Mol Genet & Biochem, Pittsburgh, PA 15261 USA. RP Gladwin, MT (reprint author), NHLBI, Vasc Med Branch, NIH, Bldg 10-CRC,Room 5-5140, Bethesda, MD 20892 USA. EM mgladwin@nih.gov RI Morris, Sidney/I-3440-2015; Kato, Gregory/I-7615-2014 OI Kato, Gregory/0000-0003-4465-3217 FU Intramural NIH HHS [Z01 CL008050-05, ZIA HL006013-01, ZIA HL006013-02]; NIGMS NIH HHS [R01 GM057384, R01 GM057384-08, R01 GM57384] NR 45 TC 59 Z9 59 U1 0 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7322 J9 CIRCULATION JI Circulation PD MAR 27 PY 2007 VL 115 IS 12 BP 1551 EP 1562 DI 10.1161/CIRCULATIONAHA.106.658641 PG 12 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 150JC UT WOS:000245211300008 PM 17353439 ER PT J AU Solomon, SD Pfeffer, MA Finn, PV Bertagnolli, MM McMurray, JJV Levin, B Eagle, C Lechuga, MJ Hawk, E Zauber, AG Arber, N Fowler, R Wittes, J AF Solomon, Scott D. Pfeffer, Marc A. Finn, Peter V. Bertagnolli, Monica M. McMurray, John J. V. Levin, Bernard Eagle, Craig Lechuga, Maria Jose Hawk, Ernest Zauber, Ann G. Arber, Nadir Fowler, Rob Wittes, Janet TI Response to letter regarding article, "Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas" SO CIRCULATION LA English DT Letter C1 Brigham & Womens Hosp, Boston, MA 02115 USA. Western Infirm & Associated Hosp, Glasgow G11 6NT, Lanark, Scotland. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Pfizer Inc, New York, NY USA. NCI, Bethesda, MD 20892 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Tel Aviv Sourasky Med Ctr, Tel Aviv, Israel. Stat Collaborat Inc, Washington, DC USA. RP Solomon, SD (reprint author), Brigham & Womens Hosp, 75 Francis St, Boston, MA 02115 USA. RI Solomon, Scott/I-5789-2013 NR 2 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 MAR 27 PY 2007 VL 115 IS 12 BP E349 EP E349 DI 10.1161/CIRCULATIONAHA.106.675553 PG 1 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 150JC UT WOS:000245211300029 ER PT J AU Mensah, GA Grant, AO Pepine, CJ AF Mensah, George A. Grant, Augustus O. Pepine, Carl J. TI ACCF/AHA/CDC Conference Report on Emerging Infectious Diseases and Biological Terrorism threats - The clinical and public health implications for the prevention and control of cardiovascular diseases SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Review ID ACUTE MYOCARDIAL-INFARCTION; WEST-NILE-VIRUS; NEW-YORK-CITY; CORONARY-ARTERY-DISEASE; AMERICAN-HEART-ASSOCIATION; ACUTE RESPIRATORY SYNDROME; NEGATIVE BLOOD CULTURES; SUDDEN CARDIAC DEATH; Q-FEVER ENDOCARDITIS; TRADE-CENTER ATTACK C1 Mayo Clin & Mayo Fdn, Coll Med, Rochester, MN 55905 USA. Michigan Dept Community Hlth, Publ Hlth Adm, Lansing, MI 48913 USA. Cambridge Dept Hlth, Cambridge, MA 02139 USA. Emory Univ, Sch Nursing, Atlanta, GA 30322 USA. Univ Calif San Francisco, Sch Nursing & Med, Dept Epidemiol & Biostat, Dept Physiol Nursing, San Francisco, CA 94143 USA. Duke Univ, Med Ctr, Durham, NC 27702 USA. Ctr Dis Control & Prevent, Div Heart Dis & Stroke Prevent, Atlanta, GA 30341 USA. Univ Minnesota, Sch Med, Minneapolis, MN 55455 USA. Univ So Calif, Keck Sch Med, Hosp Good Samaritan, Inst Heart, Los Angeles, CA 90017 USA. Assoc Black Cardiol Inc, Atlanta, GA 30349 USA. Ctr Dis Control & Prevent, Div Heart Dis & Stroke Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. Univ Minnesota, Div Epidemiol, Dept Med, Minneapolis, MN 55454 USA. Univ Texas, Hlth Sci Ctr, Houston, TX 77030 USA. Texas Heart Inst, Houston, TX 77030 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. Ctr Dis Control & Prevent, Coordinating Ctr Infect Dis, Atlanta, GA 30333 USA. VA Commonwlth Univ Hlth Syst, Dept Emergency Med, Richmond, VA USA. Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL 32608 USA. DHHS, Div Publ Hlth, Raleigh, NC 27699 USA. Amer Heart Assoc, Dallas, TX 75231 USA. Uniformed Serv Univ Hlth Sci, Div Mil Internal Med, Bethesda, MD 20814 USA. Chron Dis Prevent Program, Richmond, VA 23219 USA. Cedars Sinai Med Ctr, Div Cardiol, Los Angeles, CA 90048 USA. NHLBI, NIH, Bethesda, MD 20817 USA. RP Mensah, GA (reprint author), Mayo Clin & Mayo Fdn, Coll Med, 200 1st St SW, Rochester, MN 55905 USA. OI Mensah, George/0000-0002-0387-5326 NR 269 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 27 PY 2007 VL 49 IS 12 BP 1373 EP 1412 DI 10.1016/j.jacc.2007.01.017 PG 40 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 152TL UT WOS:000245384600023 PM 17394977 ER PT J AU Cronin, S Hardiman, O Traynor, BJ AF Cronin, Simon Hardiman, Orla Traynor, Bryan J. TI Ethnic variation in the incidence of ALS - A systematic review SO NEUROLOGY LA English DT Review ID AMYOTROPHIC-LATERAL-SCLEROSIS; MOTOR-NEURON DISEASE; UNITED-STATES; NEUROLOGICAL DISORDERS; MULTIPLE-SCLEROSIS; PAST POLIOMYELITIS; EPIDEMIOLOGY; MORTALITY; POPULATION; PREVALENCE AB Background: The findings of recent genetic polymorphism studies in ALS suggest that the influence of genetic risk factors for the disease may vary by ethnicity. It is now widely accepted that the incidence of ALS is uniform across Caucasian populations, but whether racial variation across other ethnicities exists remains unknown. Method: Systematic review of the known literature on the incidence, prevalence, and mortality of ALS across all ethnicities. To facilitate comparison, studies were grouped according to the type of data presented and examined for sources of case ascertainment and inclusion criteria. Results: The literature search identified 61 publications. Lower standardized incidence rates were observed in Asian than Caucasian populations. Within the United States, several incidence and mortality studies have identified lower ALS frequency among African American and Hispanic populations than among non-Hispanic Caucasians. These observations are supported by the other data sources. Conclusions: The incidence of ALS may be lower among African, Asian, and Hispanic ethnicities than among whites. We conclude with proposals for a prospective epidemiologic study concentrating on non-Caucasian populations. C1 Beaumont Hosp, Dept Neurol, Irish ALS Res Grp, Dublin 9, Ireland. NIH, Sect Dev Genet Epidemiol, Bethesda, MD 20892 USA. RP Hardiman, O (reprint author), Beaumont Hosp, Dept Neurol, Irish ALS Res Grp, Dublin 9, Ireland. EM ohard@iol.ie RI Traynor, Bryan/G-5690-2010 FU Intramural NIH HHS NR 73 TC 132 Z9 136 U1 1 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 MAR 27 PY 2007 VL 68 IS 13 BP 1002 EP 1007 DI 10.1212/01.wnl.0000258551.96893.6f PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 150JF UT WOS:000245211600007 PM 17389304 ER PT J AU Jefferson, AL Massaro, JM Wolf, PA Seshadri, S Au, R Vasan, RS Larson, MG Meigs, JB Keaney, JF Lipinska, I Kathiresan, S Benjamin, EJ DeCarli, C AF Jefferson, A. L. Massaro, J. M. Wolf, P. A. Seshadri, S. Au, R. Vasan, R. S. Larson, M. G. Meigs, J. B. Keaney, J. F., Jr. Lipinska, I. Kathiresan, S. Benjamin, E. J. DeCarli, C. TI Inflammatory biomarkers are associated with total brain volume - The Framingham Heart Study SO NEUROLOGY LA English DT Article ID C-REACTIVE PROTEIN; STROKE RISK PROFILE; ALZHEIMERS-DISEASE; VASCULAR DEMENTIA; ROTTERDAM SCAN; ATROPHY; MRI; RATES; AD; QUANTIFICATION AB Background: Systemic inflammation is associated with ischemia and Alzheimer disease (AD). We hypothesized that inflammatory biomarkers would be associated with neuroimaging markers of ischemia (i. e., white matter hyperintensities [WMH]) and AD (i. e., total brain volume [TCB]). Methods: MRI WMH and TCB were quantified on 1,926 Framingham Offspring participants free from clinical stroke, TIA, or dementia (mean age 60 +/- 9 years; range 35 to 85 years; 54% women) who underwent measurement of a circulating inflammatory marker panel, including CD40 ligand, C-reactive protein, interleukin-6 (IL-6), soluble intracellular adhesion molecule-1, monocyte chemoattractant protein-1, myeloperoxidase, osteoprotegerin (OPG), P-selectin, tumor necrosis factor-alpha (TNF alpha), and tumor necrosis factor receptor II. To account for head size, both TCB (TCBV) and WMH (WMH/TCV) were divided by total cranial volume. We used multivariable linear regression to relate 10 log-transformed inflammatory biomarkers to brain MRI measures. Results: In multivariable models, inflammatory markers as a group were associated with TCBV (p < 0.0001) but not WMH/TCV (p = 0.28). In stepwise models adjusted for clinical covariates with backwards elimination of markers, IL-6 and OPG were inversely associated with TCBV; TNF alpha was inversely related to TCBV in a subset of 1,430 participants. Findings were similar in analyses excluding individuals with prevalent cardiovascular disease. The relations between TCBV and inflammatory markers were modified by both sex and age, and generally were more pronounced in men and in older individuals. Conclusions: Although our observational cross-sectional data cannot establish causality, they are consistent with the hypothesis that higher inflammatory markers are associated with greater atrophy than expected for age. C1 Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Prevent Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02215 USA. Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. Massachusetts Gen Hosp, Div Gen Med, Boston, MA 02114 USA. Massachusetts Gen Hosp, Cardiovasc Dis Prevent Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Univ Calif Davis, Dept Neurol, Ctr Neurosci, Davis, CA 95616 USA. Univ Calif Davis, Imaging Dementia & Aging Lab, Davis, CA 95616 USA. RP Jefferson, AL (reprint author), Boston Univ, Sch Med, Dept Neurol, 715 Albany St,B-7800, Boston, MA 02118 USA. EM angelaj@bu.edu RI DeCarli, Charles/B-5541-2009; OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NCRR NIH HHS [M01 RR001066, M01-RR-01066]; NHLBI NIH HHS [HL064753, HL076784, HL083102, K23 HL083102, K24 HL004334, N01-HC-25195, N01HC25195, N01HV28178, P01 HL081587, R01 HL067266, R01 HL067288, R01 HL076784, R01 HL077447]; NIA NIH HHS [R01 AG016495, AG010129, AG021028, AG022773, AG028321, AG08122, AG16495, F32 AG022773, K23 AG030962, K23 AG030962-01, K23 AG030962-02, K23 AG030962-03, P30 AG010129, P30 AG013846, P30 AG013846-06, R01 AG008122, R01 AG021028, R01 AG027081, R01 AG028321]; NICHD NIH HHS [HD043444, K12 HD043444, K12 HD043444-06]; NINDS NIH HHS [NS017950, R01 NS017950] NR 36 TC 106 Z9 108 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 27 PY 2007 VL 68 IS 13 BP 1032 EP 1038 DI 10.1212/01.wnl.0000257815.20548.df PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 150JF UT WOS:000245211600012 PM 17389308 ER PT J AU Hammer, JA Wu, XF AF Hammer, John A., III Wu, Xufeng TI Slip sliding away with myosin V SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID KINESIN-RELATED PROTEIN; MELANOSOME TRANSPORT; MITOTIC SPINDLE; ACTIN; MELANOPHILIN; MICROTUBULES; YEAST; DOMAIN; RAB27A; SMY1P C1 NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hammer, JA (reprint author), NHLBI, Cell Biol Lab, NIH, Bldg 10,Room 2523, Bethesda, MD 20892 USA. EM hammerj@nhlbi.nih.gov NR 19 TC 4 Z9 4 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 27 PY 2007 VL 104 IS 13 BP 5255 EP 5256 DI 10.1073/pnas.0701071104 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 152AE UT WOS:000245331700001 PM 17374717 ER PT J AU Wei, Q Rong, YK Paterson, BM AF Wei, Qin Rong, Yikang Paterson, Bruce M. TI Stereotypic founder cell patterning and embryonic muscle formation in Drosophila require nautilus (MyoD) gene function SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE muscle organization; myogenic factors; pattern determination ID HOMEOBOX GENE; MYOGENESIS; EXPRESSION; SPECIFICATION; EMBRYOGENESIS; MELANOGASTER; PROTEIN; FUSION; FATES AB nautilus is the only MyoD-related gene in Drosophila. Nautilus expression begins around stage 9 at full germ-band extension in a subset of mesodermal cells organized in a stereotypic pattern in each hemisegment. The muscle founder cell marker Duf-LacZ, produced by the enhancer trap line rP298LacZ, is coexpressed in numerous Nautilus-positive cells when founders first appear. Founders entrain muscle identity through the restricted expression of transcription factors such as S59, eve, and Kr, all of which are observed in subsets of the nautilus expressing founders. We inactivated the nautilus gene using homology-directed gene targeting and Gal4/UAS regulated RNAi to determine whether loss of nautilus gene activity affected founder cell function. Both methods produced a range of defects that included embryonic muscle disruption, reduced viability and female sterility, which could be rescued by hsp70-nautilus cDNA transgenes. Our results demonstrate Nautilus expression marks early founders that give rise to diverse muscle groups in the embryo, and that nautilus gene activity is required to seed the correct founder myoblast pattern that prefigures the muscle fiber arrangement during embryonic development. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. NCI, Lab Mol & Cell Biol, NIH, Bethesda, MD 20892 USA. RP Paterson, BM (reprint author), NCI, Biochem Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM patersob@mail.nih.gov NR 42 TC 17 Z9 17 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 27 PY 2007 VL 104 IS 13 BP 5461 EP 5466 DI 10.1073/pnas.0608739104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 152AE UT WOS:000245331700038 PM 17376873 ER PT J AU Maier, A Logothetis, NK Leopold, DA AF Maier, Alexander Logothetis, Nikos K. Leopold, David A. TI Context-dependent perceptual modulation of single neurons in primate visual cortex SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE binocular rivalry; neurophysiology; perceptual organization; visual perception ID STRUCTURE-FROM-MOTION; BINOCULAR-RIVALRY; AREA MT; ATTENTION; CHOICE; MECHANISMS; DOMINANCE; VISION; V5/MT; UNITS AB Some neurons in the visual cortex alter their spiking rate according to the perceptual interpretation of an observed stimulus, rather than its physical structure alone. Experiments in monkeys have suggested that, although the proportion of neurons showing this effect differs greatly between cortical areas, this proportion remains similar across different stimuli. These findings have raised the intriguing questions of whether the same neurons always participate in the disambiguation of sensory patterns and whether such neurons might represent a special class of cortical cells that relay perceptual signals to higher cortical areas. Here we explore this question by measuring activity in the middle temporal cortex of monkeys and asking to what degree the percept-related responses of individual neurons depend upon the specific sensory input. In contrast to our expectations, we found that even small differences in the stimuli led to significant changes in the signaling of the perceptual state by single neurons. We conclude that nearly all feature-responsive neurons in this area, rather than a select subset, can contribute to the resolution of sensory conflict, and that the role of individual cells in signaling the perceptual outcome is tightly linked to the fine details of the stimuli involved. C1 Max Planck Inst Biol Cybernet, D-72076 Tubingen, Germany. RP Leopold, DA (reprint author), NIMH, Unit Cognit Neurophysiol & Imaging, Lab Neuropsychol, 49 Convent Dr, Bethesda, MD 20892 USA. EM leopoldd@mail.nih.gov RI Maier, Alexander/B-7489-2009; OI Maier, Alexander/0000-0002-7250-502X; Leopold, David/0000-0002-1345-6360 NR 28 TC 23 Z9 23 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 27 PY 2007 VL 104 IS 13 BP 5620 EP 5625 DI 10.1073/pnas.0608489104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 152AE UT WOS:000245331700066 PM 17369363 ER PT J AU Koizumi, K Higashida, H Yoo, S Islam, MS Ivanov, AI Guo, V Pozzi, P Yu, SH Rovescalli, AC Tang, D Nirenberg, M AF Koizumi, Keita Higashida, Haruhiro Yoo, Siuk Islam, Mohamad Saharul Ivanov, Andrej I. Guo, Vicky Pozzi, Paola Yu, Shu-Hua Rovescalli, Alessandra C. Tang, Derek Nirenberg, Marshall TI RNA interference screen to identify genes required for Drosophila embryonic nervous system development SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE high-throughput screen; neural development; neural mutants ID OF-FUNCTION SCREEN; PEROXISOMAL MEMBRANE; ADHERENS JUNCTIONS; PROSPERO GENE; PROTEIN; EXPRESSION; MUTATIONS; ENCODES; BIOGENESIS; CATENIN AB RNA interference (RNAi) has been shown to be a powerful method to study the function of genes in vivo by silencing endogenous mRNA with double-stranded (ds) RNA. Previously, we performed in vivo RNAi screening and identified 43 Drosophila genes, including 18 novel genes required for the development of the embryonic nervous system. In the present study, 22 additional genes affecting embryonic nervous system development were found. Novel RNAiinduced phenotypes affecting nervous system development were found for 16 of the 22 genes. Seven of the genes have unknown functions. Other genes found encode transcription factors, a chromatin-remodeling protein, membrane receptors, signaling molecules, and proteins involved in cell adhesion, RNA binding, and ion transport. Human orthologs were identified for proteins encoded by 16 of the genes. The total number of dsRNAs that we have tested for an RNAi-induced phenotype affecting the embryonic nervous system, including our previous study, is 7,312, which corresponds to approximate to 50% of the genes in the Drosophila genome. C1 NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. Kanazawa Univ, Century Ctr Excellence Program 21, Kanazawa, Ishikawa 9208640, Japan. Kanazawa Univ, Century Ctr Innovat Brain Sci dev Learning & Memo, Kanazawa, Ishikawa 9208640, Japan. Kanazawa Univ, Adv Sci Res Ctr, Kanazawa, Ishikawa 9208640, Japan. Kanazawa Univ, Grad Sch Med, Dept Biophys Genet, Kanazawa, Ishikawa 9208640, Japan. RP Nirenberg, M (reprint author), NHLBI, Lab Biochem Genet, NIH, Bldg 10, Bethesda, MD 20892 USA. EM mnirenberg@nih.gov OI higashida, haruhiro/0000-0002-1779-0606 NR 56 TC 25 Z9 25 U1 1 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 27 PY 2007 VL 104 IS 13 BP 5626 EP 5631 DI 10.1073/pnas.0611687104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 152AE UT WOS:000245331700067 PM 17376868 ER PT J AU O'Meara, WP Hall, BF McKenzie, FE AF O'Meara, Wendy Prudhomme Hall, B. Fenton McKenzie, F. Ellis TI Malaria vaccine efficacy: the difficulty of detecting and diagnosing malaria SO MALARIA JOURNAL LA English DT Article ID PLASMODIUM-FALCIPARUM; PARASITE DENSITY; PROTECTIVE EFFICACY; CASE DEFINITIONS; PYROGENIC THRESHOLD; ENDEMIC AREA; MICROSCOPY; VARIABILITY; POPULATIONS; CHILDREN AB New sources of funding have revitalized efforts to control malaria. An effective vaccine would be a tremendous asset in the fight against this devastating disease and increasing financial and scientific resources are being invested to develop one. A few candidates have been tested in Phase I and II clinical trials, and several others are poised to begin trials soon. Some studies have been promising, and others disappointing. It is difficult to compare the results of these clinical trials; even independent trials of the same vaccine give highly discrepant results. One major obstacle in evaluating malaria vaccines is the difficulty of diagnosing clinical malaria. This analysis evaluates the impact of diagnostic error, particularly that introduced by microscopy, on the outcome of efficacy trials of malaria vaccines and make recommendations for improving future trials. C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. NIAID, NIH, Rockville, MD USA. RP O'Meara, WP (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM prudhomw@mail.nih.gov; lhall@niaid.nih.gov; mckenzel@mail.nih.gov FU Intramural NIH HHS [Z99 TW999999] NR 22 TC 16 Z9 16 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1475-2875 J9 MALARIA J JI Malar. J. PD MAR 26 PY 2007 VL 6 AR 36 DI 10.1186/1475-2875-6-36 PG 10 WC Infectious Diseases; Parasitology; Tropical Medicine SC Infectious Diseases; Parasitology; Tropical Medicine GA 157LM UT WOS:000245721200001 PM 17386083 ER PT J AU Davis, ML Bagnato, F AF Davis, Marshall L. Bagnato, Francesca TI Long-term evaluation of nodular and ring enhancing lesion evolution in patients with multiple sclerosis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Davis, Marshall L.] Univ No Colorado, Dept Chem, Greeley, CO 80639 USA. [Bagnato, Francesca] NINDS, NIB, NIH, Bethesda, MD 20892 USA. EM davi0991@blue.unco.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 1309-CHED BP 21 EP 21 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722804020 ER PT J AU Gray, HB Winkler, JR Lee, JC AF Gray, H. B. Winkler, J. R. Lee, J. C. TI Copper(II) binding to alpha-synuclein, the Parkinson's protein SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Gray, H. B.; Winkler, J. R.] CALTECH, Beckman Inst, Pasadena, CA 91125 USA. [Lee, J. C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. EM hbgray@caltech.edu; winklerj@caltech.edu; leej4@nhlbi.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 472-INOR BP 51 EP 51 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722805042 ER PT J AU Gray, HB Kimura, T Lee, JC Winkler, JR AF Gray, H. B. Kimura, T. Lee, J. C. Winkler, J. R. TI Mapping helical bundle heme protein folding landscapes SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Gray, H. B.; Kimura, T.; Winkler, J. R.] CALTECH, Beckman Inst, Pasadena, CA 91125 USA. [Lee, J. C.] NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. EM hbgray@caltech.edu; kimtet@caltech.edu; leej4@nhlbi.nih.gov; winklerj@caltech.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 586-INOR BP 99 EP 99 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722805089 ER PT J AU Clifford-Nunn, BM Hess, S AF Clifford-Nunn, Billy M. Hess, Sonja TI Mass spectrometric determination of glycation sites in hemoglobins SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Clifford-Nunn, Billy M.] Univ Michigan, Dept Chem & Biochem, Flint, MI 48502 USA. [Hess, Sonja] NIDDK, NIH, Bethesda, MD 20892 USA. EM bcliffor@umflint.edu RI Hess, Sonja/K-4842-2013 OI Hess, Sonja/0000-0002-5904-9816 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 342-CHED BP 142 EP 142 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722804141 ER PT J AU Zheng, J Ma, BY Jang, H Nussinov, R AF Zheng, Jie Ma, Buyong Jang, Hyunbum Nussinov, Ruth TI Stability and structure of oligomers of the Alzheimer peptide from computer simulations SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Zheng, Jie] NCI, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. [Ma, Buyong; Nussinov, Ruth] NCI FCRDC, Ctr Canc Res Nanobiol Program, Basic Res Program, SAIC, Frederick, MD 21702 USA. [Jang, Hyunbum] NCI Frederick, Ctr Canc Res Nanobiol Program, Basic Res Program, SAIC Frederick Inc, Frederick, MD 21702 USA. EM jzheng@ncifcrf.gov; mab@ncifcrf.gov; jangh@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 223-COMP BP 180 EP 180 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722802178 ER PT J AU Hu, Z Yang, Y Southerland, WM AF Hu, Zengiian Yang, Yili Southerland, William M. TI Computer modeling study of small molecular inhibitors of ubiquitin-activating enzyme (E1) SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Hu, Zengiian; Southerland, William M.] Howard Univ, Coll Med, Dept Biochem & Mol Biol, Washington, DC 20059 USA. [Yang, Yili] NCI, Lab Prot Dynam & Signaling, Ctr Canc Res, NIH, Frederick, MD 21702 USA. EM zhu@howard.edu; wsoutherland@howard.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 184-COMP BP 190 EP 190 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722802188 ER PT J AU Rhodes, SD Kimura, T Yeliseev, A Gawrisch, K AF Rhodes, Steven D. Kimura, Tomohiro Yeliseev, Alexei Gawrisch, Klaus TI Functional reconstitution and 1H NMR study of recombinant peripheral cannabinoid receptor CB2 SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Rhodes, Steven D.] Wabash Coll, Dept Chem, Crawfordsville, IN 47933 USA. [Kimura, Tomohiro; Yeliseev, Alexei; Gawrisch, Klaus] NIAAA, NIH, Bethesda, MD 20892 USA. EM rhodess@wabash.edu; gawrisch@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 1079-CHED BP 218 EP 218 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722803210 ER PT J AU Cho, J Childers, M Regino, CA Brechbiel, MW DiPasquale, AG Rheingold, AL Torti, SV Torti, FM Planalp, RP AF Cho, Joohhyung Childers, Matt Regino, Celeste Aida Brechbiel, Martin W. DiPasquale, Antonio G. Rheingold, Arnold L. Torti, Suzy V. Torti, Frank M. Planalp, Roy P. TI INOR 788-Influence of ligand structure on Fe(II) spin-state and redox rate in cytotoxic tripodal chelators SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Cho, Joohhyung; Childers, Matt; Planalp, Roy P.] Univ New Hampshire, Dept Chem, Durham, NH 03824 USA. [Regino, Celeste Aida] NCI, NIH, Radiat Oncol Branch, Bethesda, MD 20892 USA. [Brechbiel, Martin W.] NCI, Radioimmune & Inorgan Chem Sect, CCR, Bethesda, MD 20892 USA. [DiPasquale, Antonio G.; Rheingold, Arnold L.] Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. [Torti, Suzy V.] Wake Forest Univ Hlth Sci, Dept Biochem, Winston Salem, NC 27157 USA. [Torti, Frank M.] Wake Forest Univ Hlth Sci, Dept Canc Biol, Winston Salem, NC 27157 USA. EM jhz3@unh.edu; reginoc@mail.nih.gov; roy.planalp@unh.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 788-INOR BP 314 EP 314 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722806314 ER PT J AU Ivanov, AA Jacobson, KA AF Ivanov, Andrei A. Jacobson, Kenneth A. TI Modeling study of the binding modes of mono- and dinucleotides at the human P2Y2 receptor SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Ivanov, Andrei A.; Jacobson, Kenneth A.] NIDDK, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. EM ivanovan@niddk.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 265-MEDI BP 544 EP 544 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722806387 ER PT J AU Gildersleeve, JC AF Gildersleeve, Jeffrey C. TI CARB 116-Carbohydrate microarrays for basic and translational cancer research SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Gildersleeve, Jeffrey C.] Natl Canc Inst, Med Chem Lab, Frederick, MD 21702 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 116-CARB BP 552 EP 552 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722800477 ER PT J AU Horkay, F Lin, DC Dimitriadis, EK Horkayne-Szakaly, I Basser, PJ AF Horkay, Ferenc Lin, David C. Dimitriadis, Emilios K. Horkayne-Szakaly, Iren Basser, Peter J. TI Interactions among the polymer components of cartilage matrix SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Horkay, Ferenc; Lin, David C.; Horkayne-Szakaly, Iren; Basser, Peter J.] NICHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. [Dimitriadis, Emilios K.] NIH, Div Bioengn & Phys Sci, ORS, Bethesda, MD 20892 USA. EM horkay@helix.nih.gov; lindavid@mail.nih.gov; dimitre@ors.od.nih.gov; horkayi@mail.nih.gov; pjbasser@helix.nih.gov RI Basser, Peter/H-5477-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 422-MEDI BP 572 EP 572 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722806414 ER PT J AU ul Hussan, SS Bewley, CA AF ul Hussan, Syed Shahzad Bewley, Carole A. TI Binding specificity of HIV-fusion blocking protein (MVL) determined by NMR techniques SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [ul Hussan, Syed Shahzad; Bewley, Carole A.] NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM hussans@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 69-MEDI BP 595 EP 595 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722806437 ER PT J AU Pandit, D Harding, W Tidgewell, K Schmidt, M Lozama, A Dersch, CM Skawinski, WJ Rothman, RB Prisinzano, T Venanzi, CA AF Pandit, Deepangi Harding, Wayne Tidgewell, Kevin Schmidt, Matthew Lozama, Anthony Dersch, Christina M. Skawinski, William J. Rothman, Richard B. Prisinzano, Thomas Venanzi, Carol A. TI 3-D-QSAR studies of Salvinorin A analogs as kappa opioid receptor agonists SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Pandit, Deepangi; Skawinski, William J.; Venanzi, Carol A.] New Jersey Inst Technol, Dept Chem & Environm Sci, Newark, NJ 07102 USA. [Harding, Wayne] Hunter Coll, Dept Chem, New York, NY 10021 USA. [Tidgewell, Kevin; Schmidt, Matthew; Lozama, Anthony; Prisinzano, Thomas] Univ Iowa, Coll Pharm, Div Med & Nat Prod Chem, Iowa City, IA 52242 USA. [Dersch, Christina M.; Rothman, Richard B.] NIDA, Clin Psychopharmacol Sect, Addict Res Ctr, Baltimore, MD 21224 USA. EM dnp5@njit.edu; venanzi@adm.njit.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 455-MEDI BP 645 EP 645 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722806487 ER PT J AU Negussie, AH Akinola, A Fung, S Li, KC Danthi, NS AF Negussie, Ayele H. Akinola, Adeniyi Fung, Selena Li, King C. Danthi, Narasimhan S. TI Synthesis of bifunctional small molecules for imaging beta-amyloid aggregation SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Negussie, Ayele H.; Akinola, Adeniyi; Fung, Selena; Danthi, Narasimhan S.] NIH, Mol Imaging Lab, Ctr Clin, Bethesda, MD 20892 USA. [Li, King C.] Methodist Hosp, Dept Radiol, Houston, TX 77030 USA. RI Danthi, Simhan/B-7639-2014 NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 312-MEDI BP 663 EP 663 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722806505 ER PT J AU Chakrapani, H Saavedra, JE Showalter, BM Keefer, LK AF Chakrapani, Harinath Saavedra, Joseph E. Showalter, Brett M. Keefer, Larry K. TI Prodrugs of PROLI/NO, a nitric oxide donor SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Chakrapani, Harinath; Showalter, Brett M.; Keefer, Larry K.] Natl Canc Inst, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD 21702 USA. [Saavedra, Joseph E.] SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. EM chakrah@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 427-MEDI BP 667 EP 667 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722806509 ER PT J AU Metaferia, BB ul Hussan, SS Bewley, CA AF Metaferia, Belhu B. ul Hussan, Syed Shahzad Bewley, Carole A. TI Small molecule inhibitors of mycothiol production from mycobacterium tuberculosis SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Metaferia, Belhu B.; ul Hussan, Syed Shahzad; Bewley, Carole A.] NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM belhum@intra.niddk.nih.gov; hussans@mail.nih.gov; caroleb@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 47-MEDI BP 717 EP 717 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722806559 ER PT J AU Marquez, VE Ludek, OR AF Marquez, Victor E. Ludek, Olaf R. TI Optimizing the synthesis of N-methanocarbathymidine, a potent and selective antiviral agent SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Marquez, Victor E.; Ludek, Olaf R.] NCI, Med Chem Lab, NIH, Frederick, MD 21702 USA. EM marquezv@dc37a.nci.nih.gov; oludek@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 61-MEDI BP 769 EP 769 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722806611 ER PT J AU Thazhathveetil, AK Liu, ST Indig, FE Seidman, MM AF Thazhathveetil, Arun Kalliat Liu, Su-Ting Indig, Fred E. Seidman, Michael M. TI Psoralen conjugates for visualization of localized genomic interstrand crosslinks SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Thazhathveetil, Arun Kalliat; Liu, Su-Ting; Seidman, Michael M.] NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. [Indig, Fred E.] NIA, Res Resources Branch, NIH, Baltimore, MD 21224 USA. EM kalliata@grc.nia.nih.gov; seidmanm@grc.nia.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 161-MEDI BP 846 EP 846 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722806688 ER PT J AU Somu, RV Wilson, D Qiao, CH Vannada, J Bennett, E Boshoff, H Barry, CE Aldrich, CC AF Somu, Ravindranadh V. Wilson, Daniel Qiao, Chunhua Vannada, Jagadeswar Bennett, Eric Boshoff, Helena Barry, Clifton E., III Aldrich, Courtney C. TI MEDI 11-Synthesis and structure-activity relationships of a series of sigma receptor ligands SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Somu, Ravindranadh V.; Wilson, Daniel; Qiao, Chunhua; Vannada, Jagadeswar; Bennett, Eric; Aldrich, Courtney C.] Univ Minnesota, Ctr Drug Design, Minneapolis, MN 55455 USA. [Boshoff, Helena; Barry, Clifton E., III] NIAID, TB Res Sect, Rockville, MD 20852 USA. EM ravin002@umn.edu NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 451-MEDI BP 850 EP 850 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722806692 ER PT J AU Kim, P Manjunatha, U Barry, CE Dowd, CS AF Kim, Pilho Manjunatha, Ujjini Barry, Clifton E., III Dowd, Cynthia S. TI MEDI 153-G-quadruplex binding agents: 2-Carboxy-4-hydroxybenzo-(h)-quinoline derivatives SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Kim, Pilho; Manjunatha, Ujjini; Barry, Clifton E., III; Dowd, Cynthia S.] NIAID, TB Res Sect, NIH, Bethesda, MD 20892 USA. EM pkim@niaid.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 46-MEDI BP 923 EP 923 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722806765 ER PT J AU Zheng, W Padia, JK AF Zheng, Wei Padia, Janak K. TI MEDI 78-Design and synthesis of carbaformycin, carbaneplanicin and their 3-deaza analogs SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Padia, Janak K.] NHGRI, NIH Chem Genom Ctr, NIH, NCGC, Bethesda, MD 20892 USA. EM wzheng@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 251-MEDI BP 948 EP 948 PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722806790 ER PT J AU Anfinrud, PA Schotte, F Hummer, G AF Anfinrud, Philip A. Schotte, Friedrich Hummer, Gerhard TI Probing ligand dynamics in heme proteins with time-resolved vibrational spectroscopy, time-resolved X-ray crystallography, and MD simulations SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Anfinrud, Philip A.; Schotte, Friedrich; Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM anfinrud@nih.gov; Gerhard.Hummer@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 1-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722807606 ER PT J AU Appella, DH AF Appella, Daniel H. TI Session: Molecular Recognition and Self-Assembly SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Appella, Daniel H.] NIDDK, Bioorgan Chem Lab, DHHS, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 10-YCC PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722808876 ER PT J AU Brooks, BR Klauda, JB Woodcock, HL Wu, XW AF Brooks, Bernard R. Klauda, Jeffery B. Woodcock, H. Lee, III Wu, Xiongwu TI PHYS 319-Photodissociation dynamics of hydrated adenine cluster cations SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Brooks, Bernard R.; Klauda, Jeffery B.; Woodcock, H. Lee, III] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. [Wu, Xiongwu] NHLBI, Lab Computat Biol, NIH, Washington, MD 20892 USA. EM brb@nih.gov; klauda@helix.nih.gov; hlwood@nih.gov; WuXW@nhlbi.nih.gov RI Woodc, Henry/D-9275-2011 NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 58-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722807826 ER PT J AU Comin, MJ Marquez, VE AF Comin, Maria J. Marquez, Victor E. TI Modifying the bicyclo[3.1.0]hexane pseudosugar ring of carbocyclic nucleosides to improve recognition by herpes thymidine kinase SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Comin, Maria J.; Marquez, Victor E.] NCI, Med Chem Lab, Ctr Canc Res, Frederick, MD 21702 USA. EM jcomin@ncifcrf.gov; marquezv@dc37a.nci.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 392-ORGN PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722808308 ER PT J AU Eaton, WA AF Eaton, William A. TI Dynamics of protein folding SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Eaton, William A.] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM eaton@helix.nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 34-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722807321 ER PT J AU Hu, ZJ Bowen, D Southerland, WM Pan, YP del Sol, A Nussinov, R Ma, BY AF Hu, Zengjian Bowen, Donnell Southerland, William M. Pan, Yongping del Sol, Antonio Nussinov, Ruth Ma, Buyong TI Ligand binding and circular permutation modify residue interaction network in DHFR SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Hu, Zengjian; Bowen, Donnell; Southerland, William M.] Howard Univ, Coll Med, Dept Biochem & Mol Biol, Washington, DC 20059 USA. [Pan, Yongping; Nussinov, Ruth; Ma, Buyong] NCI FCRDC, Ctr Canc Res Nanobiol Program, Basic Res Program, SAIC, Frederick, MD 21702 USA. [del Sol, Antonio] Fujirebio Inc, Div Res & Dev, Tokyo, Japan. EM zhu@howard.edu; wsoutherland@howard.edu; mab@ncifcrf.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 66-CINF PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722801040 ER PT J AU Hummer, G AF Hummer, Gerhard TI Protein dynamics and solvation from molecular simulations: Comparison to time-resolved and high-pressure X-ray crystallography SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Hummer, Gerhard] NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM Gerhard.Hummer@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 203-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722807345 ER PT J AU Lee, JH Frank, JA AF Lee, Jae-Ho Frank, Joseph A. TI Encapsulation of dextran coated superparamagnetic particles and drugs in liposomes for controlled release SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Lee, Jae-Ho; Frank, Joseph A.] Natl Inst Hlth, Lab Diagnost Radiol Res, Ctr Clin, Bethesda, MD 20892 USA. EM leejaeho@mail.nih.gov; jafrank@helix.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 549-COLL PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722801514 ER PT J AU Pastor, RW AF Pastor, Richard W. TI Correspondence of simulation and experiment for lipid bilayers SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Pastor, Richard W.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. EM pastorr@nhlbi.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 582-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722807350 ER PT J AU Stan, G Thirumalai, D Lorimer, GH Brooks, BR AF Stan, George Thirumalai, D. Lorimer, George H. Brooks, Bernard R. TI Computational model of chaperonin-mediated protein folding SO ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY LA English DT Meeting Abstract C1 [Stan, George] Univ Cincinnati, Dept Chem, Cincinnati, OH 45221 USA. [Thirumalai, D.; Lorimer, George H.] Univ Maryland, IPST, Inst Phys Sci & Technol, College Pk, MD 20742 USA. [Thirumalai, D.; Lorimer, George H.] Univ Maryland, IPST, Dept Chem & Biochem, College Pk, MD 20742 USA. [Brooks, Bernard R.] NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. EM george.stan@uc.edu; thirum@glue.umd.edu; GL48@umail.umd.edu; brb@nih.gov NR 0 TC 0 Z9 0 U1 1 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0065-7727 J9 ABSTR PAP AM CHEM S JI Abstr. Pap. Am. Chem. Soc. PD MAR 25 PY 2007 VL 233 MA 424-PHYS PG 1 WC Chemistry, Multidisciplinary SC Chemistry GA V14GL UT WOS:000207722807645 ER PT J AU Ledee, DR Tripathi, BK Zelenka, PS AF Ledee, Dolena R. Tripathi, Brajendra K. Zelenka, Peggy S. TI The CDK5 activator, p39, binds specifically to myosin essential light chain SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE cyclin-dependent kinase 5; Cdk5; p39; myosin essential light chain; non-muscle myosin; cytoskeleton; lens; epithelial cells ID CYCLIN-DEPENDENT KINASE-5; CELL-ADHESION; EPITHELIAL-CELLS; LENS DEVELOPMENT; BRAIN; DIFFERENTIATION; PHOSPHORYLATION; LOCALIZATION; EXPRESSION; MIGRATION AB Cyclin-dependent kinase 5 (Cdk5) has been shown to regulate adhesion and migration of lens and corneal epithelial cells. To explore protein-protein interactions that may mediate these functions, we performed yeast two-hybrid screening on an embryonic rat lens library using Cdk5 and its regulators, p35 and p39 as baits. This screen identified an interaction between p39 and non-muscle myosin essential light chain (MLC17). GST pull-down experiments demonstrated that p39 binds directly to MLC17 through a strong binding site in the N-terminal 109 amino acids of p39. Immunoprecipitation of proteins from Cost cells co-transfected with GFP-MLC17 and HA-p39 confirmed that these proteins interact intracellularly. Immunofluorescence microscopy of co-transfected lens epithelial cells showed that GFP-MLC17 and HA-p39 co-localize along cytoskeletal fibrils. Moreover, endogenous rat lens p39 co-immunoprecipitated with MLC17 and myosin heavy chain II (MHC II), demonstrating that the interaction is physiological and serves to link p39 to the cytoskeleton. Published by Elsevier Inc. C1 NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Zelenka, PS (reprint author), NEI, Mol & Dev Biol Lab, NIH, Bldg 7,Room 102,MSC 0704, Bethesda, MD 20892 USA. EM zelenkap@nei.nih.gov FU Intramural NIH HHS; NEI NIH HHS [Z01 EY000238-20] NR 22 TC 4 Z9 6 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD MAR 23 PY 2007 VL 354 IS 4 BP 1034 EP 1039 DI 10.1016/j.bbrc.2007.01.112 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 139DF UT WOS:000244411800032 PM 17276406 ER PT J AU Stefanovic, S Hegde, RS AF Stefanovic, Sandra Hegde, Rarnanujan S. TI Identification of a targeting factor for posttranslational membrane protein insertion into the ER SO CELL LA English DT Article ID SIGNAL RECOGNITION PARTICLE; TAIL-ANCHORED PROTEIN; ENDOPLASMIC-RETICULUM MEMBRANE; SACCHAROMYCES-CEREVISIAE; TRANSLOCATION COMPLEX; MECHANISM; SYNAPTOBREVIN; POLYPEPTIDE; TRANSPORTER; ELONGATION AB Hundreds of proteins are anchored in intracellular membranes by a single transmembrane domain (TMD) close to the C terminus. Although these tail-anchored (TA) proteins serve numerous essential roles in cells, components of their targeting and insertion pathways have long remained elusive. Here we reveal a cytosolic TMD recognition complex (TRC) that targets TA proteins for insertion into the ER membrane. The highly conserved, 40 kDa ATPase subunit of TRC (which we termed TRC40) was identified as Asna-1. TRC40/Asna-1 interacts posttranslationally with TA proteins in a TMD-dependent manner for delivery to a proteinaceous receptor at the ER membrane. Subsequent release from TRC40/Asna-1 and insertion into the membrane depends on ATP hydrolysis. Consequently, an ATPase-deficient mutant of TRC40/Asna-1 dominantly inhibited TA protein insertion selectively without influencing other translocation pathways. Thus, TRC40/Asna-1 represents an integral component of a posttranslational pathway of membrane protein insertion whose targeting is mediated by TRC. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Hegde, RS (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Room 101,Bldg 18T,18 Lib Dr, Bethesda, MD 20892 USA. EM hegder@mail.nih.gov OI Hegde, Ramanujan/0000-0001-8338-852X FU Intramural NIH HHS NR 37 TC 198 Z9 201 U1 1 U2 9 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD MAR 23 PY 2007 VL 128 IS 6 BP 1147 EP 1159 DI 10.1016/j.cell.2007.01.036 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 152XS UT WOS:000245396200020 PM 17382883 ER PT J AU Kim, TH Abdullaev, ZK Smith, AD Ching, KA Loukinov, DI Green, RD Zhang, MQ Lobanenkov, VV Ren, B AF Kim, Tae Hoon Abdullaev, Ziedulla K. Smith, Andrew D. Ching, Keith A. Loukinov, Dmitri I. Green, Roland D. Zhang, Michael Q. Lobanenkov, Victor V. Ren, Bing TI Analysis of the vertebrate insulator protein CTCF-binding sites in the human genome SO CELL LA English DT Article ID ENHANCER-BLOCKING ACTIVITY; C-MYC GENE; TRANSCRIPTION-FACTOR; X-INACTIVATION; WIDE ANALYSIS; DNA-SEQUENCE; H19 GENE; METHYLATION; BOUNDARIES; PROMOTERS AB Insulator elements affect gene expression by preventing the spread of heterochromatin and restricting transcriptional enhancers from activation of unrelated promoters. In vertebrates, insulator's function requires association with the CCCTC-binding factor (CTCF), a protein that recognizes long and diverse nucleotide sequences. While insulators are critical in gene regulation, only a few have been reported. Here, we describe 13,804 CTCF-binding sites in potential insulators of the human genome, discovered experimentally in primary human fibroblasts. Most of these sequences are located far from the transcriptional start sites, with their distribution strongly correlated with genes. The majority of them fit to a consensus motif highly conserved and suitable for predicting possible insulators driven by CTCF in other vertebrate genomes. In addition, CTCF localization is largely invariant across different cell types. Our results provide a resource for investigating insulator function and possible other general and evolutionarily conserved activities of CTCF sites. C1 Univ Calif San Diego, Sch Med, Dept Cellular & Mol Med, Ludwig Inst Canc Res, La Jolla, CA 92093 USA. NIAID, Rockville, MD 20852 USA. Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. NimbleGen Syst Inc, Madison, WI 53711 USA. RP Kim, TH (reprint author), Yale Univ, Sch Med, Dept Genet, 333 Cedar St,SHMl 142B,POB 208005, New Haven, CT 06120 USA. EM taehoon.kim@yale.edu; biren@ucsd.edu RI Phelps, Steve/H-2263-2011; Smith, Andrew/G-4104-2013; OI Smith, Andrew/0000-0002-3337-1970; Lobanenkov, Victor/0000-0001-6665-3635; Kim, Tae Hoon/0000-0003-3950-7557 FU Intramural NIH HHS; NCI NIH HHS [F32 CA108313, F32CA108313, R21 CA116365, R21CA116365-01, R33 CA105829, R33CA105829]; NCRR NIH HHS [P41 RR 08605, P41 RR008605]; NHGRI NIH HHS [R01 HG001696, HG001696, U01 HG003151, U01HG003151] NR 53 TC 587 Z9 602 U1 3 U2 48 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD MAR 23 PY 2007 VL 128 IS 6 BP 1231 EP 1245 DI 10.1016/j.cell.2006.12.048 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 152XS UT WOS:000245396200026 PM 17382889 ER PT J AU Vaughan, RA Sakrikar, DS Parnas, ML Adkins, S Foster, JD Duval, RA Lever, JR Kulkarni, SS Hauck-Newman, A AF Vaughan, Roxanne A. Sakrikar, Dhananjay S. Parnas, M. Laura Adkins, Steven Foster, James D. Duval, Romain A. Lever, John R. Kulkarni, Santosh S. Hauck-Newman, Amy TI Localization of cocaine analog [I-125]RTI 82 irreversible binding to transmembrane domain 6 of the dopamine transporter SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PHOTOAFFINITY LIGANDS; DOMAINS; RECOGNITION; RECEPTOR; SITE; ANTIDEPRESSANTS; ACCESSIBILITY; CONFORMATION; MUTAGENESIS; INHIBITORS AB The site of cocaine binding on the dopamine transporter (DAT) was investigated using the photoactivatable irreversible cocaine analog [I-125]3 beta-(p-chlorophenyl)tropane-2 beta-carboxylic acid, 4'-azido-3'-iodophenylethyl ester ([I-125]RTI 82). The incorporation site of this compound was mapped to transmembrane domains (TMs) 4-6 using epitope-specific immunoprecipitation of trypsin fragments and further localized using cyanogen bromide (CNBr), which hydrolyzes proteins on the C-terminal side of methionine residues. CNBr hydrolysis of [I-125]RTI 82-labeled rat striatal and expressed human DATs produced fragments of similar to 5-10 kDa consistent with labeling between Met(271/272) or Met(290) in TM5 to Met(370/371) in TM7. To further define the incorporation site, substitution mutations were made that removed endogenous methionines and inserted exogenous methionines in combinations that would generate labeled CNBr fragments of distinct masses depending on the labeling site. The results obtained were consistent with the presence of TM6 but not TMs 4, 5, or 7 in the labeled fragments, with additional support for these conclusions obtained by epitopespecific immunoprecipitation and secondary digestion of CNBr fragments with endoproteinase Lys-C. The final localization of [I-125]RTI 82 incorporation to rat DAT Met(290)-Lys(336) and human DAT I291M to R344M provides positive evidence for the proximity of cocaine binding to TM6. Residues in and near DAT TM6 regulate transport and transport-dependent conformational states, and TM6 forms part of the substrate permeation pathway in the homologous Aquifex aeolicus leucine transporter. Cocaine binding near TM6 may thus overlap the dopamine translocation pathway and function to inhibit TM6 structural rearrangements necessary for transport. C1 Univ N Dakota, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, Grand Forks, ND 58203 USA. Univ Missouri, Dept Radiol, Columbia, MO 65212 USA. Univ Missouri, Dept Med Pharmacol, Columbia, MO 65212 USA. Univ Missouri, Dept Physiol, Columbia, MO 65212 USA. Harry S Truman Mem Vet Hosp, Columbia, MO 65212 USA. NIDA, Med Chem Sect, Intramural Res Program, Baltimore, MD 21224 USA. RP Vaughan, RA (reprint author), Univ N Dakota, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, 501 N Columbia Rd, Grand Forks, ND 58203 USA. EM rvaughan@medicine.nodak.edu RI Duval, Romain/K-2299-2016 OI Duval, Romain/0000-0002-0125-506X FU Intramural NIH HHS; NCRR NIH HHS [P20 RR 016741]; NIDA NIH HHS [DA15175] NR 40 TC 20 Z9 20 U1 1 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 23 PY 2007 VL 282 IS 12 BP 8915 EP 8925 DI 10.1074/jbc.M610633200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 158GS UT WOS:000245780300038 PM 17255098 ER PT J AU Ong, HL Cheng, KT Liu, XB Bandyopadhyay, BC Paria, BC Soboloff, J Pani, B Gwack, Y Srikanth, S Singh, BB Gill, D Ambudkar, IS AF Ong, Hwei Ling Cheng, Kwong Tai Liu, Xibao Bandyopadhyay, Bidhan C. Paria, Biman C. Soboloff, Jonathan Pani, Biswaranjan Gwack, Yousang Srikanth, Sonal Singh, Brij B. Gill, Donald Ambudkar, Indu S. TI Dynamic assembly of TRPC1-STIM1-Orai1 ternary complex is involved in store-operated calcium influx - Evidence for similarities in store-operated and calcium release-activated calcium channel components SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CAPACITATIVE CA2+ ENTRY; SALIVARY-GLAND CELLS; SMOOTH-MUSCLE-CELLS; PLASMA-MEMBRANE; CRAC CHANNEL; T-LYMPHOCYTES; STIM1; PROTEIN; TRPC1; DEPLETION AB Store-operated calcium entry (SOCE) is a ubiquitous mechanism that is mediated by distinct SOC channels, ranging from the highly selective calcium release-activated Ca2+ (CRAG) channel in rat basophilic leukemia and other hematopoietic cells to relatively Ca2+-selective or non-selective SOC channels in other cells. Although the exact composition of these channels is not yet established, TRPC1 contributes to SOC channels and regulation of physiological function of a variety of cell types. Recently, Orai1 and STIM1 have been suggested to be sufficient for generating CRAC channels. Here we show that Orai1 and STIM1 are also required for TRPC1-SOC channels. Knockdown of TRPC1, Orai1, or STIM1 attenuated, whereas overexpression of TRPC1, but not Orai1 or STIM1, induced an increase in SOC entry and I-SOC in human salivary gland cells. All three proteins were co-localized in the plasma membrane region of cells, and thapsigargin increased co-immunoprecipitation of TRPC1 with STIM1, and Orai1 in human salivary gland cells as well as dispersed mouse submandibular gland cells. In aggregate, the data presented here reveal that all three proteins are essential for generation of I-SOC in these cells and that dynamic assembly of TRPC1-STIM1-Orai1 ternary complex is involved in activation of SOC channel in response to internal Ca2+ store depletion. Thus, these data suggest a common molecular basis for SOC and CRAC channels. C1 NIDCR, Secret Physiol Sect, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. Univ N Dakota, Sch Med & Hlth Sci, Dept Biochem & Mol Biol, Grand Forks, ND 58203 USA. Univ Maryland, Sch Med, Dept Biochem & Mol Biol, Baltimore, MD 21201 USA. Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. CBR, Biomed Res Inst, Boston, MA 02115 USA. RP Ambudkar, IS (reprint author), NIDCR, Secret Physiol Sect, Gene Therapy & Therapeut Branch, NIH, Bldg 10,Rm 1N-113,10 Ctr Dr, Bethesda, MD 20892 USA. EM indu.ambudkar@nih.gov RI Soboloff, Jonathan/I-6995-2012; OI Soboloff, Jonathan/0000-0001-5192-1297; Singh, Brij/0000-0003-0535-5997 FU NCRR NIH HHS [P20 RR017699, P20 RR017699-077011]; NIDCR NIH HHS [DE017102, R01 DE017102, R01 DE017102-01A1, R01 DE017102-02, R01 DE017102-03, R01 DE017102-05, R01 DE017102-06A1]; NIGMS NIH HHS [GM07525] NR 46 TC 251 Z9 257 U1 2 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 MAR 23 PY 2007 VL 282 IS 12 BP 9105 EP 9116 DI 10.1074/jbc.M608942200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 158GS UT WOS:000245780300058 PM 17224452 ER PT J AU Vega-Rocha, S Byeon, IJL Gronenborn, B Gronenborn, AM Campos-Olivas, R AF Vega-Rocha, Susana Byeon, In-Ja L. Gronenborn, Bruno Gronenborn, Angela M. Campos-Olivas, Ramon TI Solution structure, divalent metal and DNA binding of the endonuclease domain from the replication initiation protein from porcine circovirus 2 SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE circovirus; Rep; protein structure; endonuclease ID ADENOASSOCIATED-VIRUS REP; SINGLE-STRANDED-DNA; NUCLEASE DOMAIN; IN-VITRO; VIRAL ORIGIN; SEQUENCE; TYPE-1; NMR; ACID; IDENTIFICATION AB Circoviruses are the smallest circular single-stranded DNA viruses able to replicate in mammalian cells. Essential to their replication is the replication initiator, or Rep protein that initiates the rolling circle replication (RCR) of the viral genome. Here we report the NMR solution three-dimensional structure of the endonuclease domain from the Rep protein of porcine circovirus type 2 (PCV2), the causative agent of postweaning multisystemic wasting syndrome in swine. The domain comprises residues 12-112 of the full-length protein and exhibits the fold described previously for the Rep protein of the representative geminivirus tomato yellow leaf curl Sardinia virus. The structure, however, differs significantly in some secondary structure elements that decorate the central five-stranded beta-sheet, including the replacement of a beta-hairpin by an alpha-helix in PCV2 Rep. The identification of the divalent metal binding site was accomplished by following the paramagnetic broadening of NMR amide signals upon Mn2+ titration. The site comprises three conserved acidic residues on the exposed face of the central beta-sheet. For the 1:1 complex of the PCV2 Rep nuclease domain with a 22mer double-stranded DNA oligonucleotide chemical shift mapping allowed the identification of the DNA binding site on the protein and aided in constructing a model of the protein/DNA complex. (c) 2007 Elsevier Ltd. All rights reserved. C1 CNIO, Struct & Computat Biol Programme, Madrid 28029, Spain. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Dept Biol Struct, Pittsburgh, PA 15261 USA. CNRS, Inst Sci Vegetal, F-91198 Gif Sur Yvette, France. RP Campos-Olivas, R (reprint author), CNIO, Struct & Computat Biol Programme, Madrid 28029, Spain. EM rcampos@cnio.es RI Campos-Olivas, Ramon/L-9173-2014; OI Campos-Olivas, Ramon/0000-0002-5743-2221; Gronenborn, Angela M/0000-0001-9072-3525 FU Intramural NIH HHS NR 39 TC 17 Z9 19 U1 0 U2 4 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAR 23 PY 2007 VL 367 IS 2 BP 473 EP 487 DI 10.1016/j.jmb.2007.01.002 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 146TX UT WOS:000244958700015 PM 17275023 ER PT J AU Katki, HA AF Katki, Hormuzd A. TI Incorporating medical interventions into carrier probability estimation for genetic counseling SO BMC MEDICAL GENETICS LA English DT Article ID BRCA2 MUTATION CARRIERS; BREAST-CANCER; FAMILY-HISTORY; OVARIAN-CANCER; SALPINGO-OOPHORECTOMY; PROPHYLACTIC SURGERY; GERMLINE MUTATIONS; PREDICTION MODELS; RISK REDUCTION; LYNCH-SYNDROME AB Background: Mendelian models for predicting who may carry an inherited deleterious mutation of known disease genes based on family history are used in a variety of clinical and research activities. People presenting for genetic counseling are increasingly reporting risk-reducing medical interventions in their family histories because, recently, a slew of prophylactic interventions have become available for certain diseases. For example, oophorectomy reduces risk of breast and ovarian cancers, and is now increasingly being offered to women with family histories of breast and ovarian cancer. Mendelian models should account for medical interventions because interventions modify mutation penetrances and thus affect the carrier probability estimate. Methods: We extend Mendelian models to account for medical interventions by accounting for post-intervention disease history through an extra factor that can be estimated from published studies of the effects of interventions. We apply our methods to incorporate oophorectomy into the BRCAPRO model, which predicts a woman's risk of carrying mutations in BRCA1 and BRCA2 based on her family history of breast and ovarian cancer. This new BRCAPRO is available for clinical use. Results: We show that accounting for interventions undergone by family members can seriously affect the mutation carrier probability estimate, especially if the family member has lived many years post-intervention. We show that interventions have more impact on the carrier probability as the benefits of intervention differ more between carriers and non-carriers. Conclusion: These findings imply that carrier probability estimates that do not account for medical interventions may be seriously misleading and could affect a clinician's recommendation about offering genetic testing. The BayesMendel software, which allows one to implement any Mendelian carrier probability model, has been extended to allow medical interventions, so future Mendelian models can easily account for interventions. C1 DHHS, Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. RP Katki, HA (reprint author), DHHS, Natl Canc Inst, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,Room 8044, Rockville, MD 20852 USA. EM katkih@mail.nih.gov RI Katki, Hormuzd/B-4003-2015 FU Intramural NIH HHS; NCI NIH HHS [R01CA105090-01A1, R01 CA105090-03, R01 CA105090-01A1, R01 CA105090-02, R01 CA105090-04, R01 CA105090] NR 31 TC 11 Z9 11 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2350 J9 BMC MED GENET JI BMC Med. Genet. PD MAR 22 PY 2007 VL 8 AR 13 DI 10.1186/1471-2350-8-13 PG 11 WC Genetics & Heredity SC Genetics & Heredity GA 153RI UT WOS:000245452300001 PM 17378937 ER PT J AU Ivanov, AA Ko, H Cosyn, L Maddileti, S Besada, P Fricks, I Costanzi, S Harden, TK Van Calenbergh, S Jacobson, KA AF Ivanov, Andrei A. Ko, Hyojin Cosyn, Liesbet Maddileti, Savitri Besada, Pedro Fricks, Ingrid Costanzi, Stefano Harden, T. Kendall Van Calenbergh, Serge Jacobson, Kenneth A. TI Molecular modeling of the human P2Y(2) receptor and design of a selective agonist, 2 '-amino-2 '-deoxy-2-thiouridine 5 '-triphosphate SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID NUCLEOTIDE P2 RECEPTORS; UTP-GAMMA-S; ADENINE-NUCLEOTIDES; CYSTIC-FIBROSIS; PHOSPHOLIPASE-C; RECOGNITION; URACIL; MUTAGENESIS; RHODOPSIN; POTENCY AB A rhodopsin-based homology model of the nucleotide-activated human P2Y(2) receptor, including loops, termini, and phospholipids, was optimized with the Monte Carlo multiple minimum conformational search routine. Docked uridine 5'-triphosphate (UTP) formed a nucleobase pi-pi complex with conserved Phe3.32. Selectivity-enhancing 2'-amino-2'-deoxy substitution interacted through pi-hydrogen-bonding with aromatic Phe6.51 and Tyr3.33. A "sequential ligand composition" approach for docking the flexible dinucleotide agonist Up(4)U demonstrated a shift of conserved cationic Arg3.29 from the UTP gamma position to the delta position of Up(4)U and Up(4) ribose. Synthesized nucleotides were tested as agonists at human P2Y receptors expressed in 1321N1 astrocytoma cells. 2'-Amino and 2-thio modifications were synergized to enhance potency and selectivity; compound 8 (EC50 = 8 nM) was 300-fold P2Y(2)-selective versus P2Y(4). 2'-Amine acetylation reduced potency, and trifluoroacetylation produced intermediate potency. 5-Amino nucleobase substitution did not enhance P2Y(2) potency through a predicted hydrophilic interaction possibly because of destabilization of the receptor-favored Northern conformation of ribose. This detailed view of P2Y(2) receptor recognition suggests mutations for model validation. C1 NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Univ Ghent, Fac Pharmaceut Sci, Med Chem Lab, B-9000 Ghent, Belgium. Univ N Carolina, Sch Med, Dept Pharmacol, Chapel Hill, NC 27599 USA. NIDDKD, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Van Calenbergh, Serge/A-3167-2008; Jacobson, Kenneth/A-1530-2009; Besada Pereira, Pedro/E-6051-2012; Costanzi, Stefano/G-8990-2013; OI Van Calenbergh, Serge/0000-0002-4201-1264; Jacobson, Kenneth/0000-0001-8104-1493; Besada Pereira, Pedro/0000-0002-9985-9063; Costanzi, Stefano/0000-0003-3183-7332 FU Intramural NIH HHS [Z01 DK031116-20]; NHLBI NIH HHS [HL34322, P01 HL034322]; NIGMS NIH HHS [GM38213, R01 GM038213] NR 39 TC 33 Z9 35 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAR 22 PY 2007 VL 50 IS 6 BP 1166 EP 1176 DI 10.1021/jm060903o PG 11 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 145WG UT WOS:000244895900009 PM 17302398 ER PT J AU Hoofnagle, JH Seeff, LB AF Hoofnagle, Jay H. Seeff, Leonard B. TI Peginterferon and ribavirin for hepatitis C - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID INTERFERON-ALPHA THERAPY; MANAGEMENT C1 NIH, Bethesda, MD 20892 USA. RP Hoofnagle, JH (reprint author), NIH, Bethesda, MD 20892 USA. EM hoofnaglej@extra.niddk.nih.gov NR 6 TC 1 Z9 1 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 MAR 22 PY 2007 VL 356 IS 12 BP 1271 EP 1271 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 148UP UT WOS:000245101900025 ER PT J AU Wan, X Harkavy, B Shen, N Grohar, P Helman, LJ AF Wan, X. Harkavy, B. Shen, N. Grohar, P. Helman, L. J. TI Rapamycin induces feedback activation of Akt signaling through an IGF-1R-dependent mechanism SO ONCOGENE LA English DT Article DE mTOR; rapamycin; Akt; IGF-1R; rhabdomyosarcoma ID GROWTH-FACTOR-II; S6 KINASE PATHWAY; INSULIN-RESISTANCE; CANCER-THERAPY; CELL-GROWTH; MTOR; RECEPTOR; RHABDOMYOSARCOMA; PHOSPHORYLATION; SURVIVAL AB Rapamycin and several analogs, such as CCI-779 and RAD001, are currently undergoing clinical evaluation as anticancer agents. In this study, we show that inhibition of mammalian target of rapamycin ( mTOR) signaling by rapamycin leads to an increase of Akt phosphorylation in Rh30 and RD human rhabdomyosarcoma cell lines and xenografts, and insulin-like growth factor (IGF)-II-treated C2C12 mouse myoblasts and IGF-II-overexpressing Chinese hamster ovary cells. RNA interference-mediated knockdown of S6K1 also results in an increase of Akt phosphorylation. These data suggest that mTOR/S6K1 inhibition either by rapamycin or small interfering RNA ( siRNA) triggers a negative feedback loop, resulting in the activation of Akt signaling. We next sought to investigate the mechanism of this negative feedback regulation from mTOR to Akt. Suppression of insulin receptor substrate (IRS)-1 and tuberous sclerosis complex-1 by siRNAs failed to abrogate rapamycin-induced upregulation of Akt phosphorylation in both Rh30 and RD cells. However, pretreatment with h7C10 antibody directed against insulin-like growth factor-1 receptor (IGF-1R) led to a blockade of rapamycin-induced Akt activation. Combined mTOR and IGF-1R inhibition with rapamycin and h7C10 antibody, respectively, resulted in additive inhibition of cell growth and survival. These data suggest that rapamycin mediates Akt activation through an IGF-1R-dependent mechanism. Thus, combining an mTOR inhibitor and an IGF-1R antibody/inhibitor may be an appropriate strategy to enhance mTOR-targeted anticancer therapy. C1 NCI, Mol Oncol Sect, Pediat Oncol Branch, NIH,Ctr Canc Res, Bethesda, MD 20892 USA. RP Wan, X (reprint author), NCI, Mol Oncol Sect, Pediat Oncol Branch, NIH,Ctr Canc Res, Bldg 10,Rm CRC 1W 3750, Bethesda, MD 20892 USA. EM xiaolinw@mail.nih.gov FU Intramural NIH HHS NR 37 TC 436 Z9 442 U1 2 U2 14 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 22 PY 2007 VL 26 IS 13 BP 1932 EP 1940 DI 10.1038/sj.onc.1209990 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 149AE UT WOS:000245117700010 PM 17001314 ER PT J AU Evans, MK Yu, CR Lohani, A Mahdi, RM Liu, X Trzeciak, AR Egwuagu, CE AF Evans, M. K. Yu, C-R Lohani, A. Mahdi, R. M. Liu, X. Trzeciak, A. R. Egwuagu, C. E. TI Expression of SOCS1 and SOCS3 genes is differentially regulated in breast cancer cells in response to proinflammatory cytokine and growth factor signals SO ONCOGENE LA English DT Article DE breast-cancer cells; SOCS; breast cancer; STAT; BRCA1; DNA hypermethylation; interferon ID ISLAND METHYLATOR PHENOTYPE; DNA-DAMAGE; IFN-GAMMA; BRCA1; TRANSCRIPTION; ACTIVATION; CARCINOMA; HYPERMETHYLATION; TUMORIGENESIS; COACTIVATOR AB DNA-hypermethylation of SOCS genes in breast, ovarian, squamous cell and hepatocellular carcinoma has led to speculation that silencing of SOCS1 and SOCS3 genes might promote oncogenic transformation of epithelial tissues. To examine whether transcriptional silencing of SOCS genes is a common feature of human carcinoma, we have investigated regulation of SOCS genes expression by IFN gamma, IGF-1 and ionizing radiation, in a normal human mammary epithelial cell line (AG11134), two breast-cancer cell lines (MCF-7, HCC1937) and three prostate cancer cell lines. Compared to normal breast cells, we observe a high level constitutive expression of SOCS2, SOCS3, SOCS5, SOCS6, SOCS7, CIS and/or SOCS1 genes in the human cancer cells. In MCF-7 and HCC1937 breast-cancer cells, transcription of SOCS1 is dramatically up-regulated by IFN gamma and/or ionizing-radiation while SOCS3 is transiently down-regulated by IFN gamma and IGF-1, suggesting that SOCS genes are not silenced in these cells by the epigenetic mechanism of DNA-hypermethylation. We further show that the kinetics of SOCS1-mediated feedback inhibition of IFN gamma signaling is comparable to normal breast cells, indicating that the SOCS1 protein in breast-cancer cells is functional. We provide direct evidence that STAT3 pathways are constitutively activated in MCF-7 and HCC1937 cells and may drive the aberrant persistent activation of SOCS genes in breast-cancer cells. Our data therefore suggest that elevated expression of SOCS genes is a specific lesion of breast-cancer cells that may confer resistance to proinflammatory cytokines and trophic factors, by shutting down STAT1/STAT5 signaling that mediate essential functions in the mammary gland. C1 NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Evans, MK (reprint author), NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. EM evansmi@grc.nia.nih.gov; egwuaguc@nei.nih.gov FU Intramural NIH HHS NR 33 TC 46 Z9 46 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 22 PY 2007 VL 26 IS 13 BP 1941 EP 1948 DI 10.1038/sj.onc.1209993 PG 8 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 149AE UT WOS:000245117700011 PM 17001312 ER PT J AU Wong, YF Cheung, TH Lo, KWK Yim, SF Siu, NSS Chan, SCS Ho, TWF Wong, KWY Yu, MY Wang, VW Li, C Gardner, GJ Bonome, T Johnson, WB Smith, DI Chung, TKH Birrer, MJ AF Wong, Y. F. Cheung, T. H. Lo, K. W. K. Yim, S. F. Siu, N. S. S. Chan, S. C. S. Ho, T. W. F. Wong, K. W. Y. Yu, M. Y. wang, V. W. Li, C. Gardner, G. J. Bonome, T. Johnson, W. B. Smith, D. I. Chung, T. K. H. Birrer, M. J. TI Identification of molecular markers and signaling pathway in endometrial cancer in Hong Kong Chinese women by genome-wide gene expression profiling SO ONCOGENE LA English DT Article DE endometrioid endometrial cancer; signaling pathway; gene expression profiling ID DIFFERENT HISTOLOGIC TYPES; CLEAR-CELL-CARCINOMA; MATRIX-METALLOPROTEINASE; BREAST-CANCER; SEROUS CARCINOMA; MESSENGER-RNA; CYCLIN-E; NUCLEAR TRANSLOCATION; ENDOGENOUS INHIBITOR; MICROARRAY ANALYSIS AB Endometrial cancer is the third most common gynecologic malignancy and the ninth most common malignancy for females overall in Hong Kong. Approximately 80% or more of these cancers are endometrioid endometrial adenocarcinomas. The aim of this study was to reveal genes contributing to the development of endometrioid endometrial cancer, which may impact diagnosis, prognosis and treatment of the disease. Whole-genome gene expression analysis was completed for a set of 55 microdissected sporadic endometrioid endometrial adenocarcinomas and 29 microdissected normal endometrium specimens using the Affymetrix Human U133 Plus 2.0 oligonucleotide microarray. Selected genes of interest were validated by quantitative real-time-polymerase chain reaction (qRT-PCR). Pathway analysis was performed to reveal gene interactions involved in endometrial tumorigenesis. Unsupervised hierarchical clustering displayed a distinct separation between the endometrioid adenocarcinomas and normal endometrium samples. Supervised analysis identified 117 highly differentially regulated genes (>= 4.0-fold change), which distinguished the endometrial cancer specimens from normal endometrium. Twelve novel genes including DKK4, ZIC1, KIF1A, SAA2, LOC16378, ALPP2, CCL20, CXCL5, BST2, OLFM1, KLRC1 and MBC45780 were deregulated in the endometrial cancer, and further validated in an independent set of 56 cancer and 29 normal samples using qRT-PCR. In addition, 10 genes were differentially regulated in late-stage cancer, as compared to early-stage disease, and may be involved in tumor progression. Pathway analysis of the expression data from this tumor revealed an interconnected network consisting of 21 aberrantly regulated genes involved in angiogenesis, cell proliferation and chromosomal instability. The results of this study highlight the molecular features of endometrioid endometrial cancer and provide insight into the events underlying the development and progression of endometrioid endometrial cancer. C1 Chinese Univ Hong Kong, Prince Wales Hosp, Dept Obstet & Gynaecol, Shatin, Hong Kong, Peoples R China. Prince Wales Hosp, Dept Anat & Cellular Pathol, Hong Kong, Hong Kong, Peoples R China. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Obstet Gynecol & Reprod Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Biostat, Boston, MA 02115 USA. NCI, Cell & Canc Biol Branch, Bethesda, MD 20892 USA. Mayo Clin, Sch Med, Dept Expt Pathol, Rochester, MN USA. RP Wong, YF (reprint author), Chinese Univ Hong Kong, Prince Wales Hosp, Dept Obstet & Gynaecol, Shatin, Hong Kong, Peoples R China. EM yickfuwong@cuhk.edu.hk NR 67 TC 63 Z9 67 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 MAR 22 PY 2007 VL 26 IS 13 BP 1971 EP 1982 DI 10.1038/sj.onc.1209986 PG 12 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 149AE UT WOS:000245117700015 PM 17043662 ER PT J AU Fekete, CA Mitchell, SF Cherkasova, VA Applefield, D Algire, MA Maag, D Saini, AK Lorsch, JR Hinnebusch, AG AF Fekete, Christie A. Mitchell, Sarah F. Cherkasova, Vera A. Applefield, Drew Algire, Mikkel A. Maag, David Saini, Adesh K. Lorsch, Jon R. Hinnebusch, Alan G. TI N- and C-terminal residues of eIF1A have opposing effects on the fidelity of start codon selection SO EMBO JOURNAL LA English DT Article DE eIF1A; GCN4; initiation; Saccharomyces; translation ID EUKARYOTIC TRANSLATION INITIATION; PREINITIATION COMPLEX; IN-VIVO; MULTIFACTOR COMPLEX; RIBOSOMAL-SUBUNIT; GTP HYDROLYSIS; SITE SELECTION; 40S SUBUNITS; BINDING; YEAST AB Translation initiation factor eIF1A stimulates preinitiation complex (PIC) assembly and scanning, but the molecular mechanisms of its functions are not understood. We show that the F131A, F133A mutation in the C-terminal tail (CTT) of eIF1A impairs recruitment of the eIF2-GTP-Met-tRNA(i)(Met) Met ternary complex to 40S subunits, eliminating functional coupling with eIF1. Mutating residues 17 - 21 in the N-terminal tail (NTT) of eIF1A also reduces PIC assembly, but in a manner rescued by eIF1. Interestingly, the 131,133 CTT mutation enhances initiation at UUG codons (Sui(-) phenotype) and decreases leaky scanning at AUG, while the NTT mutation 17 - 21 suppresses the Sui(-) phenotypes of eIF5 and eIF2 beta mutations and increases leaky scanning. These findings and the opposite effects of the mutations on eIF1A binding to reconstituted PICs suggest that the NTT mutations promote an open, scanning-conducive conformation of the PIC, whereas the CTT mutations 131,133 have the reverse effect. We conclude that tight binding of eIF1A to the PIC is an important determinant of AUG selection and is modulated in opposite directions by residues in the NTT and CTT of eIF1A. C1 Johns Hopkins Univ, Dept Biophys & Biophys Chem, Sch Med, Baltimore, MD 21205 USA. Natl Inst Child Hlth & Human Dev, Lab Gene Regulat & Dev, NIH, Bethesda, MD USA. RP Lorsch, JR (reprint author), Johns Hopkins Univ, Dept Biophys & Biophys Chem, Sch Med, 725 N Wolfe St,625 WBSB, Baltimore, MD 21205 USA. OI Lorsch, Jon/0000-0002-4521-4999 FU Intramural NIH HHS NR 27 TC 69 Z9 70 U1 1 U2 4 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 MAR 21 PY 2007 VL 26 IS 6 BP 1602 EP 1614 DI 10.1038/sj.emboj.7601613 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 149AC UT WOS:000245117500013 PM 17332751 ER PT J AU Ambrosone, CB Shields, PG Freudenheim, JL Hong, CC AF Ambrosone, Christine B. Shields, Peter G. Freudenheim, Jo L. Hong, Chi-Chen TI Re: Commonly studied single-nucleotide polymorphisms and breast cancer: Results from the Breast Cancer Association Consortium SO JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter ID SUSCEPTIBILITY C1 NCI, Biometry Res Grp, Bethesda, MD 20892 USA. RP Ambrosone, CB (reprint author), NCI, Biometry Res Grp, EPN 3131,6130 Execut Blvd,MSC 7354, Bethesda, MD 20892 USA. EM christine.ambrosone@roswellpark.org RI Shields, Peter/I-1644-2012 NR 7 TC 4 Z9 4 U1 0 U2 0 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 MAR 21 PY 2007 VL 99 IS 6 BP 487 EP 488 DI 10.1093/jnci/djk097 PG 2 WC Oncology SC Oncology GA 153GA UT WOS:000245418900016 PM 17374839 ER PT J AU Thiebaut, ACM Kipnis, V Chang, SC Subar, AF Thompson, FE Rosenberg, PS Hollenbeck, AR Leitzmann, M Schatzkin, A AF Thiebaut, Anne C. M. Kipnis, Victor Chang, Shih-Chen Subar, Amy F. Thompson, Frances E. Rosenberg, Philip S. Hollenbeck, Albert R. Leitzmann, Michael Schatzkin, Arthur TI Dietary fat and postmenopausal invasive breast cancer in the National Institutes of Health-AARP Diet and Health Study cohort SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRES; ENERGY-ADJUSTMENT MODELS; MEASUREMENT ERROR; NUTRITIONAL EPIDEMIOLOGY; POOLED ANALYSIS; CONFIDENCE-INTERVALS; SEX-HORMONES; RISK; WOMEN; REGRESSION AB Background Although ecologic association and animal studies support a direct effect of dietary fat on the development of breast cancer, results of epidemiologic studies have been inconclusive. Methods We prospectively analyzed the association between fat consumption and the incidence of postmenopausal invasive breast cancer in the National Institutes of Health-AARP Diet and Health Study, a US cohort comprising 188736 postmenopausal women who completed a 124-item food-frequency questionnaire in 1995-1996. Hazard ratios (HRs) and 95% confidence intervals (Cls) were calculated using Cox proportional hazards regression models with adjustment for energy and potential confounding factors. All statistical tests were two-sided. Results Over an average follow-up of 4.4 years, the cohort yielded 3501 cases of invasive breast cancer. The hazard ratio of breast cancer for the highest (median intake, 40.1% energy from total fat; 434 cases per 100000 person-years) versus the lowest (median intake, 20.3% energy from total fat; 392 cases per 100000 person-years) quintile of total fat intake was 1.11 (95% Cl = 1.00 to 1.24; P-trend =.017). The corresponding hazard ratio for a twofold increase in percent energy from total fat on the continuous scale was 1.15 (95% Cl = 1.05 to 1.26). Positive associations were also found for subtypes of fat (hazard ratio for a twofold increase in percent energy from saturated fat = 1.13; 95% Cl = 1.05 to 1.22; from monounsaturated fat, HR = 1.12; 95% Cl = 1.03 to 1.21; from polyunsaturated fat, HR = 1.10, 95% Cl = 1.01 to 1.20). Correction for measurement error in nutrient intakes, on the basis of a calibration substudy that used two 24-hour dietary recalls, strengthened the associations, yielding an estimated hazard ratio for total fat of 1.32 (95% Cl = 1.11 to 1.58). Secondary analyses showed that associations between total, saturated, and monounsaturated fat intakes were confined to women who were not using menopausal hormone therapy at baseline. Conclusion In this large prospective cohort with a wide range of fat intake, dietary fat intake was directly associated with the risk of postmenopausal invasive breast cancer. C1 NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, Biometry Res Grp, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, Appl Res Program, Bethesda, MD 20892 USA. NCI, Div Canc Epidemiol & Genet, Biostat Branch, Bethesda, MD 20892 USA. RP Thiebaut, ACM (reprint author), NCI, Div Canc Epidemiol & Genet, Nutr Epidemiol Branch, 6120 Execut Blvd,Execut Plaza S Rm 3033, Bethesda, MD 20892 USA. EM thiebauta@mail.nih.gov NR 58 TC 111 Z9 115 U1 1 U2 8 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAR 21 PY 2007 VL 99 IS 6 BP 451 EP 462 DI 10.1093/jnci/djk094 PG 12 WC Oncology SC Oncology GA 153GA UT WOS:000245418900012 PM 17374835 ER PT J AU Carter, HB Ferrucci, L Kettermann, A Landis, P Wright, J Epstein, JI Trock, BJ Metter, EJ AF Carter, H. Ballentine Ferrucci, Luigi Kettermann, Anna Landis, Patricia Wright, James Epstein, Jonathan I. Trock, Bruce J. Metter, E. Jeffrey TI Re: Detection of life threatening prostate cancer with prostate-specific antigen velocity during a window of curability - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 Johns Hopkins Sch Med, James Buchanan Brady Urol Inst, Baltimore, MD 21287 USA. NIA ASTRA Harbor Hosp, NIA, Baltimore, MD USA. RP Carter, HB (reprint author), Johns Hopkins Sch Med, James Buchanan Brady Urol Inst, 600 N Wolfe St,Marburg Bldg,Rm 145, Baltimore, MD 21287 USA. EM hcarter@jhmi.edu NR 6 TC 1 Z9 1 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD MAR 21 PY 2007 VL 99 IS 6 BP 490 EP 490 DI 10.1093/jnci/djk101 PG 1 WC Oncology SC Oncology GA 153GA UT WOS:000245418900019 ER PT J AU Murakami, H Goto, DB Toda, T Chen, ES Grewal, SI Martienssen, RA Yanagida, M AF Murakami, Hiroaki Goto, Derek B. Toda, Takashi Chen, Ee Sin Grewal, Shiv I. Martienssen, Robert A. Yanagida, Mitsuhiro TI Ribonuclease Activity of Dis3 Is Required for Mitotic Progression and Provides a Possible Link between Heterochromatin and Kinetochore Function SO PLOS ONE LA English DT Article AB Background. Cellular RNA metabolism has a broad range of functional aspects in cell growth and division, but its role in chromosome segregation during mitosis is only poorly understood. The Dis3 ribonuclease is a key component of the RNA-processing exosome complex. Previous isolation of the dis3-54 cold-sensitive mutant of fission yeast Schizosaccharomyces pombe suggested that Dis3 is also required for correct chromosome segregation. Methodology/Principal Findings. We show here that the progression of mitosis is arrested in dis3-54, and that segregation of the chromosomes is blocked by activation of the mitotic checkpoint control. This block is dependent on the Mad2 checkpoint protein. Double mutant and inhibitor analyses revealed that Dis3 is required for correct kinetochore formation and function, and that this activity is monitored by the Mad2 checkpoint. Dis3 is a member of the highly conserved RNase II family and is known to be an essential subunit of the exosome complex. The dis3-54 mutation was found to alter the RNaseII domain of Dis3, which caused a reduction in ribonuclease activity in vitro. This was associated with loss of silencing of an ura4(+) reporter gene inserted into the outer repeats (otr) and central core (cnt and imr) regions of the centromere. On the other hand, centromeric siRNA maturation and formation of the RITS RNAi effector complex was normal in the dis3-54 mutant. Micrococcal nuclease assay also suggested the overall chromatin structure of the centromere was not affected in dis3-54 mutant. Conclusions/Significance. RNase activity of Dis3, a core subunit of exosome, was found to be required for proper kinetochore formation and establishment of kinetochore-microtubule interactions. Moreover, Dis3 was suggested to contribute to kinetochore formation through an involvement in heterochromatic silencing at both outer centromeric repeats and within the central core region. This activity is likely monitored by the mitotic checkpoint, and distinct from that of RNAi-mediated heterochromatin formation directly targeting outer centromeric repeats. C1 [Murakami, Hiroaki; Yanagida, Mitsuhiro] Kyoto Univ, Grad Sch Biostudies, Japan Sci & Technol Corp, CREST Res Program,Dept Gene Mech,Sakyo Ku, Kyoto, Japan. [Goto, Derek B.; Martienssen, Robert A.] Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. [Toda, Takashi] Lincolns Inn Fields Labs, London Res Inst, Canc Res UK, Lab Cell Regulat, London, England. [Chen, Ee Sin; Grewal, Shiv I.] NIH, Mol Cell Biol Lab, Bethesda, MD 20892 USA. RP Yanagida, M (reprint author), Kyoto Univ, Grad Sch Biostudies, Japan Sci & Technol Corp, CREST Res Program,Dept Gene Mech,Sakyo Ku, Kyoto, Japan. EM yanagida@kozo.lif.kyoto-u.ac.jp RI Goto, Derek/B-7053-2009 FU Ministry of Education, Culture, Sports, Science and Technology; Japan Science and Technology Corporation (JST); National Institutes of Health [R01-GM067014]; Life Sciences Research Foundation; Cancer Research UK FX This work was supported by a Specially Promoted Center of Excellence (COE) grant from the Ministry of Education, Culture, Sports, Science and Technology to M. Y., a Core Research for Evolutional Science and Technology (CREST) research grant from the Japan Science and Technology Corporation (JST) to M. Y., and a grant from the National Institutes of Health (R01-GM067014) to R. M. D. G. was a DOE-Energy Biosciences Research Fellow of the Life Sciences Research Foundation. T. T. is supported by Cancer Research UK. NR 65 TC 51 Z9 53 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 MAR 21 PY 2007 VL 2 IS 3 AR e317 DI 10.1371/journal.pone.0000317 PG 12 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10DQ UT WOS:000207445100019 PM 17380189 ER PT J AU Havlin, RH Blanco, FJ Tycko, R AF Havlin, Robert H. Blanco, Francisco J. Tycko, Robert TI Constraints on protein structure in HIV-1 Rev and Rev-RNA supramolecular assemblies from two-dimensional solid state nuclear magnetic resonance SO BIOCHEMISTRY LA English DT Article ID NMR CHEMICAL-SHIFTS; RESPONSIVE ELEMENT RNA; ANGLE-SPINNING NMR; VIRUS TYPE-1 REV; ALPHA-HELIX; FUNCTIONAL-ANALYSIS; CROSS-POLARIZATION; VIRION EXPRESSION; ROTATING SOLIDS; MESSENGER-RNAS AB The HIV-1 Rev protein is required for export of partially spliced and unspliced viral mRNA from nuclei of infected cells, and ultimately for viral replication. Rev is highly prone to aggregation, both in the absence and in the presence of the Rev responsive element (RRE) RNA to which it binds. As a result, the full molecular structures of Rev and Rev-RRE complexes are not known. We describe the results of transmission electron microscopy, atomic force microscopy, and solid state nuclear magnetic resonance (NMR) experiments on pure Rev filaments and coassemblies of Rev with a 45-base RNA sequence representing the high-affinity stem-loop IIB segment of the RRE. The morphologies of Rev filaments and Rev-RNA coassemblies are qualitatively different. Nonetheless, two-dimensional (2D) solid state C-13-C-13 NMR spectra of Rev filament and Rev-RNA coassembly samples, in which all Ile, Val, and Ala residues are uniformly labeled with C-13, are nearly indistinguishable, indicating that the protein conformation is essentially the same in the two types of supramolecular assemblies. Analysis of cross-peak patterns in the 2D spectra supports a previously developed helix-loop-helix structural model for the N-terminal half of Rev and shows that this model applies to both Rev filaments and Rev-RNA coassemblies. In addition, the 2D spectra suggest the presence of additional helix content at Ile and Val sites in the C-terminal half of Rev. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Ctr Nacl Invest Oncol, NMR Grp, E-28029 Madrid, Spain. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov RI Blanco, Francisco/D-4401-2009 OI Blanco, Francisco/0000-0003-2545-4319 FU Intramural NIH HHS NR 50 TC 15 Z9 17 U1 1 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 20 PY 2007 VL 46 IS 11 BP 3586 EP 3593 DI 10.1021/bi0622928 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 145HB UT WOS:000244854800067 PM 17311419 ER PT J AU Ton, TV Hong, HH Devereux, TR Melnick, RL Sills, RC Kim, Y AF Ton, Thai-Vu Hong, Hue-Hua Devereux, Theodora R. Melnick, Ronald L. Sills, Robert C. Kim, Yongbaek TI Evaluation of genetic alterations in cancer-related genes in lung and brain tumors from B6C3F1 mice exposed to 1,3-butadiene or chloroprene SO CHEMICO-BIOLOGICAL INTERACTIONS LA English DT Article; Proceedings Paper CT International Symposium on the Evaluation of Butadiene and Chloroprene Health Risks CY SEP 20-22, 2005 CL Charleston, SC DE 1,3-butadiene; chloroprene; brain; lung; tumor; K-ras; p53; p16; carcinogenesis; mutation; loss of heterozygosity ID MULTIPLE ORGAN CARCINOGENICITY; K-RAS; INHALATION EXPOSURE; EGF RECEPTOR; MUTATION; ADDUCTS; P53; ISOPRENE; RATS; CELL AB 1,3-Butadiene and chloroprene are multisite carcinogens in B6C3F1 mice with the strongest tumor response being the induction of lung neoplasms in females. Incidence of brain tumors in mice exposed to 1,3-butadiene was equivocal. This article reviews the efforts of our laboratory and others to uncover the mechanisms of butadiene and chloroprene induced lung and brain tumor responses in the B6C3F1 mouse. The formation of lung tumors by these chemicals involved mutations in the K-ras cancer gene and loss of heterozygosity in the region of K-ras on distal chromosome 6, while alterations in p53 and p16 were implicated in brain tumongenesis. Published by Elsevier Ireland Ltd. C1 NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. NIEHS, Environm Carcinogenesis Program, Res Triangle Pk, NC 27709 USA. RP Ton, TV (reprint author), NIEHS, Environm Toxicol Program, MD B3-08,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM ton@niehs.nih.gov FU Intramural NIH HHS NR 56 TC 9 Z9 10 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0009-2797 J9 CHEM-BIOL INTERACT JI Chem.-Biol. Interact. PD MAR 20 PY 2007 VL 166 IS 1-3 SI SI BP 112 EP 120 DI 10.1016/j.cbi.2006.04.015 PG 9 WC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Toxicology GA 162OG UT WOS:000246096600013 PM 16860786 ER PT J AU Wang, TJ Larson, MG Keyes, MJ Levy, D Benjamin, EJ Vasan, RS AF Wang, Thomas J. Larson, Martin G. Keyes, Michelle J. Levy, Daniel Benjamin, Emelia J. Vasan, Ramachandran S. TI Association of plasma natriuretic peptide levels with metabolic risk factors in ambulatory individuals SO CIRCULATION LA English DT Article DE atrial natriuretic factor; epidemiology; natriuretic peptides; risk factors ID BODY-MASS INDEX; INSULIN-RESISTANCE; ANGIOTENSIN-II; HEART-FAILURE; ESSENTIAL-HYPERTENSION; LIPID MOBILIZATION; CIRCULATING LEVELS; DIABETES-MELLITUS; INHIBITION; OBESITY AB Background-Experimental studies suggest that the natriuretic peptides influence lipid and fatty acid metabolism. Although it has been shown that obese individuals have reduced natriuretic peptide levels, conflicting data exist on the relation of natriuretic peptide levels to other metabolic risk factors. Methods and Results-We examined the association of plasma levels of B-type natriuretic peptide and N-terminal pro-atrial natriuretic peptide with metabolic risk factors, the metabolic syndrome, and insulin resistance in 3333 Framingham study participants free of heart failure (mean age, 58 years; 54% women). Regression analyses were performed, with adjustment for clinical and echocardiographic variables. Plasma natriuretic peptide levels were inversely associated with all components of the metabolic syndrome except for elevated blood pressure. Adjusted natriuretic peptide levels were lower in persons with the metabolic syndrome compared with those without the metabolic syndrome: In men, B-type natriuretic peptide was 24% lower (P < 0.001) and N-terminal pro-atrial natriuretic peptide was 16% lower (P < 0.001); in women, B-type natriuretic peptide was 29% lower (P < 0.001) and N-terminal pro-atrial natriuretic peptide was 18% lower (P < 0.001). Individuals with insulin resistance, as indicated by an elevated homeostasis model assessment (HOMA-IR) index, had lower levels of B-type natriuretic peptide (P=0.009 in men, P < 0.001 in women) and N-terminal pro-atrial natriuretic peptide (P < 0.001 in men, P < 0.001 in women). Conclusions-Having several metabolic risk factors is associated with low circulating natriuretic peptide levels, even after adjustment for body mass index. These findings raise the possibility that reduced natriuretic peptide activity is a manifestation of the metabolic syndrome, which may have important clinical and pathophysiological implications. C1 Massachusetts Gen Hosp, Cardiol Div, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. Natl Heart Lung & Blood Inst, Bethesda, MD USA. Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02118 USA. Boston Univ, Sch Med, Cardiol Sect, Boston, MA 02118 USA. RP Wang, TJ (reprint author), Massachusetts Gen Hosp, Cardiol Div, Dept Med, GRB-800,55 Fruit St, Boston, MA 02114 USA. EM tjwang@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, K23-HL-074077, N01-HC-25195] NR 48 TC 112 Z9 116 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 MAR 20 PY 2007 VL 115 IS 11 BP 1345 EP 1353 DI 10.1161/CIRCULATIONAHA.106.655142 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 147WK UT WOS:000245034300004 PM 17339551 ER PT J AU Irwin, ML Aiello, EJ McTiernan, A Bernstein, L Gilliland, FD Baumgartner, RN Baumgartner, KB Ballard-Barbash, R AF Irwin, Melinda L. Aiello, Erin J. McTiernan, Anne Bernstein, Leslie Gilliland, Frank D. Baumgartner, Richard N. Baumgartner, Kathy B. Ballard-Barbash, Rachel TI Physical activity, body mass index, and mammographic density in postmenopausal breast cancer survivors SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID SEX-HORMONES; ASSOCIATION; RISK; DIAGNOSIS; WOMEN; CARCINOMA; COHORT; TRIAL AB Purpose To investigate the association between physical activity, body mass index (BMI), and mammographic density in a racially/ethnically diverse population-based sample of 522 postmenopausal women diagnosed with stage 0-IIIA breast cancer and enrolled in the Health, Eating, Activity, and Lifestyle Study. Methods We collected information on BMI and physical activity during a clinic visit 2 to 3 years after diagnosis. Weight and height were measured in a standard manner. Using an interview-administered questionnaire, participants recalled the type, duration, and frequency of physical activities they had performed in the last year. We estimated dense area and percentage density as a continuous measure using a computer-assisted software program from mammograms imaged approximately 1 to 2 years after diagnosis. Analysis of covariance methods were used to obtain mean density across WHO BMI categories and physical activity tertiles adjusted for confounders. Results We observed a statistically significant decline in percentage density (P for trend = .0001), and mammographic dense area (P for trend = .0052), with increasing level of BMI adjusted for potential covariates. We observed a statistically significant decline in mammographic dense area (P for trend = .036) with increasing level of sports/recreational physical activity in women with a BMI of at least 30 kg/m(2). Conversely, in women with a BMI less than 25 kg/m(2), we observed a non-statistically significant increase in mammographic dense area and percentage density with increasing level of sports/recreational physical activity. Conclusion Increasing physical activity among obese postmenopausal breast cancer survivors may be a reasonable intervention approach to reduce mammographic density. C1 Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT 06520 USA. Fred Hutchinson Canc Res Ctr, Ctr Hlth Studies, Grp Hlth Cooperat, Seattle, WA USA. Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. Univ New Mexico, Dept Internal Med, Canc Res & Treatment Ctr, Albuquerque, NM 87131 USA. NCI, Div Canc Control & Populat Sci, Appl Res Program, Bethesda, MD 20892 USA. RP Irwin, ML (reprint author), Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, POB 208034, New Haven, CT 06520 USA. EM melinda.irwin@yale.edu FU NCI NIH HHS [N01-CN-05228, N01-CN-75036-20, T32 CA09661, N01 PC035138-22, T32 CA009661, N01 CN005228, N01 PC067010]; NCRR NIH HHS [M01-RR-00037, M01-RR-0997, M01 RR000037, M01 RR000997] NR 29 TC 40 Z9 40 U1 0 U2 3 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD MAR 20 PY 2007 VL 25 IS 9 BP 1061 EP 1066 DI 10.1200/JCO.2006.07.3965 PG 6 WC Oncology SC Oncology GA 152GD UT WOS:000245348600010 PM 17261853 ER PT J AU Cao, K Capell, BC Erdos, MR Djabali, K Collins, FS AF Cao, Kan Capell, Brian C. Erdos, Michael R. Djabali, Karima Collins, Francis S. TI A lamin A protein isoform overexpressed in Hutchinson-Gilford progeria syndrome interferes with mitosis in progeria and normal cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE aging; laminopathy; progerin ID NUCLEAR ARCHITECTURE; PRELAMIN-A; MISREGULATION; FARNESYLATION; ORGANIZATION AB Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder characterized by dramatic premature aging. Classic HGIPS is caused by a de novo point mutation in exon 11 (residue 1824, C -> T) of the LMNA gene, activating a cryptic splice donor and resulting in a mutant lamin A (LA) protein termed "progerin/LA Delta 50" that lacks the normal cleavage site to remove a C-terminal farnesyl group. During interphase, irreversibly farnesylated progerin/LA Delta 50 anchors to the nuclear membrane and causes characteristic nuclear blebbing. Progerin/LA Delta 50's localization and behavior during mitosis, however, are completely unknown. Here, we report that progerin/LA Delta 50 mislocalizes into insoluble cytoplasmic aggregates and membranes during mitosis and causes abnormal chromosome segregation and binucleation. These phenotypes are largely rescued with either farnesyltransferase inhibitors or a farnesylation-incompetent mutant progerin/LA Delta 50. Furthermore, we demonstrate that small amounts of progerin/LAA50 exist in normal fibroblasts, and a significant percentage of these progerin/LA Delta 50-expressing normal cells are binucleated, implicating progerin/LAA50 as causing similar mitotic defects in the normal aging process. Our findings present evidence of mitotic abnormality in HGPS and may shed light on the general phenomenon of aging. C1 NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Columbia Univ, Coll Phys & Surg, Dept Dermatol, New York, NY 10032 USA. RP Collins, FS (reprint author), NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. EM fc23a@nih.gov OI Capell, Brian/0000-0002-7036-8359 FU NIA NIH HHS [K99 AG029761-01A1, R00 AG029761, R00 AG029761-02, K99 AG029761] NR 24 TC 116 Z9 124 U1 2 U2 14 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 20 PY 2007 VL 104 IS 12 BP 4949 EP 4954 DI 10.1073/pnas.0611640104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 150YY UT WOS:000245256700035 PM 17360355 ER PT J AU Lopez-Granados, E Temmerman, ST Wu, L Reynolds, JC Follmann, D Liu, SY Nelson, DL Rauch, F Jain, A AF Lopez-Granados, Eduardo Temmerman, Stephane T. Wu, Lynne Reynolds, James C. Follmann, Dean Liu, Shuying Nelson, David L. Rauch, Frank Jain, Ashish TI Osteopenia in X-linked hyper-IgM syndrome reveals a regulatory role for CD40 ligand in osteoclastogenesis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE osteoclast; IFN-gamma; receptor activator of NF-kappa B ligand < RANKL >; bone homeostasis; T cells ID TUMOR-NECROSIS-FACTOR; BONE HISTOMORPHOMETRY; N-TELOPEPTIDES; OSTEOPROTEGERIN; DIFFERENTIATION; ACTIVATION; CHILDREN; RECEPTOR; RANKL; MICE AB We report that osteopenia is a prominent and previously unappreciated clinical feature of patients with X-linked hyper-IgM syndrome, an inherited immune deficiency disorder caused by mutations in the gene encoding CD40 ligand (CD40L). We therefore conducted studies to determine the relationship between CD40L and osteoclastogenesis. Recognizing that activated T cells express surface receptor activator of NF-kappa B ligand (RANKL) and can induce osteoclast differentiation of myeloid cells expressing RANK, we assessed the capacity of wild-type T cells and CD40L(-/-) T cells to induce osteoclastogenesis in vitro. Relative to wild-type T cells, activated CD40L(-/-) T cells from both humans and mice promoted robust osteoclast differentiation of myeloid cells. Whereas activated CD40L(-/-) T cells had normal expression of RANKL, they were deficient in IFN-gamma production. In subsequent studies, we cultured activated CD40L(-/-) T cells in the presence of IFN-gamma, and we found that the osteoclastic capacity of CD40L(-/-) T cells could be greatly diminished. These results show that CD40L can influence RANKL signaling through T cell priming, and thus they demonstrate a regulatory role for CD40L in bone mineralization that is absent in patients with X-linked hyper-IgM syndrome. C1 NIAID, Lab Host Def, NIH, Bethesda, MD 20892 USA. NIH, Nucl Med Dep, Magnuson Clin Ctr, Bethesda, MD 20892 USA. NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. McGill Univ, Shrines Hosp, Genet Unit, Montreal, PQ H3G 1A6, Canada. RP Jain, A (reprint author), NIAID, Lab Host Def, NIH, Room 5W-3950, Bethesda, MD 20892 USA. EM ajain@niaid.nih.gov FU Intramural NIH HHS NR 36 TC 25 Z9 25 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 MAR 20 PY 2007 VL 104 IS 12 BP 5056 EP 5061 DI 10.1073/pnas.0605715104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 150YY UT WOS:000245256700053 PM 17360404 ER PT J AU Lusso, P Crowley, RW Malnati, MS Di Serio, C Ponzoni, M Biancotto, A Markham, PD Gallo, RC AF Lusso, Paolo Crowley, Richard W. Malnati, Mauro S. Di Serio, Clelia Ponzoni, Maurilio Biancotto, Angelique Markham, Phillip D. Gallo, Robert C. TI Human herpesvirus 6A accelerates AIDS progression in macaques SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE simian immunodeficiency virus; animal models; herpesviruses ID SIMIAN IMMUNODEFICIENCY VIRUS; PRIMARY INFECTION; LYMPH-NODES; T-CELLS; IN-VIVO; HIV-1; HUMAN-HERPESVIRUS-6; CYTOMEGALOVIRUS; IDENTIFICATION; RANTES AB Although HIV is the necessary and sufficient causative agent of AIDS, genetic and environmental factors markedly influence the pace of disease progression. Clinical and experimental evidence suggests that human herpesvirus 6A (HHV-6A), a cytopathic T-lymphotropic DNA virus, fosters the progression to AIDS in synergy with HIV-1. In this study, we investigated the effect of coinfection with HHV-6A on the progression of simian immunodeficiency virus (SIV) disease in pig-tailed macaques (Macalcal nemestrina). Inoculation of HHV-6A resulted in a rapid appearance of plasma viremia associated with transient clinical manifestations and followed by antibody seroconversion, indicating that this primate species is susceptible to HHV-6A infection. Whereas animals infected with HHV-6A alone did not show any long-term clinical and immunological sequelae, a progressive loss of CD4(+) T cells was observed in all of the macaques inoculated with SIV. However, progression to full-blown AIDS was dramatically accelerated by coinfection with HHV-6A. Rapid disease development in dually infected animals was heralded by an early depletion of both CD4(+) and CD8(+) T cells. These results provide in vivo evidence that HHV-6A may act as a promoting factor in AIDS progression. C1 Ist Sci San Raffaele, Unit Human Virol, I-20132 Milan, Italy. Ist Sci San Raffaele, Unit Biostat, I-20132 Milan, Italy. Ist Sci San Raffaele, Unit Pathol, I-20132 Milan, Italy. Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. Adv Biosci Labs, Bethesda, MD 20894 USA. RP Lusso, P (reprint author), Ist Sci San Raffaele, Unit Human Virol, I-20132 Milan, Italy. EM paolo.lusso@hsr.it; gallo@umbi.umd.edu FU Intramural NIH HHS NR 42 TC 24 Z9 24 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 20 PY 2007 VL 104 IS 12 BP 5067 EP 5072 DI 10.1073/pnas.0700929104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 150YY UT WOS:000245256700055 PM 17360322 ER PT J AU Alteri, CJ Xicohtencatl-Cortes, J Hess, S Caballero-Olin, G Giron, JA Friedman, RL AF Alteri, Christopher J. Xicohtencatl-Cortes, Juan Hess, Sonja Caballero-Olin, Guillermo Giron, Jorge A. Friedman, Richard L. TI Mycobacterium tuberculosis produces pili during human infection SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE adherence; antigen; laminin; amyloid ID HEPARIN-BINDING HEMAGGLUTININ; ENTEROPATHOGENIC ESCHERICHIA-COLI; PE-PGRS PROTEINS; GENOME SEQUENCE; BOVIS BCG; SURFACE; IDENTIFICATION; BIOGENESIS; VIRULENCE; CELLS AB Mycobacterium tuberculosis is responsible for nearly 3 million human deaths worldwide every year. Understanding the mechanisms and bacteria[ factors responsible for the ability of M. tuberculosis to cause disease in humans is critical for the development of improved treatment strategies. Many bacterial pathogens use pili as adherence factors to colonize the host. We discovered that M. tuberculosis produces fine (2- to 3-nm-wide), aggregative, flexible pili that are recognized by IgG antibodies contained in sera obtained from patients with active tuberculosis, indicating that the bacilli produce pili or pili-associated antigen during human infection. Purified M. tuberculosis pili (MTP) are composed of low-molecular-weight protein subunits encoded by the predicted M. tuberculosis H37Rv ORF, designated Rv3312A. MTP bind to the extracellular matrix protein laminin in vitro, suggesting that MTP possess adhesive properties. Isogenic mtp mutants lost the ability to produce Mtp in vitro and demonstrated decreased laminin-binding capabilities. MTP shares morphological, biochemical, and functional properties attributed to bacterial pili, especially with curli amyloid fibers. Thus, we propose that MTP are previously unidentified host-colonization factors of M. tuberculosis. C1 Univ Arizona, Dept Immunobiol, Tucson, AZ 85724 USA. NIDDK, Proteom & Mass Spectrometry Facil, NIH, Bethesda, MD 20892 USA. Inst Mexicano Seguro Social, Monterrey 64010, Nuevo Leon, Mexico. RP Alteri, CJ (reprint author), Univ Michigan, Sch Med, Dept Microbiol & Immunol, 5641 Med Sci 2,1150 W Med Ctr Dr, Ann Arbor, MI 48109 USA. EM alteri@umich.edu RI Hess, Sonja/K-4842-2013; Alteri, Christopher/G-3243-2015 OI Hess, Sonja/0000-0002-5904-9816; Alteri, Christopher/0000-0002-6367-5684 FU NIAID NIH HHS [AI45537-01, R01 AI045537, R21 AI045537] NR 49 TC 77 Z9 88 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 MAR 20 PY 2007 VL 104 IS 12 BP 5145 EP 5150 DI 10.1073/pnas.0602304104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 150YY UT WOS:000245256700068 PM 17360408 ER PT J AU Karlsson, G Blank, U Moody, JL Ehinger, M Singbrant, S Deng, CX Karlsson, S AF Karlsson, Goran Blank, Ulrika Moody, Jennifer L. Ehinger, Mats Singbrant, Sofie Deng, Chu-Xia Karlsson, Stefan TI Smad4 is critical for self-renewal of hematopoietic stem cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID GROWTH-FACTOR-BETA; SIGNALING PATHWAYS; KNOCKOUT MICE; C-MYC; GENE; WNT; NOTCH; SUPPRESSION; DISRUPTION; POLYPOSIS AB Members of the transforming growth factor beta (TGF-beta) superfamily of growth factors have been shown to regulate the in vitro proliferation and maintenance of hematopoietic stem cells ( HSCs). Working at a common level of convergence for all TGF-beta superfamily signals, Smad4 is key in orchestrating these effects. The role of Smad4 in HSC function has remained elusive because of the early embryonic lethality of the conventional knockout. We clarify its role by using an inducible model of Smad4 deletion coupled with transplantation experiments. Remarkably, systemic induction of Smad4 deletion through activation of MxCre was incompatible with survival 4 wk after induction because of anemia and histopathological changes in the colonic mucosa. Isolation of Smad4 deletion to the hematopoietic system via several transplantation approaches demonstrated a role for Smad4 in the maintenance of HSC self-renewal and reconstituting capacity, leaving homing potential, viability, and differentiation intact. Furthermore, the observed down-regulation of notch1 and c-myc in Smad4(-/-) primitive cells places Smad4 within a network of genes involved in the regulation HSC renewal. C1 Univ Lund Hosp, Inst Lab Med, Dept Mol Med & Gene Therapy, S-22185 Lund, Sweden. Lund Strateg Res Ctr Stem Cell Biol & Cell Therap, S-22185 Lund, Sweden. Helsingborgs Lasarett, Dept Pathol, S-25187 Helsingborg, Sweden. NIDDK, NIH, Bethesda, MD 20892 USA. RP Karlsson, S (reprint author), Univ Lund Hosp, Inst Lab Med, Dept Mol Med & Gene Therapy, S-22185 Lund, Sweden. EM Stefan.Karlsson@med.lu.se RI deng, chuxia/N-6713-2016; OI Karlsson, Goran/0000-0001-8197-754X NR 30 TC 73 Z9 80 U1 1 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD MAR 19 PY 2007 VL 204 IS 3 BP 467 EP 474 DI 10.1084/jem.20060465 PG 8 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 150IX UT WOS:000245210800008 PM 17353364 ER PT J AU Lenz, G Nagel, I Siebert, R Roschke, AV Sanger, W Wright, GW Dave, SS Tan, B Zhao, H Rosenwald, A Muller-Hermelink, HK Gascoyne, RD Campo, E Jaffe, ES Smeland, EB Fisher, RI Kuehl, WM Chan, WC Staudt, LM AF Lenz, Georg Nagel, Inga Siebert, Reiner Roschke, Anna V. Sanger, Warren Wright, George W. Dave, Sandeep S. Tan, Bruce Zhao, Hong Rosenwald, Andreas Muller-Hermelink, Hans Konrad Gascoyne, Randy D. Campo, Elias Jaffe, Elaine S. Smeland, Erlend B. Fisher, Richard I. Kuehl, W. Michael Chan, Wing C. Staudt, Louis M. TI Aberrant immunoglobulin class switch recombination and switch translocations in activated B cell-like diffuse large B cell lymphoma SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CYTIDINE DEAMINASE AID; GENE-EXPRESSION; MULTIPLE-MYELOMA; SPI-B; SOMATIC HYPERMUTATION; REGION RECOMBINATION; MOLECULAR DIAGNOSIS; HODGKIN LYMPHOMA; ETS PROTEIN; DNA BREAKS AB To elucidate the mechanisms underlying chromosomal translocations in diffuse large B cell lymphoma (DLBCL), we investigated the nature and extent of immunoglobulin class switch recombination (CSR) in these tumors. We used Southern blotting to detect legitimate and illegitimate CSR events in tumor samples of the activated B cell-like (ABC), germinal center B cell-like (GCB), and primary mediastinal B cell lymphoma (PMBL) subgroups of DLBCL. The frequency of legitimate CSR was lower in ABC DLBCL than in GCB DLBCL and PMBL. In contrast, ABC DLBCL had a higher frequency of internal deletions within the switch mu (S mu) region compared with GCB DLBCL and PMBL. ABC DLBCLs also had frequent deletions within S gamma and other illegitimate switch recombinations. Sequence analysis revealed ongoing S mu deletions within ABC DLBCL tumor clones, which were accompanied by ongoing duplications and activation-induced cytidine deaminase-dependent somatic mutations. Unexpectedly, short fragments derived from multiple chromosomes were interspersed within S mu in one case. These findings suggest that ABC DLBCLs have abnormalities in the regulation of CSR that could predispose to chromosomal translocations. Accordingly, aberrant switch recombination was responsible for translocations in ABC DLBCLs involving BCL6, MYC, and a novel translocation partner, SPIB. C1 NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Lab Pathol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Div Canc Treatment & Diag, NIH, Bethesda, MD 20892 USA. Univ Hosp Schleswig Holstein, Inst Human Genet, D-24105 Kiel, Germany. Univ Nebraska, Med Ctr, Dept Pathol, Omaha, NE 68198 USA. Univ Nebraska, Med Ctr, Dept Microbiol, Omaha, NE 68198 USA. Univ Wurzburg, Dept Pathol, D-97070 Wurzburg, Germany. British Columbia Canc Agcy, Vancouver, BC V5Z 4E6, Canada. Univ Barcelona, Hosp Clin Barcelona, E-08007 Barcelona, Spain. Natl Hosp Norway, Radiumhosp Med Ctr, Dept Immunol, N-0805 Oslo, Norway. SW Oncol Grp, San Antonio, TX 78245 USA. Univ Rochester, Sch Med, James P Wilmot Canc Ctr, Rochester, NY 14627 USA. RP Staudt, LM (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov RI Siebert, Reiner/A-8049-2010; Lenz, Georg/I-6844-2012; OI Campo, elias/0000-0001-9850-9793 FU NCI NIH HHS [U01 CA084967, U01 CA114778-01, U01-CA84967] NR 51 TC 103 Z9 106 U1 0 U2 2 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD MAR 19 PY 2007 VL 204 IS 3 BP 633 EP 643 DI 10.1084/jem.20062041 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 150IX UT WOS:000245210800023 PM 17353367 ER PT J AU Mylius, V Reis, J Knaack, A Haag, A Oertel, WH Rosenow, F Schepelmann, K AF Mylius, Veit Reis, Janine Knaack, Anne Haag, Anja Oertel, Wolfgang H. Rosenow, Felix Schepelmann, Karsten TI High-frequency rTMS of the motor cortex does not influence the nociceptive flexion reflex but increases the unpleasantness of electrically induced pain SO NEUROSCIENCE LETTERS LA English DT Article DE rTMS; NFR; nociception; pain processing; motor cortex; pain unpleasantness ID TRANSCRANIAL MAGNETIC STIMULATION; MEDIAL FRONTAL-CORTEX; CORTICOSPINAL EXCITABILITY; NEUROPATHIC PAIN; PERCEPTION; THRESHOLDS; RELIEF; REPRESENTATION; MODULATION; HEADACHE AB The aim of this study was to investigate whether a 10-Hz repetitive transcranial magnetic stimulation (rTMS) applied over the motor cortex, using a stimulus paradigm employed for pain control in chronic pain, affects acute electrically induced pain. We investigated whether rTMS modulates the nociceptive flexion reflex (NFR) in addition to subjective pain perception. Pain threshold, NFR threshold, supra-threshold NFR response, and the concomitant pain intensity and pain unpleasantness visual analogue scale (VAS) scores were compared before and after 20 min of rTMS. Effects of 20 trains of 5 s' duration (55 s intertrain interval) of 10-Hz rTMS al 80% of the resting motor threshold (RMT) applied over the dominant motor cortex were compared to sham rTMS in 12 healthy volunteers. Supra-threshold NFR stimulation significantly increased pain unpleasantness VAS scores with real rTMS compared to sham rTMS (F-(1,F-10) =6.91; P=0.025). There was no significant effect of 10-Hz rTMS on the subjective pain threshold or on the NFR, neither at threshold nor at supra-threshold noxious stimulation. The rTMS paradigm used to control chronic pain is not suitable for controlling A8 fiber-mediated acute experimentally induced pain since the effects on pain perception were only marginal, with an increase in the VAS unpleasantness scores but with no effect on the NFR. The increased activity of cortico-thalamic projections might modulate the perception of A8 fiber-mediated pain within the lateral pain pathway. The type of fiber that is stimulated and neuroplastic changes in chronic pain and are thought to be critical for rTMS to have an effect. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 Univ Marburg, Dept Neurol, D-35033 Marburg, Germany. NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Mylius, V (reprint author), Univ Marburg, Dept Neurol, Rudolf Bultmann Str 8, D-35033 Marburg, Germany. EM mylius@med.uni-marburg.de NR 35 TC 16 Z9 16 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAR 19 PY 2007 VL 415 IS 1 BP 49 EP 54 DI 10.1016/j.neulet.2006.12.042 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 153ZV UT WOS:000245477500010 PM 17258394 ER PT J AU Xiromerisiou, G Hadjigeorgiou, GM Eerola, J Fernandez, HH Tsimourtou, V Mandel, R Hellstrom, O Gwinn-Hardy, K Okun, MS Tienari, PJ Singleton, AB AF Xiromerisiou, G. Hadjigeorgiou, G. M. Eerola, J. Fernandez, H. H. Tsimourtou, V. Mandel, R. Hellstrom, O. Gwinn-Hardy, K. Okun, M. S. Tienari, P. J. Singleton, A. B. TI BDNF tagging polymorphisms and haplotype analysis in sporadic Parkinson's disease in diverse ethnic groups SO NEUROSCIENCE LETTERS LA English DT Article DE BDNF; Parkinson's disease; association study; haplotype analysis ID NEUROTROPHIC FACTOR GENE; ALZHEIMERS-DISEASE; LINKAGE-DISEQUILIBRIUM; VAL66MET POLYMORPHISM; SUBSTANTIA-NIGRA; HUMAN BRAIN; ASSOCIATION; NEURONS AB Experimental and clinical data suggest that genetic variations in brain-derived neurotrophic factor (BDNF) gene may affect risk for Parkinson's disease (PD). We performed a case-control association analysis of BDNF in three independent Caucasian cohorts (Greek, North American, and Finnish) of PD using eight tagging SNPs and five constructed haplotypes. No statistically significant differences in genotype and allele frequencies were found between cases and controls in all series. A relatively rare BDNF haplotype showed a trend towards association in the Greek (p=0.02) and the Finnish (p=0.03) series (this haplotype was not detected in the North American series). However, given the large number of comparisons these associations are considered non-significant. In conclusion, our results do not provide statistically significant evidence that common genetic variability in BDNF would associate with the risk for PD in the Caucasian populations studied here. (c) 2007 Elsevier Ireland Ltd. All rights reserved. C1 Univ Thessaly, Sch Med, Dept Neurol, Neurogenet Unit, Larisa 41222, Greece. NIA, Mol Genet Unit, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Univ Helsinki, Cent Hosp, Dept Neurol, Helsinki, Finland. Univ Helsinki, Biomedicum, Neurosci Programme, Helsinki, Finland. Univ Florida, Movement Disorders Ctr, Dept Neurol, Gainesville, FL 32610 USA. Univ Florida, Movement Disorders Ctr, Dept Neurosurg, Gainesville, FL 32610 USA. Univ Florida, Movement Disorders Ctr, Dept Neurosci, Gainesville, FL 32610 USA. Seinajoki Cent Hosp, Dept Neurol, Seinajoki, Finland. NINDS, Neurogenet Unit, NIH, Bethesda, MD 20892 USA. RP Hadjigeorgiou, GM (reprint author), Univ Thessaly, Sch Med, Dept Neurol, Neurogenet Unit, Papakyriazi 22 St, Larisa 41222, Greece. EM gmhadji@med.uth.gr RI Gwinn, Katrina/C-2508-2009; Tienari, Pentti/A-4893-2012; Singleton, Andrew/C-3010-2009; OI Okun, Michael/0000-0002-6247-9358; Gwinn, Katrina/0000-0002-8277-651X NR 30 TC 17 Z9 21 U1 2 U2 4 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD MAR 19 PY 2007 VL 415 IS 1 BP 59 EP 63 DI 10.1016/j.neulet.2006.12.038 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 153ZV UT WOS:000245477500012 PM 17229524 ER PT J AU Shiva, S Huang, Z Grubina, R Sun, JH Ringwood, LA MacArthur, PH Xu, XL Murphy, E Darley-Usmar, VM Gladwin, MT AF Shiva, Sruti Huang, Zhi Grubina, Rozalina Sun, Junhui Ringwood, Lorna A. MacArthur, Peter H. Xu, Xiuli Murphy, Elizabeth Darley-Usmar, Victor M. Gladwin, Mark T. TI Deoxymyoglobin is a nitrite reductase that generates nitric oxide and regulates mitochondrial respiration SO CIRCULATION RESEARCH LA English DT Article DE nitrite; myoglobin; mitochondria ID CYTOCHROME-C-OXIDASE; NO-CENTER-DOT; MYOGLOBIN DESATURATION; ISCHEMIA-REPERFUSION; HYPOXIC CONDITIONS; DEOXYHEMOGLOBIN; OXYGEN; INHIBITION; HEMOGLOBIN; MECHANISM AB Previous studies have revealed a novel interaction between deoxyhemoglobin and nitrite to generate nitric oxide ( NO) in blood. It has been proposed that nitrite acts as an endocrine reservoir of NO and contributes to hypoxic vasodilation and signaling. Here, we characterize the nitrite reductase activity of deoxymyoglobin, which reduces nitrite approximately 36 times faster than deoxyhemoglobin because of its lower heme redox potential. We hypothesize that physiologically this reaction releases NO in proximity to mitochondria and regulates respiration through cytochrome c oxidase. Spectrophotometric and chemiluminescent measurements show that the deoxymyoglobin-nitrite reaction produces NO in a second order reaction that is dependent on deoxymyoglobin, nitrite and proton concentration, with a bimolecular rate constant of 12.4 mol/L(-1)s(-1) (pH 7.4, 37 degrees C). Because the IC50 for NO-dependent inhibition of mitochondrial respiration is approximately 100 nmol/L at physiological oxygen tensions (5 to 10 mu mol/L); we tested whether the myoglobin-dependent reduction of nitrite could inhibit respiration. Indeed, the addition of deoxymyoglobin and nitrite to isolated rat heart and liver mitochondria resulted in the inhibition of respiration, while myoglobin or nitrite alone had no effect. The addition of nitrite to rat heart homogenate containing both myoglobin and mitochondria resulted in NO generation and inhibition of respiration; these effects were blocked by myoglobin oxidation with ferricyanide but not by the xanthine oxidoreductase inhibitor allopurinol. These data expand on the paradigm that heme-globins conserve and generate NO via nitrite reduction along physiological oxygen gradients, and further demonstrate that NO generation from nitrite reduction can escape heme autocapture to regulate NO-dependent signaling. C1 NIH, Vasc Med Branch, NHLBI, Bethesda, MD 20892 USA. NIH, CCMD, Ctr Clin, Bethesda, MD 20892 USA. Univ Alabama, Ctr Free Radical Biol, Dept Cellular & Mol Pathol, Birmingham, AL USA. RP Gladwin, MT (reprint author), NIH, Vasc Med Branch, NHLBI, Bldg 10-CRC,Room 5-5410, Bethesda, MD 20892 USA. EM mgladwin@nih.gov RI Darley-Usmar, Victor/F-7656-2010 FU NHLBI NIH HHS [HL58031] NR 41 TC 329 Z9 337 U1 5 U2 47 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 MAR 16 PY 2007 VL 100 IS 5 BP 654 EP 661 DI 10.1161/01.RES.0000260171.52224.6b PG 8 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 146RX UT WOS:000244953500008 PM 17293481 ER PT J AU Isenberg, JS Romeo, MJ Abu-Asab, M Tsokos, M Oldenborg, A Pappan, L Wink, DA Frazier, WA Roberts, DD AF Isenberg, Jeff S. Romeo, Martin J. Abu-Asab, Mones Tsokos, Maria Oldenborg, Anna Pappan, Loretta Wink, David A. Frazier, William A. Roberts, David D. TI Increasing survival of ischemic tissue by targeting CD47 SO CIRCULATION RESEARCH LA English DT Article DE nitric oxide; thrombospondin-1; ischemic tissue survival; CD47; therapeutics ID VASCULAR SMOOTH-MUSCLE; INTEGRIN-ASSOCIATED PROTEIN; NITRIC-OXIDE; CELL RESPONSES; LIMB ISCHEMIA; BLOOD-FLOW; THROMBOSPONDIN-1; ANGIOGENESIS; PROLIFERATION; INHIBITION AB Thrombospondin-1 (TSP1) limits the angiogenic and vasodilator activities of NO. This activity of TSP1 can be beneficial in some disease states, but endogenous TSP1 limits recovery of tissue perfusion following fixed ischemic injury in dorsal skin flaps in mice. Using mice lacking the TSP1 receptors CD36 or CD47, we now show that CD47 is the necessary receptor for limiting NO-mediated vascular smooth muscle relaxation and tissue survival following ischemic injury in skin flaps and hindlimbs. We further show that blocking CD47 or TSP1 using monoclonal antibodies and decreasing CD47 expression using an antisense morpholino oligonucleotide are effective therapeutic approaches to dramatically increase survival of soft tissue subjected to fixed ischemia. These treatments facilitate rapid vascular remodeling to restore tissue perfusion and increase skin and muscle viability. Thus, limiting CD47-dependent antagonism of NO-mediated vasodilation and vascular remodeling is a promising therapeutic modality to preserve tissues subject to ischemic stress. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. RP Isenberg, JS (reprint author), NCI, Pathol Lab, NIH, Bldg 10,2A33, Bethesda, MD 20892 USA. EM isenberj@mail.nih.gov RI Roberts, David/A-9699-2008; OI Roberts, David/0000-0002-2481-2981; Abu-Asab, Mones/0000-0002-4047-1232 FU Intramural NIH HHS; NHLBI NIH HHS [HL54390]; NIGMS NIH HHS [GM57573] NR 40 TC 71 Z9 73 U1 1 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD MAR 16 PY 2007 VL 100 IS 5 BP 712 EP 720 DI 10.1161/01.RES.0000259579.35787.4e PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 146RX UT WOS:000244953500015 PM 17293482 ER PT J AU Goldstein, RZ Tomasi, D Alia-Klein, N Cottone, LA Zhang, L Telang, F Volkow, ND AF Goldstein, Rita Z. Tomasi, Dardo Alia-Klein, Nelly Cottone, Lisa A. Zhang, Lei Telang, Frank Volkow, Nora D. TI Subjective sensitivity to monetary gradients is associated with frontolimbic activation to reward in cocaine abusers SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE crack-cocaine addiction; mesocorticolimbic dopaminergic circuit; fMRI BOLD; monetary incentive salience; reward valence ID HUMAN ORBITOFRONTAL CORTEX; DECISION-MAKING; DRUG-ADDICTION; FRONTAL-CORTEX; BRAIN; INVOLVEMENT; RESPONSES; SUPPRESSION; AMYGDALA; EMOTION AB Drug addiction is characterized by marked disruptions in the ability to process reward. Here we evaluated in cocaine addicted and healthy control participants the subjective sensitivity to reward gradients and its association with neural responses to sustained reward. A self-report questionnaire was used to assess the former. A functional magnetic resonance imaging task that utilized monetary reward as feedback in a blocked design was used to assess the latter. Results revealed that whereas control subjects valued high money more than low money, over half of the cocaine addicted subjects valued all monetary amounts equally. This compromised subjective sensitivity to gradients in reward value was significantly correlated with higher activations to money in the lateral orbitofrontal cortex/inferior frontal gyrus (BA 47) and amygdala, and lower activations in the middle frontal gyrus (BA 6), which together explained 85% of the variability on this rating scale in the cocaine abusers only. These results provide for the first time evidence of restricted subjective sensitivity to gradients of reward in cocaine addiction and of the involvement of frontolimbic brain regions (including the orbitofrontal cortex) in this deficit. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 Brookhaven Natl Lab, Upton, NY 11973 USA. SUNY Stony Brook, Stony Brook, NY 11794 USA. Natl Inst Drug Abuse, Bethesda, MD 20892 USA. RP Goldstein, RZ (reprint author), Brookhaven Natl Lab, POB 5000, Upton, NY 11973 USA. EM rgoldstein@bnl.gov RI Tomasi, Dardo/J-2127-2015 FU NCRR NIH HHS [M01 RR010710, M01 RR010710-070110, M01-RR-10710]; NIAAA NIH HHS [AA/OD09481-04, R01 AA009481-06]; NIDA NIH HHS [K23 DA015517-01, K23 DA015517, K23 DA15517-01, R03 DA 017070-01, R03 DA017070, R03 DA017070-01] NR 47 TC 61 Z9 63 U1 3 U2 9 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 MAR 16 PY 2007 VL 87 IS 2-3 BP 233 EP 240 DI 10.1016/j.drugalcdep.2006.08.022 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 154YO UT WOS:000245544700015 PM 16997508 ER PT J AU Dams, R Choo, RE Lambert, WE Jones, H Huestis, MA AF Dams, Riet Choo, Robin E. Lambert, Willy E. Jones, Hendree Huestis, Marilyn A. TI Oral fluid as an alternative matrix to monitor opiate and cocaine use in substance-abuse treatment patients SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE oral fluid; cocaine; opiates; SAMHSA; recovery; LC-MS ID CHROMATOGRAPHY-MASS-SPECTROMETRY; ILLICIT DRUGS; CODEINE CONCENTRATIONS; BIOLOGICAL-FLUIDS; HUMAN VOLUNTEERS; HUMAN-SALIVA; PLASMA; URINE; METABOLITES; HEROIN AB Interest in oral fluid as an alternative matrix for monitoring drug use is due to its ease-of-collection and non-invasiveness; however, limited data are available on the disposition of drugs into oral fluid. The objective of this research was to provide data on the presence and concentrations of heroin, cocaine and multiple metabolites in oral fluid after illicit opioid and cocaine use. Thrice weekly oral fluid specimens (N=403) from 16 pregnant opiate-dependent women were obtained with the Salivette (R) oral fluid collection device. Evidence of heroin (N=62) and cocaine (N=130) use was detected in oral fluid by LC-APCI-MS/MS. 6-Acetylmorphine (6-AM), heroin and morphine were the major opiates detected, with median concentrations of 5.2, 2.3, and 7.5 mu g/L, respectively. Cocaine and benzoylecgonine (BE) had median concentrations of 6.4 and 3.4 mu g/L. Application of the Substance Abuse Mental Health Services Administration (SAMHSA) recommended cutoffs for morphine and codeine (40 mu g/L), 6-AM (4 mu g/L) and cocaine and BE (8 mu g/L), yielded 28 opiate- and 50 cocaine-positive specimens. Oral fluid is a promising alternative matrix to monitor opiate and cocaine use in drug testing programs. These data guide interpretation of oral fluid test results and evaluate currently proposed SAMHSA oral fluid testing cutoffs. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 NIDA, Chem & Drug Metab, Baltimore, MD 21224 USA. Johns Hopkins Bayview Med Ctr, Ctr Addict & Pregnancy, Baltimore, MD 21224 USA. Univ Ghent, Toxicol Lab, B-9000 Ghent, Belgium. RP Huestis, MA (reprint author), NIDA, Chem & Drug Metab, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mhuestis@intra.nida.nih.gov FU Intramural NIH HHS [Z01 DA000412-10, Z01 DA000433-08]; NIDA NIH HHS [DA12403-02, R01 DA012403] NR 52 TC 38 Z9 40 U1 1 U2 10 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 MAR 16 PY 2007 VL 87 IS 2-3 BP 258 EP 267 DI 10.1016/j.drugalcdep.2006.08.020 PG 10 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 154YO UT WOS:000245544700018 PM 17008030 ER PT J AU Zhao, YG Conze, DB Hanover, JA Ashwell, JD AF Zhao, Yongge Conze, Dietrich B. Hanover, John A. Ashwell, Jonathan D. TI Tumor necrosis factor receptor 2 signaling induces selective c-IAP1-dependent ASK1 ubiquitination and terminates mitogen-activated protein kinase signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NEGATIVE REGULATION; UP-REGULATION; TNF-ALPHA; T-CELLS; IN-VIVO; APOPTOSIS; TRAF2; DEGRADATION; LIGASE; MICE AB TRAF2 and ASK1 play essential roles in tumor necrosis factor alpha (TNF-alpha)-induced mitogen-activated protein kinase signaling. Stimulation through TNF receptor 2 (TNFR2) leads to TRAF2 ubiquitination and subsequent proteasomal degradation. Here we show that TNFR2 signaling also leads to selective ASK1 ubiquitination and degradation in proteasomes. c-IAP1 was identified as the ubiquitin protein ligase for ASK1 ubiquitination, and studies with primary B cells from c-IAP1 knock-out animals revealed that c-IAP1 is required for TNFR2-induced TRAF2 and ASK1 degradation. Moreover, in the absence of c-IAP1 TNFR2-mediated p38 and JNK activation was prolonged. Thus, the ubiquitin protein ligase activity of c-IAP1 is responsible for regulating the duration of TNF signaling in primary cells expressing TNFR2. C1 NCI, Lab Immune Cell Biol, Canc Res Ctr, Bethesda, MD 20892 USA. NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Ashwell, JD (reprint author), NCI, Lab Immune Cell Biol, Canc Res Ctr, Bethesda, MD 20892 USA. EM jda@pop.nci.nih.gov FU Intramural NIH HHS NR 39 TC 54 Z9 58 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 16 PY 2007 VL 282 IS 11 BP 7777 EP 7782 DI 10.1074/jbc.M609146200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148ND UT WOS:000245081000005 PM 17220297 ER PT J AU Mustafa, T Grimaldi, M Eiden, LE AF Mustafa, Tomris Grimaldi, Maurizio Eiden, Lee E. TI The hop cassette of the PAC1 receptor confers coupling to Ca2+ elevation required for pituitary adenylate cyclase-activating polypeptide-evoked neurosecretion SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ADRENAL CHROMAFFIN CELLS; INTRACELLULAR SIGNALING PATHWAYS; SUPERIOR CERVICAL-GANGLION; 4 SPLICE VARIANTS; CATECHOLAMINE SECRETION; CALCIUM-CHANNELS; PAC(1) RECEPTOR; PC12 CELLS; GENE-TRANSCRIPTION; MOLECULAR-CLONING AB We have identified the single PAC1 receptor variant responsible for Ca2+ mobilization from intracellular stores and influx through voltage-gated Ca2+ channels in bovine chromaffin cells and the domain of this receptor variant that confers coupling to [Ca2+](i) elevation. This receptor (bPAC1(hop)) contains a 28-amino acid "hop" insertion in the third intracellular loop, with a full-length 171-amino acid N terminus. Expression of the bPAC1(hop) receptor in NG108-15 cells, which lack endogenous PAC1 receptors, reconstituted high affinity PACAP binding and PACAP-dependent elevation of both cAMP and intracellular Ca2+ concentrations ([Ca2+](i)). Removal of the hop domain and expression of this receptor (bPAC1(null)) in NG108-15 cells reconstituted high affinity PACAP binding and PACAP-dependent cAMP generation but without a corresponding [Ca2+](i) elevation. PC12-G cells express sufficient levels of PAC1 receptors to provide PACAP-saturable coupling to adenylate cyclase and to drive PACAP-dependent differentiation but do not express PAC1 receptors at levels found in postmitotic neuronal and endocrine cells and do not support PACAP-mediated neurosecretion. Expression of bPAC1(hop), but not bPAC1(null), at levels comparable with those of bPAC1(hop) in bovine chromaffin cells resulted in acquisition by PC12-G cells of PACAP-dependent [Ca2+]i increase and extracellular Ca2+ influx. In addition, PC12-G cells expressing bPAC1(hop) acquired the ability to release [3 H]norepinephrine in a Ca2+ influx-dependent manner in response to PACAP. Expression of PACAP receptors in neuroendocrine rather than nonneuroendocrine cells reveals key differences between PAC1(hop) and PAC1(null) coupling, indicating an important and previously unrecognized role of the hop cassette in PAC1-mediated Ca2+ signaling in neuroendocrine cells. C1 NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, Bethesda, MD 20892 USA. So Res Inst, Neuropharmacol Lab, Dept Biochem, Drug Discovery Div, Birmingham, AL 35205 USA. RP Eiden, LE (reprint author), NIMH, Mol Neurosci Sect, Lab Cellular & Mol Regulat, Bldg 49,Rm 5A-68,9000 Rockville Pike, Bethesda, MD 20892 USA. EM eidenl@mail.nih.gov OI Grimaldi, Maurizio/0000-0002-7331-7055; Eiden, Lee/0000-0001-7524-944X FU Intramural NIH HHS [Z01 MH002386-21, Z01 MH002386-22, ZIA MH002386-23] NR 69 TC 26 Z9 26 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 MAR 16 PY 2007 VL 282 IS 11 BP 8079 EP 8091 DI 10.1074/jbc.M609638200 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148ND UT WOS:000245081000040 PM 17213203 ER PT J AU Hebbar, PB Archer, TK AF Hebbar, Pratibha B. Archer, Trevor K. TI Chromatin-dependent cooperativity between site-specific transcription factors in vivo SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID 11-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-2; TUMOR VIRUS PROMOTER; BREAST-CANCER CELLS; GLUCOCORTICOID-RECEPTOR; GENE FAMILY; NUCLEAR RECEPTORS; SWI/SNF COMPLEX; MAMMARY-GLAND; ACTIVATION; EXPRESSION AB Accessing binding sites in DNA wrapped around histories in condensed chromatin is an obstacle that transcription factors must overcome to regulate gene expression. Here we demonstrate cooperativity between two transcription factors, the glucocorticoid receptor (GR) and nuclear factor 1 (NF1) to bind the mouse mammary tumor virus promoter organized as regular chromatin in vivo. This cooperativity is not observed when the promoter is introduced transiently into cells. Using RNA interference to deplete NF1 protein levels in the cells, we confirmed that NF1 promotes binding of GR to the promoter. Furthermore, we observed a similar synergism between GR and NF1 binding on the endogenous 11 beta-hydroxysteroid dehydrogenase promoter, also regulated by GR and NF1. Our results suggest that the chromatin architecture of the promoters does not permit strong association of GR in the absence of NF1. Therefore we propose that cooperativity among DNA binding factors in binding to their cognate recognition sites in chromatin may be an important feature in the regulation of gene expression. C1 Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Archer, TK (reprint author), Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, NIH, 111 Alexander Dr,MD D4-01,POB 12233, Res Triangle Pk, NC 27709 USA. EM archer1@niehs.nih.gov FU Intramural NIH HHS [Z01 ES071006-09, Z99 ES999999] NR 36 TC 39 Z9 40 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 16 PY 2007 VL 282 IS 11 BP 8284 EP 8291 DI 10.1074/jbc.M610554200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148ND UT WOS:000245081000061 PM 17186943 ER PT J AU Kang, KR Kim, YS Wolff, EC Park, MH AF Kang, Kee Ryeon Kim, Yeon Sook Wolff, Edith C. Park, Myung Hee TI Specificity of the deoxyhypusine hydroxylase-eukaryotic translation initiation factor (eIF5A) interaction - Identification of amino acid residues of the enzyme required for binding of its substrate, deoxyhypusine-containing eIF5A SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID YEAST SACCHAROMYCES-CEREVISIAE; HUMAN CANCER-CELLS; FACTOR 5A EIF5A; PROTEIN-SYNTHESIS; POSTTRANSLATIONAL SYNTHESIS; HYPUSINE FORMATION; NUCLEAR EXPORT; MESSENGER-RNA; RAT TESTIS; IN-VIVO AB Deoxyhypusine hydroxylase (DOHH) is a novel metalloenzyme that catalyzes the final step of the post-translational synthesis of hypusine (N-epsilon-(4-amino-2-hydroxybutyl)lysine) in the eukaryotic translation initiation factor 5A (6175A). Hypusine synthesis is unique in that it occurs in only one protein, denoting the strict specificity of the modification enzymes toward the substrate protein. The specificity of the interaction between eIF5A and DOHH was investigated using human eIF5A (eIF5A-1 isoform) and human recombinant DOHH. DOHH displayed a strong preference for binding the deoxyhypusine-containing form of eIF5A, over the eIF5A precursor or the hypusine-containing eIF5A, indicating a role for the deoxyhypusine residue in binding. In addition to the deoxyhypusine residue, a large portion of the eIF5A polypeptide 1(> 20-90 amino acids) is required for effective modification by DOHH. We have identified the amino acid residues of DOHH that are critical for substrate binding by alanine substitution of 36 conserved amino 90 acid residues. Of these, alanilne substitution at Glu(57), Glu(90), GIU(208), GIU(241), Gly(63), or Gly(214) caused a severe impairment in eIF5A(Dhp) binding, with a complete loss of binding and activity in the E57A and E208A mutant enzymes. Only aspartate substitution mutants, E57D or E208D, retained partial activity and substrate binding, whereas alanine, glutamine, or asparagine mutants did not. These findings support a proposed model of DOHH-eIF5A binding in which the amino group(s) of the deoxyhypusine side chain of the substrate is primarily anchored by gamma-carboxyl groups of Glu(57) and Glu(208) at the DOHH active site. C1 NIDCR, OPCB, NIH, Bethesda, MD 20892 USA. RP Park, MH (reprint author), NIDCR, OPCB, NIH, Bldg 30,Rm 211, Bethesda, MD 20892 USA. EM mhpark@nih.gov FU Intramural NIH HHS [Z99 DE999999] NR 55 TC 19 Z9 21 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 MAR 16 PY 2007 VL 282 IS 11 BP 8300 EP 8308 DI 10.1074/jbc.M607495200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148ND UT WOS:000245081000063 PM 17213197 ER PT J AU Xu, D Song, DY Pedersen, LC Liu, J AF Xu, Ding Song, Danyin Pedersen, Lars C. Liu, Jian TI Mutational study of heparan sulfate 2-0-sulfotransferase and chondroitin sulfate 2-0-sulfotransferase SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CRYSTAL-STRUCTURE; DERMATAN SULFATE; ESTROGEN SULFOTRANSFERASE; MOLECULAR-CLONING; CAENORHABDITIS-ELEGANS; STRUCTURAL-ANALYSIS; IN-VIVO; DROSOPHILA; 2-O-SULFOTRANSFERASE; 2-SULFOTRANSFERASE AB Heparan sulfate (HS) and chondroitin sulfate (CS) are highly sulfated polysaccharides with a wide range of biological functions. Heparan sulfate 2-O-sulfotransferase (HS-2OST) transfers the sulfo group from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to the 2-OH position of the hexauronic acid that is adjacent to N-sulfated glucosamine, whereas chondroitin sulfate 2-O-sulfotransferase (CS-2OST) transfers the sulfo group to the hexauronic acid that is adjacent to N-acetylated galactosamine. Here we report a systematic mutagenesis study of HS-2OST and CS-2OST based on their structural homology to estrogen sulfotransferase and HS 3-O-sulfotransferase isoform 3 (3-OST3), for which crystal structures exist. We have identified six residues possibly involved in binding to PAPS. HS-2OST carrying mutations of these residues lacks sulfotransferase activity and the ability to bind 3'-phosphoadenosine 5'-phosphate, a PAPS analogue, as determined by isothermal titration calorimetry. Similar residues involved in binding to PAPS were also identified in CS-20ST. Additional residues that participate in carbohydrate substrate binding were also identified in both enzymes. Mutations at these residues led to the loss of sulfotransferase activity but maintained the ability to bind to phosphoadenosine 5'-phosphate. The catalytic function of HS-2OST appears to involve two histidine residues (His(140) and His(142)), whereas only one histidine (His(168)) of CS 2-OST is likely to be critical. This unique feature of HS 2-OST catalytic residues directed us to characterize the Drosophila heparan sulfate 2-O-sulfotransferase. The results from this study provide insight into the differences and similarities various residues play in the biological roles of the HS-2OST and CS-20ST enzymes. C1 Univ N Carolina, Div Med Chem & Nat Prod, Sch Pharm, Chapel Hill, NC 27599 USA. NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Liu, J (reprint author), Univ N Carolina, Div Med Chem & Nat Prod, Sch Pharm, Rm 309,Beard Hall, Chapel Hill, NC 27599 USA. EM jian_liu@unc.edu RI Xu, Ding/B-2493-2009 OI Xu, Ding/0000-0001-9380-2712 FU Intramural NIH HHS; NIAID NIH HHS [AI50050] NR 43 TC 16 Z9 16 U1 2 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 16 PY 2007 VL 282 IS 11 BP 8356 EP 8367 DI 10.1074/jbc.M608062200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148ND UT WOS:000245081000069 PM 17227754 ER PT J AU Casanovas, J Zanuy, D Nussinov, R Aleman, C AF Casanovas, Jordi Zanuy, David Nussinov, Ruth Aleman, Carlos TI Intrinsic conformational characteristics of alpha,alpha-diphenylglycine SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID CONSTRAINED AMINO-ACIDS; LOW-ENERGY CONFORMERS; CYCLOPROPANE ANALOG; MOLECULAR-DYNAMICS; PREFERRED CONFORMATION; SYSTEMATIC EVALUATION; FORCE-FIELD; PHENYLALANINE; PREFERENCES; PEPTIDES AB Quantum mechanical calculations at the B3LYP/6-31+ G(d, p) level have been used to investigate the intrinsic conformational preferences of alpha,alpha-diphenylglycine, a simple alpha,alpha-dialkylated amino acid bearing two phenyl substituents on the alpha-carbon, in both the gas phase and aqueous solution. Nine minimum energy conformations have been characterized for the N-acetyl-N'-methylamide derivative within a relative energy range of about 9 kcal/mol. The relative stability of these structures is largely influenced by specific backbone center dot center dot center dot side chain and side chain center dot center dot center dot side chain interactions that can be attractive (N-H center dot center dot center dot pi and C-H center dot center dot center dot center dot pi) or repulsive (C=O center dot center dot center dot pi). On the other hand, comparison with the minimum energy conformations calculated for alpha-aminoisobutyric acid, in which the two phenyl substituents are replaced by methyl groups, revealed that the bulky aromatic rings of alpha,alpha-diphenylglycine induce strain in the internal geometry of the peptide. Finally, a set of force-field parameters for classical Molecular Mechanics calculations was developed for the investigated amino acid. Molecular Dynamics simulations in aqueous solutions have been carried out to validate the parameters obtained. C1 Univ Lleida, Dept Quim, Escola Politecn Super, E-25001 Lleida, Spain. Univ Politecn Cataluna, Dept Engn Quim, ETS Engn Ind Barcelona, E-08028 Barcelona, Spain. NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol Program, Frederick, MD 21701 USA. Tel Aviv Univ, Dept Human Genet Sackler, Sch Med, IL-69978 Tel Aviv, Israel. RP Casanovas, J (reprint author), Univ Lleida, Dept Quim, Escola Politecn Super, C Jaume 2 69, E-25001 Lleida, Spain. EM jcasanovas@quimica.udl.es; carlos.aleman@upc.edu RI Casanovas, Jordi/B-5435-2013; Zanuy, David/G-3930-2014 OI Casanovas, Jordi/0000-0002-4914-9194; Zanuy, David/0000-0001-7704-2178 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 53 TC 18 Z9 18 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-3263 J9 J ORG CHEM JI J. Org. Chem. PD MAR 16 PY 2007 VL 72 IS 6 BP 2174 EP 2181 DI 10.1021/jo0624905 PG 8 WC Chemistry, Organic SC Chemistry GA 144CS UT WOS:000244773600034 PM 17291048 ER PT J AU Carrasco, MA Castro, P Sepulveda, FJ Tapia, JC Gatica, K Davis, MI Aguayo, LG AF Carrasco, M. A. Castro, P. Sepulveda, F. J. Tapia, J. C. Gatica, K. Davis, M. I. Aguayo, L. G. TI Regulation of glycinergic and GABAergic synaptogenesis by brain-derived neurotrophic factor in developing spinal neurons SO NEUROSCIENCE LA English DT Article DE neurotrophin; strychnine; spinal neurons; BDNF; synantogenesis; glycine receptor ID LONG-TERM POTENTIATION; CULTURED HIPPOCAMPAL-NEURONS; CEREBELLAR GRANULE NEURONS; RAT VISUAL-CORTEX; SYNAPTIC-TRANSMISSION; INHIBITORY SYNAPSES; NERVOUS-SYSTEM; TRK RECEPTORS; FACTOR BDNF; CORD AB Brain-derived neurotrophic factor (BDNF) effects on the establishment of glycinergic and GABAergic transmissions in mouse spinal neurons were examined using combined electrophysiological and calcium imaging techniques. BDNF (10 ng/ml) caused a significant acceleration in the onset of synaptogenesis without large effects on the survival of these neurons. Amplitude and frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) associated to activation of glycine and GAGA receptors were augmented in neurons cultured with BDNF. The neurotrophin effect was blocked by long term tetrodotoxin (TTX) addition suggesting a dependence on neuronal activity. In addition, BDNF caused a significant increase in glycine- and GABA-evoked current densities that partly explains the increase in synaptic transmission. Presynaptic mechanisms were also involved in BDNF effects since triethylammonium(propyl)-4-(2-(4-dibutylamino-phenyl)vinyl)pyridinium (FM1-43) destaining with high K+ was augmented in neurons incubated with the neurotrophin. The effects of BDNF were mediated by receptor tyrosine kinase B (TrkB) and mitogen-activated protein kinase kinase (MEK) activation since culturing neurons with either (9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:3',2',1'-k1] pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester (K252a) or 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one (PD98059) blocked the augmentation in synaptic activity induced by the neurotrophin. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved. C1 Univ Concepcion, Dept Physiol, Lab Neurophysiol, Concepcion, Chile. NIAAA, Lab Integrat Neurosci, NIH, Bethesda, MD 20892 USA. Harvard Univ, Mol & Cellular Dept, Cambridge, MA 02138 USA. RP Aguayo, LG (reprint author), Univ Concepcion, Dept Physiol, Lab Neurophysiol, POB 160-C, Concepcion, Chile. EM laguayo@udec.cl RI Davis, Margaret/F-4165-2010; OI Davis, Margaret/0000-0002-0489-8351 FU NIAAA NIH HHS [AA15150] NR 54 TC 18 Z9 19 U1 2 U2 3 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 MAR 16 PY 2007 VL 145 IS 2 BP 484 EP 494 DI 10.1016/j.neuroscience.2006.12.019 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 148AB UT WOS:000245045800009 PM 17306467 ER PT J AU Triboulet, R Mari, B Lin, YL Chable-Bessia, C Bennasser, Y Lebrigand, K Cardinaud, B Maurin, T Barbry, P Baillat, V Reynes, J Corbeau, P Jeang, KT Benkirane, M AF Triboulet, Robinson Mari, Bernard Lin, Yea-Lih Chable-Bessia, Christine Bennasser, Yamina Lebrigand, Kevin Cardinaud, Bruno Maurin, Thomas Barbry, Pascal Baillat, Vincent Reynes, Jacques Corbeau, Pierre Jeang, Kuan-Teh Benkirane, Monsef TI Suppression of microRNA-silencing pathway by HIV-1 during virus replication SO SCIENCE LA English DT Article ID VIRAL-INFECTIONS; LATENCY; TAT; EXPRESSION; CLUSTER; SIRNA; GENE AB MicroRNAs ( miRNAs) are single-stranded noncoding RNAs of 19 to 25 nucleotides that function as gene regulators and as a host cell defense against both RNA and DNA viruses. We provide evidence for a physiological role of the miRNA-silencing machinery in controlling HIV-1 replication. Type III RNAses Dicer and Drosha, responsible for miRNA processing, inhibited virus replication both in peripheral blood mononuclear cells from HIV-1-infected donors and in latently infected cells. In turn, HIV-1 actively suppressed the expression of the polycistronic miRNA cluster miR-17/92. This suppression was found to be required for efficient viral replication and was dependent on the histone acetyltransferase Tat cofactor PCAF. Our results highlight the involvement of the miRNA-silencing pathway in HIV-1 replication and latency. C1 Inst Genet Humaine, Mol Virol Lab, Montpellier, France. Inst Genet Humaine, Lab Lentivirus & Transfert Genes, Montpellier, France. UNSA, CNRS, UMR 6097, Inst Pharmacol Mol & Cellulaire, Sophia Antipolis, France. Hop Gui de Chauliac, Serv Malad Infect & Trop, Montpellier, France. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Benkirane, M (reprint author), Inst Genet Humaine, Mol Virol Lab, Montpellier, France. EM bmonsef@igh.cnrs.fr RI Jeang, Kuan-Teh/A-2424-2008; Mari, Bernard/F-8960-2013; Mari, Bernard/D-7445-2015; Barbry, Pascal/O-5021-2016; Maurin, thomas/O-7494-2016 OI Mari, Bernard/0000-0002-0422-9182; Barbry, Pascal/0000-0001-9632-6483; NR 22 TC 388 Z9 430 U1 3 U2 27 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD MAR 16 PY 2007 VL 315 IS 5818 BP 1579 EP 1582 DI 10.1126/science.1136319 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146LB UT WOS:000244934800054 PM 17322031 ER PT J AU Chiu, BCH Dave, BJ Blair, A Gapstur, SM Chmiel, JS Fought, AJ Zahm, SH Weisenburger, DD AF Chiu, Brian C. -H. Dave, Bhavana J. Blair, Aaron Gapstur, Susan M. Chmiel, Joan S. Fought, Angela J. Zahm, Shelia Hoar Weisenburger, Dennis D. TI Cigarette smoking, familial hematopoietic cancer, hair dye use, and risk of t(14;18)-defined subtypes of non-Hodgkin's lymphoma SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE chromosome aberrations; hair dyes; hematologic neoplasms; lymphoma, non-Hodgkin; risk factors; smoking ID AGRICULTURAL PESTICIDE USE; MOLECULAR PATHOGENESIS; FOLLICULAR LYMPHOMA; UNITED-STATES; LEUKEMIA; EPIDEMIOLOGY; WOMEN AB Some evidence suggests that smoking, a family history of hematopoietic cancer, and use of hair dyes are associated with t(14;18)-defined subsets of non-Hodgkin's lymphoma (NHL) in men. To further evaluate these associations and to expand them to women, the authors determined t(14;18)(q32;q21) status by fluorescence in situ hybridization in 172 of 175 tumor blocks from a population-based case-control study conducted in Nebraska during 1983-1986. Exposures in 65 t(14;18)-positive cases and 107 t(14;18)-negative cases were compared with those among 1,432 controls. Odds ratios and 95% confidence intervals were calculated using polytomous logistic regression. Among men, smoking was not associated with risk of t(14;18)-positive or -negative NHL. Among women who had ever smoked cigarettes, there was an association with risk of t(14;18)-negative NHL (odds ratio (OR) = 1.9, 95% confidence interval (CI): 1.1, 3.3) but not t(14;18)-positive NHL (p-difference = 0.01). The risks for t(14;18)-negative NHL among women increased with longer duration (> 30 years: OR = 2.1, 95% CI: 1.1, 4.1) and early initiation (age <= 20 years: OR = 2.2, 95% CI: 1.1, 4.4) of smoking. A family history of hematopoietic cancer was associated with a twofold higher risk for both t(14;18)-defined NHL subtypes among men and women. Hair dye use was not associated with either subtype. These findings should be interpreted cautiously because of the small sample. C1 Northwestern Univ, Sch Med, Dept Prevent Med, Chicago, IL 60611 USA. Northwestern Univ, Med Ctr, Munroe Meyer Inst Genet & Rehabil, Chicago, IL 60611 USA. Northwestern Univ, Med Ctr, Dept Pathol & Microbiol, Chicago, IL 60611 USA. Northwestern Univ, Robert H Lurie Comprehens Canc Ctr, Chicago, IL 60611 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Chiu, BCH (reprint author), Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, 680 N Lake Shore Dr,Suite 1102, Chicago, IL 60611 USA. EM bchiu@northwestern.edu RI Zahm, Shelia/B-5025-2015 FU Intramural NIH HHS; NCI NIH HHS [CA 94770] NR 31 TC 16 Z9 16 U1 0 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD MAR 15 PY 2007 VL 165 IS 6 BP 652 EP 659 DI 10.1093/aje/kwk044 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 142MY UT WOS:000244655200007 PM 17204518 ER PT J AU Mochizuki, M Philp, D Hozumi, K Suzuki, N Yamada, Y Kleinman, HK Nomizu, M AF Mochizuki, Mayumi Philp, Deborah Hozumi, Kentaro Suzuki, Nobuharu Yamada, Yoshihiko Kleinman, Hynda K. Nomizu, Motoyoshi TI Angiogenic activitiy of syndecan-binding laminin peptide AG73 (RKRLQVQLSIRT) SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE angiogenesis; laminin; synthetic peptides; syndecan; cell adhesion ID HEPARAN-SULFATE PROTEOGLYCANS; ENDOTHELIAL-CELL-GROWTH; TUMOR-GROWTH; IN-VIVO; SYNTHETIC PEPTIDES; ALPHA-1 CHAIN; G-DOMAIN; GLOBULAR DOMAIN; OVARIAN-CANCER; METASTASIS AB The AG73 peptide (RKRLQVQLSIRT, mouse laminin alpha 1 chain 2719-2730) promotes cell adhesion and tumor metastasis, and interacts with transmembrane syndecan proteoglycans. Here, we demonstrate AG73 peptide angiogenic activity using in vitro, ex vivo, and in vivo models. AG73 induced murine endothelial cell (SVEC4-10) tube formation on Cultrex Basement Membrane Extract (Cultrex BME) and stimulated sprouting of aortic rings. None of the homologous sequences from the laminin alpha 2, alpha 3, alpha 4, or alpha 5 chains was as active as AG73 in promoting sprouting formation. AG73 also mediated angiogenesis in the chick chorioallantonic membrane (CAM) assay. Using subcutaneously injected Cultrex BME supplemented with AG73, we observed a large angiogenic response. Furthermore, AG73-conjugated to a chitosan membrane promoted a strong angiogenic response in the CAM assay. These results indicate that the AG73 peptide is a potent syndecan-binding angiogenesis stimulator and may be useful for therapeutic application to treat ischemic injuries. (c) 2007 Elsevier Inc. All rights reserved. C1 Tokyo Univ Pharm & Life Sci, Tokyo 1920392, Japan. Hokkaido Univ, Grad Sch Environm Earth Sci, Sapporo, Hokkaido 0600810, Japan. Natl Inst Dental & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Nomizu, M (reprint author), Tokyo Univ Pharm & Life Sci, 1432-1 Horinouchi, Tokyo 1920392, Japan. EM nomizu@ps.toyaku.ac.jp NR 63 TC 28 Z9 28 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD MAR 15 PY 2007 VL 459 IS 2 BP 249 EP 255 DI 10.1016/j.abb.2006.12.026 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 149YS UT WOS:000245183400012 PM 17286955 ER PT J AU Luo, RB Ahvazi, B Amariei, D Shroder, D Burrola, B Losert, W Randazzo, PA AF Luo, Ruibai Ahvazi, Bijan Amariei, Diana Shroder, Deborah Burrola, Beatriz Losert, Wolfgang Randazzo, Paul A. TI Kinetic analysis of GTP hydrolysis catalysed by the Arf1-GTP-ASAP1 complex SO BIOCHEMICAL JOURNAL LA English DT Article DE Arf GAP with SH3; ankyrin repeats and PH domains 1 (ASAP1); ADP-ribosylation factor (Arf); GTPase-activating protein (GAP); GTP-binding protein; GTP hydrolysis; kinetics ID ACTIVATING PROTEIN ASAP1; TRANSITION-STATE ANALOG; ARF GAPS AGAP1; ALUMINUM FLUORIDE; N-TERMINUS; COATOMER; DOMAIN; PHOSPHOLIPIDS; CYTOSKELETON; INTERFACE AB Arf (ADP-ribosylation factor) GAPs (GTPase-activating proteins) are enzymes that catalyse the hydrolysis of GTP bound to the small GTP-binding protein Arf. They have also been proposed to function as Arf effectors and oncogenes. We have set out to characterize the kinetics of the GAP-induced GTP hydrolysis using a truncated form of ASAPI [Arf GAP with SH3 (Src homology 3) domain, ankyrin repeats and PH (pleckstrin homology) domains 1] as a model. We found that ASAPI used Arfl-GTP as a substrate with a k(cat) of 57 +/- 5 s(-1) and a K-m of 2.2 +/- 0.5 mu M determined by steady-state kinetics and a k(cat) of 56 +/- 7 s(-1) determined by single-turnover kinetics. Tetrafluoroaluminate (AIF(4)(-)), which stabilizes complexes of other Ras family members with their cognate GAPs, also stabilized a complex of Arfl-GDP with ASAP I. As anticipated, mutation of Arg-497 to a lysine residue affected k(cat) to a much greater extent than K-m. Changing Trp-479, Iso-490, Arg-505, Leu-511 or Asp-512 was predicted, based on previous studies, to affect affinity for Arfl-GTP. Instead, these mutations primarily affected the k(cat). Mutants that lacked activity in vitro similarly lacked activity in an in vivo assay of ASAPI function, the inhibition of dorsal ruffle fort-nation. Our results support the conclusion that the Arf GAP ASAP I functions in binary complex with Arfl-GTP to induce a transition state towards GTP hydrolysis. The results have led us to speculate that Arfl-GTP-ASAPI undergoes a significant confonnational change when transitioning from the ground to catalytically active state. The ramifications for the putative effector function of ASAP1 are discussed. C1 NCI, Lab Cellular Oncol, Ctr Canc Res, Bethesda, MD 20892 USA. NIAMSD, Bethesda, MD 20892 USA. Univ Maryland, Dept Phys, College Pk, MD 20742 USA. Univ Maryland, IPST, College Pk, MD 20742 USA. RP Randazzo, PA (reprint author), NCI, Lab Cellular Oncol, Ctr Canc Res, Bethesda, MD 20892 USA. EM randazzo@helix.nih.gov FU Intramural NIH HHS NR 45 TC 28 Z9 28 U1 1 U2 6 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD MAR 15 PY 2007 VL 402 BP 439 EP 447 DI 10.1042/BJ20061217 PN 3 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 146NO UT WOS:000244941400004 PM 17112341 ER PT J AU Park, MJ Kong, HJ Kim, HY Kim, HH Kim, JH Cheong, JH AF Park, Min Jung Kong, Hee Jeong Kim, Hye Young Kim, Hyeong Hoe Kim, Joon Hong Cheong, Jae Hun TI Transcriptional repression of the gluconeogenic gene PEPCK by the orphan nuclear receptor SHP through inhibitory interaction with C/EBP alpha SO BIOCHEMICAL JOURNAL LA English DT Article DE CCAAT/enhancer-binding protein alpha (C/EBP alpha); phosphoenolpyruvate carboxykinase (PEPCK); protein-protein interactions; short heterodimer partner (SHP); transcriptional repression ID PHOSPHOENOLPYRUVATE CARBOXYKINASE GENE; RAT-LIVER; GLUCOCORTICOID RESPONSE; TRANSGENIC MICE; GTP GENE; EXPRESSION; PROTEINS; PROMOTER; BETA; ISOFORMS AB SHP (short heterodimer partner) is an orphan nuclear receptor that plays an important role in regulating glucose and lipid metabolism. A variety of transcription factors are known to regulate transcription of the PEPCK (phosphoenolpyruvate carboxykinase) gene, which encodes a rate-determining enzyme in hepatic gluconeogenesis. Previous reports identified glucocorticoid receptor and Foxo1 as novel downstream targets regulating SHP inhibition [Borgius, Steffensen, Gustafsson and Treuter (2002) J. Biol. Chem. 277, 49761-49796; Yamagata, Daitokul, Shimamoto, Matsuzaki, Hirota, Ishida and Fukamizu (2004) J. Biol. Chem. 279, 23158-231651. In the present paper, we show a new molecular mechanism of SHP-mediated inhibition of PEPCK transcription. We also show that the CRE1 (cAMp regulatory element 1;-99 to -76 bp relative to the transcription start site) of the PEPCK promoter is also required for the inhibitory regulation by SHP. SHP repressed C/EBP alpha (CCAAT/enhancer-binding protein alpha)-driven transcription of PEPCK through direct interaction with C/EBP alpha protein both in vitro and in vivo. The formation of an active transcriptional complex of C/EBP alpha and its binding to DNA was inhibited by SHP, resulting in the inhibition of PEPCK gene transcription. Taken together, these results suggest that SHP might regulate a level of hepatic gluconeogenesis driven by C/EBP alpha activation. C1 Pusan Natl Univ, Dept Biol Mol, Pusan 609735, South Korea. NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Cheong, JH (reprint author), Pusan Natl Univ, Dept Biol Mol, Pusan 609735, South Korea. EM molecule85@pusan.ac.kr NR 30 TC 21 Z9 21 U1 0 U2 1 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD MAR 15 PY 2007 VL 402 BP 567 EP 574 DI 10.1042/BJ20061549 PN 3 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 146NO UT WOS:000244941400016 PM 17094771 ER PT J AU Luna, A Nicodemus, KK AF Luna, Augustin Nicodemus, Kristin K. TI snp.plotter: an R-based SNP/haplotype association and linkage disequilibrium plotting package SO BIOINFORMATICS LA English DT Article AB snp.plotter is a newly developed R package which produces high-quality plots of results from genetic association studies. The main features of the package include options to display a linkage disequilibrium (LD) plot below the P-value plot using either the r(2) or D' LD metric, to set the X-axis to equal spacing or to use the physical map of markers, and to specify plot labels, colors, symbols and LD heatmap color scheme. snp.plotter can plot single SNP and/or haplotype data and simultaneously plot multiple sets of results. R is a free software environment for statistical computing and graphics available for most platforms. The proposed package provides a simple way to convey both association and LD information in a single appealing graphic for genetic association studies. C1 GCAP CBDB, NIMH NIH, Bethesda, MD 20814 USA. Johns Hopkins SPH, Baltimore, MD USA. RP Nicodemus, KK (reprint author), GCAP CBDB, NIMH NIH, 10 Ctr Dr,Room 4S-235, Bethesda, MD 20814 USA. EM nicodemusk@mail.nih.gov NR 9 TC 50 Z9 50 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD MAR 15 PY 2007 VL 23 IS 6 BP 774 EP 776 DI 10.1093/bioinformatics/btl657 PG 3 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 154MN UT WOS:000245511800019 PM 17234637 ER PT J AU Mah, L Zarate, CA Singh, J Duan, YF Luckenbaugh, DA Manji, HK Drevets, WC AF Mah, Linda Zarate, Carlos A., Jr. Singh, Jaskaran Duan, Yu-Fei Luckenbaugh, David A. Manji, Husseini K. Drevets, Wayne C. TI Regional cerebral glucose metabolic abnormalities in bipolar II depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE cerebral metabolism; bipolar disorder; depression; striatum; prefrontal cortex; amygdala; mood stabilizers ID OBSESSIVE-COMPULSIVE DISORDER; SUBGENUAL PREFRONTAL CORTEX; MOOD DISORDERS; UNIPOLAR DEPRESSION; BRAIN ACTIVITY; 1ST-EPISODE; REDUCTION; AMYGDALA; SUBTYPE; LESIONS AB Background: Functional neuroimaging studies of bipolar disorder (BD) performed in conjunction with antidepressant treatment trials generally require that patients remain on mood stabilizers to reduce the risk of inducing mania; yet, it is unknown whether the metabolic abnormalities evident in unmedicated BD depressives remain detectable in patients receiving mood stabilizers. This study investigated whether cerebral metabolic abnormalities previously reported in unmedicated BD subjects are evident in depressed bipolar disorder type II (BD II) subjects receiving lithium or divalproex. Methods: Using [F-18]-fluorodeoxyglucose-positron-emission tomography, cerebral glucose metabolism was compared between 13 depressed BD II subjects on therapeutic doses of lithium or divalproex and 18 healthy control subjects. Regional metabolism was compared between groups in predefined regions of interest. Results: Metabolism was increased in the bilateral amygdala, accumbens area, and anteroventral putamen, left orbitofrontal cortex and right pregenual anterior cingulate cortex in depressives versus control subjects. Post hoc exploratory analysis additionally revealed increased metabolism in left parahippocampal, posterior cingulate, and right anterior insular cortices in depressives versus control subjects. Correlational analyses showed multiple limbic-cortical-striatal interactions in the BD sample not evident in the control sample, permitting sensitive and specific classification of subjects by discriminant analysis. Conclusions: These results confirm previous reports that bipolar depression is associated with abnormally increased metabolism in the amygdala, ventral striatum, orbitofrontal cortex, anterior cingulate, and anterior insula, and extend these results to bipolar disorder type II depressives on lithium or divalproex. They also implicate an extended functional anatomical network known to modulate visceromotor function in the pathophysiology of BD II depression. C1 NIMH, Sect Neuroimaging Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA. NIMH, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. NIMH, Mood & Anxiety Disorders Program, NIH, Bethesda, MD 20892 USA. RP Mah, L (reprint author), Baycrest Ctr Geriatr Care, Kunin Lunenfeld Appl Res Unit, Polsuns Bldg,Room 738,3560 Bathurst St, Toronto, ON M6A 2E1, Canada. EM mahl@intra.nimh.nih.gov FU Intramural NIH HHS NR 45 TC 71 Z9 73 U1 1 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD MAR 15 PY 2007 VL 61 IS 6 BP 765 EP 775 DI 10.1016/j.biopsych.2006.06.009 PG 11 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 147KU UT WOS:000245002700007 PM 17027930 ER PT J AU Le Hellard, S Lee, AJ Underwood, S Thomson, PA Morris, SW Torrance, HS Anderson, SM Adams, RR Navarro, P Christoforou, A Houlihan, LM Detera-Wadleigh, S Owen, MJ Asherson, P Muir, WI Blackwood, DHR Wray, NR Porteous, DI Evans, KL AF Le Hellard, Stephanie Lee, Andrew J. Underwood, Sarah Thomson, Pippa A. Morris, Stewart W. Torrance, Helen S. Anderson, Susan M. Adams, Richard R. Navarro, Pau Christoforou, Andrea Houlihan, Lorna M. Detera-Wadleigh, Sevilla Owen, Michael J. Asherson, Philip Muir, Walter I. Blackwood, Douglas H. R. Wray, Naomi R. Porteous, David I. Evans, Kathryn L. TI Haplotype analysis and a novel allele-sharing method refines a chromosome 4p locus linked to bipolar affective disorder SO BIOLOGICAL PSYCHIATRY LA English DT Article DE allele sharing; bipolar affective disorder; chromosome 4p; linkage; recurrent unipolar depression; schizophrenia ID GENOME SCAN; SUSCEPTIBILITY GENES; SCHIZOPHRENIA; IDENTIFICATION; DISEASE; ASSOCIATION; PEDIGREES; FAMILIES; GENETICS; MAPS AB Background: Bipolar affective disorder (BPAD) and schizophrenia (SCZ) are common conditions. Their causes are unknown, but they include a substantial genetic component. Previously, we described significant linkage of BPAD to a chromosome 4p locus within a large pedigree (F22). Others subsequently have found evidence for linkage of BPAD and SCZ to this region. Methods: We constructed high-resolution haplotypes for four linked families, calculated logarithm of the odds (LOD) scores, and developed a novel method to assess the extent of allele sharing within genes between the families. Results: We describe an increase in the F22 LOD score for this region. Definition and comparison of the linked haplotypes allowed us to prioritize two subregions of 3.8 and 4.4 Mb. Analysis of the extent of allele sharing within these subregions identified 200 kb that shows increased allele sharing between families. Conclusions: Linkage of BPAD to chromosome 4p has been strengthened. Haplotype analysis in the additional linked families refined the 20-Mb linkage region. Development of a novel allele-sharing method allowed us to bridge the gap between conventional linkage and association studies. Description of a 200-kb region of increased allele sharing prioritizes this region, which contains two functional candidate genes for BPAD, SLC2A9, and WDR1, for subsequent studies. C1 Univ Edinburgh, Western Gen Hosp, Mol Med Ctr, Sch Clin & Mol Med,Med Genet Sect, Edinburgh EH4 2XU, Midlothian, Scotland. Univ Edinburgh, Inst Evolut Biol, Edinburgh EH4 2XU, Midlothian, Scotland. Univ Edinburgh, Royal Edinburgh Hosp, Edinburgh EH4 2XU, Midlothian, Scotland. NIMH, MAP Genet, NIH, Bethesda, MD 20892 USA. Univ Cardiff Wales, Wales Coll Med, Dept Med Psychol, Cardiff, Wales. Kings Coll London, Inst Psychiat, London, England. RP Evans, KL (reprint author), Univ Edinburgh, Western Gen Hosp, Mol Med Ctr, Sch Clin & Mol Med,Med Genet Sect, Edinburgh EH4 2XU, Midlothian, Scotland. EM kathy.evans@ed.ac.uk RI Lopez, Lorna/F-7265-2010; turton, miranda/F-4682-2011; Evans, Kathryn /I-5910-2012; Porteous, David/C-7289-2013; Wray, Naomi/C-8639-2015 OI Navarro, Pau/0000-0001-5576-8584; Adams, Richard/0000-0003-1501-0941; Porteous, David/0000-0003-1249-6106; Wray, Naomi/0000-0001-7421-3357 FU Medical Research Council [G9810900, G0100266]; Wellcome Trust NR 28 TC 18 Z9 18 U1 0 U2 2 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 MAR 15 PY 2007 VL 61 IS 6 BP 797 EP 805 DI 10.1016/j.biopsych.2006.06.029 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 147KU UT WOS:000245002700010 PM 16996484 ER PT J AU Brotman, MA Rich, BA Schmajuk, M Reising, M Monk, CS Dickstein, DP Mogg, K Bradley, BP Pine, DS Leibenluft, E AF Brotman, Melissa A. Rich, Brendan A. Schmajuk, Mariana Reising, Michelle Monk, Christopher S. Dickstein, Daniel P. Mogg, Karin Bradley, Brendan P. Pine, Daniel S. Leibenluft, Ellen TI Attention bias to threat faces in children with bipolar disorder and comorbid lifetime anxiety disorders SO BIOLOGICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 44th Annual Meeting of the American-College-Neuropsychopharmacology CY DEC 11-15, 2005 CL Waikoloa, HI SP Vanderbilt Univ, Sch Med, Dept Psychiat DE anxiety; attention; bipolar disorder; faces; pediatric; threat ID PANIC DISORDER; RATING-SCALE; ADOLESCENTS; RELIABILITY; VALIDITY; PREVALENCE; PHENOTYPES; MANIA AB Background: Although comorbid anxiety disorders are common in children with bipolar disorder (BD), it is unclear how this comorbidity impacts the pathophysiology of the illness. Methods: Pediatric BD with lifetime anxiety (BD+ANX, n = 20), BD without lifetime anxiety (BD-ANX, n = 11), and controls (n = 14) were administered the visual-probe paradigm, which assesses attention bias to threat faces. Results: Bipolar disorder + ANX demonstrated a stronger bias toward threat relative to BD-ANX and controls; the latter two did not differ from each other. Conclusions: Bipolar disorder + ANX showed a bias toward threat while, in two previous studies, anxious children showed a bias away from threat faces. Future studies should compare the pathophysiology of BD with and without a comorbid anxiety disorder and anxiety disorders presenting alone. C1 NIMH, Mood & Anxiety Disorders Program, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Michigan, Dept Psychol, Ann Arbor, MI 48109 USA. Univ Michigan, Ctr Human Growth & Dev, Ann Arbor, MI 48109 USA. Univ Southampton, Sch Psychol, Southampton SO9 5NH, Hants, England. RP Brotman, MA (reprint author), 15K N Dr,Room 208, Bethesda, MD 20892 USA. EM brotmanm@mail.nih.gov RI Bradley, Brendan/B-9724-2008; Mogg, Karin/C-1181-2008; Brotman, Melissa/H-7409-2013; Monk, Christopher/J-1805-2014; Dickstein, Daniel/L-3210-2016; OI Mogg, Karin/0000-0002-2738-7378; Dickstein, Daniel/0000-0003-1647-5329; Bradley, Brendan/0000-0003-2801-4271 FU Intramural NIH HHS NR 25 TC 30 Z9 30 U1 3 U2 9 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 MAR 15 PY 2007 VL 61 IS 6 BP 819 EP 821 DI 10.1016/j.biopsych.2006.08.021 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 147KU UT WOS:000245002700013 PM 17338904 ER PT J AU Sloand, EM Pfannes, L Chen, GB Shah, S Solomou, EE Barrett, J Young, NS AF Sloand, Elaine M. Pfannes, Loretta Chen, Gubin Shah, Simant Solomou, Elena E. Barrett, John Young, Neal S. TI CD34 cells from patients with trisomy 8 myelodysplastic syndrome (MDS) express early apoptotic markers but avoid programmed cell death by up-regulation of antiapoptotic proteins SO BLOOD LA English DT Article ID TUMOR-NECROSIS-FACTOR; INTERFERON-GAMMA; CYTOGENETIC ABNORMALITIES; APLASTIC-ANEMIA; IN-VITRO; T-CELLS; C-MYC; HEMATOLOGICAL MALIGNANCIES; HEMATOPOIETIC-CELLS; GENE-EXPRESSION AB CD34 cells from patients with trisomy 8 myelodysplastic syndrome (MDS) are distinguished from other MDS cells and from normal hematopoietic cells by their pronounced expression of apoptotic markers. Paradoxically, trisomy 8 clones can persist in patients with bone marrow failure and expand following immunosuppression. We previously demonstrated up-regulation of c-myc and CD1 by microarray analysis. Here, we confirmed these findings by real-time polymerase chain reaction (PCR), demonstrated up-regulation of survivin, c-myc, and CD1 protein expression, and documented comparable colony formation by annexin(+) trisomy 8(-) CD34(+) and annexin(-) CD34 cells. There were low levels of DNA degradation in annexin(+) trisomy 8 CD34 cells, which were comparable with annexin- CD34 cells. Trisomy 8 cells were resistant to apoptosis induced by gamma irradiation. Knock-down of survivin by siRNA resulted in preferential loss of trisomy 8 cells. These results suggest that trisomy 8 cells undergo incomplete apoptosis and are nonetheless capable of colony formation and growth. C1 NHLBI, NIH, Bethesda, MD 20892 USA. RP Sloand, EM (reprint author), NHLBI, NIH, 9000 Rockville Pike,Bldg 10,Rm 7C108, Bethesda, MD 20892 USA. EM sloande@nhlbi.nih.gov NR 33 TC 43 Z9 47 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 15 PY 2007 VL 109 IS 6 BP 2399 EP 2405 DI 10.1182/blood-2006-01 PG 7 WC Hematology SC Hematology GA 147LO UT WOS:000245004700024 PM 17090657 ER PT J AU Mostbock, S Catalfamo, M Tagaya, Y Schlom, J Sabzevari, H AF Mostbock, Sven Catalfamo, Marta Tagaya, Yutaka Schlom, Jeffrey Sabzevari, Helen TI Acquisition of antigen presentasome (APS), an MHC/costimulatory complex, is a checkpoint of memory T-cell homeostasis SO BLOOD LA English DT Article ID IN-VIVO; INTERFERON-GAMMA; VIRAL-INFECTION; CO-RECEPTORS; GENERATION; PERFORIN; LYMPHOCYTES; ACTIVATION; APOPTOSIS; RESPONSES AB Immunologic memory is associated with the activation and expansion of antigen-specific T cells, followed by clonal deletion and survival of a small number of memory T cells. This study establishes that effector and rested memory T cells can acquire major histocompatibility complex (MHC)/CD80 molecules (antigen presentasome [APS]) upon activation in vitro and after vaccination in vivo. We demonstrate for the first time that acquisition of APS by rested memory T cells is correlated with increased levels of apoptosis in vivo and up-regulation of caspase-3, bcl-x, bak, and bax in our in vitro studies. Moreover, our results demonstrate that memory T cells with acquired APS can indeed become cytotoxic T lymphocytes and kill other cells through perforin-mediated lysis. In addition, they retained the production of interferon 7 and T-helper 2 (Th2) type cytokines. The acquisition of APS by memory T cells might be an important checkpoint leading to the clonal deletion of the majority of effector T cells, possibly allowing the surviving cells to become long-term memory cells by default. C1 NCI, Tumor Immunol & Biol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Metab Branch, Canc Res Ctr, NIH, Bethesda, MD USA. RP Schlom, J (reprint author), NCI, Tumor Immunol & Biol Lab, Canc Res Ctr, NIH, Bldg 10,Rm 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov FU Intramural NIH HHS NR 34 TC 12 Z9 12 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 MAR 15 PY 2007 VL 109 IS 6 BP 2488 EP 2495 DI 10.1182/blood-2006-09-047290 PG 8 WC Hematology SC Hematology GA 147LO UT WOS:000245004700037 PM 17105811 ER PT J AU Hursting, SD Nunez, NP Varticovski, L Vinson, C AF Hursting, Stephen D. Nunez, Nomeli P. Varticovski, Lyuba Vinson, Charles TI The obesity-cancer link: Lessons learned from a fatless mouse SO CANCER RESEARCH LA English DT Review ID CALORIE RESTRICTION; BREAST-CANCER; GROWTH; MICE; INFLAMMATION; ADIPONECTIN; MECHANISMS; OVERWEIGHT; ADULTS AB Current dogma suggests that the positive correlation between obesity and cancer is driven by white adipose tissue that accompanies obesity, possibly through excess secretion of adipokines. Recent studies in fatless A-Zip/F1 mice, which have undetectable adipokine levels but display accelerated tumor formation, suggest that adipokines are not required for the enhanced tumor development. The A-Zip/F-1 mice are also diabetic and display elevated circulating levels of other factors frequently associated with obesity (insulin, insulin-like growth factor-1, and proinflammatory cytokines) and activation of several signaling pathways associated with carcinogenesis. In view of this information, the risk factors underlying the obesity-cancer link need to be revisited. We postulate that the pathways associated with insulin resistance and inflammation, rather than adipocyte-derived factors, may represent key prevention and therapeutic targets for disrupting the obesity-cancer link. C1 NCI, Gene Regulat Sect, Human Carcinogenesis Lab, Bethesda, MD 20892 USA. NCI, Lab Metab, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Texas, Div Nutr Sci, Austin, TX 78712 USA. Univ Texas, MD Anderson Canc Ctr, Dept Carcinogenesis, Smithville, TX USA. RP Vinson, C (reprint author), NCI, Gene Regulat Sect, Human Carcinogenesis Lab, Room 2D24,Bldg 37, Bethesda, MD 20892 USA. EM vinsonc@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 20 TC 75 Z9 77 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 MAR 15 PY 2007 VL 67 IS 6 BP 2391 EP 2393 DI 10.1158/0008-5472.CAN-06-4237 PG 3 WC Oncology SC Oncology GA 147RC UT WOS:000245019100001 PM 17363554 ER PT J AU Zhao, YB Parkhurst, MR Zheng, Z Cohen, CJ Riley, JP Gattinoni, L Restifo, NP Rosenberg, SA Morgan, RA AF Zhao, Yangbing Parkhurst, Maria R. Zheng, Zhili Cohen, Cyrille J. Riley, John P. Gattinoni, Luca Restifo, Nicholas P. Rosenberg, Steven A. Morgan, Richard A. TI Extrathymic generation of tumor-specific T cells from genetically engineered human hematopoletic stem cells via notch signaling SO CANCER RESEARCH LA English DT Article ID DELTA-LIKE-1 IN-VITRO; HUMAN-LYMPHOCYTES; THYMUS MICROENVIRONMENT; METASTATIC MELANOMA; CANCER REGRESSION; PROGENITOR CELLS; TRANSFER THERAPY; TCR; ANTIGEN; TRANSPLANTATION AB Adoptive cell transfer (ACT) of tumor-reactive lymphocytes has been shown to be an effective treatment for cancer patients. Studies in murine models of ACT indicated that antitumor efficacy of adoptively transferred T cells is dependent on the differentiation status of the cells, with lymphocyte differentiation inversely correlated with in vivo antitumor effectiveness. T-cell in vitro development technologies provide a new opportunity to generate naive T cells for the purpose of ACT. In this study, we genetically modified human umbilical cord blood-derived hematopoietic stem cells (HSCs) to express tumor antigen-specific T-cell receptor (TCR) genes and generated T lymphocytes by coculture with a murine cell line expressing Notch-1 ligand, Delta-like-1 (OP9-DL1). Input HSCs were differentiated into T cells as evidenced by the expression of T-cell markers, such as CD7, CD1a, CD4, CD8, and CD3, and by detection of TCR excision circles. We found that such in vitro differentiated T cells expressed the TCR and showed HLA-A2-restricted, specific recognition and killing of tumor antigen peptide-pulsed antigen-presenting cells but manifested additional natural killer cell-like killing of tumor cell lines. The genetic manipulation of HSCs has broad implications for ACT of cancer. C1 NCI, Surg Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Morgan, RA (reprint author), NCI, Surg Branch, Ctr Canc Res, NIH, Room 3W5940,Bldg 10,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM rmorgan@mail.nih.gov RI Gattinoni, Luca/A-2281-2008; Restifo, Nicholas/A-5713-2008 OI Gattinoni, Luca/0000-0003-2239-3282; FU Intramural NIH HHS [Z01 SC003811-32, Z99 CA999999, Z01 BC010763-01] NR 19 TC 53 Z9 56 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 MAR 15 PY 2007 VL 67 IS 6 BP 2425 EP 2429 DI 10.1158/0008-5472.CAN-06-3977 PG 5 WC Oncology SC Oncology GA 147RC UT WOS:000245019100008 PM 17363559 ER PT J AU Matthews, CP Birkholz, AM Baker, AR Perella, CM Becky, GR Young, MR Colburn, NH AF Matthews, Connie P. Birkholz, Alysia M. Baker, Alyson R. Perella, Christine M. Becky, George R., Jr. Young, Matthew R. Colburn, Nancy H. TI Dominant-negative activator protein 1 (TAM67) targets cyclooxygenase-2 and osteopontin under conditions in which it specifically inhibits tumorigenesis SO CANCER RESEARCH LA English DT Article ID NF-KAPPA-B; ONCOGENE-INDUCED TUMORIGENESIS; ANCHORAGE-INDEPENDENT GROWTH; HUMAN-PAPILLOMAVIRUS; C-JUN; INDUCED TRANSFORMATION; INFLAMMATORY ANGIOGENESIS; INCREASED EXPRESSION; HUMAN KERATINOCYTES; DELETION MUTANT AB Activation of activator protein 1 (AP-1) and nuclear factor kappa B (NF kappa B)-dependent transcription is required for tumor promotion in cell culture models and transgenic mice. Dominant-negative c-Jun (TAM67) blocks AP-1 activation by dimerizing with Jun or Fos family proteins and blocks NF kappa B activation by interacting with NF kappa B p65. Two-stage [7,12-dimethylbenz(a)anthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)] skin carcinogenesis experiments in a model relevant to human cancer risk, transgenic mice expressing human papillomavirus 16 E7 oncogene (K14-HPV16-E7), show E7-enhanced tumor promotion. A cross to K14-TAM67-expressing mice results in dramatic inhibition of tumor promoter-induced AP-1 luciferase reporter activation and papillomagenesis. Epithelial specific TAM67 expression inhibits tumorigenesis without affecting TPA- or E7-induced hyperproliferation of the skin. Thus, the mouse model enriches for TAM67 targets relevant to tumorigenesis rather than to general cell proliferation or hyperplasia, implicating a subset of AP-1- and/or NF kappa B-dependent genes. The aim of the present study was to identify target genes responsible for TAM67 inhibition of DMBA-TPA-induced tumorigenesis. Microarray expression analysis of epidermal tissues revealed small sets of genes in which expression is both up-regulated by tumor promoter and down-regulated by TAM67. Among these, cyclooxygenase-2 (Cox-2/Ptgs2) and osteopontin (Opn/Spp1) are known to be functionally significant in driving carcinogenesis. Results identify both Cox-2 and Opn as transcriptional targets of TAM67 with CRE, but not NF kappa B sites important in the Cox-2 promoter and an AP-1 site important in the Opn promoter. C1 NCI, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. NCI, Sci Applicat Int Corp, Frederick, MD 21702 USA. Emory Univ, Sch Med, Atlanta, GA 30322 USA. RP Matthews, CP (reprint author), NCI, Lab Canc Prevent, Ctr Canc Res, Frederick, MD 21702 USA. EM cmatthews@mail.ncifcrf.gov FU Intramural NIH HHS NR 46 TC 25 Z9 26 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 15 PY 2007 VL 67 IS 6 BP 2430 EP 2438 DI 10.1158/0008-5472.CAN-06-0522 PG 9 WC Oncology SC Oncology GA 147RC UT WOS:000245019100009 PM 17363560 ER PT J AU Qi, CF Zhou, JX Lee, CH Naghashfar, Z Xiang, S Kovalchuk, AL Fredrickson, TN Hartley, JW Roopenian, DC Davidson, WF Janz, S Morse, HC AF Qi, Chen-Feng Zhou, Jeff X. Lee, Chang Hoon Naghashfar, Zohreh Xiang, Shao Kovalchuk, Alexandrer L. Fredrickson, Torgny N. Hartley, Janet W. Roopenian, Derry C. Davidson, Wendy F. Janz, Siegfried Morse, Herbert C., III TI Anaplastic, plasmablastic, and plasmacytic plasmacytomas of mice: Relationships to human plasma cell neoplasms and late-stage differentiation of normal B cells SO CANCER RESEARCH LA English DT Article ID BCL-X-L; MULTIPLE-MYELOMA; LYMPHOID NEOPLASMS; C-MYC; MOUSE; CLASSIFICATION; GENE; SARCOMA; DEREGULATION; EXPRESSION AB We have compared histologic features and gene expression profiles of newly identified plasmacytomas from NFS.V+ congenic mice with plasmacytomas of IL6 transgenic, Fasl mutant, and SJ-beta 2M(-/-) mice. NFS.V+ tumors comprised an overlapping morphologic spectrum of high-grade/anaplastic, intermediate-grade/plasmablastic, and low-grade/plasmacytic cases with similarities to subsets of human multiple myeloma and plasmacytoma. Microarray and immunohistochemical analyses of genes expressed by the most prevalent tumors, plasmablastic plasmacytomas, showed them to be most closely related to inummoblastic lymphomas, less so to plasmacytomas of Fasl mutant and SJL mice, and least to plasmacytic plasmacytomas of IL6 transgenic mice. Plasmablastic tumors seemed to develop in an inflammatory environment associated with gene signatures of T cells, natural killer cells, and macrophages not seen with plasmacytic plasmacytomas. Plasmablastic plasmacytomas from NFS.V+ and SJL-beta 2M(-/-) mice did not have structural alterations in Myc or T(12;15) translocations and did not express Myc at high levels, regular features of transgenic and pristane-induced plasmacytomas. These findings imply that, as for human multiple myeloma, Myc-independent routes of transformation contribute to the pathogenesis of these tumors. These findings suggest that plasma cell neoplasms of mice and humans exhibit similar degrees of complexity. Mouse plasmacytomas, previously considered to be homogeneous, may thus be as diverse as their human counterparts with respect to oncogenic mechanisms of plasma cell transformation. Selecting specific types of mouse plasmacytomas that relate most closely to subtypes of human multiple myeloma may provide new opportunities for preclinical testing of drugs for treatment of the human disease. C1 NIAID, Immunopathol Lab, NIH, Rockville, MD 20852 USA. NCI, Genet Lab, NIH, Rockville, MD USA. Jackson Lab, Bar Harbor, ME 04609 USA. Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. RP Morse, HC (reprint author), NIAID, Immunopathol Lab, NIH, Twinbrook 1,Room 1421, Rockville, MD 20852 USA. EM hm16c@nih.gov OI Morse, Herbert/0000-0002-9331-3705 FU NCI NIH HHS [CA34196, CA82872-02]; NIDDK NIH HHS [DK56597] NR 48 TC 19 Z9 20 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 MAR 15 PY 2007 VL 67 IS 6 BP 2439 EP 2447 DI 10.1158/0008-5472.CAN-06-1561 PG 9 WC Oncology SC Oncology GA 147RC UT WOS:000245019100010 PM 17363561 ER PT J AU Shen, JC Unoki, M Ythier, D Duperray, A Varticovski, L Kumamoto, K Pedeux, R Harris, CC AF Shen, Jiang-Cheng Unoki, Motoko Ythier, Damien Duperray, Alain Varticovski, Lyuba Kumamoto, Kensuke Pedeux, Remy Harris, Curtis C. TI Inhibitor of growth 4 suppresses cell spreading and cell migration by interacting with a novel binding partner, liprin alpha 1 SO CANCER RESEARCH LA English DT Article ID CANDIDATE TUMOR-SUPPRESSOR; TYROSINE-PHOSPHATASE; FOCAL ADHESIONS; ING FAMILY; GENE; PROTEIN; ACETYLATION; CANCER; SENESCENCE; APOPTOSIS AB Inhibitor of growth 4 (ING4) is a candidate tumor suppressor that plays a major role in gene regulation, cell cycle control, apoptosis, and angiogenesis. ING4 expression is down-regulated in glioblastoma cells and head and neck squamous cell carcinoma. Here, we identified liprin alpha 1/PPFIA1, a cytoplasmic protein necessary for focal adhesion formation and axon guidance, as a novel interacting protein with ING4. ING4 and liprin alpha 1 colocalized at lamellipodia in the vicinity of vinculin. Overexpressed ING4 suppressed cell spreading and cell migration. In contrast, overexpressed liprin alpha 1 enhanced cell spreading and cell migration. Knockdown of endogenous ING4 with RNA interference induced cell motility, whereas knockdown of endogenous liprin alpha 1 suppressed cell motility. ING4 also suppressed cell motility that was enhanced by liprin alpha 1. However, ING4 did not further suppress cell motility when liprin alpha 1 was suppressed with RNA interference, suggesting a functional and mechanistic interdependence between these proteins. In addition to its nuclear functions, cytoplasmic ING4 interacts with liprin alpha 1 to regulate cell migration and, with its known antiangiogenic function, may prevent invasion and metastasis. C1 NCI, Human Carcinogenesis Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Inst Albert Bonniot, INSERM U823, La Tronche, France. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, Canc Res Ctr, NIH, 37 Convent Dr,Bldg 37,Room 3068, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov RI Duperray, Alain/E-8428-2012 OI Duperray, Alain/0000-0002-2719-252X FU Intramural NIH HHS NR 26 TC 82 Z9 92 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 MAR 15 PY 2007 VL 67 IS 6 BP 2552 EP 2558 DI 10.1158/0008-5472.CAN-06-3870 PG 7 WC Oncology SC Oncology GA 147RC UT WOS:000245019100022 PM 17363573 ER PT J AU Kim, HJ Kim, JY Meng, ZJ Wang, LH Liu, F Conrads, TP Burke, TR Veenstra, TD Farrar, WL AF Kim, Han-Jong Kim, Joon-Young Meng, Zhaojing Wang, Li Hua Liu, Fa Conrads, Thomas P. Burke, Terrence R. Veenstra, Timothy D. Farrar, William L. TI 15-deoxy-Delta(12,14)-prostaglandin J(2) inhibits transcriptional activity of estrogen receptor-alpha via covalent modification of DNA-binding domain SO CANCER RESEARCH LA English DT Article ID BREAST-CANCER CELLS; KAPPA-B KINASE; PPAR-GAMMA; CYCLOPENTENONE PROSTAGLANDINS; MOLECULAR-MECHANISMS; GENE-EXPRESSION; UP-REGULATION; COLON-CANCER; CYCLIN D1; ACTIVATION AB The cyclopentenone 15-deoxy-Delta(12,14)-prostagiandin J(2) (15d-PGJ(2)) inhibits proliferation of cancer cells, including breast cancers, by peroxisome proliferator-activated receptor-gamma (PPAR gamma)-dependent and PPAR gamma-independent mechanisms. However, little is known about its effect on the transcriptional activity of estrogen receptor-alpha (ER alpha) that plays vital roles in the growth of breast cancers. Here, we show that 15d-PGJ2 inhibits both 17 beta-estradiol (E-2)-dependent and E-2-independent ER alpha transcriptional activity by PPAR gamma-independent mechanism. In addition, 15d-PGJ(2) directly modifies ER alpha protein via its reactive cyclopentenone moiety, evidenced by incorporation of biotinylated 15d-PGJ(2) into ER alpha, both in vitro and in vivo. Nanoflow reverse-phase liquid chromatography tandem mass spectrometry analysis identifies two cysteines (Cys(227) and Cys(240)) within the COOH-terminal zinc finger of ER alpha DNA-binding domain (DBD) as targets for covalent modification by 15d-PGJ2. Gel mobility shift and chromatin immunoprecipitation assays show that 15d-PGJ(2) inhibits DNA binding of ER alpha and subsequent repression of ER alpha target gene expression, such as pS2 and c-Myc. Therefore, our results suggest that 15d-PGJ(2) can block ER alpha function by covalent modification of cysteine residues within the vulnerable COOH-terminal zinc finger of ER alpha DBD, resulting in fundamental inhibition of both hormone-dependent and hormone-independent ER alpha transcriptional activity. C1 Natl Canc Inst, Ctr Canc Res, Lab Med Chem, Ft Detrick, MD 21702 USA. Sci Applicat Int Corp, Basic Res Program, Frederick, MD USA. Sci Applicat Int Corp, Canc Stem Cell Sect, Lab Canc Prevent, Frederick, MD USA. Sci Applicat Int Corp, Lab Proteom & Analyt Technol, Frederick, MD USA. RP Farrar, WL (reprint author), Natl Canc Inst, Lab Canc Prevent, Room 21-81,Bldg 560,1050 Boyles St, Ft Detrick, MD 21702 USA. EM farrar@mail.ncifcrf.gov RI Burke, Terrence/N-2601-2014 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 42 TC 38 Z9 38 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 MAR 15 PY 2007 VL 67 IS 6 BP 2595 EP 2602 DI 10.1158/0008-5472.CAN-06-3043 PG 8 WC Oncology SC Oncology GA 147RC UT WOS:000245019100027 PM 17363578 ER PT J AU Hama, Y Urano, Y Koyama, Y Kamiya, M Bernardo, M Paik, RS Shin, IS Paik, CH Choyke, PL Kobayashi, H AF Hama, Yukihiro Urano, Yasuteru Koyama, Yoshinori Kamiya, Mako Bernardo, Marcelino Paik, Ronald S. Shin, In Soo Paik, Chang H. Choyke, Peter L. Kobayashi, Hisataka TI A target cell-specific activatable fluorescence probe for in vivo molecular imaging of cancer based on a self-quenched avidin-rhodamine conjugate SO CANCER RESEARCH LA English DT Article ID TUMOR; DYES; REPORTER AB A target cell-specific activation strategy for improved molecular imaging of peritoneal implants has been proposed, in which fluorophores are activated only in living targeted cells. A current example of an activatable fluorophore is one that is normally self-quenched by attachment to a peptide backbone but which can be activated by specific proteases that degrade the peptide resulting in "dequenching." In this study, an alternate fluorescence activation strategy is proposed whereby self-quenching avidin-rhodamine X, which has affinity for lectin on cancer cells, is activated after endocytosis and degradation within the lysosome. Using this approach in a mouse model of peritoneal ovarian metastases, we document target-specific molecular imaging of submillimeter cancer nodules with minimal contamination by background signal. Cellular internalization of receptor-ligand pairs with subsequent activation of fluorescence via dequenching provides a generalizable and highly sensitive method of detecting cancer microfoci in vivo and has practical implications for assisting surgical and endoscopic procedures. C1 NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NIH, Warren G Magnuson Clin Ctr, Dept Nucl Med, Bethesda, MD 20892 USA. Univ Tokyo, Grad Sch Pharmaceut Sci, Tokyo 106, Japan. SAIC Frederick, Res Technol Program, Frederick, MD USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Room 1B40,Bldg 10,MSC 1088,10 Ctr Dr, Bethesda, MD 20892 USA. EM Kobayash@mail.nih.gov RI Urano, Yasuteru/H-1380-2012 FU Intramural NIH HHS NR 19 TC 67 Z9 67 U1 2 U2 28 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 MAR 15 PY 2007 VL 67 IS 6 BP 2791 EP 2799 DI 10.1158/0008-5472.CAN-06-3315 PG 9 WC Oncology SC Oncology GA 147RC UT WOS:000245019100050 PM 17363601 ER PT J AU Guo, ZS Restifo, NP Schrump, DS AF Guo, Z. Sheng Restifo, Nicholas P. Schrump, David S. TI 5-AZA-2 '-deoxycytidine in cancer immunotherapy: A mouse to man story - Response SO CANCER RESEARCH LA English DT Letter ID PHASE-I; DECITABINE; MELANOMA C1 Univ Pittsburgh, Inst Canc, Div Surg Oncol, Pittsburgh, PA USA. NCI, Surg Branch, NIH, Thorac Oncol Sect, Bethesda, MD 20892 USA. RP Guo, ZS (reprint author), Univ Pittsburgh, Inst Canc, Div Surg Oncol, Pittsburgh, PA USA. RI Restifo, Nicholas/A-5713-2008 NR 5 TC 0 Z9 0 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 MAR 15 PY 2007 VL 67 IS 6 BP 2901 EP 2902 DI 10.1158/0008-5472.CAN-06-4501 PG 2 WC Oncology SC Oncology GA 147RC UT WOS:000245019100066 ER PT J AU Xu, WP Neckers, L AF Xu, Wanping Neckers, Len TI Targeting the molecular chaperone heat shock protein 90 provides a multifaceted effect on diverse cell signaling pathways of cancer cells SO CLINICAL CANCER RESEARCH LA English DT Editorial Material ID UROKINASE PLASMINOGEN-ACTIVATOR; FOCAL ADHESION KINASE; TELOMERASE ACTIVITY; HSP90 FUNCTION; BREAST-CANCER; SOMATIC MUTATIONS; INHIBITORS; EXPRESSION; GROWTH; GELDANAMYCIN C1 NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, Bldg 10,CRC,Room 1-5940,9000 Rockville Pike, Bethesda, MD 20892 USA. EM len@helix.nih.gov NR 49 TC 138 Z9 140 U1 1 U2 6 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 MAR 15 PY 2007 VL 13 IS 6 BP 1625 EP 1629 DI 10.1158/1078-0432.CCR-06-2966 PG 5 WC Oncology SC Oncology GA 147VV UT WOS:000245031800002 PM 17363512 ER PT J AU Aragon-Ching, JB Zujewski, JA AF Aragon-Ching, Jeanny B. Zujewski, Jo Anne TI CNS metastasis: An old problem in a new guise SO CLINICAL CANCER RESEARCH LA English DT Article ID ACUTE LYMPHOBLASTIC-LEUKEMIA; CENTRAL-NERVOUS-SYSTEM; BREAST-CANCER; BRAIN METASTASES; PLUS; CHEMOTHERAPY; THERAPY AB It is estimated that 10% to 30% of patients with solid tumors are diagnosed with central nervous system (CNS) metastasis. Common primary sites include lung, breast, melanoma, kidney, and colorectal. Brain metastases are increasing, due to the aging population, detection of subclinical disease, and control of systemic disease. CNS metastases are a major cause of morbidity and mortality affecting survival, neurocognition, speech, coordination, behavior, and quality of life. In pediatric acute lymphocytic leukemia event-free survival rates are >80% and the CNS is an important source of extramedullary relapse. CNS metastases are an increasing problem in solid tumors. In this CCR Focus series, four main topics are reviewed: (a) HER-2-positive breast cancer as a paradigm for the problem; (b) model systems for brain metastasis and mechanistic insights into the pathogenesis of brain metastasis; (c) the unique physiology of the blood brain barrier; (d) and the evolving role of radiotherapy in CNS disease and strategies to improve the therapeutic index. Areas for future research include the need for an understanding of site-specific metastasis, effective anticancer strategies for sanctuary sites, assays to detect drug accumulation in sanctuary sites, prevention of CNS metastasis, improving the therapeutic ratio of systemic and CNS-directed therapies, behavioral tools for anticipating/measuring long-term neurocognitive defects, and quality of life assessment of the long-term effect of systemic and CNS-directed therapies. C1 NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Div Canc Therapy Diag & Treatment, Bethesda, MD 20892 USA. RP Zujewski, JA (reprint author), 6130 Rockville Pike, Rockville, MD 20852 USA. EM zujewski@nih.gov OI Aragon-Ching, Jeanny/0000-0002-6714-141X NR 19 TC 46 Z9 49 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 MAR 15 PY 2007 VL 13 IS 6 BP 1644 EP 1647 DI 10.1158/1078-0432.CCR-07-0096 PG 4 WC Oncology SC Oncology GA 147VV UT WOS:000245031800007 PM 17363516 ER PT J AU Palmieri, D Chambers, AF Felding-Habermann, B Huang, S Steeg, PS AF Palmieri, Diane Chambers, Ann F. Felding-Habermann, Brunhilde Huang, Suyun Steeg, Patricia S. TI The biology of metastasis to a sanctuary site SO CLINICAL CANCER RESEARCH LA English DT Article ID ENDOTHELIAL GROWTH-FACTOR; BREAST-CANCER METASTASIS; MELANOMA BRAIN METASTASIS; NERVOUS-SYSTEM METASTASES; TUMOR-CELL MIGRATION; NUDE-MICE; IN-VIVO; LUNG-CARCINOMA; MOUSE-BRAIN; EXPRESSION AB Metastasis to the brain is prevalent in solid tumors and lymphomas, and is associated with shortened survival. The brain is regarded as a sanctuary site for metastatic tumor cells where they exist partially protected from drugs by the blood-tumor barrier. Model systems for brain metastasis have been developed and are now yielding mechanistic insights into the roles of angiogenesis, energy metabolism, the Her-2 and Stat3 signaling pathways, and dormancy. Specific, new approaches to combat brain metastatic disease are needed. C1 NCI, Mol Therapeut Program, Ctr Canc Res, Lab Mol Pharmacol,Womens Canc Sect, Bethesda, MD 20892 USA. Univ Western Ontario, Dept Oncol, London, ON, Canada. Univ Western Ontario, Dept Pathol, London, ON, Canada. Univ Western Ontario, Dept Med Biophys, London, ON, Canada. London Reg Canc Program, London, ON, Canada. Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA USA. Univ Texas, MD Anderson Canc Ctr, Dept Neurosurg, Houston, TX 77030 USA. RP Steeg, PS (reprint author), NCI, Mol Therapeut Program, Ctr Canc Res, Lab Mol Pharmacol,Womens Canc Sect, Bldg 37,Room 1-122,37 Convent Dr,MSC 4264, Bethesda, MD 20892 USA. EM steegp@mail.nih.gov RI Palmieri, Diane/B-4258-2015; Chambers, Ann/L-6285-2015 OI Chambers, Ann/0000-0002-9509-5123 FU Intramural NIH HHS; NCI NIH HHS [CA095458] NR 73 TC 78 Z9 79 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 MAR 15 PY 2007 VL 13 IS 6 BP 1656 EP 1662 DI 10.1158/1078-0432.CCR-06-2659 PG 7 WC Oncology SC Oncology GA 147VV UT WOS:000245031800009 PM 17363518 ER PT J AU Risinger, JI Chandramouli, GVR Maxwell, GL Custer, M Pack, S Loukinov, D Aprelikova, O Litzi, T Schrump, DS Murphy, SK Berchuck, A Lobanenkov, V Barrett, JC AF Risinger, John Ian Chandramouli, Gadisetti V. R. Maxwell, G. Larry Custer, Mary Pack, Svetlana Loukinov, Dmitri Aprelikova, Olga Litzi, Tracy Schrump, David S. Murphy, Susan K. Berchuck, Andrew Lobanenkov, Victor Barrett, J. Carl TI Global expression analysis of cancer/testis genes in uterine cancers reveals a high incidence of BORIS expression SO CLINICAL CANCER RESEARCH LA English DT Article ID ENDOMETRIAL CARCINOMAS; TESTIS ANTIGENS; CTCF; FAMILY; IDENTIFICATION; GAMETOGENESIS; DEREPRESSION; EPIGENETICS; MICROARRAY; PROFILE AB Purpose: Cancer/testis (CT) genes predominantly expressed in the testis (germ cells) and generally not in other normal tissues are aberrantly expressed in human cancers. This highly restricted expression provides a unique opportunity to use these CT genes for diagnostics, immunotherapeutic, or other targeted therapies. The purpose of this study was to identify those CT genes with the greatest incidence of expression in uterine cancers. Experimental Design: We queried the expression of known and putative CT gene transcripts (representing 79 gene loci) using whole genome gene expression arrays. Specifically, the global gene expressions of uterine cancers (n = 122) and normal uteri (n = 10) were determined using expression data from the Affymetrix HG-U133A and HG-U133B chips. Additionally, we also examined the brother of the regulator of imprinted sites (BORIS) transcript by reverse transcription-PCR and quantitative PCR because its transcript was not represented on the array. Results: Global microarray analysis detected many CT genes expressed in various uterine cancers; however, no individual CT gene was expressed in more than 25% of all cancers. The expression of the two most commonly expressed CT genes on the arrays, MAGEA9 (24 of 122 cancers and 0 of 10 normal tissues) and Down syndrome critical region 8 (DSCR8)/IMMA1 (16 if 122 cancers and 0 of 10 normal tissues), was confirmed by reverse transcription-PCR methods, validating the array screening approach. In contrast to the relatively low incidence of expression of the other CT genes, BORIS expression was detected in 73 of 95 (77%) endometrial cancers and 24 of 31 (77%) uterine mixed mesodermal tumors. Conclusions: These data provide the first extensive survey of multiple CT genes in uterine cancers. Importantly, we detected a high frequency of BORIS expression in uterine cancers, suggesting its potential as an immunologic or diagnostic target for these cancers. Given the high incidence of BORIS expression and its possible regulatory role, an examination of BORIS function in the etiology of these cancers is warranted. C1 NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NIAID, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. Duke Univ, Dept Obstet & Gynecol, Div Gynecol Oncol, Durham, NC USA. Duke Univ, Duke Inst Genome Sci & Policy, Durham, NC USA. RP Risinger, JI (reprint author), Mem Hlth Univ Med Ctr, Curtis & Elizabeth Anderson Canc Inst, 4700 Waters Ave, Savannah, GA 31404 USA. EM risinJo1@memorialhealth.com RI Pack, Svetlana/C-2020-2014; OI Lobanenkov, Victor/0000-0001-6665-3635; Murphy, Susan/0000-0001-8298-7272 FU Intramural NIH HHS NR 28 TC 36 Z9 38 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 MAR 15 PY 2007 VL 13 IS 6 BP 1713 EP 1719 DI 10.1158/1078-0432.CCR-05-2569 PG 7 WC Oncology SC Oncology GA 147VV UT WOS:000245031800015 PM 17363524 ER PT J AU Ramanathan, RK Egorin, MJ Eiseman, JL Ramalingam, S Friedland, D Agarwala, SS Ivy, SP Potter, DM Chatta, G Zuhowski, EG Stoller, RG Naret, C Guo, JX Belani, CP AF Ramanathan, Ramesh K. Egorin, Merrill J. Eiseman, Julie L. Ramalingam, Suresh Friedland, David Agarwala, Sanjiv S. Ivy, S. Percy Potter, Douglas M. Chatta, Gurkamal Zuhowski, Eleanor G. Stoller, Ronald G. Naret, Cynthia Guo, Jianxia Belani, Chandra P. TI Phase I and pharmacodynamic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with refractory advanced cancers SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT 41st Annual Meeting of the American-Society-of-Clinical-Oncology CY MAY 13-17, 2005 CL Orlando, FL SP Amer Soc Clin Oncol ID ADVANCED MALIGNANCIES; HSP90 INHIBITORS; 17-ALLYLAMINO; GELDANAMYCIN; NSC-330507; 17AAG; VITRO; VIVO AB Purpose: The primary objective was to establish the dose-limiting toxicity (DLT) and recommended phase II dose of 17-(allylamino)-17-demethoxygeldanamycin (17AAG) given twice a week. Experimental Design: Escalating doses of 17AAG were given i.v. to cohorts of three to six patients. Dose levels for schedule A (twice weekly x 3 weeks, every 4 weeks) were 100, 125, 150,175, and 200 mg/m(2) and for schedule B (twice weekly x 2 weeks, every 3 weeks) were 150, 200, and 250 mg/m(2). Peripheral blood mononuclear cells (PBMC) were collected for assessment of heat shock protein (HSP) 90 and HSP90 client proteins. Results: Forty-four patients were enrolled, 32 on schedule A and 12 on schedule B. On schedule A at 200 mg/m(2), DLTs were seen in two of six patients (one grade 3 thrombocytopenia and one grade 3 abdominal pain). On schedule B, both patients treated at 250 mg/m(2) developed DLT (grade 3 headache with nausea/vomiting). Grade 3/4 toxicities seen in >5% of patients were reversible elevations of liver enzymes (47%), nausea (9%), vomiting (9%), and headache (5%). No objective tumor responses were observed. The only consistent change in PBMC proteins monitored was a 0.8- to 30-fold increase in HSP70 concentrations, but these were not dose dependent. The increase in PBMC HSP70 persisted throughout the entire cycle of treatment but returned to baseline between last 17AAG dose of cycle 1 and first 17AAG dose of cycle 2. Conclusions: The recommended phase II doses of 17AAG are 175 to 200 mg/m2 when given twice a week and consistently cause elevations in PBMC HSP70. C1 Univ Pittsburgh, Med Ctr, Sch Med, Dept Med,Div Hematol Oncol, Pittsburgh, PA 15232 USA. Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Grad Sch Publ Hlth, Mol Therapeut Drug Discovery Program, Pittsburgh, PA USA. Univ Pittsburgh, Grad Sch Publ Hlth, Dept Biostat, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Inst Canc, Biostat Facil, Pittsburgh, PA USA. NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Ctr, Bethesda, MD 20892 USA. RP Ramanathan, RK (reprint author), Univ Pittsburgh, Med Ctr, Sch Med, Dept Med,Div Hematol Oncol, Canc Pavil 562,5150 Ctr Ave, Pittsburgh, PA 15232 USA. EM ramanathanrk@upmc.edu OI Belani, Chandra/0000-0001-5049-5329 FU NCATS NIH HHS [UL1 TR000005]; NCI NIH HHS [P30 CA47904, U01-CA099168, U01-CA69855]; NCRR NIH HHS [5 M01 RR00056] NR 22 TC 68 Z9 69 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2007 VL 13 IS 6 BP 1769 EP 1774 DI 10.1158/1078-0432.CCR-06-2233 PG 6 WC Oncology SC Oncology GA 147VV UT WOS:000245031800023 PM 17363531 ER PT J AU Solit, DB Ivy, SP Kopil, C Sikorski, R Morris, MJ Slovin, SF Kelly, WK DeLaCruz, A Curley, T Heller, G Larson, S Schwartz, L Egorin, MJ Rosen, N Scher, HI AF Solit, David B. Ivy, S. Percy Kopil, Catherine Sikorski, Rachel Morris, Michael J. Slovin, Susan F. Kelly, W. Kevin DeLaCruz, Anthony Curley, Tracy Heller, Glenn Larson, Steven Schwartz, Lawrence Egorin, Merrill J. Rosen, Neal Scher, Howard I. TI Phase I trial of 17-allylamino-17-demethoxygeldanamycin in patients with advanced cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID PACLITAXEL-MEDIATED CYTOTOXICITY; RECEPTOR TYROSINE KINASES; HSP90 INHIBITORS; 17-ALLYLAMINO GELDANAMYCIN; ONCOGENIC TRANSFORMATION; ATP BINDING; DEGRADATION; VIVO; HEAT-SHOCK-PROTEIN-90; CELLS AB Purpose: To define the maximum tolerated dose (MTD), toxicities, and pharmacokinetics of 17-allylamino-17-demethoxygeldanamycin (17-AAG) when administered using continuous and intermittent dosing schedules. Experimental Design: Patients with progressive solid tumor malignancies were treated with 17-AAG using an accelerated titration dose escalation schema. The starting dose and schedule were 5 mg/m(2) daily for 5 days with cycles repeated every 21 days, Dosing modifications based on safety, pharmacodynamic modeling, and clinical outcomes led to the evaluation of the following schedules: daily x 3 repeated every 14 days; twice weekly (days 1, 4, 8, and 11) for 2 weeks every 3 weeks; and twice weekly (days 1 and 4) without interruption. During cycle 1, blood was collected for pharmacokinetic and pharmacodynamic studies. Results: Fifty-four eligible patients were treated. The MTD was schedule dependent: 56 mg/m(2) on the daily x 5 schedule; 112 mg/m(2) on the daily x 3 schedule; and 220 mg/m(2) on the days 1, 4, 8, and 11 every-21-day schedule. Continuous twice-weekly dosing was deemed too toxic because of delayed hepatotoxicity. Hepatic toxicity was also dose limiting with the daily x 5 schedule. Other common toxicities encountered were fatigue, myalgias, and nausea. This latter adverse effect may have been attributable, in part, to the DMSO-based formulation. Concentrations of 17-AAG above those required for activity in preclinical models could be safely achieved in plasma. Induction of a heat shock response and down-regulation of Akt and Raf-1 were observed in biomarker studies. Conclusion: The MTD and toxicity profile of 17-AAG were schedule dependent. Intermittent dosing schedules were less toxic and are recommended for future phase II studies. C1 Mem Sloan Kettering Canc Ctr, Dept Med, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Biostat, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Nucl Med, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Radiol, New York, NY 10021 USA. Mem Sloan Kettering Canc Ctr, Dept Mol Pharmacol & Chem, New York, NY 10021 USA. NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Ctr, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Mol Therapeut Drug Discovery Program, Pittsburgh, PA USA. RP Scher, HI (reprint author), Mem Sloan Kettering Canc Ctr, Dept Med, 1275 York Ave, New York, NY 10021 USA. EM scherh@mskcc.org OI Morris, Michael J./0000-0002-9454-0096 FU NCI NIH HHS [U01-CA69856, P50-CA92629, P50 CA092629, U01 CA069856]; PHS HHS [R21 85506-01] NR 40 TC 156 Z9 158 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 MAR 15 PY 2007 VL 13 IS 6 BP 1775 EP 1782 DI 10.1158/1078-0432.CCR-06-1863 PG 8 WC Oncology SC Oncology GA 147VV UT WOS:000245031800024 PM 17363532 ER PT J AU Bagatell, R Gore, L Egorin, MJ Ho, R Heller, G Boucher, N Zuhowski, EG Whitlock, JA Hunger, SP Narendran, A Katzenstein, HM Arceci, RJ Boklan, J Herzog, CE Whitesell, L Ivy, SP Trippett, TM AF Bagatell, Rochelle Gore, Lia Egorin, Merrill J. Ho, Richard Heller, Glenn Boucher, Nichole Zuhowski, Eleanor G. Whitlock, James A. Hunger, Stephen P. Narendran, Aru Katzenstein, Howard M. Arceci, Robert J. Boklan, Jessica Herzog, Cynthia E. Whitesell, Luke Ivy, S. Percy Trippett, Tanya M. TI Phase I pharmacokinetic and pharmacodynamic study of 17-N-allylamino-17-demethoxygeldanamycin in pediatric patients with recurrent or refractory solid tumors: A pediatric oncology experimental therapeutics investigators consortium study SO CLINICAL CANCER RESEARCH LA English DT Article ID HSP90 INHIBITORS; HSP90-BINDING AGENT; LEUKEMIA-CELLS; GELDANAMYCIN; APOPTOSIS; HEAT-SHOCK-PROTEIN-90; PROTEIN; CANCER; 17-(ALLYLAMINO)-17-DEMETHOXYGELDANAMYCIN; 17-ALLYLAMINO-17-DEMETHOXYGELDANAMYCIN AB Purpose: Heat shock protein 90 (Hsp90) is essential for the posttranslational control of many regulators of cell growth, differentiation, and apoptosis. 17-N-Allylamino-17-demethoxygeldanamycin (17-AAG) binds to Hsp90 and alters levels of proteins regulated by Hsp90. We conducted a phase I trial of 17-AAG in pediatric patients with recurrent or refractory neuroblastoma, Ewing's sarcoma, osteosarcoma, and desmoplastic small round cell tumor to determine the maximum tolerated dose, define toxicity and pharmacokinetic profiles, and generate data about molecular target modulation. Experimental Design: Escalating doses of 17-AAG were administered i.v. over 1 to 2 h twice weekly for 2 weeks every 21 days until patients experienced disease progression or toxicity. harmacokinetic and pharmacodynamic studies were done during cycle 1. Results: Fifteen patients were enrolled onto dose levels between 150 and 360 mg/m(2) 13 patients were evaluable for toxicity. The maximum tolerated dose was 270 mg/m(2). DLTs were grade 3 transaminitis and hypoxia. Two patients with osteosarcoma and bulky pulmonary metastases died during cycle 1 and were not evaluable for toxicity. No objective responses were observed. 17-AAG pharmacokinetics in pediatric patients were linear; clearance and half-life were 21.6 +/- 6.21 (mean +/- SD) L/h/m(2) and 2.6 +/- 0.95 h, respectively. Posttherapy increases in levels of the inducible isoform of Hsp70, a marker of target modulation, were detected in peripheral blood mononuclear cells at all dose levels. Conclusion: 17-AAG was well tolerated at a dose of 270 mg/m2 administered twice weekly for 2 of 3 weeks. Caution should be used in treatment of patients with bulky pulmonary disease. C1 Univ Arizona, Dept Pediat, Tucson, AZ 85721 USA. Univ Arizona, Steele Childrens Res Ctr, Tucson, AZ 85721 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA USA. Univ Pittsburgh, Dept Pharmacol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15261 USA. Vanderbilt Univ, Med Ctr, Nashville, TN USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Univ Florida, Gainesville, FL USA. Univ Calgary, Calgary, AB, Canada. So Alberta Childrens Canc Program, Calgary, AB, Canada. Childrens Healthcare Atlanta, Atlanta, GA USA. Johns Hopkins Univ, Sidney Kimmel Canc Ctr, Baltimore, MD USA. Phoenix Childrens Hosp, Phoenix, AZ USA. Univ Texas, MD Anderson Canc Ctr, Houston, TX 77030 USA. Whitehead Inst, Cambridge, MA 02142 USA. NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Ctr, Bethesda, MD 20892 USA. RP Bagatell, R (reprint author), Arizona Hlth Sci Ctr, Dept Pediat Pediat Hematol Oncol, Room 5341,1501 N Campbell Ave, Tucson, AZ 85724 USA. EM bagatell@peds.arizona.edu FU NCI NIH HHS [U54 CA090821]; NCRR NIH HHS [M01 RR-00069, M01 RR-00082, M01 RR-00095] NR 32 TC 68 Z9 71 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2007 VL 13 IS 6 BP 1783 EP 1788 DI 10.1158/1078-0432.CCR-06-1892 PG 6 WC Oncology SC Oncology GA 147VV UT WOS:000245031800025 PM 17363533 ER PT J AU Weigel, BJ Blaney, SM Reid, JM Safgren, SL Bagatell, R Kersey, J Neglia, JP Ivy, SP Ingle, AM Whitesell, L Gilbertson, RJ Krailo, M Ames, M Adamson, PC AF Weigel, Brenda J. Blaney, Susan M. Reid, Joel M. Safgren, Stephanie L. Bagatell, Rochelle Kersey, John Neglia, Joseph P. Ivy, S. Percy Ingle, Ashish M. Whitesell, Luke Gilbertson, Richard J. Krailo, Mark Ames, Matthew Adamson, Peter C. TI A phase I study of 17-allylaminogeldanamycin in relapsed/refractory pediatric patients with solid tumors: A children's oncology group study SO CLINICAL CANCER RESEARCH LA English DT Article ID CANCER CELLS; 17-ALLYLAMINO-17-DEMETHOXYGELDANAMYCIN; 17-(ALLYLAMINO)-17-DEMETHOXYGELDANAMYCIN; GELDANAMYCIN; HSP90; EXPRESSION AB Purpose: To determine the recommended phase 2 dose, dose-limiting toxicities (DLT), pharmacokinetic profile, and pharmacodynamics of the heat shock protein (Hsp) 90 inhibitor, 17-allylaminogeldanamycin (17-AAG). Experimental Design: 17-AAG was administered as a 60-min infusion, on days 1, 4, 8, and 11 of a 21-day cycle at dose levels of 150, 200, 270, and 360 mg/m(2)/dose. Pharmacokinetic studies and evaluations for Hsp72 and Akt levels in peripheral blood mononuclear cells were done during the first course of therapy. Results: Seventeen patients (7 males), median 7 years of age (range, 1-19 years), were enrolled using a standard dose escalation scheme. No DLTs were observed. Although there were no objective responses, three patients remain on therapy at 6+, 7+, and 9+ months with stable disease. One patient with hepatoblastoma had a reduction in alpha-fetoprotein and stable disease over three cycles. At 270 mg/m(2)/dose, the C-max and areas under the plasma concentration-time curves of 17-AAG were 5,303 +/- 1,591 ng/mL and 13,656 +/- 4,757 ng/mL h, respectively, similar to the exposure in adults. The mean terminal half-life for 17-AAG was 3.24 +/- 0.80 h. Induction of Hsp72, a surrogate marker for inhibition of Hsp90, was detected at the 270 mg/m2 dose level. Conclusions: Drug exposures consistent with those required for anticancer activity in preclinical models were achieved without DLT. Evidence for drug-induced modulation of Hsp90 systemically was also detected. The recommended phase II dose of 17-AAG is 360 mg/m(2)/d. Non-DMSO-containing formulations may improve acceptance of this drug by children and their families. C1 Univ Minnesota, Ctr Canc, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA. Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. Univ Arizona, Tucson, AZ USA. Natl Canc Inst, Washington, DC USA. Childrens Oncol Grp, Arcadia, CA USA. Whitehead Inst, Cambridge, MA 02142 USA. St Jude Childrens Hosp, Memphis, TN 38105 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. RP Weigel, BJ (reprint author), Univ Minnesota, Ctr Canc, MMC 366,420 Delaware St SE, Minneapolis, MN 55455 USA. EM weige007@umn.edu FU NCI NIH HHS [U01 CA97452] NR 22 TC 60 Z9 63 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2007 VL 13 IS 6 BP 1789 EP 1793 DI 10.1158/1078-0432.CCR-06-2270 PG 5 WC Oncology SC Oncology GA 147VV UT WOS:000245031800026 PM 17363534 ER PT J AU Milenic, DE Garmestani, K Brady, ED Albert, PS Abdulla, A Flynn, J Brechbiel, MW AF Milenic, Diane E. Garmestani, Kayhan Brady, Erik D. Albert, Paul S. Abdulla, Alia Flynn, Joseph Brechbiel, Martin W. TI Potentiation of high-LET radiation by gemcitabine: Targeting HER2 with trastuzumab to treat disseminated peritoneal disease SO CLINICAL CANCER RESEARCH LA English DT Article ID COLON-CARCINOMA CELLS; PANCREATIC-CANCER; ANTITUMOR-ACTIVITY; PROSTATE-CANCER; OVARIAN-CANCER; PAM4 ANTIBODY; BREAST-CANCER; IN-VITRO; RADIOIMMUNOTHERAPY; THERAPY AB Purpose: Recent studies from this laboratory with Pb-212-trastuzumab have shown the feasibility of targeted therapy for the treatment of disseminated peritoneal disease using Pb-212 as an in vivo generator of Bi-212. The objective of the studies presented here was improvement of the efficacy of a-particle radioimmunotherapy using a chemotherapeutic agent. Experimental Design: In a series of experiments, a treatment regimen was systematically developed in which athymic mice bearing i.p. LS-174T xenografts were injected i.p. with gemcitabine at 50 mg/kg followed by Pb-212 radioimmunotherapy. Results: In a pilot study, tumor-bearing mice were treated with gemcitabine and, 24 to 30 h later, with 5 or 10 mu Ci Pb-212-trastuzumab. Improvement in median survival was observed at 5 mu Ci Pb-212-trastuzumab in the absence (31 days) or presence (51 days) of gemcitabine: 45 and 70 days with 10 mu Ci versus 16 days for untreated mice (P < 0.001). Multiple doses of gemcitabine combined with a single Pb-212 radioimmunotherapy (10 mu Ci) administration was then evaluated. Mice received three doses of gemcitabine: one before Pb-212-trastuzumab and two afterwards. Median survival of mice was 63 versus 54 days for those receiving a single gemcitabine dose before radioinimunotherapy (P < 0.001), specifically attributable to Pb-212-trastuzumab (P = 0.01). Extending these findings, one versus two treatment cycles was compared. A cycle consisted of sequential treatment with gemcitabine, 10 mu Ci Pb-212 radioimmunotherapy, then one or two additional gemcitabine doses. In the first cycle, three doses of gemcitabine resulted in a median survival of 90 versus 21 days for the untreated mice. The greatest benefit was noted after cycle 2 in the mice receiving 10 mu Ci Pb-212-trastuzumab and two doses of gemcitabine with a median survival of 196.5 days (P = 0.005). Pretreatment of tumor-bearing mice with two doses of gemcitabine before Pb-212 radioimmunotherapy was also assessed with gemcitabine injected 72 and 24 h before Pb-212-trastuzumab. The median survival was 56 and 76 days with one and two doses of gemcitabine versus 49 days without gemcitabine. The effect may not be wholly specific to trastuzumab because Pb-212-HuIgG with two doses of gemcitabine resulted in a median survival of 66 days (34 days without gemcitabine). Conclusions: Treatment regimens combining chemotherapeutics with high-LET targeted therapy may have tremendous potential in the management and care of cancer patients. C1 NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. Walter Reed Med Ctr, Washington, DC USA. RP Milenic, DE (reprint author), NCI, Radioimmune & Inorgan Chem Sect, Radiat Oncol Branch, NIH, 10 Ctr Dr,MSC-1002,Bldg 10,Room 1B40, Bethesda, MD 20892 USA. EM dm71q@nih.gov FU Intramural NIH HHS NR 62 TC 38 Z9 40 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2007 VL 13 IS 6 BP 1926 EP 1935 DI 10.1158/1078-0432.CCR-06-2300 PG 10 WC Oncology SC Oncology GA 147VV UT WOS:000245031800042 PM 17363549 ER PT J AU Kudo-Saito, C Wansley, EK Gruys, ME Wiltrout, R Schlom, J Hodge, JW AF Kudo-Saito, Chie Wansley, Elizabeth K. Gruys, M. Eilene Wiltrout, Robert Schlom, Jeffrey Hodge, James W. TI Combination therapy of an orthotopic renal cell carcinoma model using intratumoral vector-mediated costimulation and systemic interleukin-2 SO CLINICAL CANCER RESEARCH LA English DT Article ID COLONY-STIMULATING FACTOR; DIVERSIFIED SUBCUTANEOUS/INTRATUMORAL VACCINATION; ANTIGEN-PRESENTING CELLS; REGIONAL LYMPH-NODES; SPONTANEOUS REGRESSION; PULMONARY METASTASES; ANTITUMOR RESPONSES; IMMUNE-RESPONSES; CANCER-CELLS; T-CELLS AB Purpose: Interleukin (IL)-2 therapy is currently used for therapy of renal cell carcinoma (RCC). However, it is only effective in approximately 10% to 15% of patients, showing a need for additional therapies. We have previously described a replication-defective fowlpox vector encoding three costimulatory molecules (B7-1, ICAM-1, and LFA-3), designated rF-TRICOM. Here, we show that intratumoral administration of rF-TRICOM in an orthotopic RCC model effectively enhances tumor immunogenicity and reduces tumor burden in mice and the combination of rF-TRICOM and IL-2 is more effective than either therapy alone. Experimental Design: RCC cells were implanted under the capsule of the kidney, and mice were given rF-TRICOM intratumorally 14 days later. We compared the effect of rF-TRICOM, rF-granulocyte macrophage colony-stimulating factor (GM-CSF), and two doses of IL-2 and combinations of the above on antitumor efficacy and survival. Host CD4(+) and CD8(+) T-cell responses were also evaluated. Results: The results show that (a) systemic IL-2 therapy was moderately effective in the reduction of tumor burden in an orthotopic RCC model; (b) a single intratumoral injection of rF-TRICOM and rF-GM-CSF significantly reduced tumor burden; (c) the addition of systemic IL-2 to intratumoral rF-TRICOM/rF-GM-CSF administration resulted in further reduction of tumor burden, decrease in the incidence of metastasis, and extended survival in tumor-bearing mice above that seen with either treatment alone; and (cl) CD8+ T cells played a critical role in the antitumor effect seen with rF-TRICOM/rF-GM-CSF + IL-2 therapy. Finally, the addition of systemic recombinant IL-15 or intratumoral vector-delivered IL-15 to intratumoral rF-TRICOM/rF-GM-CSF administration resulted in substantially more tumor-free mice than either therapy alone. Conclusions: These studies show that intratumoral administration of rF-TRICOM admixed with rF-GM-CSF is effective at reducing tumor burden in mice and the addition of IL-2 further contributes to this effect. These studies thus form the rationale for combination immunotherapy clinical trials in patients with RCC. C1 NCI, Ctr Canc Res, Tumor Immunol & Biol Lab, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Expt Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Schlom, J (reprint author), NCI, Ctr Canc Res, Tumor Immunol & Biol Lab, NIH, 10 Ctr Dr,Room 8B09, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Hodge, James/D-5518-2015; OI Hodge, James/0000-0001-5282-3154; Wansley, Elizabeth/0000-0002-0110-7550 FU Intramural NIH HHS NR 59 TC 14 Z9 15 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 15 PY 2007 VL 13 IS 6 BP 1936 EP 1946 DI 10.1158/1078-0432.CCR-06-2398 PG 11 WC Oncology SC Oncology GA 147VV UT WOS:000245031800043 PM 17363550 ER PT J AU Hens, JR Dann, P Zhang, JP Harris, S Robinson, GW Wysolmerski, J AF Hens, Julie R. Dann, Pamela Zhang, Jian-Ping Harris, Stephen Robinson, Gertraud W. Wysolmerski, John TI BMP4 and PTHrP interact to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction SO DEVELOPMENT LA English DT Article DE mammary gland; breast; hair follicle; epidermal appendages; branching morphogenesis; parathyroid hormone-related protein (PTHrP); bone morphogenic proteins ID HORMONE-RELATED PROTEIN; BONE MORPHOGENETIC PROTEIN-4; GROWTH-FACTOR-BETA; PARATHYROID-HORMONE; GLAND DEVELOPMENT; BRANCHING MORPHOGENESIS; VASCULAR CALCIFICATION; BREAST DEVELOPMENT; GENE-EXPRESSION; XENOPUS EMBRYOS AB The mammary glands develop initially as buds arising from the ventral embryonic epidermis. Recent work has shed light on signaling pathways leading to the patterning and formation of the mammary placodes and buds in mouse embryos. Relatively little is known of the signaling pathways that initiate branching morphogenesis and the formation of the ducts from the embryonic buds. Previous studies have shown that parathyroid hormone-related protein (PTHrP; also known as parathyroid hormone-like peptide, Pthlh) is produced by mammary epithelial cells and acts on surrounding mesenchymal cells to promote their differentiation into a mammary-specific dense mesenchyme. As a result of PTHrP signaling, the mammary mesenchyme supports mammary epithelial cell fate, initiates ductal development and patterns the overlying nipple sheath. In this report, we demonstrate that PTHrP acts, in part, by sensitizing mesenchymal cells to BMP signaling. PTHrP upregulates BMP receptor 1A expression in the mammary mesenchyme, enabling it to respond to BMP4, which is expressed within mesenchymal cells underlying the ventral epidermis during mammary bud formation. We demonstrate that BMP signaling is important for outgrowth of normal mammary buds and that BMP4 can rescue outgrowth of PTHrP(-/-) mammary buds. In addition, the combination of PTHrP and BMP signaling is responsible for upregulating Msx2 gene expression within the mammary mesenchyme, and disruption of the Msx2 gene rescues the induction of hair follicles on the ventral surface of mice overexpressing PTHrP in keratinocytes (K14-PTHrP). Our data suggest that PTHrP signaling sensitizes the mammary mesenchyme to the actions of BMP4, triggering outgrowth of the mammary buds and inducing MSX2 expression, which, in turn, leads to lateral inhibition of hair follicle formation within the developing nipple sheath. C1 Yale Univ, Sch Med, Dept Internal Med, Sect Endocrinol & Metab, New Haven, CT 06520 USA. Univ Texas, Hlth Sci Ctr, Dept Periodont, San Antonio, TX 78229 USA. NIDDK, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. RP Wysolmerski, J (reprint author), Yale Univ, Sch Med, Dept Internal Med, Sect Endocrinol & Metab, New Haven, CT 06520 USA. EM john.wysolmerski@yale.edu RI Robinson, Gertraud/I-2136-2012 FU Intramural NIH HHS; NIAMS NIH HHS [P30AR46032]; NIDDK NIH HHS [P30DK45735, R01DK55501, R01DK69542, T32DK07058] NR 68 TC 58 Z9 61 U1 0 U2 8 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD MAR 15 PY 2007 VL 134 IS 6 BP 1221 EP 1230 DI 10.1242/dev.000182 PG 10 WC Developmental Biology SC Developmental Biology GA 144YJ UT WOS:000244832200020 PM 17301089 ER PT J AU Iser, WB Gami, MS Wolkow, CA AF Iser, Wendy B. Gami, Minaxi S. Wolkow, Catherine A. TI Insulin signaling in Caenorhabditis elegans regulates both endocrine-like and cell-autonomous outputs SO DEVELOPMENTAL BIOLOGY LA English DT Article DE insulin; phosphoinositide 3-kinase; FCXO; Caenorhabditis elegans; aging; lifespan; Dauer; diapause ID TISSUE-SPECIFIC ACTIVITIES; HEAT-SHOCK FACTOR; AGE-1 PI3 KINASE; LIFE-SPAN; C-ELEGANS; TRANSCRIPTION FACTOR; SYNAPTIC INPUT; MOTOR NEURONS; FAMILY-MEMBER; DAUER LARVA AB In C elegans, insulin signaling affects development, lifespan and stress resistance. Several studies have shown that insulin signaling affects lifespan in an endocrine-like manner from different cells, while the major downstream target of insulin, the FOXO transcription factor encoded by daf-16, may act preferentially in intestinal cells to prolong lifespan. This discrepancy raised the possibility that insulin may have both endocrine and cell-intrinsic outputs. Here, we further investigated the types of cells capable of producing endocrine outputs of insulin and also identified a new cell-intrinsic insulin output. We found that insulin signaling within groups of neurons promoted wildtype lifespan, showing that the endocrine outputs of insulin were not restricted to specific cells. In contrast, DAT-16 appeared to have a greater effect on lifespan when expressed in a combination of tissues. These results suggest that insulin signaling may regulate DAF-16 through cell-intrinsic and endocrine pathways. We also found that an insulin-dependent response to fasting in intestinal cells was preferentially regulated by intestinal insulin signaling and was less responsive to insulin signaling from non-intestinal cells. Together, these results show that C elegans insulin signaling has endocrine as well as tissue-specific outputs which could influence lifespan in a combinatorial fashion. Published by Elsevier Inc. C1 NIA, IRP, Neurosci Lab, Baltimore, MD 21224 USA. RP Wolkow, CA (reprint author), NIA, IRP, Neurosci Lab, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM wolkowca@grc.nia.nih.gov FU Intramural NIH HHS [Z01 AG000320-06] NR 45 TC 24 Z9 28 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD MAR 15 PY 2007 VL 303 IS 2 BP 434 EP 447 DI 10.1016/j.ydbio.2006.04.467 PG 14 WC Developmental Biology SC Developmental Biology GA 147GN UT WOS:000244991500003 PM 17257591 ER PT J AU Buchholz, DR Heimeier, RA Das, B Washington, T Shi, YB AF Buchholz, Daniel R. Heimeier, Rachel A. Das, Biswajit Washington, Teresa Shi, Yun-Bo TI Pairing morphology with gene expression in thyroid hormone-induced intestinal remodeling and identification of a core set of TH-induced genes across tadpole tissues SO DEVELOPMENTAL BIOLOGY LA English DT Article DE frog metamorphosis; thyroid hormone; intestine remodeling; microarray ID ADULT EPITHELIAL DEVELOPMENT; XENOPUS-LAEVIS TADPOLES; ACID-BINDING PROTEIN; FROG METAMORPHOSIS; CELL-PROLIFERATION; TRANSCRIPTIONAL ACTIVATION; AMPHIBIAN METAMORPHOSIS; MICROARRAY DATA; SONIC HEDGEHOG; RESPONSE GENES AB Thyroid hormone (T3) plays a central role in vertebrate post-embryonic development, and amphibian metamorphosis provides a unique opportunity to examine T3-dependent developmental changes. To establish a molecular framework for understanding T3-induced morphological change, we identified a set of gene expression profiles controlled by T3 in the intestine via microarray analysis. Samples were obtained from premetamorphic Xenopus laevis tadpole intestines after 0, 1, 3, and 6 days of T3 treatment, which induces successive cell death and proliferation essential for intestinal remodeling. Using a set of 21,807 60-mer oligonucleotide probes representing > 98% of the Unigene clusters, we found that 1997 genes were differentially regulated by 1.5-fold or more during this remodeling process and were clustered into four temporal expression profiles; transiently up- or downregulated and late up- or downregulated. Gene Ontology categories most significantly associated with these clusters were proteolysis, cell cycle, development and transcription, and electron transport and metabolism, respectively. These categories are common with those found for T3-regulated genes from brain, limb, and tail, although more than 70% of T3-regulated genes are tissue-specific, likely due to the fact that not all genes are annotated into GO categories and that GO categories common to different organs also contain genes regulated by T3 tissue specifically. Finally, a core set of upregulated genes, most previously unknown to be T3-regulated, were identified and enriched in genes involved in transcription and cell signaling. (c) 2006 Elsevier Inc. All rights reserved. C1 NICHD, Sect Mol Morphogenesis, Program Cell Regulat & Metab, LGRD,NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), NICHD, Sect Mol Morphogenesis, Program Cell Regulat & Metab, LGRD,NIH, Bldg 18 T,Room 106, Bethesda, MD 20892 USA. EM shi@helix.nih.gov FU Intramural NIH HHS NR 53 TC 53 Z9 55 U1 1 U2 10 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0012-1606 EI 1095-564X J9 DEV BIOL JI Dev. Biol. PD MAR 15 PY 2007 VL 303 IS 2 BP 576 EP 590 DI 10.1016/j.ydbio.2006.11.037 PG 15 WC Developmental Biology SC Developmental Biology GA 147GN UT WOS:000244991500015 PM 17214978 ER PT J AU Pham, VN Lawson, ND Mugford, JW Dye, L Castranova, D Lo, B Weinstein, BM AF Pham, Van N. Lawson, Nathan D. Mugford, Joshua W. Dye, Louis Castranova, Daniel Lo, Brigid Weinstein, Brant M. TI Combinatorial function of ETS transcription factors in the developing vasculature SO DEVELOPMENTAL BIOLOGY LA English DT Article DE zebrafish; ETS transcription factors; intersegmental vessels; vascular development; angiogenesis ID ENDOTHELIAL-CELL DIFFERENTIATION; IN-SITU HYBRIDIZATION; XI-FLI GENE; ZEBRAFISH EMBRYOS; CHICK-EMBRYO; EXPRESSION; FAMILY; ANGIOGENESIS; APOPTOSIS; MICE AB Members of the ETS family of transcription factors are among the first genes expressed in the developing vasculature, but loss-of-function experiments for individual ETS factors in mice have not uncovered important early functional roles for these genes. However, multiple ETS factors are expressed in spatially and temporally overlapping patterns in the developing vasculature, suggesting possible functional overlap. We have taken a comprehensive approach to exploring the function of these factors during vascular development by employing the genetic and experimental tools available in the zebrafish to analyze four ETS family members expressed together in the zebrafish vasculature; fli1, fli1b, ets1, and etsrp. We isolated and characterized an ENU-induced mutant with defects in trunk angiogenesis and positionally cloned the defective gene from this mutant, etsrp. Using the etsrp morpholinos targeting each of the four genes, we show that the four ETS factors function combinatorially during vascular and hematopoietic development. Reduction of etsrp or any of the other genes alone results in either partial or no defects in endothelial differentiation, while combined reduction in the function of all four genes causes dramatic loss of endothelial cells. Our results demonstrate that combinatorial ETS factor function is essential for early endothelial specification and differentiation. (c) 2006 Elsevier Inc. All rights reserved. C1 NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. NICHD, Microscopy & Imaging Core, NIH, Bethesda, MD USA. RP Weinstein, BM (reprint author), NICHD, Mol Genet Lab, NIH, Bldg 6B,Room 309,6 Ctr Dr, Bethesda, MD 20892 USA. EM bw96w@nih.gov FU Intramural NIH HHS; NICHD NIH HHS [Z01 HD001011-09] NR 42 TC 102 Z9 107 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 0012-1606 J9 DEV BIOL JI Dev. Biol. PD MAR 15 PY 2007 VL 303 IS 2 BP 772 EP 783 DI 10.1016/j.ydbio.2006.10.030 PG 12 WC Developmental Biology SC Developmental Biology GA 147GN UT WOS:000244991500030 PM 17125762 ER PT J AU Dong, HT Deng, Y Chen, J Wang, S Peng, SH Dai, C Fang, YQ Shao, J Lou, YC Li, DB AF Dong, Haitao Deng, Ye Chen, Jack Wang, Sheng Peng, Sihua Dai, Cheng'en Fang, Yongqi Shao, Jing Lou, Yichun Li, Debao TI An exploration of 3 '-end processing signals and their tissue distribution in Oryza sativa SO GENE LA English DT Article DE 3 '-UTR; rice; downstream sequences; cleavage site ID MESSENGER-RNA POLYADENYLATION; ALTERNATE POLYADENYLATION; DRAFT SEQUENCE; EUKARYOTES; MECHANISM; ENDS AB The 3' untranslated regions deeply affect many properties of eukaryotic mRNA. In plants, the polyadenine control signals contained in these regions seem to be more variable than of mammals. Three cDNA libraries derived from the leaf. endosperm and stem tissues of rice were sequenced from the 3'-end. Of the 9911 transcripts analyzed, 5723 unique transcripts were identified from the leaf sequences, 2934 from the endosperm and 1254 from the stem. The information entropy and two statistical methods were used to compile a list of rice poly(A) control signals. Based on their distribution, these signals call be roughly grouped into far-upstream element (FUE), near-upstream element (NUE), T-rich region (TRE) and downstream element (DE). The distribution of rice conserved regions is similar to the previous model from Arabidopsis and yeast, with a few differences in word constructions. Interestingly, we also found the word distributions were diverse in the cleavage sate of downstream sequences of different rice tissues. The signal bias in downstream sequences may lead mRNA to be differently cleaved in different rice tissues. (c) 2006 Elsevier B.V. All rights reserved. C1 Zhejiang Univ, Coll Agr & Biotechnol, Bioinformat & Gene Network Res Grp, Hangzhou 310029, Peoples R China. Zhejiang Univ, Coll Mech & Energy Engn, Hangzhou 310027, Peoples R China. NICHD, Bioinformat Unit, NIH, Bethesda, MD 20892 USA. RP Dong, HT (reprint author), Zhejiang Univ, Coll Agr & Biotechnol, Bioinformat & Gene Network Res Grp, Hangzhou 310029, Peoples R China. EM htdong@zjuem.zju.edu.cn RI peng, sihua/C-2730-2009; Deng, Ye/A-2571-2013; OI ?, ?/0000-0002-7584-0632 NR 24 TC 13 Z9 14 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD MAR 15 PY 2007 VL 389 IS 2 BP 107 EP 113 DI 10.1016/j.gene.2006.10.015 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 141TZ UT WOS:000244603000001 PM 17187943 ER PT J AU Kutty, G Kovacs, JA AF Kutty, Geetha Kovacs, Joseph A. TI Identification and characterization of rad51 of Pneumocystis SO GENE LA English DT Article DE recombination; enzymatic activity; Pneumocystis pneumonia; fungus ID MAJOR-SURFACE-GLYCOPROTEIN; HOMOLOGOUS RECOMBINATION; ANTIGENIC VARIATION; EXPRESSION SITE; DIHYDROPTEROATE SYNTHASE; DIHYDROFOLATE-REDUCTASE; TRYPANOSOMA-BRUCEI; STRAND EXCHANGE; SP-NOV.; CARINII AB Rad51, a eukaryotic homolog of RecA, is an important protein involved in DNA recombination and repair. We have characterized rad51 of Pneumocystis carinii and Pneumocystis murina. rad51 is a single copy gene that encodes a 1.2 kb mRNA, which contains an open reading frame encoding 343 amino acids. Rad51 from Pneumocystis showed high homology to those from yeast. ATP binding motifs GEFRTGKS and LLIVD, similar to those of Saccharomyces cerevisiae and Schizosaccharomyces pombe, are conserved in Pneumocystis Rad51. The recombinant protein when expressed in E. coli showed DNA-dependent ATPase activity. Since Rad51 is a key enzyme in DNA repair and recombination, it potentially plays an important role in the recombination process leading to antigenic variation and thereby resistance to host immune responses in Pneumocystis. Published by Elsevier B.V. C1 NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. RP Kovacs, JA (reprint author), Bldg 10,Room 2C145,MSC 1662, Bethesda, MD 20892 USA. EM jkovacs@nih.gov FU Intramural NIH HHS NR 42 TC 2 Z9 2 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-1119 J9 GENE JI Gene PD MAR 15 PY 2007 VL 389 IS 2 BP 204 EP 211 DI 10.1016/j.gene.2006.11.011 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 141TZ UT WOS:000244603000012 PM 17207588 ER PT J AU Bertelsen, L Mellemkjaer, L Frederiksen, K Kjaer, SK Brinton, LA Sakoda, LC van Valkengoed, I Olsen, JH AF Bertelsen, Lisbeth Mellemkjaer, Lene Frederiksen, Kirsten Kjaer, Susanne K. Brinton, Louise A. Sakoda, Lori C. van Valkengoed, Irene Olsen, Jorgen H. TI Risk for breast cancer among women with endometriosis SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE endometriosis; breast cancer; record linkage case-cohort ID MEDICAL CONDITIONS; EPIDEMIOLOGY; DIAGNOSIS; REGISTRY; HISTORY; COHORT; HEALTH AB Although several risk factors are common to endometriosis and breast cancer, the results of observational studies of an association have so far been inconsistent. We evaluated the relationship between endometriosis and breast cancer on the basis of data on selected cancers and medical histories from the Danish nationwide cancer and hospital registries used in a large case-cohort study. A total of 114,327 women were included in the study of whom 1,978 women had received a diagnosis of endometriosis and 16,983 had had a diagnosis of breast cancer between 1978 and 1998. Of the women with endometriosis, 236 subsequently received a diagnosis of breast cancer. The crude overall rate ratio for breast cancer after endometriosis was 1.00 and after adjustment for reproductive factors, calendar-period, bilateral oophorectomy and benign breast disease, the rate ratio was 0.97 (95% confidence interval, 0.85-1.11). The risk for breast cancer increased with age at diagnosis of endometriosis, so that women in whom endometriosis was diagnosed at a young age,(approximately < 40 years) had a reduced risk for breast cancer and women in whom endometriosis was diagnosed at older ages (approximately >= 40 years) tended to have an increased risk for breast cancer. The reduced risks observed among young women may reflect their exposure to drugs with antiestrogenic effects. The increased risk associated with endometriosis among postmenopausal women may be due to common risk factors between postmenopausal endometriosis and breast cancer or an altered endogenous estrogen. (c) 2006 Wiley-Liss, Inc. C1 Danish Canc Soc, Inst Canc Epidemiol, DK-2100 Copenhagen O, Denmark. NCI, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD USA. Univ Amsterdam, Acad Med Ctr, Dept Social Med, NL-1105 AZ Amsterdam, Netherlands. RP Bertelsen, L (reprint author), Danish Canc Soc, Inst Canc Epidemiol, Strandboulevarden 49, DK-2100 Copenhagen O, Denmark. EM lisbethb@cancer.dk RI van Valkengoed, Irene/B-2974-2013; Brinton, Louise/G-7486-2015; OI Brinton, Louise/0000-0003-3853-8562; Olsen, Jorgen Helge/0000-0001-9633-5662; Kjaer, Susanne/0000-0002-8347-1398 FU Intramural NIH HHS NR 28 TC 26 Z9 26 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD MAR 15 PY 2007 VL 120 IS 6 BP 1372 EP 1375 DI 10.1002/ijc.22490 PG 4 WC Oncology SC Oncology GA 134XU UT WOS:000244118600029 PM 17187365 ER PT J AU Hryniewicz, A Price, DA Moniuszko, M Boasso, A Edghill-Spano, Y West, SM Venzon, D Vaccari, M Tsai, WP Tryniszewska, E Nacsa, J Villinger, F Ansari, AA Trindade, CJ Morre, M Brooks, D Arlen, P Brown, HJ Kitchen, CMR Zack, JA Douek, DC Shearer, GM Lewis, MG Koup, RA Franchini, G AF Hryniewicz, Anna Price, David A. Moniuszko, Marcin Boasso, Adriano Edghill-Spano, Yvette West, Sadie M. Venzon, David Vaccari, Monica Tsai, Wen-Po Tryniszewska, Elzbieta Nacsa, Janos Villinger, Francois Ansari, Aftab A. Trindade, Christopher J. Morre, Michel Brooks, David Arlen, Philip Brown, Helen J. Kitchen, Christina M. R. Zack, Jerome A. Douek, Daniel C. Shearer, Gene M. Lewis, Mark G. Koup, Richard A. Franchini, Genoveffa TI Interleukin-15 but not interleukin-7 abrogates vaccine-induced decrease in virus level in simian immunodeficiency virus(mac251)-infected macaques SO JOURNAL OF IMMUNOLOGY LA English DT Article ID CD8(+) T-CELLS; HIV-INFECTED PATIENTS; MAJOR HISTOCOMPATIBILITY COMPLEX; BLOOD MONONUCLEAR-CELLS; IN-VIVO; ANTIRETROVIRAL THERAPY; RHESUS MACAQUES; TRANSFORMING GROWTH-FACTOR-BETA-1; LYMPHOID HOMEOSTASIS; DISEASE PROGRESSION AB The loss of CD4(+) T cells and the impairment of CD8(+) T cell function in HIV infection suggest that pharmacological treatment with IL-7 and IL-15, cytokines that increase the homeostatic proliferation of T cells and improve effector function, may be beneficial. However, these cytokines could also have a detrimental effect in HIV-1-infected individuals, because both cytokines increase HIV replication in vitro. We assessed the impact of IL-7 and IL-15 treatment on viral replication and the immunogenicity of live poxvirus vaccines in SIV(mac251)-infected macaques (Macaca mulatta). Neither cytokine augmented the frequency of vaccine-expanded CD4(+) or CD8(+) memory T cells, clonal recruitment to the SIV-specific CD8(+) T cell pool, or CD8(+) T cell function. Vaccination alone transiently decreased the viral set point following antiretroviral therapy suspension. IL-15 induced massive proliferation of CD4(+) effector T cells and abrogated the ability of vaccination to decrease set point viremia. In contrast, IL-7 neither augmented nor decreased the vaccine effect and was associated with a decrease in TGF-beta expression. These results underscore the importance of testing immunomodulatory approaches in vivo to assess potential risks and benefits for HIV-1-infected individuals. C1 NCI, Anim Models & Retroviral Sect, Bldg 41,Room D804, Bethesda, MD 20892 USA. Med Univ Bialystok, Bialystok, Poland. NIAID, Vaccine Res Ctr, Human Immunol Sect, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. NIAID, Immunol Lab, Vaccine Res Ctr, Bethesda, MD 20892 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. Emory Univ, Dept Pathol & Lab Med, Sch Med, Atlanta, GA 30322 USA. Cytheris, Issy Les Moulineaux, France. Univ Calif Los Angeles, David Geffen Med Sch, Los Angeles, CA 90095 USA. Bioqual, Rockville, MD 20850 USA. So Res Inst, Frederick, MD 21701 USA. Univ Calif Los Angeles, Sch Publ Hlth, Dept Biostat, Los Angeles, CA 90095 USA. RP Franchini, G (reprint author), NCI, Anim Models & Retroviral Sect, Bldg 41,Room D804, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov RI Price, David/C-7876-2013; OI Price, David/0000-0001-9416-2737; Boasso, Adriano/0000-0001-9673-6319 FU Intramural NIH HHS; Medical Research Council [G0501963] NR 76 TC 37 Z9 37 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 MAR 15 PY 2007 VL 178 IS 6 BP 3492 EP 3504 PG 13 WC Immunology SC Immunology GA 146NX UT WOS:000244942400019 PM 17339444 ER PT J AU Cuesta, N Nhu, QM Zudaire, E Polumuri, S Cuttitta, F Vogel, SN AF Cuesta, Natalia Nhu, Quan M. Zudaire, Enrique Polumuri, Swamy Cuttitta, Frank Vogel, Stefanie N. TI IFN regulatory factor-2 regulates macrophage apoptosis through a STAT1/3-and caspase-1-dependent mechanism SO JOURNAL OF IMMUNOLOGY LA English DT Article ID STAT-1 TRANSCRIPTION FACTOR; DAMAGE-INDUCED APOPTOSIS; TOLL-LIKE RECEPTORS; GENE-EXPRESSION; IMMUNE-SYSTEM; DNA-DAMAGE; CELL-DEATH; SERINE PHOSPHORYLATION; SIGNAL TRANSDUCER; HOST-DEFENSE AB IFN regulatory factor (IRF)-2(-/-) mice are significantly more resistant to LPS challenge than wild-type littermates, and this was correlated with increased numbers of apoptotic Kupffer cells. To assess the generality of this observation, and to understand the role of IRF-2 in apoptosis, responses of peritoneal macrophages from IRF-2(+/+) and IRF-2(-/-) mice to apoptotic stimuli, including the fungal metabolite, gliotoxin, were compared. IRF-2(-/-) macrophages exhibited a consistently higher incidence of apoptosis that failed to correlate with caspase-3/7 activity. Using microarray gene expression profiling of liver RNA samples derived from IRF-2(+/+) and IRF-2(-/-) mice treated with saline or LPS, we identified > 40 genes that were significantly down-regulated in IRF-2(-/-) mice, including Stat3, which has been reported to regulate apoptosis. Compared with IRF-2(+/+) macrophages, STAT3 alpha mRNA was up-regulated constitutively or after gliotoxin treatment of IRF-2(-/-) macrophages, whereas STAT3/3 mRNA was down-regulated. Phospho-Y705-STAT3, phospho-5727-STATl, and phospho-p38 protein levels were also significantly higher in IRF-2-1- than control macrophages. Activation of the STAT signaling pathway has been shown to elicit expression of CASPI and apoptosis. IRF-2-'- macrophages exhibited increased basal and gliotoxin-induced caspase-1 mRNA expression and enhanced caspase-1 activity. Pharmacologic inhibition of STAT3 and caspase-1 abolished gliotoxin-induced apoptosis in IRF-2(-/-) macrophages. A novel IFN-stimulated response element, identified within the murine promoter of Cusp], was determined to be functional by EMSA and supershift analysis. Collectively, these data support the hypothesis that IRF-2 acts as a transcriptional repressor of Caspl, and. that the absence of IRF-2 renders macrophages more sensitive to apoptotic stimuli in a caspase-1-dependent process. The Journal of Immunology, 2007, 178: 3602-3611. C1 Univ Maryland, Dept Microbiol & Immunol, Sch Med, Baltimore, MD 21201 USA. NCI, Cell & Canc Biol Branch, NIH, Bethesda, MD 20892 USA. RP Vogel, SN (reprint author), Univ Maryland, Dept Microbiol & Immunol, Sch Med, 660 W Baltimore St,Suite 324, Baltimore, MD 21201 USA. EM svogel@som.umaryland.edu RI Cuesta, Natalia/C-1358-2012; Cuesta, Natalia/J-7761-2015; Cuttitta, Frank/B-4758-2016 OI Cuesta, Natalia/0000-0003-0809-2934; FU NIAID NIH HHS [AI 18797, T32 AI007540] NR 73 TC 13 Z9 15 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 MAR 15 PY 2007 VL 178 IS 6 BP 3602 EP 3611 PG 10 WC Immunology SC Immunology GA 146NX UT WOS:000244942400032 PM 17339457 ER PT J AU Cohen, LG Birbaumer, N AF Cohen, Leonardo G. Birbaumer, Niels TI The physiology of brain-computer interfaces SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Editorial Material C1 NINDS, NIH, Human Cort Physiol Sect, Bethesda, MD 20892 USA. Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Tubingen, Germany. RP Cohen, LG (reprint author), NINDS, NIH, Human Cort Physiol Sect, Bldg 10,Room 5N226,10 Ctr Dr,MSC 1430, Bethesda, MD 20892 USA. EM cohenl@ninds.nih.gov; niels.birbaumer@uni-tuebingen.de NR 6 TC 3 Z9 3 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAR 15 PY 2007 VL 579 IS 3 BP 570 EP 570 DI 10.1113/jphysiol.2007.129346 PG 1 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 145TH UT WOS:000244886900005 ER PT J AU Birbaumer, N Cohen, LG AF Birbaumer, Niels Cohen, Leonardo G. TI Brain-computer interfaces: communication and restoration of movement in paralysis SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article; Proceedings Paper CT Journal of Physiology Symposium on Physiology of Brain-Computer Interfaces CY OCT 13, 2006 CL Atlanta, GA ID SLOW CORTICAL POTENTIALS; FOREBRAIN INHIBITORY MECHANISMS; AMYOTROPHIC-LATERAL-SCLEROSIS; RESONANCE-IMAGING FMRI; SELF-REGULATION; HASTENED DEATH; MOTOR FUNCTION; BIOFEEDBACK; CORTEX; BEHAVIOR AB The review describes the status of brain-computer or brain-machine interface research. We focus on non-invasive brain-computer interfaces (BCIs) and their clinical utility for direct brain communication in paralysis and motor restoration in stroke. A large gap between the promises of invasive animal and human BCI preparations and the clinical reality characterizes the literature: while intact monkeys learn to execute more or less complex upper limb movements with spike patterns from motor brain regions alone without concomitant peripheral motor activity usually after extensive training, clinical applications in human diseases such as amyotrophic lateral sclerosis and paralysis from stroke or spinal cord lesions show only limited success, with the exception of verbal communication in paralysed and locked-in patients. BCIs based on electroencephalographic potentials or oscillations are ready to undergo large clinical studies and commercial production as an adjunct or a major assisted communication device for paralysed and locked-in patients. However, attempts to train completely locked-in patients with BCI communication after entering the complete locked-in state with no remaining eye movement failed. We propose that a lack of contingencies between goal directed thoughts and intentions may be at the heart of this problem. Experiments with chronically curarized rats support our hypothesis; operant conditioning and voluntary control of autonomic physiological functions turned out to be impossible in this preparation. In addition to assisted communication, BCIs consisting of operant learning of EEG slow cortical potentials and sensorimotor rhythm were demonstrated to be successful in drug resistant focal epilepsy and attention deficit disorder. First studies of non-invasive BCIs using sensorimotor rhythm of the EEG and MEG in restoration of paralysed hand movements in chronic stroke and single cases of high spinal cord lesions show some promise, but need extensive evaluation in well-controlled experiments. Invasive BMIs based on neuronal spike patterns, local field potentials or electrocorticogram may constitute the strategy of choice in severe cases of stroke and spinal cord paralysis. Future directions of BCI research should include the regulation of brain metabolism and blood flow and electrical and magnetic stimulation of the human brain (invasive and non-invasive). A series of studies using BOLD response regulation with functional magnetic resonance imaging (fMRI) and near infrared spectroscopy demonstrated a tight correlation between voluntary changes in brain metabolism and behaviour. C1 Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Tubingen, Germany. NINDS, NIH, Human Cort Physiol Sect, Bethesda, MD 20892 USA. RP Birbaumer, N (reprint author), Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Tubingen, Germany. EM niels.birbaumer@uni-tuebingen.de FU Intramural NIH HHS NR 90 TC 294 Z9 308 U1 15 U2 121 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAR 15 PY 2007 VL 579 IS 3 BP 621 EP 636 DI 10.1113/jphysiol.2006.125633 PG 16 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 145TH UT WOS:000244886900010 PM 17234696 ER PT J AU Wedel, B Boyles, RR Putney, J Bird, GS AF Wedel, Barbara Boyles, Rebecca R. Putney, JamesW., Jr. Bird, Gary S. TI Role of the store-operated calcium entry proteins Stim1 and Orai1 in muscarinic cholinergic receptor-stimulated calcium oscillations in human embryonic kidney cells SO JOURNAL OF PHYSIOLOGY-LONDON LA English DT Article ID CRAC CHANNEL; CA2+ ENTRY; ARC CHANNELS; HEK293 CELLS; INFLUX; ACTIVATION; DEPLETION; PATHWAYS; SENSOR; MODEL AB We have investigated the nature of the Ca2+ entry supporting [Ca2+](i) oscillations in human embryonic kidney (HEK293) cells by examining the roles of recently described store-operated Ca2+ entry proteins, Stim1 and Orai1. Knockdown of Stim1 by RNA interference (RNAi) reduced the frequency of [Ca2+](i) oscillations in response to a low concentration of methacholine to the level seen in the absence of external Ca2+. However, knockdown of Stim1 did not block oscillations in canomical transient receptor potential 3 channel (TRPC3)-expressing cells and did not affect Ca2+ entry in response to arachidonic acid. The effects of knockdown of Stim1 could be reversed by inhibiting Ca2+ extrusion with a high concentration of Gd3+, or by rescuing the knockdown by overexpression of Stim1. Similarly, knockdown of Orai1 abrogated [Ca2+](i) oscillations, and this was reversed by use of high concentrations of Gd3+; however, knockdown of Orai1 did not affect arachidonic acid-activated entry. RNAi targeting 34 members of the transient receptor potential (TRP) channel superfamily did not reveal a role for any of these channel proteins in store-operated Ca2+ entry in HEK293 cells. These findings indicate that the Ca2+ entry supporting [Ca2+](i) oscillations in HEK293 cells depends upon the Ca2+ sensor, Stim1, and calcium release-activated Ca2+ channel protein, Orai1, and provide further support for our conclusion that it is the store-operated mechanism that plays the major role in this pathway. C1 NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Bird, GS (reprint author), NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, POB 12233, Res Triangle Pk, NC 27709 USA. EM bird@niehs.nih.gov OI Boyles, Rebecca/0000-0003-0073-6854 FU Intramural NIH HHS NR 28 TC 66 Z9 66 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0022-3751 J9 J PHYSIOL-LONDON JI J. Physiol.-London PD MAR 15 PY 2007 VL 579 IS 3 BP 679 EP 689 DI 10.1113/jphysiol.2006.125641 PG 11 WC Neurosciences; Physiology SC Neurosciences & Neurology; Physiology GA 145TH UT WOS:000244886900015 PM 17218358 ER PT J AU Lou, H Smith, AM Coates, LC Cawley, NX Loh, YP Birch, NP AF Lou, Hong Smith, Angela M. Coates, Leigh C. Cawley, Niamh X. Loh, Y. Peng Birch, Nigel P. TI The transmembrane domain of the prohormone convertase PC3: A key motif for targeting to the regulated secretory pathway SO MOLECULAR AND CELLULAR ENDOCRINOLOGY LA English DT Article DE prohormone convertase; enzyme; sorting; lipid raft; transmembrane protein ID CARBOXYPEPTIDASE-E; SORTING RECEPTOR; MEMBRANE-ASSOCIATION; CELLULAR TRAFFICKING; LIPID RAFTS; PROTEINS; SEQUENCE; GRANULES; FURIN; SPC3 AB The biosynthesis of hormones and neuropeptides involves post-translational cleavage of precursors at basic amino acids by prohormone convertases (PCs) predominantly in secretory granules that bud from the trans-Golgi Network. This study reports that the amino acid sequence of PC3 (aa617-638), previously identified as a novel transmembrane (TM) domain, confers lipid raft association and facilitates sorting of the enzyme to the secretory granules of Neuro2A cells for prohormone cleavage. Floatation analysis on sucrose density gradients showed that a proportion of full length (PC3-FL) and carboxyl terminus-truncated PC3(1-638) (PC3-638) containing the TM domain were associated with lipid rafts in Neuro2A cells, while PC3(1-616) (PC3-616) and PC3-Delta TM lacking the TM domain were not. Secondly, PC3-FL and PC3-638 underwent stimulated secretion and were shown to be colocalized with a secretory granule marker, chromogranin A, by immunocytochemistry. In contrast, PC3-616 and PC3-Delta TM were constitutively secreted and primarily localized in the Golgi. These data indicate that the transmembrane domain of PC3 plays a key role in sorting the enzyme to the regulated secretory pathway. Published by Elsevier Ireland Ltd. C1 NICHHD, Cellular Neurobiol Sect, NIH, Bethesda, MD 20892 USA. Univ Auckland, Sch Biol Sci, Lab Mol Neuroendocrinol, Auckland 1, New Zealand. RP Loh, YP (reprint author), NICHHD, Cellular Neurobiol Sect, NIH, Bldg 49,Room 5A22, Bethesda, MD 20892 USA. EM lohp@mail.nih.gov RI Birch, Nigel/H-2498-2011 OI Birch, Nigel/0000-0002-8417-3587 FU Intramural NIH HHS; NICHD NIH HHS [Z01 HD000056-30] NR 40 TC 12 Z9 13 U1 0 U2 2 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0303-7207 J9 MOL CELL ENDOCRINOL JI Mol. Cell. Endocrinol. PD MAR 15 PY 2007 VL 267 IS 1-2 BP 17 EP 25 DI 10.1016/j.mce.2006.11.011 PG 9 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 153JP UT WOS:000245429200003 PM 17240044 ER PT J AU Li, W Tu, DQ Brunger, AT Ye, YH AF Li, Wei Tu, Daqi Brunger, Axel T. Ye, Yihong TI A ubiquitin ligase transfers preformed polyubiquitin chains from a conjugating enzyme to a substrate SO NATURE LA English DT Article ID ENDOPLASMIC-RETICULUM STRESS; PROTEIN LIGASE; DEGRADATION; DOMAIN; HERP; COMPLEX; CDC34; PATHWAY; LYSINE; GP78 AB In eukaryotic cells, many short-lived proteins are conjugated with Lys48-linked ubiquitin chains and degraded by the proteasome(1). Ubiquitination requires an activating enzyme (E1), a conjugating enzyme (E2) and a ligase (E3)(2). Most ubiquitin ligases use either a HECT (homologous to E6-associated protein C terminus) or a RING (really interesting new gene) domain to catalyse polyubiquitination(3), but the mechanism of E3 catalysis is poorly defined(4). Here we dissect this process using mouse Ube2g2 (E2; identical at the amino acid level to human Ube2g2) and human gp78 (E3), an endoplasmic reticulum (ER)-associated conjugating system essential for the degradation of misfolded ER proteins(5,6). We demonstrate by expressing recombinant proteins in Escherichia coli that Ube2g2/gp78-mediated polyubiquitination involves preassembly of Lys48-linked ubiquitin chains at the catalytic cysteine of Ube2g2. The growth of Ube2g2-anchored ubiquitin chains seems to be mediated by an aminolysis-based transfer reaction between two Ube2g2 molecules that each carries a ubiquitin moiety in its active site. Intriguingly, polyubiquitination of a substrate can be achieved by transferring preassembled ubiquitin chains from Ube2g2 to a lysine residue in a substrate. C1 NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. Stanford Univ, Howard Hughes Med Inst, Dept Mol & Cellular Physiol Neurol & Neurol Sci S, Stanford, CA 94305 USA. Stanford Univ, SSRL, Stanford, CA 94305 USA. RP Ye, YH (reprint author), NIDDKD, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM yihongy@mail.nih.gov OI Brunger, Axel/0000-0001-5121-2036 FU Intramural NIH HHS NR 26 TC 143 Z9 146 U1 2 U2 17 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD MAR 15 PY 2007 VL 446 IS 7133 BP 333 EP 337 DI 10.1038/nature05542 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 145VC UT WOS:000244892900049 PM 17310145 ER PT J AU Plested, AJR Mayer, ML AF Plested, Andrew J. R. Mayer, Mark L. TI Structure and mechanism of kainate receptor modulation by anions SO NEURON LA English DT Article ID LIGAND-BINDING CORE; PARTIAL AGONIST ACTION; AMINO-ACID RECEPTORS; GLUTAMATE-RECEPTOR; CRYSTAL-STRUCTURES; NMDA RECEPTORS; AMPA RECEPTORS; SYNAPTIC PLASTICITY; ALPHA-AMYLASE; BIPOLAR CELLS AB L-glutamate, the major excitatory neurotransmitter in the human brain, activates a family of ligand-gated ion channels, the major subtypes of which are named AMPA, kainate, and NMDA receptors. In common with many signal transduction proteins, glutamate receptors are modulated by ions and small molecules, including Ca(2+), Mg(2+), Zn(2+), protons, polyamines, and ste roids. Strikingly, the activation of kainate receptors by glutamate requires the presence of both Na(+) and Cl(-) in the extracellular solution, and in the absence of these ions, receptor activity is abolished. Here, we identify the site and mechanism of action of anions. Surprisingly, we find that Cl(-) ions are essential structural components of kainate receptors. Cl(-) ions bind in a cavity formed at the interface between subunits in a dimer pair. In the absence of Cl(-), dinner stability is reduced, the rate of desensitization increases, and the fraction of receptors competent for activation by glutamate drops precipitously. C1 NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Mayer, ML (reprint author), NICHHD, Lab Cellular & Mol Neurophysiol, Porter Neurosci Res Ctr, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM mlm@helix.nih.gov RI Mayer, Mark/H-5500-2013; OI Plested, Andrew/0000-0001-6062-0832 FU Intramural NIH HHS NR 54 TC 76 Z9 77 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0896-6273 J9 NEURON JI Neuron PD MAR 15 PY 2007 VL 53 IS 6 BP 829 EP 841 DI 10.1016/j.neuron.2007.02.025 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 151LV UT WOS:000245292800008 PM 17359918 ER PT J AU Bosmans, F Tytgat, J AF Bosmans, Frank Tytgat, Jan TI Sea anemone venom as a source of insecticidal peptides acting on voltage-gated Na+ channels SO TOXICON LA English DT Review DE sea anemone; voltage-gated sodium channel; insecticide; toxin; site 3; ATX-II ID POLYPEPTIDE ANTHOPLEURIN-B; AMINO-ACID-RESIDUES; NUCLEAR MAGNETIC-RESONANCE; HIGH-AFFINITY BINDING; ALPHA-SCORPION TOXIN; SODIUM-CHANNEL; PHARMACOLOGICAL PROPERTIES; 3-DIMENSIONAL STRUCTURE; FUNCTIONAL EXPRESSION; CONDYLACTIS-GIGANTEA AB Sea anemones produce a myriad of toxic peptides and proteins of which a large group acts on voltage-gated Na+ channels. However, in comparison to other organisms, their venoms and toxins are poorly studied. Most of the known voltage-gated Na+ channel toxins isolated from sea anemone venoms act on neurotoxin receptor site 3 and inhibit the inactivation of these channels. Furthermore, it seems that most of these toxins have a distinct preference for crustaceans. Given the close evolutionary relationship between crustaceans and insects, it is not surprising that sea anemone toxins also profoundly affect insect voltage-gated Na+ channels, which constitutes the scope of this review. For this reason, these peptides can be considered as insecticidal lead compounds in the development of insecticides. (c) 2006 Elsevier Ltd. All rights reserved. C1 Katholieke Univ Leuven VIB, Toxicol Lab, B-3000 Louvain, Belgium. NINDS, Mol Physiol & Biophys Sect, NIH, Bethesda, MD 20892 USA. RP Tytgat, J (reprint author), Katholieke Univ Leuven VIB, Toxicol Lab, O&N 2,Postbus 922,Here Str 49, B-3000 Louvain, Belgium. EM Jan.Tytgat@pharm.kuleuven.be RI Tytgat, Jan/F-1560-2010; Bosmans, Frank/A-9660-2013 OI Bosmans, Frank/0000-0002-6476-235X FU Intramural NIH HHS [Z99 NS999999] NR 71 TC 58 Z9 63 U1 0 U2 6 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 MAR 15 PY 2007 VL 49 IS 4 BP 550 EP 560 DI 10.1016/j.toxicon.2006.11.029 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 154RU UT WOS:000245526000009 PM 17224168 ER PT J AU Sanchez, MD Pierson, TC DeGrace, MM Mattei, LM Hanna, SL Del Piero, F Doms, RW AF Sanchez, Melissa D. Pierson, Theodore C. DeGrace, Marciela M. Mattei, Lisa M. Hanna, Sheri L. Del Piero, Fabio Doms, Robert W. TI The neutralizing antibody response against West Nile virus in naturally infected horses SO VIROLOGY LA English DT Article DE West Nile virus; neutralization; flavivirus; domain III; envelope protein; horses ID BORNE ENCEPHALITIS-VIRUS; DENGUE TYPE-2 VIRUS; RECOMBINANT SUBVIRAL PARTICLES; MAMMALIAN-CELL LINE; ENVELOPE GLYCOPROTEIN; MONOCLONAL-ANTIBODY; WILD-TYPE; PRECLINICAL EVALUATION; ANTIGENIC STRUCTURE; DOMAIN-III AB A major neutralizing epitope (here referred to as the T332 epitope) located on the lateral surface of domain III (DIII) of the West Nile virus (WNV) envelope protein has been identified based on the analysis of murine monoclonal antibodies. However, little is known about the humoral immune response against WNV in a natural host or whether DIII in general or the T332 epitope in particular are important targets of neutralizing antibodies in vivo. To characterize the types of antibodies produced during infection with WNV, we studied a group of naturally infected horses. Using immune adsorption assays coupled with the use of virus particles bearing mutations in the T332 epitope, we found that in some animals neutralizing activity against DIII and the T332 epitope was below the limit of detection. In contrast, some animals generated a significant fraction of neutralizing activity to DIII and the T332 epitope. Thus, while antibodies to the T332 epitope did not represent a significant fraction of the total antibody response in the infected animals studied, in some horses, they comprised a significant fraction of neutralizing activity, making this an important but far from dominant neutralizing epitope. Rather, the neutralizing response to WNV generated in infected horses is both variable and polyclonal in nature, with epitopes within and outside of DIII playing important roles. (c) 2006 Elsevier Inc. All rights reserved. C1 Univ Penn, Dept Microbiol, Philadelphia, PA 19104 USA. Univ Penn, Sch Vet Med, Dept Pathobiol, Philadelphia, PA 19104 USA. NIH, Viral Pathogenesis Sect, Viral Dis Lab, Bethesda, MD 20892 USA. RP Doms, RW (reprint author), Univ Penn, Dept Microbiol, 225 Johnson Pavil,3610 Hamilton Walk, Philadelphia, PA 19104 USA. EM doms@mail.med.upenn.edu FU NCRR NIH HHS [F31 RR05074]; NIAID NIH HHS [T32 AI-07324]; PHS HHS [U54 457173] NR 59 TC 26 Z9 27 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 15 PY 2007 VL 359 IS 2 BP 336 EP 348 DI 10.1016/j.virol.2006.08.047 PG 13 WC Virology SC Virology GA 144SM UT WOS:000244816400010 PM 17055550 ER PT J AU Small, C Barro, M Brown, TL Patton, JT AF Small, Catie Barro, Mario Brown, Thomas L. Patton, John T. TI Genome heterogeneity of SA11 rotavirus due to reassortment with "O" agent SO VIROLOGY LA English DT Article DE rotavirus; Reoviridae; double-strand RNA virus; reassortment; genome sequence ID COMPLETE NUCLEOTIDE-SEQUENCE; SIMIAN ROTAVIRUS-SA11; REGULATORY FACTOR-3; PROTEIN; VIRUS; VP3; MORPHOGENESIS; RESTRICTION; REPLICATION; ASSIGNMENT AB Derivatives of the rotavirus SA11-H96 strain, isolated in 1958 from an overtly healthy vervet monkey, have been used extensively to probe the viral life cycle. To gain insight into the phenotypic and genotypic differences among SA11 isolates, we sequenced the segmented double-stranded RNA genomes of SA11-H96 (P5B[2]:G3), two SA11-4F-like viruses (P6[1]:G3), two SA11-4F-like viruses with gene 5 rearrangements, and relevant segments of SA11 temperature-sensitive mutants and the "O" (Offal) agent (P6[1]:G8), a rotavirus isolated in 1965 from abattoir waste. This analysis indicates that the only complete genomic sequence previously reported for SA I I (Both) is instead that of a reassortant, originating like the SA11-4F-like viruses, from the introduction of an "O" agent gene into the SA11 genetic background. These results, combined with identification of mutations that correlate with altered growth properties and ts phenotype, emphasize the importance of considering segment origin and sequence variation in interpreting experimental outcomes with SA11 strains. Published by Elsevier Inc. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. RP Patton, JT (reprint author), NIAID, Infect Dis Lab, NIH, 50 S Dr,MSC 8026,Room 6314, Bethesda, MD 20892 USA. EM jpatton@niaid.nih.gov RI Patton, John/P-1390-2014 FU Intramural NIH HHS [Z01 AI000788-10] NR 41 TC 18 Z9 38 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 15 PY 2007 VL 359 IS 2 BP 415 EP 424 DI 10.1016/j.virol.2006.09.024 PG 10 WC Virology SC Virology GA 144SM UT WOS:000244816400017 PM 17059839 ER PT J AU Berezhkovskii, AM Barzykin, AV AF Berezhkovskii, A. M. Barzykin, A. V. TI Simple formulas for the trapping rate by nonspherical absorber and capacitance of nonspherical conductor SO JOURNAL OF CHEMICAL PHYSICS LA English DT Letter ID LIQUID SOLUTIONS C1 NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. Natl Inst Adv Ind Sci & Technol, Nanotechnol Res Inst, Tsukuba, Ibaraki 3058565, Japan. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. EM berezh@mail.nih.gov; a.barzykin@aist.go.jp NR 8 TC 0 Z9 0 U1 0 U2 0 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD MAR 14 PY 2007 VL 126 IS 10 AR 106102 DI 10.1063/1.2711177 PG 3 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 145WD UT WOS:000244895600039 PM 17362091 ER PT J AU Wu, XS Xue, L Mohan, R Paradiso, K Gillis, KD Wu, LG AF Wu, Xin-Sheng Xue, Lei Mohan, Raja Paradiso, Kenneth Gillis, Kevin D. Wu, Ling-Gang TI The origin of quantal size variation: Vesicular glutamate concentration plays a significant role SO JOURNAL OF NEUROSCIENCE LA English DT Article DE mEPSC; capacitance; glutamate; quantal content; synaptic; transmission ID MINIATURE SYNAPTIC EVENTS; AMPA RECEPTORS; TRAPEZOID BODY; MEDIAL NUCLEUS; FUSION PORE; NEUROTRANSMITTER CONCENTRATION; POSTSYNAPTIC CURRENTS; VESICLE SIZE; RAT; CALYX AB Fusion of a single vesicle induces a quantal response, which is critical in determining synaptic strength. Quantal size varies at most synapses. Its underlying mechanisms are not well understood. Here, we examined five sources of variation: vesicular glutamate concentration ([Glu](v)), vesicle volume, ultrafast fusion pore closure, the postsynaptic receptor, and the location between release and the postsynaptic receptor cluster at glutamatergic, calyx of Held synapses. By averaging 2.66 million fusion events from 459 synapses, we resolved the capacitance jump evoked by single vesicle fusion. This capacitance jump, an indicator of vesicle volume, was independent of the amplitude of the miniature EPSC (mEPSC) recorded simultaneously at the same synapses. Thus, vesicle volume is not the main source of mEPSC variation. The capacitance jump was not followed by submillisecond endocytosis, excluding ultrafast endocytosis as a source of variation. Larger mEPSCs were increased to a lesser extent by presynaptic glutamate dialysis, and reduced to a lesser extent by gamma-DGG (gamma-D-glutamylglycine), a competitive AMPA receptor blocker, suggesting that a higher glutamate concentration in the synaptic cleft contributes to the large size of mEPSCs. Larger mEPSCs were not accompanied by briefer rise times, inconsistent with the prediction by, and thus arguing against, the scenario that larger mEPSCs are caused by a shorter distance between the release site and the postsynaptic receptor cluster. In summary, the different amplitudes of mEPSCs were mainly attributable to release of vesicles having similar volumes, but different glutamate amounts, suggesting that [Glu](v) is a main source of quantal size variation. C1 NINDS, NIH, Bethesda, MD 20892 USA. Univ Missouri, Dalton Cardiovasc Res Ctr, Columbia, MO 65211 USA. RP Wu, LG (reprint author), NINDS, NIH, 35 Convent Dr,Bldg 35,Room 2B-1012, Bethesda, MD 20892 USA. EM wul@ninds.nih.gov OI Paradiso, Kenneth/0000-0002-6396-9412 FU Intramural NIH HHS NR 53 TC 50 Z9 52 U1 0 U2 9 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 MAR 14 PY 2007 VL 27 IS 11 BP 3046 EP 3056 DI 10.1523/JNEUROSCI.4415-06.2007 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 148VB UT WOS:000245103600035 PM 17360928 ER PT J AU Iwahara, J Jung, YS Clore, GM AF Iwahara, Junji Jung, Young-Sang Clore, G. Marius TI Heteronuclear NMR spectroscopy for lysine NH3 groups in proteins: Unique effect of water exchange on N-15 transverse relaxation SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID SUGAR PHOSPHOTRANSFERASE SYSTEM; NUCLEAR MAGNETIC-RESONANCE; HOMEODOMAIN-DNA COMPLEX; PROTON-EXCHANGE; SIDE-CHAIN; AMIDE-PROTON; ENZYME-I; INTERMOLECULAR NOES; CRYSTAL-STRUCTURE; METHYL-GROUPS AB In this paper, we present a series of heteronuclear NMR experiments for the direct observation and characterization of lysine NH3 groups in proteins. In the context of the HoxD9 homeodomain bound specifically to DNA we were able to directly observe three cross-peaks, arising from lysine NH3 groups, with N-15 chemical shifts around similar to 33 ppm at pH 5.8 and 35 degrees C. Measurement of water-exchange rates and various types of N-15 transverse relaxation rates for these NH3 groups, reveals that rapid water exchange dominates the N-15 relaxation for antiphase coherence with respect to H-1 through scalar relaxation of the second kind. As a consequence of this phenomenon, N-15 line shapes of NH3 signals in a conventional H-1-N-15 heteronuclear single quantum coherence (HSQC) correlation experiment are much broader than those of backbone amide groups. A 2D H-1-N-15 correlation experiment that exclusively observes in-phase N-15 transverse coherence (termed HISQC for heteronuclear in-phase single quantum coherence spectroscopy) is independent of scalar relaxation in the t(1) (N-15) time domain and as a result exhibits strikingly sharper N-15 line shapes and higher intensities for NH3 cross-peaks than either HSQC or heteronuclear multiple quantum coherence (HMQC) correlation experiments. Coherence transfer through the relatively small J-coupling between N-15 zeta and C-13 epsilon (4.7-5.0 Hz) can be achieved with high efficiency by maintaining in-phase N-15 coherence owing to its slow relaxation. With the use of a suite of triple resonance experiments based on the same design principles as the HISQC, all the NH3 cross-peaks observed in the HISQC spectrum could be assigned to lysines that directly interact with DNA phosphate groups. Selective observation of functional NH3 groups is feasible because of hydrogen bonding or salt bridges that protect them from rapid water exchange. Finally, we consider the potential use of lysine NH3 groups as an alternative probe for larger systems as illustrated by data obtained on the 128-kDa enzyme I dimer. C1 NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Clore, GM (reprint author), NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. EM mariusc@intra.niddk.nih.gov RI Clore, G. Marius/A-3511-2008; Jung, Young-Sang/H-1169-2011; OI Clore, G. Marius/0000-0003-3809-1027; Iwahara, Junji/0000-0003-4732-2173 FU Intramural NIH HHS NR 53 TC 51 Z9 51 U1 1 U2 22 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 MAR 14 PY 2007 VL 129 IS 10 BP 2971 EP 2980 DI 10.1021/ja0683436 PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA 143OH UT WOS:000244731500048 PM 17300195 ER PT J AU Chen, L Shen, RL Ye, Y Pu, XA Liu, XL Duan, WR Wen, J Zimmerer, J Wang, Y Liu, Y Lasky, LC Heerema, NA Perrotti, D Ozato, K Kuramochi-Miyagawa, S Nakano, T Yates, AJ Carson, WE Lin, HF Barsky, SH Gao, JX AF Chen, Li Shen, Rulong Ye, Yin Pu, Xin-An Liu, Xingluo Duan, Wenrui Wen, Jing Zimmerer, Jason Wang, Ying Liu, Yan Lasky, Larry C. Heerema, Nyla A. Perrotti, Danilo Ozato, Keiko Kuramochi-Miyagawa, Satomi Nakano, Toru Yates, Allen J. Carson, William E., III Lin, Haifan Barsky, Sanford H. Gao, Jian-Xin TI Precancerous Stem Cells Have the Potential for both Benign and Malignant Differentiation SO PLOS ONE LA English DT Article AB Cancer stem cells (CSCs) have been identified in hematopoietic and solid tumors. However, their precursors-namely, precancerous stem cells (pCSCs) -have not been characterized. Here we experimentally define the pCSCs that have the potential for both benign and malignant differentiation, depending on environmental cues. While clonal pCSCs can develop into various types of tissue cells in immunocompetent mice without developing into cancer, they often develop, however, into leukemic or solid cancers composed of various types of cancer cells in immunodeficient mice. The progress of the pCSCs to cancers is associated with the up-regulation of c-kit and Sca-1, as well as with lineage markers. Mechanistically, the pCSCs are regulated by the PIWI/AGO family gene called piwil2. Our results provide clear evidence that a single clone of pCSCs has the potential for both benign and malignant differentiation, depending on the environmental cues. We anticipate pCSCs to be a novel target for the early detection, prevention, and therapy of cancers. C1 [Chen, Li; Shen, Rulong; Ye, Yin; Wang, Ying; Liu, Yan; Lasky, Larry C.; Heerema, Nyla A.; Yates, Allen J.; Barsky, Sanford H.; Gao, Jian-Xin] Ohio State Univ, Med Ctr, Dept Pathol, Columbus, OH 43210 USA. [Liu, Xingluo; Duan, Wenrui; Wen, Jing; Zimmerer, Jason; Heerema, Nyla A.; Perrotti, Danilo; Carson, William E., III; Gao, Jian-Xin] Ohio State Univ, Med Ctr, Ctr Comprehens Canc, Columbus, OH 43210 USA. [Pu, Xin-An] Ohio State Univ, Med Ctr, Ctr Mol Neurobiol, Columbus, OH 43210 USA. [Lasky, Larry C.] Ctr Stem Cell & Regenerat Med, Cleveland, OH USA. [Lin, Haifan] Yale Univ, Sch Med, Yale Stem Cell Ctr, New Haven, CT USA. [Ozato, Keiko] NICHHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. [Kuramochi-Miyagawa, Satomi; Nakano, Toru] Osaka Univ, Microbial Dis Res Inst, Dept Mol Cell Biol, Osaka, Japan. RP Gao, JX (reprint author), Ohio State Univ, Med Ctr, Dept Pathol, Columbus, OH 43210 USA. EM Jian-Xin.Gao@osumc.edu RI Perrotti, Danilo/E-3852-2011; Carson, William/E-2846-2011; Shen, Rulong/E-4079-2011 FU Department of Pathology; Ohio State University (OSU); Strategy Initiative [2005/2006]; American Cancer Society [IRG-112367]; Immunology Program; Davis/Bremer Medical Research; National Cancer Institute [CA095512]; United States Army; Chronic Myelogenous Leukemia (CML) Research Program [DAMD17-03-1-0184]; National Institute of Child and Human Development [HD42012] FX The work is supported from the Grants of Start-up funding, Department of Pathology, Ohio State University (OSU) (JXG); Strategy Initiative Grant (SIG) 2005/2006, OSU (JXG); American Cancer Society grant IRG-112367 (JXG); Immunology Program Award 2007 (OSU) (JXG); Davis/Bremer Medical Research Grant, OSU (RS); Strategy Initiative Grant (SIG) 2006, OSU (SHB); National Cancer Institute CA095512 (D. P.); the United States Army, Chronic Myelogenous Leukemia (CML) Research Program DAMD17-03-1-0184 (D. P.); and National Institute of Child and Human Development HD42012 (H. L.). NR 65 TC 71 Z9 75 U1 0 U2 2 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD MAR 14 PY 2007 VL 2 IS 3 AR e293 DI 10.1371/journal.pone.0000293 PG 16 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10DN UT WOS:000207444800016 PM 17356702 ER PT J AU Wei, SK Ruknudin, AM Shou, M McCurley, JM Hanlon, SU Elgin, E Schulze, DH Haigney, MCP AF Wei, Shao-kui Ruknudin, Abdul M. Shou, Matie McCurley, John M. Hanlon, Stephen U. Elgin, Eric Schulze, Dan H. Haigney, Mark C. P. TI Muscarinic modulation of the sodium-calcium exchanger in heart failure SO CIRCULATION LA English DT Article DE calcium; electrophysiology; heart failure; receptors, adrenergic, beta; sodium ID BETA-ADRENERGIC RESPONSIVENESS; TACHYCARDIA-INDUCED CARDIOMYOPATHY; PIG VENTRICULAR MYOCYTES; DEPENDENT PROTEIN-KINASE; CATALYTIC SUBUNIT; GUINEA-PIG; RYANODINE RECEPTOR; NA+-CA2+ EXCHANGER; NA+/CA2+ EXCHANGE; XENOPUS-OOCYTES AB Background - The Na-Ca exchanger (NCX) is a critical calcium efflux pathway in excitable cells, but little is known regarding its autonomic regulation. Methods and Results - We investigated beta-adrenergic receptor and muscarinic receptor regulation of the cardiac NCX in control and heart failure (HF) conditions in atrially paced pigs. NCX current in myocytes from control swine hearts was significantly increased by isoproterenol, and this response was reversed by concurrent muscarinic receptor stimulation with the addition of carbachol, demonstrating "accentuated antagonism." Okadaic acid eliminated the inhibitory effect of carbachol on isoproterenol-stimulated NCX current, indicating that muscarinic receptor regulation operates via protein phosphatase induced dephosphorylation. However, in myocytes from atrially paced tachycardia-induced HF pigs, the NCX current was significantly larger at baseline but less responsive to isoproterenol compared with controls, whereas carbachol failed to inhibit isoproterenol-stimulated NCX current, and 8-Br-cGMP did not restore muscarinic responsiveness. Protein phosphatase type 1 dialysis significantly reduced NCX current in failing but not control cells, consistent with NCX hyperphosphorylation in HF. Protein phosphatase type 1 levels associated with NCX were significantly depressed in HF pigs compared with control, and total phosphatase activity associated with NCX was significantly decreased. Conclusions - We conclude that the NCX is autonomically modulated, but HF reduces the level and activity of associated phosphatases; defective dephosphorylation then "locks" the exchanger in a highly active state. C1 Uniformed Serv Univ Hlth Sci, Div Cardiol, Dept Med, Bethesda, MD 20814 USA. Univ Maryland, Sch Med, Dept Microbiol & Immunol, Baltimore, MD 21201 USA. NIA, Gerontol Res Ctr, Cardiovasc Sci Lab, Baltimore, MD 21224 USA. Walter Reed Army Med Ctr, Div Cardiol, Washington, DC 20307 USA. RP Haigney, MCP (reprint author), Uniformed Serv Univ Hlth Sci, Div Cardiol, Dept Med, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM MCPH@aol.com FU NHLBI NIH HHS [HL62521]; NIA NIH HHS [AG-020823] NR 45 TC 13 Z9 15 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 MAR 13 PY 2007 VL 115 IS 10 BP 1225 EP 1233 DI 10.1161/CIRCULATIONAHA.106.650416 PG 9 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 145KQ UT WOS:000244864100011 PM 17339552 ER PT J AU Spina, S Murrell, JR Huey, ED Wassermann, EM Pietrini, P Baraibar, MA Barbeito, AG Troncoso, JC Vidal, R Ghetti, B Grafman, J AF Spina, S. Murrell, J. R. Huey, E. D. Wassermann, E. M. Pietrini, P. Baraibar, M. A. Barbeito, A. G. Troncoso, J. C. Vidal, R. Ghetti, B. Grafman, J. TI Clinicopathologic features of frontotemporal dementia with Progranulin sequence variation SO NEUROLOGY LA English DT Article ID AMYOTROPHIC-LATERAL-SCLEROSIS; MOTOR-NEURON DISEASE; INTRANUCLEAR INCLUSIONS; LOBAR DEGENERATION; INTRANEURONAL INCLUSIONS; TAU; CHROMOSOME-17; MUTATION; PARKINSONISM; ASSOCIATION AB Background: Frontotemporal lobar degeneration with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) has been associated with frontotemporal dementia (FTD) and ALS. Recently, mutations in Progranulin (PGRN), predicted to cause premature truncation of the PGRN coding sequence, were found in patients with inherited FTLD-U and ub-ir neuronal intranuclear inclusions (NII). Objective: To describe clinical, pathologic, and genetic features of three FTD patients having either a family history of FTD (A.III.1 and B.II.1) or of ALS (C.III.1). Methods: Patients underwent a single clinical assessment, MRI, and [(18)F] fluorodeoxyglucose PET brain scan. Neuropathologic examination and genetic analyses were carried out. Results: Patients presented clinically with the behavioral variant of FTD. Language dysfunctions were marked with comprehension being particularly affected. Neuroimaging revealed frontotemporal atrophy and glucose hypometabolism, with predominant left-side involvement, in Patients A.III.1 and B.II.1. Subject C.III.1 displayed mild atrophy and symmetric anterior hypometabolism. All patients were neuropathologically diagnosed with FTLD-U. Ub-ir NII were noted in Patients A.III.1 and B. II. 1 but were absent in Patient C.III.1. The following PGRN sequence variations were found: IVS6-2A -> G ( A.III.1), R493X ( B. II. 1), and R433W ( C.III.1). IVS6-2A -> G may lead to skipping of exon 7 with consequent frameshift of the coding sequence and premature termination of PGRN translation. Conclusions: We have found two PGRN mutations associated with FTD, in affected individuals who are members of families with possible autosomal dominant FTD. A third PGRN sequence variation ( R433W) was found in an FTD patient with family history of ALS. C1 Indiana Univ, Sch Med, Dept Pathol, Indiana Alzheimer Dis Ctr, Indianapolis, IN 46202 USA. Indiana Univ, Sch Med, Lab Med, Indianapolis, IN 46202 USA. NINDS, Cognit Neurosci Sect, NIH, Bethesda, MD USA. NINDS, Brain Stimulat Unit, NIH, Bethesda, MD USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD USA. Univ Pisa, Lab Clin Biochem & Mol Biol, I-56100 Pisa, Italy. RP Ghetti, B (reprint author), Indiana Univ, Sch Med, Dept Pathol, Indiana Alzheimer Dis Ctr, Med Sci Bldg A138,635 Barnhill Dr, Indianapolis, IN 46202 USA. EM bghetti@iupui.edu OI Grafman, Jordan H./0000-0001-8645-4457 FU Intramural NIH HHS; NIA NIH HHS [P30AG10133, P50AG05146] NR 45 TC 49 Z9 50 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 MAR 13 PY 2007 VL 68 IS 11 BP 820 EP 827 DI 10.1212/01.wnl.0000254460.31273.2d PG 8 WC Clinical Neurology SC Neurosciences & Neurology GA 145KP UT WOS:000244864000005 PM 17202431 ER PT J AU Guo, FS Adhya, S AF Guo, Fusheng Adhya, Sankar TI Spiral structure of Escherichia coli HU alpha beta provides foundation for DNA supercoiling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE HU-multimers; nucleoid; x-ray crystallography ID BINDING PROTEIN HU; REPRESSOSOME FORMATION; RESOLUTION; COMPLEXES; MUTANTS; PROGRAM; REPAIR; GALR; IHF AB We determined the crystal structure of the Escherichia coli nucleoid-associated HU alpha beta protein by x-ray diffraction and observed that the heterodimers form multimers with octameric units in three potential arrangements, which may serve specialized roles in different DNA transaction reactions. It is of special importance that one of the structures forms spiral filaments with left-handed rotations. A negatively superhelical DNA can be modeled to wrap around this left-handed HU alpha beta multimer. Whereas the wild-type HU generated negative DNA supercoiling in vitro, an engineered heterodimer with an altered amino acid residue critical for the formation of the left-handed spiral protein in the crystal was defective in the process, thus providing the structural explanation for the classical property of HU to restrain negative supercoils in DNA. C1 NCI, Mol Biol Lab, Bethesda, MD 20892 USA. RP Adhya, S (reprint author), NCI, Mol Biol Lab, 37 Convent Dr,Room 5138, Bethesda, MD 20892 USA. EM sadhya@helix.nih.gov FU Intramural NIH HHS NR 40 TC 48 Z9 50 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 MAR 13 PY 2007 VL 104 IS 11 BP 4309 EP 4314 DI 10.1073/pnas.0611686104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146ZH UT WOS:000244972700014 PM 17360520 ER PT J AU Pero, RS Borchers, MT Spicher, K Ochkur, SI Sikora, L Rao, SP Abdala-Valencia, H O'Neill, KR Shen, H McGarry, MP Lee, NA Cook-Mills, JM Sriramarao, P Simon, MI Birnbaumer, L Lee, JJ AF Pero, Ralph S. Borchers, Michael T. Spicher, Karsten Ochkur, Sergei I. Sikora, Lyudmila Rao, Savita P. Abdala-Valencia, Hiam O'Neill, Katie R. Shen, Huahao McGarry, Michael P. Lee, Nancy A. Cook-Mills, Joan M. Sriramarao, P. Simon, Melvin I. Birnbaumer, Lutz Lee, James J. TI G alpha(i2)-mediated signaling events in the endotheliurn are involved in controlling leukocyte extravasation SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE G proteins; inflammation; knockout mice; leukocyte trafficking; pulmonary models ID AIRWAY PATHOLOGIES; G-PROTEINS; ASTHMA; CELLS; MICE; EXPRESSION; CHEMOKINES; MICRODOMAINS; INFLAMMATION; EOSINOPHILIA AB The trafficking of leukocytes from the blood to sites of inflammation is the cumulative result of receptor-ligand-mediated signaling events associated with the leukocytes themselves as well as with the underlying vascular endothelium. Our data show that Gal signaling pathways in the vascular endothelium regulate a critical step required for leukocyte diapedesis. In vivo studies using knockout mice demonstrated that a signaling event in a non-lymphohematopoietic compartment of the lung prevented the recruitment of proinflammatory leukocytes. Intravital microscopy showed that blockade was at the capillary endothelial surface and ex vivo studies of leukocyte trafficking demonstrated that a G alpha(i)-signaling event in endothelial cells was required for transmigration. Collectively, these data suggest that specific G alpha(i2)-mediated signaling between endothelial cells and leukocytes is required for the extravasation of leukocytes and for tissue-specific accumulation. C1 Mayo Clin Arizona, SCIMRB Res, Div Hematol Oncol, Scottsdale, AZ 85259 USA. Mayo Clin Arizona, SCIMRB Res, Div Pulm Med, Dept Biochem & Mol Biol, Scottsdale, AZ 85259 USA. Univ Cincinnati, Coll Med, Dept Environm Hlth, Div Environm Genet & Mol Toxicol, Cincinnati, OH 45267 USA. Univ Dusseldorf, Inst Biochem & Mol Biol, D-40225 Dusseldorf, Germany. La Jolla Inst Mol Med, Div Vasc Biol, San Diego, CA 92121 USA. Northwestern Univ, Div Allergy Immunol, Feinberg Sch Med, Chicago, IL 60611 USA. Zhejiang Univ, Coll Med, Dept Resp Med, Hosp 2, Hangzhou 310009, Peoples R China. Arizona State Univ, Tempe, AZ 85287 USA. CALTECH, Div Biol, Pasadena, CA 91125 USA. Natl Inst Environm Hlth Sci, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. RP Lee, JJ (reprint author), Mayo Clin Arizona, SCIMRB Res, Div Hematol Oncol, 13400 E Shea Blvd, Scottsdale, AZ 85259 USA. EM jjlee@mayo.edu FU NCRR NIH HHS [K26 RR 019709, K26 RR019709]; NHLBI NIH HHS [R01 HL065228, HL 058723, HL 065228, HL 079304, HL 68171, R01 HL058723, R01 HL068171, R01 HL079304, R56 HL058723]; NIAID NIH HHS [AI 35796, R01 AI035796, R29 AI035796]; NIDDK NIH HHS [DK 19318]; NIGMS NIH HHS [GM 34236, R37 GM034236] NR 29 TC 43 Z9 44 U1 0 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 13 PY 2007 VL 104 IS 11 BP 4371 EP 4376 DI 10.1073/pnas.0700185104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146ZH UT WOS:000244972700025 PM 17360531 ER PT J AU Liao, Y Erxleben, C Yildirim, E Abramowitz, J Armstrong, DL Birnbaumer, L AF Liao, Yanhong Erxleben, Christian Yildirim, Eda Abramowitz, Joel Armstrong, David L. Birnbaumer, Lutz TI Orai proteins interact with TRPC channels and confer responsiveness to store depletion SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE capacitative calcium entry; ion channels; thapsigargin; transmembrane signaling ID OPERATED CA2+ ENTRY; CA2+-PERMEABLE CATION CHANNEL; RECEPTOR POTENTIAL CHANNEL; CALCIUM-ENTRY; TRANSIENT RECEPTOR; PLASMA-MEMBRANE; MAST-CELLS; CRAC CHANNEL; FUNCTIONAL EXPRESSION; MOLECULAR-CLONING AB The TRPC (C-type transient receptor potential) class of ion channels has been hypothesized to participate in store-operated Ca2+ entry (SOCE). Recently, however, STIM1 and Orai1 proteins have been proposed to form SOCE channels. Whether TRPCs participate in SOCE that is dependent on or regulated by Orai has not been explored. Here we show that Orai1 physically interacts with the N and C termini of TRPC3 and TRIPC6, and that in cells overexpressing either TRIPC3 or TRIPC6 in a store-depletion insensitive manner, these TRPCs become sensitive to store depletion upon expression of an exogenous Orai. Thus, Orai-1, -2, and -3 enhanced thapsigargin-induced calcium entry by 50-150% in cells stably overexpressing either TRPC3 or TRPC6. Orai1 expression had nosignificant effect on endogenous, thapsigargin-induced calcium entry in wildtype cells (HEK-293, COS1), in HEK cells expressing a thapsigargin-sensitive variant of TRPC3 (TRPC3a), or in HEK cells overexpressing another membrane protein, V1aR. Single-channel cation currents present in membrane patches of TRPC31-overexpressing cells were suppressed by expression of Orai1. We propose that Orai proteins by interacting with TRPCs act as regulatory subunits that confer STIM1-mediated store depletion sensitivity to these channels. C1 NIEHS, Div Intramural Res, Neurobiol Labs, NIH, Res Triangle Pk, NC 27709 USA. RP Armstrong, DL (reprint author), NIEHS, Div Intramural Res, Neurobiol Labs, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM armstro3@niehs.nih.gov; birnbau1@niehs.nih.gov RI Abramowitz, Joel/A-2620-2015; OI Yildirim, Eda/0000-0002-4796-3854 FU Intramural NIH HHS NR 58 TC 194 Z9 203 U1 0 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 13 PY 2007 VL 104 IS 11 BP 4682 EP 4687 DI 10.1073/pnas.0611692104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146ZH UT WOS:000244972700078 PM 17360584 ER PT J AU Zhou, QF Sharp, C Cannata, JM Shung, KK Feng, GH Kim, ES AF Zhou, Q. F. Sharp, C. Cannata, J. M. Shung, K. K. Feng, G. H. Kim, E. S. TI Self-focused high frequency ultrasonic transducers based on ZnO piezoelectric films SO APPLIED PHYSICS LETTERS LA English DT Article ID THIN-FILMS; MHZ; FABRICATION AB A micromachined self-focusing high frequency ultrasonic transducer was fabricated with a 13 mu m thick ZnO film deposited on a silicon substrate by sputtering. X-ray diffraction shows that the film has a high (002) orientation. The element aperture size of the transducer was 2.5 mm, and the fundamental resonant frequency was designed to be over 200 MHz with approximately 28% bandwidth through only one matching layer. Experimental results show that this type of focused high frequency ultrasound device may have potential for cellular microstructure imaging and skin cancer detection. (c) 2007 American Institute of Physics. C1 Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. Univ So Calif, NIH Transducer Resource Ctr, Los Angeles, CA 90089 USA. Univ So Calif, Dept Elect Engn Electrophys, Los Angeles, CA 90089 USA. RP Zhou, QF (reprint author), Univ So Calif, Dept Biomed Engn, Los Angeles, CA 90089 USA. EM qifazhou@usc.edu NR 17 TC 45 Z9 46 U1 3 U2 17 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0003-6951 J9 APPL PHYS LETT JI Appl. Phys. Lett. PD MAR 12 PY 2007 VL 90 IS 11 AR 113502 DI 10.1063/1.2712813 PG 3 WC Physics, Applied SC Physics GA 146UC UT WOS:000244959200095 ER PT J AU Krohmal, BJ Emanuel, EJ AF Krohmal, Benjamin J. Emanuel, Ezekiel J. TI Access and ability to pay - The ethics of a tiered health care system SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID PROPOSAL C1 NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. RP Emanuel, EJ (reprint author), NIH, Dept Clin Bioeth, Bldg 10,Room 1C118,10 Ctr Dr, Bethesda, MD 20892 USA. EM eemanuel@nih.gov FU Intramural NIH HHS NR 23 TC 6 Z9 6 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAR 12 PY 2007 VL 167 IS 5 BP 433 EP 437 DI 10.1001/archinte.167.5.433 PG 5 WC Medicine, General & Internal SC General & Internal Medicine GA 145GX UT WOS:000244854400003 PM 17353489 ER PT J AU Terry, DF Evans, JC Pencina, MJ Murabito, JM Vasan, RS Wolf, PA Kelly-Hayes, M Levy, D D'Agostino, RB Benjamin, EJ AF Terry, Dellara F. Evans, Jane C. Pencina, Michael J. Murabito, Joanne M. Vasan, Ramachandran S. Wolf, Philip A. Kelly-Hayes, Margaret Levy, Daniel D'Agostino, Ralph B. Benjamin, Emelia J. TI Characteristics of Framingham offspring participants with long-lived parents SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID CORONARY-HEART-DISEASE; BODY-WEIGHT; MORTALITY; RISK; LONGEVITY; WOMEN; AGE; INITIATION; FAMILIES; SMOKING AB Background: Prior research has suggested that delay or avoidance of cardiovascular disease and cardiovascular disease risk factors plays an important role in longevity. Methods: We studied 1697 Framingham Heart Study (FHS) offspring members 30 years or older, whose parents (1) participated in the original FHS cohort and (2) achieved age 85 years or died before January 1, 2005. Offspring participants (mean +/- SDage, 40 +/- 7 years; 51% women) were grouped according to whether neither (n= 705), one (n= 804), or both parents ( n= 188) survived to 85 years or older. We examined offspring risk factors at examination cycle 1 (1971-1975) including age, sex, education, cigarette smoking, systolic and diastolic blood pressures, total-high-density lipoprotein cholesterol ratio, body mass index, and Framingham Risk Score. Participants returning for examination cycle 3 (1983-1987; n= 1319) were eligible for inclusion in longitudinal analyses evaluating risk factor progression from baseline to a higher follow-up risk category. Results: For all factors studied, except body mass index, we observed statistically significant linear trends for lower offspring examination 1 risk factor levels with increasing parental survival category. The mean Framingham Risk Score was most favorable in offspring with both parents surviving to 85 years or older and was progressively worse in those with one or no long-lived parent (0.55, 1.08, and 1.71, respectively; P value for trend, <.001). Longitudinally, offspring of parents who lived longer had lower risk of blood pressure and Framingham Risk Score progression. Conclusions: Our findings suggest that individuals with long-lived parents have advantageous cardiovascular risk profiles in middle age compared with those whose parents died younger. The risk factor advantage persists over time. C1 Boston Univ, Med Ctr, Geriatr Sect, Sch Med, Boston, MA 02118 USA. Boston Univ, Med Ctr, Sect Prevent Med, Sch Med, Boston, MA 02118 USA. Boston Univ, Med Ctr, Gen Internal Med Sect, Sch Med, Boston, MA 02118 USA. Boston Univ, Med Ctr, Cardiol Sect, Sch Med, Boston, MA 02118 USA. Boston Univ, Med Ctr, Dept Med, Sch Med, Boston, MA 02118 USA. Boston Univ, Med Ctr, Dept Neurol, Sch Med, Boston, MA 02118 USA. NHLBI, Framingham Heart Study, NIH, Boston, MA USA. Boston Univ, Dept Math & Stat, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. RP Terry, DF (reprint author), Boston Univ, Med Ctr, Geriatr Sect, Sch Med, 88 E Newton St,Robinson 2, Boston, MA 02118 USA. EM laterry@bu.edu OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K24-HL04334, N01-HC25195]; NIA NIH HHS [1K08-AG022785, 1K23-AG026754, R01-AG028321]; NINDS NIH HHS [5R01-NS17950] NR 26 TC 39 Z9 39 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD MAR 12 PY 2007 VL 167 IS 5 BP 438 EP 444 DI 10.1001/archinte.167.5.438 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 145GX UT WOS:000244854400004 PM 17353490 ER PT J AU Kreuter, J Hekmatara, T Dreis, S Vogel, T Gelperina, S Langer, K AF Kreuter, Jorg Hekmatara, Telli Dreis, Sebastian Vogel, Tikva Gelperina, Svetlana Langer, Klaus TI Covalent attachment of apolipoprotein A-I and apolipoprotein B-100 to albumin nanoparticles enables drug transport into the brain SO JOURNAL OF CONTROLLED RELEASE LA English DT Article DE nanoparticles; apolipoprotein A-I; apolipoprotein B-100; apolipoprotein E3; human serum albumin (HSA); brain uptake; drug targeting ID LOW-DENSITY-LIPOPROTEIN; 80-COATED POLYBUTYLCYANOACRYLATE NANOPARTICLES; DESOLVATION PROCESS; MEDIATED TRANSPORT; RECEPTOR; BARRIER; PROTEIN; PLASMA; BINDING; IDENTIFICATION AB Apolipoprotein E3, A-I as well as B-100 were covalently attached to human serum albumin nanoparticles via the NES-PEG-Mal 3400 linker. Loperamide as a model drug was bound to these nanoparticles, and the antinociceptive reaction of these preparations was recorded after intravenous injection in mice by the tail-flick test. After 15 min, all three nanoparticle preparations with the coupled apolipoproteins E3, A-I, and B-100 yielded considerable antinociceptive effects, which lasted over 1 h. The maximally possible effects [MPE] of these preparations amounted to 95%, 65%, and 50%, respectively, and were statistically different from the controls (p < 0.02), whereas the loperamide solution achieved no effect. This result demonstrates that more than one mechanism is involved in the interaction of nanoparticles with the brain endothelial cells and the resulting delivery of drugs to the central nervous system. (c) 2007 Elsevier B.V. All rights reserved. C1 Univ Frankfurt, Inst Pharmazeut Technol, Biozentrum, D-60438 Frankfurt, Germany. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. Res Ctr Mol Diagnost & Therapy, Moscow, Russia. RP Kreuter, J (reprint author), Univ Frankfurt, Inst Pharmazeut Technol, Biozentrum, Max von Laue Str 9, D-60438 Frankfurt, Germany. EM Kreuter@em.uni-frankfurt.de RI Fachbereich14, Dekanat/C-8553-2015; OI Gelperina, Svetlana/0000-0003-1113-6715 NR 28 TC 118 Z9 128 U1 0 U2 26 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 MAR 12 PY 2007 VL 118 IS 1 BP 54 EP 58 DI 10.1016/j.jconrel.2006.12.012 PG 5 WC Chemistry, Multidisciplinary; Pharmacology & Pharmacy SC Chemistry; Pharmacology & Pharmacy GA 150VX UT WOS:000245248800006 PM 17250920 ER PT J AU Bonde, JPE Wilcox, A AF Bonde, Jens Peter Ellekilde Wilcox, Allen TI Ratio of boys to girls at birth - Is not related to the time taken to conceive, or exposure to environmental agents SO BRITISH MEDICAL JOURNAL LA English DT Editorial Material ID SEX-RATIO; COHORT C1 Aarhus Univ Hosp, Dept Occupat Med, DK-8000 Aarhus, Denmark. NIEHS, Epidemiol Branch, Durham, NC USA. RP Bonde, JPE (reprint author), Aarhus Univ Hosp, Dept Occupat Med, DK-8000 Aarhus, Denmark. EM jpbon@as.aaa.dk OI Wilcox, Allen/0000-0002-3376-1311 NR 12 TC 11 Z9 11 U1 0 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-8146 J9 BRIT MED J JI Br. Med. J. PD MAR 10 PY 2007 VL 334 IS 7592 BP 486 EP 487 DI 10.1136/bmj.39141.622917.80 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 148VV UT WOS:000245106400004 PM 17347191 ER PT J AU Dickert, N DeRiemer, K Duffy, PE Garcia-Garcia, L Mutabingwa, TK Sina, BJ Tindana, P Lie, R AF Dickert, N. DeRiemer, K. Duffy, P. E. Garcia-Garcia, L. Mutabingwa, T. K. Sina, B. J. Tindana, P. Lie, R. TI Ancillary-care responsibilities in observational research: two cases, two issues SO LANCET LA English DT Article ID INTERNATIONAL CONSENSUS OPINION; RESISTANT TUBERCULOSIS; DEVELOPING-COUNTRIES; MEDICAL RESEARCHERS; CLINICAL CARE; STANDARD; DEBATE C1 Johns Hopkins Univ, Sch Med, Baltimore, MD 21287 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21287 USA. Univ Calif Davis, Sch Med, Davis, CA 95616 USA. Seattle Biomed Res Inst, Seattle, WA 98109 USA. Inst Nacl Salud Publ, TB Unit, Cuernavaca 62508, Morelos, Mexico. London Sch Hyg & Trop Med, London WC1, England. Muheza, Tanga, Tanzania. NIH, Div Int Training & Res, Fogarty Int Ctr, Bethesda, MD 20892 USA. NIH, Dept Clin Bioeth, Bethesda, MD 20892 USA. Ghana Hlth Serv, Navrongo Hlth Res Ctr, Navrongo, Ghana. RP Dickert, N (reprint author), Johns Hopkins Univ, Sch Med, 600 N Wolfe St, Baltimore, MD 21287 USA. EM dicker@jhmi.edu OI DeRiemer, Kathryn/0000-0002-8375-7505 FU FIC NIH HHS [K01 TW000001, K01 TW000001-07, K01 TW000001-08] NR 15 TC 11 Z9 11 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0140-6736 J9 LANCET JI Lancet PD MAR 10 PY 2007 VL 369 IS 9564 BP 874 EP 877 DI 10.1016/S0140-6736(07)60416-4 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 144JC UT WOS:000244791300037 PM 17350458 ER PT J AU Xiao, CY Sharp, JA Kawahara, M Davalos, AR Difilippantonio, MJ Hu, Y Li, WM Cao, L Buetow, K Ried, T Chadwick, BP Deng, CX Panning, B AF Xiao, Cuiying Sharp, Judith A. Kawahara, Misako Davalos, Albert R. Difilippantonio, Michael J. Hu, Ying Li, Wenmei Cao, Liu Buetow, Ken Ried, Thomas Chadwick, Brian P. Deng, Chu-Xia Panning, Barbara TI The XIST noncoding RNA functions independently of BRCA1 in X inactivation SO CELL LA English DT Editorial Material ID SEX-CHROMOSOME INACTIVATION; CELL-CYCLE CHECKPOINT; HUMAN BREAST-CANCER; CENTROSOME AMPLIFICATION; H2AX PHOSPHORYLATION; GENETIC INSTABILITY; MUTATION CARRIER; DNA-DAMAGE; ACTIVE-X; S-PHASE AB Females with germline mutations in BRCA1 are predisposed to develop breast and ovarian cancers. A previous report indicated that BRCA1 colocalizes with and is necessary for the correct localization of XIST, a noncoding RNA that coats the inactive X chromosome (Xi) to mediate formation of facultative heterochromatin. A model emerged from this study suggesting that loss of BRCA1 in female cells could reactivate genes on the Xi through loss of the XIST RNA. However, our independent studies of BRCA1 and XIST RNA revealed little evidence to support this model. We report that BRCA1 is not enriched on XIST RNA-coated chromatin of the Xi. Neither mutation nor depletion of BRCA1 causes significant changes in XIST RNA localization or X-linked gene expression. Together, these results do not support a role for BRCA1 in promoting XIST RNA localization to the Xi or regulating X/ST-dependent functions in maintaining the stability of facultative heterochromatin. C1 NIDDKD, NIH, Genet Dev & Dis Branch, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA 94158 USA. Lawrence Berkeley Natl Lab, Div Life Sci, Berkeley, CA 94720 USA. NCI, NIH, Sect Canc Genom, Genet Branch,CCR, Bethesda, MD 20892 USA. NCI, Ctr Bioinformat, Lab Populat Genet, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Cell Biol, Inst Genome Sci & Policy, Durham, NC 27710 USA. RP Deng, CX (reprint author), NIDDKD, NIH, Genet Dev & Dis Branch, 10-9N105, Bethesda, MD 20892 USA. EM chuxiad@bdg10.niddk.nih.gov; bpanning@biochem.ucsf.edu RI deng, chuxia/N-6713-2016 FU Intramural NIH HHS [Z99 CA999999]; NIGMS NIH HHS [R01 GM 63671] NR 45 TC 32 Z9 32 U1 1 U2 9 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD MAR 9 PY 2007 VL 128 IS 5 BP 977 EP 989 DI 10.1016/j.cell.2007.01.034 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 148KN UT WOS:000245073400020 PM 17350580 ER PT J AU Scarselli, M Li, B Kim, SK Wess, J AF Scarselli, Marco Li, Bo Kim, Soo-Kyung Wess, Juergen TI Multiple residues in the second extracellular loop are critical for M-3 muscarinic acetylcholine receptor activation SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTORS; 3RD CYTOPLASMIC LOOP; RANDOM MUTAGENESIS; 7-TRANSMEMBRANE RECEPTORS; TRANSMEMBRANE SEGMENTS; MOLECULAR-MECHANISMS; BINDING-SITE; YEAST; IDENTIFICATION; MUTATIONS AB Recent studies suggest that the second extracellular loop (o2 loop) of bovine rhodopsin and other class I G protein-coupled receptors (GPCRs) targeted by biogenic amine ligands folds deeply into the transmembrane receptor core where the binding of cis-retinal and biogenic amine ligands is known to occur. In the past, the potential role of the o2 loop in agonist-dependent activation of biogenic amine GPCRs has not been studied systematically. To address this issue, we used the M-3 muscarinic acetylcholine receptor (M3R), a prototypic class I GPCR, as a model system. Specifically, we subjected the o2 loop of the M3R to random mutagenesis and subsequently applied a novel yeast genetic screen to identity single amino acid substitutions that interfered with M3R function. This screen led to the recovery of about 20 mutant M3Rs containing single amino acid changes in the o2 loop that were inactive in yeast. In contrast, application of the same strategy to the extracellular N-terminal domain of the M3R did not yield any single point mutations that disrupted M3R function. Pharmacological characterization of many of the recovered mutant M3Rs in mammalian cells, complemented by site-directed mutagenesis studies, indicated that the presence of several o2 loop residues is important for efficient agonist-induced M3R activation. Besides the highly conserved Cys(220) residue, Gln(207), Gly(211), Arg(213), Gly(218), Ile(222), Phe(224), Leu(225), and Pro(228) were found to be of particular functional importance. In general, mutational modification of these residues had little effect on agonist binding affinities. Our findings are therefore consistent with a model in which multiple o2 loop residues are involved in stabilizing the active state of the M3R. Given the high degree of structural homology found among all biogenic amine GPCRs, our findings should be of considerable general relevance. C1 NIDDK, Mol Signaling Sect, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. NIDDK, Mol Recognit Sect, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. RP Wess, J (reprint author), NIDDK, Mol Signaling Sect, Lab Bioorgan Chem, NIH, Bldg 8A,Rm B1A-05,8 Ctr Dr,MSC 0810, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov OI Scarselli, Marco/0000-0001-5087-3182 FU Intramural NIH HHS NR 48 TC 74 Z9 75 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 MAR 9 PY 2007 VL 282 IS 10 BP 7385 EP 7396 DI 10.1074/jbc.M610394200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148NC UT WOS:000245080900050 PM 17213190 ER PT J AU Lemmers, B Salmena, L Bidere, N Su, H Matysiak-Zablocki, E Murakami, K Ohashi, PS Jurisicova, A Lenardo, M Hakem, R Hakem, A AF Lemmers, Benedicte Salmena, Leonardo Bidere, Nicolas Su, Helen Matysiak-Zablocki, Elzvieta Murakami, Kiichi Ohashi, Pamela S. Jurisicova, Andrea Lenardo, Michael Hakem, Razqallah Hakem, Anne TI Essential role for caspase-8 in toll-like receptors and NF kappa B signaling SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID T-CELL PROLIFERATION; BACTERIAL LIPOPOLYSACCHARIDE; LYMPHOCYTE STIMULATION; INNATE IMMUNITY; BCL-2 FAMILY; ACTIVATION; APOPTOSIS; RESPONSES; KINASE; MICE AB In addition to its pro-apoptotic function in the death receptor pathway, roles for caspase-8 in mediating T-cell proliferation, maintaining lymphocyte homeostasis, and suppressing immunodeficiency have become evident. Humans with a germline point mutation of CASPASE-8 have multiple defects in T cells, B cells, and NK cells, most notably attenuated activation and immunodeficiency. By generating mice with B-cell-specific inactivation of caspase-8 (bcasp8(-/-)), we show that caspase-8 is dispensable for B-cell development, but its loss in B cells results in attenuated antibody production upon in vivo viral infection. We also report an important role for caspase-8 in maintaining B-cell survival following stimulation of the Toll-like receptor (TLR)2,-3, and -4. In response to TLR4 stimulation, caspase-8 is recruited to a complex containing IKK alpha beta, and its loss resulted in delayed NF kappa B nuclear translocation and impaired NF kappa B transcriptional activity. Our study supports dual roles for caspase-8 in apoptotic and nonapoptotic functions and demonstrates its requirement for TLR signaling and in the regulation of NF kappa B function. C1 Univ Toronto, Adv Med Discovery Inst, Ontario Canc Inst, Toronto, ON M5G 2C1, Canada. Univ Toronto, Dept Med Biophys, Toronto, ON M5G 2C1, Canada. NIAID, Lab Immunol, NIH, Bethesda, MD 20892 USA. Mt Sinai Hosp, Samuel Lunenfeld Res Inst, Toronto, ON M5G 2X1, Canada. RP Hakem, R (reprint author), Univ Toronto, Adv Med Discovery Inst, Ontario Canc Inst, 620 Univ Ave,Suite 706, Toronto, ON M5G 2C1, Canada. EM rhakem@uhnres.utoronto.ca RI Jurisicova, Andrea/E-4580-2013; Su, Helen/H-9541-2015; bidere, nicolas/K-8887-2015 OI Su, Helen/0000-0002-5582-9110; bidere, nicolas/0000-0001-9177-0008 NR 52 TC 76 Z9 78 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 9 PY 2007 VL 282 IS 10 BP 7416 EP 7423 DI 10.1074/jbc.M606721200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148NC UT WOS:000245080900053 PM 17213198 ER PT J AU Paul, BD Buchholz, DR Fu, LZ Shi, YB AF Paul, Bindu D. Buchholz, Daniel R. Fu, Liezhen Shi, Yun-Bo TI SRC-p300 coactivator complex is required for thyroid hormone-induced amphibian metamorphosis SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID XENOPUS-LAEVIS METAMORPHOSIS; STEROID-RECEPTOR COACTIVATOR-1; CREB-BINDING PROTEIN; IN-VIVO ANALYSIS; NUCLEAR-RECEPTOR; TRANSCRIPTIONAL COACTIVATOR; HISTONE ACETYLTRANSFERASE; FROG METAMORPHOSIS; P160 COACTIVATOR; GLUCOCORTICOID-RECEPTOR AB Gene activation by the thyroid hormone (T3) receptor (TR) involves the recruitment of specific coactivator complexes to T3-responsive promoters. A large number of coactivators for TR have been isolated and characterized in vitro. However, their roles and functions in vivo during development have remained largely unknown. We have utilized metamorphosis in Xenopus laevis to study the role of these coactivators during post-embryonic development. Metamorphosis is totally dependent on the thyroid hormone, and TR mediates a vast majority, if not all, of the developmental effects of the hormone. We have previously shown that TR recruits the coactivator SRC3 (steroid receptor coactivator-3) and that coactivator recruitment is essential for metamorphosis. To determine whether SRCs are indeed required, we have analyzed the in vivo role of the histone acetyltransferase p300/CREB-binding protein (CBP), which was reported to be a component of the SRC-coactivator complexes. Chromatin immunoprecipitation revealed that p300 is recruited to T3-responsive promoters, implicating a role of p300 in TR function. Further, transgenic tadpoles overexpressing a dominant negative form of p300, F-dnp300, containing only the SRC-interacting domain, displayed arrested or delayed metamorphosis. Molecular analyses of the transgenic F-dnp300 animals showed that F-dnp300 was recruited by TR (displacing endogenous p300) and inhibited the expression of T3-responsive genes. Our results thus suggest that p300 and/or its related CBP is an essential component of the TR-signaling pathway in vivo and support the notion that p300/CBP and SRC proteins are part of the same coactivator complex in vivo during postembryonic development. C1 NICHD, Lab Gene Regulat & Dev, NIH, Bethesda, MD 20892 USA. RP Shi, YB (reprint author), NICHD, Lab Gene Regulat & Dev, NIH, Bldg 18T,Room 106,LGRD, Bethesda, MD 20892 USA. EM shi@helix.nih.gov FU Intramural NIH HHS NR 78 TC 30 Z9 30 U1 1 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 MAR 9 PY 2007 VL 282 IS 10 BP 7472 EP 7481 DI 10.1074/jbc.M607589200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 148NC UT WOS:000245080900060 PM 17218308 ER PT J AU Lee, B Galli, S Tsokos, M AF Lee, Betty Galli, Susanna Tsokos, Maria TI Sensitive Ewing sarcoma and neuroblastoma cell lines have increased levels of BAD expression and decreased levels of BAR expression compared to resistant cell lines SO CANCER LETTERS LA English DT Article DE apoptosis; neuroblastoma; Ewing sarcoma; GS320 system; RAGEtags; BAR; BAD; SMAC ID APOPTOSIS-INDUCING LIGAND; BCL-2 FAMILY; DEATH; REGULATOR; TUMORS AB The purpose of the study is to compare the mRNA expression of pro-apoptotic and anti-apoptotic genes by using the Genesystem 320 (Capital Genomix Inc., Gaithersburg, MD) to examine the differential expression in Ewing sarcoma and neuroblastoma cell lines. This is an alternate method for which internal controls have been built into the system for comparing mRNA. The tumor cell lines were chosen based on their previously characterized Fas-resistance or Fas-sensitive properties in order to determine the differences in their response to apoptotic signals. Two representative pro-apoptotic genes (BAD and SMAC) and one anti-apoptotic gene (BAR) were chosen for the study. The results of mRNA expression were correlated with protein expression by Western analysis. BAD was highly expressed in the Fas-sensitive cell lines while SMAC was equally expressed in both Fas-sensitive and Fas-resistant cell lines. On the other hand, BAR was highly expressed in Fas-resistant cell lines and minimally expressed in the Fas-sensitive cell lines. Our data suggests that levels of BAD and BAR mRNA expression predict sensitivity to apoptosis. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Tsokos, M (reprint author), NCI, Pathol Lab, NIH, Bldg 10,Rm2A-10, Bethesda, MD 20892 USA. EM mtsokos@mail.nih.gov FU Intramural NIH HHS NR 11 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD MAR 8 PY 2007 VL 247 IS 1 BP 110 EP 114 DI 10.1016/j.canlet.2006.03.033 PG 5 WC Oncology SC Oncology GA 138SX UT WOS:000244383900012 PM 16690206 ER PT J AU Malolanarasimhan, K Kedei, N Sigano, DM Kelley, JA Lai, CC Lewin, NE Surawski, RJ Pavlyukovets, VA Garfield, SH Wincovitch, S Blumberg, PM Marquez, VE AF Malolanarasimhan, Krishnan Kedei, Noemi Sigano, Dina M. Kelley, James A. Lai, Christopher C. Lewin, Nancy E. Surawski, Robert J. Pavlyukovets, Vladimir A. Garfield, Susan H. Wincovitch, Stephen Blumberg, Peter M. Marquez, Victor E. TI Conformationally constrained analogues of diacylglycerol (DAG). 27. Modulation of membrane translocation of protein kinase C (PKC) isozymes alpha and delta by diacylglycerol lactones (DAG-lactones) containing rigid-rod acyl groups SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID PHORBOL 12-MYRISTATE 13-ACETATE; CD-1 MOUSE SKIN; BINDING-AFFINITY; ESTERS; CHOLESTEROL; SELECTIVITY; SOLUBILITY; ACTIVATION; HYDROGEN; DOMAINS AB Highly rigid and geometrically well-defined rods composed of ethynylene-substituted aromatic spacers [oligo(p-phenyleneethynylene), OPE] were incorporated as acyl moieties on diacylglycerol lactones (DAG-lactones) and investigated for their ability to bind to protein kinase C (PKC) and translocate PKC alpha and delta isoforms to plasma and internal membranes. The kinetics of PKC translocation were correlated with biological responses, viz. ERK phosphorylation, induction of IL-6 secretion, inhibition of cell proliferation, and induction of cellular attachment, that display very different time courses. Because OPE rods assemble through noncovalent forces and form stable films, they may influence the microdomain environment around the DAG-lactone membrane-binding site. A comparison of two DAG-lactones (1 and 10), one with two PE units (1) and the other with an equivalent flexible acyl chain (10) of matching lipophilicity, clearly demonstrated the effect of the rigid OPE chain in substantially prolonging the translocated state of both PKC alpha and delta. C1 Natl Canc Inst, Med Chem Lab, NIH, Frederick, MD 21702 USA. NCI, Ctr Canc Res, Lab Canc Biol & Genet, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Lab Cellular Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Marquez, VE (reprint author), Natl Canc Inst, Med Chem Lab, NIH, Frederick, MD 21702 USA. EM marquezv@mail.nih.gov RI Sigano, Dina/M-6144-2014 OI Sigano, Dina/0000-0001-7489-9555 FU Intramural NIH HHS NR 45 TC 16 Z9 16 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD MAR 8 PY 2007 VL 50 IS 5 BP 962 EP 978 DI 10.1021/jm061289j PG 17 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 140TU UT WOS:000244530400008 PM 17284021 ER PT J AU Szabo, R Molinolo, A List, K Bugge, TH AF Szabo, R. Molinolo, A. List, K. Bugge, T. H. TI Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development SO ONCOGENE LA English DT Article DE placenta development; labyrinth formation; membrane proteolysis; trophoblast differentiation; basement membrane; protease inhibition ID SERINE-PROTEASE INHIBITOR; BARRIER FUNCTION; MICE; EXPRESSION; LETHALITY; HEPSIN; GENE; CARCINOGENESIS; IDENTIFICATION; MORPHOGENESIS AB Hepatocyte growth factor activator inhibitor-1 (HAI-1) is a Kunitz-type transmembrane serine protease inhibitor that forms inhibitor complexes with several trypsin-like serine proteases and is required for mouse placental development and embryo survival. Here we show that the essential function of HAI-1 in placentation and all other embryonic processes is to restrict the activity of the type II transmembrane serine protease, matriptase. Enzymatic gene trapping of matriptase combined with HAI-1 immunohistochemistry revealed that matriptase is co-expressed with HAI-1 in both extraembryonic and embryonic tissues. As early as embryonic day 8.5, matriptase and HAI-1 were expressed in a population of chorionic trophoblasts. Ablation of HAI-1 disrupted the epithelial integrity of this cell population, causing disorganized laminin deposition and altered expression of E-cadherin and beta-catenin. This led to a complete loss of undifferentiated chorionic trophoblasts after embryonic day 9.5 and prevented the formation of the placental labyrinth. Genetic ablation of matriptase activity in HAI-1-deficient embryos, however, restored the integrity of chorionic trophoblasts and enabled placental labyrinth formation and development to term. Furthermore, matriptase/HAI-1 double-deficient mice were phenotypically indistinguishable from matriptase single-deficient litter-mates. Oncogene C1 Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Unit, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Bugge, TH (reprint author), Natl Inst Dent & Craniofacial Res, Proteases & Tissue Remodeling Unit, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Room 211, Bethesda, MD 20892 USA. EM thomas.bugge@nih.gov FU Intramural NIH HHS NR 26 TC 74 Z9 75 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 8 PY 2007 VL 26 IS 11 BP 1546 EP 1556 DI 10.1038/sj.onc.1209966 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 144FV UT WOS:000244782500004 PM 16983341 ER PT J AU Cotroneo, MS Haag, JD Zan, Y Lopez, CC Thuwajit, P Petukhova, GV Camerini-Otero, RD Gendron-Fitzpatrick, A Griep, AE Murphy, CJ Dubielzig, RR Gould, MN AF Cotroneo, M. S. Haag, J. D. Zan, Y. Lopez, C. C. Thuwajit, P. Petukhova, G. V. Camerini-Otero, R. D. Gendron-Fitzpatrick, A. Griep, A. E. Murphy, C. J. Dubielzig, R. R. Gould, M. N. TI Characterizing a rat Brca2 knockout model SO ONCOGENE LA English DT Article DE Brca2; knockout; rat; carcinogenesis; tumors ID DOUBLE-STRAND BREAKS; DNA-REPAIR; MEIOTIC RECOMBINATION; SYNAPTONEMAL COMPLEX; MICE; CANCER; LOCALIZATION; CATARACTS; RADIATION; MUTATION AB Evidence exists that BRCA2 carriers may have an elevated risk of breast, ovarian, colon, prostate, and pancreatic cancer. In general, carriers are defined as individuals with protein truncating mutations within the BRCA2 gene. Many Brca2 knockout lines have been produced and characterized in the mouse. We previously produced a rat Brca2 knockout strain in which there is a nonsense mutation in exon 11 between BRC repeats 2 and 3, and a truncated protein is produced. Interestingly, while such a mutation in homozygous mice would lead to limited survival of approximately 3 months, the Brca2(-/-) rats are 100% viable and the vast majority live to over 1 year of age. Brca2(-/-) rats show a phenotype of growth inhibition and sterility in both sexes. Aspermatogenesis in the Brca2(-/-) rats is due to a failure of homologous chromosome synapsis. Long-term phenotypes include underdeveloped mammary glands, cataract formation and lifespan shortening due to the development of tumors and cancers in multiple organs. The establishment of the rat Brca2 knockout model provides a means to study the role of Brca2 in increasing cancer susceptibility and inducing a novel ocular phenotype not previously associated with this gene. C1 Univ Wisconsin, Canc Res Lab, Madison, WI 53706 USA. NIDDK, Genet & Biochem Branch, NIH, Bethesda, MD USA. Univ Wisconsin, Res Anim Resource Ctr, Comparat Pathol Lab, Madison, WI 53706 USA. Univ Wisconsin, Sch Med, Dept Anat, Madison, WI 53706 USA. Univ Wisconsin, Sch Vet Med, Dept Surg Sci, Madison, WI 53706 USA. Univ Wisconsin, Sch Vet Med, Dept Pathobiol Sci, Madison, WI 53706 USA. RP Gould, MN (reprint author), Univ Wisconsin, Canc Res Lab, 1400 Univ Ave, Madison, WI 53706 USA. EM gould@oncology.wisc.edu RI Gould, Michael/C-7414-2014 FU NCI NIH HHS [CA106216] NR 43 TC 19 Z9 19 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD MAR 8 PY 2007 VL 26 IS 11 BP 1626 EP 1635 DI 10.1038/sj.onc.1209960 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 144FV UT WOS:000244782500012 PM 16964288 ER PT J AU Vogel, LN Roberts, A Paddock, CD Genrich, GL Lamirande, EW Kapadia, SU Rose, JK Zaki, SR Subbarao, K AF Vogel, Leatrice N. Roberts, Anjeanette Paddock, Christopher D. Genrich, Gillian L. Lamirande, Elaine W. Kapadia, Sagar U. Rose, John K. Zaki, Sherif R. Subbarao, Kanta TI Utility of the aged BALB/c mouse model to demonstrate prevention and control strategies for Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) SO VACCINE LA English DT Article DE SARS-CoV; aged mouse model; prophylaxis ID HUMAN MONOCLONAL-ANTIBODY; VIRUS; MICE; INFECTION; RESPONSES; GAG AB The causative agent of Severe Acute Respiratory Syndrome (SARS) was identified as a coronavirus (CoV) following the outbreak of 2002-2003. There are currently no licensed vaccines or treatments for SARS-CoV infections. Potential prevention and control strategies that show promise in vitro must be evaluated in animal models. The aged BALB/c mouse model for SARS supports a high level of viral replication in association with clinical illness and disease that mimics SARS in the elderly. We tested two preventive strategies, vaccination and passive transfer of serum antibody, to determine the extent of protection achieved against SARS-CoV challenge in this model. These approaches were able to achieve or induce antibody titers sufficient to reduce viral load, protect from weight loss and reduce or eliminate histopathologic changes in the lungs of aged mice. This study validates the utility of the aged BALB/c mouse model for evaluation of the efficacy of vaccines and immunoprophylaxis. Published by Elsevier Ltd. C1 NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Natl Ctr Infect Dis, Infect Dis Pathol Activ, Atlanta, GA 30333 USA. Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. RP Subbarao, K (reprint author), NIAID, Infect Dis Lab, NIH, Bldg 50,Room 6132,50 S Dr,MSC 8007, Bethesda, MD 20892 USA. EM Ksubbarao@niaid.nih.gov FU Intramural NIH HHS; NIAID NIH HHS [Z01 AI000934-03, AI057158, U54 AI057158] NR 14 TC 17 Z9 17 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 MAR 8 PY 2007 VL 25 IS 12 BP 2173 EP 2179 DI 10.1016/j.vaccine.2006.11.055 PG 7 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 146HN UT WOS:000244925200003 PM 17227689 ER PT J AU Okamoto, Y Nakano, M Ohzeki, JI Larionov, V Masumoto, H AF Okamoto, Yasuhide Nakano, Megumi Ohzeki, Jun-ichirou Larionov, Vladimir Masumoto, Hiroshi TI A minimal CENP-A core is required for nucleation and maintenance of a functional human centromere SO EMBO JOURNAL LA English DT Article DE alphoid DNA; artificial chromosome; centromere chromatin; epigenetics; heterochromatin ID HUMAN ARTIFICIAL CHROMOSOME; ALPHA-SATELLITE ARRAY; MODIFICATION PATTERN; HUMAN NEOCENTROMERE; HELA-CELLS; B BOX; CHROMATIN; DNA; HETEROCHROMATIN; COMPLEX AB Chromatin clusters containing CENP-A, a histone H3 variant, are found in centromeres of multicellular eukaryotes. This study examines the ability of alpha-satellite (alphoid) DNA arrays in different lengths to nucleate CENP-A chromatin and form functional kinetochores de novo. Kinetochore assembly was followed by measuring human artificial chromosome formation in cultured human cells and by chromatin immunoprecipitation analysis. The results showed that both the length of alphoid DNA arrays and the density of CENP-B boxes had a strong impact on nucleation, spreading and/or maintenance of CENP-A chromatin, and formation of functional kinetochores. These effects are attributed to a change in the dynamic balance between assembly of chromatin containing trimethyl histone H3-K9 and chromatin containing CENP-A/C. The data presented here suggest that a functional minimum core stably maintained on 30-70 kb alphoid DNA arrays represents an epigenetic memory of centromeric chromatin. C1 Nagoya Univ, Grad Sch Sci, Div Biol Sci, Chikusa Ku, Nagoya, Aichi 4648602, Japan. NCI, NIH, Lab Biosyst & Canc, Bethesda, MD 20892 USA. RP Masumoto, H (reprint author), Nagoya Univ, Grad Sch Sci, Div Biol Sci, Chikusa Ku, Nagoya, Aichi 4648602, Japan. EM g44478a@nucc.cc.nagoya-u.ac.jp NR 53 TC 42 Z9 47 U1 3 U2 7 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 MAR 7 PY 2007 VL 26 IS 5 BP 1279 EP 1291 DI 10.1038/sj.emboj.7601584 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 143JE UT WOS:000244716000008 PM 17318187 ER PT J AU Gehlert, DR Cippitelli, A Thorsell, A Le, AD Hipskind, PA Hamdouchi, C Lu, JL Hembre, EJ Cramer, J Song, M McKinzie, D Morin, M Ciccocioppo, R Heilig, M AF Gehlert, Donald R. Cippitelli, Andrea Thorsell, Annika Le, Anh Dzung Hipskind, Philip A. Hamdouchi, Chafiq Lu, Jianliang Hembre, Erik J. Cramer, Jeffrey Song, Min McKinzie, David Morin, Michelle Ciccocioppo, Roberto Heilig, Markus TI 3-(4-Chloro-2-morpholin-4-yl-thiazol-5-yl)-8-(1-ethylpropyl)-2,6-dimethy l-imidazo[1,2-b]pyridazine: A novel brain-penetrant, orally available corticotropin-releasing factor receptor 1 antagonist with efficacy in animal models of alcoholism SO JOURNAL OF NEUROSCIENCE LA English DT Article DE alcoholism; drug seeking; self-administration; relapse; stress; CRF ID ANXIETY-LIKE BEHAVIOR; ETHANOL-DEPENDENT RATS; HYDROCHLORIDE SSR125543A; SEEKING BEHAVIOR; CENTRAL NUCLEUS; STRESS; WITHDRAWAL; REINSTATEMENT; RELAPSE; POTENT AB We describe a novel corticotropin- releasing factor receptor 1 ( CRF1) antagonist with advantageous properties for clinical development, and its in vivo activity in preclinical alcoholism models. 3-( 4- Chloro- 2- morpholin- 4- yl- thiazol- 5- yl)- 8-( 1- ethylpropyl)- 2,6- dimethylimidazo[ 1,2- b] pyridazine ( MTIP) inhibited I-125- sauvagine binding to rat pituitary membranes and cloned human CRF1 with subnanomolar affinities, with no detectable activity at the CRF2 receptor or other common drug targets. After oral administration to rats, MTIP inhibited 125I- sauvagine binding to rat cerebellar membranes ex vivo with an ED50 of similar to 1.3 mg/ kg and an oral bioavailability of 91.1%. Compared with R121919 ( 2,5- dimethyl- 3-( 6- dimethyl- 4- methylpyridin- 3- yl)- 7- dipropylamino- pyrazolo[ 1,5- a] pyrimidine) and CP154526 ( N-butyl-N-ethyl-4,9- dimethyl- 7-( 2,4,6- trimethylphenyl)- 3,5,7- triazabicyclo[ 4.3.0] nona- 2,4,8,10- tetraen- 2- amine), MTIP had a markedly reduced volume of distribution and clearance. Neither open-field activity nor baseline exploration of an elevated plusmaze was affected by MTIP ( 1 - 10 mg/ kg). In contrast, MTIP dose- dependently reversed anxiogenic effects of withdrawal from a 3 g/ kg alcohol dose. Similarly, MTIP blocked excessive alcohol self- administration in Wistar rats with a history of dependence, and in a genetic model of high alcohol preference, the msP rat, at doses that had no effect in nondependent Wistar rats. Also, MTIP blocked reinstatement of stress-induced alcohol seeking both in postdependent and in genetically selected msP animals, again at doses that were ineffective in nondependent Wistar rats. Based on these findings, MTIP is a promising candidate for treatment of alcohol dependence. C1 NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. Eli Lilly & Co, Lilly Res Labs, Discovery Res, Indianapolis, IN 46285 USA. Univ Toronto, Ctr Addict & Mental Hlth, Toronto, ON M5S 2S1, Canada. Univ Camerino, Dept Expt Med & Publ Hlth, I-62032 Camerino, Italy. RP Heilig, M (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, 10 Ctr Dr,10-5334, Bethesda, MD 20892 USA. EM Markus.Heilig@mail.nih.gov OI Thorsell, Annika/0000-0003-3535-3845 NR 41 TC 145 Z9 146 U1 5 U2 9 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 MAR 7 PY 2007 VL 27 IS 10 BP 2718 EP 2726 DI 10.1523/JNEUROSCI.4985-06.2007 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 143XE UT WOS:000244758900030 PM 17344409 ER PT J AU Chen, YG Hummer, G AF Chen, Yng-Gwei Hummer, Gerhard TI Slow conformational dynamics and unfolding of the calmodulin C-terminal domain SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CALCIUM-FREE CALMODULIN; APO-CALMODULIN; PROTEIN; TRANSITION; BINDING; SIMULATIONS; PLASTICITY; RESOLUTION; STABILITY; DISORDER AB Calmodulin (CaM) is a calcium-sensing protein whose physiological function requires large-scale conformational changes. In the absence of Ca2+, the C-terminal domain of CaM exhibits conformational dynamics on a microseconds time scale. This dynamics has been interpreted as transitions between closed (apo) and open (hololike) conformers based on NMR experiments and, alternatively, as a two-state unfolding process based on temperature-jump fluorescence absorption spectroscopy. We develop a coarse-grained model to study the conformational dynamics of the CaM C-terminal domain. By construction, the coarse Hamiltonian reproduces the experimentally estimated conformer populations, melting temperature, and the microseconds time scale of the structural relaxation process. Simulations of this model suggest a three-state equilibrium among the closed apo form, an open hololike form, and a ( partially) unfolded form. At lower temperatures, the well-folded apo conformation exchanges with hololike conformers; at elevated temperatures, the dynamics is dominated by exchange between the apo and unfolded states. The resulting dynamics of the C-terminal domain appears to be effectively two-state-like, with the respective third state being only scarcely populated at most temperatures. The transition between the two dominant exchange mechanisms occurs near the melting temperature (similar to 40 degrees C) of the CaM C-terminal domain, close to physiological temperatures. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Hummer, G (reprint author), NIDDK, Chem Phys Lab, NIH, Bldg 5, Bethesda, MD 20892 USA. EM gerhard.hummer@nih.gov RI Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X FU Intramural NIH HHS NR 33 TC 36 Z9 37 U1 3 U2 11 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 MAR 7 PY 2007 VL 129 IS 9 BP 2414 EP + DI 10.1021/ja067791a PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 143OF UT WOS:000244731300003 PM 17290995 ER PT J AU Metaferia, BB Chen, L Baker, HL Huang, XY Bewley, CA AF Metaferia, Belhu B. Chen, Lin Baker, Heather L. Huang, Xin-Yun Bewley, Carole A. TI Synthetic macrolides that inhibit breast cancer cell migration in vitro SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID DIVERSITY-ORIENTED SYNTHESIS; RING-CLOSING METATHESIS; NATURAL-PRODUCTS; MIGRASTATIN; DISCOVERY AB The design and synthesis of a series of natural product-like synthetic macrolides built upon a quinic acid-containing scaffold are described. Three of the macrolides ( 1, 3, and 6) have been shown to inhibit 4T1 breast cancer cell migration with low nanomolar to sub-micromolar IC50 values ( 77, 525, and 550 nM, respectively) in complementary assays including a quantitative cell migration assay and a semiquantitative wound healing assay. C1 NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. Cornell Univ, Weill Med Coll, Dept Physiol, New York, NY 10021 USA. RP Bewley, CA (reprint author), NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. EM caroleb@mail.nih.gov FU Intramural NIH HHS; NIA NIH HHS [AG 23202] NR 16 TC 25 Z9 26 U1 0 U2 5 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 MAR 7 PY 2007 VL 129 IS 9 BP 2434 EP + DI 10.1021/ja068538d PG 3 WC Chemistry, Multidisciplinary SC Chemistry GA 143OF UT WOS:000244731300013 PM 17295491 ER PT J AU Kerlikowske, K Ichikawa, L Miglioretti, DL Buist, DSM Vacek, PM Smith-Bindman, R Yankaskas, B Carney, PA Ballard-Barbash, R AF Kerlikowske, Karla Ichikawa, Laura Miglioretti, Diana L. Buist, Diana S. M. Vacek, Pamela M. Smith-Bindman, Rebecca Yankaskas, Bonnie Carney, Patricia A. Ballard-Barbash, Rachel TI Longitudinal measurement of clinical mammographic breast density to improve estimation of breast cancer risk SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID PARENCHYMAL PATTERNS; FAMILY-HISTORY; SCREENING MAMMOGRAPHY; UNITED-STATES; TAMOXIFEN; AGE; WOMEN; ASSOCIATION; POPULATION; PREVENTION AB Background Whether a change over time in clinically measured mammographic breast density influences breast cancer risk is unknown. Methods From January 1993 to December 2003, data that included American College of Radiology Breast Imaging Reporting and Data System (BI-RADS) breast density categories (1-4 in order of increasing density) were collected prospectively on 301955 women aged 30 and older who were not using postmenopausal hormone replacement therapy and underwent at least two screening mammography examinations; 2639 of the women were diagnosed with breast cancer within 1 year of the last examination. Women's first and last BI-RADS breast density (average 3.2 years apart) and logistic regression were used to model the odds of having invasive breast cancer or ductal carcinoma in situ diagnosed within 12 months of the last examination by change in BI-RADS category. Rates of breast cancer adjusted for age, mammography registry, and time between screening examinations were estimated from this model. All statistical tests were two-sided. Results The rate (breast cancers per 1000 women) of breast cancer was higher if BI-RADS breast density category increased from 1 to 2 (5.6, 95% confidence interval [CI] = 4.7 to 6.9) or 1 to 3 (9.9, 95% Cl = 6.4 to 15.5) compared to when it remained at BI-RADS density of 1 (3.0, 95% Cl = 2.3 to 3.9; P <.001 for trend). Similar and statistically significant trends between increased or decreased density and increased or decreased risk of breast cancer, respectively, were observed for women whose breast density category was initially 2 or 3 and changed categories. BI-RADS density of 4 on the first examination was associated with a high rate of breast cancer (range 9.1-13.4) that remained high even if breast density decreased. Conclusion An increase in BI-RADS breast density category within 3 years may be associated with an increase in breast cancer risk and a decrease in density category with a decrease in risk compared to breast cancer risk in women in whom breast density category remains unchanged. Two longitudinal measures of BI-RADS breast density may better predict a woman's risk of breast cancer than a single measure. C1 Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Vet Affairs, Gen Internal Med Sect, San Francisco, CA 94143 USA. Grp Hlth Ctr Hlth Studies, Seattle, WA USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Univ Vermont, Coll Med, Dept Med Biostat, Burlington, VT USA. Univ Vermont, Coll Med, Dept Pathol, Burlington, VT 05405 USA. Univ N Carolina, Dept Radiol, Chapel Hill, NC USA. Oregon Hlth Sci Univ, Dept Family Med, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Publ Hlth & Prevent Med, Portland, OR 97201 USA. NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Kerlikowske, K (reprint author), San Francisco VA Med Ctr, Gen Internal Med Sect, 111A1,4150 Clement St, San Francisco, CA 94121 USA. EM karla.kerlikowske@ucsf.edu FU NCI NIH HHS [U01CA69976, U01CA63736, U01 CA086076-06, P01 CA107584, U01CA70040, U01CA63740, U01CA63731, R01 CA080888, U01CA70013, U01 CA086076, U01CA86082, U01CA86076, U01 CA086082] NR 51 TC 115 Z9 115 U1 1 U2 5 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 MAR 7 PY 2007 VL 99 IS 5 BP 386 EP 395 DI 10.1093/jnci/djk066 PG 10 WC Oncology SC Oncology GA 145PV UT WOS:000244877900011 PM 17341730 ER PT J AU Welzel, TM McGlynn, KA Hsing, AW O'Brien, TR Pfeiffer, RM AF Welzel, Tania M. McGlynn, Katherine A. Hsing, Ann W. O'Brien, Thomas R. Pfeiffer, Ruth M. TI Re: Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on incidence of intra- and extrahepatic cholangiocarcinorna in the United States - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Welzel, TM (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS Ste 500, Bethesda, MD 20892 USA. EM tmwelzel@web.de RI Pfeiffer, Ruth /F-4748-2011 NR 7 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 MAR 7 PY 2007 VL 99 IS 5 BP 407 EP 408 DI 10.1093/jnci/djk069 PG 2 WC Oncology SC Oncology GA 145PV UT WOS:000244877900014 ER PT J AU Kim, H Dionne, RA AF Kim, Hyungsuk Dionne, Raymond A. TI Lack of influence of GTP cyclohydrolase gene (GCH1) variations on pain sensitivity in humans SO MOLECULAR PAIN LA English DT Article ID SUSCEPTIBILITY; ASSOCIATION; PERCEPTION; VARIANTS AB Objectives: To assess the effect of variations in GTP cyclohydrolase gene (GCHI) on pain sensitivity in humans. Methods: Thermal and cold pain sensitivity were evaluated in a cohort of 735 healthy volunteers. Among this cohort, the clinical pain responses of 221 subjects after the surgical removal of impacted third molars were evaluated. Genotyping was done for 38 single nucleotide polymorphisms (SNPs) whose heterozygosity > 0.2 in GCHI. Influence of the genetic variations including SNPs and haplotypes on pain sensitivity were analyzed. Results: Minor allele frequencies and linkage disequilibrium show significant differences in European Americans, African Americans, Hispanic Americans and Asian Americans. Association analyses in European Americans do not replicate the previously reported important influence of GCHI variations on pain sensitivity. Conclusion: Considering population stratification, previously reported associations between GCH1 genetic variations and pain sensitivity appear weak or negligible in this well characterized model of pain. C1 NINR, NIH, Bethesda, MD 20892 USA. RP Dionne, RA (reprint author), NINR, NIH, Bethesda, MD 20892 USA. EM kimhy@mail.nih.gov; dionner@mail.nih.gov FU Intramural NIH HHS NR 16 TC 49 Z9 52 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1744-8069 J9 MOL PAIN JI Mol. Pain PD MAR 7 PY 2007 VL 3 AR 6 DI 10.1186/1744-8069-3-6 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 166CC UT WOS:000246353800001 PM 17343757 ER PT J AU Rodriguez, H Jaruga, P Leber, D Nyaga, SG Evans, MK Dizdaroglu, M AF Rodriguez, Henry Jaruga, Pawel Leber, Dennis Nyaga, Simon G. Evans, Michele K. Dizdaroglu, Miral TI Lymphoblasts of women with BRCA1 mutations are deficient in cellular repair of 8,5 '-cyclopurine-2 '-deoxynucleosides and 8-hydroxy-2 '-deoxyguanosine SO BIOCHEMISTRY LA English DT Article ID OXIDATIVE DNA-DAMAGE; NUCLEOTIDE EXCISION-REPAIR; BREAST-CANCER; HUMAN-CELLS; GENETIC INSTABILITY; BINDING PROTEIN; FEMALE BREAST; MAMMALIAN DNA; FREE-RADICALS; DIETARY-FAT AB Mutations in breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 predispose women to a high risk of these cancers. Here, we show that lymphoblasts of women with BRCA1 mutations who had been diagnosed with breast cancer are deficient in the repair of some products of oxidative DNA damage, namely, 8-hydroxy-2'-deoxyguanosine and 8,5'-cyclopurine-2'-deoxynucleosides. Cultured lymphoblasts from 10 individuals with BRCA1 mutations and those from 5 control individuals were exposed to 5 Gy of ionizing radiation to induce oxidative DNA damage and then allowed to repair this damage. DNA samples isolated from these cells were analyzed by liquid chromatography/mass spectrometry and gas chromatography/mass spectrometry to measure 8-hydroxy-2'-deoxyguanosine, (5'-S)-8,5'-cyclo-2'-deoxyadenosine, (5'-R)-8,5'-cyclo-2'-deoxyguanosine, and (5'-S)-8,5'-cyclo-2'-deoxyguanosine. After irradiation and a subsequent period of repair, no significant accumulation of these lesions was observed in the DNA from control cells. In contrast, cells with BRCA1 mutations accumulated statistically significant levels of these lesions in their DNA, providing evidence of a deficiency in DNA repair. In addition, a commonly used breast tumor cell line exhibited the same effect when compared to a relevant control cell line. The data suggest that BRCA1 plays a role in cellular repair of oxidatively induced DNA lesions. The failure of cells with BRCA1 mutations to repair 8,5'-cyclopurine-2'-deoxynucleosides indicates the involvement of BRCA1 in nucleotide-excision repair of oxidative DNA damage. This work suggest that accumulation of these lesions may lead to a high rate of mutations and to deleterious changes in gene expression, increasing breast cancer risk and contributing to breast carcinogenesis. C1 NIST, Chem Sci & Technol Lab, Gaithersburg, MD 20899 USA. NIST, Stat Engn Div, Gaithersburg, MD 20899 USA. Univ Maryland Baltimore Cty, Dept Chem & Biochem Engn, Baltimore, MD 21250 USA. Nicholas Copernicus Univ, Coll Med, Dept Clin Biochem, Bydgoszcz, Poland. NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. RP Dizdaroglu, M (reprint author), NIST, Chem Sci & Technol Lab, 100 Bur Dr,Stop 8311, Gaithersburg, MD 20899 USA. EM miral@nist.gov RI Jaruga, Pawel/M-4378-2015 FU Intramural NIH HHS NR 64 TC 42 Z9 42 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD MAR 6 PY 2007 VL 46 IS 9 BP 2488 EP 2496 DI 10.1021/bi062022p PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 139YE UT WOS:000244468000022 PM 17288454 ER PT J AU Duelli, DM Padilla-Nash, HM Berman, D Murphy, KM Ried, T Lazebnik, Y AF Duelli, Dominik M. Padilla-Nash, Hesed M. Berman, David Murphy, Kathleen M. Ried, Thomas Lazebnik, Yuri TI A virus causes cancer by inducing massive chromosomal instability through cell fusion SO CURRENT BIOLOGY LA English DT Article ID GENOMIC INSTABILITY; TRANSFORMATION; TUMOR; MECHANISMS; ANEUPLOIDY; APOPTOSIS AB Chromosomal instability (CIN) underlies malignant properties of many solid cancers and their ability to escape therapy, and it might itself cause cancer [1, 2]. CIN is sustained by deficiencies in proteins, such as the tumor suppressor p53 [3-5], that police genome integrity, but the primary cause of CIN in sporadic cancers remains uncertain [6,7]. The primary suspects are mutations that deregulate telomere maintenance, or mitosis, yet such mutations have not been identified in the majority of sporadic cancers [6]. Alternatively, CIN could be caused by a transient event that destabilizes the genome without permanently affecting mechanisms of mitosis or proliferation [5, 8]. Here, we show that an otherwise harmless virus rapidly causes massive chromosomal instability by fusing cells whose cell cycle is deregulated by oncogenes. This synergy between fusion and oncogenes "randomizes" normal diploid human fibroblasts so extensively that each analyzed cell has a unique karyotype, and some produce aggressive, highly aneuploid, heterogeneous, and transplantable epithelial cancers in mice. Because many viruses are fusogenic, this study suggests that viruses, including those that have not been linked to carcinogenesis, can cause chromosomal instability and, consequently, cancer by fusing cells. C1 Cold Spring Harbor Lab, Cold Spring Harbor, NY 11724 USA. NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21231 USA. Johns Hopkins Univ, Sch Med, Mol Diagnost Lab, Baltimore, MD 21287 USA. RP Lazebnik, Y (reprint author), Cold Spring Harbor Lab, 1 Bungtown Rd, Cold Spring Harbor, NY 11724 USA. EM lazebnik@cshl.edu FU Intramural NIH HHS; NCI NIH HHS [CA 009176]; NIGMS NIH HHS [R21 GM 69357] NR 25 TC 66 Z9 69 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD MAR 6 PY 2007 VL 17 IS 5 BP 431 EP 437 DI 10.1016/j.cub.2007.01.049 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 144SR UT WOS:000244817000026 PM 17320392 ER PT J AU Ostroumova, OS Gurnev, PA Schagina, LV Bezrukov, SM AF Ostroumova, Olga S. Gurnev, Philip A. Schagina, Ludmila V. Bezrukov, Sergey M. TI Asymmetry of syringomycin E channel studied by polymer partitioning SO FEBS LETTERS LA English DT Article DE syringomycin E; channel sizing; polymer exclusion; lipid bilayers; poly(ethylene glycol)s ID PLANAR LIPID-BILAYERS; ION CHANNELS; VOLUME CHANGES; PORE-SIZE; MEMBRANES; GEOMETRY; CONDUCTANCE; DIFFUSION; EXCLUSION; STATES AB To probe the size of the ion channel formed by Pseudomonas syringae lipodepsipeptide syringomycin E, we use the partial blockage of ion current by penetrating poly(ethylene glycol)s. Earlier experiments with symmetric application of these polymers yielded a radius estimate of similar to 1 nm. Now, motivated by the asymmetric non-ohmic current-voltage curves reported for this channel, we explore its structural asymmetry. We gauge this asymmetry by studying the channel conductance after one-sided addition of differently sized poly(ethylene glycol)s. We find that small polymers added to the cis-side of the membrane (the side of lipodepsipeptide addition) reduce channel conductance much less than do the same polymers added to the trans-side. We interpret our results to suggest that the water-filled pore of the channel is conical with cis- and trans-radii differing by a factor of 2-3 and that the smaller cis-radius is in the 0.25-0.35 nm range. In symmetric, two-sided addition, polymers entering the pore from the larger opening dominate blockage. (c) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 NICHHD, NIH, Bethesda, MD 20892 USA. Russian Acad Sci, Inst Cytol, St Petersburg 194064, Russia. RP Bezrukov, SM (reprint author), NICHHD, NIH, 9000 Rockville Pk,Bldg 9,Rm 1N-124B, Bethesda, MD 20892 USA. EM bezrukos@mail.nih.gov RI Ostroumova, Olga/N-8636-2013 FU Intramural NIH HHS; NICHD NIH HHS [Z01 HD000072-02] NR 30 TC 13 Z9 15 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 MAR 6 PY 2007 VL 581 IS 5 BP 804 EP 808 DI 10.1016/j.febslet.2007.01.063 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 146NL UT WOS:000244941100003 PM 17289034 ER PT J AU Kim, YS Kang, HS Jetten, AM AF Kim, Yong-Sik Kang, Hong Soon Jetten, Anton M. TI The Kruppel-like zinc finger protein Glis2 functions as a negative modulator of the Wnt/beta-catenin signaling pathway SO FEBS LETTERS LA English DT Article DE Gli-similar; Kruppel-like zinc finger protein; beta-catenin; gene expression ID REPRESSOR FUNCTIONS; KIDNEY DEVELOPMENT; BETA-CATENIN; IDENTIFICATION; TRANSCRIPTION; HEDGEHOG; GENE; WNT; TRANSACTIVATION; DIFFERENTIATION AB To gain insight into the mechanism by which Gli-similar 2 (Glis2) regulates transcription, we performed yeast-two hybrid cDNA library screening using Glis2 as bait. This screening identified beta-catenin as a potential Glis2-interacting protein. Mammalian two-hybrid, co-inummoprecipitation, and GST-pull-down analyses supported the interaction between Glis2 and beta-catenin. Pulldown analyses with several Glis2 deletion mutants indicated that the 1st zinc finger motif of Glis2 is critical for its interaction with beta-catenin, while the armadillo repeats of beta-catenin are important in its interaction with Glis2. Reporter analyses showed that Glis2 represses T-cell factor (TCF)-mediated transcriptional activation. In addition, Glis2 represses the expression of the TCF target gene cyclln D1. Our results indicate that Gfis2 interacts with beta-catenin and suggest that Glis2 functions as a negative modulator of beta-catenin/TCF-mediated transcription. Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 NIEHS, Cell Biol Sect, LRB, Div Intramural Res,NIH, Res Triangle Pk, NC 27709 USA. RP Jetten, AM (reprint author), NIEHS, Cell Biol Sect, LRB, Div Intramural Res,NIH, Res Triangle Pk, NC 27709 USA. EM jetten@niehs.nih.gov OI Jetten, Anton/0000-0003-0954-4445 FU Intramural NIH HHS [Z01 ES100485-06] NR 20 TC 20 Z9 26 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD MAR 6 PY 2007 VL 581 IS 5 BP 858 EP 864 DI 10.1016/j.febslet.2007.01.058 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 146NL UT WOS:000244941100012 PM 17289029 ER PT J AU Ahmet, I Poosala, S Lakatta, EG Talan, MI AF Ahmet, Ismayil Poosala, Suresh Lakatta, Edward G. Talan, Mark I. TI beta(2)-adrenergic receptors agonists - a new therapeutic strategy for the treatment of chronic heart failure SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 56th Annual Scientific Session of the American-College-of-Cardiology CY MAR 24-27, 2007 CL New Orleans, LA SP Amer Coll Cardiol C1 NIA, NIH, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2007 VL 49 IS 9 SU A BP 43A EP 43A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 142LQ UT WOS:000244651800174 ER PT J AU Mordini, FE Haddad, TM Hsu, LY Bandettini, WP Kellman, P Lowrey, TB Aletras, AH Arai, AE AF Mordini, Federico E. Haddad, Tariq M. Hsu, Li-Yueh Bandettini, W. Patricia Kellman, Peter Lowrey, Tracy B. Aletras, Anthony H. Arai, Andrew E. TI Accuracy of fully quantitative cardiac magnetic resonance myocardial perfusion in detection of coronary disease as measured by quantitative coronary angiography SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 56th Annual Scientific Session of the American-College-of-Cardiology CY MAR 24-27, 2007 CL New Orleans, LA SP Amer Coll Cardiol C1 Natl Inst Hlth, Bethesda, MD USA. Suburban Hosp, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2007 VL 49 IS 9 SU A BP 105A EP 105A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 142LQ UT WOS:000244651800429 ER PT J AU Shizukuda, Y Bolan, CD Tripodi, DJ Sachdev, V Nguyen, T Botello, G Yau, YY Emst, I Mir, AI Leitman, S Rosing, DR AF Shizukuda, Yukitaka Bolan, Charles D. Tripodi, Dorothy J. Sachdev, Vandana Nguyen, Tammy Botello, Gilberto Yau, Yu-Ying Emst, Inez Mir, Ali I. Leitman, Susan Rosing, Douglas R. TI Oxidative stress, not iron overload; Is associated with systolic and diastolic strain rate in asymptomatic subjects with hereditary hemochromatosis SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 56th Annual Scientific Session of the American-College-of-Cardiology CY MAR 24-27, 2007 CL New Orleans, LA SP Amer Coll Cardiol C1 NIH, NHLBI, Bethesda, MD 20892 USA. NIH, Dept Transfus Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2007 VL 49 IS 9 SU A BP 126A EP 126A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 142LQ UT WOS:000244651800513 ER PT J AU Chantler, PD Melenovsky, V Schulman, SP Gerstenblith, G Fleg, JL Becker, LC Ferrucci, L Lakatta, EG Najjar, SS AF Chantler, Paul D. Melenovsky, Vojtech Schulman, Steven P. Gerstenblith, Gary Fleg, Jerome L. Becker, Lewis C. Ferrucci, Luigi Lakatta, Edward G. Najjar, Samer S. TI Synergistic effects of systolic hypertension and female sex on the arterial-ventricular coupling ratio. SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 56th Annual Scientific Session of the American-College-of-Cardiology CY MAR 24-27, 2007 CL New Orleans, LA SP Amer Coll Cardiol C1 NIH, NIA, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2007 VL 49 IS 9 SU A BP 129A EP 129A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 142LQ UT WOS:000244651800527 ER PT J AU Bandettini, WP McUsic, AC Rosing, DR Stratakis, CA Arai, AE AF Bandettini, W. Patricia McUsic, Andrew C. Rosing, Douglas R. Stratakis, Constantine A. Arai, Andrew E. TI Thi relative value of cardiac magnetic resonance and echocardiography for diagnosing myxoma in patients with carney complex SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 56th Annual Scientific Session of the American-College-of-Cardiology CY MAR 24-27, 2007 CL New Orleans, LA SP Amer Coll Cardiol C1 Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2007 VL 49 IS 9 SU A BP 161A EP 161A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 142LQ UT WOS:000244651801100 ER PT J AU Koh, KK Quon, MJ Chung, WJ Moon, CI Park, SM Shin, EK AF Koh, Kwang K. Quon, Michael J. Chung, Wook-Jin Moon, Chan I. Park, Sang M. Shin, Eak K. TI Efonidipine simultaneously improves endothelial function and metabolic parameters in patients with hypertension SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 56th Annual Scientific Session of the American-College-of-Cardiology CY MAR 24-27, 2007 CL New Orleans, LA SP Amer Coll Cardiol C1 Gil Med Ctr, Gachon Med Sch, Inchon, South Korea. NIH, Diabet Unit, Bethesda, MD 20892 USA. RI Quon, Michael/B-1970-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2007 VL 49 IS 9 SU A BP 316A EP 316A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 142LQ UT WOS:000244651802171 ER PT J AU Levitzky, YS Guo, CY Rong, J Larson, MG Walter, RE Keaney, JF Sutherland, PA Vasan, A Lipinska, I Evans, JC Benjamin, EJ AF Levitzky, Yamini S. Guo, Chao-Yu Rong, Jian Larson, Martin G. Walter, Robert E. Keaney, John F., Jr. Sutherland, Patrice A. Vasan, Aditi Lipinska, Izabella Evans, Jane C. Benjamin, Emelia J. TI Relation of smoking status to a panel of inflammatory markers: The Framingham offspring study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 56th Annual Scientific Session of the American-College-of-Cardiology CY MAR 24-27, 2007 CL New Orleans, LA SP Amer Coll Cardiol C1 Framingham Heart Dis Epidemiol Study, Natl Heart Lung & Blood Inst, Framingham, MA USA. Boston Univ, Boston, MA 02215 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2007 VL 49 IS 9 SU A BP 328A EP 328A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 142LQ UT WOS:000244651802225 ER PT J AU de Backer, TL Peterson, G Lansky, AJ Agodoa, L Appel, L Brittain, K Gassmann, J Kendrick, C Lipkowitz, M Wright, JT Phillips, RA AF de Backer, Tine L. Peterson, Gail Lansky, Alexandra J. Agodoa, Larry Appel, Larry Brittain, Karen Gassmann, Jennifer Kendrick, Cindy Lipkowitz, Michael Wright, Jackson T. Phillips, Robert A. TI Left ventricular geometric patterns in the African American study of kidney disease and hypertension (AASK) cohort SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Meeting Abstract CT 56th Annual Scientific Session of the American-College-of-Cardiology CY MAR 24-27, 2007 CL New Orleans, LA SP Amer Coll Cardiol C1 Cardiovasc Res Fdn, New York, NY USA. NIDDK, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 6 PY 2007 VL 49 IS 9 SU A BP 399A EP 399A PG 1 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 142LQ UT WOS:000244651802521 ER PT J AU Thacker, EL O'Reilly, EJ Weisskopf, MG Chen, H Schwarzschild, MA McCullough, ML Calle, EE Thun, MJ Ascherio, A AF Thacker, E. L. O'Reilly, E. J. Weisskopf, M. G. Chen, H. Schwarzschild, M. A. McCullough, M. L. Calle, E. E. Thun, M. J. Ascherio, A. TI Temporal relationship between cigarette smoking and risk of Parkinson disease SO NEUROLOGY LA English DT Article ID ASSOCIATION; COHORT; DIAGNOSIS; MORTALITY; NICOTINE; ACCURACY; CAFFEINE; ALCOHOL; TRAITS; COFFEE AB Objective: To characterize further the relationship between smoking history and Parkinson disease (PD) risk by considering temporal and qualitative features of smoking exposure, including duration, average intensity, and recentness, as well as the relative importance of smoking during different periods of life. Methods: We prospectively assessed incident PD from 1992 to 2001 among 79,977 women and 63,348 men participating in the Cancer Prevention Study II Nutrition Cohort, according to their cigarette smoking status and lifetime smoking histories. Results: During follow-up, 413 participants had definite or probable PD confirmed by their treating neurologists or medical record review. Compared with never smokers, former smokers had a relative risk (RR) of 0.78 (95% CI 0.64 to 0.95) and current smokers had an RR of 0.27 (95% CI 0.13 to 0.56). On average, participants with more years smoked, more cigarettes per day, older age at quitting smoking, and fewer years since quitting smoking had lower PD risk. The relative risks and trends did not vary significantly by sex. The cumulative incidence of PD was lowest among participants who quit smoking at later ages. A 30% to 60% decreased risk of PD was apparent for smoking as early as 15 to 24 years before symptom onset, but not for smoking 25 or more years before onset. Conclusions: The lower risk of Parkinson disease among current and former smokers varied with smoking duration, intensity, and recentness. The dependence of this association on the timing of smoking during life is consistent with a biologic effect. C1 Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Amer Canc Soc, Epidemiol & Surveillance Res Dept, Atlanta, GA 30329 USA. RP Thacker, EL (reprint author), 655 Huntington Ave,Bldg 2, Boston, MA 02115 USA. EM ethacker@post.harvard.edu OI Thacker, Evan/0000-0002-3813-0885; Chen, Honglei/0000-0003-3446-7779 FU Intramural NIH HHS; NINDS NIH HHS [NS048517, R01 NS048517, R01 NS048517-03] NR 20 TC 73 Z9 75 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD MAR 6 PY 2007 VL 68 IS 10 BP 764 EP 768 DI 10.1212/01.wnl.0000256374.50227.4b PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 142VX UT WOS:000244679900009 PM 17339584 ER PT J AU Zhang, PJ Khursigara, CM Hartnell, LM Subramaniam, S AF Zhang, Peijun Khursigara, Cezar M. Hartnell, Lisa M. Subramaniam, Sriram TI Direct visualization of Escherichia coli chemotaxis receptor arrays using cryo-electron microscopy SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cryo-tomography; signal transduction; molecular architecture ID BACTERIAL CHEMOTAXIS; CROSS-LINKING; CHEMORECEPTORS; SENSITIVITY; COMPONENTS; COMPLEX; PROTEIN; TSR; LOCALIZATION; ORGANIZATION AB Signal transduction in bacterial chemotaxis is initiated by the binding of extracellular ligands to a specialized family of methyl-accepting chemoreceptor proteins. Chemoreceptors cluster at distinct regions of the cell and form stable ternary complexes with the histidine autokinase CheA and the adapter protein CheW. Here we report the direct visualization and spatial organization of chemoreceptor arrays in intact Escherichia coli cells by using cryo-electron tomography and biochemical techniques. In wild-type cells, ternary complexes are arranged as an extended lattice, which may or may not be ordered, with significant variations in the size and specific location among cells in the same population. In the absence of CheA and CheW, chemoreceptors do not form observable clusters and are diffusely localized to the cell pole. At disproportionately high receptor levels, membrane invaginations containing nonfunctional, axially interacting receptor assemblies are formed. However, functional chemoreceptor arrays can be reestablished by increasing cellular levels of CheA and CheW. Our results demonstrate that chemotaxis in E. coli requires the presence of chemoreceptor arrays and that the formation of these arrays requires the scaffolding interactions of the signaling molecules CheA and CheW. C1 NIH, NCI, Ctr Canc Res, Cell Biol Lab, Bethesda, MD 20892 USA. RP Subramaniam, S (reprint author), NIH, NCI, Ctr Canc Res, Cell Biol Lab, Bethesda, MD 20892 USA. EM ss1@nih.gov FU Intramural NIH HHS NR 37 TC 122 Z9 124 U1 0 U2 9 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 6 PY 2007 VL 104 IS 10 BP 3777 EP 3781 DI 10.1073/pnas.0610106104 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146ZE UT WOS:000244972400022 PM 17360429 ER PT J AU Zoncu, R Perera, RM Sebastian, R Nakatsu, F Chen, H Balla, T Ayala, G Toomre, D De Camilli, PV AF Zoncu, Roberto Perera, Rushika M. Sebastian, Rafael Nakatsu, Fubito Chen, Hong Balla, Tamas Ayala, Guillermo Toomre, Derek De Camilli, Pietro V. TI Loss of endocytic clathrin-coated pits upon acute depletion of phosphatidylinositol 4,5-bisphosphate SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE actin; dynamin; epsin; phosphoinositides; rapamycin ID INOSITOL POLYPHOSPHATE 5-PHOSPHATASE; ACTIN CYTOSKELETON; PLASMA-MEMBRANE; MEDIATED ENDOCYTOSIS; N-WASP; BINDING-PROTEIN; ARP2/3 COMPLEX; LIVING CELLS; CRYSTAL-STRUCTURE; HOMOLOGY DOMAINS AB Phosphaticlylinositol 4,5-bisphosphate [PI(4,5)P-2], a phosphoinositide concentrated predominantly in the plasma membrane, binds endocytic clathrin adaptors, many of their accessory factors, and a variety of actin-regulatory proteins. Here we have used fluorescent fusion proteins and total internal reflection fluorescence microscopy to investigate the effect of acute PI(4,5)P-2 breakdown on the dynamics of endocytic clathrin-coated pit components and of the actin regulatory complex, Arp2/3. PI(4,5)P-2 breakdown was achieved by the inducible recruitment to the plasma membrane of an inositol 5-phosphatase module through the rapamycin/FRB/FKBP system or by treatment with ionomycin. PI(4,5)P-2 depletion resulted in a dramatic loss of clathrin puncta, which correlated with a massive dissociation of endocytic adaptors from the plasma membrane. Remaining clathrin spots at the cell surface had only weak fluorescence and were static over time. Dynamin and the p20 subunit of the Arp2/3 actin regulatory complex, which were concentrated at late-stage clathrin-coated pits and in lamellipodia, also dissociated from the plasma membrane, and these changes correlated with an arrest of motility at the cell edge. These findings demonstrate the critical importance of PI(4,5)P-2 in clathrin coat dynamics and Arp2/3-dependent actin regulation. C1 Yale Univ, Sch Med, Dept Cell Biol, New Haven, CT 06510 USA. Yale Univ, Sch Med, Howard Hughes Med Inst, Kavli Inst Neurosci, New Haven, CT 06510 USA. Yale Univ, Sch Med, Program Cellular Neurosci Neurodegenerat & Repair, New Haven, CT 06510 USA. Univ Valencia, Dept Informat, E-46100 Burjassot, Spain. NICHHD, Sect Mol Signal Transduct, NIH, Bethesda, MD 20892 USA. RP Toomre, D (reprint author), Yale Univ, Sch Med, Dept Cell Biol, 333 Cedar St, New Haven, CT 06510 USA. EM derek.toomre@yale.edu; pietro.decamilli@yale.edu RI Ayala, Guillermo/A-8077-2008; SEBASTAN, RAFAEL/E-9386-2011; OI Ayala, Guillermo/0000-0002-6231-2865; SEBASTAN, RAFAEL/0000-0001-6746-5740; Balla, Tamas/0000-0002-9077-3335 FU Intramural NIH HHS; NCI NIH HHS [CA 46128, P01 CA046128]; NIDA NIH HHS [DA 018343, P30 DA018343]; NIDDK NIH HHS [DK 45735, P30 DK045735]; NINDS NIH HHS [NS 36251, R01 NS036251, R37 NS036251] NR 65 TC 147 Z9 148 U1 1 U2 7 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 6 PY 2007 VL 104 IS 10 BP 3793 EP 3798 DI 10.1073/pnas.0611733104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146ZE UT WOS:000244972400025 PM 17360432 ER PT J AU Boulanger, CA Mack, DL Booth, BW Smith, GH AF Boulanger, Corinne A. Mack, David L. Booth, Brian W. Smith, Gilbert H. TI Interaction with the mammary microenvironment redirects spermatogenic cell fate in vivo SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE transdifferentiation; transplantation; niche; stem cell ID LIFE SPAN; MORPHOLOGICAL CHARACTERIZATION; EPITHELIAL-CELLS; MOUSE; EXPRESSION; MICE; GLAND; GENE; GROWTH AB Previously, we characterized a parity-induced mammary epithelial cell population that possessed the properties of pluripotency and self-renewal upon transplantation. These cells were lineally marked by the expression of beta-galactosidase (LacZ) as a result of mammary-specific activation of a reporter gene through Cre-lox recombination during pregnancy. We used this experimental model to determine whether testicular cells would alter their cell fate upon interaction with the mammary gland microenvironment during pregnancy, lactation, and involution. Adult testicular cells, isolated from seminiferous tubules, were mixed with limiting dilutions of dispersed mammary epithelial cells and injected into epithelium-divested mammary fat pads. The host mice were bred 6-8 weeks later and examined 20-30 days postinvolution. This approach allowed for the growth of mammary tissue from the injected cells and transient activation of the whey acidic protein promoter-Cre gene during pregnancy and lactation, leading to Cre-lox recombination and constitutive expression of LacZ from its promoter. Here we show that cells from adult seminiferous tubules interact with mammary epithelial cells during regeneration of the gland. They adopt mammary epithelial progenitor cell properties, including self-renewal and the production of cell progeny, which differentiate into functional mammary epithelial cells. Our results provide evidence for the ascendancy of the tissue microenvironment over the intrinsic nature of cells from an alternative adult tissue. C1 NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Smith, GH (reprint author), NCI, Mammary Biol & Tumorigenesis Lab, Ctr Canc Res, NIH, 37 Convent Dr,Bldg 37,Room 1106, Bethesda, MD 20892 USA. EM gs4d@nih.gov NR 23 TC 88 Z9 93 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 MAR 6 PY 2007 VL 104 IS 10 BP 3871 EP 3876 DI 10.1073/pnas.0611637104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146ZE UT WOS:000244972400038 PM 17360445 ER PT J AU Airoldi, I Di Carlo, E Cocco, C Taverniti, G D'Antuono, T Ognio, E Watanabe, M Ribatti, D Pistoia, V AF Airoldi, Irma Di Carlo, Emma Cocco, Claudia Taverniti, Giuseppe D'Antuono, Tommaso Ognio, Emanuela Watanabe, Morihiro Ribatti, Domenico Pistoia, Vito TI Endogenous IL-12 triggers an antiangiogenic program in melanoma cells SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE angiogenesis; tumor immunology; cytokines ID SMOOTH-MUSCLE-CELLS; TUMOR-GROWTH; IN-VIVO; INTERLEUKIN-12; ANGIOGENESIS; RECEPTOR; EXPRESSION; IMMUNITY; ANTITUMOR; RESPONSES AB The Il12RB2 gene acts as a tumor suppressor in human B cell malignancies. Indeed, Il12rb2 knockout (KO) mice develop spontaneously B cell tumors, but also lung epithelial tumors. This latter phenotype may be related to (i) impairment of host IL-12-mediated immunosurveillance and/or (it) IL-12 inability to inhibit directly the growth of IL-12 unresponsive malignant cells. To address this issue, we transplanted IL-12R(+) B16 melanoma cells into syngeneic Il12rb2 KO mice with the following rationale: (t) these mice have severe defects in IFN-gamma production, as well as in cytotoxic T lymphocyte and natural killer cell cytotoxicity, and (ii) they produce but do not use IL-12 that can potentially bind to and target tumor cells only. Il12rb2 KO mice displayed higher endogenous serum levels of IL-12 and developed smaller B16 tumors than WT animals. These tumors showed reduced proliferation, increased apoptosis, and defective microvessel formation related to down-regulated expression of a set of proangiogenic genes previously unrelated to IL-12. Such effects depended on direct activity of endogenous IL-12 on tumor cells in KO mice, and hydrodynamic delivered IL-12 caused further reduced tumorigenicity of B16 cells in these mice. A previously undescribed mechanism of the IL-12 antitumor activity has been here identified and characterized. C1 Ist Giannina Gaslini, Lab Oncol, I-16148 Genoa, Italy. Univ G DAnnunzio, Dept Oncol & Neurosci, I-66013 Chieti, Italy. G DAnnunzio Univ Fdn, CeSI Aging Res Ctr, I-66013 Chieti, Italy. Ist Nazl Ric Canc, Anim Model Facil, I-16132 Genoa, Italy. NCI, Lab Expt Immunol, Ctr Canc Res, Frederick, MD 21702 USA. Univ Bari, Dept Human Anat & Histol, I-70124 Bari, Italy. RP Airoldi, I (reprint author), Ist Giannina Gaslini, Lab Oncol, Largo G Gaslini 5, I-16148 Genoa, Italy. EM irmaairoldi@ospedale-gaslini.ge.it NR 47 TC 58 Z9 60 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 MAR 6 PY 2007 VL 104 IS 10 BP 3996 EP 4001 DI 10.1073/pnas.0609028104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146ZE UT WOS:000244972400059 PM 17360466 ER PT J AU Scott, AM Lee, FT Tebbutt, N Herbertson, R Gill, SS Liu, ZQ Skrinos, E Murone, C Saunder, TH Chappell, B Papenfuss, AT Poon, AMT Hopkins, W Smyth, FE MacGregor, D Cher, LM Jungbluth, AA Brechbiel, MW Murphy, R Burgess, AW Hoffman, EW Johns, TG Old, LJ AF Scott, Andrew M. Lee, Fook-Thean Tebbutt, Niall Herbertson, Rebecca Gill, Sanjeev S. Liu, Zhanqi Skrinos, Effie Murone, Carmel Saunder, Timothy H. Chappell, Bridget Papenfuss, Anthony T. Poon, Aurora M. T. Hopkins, Wendie Smyth, Fiona E. MacGregor, Duncan Cher, Lawrence M. Jungbluth, Achim A. Brechbiel, Martin W. Murphy, Roger Burgess, Antony W. Hoffman, Eric W. Johns, Terrance G. Old, Lloyd J. TI A phase I clinical trial with monoclonal antibody ch806 targeting transitional state and mutant epidermal growth factor receptors SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE tumor; immunotherapy; anti-erbB1; biodistribution ID METASTATIC COLON-CANCER; CELL-SURFACE; EGF RECEPTOR; CHIMERIC ANTIBODY; TUMOR XENOGRAFTS; SOLID TUMORS; MONOCLONAL-ANTIBODY-806; PHARMACOKINETICS; IMMUNOTHERAPY; RECOGNIZES AB An array of cell-surface antigens expressed by human cancers have been identified as targets for antibody-based therapies. The great majority of these antibodies do not have specificity for cancer but recognize antigens expressed on a range of normal cell types (differentiation antigens). Over the past two decades, our group has analyzed thousands of mouse monoclonal antibodies for cancer specificity and identified a battery of antibodies with limited representation on normal human cells. The most tumor-specific of these antibodies is 806, an antibody that detects a unique epitope on the epidermal growth factor receptor (EGFR) that is exposed only on overexpressed, mutant, or ligand-activated forms of the receptor in cancer. In vitro immunohistochemical specificity analysis shows little or no detectable 806 reactivity with normal tissues, even those with high levels of wild-type (wt)EGFR expression. Preclinical studies have demonstrated that 806 specifically targets a subset of EGFR expressed on tumor cells, and has significant anti-tumor effects on human tumor xenografts, primarily through abrogation of signaling pathways. The present clinical study was designed to examine the in vivo specificity of a chimeric form of mAb 806 (ch806) in a tumor targeting/biodistribution/ pharmacokinetic analysis in patients with diverse tumor types. ch806 showed excellent targeting of tumor sites in all patients, no evidence of normal tissue uptake, and no significant toxicity. These in vitro and in vivo characteristics of ch806 distinguish it from all other antibodies targeting EGFR. C1 Ludwig Inst Canc Res, Melbourne, Vic 3084, Australia. Austin Hosp, Dept Nucl Med, Melbourne, Vic 3084, Australia. Austin Hosp, Ctr PET, Melbourne, Vic 3084, Australia. Austin Hosp, Ludwig Inst Oncol Unit, Melbourne, Vic 3084, Australia. Austin Hosp, Canc Clin Trials Ctr, Melbourne, Vic 3084, Australia. Austin Hosp, Dept Anat Pathol, Melbourne, Vic 3084, Australia. Walter & Eliza Hall Inst Med Res, Div Genet & Bioinformat, Melbourne, Vic 3050, Australia. Ludwig Inst Canc Res, New York, NY 10021 USA. NCI, NIH, Radioimmune & Inorgan Chem Sect, Bethesda, MD 20892 USA. RP Scott, AM (reprint author), Austin Hosp, Ludwig Inst Canc Res, Level 1,Harold Stokes Bldg,143-165 Studley Rd, Heidelberg, Vic 3084, Australia. EM andrew.scott@ludwig.edu.au; lold@licr.org RI Johns, Terrance/C-2441-2008; Scott, Fiona/K-8106-2013; Papenfuss, Anthony/C-6297-2008 OI Johns, Terrance/0000-0002-8874-4543; Papenfuss, Anthony/0000-0002-1102-8506 FU Intramural NIH HHS NR 42 TC 116 Z9 128 U1 1 U2 6 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 6 PY 2007 VL 104 IS 10 BP 4071 EP 4076 DI 10.1073/pnas.0611693104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146ZE UT WOS:000244972400072 PM 17360479 ER PT J AU Lee, CR Cho, SH Yoon, MJ Peterkofsky, A Seok, YJ AF Lee, Chang-Ro Cho, Seung-Hyon Yoon, Mi-Jeong Peterkofsky, Alan Seok, Yeong-Jae TI Escherichia coli enzyme IIA(Ntr) regulates the K+ transporter TrkA SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE leucine toxicity; nitrogen-metabolic phosphotransferase system (PTS); potassium transporter TrkA; protein-protein interaction; signal transduction ID GLOBAL REPRESSOR MLC; PHOSPHOTRANSFERASE SYSTEM; GLUCOSE-TRANSPORTER; GLYCOGEN-PHOSPHORYLASE; ALLOSTERIC REGULATION; CYTOPLASMIC MEMBRANE; PROTEIN; POTASSIUM; EXPRESSION; LEUCINE AB The maintenance of ionic homeostasis in response to changes in the environment is essential for all living cells. Although there are still many important questions concerning the role of the major monovalent cation K+, cytoplasmic K+ in bacteria is required for diverse processes. Here, we show that enzyme IIA(Ntr) (EIIA(Ntr)) of the nitrogen-metabolic phosphotransferase system interacts with and regulates the Escherichia coli K+ transporter TrkA. Previously we reported that an E. coli K-12 mutant in the ptsN gene encoding EIIANtr was extremely sensitive to growth inhibition by leucine or leucine-containing peptides (LCPs). This sensitivity was due to the requirement of the dephosphorylated form of EIIA(Ntr) for the derepression of ilvBN expression. Whereas the ptsN mutant is extremely sensitive to LCPs, a ptsN trkA double mutant is as resistant as WT. Furthermore, the sensitivity of the ptsN mutant to LCPs decreases as the K+ level in culture media is lowered. We demonstrate that dephosphorylated EIIANtr, but not its phosphorylated form, forms a tight complex with TrkA that inhibits the accumulation of high intracellular concentrations of K+. High cellular K+ levels in a ptsN mutant promote the sensitivity of E. coli K-12 to leucine or LCPs by inhibiting both the expression of ilvBN and the activity of its gene products. Here, we delineate the similarity of regulatory mechanisms for the paralogous carbon and nitrogen phosphotransferase systems. Dephosphorylated EIIA(Glc) regulates a variety of transport systems for carbon sources, whereas dephosphorylated EIIA(Ntr) regulates the transport system for K+, which has global effects related to nitrogen metabolism. C1 Seoul Natl Univ, Lab Macromol Interact, Dept Biol Sci, Seoul 151742, South Korea. Seoul Natl Univ, Inst Microbiol, Seoul 151742, South Korea. NHLBI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Seok, YJ (reprint author), Seoul Natl Univ, Lab Macromol Interact, Dept Biol Sci, Seoul 151742, South Korea. EM yjseok@plaza.snu.ac.kr FU Intramural NIH HHS NR 35 TC 77 Z9 77 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 6 PY 2007 VL 104 IS 10 BP 4124 EP 4129 DI 10.1073/pnas.0609897104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146ZE UT WOS:000244972400081 PM 17289841 ER PT J AU Huang, YF Higginson, DS Hester, L Park, MH Snyder, SH AF Huang, Yunfei Higginson, Daniel S. Hester, Lynda Park, Myung Hee Snyder, Solomon H. TI Neuronal growth and survival mediated by eIF5A, a polyamine-modified translation initiation factor SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE hypusine; spermidine; nerve growth factor; arginase; deoxyhypusine synthase ID YEAST SACCHAROMYCES-CEREVISIAE; FACTOR 5A EIF5A; DEOXYHYPUSINE SYNTHASE; ORNITHINE-DECARBOXYLASE; SYMPATHETIC NEURONS; PROTEIN-SYNTHESIS; CELL VIABILITY; NITRIC-OXIDE; GENE-EXPRESSION; PC12 CELLS AB Eukaryotic translation initiation factor 5A (elF5A) the only known protein containing the polyamine-derived amino acid hypusine, modulates protein synthesis. We show that neurotrophic and neuroprotective actions of nerve growth factor (NGF) are mediated by hypusinated elF5A, which can account for the known roles of polyamines in cell growth and survival. NGF treatment of PC12 cells stimulates elF5A formation. Moreover, prevention of hypusine formation by a selective inhibitor of deoxyhypusine synthase and by its depletion with RNA interference blocks the NGF-elicited augmentation of neurite outgrowth and cell survival of PC12 cells. In brain cultures, inhibition of hypusine formation also inhibits neuronal process extension. C1 Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP Snyder, SH (reprint author), Johns Hopkins Univ, Sch Med, Solomon H Snyder Dept Neurosci, 725 N Wolfe St, Baltimore, MD 21205 USA. EM ssnyder@jhmi.edu FU Intramural NIH HHS [Z01 DE000608-14, Z99 DE999999]; NIDA NIH HHS [DA 00074, K05 DA000074]; NIMH NIH HHS [R37 MH018501, MH 18501, R01 MH018501] NR 47 TC 21 Z9 25 U1 0 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 6 PY 2007 VL 104 IS 10 BP 4194 EP 4199 DI 10.1073/pnas.0611609104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 146ZE UT WOS:000244972400093 PM 17360499 ER PT J AU Kahn, AB Ryan, MC Liu, HF Zeeberg, BR Jamison, DC Weinstein, JN AF Kahn, Ari B. Ryan, Michael C. Liu, Hongfang Zeeberg, Barry R. Jamison, D. Curtis Weinstein, John N. TI SpliceMiner: a high-throughput database implementation of the NCBI Evidence Viewer for microarray splice variant analysis SO BMC BIOINFORMATICS LA English DT Article ID GENOME-WIDE DETECTION; HUMAN-DISEASE; HUMAN GENES; MECHANISMS; DIVERSITY; RESOURCE; BIOINFORMATICS; INFORMATION; ANNOTATION; EXPRESSION AB Background: There are many fewer genes in the human genome than there are expressed transcripts. Alternative splicing is the reason. Alternatively spliced transcripts are often specific to tissue type, developmental stage, environmental condition, or disease state. Accurate analysis of microarray expression data and design of new arrays for alternative splicing require assessment of probes at the sequence and exon levels. Description: SpliceMiner is a web interface for querying Evidence Viewer Database (EVDB). EVDB is a comprehensive, non-redundant compendium of splice variant data for human genes. We constructed EVDB as a queryable implementation of the NCBI Evidence Viewer (EV). EVDB is based on data obtained from NCBI Entrez Gene and EV. The automated EVDB build process uses only complete coding sequences, which may or may not include partial or complete 5' and 3' UTRs, and filters redundant splice variants. Unlike EV, which supports only one-at-a-time queries, SpliceMiner supports high-throughput batch queries and provides results in an easily parsable format. SpliceMiner maps probes to splice variants, effectively delineating the variants identified by a probe. Conclusion: EVDB can be queried by gene symbol, genomic coordinates, or probe sequence via a user-friendly web-based tool we call SpliceMiner (http://discover.nci.nih.gov/spliceminer). The EVDB/SpliceMiner combination provides an interface with human splice variant information and, going beyond the very valuable NCBI Evidence Viewer, supports fluent, high-throughput analysis. Integration of EVDB information into microarray analysis and design pipelines has the potential to improve the analysis and bioinformatic interpretation of gene expression data, for both batch and interactive processing. For example, whenever a gene expression value is recognized as important or appears anomalous in a microarray experiment, the interactive mode of SpliceMiner can be used quickly and easily to check for possible splice variant issues. C1 NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. George Mason Univ, Dept Informat, Fairfax, VA 22030 USA. Tiger Team Consulting, Fairfax, VA USA. Georgetown Univ, Washington, DC USA. No Kentucky Univ, Sch Informat, Highland Hts, KY 41076 USA. RP Weinstein, JN (reprint author), NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. EM arik@mail.nih.gov; mryan@tigerteamconsulting.com; hl224@georgetown.edu; zeebergb@mail.nih.gov; jamisond1@nku.edu; weinstein@dtpax2.ncifcrf.gov FU Intramural NIH HHS; NLM NIH HHS [R01 LM009959] NR 55 TC 15 Z9 16 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2105 J9 BMC BIOINFORMATICS JI BMC Bioinformatics PD MAR 5 PY 2007 VL 8 AR 75 DI 10.1186/1471-2105-8-75 PG 9 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 154BP UT WOS:000245482100001 PM 17338820 ER PT J AU Kim, BJ Mangala, SL Muralidhara, BK Hayashi, K AF Kim, Bong-Jo Mangala, Selanere L. Muralidhara, B. K. Hayashi, Kiyoshi TI Fragment complementation for the co-refolding of Thermotoga maritima beta-glucosidase by gene splitting at non-homologous region SO ENZYME AND MICROBIAL TECHNOLOGY LA English DT Article DE beta-glucosidase; Thermotoga maritima; non-homologous region; co-refolding; gene splitting; inclusion bodies; fragment complementation ID TRANSGLYCOSYLATION ACTIVITY; CONSTRUCTION AB beta-Glucosidase from Thermotoga maritima is a 721 amino acid protein consisting of structurally distinct non-homologous region connecting the N- and C-terminal domains. To investigate the functional role of the non-homologous region in co-refolding, the gene was split at four sites (370, 403, 419 and 435) of the non-homologous region, cloned and separately expressed in E. coli generating eight peptide fragments (N370, N403, N419, N435, 371C, 404C, 420C and 436C). All eight fragments were recovered as insoluble inclusion bodies and found to be catalytically inactive. No catalytic activity was observed when these eight fragments were refolded individually. However, the catalytic activity was recovered when the two fragments derived from N- and C-terminal peptides were co-refolded together. Truncation of almost all amino acid residues in non-homologous region resulted in extremely low catalytic activity, which strongly suggests that non-homologous region is very important for the proper refolding of the peptides to reconstitute the catalytic activity. We succeeded in refolding the protein into an active form after splitting the gene at non-homologous region, denaturing and co-refolding the two domains. These results demonstrates the importance of structural elements that are not involved in the active site play an important role in protein folding to assemble the active site elements. (c) 2006 Elsevier Inc. All rights reserved. C1 Natl Food Res Inst, Enzyme Lab, Tsukuba, Ibaraki 3058642, Japan. Univ Texas, Med Branch, Dept Pharmacol & Toxicol, Galveston, TX 77550 USA. RP Kim, BJ (reprint author), NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. EM bjkim@mail.nih.gov NR 24 TC 1 Z9 1 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0141-0229 J9 ENZYME MICROB TECH JI Enzyme Microb. Technol. PD MAR 5 PY 2007 VL 40 IS 4 BP 732 EP 739 DI 10.1016/j.enzmictec.2006.06.005 PG 8 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 147PT UT WOS:000245015600033 ER PT J AU Wilcox, AJ Lie, RT Solvoll, K Taylor, J McConnaughey, DR Abyholm, F Vindenes, H Vollset, SE Drevon, CA AF Wilcox, Allen J. Lie, Rov Terje Solvoll, Kari Taylor, Jack McConnaughey, D. Robert Abyholm, Frank Vindenes, Hallvard Vollset, Stein Emil Drevon, Christian A. TI Folic acid supplements and risk of facial clefts: national population based case-control study SO BRITISH MEDICAL JOURNAL LA English DT Article ID FOOD FREQUENCY QUESTIONNAIRE; OROFACIAL CLEFTS; WOMEN AB Objective To explore the role of folic acid supplements, dietary folates, and multivitamins in the prevention of facial clefts. Design National population based case-control study. Setting Infants born 1996-2001 in Norway. Participants 377 infants with cleft lip with or without cleft palate; 196 infants with cleft palate alone; 763 controls. Main outcome measures Association of facial clefts with maternal intake of folic acid supplements, multivitamins, and folates in diet. Results Folic acid supplementation during early pregnancy (>= 400 mu g/day) was associated with a reduced risk of isolated cleft lip with or without cleft palate after adjustment for multivitamins, smoking, and other potential confounding factors (adjusted odds ratio 0.61, 95% confidence interval 0.39 to 0.96). Independent of supplements, diets rich in fruits, vegetables, and other high folate containing foods reduced the risk somewhat (adjusted odds ratio 0.75, 0.50 to 1.11). The lowest risk of cleft lip was among women with folate rich diets who also took folic acid supplements and multivitamins (0.36, 0.17 to 0.77). Folic acid provided no protection against cleft palate alone (1.07, 0.56 to 2.03). Conclusions Folic acid supplements during early pregnancy seem to reduce the risk of isolated cleft lip (with or without cleft palate) by about a third. Other vitamins and dietary factors may provide additional benefit. C1 NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. Univ Bergen, Dept Publ Hlth & Primary Care, Sect Epidemiol & Med Stat, N-5020 Bergen, Norway. Univ Oslo, Fac Med, Inst Basic Med Sci, Dept Nutr, Oslo, Norway. WESTAT Corp, Durham, NC USA. Univ Oslo, Rikshosp, Dept Plast Surg, N-0027 Oslo, Norway. Haukeland Hosp, Dept Plast Surg, N-5021 Bergen, Norway. RP Wilcox, AJ (reprint author), NIEHS, Epidemiol Branch, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM wilcox@niehs.nih.gov RI Drevon, Christian /F-6012-2010; OI Wilcox, Allen/0000-0002-3376-1311; taylor, jack/0000-0001-5303-6398 FU Intramural NIH HHS [Z99 ES999999] NR 14 TC 153 Z9 174 U1 2 U2 20 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0959-535X J9 BRIT MED J JI Br. Med. J. PD MAR 3 PY 2007 VL 334 IS 7591 BP 464 EP 467 DI 10.1136/bmj.39079.618287.0B PG 6 WC Medicine, General & Internal SC General & Internal Medicine GA 144NB UT WOS:000244802000033 PM 17259187 ER PT J AU Kang, SG Brown, AL Chung, JH AF Kang, Sung Gyun Brown, Alexandra L. Chung, Jay H. TI Oxygen tension regulates the stability of insulin receptor substrate-1 (IRS-1) through caspase-mediated cleavage SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATES PHOSPHATIDYLINOSITOL 3-KINASE; COOH-TERMINAL TRUNCATION; OBSTRUCTIVE SLEEP-APNEA; PROTEIN-KINASE; TYROSINE PHOSPHORYLATION; SERINE PHOSPHORYLATION; 3T3-L1 ADIPOCYTES; SERINE/THREONINE PHOSPHORYLATION; SIGNAL-TRANSDUCTION; INDUCED DEGRADATION AB The insulin and insulin-like growth factor-1 (IGF-1) receptors mediate signaling for energy uptake and growth through insulin receptor substrates (IRSs), which interact with these receptors as well as with downstream effectors. Oxygen is essential not only for ATP production through oxidative phosphorylation but also for many cellular processes, particularly those involved in energy homeostasis. The oxygen tension in vivo is significantly lower than that in the air and can vary widely depending on the tissue as well as on perfusion and oxygen consumption. How oxygen tension affects IRSs and their functions is poorly understood. Our findings indicate that transient hypoxia (1% oxygen) leads to caspase-mediated cleavage of IRS-1 without inducing cell death. The IRS-1 protein level rebounds rapidly upon return to normoxia. Protein tyrosine phosphatases (PTPs) appear to be important for the IRS-1 cleavage because tyrosine phosphorylation of the insulin receptor was decreased in hypoxia and IRS-1 cleavage could be blocked either with H2O2 or with vanadate, each of which inhibits PTPs. Activity of Akt, a downstream effector of insulin and IGF-1 signaling that is known to suppress caspase activation, was suppressed in hypoxia. Overexpression of dominant-negative Akt led to IRS-1 cleavage even in normoxia, and overexpression of constitutively active Akt partially suppressed IRS-1 cleavage in hypoxia, suggesting that hypoxiamediated suppression of Akt may induce caspase-mediated IRS-1 cleavage. In conclusion, our study elucidates a mechanism by which insulin and IGF-1 signaling can be matched to the oxygen level that is available to support growth and energy metabolism. C1 NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. Korea Ocean Res & Dev Inst, Marine Biotechnol Ctr, Seoul 425600, South Korea. RP Chung, JH (reprint author), NHLBI, Lab Biochem Genet, NIH, Bldg 10,Rm 7D14,10 Ctr Dr, Bethesda, MD 20892 USA. EM chungj@nhlbi.nih.gov FU Intramural NIH HHS NR 58 TC 10 Z9 10 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD MAR 2 PY 2007 VL 282 IS 9 BP 6090 EP 6097 DI 10.1074/jbc.M610659200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 145LS UT WOS:000244867200014 PM 17179152 ER PT J AU Dey, M Cao, C Sicheri, F Dever, TE AF Dey, Madhusudan Cao, Chune Sicheri, Frank Dever, Thomas E. TI Conserved intermolecular salt bridge required for activation of protein kinases PKR, GCN2, and PERK SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DOUBLE-STRANDED-RNA; INITIATION-FACTOR 2; ENDOPLASMIC-RETICULUM STRESS; WOLCOTT-RALLISON-SYNDROME; SUBSTRATE RECOGNITION; TRANSLATIONAL CONTROL; FUNCTIONALLY SUBSTITUTE; EIF-2-ALPHA KINASE; UNFOLDED-PROTEIN; DIMERIZATION AB The protein kinases PKR, GCN2, and PERK phosphorylate translation initiation factor eIF2 alpha to regulate general and gene-specific protein synthesis under various cellular stress conditions. Recent x-ray crystallographic structures of PKR and GCN2 revealed distinct dimeric configurations of the kinase domains. Whereas PKR kinase domains dimerized in a back-to-back and parallel orientation, the GCN2 kinase domains displayed an antiparallel orientation. The dimerization interfaces on PKR and GCN2 were localized to overlapping surfaces on the N-terminal lobes of the kinase domains but utilized different intermolecular contacts. A key feature of the PKR dimerization interface is a salt bridge interaction between Arg(262) from one protomer and Asp(266) from the second protomer. Interestingly, these two residues are conserved in all eIF2 alpha kinases, although in the GCN2 structure, the two residues are too remote to interact. To test the importance of this potential salt bridge interaction in PKR, GCN2, and PERK, the residues constituting the salt bridge were mutated either independently or together to residues with the opposite charge. Single mutations of the Asp (or Glu) and Arg residues blocked kinase function both in yeast cells and in vitro. However, for all three kinases, the double mutation designed to restore the salt bridge interaction with opposite polarity resulted in a functional kinase. Thus, the salt bridge interaction and dimer interface observed in the PKR structure is critical for the activity of all three eIF2 alpha kinases. These results are consistent with the notion that the PKR structure represents the active state of the eIF2 alpha kinase domain, whereas the GCN2 structure may represent an inactive state of the kinase. C1 NICHD, Lab Gene Regulat & Dev, NICHD, Bethesda, MD 20892 USA. Mt Sinai Hosp, Program Mol Biol & Canc, Samuel Lunenfeld Res Inst, Toronto, ON M5G 1X5, Canada. Univ Toronto, Dept Mol & Med Genet, Toronto, ON M5S 1A8, Canada. RP Dever, TE (reprint author), NICHD, Lab Gene Regulat & Dev, NICHD, Bldg 6A,Rm B1A-03, Bethesda, MD 20892 USA. EM tdever@nih.gov RI Sicheri, Frank/F-8856-2013; OI Dever, Thomas/0000-0001-7120-9678 FU Intramural NIH HHS NR 33 TC 29 Z9 30 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 MAR 2 PY 2007 VL 282 IS 9 BP 6653 EP 6660 DI 10.1074/jbc.M607897200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 145LS UT WOS:000244867200074 PM 17202131 ER PT J AU Basile, JR Holmbeck, K Bugge, TH Gutkind, JS AF Basile, John R. Holmbeck, Kenn Bugge, Thomas H. Gutkind, J. Silvio TI MT1-MMP controls tumor-induced angiogenesis through the release of semaphorin 4D SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MEMBRANE-TYPE-1 MATRIX-METALLOPROTEINASE; ENDOTHELIAL GROWTH-FACTOR; UP-REGULATION; CELL CARCINOMA; AXON GUIDANCE; EXPRESSION; PLEXIN; SURFACE; ACTIVATION; TRANSMEMBRANE AB The semaphorins are a family of proteins originally identified as regulators of axon growth that recently have been implicated in blood vessel development. The plexins are high affinity receptors for the semaphorins and are responsible for initiation of signaling upon ligation. Emerging evidence indicates that many human cancers overexpress Semaphorin 4D, which promotes neovascularization upon stimulating its receptor, Plexin-B1, on endothelial cells. However, to exert its pro-angiogenic functions, Semaphorin 4D must be processed and released from its membrane bound form to act in a paracrine manner on endothelial cells. Here we show that Semaphorin 4D is a novel target for the membrane-tethered collagenase membrane type I-matrix metalloproteinase. We demonstrate that this metalloproteinase, which is not expressed in normal or immortal but non-tumorigenic epithelial cell lines, was present in several head and neck squamous cell carcinoma cell lines and was required for processing and release of Semaphorin 4D into its soluble form from these cells, thereby inducing endothelial cell chemotaxis in vitro and blood vessel growth in vivo. These results suggest that the proteolytic cleavage of Semaphorin 4D may provide a novel molecular mechanism by which membrane type 1-matrix metalloproteinase controls tumor-induced angiogenesis. C1 NIDCR, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. NIDCR, Matrix Metalloprot Unit, NIH, Bethesda, MD 20892 USA. RP Basile, JR (reprint author), NIDCR, Oral & Pharyngeal Canc Branch, NIH, 30 Convent Dr,Rm 211, Bethesda, MD 20892 USA. EM jbasile@mail.nih.gov RI Gutkind, J. Silvio/A-1053-2009 FU Intramural NIH HHS NR 52 TC 89 Z9 106 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 MAR 2 PY 2007 VL 282 IS 9 BP 6899 EP 6905 DI 10.1074/jbc.M609570200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 145LS UT WOS:000244867200099 PM 17204469 ER PT J AU Korepanov, AP Gongadze, GM Garber, MB Court, DL Bubunenko, MG AF Korepanov, Alexey P. Gongadze, George M. Garber, Maria B. Court, Donald L. Bubunenko, Mikhail G. TI Importance of the 5 S rRNA-binding ribosomal proteins for cell viability and translation in Escherichia coli SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE 5 S rRNA-binding proteins; ribosomal protein L25; ribosome; translation; Escherichia coli ID BACILLUS-SUBTILIS; THERMUS-THERMOPHILUS; RECYCLING FACTOR; STRESS PROTEINS; SUBUNIT; 50S; RECOMBINATION; COMPLEXES; SYSTEM; L5 AB A specific complex of 5 S rRNA and several ribosomal proteins is an integral part of ribosomes in all living organisms. Here we studied the importance of Escherichia coli genes rplE, rplR and rplY, encoding 5 S rRNA-binding ribosomal proteins L5, L18 and L25, respectively, for cell growth, viability and translation. Using recombineering to create gene replacements in the E. coli chromosome, it was shown that rplE and rplR are essential for cell viability, whereas cells deleted for rplY are viable, but grow noticeably slower than the parental strain. The slow growth of these L25-defective cells can be stimulated by a plasmid expressing the rplY gene and also by a plasmid bearing the gene for homologous to L25 general stress protein CTC from Bacillus subtilis. The rplY mutant ribosomes are physically normal and contain all ribosomal proteins except L25. The ribosomes from L25-defective and parental cells translate in vitro at the same rate either poly(U) or natural mRNA. The difference observed was that the mutant ribosomes synthesized less natural polypeptide, compared to wild-type ribosomes both in vivo and in vitro. We speculate that the defect is at the ribosome recycling step. (c) 2006 Elsevier Ltd. All rights reserved. C1 Russian Acad Sci, Inst Prot Res, Pushchino 142290, Moscow Region, Russia. NCI, Gene Regulat & Chromosomal Biol Lab, Frederick, MD 21702 USA. NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. RP Gongadze, GM (reprint author), Russian Acad Sci, Inst Prot Res, Pushchino 142290, Moscow Region, Russia. EM gongadze@vega.protres.ru; mbubunenko@ncifcrf.gov RI Gongadze, George/E-6674-2012; Korepanov, Alexey/I-9052-2012; Garber, Maria/I-4262-2013 OI Garber, Maria/0000-0002-3986-4848 FU Intramural NIH HHS [001-0296-364, Z01 BC010336-07, Z99 CA999999]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 47 TC 24 Z9 28 U1 0 U2 4 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD MAR 2 PY 2007 VL 366 IS 4 BP 1199 EP 1208 DI 10.1016/j.jmb.2006.11.097 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 142KW UT WOS:000244649500012 PM 17198710 ER PT J AU Brown, PL Bae, D Kiyatkin, EA AF Brown, P. L. Bae, D. Kiyatkin, E. A. TI Relationships between locomotor activation and alterations in brain temperature during selective blockade and stimulation of dopamine transmission SO NEUROSCIENCE LA English DT Article DE SCH-23390; eticlopride; apomorphine; metabolic brain activation; vasoconstriction and vasodilatation; behavioral activation; functional role of the dopamine system ID FREELY MOVING RATS; NUCLEUS-ACCUMBENS; BODY-TEMPERATURE; SUBSTANTIA-NIGRA; INDUCED HYPOTHERMIA; UNRESTRAINED RATS; MOLECULAR-BIOLOGY; STRIATAL NEURONS; HEAT-PRODUCTION; IN-VIVO AB It is well known that the dopamine (DA) system plays an essential role in the organization and regulation of brain activational processes. Various environmental stimuli that induce locomotor activation also increase DA transmission, while DA antagonists decrease spontaneous locomotion. Our previous work supports close relationships between locomotor activation and brain and body temperature increases induced by salient environmental challenges or occurring during motivated behavior. While this correlation was also true for psychomotor stimulant drugs such as methamphetamine and MDMA, more complex relationships or even inverted correlations were found for other drugs that are known to increase DA transmission (i.e. heroin and cocaine). In the present study we examined brain, muscle and skin temperatures together with conventional locomotion during selective interruption of DA transmission induced by a mixture of 131 and D2 antagonists (SCH-23390 and eticlopride at 0.2 mg/kg, s.c.) and its selective activation by apomorphine (APO; 0.05 and 0.25 mg/kg, i.v.) in rats. While full DA receptor blockade decreased spontaneous locomotion, it significantly increased brain, muscle and skin temperatures, suggesting metabolic brain activation under conditions of vasodilatation (or weakening of normal vascular tone). In contrast, APO strongly decreased skin temperature but tended to decrease brain and muscle temperatures despite strong hyperlocomotion and stereotypy. The brain temperature response to APO was strongly dependent on basal brain temperature, with hypothermia at high basal temperatures and weak hyperthermia at low temperatures. While supporting the role of DA in locomotor activation, these data suggest more complex relationships between drug-induced alterations in DA transmission, behavioral activation and metabolic brain activation. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved. C1 NIDA, Cellular Neurobiol Branch, Intramural Res Program, NIH,DHHS, Baltimore, MD 21224 USA. RP Kiyatkin, EA (reprint author), NIDA, Cellular Neurobiol Branch, Intramural Res Program, NIH,DHHS, 333 Cassell Dr, Baltimore, MD 21224 USA. EM ekiyatki@intra.nida.nih.gov FU Intramural NIH HHS; NIDA NIH HHS [Z01 DA000445-05] NR 52 TC 9 Z9 9 U1 0 U2 0 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 MAR 2 PY 2007 VL 145 IS 1 BP 335 EP 343 DI 10.1016/j.neuroscience.2006.11.028 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 140FE UT WOS:000244489100032 PM 17196751 ER PT J AU Dina, OA Gear, RW Messing, RO Levine, JD AF Dina, O. A. Gear, R. W. Messing, R. O. Levine, J. D. TI Severity of alcohol-induced painful peripheral neuropathy in female rats: Role of estrogen and protein kinase (A and C epsilon) SO NEUROSCIENCE LA English DT Article DE ethanol; hyperalgesia; estrogen; second messenger signaling ID ROOT GANGLION NEURONS; SEXUAL-DIMORPHISM; ETHANOL WITHDRAWAL; INFLAMMATORY PAIN; SENSORY NEURONS; RECEPTOR-ALPHA; CELLS; HYPERALGESIA; ACTIVATION; BETA AB Small-fiber painful peripheral neuropathy, a complication of chronic ethanol ingestion, is more severe in women. In the present study, we have replicated this clinical finding in the rat and evaluated for a role of estrogen and second messenger signaling pathways. The alcohol diet (6.5% ethanol volume:volume in Lieber-DeCarli formula) induced hyperalgesia with more rapid onset and severity in females. Following ovariectomy, alcohol failed to induce hyperalgesia in female rats, well past its time to onset in gonad intact males and females. Estrogen replacement reinstated alcohol neuropathy in the female rat. The protein kinase A (PKA) inhibitor (Walsh inhibitor peptide, WIPTIDE) only attenuated alcohol-induced hyperalgesia in female rats. Inhibitors of protein kinase C epsilon, (PKC epsilon-I) and extracellular-signal related kinase (ERK) 1/2 (2'-amino-3'-methoxyflavone (PD98059) and 1,4-diamino-2, 3-dicyano-1, 4-bis (2-aminophenylthio) butadiene (UO126)) attenuated hyperalgesia in males and females, however the degree of attenuation produced by PKC epsilon-I was much greater in females. In conclusion, estrogen plays an important role in the expression of pain associated with alcohol neuropathy in the female rat. In contrast to inflammatory hyperalgesia, in which only the contribution of PKC epsilon signaling is sexually dimorphic, in alcohol neuropathy PKA as well as PKC epsilon signaling is highly sexually dimorphic. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved. C1 Univ Calif San Francisco, NIH Pain Ctr, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Oral & Maxillofacial Surg, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94143 USA. Univ Calif San Francisco, Program Neurosci, San Francisco, CA 94143 USA. Ernest Gallo Clin & Res Ctr, Emeryville, CA 94608 USA. RP Levine, JD (reprint author), Univ Calif San Francisco, NIH Pain Ctr, Dept Med, Box 0440,C-522, San Francisco, CA 94143 USA. EM Jon.Levine@ucsf.edu RI Messing, Robert/D-3642-2015 OI Messing, Robert/0000-0002-5345-4431 FU NIAAA NIH HHS [R01 AA013875]; PHS HHS [013875] NR 66 TC 18 Z9 21 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 MAR 2 PY 2007 VL 145 IS 1 BP 350 EP 356 DI 10.1016/j.neuroscience.2006.11.053 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 140FE UT WOS:000244489100034 PM 17204374 ER PT J AU Drain, PK Primack, A Hunt, DD Fawzi, WW Holmes, KK Gardner, P AF Drain, Paul K. Primack, Aron Hunt, D. Dan Fawzi, Wafaie W. Holmes, King K. Gardner, Pierce TI Global health in medical education: A call for more training and opportunities SO ACADEMIC MEDICINE LA English DT Article ID INTERNATIONAL HEALTH; TRAVEL MEDICINE; EXPERIENCE; STUDENTS; ISSUES; US; PHYSICIANS; ELECTIVES; SCHOOL AB Worldwide increases in global migration and trade have been making communicable diseases a concern throughout the world and have highlighted the connections in health and medicine among and between continents. Physicians in developed countries are now expected to have a broader knowledge of tropical disease and newly emerging infections, while being culturally sensitive to the increasing number of international travelers and ethnic minority populations. Exposing medical students to these global health issues encourages students to enter primary care medicine, obtain public health degrees, and practice medicine among the poor and ethnic minorities. In addition, medical students who have completed an international clinical rotation often report a greater ability to recognize disease presentations, more comprehensive physical exam skills with less reliance on expensive imaging, and greater cultural sensitivity. American medical students have become increasingly more interested and active in global health, but medical schools have been slow to respond. The authors review the evidence supporting the benefits of promoting more global health teaching and opportunities among medical students. Finally, the authors suggest several steps that medical schools can take to meet the growing global health interest of medical students, which will make them better physicians and strengthen our medical system. C1 Univ Washington, Sch Med, Seattle, WA 98195 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. No Ontario Sch Med, Thunder Bay, ON, Canada. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. RP Drain, PK (reprint author), Univ Washington, Sch Med, 1959 NE Pacific Ave,Box 356340, Seattle, WA 98195 USA. EM pkdrain@u.washington.edu OI Drain, Paul/0000-0003-3300-3817 NR 49 TC 188 Z9 188 U1 3 U2 19 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 MAR PY 2007 VL 82 IS 3 BP 226 EP 230 DI 10.1097/ACM.0b013e3180305cf9 PG 5 WC Education, Scientific Disciplines; Health Care Sciences & Services SC Education & Educational Research; Health Care Sciences & Services GA 144SU UT WOS:000244817300004 PM 17327707 ER PT J AU Kelloff, GJ Sullivan, DM Wilson, W Cheson, B Juweid, M Mills, GQ Zelenetz, AD Horning, SJ Weber, W Sargent, DJ Dodd, L Korn, E Armitage, J Schilsky, R Christian, M O'Connor, OA Wang, SJ Farrell, AT Pazdur, R Graham, M Wahl, RL Larson, SM Kostakoglu, L Daube-Witherspoon, M Gastonis, C Siegel, BA Shankar, LK Lee, DB Higley, HR Sigman, CC Carucci, D Timko, D Degennaro, LJ Sigal, E Barker, A Woodcock, J AF Kelloff, Gary J. Sullivan, Daniel M. Wilson, Wyndham Cheson, Bruce Juweid, Malik Mills, George Q. Zelenetz, Andrew D. Horning, Sandra J. Weber, Wolfgang Sargent, Daniel J. Dodd, Lori Korn, Edward Armitage, James Schilsky, Richard Christian, Michaele O'Connor, Owen A. Wang, Sue Jane Farrell, Ann T. Pazdur, Richard Graham, Michael Wahl, Richard L. Larson, Steven M. Kostakoglu, Lale Daube-Witherspoon, Margaret Gastonis, Constantine Siegel, Barry A. Shankar, Lalitha K. Lee, David B. Higley, Howard R. Sigman, Caroline C. Carucci, Daniel Timko, David deGennaro, Louis J. Sigal, Ellen Barker, Anna Woodcock, Janet TI FDG-PET lymphoma demonstration project invitational workshop SO ACADEMIC RADIOLOGY LA English DT Article DE FDG-PET; lymphoma; imaging biomarker; chemotherapy response; drug development ID POSITRON-EMISSION-TOMOGRAPHY; NON-HODGKINS-LYMPHOMA; INTERNATIONAL WORKSHOP; AGGRESSIVE LYMPHOMA; TREATMENT FAILURE; PROGRESSION-FREE; CANCER-THERAPY; CHEMOTHERAPY; CYCLES; SURVIVAL AB The proceedings of a workshop focusing on a project to evaluate the use of fluorodeoxyglucose-positron emission tomography (FDG-PET) as a tool to measure treatment response in non-Hodgkin lymphoma (NHL) are described. Sponsored by the Leukemia & Lymphoma Society, the Foundation of the National Institutes of Health, and the National Cancer Institute, and attended by representatives of the Food and Drug Administration, the Centers for Medicare and Medicaid Services, and scientists and clinical researchers from academia and the pharmaceutical and medical imaging industries, the workshop reviewed the etiology and current standards of care for NHL and proposed the development of a clinical trial to validate FDG-PET imaging techniques as a predictive biomarker for cancer therapy response. As organized under the auspices of the Oncology Biomarker Qualification Initiative, the three federal health agencies and their private sector and nonprofit/advocacy group partners believe that FDG-PET not only demonstrates the potential to be used for the diagnosis and staging of many cancers but in particular can provide an early indication of therapeutic response that is well correlated with clinical outcomes for chemotherapy for this common form of lymphoma. The development of standardized criteria for FDG-PET imaging and establishment of procedures for transmission, storage, quality assurance, and analysis of PET images afforded by this demonstration project could streamline clinical trials of new treatments for more intractable forms of lymphoma and other cancers and, hence, accelerate new drug approvals. C1 CCS Associates, Mountain View, CA USA. NCI, DCTC, Canc Imaging Program, NIH, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Metab Branch, NIH, Bethesda, MD 20892 USA. NCI, DCTC, Biometr Res Branch, NIH, Bethesda, MD 20892 USA. NCI, Off Director, NIH, Bethesda, MD 20892 USA. Lombardi Comprehens Canc Ctr, Washington, DC USA. Univ Iowa, Coll Med, Iowa City, IA USA. US FDA, Rockville, MD 20857 USA. Mem Sloan Kettering Canc Ctr, New York, NY 10021 USA. Stanford Univ, Stanford, CA 94305 USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. Mayo Clin & Coll Med, Rochester, MN USA. Univ Nebraska, Omaha, NE 68182 USA. Univ Chicago, Canc & Leukemia Grp B, Chicago, IL 60637 USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. Mt Sinai Med Ctr, New York, NY 10029 USA. Univ Penn, Philadelphia, PA 19104 USA. Brock Univ, St Catharines, ON L2S 3A1, Canada. Washington Univ, Sch Med, St Louis, MO 63130 USA. Fdn Natl Inst Hlth, Bethesda, MD USA. Leukemia & Lymphoma Soc, White Plains, NY USA. RP Higley, HR (reprint author), CCS Associates, Mountain View, CA USA. EM hhigley@ccsain.com OI Sargent, Daniel/0000-0002-2684-4741 NR 22 TC 22 Z9 22 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD MAR PY 2007 VL 14 IS 3 BP 330 EP 339 DI 10.1016/j.acra.2006.12.003 PG 10 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 173GI UT WOS:000246861100011 PM 17307666 ER PT J AU Dauter, Z Baker, T AF Dauter, Zbigniew Baker, Ted TI Numerology SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Editorial Material C1 NCI, MCL, Argonne Natl Lab, Biosci Div, Argonne, IL 60439 USA. Univ Auckland, Sch Biol Sci, Auckland 1, New Zealand. RP Dauter, Z (reprint author), NCI, MCL, Argonne Natl Lab, Biosci Div, Bldg 202,Room Q142, Argonne, IL 60439 USA. NR 1 TC 2 Z9 2 U1 0 U2 2 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 MAR PY 2007 VL 63 BP 275 EP 275 DI 10.1107/S0907444907005185 PN 3 PG 1 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 139QW UT WOS:000244448400001 PM 17327662 ER PT J AU Wlodawer, A AF Wlodawer, Alexander TI Deposition of structural data redux SO ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY LA English DT Letter C1 NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Wlodawer, A (reprint author), NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. EM wlodawer@ncifcrf.gov NR 8 TC 3 Z9 3 U1 0 U2 0 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 MAR PY 2007 VL 63 BP 421 EP 423 DI 10.1107/S0907444907006336 PN 3 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 139QW UT WOS:000244448400019 PM 17327681 ER PT J AU Barinka, C Starkova, J Konvalinka, J Lubkowski, J AF Barinka, Cyril Starkova, Jana Konvalinka, Jan Lubkowski, Jacek TI A high-resolution structure of ligand-free human glutamate carboxypeptidase II SO ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY AND CRYSTALLIZATION COMMUNICATIONS LA English DT Article ID MEMBRANE ANTIGEN; PROSTATE-CANCER; EXPRESSION; PEPTIDASE; MODELS; BRAIN AB Human glutamate carboxypeptidase II ( GCPII; EC 3.4.17.21) is an established marker for prostate-cancer diagnosis as well as a candidate therapeutic target for the treatment of diverse pathologies that involve glutamatergic transmission. Structural data on GCPII are thus valuable for the design and optimization of GCPII-specific inhibitors and diagnostic probes. The currently available structure of ligand-free GCPII was refined to a resolution of 3.5 angstrom. This work reports the structure of the protein refined to 1.65 angstrom resolution, with crystallographic values of R = 0.207 and R-free = 0.228. The new structure extends the resolution appreciably and the new model based on this data shows significant differences when compared with the previously published model. C1 Ctr Canc Res, Natl Canc Inst Frederick, Frederick, MD 21702 USA. Acad Sci Czech Republic, Gilead Sci Inc, CZ-6610 Prague 6, Czech Republic. Acad Sci Czech Republic, IOCB Res Ctr, CZ-6610 Prague 6, Czech Republic. Charles Univ Prague, Dept Biochem, Fac Nat Sci, CZ-2030 Prague, Czech Republic. RP Barinka, C (reprint author), Ctr Canc Res, Natl Canc Inst Frederick, Frederick, MD 21702 USA. EM cyril@ncifcrf.gov RI Konvalinka, Jan/G-7518-2014; Barinka, Cyril/G-9803-2014; OI Konvalinka, Jan/0000-0003-0695-9266 FU Intramural NIH HHS NR 18 TC 30 Z9 30 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1744-3091 J9 ACTA CRYSTALLOGR F JI Acta Crystallogr. F-Struct. Biol. Cryst. Commun. PD MAR PY 2007 VL 63 BP 150 EP 153 DI 10.1107/S174430910700379X PN 3 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Biophysics; Crystallography SC Biochemistry & Molecular Biology; Biophysics; Crystallography GA 140QN UT WOS:000244520800001 PM 17329803 ER PT J AU Nussenblatt, RB Coleman, H Jirawuthiworavong, G Davuluri, G Potapova, N Dahr, SS Ragheb, JA Levy-Clarke, G AF Nussenblatt, Robert B. Coleman, Hanna Jirawuthiworavong, Guy Davuluri, Geetanjali Potapova, Natalia Dahr, Sam S. Ragheb, Jack A. Levy-Clarke, Grace TI The treatment of multifocal choroiditis associated choroidal neovascularization with sirolimus (rapamycin) SO ACTA OPHTHALMOLOGICA SCANDINAVICA LA English DT Letter ID PANUVEITIS C1 NEI, Immunol Lab, NIH, Bethesda, MD 20892 USA. NEI, Div Epidemiol & Clin Res, Bethesda, MD 20892 USA. RP Nussenblatt, RB (reprint author), NEI, Immunol Lab, NIH, Bldg 10,Room 10S219,10 Ctr Dr, Bethesda, MD 20892 USA. EM drbob@nei.nih.gov NR 5 TC 18 Z9 18 U1 1 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1395-3907 J9 ACTA OPHTHALMOL SCAN JI Acta Ophthalmol. Scand. PD MAR PY 2007 VL 85 IS 2 BP 230 EP 231 DI 10.1111/j.1600-0420.2006.00858.x PG 3 WC Ophthalmology SC Ophthalmology GA 136MA UT WOS:000244226200026 PM 17305748 ER PT J AU Heidbreder, CA Andreoli, M Marcon, C Hutcheson, DM Gardner, EL Ashby, CR AF Heidbreder, Christian A. Andreoli, Michela Marcon, Cristina Hutcheson, Daniel M. Gardner, Eliot L. Ashby, Charles R., Jr. TI Evidence for the role of dopamine D-3 receptors in oral operant alcohol self-administration and reinstatement of alcohol-seeking behavior in mice SO ADDICTION BIOLOGY LA English DT Review DE acamprosate; alcohol self-administration; baclofen; dopamine D-3 receptors; naltrexone; SB-277011A ID COCAINE-INDUCED REINSTATEMENT; CONDITIONED PLACE PREFERENCE; STRESS-INDUCED REINSTATEMENT; CUE-INDUCED REINSTATEMENT; DRUG-ASSOCIATED STIMULI; ENHANCED BRAIN REWARD; PREFERRING AA RATS; NUCLEUS-ACCUMBENS; ETHANOL-CONSUMPTION; D-AMPHETAMINE AB The present study examined the effects of the acute intraperitoneal (i.p.) administration of the selective dopamine (DA) D-3 receptor antagonist SB-277011A (10, 20 or 30 mg/kg i.p.) on the oral operant self-administration of alcohol in male C57BL/6N mice. These effects were compared with those of naltrexone (0.5, 1 and 2 mg/kg i.p.) and acamprosate (100, 200 and 400 mg/kg i.p.). Compared with vehicle, the acute administration of SB-277011A (10 or 20 mg/kg) did not significantly alter the operant self-administration of alcohol, whereas the 30 mg/kg dose significantly reduced alcohol intake (g/kg), the number of reinforcers, and the number of active lever presses. The oral self-administration of alcohol was not significantly altered by the acute administration of either naltrexone or acamprosate, compared with vehicle-treated mice. SB-277011A, naltrexone and acamprosate were also tested in a model of drug/cue-triggered reinstatement of alcohol-seeking behavior. In this model, neither naltrexone (2 mg/kg) nor acamprosate (400 mg/kg) prevented relapse to alcohol-seeking behavior. In contrast, SB-277011A significantly reduced reinstatement of alcohol seeking in a dose-dependent manner. Provided these results can be extrapolated to humans, they suggest that selective DA D-3 receptor antagonists may be useful in the harmacotherapeutic management of alcohol intake and prevention of relapse to alcohol-seeking behavior. C1 GlaxoSmithKline Inc, Ctr Excellence Drug Discovery Psychiat, Dept Neuropsychopharmacol, I-37135 Verona, Italy. Natl Inst Drug Abuse, Neuropsychopharmacol Sect, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. RP Heidbreder, CA (reprint author), GlaxoSmithKline Inc, Ctr Excellence Drug Discovery Psychiat, Dept Neuropsychopharmacol, Via A Fleming 4, I-37135 Verona, Italy. EM christian.a.heidbreder@gsk.com NR 123 TC 51 Z9 51 U1 2 U2 5 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1355-6215 J9 ADDICT BIOL JI Addict. Biol. PD MAR PY 2007 VL 12 IS 1 BP 35 EP 50 DI 10.1111/j.1369-1600.2007.00051.x PG 16 WC Biochemistry & Molecular Biology; Substance Abuse SC Biochemistry & Molecular Biology; Substance Abuse GA 139FF UT WOS:000244417000006 PM 17407496 ER PT J AU Jaszyna-Gasior, M Schroeder, JR Moolchan, ET AF Jaszyna-Gasior, Maria Schroeder, Jennifer R. Moolchan, Eric T. TI Alcohol use and tobacco abstinence among adolescents in cessation treatment: Preliminary findings SO ADDICTIVE BEHAVIORS LA English DT Article DE adolescent; alcohol; tobacco smoking; abstinence ID SMOKING CESSATION; CIGARETTE-SMOKING; SUCCESS AB Although adult alcohol use is negatively associated with tobacco cessation, this relationship has not been reported for adolescents. We assessed the relationship between alcohol use and point prevalence abstinence from smoking in a sample of tobacco-dependent adolescents undergoing cessation treatment. Alcohol use both at baseline and) during tobacco cessation treatment was examined as predicting smoking abstinence in 101 adolescents (age = 15.1 years, S. D. = 1.31 years; age at first cigarette = 11.3 years, S.D. = 1.93 years; age at first drink = 12.01 years, S.D. = 2.87 years) attending a total of 642 treatment visits. Mixed regression analysis showed that participants who reported alcohol use during tobacco cessation treatment were significantly less likely to abstain from tobacco smoking (OR = 0.42, 95% CI=0.23-0.78, t=-2.78, df=540, p=0.0057). However, pre-enrollment alcohol use was not significantly associated with either short- or long-term tobacco abstinence. If confirmed in a larger group of adolescents, our findings suggest that youths attempting to quit smoking should abstain from alcohol. (c) 2006 Elsevier Ltd. All rights reserved. C1 NIDA, Intramural Res Program, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Moolchan, ET (reprint author), NIDA, Teen Tobacco Addict Treatment Res Clin, Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM emoolcha@intra.nida.nih.gov FU Intramural NIH HHS NR 11 TC 2 Z9 2 U1 1 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 MAR PY 2007 VL 32 IS 3 BP 617 EP 621 DI 10.1016/j.addbeh.2006.05.009 PG 5 WC Psychology, Clinical; Substance Abuse SC Psychology; Substance Abuse GA 133AZ UT WOS:000243985300015 PM 16814935 ER PT J AU Moore, CM Dunn, BG McMahan, CA Lane, MA Roth, GS Ingram, DK Mattison, JA AF Moore, Charleen M. Dunn, Betty G. McMahan, C. Alex Lane, Mark A. Roth, George S. Ingram, Donald K. Mattison, Julie A. TI Effects of calorie restriction on chromosomal stability in rhesus monkeys (Macaca mulatta) SO AGE LA English DT Article DE aging; calorie restriction; chromosomal stability; diet; rhesus monkeys ID PERIPHERAL-BLOOD LYMPHOCYTES; CHROMATID EXCHANGE FREQUENCIES; HUMAN-POPULATION SAMPLE; CULTURED LYMPHOCYTES; DIETARY RESTRICTION; SEX-CHROMOSOMES; Y-CHROMOSOME; VITAMIN-C; AGE; ABERRATIONS AB The basic tenet of several theories on aging is increasing genomic instability resulting from interactions with the environment. Chromosomal aberrations have been used as classic examples of increasing genomic instability since they demonstrate an increase in numerical and structural abnormalities with age in many species including humans. This accumulating damage may augment many aging processes and initiate age-related diseases, such as neoplasias. Calorie restriction (CR) is one of the most robust interventions for reducing the frequency of age-related diseases and for extending life span in many short-lived organisms. However, the mechanisms for the anti-aging effects of CR are not yet well understood. A study of rhesus monkeys was begun in 1987 to determine if CR is also effective in reducing the frequency of age-related diseases and retarding aging in a long-lived mammal. Male monkeys were begun on the diet in 1987, and females were added in 1992 to examine a possible difference in response to CR by sex. The CR monkeys have been maintained for over 10 years on a low-fat nutritional diet that provides a 30% calorie reduction compared to a control (CON) group. Because of the greater similarity of nonhuman primates to humans in life span and environmental responses to diet compared with those of rodents, the rhesus monkey provides an excellent model for the effects of CR in humans. This study examined the effects of CR on chromosomal instability with aging. Significant age effects were found in both CR and CON groups for the number of cells with aneuploidy: old animals had a higher loss and a higher gain than young animals. However, there was no effect of age on chromosomal breakage or structural aberrations in either diet group. Diet had only one significant effect: the CR group had a higher frequency of chromatid gaps than did the CON group. CR, implemented in adult rhesus monkeys, does not have a major effect on the reduction of numerical or structural aberrations related to aging. C1 Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Clin Lab Sci, San Antonio, TX 78229 USA. Univ Texas, Hlth Sci Ctr, Dept Pathol, San Antonio, TX 78229 USA. NIA, Gerontol Res Ctr, Lab Expt Gerontol, Baltimore, MD 21224 USA. GeroSci, Pylesville, MD 21132 USA. Louisiana State Univ Syst, Pennington Biomed Res Ctr, Nutr Neurosci & Aging Lab, Baton Rouge, LA 70808 USA. RP Moore, CM (reprint author), Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, 7703 Floyd Curl Dr, San Antonio, TX 78229 USA. EM moorec@uthscsa.edu NR 69 TC 3 Z9 3 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0161-9152 J9 AGE JI Age PD MAR PY 2007 VL 29 IS 1 BP 15 EP 28 DI 10.1007/s11357-006-9016-6 PG 14 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 162QE UT WOS:000246102400002 PM 19424827 ER PT J AU Kuwata, T Kodama, M Sato, A Suzuki, H Miyazaki, Y Miura, T Hayami, M AF Kuwata, Takeo Kodama, Makoto Sato, Akihiko Suzuki, Hajime Miyazaki, Yasuyuki Miura, Tomoyuki Hayami, Masanori TI Contribution of monocytes to viral replication in macaques during acute infection with simian immunodeficiency virus SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID CD4(+) T-CELLS; PERIPHERAL-BLOOD MONOCYTES; IN-VITRO; HIV-INFECTION; GASTROINTESTINAL-TRACT; TYPE-1 REPLICATION; MONONUCLEAR-CELLS; MOLECULAR CLONES; RHESUS-MONKEYS; SIV INFECTION AB Monocytes are known as an alternative target for HIV/SIV infection, but the contribution of monocytes to viral spread in a host is unclear. In this study, CD14(+) monocytes were monitored in 6 macaques until six weeks postinfection (wpi) with SIVmac239 to evaluate their contribution to viral load. The monocyte count in blood significantly increased with peak viremia at 2 wpi and the expression level of CD14 on monocytes significantly decreased at 1-2 wpi, though the number of CD4(+) T cells was stable in these macaques. The number of CD14(+) monocytes and the expression level of CD14 on monocytes at 2 wpi were also significantly related to the extent of viremia in plasma. An increased number of monocytes at 2 wpi was associated with a lower postacute viral load, suggesting that monocytes have a role in suppressing the virus. The lower expression level of CD14 in monocytes at 2 wpi was associated with a higher viral load and greater degree of infection of monocytes. This correlation suggests that monocytes with a low level of CD14 may be more susceptible to SIV and may enhance viral replication. The analysis of monocytes in persistently infected macaques revealed that the expression level of CD14 was also significantly low during persistent infection compared with naive macaques, though the monocyte count was within the normal range. Monocytes may suppress viruses, perhaps by their immune function, during acute infection. However, infection of monocytes may increase the viral load and spread viruses in a host. C1 Kyoto Univ, Inst Virus Res, Expt Res Ctr Infect Dis, Lab Primate Model, Kyoto 6068507, Japan. Shionogi Inst Med Sci, Osaka 5660022, Japan. RP Kuwata, T (reprint author), NIAID, LMM, NIH, Bldg 4,Room B1-33,4 Ctr Dr, Bethesda, MD 20892 USA. EM tkuwata@niaid.nih.gov RI Kuwata, Takeo/F-5809-2013 NR 46 TC 7 Z9 8 U1 0 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD MAR PY 2007 VL 23 IS 3 BP 372 EP 380 DI 10.1089/aid.2006.0208 PG 9 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 157SE UT WOS:000245740300005 PM 17411370 ER PT J AU Persaud, D Ray, SC Kajdas, J Ahonkhai, A Siberry, GK Ferguson, K Ziemniak, C Quinn, TC Casazza, JP Zeichner, S Gange, SJ Watson, DC AF Persaud, Deborah Ray, Stuart C. Kajdas, Joleen Ahonkhai, Aima Siberry, George K. Ferguson, Kimberly Ziemniak, Carrie Quinn, Thomas C. Casazza, Joseph P. Zeichner, Steven Gange, Stephen J. Watson, Douglas C. TI Slow human immunodeficiency virus type 1 evolution in viral reservoirs in infants treated with effective antiretroviral therapy SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID T-CELL RESPONSES; LATENT RESERVOIR; INFECTED CHILDREN; HIV-1 INFECTION; REPLICATION; TRANSMISSION; INDINAVIR; VARIANTS; DYNAMICS; MOTHERS AB A longitudinal study of viral reservoirs in children initiating highly active antiretroviral therapy (HAART) in early infancy was undertaken to test the hypothesis that early effective treatment affects the persistence of replication-competent viral latency and the evolution of HIV-1 in resting CD4(+)T cells. An end point dilution culture assay was used to measure the frequencies of latently-infected resting CD4(+)T cells harboring replication-competent virus in early and late treated children. Gag, pol, and env also were sequenced and compared to pretreatment sequences. HIV-1-specific humoral and cellular immune responses were also assessed. Blood samples were obtained from 12 HIV-1-infected children who started HAART at a median of 1.9 months of age and who maintained suppression of HIV-1 replication for up to 5.5 years. Replication-competent HIV-1 was recovered from 10/12 (84%) subjects. Evolution in gag, pol, and env was restricted for years in early-treated children. HAART initiated from early infancy does not prevent the establishment of a reservoir of latent provirus, but does significantly limit the evolution of HIV-1 in viral reservoirs. The effect of early therapy on HIV-1 evolution may have implications for long-term pharmacologic control of HIV-1. C1 Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. George Washington Univ, Sch Med, Childrens Res Inst, Childrens Natl Med Ctr, Washington, DC USA. George Washington Univ, Sch Med, Dept Pediat, Washington, DC USA. George Washington Univ, Sch Med, Dept Microbiol, Washington, DC USA. George Washington Univ, Sch Med, Dept Immunol, Washington, DC USA. George Washington Univ, Sch Med, Dept Trop Med, Washington, DC USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. RP Persaud, D (reprint author), Johns Hopkins Univ, Sch Med, Dept Pediat, PMOB-3-3151,200 N Wolfe St, Baltimore, MD 21287 USA. EM dpers@jhmi.edu RI Ray, Stuart/B-7527-2008; OI Ray, Stuart/0000-0002-1051-7260; Gange, Stephen/0000-0001-7842-512X FU NIAID NIH HHS [R01 AI 055312] NR 30 TC 29 Z9 29 U1 1 U2 2 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD MAR PY 2007 VL 23 IS 3 BP 381 EP 390 DI 10.1089/aid.2006.0175 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 157SE UT WOS:000245740300006 PM 17411371 ER PT J AU Kinter, AL Horak, R Sion, M Riggin, L McNally, J Lin, Y Jackson, R O'Shea, A Roby, G Kovacs, C Connors, M Migueles, SA Fauci, AS AF Kinter, Audrey L. Horak, Robin Sion, Melanie Riggin, Lindsey McNally, Jonathan Lin, Yin Jackson, Robert O'Shea, Angeline Roby, Gregg Kovacs, Colin Connors, Mark Migueles, Stephen A. Fauci, Anthony S. TI CD25(+) regulatory T cells isolated from HIV-infected individuals suppress the cytolytic and nonlytic antiviral activity of HIV-specific CD8(+) T cells in vitro SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; VIRAL LOAD; ANTIRETROVIRAL TREATMENT; IMMUNE-RESPONSES; BETA-CHEMOKINES; CUTTING EDGE; CD4(+); PROLIFERATION; VIREMIA; TYPE-1 AB HIV infection is characterized by CD4(+) T cell depletion and progressive immune dysfunction; particularly impacted are HIV-specific T cell responses. An important component of immune-mediated control of HIV replication, killing of infected cells, appears to be impaired, in part due to poor cytolytic activity of HIV-specific cytotoxic T cells (CTL). In vitro, several functions of HIV-specific T cells, such as cytokine production, can be enhanced by the depletion of the immunosuppressive CD25(+) FoxP3(+) CD4(+) regulatory (Treg) cell subset. However, the effect of CD25(+) Treg cells on virus-specific cytolytic activity in the context of HIV or any human viral infection has not been investigated. The present study demonstrates that CD25(+) Treg cells isolated from the peripheral blood of HIV-infected subjects significantly suppress HIV Gag-specific cytolytic activity in vitro. In addition, CD25(+) Treg cells suppress effector function (coexpression of TNF-alpha and IFN-gamma) of HIV-specific CD8(+) T cells that proliferate in response to HIV antigen. Finally, the secretion of HIV-inhibitory CC-chemokines by HIV-specific and nonspecific CD8(+) T cells is significantly reduced in the presence of CD25(+) Treg cells. These data suggest that CD25(+) Treg- mediated suppression of the antiviral activity of HIV-specific CD8(+) T cells could impact the ability of HIV-infected individuals to control HIV replication in vivo. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Univ Toronto, Dept Med, Toronto, ON, Canada. RP Kinter, AL (reprint author), 9000 Rockville Pike,Bldg 10,Rm 6A33,MSC-1576, Bethesda, MD 20892 USA. EM AKinter@niaid.nih.gov NR 66 TC 85 Z9 88 U1 0 U2 3 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 MAR PY 2007 VL 23 IS 3 BP 438 EP 450 DI 10.1089/aid.2006.0162 PG 13 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 157SE UT WOS:000245740300012 PM 17411377 ER PT J AU Gillespie, GMA Bashirova, A Dong, T McVicar, DW Rowland-Jones, SL Carrington, M AF Gillespie, Geraldine M. A. Bashirova, Arman Dong, Tao McVicar, Daniel W. Rowland-Jones, Sarah L. Carrington, Mary TI Lack of KIR3DS1 binding to MHC class I Bw4 tetramers in complex with CD8(+) T cell epitopes SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID IMMUNOGLOBULIN-LIKE RECEPTORS; HLA-B; CRYSTAL-STRUCTURES; CUTTING EDGE; KILLER; RECOGNITION; NK; HLA-B-ASTERISK-2705; FREQUENCIES; INFECTION AB In HIV-1 infection, the synergistic association of a subset of Bw4 MHC class I molecules and the activating killer inhibitory receptor (KIR), KIR3DS1, with prolonged AIDS-free survival has been reported. As KIRs represent a diverse group of MHC class I receptors, we questioned whether Bw4 MHC class I molecules expressing isoleucine at position 80 (Bw4Ile80) and in complex with HIV-1-derived T cell epitopes represented KIR3DS1 ligands. MHC class I tetramers are powerful tools for the detection of T cell receptor-MHC class I interactions, and have recently been used to evaluate KIR-MHC class I binding ex vivo. Specifically, this approach has been successfully utilized to assess binding of Bw4 MHC class I tetramers to KIR3DL1, an inhibitory KIR and allele of KIR3DS1. In this study we generated a diverse panel of HIV-1-specific Bw4Ile80 MHC class I tetramers and tested its ability to bind transiently expressed KIR3DS1 on 293-T cells. Using flow cytometry analysis, the expression of KIR3DS1 on 293-T cells was confirmed by anti-FLAG BioM2 staining, prior to incubation with PE-conjugated MHC class I tetramers. Despite choosing a broad array of peptide epitopes and diverse Bw4Ile80 MHC class I molecules, we were unable to detect tetramer binding to KIR3DS1. We speculate that our negative finding may be a consequence of the MHC class I molecules and peptide epitopes chosen, but could also relate to key amino acid differences that distinguish KIR3DS1 from KIR3DL1. C1 John Radcliffe Hosp, Weatherall Inst Mol Med, MRC, Human Immunol Unit, Oxford OX3 9DS, England. Johns Hopkins Univ, Dept Med, Baltimore, MD 21231 USA. NCI, Expt Immunol Lab, Frederick, MD 21702 USA. MRC Labs, Fajara, Gambia. NCI, SIAC Frederick Inc, Lab Genom Divers, Frederick, MD 21702 USA. RP Gillespie, GMA (reprint author), John Radcliffe Hosp, Weatherall Inst Mol Med, MRC, Human Immunol Unit, Oxford OX3 9DS, England. EM ggillesp@hammer.imm.ox.ac.uk RI McVicar, Daniel/G-1970-2015 FU Intramural NIH HHS; Medical Research Council [MC_U137884180]; NCI NIH HHS [N01-CO-12400]; Wellcome Trust NR 23 TC 44 Z9 44 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 MAR PY 2007 VL 23 IS 3 BP 451 EP 455 DI 10.1089/aid.2006.0165 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 157SE UT WOS:000245740300013 PM 17411378 ER PT J AU Andersen, H Barsov, EV Trivett, MT Trubey, CM Giavedoni, LD Lifson, JD Ott, DE Ohlen, C AF Andersen, Hanne Barsov, Eugene V. Trivett, Matthew T. Trubey, Charles M. Giavedoni, Luis D. Lifson, Jeffrey D. Ott, David E. Ohlen, Claes TI Transduction with human telomerase reverse transcriptase immortalizes a rhesus macaque CD8(+) T cell clone with maintenance of surface marker phenotype and function SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID SIMIAN-IMMUNODEFICIENCY-VIRUS; IN-VIVO PERSISTENCE; IMMUNE-RESPONSES; LIFE-SPAN; LYMPHOCYTES; INFECTION; MEMORY; VIREMIA; CHALLENGE; SUBSETS AB T cell lines and clones play a key role in basic studies of cellular immunology, and are also finding applications in adoptive immunotherapy. However, with proliferative expansion, T cells ultimately undergo cellular senescence and death, so that long-term culture of T cell clones is difficult to achieve. Expression of telomerase reverse transcriptase (TERT) in differentiated cells can maintain telomere length over many cell divisions, preventing senescence. We used a retroviral vector that expresses the human TERT (hTERT) gene to transduce a rhesus macaque-derived CD8(+) T cell clone specific for the MamuA*01-restricted immunodominant SIV gag epitope CM9. Extensive in vitro characterization revealed that the untransduced parental cells and the hTERT-transduced cells displayed comparable proliferation capacity, effector memory surface marker profiles, cytolytic activities, and cytokine profiles following antigen stimulation. The hTERT-transduced cells showed improved survival compared to parallel nontransduced cultures during in vitro propagation in longterm culture. Such immortalized T cells may be useful as a source of consistent controls for in vitro assays of cellular immune function, and as a potentially important reagent for autologous adoptive cellular immunotherapy studies in macaques. C1 NCI, SAIC Frederick Inc, AIDS Vaccine Program, Frederick, MD 21702 USA. SW Fdn Biomed Res, SW Natl Primate Res Ctr, San Antonio, TX 78284 USA. RP Ohlen, C (reprint author), NCI, SAIC Frederick Inc, AIDS Vaccine Program, POB B, Frederick, MD 21702 USA. EM cohlen@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 42 TC 15 Z9 16 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 MAR PY 2007 VL 23 IS 3 BP 456 EP 465 DI 10.1089/aid.2006.0194 PG 10 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 157SE UT WOS:000245740300014 PM 17411379 ER PT J AU Li, TK Hewitt, BG Grant, BF AF Li, Ting-Kai Hewitt, Brenda G. Grant, Bridget F. TI Is there a future for quantifying drinking in the diagnosis, treatment, and prevention of alcohol use disorders? SO ALCOHOL AND ALCOHOLISM LA English DT Editorial Material ID NATIONAL EPIDEMIOLOGIC SURVEY; ITEM RESPONSE THEORY; DSM-IV; DEPENDENCE; RISK; ABUSE; DISEASE; AGE; METAANALYSIS; CONSUMPTION C1 NIAAA, NIH, US Dept HHS, Bethesda, MD 20892 USA. RP Hewitt, BG (reprint author), NIAAA, NIH, US Dept HHS, Bethesda, MD 20892 USA. EM bhewitt@mail.nih.gov NR 40 TC 54 Z9 54 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0735-0414 J9 ALCOHOL ALCOHOLISM JI Alcohol Alcohol. PD MAR-APR PY 2007 VL 42 IS 2 BP 57 EP 63 DI 10.1093/alcalc/ag1125 PG 7 WC Substance Abuse SC Substance Abuse GA 161KY UT WOS:000246015000001 PM 17307789 ER PT J AU Visvanathan, K Crum, RM Strickland, PT You, XJ Ruczinski, I Berndt, SI Alberg, AJ Hoffman, SC Comstock, GW Bell, DA Helzlsouer, KJ AF Visvanathan, Kala Crum, Rosa M. Strickland, Paul T. You, Xiaojun Ruczinski, Ingo Berndt, Sonja I. Alberg, Anthony J. Hoffman, Sandra C. Comstock, George W. Bell, Douglas A. Helzlsouer, Kathy J. TI Alcohol dehydrogenase genetic polymorphisms, low-to-moderate alcohol consumption, and risk of breast cancer SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE alcohol dehydrogenase; genotypes; breast cancer ID HUMAN-LIVER ALCOHOL; AGE 50 YEARS; POSTMENOPAUSAL WOMEN; PREMENOPAUSAL WOMEN; ALCOHOL-DEHYDROGENASE-3 GENOTYPE; HORMONE CONCENTRATIONS; POOLED ANALYSIS; ADH3 GENOTYPE; LINKAGE PHASE; NECK-CANCER AB Background: In vitro, human isoenzymes encoded by genes homozygous for the ADH1C(*)1 or ADH1B(*)2 alleles metabolize ethanol to acetaldehyde at a faster rate than those homozygous for the ADH1C(*)2 or ADH1B(*)1 allele. Because alcohol is a known risk factor for breast cancer, we evaluated the joint association of genetic variants in ADH and alcohol consumption in relation to breast cancer. Methods: A nested case-control study of 321 cases and matched controls was conducted. Five single nucleotide polymorphisms (SNPs) in the ADH1C and ADH1B genes were genotyped. Logistic regression was used to assess odds ratios (ORs) and 95% confidence limits (CIs) for each SNP. Haplotype analysis of all 5 SNPs was also undertaken. Results: Among drinkers, the median intake of total alcohol was 13 g/wk (10th-90th percentiles; 4.5-135.9) in cases and 18 g/wk (10th-90th percentiles; 4.5-104.1) in controls. Women who drank alcohol tended to be at an increased risk of developing breast cancer compared with those who did not drink (OR=1.40%, 95% CI 0.97-2.03), particularly those who were premenopausal at the time of breast cancer diagnosis (OR=2.69%, 95% CI: 1.00-7.26). Of the known functional alleles, breast cancer risk was not significantly increased among carriers of at least 1 ADH1C(*)1 or ADH1B(*)2 allele, when compared with those homozygous for the genotype at each locus. However, breast cancer risk tended to be lower among women who inherited the G allele at ADH1B IVS1+896A > G (OR=0.62, 95% CI 0.37-1.04). Overall haplotype frequencies were not significantly different between cases and controls. Conclusions: In this study low levels of alcohol are associated with a modest increase in breast cancer risk that is not altered by known functional allelic variants of the ADH1B and 1C gene. The protective association conferred by the G allele at ADH1B IVS1+896A > G needs further evaluation. C1 Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Environm Hlth Sci, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Biostat, Bloomberg Sch Publ Hlth, Baltimore, MD 21205 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Visvanathan, K (reprint author), Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, 615 N Wolfe St, Baltimore, MD 21205 USA. EM kvisvana@jhsph.edu FU Intramural NIH HHS [Z01 ES046008-17]; NCI NIH HHS [CA111948, P50 CA88843, 5U0A1CA/ES62988]; NIEHS NIH HHS [ES060520] NR 60 TC 27 Z9 29 U1 0 U2 5 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 MAR PY 2007 VL 31 IS 3 BP 467 EP 476 DI 10.1111/j.1530-0277.2006.00334.x PG 10 WC Substance Abuse SC Substance Abuse GA 134QE UT WOS:000244097900014 PM 17295732 ER PT J AU Stark, KD Pawlosky, RJ Sokol, RJ Hannigan, JH Salem, N AF Stark, Ken D. Pawlosky, Robert J. Sokol, Robert J. Hannigan, John H. Salem, Norman, Jr. TI Maternal smoking is associated with decreased 5-methyltetrahydrofolate in cord plasmas SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE 5-methyltetrahydrofolic acid; folate; folic acid; African American women; pregnancy; smoking; electrospray mass spectrometry; infants; umbilical cord; placenta ID NUTRITION EXAMINATION SURVEY; FOLIC-ACID FORTIFICATION; AFRICAN-AMERICAN WOMEN; CEREAL-GRAIN PRODUCTS; NEURAL-TUBE DEFECTS; PREGNANT-WOMEN; SPINA-BIFIDA; ALCOHOL-CONSUMPTION; NATIONAL-HEALTH; FOOD FREQUENCY AB Background: Maternal-fetal folate transport via the placenta has been shown to be concentrative. Exposure to cigarette smoke is associated with decreased maternal folate status through altered dietary intakes and possibly through nondietary mechanisms such as increased folate turnover. The effect of maternal smoking on fetal folate status has not been documented. Objective: The objective was to determine the effect of maternal smoking on plasma 5-methyltetrahydrofolic acid (5-MTHFA) concentrations in umbilical cord blood. Design: African American women were recruited from an antenatal clinic in Detroit, MI. Plasma 5-MTHFA concentrations were measured in maternal-umbilical cord pairings (n = 58). The participants completed a structured interview to determine demographic characteristics, including smoking. Results: Concentrations of 5-MTHFA were significantly higher in venous cord plasma (16.8 +/- 7.5 ng/mL) than in maternal plasma (13.0 +/- 7.5 ng/mL) but remained associated (r = 0.60, P < 0.001) with each other. Cigarettes smoked by the mothers was negatively associated (r = -0.31, P = 0.019) with venous cord 5-MTHFA concentrations and remained so after control for maternal plasma 5-MTHFA and other variables. Venous cord plasma 5-MTHFA was significantly lower in smoking (15.1 +/- 7.6 ng/mL; n = 32) than in nonsmoking (19.0 +/- 7.0 ng/mL; n = 26) mothers. Conclusions: Cord plasma 5-MTHFA concentrations were elevated relative to maternal blood, as expected, because the placenta is capable of concentrative folate transport to the fetus. The negative effect of maternal smoking on infant, but not on maternal, 5-MTHFA status indicates that maternal smoking may impair folate transport to the fetus. C1 Univ Waterloo, Lab Nutr & Nutraceut Res, Dept Kinesiol, Waterloo, ON N2L 3G1, Canada. NIAAA, Lab Membrane Biochem & Biophys, Div Intramural Clin & Biol Res, NIH, Bethesda, MD USA. Wayne State Univ, Dept Obstet & Gynecol, Sch Med, Detroit, MI USA. Wayne State Univ, Dept Psychol, Detroit, MI USA. RP Stark, KD (reprint author), Univ Waterloo, Lab Nutr & Nutraceut Res, Dept Kinesiol, Waterloo, ON N2L 3G1, Canada. EM kstark@uwaterloo.ca RI Stark, Ken/I-1347-2016 OI Stark, Ken/0000-0001-7828-4072 FU Intramural NIH HHS; NIAAA NIH HHS [N01-AA83019] NR 48 TC 8 Z9 10 U1 1 U2 3 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 MAR PY 2007 VL 85 IS 3 BP 796 EP 802 PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 146ES UT WOS:000244917900020 PM 17344502 ER PT J AU Stergiopoulou, T Meletiadis, J Roilides, E Kleiner, DE Schaufele, R Roden, M Harrington, S Dad, L Segal, B Walsh, TJ AF Stergiopoulou, Theodouli Meletiadis, Joseph Roilides, Emmanuel Kleiner, David E. Schaufele, R. Roden, Maureen Harrington, Susan Dad, Luqman Segal, Brahm Walsh, Thomas J. TI Host-dependent patterns of tissue injury in invasive pulmonary aspergillosis SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE invasive pulmonary aspergillosis; neutropenia; hematopoietic stem cell transplant recipients; angioinvasion; corticosteroids; pulmonary infarct ID STEM-CELL TRANSPLANTATION; CT HALO SIGN; FUNGAL-INFECTIONS; COMPUTED-TOMOGRAPHY; PATHOGENESIS; CHEMOTHERAPY; NEUTROPENIA; MANAGEMENT; FUMIGATUS; DIAGNOSIS AB Invasive pulmonary aspergillosis (IPA) is an important cause of morbidity and mortality in neutropenic, nonneutropenic, and other immunocompromised patients. We therefore compared the patterns of infection and inflammation among 3 cohorts of immunocompromised patients with profound neutropenia, nonneutropenic immunosuppression, and hematopoietic stem cell transplantation. Lesions of IPA in neutropenic patients and hematopoietic stem cell transplant (HSCT) recipients were similar and consisted predominantly of angioinvasion and intraalveolar hemorrhage. The frequency of these histologic findings in neutropenic patients and HSCT recipients differed significantly from those of nonneutropenic patients (P < .05). It is noteworthy that even if HSCT recipients have normal peripheral blood neutrophil counts, there may be no influx into sites of infection. In the nonneutropenic cohort, lesions of IPA consisted mainly of neutrophilic and monocytic infiltrates and inflammatory necrosis. Thus, the status of innate host defenses contributes significantly to the histologic patterns observed in IPA. C1 NCI, CRC, POB, Immunocompromised Host Sect, Bethesda, MD 20892 USA. NCI, Lab Pathol Dept, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Lab Med, Bethesda, MD 20892 USA. Aristotle Univ Thessaloniki, Hippokrat Hosp, Pediat Dept 3, GR-54006 Thessaloniki, Greece. Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14263 USA. RP Walsh, TJ (reprint author), NCI, CRC, POB, Immunocompromised Host Sect, Room 1-5750 MSC 1100,10 Ctr Dr, Bethesda, MD 20892 USA. OI Kleiner, David/0000-0003-3442-4453 FU Intramural NIH HHS NR 29 TC 63 Z9 68 U1 0 U2 3 PU AMER SOC CLINICAL PATHOLOGY PI CHICAGO PA 2100 W HARRISON ST, CHICAGO, IL 60612 USA SN 0002-9173 J9 AM J CLIN PATHOL JI Am. J. Clin. Pathol. PD MAR PY 2007 VL 127 IS 3 BP 349 EP 355 DI 10.1309/UJRV9DLC11RM3G8R PG 7 WC Pathology SC Pathology GA 139CO UT WOS:000244409900003 PM 17276936 ER PT J AU Lea, CS Holly, EA Hartge, P Lee, JS Guerry, D Elder, DE Halpern, A Sagebiel, RW Tucker, MA AF Lea, C. Suzanne Holly, Elizabeth A. Hartge, Patricia Lee, Jennifer S. Guerry, DuPont Elder, David E. Halpern, Allan Sagebiel, Richard W. Tucker, Margaret A. TI Reproductive risk factors for cutaneous melanoma in women: A case-control study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE case-control studies; contraceptives, oral; hormone replacement therapy; melanoma; nevus, pigmented; parity ID ORAL-CONTRACEPTIVE USE; MALIGNANT-MELANOMA; HORMONAL FACTORS; DYSPLASTIC NEVI; POOLED ANALYSIS; PREGNANCY AB Reproductive hormonal factors may have a potential role in cutaneous melanoma. This study estimated the risk of melanoma in women related to self-reported changes in nevi during pregnancy, while using oral contraceptives and/or hormone replacement therapy. Trained interviewers administered a questionnaire obtaining information about oral contraceptive use, hormone replacement therapy, reproductive history, sun exposure, occupation, and medical history from 318 Caucasian women newly diagnosed between 1991 and 1992 from two pigmented lesion clinics in San Francisco, California, and Philadelphia, Pennsylvania. A total of 395 frequency-matched control participants were recruited from hospital-affiliated outpatient clinics. Clinicians conducted skin examinations to assess the number and type of nevi, extent of freckling, solar damage, and skin type. For women aged less than 55 years, there was an association between a livebirth 5 years before diagnosis (odds ratio = 2.6, 95% confidence interval: 1.3, 5.3) and between number of births and melanoma risk (for >= 3 births: odds ratio = 3.3, 95% confidence interval: 1.7, 6.5; p(trend) < 0.001). Changes in nevi during recent pregnancies were a risk factor for melanoma, based upon small numbers (odds ratio = 2.9, 95% confidence interval: 1.1, 8.1). Oral contraceptive use and hormone replacement therapy were not associated with melanoma risk. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Epidemiol & Biostat Program, Bethesda, MD 20892 USA. Res Triangle Inst Int, Stat & Epidemiol Program, Res Triangle Pk, NC USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, Div Endocrinol & Metab, San Francisco, CA 94143 USA. Univ Penn, Pigmented Lesion Study Grp, Sch Med, Philadelphia, PA 19104 USA. Mem Sloan Kettering Canc Ctr, Dermatol Sect, New York, NY 10021 USA. Univ Calif San Francisco, Melanoma Clin, San Francisco, CA 94143 USA. RP Tucker, MA (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Epidemiol & Biostat Program, 6120 Execut Blvd,EPS7122, Bethesda, MD 20892 USA. EM tuckerp@mail.nih.gov RI Tucker, Margaret/B-4297-2015 FU Intramural NIH HHS; NCI NIH HHS [CP33045, CP0568] NR 37 TC 33 Z9 33 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 MAR 1 PY 2007 VL 165 IS 5 BP 505 EP 513 DI 10.1093/aje/kwk040 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 139JC UT WOS:000244427100004 PM 17158470 ER PT J AU Brenes, GA Kritchevsky, SB Mehta, KM Yaffe, K Simonsick, EM Ayonayon, HN Rosano, C Rubin, SM Satterfield, S Penninx, BWJH AF Brenes, Gretchen A. Kritchevsky, Stephen B. Mehta, Kala M. Yaffe, Kristine Simonsick, Eleanor M. Ayonayon, Hilsa N. Rosano, Caterina Rubin, Susan M. Satterfield, Suzanne Penninx, Brenda W. J. H. CA Hlth ABC Study TI Scared to death: Results from the health, aging, and body composition study SO AMERICAN JOURNAL OF GERIATRIC PSYCHIATRY LA English DT Article DE anxiety; mortality; race; depression ID CARDIOVASCULAR-DISEASE; RISK; DEPRESSION; MORTALITY; ANXIETY; MEN AB Objective: The purpose of this study is to determine if anxiety is associated with mortality and if race moderates and depression mediates this relationship. Method: Participants are 3,015 adults aged 70-79 years. Results: Anxiety symptoms were significant predictors of all-cause, cardiovascular, and noncardiovascular mortality among blacks but not whites. Depression was not related to mortality. Conclusions: Although the mechanisms that underlie the relationship between anxiety and mortality are unknown, routine assessment of anxiety symptoms in clinical practice, particularly in black older adults, seems prudent. C1 Wake Forest Univ, Sch Med, Dept Psychiat & Behav Med, Winston Salem, NC 27157 USA. Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27157 USA. Univ Calif San Francisco, Div Geriatr, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Psychiat Neurol & Epidemiol, San Francisco, CA 94143 USA. NIA, Clin Res Branch, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Tennessee, Dept Prevent Med, Knoxville, TN USA. VU Univ Med Ctr, Inst Res Extramural Med, Amsterdam, Netherlands. VU Univ Med Ctr, Dept Psychiat, Amsterdam, Netherlands. RP Brenes, GA (reprint author), Wake Forest Univ, Sch Med, Dept Psychiat & Behav Med, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM gbrenes@wfubmc.edu OI Rosano, Caterina/0000-0002-0909-1506; Rosano, Caterina/0000-0002-4271-6010 FU Intramural NIH HHS; NIA NIH HHS [N01-AG-6-2103, N01-AG-6-2101, N01-AG-6-2106, P30 AG021332, P30AG021332]; NIMH NIH HHS [K23 MH065281, MH65281, K23 MH065281-01A2] NR 9 TC 11 Z9 12 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1064-7481 J9 AM J GERIAT PSYCHIAT JI Am. J. Geriatr. Psychiatr. PD MAR PY 2007 VL 15 IS 3 BP 262 EP 265 DI 10.1097/JGP.0b013e31802e21f0 PG 4 WC Geriatrics & Gerontology; Gerontology; Psychiatry SC Geriatrics & Gerontology; Psychiatry GA 147HE UT WOS:000244993200011 PM 17322138 ER PT J AU Kaphingst, KA Lobb, R Fay, ME Hunt, MK Suarez, EG Fletcher, RH Emmons, KM AF Kaphingst, Kimberly A. Lobb, Rebecca Fay, Martha E. Hunt, Mary K. Suarez, Elizabeth Gonzalez Fletcher, Robert H. Emmons, Karen M. TI Impact of intervention dose on cancer-related health behaviors among working-class, multiethnic, community health center patients SO AMERICAN JOURNAL OF HEALTH PROMOTION LA English DT Article DE intervention dose; process evaluation; multiethnic patients; health centers ID PREVENTION; POPULATIONS; DIRECTIONS AB Purpose. To examine the relationship between intervention dose and health behavior change in Healthy Directions-Health Centers, an intervention designed to reduce cancer risk factors. Design. Analysis of intervention condition participant data from a randomized controlled trial. Setting. Community health centers in Massachusetts. Subjects. Patients residing in low-income, working-class, multiethnic neighborhoods. Intervention. Components were clinician endorsement, in-person counseling session and four telephone counseling sessions with a trained health advisor, and social-contextual tailored materials. Measures. Intervention dose was number of six possible intervention components completed by each participant. Changes in fruit and vegetable consumption, red meat consumption, physical activity, and multivitamin intake between baseline (n = 1088) and 8-month follow-up (n = 967; 89% of baseline sample) were determined. Analysis. Bivariate and multivariate associations between intervention dose and change in health behaviors were examined. Results. In multivaiiate analysis, the association between intervention dose and increase in multivitamin intake approached significance (p < .07). Seventy Percent of Participants completed all intervention activities. In bivariate analysis, completion of four telephone counseling calls was associated with decrease in red meat consumption (p < .05). Conclusion. These findings indicate that future studies should examine the number, content, and length of contacts needed for behavior change. The results also suggest that health centers are a channel for reaching diverse populations, as shown by the high Level of intervention implementation. C1 NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. Harvard Univ, Pilgrim Hlth Care, Dept Ambulatory Care & Prevent, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Soc Human Dev & Hlth, Boston, MA 02115 USA. Dana Farber Canc Inst, Ctr Community Based Res, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA USA. RP Kaphingst, KA (reprint author), NHGRI, Social & Behav Res Branch, 2 Ctr Dr,MSC 0249,Bldg 2,Room 4E30, Bethesda, MD 20892 USA. EM kkaphing@mail.nih.gov OI Lobb, Rebecca/0000-0003-3503-0675 FU NCI NIH HHS [5 P01 CA75308] NR 9 TC 1 Z9 1 U1 2 U2 5 PU AMER J HEALTH PROMOTION INC PI KEEGO HARBOR PA 1660 CASS LAKE RD, STE 104, KEEGO HARBOR, MI 48320 USA SN 0890-1171 J9 AM J HEALTH PROMOT JI Am. J. Health Promot. PD MAR-APR PY 2007 VL 21 IS 4 BP 262 EP 266 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 150QO UT WOS:000245231500007 PM 17375492 ER PT J AU Shizukuda, Y Bolan, CD Nguyen, TT Botello, G Tripodi, DJ Yau, YY Waclawiw, MA Leitman, SF Rosing, DR AF Shizukuda, Yukitaka Bolan, Charles D. Nguyen, Tammy T. Botello, Gilberto Tripodi, Dorothy J. Yau, Yu-Ying Waclawiw, Myron A. Leitman, Susan F. Rosing, Douglas R. TI Oxidative stress in asymptomatic subjects with hereditary hemochromatosis SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Letter C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Shizukuda, Y (reprint author), NHLBI, Cardiovasc Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 3 TC 19 Z9 19 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD MAR PY 2007 VL 82 IS 3 BP 249 EP 250 DI 10.1002/ajh.20743 PG 2 WC Hematology SC Hematology GA 142NW UT WOS:000244657700023 PM 16955456 ER PT J AU Hediger, ML England, LJ Molloy, CA Yu, KF Manning-Courtney, P Mills, JL AF Hediger, M. L. England, L. J. Molloy, C. A. Yu, K. F. Manning-Courtney, P. Mills, J. L. TI Reduced bone cortical thickness in boys with autism or autism spectrum disorder. SO AMERICAN JOURNAL OF HUMAN BIOLOGY LA English DT Meeting Abstract C1 NICHD, DESPR, Bethesda, MD USA. CDC, NCCDPHP, Atlanta, GA 30333 USA. CCHMC, Cincinnati, OH USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1042-0533 J9 AM J HUM BIOL JI Am. J. Hum. Biol. PD MAR-APR PY 2007 VL 19 IS 2 BP 259 EP 260 PG 2 WC Anthropology; Biology SC Anthropology; Life Sciences & Biomedicine - Other Topics GA 141AB UT WOS:000244547100039 ER PT J AU Blair, A Stewart, P Lubin, JH Forastiere, F AF Blair, Aaron Stewart, Patricia Lubin, Jay H. Forastiere, Francesco TI Methodological issues regarding confounding and exposure misclassification in epidemiological studies of occupational exposures SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article; Proceedings Paper CT International Conference on Ethical Considerations and Future Challenges in Occupational and Enviromental Health CY MAY 19-20, 2005 CL Oland, SWEDEN DE confounding; exposure misclassification; methods; occupational epidemiology ID COPPER SMELTER WORKERS; LUNG-CANCER; NONDIFFERENTIAL MISCLASSIFICATION; RETROSPECTIVE ASSESSMENT; RESPIRATORY CANCER; SMOKING; COHORT; MORTALITY; RISK; BIAS AB Background Confounding and exposure misclassification are issues that concern epidemiologists because of their potential to bias results of studies and complicate interpretations. In occupational epidemiology both are routinely raised to argue that an observed result is either a false positive or a false negative finding. Although it is important to consider the potential for limitations of epidemiologic investigations, judgment regarding their importance should be based on their actual likelihood of occurrence. Methods This paper is based on our experience in epidemiologic analyses and a brief review of the literature regarding confounding and exposure misclassification. Results Examples of substantial confounding are rare in occupational epidemiology. In fact, even for studies of occupational exposures and lung cancer, tobacco-adjusted relative risks rarely differ appreciably from the unadjusted estimates. This is surprising because it seems the perfect situation for confounding to occur Yet, despite the lack of evidence that confounding is a common problem, nearly every epidemiologic paper includes a lengthy discussion on uncontrolled or residual confounding. On the other hand, exposure misclassification probably occurs in all studies. The only question is, how much? The direction and magnitude of nondifferential exposure misclassification (the type most likely to occur in cohort studies) on estimates of relative risks can be largely predicted given knowledge on the degree of misclassification, that is, relatively small amounts of misclassification can bias relative risks substantially towards the null. The literature, however; is full of discussions implying that misclassification of exposure is an explanation for a positive finding. Conclusions These comments are not to suggest that all potential limitations for epidemiologic studies should not be considered and evaluated. We do believe, however, that the likelihood of occurrence and the direction and magnitude of the effect should be more carefully and realistically considered when making judgments about study design or data interpretation. (c) 2006 Wiley-Liss, Inc. C1 NCI, NIH, DHHS, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. ASL roma, Dept Epidemiol, Rome, Italy. RP Blair, A (reprint author), NCI, NIH, DHHS, Div Canc Epidemiol & Genet, Execut Plaza S,Room 8118, Bethesda, MD 20892 USA. RI Forastiere, Francesco/J-9067-2016 OI Forastiere, Francesco/0000-0002-9162-5684 FU Intramural NIH HHS NR 37 TC 125 Z9 126 U1 0 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD MAR PY 2007 VL 50 IS 3 BP 199 EP 207 DI 10.1002/ajim.20281 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 142QY UT WOS:000244666000006 PM 17096363 ER PT J AU Parikh, NI Pencina, MJ Wang, TJ Lanier, KJ Fox, CS D'Agostino, RB Vasan, RS AF Parikh, Nisha I. Pencina, Michael J. Wang, Thomas J. Lanier, Katherine J. Fox, Caroline S. D'Agostino, Ralph B. Vasan, Ramachandran S. TI Increasing trends in incidence of overweight and obesity over 5 decades SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE body mass index; obesity; overweight; trends; epidemiology ID BODY-MASS INDEX; UNITED-STATES; US ADULTS; PHYSICAL-ACTIVITY; SECULAR TRENDS; HEART-DISEASE; WEIGHT CHANGE; RISK-FACTORS; PREVALENCE; FRAMINGHAM AB PURPOSE: We evaluated trends in the incidence of overweight and obesity over the past 50 years. METHODS: We evaluated trends in the incidence of overweight (25 <= body mass index [BMI] < 30 kg/m(2)), obesity (BMI >= 30 kg/m(2)) and stage 2 obesity (BMI >= 35 kg/m(2)) from 1950 to 2000 in Framingham Study participants (n = 6798, 54% women). Individuals aged 40-55 years who attended 2 examinations 8 years apart in each decade were eligible. RESULTS: The incidences of overweight, obesity, and stage 2 obesity increased across the decades in both sexes (P for trend <.001). For men, the incidence of overweight rose from 21.8% (95% confidence interval [CI], 17.6- 26.5) in the 1950s to 35.2% (95% CI, 28.6- 42.5) in the 1990s; of obesity from 5.8% (95% CI, 4.4-7.6) to 14.8% (95% CI, 12.2-17.9); and of stage 2 obesity from 0.2% (95% CI, 0.1-0.9) to 5.4% (95% CI, 4.0-7.2). For women, incidence rates of overweight increased from 15.0% (95% CI, 12.3-18.1) to 33.1% (95% CI, 29.0- 37.4); of obesity from 3.9% (95% CI, 2.9- 5.3) to 14% (95% CI, 11.6- 16.7); and of stage 2 obesity from 1.7% (95% CI, 1.1- 2.6) to 4.4% (95% CI, 3.2- 6.0). Overall, incidence rates of overweight increased 2-fold and that of obesity more than 3-fold over 5 decades, findings that remained robust upon additional adjustment for baseline BMI in each decade. CONCLUSIONS: The incidence of overweight and obesity increased progressively over the last 5 decades, suggesting that the rising trend in prevalence is not a recent phenomenon. (c) 2007 Elsevier Inc. All rights reserved. C1 Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Div Cardiol,Dept Med, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Endocrinol Diabet & Hypertens, Boston, MA 02115 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. Boston Univ, Sch Med, Prevent Med Sect, Boston, MA 02215 USA. Boston Univ, Sch Med, Cardiol Sect, Boston Med Ctr, Boston, MA 02215 USA. RP Vasan, RS (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave,Suite 2, Framingham, MA 01702 USA. EM vasan@bu.edu OI Ramachandran, Vasan/0000-0001-7357-5970 FU NHLBI NIH HHS [N01-HC-25195, 2K24HL04334, K23HL074077] NR 46 TC 94 Z9 97 U1 2 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD MAR PY 2007 VL 120 IS 3 BP 242 EP U6 DI 10.1016/j.amjmed.2006.06.004 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 143WF UT WOS:000244756400013 PM 17349447 ER PT J AU Suter, LG Murabito, JM Felson, DT Fraenkel, L AF Suter, Lisa G. Murabito, Joanne M. Felson, David T. Fraenkel, Liana TI Smoking, alcohol consumption, and Raynaud's phenomenon in middle age SO AMERICAN JOURNAL OF MEDICINE LA English DT Article DE Raynaud's phenomenon; risk factors; cigarette smoking; alcohol consumption; cardiovascular disease; gender differences ID CIGARETTE-SMOKING; PREVALENCE; POPULATION; RISK; ASSOCIATION; WOMEN; MEN; MORTALITY; COMMUNITY; DIAGNOSIS AB BACKGROUND: Data suggest Raynaud's phenomenon shares risk factors with cardiovascular disease. Studies of smoking, alcohol consumption, and Raynaud's have produced conflicting results and were limited by small sample size and failure to adjust for confounders. Our objective was to determine whether smoking and alcohol are independently associated with Raynaud's in a large, community-based cohort. METHODS: By using a validated survey to classify Raynaud's in the Framingham Heart Study Offspring Cohort, we performed sex-specific analyses of Raynaud's status by smoking and alcohol consumption in 1840 women and 1602 men. Multivariable logistic regression analyses were used to examine the relationship of Raynaud's to smoking and alcohol consumption. RESULTS: Current smoking was not associated with Raynaud's in women but was associated with increased risk in men (adjusted odds ratio [OR] 2.59, 95% confidence interval [CI], 1.11-6.04). Heavy alcohol consumption in women was associated with increased risk of Raynaud's ( adjusted OR 1.69, 95% CI, 1.02- 2.82), whereas moderate alcohol consumption in men was associated with reduced risk (adjusted OR 0.51, 95% CI, 0.29-0.89). In both genders, red wine consumption was associated with a reduced risk of Raynaud's ( adjusted OR 0.59, 95% CI, 0.36-0.96 in women and adjusted OR 0.30, 95% CI, 0.15-0.62 in men). CONCLUSIONS: Our data suggest that middle-aged women and men may have distinct physiologic mechanisms underlying their Raynaud's, and thus sex-specific therapeutic approaches may be appropriate. Our data also support the possibility that moderate red wine consumption may protect against Raynaud's. (c) 2007 Elsevier Inc. All rights reserved. C1 Yale Univ, Sch Med, Dept Internal Med, Rheumatol Sect, New Haven, CT 06520 USA. VA Connecticut Healthcare Syst, West Haven, CT USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Boston Univ, Sch Med, Gen Internal Med Sect, Boston, MA 02118 USA. RP Suter, LG (reprint author), Yale Univ, Sch Med, Dept Internal Med, Rheumatol Sect, 300 Cedar St,Room TAC S541,POB 208031, New Haven, CT 06520 USA. EM lisa.suter@yale.edu OI Murabito, Joanne/0000-0002-0192-7516; Felson, David/0000-0002-2668-2447 FU NHLBI NIH HHS [N01-HC-25195]; NIAMS NIH HHS [AR47785, K23 AR048826-01] NR 34 TC 13 Z9 15 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-9343 J9 AM J MED JI Am. J. Med. PD MAR PY 2007 VL 120 IS 3 BP 264 EP 271 DI 10.1016/j.amjmed.2006.06.007 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 143WF UT WOS:000244756400016 PM 17349450 ER PT J AU Toso, L Roberson, R Abebe, D Spong, CY AF Toso, Laura Roberson, Robin Abebe, Daniel Spong, Catherine Y. TI Neuroprotective peptides prevent some alcohol-induced alteration in raminobutyric acid A-beta 3, which plays a role in cleft lip and palate and learning in fetal alcohol syndrome 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 C1 NICHHD, Unit Perinatal & Dev Neurobiol, NIH, Bethesda, MD 20892 USA. RP Toso, L (reprint author), NICHHD, Unit Perinatal & Dev Neurobiol, NIH, Bethesda, MD 20892 USA. NR 0 TC 6 Z9 6 U1 0 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 MAR PY 2007 VL 196 IS 3 BP 259 EP 261 DI 10.1016/j.ajog.2007.01.015 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 144AO UT WOS:000244767700028 ER PT J AU Pineles, BL Romero, R Montenegro, D Tarca, AL Han, YM Kim, YM Draghici, S Espinoza, J Kusanovic, JP Mittal, P Hassan, SS Kim, CJ AF Pineles, Beth L. Romero, Roberto Montenegro, Daniel Tarca, Adi L. Han, Yu Mi Kim, Yeon Mee Draghici, Sorin Espinoza, Jimmy Kusanovic, Juan Pedro Mittal, Pooja Hassan, Sonia S. Kim, Chong Jai TI Distinct subsets of microRNAs are expressed differentially in the human placentas of patients with preeclampsia 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 C1 NICHHD, Perinatol Res Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. NICHHD, Perinatol Res Branch, Dept Hlth & Human Serv, NIH, Detroit, MI USA. Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI USA. Wayne State Univ, Dept Comp Sci, Detroit, MI 48202 USA. Wayne State Univ, Sch Med, Dept Pathol, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. RP Pineles, BL (reprint author), NICHHD, Perinatol Res Branch, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. RI Draghici, Sorin/B-3074-2013 OI Draghici, Sorin/0000-0002-0786-8377 NR 0 TC 158 Z9 162 U1 0 U2 7 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 MAR PY 2007 VL 196 IS 3 BP 261 EP 263 DI 10.1016/j.ajog.2007.01.008 PG 3 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 144AO UT WOS:000244767700029 ER PT J AU Iantorno, M Chen, H Kim, JA Tesauro, M Lauro, D Cardillo, C Quon, MJ AF Iantorno, Micaela Chen, Hui Kim, Jeong-a Tesauro, Manfredi Lauro, Davide Cardillo, Carmine Quon, Michael J. TI Ghrelin has novel vascular actions that mimic PI 3-kinase-dependent actions of insulin to stimulate production of NO from endothelial cells SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE ghrelin; nitric oxide; endothelium ID NITRIC-OXIDE SYNTHASE; SPONTANEOUSLY HYPERTENSIVE-RATS; HORMONE-RELEASING PEPTIDE; ACTIVATED PROTEIN-KINASE; IMPAIRED GLUCOSE-TOLERANCE; LOW PLASMA GHRELIN; SECRETAGOGUE RECEPTOR; METABOLIC SYNDROME; GROWTH; RESISTANCE AB Ghrelin is an orexigenic peptide hormone secreted by the stomach. In patients with metabolic syndrome and low ghrelin levels, intra-arterial ghrelin administration acutely improves their endothelial dysfunction. Therefore, we hypothesized that ghrelin activates endothelial nitric oxide synthase ( eNOS) in vascular endothelium, resulting in increased production of nitric oxide ( NO) using signaling pathways shared in common with the insulin receptor. Similar to insulin, ghrelin acutely stimulated increased production of NO in bovine aortic endothelial cells ( BAEC) in primary culture ( assessed using NO-specific fluorescent dye 4,5-diaminofluorescein) in a time-and dose-dependent manner. Production of NO in response to ghrelin ( 100 nM, 10 min) in human aortic endothelial cells was blocked by pretreatment of cells with N-G-nitro-L-arginine methyl ester ( nitric oxide synthase inhibitor), wortmannin [phosphatidylinositol (PI) 3-kinase inhibitor], or (D-Lys(3))-GHRP-6 ( selective antagonist of ghrelin receptor GHSR-1a), as well as by knockdown of GHSR-1a using small-interfering ( si) RNA ( but not by mitogen/extracellular signal-regulated kinase inhibitor PD-98059). Moreover, ghrelin stimulated increased phosphorylation of Akt (Ser(473)) and eNOS ( Akt phosphorylation site Ser(1179)) that was inhibitable by knockdown of GHSR-1a using siRNA or by pretreatment of cells with wortmannin but not with PD-98059. Ghrelin also stimulated phosphorylation of mitogen-activated protein ( MAP) kinase in BAEC. However, unlike insulin, ghrelin did not stimulate MAP kinase-dependent secretion of the vasoconstrictor endothelin-1 from BAEC. We conclude that ghrelin has novel vascular actions to acutely stimulate production of NO in endothelium using a signaling pathway that involves GHSR-1a, PI3-kinase, Akt, and eNOS. Our findings may be relevant to developing novel therapeutic strategies to treat diabetes and related diseases characterized by reciprocal relationships between endothelial dysfunction and insulin resistance. C1 NC CAM, Diabet Unit, NIH, Bethesda, MD 20892 USA. Univ Roma Tor Vergata, Dept Internal Med, Rome, Italy. Univ Cattolica Sacro Cuore, Dept Internal Med, Rome, Italy. RP Quon, MJ (reprint author), NC CAM, Diabet Unit, NIH, 10 Ctr Dr,Bldg 10,Rm 6C-205, Bethesda, MD 20892 USA. EM quonm@nih.gov RI Quon, Michael/B-1970-2008; OI Quon, Michael/0000-0002-9601-9915; Lauro, Davide/0000-0002-8597-4415; Quon , Michael /0000-0002-5289-3707 FU Intramural NIH HHS NR 75 TC 58 Z9 63 U1 1 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD MAR PY 2007 VL 292 IS 3 BP E756 EP E764 DI 10.1152/ajpendo.00570.2006 PG 9 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 143LB UT WOS:000244722000014 PM 17106060 ER PT J AU Mochizuki, K Kagawa, T Numari, A Harris, MJ Itoh, J Watanabe, N Mine, T Arias, IM AF Mochizuki, Kaori Kagawa, Tatehiro Numari, Asano Harris, Matthew J. Itoh, Johbu Watanabe, Norihito Mine, Tetsuya Arias, Irwin M. TI Two N-linked glycans are required to maintain the transport activity of the bile salt export pump (ABCB11) in MDCK II cells SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE cholestasis; bile acid; bile secretion ID TRANSMEMBRANE CONDUCTANCE REGULATOR; FAMILIAL INTRAHEPATIC CHOLESTASIS; CANALICULAR MEMBRANE-VESICLES; RAT-LIVER; P-GLYCOPROTEIN; PHOSPHOINOSITIDE 3-KINASE; ENDOPLASMIC-RETICULUM; SURFACE TRAFFICKING; ACID COTRANSPORTER; PROTEIN STABILITY AB The aim of this study was to determine the role of N-linked glycosylation in protein stability, intracellular trafficking, and bile acid transport activity of the bile salt export pump [Bsep (ATP-binding cassette B11)]. Rat Bsep was fused with yellow fluorescent protein, and the following mutants, in which Asn residues of putative glycosylation sites (Asn(109), Asn(116), Asn(122), and Asn(125)) were sequentially replaced with Gln, were constructed by site-directed mutagenesis: single N109Q, double N109Q + N116Q, triple N109Q + N116Q + N122Q, and quadruple N109Q + N116Q + N122Q + N125Q. Immunoblot and glycosidase cleavage analysis demonstrated that each site was glycosylated. Removal of glycans decreased taurocholate transport activity as determined in polarized MDCK II cells. This decrease resulted from rapid decay of the mutant Bsep protein; biochemical half-lives were 3.76, 3.65, 3.24, 1.35, and 0.52 h in wild-type, single-mutant, double-mutant, triple-mutant, and quadruple-mutant cells, respectively. Wild-type and single- and double-mutant proteins were distributed exclusively along the apical membranes, whereas triple- and quadruple-mutant proteins remained intracellular. MG-132 but not bafilomycin A(1) extended the half-life, suggesting a role for the proteasome in Bsep degradation. To determine whether a specific glycosylation site or the number of glycans was critical for protein stability, we studied the protein expression of combinations of N-glycan-deficient mutants and observed that Bsep with one glycan was considerably unstable compared with Bsep harboring two or more glycans. In conclusion, at least two N-linked glycans are required for Bsep protein stability, intracellular trafficking, and function in the apical membrane. C1 Tokai Univ, Sch Med, Dept Internal Med, Div Gastroenterol, Isehara, Kanagawa 2591193, Japan. Tokai Univ, Sch Med, Labs Struct & Funct Res, Isehara, Kanagawa 2591193, Japan. Tufts Univ, Sch Med, Dept Physiol, Boston, MA USA. Natl Inst Child Hlth & Human Dev, Unit Cellular Polar Cell Biol, NIH, Bethesda, MD USA. Natl Inst Child Hlth & Human Dev, Metab Branch, NIH, Bethesda, MD USA. RP Kagawa, T (reprint author), Tokai Univ, Sch Med, Dept Internal Med, Div Gastroenterol, Isehara, Kanagawa 2591193, Japan. EM kagawa@is.icc.u-tokai.ac.jp FU NIDDK NIH HHS [DK-54785, DK-35652] NR 36 TC 27 Z9 28 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 MAR PY 2007 VL 292 IS 3 BP G818 EP G828 DI 10.1152/ajpgi.00415.2006 PG 11 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 144HN UT WOS:000244787200014 PM 17082223 ER PT J AU Segal, BH Davidson, BA Hutson, AD Russo, TA Holm, BA Mullan, B Habitzruther, M Holland, SM Knight, PR AF Segal, Brahm H. Davidson, Bruce A. Hutson, Alan D. Russo, Thomas A. Holm, Bruce A. Mullan, Barbara Habitzruther, Michael Holland, Steven M. Knight, Paul R., III TI Acid aspiration-induced lung inflammation and injury are exacerbated in NADPH oxidase-deficient mice SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE acid aspiration pneumonitis; chronic granulomatous disease; reactive oxidants; acute respiratory distress syndrome ID CHRONIC GRANULOMATOUS-DISEASE; RESPIRATORY-DISTRESS-SYNDROME; HOST-DEFENSE; ASPERGILLUS-FUMIGATUS; GASTRIC ASPIRATION; GENE-TRANSFER; MURINE MODEL; HYPEROXIA; NEUTROPHILS; COMPLEMENT AB Increased reactive oxidant intermediates (ROIs) from primed leukocytes have been implicated in the pathogenesis of acid aspiration lung injury. To evaluate the specific role of the phagocyte NADPH oxidase-derived ROIs in acid lung injury, the p47(phox-/-) knockout mouse model of chronic granulomatous disease was used. p47(phox-/-) mice developed a significantly greater alveolar neutrophilic leukocytosis compared with wild-type mice at all time points after acid injury, with the difference between genotypes being most marked at 48 h. In contrast, the p47(phox-/-) mice had a decreased number of macrophages in bronchoalveolar lavage (BAL) compared with wild-type at 48 h after acid or saline aspiration. Albumin concentration in BAL reflecting capillary leak was also greater in p47(phox-/-) compared with wild-type mice. BAL concentrations of proinflammatory cytokines and chemokines were greater in p47(phox-/-) compared with wild-type mice. These findings suggest that NADPH oxidase, directly or indirectly, plays a role in attenuating the acute neutrophilic response after acid lung injury. We speculate that this downmodulating effect may be mediated by promoting the transition from production of cytokines and chemokines involved in neutrophilic infiltration to a less injurious, chronic inflammatory response. C1 SUNY Buffalo, Sch Med, Dept Anesthesiol, Buffalo, NY 14214 USA. SUNY Buffalo, Sch Med, Dept Microbiol, Buffalo, NY 14214 USA. SUNY Buffalo, Sch Med, Roswell Pk Canc Inst, Dept Med, Buffalo, NY 14214 USA. SUNY Buffalo, Sch Med, Roswell Pk Canc Inst, Dept Immunol, Buffalo, NY 14214 USA. SUNY Buffalo, Sch Med, Dept Pathol, Buffalo, NY 14214 USA. SUNY Buffalo, Sch Publ Hlth & Hlth Profess, Dept Biostat, Buffalo, NY 14214 USA. SUNY Buffalo, Sch Med, Dept Med, Buffalo, NY 14214 USA. SUNY Buffalo, Sch Med, Dept Pediat, Buffalo, NY 14214 USA. SUNY Buffalo, Sch Med, Dept Obstet Gynecol, Buffalo, NY 14214 USA. SUNY Buffalo, Sch Med, Dept Pharmacol, Buffalo, NY 14214 USA. SUNY Buffalo, Sch Med, Dept Anesthesiol, Buffalo, NY 14214 USA. NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA. RP Knight, PR (reprint author), SUNY Buffalo, Sch Med, Dept Anesthesiol, 245 Biomed Res Bldg,3435 Main St, Buffalo, NY 14214 USA. EM pknight@buffalo.edu FU NHLBI NIH HHS [R01 HL048889, HL-48889]; NIAID NIH HHS [AI/HL-44843, AI-46534] NR 39 TC 33 Z9 33 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD MAR PY 2007 VL 292 IS 3 BP L760 EP L768 DI 10.1152/ajplung.00281.2006 PG 9 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 143LD UT WOS:000244722200019 PM 17114280 ER PT J AU Chen, Y Schnetz, MP Irarrazabal, CE Shen, RF Williams, CK Burg, MB Ferraris, JD AF Chen, Ye Schnetz, Michael P. Irarrazabal, Carlos E. Shen, Rong-Fong Williams, Chester K. Burg, Maurice B. Ferraris, Joan D. TI Proteomic identification of proteins associated with the osmoregulatory transcription factor TonEBP/OREBP: functional effects of Hsp90 and PARP-1 SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE osmolarity; immunoprecipitation; mass spectrometry ID ENHANCER-BINDING PROTEIN; HETEROGENEOUS NUCLEAR RIBONUCLEOPROTEINS; BOX RNA HELICASES; DNA-DAMAGE; POLY(ADP-RIBOSE) POLYMERASE-1; HIGH NACL; STIMULATES TRANSCRIPTION; CELLULAR-RESPONSE; GENE-EXPRESSION; KINASE-ACTIVITY AB Hypertonicity ( e. g., high NaCl) activates the transcription factor tonicity- responsive enhancer/ osmotic response element- binding protein ( TonEBP/ OREBP), increasing transcription of protective genes. In the present studies, by stably expressing amino acids 1- 547 of TonEBP/ OREBP in HEK 293 cells and immunoprecipitating it plus associated proteins from the nuclei of cells exposed to high NaCl, we identify 14 proteins that are physically associated with TonEBP/ OREBP. The associated proteins fall into several classes: 1) DNA- dependent protein kinase, both its catalytic subunit and regulatory subunit, Ku86; 2) RNA helicases, namely RNA helicase A, nucleolar RNA helicase II/ Gu, and DEAD- box RNA helicase p72; 3) small or heterogeneous nuclear ribonucleoproteins ( snRNPs or hnRNPs), namely U5 snRNP- specific 116 kDa protein, U5 snRNP- specific 200 kDa protein, hnRNP U, hnRNP M, hnRNP K, and hnRNP F; 4) heat shock proteins, namely Hsp90 beta and Hsc70; and 5) poly( ADP- ribose) polymerase- 1 ( PARP- 1). We confirm identification of most of the proteins by Western analysis and also demonstrate by electrophoretic mobility- shift assay that they are present in the large complex that binds specifically along with TonEBP/ OREBP to its cognate DNA element. In addition, we find that PARP- 1 and Hsp90 modulate TonEBP/ OREBP activity. PARP- 1 expression reduces TonEBP/ OREBP transcriptional activity and the activity of its transactivating domain. Hsp90 enhances those activities and sustains the increased abundance of TonEBP/ OREBP protein in cells exposed to high NaCl. C1 NHLBI, NIH, Lab Kidney & Electrolyte Metab, Bethesda, MD 20892 USA. NHLBI, NIH, Proteom Core Facil, Bethesda, MD 20892 USA. RP Burg, MB (reprint author), NHLBI, NIH, Lab Kidney & Electrolyte Metab, Bldg 10,Rm 6N260, Bethesda, MD 20892 USA. EM maurice_burg@nih.gov FU Intramural NIH HHS NR 60 TC 25 Z9 25 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 MAR PY 2007 VL 292 IS 3 BP F981 EP F992 DI 10.1152/ajprenal.00493.2005 PG 12 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 143LE UT WOS:000244722300010 PM 17148781 ER PT J AU Stroup, TS Lieberman, JA McEvoy, JP Swartz, MS Davis, SM Capuano, GA Rosenheck, RA Keefe, RSE Miller, AL Belz, I Hsiao, JK AF Stroup, T. Scott Lieberman, Jeffrey A. McEvoy, Joseph P. Swartz, Marvin S. Davis, Sonia M. Capuano, George A. Rosenheck, Robert A. Keefe, Richard S. E. Miller, Alexander L. Belz, Irving Hsiao, John K. CA CATIE Investigators TI Effectiveness of olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia after discontinuing perphenazine: A CATIE study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID INTERVENTION EFFECTIVENESS CATIE; CLINICAL ANTIPSYCHOTIC TRIALS; PROJECT; DRUGS AB Objective: The relative effectiveness of newly started antipsychotic drugs for individuals with schizophrenia may depend on multiple factors, including each patient's previous treatment response and the reason for a new medication trial. This randomized, double-blind study compared olanzapine, quetiapine, and risperidone in patients who had just discontinued the older antipsychotic perphenazine. Method: Subjects with schizophrenia (N= 114) who had been randomly assigned to and then discontinued perphenazine in phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia study were reassigned randomly to double-blinded treatment with olanzapine, 7.5-30.0 mg/ day (N= 38); quetiapine, 200-800 mg/ day (N= 38); or risperidone, 1.5-6.0 mg/ day (N= 38). The primary aim was to determine whether there were differences among these three treatments in effectiveness, as measured by time to treatment discontinuation for any reason. Secondary outcomes included reasons for treatment discontinuation and measures of drug tolerability. Results: The time to treatment discontinuation was longer for patients treated with quetiapine (median, 9.9 months) and olanzapine (7.1 months) than with risperidone (3.6 months). There were no significant differences between treatments on discontinuation due to inefficacy, intolerability, or patient decision. Conclusions: Among this group of patients with chronic schizophrenia who had just discontinued the older antipsychotic perphenazine, quetiapine and olanzapine were more effective than risperidone, as reflected by longer time to discontinuation for any reason. In the context of other results from the CATIE study, the effectiveness and acceptability of antipsychotic drugs appears to vary considerably according to clinical circumstances. C1 Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27599 USA. Duke Univ, Med Ctr, Dept Psychiat & Behav Sci, Durham, NC USA. Quintiles Inc, Res Triangle Pk, NC USA. Johnson & Johnson Consumer Prod Inc, New Brunswick, NJ USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. Univ Utah, Med Ctr, Dept Psychiat, Salt Lake City, UT USA. Appalachian Behav Healthcare Syst, Athens, OH USA. TriCty Mental Hlth Mental Retardat Serv, Conroe, TX USA. Univ Texas, Hlth Sci Ctr, Dept Psychiat, San Antonio, TX 78284 USA. NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. RP Stroup, TS (reprint author), Univ N Carolina, Dept Psychiat, CB 7160, Chapel Hill, NC 27599 USA. EM sstroup@med.unc.edu RI Stroup, Thomas/F-9188-2014 OI Stroup, Thomas/0000-0002-3123-0672 FU NIMH NIH HHS [N01 MH-90001] NR 13 TC 89 Z9 90 U1 1 U2 2 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD MAR PY 2007 VL 164 IS 3 BP 415 EP 427 DI 10.1176/appi.ajp.164.3.415 PG 13 WC Psychiatry SC Psychiatry GA 141DN UT WOS:000244557800011 PM 17329466 ER PT J AU Swartz, MS Perkins, DO Stroup, TS Davis, SM Capuano, G Rosenheck, RA Reimherr, F McGee, MF Keefe, RSE McEvoy, JP Hsiao, JK Lieberman, JA AF Swartz, Marvin S. Perkins, Diana O. Stroup, T. Scott Davis, Sonia M. Capuano, George Rosenheck, Robert A. Reimherr, Fred McGee, Mark F. Keefe, Richard S. E. McEvoy, Joseph P. Hsiao, John K. Lieberman, Jeffrey A. CA CATIE Investigators TI Effects of antipsychotic medications on psychosocial functioning in patients with chronic schizophrenia: Findings from the NIMH CATIE Study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID QUALITY-OF-LIFE; INTERVENTION EFFECTIVENESS CATIE; RANDOMIZED-TRIAL; SUBSTANCE USE; RELIABILITY; OLANZAPINE; OUTCOMES; SCALE; 2ND-GENERATION; HALOPERIDOL AB Objective: This study examined the relative effects of the second-generation antipsychotic drugs and an older representative agent on psychosocial functioning in patients with chronic schizophrenia. Method: Consenting patients were enrolled in the NIMH Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) project. In phase 1, patients were randomly assigned to receive olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone for up to 18 months. Clozapine was included for patients who chose this pathway after discontinuing phase 1 due to inefficacy; all other patients received another second-generation antipsychotic. Psychosocial functioning was assessed using the Quality of Life Scale. Results: Psychosocial functioning modestly improved for the one-third of phase 1 patients who reached the primary Quality of Life Scale analysis endpoint of 12 months (average effect size 0.19 SD units). Although for several of the drugs individually there were significant changes from baseline, overall there were no significant differences between the different agents. Results were similar at 6 and 18 months. There were no significant differences among the treatment groups in the amount of change in the Quality of Life Scale total score or subscale scores at 6, 12, or 18 months. Patients treated with clozapine in the efficacy pathway made comparable gains. Early treatment discontinuations, especially among patients most impaired at baseline, limited the ability to achieve more substantial functional gains. Conclusions: All antipsychotic treatment groups in all phases made modest improvements in psychosocial functioning. There were no differences among them after 6, 12, or 18 months. More substantial improvements would likely require more intensive adjunctive psychosocial rehabilitation interventions. C1 Duke Univ, Sch Med, Dept Psychiat & Behav Sci, Durham, NC 27710 USA. Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC USA. Quintiles Inc, Res Triangle Pk, NC USA. Johnson & Johnson Consumer Prod Inc, New Haven, CT USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. Univ Utah, Med Ctr, Dept Psychiat, Salt Lake City, UT USA. Appalachian Behav Healthcare Syst, Athens, OH USA. NIMH, Div Serv & Intervent Res, Bethesda, MD 20892 USA. Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. RP Swartz, MS (reprint author), Duke Univ, Sch Med, Dept Psychiat & Behav Sci, DUMC Box 3173, Durham, NC 27710 USA. EM swart001@mc.duke.edu RI Stroup, Thomas/F-9188-2014 OI Stroup, Thomas/0000-0002-3123-0672 FU NIMH NIH HHS [N01 MH90001] NR 34 TC 133 Z9 142 U1 2 U2 7 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 MAR PY 2007 VL 164 IS 3 BP 428 EP 436 DI 10.1176/appi.ajp.164.3.428 PG 9 WC Psychiatry SC Psychiatry GA 141DN UT WOS:000244557800012 PM 17329467 ER PT J AU Samuels, J Shugart, YY Grados, MA Willour, VL Bienvenu, OJ Greenberg, BD Knowles, JA McCracken, JT Rauch, SL Murphy, DL Wang, Y Pinto, A Fyer, AJ Piacentini, J Pauls, DL Cullen, B Rasmussen, SA Hoehn-Saric, R Valle, D Liang, KY Riddle, MA Nestadt, G AF Samuels, Jack Shugart, Yin Yao Grados, Marco A. Willour, Virginia L. Bienvenu, O. Joseph Greenberg, Benjamin D. Knowles, James A. McCracken, James T. Rauch, Scott L. Murphy, Dennis L. Wang, Ying Pinto, Anthony Fyer, Abby J. Piacentini, John Pauls, David L. Cullen, Bernadette Rasmussen, Steven A. Hoehn-Saric, Rudolf Valle, David Liang, Kung-Yee Riddle, Mark A. Nestadt, Gerald TI Significant linkage to compulsive hoarding on chromosome 14 in families with obsessive-compulsive disorder: Results from the OCD collaborative genetics study SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID COMPLEX SEGREGATION ANALYSIS; PEDIATRIC PROBANDS; SYMPTOM DIMENSIONS; SCAN; HETEROGENEITY; PREDICTORS; PHENOTYPES; TRAITS; MODEL AB Objective: Individuals with obsessive-compulsive disorder (OCD) who have compulsive hoarding behavior are clinically different from other OCD-affected individuals. The objective of this study was to determine whether there are chromosomal regions specifically linked to compulsive hoarding behavior in families with obsessive-compulsive disorder. Methods: The authors used multipoint allele-sharing methods to assess for linkage in 219 multiplex OCD families collected as part of the OCD Collaborative Genetics Study. The authors treated compulsive hoarding as the phenotype of interest and also stratified families into those with and without two or more relatives affected with compulsive hoarding. Results: Using compulsive hoarding as the phenotype, there was suggestive linkage to chromosome 14 at marker D14S588 (Kong and Cox logarithm of the odds ratio [LOD] [KAC(all)=2.9]). In families with two or more hoarding relatives, there was significant linkage of OCD to chromosome 14 at marker C14S1937 (KAC(all)= 3.7), whereas in families with fewer than two hoarding relatives, there was suggestive linkage to chromosome 3 at marker D3S2398 (KAC(all)= 2.9). Conclusions: The findings suggest that a region on chromosome 14 is linked with compulsive hoarding behavior in families with OCD. C1 Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21287 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD 21287 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21287 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21287 USA. Brown Univ, Sch Med, Butler Hosp, Dept Psychiat & Human Behav, Providence, RI 02912 USA. Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. Univ Calif Los Angeles, Sch Med, Dept Psychiat & Biobehav Sci, Los Angeles, CA 90024 USA. Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA USA. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. RP Samuels, J (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, 600 N Wolfe St,Meyer 4-181, Baltimore, MD 21287 USA. EM jacks@jhmi.edu RI Piacentini, John/C-4645-2011; Liang, Kung-Yee/F-8299-2011; Pinto, Anthony/D-2718-2017; OI Pinto, Anthony/0000-0002-6078-7242; Samuels, Jack/0000-0002-6715-7905 FU NCRR NIH HHS [RR00052]; NIMH NIH HHS [K23-MH-64543, R01-MH-50214] NR 40 TC 85 Z9 90 U1 0 U2 7 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 MAR PY 2007 VL 164 IS 3 BP 493 EP 499 DI 10.1176/appi.ajp.164.3.493 PG 7 WC Psychiatry SC Psychiatry GA 141DN UT WOS:000244557800020 PM 17329475 ER PT J AU Gould, NF Holmes, MK Fantie, BD Luckenbaugh, DA Pine, DS Gould, TD Burgess, N Manji, HK Zarate, CA AF Gould, Neda F. Holmes, M. Kathleen Fantie, Bryan D. Luckenbaugh, David A. Pine, Daniel S. Gould, Todd D. Burgess, Neil Manji, Husseini K. Zarate, Carlos A., Jr. TI Performance on a virtual reality spatial memory navigation task in depressed patients SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 113th Annual Convention of the American-Psychological-Association CY AUG 18-21, 2005 CL Washington, DC SP Amer Psychol Assoc ID HIPPOCAMPAL VOLUME; BIPOLAR DISORDER; EPISODIC MEMORY AB Objective: Findings on spatial memory in depression have been inconsistent. A navigation task based on virtual reality may provide a more sensitive and consistent measure of the hippocampal-related spatial memory deficits associated with depression. Method: Performance on a novel virtual reality navigation task and a traditional measure of spatial memory was assessed in 30 depressed patients (unipolar and bipolar) and 19 normal comparison subjects. Results: Depressed patients performed significantly worse than comparison subjects on the virtual reality task, as assessed by the number of locations found in the virtual town. Between-group differences were not detected on the traditional measure. The navigation task showed high test-retest reliability. Conclusions: Depressed patients performed worse than healthy subjects on a novel spatial memory task. Virtual reality navigation may provide a consistent, sensitive measure of cognitive deficits in patients with affective disorders, representing a mechanism to study a putative endophenotype for hippocampal function. C1 NIMH, Mood & Anxiety Disorders Program, Mark O Hatfield Clin Res Ctr, Bethesda, MD 20892 USA. NIMH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. American Univ, Dept Psychol, Washington, DC 20016 USA. UCL, Inst Cognit Neurosci, London, England. UCL, Dept Anat, London, England. RP Zarate, CA (reprint author), NIMH, Mood & Anxiety Disorders Program, Mark O Hatfield Clin Res Ctr, 10 Ctr Dr, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov RI Burgess, Neil/B-2420-2009 OI Burgess, Neil/0000-0003-0646-6584 FU Intramural NIH HHS; Medical Research Council [G0501672] NR 16 TC 42 Z9 43 U1 3 U2 19 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 MAR PY 2007 VL 164 IS 3 BP 516 EP U6 DI 10.1176/appi.ajp.164.3.516 PG 4 WC Psychiatry SC Psychiatry GA 141DN UT WOS:000244557800023 PM 17329478 ER PT J AU Resnik, DB Wing, S AF Resnik, David B. Wing, Steven TI Lessons learned from the children's environmental exposure research study SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article AB We examined 5 different ethical concerns about the Children's Environmental Exposure Research Study and make some recommendations for future studies of exposure to hazardous environmental agents in the home. Researchers should seek community consultation and participation; make participants aware of all the risks associated with the research, including hazards discovered in the home and uncertainties about the risks of agents under investigation; and take steps to ensure that their studies will not have unfair representation of the poor or people of color. Researchers should also avoid even the appearance of a financial conflict of interest in studies that are likely to be controversial and make it clear to all parties that studies will not intentionally expose subjects to hazardous environmental agents. C1 NIEHS, NIH, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC USA. RP Resnik, DB (reprint author), NIEHS, NIH, Box 12233,Mail Drop NH06, Res Triangle Pk, NC 27709 USA. EM resnikd@niehs.nih.gov FU NIAAA NIH HHS [T15 AA149650]; NIEHS NIH HHS [R25 ES008206, R25-ES08206, R25 ES012079, R25-ES12079] NR 20 TC 5 Z9 5 U1 0 U2 3 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAR PY 2007 VL 97 IS 3 BP 414 EP 418 DI 10.2105/AJPH.2005.081729 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 142GD UT WOS:000244636500014 PM 17267718 ER PT J AU Vines, AI Baird, DD Stevens, J Hertz-Picciotto, I Light, KC McNeilly, M AF Vines, Anissa I. Baird, Donna Day Stevens, June Hertz-Picciotto, Irva Light, Kathleen C. McNeilly, Maya TI Associations of abdominal fat with perceived racism and passive emotional responses to racism in African American women SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Article ID ADIPOSE-TISSUE DISTRIBUTION; TO-HIP RATIO; MIDDLE-AGED MEN; BODY-FAT; PSYCHOSOCIAL FACTORS; INTERNALIZED RACISM; DIABETES-MELLITUS; UTERINE LEIOMYOMA; BLOOD-PRESSURE; CHRONIC STRESS AB Objectives. An excess in abdominal fat may predispose African American women to chronic health conditions such as diabetes and cardiovascular disease. Because stress may increase body fat in the center-body region, we used the waist-to-hip ratio (WHR) to examine associations between excess abdominal fat and perceived racism (a chronic stressor) and daily stress. Passive emotional responses to perceived racism, hypothesized to have particularly adverse effects, were also examined. Methods. We controlled for body mass index in multiple logistic regression models among 447 African American women who completed a telephone interview on perceived racism. Results. Passive emotional responses were not related to WHR (odds ratio [OR] = 1.4; 95% confidence interval [01 =0.8, 2.4). High perceived racism was associated with a low WHR in this population (OR =0.4; 95% Cl = 0.3, 0.8). However, high daily stress was related to a high WHR (OR = 2.7; 95% Cl = 1.1, 6.7). Conclusions. Findings support an association between daily stress and WHR but do not support our hypothesis that passive emotional responses to perceived racism increase abdominal fat. Further study of the stress physiology of perceived racism in African American women is warranted. C1 Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27516 USA. NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Sch Med, Dept Psychiat, Chapel Hill, NC 27516 USA. Duke Univ, Durham, NC 27706 USA. RP Vines, AI (reprint author), Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27516 USA. EM avines@email.unc.edu RI Baird, Donna/D-5214-2017 OI Baird, Donna/0000-0002-5544-2653 FU Intramural NIH HHS; NIMH NIH HHS [1-R03-MH61057-01] NR 40 TC 31 Z9 31 U1 1 U2 6 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD MAR PY 2007 VL 97 IS 3 BP 526 EP 530 DI 10.2105/AJPH.2005.080663 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 142GD UT WOS:000244636500031 PM 17267721 ER PT J AU Sampson, JH Raghavan, R Provenzale, JM Croteau, D Reardon, DA Coleman, RE Ponce, IR Pastan, I Puri, RK Pedain, C AF Sampson, John H. Raghavan, Raghu Provenzale, James M. Croteau, David Reardon, David A. Coleman, R. Edward Ponce, Inmaculada Rodriguez Pastan, Ira Puri, Raj K. Pedain, Christoph TI Induction of hyperintense signal on T2-weighted MR images correlates with infusion distribution from intracerebral convection-enhanced delivery of a tumor-targeted cytotoxin SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE brain; convection-enhanced delivery; drug delivery; glioma; MRI; oncology ID RECURRENT MALIGNANT GLIOMA; IL4-PSEUDOMONAS EXOTOXIN NBI-3001; NEUROTROPHIC FACTOR; BRAIN-TUMORS; MICROINFUSION; EFFICACY; PATIENT; PROTEIN; SAFETY; MODEL AB OBJECTIVE. Convection-enhanced delivery is a promising approach to intracerebral drug delivery in which a fluid pressure gradient is used to infuse therapeutic macromolecules through an indwelling catheter into the interstitial spaces of the brain. Our purpose was to test the hypothesis that hyperintense signal changes on T2-weighted images produced by such infusions can be used to track drug distribution. SUBJECTS AND METHODS. Seven adults with recurrent malignant glioma underwent concurrent intracerebral infusions of the tumor-targeted cytotoxin cintredekin besudotox and I-123-labeled human serum albumin. The agents were administered through a total of 18 catheters among the seven patients. Adequacy of distribution of drug was determined by evidence of distribution of I-123-labeled human serum albumin on SPECT images coregistered with MR images. Qualitative analysis was performed by three blinded observers. Quantitative analysis also was performed. RESULTS. Infusions into 12 catheters produced intraparenchymal distribution as seen on SPECT images, but infusions into six catheters did not. At qualitative assessment of signal changes on MR images, reviewers correctly predicted which catheters would produce extraparenchymal distribution and which catheters would produce parenchymal distribution. Of the 12 infusions that produced intraparenchymal distribution, four catheters had been placed in regions of relatively normal signal intensity and produced regions of newly increased signal intensity, the volume of which highly correlated with the volume and geometry of distribution on SPECT (r(2) = 0.9502). Eight infusions that produced intraparenchymal distribution were performed in regions of preexisting hyperintense signal. In these brains, additional signal changes were always produced, but quantitative correlations between areas of newly increased signal intensity and the volume and geometry of distribution on SPECT could not be established. CONCLUSION. Convection-enhanced infusions frequently do not provide intraparenchymal drug distribution, and these failures can be identified with MRI soon after infusion. When infusions are performed into regions of normal signal intensity, development of hyperintense signal change strongly correlates with the volume and geometry of distribution of infusate. C1 Duke Univ, Med Ctr, Dept Radiol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. Therataxis Inc, Baltimore, MD 21218 USA. NeoPharm Inc, Waukegan, IL 60085 USA. Brain LAB AG, Feldkirchen, Germany. NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. US FDA, Div Cellular & Gene Therapies, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Provenzale, JM (reprint author), Duke Univ, Med Ctr, Dept Radiol, Box 3808, Durham, NC 27710 USA. EM prove001@mc.duke.edu RI Coleman, Ralph/A-7865-2009 FU Intramural NIH HHS; NCI NIH HHS [R01 CA97611, 5P50-CA108786]; NCRR NIH HHS [K23 RR16065, S10 RR15697]; NINDS NIH HHS [2P50-NS20023] NR 35 TC 48 Z9 49 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 MAR PY 2007 VL 188 IS 3 BP 703 EP 709 DI 10.2214/AJR.06.0428 PG 7 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 156QE UT WOS:000245663300016 PM 17312057 ER PT J AU Nava, VE Cohen, P Bishop, M Fowler, D Jaffe, ES Ozdemirli, M AF Nava, Victor E. Cohen, Philip Bishop, Michael Fowler, Daniel Jaffe, Elaine S. Ozdemirli, Metin TI Enteropathy-type T-cell lymphoma after intestinal diffuse large B-cell lymphoma SO AMERICAN JOURNAL OF SURGICAL PATHOLOGY LA English DT Article DE enteropathy; lymphoma; T cell; B cell; celiac disease ID NON-HODGKINS-LYMPHOMA; CHRONIC LYMPHOCYTIC-LEUKEMIA; CELIAC-DISEASE; CLINICOPATHOLOGICAL ANALYSIS; GASTROINTESTINAL LYMPHOMA; MALIGNANT-LYMPHOMAS; HEPATITIS-B; FOLLOW-UP; PRECURSOR; RISK AB A rare case of enteropathy-type T-cell lymphoma (ETL) developed in a 47-year-old Chinese male 6 years after the diagnosis of diffuse large B-cell lymphoma (DLBCL) in the small intestine. The patient initially presented with vague gastrointestinal complaints. Work-up demonstrated an ulcerated mass in the small intestine. Partial resection and histologic examination of the intestine showed a DLBCL, positive for CD20 and Bcl-2, involving the jejunum transmurally. Further staging work-up demonstrated mesenteric and retroperitoneal lymphadenopathy, splenomegaly, and ascites. The patient was treated aggressively with radiotherapy, chemotherapy, and autologous bone marrow transplant, and complete remission was obtained. Six years later, the patient presented with diarrhea and dehydration. Clinical work-up revealed thickening of the small intestinal wall, and biopsies demonstrated ETL based on morphology, immunohistochemistry, and polymerase chain reaction analysis. Celiac disease was diagnosed concurrently. The patient responded to chemotherapy, received allogeneic peripheral blood stem cell transplantation from an HLA-matched sibling donor, and remains in remission. To our best knowledge, this is the first reported case of metachronous ETL and DLBCL. Possible associations between the 2 types of lymphoma are discussed. C1 Georgetown Univ Hosp, Dept Pathol, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. Georgetown Univ Hosp, Dept Oncol & Med, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. VA Affairs Med Ctr, Pathol & Lab Med Serv, Washington, DC USA. NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NCI, Hematopathol Sect, Bethesda, MD 20892 USA. RP Ozdemirli, M (reprint author), Georgetown Univ Hosp, Dept Pathol, Lombardi Comprehens Canc Ctr, 3900 Resevoir Rd NW, Washington, DC 20007 USA. EM mo7@gunet.georgetown.edu NR 29 TC 7 Z9 8 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0147-5185 J9 AM J SURG PATHOL JI Am. J. Surg. Pathol. PD MAR PY 2007 VL 31 IS 3 BP 476 EP 480 DI 10.1097/01.pas.0000213391.49698.57 PG 5 WC Pathology; Surgery SC Pathology; Surgery GA 141JN UT WOS:000244574700018 PM 17325491 ER PT J AU Mengel, M Chapman, JR Cosio, FG Cavaille-Coll, MW Haller, H Halloran, PF Kirk, AD Mihatsch, MJ Nankivell, BJ Racusen, LC Roberts, IS Rush, DN Schwarz, A Seron, D Stegall, MD Colvin, RB AF Mengel, M. Chapman, J. R. Cosio, F. G. Cavaille-Coll, M. W. Haller, H. Halloran, P. F. Kirk, A. D. Mihatsch, M. J. Nankivell, B. J. Racusen, L. C. Roberts, I. S. Rush, D. N. Schwarz, A. Seron, D. Stegall, M. D. Colvin, R. B. TI Protocol biopsies in renal transplantation: Insights into patient management and pathogenesis SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Editorial Material DE biopsy; kidney; protocol; rejection; subclinical; surrogate ID CHRONIC ALLOGRAFT NEPHROPATHY; EARLY CYCLOSPORINE WITHDRAWAL; SUBCLINICAL REJECTION; KIDNEY-TRANSPLANTATION; DIAGNOSIS; CRITERIA; INJURY; CELLS AB A 1-day symposium on the application of protocol biopsies in renal transplantation was held in Boston, 21 July 2006. Representatives from centers with extensive experience in the use of protocol biopsies for routine patient care and research reported results on the pathological findings and their value in patient management. The consensus was that protocol biopsies, in experienced hands, are a safe and valuable means of detecting subclinical disease that can benefit from modification of therapy. Furthermore, molecular studies reveal evidence of activity or progression not readily appreciated by histological techniques. Wider application is expected in multicenter clinical trials to predict and validate outcomes. The principal barrier to wider use of protocol biopsies is knowledge of the benefits of intervention. C1 Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Hannover Med Sch, Inst Pathol, D-3000 Hannover, Germany. Westmead Hosp, Ctr Transplant Res & Renal Res, Sydney, NSW, Australia. Mayo Clin & Mayo Fdn, Div Nephrol & Hypertens, Rochester, MN 55905 USA. US FDA, CDER, Div Special Pathogen & Transplantat Prod, Rockville, MD 20857 USA. Hannover Med Sch, Dept Nephrol, D-3000 Hannover, Germany. Univ Alberta, Alberta Transplant Appl Genom Ctr, Edmonton, AB, Canada. Natl Inst Digest & Kidney Dis, Transplantat Branch, NIH, Bethesda, MD USA. Univ Basel, Inst Pathol, CH-4003 Basel, Switzerland. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. Oxford Radcliffe Hosp, Dept Pathol, Oxford, England. Univ Manitoba, Dept Nephrol, Winnipeg, MB, Canada. Univ Bellvitge, Dept Nephrol, Hosp, Barcelona, Spain. Mayo Clin & Mayo Fdn, Dept Surg, Rochester, MN 55905 USA. RP Colvin, RB (reprint author), Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA. EM Colvin@helix.mgh.harvard.edu RI Kirk, Allan/B-6905-2012; Halloran, Philip/J-1390-2012 OI Halloran, Philip/0000-0003-1371-1947 NR 26 TC 64 Z9 66 U1 0 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAR PY 2007 VL 7 IS 3 BP 512 EP 517 DI 10.1111/j.1600-6143.2006.01677.x PG 6 WC Surgery; Transplantation SC Surgery; Transplantation GA 143JD UT WOS:000244715800006 PM 17250556 ER PT J AU Solez, K Colvin, RB Racusen, LC Sis, B Halloran, PF Birk, PE Campbell, PM Cascalho, M Collins, AB Demetris, AJ Drachenberg, CB Gibson, IW Grimm, PC Haas, M Lerut, E Liapis, H Mannon, RB Marcus, PB Mengel, M Mihatsch, MJ Nankivell, BJ Nickeleit, V Papadimitriou, JC Platt, JL Randhawa, P Roberts, I Salinas-Madriga, L Salomon, DR Seron, D Sheaff, M Weening, JJ AF Solez, K. Colvin, R. B. Racusen, L. C. Sis, B. Halloran, P. F. Birk, P. E. Campbell, P. M. Cascalho, M. Collins, A. B. Demetris, A. J. Drachenberg, C. B. Gibson, I. W. Grimm, P. C. Haas, M. Lerut, E. Liapis, H. Mannon, R. B. Marcus, P. B. Mengel, M. Mihatsch, M. J. Nankivell, B. J. Nickeleit, V. Papadimitriou, J. C. Platt, J. L. Randhawa, P. Roberts, I. Salinas-Madriga, L. Salomon, D. R. Seron, D. Sheaff, M. Weening, J. J. TI Banff '05 Meeting report: Differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy ('CAN') SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Editorial Material DE Banff classification; central slide review; scoring ID INTERTUBULAR CAPILLARY CHANGES; INCOMPATIBLE RENAL-ALLOGRAFTS; POSITIVE CROSS-MATCH; TRANSPLANT GLOMERULOPATHY; PERITUBULAR CAPILLARIES; C4D DEPOSITS; HISTOLOGIC-FINDINGS; CYCLOSPORINE NEPHROTOXICITY; KIDNEY-TRANSPLANTATION; HUMORAL REJECTION AB The 8th Banff Conference on Allograft Pathology was held in Edmonton, Canada, 15-21 July 2005. Major outcomes included the elimination of the non-specific term 'chronic allograft nephropathy' (CAN) from the Banff classification for kidney allograft pathology, and the recognition of the entity of chronic antibody-mediated rejection. Participation of B cells in allograft rejection and genomics markers of rejection were also major subjects addressed by the conference. C1 Univ Alberta, Edmonton, AB, Canada. Massachusetts Gen Hosp, Boston, MA 02114 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. Univ Manitoba, Winnipeg, MB, Canada. Mayo Clin, Rochester, MN USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Maryland, Baltimore, MD 21201 USA. Univ Calif San Diego, La Jolla, CA 92093 USA. Univ Hosp, Louvain, Belgium. Washington Univ, Sch Med, St Louis, MO USA. NIDDK, NIH, Bethesda, MD 20892 USA. Methodist Hlth Syst, Dallas, TX USA. Hannover Med Sch, Inst Pathol, Hannover, Germany. Univ Basel, Basel, Switzerland. Univ Sydney, Sydney, NSW 2006, Australia. Univ N Carolina, Chapel Hill, NC USA. John Radcliffe Hosp, Dept Cellular Pathol, Oxford OX3 9DU, England. St Louis Univ, Hlth Sci Ctr, St Louis, MO 63103 USA. Scripps Inst, La Jolla, CA USA. Univ Barcelona, Barcelona, Spain. Royal London Hosp, London E1 1BB, England. Univ Amsterdam, Amsterdam, Netherlands. RP Solez, K (reprint author), Univ Alberta, Edmonton, AB, Canada. EM Kim.Solez@ualberta.ca RI Salomon, Daniel/E-9380-2012; Halloran, Philip/J-1390-2012; OI Halloran, Philip/0000-0003-1371-1947; Cascalho, Marilia/0000-0002-2695-3921 NR 54 TC 662 Z9 718 U1 0 U2 9 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAR PY 2007 VL 7 IS 3 BP 518 EP 526 DI 10.1111/j.1600-6143.2006.01688.x PG 9 WC Surgery; Transplantation SC Surgery; Transplantation GA 143JD UT WOS:000244715800007 PM 17352710 ER PT J AU Dharnidharka, VR Agodoa, LY Abbott, KC AF Dharnidharka, V. R. Agodoa, L. Y. Abbott, K. C. TI Risk factors for hospitalization for bacterial or viral infection in renal transplant recipients - An analysis of USRDS data SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article; Proceedings Paper CT 3rd Annual Congress of the International-Pediatric-Transplant-Association CY AUG 06-09, 2005 CL Innsbruck, AUSTRIA SP Int Pediat Transplant Assoc DE bacterial; infection; kidney transplantation; pediatrics; viral infection ID UNITED-STATES; ALLOGRAFT-REJECTION; CYTOMEGALOVIRUS-INFECTION; LIVER-TRANSPLANTATION; SURVIVAL; COMPLICATIONS; KIDNEY; SEPTICEMIA; REDUCTION; DISEASE AB We previously showed that children are more likely to develop viral infections post-kidney transplant while adults are more likely to develop bacterial infections. In this study we determined the overall risk factors for hospitalization with either a bacterial (HBI) or a viral infection (HVI). We analyzed data from 28 924 United States Renal Data System (USRDS) Medicare primary renal transplant recipients from January 1996 to July 2000, for adjusted hazard ratio (AHR) for HBI or HVI in the first 3 years posttransplant. For HVI, significantly higher AHR was seen with (a) recipient age < 18 years (AHR 1.57, 95% CI = 1.02, 2.42), (b) donor CMV positive (AHR 1.72, 95% CI = 1.34, 2.19). For HBI, significantly higher AHR was seen with (i) delayed graft function (AHR 1.28, 95% CI = 1.076, 1.518), (ii) primary renal diagnosis chronic pyelonephritis (AHR 1.71, 95% CI = 1.18, 2.49); (iii) associated pretransplant diabetes (AHR 1.80, 95% CI = 1.53, 2.12); (iv) female gender AHR 1.63, 95% CI = 1.41, 1.88). Lower AHR for HVI was seen in CMV-positive recipients and for HBI with more recent year of transplant. Other covariates did not impact significantly in either HVI or HBI. C1 Univ Florida, Coll Med, Div Pediat Nephrol, Gainesville, FL 32611 USA. NIDDK, NIH, Bethesda, MD USA. Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Dharnidharka, VR (reprint author), Univ Florida, Coll Med, Div Pediat Nephrol, Gainesville, FL 32611 USA. EM vikasmd@ufl.edu OI Abbott, Kevin/0000-0003-2111-7112 FU NIDDK NIH HHS [1R02 DK 069535] NR 36 TC 34 Z9 34 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAR PY 2007 VL 7 IS 3 BP 653 EP 661 DI 10.1111/j.1600-6143.2006.01674.x PG 9 WC Surgery; Transplantation SC Surgery; Transplantation GA 143JD UT WOS:000244715800022 PM 17250559 ER PT J AU Palmer, SM Klimecki, W Yu, L Reinsmoen, NL Snyder, LD Ganous, TM Burch, L Schwartz, DA AF Palmer, S. M. Klimecki, W. Yu, L. Reinsmoen, N. L. Snyder, L. D. Ganous, T. M. Burch, L. Schwartz, D. A. TI Genetic regulation of rejection and survival following human lung transplantation by the innate immune receptor CD14 SO AMERICAN JOURNAL OF TRANSPLANTATION LA English DT Article DE allograft rejection; CD14; innateimmunity; lung transplant ID ALLOGRAFT-REJECTION; WORKING FORMULATION; POLYMORPHISM; PROTEIN AB We have developed the hypothesis that genetic polymorphisms which alter the expression or function of innate immune receptors contribute to the marked interindividual differences in the onset and severity of lung transplant rejection. In this analysis, we considered the effects of a common promotor polymorphism of the lipopolysaccharide receptor CD14 associated with increased transcriptional activity upon the development of posttransplant rejection and graft survival. Genotyping was performed in 226 lung transplant recipients well characterized with regards to clinical outcomes. An earlier onset of acute rejection, bronchiolitis obliterans syndrome (BOS) and worse posttransplant graft survival due to greater BOS related deaths was evident in patients with the CD14 -159 TT genotype (TT). The adverse effect upon graft survival of the TT genotype remained significant in a multivariate Cox model (Hazard Ratio 1.65, 95% CI, 1.03-2.64, p-value = 0.04) after adjusting for other important covariates. Furthermore, TT patients have significantly greater sCD14, TNF-alpha and IFN-gamma in the peripheral blood implying a heightened state of innate immune activation drives the development of increased post-transplant rejection. Inhibition of innate immune activation through CD14 represents a novel and potentially important therapeutic target to prevent post-transplant rejection and improve outcomes after human lung transplantation. C1 Univ Arizona, Dept Med, Tucson, AZ 85721 USA. Univ Arizona, Arizona Resp Ctr, Tucson, AZ USA. Duke Univ, Med Ctr, Durham, NC USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Palmer, SM (reprint author), Univ Arizona, Dept Med, Tucson, AZ 85721 USA. EM Palme002@mc.duke.edu FU Intramural NIH HHS; NHLBI NIH HHS [HL 69978] NR 18 TC 42 Z9 43 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1600-6135 J9 AM J TRANSPLANT JI Am. J. Transplant. PD MAR PY 2007 VL 7 IS 3 BP 693 EP 699 DI 10.1111/j.1600-6143.2007.01669.x PG 7 WC Surgery; Transplantation SC Surgery; Transplantation GA 143JD UT WOS:000244715800028 PM 17217435 ER PT J AU Pfeiffer, JBR Mevissen, M Steiner, A Portier, CJ Meylan, M AF Pfeiffer, Julia B. R. Mevissen, Meike Steiner, Adrian Portier, Christopher J. Meylan, Mireille TI In vitro effects of bethanechol on specimens of intestinal smooth muscle obtained from the duodenum and jejunum of healthy dairy cows SO AMERICAN JOURNAL OF VETERINARY RESEARCH LA English DT Article ID MUSCARINIC RECEPTOR SUBTYPES; GUINEA-PIG ILEUM; ACETYLCHOLINE-RECEPTORS; KNOCKOUT MICE; GASTROINTESTINAL MOTILITY; FUNCTIONAL-CHARACTERIZATION; MYOELECTRIC ACTIVITY; PERIPHERAL-TISSUES; ABOMASAL ANTRUM; VAS-DEFERENS AB Objective-To describe the in vitro effects of bethanechol on contractility of smooth muscle preparations from the small intestines of healthy cows and define the muscarinic receptor subtypes involved in mediating contraction. Sample Population-Tissue samples from the duodenum and jejunum collected immediately after slaughter of 40 healthy cows. Procedures-Cumulative concentration-response curves were determined for the muscarinic receptor agonist bethanechol with or without prior incubation with subtype-specific receptor antagonists in an organ bath. Effects of bethanechol and antagonists and the influence of intestinal location on basal tone, maximal amplitude (A(max)), and area under the curve (AUC) were evaluated. Results-Bethanechol induced a significant, concentration-dependent increase in all preparations and variables. The effect of bethanechol was more pronounced in jejunal than in duodenal samples and in circular than in longitudinal preparations. Significant inhibition of the effects of bethanechol was observed after prior incubation with muscarinic receptor subtype M-3 antagonists (more commonly for basal tone than for A(max) and AUC). The M-2 receptor antagonists partly inhibited the response to bethanechol, especially for basal tone. The M-3 receptor antagonists were generally more potent than the M-2 receptor antagonists. In a protection experiment, an M-3 receptor antagonist was less potent than when used in combination with an M-2 receptor antagonist. Receptor antagonists for M, and M, did not affect contractility variables, Conclusions and Clinical Relevance-Bethanechol acting on muscarinic receptor subtypes M-2 and M-3 may be of clinical use as a prokinetic drug for motility disorders of the duodenum and jejunum in dairy cows. C1 Univ Bern, Clin Ruminants, Vetsuisse Fac, CH-3012 Bern, Switzerland. Univ Bern, Div Vet Pharmacol & Toxicol, Vetsuisse Fac, CH-3012 Bern, Switzerland. NIEHS, Lab Mol Toxicol Environm Syst Biol & Risk Assessm, Res Triangle Pk, NC 27709 USA. RP Meylan, M (reprint author), Univ Bern, Clin Ruminants, Vetsuisse Fac, CH-3012 Bern, Switzerland. RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 FU Intramural NIH HHS [Z01 ES048002-20] NR 63 TC 6 Z9 6 U1 0 U2 4 PU AMER VETERINARY MEDICAL ASSOC PI SCHAUMBURG PA 1931 N MEACHAM RD SUITE 100, SCHAUMBURG, IL 60173-4360 USA SN 0002-9645 J9 AM J VET RES JI Am. J. Vet. Res. PD MAR PY 2007 VL 68 IS 3 BP 313 EP 322 DI 10.2460/ajvr.68.3.313 PG 10 WC Veterinary Sciences SC Veterinary Sciences GA 142CD UT WOS:000244625700015 PM 17331022 ER PT J AU Belfort-Neto, R Nussenblatt, V Rizzo, L Muccioli, C Silveira, C Nussenblatt, R Khan, A Sibley, LD Belfort, R AF Belfort-Neto, Rubens Nussenblatt, Veronique Rizzo, Luiz Muccioli, Cristina Silveira, Claudio Nussenblatt, Robert Khan, Assis Sibley, L. David Belfort, Rubens, Jr. TI High prevalence of unusual genotypes of Toxoplasma gondii infection in pork meat samples from Erechim, Southern Brazil SO ANAIS DA ACADEMIA BRASILEIRA DE CIENCIAS LA English DT Article DE ocular toxoplasmosis; Toxoplasma gondii; genotypes ID OCULAR TOXOPLASMOSIS; STRAINS; DISEASE AB Toxoplasmosis is the most common cause of infectious uveitis in Brazil, with a higher frequency in the South of the country. We have collected samples from porcine tongue and diaphragm obtained in both large and small abattoirs and used molecular biological technique to determine the prevalence of infection and RFLP analysis to type the parasites. Seventeen out of 50 ( 34%) samples from the diaphragm and 33 out of 50 ( 66%) samples from the tongue demonstrated a positive PCR reaction for T. gondii and restriction analysis of four of the positive samples revealed that all had a type I genotype at SAG2. However, when other unlinked loci were analyzed, these strains had a type III genotype at markers BTUB, SAG3, and GRA6. One of the strains ( 8T) had a type II allele at SAG3, indicating it has a combination of alleles normally seen in the clonal lineages. Our sampling indicates a high prevalence of infection and suggests that unusual genotypes of T. gondii are found in Brazil even among domesticated pigs. C1 Univ Fed Sao Paulo, Dept Oftalmol, BR-04023062 Sao Paulo, Brazil. Univ Maryland, Sch Med, Baltimore, MD 21201 USA. Univ Sao Paulo, Dept Imunol, ICB, BR-05508900 Sao Paulo, Brazil. Clin Silveira, BR-99700000 Erechim, RS, Brazil. NEI, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Mol Biol, St Louis, MO 63110 USA. RP Belfort-Neto, R (reprint author), Univ Fed Sao Paulo, Dept Oftalmol, Rua Botucatu 820, BR-04023062 Sao Paulo, Brazil. EM epm@belfort.med.br RI Sibley, L. David/C-4616-2008; Belfort Jr, Rubens/E-2252-2012; Muccioli, Cristina/C-3419-2013 OI Belfort Jr, Rubens/0000-0002-8422-3898; FU NIAID NIH HHS [R01 AI059176] NR 13 TC 40 Z9 40 U1 0 U2 3 PU ACAD BRASILEIRA DE CIENCIAS PI RIO JANEIRO PA RUA ANFILOFIO DE CARVALHO, 29, 3 ANDAR, 20030-060 RIO JANEIRO, BRAZIL SN 0001-3765 J9 AN ACAD BRAS CIENC JI An. Acad. Bras. Cienc. PD MAR PY 2007 VL 79 IS 1 BP 111 EP 114 DI 10.1590/S0001-37652007000100013 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 153MP UT WOS:000245439900013 PM 17401480 ER PT J AU Bi, XH Yang, X Bostrom, MPG Bartusik, D Ramaswamy, S Fishbein, KW Spencer, RG Camacho, NP AF Bi, Xiaohong Yang, Xu Bostrom, Mathias P. G. Bartusik, Dorota Ramaswamy, Sharan Fishbein, Kenneth W. Spencer, Richard G. Camacho, Nancy Pleshko TI Fourier transform infrared imaging and MR microscopy studies detect compositional and structural changes in cartilage in a rabbit model of osteoarthritis SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article; Proceedings Paper CT SPEC 2006 CY MAY 20-24, 2006 CL Heidelberg, GERMANY DE infrared spectroscopy; magnetic resonance imaging; osteoarthritis; cartilage; collagen; proteoglycan ID MAGNETIC-RESONANCE MICROSCOPY; ANTERIOR CRUCIATE LIGAMENT; ARTICULAR-CARTILAGE; COLLAGEN DEGRADATION; CONFORMATIONAL ORDER; TRANSECTION MODEL; HYALINE CARTILAGE; T-2 RELAXATION; IN-VITRO; MU-MRI AB Assessment of subtle changes in proteoglycan (PG) and collagen, the primary macromolecular components of cartilage, which is critical for diagnosis of the early stages of osteoarthritis (OA), has so far remained a challenge. In this study we induced osteoarthritic cartilage changes in a rabbit model by ligament transection and medial meniscectomy and monitored disease progression by infrared fiber optic probe (IFOP) spectroscopy, Fourier transform infrared imaging spectroscopy (FT-IRIS), and magnetic resonance imaging (MRI) microscopy. IFOP studies combined with chemometric partial least-squares analysis enabled us to monitor progressive cartilage surface changes from two to twelve weeks post-surgery. FT-IRIS studies of histological sections of femoral condyle cartilage revealed that compared with control cartilage the OA cartilage had significantly reduced PG content 2 and 4 weeks post-surgery, collagen fibril orientation changes 2 and 4 weeks post-surgery, and changes in collagen integrity 2 and 10 weeks post-surgery, but no significant changes in collagen content at any time. MR microscopy studies revealed reduced fixed charge density (FCD), indicative of reduced PG content, in the OA cartilage, compared with controls, 4 weeks post-surgery. A non-significant trend toward higher apparent MT exchange rate, k(m), was also found in the OA cartilage at this time point, suggesting changes in collagen structural features. These two MR findings for FCD and k(m) parallel the FT-IRIS findings of reduced PG content and altered collagen integrity, respectively. MR microscopy studies of the cartilage at the 12-week time point also found a trend toward longer T-2 values and reduced anisotropy in the deep zone of the OA cartilage, consistent with increased hydration and less ordered collagen. These studies reveal that FT-IRIS and MR microscopy provide complementary data on compositional changes in articular cartilage in the early stages of osteoarthritic degradation. C1 Hosp Special Surg, Div Res, Musculoskeletal Imaging & Spect Lab, New York, NY 10021 USA. NIA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Camacho, NP (reprint author), Hosp Special Surg, Div Res, Musculoskeletal Imaging & Spect Lab, 535 E 70th St, New York, NY 10021 USA. EM camachon@hss.edu OI Fishbein, Kenneth/0000-0002-6353-4603 FU Intramural NIH HHS; NIAMS NIH HHS [AR46121, P30 AR046121, P30 AR046121-06A1]; NIBIB NIH HHS [EB000744, R01 EB000744, R01 EB000744-01, R01 EB000744-03] NR 58 TC 52 Z9 54 U1 0 U2 6 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD MAR PY 2007 VL 387 IS 5 BP 1601 EP 1612 DI 10.1007/s00216-006-0910-7 PG 12 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 138AO UT WOS:000244335000006 PM 17143596 ER PT J AU Panyutin, IG Panyutin, IV Demidov, VV AF Panyutin, Igor G. Panyutin, Irina V. Demidov, Vadim V. TI Targeting linear duplex DNA with mixed-base peptide nucleic acid oligomers facilitated by bisPNA openers SO ANALYTICAL BIOCHEMISTRY LA English DT Editorial Material ID STRANDED-DNA; PNA; CLEAVAGE; CYTOSINE; LOOP C1 Boston Univ, Ctr Adv Biotechnol, Boston, MA 02215 USA. NIH, Dept Nucl Med, Ctr Clin, Bethesda, MD 20892 USA. RP Demidov, VV (reprint author), Boston Univ, Ctr Adv Biotechnol, Boston, MA 02215 USA. EM vvd@bu.edu NR 13 TC 6 Z9 8 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD MAR 1 PY 2007 VL 362 IS 1 BP 145 EP 147 DI 10.1016/j.ab.2006.11.014 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 137AD UT WOS:000244264300018 PM 17184722 ER PT J AU Yamada, S Itoh, H Uwabe, C Fujihara, S Nishibori, C Wada, M Fujii, S Shiota, K AF Yamada, Shigehito Itoh, Hitoshi Uwabe, Chigako Fujihara, Sachiko Nishibori, Chiaki Wada, Masaaki Fujii, Shingo Shiota, Kohei TI Computerized three-dimensional analysis of the heart and great vessels in normal and holoprosencephalic human embryos SO ANATOMICAL RECORD-ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY LA English DT Article DE three-dimensional reconstruction; organogenesis; human embryo; holoprosencephaly; heart defect ID CARDIAC DEVELOPMENT; OUTFLOW TRACT; MALFORMATIONS; RECONSTRUCTION; PERSPECTIVES; MICROSCOPY; SEQUENCE; ARTERIES; DEFECTS AB The developing heart and great vessels undergo drastic morphogenetic changes during the embryonic period. To analyze the normal and abnormal development of these organs, it is essential to visualize their structures in three and four dimensions, including the changes occurring with time. We have reconstructed the luminal structure of the hearts and great vessels of staged human embryos from serial histological sections to demonstrate their sequential morphological changes in three dimensions. The detailed structures of the embryonic heart and major arteries in normal and holoprosencephalic (HPE) human embryos could be reconstructed and visualized, and anatomical structures were analyzed using 3D images. By 3D analysis, cardiac anomalies such as double-outlet right ventricle and malrotation of the heart tube were identified in HPE embryos, which were not easily diagnosed by histological observation. Reconstruction and analysis of 3D images are useful for the study of anatomical structures of developing embryos and for identifying their abnormalities. C1 Kyoto Univ, Grad Sch Med, Congenital Anomaly Res Ctr, Kyoto 6068501, Japan. Kyoto Univ, Grad Sch Med, Dept Gynecol & Obstet, Kyoto 6068501, Japan. NHLBI, Lab Dev Biol, NIH, Bethesda, MD 20892 USA. Nara Womens Univ, Grad Sch Humanities & Sci, Nara 630, Japan. Nara Womens Univ, Dept Informat & Comp Sci, Nara 630, Japan. Kyoto Univ, Grad Sch Med, Dept Anat & Dev Biol, Kyoto 6068501, Japan. RP Yamada, S (reprint author), Kyoto Univ, Grad Sch Med, Congenital Anomaly Res Ctr, Kyoto 6068501, Japan. EM shyamada@cac.med.kyoto-u.ac.jp NR 39 TC 5 Z9 8 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA J9 ANAT REC JI Anat. Rec. PD MAR PY 2007 VL 290 IS 3 BP 259 EP 267 DI 10.1002/ar.20427 PG 9 WC Anatomy & Morphology SC Anatomy & Morphology GA 150RD UT WOS:000245233100005 PM 17525942 ER PT J AU Zheng, P AF Zheng, P. TI Effects of in vitro maturation of monkey oocytes on their developmental capacity SO ANIMAL REPRODUCTION SCIENCE LA English DT Review DE rhesus monkey; oocyte in vitro maturation; embryo development ID PREIMPLANTATION STAGE EMBRYOS; ENCLOSED MOUSE OOCYTES; AMINO-ACID-TRANSPORT; ADULT RHESUS-MONKEYS; BOVINE OOCYTES; TRANSCRIPTIONAL ACTIVITY; GENE-EXPRESSION; GLUCOSE-TRANSPORTER; MEIOTIC MATURATION; CATTLE EMBRYOS AB The study of in vitro maturation (IVM) of rhesus monkey oocytes has important implications for biomedical research and human infertility treatment. In vitro-matured rhesus monkey oocytes show much less developmental potential than IVM oocytes of other species. Since about 1980 when rhesus monkey IVM, in vitro fertilization (IVF) and in vitro embryo culture (IVC) systems were established, numerous efforts have been made to improve the developmental competence of oocytes and to understand the mechanisms regulating oocyte maturation. This review describes recent progress in this area, particularly the effects of factors such as steroid hormones, energy substrates, amino acids, ovarian follicle status, maternal age and breeding season on the developmental competence, gene expression patterns and genome integrity of rhesus IVM oocytes. (c) 2006 Elsevier B.V. All rights reserved. C1 NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Zheng, P (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bldg 50,Rm 3132,9000 Rockville Pike, Bethesda, MD 20892 USA. EM zhengp@mail.nih.gov FU NCRR NIH HHS [R24 RR015253, RR15253] NR 124 TC 13 Z9 14 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-4320 J9 ANIM REPROD SCI JI Anim. Reprod. Sci. PD MAR PY 2007 VL 98 IS 1-2 BP 56 EP 71 DI 10.1016/j.anireprosci.2006.10.005 PG 16 WC Agriculture, Dairy & Animal Science; Reproductive Biology SC Agriculture; Reproductive Biology GA 144NS UT WOS:000244803700005 PM 17081707 ER PT J AU Farin, CE Rodriguez, KF Alexander, JE Hockney, JE Herrick, JR Kennedy-Stoskopf, S AF Farin, C. E. Rodriguez, K. F. Alexander, J. E. Hockney, J. E. Herrick, J. R. Kennedy-Stoskopf, S. TI The role of transcription in EGF- and FSH-mediated oocyte maturation in vitro SO ANIMAL REPRODUCTION SCIENCE LA English DT Article DE meiosis; FSH; EGF; oocyte maturation; gene transcription ID EPIDERMAL-GROWTH-FACTOR; FOLLICLE-STIMULATING-HORMONE; GERMINAL VESICLE BREAKDOWN; ACTIVATED PROTEIN-KINASE; CUMULUS CELL COMPLEX; EARLY EMBRYO DEVELOPMENT; BOVINE OOCYTES; DEVELOPMENTAL COMPETENCE; MOUSE OOCYTES; GRANULOSA-CELLS AB Understanding mechanisms responsible for meiotic resumption in mammalian oocytes is critical for the identification of strategies to enhance developmental competence of in vitro-matured oocytes. Improvement of in vitro oocyte maturation systems is dependent on a better understanding of mechanisms that regulate oocyte maturation both in vivo and in vitro as well as on the identification of methods to manipulate the meiotic progression of oocytes matured in vitro in a physiological manner. The purpose of this review is twofold: first, to examine the mechanisms that underlie the acquisition of oocyte developmental competence and regulation of oocyte maturation in vivo and in vitro; second, to present data examining the role of transcription in mediating the ability of EGF and FSH to induce oocyte maturation in vitro. Results presented support the conclusions that (1) EGF-induced oocyte maturation does not require nascent gene transcription in both mice and domestic cats; (2) FSH requires gene transcription to induce oocyte maturation in both species; (3) EGF must be present in the maturation medium to optimize the effectiveness of FSH to promote oocyte maturation; (4) the mechanism used by FSH to induce oocyte maturation in vitro appears to predominate over that used by EGF when both EGF and FSH are present in maturation medium used for either murine or feline cumulus oocyte complexes. (c) 2006 Elsevier B.V. All rights reserved. C1 N Carolina State Univ, Dept Anim Sci, Raleigh, NC 27695 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Cincinnati Zoo, Ctr Conservat & Res Endangered Wildlife, Cincinnati, OH USA. N Carolina State Univ, Dept Populat Hlth & Pathobiol, Raleigh, NC 27695 USA. RP Farin, CE (reprint author), N Carolina State Univ, Dept Anim Sci, Box 7621,231 B Polk Hall, Raleigh, NC 27695 USA. EM Char_Farin@ncsu.edu OI Herrick, Jason/0000-0002-1123-0958 FU NICHD NIH HHS [R03 HD043875-02, 1 R03 HD043875-01, R03 HD043875, R03 HD043875-01] NR 96 TC 22 Z9 22 U1 1 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-4320 J9 ANIM REPROD SCI JI Anim. Reprod. Sci. PD MAR PY 2007 VL 98 IS 1-2 BP 97 EP 112 DI 10.1016/j.anireprosci.2006.10.007 PG 16 WC Agriculture, Dairy & Animal Science; Reproductive Biology SC Agriculture; Reproductive Biology GA 144NS UT WOS:000244803700007 PM 17101244 ER PT J AU Van Waes, C AF Van Waes, Carter TI Genomic and proteomic markers of response in clinical investigation of molecularly targeted therapy. SO ANNALS OF CLINICAL AND LABORATORY SCIENCE LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSN CLINICAL SCIENTISTS PI MIDDLEBURY PA PO BOX 1287, MIDDLEBURY, VT 05753 USA SN 0091-7370 J9 ANN CLIN LAB SCI JI Ann. Clin. Lab. Sci. PD SPR PY 2007 VL 37 IS 2 BP 195 EP 195 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 164WE UT WOS:000246264700017 ER PT J AU Snyder, JW AF Snyder, Jack W. TI Can we better define roles for clinical laboratory professionals in radiation event medical management? SO ANNALS OF CLINICAL AND LABORATORY SCIENCE LA English DT Meeting Abstract C1 Natl Lib Med, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSN CLINICAL SCIENTISTS PI MIDDLEBURY PA PO BOX 1287, MIDDLEBURY, VT 05753 USA SN 0091-7370 J9 ANN CLIN LAB SCI JI Ann. Clin. Lab. Sci. PD SPR PY 2007 VL 37 IS 2 BP 200 EP 201 PG 2 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 164WE UT WOS:000246264700034 ER PT J AU Kasprzak, KS Salnikow, K Kaczmarek, M AF Kasprzak, Kazimierz S. Salnikow, Konstantin Kaczmarek, Monika TI Role of ascorbic acid in the toxicity of metals. SO ANNALS OF CLINICAL AND LABORATORY SCIENCE LA English DT Meeting Abstract C1 NCI, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ASSN CLINICAL SCIENTISTS PI MIDDLEBURY PA PO BOX 1287, MIDDLEBURY, VT 05753 USA SN 0091-7370 J9 ANN CLIN LAB SCI JI Ann. Clin. Lab. Sci. PD SPR PY 2007 VL 37 IS 2 BP 206 EP 206 PG 1 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 164WE UT WOS:000246264700054 ER PT J AU Nguyen, RHN Wilcox, AJ Baird, DD AF Nguyen, Ruby H. N. Wilcox, Allen J. Baird, Donna D. TI Can men provide accurate confounder data about their partners for time-to-pregnancy studies? SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE men; confounding factors; reproducibility of results; self-disclosure; fertility ID SURROGATE INFORMATION; CIGARETTE-SMOKING; FERTILITY; RELIABILITY; EXPOSURE; WOMEN; PESTICIDES; WORKERS AB PURPOSE: In studies of time to pregnancy (TTP), women's health-related behaviors may confound other determinants of TTP. In many occupation-based TTP studies, all information is collected through the male partner. There are no data on the validity of the man's report of his partner's fertility-related behavior. METHODS: We studied 202 men and their partners from the most recent pregnancy. Validity of men's reporting on their partner's use of oral contraceptives (OCS) as the last birth control method and her smoking around the beginning of TTP and agreement of coital frequency were assessed. RESULTS: The index pregnancy was an average of 6 years before interview. Overall percentage of agreement was 81% for OCs as the last contraceptive method (kappa agreement = 0.44). Ninety-five percent of men accurately reported whether their partner smoked (kappa agreement = 0.83). Among couples agreeing on smoking status, 90% agreed on the categorical cigarette number (weighted kappa = 0.60). Reporting accuracy was not influenced by men's characteristics. Median coital frequency was eight times per month, with a weighted kappa = 0.34 after categorization. CONCLUSIONS: Our data generally justify the use of men's reports of potential confounders in TTP studies when women's reports are not available. C1 Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. RP Nguyen, RHN (reprint author), 111 TW Alexander Dr,POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27703 USA. EM nguyen5@niehs.nih.gov RI Baird, Donna/D-5214-2017; OI Baird, Donna/0000-0002-5544-2653; Wilcox, Allen/0000-0002-3376-1311 NR 22 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 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD MAR PY 2007 VL 17 IS 3 BP 186 EP 190 DI 10.1016/j.annepidem.2006.07.007 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 144SW UT WOS:000244817600004 PM 17161955 ER PT J AU Wang, XY Svedin, P Nie, CX Lapatto, R Zhu, CL Gustavsson, M Sandberg, M Karlsson, JO Romero, R Hagberg, H Mallard, C AF Wang, Xiaoyang Svedin, Pernilla Nie, Chunxia Lapatto, Risto Zhu, Changlian Gustavsson, Malin Sandberg, Mats Karlsson, Jan-Olof Romero, Roberto Hagberg, Henrik Mallard, Carina TI N-acetylcysteine reduces lipopolysaccharide-sensitized hypoxic-ischemic brain injury SO ANNALS OF NEUROLOGY LA English DT Article ID WHITE-MATTER INJURY; DEVELOPING RAT-BRAIN; NORMAL BIRTH-WEIGHT; NEONATAL-RAT; CELL-DEATH; ANTIOXIDANT THIOREDOXIN-2; SUPEROXIDE-DISMUTASE; OXIDATIVE STRESS; IMMATURE BRAIN; CEREBRAL-PALSY AB Objective: Maternal inflammation/infection alone or in combination with birth asphyxia increases the risk for perinatal brain injury. Free radicals are implicated as major mediators of inflammation and hypoxia-ischemia (HI)-induced perinatal brain injury. This study evaluated the neuroprotective efficacy of a scavenging agent, N-acetylcysteine (NAC) in a clinically relevant model. Methods: Lipopolysaccharide (LPS)-sensitized HI brain injury was induced in 8-day-old neonatal rats. NAC was administered in multiple doses, and brain injury was evaluated at 7 days after HI. Results: NAC (200mg/kg) provided marked neuroprotection with up to 78% reduction of brain injury in the pre+post-HI treatment group and 41% in the early (0 hour) post-HI treatment group, which was much more pronounced protection than another free radical scavenger, melatonin. Protection by NAC was associated with the following factors: (1) reduced isoprostane activation and nitrotyrosine formation; (2) increased levels of the antioxidants glutathione, thioredoxin-2, and (3) inhibition of caspase-3, calpain, and caspase-1 activation. Interpretation: NAC provides substantial neuroprotection against brain injury in a model that combines infection/inflammation and HI. Protection by NAC was associated with improvement of the redox state and inhibition of apoptosis, suggesting that these events play critical roles in the development of lipopolysaccharide-sensitized HI brain injury. C1 Univ Gothenburg, Sahlgrenska Acad, Dept Physiol, Perinatal Ctr, S-40530 Gothenburg, Sweden. Zhengzhou Univ, Affiliated Hosp 3, Dept Pediat, Zhengzhou 450052, Peoples R China. Univ Helsinki, Hosp Childrens & Adolescents, Helsinki, Finland. Univ Gothenburg, Dept Clin Neurosci, Gothenburg, Sweden. Univ Gothenburg, Inst Anat & Cell Biol, Gothenburg, Sweden. NICHHD, Perinatol Res Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Sahlgrens Acad, Dept Obstet & Gynecol, Perinatal Ctr, Gothenburg, Sweden. RP Wang, XY (reprint author), Univ Gothenburg, Sahlgrenska Acad, Dept Physiol, Perinatal Ctr, Box 432, S-40530 Gothenburg, Sweden. EM xiaoyang.wang@fysiologi.gu.se OI Hagberg, Henrik/0000-0003-3962-1448 FU Intramural NIH HHS; NICHD NIH HHS [N01-HD-2-3342]; NIGMS NIH HHS [GM 44842] NR 62 TC 72 Z9 78 U1 0 U2 7 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD MAR PY 2007 VL 61 IS 3 BP 263 EP 271 DI 10.1002/ana.21066 PG 9 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 153EZ UT WOS:000245416100012 PM 17253623 ER PT J AU Christodoulou, MI Kapsogeorgou, EK Moutsopoulos, NM Moutsopoulos, HM AF Christodoulou, M. I. Kapsogeorgou, E. K. Moutsopoulos, N. M. Moutsopoulos, H. M. TI T regulatory cells in Sjogren's syndrome (SS): Correlation with the progression of the autoimmune lesion SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT 27th European Workshop for Rheumatology Research CY FEB 22-24, 2007 CL Florence, ITALY C1 Univ Athens, Sch Med, Dept Pathophysiol, GR-11527 Athens, Greece. Natl Inst Dent & Craniofacial Res, Oral Infect & Immun Branch, NIH, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD MAR 1 PY 2007 VL 66 SU 1 MA 092 BP A35 EP A35 PG 1 WC Rheumatology SC Rheumatology GA 138BN UT WOS:000244337600108 ER PT J AU Fragouli, E Eliopoulos, E Sidiropoulos, P Aksentijevich, I Boumpas, DT Goulielmos, GN AF Fragouli, E. Eliopoulos, E. Sidiropoulos, P. Aksentijevich, I. Boumpas, D. T. Goulielmos, G. N. TI Three dimensional (3-D) model of the pryspry domain of pyrin: Implications for disease severity in familial mediterranean fever (FMF) SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT 27th European Workshop for Rheumatology Research CY FEB 22-24, 2007 CL Florence, ITALY C1 Univ Crete, Dept Internal Med, Athens, Greece. Agr Univ Athens, Genet Lab, Athens, Greece. Univ Hosp Heraklion, Dept Rheumatol Clin Immunol & Allergy, Iraklion, Greece. NIAMSD, Arthritis & Rheumatism Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD MAR 1 PY 2007 VL 66 SU 1 MA 083 BP A32 EP A32 PG 1 WC Rheumatology SC Rheumatology GA 138BN UT WOS:000244337600099 ER PT J AU Neugebauer, K Herzog, C Pundt, N Meyer, LH Kollias, G Blackshear, PJ Schett, G Pap, T Echtermeyer, F AF Neugebauer, K. Herzog, C. Pundt, N. Meyer, L. H. Kollias, G. Blackshear, P. J. Schett, G. Pap, T. Echtermeyer, F. TI Syndecan-4 modulates TNF-alpha induced MMP production in rheumatoid arthritis synovial fibroblasts SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT 27th European Workshop for Rheumatology Research CY FEB 22-24, 2007 CL Florence, ITALY C1 Div Mol Med Musculoskel Tissue, Munster, Germany. Dept Anat & Anaesthesiol, Munster, Germany. Alexander Fleming Biomed Sci Res Ctr, Vari, Greece. NIEHS, Res Triangle Pk, NC 27709 USA. Univ Hosp Erlangen, Dept Rheumatol, Erlangen, Germany. RI Kollias, George/A-7079-2012 OI Kollias, George/0000-0003-1867-3150 NR 0 TC 0 Z9 0 U1 0 U2 0 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD MAR 1 PY 2007 VL 66 SU 1 MA 201 BP A68 EP A68 PG 1 WC Rheumatology SC Rheumatology GA 138BN UT WOS:000244337600217 ER PT J AU Targoff, IN Trieu, EP Levy, M Prasertsuntarasai, T Miller, F AF Targoff, I. N. Trieu, E. P. Levy, M. Prasertsuntarasai, T. Miller, F. TI Autoantibodies to transcriptional intermediary factor 1-gamma in dermatomyositis SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Meeting Abstract CT 27th European Workshop for Rheumatology Research CY FEB 22-24, 2007 CL Florence, ITALY C1 Univ Oklahoma, Ctr Hlth Sci, VAMC, Oklahoma Med Res Fdn, Norman, OK 73019 USA. NIEHS, DHHS, NIH, Res Triangle Pk, NC USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD MAR 1 PY 2007 VL 66 SU 1 MA 005 BP A7 EP A7 PG 1 WC Rheumatology SC Rheumatology GA 138BN UT WOS:000244337600021 ER PT J AU Antachopoulos, C Meletiadis, J Sein, T Roilides, E Walsh, TJ AF Antachopoulos, Charalampos Meletiadis, Joseph Sein, Tin Roilides, Emmanuel Walsh, Thomas J. TI Concentration-dependent effects of caspofungin on the metabolic activity of Aspergillus species SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID INVASIVE PULMONARY ASPERGILLOSIS; HIGH DRUG CONCENTRATIONS; IN-VITRO; SUSCEPTIBILITY; EFFICACY; PHARMACOKINETICS; CANDIDIASIS; THERAPY; MK-0991; TERREUS AB The minimum effective concentration (MEC) used to assess the in vitro antifungal activity of caspofungin against Aspergillus spp. is a qualitative endpoint requiring microscopic examination of hyphae. We therefore developed a tool for the quantitative assessment of caspofungin activity against Aspergillus spp. at clinically applicable concentrations. Susceptibility to caspofungin (0.008 to 8 mu g/ml) was studied for 9 A. fumigatus, 8 A. flavus, and 12 A. terreus isolates based on the Clinical and Laboratory Standards Institute M38-A protocol. After 48 h of incubation, the MEC was defined microscopically, and metabolic activity assessed with a modified XTT assay, using 100 mu g of the tetrazolium salt XTT/ml and 6.25 mu M menadione. A significant reduction in metabolic activity was demonstrated at the MEC (0.25 to 0.5 mu g/ml) for all Aspergillus spp. and was more pronounced for A. flavus (median metabolic activity, 25% of control) compared to A. fumigatus and A. terreus (median metabolism, 42 and 53%, respectively), allowing determination of MEC with the XTT assay (93 to 100% agreement with microscopic MEC). Fungal metabolism tended to reach the lowest levels (median, 17 to 38% of control) one to two dilutions higher than the MEC, at the minimum metabolic activity concentration (MMC). For 5 of 9 A. fumigatus isolates, 6 of 12 A. terreus isolates, and I of 8 A. flavus isolates, a paradoxical increase in metabolism was observed at concentrations greater than the MMC. Sigmoid (E-max) or bell-shaped models described accurately (median R-2 = 0.97) the concentration-dependent metabolic changes in the absence or presence, respectively, of paradoxical response. Assessment of metabolic activity may provide useful quantitative endpoints for in vitro studies of caspofungin against Aspergillus spp. C1 NCI, Pediat Oncol Branch, CRC, Immunocompromised Host Sect, Bethesda, MD 20892 USA. Aristotle Univ Thessaloniki, Hippokrat Hosp, Dept Pediat 3, Thessaloniki, Greece. RP Walsh, TJ (reprint author), NCI, Pediat Oncol Branch, CRC, Immunocompromised Host Sect, Rm 1-5750,MSC 1100,10 Ctr Dr, Bethesda, MD 20892 USA. EM waisht@mail.nih.gov FU Intramural NIH HHS NR 29 TC 31 Z9 31 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 MAR PY 2007 VL 51 IS 3 BP 881 EP 887 DI 10.1128/AAC.01160-06 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 142QT UT WOS:000244665500013 PM 17145783 ER PT J AU Simitsopoulou, M Roilides, E Likartsis, C Ioannidis, J Orfanou, A Paliogianni, F Walsh, TJ AF Simitsopoulou, M. Roilides, E. Likartsis, C. Ioannidis, J. Orfanou, A. Paliogianni, F. Walsh, T. J. TI Expression of immunomodulatory genes in human monocytes induced by voriconazole in the presence of Aspergillus fumigatus SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article ID INVASIVE PULMONARY ASPERGILLOSIS; CELL TRANSPLANT RECIPIENTS; HUMAN MONONUCLEAR-CELLS; FUNGAL-INFECTIONS; AMPHOTERICIN-B; HOST-DEFENSE; FILAMENTOUS FUNGI; TNF-ALPHA; CYTOKINE; EPIDEMIOLOGY AB We assessed the effect of voriconazole (VRC) on the expression and release of selected cytokines and chemokines in the THP-1 human monocytic cell line in response to Aspergillus fumigatus hyphal fragments (HF) by cDNA microarray analysis, reverse transcriptase (RT) PCR, and enzyme-linked immunosorbent assay. Stimulation of THP-1 cells by HIT alone caused a significant up-regulation of CCL4 (MIP1B) and CCL16, while CCL2 (MCPI) was down-regulated. By comparison, in the presence of VRC, a large number of genes such as CCL3 (MIPIA), CCL4 (MIPIB), CCL5 (RANTES), CCL7 (MCP3), CCL11 (EOTAXIN), CCL15 (MIP1 Delta), CXCL6, and CXCL13 were strongly up-regulated in THP-1 cells challenged by HF, whereas CCL20 (MIP3A) and CCL21 (MIP2) were down-regulated. Among five genes differentially expressed in THP-1 cells, IL12A, IL12B, and IL-16 were down-regulated whereas IL-11 and TGFBI were significantly up-regulated in the presence of VRC. The inflammation-related genes IFN gamma, ILIR1, and TNFA were also up-regulated in THP-1 cells exposed to HF only in the presence of VRC. RT-PCR of four selected genes validated the results of microarrays. The release of interieukin 1 beta (IL-1 beta) and IL-12 was significantly increased from monocytes stimulated either by HF alone (P < 0.05) or in the presence of VRC (P < 0.01 and P < 0.05, respectively). In contrast, tumor necrosis factor alpha release from monocytes was enhanced only in the presence of VRC (P < 0.01). The chemokines monocyte chemoattractant protein 1 and macrophage inflammatory protein 1 beta were decreased under both conditions (P < 0.01). These results demonstrate that in the presence of VRC, HF induces a more pronounced profile of gene expression in THP-1 cells than HIT alone, potentially leading to more-efficient host resistance to A. fumigatus. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. Aristotle Univ Thessaloniki, Hippokratio Gen Hosp, Sch Med, Dept Pediat 3,Lab Infect Dis, Thessaloniki 54642, Greece. Technol Educ Inst Thessaloniki, Dept Med Labs, Lab Med Biotechnol, Thessaloniki 57400, Greece. Univ Patras, Sch Med, Dept Microbiol, Patras 26500, Greece. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bldg 10,CRC 1-5750, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov RI Ioannidis, John/G-9836-2011 NR 48 TC 30 Z9 31 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 MAR PY 2007 VL 51 IS 3 BP 1048 EP 1054 DI 10.1128/AAC.01095-06 PG 7 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 142QT UT WOS:000244665500036 PM 17178797 ER PT J AU Barr, CS Schwandt, M Lindell, SG Chen, SA Goldman, D Suomi, SJ Higley, JD Heilig, M AF Barr, Christina S. Schwandt, Melanie Lindell, Stephen G. Chen, Scott A. Goldman, David Suomi, Stephen J. Higley, J. Dee Heilig, Markus TI Association of a functional polymorphism in the mu-opioid receptor gene with alcohol response and consumption in male rhesus macaques SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 28th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 25-30, 2005 CL Santa Barbara, CA SP Res Soc Alcoholism ID SINGLE-NUCLEOTIDE POLYMORPHISM; NONHUMAN PRIMATE MODEL; 5-HYDROXYINDOLEACETIC ACID CONCENTRATIONS; DIMINISHED SOCIAL COMPETENCE; RANDOMIZED CONTROLLED-TRIAL; LIMITED-ACCESS PROCEDURE; ETHANOL-CONSUMPTION; GENDER DIFFERENCES; BETA-ENDORPHIN; KNOCKOUT MICE AB Context: Innate differences in opioid neurotransmission are hypothesized to influence abuse liability of alcohol. In humans, a variant of the mu-opioid receptor gene (OPRM1A118G) increases receptor affinity, alcohol-induced euphoria, and risk for alcohol use disorders. Objective: To determine whether a variant in the mu-opioid receptor gene (OPRM1C77G) that increases affinity of the receptor is associated with alcohol response and consumption in macaques. Design: Young adult rhesus macaques (Macaca mulatta) were intravenously administered 2.0 to 2.1 g of ethanol per kilogram of body weight and assessed for alcohol response. Animals were later given simultaneous access to an aspartame-sweetened 8.4% (vol/vol) ethanol solution and a vehicle for 1 hour per day, 5 days a week, for a period of 6 weeks. Animals (N = 82) were genotyped for the OPRM1C77G polymorphism; the effects of the genotype on alcohol response and consumption were determined by analysis of variance, with sex included as a nominal independent variable. Main Outcome Measures: Alcohol response (ataxia, stimulation, and sedation), average alcohol consumption, the percentage of days during which an animal consumed alcohol at a level sufficient to produce intoxication (>= 0.67 g of alcohol per kilogram of body weight), and alcohol preference (calculated as 100 x{alcoholic solution/[alcoholic solution + nonalcoholic solution]}). Results: Increased alcohol-induced stimulation was observed among male macaques carrying the OPRM1C77G allele. OPRM1C77G allele carriers consumed more ethanol and exhibited increased ethanol preference. Male carriers of the OPRM1C77G allele exhibited higher alcohol preference and consumption, and drank to intoxication more frequently than did C/C males. Conclusions: These findings demonstrate that the rhesus macaques' equivalent of the OPRM1A118G variant is associated with increased alcohol response, consumption, and preference. Our results reveal effects of the OPRM1C77G genotype to be male-restricted or more marked among male macaques. This is of interest, given the fact that early-onset type II alcoholism is more common among men and that, among addicted individuals, men are more responsive to mu-opioid receptor blockade. C1 NIAAA, Lab Clin & Translat Studies, NIH, Natl Inst Hlth Anim Ctr, Poolesville, MD 20837 USA. NIAAA, Lab Neurogenet, NIH, Natl Inst Hlth Anim Ctr, Poolesville, MD 20837 USA. NICHHD, Lab Comparat Ethol, NIH, Bethesda, MD 20892 USA. RP Barr, CS (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, Natl Inst Hlth Anim Ctr, POB 529, Poolesville, MD 20837 USA. EM cbarr@mail.nih.gov RI Goldman, David/F-9772-2010; Schwandt, Melanie/L-9866-2016; OI Goldman, David/0000-0002-1724-5405; Heilig, Markus/0000-0003-2706-2482 FU Intramural NIH HHS NR 58 TC 81 Z9 82 U1 0 U2 5 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 MAR PY 2007 VL 64 IS 3 BP 369 EP 376 DI 10.1001/archpsyc.64.3.369 PG 8 WC Psychiatry SC Psychiatry GA 142LB UT WOS:000244650200014 PM 17339526 ER PT J AU Grant, BF Compton, WM Crowley, TJ Hasin, DS Helzer, JE Li, TK Rounsaville, BJ Volkow, ND Woody, GE AF Grant, Bridget F. Compton, Wilson M. Crowley, Thomas J. Hasin, Deborah S. Helzer, John E. Li, Ting-Kai Rounsaville, Bruce J. Volkow, Nora D. Woody, George E. TI Errors in assessing DSM-IV substance use disorders SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Letter ID NATIONAL-COMORBIDITY-SURVEY; ALCOHOL-USE DISORDER; INTERVIEW SCHEDULE AUDADIS; WORLD-HEALTH-ORGANIZATION; GENERAL-POPULATION SAMPLE; 5-YEAR CLINICAL COURSE; UNITED-STATES; EPIDEMIOLOGIC SURVEY; SURVEY REPLICATION; 12-MONTH PREVALENCE C1 NIAAA, Lab Epidemiol & Biometry, Bethesda, MD 20892 USA. RP Grant, BF (reprint author), NIAAA, Lab Epidemiol & Biometry, 5635 Fishers Ln,MSC 9304, Bethesda, MD 20892 USA. EM bgrant@willco.niaaa.nih.gov NR 32 TC 45 Z9 45 U1 3 U2 4 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 MAR PY 2007 VL 64 IS 3 BP 379 EP 380 DI 10.1001/archpsyc.64.3.379 PG 3 WC Psychiatry SC Psychiatry GA 142LB UT WOS:000244650200018 PM 17339528 ER PT J AU Christen, WG Manson, JE Glynn, RJ Gaziano, JM Chew, EY Buring, JE Hennekens, CH AF Christen, William G. Manson, JoAnn E. Glynn, Robert J. Gaziano, J. Michael Chew, Emily Y. Buring, Julie E. Hennekens, Charles H. TI Beta carotene supplementation and age-related maculopathy in a randomized trial of US physicians SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID SUBFOVEAL CHOROIDAL NEOVASCULARIZATION; MACULAR DEGENERATION; CARDIOVASCULAR-DISEASE; CLINICAL-TRIALS; VITAMIN-E; LASER PHOTOCOAGULATION; PHOTODYNAMIC THERAPY; ALPHA-TOCOPHEROL; WOMENS HEALTH; FOLLOW-UP AB Objective: To test whether beta carotene supplementation affects the incidence of age-related maculopathy ( ARM) in a large-scale randomized trial. D esign: Randomized, double-masked, placebo-controlled trial among 22 071 apparently healthy US male physicians aged 40 to 84 years. Participants were randomly assigned to receive beta carotene (50 mg every other day) or placebo. Main Outcome Measure: Incident ARM responsible for a reduction in best-corrected visual acuity to 20/30 or worse. Results: After 12 years of treatment and follow-up, there were 162 cases of ARM in the beta carotene group vs 170 cases in the placebo group ( relative risk [RR], 0.96; 95% confidence interval [CI], 0.78-1.20). The results were similar for the secondary end points of ARM with or without vision loss ( 275 vs 274 cases; RR, 1.01; 95% CI, 0.86-1.20) and advanced ARM ( 63 vs 66 cases; RR, 0.97; 95% CI, 0.69-1.37). Conclusions: These randomized data relative to 12 years of treatment among a large population of apparently healthy men indicate that beta carotene supplementation has no beneficial or harmful effect on the incidence of ARM. Long-term supplemental use of beta carotene neither decreases nor increases the risk of ARM. C1 Brigham & Womens Hosp, Div Prevent Med, Dept Med, Boston, MA 02215 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA USA. Massachusetts Vet Epidemiol Res & Informat Ctr, Dept Vet Affairs Boston Healthcare Syst, Boston, MA USA. NEI, Bethesda, MD 20892 USA. Univ Miami, Sch Med, Dept Med, Miami, FL USA. Univ Miami, Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL USA. Florida Atlantic Univ, Dept Biomed Sci, Ctr Excellence Biomed & Marine Biotechnol, Boca Raton, FL 33431 USA. RP Christen, WG (reprint author), Brigham & Womens Hosp, Div Prevent Med, Dept Med, 900 Commonwealth Ave E, Boston, MA 02215 USA. EM wchristen@rics.bwh.harvard.edu FU Intramural NIH HHS [Z99 EY999999]; NCI NIH HHS [R01 CA097193, CA 34944, CA 40360, R01 CA034944, R01 CA040360]; NEI NIH HHS [EY 06633]; NHLBI NIH HHS [HL 26490, HL 34595, R01 HL026490, R01 HL034595]; NIDDK NIH HHS [P30 DK040561, P30 DK040561-11] NR 35 TC 15 Z9 15 U1 1 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD MAR PY 2007 VL 125 IS 3 BP 333 EP 339 DI 10.1001/archopht.125.3.333 PG 7 WC Ophthalmology SC Ophthalmology GA 145DR UT WOS:000244846000005 PM 17353403 ER PT J AU Bodenreider, O Smith, B Kumar, A Burgun, A AF Bodenreider, Olivier Smith, Barry Kumar, Anand Burgun, Anita TI Investigating subsumption in SNOMED CT: An exploration into large description logic-based biomedical terminologies SO ARTIFICIAL INTELLIGENCE IN MEDICINE LA English DT Article; Proceedings Paper CT 1st International Workshop on Formal Biomedical Knowledge Representation (KR-MED 2004) CY JUN 01, 2004 CL Whistler, CANADA DE biomedical ontologies; SNOMED CT; description logics; ontological analysis AB Objective: Formalisms based on one or other flavor of description logic (DL) are sometimes put forward as helping to ensure that terminologies and controlled vocabularies comply with sound ontological principles. The objective of this paper is to study the degree to which one DL-based biomedical terminology (SNOMED CT) does indeed comply with such principles. Materials and methods: We defined seven ontological principles (for example: each class must have at least one parent, each class must differ from its parent) and examined the properties of SNOMED CT classes with respect to these principles. Results: Our major results are 31% of these classes have a single child; 27% have multiple parents; 51 % do not exhibit any differentiae between the description of the parent and that of the child. Conclusions: The applications of this principles to quality assurance for ontologies are discussed and suggestions are made for dealing with the phenomenon of multiple inheritance. The advantages and limitations of our approach are also discussed. (c) 2006 Elsevier B.V. All rights reserved. C1 Natl Lib Med, NIH, Bethesda, MD 20894 USA. Univ Saarland, Inst Formal Ontol & Med Informat Sci, Saarbrucken, Germany. SUNY Coll Buffalo, Dept Philosophy, Buffalo, NY 14222 USA. Univ Rennes 1, Lab Informat Med, EA 3888, Rennes, France. RP Bodenreider, O (reprint author), Natl Lib Med, NIH, Bethesda, MD 20894 USA. EM olivier@nlm.nih.gov RI Smith, Barry/A-9525-2011 OI Smith, Barry/0000-0003-1384-116X FU Intramural NIH HHS [Z99 LM999999]; NHGRI NIH HHS [U54 HG004028] NR 21 TC 46 Z9 47 U1 1 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0933-3657 J9 ARTIF INTELL MED JI Artif. Intell. Med. PD MAR PY 2007 VL 39 IS 3 BP 183 EP 195 DI 10.1016/j.artmed.2006.12.003 PG 13 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Medical Informatics SC Computer Science; Engineering; Medical Informatics GA 170IR UT WOS:000246657200002 PM 17241777 ER PT J AU Zhang, SM Mork, P Bodenreider, O Bernstein, PA AF Zhang, Songmao Mork, Peter Bodenreider, Olivier Bernstein, Philip A. TI Comparing two approaches for aligning representations of anatomy SO ARTIFICIAL INTELLIGENCE IN MEDICINE LA English DT Article; Proceedings Paper CT 1st International Workshop on Formal Biomedical Knowledge Representation (KR-MED 2004) CY JUN 01, 2004 CL Whistler, CANADA DE ontology; anatomy; Foundational Model Anatomy (FMA); GALEN; ontology alignment ID ONTOLOGY; ALGORITHM; MODEL AB Objective: To analyze the comparison, through their results, of two distinct approaches applied to aligning two representations of anatomy. Materials: Both approaches use a combination of lexical and structural techniques. In addition, the first approach takes advantage of domain knowledge, while the second approach treats alignment as a special case of schema matching. The same versions of FMA and GALEN were aligned by each approach. Two thousand one hundred and ninety-nine concept matches were obtained by both approaches. Methods and results: For matches identified by one approach only (337 and 336, respectively), we analyzed the reasons that caused the other approach to fail. Conclusions: The first approach could be improved by addressing partial lexical matches and identifying matches based solely on structural similarity. The second approach may be improved by taking into account synonyms in FMA and identifying semantic mismatches. However, only 33% of the possible one-to-one matches among anatomical concepts were identified by the two approaches together. New directions need to be explored in order to handle more complex matches. (c) 2007 Elsevier B.V. All rights reserved. C1 Natl Lib Med, NIH, Bethesda, MD 20892 USA. Microsoft Res, Redmond, WA USA. Mitre Corp, Mclean, VA USA. Chinese Acad Sci, Acad Math & Syst Sci, Math Inst, Beijing, Peoples R China. RP Bodenreider, O (reprint author), Natl Lib Med, NIH, Bethesda, MD 20892 USA. EM smzhang@math.ac.cn; pmork@mitre.org; olivier@nlm.nih.gov; philbe@microsoft.com FU Intramural NIH HHS [Z99 LM999999]; NLM NIH HHS [T15LM07442, T15 LM007442] NR 22 TC 5 Z9 5 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0933-3657 EI 1873-2860 J9 ARTIF INTELL MED JI Artif. Intell. Med. PD MAR PY 2007 VL 39 IS 3 BP 227 EP 236 DI 10.1016/j.artmed.2006.12.002 PG 10 WC Computer Science, Artificial Intelligence; Engineering, Biomedical; Medical Informatics SC Computer Science; Engineering; Medical Informatics GA 170IR UT WOS:000246657200005 PM 17250997 ER PT J AU Rider, LG AF Rider, Lisa G. TI The heterogeneity of juvenile myositis SO AUTOIMMUNITY REVIEWS LA English DT Article DE juvenile dermatomyositis; autoantibodies; immunogenetics; environmental factors; treatment ID IDIOPATHIC INFLAMMATORY MYOPATHIES; DISTINCT HLA-A; NATIONAL-INSTITUTE; IMMUNOGENETIC RISK; PROTECTIVE FACTORS; ALLELIC PROFILES; DERMATOMYOSITIS; EXPRESSION; CHILDREN; POLYMYOSITIS AB Juvenile myositis is a heterogeneous group of systemic autoimmune diseases, in which clinical and serologic subgroups result in subsets of patients with distinct clinical manifestations, disease courses, immunogenctic associations, responses to therapy, and prognoses. A newly identified autoantibody of unknown specificity, anti-p155, is myositis-associated and seen in up to 20-30% of juvenile and adult DM patients. HLA DRB1*0301 and its linked allele DQA1*0501 have been identified as the major immunogenetic risk factor for juvenile and adult DM in both European- and African-American patients, and DQA1*0301 is an additional risk factor in European-American patients. Several DQA1 alleles also are protective for juvenile DM. Environmental risk factors are poorly understood, but growing evidence suggests a role for infectious agents and ultraviolet radiation. The current therapy of juvenile DM consists of corticosteroids and other immunosuppressive agents, with the adjunctive treatment of cutaneous manifestations and rehabilitation. Therapeutic trials of biologic agents, including anti-TNF alpha and anti-CD20, may aid in developing promising new therapies for these disorders. (c) 2006 Elsevier B.V. All rights reserved. C1 NIEHS, Environm Autoimmun Grp, NIH, Dept HHS, Bethesda, MD 20892 USA. RP Rider, LG (reprint author), NIEHS, Environm Autoimmun Grp, NIH, Dept HHS, CRC 4-2332,MSC 1301,10 Ctr Dr, Bethesda, MD 20892 USA. EM riderl@mail.nih.gov OI Rider, Lisa/0000-0002-6912-2458 NR 39 TC 20 Z9 20 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-9972 J9 AUTOIMMUN REV JI Autoimmun. Rev. PD MAR PY 2007 VL 6 IS 4 BP 241 EP 247 DI 10.1016/j.autrev.2006.08.009 PG 7 WC Immunology SC Immunology GA 148YB UT WOS:000245112200010 PM 17317616 ER PT J AU Mavrakis, M Lippincott-Schwartz, J Stratakis, CA Bossis, I AF Mavrakis, Manos Lippincott-Schwartz, Jennifer Stratakis, Constantine A. Bossis, Ioannis TI mTOR kinase and the regulatory subunit of protein kinase A (PRKAR1A) spatially and functionally interact during autophagosorne maturation SO AUTOPHAGY LA English DT Article DE PKA; RI alpha; autophagy; mTOR; LC3 ID MAMMALIAN-CELLS; CARNEY COMPLEX; ALPHA; RAB7; ACCUMULATION; LIPOFUSCIN; MUTATIONS; VACUOLES AB The regulatory subunit 1-alpha (RI alpha) of protein kinase A (PKA) and the mTOR kinase are involved in a common pathway regulating mammalian autophagy. RICE was found to localize on Rab7-positive late endosomes and on LC3-positive autophagosomal membranes in cultured cells. RI alpha was also shown to physically interact with mTOR kinase and affect its phosphorylation and activity.(1) In this addendum, we further explore the subcellular distribution of mTOR related to RI alpha and LC3. We present experiments showing that mTOR colocalizes with RI alpha-, Rab7- and LC3-positive membranes in cultured cells. Because RI alpha regulates the phosphorylation and activity of mTOR kinase, which we now show localizes on autophagosomal membranes, the possibility emerges that the RI alpha-mTOR complex acts at the level of autophagosome maturation. C1 NICHD, CBMB, NIH, Bethesda, MD 20892 USA. NICHD, Sect Endocrinol & Genet, NIH, Bethesda, MD 20892 USA. RP Mavrakis, M (reprint author), NICHD, CBMB, NIH, Bldg 18T,Room 101,18 Library Dr, Bethesda, MD 20892 USA. EM mavrakim@mail.nih.gov NR 14 TC 21 Z9 21 U1 0 U2 1 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1554-8627 J9 AUTOPHAGY JI Autophagy PD MAR-APR PY 2007 VL 3 IS 2 BP 151 EP 153 PG 3 WC Cell Biology SC Cell Biology GA 153QD UT WOS:000245449200016 PM 17204847 ER PT J AU Costa, PT Terracciano, A Uda, M Vacca, L Mameli, C Pilia, G Zonderman, AB Lakatta, E Schlessinger, D McCrae, RR AF Costa, Paul T., Jr. Terracciano, Antonio Uda, Manuela Vacca, Loredana Mameli, Cinzia Pilia, Giuseppe Zonderman, Alan B. Lakatta, Edward Schlessinger, David McCrae, Robert R. TI Personality traits in Sardinia: Testing founder population effects on trait means and variances SO BEHAVIOR GENETICS LA English DT Article DE five-factor model of personality; genetic homogeneity; founder population; cross-cultural; complex trait; QTL ID NEO-PI-R; GENETIC DIVERSITY; OBSERVER RATINGS; 5-FACTOR MODEL; SELF-REPORTS; CULTURES; ROTATION; COMPARABILITY; HERITABILITY; INVENTORY AB Potential founder population effects on personality trait means and variances were examined in a large, genetically homogeneous sample (N = 5,669) from the Ogliastra, an isolated region within Sardinia, Italy. The Italian version of the Revised NEO Personality Inventory showed good psychometric properties: Internal consistency reliabilities ranged from 0.80 to 0.87; the factor structure replicated the American normative structure; and associations with education and gender replicated cross-cultural patterns. The hypothesis that mean trait levels in the Sardinian founder population would differ from mainland Italian values was not supported. Phenotypic variation in this founder population was within the range found in other cultures. However, the hypothesis of restricted phenotypic variation was supported for all five factors and 28 of the 30 facets when a Sardinian subsample matched on age, sex, and education was compared to a mainland Italian sample. The genetic homogeneity effect on the phenotypic expression of complex traits merits further exploration. C1 NIA, US Dept HHS, NIH, Baltimore, MD 21224 USA. CNR, INN, Cagliari, Italy. RP Costa, PT (reprint author), NIA, US Dept HHS, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM costap@mail.nih.gov RI terracciano, antonio/B-1884-2008; OI Costa, Paul/0000-0003-4375-1712; Zonderman, Alan B/0000-0002-6523-4778 FU Intramural NIH HHS [Z99 AG999999] NR 35 TC 17 Z9 17 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0001-8244 J9 BEHAV GENET JI Behav. Genet. PD MAR PY 2007 VL 37 IS 2 BP 376 EP 387 DI 10.1007/s10519-006-9103-6 PG 12 WC Behavioral Sciences; Genetics & Heredity; Psychology, Multidisciplinary SC Behavioral Sciences; Genetics & Heredity; Psychology GA 153BQ UT WOS:000245407100011 PM 16972192 ER PT J AU Jung, YJ Xu, WP Kim, H Ha, N Neckers, L AF Jung, Yunjin Xu, Wanping Kim, Heejung Ha, Namchul Neckers, Len TI Curcumin-induced degradation of ErbB2: A role for the E3 ubiquitin ligase CHIP and the Michael reaction acceptor activity of curcumin SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH LA English DT Article DE curcumin; ErbB2; Michael reaction; E3 ubiquitin ligase; molecular chaperones ID KINASE DOMAIN; CHAPERONE; GELDANAMYCIN; MECHANISM; PATHWAY; HSP90 AB We investigated the molecular mechanism underlying curcurnin depletion of ErbB2 protein. Curcumin induced ErbB2 ubiquitination but pretreatment with proteasome inhibitors neither prevented curcurnin depletion of ErbB2 protein nor further accumulated ubiquitinated ErbB2. Curcumin increased association of endogenous and ectopically expressed CHIP, a chaperone-dependent ubiquitin ligase, with ErbB2. In COS7 cells cotransfected with ErbB2 and various CHIP plasmids followed by curcurnin treatment, CHIP-H260Q (a mutant lacking ubiquitin ligase activity) promoted less curcumin-induced ErbB2 ubiquitination than did wild type CHIP, and CHIP-K30A (a mutant incapable of binding Hsp90 and Hsp70) neither associated with ErbB2 nor promoted its ubiquitination. ErbB2 mutants lacking the kinase domain failed to associate with CHIP and were completely resistant to ubiquitination and depletion induced by curcumin. Finally, curcumin's Michael reaction acceptor functionality was required for both covalent association of curcurnin with ErbB2 and curcumin-mediated ErbB2 depletion. These data suggest (1) that CHIP-dependent ErbB2 ubiquitination is implicated in curcumin-stimulated ErbB2 depletion, and (2) that covalent modification of ErbB2 by curcurnin is the proximal signal which initiates this process. (c) 2006 Elsevier B.V. All rights reserved. C1 Pusan Natl Univ, Coll Pharm, Res Inst Drug Dev, Pusan 609735, South Korea. Natl Canc Inst, Urol Oncol Branch, Bethesda, MD 20894 USA. RP Jung, YJ (reprint author), Pusan Natl Univ, Coll Pharm, Res Inst Drug Dev, Pusan 609735, South Korea. EM jungy@pusan.ac.kr NR 20 TC 34 Z9 37 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-4889 J9 BBA-MOL CELL RES JI Biochim. Biophys. Acta-Mol. Cell Res. PD MAR PY 2007 VL 1773 IS 3 BP 383 EP 390 DI 10.1016/j.bbamcr.2006.11.004 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 147LS UT WOS:000245005100010 PM 17239458 ER PT J AU Thazhathveetil, AK Liu, ST Indig, FE Seidman, MM AF Thazhathveetil, Arun Kalliat Liu, Su-Ting Indig, Fred E. Seidman, Michael M. TI Psoralen conjugates for visualization of genomic interstrand cross-links localized by laser photoactivation SO BIOCONJUGATE CHEMISTRY LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; DOUBLE-STRAND BREAKS; OXIDATIVE DNA-DAMAGE; HUMAN-CELLS; RNA; DERIVATIVES; CANCER AB DNA interstrand cross-links are formed by chemotherapy drugs as well as by products of normal oxidative metabolism. Despite their importance, the pathways of cross-link metabolism are poorly understood. Laser confocal microscopy has become a powerful tool for studying the repair of DNA lesions that can be detected by immunofluorescent reagents. In order to apply this approach to cross-link repair, we have synthesized conjugates of 4,5',8-trimethylpsoralen (TMP) and easily detected compounds such as Lissamine rhodamine B sulfonyl chloride (LRB-SC), biotin, and digoxigenin. These conjugates are activated by UVA, and we have analyzed the intracellular localization of DNA damage and DNA reactivity by confocal and immunofluorescence microscopy. The LRB-SC-TMP conjugate 2 appeared mainly in the mitochondria, while the biotin-TMP conjugate 4 preferentially localized in the cytoplasm. Adducts formed by UVA and digoxigenin conjugates of TMP 7a and 4,5'-dimethylangelicin (DMA) 7b, which forms only monoadducts, were largely localized to the nucleus. Exposure of cells incubated with 7a and 7b to a 364 nm UV laser directed toward defined nuclear regions of interest resulted in localized adduct formation which could be visualized by immunofluorescence. Repair-proficient cells were able to remove the photoadducts, while repair-deficient cells were unable to repair the damage. The results indicated that the digoxigenin-TMP conjugate 7a and digoxigenin-DMA conjugate 7b can be used for studying the repair of laser localized DNA monoadducts and cross-links. C1 NIA, Lab Mol Gerontol, Baltimore, MD 21224 USA. NIA, Res Resources Branch, NIH, Baltimore, MD 21224 USA. RP Seidman, MM (reprint author), NIA, Lab Mol Gerontol, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM seidmanm@grc.nia.nih.gov FU Intramural NIH HHS NR 24 TC 27 Z9 27 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1043-1802 J9 BIOCONJUGATE CHEM JI Bioconjugate Chem. PD MAR-APR PY 2007 VL 18 IS 2 BP 431 EP 437 DI 10.1021/bc060309t PG 7 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Multidisciplinary; Chemistry, Organic SC Biochemistry & Molecular Biology; Chemistry GA 147YK UT WOS:000245041500021 PM 17373769 ER PT J AU Ressom, HW Varghese, RS Drake, SK Hortin, GL Abdel-Hamid, M Loffredo, CA Goldman, R AF Ressom, H. W. Varghese, R. S. Drake, S. K. Hortin, G. L. Abdel-Hamid, M. Loffredo, C. A. Goldman, R. TI Peak selection from MALDI-TOF mass spectra using ant colony optimization SO BIOINFORMATICS LA English DT Article ID HEPATOCELLULAR-CARCINOMA; SERUM; CANCER; CLASSIFICATION; DISCOVERY AB Motivation: Due to the large number of peaks in mass spectra of low-molecular-weight (LMW) enriched sera, a systematic method is needed to select a parsimonious set of peaks to facilitate biomarker identification. We present computational methods for matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) spectral data preprocessing and peak selection. In particular, we propose a novel method that combines ant colony optimization (ACO) with support vector machines (SVM) to select a small set of useful peaks. Results: The proposed hybrid ACO-SVM algorithm selected a panel of eight peaks out of 228 candidate peaks from MALDI-TOF spectra of LMW enriched sera. An SVM classifier built with these peaks achieved 94% sensitivity and 100% specificity in distinguishing hepatocellular carcinoma from cirrhosis in a blind validation set of 69 samples. Area under the receiver operating characteristic (ROC) curve was 0.996. The classification capability of these peaks is compared with those selected by the SVM-recursive feature elimination method. Availability: Supplementary material and MATLAB scripts to implement the methods described in this article are available at http://microarray.georgetown.edu/web/files/bioinf.htm Contact: hwr@georgetown.edu Supplementary information: Supplementary data are available at Bioinformatics online. C1 Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. NIH, Bethesda, MD 20792 USA. NIH, Clin Chem Serv, Dept Lab Med, Bethesda, MD 20892 USA. NHTMRI, Viral Hepatitis Res Lab, Cairo, Egypt. RP Ressom, HW (reprint author), Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20057 USA. EM hwr@georgetown.edu RI Varghese, Rency/A-8770-2012 FU NCI NIH HHS [2R01CA85888, 1R03CA119288-01A1] NR 17 TC 60 Z9 62 U1 0 U2 6 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD MAR PY 2007 VL 23 IS 5 BP 619 EP 626 DI 10.1093/bioinformatics/btl678 PG 8 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 152GS UT WOS:000245350200013 PM 17237065 ER PT J AU Pugalenthi, G Suganthan, PN Sowdhamini, R Chakrabarti, S AF Pugalenthi, Ganesan Suganthan, P. N. Sowdhamini, R. Chakrabarti, Saikat TI SMotif: a server for structural motifs in proteins SO BIOINFORMATICS LA English DT Article ID SEQUENCE; SUPERFAMILIES; DATABASE AB SMotif is a server that identifies important structural segments or motifs for a given protein structure(s) based on conservation of both sequential as well as important structural features such as solvent inaccessibility, secondary structural content, hydrogen bonding pattern and residue packing. This server also provides three-dimensional orientation patterns of the identified motifs in terms of inter-motif distances and torsion angles. These motifs may form the common core and therefore, can also be employed to design and rationalize protein engineering and folding experiments. Availability: SMotif server is available via the URL http://caps.ncbs.res.in/SMotif/index.html. Contact: chakraba@mail.nih.gov, mini@ncbs.res.in or EPNSugan@ ntu.edu.sg Supplementary information: Supplementary data are available at Bioinformatics online. C1 Natl Ctr Biol Sci, Bangalore 560065, Karnataka, India. Nanyang Technol Univ, Sch Elect & Elect Engn, Singapore 639798, Singapore. NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20892 USA. RP Chakrabarti, S (reprint author), Natl Ctr Biol Sci, Bangalore 560065, Karnataka, India. EM chakraba@mail.nih.gov RI Suganthan, .Ponnuthurai /A-5023-2011 OI Suganthan, .Ponnuthurai /0000-0003-0901-5105 FU Intramural NIH HHS NR 12 TC 10 Z9 10 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD MAR PY 2007 VL 23 IS 5 BP 637 EP 638 DI 10.1093/bioinformatics/btl679 PG 2 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 152GS UT WOS:000245350200018 PM 17237055 ER PT J AU Lu, L Uejima, JL Gray, SM Bossert, JM Shaham, Y AF Lu, Lin Uejima, Jamie L. Gray, Sarah M. Bossert, Jennifer M. Shaham, Yavin TI Systemic and central amygdala injections of the mGluR(2/3) agonist LY379268 attenuate the expression of incubation of cocaine craving SO BIOLOGICAL PSYCHIATRY LA English DT Article DE basolateral amygdala; drug seeking; glutamate; reinstatement; relapse ID METABOTROPIC GLUTAMATE RECEPTORS; SIGNAL-REGULATED KINASE; MESOLIMBIC DOPAMINE SYSTEM; SELF-ADMINISTERED COCAINE; CUE-INDUCED REINSTATEMENT; MEDIAL PREFRONTAL CORTEX; REWARD-RELATED STIMULI; SEEKING BEHAVIOR; BASOLATERAL AMYGDALA; VENTRAL SUBICULUM AB Background: We and others reported time-dependent increases in cue-induced cocaine seeking after withdrawal, suggesting that craving incubates overtime. Recently, we found that central amygdala extracellular signal-regulated kinases (ERK) and glutamate are involved in this incubation. Here, we further explored the role of central amygdala glutamate in the incubation of cocaine craving by determining the effect of systemic or central amygdala injections of the mGluR(2/3) agonist LY379268 (which decreases glutamate release) on cue-induced cocaine seeking during early and late withdrawal. Methods: Rats were trained to self-administer cocaine for 10 days (6 hours/day); infusions were paired with a tone-light cue. Cocaine seeking and craving after systemic or central amygdala injections of LY379268 were then assessed in extinction tests in the presence of the cocaine-associated cues during early (day 3) or late (day 21) withdrawal. Results: Systemic (1.5 or 3 mg/kg) or central amygdala (.5 or 1.0 mu g/side) injections of LY379268 attenuated enhanced extinction responding on day 21 but had no effect on lower extinction responding on day 3. Conclusions: Results confirm our previous findings on the role of central amygdala glutamate in the incubation of cocaine craving and together with previous reports suggest that mGluR(2/3), agonists should be considered in the treatment of drug relapse. C1 Natl Inst Drug Abuse, Behav Neurosci Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD USA. RP Lu, L (reprint author), Peking Univ, Natl Inst Drug Dependence, 38 Yixueyuan Rd, Beijing 100083, Peoples R China. EM linlu@bjmu.edu.cn RI shaham, yavin/G-1306-2014 FU Intramural NIH HHS NR 86 TC 80 Z9 82 U1 0 U2 2 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 MAR 1 PY 2007 VL 61 IS 5 BP 591 EP 598 DI 10.1016/j.biopsych.2006.04.011 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 140BI UT WOS:000244476800003 PM 16893525 ER PT J AU Hasler, G Pinto, A Greenberg, BD Samuels, J Fyer, AJ Pauls, D Knowles, JA McCracken, JT Piacentini, J Riddle, MA Rauch, SL Rasmussen, SA Willour, VL Grados, MA Cullen, B Bienvenu, JO Shugart, YY Liang, KY Hoehn-Saric, R Wang, Y Ronquillo, J Nestadt, G Murphy, DL AF Hasler, Gregor Pinto, Anthony Greenberg, Benjamin D. Samuels, Jack Fyer, Abby J. Pauls, David Knowles, James A. McCracken, James T. Piacentini, John Riddle, Mark A. Rauch, Scott L. Rasmussen, Steven A. Willour, Virginia L. Grados, Marco A. Cullen, Bernadette Bienvenu, O. Joseph Shugart, Yin-Yao Liang, Kung-yee Hoehn-Saric, Rudolf Wang, Ying Ronquillo, Jonne Nestadt, Gerald Murphy, Dennis L. TI Familiality of factor analysis-derived YBOCS dimensions in OCD-affected sibling pairs from the OCD collaborative genetics study SO BIOLOGICAL PSYCHIATRY LA English DT Article DE comorbidity; endophenotypes; epidemiology; genetics; obsessive-compulsive disorder; symptom dimensions ID OBSESSIVE-COMPULSIVE DISORDER; LA-TOURETTE-SYNDROME; SYMPTOM DIMENSIONS; SEGREGATION ANALYSIS; COMORBIDITY; SCHIZOPHRENIA; EPIDEMIOLOGY; ASSOCIATION; FAMILY; POLYMORPHISM AB Background: Identification of familial, more homogenous characteristics of obsessive-compulsive disorder (OCD) may help to define relevant subtypes and increase the power of genetic and neurobiological studies of OCD. While factor-analytic studies have found consistent, clinically meaningful OCD symptom dimensions, there have been only limited attempts to evaluate the familiality and potential genetic basis of such dimensions. Methods: Four hundred eighteen sibling pairs with OCD were evaluated using the Structured Clinical Interview for DSM-IV and the Yale-Brown Obsessive Compulsive Scale (YBOCS) Symptom Checklist and Severity scales. Results: After controlling for sex, age, and age of onset, robust sib-sib intraclass correlations were found for two of the four YBOCS factors: Factor IV (hoarding obsessions and compulsions (p = .001) and Factor I (aggressive, sexual, and religious obsessions, and checking compulsions; p = .002). Smaller, but still significant, familiality was found for Factor III (contamination/cleaning; p = .02) and Factor 11 (symmetry/ordering/arranging;p = .04). Limiting the sample to female subjects more than doubled the familiality estimates for Factor 11 (p = .003). Among potentially relevant comorbid conditions for genetic studies, bipolar I/II and major depressive disorder were strongly associated with Factor I (p < .001), whereas ADHD, alcohol dependence, and bulimia were associated with Factor 11 (p < .01). Conclusions: Factor-analyzed OCD symptom dimensions in sibling pairs with OCD are familial with some gender-dependence, exhibit relatively specific relationships to comorbid psychiatric disorders and thus may be useful as refined phenotypes for molecular genetic studies of OCD. C1 NIMH, Clin Sci Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA. Butler Hosp, Brown Med Sch, Dept Psychiat & Human Behav, Providence, RI 02906 USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21205 USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. New York State Psychiat Inst & Hosp, New York, NY 10032 USA. Massachusetts Gen Hosp, Psychiat & Neurodev Genet Unit, Charlestown, MA USA. Harvard Univ, Sch Med, Charlestown, MA USA. Univ Calif Los Angeles, Dept Psychiat & Biobehav Sci, Sch Med, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Div Child & Adolescent Psychiat, Sch Med, Los Angeles, CA 90024 USA. Massachusetts Gen Hosp, Psychiat Neuroimaging Res Program, Charlestown, MA USA. Massachusetts Gen Hosp, Obsess Compuls Disorders Program, Dept Psychiat, Charlestown, MA USA. RP Murphy, DL (reprint author), NIMH, Clin Sci Lab, Intramural Res Program, NIH, Bldg 10,Room 3D41,10 Ctr Dr,MSC 1264, Bethesda, MD 20892 USA. EM dm30h@nih.gov RI Piacentini, John/C-4645-2011; Liang, Kung-Yee/F-8299-2011; Hasler, Gregor/E-4845-2012; Pinto, Anthony/D-2718-2017; OI Hasler, Gregor/0000-0002-8311-0138; Pinto, Anthony/0000-0002-6078-7242; Samuels, Jack/0000-0002-6715-7905 FU Intramural NIH HHS; NIMH NIH HHS [R01 MH50214]; PHS HHS [OPD-GERCRR00052] NR 56 TC 93 Z9 96 U1 3 U2 8 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 MAR 1 PY 2007 VL 61 IS 5 BP 617 EP 625 DI 10.1016/j.biopsych.2006.05.040 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 140BI UT WOS:000244476800006 PM 17027929 ER PT J AU Willour, VL Zandi, PP Badner, JA Steele, J Miao, KY Lopez, V MacKinnon, DF Mondimore, FM Schweizer, B McInnis, MG Miller, EB DePaulo, JR Gershon, ES McMahon, FJ Potash, JB AF Willour, Virginia L. Zandi, Peter P. Badner, Judith A. Steele, Jo Miao, Kuangyi Lopez, Victor MacKinnon, Dean F. Mondimore, Francis M. Schweizer, Barbara McInnis, Melvin G. Miller, Erin B. DePaulo, J. Raymond, Jr. Gershon, Elliot S. McMahon, Francis J. Potash, James B. TI Attempted suicide in bipolar disorder pedigrees: Evidence for linkage to 2p12 SO BIOLOGICAL PSYCHIATRY LA English DT Article DE alcoholism; attempted suicide; bipolar disorder; COGA; depression; linkage ID MAJOR DEPRESSION; COMPLEX TRAITS; SUBSTANCE-P; BEHAVIOR; ONSET; ASSOCIATION; RECEPTOR; RISK AB Background: We are interested in identifying susceptibility genes that predispose subjects to attempted suicide.. Methods: We conducted a secondary analysis of genome-wide linkage data from 162 bipolar pedigrees that incorporated attempted suicide as a clinical covariate. Results: The strongest covariate-based linkage signal was seen on 2p12 at marker D2S1777. The logarithm of odds (LOD) score at marker D2S1777 rose from 1.56 to 3.82 after inclusion of the suicide covariate, resulting in significant chromosome-wide empirically derived p-values for the overall linkage finding (p =.01) and for the change in LOD score after the inclusion of the covariate (p =.02). Conclusions: The finding on chromosome 2 replicates results from two previous studies of attempted suicide in pedigrees with alcohol dependence and in pedigrees with recurrent early-onset depression. Combined, these three studies provide compelling evidence fora locus influencing attempted suicide on 2p12. C1 Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD 21287 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD 21287 USA. Univ Chicago, Chicago, IL 60637 USA. NIMH, US Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Univ Michigan, Ann Arbor, MI 48109 USA. RP Willour, VL (reprint author), Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Meyer Bldg Room 4-143,600 N Wolfe St, Baltimore, MD 21287 USA. EM willour@jhmi.edu RI McMahon, Francis/A-7290-2009; McInnis, Melvin/F-6963-2012; OI McInnis, Melvin/0000-0002-0375-6247; McMahon, Francis/0000-0002-9469-305X FU NIMH NIH HHS [K01 MH072866, K01 MH072866-01] NR 17 TC 25 Z9 25 U1 1 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 MAR 1 PY 2007 VL 61 IS 5 BP 725 EP 727 DI 10.1016/j.biopsych.2006.05.014 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 140BI UT WOS:000244476800020 PM 17046723 ER PT J AU Singh, AK Savani, BN Albert, PS Barrett, AJ AF Singh, Anurag K. Savani, Bipin N. Albert, Paul S. Barrett, A. John TI Efficacy of CD34(+) stem cell dose in patients undergoing allogeneic peripheral blood stem cell transplantation after total body irradiation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Article DE CD34(+) dose; lung shielding; lung dose reduction; peripheral blood stem cell transplantation; total body irradiation ID VERSUS-HOST-DISEASE; IDENTICAL SIBLING TRANSPLANTATION; ENGRAFTMENT KINETICS; UNRELATED DONORS; ACUTE GRAFT; MORTALITY; SURVIVAL; MALIGNANCIES; PROPHYLAXIS; MULTICENTER AB We estimated the effect of CD34(+) stem cell dose during peripheral blood stem cell transplantation (PBSCT) in predicting mortality after total body irradiation (TBI). Between 1997 and 2004, 146 consecutive patients with hematologic malignancies received fractionated TBI (12-13.6 Gy) in 8 fractions over 4 days before undergoing PBSCT; 61 patients received TBI with reduced radiation dose to the lung (6-9 Gy). The number of CD34(+) cells transplanted was recorded for all patients. A cubic spline representation for CD34(+) dose within a Cox proportional hazards model was used to model the relationship between the CD34(+) dose and mortality. Median follow-up was 44 months (range, 12-90 months). The CD34(+) cell dose ranged from 2.45 to 15.90 X 10(6) cells/kg (median, 5.15 X 10(6) cells/kg). Risk of mortality decreased with CD34(+) doses between 4-8 X 10(6) cells/kg and then began to increase. For all patients, CD34(+) doses of 5.1-12.9 X 10(6) /kg resulted in at least a doubling of median survival associated with the lowest CD34(+) value. In patients treated with lung dose reduction, a similar range of CD34(+) dose (4.3-10.2 x 10(6) cells/kg) produced at least a 5-fold improvement from the survival associated with the lowest CD34(+) dose; however, the relationship between CD34(+) dose and mortality was not statistically different when analyzed by lung dose reduction. A method for assessing risk of mortality by CD34(+) dose as a continuous variable is presented. Risk of mortality decreased with CD34(+) doses between 4-8 X 10(6) cells/kg and then began to increase. (C) 2007 American Society for Blood and Marrow Transplantation. C1 NCI, Radiat Oncol Branch, Bethesda, MD 20892 USA. NHLBI, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Bethesda, MD 20892 USA. RP Singh, AK (reprint author), NCI, Radiat Oncol Branch, 10 Ctr Dr,Bldg 10 CRC,Room B2-3500,MSC 1642, Bethesda, MD 20892 USA. EM singan@mail.nih.gov FU Intramural NIH HHS NR 23 TC 8 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 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD MAR PY 2007 VL 13 IS 3 BP 339 EP 344 DI 10.1016/j.bbmt.2006.10.029 PG 6 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 145FC UT WOS:000244849700012 PM 17317587 ER PT J AU Garner, CE Sloan, C Sumner, SCJ Burgess, J Davis, J Etheridge, A Parham, A Ghanayem, BI AF Garner, C. Edwin Sloan, C. Sumner, S. C. J. Burgess, J. Davis, J. Etheridge, A. Parham, A. Ghanayem, B. I. TI CYP2E1-catalyzed oxidation contributes to the sperm toxicity of 1-bromopropane in mice SO BIOLOGY OF REPRODUCTION LA English DT Article DE epididymis; male reproductive tract; sperm; sperm motility and transport; toxicology ID BOAR SPERMATOZOA; CYTOCHROME-P450 2E1; IN-VITRO; RAT; INHIBITION; METABOLISM; EXPOSURE; MOTILITY; LIVER; DEHYDROGENASE AB 1-Bromopropane (1-BrP) induces dose- and time-dependent reproductive organ toxicity and reduced sperm motility in rodents. The contribution of cytochrome P4502E1 (CYP2E1) to both 1-BrP metabolism and the induction of male reproductive toxicity was investigated using wild-type (WT) and Cyp2e1(-/-)mice. In gas uptake inhalation studies, the elimination half-life of [1,2,3-C-13]-1-BrP was longer in Cyp2e1(-/-) mice relative to WT (3.2 vs. 1.3 h). Urinary metabolites were identified by C-13 nuclear magnetic resonance. The mercapturic acid of 1-bromo2-hydroxypropane (2OHBrP) was the major urinary metabolite in WT mice, and products of conjugation of 1-BrP with glutathione (GSH) were insignificant. The ratio of GSH conjugation to 2-hydroxylation increased 5-fold in Cyp2e1(-/-) mice relative to WT. After 1-BrP exposure, hepatic GSH was decreased by 76% in WT mice vs. 47% in Cyp2e1(-/-) mice. Despite a 170% increase in 1-BrP exposure in Cyp2e1(-/-) vs. WT mice, sperm motility in exposed Cyp2e1(-/-) mice did not change relative to unexposed matched controls. This suggests that metabolites produced through CYP2E1-mediated oxidation may be responsible for 1-BrP-induced sperm toxicity. Both 1-BrP and 2OHBrP inhibited the motility of sperm obtained from WT mice in vitro. However, only 2OHBrP reduced the motility of sperm obtained from Cyp2e1(-/-) mice in vitro, suggesting that conversion of parent compound to 2OHBrP within the spermatozoa may contribute, at least in part, to reduced motility. Overall, these data suggest that metabolism of 1-BrP is mediated in part by CYP2E1, and activation of 1BrP via this enzyme may contribute to the male reproductive toxicity of this chemical. C1 RTI Int, Dept Drug Metab & Pharmacokinet, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Garner, CE (reprint author), RTI Int, Dept Drug Metab & Pharmacokinet, Res Triangle Pk, NC 27709 USA. EM cegarner@rti.org FU Intramural NIH HHS NR 33 TC 10 Z9 10 U1 0 U2 4 PU SOC STUDY REPRODUCTION PI MADISON PA 1603 MONROE ST, MADISON, WI 53711-2021 USA SN 0006-3363 J9 BIOL REPROD JI Biol. Reprod. PD MAR PY 2007 VL 76 IS 3 BP 496 EP 505 DI 10.1095/biolreprod.106.055004 PG 10 WC Reproductive Biology SC Reproductive Biology GA 139OD UT WOS:000244440600018 PM 17093198 ER PT J AU Hanson, T Yang, MG AF Hanson, Timothy Yang, Mingan TI Bayesian semiparametric proportional odds models SO BIOMETRICS LA English DT Article DE frailty; generalized odds rate; hazard curve; mixture of Polya trees; regression; survival analysis; transformation model ID MAXIMUM-LIKELIHOOD-ESTIMATION; GENERALIZED LINEAR-MODELS; SURVIVAL-DATA; TRANSFORMATION MODELS; REGRESSION-MODELS; DISTRIBUTIONS; INFERENCE AB Methodology for implementing the proportional odds regression model for survival data assuming a mixture of finite Polya trees (MPT) prior on baseline survival is presented. Extensions to frailties and generalized odds rates are discussed. Although all manner of censoring and truncation can be accommodated, we discuss model implementation, regression diagnostics, and model comparison for right-censored data. An advantage of the MPT model is the relative ease with which predictive densities, survival, and hazard curves are generated. Much discussion is devoted to practical implementation of the proposed models., and a novel MCMC algorithm based on an approximating parametric normal model is developed. A modest simulation study comparing the small sample behavior of the MPT model to a rank-based estimator and a real data example is presented. C1 Univ Minnesota, Div Biostat, Sch Publ Hlth, Minneapolis, MN 55455 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Hanson, T (reprint author), Univ Minnesota, Div Biostat, Sch Publ Hlth, Minneapolis, MN 55455 USA. EM hanson@biostat.umn.edu RI Hanson, Timothy/A-9127-2016 NR 37 TC 16 Z9 16 U1 0 U2 4 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD MAR PY 2007 VL 63 IS 1 BP 88 EP 95 DI 10.1111/j.1541-0420.2006.00671.x PG 8 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 142KA UT WOS:000244647100010 PM 17447933 ER PT J AU Huang, L Kulldorff, M Gregorio, D AF Huang, Lan Kulldorff, Martin Gregorio, David TI A spatial scan statistic for survival data SO BIOMETRICS LA English DT Article DE censoring; covariate adjustment; exponential model; geographical surveillance; spatial scan statistic; survival data ID CANCER; CLUSTERS; DISEASE; SURVEILLANCE; MINNESOTA; MODELS; BREAST AB Spatial scan statistics with Bernoulli and Poisson models are commonly used for geographical disease surveillance and cluster detection. These models. suitable for count data were not designed for data with continuous outcomes. We propose a spatial scan statistic based on an exponential model to handle either uncensored or censored continuous survival data. The power and sensitivity of the developed model are investigated through intensive simulations. The method performs well for different survival distribution finictious including tile exponential, gainnia, and log-norinal distributions. We also present a method to adjust the analysis for covariates. The cluster detection rnethod is illustrated rising survival data for inen diagnosed with prostate cancer in Connecticut from 1984 to 1995. C1 NCI, Stat Res & Applicat Branch, Div Canc Control & Populat Sci, Rockville, MD 20852 USA. Harvard Univ, Sch Med, Dept Ambulatory Care & Prevent, Boston, MA 02215 USA. Harvard Pilgrim Hlth Care, Boston, MA 02215 USA. Univ Connecticut, Sch Med, Dept Community Med, Farmington, CT 06030 USA. RP Huang, L (reprint author), NCI, Stat Res & Applicat Branch, Div Canc Control & Populat Sci, 6116 Execut Blvd, Rockville, MD 20852 USA. EM huangla@mail.nih.gov RI Kulldorff, Martin/H-4282-2011; OI Kulldorff, Martin/0000-0002-5284-2993 FU PHS HHS [U50/CCU300860] NR 24 TC 53 Z9 55 U1 4 U2 14 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD MAR PY 2007 VL 63 IS 1 BP 109 EP 118 DI 10.1111/j.1541-0420.2006.00661.x PG 10 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 142KA UT WOS:000244647100012 PM 17447935 ER PT J AU Berger, VW AF Berger, Vance W. TI Drawbacks to noninteger scoring for ordered categorical data - Reply SO BIOMETRICS LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. Univ Maryland Baltimore Cty, Biometry Res Grp, Natl Canc Inst, Bethesda, MD 20892 USA. RP Berger, VW (reprint author), NCI, Execut Plaza N,Suite 3131,6130 Execut Blvd,MSC 73, Bethesda, MD 20892 USA. EM vb78c@nih.gov NR 4 TC 2 Z9 2 U1 1 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0006-341X J9 BIOMETRICS JI Biometrics PD MAR PY 2007 VL 63 IS 1 BP 298 EP 299 DI 10.1111/j.1541-0420.2007.00739_2.x PG 2 WC Biology; Mathematical & Computational Biology; Statistics & Probability SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology; Mathematics GA 142KA UT WOS:000244647100035 ER PT J AU Hwang, Y Ganguly, S Ho, AK Klein, DC Cole, PA AF Hwang, Yousang Ganguly, Surajit Ho, Anthony K. Klein, David C. Cole, Philip A. TI Enzymatic and cellular study of a serotonin N-acetyltransferase phosphopantetheine-based prodrug SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE melatonin; prodrug; POM; pantetheine; enzyme; inhibition ID MELATONIN RHYTHM ENZYME; PHOSPHATE-PROTECTIVE GROUPS; PINEAL-GLAND; 5'-MONOPHOSPHATE; INHIBITION; MECHANISM; DERIVATIVES; ANALOGS; DELIVERY; STRESS AB Serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT) regulates the daily rhythm in the production of melatonin and is therefore an attractive target for pharmacologic modulation of the synthesis of this hormone. Previously prepared bisubstrate analogs show potent inhibition of AANAT but have unfavorable pharmacokinetic properties due to the presence of phosphate groups which prevents transfer across the plasma membrane. Here, we examine a bis-pivaloyloxymethylene (POM)-tryptamine-phosphopantetheine prodrug (2) and its biotransformations in vitro by homogenates and pineal cells. Compound 2 is an efficient porcine liver esterase substrate for POM cleavage in vitro although cyclization of the phosphate moiety is a potential side product. Tryptamine phosphopantetheine (3) is converted to tryptamine-coenzyme A (CoA) bisubstrate analog (1) by human phosphoribosyl pyrophosphate amidotransferase (PPAT) and dephosphocoenzyme A kinase (DPCK) in vitro. Compound 2 was found to inhibit melatonin production in rat pineal cell culture. It was also found that the POM groups are readily removed to generate 3; however, further processing to tryptamine-CoA (1) is much slower in pineal extracts or cell culture. Implications for CoA prodrug development based on the strategy used here are discussed. (c) 2006 Elsevier Ltd. All rights reserved. C1 Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. NICHD, Sect Neuroendocrinol, Off Sci Director, NIH, Bethesda, MD 20892 USA. Univ Alberta, Dept Physiol, Edmonton, AB T6G 2H7, Canada. RP Cole, PA (reprint author), Johns Hopkins Univ, Sch Med, Dept Pharmacol & Mol Sci, Baltimore, MD 21205 USA. EM pcole@jhmi.edu FU Intramural NIH HHS; NIA NIH HHS [AG19186, R01 AG019186] NR 44 TC 8 Z9 8 U1 1 U2 9 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD MAR 1 PY 2007 VL 15 IS 5 BP 2147 EP 2155 DI 10.1016/j.bmc.2006.12.016 PG 9 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 141CH UT WOS:000244553700024 PM 17258461 ER PT J AU Chi, GC Nair, V Semenova, E Pommier, Y AF Chi, Guochen Nair, Vasu Semenova, Elena Pommier, Yves TI A novel diketo phosphonic acid that exhibits specific, strand-transfer inhibition of HIV integrase and anti-HIV activity SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE synthesis; phosphonates; HIV integrase inhibitors; mechanism of inhibition; anti-HIV activity ID HUMAN-IMMUNODEFICIENCY-VIRUS; NUCLEOBASE SCAFFOLDS; VIRAL REPLICATION; CATALYTIC DOMAIN; DNA; ACYLPHOSPHONATES; DINUCLEOTIDES; CHEMOTHERAPY; ENZYMES; DESIGN AB We have synthesized novel phosphonic acid analogues of P-diketo acids. Interestingly, the phosphonic acid isostere, 2, of our anti-HIV compound, 1, was an inhibitor of only the strand transfer step, in stark contrast to 1. Compound 2 had lower anti-HIV activity than 1, but was more active and less toxic than the phosphonic acid analogue of L-708906. These isosteric compounds represent the first examples of beta-diketo phosphonic acids of structural, synthetic, and antiviral interest. (c) 2006 Elsevier Ltd. All rights reserved. C1 Univ Georgia, Ctr Drug Discovery, Athens, GA 30602 USA. Univ Georgia, Dept Pharmaceut & Biomed Sci, Athens, GA 30602 USA. NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. RP Nair, V (reprint author), Univ Georgia, Ctr Drug Discovery, Athens, GA 30602 USA. EM vnair@rx.uga.edu FU Intramural NIH HHS; NIAID NIH HHS [R01 AI043181-08, R10 AI 43181, R01 AI043181] NR 36 TC 6 Z9 8 U1 1 U2 2 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 MAR 1 PY 2007 VL 17 IS 5 BP 1266 EP 1269 DI 10.1016/j.bmcl.2006.12.009 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 146OG UT WOS:000244943300026 PM 17188872 ER PT J AU Shults, EE Semenova, EA Johnson, AA Bondarenko, SP Bagryanskaya, IY Gatilov, YV Tolstikov, GA Pommier, Y AF Shults, Elvira E. Semenova, Elena A. Johnson, Allison A. Bondarenko, Svetlana P. Bagryanskaya, Irina Y. Gatilov, Yuri V. Tolstikov, Genrikh A. Pommier, Yves TI Synthesis and HIV-1 integrase inhibitory activity of spiroundecane(ene) derivatives SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article AB Fifteen 2,4-dioxaspiro[5.5]undecane ketone and 2,4-dioxa-spiro[5.5]undec-8-ene (spiroundecane(ene)) derivatives were synthesized using the Diels-Alder reaction. Inhibition of human immunodeficiency virus integrase (IN) was examined. Eight spiroundecane(ene) derivatives inhibited both 3'-processing and strand transfer reactions catalyzed by IN. SAR studies showed that the undecane core with at least one furan moiety is preferred for IN inhibition. Moreover, crosslinking experiments showed that spiroundecane derivatives did not affect IN-DNA binding at concentrations that block IN catalytic activity, indicating spiroundecane derivatives inhibit preformed IN-DNA complex. The moderate toxicity of spiroundecane(ene) derivatives encourages the further design of therapeutically relevant analogues based on this novel chemotype of IN inhibitors. (c) 2006 Elsevier Ltd. All rights reserved. C1 Russian Acad Sci, Siberian Branch, NN Vorozhtsov Novosibirsk Inst Organ Chem, Novosibirsk, Russia. NCI, Mol Pharmacol Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Shults, EE (reprint author), Russian Acad Sci, Siberian Branch, NN Vorozhtsov Novosibirsk Inst Organ Chem, Novosibirsk, Russia. EM schultz@nioch.nsc.ru; pommier@nih.gov RI Shults, Elvira/I-3916-2014 OI Shults, Elvira/0000-0002-0761-9696 FU Intramural NIH HHS; NCI NIH HHS [Z01 BC007333-14] NR 22 TC 21 Z9 21 U1 0 U2 2 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 MAR 1 PY 2007 VL 17 IS 5 BP 1362 EP 1368 DI 10.1016/j.bmcl.2006.11.094 PG 7 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 146OG UT WOS:000244943300046 PM 17189685 ER PT J AU Rohrbaugh, ML AF Rohrbaugh, Mark L. TI NIH offers licensing agreements to commercialize technologies SO BIOPHARM INTERNATIONAL LA English DT Article C1 NIH, Off Technol Transfer, Rockville, MD 20852 USA. RP Rohrbaugh, ML (reprint author), NIH, Off Technol Transfer, Rockville, MD 20852 USA. EM Mark.Rohrbaugh@mail.nih.gov OI Rohrbaugh, Mark/0000-0002-6136-3337 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ADVANSTAR COMMUNICATIONS PI DULUTH PA 131 W FIRST ST, DULUTH, MN 55802 USA SN 1542-166X J9 BIOPHARM INT JI Biopharm. Int. PD MAR PY 2007 VL 20 IS 3 BP 60 EP 66 PG 7 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 149TN UT WOS:000245169800014 ER PT J AU Ermolenko, DN Dangi, B Gvritishvili, A Gronenborn, AM Makhatadze, GI AF Ermolenko, Dmitri N. Dangi, Bindi Gvritishvili, Anzor Gronenborn, Angela M. Makhatadze, George I. TI Elimination of the C-cap in ubiquitin - structure, dynamics and thermodynamic consequences SO BIOPHYSICAL CHEMISTRY LA English DT Article DE protein structure; protein stability; cooperativity of unfolding; differential scanning calorimetry; heteronuclear NMR; circular dichroism spectroscopy ID HETERONUCLEAR NMR-SPECTROSCOPY; AMINO-ACID-RESIDUES; HELIX-COIL TRANSITION; HEAT-CAPACITY CHANGES; PROTEIN-STRUCTURE; SIDE-CHAIN; BIOLOGICAL MACROMOLECULES; SOLVENT DENATURATION; BACKBONE DYNAMICS; GLOBULAR-PROTEINS AB Single amino acid substitutions rarely produce substantial changes in protein structure. Here we show that substitution of the C-cap residue in the a-helix of ubiquitin with proline (34P variant) leads to dramatic structural changes. The resulting conformational perturbation extends over the last two turns of the alpha-helix and leads to enhanced flexibility for residues 27-37. Thermodynamic analysis of this ubiquitin variant using differential scanning calorimetry reveals that the thermal unfolding transition remains highly cooperative, exhibiting two-state behavior. Similarities with the wild type in the thermodynamic parameters (heat capacity change upon unfolding and in-value) of unfolding monitored by DSC and chemical denaturation suggests that the 34P variant has comparable buried surface area. The hydrophobic core of 34P variant is not packed as well as that of the wild type protein as manifested by a lower enthalpy of unfolding. The increased mobility of the polypeptide chain of this ubiquitin variant allows the transient opening of the hydrophobic core as evidenced by ANS binding. Taken together, these results suggest exceptional robustness of cooperativity in protein structures. (c) 2006 Elsevier B.V. All rights reserved. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Biochem & Mol Biol, Hershey, PA 17033 USA. Russian Acad Sci, Bach Inst Biochem, Moscow 119071, Russia. Martek Biosci, Columbia, MD 21045 USA. RP Gronenborn, AM (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM makhatadze@psu.edu OI Gronenborn, Angela M/0000-0001-9072-3525 FU Intramural NIH HHS; NIGMS NIH HHS [GM54537] NR 64 TC 8 Z9 8 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0301-4622 J9 BIOPHYS CHEM JI Biophys. Chem. PD MAR PY 2007 VL 126 IS 1-3 BP 25 EP 35 DI 10.1016/j.bpc.2006.03.017 PG 11 WC Biochemistry & Molecular Biology; Biophysics; Chemistry, Physical SC Biochemistry & Molecular Biology; Biophysics; Chemistry GA 141CK UT WOS:000244554000007 PM 16713063 ER PT J AU Bertram, R Satin, LS Pedersen, MG Luciani, DS Sherman, A AF Bertram, Richard Satin, Leslie S. Pedersen, Morten Gram Luciani, Dan S. Sherman, Arthur TI Interaction of glycolysis and mitochondrial respiration in metabolic oscillations of pancreatic islets SO BIOPHYSICAL JOURNAL LA English DT Article ID PULSATILE INSULIN-SECRETION; INDUCED ELECTRICAL-ACTIVITY; PURINE NUCLEOTIDE CYCLE; GLUCOSE-INDUCED OSCILLATIONS; MOUSE BETA-CELLS; CYTOPLASMIC CA2+; ENDOPLASMIC-RETICULUM; MUSCLE EXTRACTS; B-CELLS; PHOSPHOFRUCTOKINASE AB Insulin secretion from pancreatic beta-cells is oscillatory, with a typical period of 2-7 min, reflecting oscillations in membrane potential and the cytosolic Ca2+ concentration. Our central hypothesis is that the slow 2-7 min oscillations are due to glycolytic oscillations, whereas faster oscillations that are superimposed are due to Ca2+ feedback onto metabolism or ion channels. We extend a previous mathematical model based on this hypothesis to include a more detailed description of mitochondrial metabolism. We demonstrate that this model can account for typical oscillatory patterns of membrane potential and Ca2+ concentration in islets. It also accounts for temporal data on oxygen consumption in islets. A recent challenge to the notion that glycolyfic oscillations drive slow Ca2+ Oscillations in islets are data showing that oscillations in Ca2+, mitochondrial oxygen consumption, and NAD(P)H levels are all terminated by membrane hyperpolarization. We demonstrate that these data are in fact compatible with a model in which glycolytic oscillations are the key player in rhythmic islet activity. Finally, we use the model to address the recent finding that the activity of islets from some mice is uniformly fast, whereas that from islets of other mice is slow. We propose a mechanism for this dichotomy. C1 Florida State Univ, Dept Math, Tallahassee, FL 32306 USA. Florida State Univ, Neurosci Program, Tallahassee, FL 32306 USA. Florida State Univ, Program Mol Biophys, Tallahassee, FL 32306 USA. Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA USA. Tech Univ Denmark, Dept Phys, DK-2800 Lyngby, Denmark. Univ British Columbia, Dept Cellular & Physiol Sci, Vancouver, BC V5Z 1M9, Canada. NIDDKD, Lab Biol Modeling, NIH, Bethesda, MD 20892 USA. RP Bertram, R (reprint author), Florida State Univ, Dept Math, Tallahassee, FL 32306 USA. EM bertram@math.fsu.edu RI Pedersen, Morten/F-4134-2012; OI Pedersen, Morten/0000-0002-2639-2394; Luciani, Dan/0000-0002-4318-4159 FU NIDDK NIH HHS [R01 DK046409, R01-DK-46409] NR 54 TC 48 Z9 49 U1 0 U2 7 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAR 1 PY 2007 VL 92 IS 5 BP 1544 EP 1555 DI 10.1529/biophysj.106.097154 PG 12 WC Biophysics SC Biophysics GA 138PD UT WOS:000244373800009 PM 17172305 ER PT J AU Sharp, JS Tomer, KB AF Sharp, Joshua S. Tomer, Kenneth B. TI Analysis of the oxidative damage-induced conformational changes of apo- and holocalmodulin by dose-dependent protein oxidative surface mapping SO BIOPHYSICAL JOURNAL LA English DT Article ID MEMBRANE CA-ATPASE; SEQUENCE-INDEPENDENT RECOGNITION; IONIZATION MASS-SPECTROMETRY; HYDROXYL RADICAL PROBE; AMINO-ACID-RESIDUES; OXIDIZED CALMODULIN; RADIOLYTIC MODIFICATION; PHOTOCHEMICAL OXIDATION; METHIONINE OXIDATION; HYDROGEN-PEROXIDE AB Calmodulin (CaM) is known to undergo conformational and functional changes on oxidation, allowing CaM to function as an oxidative stress sensor. We report the use of a novel mass spectrometry-based methodology to monitor the structure of apo- and holo-CaM as it undergoes conformational changes as a result of increasing amounts of oxidative damage. The kinetics of oxidation for eight peptides are followed by mass spectrometry, and 12 sites of oxidation are determined by MS/MS. Changes in the pseudo-first-order rate constant of oxidation for a peptide after increasing radiation exposure reveal changes in the accessibility of the peptide to the diffusing hydroxyl radical, indicating conformational changes as a function of increased oxidative damage. For holo-CaM, most sites rapidly become less exposed to hydroxyl radicals as the protein accumulates oxidative damage, indicating a closing of the hydrophobic pockets in the N- and C-terminal lobes. For apo-CaM, many of the sites rapidly become more exposed until they resemble the solvent accessibility of holo-CaM in the native structure and then rapidly become more buried, mimicking the conformational changes of holo-CaM. At the most heavily damaged points measured, the rates of oxidation for both apo- and holo-CaM are essentially identical, suggesting the two assume similar structures. C1 Natl Inst Environm Hlth Sci, Lab Struct Biol, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Sharp, JS (reprint author), Natl Inst Environm Hlth Sci, Lab Struct Biol, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RI Tomer, Kenneth/E-8018-2013 FU Intramural NIH HHS NR 58 TC 37 Z9 37 U1 0 U2 6 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAR 1 PY 2007 VL 92 IS 5 BP 1682 EP 1692 DI 10.1529/biophysj.106.099093 PG 11 WC Biophysics SC Biophysics GA 138PD UT WOS:000244373800023 PM 17158574 ER PT J AU Svitel, J Boukari, H Van Ryk, D Willson, RC Schuck, P AF Svitel, Juraj Boukari, Hacene Van Ryk, Donald Willson, Richard C. Schuck, Peter TI Probing the functional heterogeneity of surface binding sites by analysis of experimental binding traces and the effect of mass transport limitation SO BIOPHYSICAL JOURNAL LA English DT Article ID FLUORESCENCE CORRELATION SPECTROSCOPY; ADSORPTION ENERGY-DISTRIBUTION; PLASMON RESONANCE BIOSENSORS; PROTEIN-PROTEIN INTERACTIONS; TOTAL INTERNAL-REFLECTION; MACROMOLECULAR INTERACTIONS; DISSOCIATION KINETICS; MONOCLONAL-ANTIBODIES; IMMOBILIZED PROTEINS; INTEGRAL-EQUATIONS AB Many techniques rely on the binding activity of surface-immobilized proteins, including antibody-based affinity biosensors for the detection of analytes, immunoassays, protein arrays, and surface plasmon resonance biosensors for the study of thermodynamic and kinetic aspects of protein interactions. To study the functional homogeneity of the surface sites and to characterize their binding properties, we have recently proposed a computational tool to determine the distribution of affinity and kinetic rate constants from surface binding progress curves. It is based on modeling the experimentally measured binding signal as a superposition of signals from binding to sites spanning a range of rate and equilibrium constants, with regularization providing the most parsimonious distribution consistent with the data. In the present work, we have expanded the scope of this approach to include a compartment-like transport step, which can describe competitive binding to different surface sites in a zone of depleted analyte close to the sensor surface. This approach addresses a major difficulty in the analysis of surface binding where both transport limitation as well as unknown surface site heterogeneity may be present. In addition to the kinetic binding parameters of the ensemble of surface sites, it can provide estimates for effective transport rate constants. Using antibody-antigen interactions as experimental model systems, we studied the effects of the immobilization matrix and of the analyte flow-rate on the effective transport rate constant. Both were experimentally observed to influence mass transport. The approximate description of mass transport by a compartment model becomes critical when applied to strongly transport-controlled data, and we examined the limitations of this model. In the presence of only moderate mass transport limitation the compartment model provides a good description, but this approximation breaks down for strongly transport-limited surface binding. In the latter regime, we report experimental evidence for the formation of gradients within the sensing volume of the evanescent field biosensor used. C1 NIH, Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. NICHHD, Lab Integrat & Med Biophys, NIH, Bethesda, MD 20892 USA. Univ Houston, Dept Chem Engn, Houston, TX 77204 USA. Univ Houston, Dept Biol & Biochem, Houston, TX 77204 USA. RP Schuck, P (reprint author), NIH, Natl Inst Biomed Imaging & Bioengn, Bethesda, MD 20892 USA. EM pschuck@helix.nih.gov OI Schuck, Peter/0000-0002-8859-6966 FU Intramural NIH HHS NR 74 TC 46 Z9 46 U1 2 U2 11 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD MAR 1 PY 2007 VL 92 IS 5 BP 1742 EP 1758 DI 10.1529/biophysj.106.094615 PG 17 WC Biophysics SC Biophysics GA 138PD UT WOS:000244373800029 PM 17158569 ER PT J AU Bai, XY Wu, J Zhang, QY Alesci, S Manoli, I Blackman, MR Chrousos, GP Goldstein, AL Rennert, OM Su, YA AF Bai, Xueyan Wu, Jun Zhang, Qiuyang Alesci, Salvatore Manoli, Irini Blackman, Marc R. Chrousos, George P. Goldstein, Allan L. Rennert, Owen M. Su, Yan A. TI Third-generation human mitochondria-focused cDNA microarray and its bioinformatic tools for analysis of gene expression SO BIOTECHNIQUES LA English DT Article ID SKELETAL-MUSCLE CELLS; NORMALIZATION METHODS; CANCER-THERAPY; CLASSIFICATION; TRANSCRIPTION; DISORDERS; TUMORIGENICITY; MELANOMA; DISEASES; DEFECTS AB To facilitate profiling mitochondrial transcriptomes, we developed a third-generation human mitochondria -focused cDNA microarray (hMitChip3) and its bioinformatic tools. hMitChip3 consists of the 37 mitochondrial DNA-encoded genes, 1098 nuclear DNA-encoded and in mitochondria -related genes, and 225 controls, each in triplicate. The bioinformatic tools included data anal sis procedures and customized database for interpretation of results. The database associated 645 molecular,functions with 946 hMitChip3 genes, 612 biological processes with 930 genes, 172 cellular components with 869 genes, 107 biological chemistry pathways with 476 genes, 23 reactome events with 227 genes, 320 genetic disorders with 237 genes, and 87 drugs targets with 55 genes. To test these tools, hMitChip3 was used to compare expression profiles between human melanoma cell lines UACC903 (rapidlly dividing) and UACC903(+6) (slowly dividing). Our results demonstrated internal gene-set consistency (correlation R > 0.980 +/- 10.005) and interexperimental reproducibility (R >= 0.931 +/- 0.013). Expression patterns of 16 genes, involved in DNA, RNA, or protein biosyntheses in mitochondrial and other organelles, were consistent with the proliferation rates of both cell lines, and the pattern. of 6 tested genes were verified by quantitative reverse transcription PCR (RT-PCR). Thus, hMitChip3 and its bioinformatics software provide an integrated tool for profliling mitochondria-focused gene expression. C1 George Washington Univ, Sch Med & Hlth Sci, Washington, DC 20037 USA. NIH, Bethesda, MD 20892 USA. RP Su, YA (reprint author), George Washington Univ, Sch Med & Hlth Sci, Ross Hall,Rm 530,2300 EYE St,NW, Washington, DC 20037 USA. EM bcmyas@gwumc.edu OI Manoli, Irini/0000-0003-1543-2941 NR 44 TC 18 Z9 19 U1 0 U2 0 PU BIOTECHNIQUES OFFICE PI NEW YORK PA 52 VANDERBILT AVE, NEW YORK, NY 10017 USA SN 0736-6205 EI 1940-9818 J9 BIOTECHNIQUES JI Biotechniques PD MAR PY 2007 VL 42 IS 3 BP 365 EP 375 DI 10.2144/000112388 PG 11 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 203BC UT WOS:000248949100024 PM 17390543 ER PT J AU Wu, SL Jones, E Gulley, JL Arlen, PM Chen, CC Figg, WD Dahut, WL AF Wu, Shenhong L. Jones, Elizabeth Gulley, James L. Arlen, Philip M. Chen, Clara C. Figg, William D. Dahut, William L. TI Routine interval computed tomography to detect new soft-tissue disease might be unnecessary in patients with androgen-independent prostate cancer and metastasis only to bone SO BJU INTERNATIONAL LA English DT Article DE CT; soft-tissue metastasis; androgen-independent prostate cancer; bone metastasis ID RANDOMIZED PHASE-II; DOCETAXEL; TRIAL; AUTOPSY; MITOXANTRONE; GUIDELINES; PREDNISONE; FLUTAMIDE; ANTIGEN; RISK AB OBJECTIVE To identify patients with androgen-independent prostate cancer (AIPC) with bone metastasis and no soft-tissue metastases at the time of protocol enrolment, and analyse their disease progression by computed tomography (CT), bone scan, and prostate-specific antigen (PSA) level to determine the utility of routine interval CT in such patients. PATIENTS AND METHODS Bone is the most common metastatic site in patients with AIPC and the only site of metastatic disease for many; because some with initial bone metastasis eventually develop soft-tissue disease, many clinical trials use routine CT to monitor for the latter as a sign of disease progression, but the actual incidence of new soft-tissue metastases is unknown and the role of routine interval CT in monitoring for disease progression, especially for asymptomatic patients, is unclear. Thus we reviewed 175 cases of metastatic AIPC from three randomized phase II clinical trials (docetaxel/thalidomide, docetaxel/vaccine, and ketoconazole/alendronate) at the National Cancer Institute between 1995 and 2004. The patients' PSA levels were assessed every 4 weeks, and CT and bone scans were done every 2-3 months. We retrospectively identified patients with bone metastasis only and examined subsequent CT for the occurrence of soft-tissue disease. For patients with progressive disease, we also examined bone scan and PSA progression. RESULTS Of 175 patients with metastatic prostate cancer, 105 (60%) had bone metastasis only, 12 (6.9%) had soft-tissue metastases only, and 58 (33.1%) had both bone and soft-tissue metastases. The median (range) follow-up was 8 (1-44) months for the 105 patients with bone metastasis only. During that time, two patients (1.9%) developed new soft-tissue disease; one developed right iliac fossa lymphadenopathy after 8 months and the other developed a perirectal mass after 12 months. The patient with new lymphadenopathy also had multiple new bone lesions identified by bone scan and PSA progression. The patient with the perirectal mass had PSA progression and a palpable abnormality. CONCLUSION This review of patients with AIPC and bone metastasis only, followed for a median of 8 months on clinical trials, shows that the incidence of asymptomatic new soft-tissue disease as the only sign of disease progression is quite low. Therefore, routine CT to exclude new soft-tissue disease in this population appears to be unwarranted. We recommend that for these patients CT is done only at the time of disease progression, as shown by bone scan, PSA level, or clinical presentation. We do not exclude the possibility that patients who remain on trial for significantly longer periods might benefit from routine interval CT. C1 NCI, Med Oncol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Dept Diagnost Radiol, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Dept Nucl Med, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Tumor Immunol & Biol Lab, Canc Res Ctr, Bethesda, MD 20892 USA. RP Dahut, WL (reprint author), NCI, Med Oncol Branch, Canc Res Ctr, 10 Ctr Dr,Room 12N266, Bethesda, MD 20892 USA. EM dahutw@mail.nih.gov RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; FU Intramural NIH HHS NR 25 TC 2 Z9 2 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1464-4096 J9 BJU INT JI BJU Int. PD MAR PY 2007 VL 99 IS 3 BP 525 EP 528 DI 10.1111/j.1464-410X.2006.06654.x PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 134AF UT WOS:000244054300011 PM 17155971 ER PT J AU Appelbaum, FR Rosenblum, D Arceci, RJ Carroll, WL Breitfeld, PP Forman, SJ Larson, RA Lee, SJ Murphy, SB O'Brien, S Radich, J Scher, NS Smith, FO Stone, RM Tallman, MS AF Appelbaum, Frederick R. Rosenblum, Daniel Arceci, Robert J. Carroll, William L. Breitfeld, Philip P. Forman, Stephen J. Larson, Richard A. Lee, Stephanie J. Murphy, Sharon B. O'Brien, Susan Radich, Jerald Scher, Nancy S. Smith, Franklin O. Stone, Richard M. Tallman, Martin S. TI End points to establish the efficacy of new agents in the treatment of acute leukemia SO BLOOD LA English DT Article ID ACUTE-MYELOID-LEUKEMIA; ACUTE LYMPHOBLASTIC-LEUKEMIA; MINIMAL RESIDUAL DISEASE; BONE-MARROW-TRANSPLANTATION; ACUTE MYELOGENOUS LEUKEMIA; QUALITY-OF-LIFE; STEM-CELL TRANSPLANTATION; ONCOLOGY-GROUP; RETROSPECTIVE ANALYSIS; GEMTUZUMAB OZOGAMICIN AB Federal regulations provide 2 pathways for approval of new agents for the treatment of acute leukemia, regular and accelerated approval. Regular approval requires evidence of clinical benefit, which is generally defined as either prolongation of life or improved quality of life, or an effect on an end point established as a surrogate for clinical benefit. Accelerated approval can be obtained based on demonstration of an effect on a surrogate measure "reasonably likely" to predict clinical benefit, but requires demonstration of clinical benefit after approval as well. The acute leukemias are a heterogeneous and relatively uncommon group of diseases. The design and execution of prospective randomized clinical trials demonstrating prolongation of life or improved quality of life for patients with these disorders can be difficult and costly and require lengthy follow-up. Thus, the development of novel trial design and inclusion of validated surrogate markers for clinical benefit are needed. To explore some of the issues pertinent to the choice of end points for drug approval in acute leukemia, the Food and Drug Administration invited the American Society of Hematology to participate in the organization and conduct of a joint workshop. In this report, we present the results of that effort. C1 Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. NIH, Bethesda, MD 20892 USA. Johns Hopkins, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. Mt Sinai Sch Med, Sch Med, New York, NY USA. NYU, Sch Med, New York, NY USA. Duke Univ, Sch Med, Durham, NC USA. City Hope Natl Med Ctr, Duarte, CA 91010 USA. Univ Chicago, Med Ctr, Chicago, IL 60637 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Texas, Hlth Sci Ctr, Childrens Canc Res Inst, San Antonio, TX 78285 USA. MD Anderson Canc Ctr, Houston, TX USA. US FDA, Rockville, MD 20857 USA. Cincinnati Childrens Hosp, Med Ctr, Cincinnati, OH USA. Northwestern Univ, Sch Med, Chicago, IL 60611 USA. RP Appelbaum, FR (reprint author), Fred Hutchinson Canc Res Ctr, Div Clin Res, 1100 Fairview Ave N,D5-310,POB 19024, Seattle, WA 98109 USA. EM fappelba@fhcrc.org OI Larson, Richard/0000-0001-9168-3203 NR 41 TC 47 Z9 50 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 MAR 1 PY 2007 VL 109 IS 5 BP 1810 EP 1816 DI 10.1182/blood-2006-08-041152 PG 7 WC Hematology SC Hematology GA 142HW UT WOS:000244641100011 PM 17095617 ER PT J AU Fakruddin, JM Lempicki, RA Gorelick, RJ Yang, J Adelsberger, JW Garcia-Pineres, AJ Pinto, LA Lanes, HC Imamichi, T AF Fakruddin, J. Mohamad Lempicki, Richard A. Gorelick, Robert J. Yang, Jun Adelsberger, Joseph W. Garcia-Pineres, Alfonso J. Pinto, Ligia A. Lanes, H. Clifford Imamichi, Tomozumi TI Noninfectious papilloma virus-like particles inhibit HIV-1 replication: implications for immune control of HIV-1 infection by IL-27 SO BLOOD LA English DT Article ID CD4(+) T-CELLS; HUMAN IMMUNODEFICIENCY VIRUS-1; CC-CHEMOKINE RECEPTOR-5; HUMAN DENDRITIC CELLS; BETA-CHEMOKINES; IN-VITRO; REVERSE TRANSCRIPTION; TYPE-1 REPLICATION; MOLECULAR CLONE; ACTINOMYCIN-D AB Human papilloma virus (HPV)-like particles (VLPs) have been used as a vaccine to prevent HPV infection. Recent studies demonstrate that VLPs bind to dendritic cells and induce the expression of antiviral cytokines such as interferon-alpha (IFN-alpha), interleukin-10 (IL-10) and IFN-gamma. In the present study, we evaluated the effect of VLPs on HIV-1 replication in peripheral blood mononuclear cells (PBMCs), CD4(+) T cells, and macrophages. Here, we show that VLPs suppress the replication of both X4 and R5 HIV-1 without affecting the expression of CD4, CXCR4, and CCR5. Soluble factor(s) released by PBMCs and macrophages on VLPs treatment inhibited HIV-1 replication. To determine the inhibitory factors, DNA microarray analysis was performed using VLP-treated PBMCs and macrophages. VLPs induced the genes associated with IFN induction, immune responses, and antiviral responses, among with the recently described cytokine IL-27. Subsequently, IL-27 was found to be a potent inhibitor of HIV-1 replication in PBMCs, CD4(+) T cells, and macrophages. Taken together, our studies identify a novel role of IL-27 in restricting HIV-1 replication and suggest that further examination of the inhibitory property of IL-27 may pave the way for a novel therapy for HIV-1 infection. C1 NCI, SAIC Frederick Inc, Lab Human Retrovirol, CSP, Frederick, MD 21702 USA. NCI, SAIC Frederick Inc, Lab Immunopathogenesis & Bioinformat, CSP, Frederick, MD 21702 USA. NCI, SAIC Frederick Inc, AIDS Vaccine Program, Retroviral Mutagenesis Sect, Frederick, MD 21702 USA. NCI, SAIC Frederick Inc, AIDS Monitoring Lab, CSP, Frederick, MD 21702 USA. NCI, SAIC Frederick Inc, HPV Monitoring Lab, CSP, Frederick, MD 21702 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Imamichi, T (reprint author), NCI, SAIC Frederick Inc, Lab Human Retrovirol, CSP, Bldg 550,Rm 126,Sultan Dr,POB B, Frederick, MD 21702 USA. EM timamichi@mail.nih.gov RI Lempicki, Richard/E-1844-2012 OI Lempicki, Richard/0000-0002-7059-409X FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 65 TC 45 Z9 50 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 MAR 1 PY 2007 VL 109 IS 5 BP 1841 EP 1849 DI 10.1182/blood-2006-02-001578 PG 9 WC Hematology SC Hematology GA 142HW UT WOS:000244641100016 PM 17068156 ER PT J AU Isenberg, JS Hyodo, F Matsumoto, KI Romeo, MJ Abu-Asab, M Tsokos, M Kuppusamy, P Wink, DA Krishna, MC Roberts, DD AF Isenberg, Jeff S. Hyodo, Fuminori Matsumoto, Ken-Ichiro Romeo, Martin J. Abu-Asab, Mones Tsokos, Maria Kuppusamy, Periannan Wink, David A. Krishna, Murali C. Roberts, David D. TI Thrombospondin-1 limits ischemic tissue survival by inhibiting nitric oxide-mediated vascular smooth muscle relaxation SO BLOOD LA English DT Article ID CELL RESPONSES; IN-VIVO; ENDOGENOUS THROMBOSPONDIN-1; ANGIOGENESIS; FLAPS; RAT; CONTRACTION; PROTEINS; ARTERIES; PATHWAY AB The nitric oxide (NOYcGMP pathway, by relaxing vascular smooth muscle cells, is a major physiologic regulator of tissue perfusion. We now identify thrombospondin-1 as a potent antagonist of NO for regulating F-actin assembly and myosin light chain phosphorylation in vascular smooth muscle cells. Thrombospondin-1 prevents NO-mediated relaxation of precontracted vascular smooth muscle cells in a collagen matrix. Functional magnetic resonance imaging demonstrated that an NO-mediated increase in skeletal muscle perfusion was enhanced in thrombospondin-1-null relative to wildtype mice, implicating endogenous thrombospondin-1 as a physiologic antagonist of NO-mediated vasodilation. Using a random myocutaneous flap model for ischemic injury, tissue survival was significantly enhanced in thrombospondin-1-null mice. Improved flap survival correlated with increased recovery of oxygen levels in the ischemic tissue of thrombospondin-1-null mice as measured by electron paramagnetic resonance oximetry. These findings demonstrate an important antagonistic relation between NO/cGMP signaling and thrombospondin-1 in vascular smooth muscle cells to regulate vascular tone and tissue perfusion. C1 NCI, Lab Pathol, NIH, Bethesda, MD 20892 USA. Ohio State Univ, Dept Internal Med, Davis Heart & Lung Res Inst, Columbus, OH 43210 USA. NCI, Radiat Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Roberts, DD (reprint author), NCI, Lab Pathol, NIH, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008; OI Roberts, David/0000-0002-2481-2981; Abu-Asab, Mones/0000-0002-4047-1232 FU Intramural NIH HHS NR 49 TC 68 Z9 69 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 1 PY 2007 VL 109 IS 5 BP 1945 EP 1952 DI 10.1182/blood-2006-08-041368 PG 8 WC Hematology SC Hematology GA 142HW UT WOS:000244641100030 PM 17082319 ER PT J AU Ramilo, O Allman, W Chung, W Mejias, A Ardura, M Glaser, C Wittkowski, KM Piqueras, B Banchereau, J Palucka, AK Chaussabel, D AF Ramilo, Octavio Allman, Windy Chung, Wendy Mejias, Asuncion Ardura, Monica Glaser, Casey Wittkowski, Knut M. Piqueras, Bernard Banchereau, Jacques Palucka, A. Karolina Chaussabel, Damien TI Gene expression patterns in blood leukocytes discriminate patients with acute infections SO BLOOD LA English DT Article ID HOST-DEFENSE MOLECULES; NORMAL HUMAN MONOCYTES; MICROARRAY PLATFORMS; HUMAN MACROPHAGES; IMMUNE-RESPONSES; HUMAN NEUTROPHIL; DENDRITIC CELLS; INTERFERON; VIRUS; ACTIVATION AB Each infectious agent represents a unique combination of pathogen-associated molecular patterns that interact with specific pattern-recognition receptors expressed on immune cells. Therefore, we surmised that the blood immune cells of individuals with different infections might bear discriminative transcriptional signatures. Gene expression profiles were obtained for 131 peripheral blood samples from pediatric patients with acute infections caused by influenza A virus, Gram-negative (Escherichia coli) or Gram-positive (Staphylococcus aureus and Streptococcus pneumoniae) bacteria. Thirty-five genes were identified that best discriminate patients with influenza A virus infection from patients with either E coli or S pneumoniae infection. These genes classified with 95% accuracy (35 of 37 samples) an independent set of patients with either influenza A, E coli, or S pneumoniae infection. A different signature discriminated patients with E coli versus S aureus infections with 85% accuracy (34 of 40). Furthermore, distinctive gene expression patterns were observed in patients presenting with respiratory infections of different etiologies. Thus, microarray analyses of patient peripheral blood leukocytes might assist in the differential diagnosis of infectious diseases. C1 NIAID, Cooperat Ctr Translat Res Human Immunol & Biodef, Dallas, TX USA. NIAID, Baylor Inst Immunol Res, Dallas, TX USA. Univ Texas, Southwestern Med Ctr, Div Pediat Infect Dis, Dallas, TX 75230 USA. Childrens Med Ctr, Dallas, TX 75235 USA. Rockefeller Univ, Gen Clin Res Ctr, New York, NY USA. RP Ramilo, O (reprint author), NIAID, Cooperat Ctr Translat Res Human Immunol & Biodef, Dallas, TX USA. EM octavio.ramilo@utsouthwestern.edu; jacquesb@baylorhealth.edu; damienc@baylorhealth.edu RI Mejias, Maria Asuncion/E-3659-2011; OI Chaussabel, Damien/0000-0002-6131-7242 FU NCI NIH HHS [CA78846, R01 CA078846]; NIAID NIH HHS [U19 AI057234, U19 AI057234-02] NR 44 TC 234 Z9 243 U1 0 U2 12 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 MAR 1 PY 2007 VL 109 IS 5 BP 2066 EP 2077 DI 10.1182/blood-2006-02-002477 PG 12 WC Hematology SC Hematology GA 142HW UT WOS:000244641100046 PM 17105821 ER PT J AU Malaspina, A Moir, S Chaitt, DG Rehm, CA Kottilil, S Falloon, J Fauci, AS AF Malaspina, Angela Moir, Susan Chaitt, Doreen G. Rehm, Catherine A. Kottilil, Shyam Falloon, Judith Fauci, Anthony S. TI Idiopathic CD4(+) T lymphocytopenia is associated with increases in immature/transitional B cells and serum levels of IL-7 SO BLOOD LA English DT Article ID PRIMARY IMMUNODEFICIENCY DISEASES; HIV-INFECTED INDIVIDUALS; OPPORTUNISTIC INFECTIONS; HOMEOSTASIS; INTERLEUKIN-7; STATES AB Idiopathic CD4(+) T lymphocytopenia (ICL) is a rare heterogeneous disorder defined by CD4(+) T-cell counts below 300 cells/mu L in the absence of human immunodeficiency virus (HIV) infection or other known immune deficiency disorders. Here, we report the expansion of immature/transitional B cells in patients with ICL, which is associated with elevated serum levels of IL-7. Both the percentage of immature/transitional B cells and levels of IL-7 were inversely correlated with levels of CD4(+) T-cell counts and directly correlated to each other. Further analyses of B cells indicated that, in contrast to the activating effects of HIV disease on mature B cells, the expansion of immature/transitional B cells in patients with ICL occurred at the expense of memory B cells. These findings extend previous reports on primary immunodeficiencies as well as HIV disease by suggesting that CD4(+) T-cell lymphopenia has an impact on human B-cell development either directly or indirectly via the associated elevation of IL-7 levels. C1 NIAID, Lab Immunoregulat, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Moir, S (reprint author), NIAID, Lab Immunoregulat, NIH, Dept Hlth & Human Serv, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM smoir@niaid.nih.gov FU Intramural NIH HHS NR 22 TC 64 Z9 66 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 1 PY 2007 VL 109 IS 5 BP 2086 EP 2088 DI 10.1182/blood-2006-06-031385 PG 3 WC Hematology SC Hematology GA 142HW UT WOS:000244641100048 PM 17053062 ER PT J AU Landgren, O Rapkin, JS Caporaso, NE Mellemkjaer, L Gridley, G Goldin, LR Engels, EA AF Landgren, Ola Rapkin, Joshua S. Caporaso, Neil E. Mellemkjaer, Lene Gridley, Gloria Goldin, Lynn R. Engels, Eric A. TI Respiratory tract infections and subsequent risk of chronic lymphocytic leukemia SO BLOOD LA English DT Article ID UNDETERMINED SIGNIFICANCE; MULTIPLE-MYELOMA; MONOCLONAL GAMMOPATHY; HODGKIN-LYMPHOMA; CELL; CLASSIFICATION; AUTOIMMUNITY; SCANDINAVIA; PATTERNS; USAGE AB Recent evidence suggests that chronic lymphocytic leukemia (CLL) might occur following a response to an infectious agent. We conducted a population-based study including 4249 CLL patients diagnosed in Denmark from 1977 to 1997 and 15 690 frequency-matched controls to quantify risk of CLL following various airway infections. Through data linkage we gathered information on hospital inpatient/outpatient discharges that listed infections present at least 1 year prior to CLL. Using logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs). Personal history of pneumonia was associated with significantly increased CLL risk (OR = 1.4; 1.2-1.8); risk was restricted to 1 to 4.99 years prior to CLL diagnosis (OR = 1.6; 1.2-2.0). Individuals with 3 or more prior pneumonia events had a significant 2.5-fold (1.1-5.6) elevated CLL risk, and risk increased with the number of pneumonia episodes (P-trend < .001). None of 9 other respiratory-tract infections was significantly associated with CLL risk. Pneumonia might be a potential CLL trigger or it could represent premalignant immune disruption preceding CLL. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. RP Landgren, O (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,Bldg EPS Room 7110, Bethesda, MD 20892 USA. EM landgreo@mail.nih.gov FU Intramural NIH HHS NR 25 TC 57 Z9 58 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD MAR 1 PY 2007 VL 109 IS 5 BP 2198 EP 2201 DI 10.1182/blood-2006-08-044008 PG 4 WC Hematology SC Hematology GA 142HW UT WOS:000244641100062 PM 17082317 ER PT J AU Fu, HQ Wang, LX Lin, CM Bouhassira, EE Aladjem, MI AF Fu, Haiqing Wang, Lixin Lin, Chii-Mei Bouhassira, Eric E. Aladjem, Mirit I. TI Interactions between replication and chromatin condensation in the human beta-globin locus SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 15th Conference on Hemoglobin Switching CY SEP 14-18, 2006 CL St Johns Coll, Oxford, ENGLAND HO St Johns Coll C1 NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. Yeshiva Univ Albert Einstein Coll Med, Bronx, NY 10461 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAR-APR PY 2007 VL 38 IS 2 MA 1 BP 123 EP 124 DI 10.1016/j.bcmd.2006.10.012 PG 2 WC Hematology SC Hematology GA 140OB UT WOS:000244513900011 ER PT J AU Bishop, TR AF Bishop, Terry Rogers TI NIH grant applications: BIG changes! SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 15th Conference on Hemoglobin Switching CY SEP 14-18, 2006 CL St Johns Coll, Oxford, ENGLAND HO St Johns Coll C1 NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAR-APR PY 2007 VL 38 IS 2 MA 5 BP 125 EP 125 DI 10.1016/j.bcmd.2006.10.016 PG 1 WC Hematology SC Hematology GA 140OB UT WOS:000244513900015 ER PT J AU Bodine, DM Owen, AN Maksimova, Y Elnitski, L Wong, C Seidel, NE Cline, AP Gallagher, PG AF Bodine, David M. Owen, Ashley N. Maksimova, Yelena Elnitski, Laura Wong, Clara Seidel, Nancy E. Cline, Amanda P. Gallagher, Patrick G. TI Erythroid specific activation of the ankyrin-1E promoter by the formation of a chromatin loop SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 15th Conference on Hemoglobin Switching CY SEP 14-18, 2006 CL St Johns Coll, Oxford, ENGLAND HO St Johns Coll C1 NHGRI, NIH, Hematopoiesis Sect, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Pediat, New Haven, CT USA. NR 0 TC 0 Z9 0 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAR-APR PY 2007 VL 38 IS 2 MA 7 BP 126 EP 127 DI 10.1016/j.bcmd.2006.10.018 PG 2 WC Hematology SC Hematology GA 140OB UT WOS:000244513900017 ER PT J AU Cokic, VP Bhattacharya, B Smith, RD Beleslin-Cokic, BB Noguchi, CT Puri, RK Schechter, AN AF Cokic, Vladan P. Bhattacharya, Bhaskar Smith, Reginald D. Beleslin-Cokic, Bojana B. Noguchi, Constance T. Puri, Raj K. Schechter, Alan N. TI Gene expression profiling in fetal and adult definitive erythropoiesis SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 15th Conference on Hemoglobin Switching CY SEP 14-18, 2006 CL St Johns Coll, Oxford, ENGLAND HO St Johns Coll C1 Inst Med Res, Lab Expt Hematol, Belgrade, Serbia. US FDA, Ctr Biol Evaluat & Res, Div Cellular & Gene Therapies, Tumor Vaccines & Biotechnol Branch, Bethesda, MD USA. GE Global Res Ctr, Biosci Technol, Niskayuna, NY USA. Inst Endocrinol Diabetes & Dis Metab, Belgrade, Serbia. NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAR-APR PY 2007 VL 38 IS 2 MA 20 BP 131 EP 132 DI 10.1016/j.bcmd.2006.10.031 PG 2 WC Hematology SC Hematology GA 140OB UT WOS:000244513900030 ER PT J AU Kim, A Kiefer, CM Dean, A AF Kim, AeRi Kiefer, Christine M. Dean, Ann TI Chromatin structure and epigenetic modification in the human beta-globin locus SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 15th Conference on Hemoglobin Switching CY SEP 14-18, 2006 CL St Johns Coll, Oxford, ENGLAND HO St Johns Coll C1 NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAR-APR PY 2007 VL 38 IS 2 MA 27 BP 135 EP 135 DI 10.1016/j.bcmd.2006.10.038 PG 1 WC Hematology SC Hematology GA 140OB UT WOS:000244513900037 ER PT J AU Gaszner, M Huang, S West, A Felsenfeld, G AF Gaszner, Miklos Huang, Surning West, Adam Felsenfeld, Gary TI Epigenetic regulation at the chicken beta-globin locus SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 15th Conference on Hemoglobin Switching CY SEP 14-18, 2006 CL St Johns Coll, Oxford, ENGLAND HO St Johns Coll C1 NIDDK, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAR-APR PY 2007 VL 38 IS 2 BP 137 EP 138 DI 10.1016/j.bcmd.2006.10.044 PG 2 WC Hematology SC Hematology GA 140OB UT WOS:000244513900043 ER PT J AU Gallagher, PG Pilon, AM Arcasoy, MO Vayda, SE Dressman, HK Bieker, JJ Bodine, DM AF Gallagher, Patrick G. Pilon, Andre M. Arcasoy, Murat O. Vayda, Serena E. Dressman, Holly K. Bieker, James J. Bodine, David M. TI Failure of definitive erythropoiesis in EKLF-deficient mice SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 15th Conference on Hemoglobin Switching CY SEP 14-18, 2006 CL St Johns Coll, Oxford, ENGLAND HO St Johns Coll C1 Yale Univ, Sch Med, New Haven, CT USA. NHGRI, NIH, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Durham, NC USA. Mt Sinai Sch Med, New York, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAR-APR PY 2007 VL 38 IS 2 MA 39 BP 140 EP 141 DI 10.1016/j.bcmd.2006.10.050 PG 2 WC Hematology SC Hematology GA 140OB UT WOS:000244513900049 ER PT J AU Huang, S Felsenfeld, G AF Huang, Surning Felsenfeld, Gary TI Histone methylations are important for USF1 mediated chromatin barrier function at the chicken beta-globin locus SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 15th Conference on Hemoglobin Switching CY SEP 14-18, 2006 CL St Johns Coll, Oxford, ENGLAND HO St Johns Coll C1 NIDDK, NIH, Mol Biol Lab, Bethesda, MD 20892 USA. Univ Florida, Coll Med, Inst Genet, Dept Biochem & Mol Biol, Gainesville, FL 32610 USA. NR 0 TC 0 Z9 0 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAR-APR PY 2007 VL 38 IS 2 MA 52 BP 145 EP 146 DI 10.1016/j.bcmd.2006.10.063 PG 2 WC Hematology SC Hematology GA 140OB UT WOS:000244513900062 ER PT J AU Miller, JL AF Miller, Jeffery L. TI Silencing and reactivation of gamma-globin expression in humans SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 15th Conference on Hemoglobin Switching CY SEP 14-18, 2006 CL St Johns Coll, Oxford, ENGLAND HO St Johns Coll C1 NIH, NIDDK, Mol Med Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAR-APR PY 2007 VL 38 IS 2 MA 84 BP 160 EP 160 DI 10.1016/j.bcmd.2006.10.095 PG 1 WC Hematology SC Hematology GA 140OB UT WOS:000244513900094 ER PT J AU Schweers, RL Loyd, MR Randall, MS Zhang, J Dorsey, C Li, WM Miller, JL Ney, PA AF Schweers, Rachel L. Loyd, Melanie R. Randall, Mindy S. Zhang, Ji Dorsey, Chuck Li, Weimin Miller, Jeffery L. Ney, Paul A. TI BNIP3L promotes mitochondrial destruction and ribosome clearance in maturing reticulocytes SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 15th Conference on Hemoglobin Switching CY SEP 14-18, 2006 CL St Johns Coll, Oxford, ENGLAND HO St Johns Coll C1 St Jude Childrens Res Hosp, Dept Biochem, Memphis, TN 38105 USA. St Jude Childrens Res Hosp, Dept Biochem, Memphis, TN 38105 USA. Natl Inst Diabetes & Digest & Kidney Dis & Hlth, Dept Biochem, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 EI 1096-0961 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAR-APR PY 2007 VL 38 IS 2 MA 87 BP 161 EP 162 DI 10.1016/j.bcmd.2006.10.098 PG 2 WC Hematology SC Hematology GA 140OB UT WOS:000244513900097 ER PT J AU Noguchi, CT Rogers, H AF Noguchi, Constance Tom Rogers, Heather TI Hypoxia alters progression of the erythroid program SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 15th Conference on Hemoglobin Switching CY SEP 14-18, 2006 CL St Johns Coll, Oxford, ENGLAND HO St Johns Coll C1 NIH, NIDDK, Mol Med Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAR-APR PY 2007 VL 38 IS 2 MA 90 BP 163 EP 163 DI 10.1016/j.bcmd.2006.10.101 PG 1 WC Hematology SC Hematology GA 140OB UT WOS:000244513900100 ER PT J AU Owen, AN Pilon, AM Wong, C Seidel, NE Cline, AP Gallagher, PG Bodine, DM AF Owen, Ashley N. Pilon, Andre M. Wong, Clara Seidel, Nancy E. Cline, Amanda P. Gallagher, Patrick G. Bodine, David M. TI Structure and function of the chromatin surrounding the erythroid ankyrin promoter (ANK-1E) SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 15th Conference on Hemoglobin Switching CY SEP 14-18, 2006 CL St Johns Coll, Oxford, ENGLAND HO St Johns Coll C1 NHGRI, NIH, Hematopoiesis Sect, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA. NR 0 TC 0 Z9 0 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 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAR-APR PY 2007 VL 38 IS 2 MA 94 BP 165 EP 165 DI 10.1016/j.bcmd.2006.10.1005 PG 1 WC Hematology SC Hematology GA 140OB UT WOS:000244513900104 ER PT J AU Pilon, AM Arcasoy, MO Vayda, SE Dressman, HK Bieker, JJ Bodine, DM Gallagher, PG AF Pilon, Andre M. Arcasoy, Murat O. Vayda, Serena E. Dressman, Holly K. Bieker, James J. Bodine, David M. Gallagher, Patrick G. TI EKLF-deficiency leads to multiple defects in erythropoiesis: Dysregulation of AHSP and E2F SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 15th Conference on Hemoglobin Switching CY SEP 14-18, 2006 CL St Johns Coll, Oxford, ENGLAND HO St Johns Coll C1 NHGRI, NIH, Bethesda, MD 20892 USA. Duke Univ, Sch Med, Durham, NC USA. Mt Sinai Sch Med, New York, NY USA. Yale Univ, Sch Med, New Haven, CT USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAR-APR PY 2007 VL 38 IS 2 MA 107 BP 172 EP 172 DI 10.1016/j.bcmd.2006.10.118 PG 1 WC Hematology SC Hematology GA 140OB UT WOS:000244513900117 ER PT J AU Ryu, BY Gray, JT Bodine, DM Nienhuis, AW AF Ryu, Byoung Y. Gray, John T. Bodine, David M. Nienhuis, Arthur W. TI Activation of the LMO2 gene in human lymphoid cells by targeted insertion of a single retroviral LTR expression cassette into the first intron SO BLOOD CELLS MOLECULES AND DISEASES LA English DT Meeting Abstract CT 15th Conference on Hemoglobin Switching CY SEP 14-18, 2006 CL St Johns Coll, Oxford, ENGLAND HO St Johns Coll C1 St Jude Childrens Hosp, Dept Hematol, Memphis, TN 38105 USA. NHGRI, Genet & Mol Biol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1079-9796 J9 BLOOD CELL MOL DIS JI Blood Cells Mol. Dis. PD MAR-APR PY 2007 VL 38 IS 2 MA 115 BP 176 EP 176 DI 10.1016/j.bcmd.2006.10.126 PG 1 WC Hematology SC Hematology GA 140OB UT WOS:000244513900125 ER PT J AU Lazarus, JE Hegde, A Andrade, AC Nilsson, O Baron, J AF Lazarus, Jacob E. Hegde, Anita Andrade, Anenisia C. Nilsson, Ola Baron, Jeffrey TI Fibroblast growth factor expression in the postnatal growth plate SO BONE LA English DT Article DE FGF; EGER; growth plate; senescence; chondrocyte ID LONGITUDINAL BONE-GROWTH; FACTOR RECEPTOR 3; ENDOCHONDRAL OSSIFICATION; THANATOPHORIC DYSPLASIA; TRANSGENIC MICE; FGF; MUTATIONS; ACHONDROPLASIA; CHONDROGENESIS; OSTEOGENESIS AB Fibroblast growth factor (FGF) signaling is essential for endochondral bone formation. Mutations cause skeletal dysplasias including achondroplasia, the most common human skeletal dysplasia. Most previous work in this area has focused on embryonic chondrogenesis. To explore the role of FGF signaling in the postnatal growth plate, we quantitated expression of FGFs and FGF receptors (FGFRs) and examined both their spatial and temporal regulation. Toward this aim, rat proximal tibial growth plates and surrounding tissues were microdissected, and specific mRNAs were quantitated by real-time RT-PCR. To assess the FGF system without bias, we first screened for expression of all known FGFs and major FGFR isoforms. Perichondrium expressed FGFs 1, 2, 6, 7, 9, and 18 and, at lower levels, FGFs 21 and 22. Growth plate expressed FGFs 2, 7, 18, and 22. Perichondrial expression was generally greater than growth plate expression, supporting the concept that perichondrial FGFs regulate growth plate chondrogenesis. Nevertheless, FGFs synthesized by growth plate chondrocytes may be physiologically important because of their proximity to target receptors. In growth plate, we found expression of FGFRs 1, 2, and 3, primarily, but not exclusively, the c isoforms. FGFRs1 and 3, thought to negatively regulate chondrogenesis, were expressed at greater levels and at later stages of chondrocyte differentiation, with FGFR1 upregulated in the hypertrophic zone and FGFR3 upregulated in both proliferative and hypertrophic zones. In contrast, FGFRs 2 and 4, putative positive regulators, were expressed at earlier stages of differentiation, with FGFR2 upregulated in the resting zone and FGFR4 in the resting and proliferative zones. FGFR-L1, a presumed decoy receptor, was expressed in the resting zone. With increasing age and decreasing growth velocity, FGFR2 and 4 expression was downregulated in proliferative zone. Perichondrial FGF1, FGF7, FGF18, and FGF22 were upregulated. In summary, we have analyzed the expression of all known FGFs and FGFRs in the postnatal growth plate using a method that is quantitative and highly sensitive. This approach identified ligands and receptors not previously known to be expressed in growth plate and revealed a complex pattern of spatial regulation of FGFs and FGFRs in the different zones of the growth plate. We also found temporal changes in FGF and FGFR expression which may contribute to growth plate senescence and thus help determine the size of the adult skeleton. (c) 2006 Elsevier Inc. All rights reserved. C1 NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Karolinska Inst, Dept Woman & Child Hlth, Pediat Endocrinol Unit, Stockholm, Sweden. RP Baron, J (reprint author), CRC, Room 1-3330,10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. EM jeffrey.baron@nih.gov OI Nilsson, Ola/0000-0002-9986-8138 FU Intramural NIH HHS NR 50 TC 48 Z9 54 U1 3 U2 8 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 8756-3282 J9 BONE JI Bone PD MAR PY 2007 VL 40 IS 3 BP 577 EP 586 DI 10.1016/j.bone.2006.10.013 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 141CA UT WOS:000244552800003 PM 17169623 ER PT J AU Geyer, CE Mamounas, E Jeong, JH Wickerham, L Ganz, P Hutchins, L Eisen, A Ingle, J Costantino, J Wolmark, N AF Geyer, C. E. Mamounas, E. Jeong, J. -H. Wickerham, L. Ganz, P. Hutchins, L. Eisen, A. Ingle, J. Costantino, J. Wolmark, N. TI Exemestane (EXE) as extended adjuvant therapy after 5 years of tamoxifen (TAM): results of NSABP B-33 SO BREAST LA English DT Meeting Abstract C1 [Geyer, C. E.; Mamounas, E.; Jeong, J. -H.; Wickerham, L.; Costantino, J.; Wolmark, N.] Natl Surg Adjuvant Breast & Bowel Project, Pittsburgh, PA 15212 USA. [Geyer, C. E.; Wolmark, N.] Allegheny Gen Hosp, Pittsburgh, PA USA. [Mamounas, E.] Aultman Hlth Fdn, Canton, OH USA. [Ganz, P.] Univ Calif Los Angeles, Los Angeles, CA USA. [Hutchins, L.] Arkansas Canc Res Ctr, Little Rock, AR USA. [Eisen, A.] Toronto Sunnybrook Reg Canc Ctr, N York, ON, Canada. [Ingle, J.] Mayo Clin, Rochester, MN USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0960-9776 J9 BREAST JI Breast PD MAR PY 2007 VL 16 BP S46 EP S46 DI 10.1016/S0960-9776(07)70177-7 PG 1 WC Oncology; Obstetrics & Gynecology SC Oncology; Obstetrics & Gynecology GA 320ZU UT WOS:000257274600147 ER PT J AU Ferrucci, L Guralnik, JM Bandinelli, S Semba, RD Lauretani, F Corsi, A Ruggiero, C Ershler, WB Longo, DL AF Ferrucci, Luigi Guralnik, Jack M. Bandinelli, Stefania Semba, Richard D. Lauretani, Fulvio Corsi, Annamaria Ruggiero, Carmelinda Ershler, William B. Longo, Dan L. TI Unexplained anaemia in older persons is characterised by low erythropoietin and low levels of pro-inflammatory markers SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE unexplained anaemia; ageing; erythropoietin; inflammation; Invecchiare in Chianti ID HEMOGLOBIN CONCENTRATION; PHYSICAL PERFORMANCE; INCHIANTI; MECHANISMS; WOMEN; VITAMIN-B-12; DEFICIENCY; MORTALITY; ILLNESS; DECLINE AB Epidemiological studies report that a third of the cases of anaemia in older persons is unexplained. We compared erythropoietin (EPO), inflammatory markers and major comorbidities between older subjects with normal haemoglobin levels and those with different aetiologic forms of anaemia, including unexplained anaemia. Participants were a representative sample of 964 persons aged >= 65 years, with no evidence of bleeding, complete blood tests, and a complete blood count within 6 h of phlebotomy. Anaemia was defined as haemoglobin < 130 g/l in men and 120 g/l in women, and classified as a result of chronic kidney disease, iron deficiency, chronic disease and B12/folate deficiency anaemia, or unexplained anaemia based on standard criteria. Of the 124 anaemic participants, 42 (36.8%) had unexplained anaemia. Participants with anaemia of chronic diseases had significantly higher interleukin-6 (IL-6) and C-reactive protein (CRP) levels, while those with unexplained anaemia had significantly lower CRP than non-anaemic controls. Iron deficiency anaemia was characterised by significantly higher EPO levels compared with other types of anaemia and normal haemoglobin, B12 and/or folate deficiency. Unexplained anaemia was characterised by unexpectedly low EPO and low lymphocyte count. Unexplained anaemia is associated with reduced kidney EPO response, low levels of pro-inflammatory markers and low lymphocyte counts. C1 Johns Hopkins Med Inst, Intramural Res Program, NIA, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Ophthalmol, Baltimore, MD 21205 USA. Univ Florence, Geriatr Rehabil Unit, ASF, Florence, Italy. Univ Florence, Dept Med & Surg Crit Area, Florence, Italy. RP Ferrucci, L (reprint author), Harbor Hosp, NIA, Longitudinal Studies Sect, Clin Res Branch,ASTRA Unit, 5th Floor,3001 S Hanover St, Baltimore, MD 21225 USA. EM ferruccilu@grc.nia.nih.gov RI Lauretani, Fulvio/K-5115-2016 OI Lauretani, Fulvio/0000-0002-5287-9972 FU Intramural NIH HHS [Z99 AG999999]; NIA NIH HHS [R01 AG027012, N01-AG-821336, N01-AG-916413]; NIMHD NIH HHS [263 MD 821336, 263 MD 9164 13, R01 MD009164] NR 30 TC 66 Z9 69 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD MAR PY 2007 VL 136 IS 6 BP 849 EP 855 DI 10.1111/j.1365-2141.2007.06502.x PG 7 WC Hematology SC Hematology GA 141XF UT WOS:000244611600011 PM 17341272 ER PT J AU Srinivasan, R Balow, JE Sabnis, S Lundqvist, A Igarashi, T Takahashi, Y Austin, H Tisdale, J Barrett, J Srivastava, S Savani, B Geller, N Childs, R AF Srinivasan, R. Balow, J. E. Sabnis, S. Lundqvist, A. Igarashi, T. Takahashi, Y. Austin, H. Tisdale, J. Barrett, J. Srivastava, S. Savani, B. Geller, N. Childs, R. TI Nephrotic syndrome associated with thrombotic microangiopathy following allogeneic stem cell transplantation for myelodysplastic syndrome - response to Nakamura et al SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Letter DE stem cell transplantation; nephrotic syndrome; thrombotic microangiopathy ID BONE-MARROW-TRANSPLANTATION; CHRONIC MYELOID-LEUKEMIA C1 NHLBI, Hematol Branch, Bethesda, MD 20892 USA. NHLBI, NCI, Urol Oncol Branch, Bethesda, MD 20892 USA. NHLBI, NIDDK, Bethesda, MD 20892 USA. NHLBI, Armed Forces Inst Pathol, Bethesda, MD 20892 USA. NHLBI, Off Biostat, Bethesda, MD 20892 USA. RP Srinivasan, R (reprint author), NHLBI, Hematol Branch, Bldg 10, Bethesda, MD 20892 USA. EM ramasrin@mail.nih.gov OI Lundqvist, Andreas/0000-0002-9709-2970 NR 5 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD MAR PY 2007 VL 136 IS 6 BP 859 EP 860 DI 10.1111/j.1365-2141.2007.06516.x PG 3 WC Hematology SC Hematology GA 141XF UT WOS:000244611600014 ER PT J AU Cantor, D AF Cantor, David TI Uncertain enthusiasm: The American Cancer Society, public education, and the problems of the movie, 1921-1960 SO BULLETIN OF THE HISTORY OF MEDICINE LA English DT Article; Proceedings Paper CT Cancer in the Twentieth Century Workshop CY NOV 15-17, 2004 CL NIH, Bethesda, MD SP Natl Lib Med, Hist Med Div, Wellcome Unit, Univ Manchester, Ctr Hist Sci, Technol & Med, Soc Social Hist Med HO NIH DE public-education movies; cancer education; American Society for the Control of Cancer; American Cancer Society; cancerphobia ID CULTURE AB Historians have highlighted a growing medical enthusiasm for public health education movies in the early twentieth century. This essay suggests that there is another historiographic tale to tell, of concerns that films might undermine the public health messages they were designed to promote-concerns that threatened continued interest in movies during the Depression of the 1930s. First, focusing on cancer-education movies aimed at the general public released by the American Society for the Control of Cancer (ASCC, founded 1913), the paper argues that the organization's initial enthusiasm for movies was tempered from the late 1920s by a combination of high production costs, uncertainty as to the effectiveness of movies as public-education tools, and the hard economic situation. It was only after 1944 that motion pictures became a stable part of the propaganda efforts of the renamed American Cancer Society. This transformation followed the takeover of the Society by advertisers and businesspeople, led by Mary Lasker, who introduced business models of fund-raising and education, and made expensive communication technologies, such as movies, central to cancer control. Second, the article also traces the persistence of anxieties that movies might undermine cancer control by encouraging emotional responses C1 Natl Lib Med, Bethesda, MD 20894 USA. NCI, Bethesda, MD 20892 USA. RP Cantor, D (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. EM cantord@mail.nih.gov NR 102 TC 16 Z9 16 U1 1 U2 8 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 0007-5140 J9 B HIST MED JI Bull. Hist. Med. PD SPR PY 2007 VL 81 IS 1 BP 39 EP 69 DI 10.1353/bhm.2007.0002 PG 31 WC Health Care Sciences & Services; History & Philosophy Of Science SC Health Care Sciences & Services; History & Philosophy of Science GA 145PH UT WOS:000244876500002 PM 17369662 ER PT J AU Solomon, D Breen, N McNeel, T AF Solomon, Diane Breen, Nancy McNeel, Timothy TI Cervical cancer screening rates in the United States and the potential impact of implementation of screening guidelines SO CA-A CANCER JOURNAL FOR CLINICIANS LA English DT Article ID PARTICLE VACCINE; YOUNG-WOMEN; NEOPLASIA; TRIAL; MANAGEMENT; EFFICACY; CYTOLOGY; TYPE-18; RISK AB The remarkable success achieved in cervical cancer prevention is largely attributable to cervical cytology screening, also known as the Papanicolaou (Pap) test. The American Cancer Society (ACS) revised screening guidelines for Pap testing in 2002. The impact of these changes on future numbers of Pap tests has not been assessed. Using National Health Interview Survey (NHIS) data to determine historical screening patterns, we extrapolate the numbers of Pap tests that would be performed through 2010, under 5 different scenarios of implementation of screening guidelines. From 1993 to 2003, there was a steady increase in the number of Pap tests, with an estimated 65.6 million Pap tests performed in 2003. Approximately two thirds of women born after 1930 reported having been screened within the previous year, and 85% within the previous 3 Fifteen percent of Pap tests were performed in hysterectomized women, most of whom, according to current guidelines, should be screened. Based on population projections, if screening behavior remains unchanged, 75 million Pap tests will be 2010. Full compliance with ACS guidelines would approximately halve the total number of tests to 34 million. Potentially, with appropriate allocation of resources according to guidelines, all women could be screened and the total number of Pap tests despite projected increases in the population. C1 NCI, Div Canc Prevent, Rockville, MD USA. Natl Canc Inst, Div Canc Control & Populat Sci, Rockville, MD USA. Informat Management Serv Inc, Silver Spring, MD USA. RP Solomon, D (reprint author), NCI, Div Canc Prevent, Rockville, MD USA. NR 21 TC 79 Z9 80 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0007-9235 J9 CA-CANCER J CLIN JI CA-Cancer J. Clin. PD MAR-APR PY 2007 VL 57 IS 2 BP 105 EP 111 PG 7 WC Oncology SC Oncology GA 152UQ UT WOS:000245387900006 PM 17392387 ER PT J AU Wright, ME Virtamo, J Hartman, AM Pietinen, P Edwards, BK Taylor, PR Huttunen, JK Albanes, D AF Wright, Margaret E. Virtamo, Jarmo Hartman, Anne M. Pietinen, Pirjo Edwards, Brenda K. Taylor, Philip R. Huttunen, Jussi K. Albanes, Demetrius TI Effects of alpha-tocopherol and beta-carotene supplementation on upper aerodigestive tract cancers in a large, randomized controlled trial SO CANCER LA English DT Article DE beta-carotene; chemoprevention; randomized trial; alpha-tocopherol; upper aerodigestive tract cancers ID NUTRITION INTERVENTION TRIALS; DISEASE-SPECIFIC MORTALITY; NECK-CANCER; SERUM MICRONUTRIENTS; LUNG-CANCER; VITAMIN-E; GASTRIC CANCERS; ESOPHAGEAL; HEAD; CHINA AB BACKGROUND. Although smoking and alcohol consumption are the major risk factors for upper aerodigestive tract cancers, observational studies indicate a protective role for fruits, vegetables, and antioxidant nutrients. METHODS. The authors examined whether daily supplementation with 50 mg CH alpha-tocopheryl acetate and/or 20 mg beta-carotene reduced the incidence of or mortality from oral/pharyngeal, esophageal, and laryngeal cancers in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) study, a double-blind, placebo-controlled primary prevention trial conducted in southwestern Finland. A total of 29,133 male smokers, aged 50-69 years and free of cancer at baseline, were randomized in a 2 x 2 factorial design to the supplementation regimen for 5-8 years (median, 6.1 years). Incident cancers of the oral cavity and pharynx (n = 65), esophagus (n = 24), and larynx (n = 56) were identified through the Finnish Cancer Registry. Intervention effects were assessed using survival analysis and proportional hazards models. RESULTS. There was no effect of either agent on the overall incidence of any upper aerodigestive tract cancer. For larynx, however, exploratory subgroup analyses were suggestive of a protective effect of beta-carotene supplementation on the incidence of early stage malignancies (stage I, relative risk [RR], 0.28, 95% confidence interval [CI]: 0.10-0.75). Neither agent affected mortality from these neoplasms. CONCLUSIONS. The results do not provide support for a protective effect of vitamin E or beta-carotene supplementation on upper aerodigestive tract cancers, although beta-carotene supplementation may impact the incidence of some subtypes of laryngeal tumors. C1 NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. Natl Publ Hlth Inst, Dept Hlth Promot & Chron Dis Prevent, Helsinki, Finland. NCI, Div Canc Control & Populat Sci, NIH, DHHS, Bethesda, MD 20892 USA. RP Wright, ME (reprint author), Univ Illinois, Dept Pathol MC847, 840 S Wood St,Room 130 CSN, Chicago, IL USA. EM mewright@uic.ed RI Albanes, Demetrius/B-9749-2015 FU CCR NIH HHS [N01-RC-45035, N01-RC-37004]; Intramural NIH HHS; NCI NIH HHS [N01-CN-45165] NR 34 TC 25 Z9 25 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 MAR 1 PY 2007 VL 109 IS 5 BP 891 EP 898 DI 10.1002/cncr.22482 PG 8 WC Oncology SC Oncology GA 141MK UT WOS:000244582600010 PM 17265529 ER PT J AU Robey, RW Polgar, O Deeken, J To, KW Bates, SE AF Robey, Robert W. Polgar, Orsolya Deeken, John To, Kin Wah Bates, Susan E. TI ABCG2: determining its relevance in clinical drug resistance SO CANCER AND METASTASIS REVIEWS LA English DT Review DE ABCG2; multidrug resistance; ABC transporters ID BINDING CASSETTE TRANSPORTER; ACUTE-MYELOID-LEUKEMIA; BREAST-CANCER CELLS; SIDE POPULATION CELLS; SINGLE NUCLEOTIDE POLYMORPHISMS; ACUTE LYMPHOBLASTIC-LEUKEMIA; TYROSINE KINASE INHIBITOR; TOPOISOMERASE-I INHIBITORS; MESSENGER-RNA EXPRESSION; CALCIUM-CHANNEL BLOCKERS AB Multidrug resistance is a major obstacle to successful cancer treatment. One mechanism by which cells can become resistant to chemotherapy is the expression of ABC transporters that use the energy of ATP hydrolysis to transport a wide variety of substrates across the cell membrane. There are three human ABC transporters primarily associated with the multidrug resistance phenomenon, namely Pgp, MRPI, and ABCG2. All three have broad and, to a certain extent, overlapping substrate specificities, transporting the major drugs currently used in cancer chemotherapy. ABCG2 is the most recently described of the three major multidrug-resistance pumps, and its substrates include mitoxantrone, topotecan, irinotecan, flavopiridol, and methotrexate. Despite several studies reporting ABCG2 expression in normal and malignant tissues, no trials have thus far addressed the role of ABCG2 in clinical drug resistance. This gives us an opportunity to critically review the disappointing results of past clinical trials targeting Pgp and to propose strategies for ABCG2. We need to know in which tumor types ABCG2 contributes to the resistance phenotype. We also need to develop standardized assays to detect ABCG2 expression in vivo and to carefully select the chemotherapeutic agents and clinical trial designs. This review focuses on our current knowledge about normal tissue distrubution, tumor expression profiles, and substrates and inhibitors of ABCG2, together with lessons learned from clinical trials with Pgp inhibitors. Implications of SNPs in the ABCG2 gene affecting the pharmacokinetics of substrate drugs, including many non-chemotherapy agents and ABCG2 expression in the SP population of stem cells are also discussed. C1 NCI, Ctr Canc Res, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Ctr Canc Res, Med Oncol Branch, NIH, Bethesda, MD 20892 USA. EM sebates@helix.nih.gov RI To, Kenneth /M-4500-2013 OI To, Kenneth /0000-0003-2755-0283 FU Intramural NIH HHS NR 204 TC 214 Z9 228 U1 0 U2 28 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-7659 J9 CANCER METAST REV JI Cancer Metastasis Rev. PD MAR PY 2007 VL 26 IS 1 BP 39 EP 57 DI 10.1007/s10555-007-9042-6 PG 19 WC Oncology SC Oncology GA 159VF UT WOS:000245895000004 PM 17323127 ER PT J AU Al-Chalabi, T Figg, WD AF Al-Chalabi, Tania Figg, William D. TI Benefits of the combination of thalidomide plus cyclophosphamide in hormone refractory prostate cancer patients SO CANCER BIOLOGY & THERAPY LA English DT Editorial Material DE hormone refractory prostate cancer; oral chemotherapy; angiogenesis inhibitors AB Prostate cancer is the most commonly diagnosed visceral cancer in men and the second leading cause of cancer related deaths in United States. Prostate cancer is a major clinical problem, not only because of its high incidence, but also due to high morbidity. 1 The growth of prostate cancer is driven by circulating androgens; thus, the initial treatment for metastatic disease is medical or surgical castration. 2 The duration of response for androgen ablation can vary depending on tumor burden, but in general averages 24 months. 3 After failure of hormone therapy, chemotherapy is often introduced. Ideally, a chemotherapeutic regime for patients with hormone refractory prostate cancer (HRPC) should be efficacious, improve survival, palliate symptoms, be nontoxic and improve quality of life compared to best standards of care. The use of thalidomide is based on data suggesting it inhibit angiogenesis. 4 Angiogenesis appears to be important to the growth and spread of prostate cancer. 5 Microvessel density, a measure of tumor angiogenesis, is significantly greater in tumors from men with metastatic prostate cancer than in lesions from those with localized disease. 6 Thalidomide was first used as a sedative hypnotic and antiemesis agent in pregnant women until teratogenic effects were reported in the early 1960s, it was found that teratogenisity was cause by the drug's ability to disrupt, vasculogenesis, that same effect was used then to inhibit angiogenesis of tumor cells. 7 There is increased interest in the treatment of cancer with thalidomide because of its antiangiogenic and immunomodulating properties. Cyclophosphamide is a pro-drug that requires hepatic metabolism to be converted into alkylating agent. 1 It is used as a single agent and in combination with other chemotherapy agents in several tumor types. There has been mixed results reported for cyclophosphamide in patients with HRPC. 1 However, one preclinical experiment examined continuous low doses of cyclophosphamide combined with thalidomide in rat prostate tumors. 8 The results showed significantly delay in tumor growth associated with the combination therapy. Based on those animal data and hints that the thalidomide and cyclophosphamide showed clinical activity as monotherapy, the aim of the clinical trial reported by Dr. Lorenzo and colleagues was to combine these agents in patients with HPRC. 9 This study is a phase I study, for patients with HRPC who had been previously treated with docetaxel-chemotherapy as first line therapy. Patients were required to continue using LHRH agonist for those who had not undergone bilateral orchiectomy. Sixteen patients were enrolled. The clinical results from this small phase I are extremely encouraging. The maximum tolerated dose for thalidomide was 100 mg/ day with 50 mg/ day of cyclophosphamide. 15% of patients had a greater than 50% decline in PSA and additional patients had a decline that was slightly less than 50%. Fifteen percent had a reduction in pain, concurrent with a reduction in analgesic consumption. The side effects of this combination regimen, at the MTD, were manageable: neutropenia 20% and anemia 10%. At the higher dose of 200 mg/ day of thalidomide the side effect profile was significantly greater ( thrombocytopenia, constipation, peripheral neuropathy, fatigue, skin rash, venous thrombosis, neutropenia, and anemia). All the above findings share two common things, an aim to prolong the survival and more important; an aim to improve the quality of life for patients where cure is no longer an option. C1 NCI, Natl Inst Hlth, Ctr Canc Res, Mol Pharmacol Sect, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Natl Inst Hlth, Ctr Canc Res, Mol Pharmacol Sect, 9000 Rockville Pike,Bldg 10 Room 5A01,MSC1910, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 NR 9 TC 0 Z9 0 U1 1 U2 1 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD MAR PY 2007 VL 6 IS 3 BP 318 EP 319 PG 2 WC Oncology SC Oncology GA 190TF UT WOS:000248082500008 PM 17471018 ER PT J AU Glasker, S Lonser, RR Okamoto, H Li, J Jaffee, H Oldfield, EH Zhuang, ZP Vortmeyer, AO AF Glaesker, Sven Lonser, Russell R. Okamoto, Hiroaki Li, Jie Jaffee, Howard Oldfield, Edward H. Zhuang, Zhengping Vortmeyer, Alexander O. TI Proteomic profiling - A novel method for differential diagnosis? SO CANCER BIOLOGY & THERAPY LA English DT Article DE hemangioblastoma; von Hippel Lindau disease; proteomics; renal carcinoma ID HEMANGIOBLASTOMA AB Tumors with identical phenotype can have markedly different biologic behavior. The differentiation between hemangioblastoma, a benign vascular brain tumor, and renal cell carcinoma (RCC), a malignant tumor that can metastasize to the brain, is a well-known pathological quandary. We report a 59-year-old female with von Hippel-Lindau disease and known RCC. She presented with a cystic cerebellar tumor that had typical MRI appearance of a hemangioblastoma. Progressive symptoms led to surgical intervention. The histology included features consistent with either hemangioblastoma with epitheloid phenotype or atypical RCC metastasis mimicking hemangioblastoma. The discrepancy between the benign clinical course and the histologic phenotype could not be clearly resolved using conventional clinical techniques. We used proteomic profiling to clarify this diagnostic dilemma. We compared the proteomic expression pattern of the unknown lesion with the patterns of three typical hemangioblastomas and three typical RCCs by using selective tissue microdissection combined with two-dimensional proteomic profiling and protein sequencing. The results clearly indicated a protein profile consistent with RCC. Proteomics may complement pathological evaluation and characterization of tumors in the future. Furthermore, these results show that metastasis of malignant RCC is not necessarily equivalent to aggressive growth patterns. C1 NINDS, Surg Neurol Branch, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, NIH, Surg Neurol Branch, Neurochem Lab, Bethesda, MD 20892 USA. RP Glasker, S (reprint author), NINDS, Surg Neurol Branch, Bldg 10,Room 5D37,10 Ctr Dr, Bethesda, MD 20892 USA. EM sven.glaesker@uniklinikfreiburg.de FU Intramural NIH HHS NR 4 TC 5 Z9 5 U1 0 U2 0 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD MAR PY 2007 VL 6 IS 3 BP 343 EP 345 PG 3 WC Oncology SC Oncology GA 190TF UT WOS:000248082500013 PM 17471020 ER PT J AU Okamoto, H Li, J Glasker, S Vortmeyer, AO Jaffe, H Robison, RA Bogler, O Mikkelsen, T Lubensky, IA Oldfield, EH Zhuang, ZP AF Okamoto, Hiroaki Li, Jie Glaesker, Sven Vortmeyer, Alexander O. Jaffe, Howard Robison, R. Aaron Bogler, Oliver Mikkelsen, Tom Lubensky, Irina A. Oldfield, Edward H. Zhuang, Zhengping TI Proteomic comparison of oligodendrogliomas with and without 1pLOH SO CANCER BIOLOGY & THERAPY LA English DT Article DE oligodendroglioma; loss of heterozygosity; chromosome 1p; proteomics; two-dimensional electrophoresis; mass spectrometry ID DRUG-INDUCED APOPTOSIS; APC TUMOR-SUPPRESSOR; GLYCOGEN-PHOSPHORYLASE; GLYOXALASE-I; CATHEPSIN-D; GLIOBLASTOMA-MULTIFORME; CANCER-CHEMOTHERAPY; GENE-EXPRESSION; BREAST-CANCER; CELL LINES AB Objective: Chemoresistance is a widespread therapeutic challenge in glial tumors. The molecular basis of chemoresistance is poorly understood, precluding advances in glioma treatment and leaving gliomas among the most lethal tumors. Oligodendrogliomas provide a unique model to study the molecular basis of chemoresistance, as there are two distinct genetic subtypes with significant differences in chemosensitivity. Despite a high morphological similarity, tumors with allelic loss on the short arm of chromosome 1 (1pLOH) are more chemosensitive than those without 1pLOH. Methods: In order to identify candidate proteins potentially responsible for glioma chemosensitivity, we compared the proteome of four oligodendrogliomas with and five without 1pLOH using comparative proteomic profiling. Proteomic analysis was performed by two-dimensional protein gel electrophoresis and subsequent computerized gel analysis for detection of distinguishing patterns of protein expression. Differentially expressed proteins were identified using Liquid Chromatography/Mass Spectrometry. Differential expression of select proteins was confirmed by Western blotting. Results: We identified seven candidate proteins that are overexpressed in oligodendrogliomas without 1pLOH. Two of these proteins ( glyoxalase I and Rho GDP dissociation inhibitor) have previously been shown to enhance chemoresistance in other tumors. In turn, we identified twelve overexpressed proteins in tumors with 1pLOH that have previously been reported to induce chemosensitivity in other forms of human neoplasia. Conclusions: These identified proteins are potential targets for pharmacological therapy and may also be useful as biomarkers for differentiation of chemoresistant and chemosensitive oligodendroglioma. C1 NINDS, NIH, Prot Peptide Sequencing Fac, Surg Neurol Branch, Bethesda, MD 20892 USA. Saga Univ, Fac Med, Dept Neurosurg, Saga, Japan. Henry Ford Hosp, Hermelin Brain Tumor Ctr, Dept Neurosurg, William & Karen Davidson Lab Brain Tumor Biol, Detroit, MI 48202 USA. RP Zhuang, ZP (reprint author), NINDS, NIH, Prot Peptide Sequencing Fac, Surg Neurol Branch, Bldg 10,Room 5D 37, Bethesda, MD 20892 USA. EM zhuangp@ninds.nih.gov OI Bogler, Oliver/0000-0002-3700-0480; Robison, Richard Aaron/0000-0001-8014-9451 FU Intramural NIH HHS; NCI NIH HHS [CA095809-04] NR 44 TC 13 Z9 14 U1 0 U2 2 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD MAR PY 2007 VL 6 IS 3 BP 391 EP 396 PG 6 WC Oncology SC Oncology GA 190TF UT WOS:000248082500020 PM 17264672 ER PT J AU Li, J Cusatis, G Brahmer, J Sparreboom, A Robey, RW Bates, SE Hidalgo, M Baker, SD AF Li, Jing Cusatis, George Brahmer, Julie Sparreboom, Alex Robey, Robert W. Bates, Susan E. Hidalgo, Manuel Baker, Sharyn D. TI Association of variant ABCG2 and the pharmacokinetics of epidermal growth factor receptor tyrosine kinase inhibitors in cancer patients SO CANCER BIOLOGY & THERAPY LA English DT Article DE gefitinib; erlotinib; EGFR tyrosine kinase inhibitor; ABCG2; polymorphism; pharma-cokinetics ID RESISTANCE PROTEIN BCRP/ABCG2; BINDING CASSETTE TRANSPORTERS; TANDEM MASS-SPECTROMETRY; ORAL BIOAVAILABILITY; DRUG-RESISTANCE; METHOTREXATE TRANSPORT; MULTIDRUG TRANSPORTER; IMATINIB MESYLATE; HUMAN PLASMA; EFFLUX PUMP AB The purpose of the study was to determine if the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib, are substrates for the efflux transporter ABCG2, and to investigate the relevance of the ABCG2 421C > A (Q141K) polymorphism to the pharmacokinetics of gefitinib. Gefitinib and erlotinib transport in vitro was studied using HEK293 cells transfected with wild-type ABCG2 or a Q141K clone. Gefitinib pharmacokinetics was determined in 27 cancer patients. ABCG2 421C > A and ABCB1 3435C > T genotypes were determined using direct sequencing. Cells expressing wild-type ABCG2 exhibited lower intracellular accumulation of gefitinib and erlotinib at concentrations of 0.1 and 1 mu M, and higher efflux at 10 mu M than cells lacking ABCG2 (p < 0.05); no significant difference in cellular efflux and accumulation was observed in the variant cell line at lower concentrations nor in the three cell lines at 10 mM. In the presence of the ABCG2 inhibitor fumitremorgin C, cellular accumulation of gefitinib and erlotinib 1mM was increased in wild-type ( p < 0.05), but not in variant or null cells. Gefitinib accumulation during 28 days of treatment (C-ss,C-min/ C-1,C-min) was higher in patients heterozygous at the ABCG2 421C > A locus than those with a wild-type genotype (median, 5.07 vs. 3.60, p = 0.004). No significant associations were observed between the ABCB1 3435C > T genotype and gefitinib pharmacokinetics. In conclusion, gefitinib and erlotinib are ABCG2 substrates, while they inhibit ABCG2 at higher concentrations. A functional variant of ABCG2 is associated with greater gefitinib accumulation at steady-state and may be relevant to toxicity and antitumor activity of EGFR TKIs. C1 Sidney Kimmel Compreshens Canc Ctr Johns Hopkins, Baltimore, MD USA. Natl Canc Inst, Bethesda, MD USA. RP Baker, SD (reprint author), St Jude Childrens Res Hosp, Dept Pharmaceut Sci, 332 N Lauderdale St,DTRC Room D1034,Mail Stop 314, Memphis, TN 38105 USA. EM sharyn.baker@stjude.org RI Sparreboom, Alex/B-3247-2008; Cusatis, Gianluca/G-2539-2011; HIDALGO, MANUEL/I-4995-2015 OI HIDALGO, MANUEL/0000-0002-3765-3318 NR 41 TC 109 Z9 113 U1 0 U2 4 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4047 J9 CANCER BIOL THER JI Cancer Biol. Ther. PD MAR PY 2007 VL 6 IS 3 BP 432 EP 438 PG 7 WC Oncology SC Oncology GA 190TF UT WOS:000248082500026 PM 17312388 ER PT J AU Clegg, LX Reichman, ME Hankey, BF Miller, BA Lin, YD Johnson, NJ Schwartz, SM Bernstein, L Chen, VW Goodman, MT Gomez, SL Graff, JJ Lynch, CF Lin, CC Edwards, BK AF Clegg, Limin X. Reichman, Marsha E. Hankey, Benjamin F. Miller, Barry A. Lin, Yi D. Johnson, Norman J. Schwartz, Stephen M. Bernstein, Leslie Chen, Vivien W. Goodman, Marc T. Gomez, Scarlett L. Graff, John J. Lynch, Charles F. Lin, Charles C. Edwards, Brenda K. TI Quality of race, Hispanic ethnicity, and immigrant status in population-based cancer registry data: implications for health disparity studies SO CANCER CAUSES & CONTROL LA English DT Article DE National Longitudinal Mortality Study; NLMS; race; ethnicity and immigrant status; surveillance; epidemiology; End Results; SEER ID NATIONAL DEATH INDEX; END RESULTS PROGRAM; UNITED-STATES; AMERICAN-INDIANS; BREAST-CANCER; BIRTHPLACE; SURVEILLANCE; SELF; EPIDEMIOLOGY; WOMEN AB Population-based cancer registry data from the Surveillance, Epidemiology, and End Results (SEER) Program at the National Cancer Institute are based on medical records and administrative information. Although SEER data have been used extensively in health disparities research, the quality of information concerning race, Hispanic ethnicity, and immigrant status has not been systematically evaluated. The quality of this information was determined by comparing SEER data with self-reported data among 13,538 cancer patients diagnosed between 1973-2001 in the SEER-National Longitudinal Mortality Study linked database. The overall agreement was excellent on race (kappa = 0.90, 95% CI = 0.88-0.91), moderate to substantial on Hispanic ethnicity (kappa = 0.61, 95% CI = 0.58-0.64), and low on immigrant status (kappa = 0.21. 95% CI = 0.10, 0.23). The effect of these disagreements was that SEER data tended to under-classify patient numbers when compared to self-identifications, except for the non-Hispanic group which was slightly over-classified. These disagreements translated into varying racial-, ethnic-, and immigrant status-specific cancer statistics, depending on whether self-reported or SEER data were used. In particular, the 5-year Kaplan-Meier survival and the median survival time from all causes for American Indians/Alaska Natives were substantially higher when based on self-classification (59% and 140 months, respectively) than when based on SEER classification (44% and 53 months, respectively), although the number of patients is small. These results can serve as a useful guide to researchers contemplating the use of population-based registry data to ascertain disparities in cancer burden. In particular, the study results caution against evaluating health disparities by using birthplace as a measure of immigrant status and race information for American Indians/Alaska Natives. C1 US Dept Vet Affairs, Off Healthcare Inspect, Off Inspector Gen, Washington, DC 20001 USA. NCI, Surveillance Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Monash Univ, Sch Med, Melbourne, Vic 3004, Australia. US Bur Census, Suitland, MD USA. Fred Hutchinson Canc Res Ctr, Program Epidemiol, Div Publ Hlth Sci, Seattle, WA 98104 USA. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. LSU Sch Publ Hlth, Louisiana Tumor Registry, New Orleans, LA USA. Univ Hawaii, Canc Res Ctr, Honolulu, HI 96822 USA. No Calif Canc Ctr, Fremont, CA USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI 48202 USA. Univ Iowa, State Hlth Registry Iowa, Iowa City, IA 52242 USA. RP Clegg, LX (reprint author), US Dept Vet Affairs, Off Healthcare Inspect, Off Inspector Gen, 801 I St,NW,Room 1018, Washington, DC 20001 USA. EM Lin.clegg@va.gov NR 43 TC 93 Z9 97 U1 0 U2 3 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD MAR PY 2007 VL 18 IS 2 BP 177 EP 187 DI 10.1007/s10552-006-0089-4 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 134EL UT WOS:000244065700007 PM 17219013 ER PT J AU Folger, SG Marchbanks, PA McDonald, JA Bernstein, L Ursin, G Berlin, JA Daling, JR Norman, SA Strom, BL Weiss, LK Simon, MS Burkman, RT Malone, KE Spirtas, R AF Folger, Suzanne G. Marchbanks, Polly A. McDonald, Jill A. Bernstein, Leslie Ursin, Giske Berlin, Jesse A. Daling, Janet R. Norman, Sandra A. Strom, Brian L. Weiss, Linda K. Simon, Michael S. Burkman, Ronald T. Malone, Kathleen E. Spirtas, Robert TI Risk of breast cancer associated with short-term use of oral contraceptives SO CANCER CAUSES & CONTROL LA English DT Article DE oral contraceptives; breast cancer; epidemiology; case control studies ID EPITHELIAL OVARIAN-CANCER; HEALTH-BENEFITS; ENDOMETRIOSIS; WOMEN AB To estimate breast cancer risk associated with short-term (< 6 months) oral contraceptive use, and explore variation in estimates by use characteristics and medical, menstrual, and reproductive history. We analyzed data from the Women's Contraceptive and Reproductive Experiences Study. Case subjects were white women and black women, 35-64 years old, diagnosed with invasive breast cancer in July 1994-April 1998. Control subjects identified by random-digit dialing were matched to case subjects by age, race, and study site. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Overall, short-term oral contraceptive use was not associated with breast cancer risk (OR = 1.0; 95% CI = 0.8-1.1). However, significant interaction between short-term use and menopausal status led to an observed increased breast cancer risk in pre-menopausal women (OR = 1.3; 95% CI = 1.0-1.7) and a reduced risk in post-menopausal women (OR = 0.8; 95% CI = 0.6-1.0) associated with short-term use. The association was more pronounced in women with non-contraceptive reasons for use and underlying risk factors for breast cancer. These associations may result from underlying characteristics of users or unmeasured factors influencing duration of use and breast cancer risk. C1 Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA 30333 USA. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA. Univ Oslo, Dept Nutr, N-0316 Oslo, Norway. Johnson & Johnson Pharmaceut Res & Dev, Titusville, NJ USA. Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. NCI, Canc Ctr Branch, Bethesda, MD 20892 USA. Wayne State Univ, Karmanos Canc Inst, Div Hematol & Oncol, Detroit, MI 48202 USA. Baystate Med Ctr, Dept Obstet & Gynecol, Springfield, MA 01199 USA. NICHHD, Contracept & Reprod Hlth Branch, Populat Res Ctr, NIH, Bethesda, MD 20892 USA. RP Folger, SG (reprint author), 4770 Buford Highway NE,Mailstop K34, Atlanta, GA 30341 USA. EM sxgl@cdc.gov FU NCI NIH HHS [N01 CN0532, N01 PC67006, N01 CN65064, N01 PC67010]; NICHD NIH HHS [N01 HD33174, N01 HD33168, N01 HD23166, N01 HD33176, N01 HD33175, Y01 HD7022] NR 26 TC 8 Z9 12 U1 2 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 MAR PY 2007 VL 18 IS 2 BP 189 EP 198 DI 10.1007/s10552-006-0086-7 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 134EL UT WOS:000244065700008 PM 17216547 ER PT J AU Izeradjene, K Combs, C Best, M Gopinathan, A Wagner, A Girady, WM Deng, CX Hruban, RH Adsay, NV Tuveson, DA Hingorani, SR AF Izeradjene, Kamel Combs, Chelsea Best, Melissa Gopinathan, Aarthi Wagner, Amary Girady, William M. Deng, Chu-Xia Hruban, Ralph H. Adsay, N. Volkan Tuveson, David A. Hingorani, Sunil R. TI Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas SO CANCER CELL LA English DT Article ID GROWTH-FACTOR-BETA; TGF-BETA; INTRAEPITHELIAL NEOPLASIA; DUCTAL ADENOCARCINOMA; MESENCHYMAL TRANSITION; KNOCKOUT MICE; MOUSE MODELS; HUMAN CANCER; PROGRESSION; PATHWAY AB Oncogenic Kras initiates pancreatic tumorigenesis, while subsequent genetic events shape the resultant disease. We show here that concomitant expression of Kras(G12D) and haploinsufficiency of the Smad4/Dpc4 tumor suppressor gene engenders a distinct class of pancreatic tumors, mucinous; cystic neoplasms (MCNs), which culminate in invasive ductal adenocarcinomas. Disease evolves along a progression scheme analogous to, but distinct from, the classical PanIN-to-ductal adenocarcinoma sequence, and also portends a markedly different prognosis. Progression of MCNs; is accompanied by LOH of Dpc4 and mutation of either p53 or p16. Thus, these distinct phenotypic routes to invasive adenocarcinoma nevertheless share the same overall mutational spectra. Our findings suggest that the sequence, as well as the context, in which these critical mutations are acquired helps determine the ensuing pathology. C1 Fred Hutchinson Canc Res Ctr, Clin Res Div, Seattle, WA 98109 USA. Fred Hutchinson Canc Res Ctr, Publ Hlth Sci Div, Seattle, WA 98109 USA. Univ Washington, Sch Med, Seattle, WA 98109 USA. Univ Penn, Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Abramson Canc Ctr, Philadelphia, PA 19104 USA. NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Sol Goldman Canc Res Ctr, Dept Pathol, Baltimore, MD 21287 USA. Johns Hopkins Univ, Sch Med, Sol Goldman Canc Res Ctr, Dept Oncol, Baltimore, MD 21287 USA. Wayne State Univ, Sch Med, Detroit, MI 48201 USA. Harper Grace Hosp, Dept Pathol, Detroit, MI 48201 USA. RP Hingorani, SR (reprint author), Fred Hutchinson Canc Res Ctr, Clin Res Div, Seattle, WA 98109 USA. EM srh@fhcrc.org RI Tang, Amy/L-3226-2016; deng, chuxia/N-6713-2016 OI Tang, Amy/0000-0002-5772-2878; FU NCI NIH HHS [P30 CA15704, P50 CA62924, R01 CA101973, U01 CA084291] NR 48 TC 156 Z9 162 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1535-6108 J9 CANCER CELL JI Cancer Cell PD MAR PY 2007 VL 11 IS 3 BP 229 EP 243 DI 10.1016/j.ccr.2007.01.017 PG 15 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 149MU UT WOS:000245151800005 PM 17349581 ER PT J AU Caporaso, NE AF Caporaso, Neil E. TI Integrative study designs - Next step in the evolution of molecular epidemiology? SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material ID LUNG-CANCER; SMOKING; PREDICTION; DEPENDENCE; CAUSATION; DENMARK; OBESITY; SWEDEN; ADULT; GENES C1 NIH, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, Bethesda, MD 20892 USA. RP Caporaso, NE (reprint author), NIH, Div Canc Epidemiol & Genet, Genet Epidemiol Branch, 6120 Execut Blvd,EPS 7116, Bethesda, MD 20892 USA. EM caporasn@exchange.nih.gov NR 23 TC 12 Z9 12 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 MAR PY 2007 VL 16 IS 3 BP 365 EP 366 DI 10.1158/1055-9965.EPI-07-0142 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 148SC UT WOS:000245093900001 PM 17372231 ER PT J AU Hartge, P Smith, MT AF Hartge, Patricia Smith, Martyn T. TI Environmental and behavioral factors and the risk of non-Hodgkin lymphoma SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material C1 NCI, US Dept HHS, NIH, Bethesda, MD 20892 USA. Univ Calif Berkeley, Sch Publ Hlth, Div Environm Hlth Sci, Berkeley, CA 94720 USA. RP Hartge, P (reprint author), NCI, US Dept HHS, NIH, Bethesda, MD 20892 USA. EM hartge@nih.gov FU Intramural NIH HHS; NIEHS NIH HHS [P42 ES04705] NR 0 TC 14 Z9 14 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2007 VL 16 IS 3 BP 367 EP 368 DI 10.1158/1055-9965.EPI-07-0031 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 148SC UT WOS:000245093900002 PM 17344463 ER PT J AU Engel, LS Lan, Q Rothman, N AF Engel, Lawrence S. Lan, Qing Rothman, Nathaniel TI Polychlorinated biphenyls and non-Hodgkin lymphoma SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CAPACITOR MANUFACTURING WORKERS; CANCER-MORTALITY; UNITED-STATES; PCBS; RISK; PESTICIDES; EXPOSURE; DIOXINS; UPDATE; PLANT AB Several epidemiologic studies suggest that polychlorinated biphenyl (PCB) levels measured in peripheral blood or adipose tissue are related to increased risk of non-Hodgkin lymphoma WHO and, therefore, may be at least partially responsible for the rising incidence of NHL unrelated to HIV infection in recent decades. Case-control studies that measured PCBs in blood, adipose tissue, or household carpet dust, at the time of diagnosis, have observed elevated NHL risk associated with concentrations of either total PCBs or of specific congeners. Similar associations have been found in a number of prospective cohorts. These associations do not seem to be due to confounding by other organochlorines or by other known NHL risk factors. These results support evidence of PCB carcinogenicity from animal studies. However, interpretation of the epidemiologic evidence is limited by the wide range in measurement precision across congeners and by the moderate to high correlation among many congeners. Occupational cohort studies provide very limited support for a relationship between PCBs and NHL. In conclusion, there is mounting evidence of a relationship between certain PCBs and risk of NHL, but important questions remain, especially regarding the magnitude, timing, and causality of that relationship. C1 Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, Epidemiol Serv, New York, NY 10021 USA. NCI, Div Canc Epidemiol & Genet, US Dept HHS, NIH, Bethesda, MD 20892 USA. RP Engel, LS (reprint author), Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, Epidemiol Serv, 307 E 63rd St,3rd Floor, New York, NY 10021 USA. EM engell@mskcc.org OI Engel, Lawrence/0000-0001-9268-4830 NR 43 TC 28 Z9 29 U1 1 U2 10 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 MAR PY 2007 VL 16 IS 3 BP 373 EP 376 DI 10.1158/1055-9965.EPI-07-0055 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 148SC UT WOS:000245093900004 PM 17337641 ER PT J AU Engels, EA AF Engels, Eric A. TI Infectious agents as causes of non-Hodgkin lymphoma SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID HEPATITIS-C VIRUS; EPSTEIN-BARR-VIRUS; SARCOMA-ASSOCIATED HERPESVIRUS; BURKITTS-LYMPHOMA; KAPOSIS-SARCOMA; DISEASE; AIDS; ASSOCIATION; RISK; TRANSLOCATION AB Among exposures presently viewed as possible etiologic factors in non-Hodgkin lymphoma (NHL), infections are close to being regarded as established causes. Infectious agents causing NHL can be classified, according to mechanism, into three broad groups. First, some viruses can directly transform lymphocytes. Lymphocyte-transforming viruses include Epstein Barr virus (linked to Burkitt's lymphoma, NHLs in immunosuppressed individuals, and extranodal natural killer/T-cell NHL), human herpesvirus 8 (primary effusion lymphoma), and human T lymphotropic virus type I (adult T-cell leukemia/lymphoma). Second, human immunodeficiency virus is unique in causing profound depletion of CD4(+) T lymphocytes, leading to acquired immunodeficiency syndrome and an associated high risk for some NHL subtypes. Third, recent evidence suggests that some infections increase NHL risk through chronic immune stimulation. These infections include hepatitis C virus as well as certain bacteria that cause chronic site-specific inflammation and seem to increase risk for localized mucosa-associated lymphoid tissue NHLs. Establishing that an infectious agent causes NHL depends on showing that the agent is present in persons with NHL as well as laboratory experiments elucidating the mechanisms involved. Only epidemiologic studies can provide evidence that infection is actually a risk factor by showing that infection is more frequent in NHL cases than in controls. Given the range of mechanisms by which infections could plausibly cause NHL and our growing molecular understanding of this malignancy, this field of research deserves continued attention. C1 NCI, Div Canc Epidemiol & Genet, Viral Epidemiol Branch, US Dept HHS,NIH, Rockville, MD 20852 USA. RP Engels, EA (reprint author), NCI, Div Canc Epidemiol & Genet, Viral Epidemiol Branch, US Dept HHS,NIH, 6120 Execut Blvd,EPS 7076, Rockville, MD 20852 USA. EM engelse@exchange.nih.gov FU Intramural NIH HHS NR 28 TC 73 Z9 75 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2007 VL 16 IS 3 BP 401 EP 404 DI 10.1158/1055-9965.EPI-06-1056 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 148SC UT WOS:000245093900010 PM 17337646 ER PT J AU Yang, XR Sherman, ME Rimm, DL Lissowska, J Brinton, LA Peplonska, B Hewitt, SM Anderson, WF Szeszenia-Dabrowska, N Bardin-Mikolajczak, A Zatonski, W Cartun, R Mandich, D Rymkiewicz, G Ligaj, M Lukaszek, S Kordek, R Garcia-Closas, M AF Yang, Xiaohong R. Sherman, Mark E. Rimm, David L. Lissowska, Jolanta Brinton, Louise A. Peplonska, Beata Hewitt, Stephen M. Anderson, William F. Szeszenia-Dabrowska, Neonila Bardin-Mikolajczak, Alicja Zatonski, Witold Cartun, Richard Mandich, Daniza Rymkiewicz, Grzegorz Ligaj, Marcin Lukaszek, Stanislaw Kordek, Radzisaw Garcia-Closas, Montserrat TI Differences in risk factors for breast cancer molecular subtypes in a population-based study SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID PROGESTERONE-RECEPTOR STATUS; BRCA2 MUTATION CARRIERS; ESTROGEN-RECEPTOR; AGE; MENARCHE; TUMORS AB Analysis of gene expression data suggests that breast cancers are divisible into molecular subtypes which have distinct clinical features. This study evaluates whether pathologic features and etiologic associations differ among molecular subtypes. We evaluated 804 women with invasive breast cancers and 2,502 controls participating in a Polish Breast Cancer Study. Immunohistochemical stains for estrogen receptor alpha, progesterone receptor, human epidermal growth factor receptors (HER2 and HER1), and cytokeratin 5 were used to classify cases into five molecular subtypes: luminal A, luminal B. HER2-expresing, basal-like, and unclassified. Relative risks were estimated using adjusted odds ratios and 95% confidence intervals. We observed that compared with the predominant luminal A tumors (69%), other subtypes were associated with unfavorable clinical features at diagnosis, especially HER2-expressing (8%) and basal-like (12%) tumors. Increasing body mass index significantly reduced the risk of luminal A tumors among premenopausal women (odds ratios, 0.71; 95% confidence intervals, 0.57-0.88 per five-unit increase), whereas it did not reduce risk for basal-like tumors (1.18; 0.86-1.64; P-heterogeneity = 0.003). On the other hand, reduced risk associated with increasing age at menarche was stronger for basal-like (0.78; 0.68-0.89 per 2-year increase) than luminal A tumors (0.90; 0.95-1.08; Pheterogeneity = 0.0009). Although family history increased risk for all subtypes (except for unclassified tumors), the magnitude of the relative risk was highest for basal-like tumors. Results from this study have shown that breast cancer risk factors may vary by molecular subtypes identified in expression studies, suggesting etiologic, in addition to clinical, heterogeneity of breast cancer. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, NIH, Dept Hlth & Human Serv, Tissue Array Res Program,Lab Pathol,Ctr Canc Res, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA. Ctr Canc, Dept Canc Epidemiol & Prevent, Warsaw, Poland. Ctr Canc, Dept Pathol, Warsaw, Poland. M Sklodowska Curie Inst Oncol, Warsaw, Poland. Med Univ Lodz, Dept Occupat & Environm Epidemiol, Nofer Inst Occupat Med, PL-90131 Lodz, Poland. Med Univ Lodz, Dept Pathol, PL-90131 Lodz, Poland. Polish Mothers Mem Hosp Res Inst, Dept Clin Pathomorphol, Lodz, Poland. Hartford Hosp, Dept Pathol, Hartford, CT 06115 USA. RP Yang, XR (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Room 7014,6120 Execut Blvd, Bethesda, MD 20892 USA. EM royang@mail.nih.gov RI Peplonska, Beata/F-6004-2010; Szeszenia-Dabrowska, Neonila/F-7190-2010; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; Kordek, Radzislaw/S-9616-2016; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Hewitt, Stephen/0000-0001-8283-1788; Lissowska, Jolanta/0000-0003-2695-5799 FU Intramural NIH HHS NR 24 TC 250 Z9 258 U1 3 U2 24 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 MAR PY 2007 VL 16 IS 3 BP 439 EP 443 DI 10.1158/1055-9965.EPI-06-0806 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 148SC UT WOS:000245093900016 PM 17372238 ER PT J AU Han, PKJ Kobrin, SC Klein, WMP Davis, WW Stefanek, M Taplin, SH AF Han, Paul K. J. Kobrin, Sarah C. Klein, William M. P. Davis, William W. Stefanek, Michael Taplin, Steven H. TI Perceived ambiguity about screening mammography recommendations: Association with future mammography uptake and perceptions SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SHARED DECISION-MAKING; AFRICAN-AMERICAN MEN; PROSTATE-CANCER; BREAST-CANCER; INFORMED-CONSENT; RISK INFORMATION; MEDIA COVERAGE; WOMEN; CONTROVERSY; UNCERTAINTY AB Conflicting expert recommendations regarding cancer screening and prevention are growing in number, visibility, and importance, but their impact are not well understood. In this study, we examined the impact of conflicting recommendations about mammography screening on women's mammography behavior and perceptions. We conducted a secondary analysis of longitudinal data from the 1995 Maximizing Mammography Participation Trial, a large randomized interventional trial examining the effectiveness of patient reminders in increasing mammography utilization among women ages 50 to 79. Using the decision theory concept of "ambiguity" as an analytic framework, we tested several predictions about the effects of conflicting recommendations regarding mammography recommendations on behavior, cognitions, and emotions related to mammography screening. We found high perceived ambiguity about mammography recommendations to be associated with both diminished uptake of mammography over time [odds ratio (OR), 0.42; 95% confidence interval (95% CI), 0.23-0.76; P < 0.0001] and lower intentions for future mammography (OR, 0.34; 95% CI, 0.20-0.55; P < 0.0001). High perceived ambiguity also predicted greater mammography-related worry over time (OR, 2.60; 95% CI, 1.79-3.78; P < 0.0001). These findings suggest that conflicting recommendations regarding cancer screening and prevention have important effects, and we discuss the implications of these findings for future research. C1 NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Amer Canc Soc, Behav Res Ctr, Atlanta, GA 30329 USA. Univ Pittsburgh, Dept Psychol, Pittsburgh, PA 15260 USA. RP Han, PKJ (reprint author), NCI, Outcomes Res Branch, Div Canc Control & Populat Sci, 6130 Execut Blvd,EPN 4091,MSC 7344, Bethesda, MD 20892 USA. EM hanp@mail.nih.gov OI Han, Paul/0000-0003-0165-1940 NR 67 TC 39 Z9 39 U1 0 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2007 VL 16 IS 3 BP 458 EP 466 DI 10.1158/1055-9965.EPI-06-0533 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 148SC UT WOS:000245093900019 PM 17372241 ER PT J AU Mariotto, AB Rowland, JH Ries, LAG Scoppa, S Feuer, EJ AF Mariotto, Angela B. Rowland, Julia H. Ries, Lynn A. G. Scoppa, Steve Feuer, Eric J. TI Multiple cancer prevalence: A growing challenge in long-term survivorship SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID BREAST-CANCER; 2ND CANCERS; HODGKIN LYMPHOMA; TEACHABLE MOMENT; HEALTH; REGISTRIES; DISEASE; RISK; CARE AB Objective: The present study was designed to estimate the number of and describe the pattern of disease among cancer survivors living with a history of multiple malignant tumors in the United States. Methods: Incidence and follow-up data from the Surveillance, Epidemiology, and End Results program (1975-2001) were used to calculate the number of survivors with more than one malignant primary at January 1, 2002. U.S. prevalence counts were calculated by multiplying the age, sex, and race-specific prevalence proportions from the Surveillance, Epidemiology, and End Results program by the corresponding U.S. populations. Results: We estimate that 756,467 people in the United States have been affected by cancer more than once between 1975 and 2001, representing almost 8% of the current cancer survivor population. Women whose first primary in that period was breast cancer represent 25% of survivors with multiple cancers, followed by men and women (15%) whose first primary was colorectal cancer and men (13%) whose first primary was prostate cancer. Discussion: The findings in this report have important implications for public health practice. With individuals diagnosed with cancer living longer and the aging of the U.S. population, the number who will develop multiple malignancies is expected to increase. As a consequence, there is a growing need to promote effective cancer screening along with healthy life-styles among these at-risk populations if we are to ensure optimal physical and psychosocial well-being of these long-term cancer survivors and their families. Efforts to design and evaluate effective, efficient, and equitable approaches to surveillance for second malignancies will be critical in reducing the national burden of cancer. C1 NCI, Div Canc Control & Populat Sci, Surveillance Res Program, NIH, Bethesda, MD 20892 USA. NCI, Off Canc Survivorship, NIH, Bethesda, MD 20892 USA. Informat Management Serv Inc, Silver Spring, MD USA. RP Mariotto, AB (reprint author), NCI, Div Canc Control & Populat Sci, Surveillance Res Program, NIH, Suite 540,MSC 8317, Bethesda, MD 20892 USA. EM mariotta@mail.nih.gov NR 30 TC 93 Z9 103 U1 2 U2 11 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 MAR PY 2007 VL 16 IS 3 BP 566 EP 571 DI 10.1158/1055-9965.EPI-06-0782 PG 6 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 148SC UT WOS:000245093900034 PM 17372253 ER PT J AU Chen, JP Lam, S Pilon, A McWilliams, A Melby, J Szabo, E AF Chen, Jiping Lam, Stephen Pilon, Aprile McWilliams, Annette Melby, James Szabo, Eva TI The association between the anti-inflammatory protein CC10 and smoking status among participants in a chemoprevention trial SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID CLARA CELL PROTEIN; LUNG-CANCER; BRONCHOALVEOLAR LAVAGE; 10-KDA PROTEIN; FORMER SMOKERS; SERUM-LEVELS; BRONCHIAL EPITHELIUM; CIGARETTE-SMOKING; SECRETORY PROTEIN; HEALTHY-SUBJECTS AB CC10, the secretory product of bronchiolar Clara cells, is infrequently expressed in non-small cell lung cancer (NSCLC), and its overexpression in NSCLC cell lines results in a less malignant phenotype. CC10 levels in bronchoalveolar lavage fluid (BAL) and serum are significantly lower in current smokers than healthy nonsmokers, but the effect of long-term smoking cessation on CC10 is unknown. We measured CC10 in baseline BAL and plasma collected from current (n = 81) and former (n = 23) smokers participating in a chemoprevention trial. Former smokers had significantly higher plasma CC10 levels compared with current smokers [mean, 62.1 ng/mL (95% CI, 43.0-81.2); range, 23.0-175.0 ng/mL for former smokers; and mean, 37.1 ng/mL (95% CI, 29.8-44.4); range, 5.0-171.0 ng/mL for current smokers; P < 0.001]. BAL CC10 levels also trended in the same direction. A significant positive correlation was found between CC10 plasma and BAL levels. After adjustment for age, sex, and pack-years of cigarette consumption, former smokers had 1.70 (95% CI, 1.23-2.36) times higher plasma CC10 levels than current smokers (P < 0.01), whereas former smokers also had nonsignificantly higher baseline BAL CC10 levels compared with current smokers [adjusted mean ratio (95% CI), 1.60 (0.92-2.80), P = 0.094 and 1.35 (0.86-2.10), P = 0.193 for the absolute and normalized BAL CC10, respectively]. These results show that sustained smoking cessation is associated with higher plasma CC10 levels, suggesting that at least some of the damage associated with tobacco smoke may be repaired by long-term smoking cessation. C1 NCI, Lung & Upper Aerodigest Canc Res Grp, Div Canc Prevent, Canc Prevent Fellowship Program,NIH, Bethesda, MD 20892 USA. NCI, Upper Aerodigest Canc Res Grp, Div Canc Prevent, Lung & Upper Aerodigest Canc Res Grp,NIH, Bethesda, MD 20892 USA. British Columbia Canc Agcy, Lung Tumor Grp, Vancouver, BC V5Z 4E6, Canada. Univ British Columbia, Vancouver, BC V5Z 1M9, Canada. Claragen Inc, Rockville, MD USA. RP Szabo, E (reprint author), NCI, Lung & Upper Aerodigest Canc Res Grp, Div Canc Prevent, Canc Prevent Fellowship Program,NIH, 6130 Execut Blvd,Room 2132, Bethesda, MD 20892 USA. EM szaboe@mail.nih.gov FU NCI NIH HHS [N01-CN-85188] NR 48 TC 12 Z9 12 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 MAR PY 2007 VL 16 IS 3 BP 577 EP 583 DI 10.1158/1055-9965.EPI-06-0923 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 148SC UT WOS:000245093900036 PM 17372255 ER PT J AU Kamangar, F Gao, YT Shu, XO Kahkeshani, K Ji, BT Yang, G Li, HL Rothman, N Chow, WH Zheng, W AF Kamangar, Farin Gao, Yu-Tang Shu, Xiao-Ou Kahkeshani, Kourosh Ji, Bu-Tian Yang, Gong Li, Hong-Lan Rothman, Nathaniel Chow, Wong-Ho Zheng, Wei TI Ginseng intake and gastric cancer risk in the Shanghai Women's Health Study cohort SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Dept Med, Nashville, TN USA. Vanderbilt Univ, Ctr Hlth Serv Res, Dept Med, Nashville, TN USA. RP Kamangar, F (reprint author), NCI, Div Canc Epidemiol & Genet, 6120 Execut Blvd,Room 3034, Bethesda, MD 20892 USA. EM Kamangaf@mail.nih.gov FU Intramural NIH HHS NR 12 TC 13 Z9 14 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD MAR PY 2007 VL 16 IS 3 BP 629 EP 630 DI 10.1158/1055-9965.EPI-06-1009 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 148SC UT WOS:000245093900047 PM 17372265 ER PT J AU Rabkin, CS Kamangar, F Abnet, CC AF Rabkin, Charles S. Kamangar, Farin Abnet, Christian C. TI IL1B polymorphisms and gastric cancer risk - Response SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Letter ID HELICOBACTER-PYLORI; GENE POLYMORPHISMS; INTERLEUKIN-1-BETA; METAANALYSIS C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Rabkin, CS (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 7 TC 0 Z9 0 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 MAR PY 2007 VL 16 IS 3 BP 635 EP 636 DI 10.1158/1055-9965.EPI-06-0925 PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 148SC UT WOS:000245093900052 ER PT J AU Mitchell, MS Lund, TA Sewell, AK Marincola, FM Paul, E Schroder, K Wilson, DB Kan-Mitchell, J AF Mitchell, Malcolm S. Lund, Teri A. Sewell, Andrew K. Marincola, Francesco M. Paul, Elyse Schroder, Kim Wilson, Darcy B. Kan-Mitchell, June TI The cytotoxic T cell response to peptide analogs of the HLA-A*0201-restricted MUC1 signal sequence epitope, M1.2 SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE cancer; CTL epitope; agonist peptide; immunotherapy ID POLYMORPHIC EPITHELIAL MUCIN; ENZYME-LINKED IMMUNOSPOT; PULSED DENDRITIC CELLS; TUMOR-ANTIGEN; IMMUNE-RESPONSE; CD8 CORECEPTOR; HUMAN-BREAST; IN-VIVO; CANCER; DIFFERENTIATION AB The mucin MUC1 molecule is overexpressed on a variety of adenocarcinomas and is thus, a potential target for immunotherapy. Of the MUC1 peptides that bind to HLA-A*0201(A2), M1.2 (LLLLTVLTV) from the signal sequence appears to be the most immunogenic in humans. Here we have shown that large numbers (10(9)) of tetramer-binding M1.2-specific cytotoxic T lymphocytes (CTL) can be generated ex vivo from circulating precursors, derived from healthy adults. However, there was significant interpersonal variation in the level of co-stimulatory signal required. Tetramer-binding cells also required maturation in culture to become proficient killers of the HLA-A2(+)MUC1(+) MCF7 cell line, known to express a low number of endogenously processed M1.2. The functional avidity of M1.2-specific CTL, however, was low as compared to CTL specific for an HIV-1 epitope. Despite the low avidity, M1.2-specific CTL were polyfunctional, secreting multiple cytokines upon degranulation with antigen recognition. To identify potential agonist peptides that may be superior immunogens, an M1.2-specific CTL culture was used to scan a large nonameric combinatorial peptide library. Of 54 predicted peptides, 4 were "consensus" agonists because they were recognized by CTL from two other donors. Two agonists, p29 (LLP-(W) under bar TVLTV) and p15 ( (V) under bar LL (W) under bar TVLTV), were equally stimulatory when loaded onto C1R target cells transfected with wild-type HLA-A2. Both agonists induced IL-2, TNF-alpha, IFN-gamma, and degranulation with M1.2-specific CTL. In contrast, production of these cytokines, which are tightly regulated by specific activation through the T cell receptor, was restricted when the CTL were stimulated with peptides loaded onto C1R cells that were transfected with an HLA-A2 molecule bearing a mutation that abrogates binding to the CD8 co-receptor. Thus, activation by both M1.2 and its agonists was dependent upon CD8, showing that compensation by the co-receptor was necessary for the human T cell response to M1.2. C1 Wayne State Univ, Sch Med, Karmanos Canc Inst, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Dept Med, Detroit, MI 48201 USA. Wayne State Univ, Sch Med, Dept Immunol & Microbiol, Detroit, MI 48201 USA. Univ Oxford, Nuffield Dept Med, T Cell Modulat Grp, Oxford, England. Ctr Clin, Dept Transfus Med, Immunogenet Sect, NIH, Bethesda, MD 20892 USA. Torrey Pines Inst Mol Studies, La Jolla, CA USA. RP Mitchell, MS (reprint author), Wayne State Univ, Sch Med, Karmanos Canc Inst, 110 E Warren Ave, Detroit, MI 48201 USA. EM malcolmsmitchell@yahoo.com OI Sewell, Andrew/0000-0003-3194-3135 FU NCI NIH HHS [CA 78040]; NIAID NIH HHS [R01 AI 064069, R21 AI 44372] NR 55 TC 7 Z9 7 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD MAR PY 2007 VL 56 IS 3 BP 287 EP 301 DI 10.1007/s00262-006-0191-1 PG 15 WC Oncology; Immunology SC Oncology; Immunology GA 121VX UT WOS:000243186200002 PM 16874487 ER PT J AU Berencsi, K Meropol, NJ Hoffman, JP Sigurdson, E Giles, L Rani, P Somasundaram, R Zhang, TQ Kalabis, J Caputo, L Furth, E Swoboda, R Marincola, F Herlyn, D AF Berencsi, Klara Meropol, Neal J. Hoffman, John P. Sigurdson, Elin Giles, Lydia Rani, Pyapalli Somasundaram, Rajasekharan Zhang, Tianqian Kalabis, Jiri Caputo, Laura Furth, Emma Swoboda, Rolf Marincola, Francesco Herlyn, Dorothee TI Colon carcinoma cells induce CXCL11-dependent migration of CXCR3-expressing cytotoxic T lymphocytes in organotypic culture SO CANCER IMMUNOLOGY IMMUNOTHERAPY LA English DT Article DE CTL; chemokines; chemotaxis; apoptosis; tumor immunity ID CXC-CHEMOKINE; GROWTH-FACTOR; IN-VIVO; FIBROBLAST INTERACTIONS; DENDRITIC CELLS; COLLAGEN MATRIX; CANCER PATIENTS; TUMOR-GROWTH; EXPRESSION; INHIBITION AB Adoptive immunotherapy of cancer patients with cytolytic T lymphocytes (CTL) has been hampered by the inability of the CTL to home into tumors in vivo. Chemokines can attract T lymphocytes to the tumor site, as demonstrated in animal models, but the role of chemokines in T-lymphocyte trafficking toward human tumor cells is relatively unexplored. In the present study, the role of chemokines and their receptors in the migration of a colon carcinoma (CC) patient's CTL toward autologous tumor cells has been studied in a novel three-dimensional organotypic CC culture. CTL migration was mediated by chemokine receptor CXCR3 expressed by the CTL and CXCL11 chemokine secreted by the tumor cells. Excess CXCL11 or antibodies to CXCL11 or CXCR3 inhibited migration of CTL to tumor cells. T cell and tumor cell analyses for CXCR3 and CXCL11 expression, respectively, in ten additional CC samples, may suggest their involvement in other CC patients. Our studies, together with previous studies indicating angiostatic activity of CXCL11, suggest that CXCL11 may be useful as an immunotherapeutic agent for cancer patients when transduced into tumor cells or fused to tumor antigen-specific Ab. C1 Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA. Fox Chase Canc Ctr, Div Med Sci, Philadelphia, PA 19111 USA. Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. Hosp Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Ctr Clin, Dept Transfus Med, Immunogenet Sect, NIH, Bethesda, MD 20892 USA. RP Herlyn, D (reprint author), Wistar Inst Anat & Biol, 3601 Spruce St, Philadelphia, PA 19104 USA. EM dherlyn@wistar.org FU Intramural NIH HHS; NCI NIH HHS [CA 10815, CA 74294] NR 54 TC 13 Z9 15 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0340-7004 J9 CANCER IMMUNOL IMMUN JI Cancer Immunol. Immunother. PD MAR PY 2007 VL 56 IS 3 BP 359 EP 370 DI 10.1007/s00262-006-0190-2 PG 12 WC Oncology; Immunology SC Oncology; Immunology GA 121VX UT WOS:000243186200007 PM 16783574 ER PT J AU Bates, SE Piekarz, RL AF Bates, Susan E. Piekarz, Richard L. TI Histone deacetylase inhibitors in combinations: Will the preclinical promises be kept? SO CANCER JOURNAL LA English DT Editorial Material ID GROWTH-FACTOR RECEPTOR; TYROSINE KINASE INHIBITOR; SUBEROYLANILIDE HYDROXAMIC ACID; TUMOR CONSORTIUM REPORT; MALIGNANT GLIOMA-CELLS; CANCER-CELLS; PHASE-I; SYNERGISTIC INTERACTION; DEPSIPEPTIDE FR901228; LEUKEMIA-CELLS C1 NCI, Mol Therapeut Sect, Med Oncol Branch, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Mol Therapeut Sect, Med Oncol Branch, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM sebates@helix.nih.gov NR 45 TC 9 Z9 11 U1 0 U2 0 PU JONES AND BARTLETT PUBLISHERS PI SUDBURY PA 40 TALL PINE DR, SUDBURY, MA 01776 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD MAR-APR PY 2007 VL 13 IS 2 BP 80 EP 83 DI 10.1097/PPO.0b013e318063bd9f PG 4 WC Oncology SC Oncology GA 162JO UT WOS:000246083300003 PM 17476134 ER PT J AU Yu, XD Wang, SY Chen, GA Hou, CM Zhao, M Hong, JA Nguyen, DM Schrump, DS AF Yu, Xiao-Dan Wang, Sheng-Yu Chen, G. Aaron Hou, Chun-Mei Zhao, Ming Hong, Julie A. Nguyen, Dao M. Schrump, David S. TI Apoptosis induced by depsipeptide FK228 coincides with inhibition of survival signaling in lung cancer cells SO CANCER JOURNAL LA English DT Article DE FK228; lung cancer; epigenetics; mitogen-activated protein kinase ID HISTONE DEACETYLASE INHIBITORS; GROWTH-FACTOR RECEPTOR; SUBEROYLANILIDE HYDROXAMIC ACID; KINASE DOMAIN MUTATIONS; HUMAN LEUKEMIA-CELLS; TRANSCRIPTIONAL ACTIVATION; MEDIATED APOPTOSIS; KAPPA-B; GEFITINIB; EXPRESSION AB Background: Whereas histone deacetylase inhibitors are known to modulate chromatin structure, the precise mechanisms by which these novel agents induce apoptosis in cancer cells remain unknown. Previously we reported that depsipeptide FK228 depletes epidermal growth factor receptor (EGFR), erbB2, and Raf-1 kinases in nonsmall cell lung cancer cells. In the present study we sought to further define the mechanisms by which FK228 modulates oncoprotein signaling and to ascertain whether altered signal transduction contributes to FK228-mediated apoptosis in lung cancer cells. Methods: Cultured non-small cell lung cancer cells were treated with FK228 alone or FK228 with a variety of kinase inhibitors. Proliferation and apoptosis mediated by drug exposure were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium, and Apo-BrdU techniques. Western blot and kinase assays were used to evaluate EGFR-related signal transduction pathways. Lung cancer cells were transduced with adenoviral vectors expressing activated AKT or mitogen-activated protein kinase kinase (MEK) 1 or beta-galactosidase to determine whether constitutive activation of mitogen-activated protein kinase signaling could abrogate FK228-mediated apoptosis. Results: FK228 treatment induced time-dependent apoptosis in lung cancer cells expressing wild-type or mutant EGFR. FK228 inhibited a variety of EGFR-related pathways including Src, RAF-MEK-extracellular signal-regulated kinase (ERK) 1/2 and phosphatidyl inositol-3 kinase (PI3K)/AKT, resulting in down-regulation of Bcl-2 and Bcl-xL and up-regulation of Bax. The kinase inhibitors AG1478, AG825, PD98059, and LY294002 markedly enhanced FK228-induced apoptosis in lung cancer cells. Coincident with inhibition of ERK1/2 and PI3K/AKT survival pathways, FK228 enhanced p38 and stress-activated protein kinase/c-Jun NH2-terminal kinase stress signaling. Constitutive expression of MEK1 but not AKT markedly reduced FK228-mediated apoptosis in lung cancer cells. Conclusions: FK228 inhibits EGFR expression and modulates a variety of downstream mediators regulating proliferation and stress responses in lung cancer cells. These data highlight the significance of MEK signaling with respect to FK228-mediated apoptosis and support evaluation of histone deacetylase inhibitors in conjunction with agents specifically targeting mitogen-activated protein kinases in patients with lung cancer. C1 NCI, Surg Branch, Thorac Oncol Sect, Canc Res Ctr,NIH, Bethesda, MD 20892 USA. Chinese Acad Med Sci, Inst Basic Med Sci, Dept Pathol, Beijing 100730, Peoples R China. RP Schrump, DS (reprint author), NCI, Surg Branch, Thorac Oncol Sect, Canc Res Ctr,NIH, Bldg 10,Room 4-3920,10 Ctr Dr,MSC 1201, Bethesda, MD 20892 USA. EM David_schrump@nih.gov NR 43 TC 26 Z9 30 U1 0 U2 4 PU JONES AND BARTLETT PUBLISHERS PI SUDBURY PA 40 TALL PINE DR, SUDBURY, MA 01776 USA SN 1528-9117 J9 CANCER J JI Cancer J. PD MAR-APR PY 2007 VL 13 IS 2 BP 105 EP 113 DI 10.1097/PPO.0b013e318046eedc PG 9 WC Oncology SC Oncology GA 162JO UT WOS:000246083300007 PM 17476138 ER PT J AU Haiman, CA Dossus, L Setiawan, VW Stram, DO Dunning, AM Thomas, G Thun, MJ Albanes, D Altshuler, D Ardanaz, E Boeing, H Buring, J Burtt, N Calle, EE Chanock, S Clavel-Chapelon, F Colditz, GA Cox, DG Feigelson, HS Hankinson, SE Hayes, RB Henderson, BE Hirschhorn, JN Hoover, R Hunter, DJ Kaaks, R Kolonel, LN Le Marchand, L Lenner, P Lund, E Panico, S Peeters, PH Pike, MC Riboli, E Tjonneland, A Travis, R Trichopoulos, D Wacholder, S Ziegler, RG AF Haiman, Christopher A. Dossus, Laure Setiawan, V. Wendy Stram, Daniel O. Dunning, Alison M. Thomas, Gilles Thun, Michael J. Albanes, Demetrius Altshuler, David Ardanaz, Eva Boeing, Heiner Buring, Julie Burtt, Noel Calle, Eugenia E. Chanock, Stephen Clavel-Chapelon, Francoise Colditz, Graham A. Cox, David G. Feigelson, Heather Spencer Hankinson, Susan E. Hayes, Richard B. Henderson, Brian E. Hirschhorn, Joel N. Hoover, Robert Hunter, David J. Kaaks, Rudolf Kolonel, Laurence N. Le Marchand, Loic Lenner, Per Lund, Eiliv Panico, Salvatore Peeters, Petra H. Pike, Malcolm C. Riboli, Elio Tjonneland, Anne Travis, Ruth Trichopoulos, Dimitrios Wacholder, Sholom Ziegler, Regina G. TI Genetic variation at the CYP19A1 locus predicts circulating estrogen levels but not breast cancer risk in postmenopausal women SO CANCER RESEARCH LA English DT Article ID BASE-LINE CHARACTERISTICS; MULTIETHNIC COHORT; HUMAN GENOME; POLYMORPHISMS; AROMATASE; NUTRITION; ASSOCIATION; HORMONES; HEALTH AB The CYP19A1 gene encodes the enzyme aromatase, which is responsible for the final step in the biosynthesis of estrogens. In this study, we used a systematic two-step approach that included gene resequencing and a haplotype-based analysis to comprehensively survey common genetic variation across the CYP19A1 locus in relation to circulating postmenopausal steroid hormone levels and breast cancer risk. This study was conducted among 5,356 invasive breast cancer cases and 7,129 controls comprised primarily of White women of European descent drawn from five large prospective cohorts within the National Cancer Institute Breast and Prostate Cancer Cohort Consortium. A high-density single-nucleotide polymorphism (SNP) map of 103 common SNPs (>= 5% frequency) was used to identify the linkage disequilibrium and haplotype patterns across the CYP19A1 locus, and 19 haplotype-tagging SNPs were selected to provide high predictability of the common haplotype patterns. We found haplotype-tagging SNPs and common haplotypes spanning the coding and proximal 5' region of CYP-19A1 to be significantly associated with a 10% to 20% increase in endogenous estrogen levels in postmenopausal women [effect per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 4.4 X 10(-15)]. No significant associations were observed, however, with these SNPs or common haplotypes and breast cancer risk. Thus, although genetic variation in CM19A1 produces measurable differences in estrogen levels among postmenopausal women, the magnitude of the change was insufficient to contribute detectably to breast cancer. C1 Univ So Calif, Dept Prevent Med, Sch Med, Los Angeles, CA 90033 USA. German Canc Res Ctr, Div Canc Epidemiol, D-6900 Heidelberg, Germany. Univ Cambridge, Canc Res United Kingdom, Dept Oncol, Strangeways Res Lab, Cambridge, England. Natl Canc Inst, Div Canc Epidemiol & Genet, Rockville, MD USA. Amer Canc Soc, Atlanta, GA 30329 USA. Harvard Univ, Broad Inst, Cambridge, MA 02138 USA. MIT, Cambridge, MA 02139 USA. Publ Hlth Inst Navarra, Pamplona, Spain. German Inst Human Nutr, Dept Epidemiol, Potsdam, Germany. Harvard Univ, Sch Med, Div Prevent Med, Boston, MA USA. Harvard Univ, Sch Med, Channing Lab, Brigham & Womens Hosp,Dept Med, Boston, MA USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. Inst Gustave Roussy, INSERM, F-94805 Villejuif, France. Univ Hawaii, Program Epidemiol, Canc Res Ctr, Honolulu, HI 96822 USA. Umea Univ, Dept Radiat Sci Oncol, Umea, Sweden. Univ Tromso, Inst Community Med, Tromso, Norway. Univ Naples Federico II, Dept Clin & Expt Med, Naples, Italy. Univ Utrecht, Julius Ctr Hlth Sci & Primary Care, Med Ctr, Utrecht, Netherlands. Imperial Coll Sch Med, London, England. Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. Univ Oxford, Canc Res United Kingdom Epidemiol Unit, Oxford, England. Univ Athens, Sch Med, Dept Hyg & Epidemiol, Athens, Greece. RP Haiman, CA (reprint author), Univ So Calif, Dept Prevent Med, Sch Med, 1441 Eastlake Ave,MS 44,Room 4441, Los Angeles, CA 90033 USA. EM haiman@usc.edu RI Cox, David/A-2023-2009; Altshuler, David/A-4476-2009; Dossus, Laure/B-2875-2013; Clavel-Chapelon, Francoise/G-6733-2014; Albanes, Demetrius/B-9749-2015; Panico, Salvatore/K-6506-2016; Colditz, Graham/A-3963-2009 OI Dunning, Alison Margaret/0000-0001-6651-7166; Hayes, Richard/0000-0002-0918-661X; Cox, David/0000-0002-2152-9259; Altshuler, David/0000-0002-7250-4107; Dossus, Laure/0000-0003-2716-5748; Panico, Salvatore/0000-0002-5498-8312; Colditz, Graham/0000-0002-7307-0291 FU Intramural NIH HHS; NCI NIH HHS [U01 CA 98216, U01 CA 98233, U01 CA 98710, U01 CA 98758] NR 20 TC 112 Z9 115 U1 0 U2 6 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 MAR 1 PY 2007 VL 67 IS 5 BP 1893 EP 1897 DI 10.1158/0008-5472.CAN-06-4123 PG 5 WC Oncology SC Oncology GA 143QQ UT WOS:000244738100004 PM 17325027 ER PT J AU Chun, KS Akunda, JK Langenbach, R AF Chun, Kyung-Soo Akunda, Jacqueline K. Langenbach, Robert TI Cyclooxygenase-2 inhibits UVB-induced apoptosis in mouse skin by activating the prostaglandin E-2 receptors, EP2 and EP4 SO CANCER RESEARCH LA English DT Article ID COLON-CANCER CELLS; NF-KAPPA-B; PROTEIN-KINASE; PROSTANOID RECEPTORS; P53; EXPRESSION; COX-2; MECHANISM; RADIATION; SURVIVAL AB Cyclooxygenase-2 (COX-2) is induced by UVB light and reduces UVB-induced epidermal apoptosis; however, the mechanism is unclear. Therefore, wild-type (WT) and COX-2-/- mice were acutely treated with UVB (5 kj/m(2)), and apoptotic signaling pathways were compared. Following exposure, apoptosis was 2.5-fold higher in COX-2-/- compared with WT mice. Because prostaglandin E-2 (PGE(2)) is the major UV-induced prostaglandin and manifests its activity via four receptors, EP1 to EP4, possible differences in EP signaling were investigated in WT and COX-2-/- mice. Following LTVB exposure, protein levels of EP1, EP2, and EP4 were elevated in WT mice, but EP2 and EP4 levels were 50% lower in COX2-/- mice. Activated cyclic AMP-dependent protein kinase (PKA) and Akt are downstream in EP2 and EP4 signaling, and their levels were reduced in UVB-exposed COX-2-/- mice. Furthermore, p-Bad (Ser(136) and Ser(155)), antiapoptotic products of activated Akt and PKA, respectively, were significantly reduced in UVB-exposed COX-2-/- mice. To further study the roles of EP2 and EP4, UVB-exposed CD-1 mice were topically treated with indomethacin to block endogenous PGE2 production, and PGE(2) the EP2 agonist (butaprost) or EP4 agonist (PGE, alcohol), was applied. Indomethacin reduced PKA and Akt activation by similar to 60%, but PGE(2) and the agonists restored their activities. Furthermore, both agonists decreased apoptosis in COX-2-/- mice by 50%. The data suggest that COX-2-generated PGE(2) has antiapoptotic roles in UVB-exposed mouse skin that involves EP2- and EP4-mediated signaling. C1 Natl Inst Environm Hlth Sci, Lab Mol Carcinogenesis, NIH, Res Triangle Pk, NC 27709 USA. RP Langenbach, R (reprint author), Natl Inst Environm Hlth Sci, Lab Mol Carcinogenesis, NIH, MD C4-09,POB 12233, Res Triangle Pk, NC 27709 USA. EM langenb1@niehs.nih.gov FU Intramural NIH HHS [Z01 ES021229-08] NR 42 TC 62 Z9 64 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD MAR 1 PY 2007 VL 67 IS 5 BP 2015 EP 2021 DI 10.1158/0008-5472.CAN-06-3617 PG 7 WC Oncology SC Oncology GA 143QQ UT WOS:000244738100019 PM 17332329 ER PT J AU Lunn, JC Kuhnle, G Mai, V Frankenfeld, C Shuker, DEG Glen, RC Goodman, JM Pollock, JRA Bingham, SA AF Lunn, J. C. Kuhnle, G. Mai, V. Frankenfeld, C. Shuker, D. E. G. Glen, R. C. Goodman, J. M. Pollock, J. R. A. Bingham, S. A. TI The effect of haem in red and processed meat on the endogenous formation of N-nitroso compounds in the upper gastrointestinal tract SO CARCINOGENESIS LA English DT Article ID 16S RIBOSOMAL-RNA; IN-SITU HYBRIDIZATION; HUMAN FECES; OLIGONUCLEOTIDE PROBES; FECAL SAMPLES; NITRIC-OXIDE; COLON-CANCER; HOT DOGS; RATS; MICROFLORA AB Red and processed meat (PM) consumption increases the risk of large bowel cancer and it has been demonstrated that haem in red meat (RM) stimulates the endogenous production of N-nitroso compounds (NOCs) within the human intestine. To investigate whether N-nitrosation occurs in the upper gastrointestinal tract, 27 ileostomists were fed diets containing no meat, or 240 g RM or 240 g PM in a randomly assigned crossover intervention design carried out in a volunteer suite. Endogenous NOC were assessed as apparent total N-nitroso compounds (ATNC) in the ileostomy output. ATNC concentration in the diets was 22 mu g ATNC/kg (RM) and 37 mu g ATNC/kg (PM), and 9 mu g ATNC/kg in the no meat diet. Levels significantly increased to 1175 mu g ATNC/kg SEM = 226 mu g ATNC/kg) following the RM (P = 0.001) and 1832 mu g ATNC/kg (SEM = 294 mu g ATNC/kg) following PM (P < 0.001) compared to the no meat diet (283 mu g ATNC/kg, SEM = 74 mu g ATNC/kg). ATNC concentrations in the ileal output were equivalent to those measured in faeces in similarly designed feeding studies. Supplementation with either 1 g ascorbic acid or 400 IU alpha-tocopherol had no effect on the concentration of ATNC detected in the ileal output. In in vitro experiments, N-nitrosomorpholine (NMor) was formed in the presence of nitrosated haemoglobin, at pH 6.8 but not in the absence of nitrosated haemoglobin. These findings demonstrate that haem may facilitate the formation of NOC in the absence of colonic flora in the upper human gastrointestinal tract. C1 MRC, Dunn Human Nutr Unit, Cambridge CB2 2XY, England. Univ Maryland, Dept Epidemiol & Prevent Med, Sch Med, Baltimore, MD 21201 USA. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Univ Cambridge, Unilever Ctr Mol Sci Informat, Cambridge, England. Open Univ, Dept Chem, Milton Keynes MK7 6AA, Bucks, England. Pollock & Pool Ltd, Reading RG5 4DX, Berks, England. RP Bingham, SA (reprint author), MRC, Dunn Human Nutr Unit, Wellcome Trust MRC Bldg, Cambridge CB2 2XY, England. EM sheila.bingham@mrc-dunn.cam.ac.uk RI Goodman, Jonathan/A-2123-2008; Kuhnle, Gunter/B-8443-2008; Kuhnle, Gunter/B-6819-2012; OI Goodman, Jonathan/0000-0002-8693-9136; Frankenfeld, Cara/0000-0002-2318-0791; Kuhnle, Gunter/0000-0002-8081-8931 FU Medical Research Council [MC_U105630924] NR 32 TC 47 Z9 47 U1 2 U2 15 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD MAR PY 2007 VL 28 IS 3 BP 685 EP 690 DI 10.1093/carcin/bgl192 PG 6 WC Oncology SC Oncology GA 152HB UT WOS:000245351100020 PM 17052997 ER PT J AU Purdue, MP Lan, Q Kricker, A Grulich, AE Vajdic, CM Turner, J Whitby, D Chanock, S Rothman, N Armstrong, BK AF Purdue, Mark P. Lan, Qing Kricker, Anne Grulich, Andrew E. Vajdic, Claire M. Turner, Jennifer Whitby, Denise Chanock, Stephen Rothman, Nathaniel Armstrong, Bruce K. TI Polymorphisms in immune function genes and risk of non-Hodgkin lymphoma: findings from the New South Wales non-Hodgkin Lymphoma Study SO CARCINOGENESIS LA English DT Article ID TUMOR-NECROSIS-FACTOR; B-CELL LYMPHOMA; SINGLE-NUCLEOTIDE POLYMORPHISMS; ACQUIRED-IMMUNODEFICIENCY-SYNDROME; INFLAMMATORY-BOWEL-DISEASE; FACTOR-ALPHA; SERUM-LEVELS; SOLUBLE CD23; TNF-ALPHA; PROMOTER POLYMORPHISMS AB Recent findings suggest that genetic polymorphisms in TNF and IL10 are associated with an increased risk of non-Hodgkin lymphoma (NHL), particularly for diffuse large B-cell lymphoma (DLBCL). To further investigate the contribution of common genetic variation in key cytokine and innate immunity genes to the etiology of NHL, we genotyped participants in a case-control study of NHL conducted in Australia (545 cases, 498 controls). We investigated 36 single nucleotide polymorphisms in IL10, TNF and 21 other immune function genes. We observed an elevated risk of DLBCL with the IL10 -3575T > A polymorphism [TA genotype: odds ratio (OR) = 1.32, 95% confidence interval (CI) = 0.86-2.02; AA, OR = 1.84, 95% CI = 1.10-3.08; trend test, P = 0.02]. Our most noteworthy TNF finding was an association between -857C > T and a decreased risk of NHL (CT or TT, OR = 0.59, 95% CI = 0.42-0.84, P = 0.003) and particularly follicular lymphoma (OR = 0.40, 95% CI = 0.23-0.68, P = 0.0009). Additionally, TNF -863C > A was associated with an elevated risk of DLBCL (CA, OR = 1.45, 95% CI = 0.95-2.21; AA, OR = 2.06, 95% CI = 0.88-4.83; trend test, P = 0.02). Our findings offer further evidence that variation in the IL10 and TNF loci influences NHL risk. Additional studies are needed to clarify the genetic and biologic basis for these relationships. C1 NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20892 USA. Univ Sydney, Sydney, NSW 2006, Australia. Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW, Australia. St Vincents Hosp, Sydney, NSW 2010, Australia. NCI, Viral Epidemiol Sect, AVP, SAIC, Frederick, MD 21701 USA. NCI, Core Genotyping Facil, Gaithersburg, MD USA. RP Purdue, MP (reprint author), NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd,EPS 8121,MSC 7240, Rockville, MD 20892 USA. EM purduem@mail.nih.gov RI Armstrong, Bruce/K-9464-2015; Purdue, Mark/C-9228-2016; OI Armstrong, Bruce/0000-0001-8940-7525; Purdue, Mark/0000-0003-1177-3108; Vajdic, Claire/0000-0002-3612-8298 FU Intramural NIH HHS NR 51 TC 95 Z9 98 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 MAR PY 2007 VL 28 IS 3 BP 704 EP 712 DI 10.1093/carcin/bgl200 PG 9 WC Oncology SC Oncology GA 152HB UT WOS:000245351100023 PM 17056605 ER PT J AU Ma, XC Idle, JR Malfatti, MA Krausz, KW Nebert, DW Chen, CS Felton, JS Waxman, DJ Gonzalez, FJ AF Ma, Xiaochao Idle, Jeffrey R. Malfatti, Michael A. Krausz, Kristopher W. Nebert, Daniel W. Chen, Chong-Sheng Felton, James S. Waxman, David J. Gonzalez, Frank J. TI Mouse lung CYP1A1 catalyzes the metabolic activation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) SO CARCINOGENESIS LA English DT Article ID DNA ADDUCT LEVELS; 2-AMINO-1-METHYL-6-PHENYLIMIDAZO<4,5-B>PYRIDINE PHIP; HUMAN CYTOCHROME-P450; HETEROCYCLIC AMINES; AROMATIC-AMINES; MONOCLONAL-ANTIBODIES; GENE-EXPRESSION; CHINESE-WOMEN; CANCER; MICE AB 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) carcinogenesis is initiated by N-2-hydroxylation, mediated by several cytochromes P450, including CYP1A1. However, the role of CYP1A1 in PhIP metabolic activation in vivo is unclear. In this study, Cyp1a1-null and wild-type (WT) mice were used to investigate the potential role of CYP1A1 in PhIP metabolic activation in vivo. PhIP N-2-hydroxylation was actively catalyzed by lung homogenates of WT mice, at a rate of 14.9 +/- 5.0 pmol/min/g tissue, but < 1 pmol/min/g tissue in stomach and small intestine, and almost undetectable in mammary gland and colon. PhIP N-2-hydroxylation catalyzed by lung homogenates of Cyp1a1-null mice was similar to 10-fold lower than that of WT mice. In contrast, PhIP N-2-hydroxylation activity in lung homogenates of Cyp1a2-null versus WT mice was not decreased. Pretreatment with 2,3,7,8-tetrachlorodibenzo-p-dioxin increased lung Cyp1a1 mRNA and lung homogenate PhIP N-2-hydroxylase activity similar to 50-fold in WT mice, where the activity was substantially inhibited (70%) by monoclonal antibodies against CYP1A1. In vivo, 30 min after oral treatment with PhIP, PhIP levels in lung were similar to those in liver. After a single dose of 0.1 mg/kg [C-14]PhIP, lung PhIP-DNA adduct levels in Cyp1a1-null mice, but not in Cyp1a2-null mice, were significantly lower (P = 0.0028) than in WT mice. These results reveal that mouse lung has basal and inducible PhIP N-2-hydroxylase activity predominantly catalyzed by CYP1A1. Because of the high inducibility of human CYP1A1, especially in cigarette smokers, the role of lung CYP1A1 in PhIP carcinogenesis should be considered. (237 words). C1 NCI, Lab Metab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. Charles Univ Prague, Inst Pharmacol, Fac Med 1, Prague 12800 2, Czech Republic. Lawrence Livermore Natl Lab, Biosci Directorate, Livermore, CA 94551 USA. Univ Cincinnati, Med Ctr, Dept Environm Hlth, Cincinnati, OH 45267 USA. Boston Univ, Dept Biol, Boston, MA 02215 USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Canc Res Ctr, NIH, Bldg 37,Room 3106, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov OI Waxman, David/0000-0001-7982-9206; Idle, Jeff/0000-0002-6143-1520 FU Intramural NIH HHS; NCI NIH HHS [CA55861, P01 CA055861, Z01 BC005562-18]; NCRR NIH HHS [P41 RR013461, P41 RR13461]; NIEHS NIH HHS [P42 ES007381, 5 P42 ES07381, R01 ES008147, R01 ES08147] NR 45 TC 17 Z9 17 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD MAR PY 2007 VL 28 IS 3 BP 732 EP 737 DI 10.1093/carcin/bgl184 PG 6 WC Oncology SC Oncology GA 152HB UT WOS:000245351100026 PM 17052995 ER PT J AU Beck, B Bidauxab, G Bavencoffe, A Lemonnier, L Thebault, S Shuba, Y Barrit, G Skryma, R Prevarskaya, N AF Beck, Benjamin Bidauxab, Gabriel Bavencoffe, Alexis Lemonnier, Loic Thebault, Stephanie Shuba, Yaroslav Barrit, Greg Skryma, Roman Prevarskaya, Natalia TI Prospects for prostate cancer imaging and therapy using high-affinity TRPM8 activators SO CELL CALCIUM LA English DT Article DE TRPM8 channels; cold; menthol; imaging; radiotherapy; prostate cancer ID OPERATED CA2+ CHANNELS; EPITHELIAL-CELLS; RECEPTOR TRPM8; COLD; MENTHOL; REVEALS; IDENTIFICATION; EXPRESSION; SENSATION; SURVIVAL AB One of the best-studied temperature-gated channels is transient receptor potential melastatin 8 (TRPM8), which is activated by cold and cooling agents, such as menthol. Besides inducing a cooling sensation in sensory neurons, TRPM8 channel activation also plays a major role in physiopathology. Indeed, TRPMP8 expression increases in early stages of prostate cancer and its involvement in prostate cell apoptosis has recently been demonstrated. Thus, as TRPM8 is a tumor marker with significant potential use in diagnosis, as well as a target for cancer therapy, there is a need for new TRPM8-specific ligands. In this study, we investigated the action of "WS" compounds on TRPM8 channels. We compared the affinity of these molecules to that of menthol and icilin. This enabled us to identify new TRPM8 agonists. The menthol analog with the highest affinity, WS-12, had an EC50 value about 2000 times lower than that of menthol and is, therefore, the highest-affinity TRPM8 ligand known to date. Finally, incorporating a fluorine atom in the WS-12 retained 75% of the activity of the parent compound. The high affinity of this new TRPM8 ligand and the possibility of incorporating a radiohalogen could thus be useful for diagnosis, monitoring and, perhaps, even therapy of prostate cancer. (c) 2006 Elsevier Ltd. All rights reserved. C1 INSERM, U800, F-59650 Villeneuve Dascq, France. Univ Lille 1, F-59650 Villeneuve Dascq, France. NIEHS, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. Univ Nijmegen, Dept Physiol, Nijmegen Ctr Mol Life Sci, Med Ctr, NL-6500 HB Nijmegen, Netherlands. NASU, Bogomoletz Inst Physiol, Kiev, Ukraine. Flinders Univ S Australia, Dept Med Biochem, Sch Med, Adelaide, SA 5001, Australia. RP Prevarskaya, N (reprint author), INSERM, U800, F-59650 Villeneuve Dascq, France. EM natacha.prevarskaya@univ-lille1.fr RI Bidaux, Gabriel/F-1294-2016; OI Bidaux, Gabriel/0000-0002-6162-3223; Barritt, Greg/0000-0002-7472-4250 NR 29 TC 41 Z9 44 U1 1 U2 9 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 J9 CELL CALCIUM JI Cell Calcium PD MAR PY 2007 VL 41 IS 3 BP 285 EP 294 DI 10.1016/j.ceca.2006.07.002 PG 10 WC Cell Biology SC Cell Biology GA 144BR UT WOS:000244770700009 PM 16949669 ER PT J AU Tominaga, Y Wang, A Wang, RH Wang, X Cao, L Deng, CX AF Tominaga, Y. Wang, A. Wang, R-H Wang, X. Cao, L. Deng, C-X TI Genistein inhibits Brca1 mutant tumor growth through activation of DNA damage checkpoints, cell cycle arrest, and mitotic catastrophe SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE genistein; BRCA1; DNA damage; cell cycle; chemoprevention ID BREAST-CANCER RISK; UNKNOWN SUSCEPTIBILITY GENES; OVARIAN-CANCER; STEROID-RECEPTORS; TOPOISOMERASE-II; STIMULATE GROWTH; MCF-7 TUMORS; MUTATIONS; SOY; DECATENATION AB Epidemiological studies revealed that amount of consumption of soy was inversely related to incidence of breast cancer. Genistein, the predominant isoflavone in soy, has been reported to reduce the incidence of breast cancer in animal models. To investigate whether genistein has a therapeutic effect on BRCA1-associated breast cancer, we treated Brca1 mutant mammary tumor cells with genistein. We showed that genistein treatment depleted the G1 population of cells, which was accompanied by an accumulation of cells at G2. Some genistein-treated cells entered mitosis; however, they exhibited chromosome abnormalities and maintained tetraploidy owing to abortive mitotic exit. A fraction of G2 cells underwent endoreduplication and became polyploid, which was accompanied by increased cell death through activating DNA damage response. Furthermore, our data indicated that Brca1 mutant cells were more sensitive to genistein than some other types of cancer cells, highlighting a good therapeutic potential of genistein for BRCA1-associated breast cancer. C1 NIDDK, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. RP Deng, CX (reprint author), NIDDK, Genet Dev & Dis Branch, NIH, 10-9N105,10 Ctr Dr, Bethesda, MD 20892 USA. EM chuxiad@bdg10.niddk.nih.gov RI deng, chuxia/N-6713-2016 FU Intramural NIH HHS NR 41 TC 26 Z9 29 U1 2 U2 3 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD MAR PY 2007 VL 14 IS 3 BP 472 EP 479 DI 10.1038/sj.cdd.4402037 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 137EI UT WOS:000244275400010 PM 17024228 ER PT J AU Zhou, ZH Zhang, YH Hu, YF Wahl, LM Cisar, JO Notkins, AL AF Zhou, Zhao-Hua Zhang, Yahong Hu, Ya-Fang Wahl, Larry M. Cisar, John O. Notkins, Abner Louis TI The broad antibacterial activity of the natural antibody repertoire is due to polyreactive antibodies SO CELL HOST & MICROBE LA English DT Article ID B-CELL REPERTOIRE; MONOREACTIVE HIGH-AFFINITY; POSITIVE SELECTION; INTRAVENOUS IMMUNOGLOBULIN; MONOCLONAL AUTOANTIBODIES; STREPTOCOCCUS-PNEUMONIAE; MULTIPLE-SCLEROSIS; SOMATIC MUTATION; B-1 CELLS; GERM-LINE AB Polyreactive antibodies bind to a variety of structurally unrelated antigens. The function of these antibodies, however, has remained an enigma, and because of their low binding affinity their biological relevance has been questioned. Using a panel of monoclonal polyreactive antibodies, we showed that these antibodies can bind to both Gram-negative and Gram-positive bacteria and acting through the classical complement pathway can inhibit bacterial growth by lysis, generate anaphylatoxin C5a, enhance phagocytosis, and neutralize the functional activity of endotoxin. Polyreactive anti body-enriched, but not polyreactive antibody-reduced, IgM prepared from normal human serum displays antibacterial activity similar to that of monoclonal polyreactive IgM. We conclude that polyreactive antibodies are a major contributor to the broad antibacterial activity of the natural antibody repertoire. C1 NCI, Expt Med Sect, Bethesda, MD 20892 USA. NCI, Immunol Sect, Bethesda, MD 20892 USA. NCI, Natl Inst Dent & Craniogacial Res, Microbial Receptors Unit, Bethesda, MD 20892 USA. RP Notkins, AL (reprint author), NCI, Expt Med Sect, Bethesda, MD 20892 USA. EM anotkins@mail.nih.gov FU Intramural NIH HHS [Z99 OD999999] NR 50 TC 105 Z9 112 U1 1 U2 8 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 MAR PY 2007 VL 1 IS 1 BP 51 EP 61 DI 10.1016/j.chom.2007.01.002 PG 11 WC Microbiology; Parasitology; Virology SC Microbiology; Parasitology; Virology GA 220GX UT WOS:000250146300009 PM 18005681 ER PT J AU Goulley, J Dahl, U Baeza, N Mishina, Y Edlund, H AF Goulley, Joan Dahl, Ulf Baeza, Nathalie Mishina, Yuji Edlund, Helena TI BMP4-BMPR1A signaling in beta cells is required for and augments glucose-stimulated insulin secretion SO CELL METABOLISM LA English DT Article ID BONE MORPHOGENETIC PROTEIN; GLUCAGON-LIKE PEPTIDE-1; DIABETES-MELLITUS; MOUSE PANCREAS; CROSS-TALK; EXPRESSION; RECEPTOR; DIFFERENTIATION; MECHANISMS; MICE AB Impaired glucose-stimulated insulin secretion (GSIS) and perturbed proinsulin processing are hallmarks of beta cell dysfunction in type 2 diabetes. Signals that can preserve and/or enhance beta cell function are therefore of great therapeutic interest. Here we show that bone morphogenetic protein 4 (Bmp4) and its high-affinity receptor, Bmpr1a, are expressed in beta cells. Mice with attenuated BMPR1A signaling in beta cells show decreased expression of key genes involved in insulin gene expression, proinsulin processing, glucose sensing, secretion stimulus coupling, incretin signaling, and insulin exocytosis and develop diabetes due to impaired insulin secretion. We also show that transgenic expression of Bmp4 in beta cells enhances GSIS and glucose clearance and that systemic administration of BMP4 protein to adult mice significantly stimulates GSIS and ameliorates glucose tolerance in a mouse model of glucose intolerance. Thus, BMP4-BMPR1A signaling in beta cells plays a key role in GSIS. C1 Umea Univ, Umea Ctr Mol Med, SE-90187 Umea, Sweden. Betagenon AB, SE-90719 Umea, Sweden. NIEHS, Lab Reprod & Dev Toxicol, Res Triangle Pk, NC 27709 USA. RP Edlund, H (reprint author), Umea Univ, Umea Ctr Mol Med, SE-90187 Umea, Sweden. EM helena.edlund@ucmm.umu.se NR 53 TC 72 Z9 76 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD MAR PY 2007 VL 5 IS 3 BP 207 EP 219 DI 10.1016/j.cmet.2007.01.009 PG 13 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 144OQ UT WOS:000244806100008 PM 17339028 ER PT J AU Pitt, KE Vaught, JB Henderson, MK AF Pitt, K. E. Vaught, J. B. Henderson, M. K. TI Considerations in the development and implementation of sample culling policies and practices SO CELL PRESERVATION TECHNOLOGY LA English DT Meeting Abstract C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Pitt, KE (reprint author), NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NR 0 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 1538-344X J9 CELL PRESERV TECHNOL JI Cell Preserv. Technol. PD SPR PY 2007 VL 5 IS 1 BP 63 EP 64 PG 2 WC Cell Biology; Medical Laboratory Technology SC Cell Biology; Medical Laboratory Technology GA 162XM UT WOS:000246122800053 ER PT J AU Henderson, MK Vaught, JB Pitt, KE Cosentino, LM AF Henderson, M. K. Vaught, J. B. Pitt, K. E. Cosentino, L. M. TI Economics and financial management of a large biomedical repository program SO CELL PRESERVATION TECHNOLOGY LA English DT Meeting Abstract C1 NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. NCI, SAIC, Frederick, MD 21701 USA. RP Henderson, MK (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. NR 0 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 1538-344X J9 CELL PRESERV TECHNOL JI Cell Preserv. Technol. PD SPR PY 2007 VL 5 IS 1 BP 64 EP 64 PG 1 WC Cell Biology; Medical Laboratory Technology SC Cell Biology; Medical Laboratory Technology GA 162XM UT WOS:000246122800054 ER PT J AU You, YP Geng, XZ Zhao, P Fu, Z Wang, CZ Chao, SW Liu, N Lu, AL Gardner, K Pu, PY Kong, CS Ge, Y Judge, SIV Li, QDQ AF You, Yongping Geng, Xiaozeng Zhao, Peng Fu, Zhen Wang, Cunzu Chao, Shengwu Liu, Ning Lu, Ailing Gardner, Kevin Pu, Peiyu Kong, Chunsheng Ge, Yun Judge, Susan I. V. Li, Qingdi Q. TI Evaluation of combination gene therapy with PTEN and antisense hTERT for malignant glioma in vitro and xenografts SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Article DE antisense hTERT; PTEN; glioma; gene therapy; combination therapy; xenograft ID TELOMERASE REVERSE-TRANSCRIPTASE; ENDOMETRIAL CANCER-CELLS; MESSENGER-RNA; CERVICAL-CANCER; TUMOR-GROWTH; GLIOBLASTOMA CELLS; DOWN-REGULATION; SUBUNIT HTERT; CYCLE ARREST; EXPRESSION AB Telomerase activation is a critical event in cell immortalization, and an increase in human telomerase reverse transcriptase (hTERT) expression is the key step in activating telomerase. The phosphatase and tensin homolog (PTEN) gene encodes a double-specific phosphatase that induces cell cycle arrest, inhibits cell growth, and causes apoptotic cell death. Here, we evaluated a combined PTEN and antisense hTERT gene therapy for experimental glioma in vitro and in vivo. We demonstrated that infection with antisense-hTERT and wild-type-PTEN adenoviruses significantly inhibited human U251 glioma cell proliferation in vitro and glioma growth in a xenograft mouse model. The efficacy of therapy was obviously higher in the tumor xenografts infected with both PTEN and antisense hTERT than in the gliomas infected with either agent alone at the same total viral dose. Consistent with these results, we showed that telomerase activity and hTERT protein levels were markedly reduced in the glioma cells following adenovirus infection. In contrast, the levels of PTEN protein expression were dramatically increased in these cells. Our data indicate that combination treatment with antisense hTERT and wild-type PTEN effectively suppresses the malignant growth of human glioma cells in vitro and in tumor xenografts, suggesting a promising new approach in glioma gene therapy that warrants further investigation. C1 Nanjing Med Univ, Affiliated Hosp 1, Dept Neurosurg, Nanjing 210029, Peoples R China. NCI, Ctr Canc Res, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. Tianjin Med Univ, Gen Hosp, Dept Neurosurg, Tianjin 300052, Peoples R China. Univ Maryland, Sch Med, VA Maryland Hlth Care Syst, MS Ctr Excellence East, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA. RP Li, QDQ (reprint author), Nanjing Med Univ, Affiliated Hosp 1, Dept Neurosurg, Nanjing 210029, Peoples R China. EM liquenti@mail.nih.gov NR 48 TC 15 Z9 21 U1 1 U2 2 PU BIRKHAUSER VERLAG AG PI BASEL PA VIADUKSTRASSE 40-44, PO BOX 133, CH-4010 BASEL, SWITZERLAND SN 1420-682X J9 CELL MOL LIFE SCI JI Cell. Mol. Life Sci. PD MAR PY 2007 VL 64 IS 5 BP 621 EP 631 DI 10.1007/s00018-007-6424-4 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 143IL UT WOS:000244713900011 PM 17310280 ER PT J AU Dupre, DJ Baragli, A Rebois, RV Ethier, N Hebert, TE AF Dupre, Denis J. Baragli, Alessandra Rebois, R. Victor Ethier, Nathalie Hebert, Terence E. TI Signalling complexes associated with adenylyl cyclase II are assembled during their biosynthesis SO CELLULAR SIGNALLING LA English DT Article DE BRET; adenylyl cyclase; protein-protein interactions and assembly; 7-transmembrane domain receptor; signalling complexes; trafficking ID G-BETA-GAMMA; PROTEIN-COUPLED RECEPTOR; RECTIFYING POTASSIUM CHANNELS; HETEROTRIMERIC G-PROTEINS; FORM STABLE COMPLEXES; PLASMA-MEMBRANE; BETA(2)-ADRENERGIC RECEPTOR; ENDOPLASMIC-RETICULUM; CELL-SURFACE; LIVING CELLS AB We have previously demonstrated that adenylyl cyclase II (ACII) interacts with beta(2)-adrenergic receptors and heterotrimeric G proteins as part of a pre-assembled signalling complex. In this study, we further show that AC interacts with these proteins before it is targetted to the cell surface. Using a combination of approaches including bioluminescence resonance energy transfer (BRET) in concert with subcellular fractionation, we show that ACII and beta(2)AR initially interact in the ER. Further, dominant-negative Rab1 and Sar1 GTPases which block anterograde trafficking out of the ER have no effect on either ACII/receptor or ACII/G beta gamma protein interactions. However, DN Rab1 and Sar1 constructs (but not DN Rabs 2, 6, 8 or 11) prevent the inclusion of G alpha subunits in ACII signalling complexes suggesting it assembles into the complex at a slightly later stage. Thus, like Kir3.1 inwardly rectifying potassium channels, signalosomes containing ACII are formed during their biosynthesis and not in response to agonist at the cell surface. (c) 2006 Elsevier Inc. All rights reserved. C1 McGill Univ, Dept Pharmacol & Therapeut, Fac Med, Montreal, PQ H3G 1Y6, Canada. Natl Inst Deafness & Commun Disorders, Lab Cellular Biol, NIH, Rockville, MD USA. RP Hebert, TE (reprint author), McGill Univ, Dept Pharmacol & Therapeut, Fac Med, 13th Floor,Room 1303,McIntyre Med Sci Bldg,3655, Montreal, PQ H3G 1Y6, Canada. EM terence.hebert@mcgill.ca RI Dupre, Denis/F-3044-2014 NR 59 TC 44 Z9 44 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 J9 CELL SIGNAL JI Cell. Signal. PD MAR PY 2007 VL 19 IS 3 BP 481 EP 489 DI 10.1016/j.cellsig.2006.07.021 PG 9 WC Cell Biology SC Cell Biology GA 136RW UT WOS:000244242800006 PM 16979872 ER PT J AU Weisberg, J van Turennout, M Martin, A AF Weisberg, Jill van Turennout, Miranda Martin, Alex TI A neural system for learning about object function SO CEREBRAL CORTEX LA English DT Article DE object recognition; neural plasticity; FMRI; tools; concepts; temporal lobes; parietal lobes; premotor cortex ID CONCEPTUAL KNOWLEDGE; MANIPULATABLE OBJECTS; GRASPABLE OBJECTS; SEMANTIC MEMORY; FACE PERCEPTION; PREMOTOR CORTEX; REPRESENTATION; MOTOR; BRAIN; TOOL AB Does our ability to visually identify everyday objects rely solely on access to information about their appearance or on a more distributed representation incorporating other object properties? Using functional magnetic resonance imaging, we addressed this question by having subjects visually match pictures of novel objects before and after extensive training to use these objects to perform specific tool-like tasks. After training, neural activity emerged in regions associated with the motion (left middle temporal gyrus) and manipulation (left intraparietal sulcus and premotor cortex) of common tools, whereas activity became more focal and selective in regions representing their visual appearance (fusiform gyrus). These findings indicate that this distributed network is automatically engaged in support of object identification. Moreover, the regions included in this network mirror those active when subjects retrieve information about tools and their properties, suggesting that, as a result of training, these previously novel objects have attained the conceptual status of "tools." C1 NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Martin, A (reprint author), NIMH, Lab Brain & Cognit, Bldg 10,Room 4C-104,10 Ctr Dr MSC1366, Bethesda, MD 20892 USA. EM alexmartin@mail.nih.gov RI martin, alex/B-6176-2009 FU Intramural NIH HHS [Z99 MH999999] NR 62 TC 118 Z9 119 U1 1 U2 10 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 MAR PY 2007 VL 17 IS 3 BP 513 EP 521 DI 10.1093/cercor/bhj176 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 135AD UT WOS:000244125200002 PM 16581980 ER PT J AU Tovar-Moll, F Moll, J de Oliveira-Souza, R Bramati, I Andreiuolo, PA Lent, R AF Tovar-Moll, Fernanda Moll, Jorge de Oliveira-Souza, Ricardo Bramati, Ivanei Andreiuolo, Pedro A. Lent, Roberto TI Neuroplasticity in human callosal dysgenesis: A diffusion tensor imaging study SO CEREBRAL CORTEX LA English DT Article DE callosal agenesis; callosal development; corpus callosum; cortex development; cortical commissures; DTI ID HUMAN CORPUS-CALLOSUM; HORSERADISH-PEROXIDASE TECHNIQUE; PROBST LONGITUDINAL BUNDLE; COMMISSURAL FIBERS; ACALLOSAL MOUSE; RHESUS-MONKEY; BRAIN REORGANIZATION; SYNAPTIC PLASTICITY; AXONAL PROJECTIONS; CONGENITAL ABSENCE AB Callosal dysgenesis (CD) is observed in many neurodevelopmental conditions, but its subjacent mechanisms are unknown, despite extensive research on animals. Here we employ magnetic resonance diffusion tensor imaging and tractography in human CD to reveal the aberrant circuitry of these brains. We searched particularly for evidence of plasticity. Four main findings are described-1) in the presence of a callosal remnant or a hypoplastic corpus callosum (CC), fibers therein largely connect the expected neocortical regions; 2) callosal remnants and hypoplastic CCs display a fiber topography similar to normal; 3) at least 2 long abnormal tracts are formed in patients with defective CC: the well-known Probst bundle (PB) and a so far unknown sigmoid, asymmetrical aberrant bundle connecting the frontal lobe with the contralateral occipitoparietal cortex; and 4) whereas the PB is topographically organized and has an ipsilateral U-connectivity, the sigmoid bundle is a long, heterotopic commissural tract. These observations suggest that when the developing human brain is confronted with factors that hamper CC fibers to cross the midline, some properties of the miswired fibers are maintained (such as side-by-side topography), whereas others are dramatically changed, leading to the formation of grossly abnormal white matter tracts. C1 Univ Fed Rio de Janeiro, Inst Biomed Sci, Dept Anat, BR-21941 Rio De Janeiro, Brazil. Labs Or Hosp Network, Cognit Behav Neurosci Unit, Rio De Janeiro, Brazil. RP Tovar-Moll, F (reprint author), Natl Inst Neurol Disorders & Stroke, Neuroimmunol Branch, NIH, 10 Ctr Dr,Bldg 10,Room 5B08, Bethesda, MD 20892 USA. EM tovarmof@ninds.nih.gov RI Moll, Jorge/B-2654-2013; PCM, PG/D-1034-2013 NR 74 TC 59 Z9 61 U1 0 U2 3 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 MAR PY 2007 VL 17 IS 3 BP 531 EP 541 DI 10.1093/cercor/bhj178 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 135AD UT WOS:000244125200004 PM 16627861 ER PT J AU Tarasova, NI Loeppky, RN Byrd, RA Keefer, LK AF Tarasova, Nadya I. Loeppky, Richard N. Byrd, R. Andrew Keefer, Larry K. TI In memoriam: Christopher J. Michejda (December 19, 1937 January 9, 2007) SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Biographical-Item C1 Univ Missouri, Dept Chem, Columbia, MO 65211 USA. NCI, Frederick, MD 21701 USA. RP Tarasova, NI (reprint author), Univ Missouri, Dept Chem, Columbia, MO 65211 USA. RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD MAR PY 2007 VL 20 IS 3 BP 323 EP 325 DI 10.1021/tx700056k PG 3 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 146TU UT WOS:000244958400001 PM 17335248 ER PT J AU Chen, C Ma, XC Malfatti, MA Krausz, KW Kimura, S Felton, JS Idle, JR Gonzalez, FJ AF Chen, Chi Ma, Xiaochao Malfatti, Michael A. Krausz, Kristopher W. Kimura, Shioko Felton, James S. Idle, Jeffrey R. Gonzalez, Frank J. TI A comprehensive investigation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) metabolism in the mouse using a multivariate data analysis approach SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID FLIGHT MASS-SPECTROMETRY; DNA ADDUCT FORMATION; 2-AMINO-1-METHYL-6-PHENYLIMIDAZO<4,5-B>PYRIDINE PHIP; HETEROCYCLIC AMINES; FOOD MUTAGEN; CYTOCHROME-P450 ENZYMES; DIFFERENTIAL METABOLISM; MONOCLONAL-ANTIBODIES; STATISTICAL-ANALYSIS; LIVER-MICROSOMES AB 2-Amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) is a potent rodent carcinogen and a potential human carcinogen because of its existence in the normal human diet. N-2-OH-PhIP, a major PhIP metabolite, has been identified as a precursor of genotoxic species. In vitro data supported the view that CYP1A2 is the major enzyme responsible for the formation of N-2-OH-PhIP. However, disruption of the CYP1A2 gene in mouse failed to inhibit PhIP-induced carcinogenesis. To investigate the mechanism underlying this observation, the metabolism of PhIP in wild-type, Cyp1a2-null, and CYP1A2-humanized mice was examined in detail using a metabolomic approach. Following data acquisition in a high-resolution LC-MS system, urinary metabolomes of the control and PhIP-treated mice were characterized in a principal component analysis (PCA) model. Comprehensive metabolite profiles of PhIP in high dose (10 mg/kg) and low dose (100 mu g/kg) were established through analyzing urinary ions contributing to the separation of three mouse lines in the multivariate model and by measuring radiolabled PhIP metabolite in a radio-HPLC assay, respectively. The genotoxicity of PhIP to three mouse lines was evaluated by measuring DNA adduction levels in liver, lung, colon, and mammary gland. On the basis of the chemical identities of 17 urinary PhIP metabolites, including eight novel metabolites, multivariate data analysis revealed the role of CYP1A2 in PhIP metabolism and a human-mouse interspecies difference in the catalytic activity of CYP1A2. In addition, the results also showed that Cyp1a2-null mice still possess significant N-2-hydroxylation and DNA adduction activities, which may be partially attributed to mouse CYP2C enzymes according to the results from in vitro microsome and Supersome incubations and antibody inhibition experiments. C1 NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Charles Univ Prague, Fac Med 1, Inst Pharmacol, Prague, Czech Republic. Lawrence Livermore Natl Lab, Biosci Directorate, Livermore, CA USA. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov RI Chen, Chi/B-4618-2008; OI Idle, Jeff/0000-0002-6143-1520 FU NCI NIH HHS [Z01 BC005562-18, P01 CA055861, CA55861]; NCRR NIH HHS [P41 RR013461, RR13461] NR 43 TC 35 Z9 36 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD MAR PY 2007 VL 20 IS 3 BP 531 EP 542 DI 10.1021/tx600320w PG 12 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 146TU UT WOS:000244958400021 PM 17279779 ER PT J AU Panchal, RG Ruthel, G Brittingham, KC Lane, D Kenny, TA Gussio, R Lazo, JS Bavari, S AF Panchal, Rekha G. Ruthel, Gordon Brittingham, Katherine C. Lane, Douglas Kenny, Tara A. Gussio, Rick Lazo, John S. Bavari, Sina TI Chemical genetic screening identifies critical pathways in anthrax lethal toxin-induced pathogenesis SO CHEMISTRY & BIOLOGY LA English DT Article ID SPECIFICITY PHOSPHATASE INHIBITORS; PROTEIN-KINASE KINASE; NECROSIS-FACTOR-ALPHA; NF-KAPPA-B; BACILLUS-ANTHRACIS; TNF-ALPHA; MACROPHAGE APOPTOSIS; SMALL-MOLECULE; PROTEOLYTIC INACTIVATION; INDUCED CYTOTOXICITY AB Anthrax lethal toxin (LT)-induced cell death via mitogen-activated protein kinase kinase (MAPKK) cleavage remains questionable. Here, a chemical genetics approach was used to investigate what pathways mediate LT-induced cell death. Several small molecules were found to protect macrophages from anthrax LT cytotoxicity and MAPKK from cleavage by lethal factor (LF), without inhibiting LF enzymatic activity or cellular proteasome activity. Interestingly, the compounds activated MAPK-signaling molecules, induced proinflammatory cytokine production, and inhibited LT-induced macrophage apoptosis in a concentration-dependent manner. We propose that induction of antiapoptotic responses by MAPK-dependent or -independent pathways and activation of host innate responses may protect macrophages; from anthrax LT-induced cell death. Altering host responses through a chemical genetics approach can help identify critical cellular pathways involved in the pathogenesis of anthrax and can be exploited to further explore host-pathogen interactions. C1 SAIC Frederick Inc, NCI Frederick, Target Struct Based Drug Discovery Grp, Ft Detrick, MD 21702 USA. USA, Res Inst Infect Dis, Ft Detrick, MD 21702 USA. NCI, Dev Therapeut Program, Informat Technol Branch, Target Struct Based Drug Discovery Grp, Ft Detrick, MD 21702 USA. Univ Pittsburgh, Dept Pharmacol, Pittsburgh, PA 15260 USA. RP Panchal, RG (reprint author), SAIC Frederick Inc, NCI Frederick, Target Struct Based Drug Discovery Grp, Ft Detrick, MD 21702 USA. EM rekha.panchal@amedd.army.mil; sina.bavari@amedd.army.mil FU NCI NIH HHS [N01-CO-12400] NR 44 TC 11 Z9 11 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-5521 J9 CHEM BIOL JI Chem. Biol. PD MAR PY 2007 VL 14 IS 3 BP 245 EP 255 DI 10.1016/j.chembiol.2007.01.007 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 151QU UT WOS:000245306500006 PM 17379140 ER PT J AU Zarin, DA Keselman, A AF Zarin, Deborah A. Keselman, Alla TI Registering a clinical trial in ClinicalTrials.gov SO CHEST LA English DT Article DE compliance; computer; epidemiology ID MEDICAL-JOURNAL-EDITORS; INTERNATIONAL-COMMITTEE; REGISTRATION; STATEMENT; PRINCIPLES C1 Natl Lib Med, Bethesda, MD 20894 USA. RP Zarin, DA (reprint author), Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM dzarin@mail.nih.gov NR 11 TC 24 Z9 24 U1 0 U2 1 PU AMER COLL CHEST PHYSICIANS PI NORTHBROOK PA 3300 DUNDEE ROAD, NORTHBROOK, IL 60062-2348 USA SN 0012-3692 J9 CHEST JI Chest PD MAR PY 2007 VL 131 IS 3 BP 909 EP 912 DI 10.1378/chest.06-2450 PG 4 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 148KI UT WOS:000245072900045 PM 17303677 ER PT J AU Bowen, RAR Vu, C Remaley, AT Hortin, GL Csako, G AF Bowen, Raffick A. R. Vu, Chi Remaley, Alan T. Hortin, Glen L. Csako, Gyorgy TI Differential effect of blood collection tubes on total free fatty acids (FFA) and total triiodothyronine (TT3) concentration: A model for studying interference from tube constituents SO CLINICA CHIMICA ACTA LA English DT Article DE separator gel; surfactant; silicone; interference; reformulation; Silwet L-720 ID SERUM-SEPARATOR TUBES; ENZYMATIC DETERMINATION; CLINICAL-CHEMISTRY; THERAPEUTIC DRUGS; PLASMA; STORAGE; ASSAY; STABILITY; GLASS; TETRAHYDROLIPSTATIN AB Background: Besides total triiodothyronine (TT3) total free fatty acids (FFA) concentrations were higher with serum separator tube (SST (TM)) than Vacuette (TM) tubes. Methods: The effects of surfactant, rubber stopper, and separator gel from various tubes were investigated on FFA, beta-hydroxybutyrate (beta-HD), and TT3 with 8 different tube types in blood specimens of apparently healthy volunteers. Results: Compared to Vacuette tubes, serum FFA and TT3 concentrations were significantly higher in SST than glass tubes. Reformulated SST eliminated the increase in TT3 but not FFA. No significant difference was observed for beta-HB concentration among tube types. Surfactant and rubber stoppers from the different tube types significantly increased TT3 but not FFA and beta-HB concentrations. Agitation of whole blood but not serum or plasma specimens with separator gel from SST, reformulated SST and plasma preparation tube (PPT (TM)) tubes compared to Vacuette tubes gave higher FFA but not beta-HB levels. Conclusions: Unidentified component(s) from the separator gel in SST, reformulated SST and PPT tubes cause falsely high FFA concentration. In contrast to TT3, falsely high FFA results require exposure of whole blood and not serum to tube constituent(s). The approach employed here may serve as a model for assessing interference(s) from tube constituent(s). (c) 2006 Elsevier B.V. All rights reserved. C1 NIH, Clin Chem Serv, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Csako, G (reprint author), NIH, Clin Chem Serv, Dept Lab Med, Ctr Clin, Bldg 10,Rm 2C-407, Bethesda, MD 20892 USA. EM gcsako@nih.gov FU Intramural NIH HHS NR 40 TC 18 Z9 19 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD MAR PY 2007 VL 378 IS 1-2 BP 181 EP 193 DI 10.1016/j.cca.2006.11.020 PG 13 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 147IW UT WOS:000244997600030 PM 17234171 ER PT J AU Stickle, DF Seligman, ML Landmark, JD Quon, MJ AF Stickle, Douglas F. Seligman, Mark L. Landmark, James D. Quon, Michael J. TI Predicted effects of hemoglobin A1c assay precision on a patient population distribution of serial hemoglobin A1c difference values SO CLINICA CHIMICA ACTA LA English DT Article DE glycated hemoglobin; hemoglobin A1c; diabetes; precision; point-of-care testing ID ANALYTICAL QUALITY SPECIFICATIONS; GLYCATED HEMOGLOBIN; LABORATORY TESTS; ANALYTICAL GOALS; IMPRECISION; PERSPECTIVE; CRITERIA AB Background: Interpretation of serial measurements of % hemoglobin A1c includes an assessment of differences from preceding values (DHbA1c). We examined predicted effects of different assay precisions on an observed population distribution for DHbA1c. Methods: Primary data were 5260 DHbA1c values from sequential HbA1c measurement pairs obtained within 1 calendar year. Each DHbA1c was replaced by a distribution obtained from sampling each component HbA1c value according to a normal distribution characterized by a fixed coefficient of variation (CV) of either 1%, 3% or 5% (forming data sets A, B and C, respectively). Data sets B and C, with inferior precision, were compared with the reference data set A (highest precision). Results: Using DHbA1c bin widths of 0.5% HbA1c, differences in assay precision caused significant redistribution of numbers within bins. For instance, for CV=5%, there was a 7.2% decrease in the number of results within the DHbA1c bin=(-0.5 to <= 0.0)% compared with the number for CV=1%, and a 6.4% increase in numbers of results for DHbA1c > 0.5. Conclusion: Different HbA1c assay CVs can significantly affect the fraction of patients within different clinical categorizations for DHbA1c and consequently may differently influence patient care recommendations. (c) 2006 Elsevier B.V. All rights reserved. C1 Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA. Univ Washington, Dept Stat, Seattle, WA 98195 USA. NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Stickle, DF (reprint author), Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA. EM dstickle@unmc.edu RI Quon, Michael/B-1970-2008; Stickle, Douglas/A-9682-2009; OI Quon, Michael/0000-0002-9601-9915; Quon , Michael /0000-0002-5289-3707 NR 21 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD MAR PY 2007 VL 378 IS 1-2 BP 201 EP 205 DI 10.1016/j.cca.2006.11.022 PG 5 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 147IW UT WOS:000244997600032 PM 17229418 ER PT J AU Giannakopoulos, B Shi, T Yan, X Yu, P Berndt, MC Andrew, RK Rivera, J Iverson, GM Cockerill, KA Linnik, MD Krilis, SA AF Giannakopoulos, B. Shi, T. Yan, X. Yu, P. Berndt, M. C. Andrew, R. K. Rivera, J. Iverson, G. M. Cockerill, K. A. Linnik, M. D. Krilis, S. A. TI Anti-beta(2)-glycoprotein I antibodies in complex with beta(2)-glycoprotein I can activate platelets via glycoprotein Ib-IX-V SO CLINICAL AND EXPERIMENTAL RHEUMATOLOGY LA English DT Meeting Abstract C1 Univ New S Wales, St George Hosp, Dept Immunol Allergy & Infect Dis, Sydney, NSW, Australia. Monash Univ, Dept Mol Biol, Clayton, Vic 3168, Australia. NIH, Mol Inflammat Sect, Bethesda, MD 20892 USA. La Jolla Pharmaceut Co, San Diego, CA USA. RI Berndt, Michael/D-5580-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU CLINICAL & EXPER RHEUMATOLOGY PI PISA PA VIA SANTA MARIA 31, 56126 PISA, ITALY SN 0392-856X J9 CLIN EXP RHEUMATOL JI Clin. Exp. Rheumatol. PD MAR-APR PY 2007 VL 25 IS 2 BP 159 EP 160 PG 2 WC Rheumatology SC Rheumatology GA 173OK UT WOS:000246882200181 ER PT J AU Siegel, KL Kepple, TM Stanhope, SJ AF Siegel, Karen Lohmann Kepple, Thomas M. Stanhope, Steven J. TI A case study of gait compensations for hip muscle weakness in idiopathic inflammatory myopathy SO CLINICAL BIOMECHANICS LA English DT Article DE myositis; muscle weakness; hip; gait ID SUPPORT; WALKING; INDIVIDUALS; PROGRESSION; STRENGTH; FORCE AB Background. The purpose of this case series was to quantify different strategies used to compensate in gait for hip muscle weakness. Methods. An instrumented gait analysis was performed of three females diagnosed with idiopathic inflammatory myopathies and compared to a healthy unimpaired subject. Lower extremity joint moments obtained from the gait analysis were used to drive an induced acceleration model which determined each moment's contribution to upright support, forward progression, and hip joint acceleration. Findings. Results showed that after midstance, the ankle plantar flexors normally provide upright support and forward progression while producing hip extension acceleration. In normal gait, the hip flexors eccentrically resist hip extension, but the hip flexor muscles of the impaired subjects (S1-3) were too weak to control extension. Instead S1-3 altered joint positions and Muscle function to produce forward progression while minimizing hip extension acceleration. SI increased knee flexion angle to decrease the hill extension effect of the ankle plantar flexors. S2 and S3 used either a knee flexor moment or gravity to produce forward progression, which had the advantage of accelerating the hip into flexion rather than extension, and decreased the demand on the hip flexors. Interpretation. Results showed how gait compensations for hip muscle weakness can produce independent (i.e. successful) ambulation, although at a reduced speed as compared to normal gait. Knowledge of these successful strategies can assist the rehabilitation of patients with hip muscle weakness who are unable to ambulate and potentially be used to reduce their disability. Published by Elsevier Ltd. C1 CRC, Phys Disabil Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Siegel, KL (reprint author), CRC, Phys Disabil Branch, NIH, Dept Hlth & Human Serv, Bldg 10,Rm 1-1469,10 Ctr Dr,MSC 1604, Bethesda, MD 20892 USA. EM karen_siegel@nih.gov RI Siegel, Karen Lohmann/B-5898-2008; OI Siegel, Karen Lohmann/0000-0002-0788-6612 FU Intramural NIH HHS [NIH0010040242]; PHS HHS [NIH0010040242] NR 26 TC 5 Z9 5 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0268-0033 J9 CLIN BIOMECH JI Clin. Biomech. PD MAR PY 2007 VL 22 IS 3 BP 319 EP 326 DI 10.1016/j.clinbiomech.2006.11.002 PG 8 WC Engineering, Biomedical; Orthopedics; Sport Sciences SC Engineering; Orthopedics; Sport Sciences GA 142ED UT WOS:000244631300009 PM 17187908 ER PT J AU Ratnam, K Low, JA AF Ratnam, Kapila Low, Jennifer A. TI Current development of clinical inhibitors of poly (ADP-ribose) polymerase in oncology SO CLINICAL CANCER RESEARCH LA English DT Review ID DEPENDENT PROTEIN-KINASE; DOUBLE-STRAND BREAKS; POLY(ADP-RIBOSE) POLYMERASE; DNA-DAMAGE; HOMOLOGOUS RECOMBINATION; THERAPEUTIC STRATEGY; IONIZING-RADIATION; ANTITUMOR-ACTIVITY; POTENT INHIBITORS; CELL-DEATH AB Poly (ADP-ribose) polymerase (PARP) is a nuclear enzyme that signals the presence of DNA damage by catalyzing the addition of ADP-ribose units to DNA, histones, and various DNA repair enzymes and by facilitating DNA repair. PARP has been gaining increasing interest as a therapeutic target for many diseases and especially for cancer. Inhibition of PARP potentiates the activity of DNA-damaging agents, such as alkylators, platinums, topoisomerase inhibitors, and radiation in in vitro and in vivo models. In addition, tumors with DNA repair defects, such as those arising from patients with BRCA mutations, may be more sensitive to PARP inhibition. At least five different companies have now initiated oncology clinical trials with PARP inhibitors, ranging in stage from phase 0 to phase 2. This review summarizes the preclinical and clinical data currently available for these agents and some of the challenges facing the clinical development of these agents. C1 PSI Int Inc, Bethesda, MD USA. NCI, Invest Drug Branch, Canc Therapy Evaluat Program, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Low, JA (reprint author), Genentech Inc, Biooncol, 1 DNA Way,Mail Code 442A, San Francisco, CA 94080 USA. EM low.jennifer@gene.com NR 72 TC 197 Z9 203 U1 0 U2 13 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 MAR 1 PY 2007 VL 13 IS 5 BP 1383 EP 1388 DI 10.1158/1078-0432.CCR-06-2260 PG 6 WC Oncology SC Oncology GA 144CL UT WOS:000244772800006 PM 17332279 ER PT J AU Horton, TM Pati, D Plon, SE Thompson, PA Bomgaars, LR Adamson, PC Ingle, AM Wright, J Brockman, AH Paton, M Blaney, SM AF Horton, Terzah M. Pati, Debananda Plon, Sharon E. Thompson, Patrick A. Bomgaars, Lisa R. Adamson, Peter C. Ingle, Ashish M. Wright, John Brockman, Adam H. Paton, Martin Blaney, Susan M. TI A phase 1 study of the proteasome inhibitor bortezomib in pediatric patients with refractory leukemia: A Children's Oncology Group study SO CLINICAL CANCER RESEARCH LA English DT Article ID NON-HODGKINS-LYMPHOMA; B-CLL LYMPHOCYTES; I TRIAL; APOPTOSIS; CANCER; SYSTEM; PS-341; CELLS AB Purpose: A phase 1 study to determine the maximum-tolerated dose, dose-limiting toxicity, pharmacokinetics, and biological effects of bortezomib in children with recurrent/refractory leukemia. Experimental Design: Bortezomib was administered twice weekly for 2 consecutive weeks at either 1.3 or 1.7 mg/m(2) dose followed by a 1-week rest. Bortezomib pharmacokinetics and nuclear factor kappa B (NF-kappa B) binding activity were evaluated during the first treatment cycle. Results: Twelve patients (nine with acute lymphoblastic leukemia, three with acute myelogenous leukemia), median age 11 years (range, 1-18 years), were enrolled between May 2004 and November 2005, of whom seven were not fully evaluable for toxicity due to rapidly progressive disease or uncontrolled infection. Dose-limiting toxicities occurred in two patients at the 1.7 mg/m(2) dose level. One patient experienced grade 3 confusion and the other patient had grade 4 febrile neutropenia associated with grade 4 hypotension and grade 3 creatinine. Pharmacokinetic analysis 2 at 1.3 mg/m(2) revealed a clearance of 11 mL/h/m(2), a central volume of distribution of 6.7 L/m(2), and a terminal half-life of 12.6 h. NF-kappa B activity was examined in five patients and was noted to transiently increase and then decrease 4- to 6 -fold by 24 h following bortezomib in two patients. There were no objective clinical responses. Conclusions: For children with leukemia, the recommended phase 2 dose of bortezomib, administered twice weekly for 2 weeks followed by a 1-week rest, is 1.3 mg/m(2) /dose. Although bortezomib treatment inhibited NF-kappa B activity, bortezomib had little activity as a single agent in this population. C1 Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA. Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Childrens Oncol Grp Operat Ctr, Arcadia, CA USA. NCI, Invest Drug Branch, Canc Therapy Evaluat Program, NIH, Bethesda, MD 20892 USA. Millennium Pharmaceut Inc, Dept Drug Metab & Pharmacokinet, Cambridge, MA USA. Merck Res Labs, Dept Drug Metab & Pharmacokinet, Boston, MA USA. RP Horton, TM (reprint author), Baylor Coll Med, Texas Childrens Canc Ctr, 6621 Fannin St,MC 3-3320, Houston, TX 77030 USA. EM tmhorton@txccc.org FU NCI NIH HHS [U01-CA97452, U10 CA098543, K12CA90433, R01 CA109478, R01 CA109478-02] NR 19 TC 89 Z9 89 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 1 PY 2007 VL 13 IS 5 BP 1516 EP 1522 DI 10.1158/1078-0432.CCR-06-2173 PG 7 WC Oncology SC Oncology GA 144CL UT WOS:000244772800024 PM 17332297 ER PT J AU Ho, M Bera, TK Willingham, MC Onda, M Hassan, R FitzGerald, D Pastan, I AF Ho, Mitchell Bera, Tapan K. Willingham, Mark C. Onda, Masanori Hassan, Raffit FitzGerald, David Pastan, Ira TI Mesothelin expression in human lung cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID OVARIAN-CANCER; MONOCLONAL-ANTIBODY; MOLECULAR-CLONING; TUMOR-CELLS; DIAGNOSIS; CARCINOMA; ADENOCARCINOMA; BINDING; MARKER; FAMILY AB Purpose: To investigate mesothelin as a new target for immunotherapy in lung cancer. Experimental Design: Mesothelin mRNA and protein expression were assessed by reverse transcription-PCR, immunoblotting, and immunohistochemistry in human lung cancer specimens. Expression was also characterized in human lung cancer cell lines by flow cytometry and immunoblotting. The SS1P immunotoxin specific for mesothelin was assessed for its cytotoxic activity against lung cancer cells. Results: We found that mesothelin mRNA was expressed in 83% of lung adenocarcinomas (10 of 12 patients). The mesothelin precursor protein was detected in 82% of lung adenocarcinoma (9 of 11 patients), and its mature form was detected in 55% (6 of 11 patients). Immunohistochemistry showed strong and diffuse mesothelin staining in human lung adenocarcinomas and weak or modest staining in squamous cell carcinomas. We detected mesothelin mRNA in 78% of lung cancer cell lines (7 of 9) of the NCl-60 cell line panel. Mesothelin mRNA and proteins were expressed at a high level in non-small cell lung cancer lines EKVX, NCl-H460, NCl-H322M, and NCl-H522. Flow cytometric analysis showed high surface expression of mesothelin in NCl-H322M and EKVX cell lines. Immunotoxin SS1P showed high cytotoxic activity on NCl-H322M and EKVX cells with IC50 values ranging from 2 to 5 ng/mL. Conclusions: Mesothelin is expressed on the surface of most lung adenocarcinoma cells. Immunotoxin SS1P is cytotoxic against mesothelin-expressing lung cancer cell lines and merits evaluation as a new therapeutic agent in treating non-small cell lung cancer. C1 NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Sch Med, Dept Pathol, Winston Salem, NC 27109 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov RI Ho, Mitchell/F-5059-2015 FU Intramural NIH HHS NR 29 TC 68 Z9 68 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 1 PY 2007 VL 13 IS 5 BP 1571 EP 1575 DI 10.1158/1078-0432.CCR-06-2161 PG 5 WC Oncology SC Oncology GA 144CL UT WOS:000244772800030 PM 17332303 ER PT J AU Sconocchia, G Del Principe, D Barrett, AJ AF Sconocchia, Giuseppe Del Principe, Domenico Barrett, A. John TI CD16(low/negative) tumor-infiltrating lymphocyte: Lymphoid or myeloid in origin? SO CLINICAL CANCER RESEARCH LA English DT Letter ID NATURAL-KILLER-CELLS; PROGNOSTIC-SIGNIFICANCE; CARCINOMA; MONOCYTE C1 CNR, Inst Organ Transplantat & Immunocytol, Rome, Italy. Univ Tor Vergata, Sch Med, Dept Pediat, Rome, Italy. NHLBI, Allogene Stem Cell Transplantat Hematol Branch, NIH, Bethesda, MD 20892 USA. RP Sconocchia, G (reprint author), CNR, Inst Organ Transplantat & Immunocytol, Rome, Italy. NR 7 TC 3 Z9 3 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD MAR 1 PY 2007 VL 13 IS 5 BP 1620 EP 1620 DI 10.1158/1078-0432.CCR-06-2247 PG 1 WC Oncology SC Oncology GA 144CL UT WOS:000244772800036 PM 17332309 ER PT J AU Ling, JC Freeman, AF Gharib, AM Arai, AE Lederman, RJ Rosing, DR Holland, SM AF Ling, Jennifer C. Freeman, Alexandra F. Gharib, Ahmed M. Arai, Andrew E. Lederman, Robert J. Rosing, Douglas R. Holland, Steven M. TI Coronary artery aneurysms in patients with hyper IgE recurrent infection syndrome SO CLINICAL IMMUNOLOGY LA English DT Article DE hyper IgE syndrome; job syndrome; coronary artery aneurysm ID HYPERIMMUNOGLOBULIN-E SYNDROME; AORTIC-ANEURYSM; MARFAN-SYNDROME; DISEASE; ADULT AB Hyper IgE recurrent infection syndrome (HIES, or Job's syndrome) is a primary immunodeficiency characterized by recurrent skin and lung infections, eczema, elevated serum immunoglobulin E (IgE) levels, and various connective tissue and skeletal system abnormalities including characteristic facies, scoliosis, joint hyperextensibility, retained primary dentition, craniosynostosis, osteopenia, and pathotogic fractures. We have identified two patients with aneurysmal coronary artery disease. One was a forty-three-year-old man with HIES and coronary artery aneurysms and ectasia identified on cardiac catheterization following myocardial infarction. The other was a 48-year-otd man with coronary artery ectasia-aneurysm identified after cardiac catheterization for evaluation of chest pain. Although connective tissue abnormalities are common in HIES, this is the first report of coronary artery aneurysms in HIES. Further studies are necessary to determine the incidence, pathogenesis, and optimal therapy of these arterial abnormalities in HIES. Published by Elsevier Inc. C1 NIAID, NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Freeman, AF (reprint author), NIAID, NIH, Bldg 10,Room 11N234,9000 Rockville Pike, Bethesda, MD 20892 USA. EM Freemaal@mail.nih.gov RI Gharib, Ahmed/O-2629-2016; OI Gharib, Ahmed/0000-0002-2476-481X; lederman, robert/0000-0003-1202-6673 FU Intramural NIH HHS [Z01 HL005062-05] NR 28 TC 33 Z9 35 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 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD MAR PY 2007 VL 122 IS 3 BP 255 EP 258 DI 10.1016/j.clim.2006.10.005 PG 4 WC Immunology SC Immunology GA 139KJ UT WOS:000244430400003 PM 17098478 ER PT J AU Morse, CG Mican, JM Jones, EC Joe, GO Rick, ME Formentini, E Kovacs, JA AF Morse, Caryn G. Mican, Joann M. Jones, Elizabeth C. Joe, Galen O. Rick, Margaret E. Formentini, Elizabeth Kovacs, Joseph A. TI The incidence and natural history of osteonecrosis in HIV-Infected adults SO CLINICAL INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 7th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV CY NOV 13-16, 2005 CL Dublin, IRELAND ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; SYSTEMIC-LUPUS-ERYTHEMATOSUS; AVASCULAR NECROSIS; FEMORAL-HEAD; AQUITAINE COHORT; BONE; EPIDEMIOLOGY; ALENDRONATE; MRI AB Background. Osteonecrosis is increasingly recognized as a debilitating complication of human immunodeficiency virus (HIV) infection, but the natural history has not been well described. We previously documented a high prevalence (4.4%) of magnetic resonance imaging (MRI) - documented osteonecrosis of the hip in a cohort of 339 asymptomatic HIV-infected patients. The present study was designed to determine the incidence of newly diagnosed osteonecrosis in this cohort and to describe the natural history of osteonecrosis in HIV-infected patients. Methods. Asymptomatic HIV-infected patients with a previous hip MRI negative for osteonecrosis underwent follow-up MRI. Patients with asymptomatic or symptomatic osteonecrosis were enrolled in a natural history study, which included serial MRIs and a physiotherapy follow-up. Results. Two hundred thirty-nine patients underwent a second MRI a median of 23 months after the initial MRI. Osteonecrosis of the femoral head was diagnosed in 3 patients (incidence, 0.65 cases per 100 person- years). During the period of January 1999 through April 2006, symptomatic hip osteonecrosis developed in 13 clinic patients (incidence, 0.26 cases per 100 person- years). Among 22 patients enrolled with symptomatic hip osteonecrosis, 18 had bilateral involvement of the femoral heads, and 7 had osteonecrosis involving other bones. Two (11%) of 18 asymptomatic patients and 13 (59%) of 22 symptomatic patients underwent total hip replacement. The percentage of involvement of the weight- bearing surface of the femoral head and the rate of progression to total hip replacement was significantly greater (P < .001) in symptomatic patients than in asymptomatic patients. Conclusions. HIV-infected patients are at similar to 100-fold greater risk of developing osteonecrosis than the general population. Disease progression is slower in asymptomatic patients than in symptomatic patients. Given the high frequency of total hip replacement in symptomatic patients, studies to assess preventive and treatment strategies are essential. C1 NIAID, Off Clin Res, NIH, Bethesda, MD 20892 USA. NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. NIH, Dept Radiol, Ctr Clin, Bethesda, MD 20892 USA. NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Morse, CG (reprint author), NIAID, Off Clin Res, NIH, 9000 Rockville Pike,Bldg 10,Rm 2C145,MSC 1662, Bethesda, MD 20892 USA. EM cmorse@mail.nih.gov OI Morse, Caryn/0000-0002-1177-4365 FU Intramural NIH HHS NR 44 TC 42 Z9 45 U1 0 U2 5 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 MAR 1 PY 2007 VL 44 IS 5 BP 739 EP 748 DI 10.1086/511683 PG 10 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 132FP UT WOS:000243928600020 PM 17278070 ER PT J AU Pritsch, T Bickels, J Wu, CC Squires, MH Malawer, MM AF Pritsch, Tamir Bickels, Jacob Wu, Chia Chun Squires, Malcolm H. Malawer, Martin M. TI Is scapular endoprosthesis functionally superior to humeral suspension? SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID TIKHOFF-LINBERG PROCEDURE; SOFT-TISSUE TUMORS; SHOULDER GIRDLE; LIMB SALVAGE; MALIGNANT BONE; RESECTION; RECONSTRUCTION; SCAPULECTOMY; EXTREMITY; SARCOMA AB Humeral suspension was the most popular reconstructive procedure after total scapulectomy until the early 1990s. Since 1992 the senior author has been performing scapular endoprosthetic reconstruction after total scapulectomy whenever the rhomboids, latissimus dorsi, deltoid, and trapezius were preserved. We hypothesized that scapular endoprosthetic reconstruction resulted in better functional and cosmetic results than humeral suspension. From 1979 to 2003, 32 consecutive patients had total scapulectomies. Reconstructions included humeral suspensions in 16 patients and scapular endoprostheses in 16 patients. Functional and cosmetic results were compared retrospectively between the two groups. Patients with scapular endoprostheses had better functional results and superior cosmesis as compared with patients with humeral suspension. The mean Musculoskeletal Tumor Society scores for patients with scapular endoprostheses and humeral suspensions were 78.5% and 58.5% respectively. Seven patients with scapular endoprostheses had greater than 40 degrees abduction and It patients with humeral suspensions could not abduct the shoulder greater than 20 degrees. Twelve patients with humeral suspensions and none with scapular endoprostheses wore shoulder pads or customized orthoses for cosmetic purposes. After total scapulectomy, scapular endoprosthetic reconstruction led to better functional and cosmetic results than humeral suspension and therefore we recommend performing this reconstructive procedure whenever the rhomboids, latissimus dorsi, deltoid, and trapezius are preserved. C1 Washington Hosp Ctr, Inst Canc, Dept Orthopaed Oncol, Washington, DC 20010 USA. Tel Aviv Sourasky Med Ctr, Natl Unit Orthoped Oncol, Tel Aviv, Israel. NCI, Pediat & Surg Branch, Bethesda, MD USA. Georgetown Univ, Washington, DC USA. RP Pritsch, T (reprint author), Washington Canc Inst, Dept Orthopaed Oncol, C2173,110 Irving St NW, Washington, DC 20010 USA. EM pritscht@yahoo.com NR 19 TC 14 Z9 14 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-921X J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD MAR PY 2007 IS 456 BP 188 EP 195 DI 10.1097/01.blo.0000238840.26423.b6 PG 8 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 142UN UT WOS:000244675800033 ER PT J AU Long, RM AF Long, R. M. TI Planning for a national effort to enable and accelerate discoveries in pharmacogenetics: The NIH pharmacogenetics research network SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article AB The Pharmacogenetics Research Network (PGRN) was conceived as a broad network-based approach to research studies in pharmacogenetics and pharmacogenomics, with the central feature of a database that would be hypothesis-generating and open to all scientific investigators. The original working group emphasized the importance of carefully relating phenotypes for drug responses to genotypes, and understanding the relationships functionally and mechanistically. The mission of the PGRN is to advance our knowledge of the genetic basis for variable drug responses. The ultimate goal of the effort is to determine clinically significant sequence variations in order to predict the right choice and dose of medications for individuals and to prepare for implementation of this information to improve health care. C1 NIGMS, DHHS, NIH, Bethesda, MD USA. RP Long, RM (reprint author), NIGMS, DHHS, NIH, Bethesda, MD USA. EM rochelle.long@nih.gov NR 0 TC 6 Z9 7 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2007 VL 81 IS 3 BP 450 EP 454 DI 10.1038/sj.clpt.6100099 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 145FI UT WOS:000244850300026 PM 17339874 ER PT J AU Dreisbach, AW Japa, S Newman, JW Sigel, A Gill, RS Hess, AE Hammock, BD Lertora, JJ AF Dreisbach, A. W. Japa, S. Newman, J. W. Sigel, A. Gill, R. S. Hess, A. E. Hammock, B. D. Lertora, J. J. TI Salt loading increases the urinary excretion of linoleic acid diols and triols in healthy human subjects. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of American-Society-for-Clinical-Pharmacology-and-Therapeutics CY MAR 21-24, 2007 CL Anaheim, CA SP Amer Soc Clin Pharmacol & Therapeut C1 Univ Mississippi, Jackson, MS 39216 USA. Tulane Univ, Jackson, MS USA. Univ Calif Davis, Jackson, MS USA. Univ Calif Los Angeles, Jackson, MS USA. NIH, Jackson, MS USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2007 VL 81 SU 1 BP S55 EP S55 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 144FW UT WOS:000244782900161 ER PT J AU Hilmer, SN Mager, DE Simonsick, EM Cao, Y Ling, SM Windham, BG Harris, TB Hanlon, JT Rubin, SM Shorr, RI Bauer, DC Abernethy, DR AF Hilmer, S. N. Mager, D. E. Simonsick, E. M. Cao, Y. Ling, S. M. Windham, B. G. Harris, T. B. Hanlon, J. T. Rubin, S. M. Shorr, R. I. Bauer, D. C. Abernethy, D. R. TI A drug burden index to define the functional burden of medications in older people. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 108th Annual Meeting of American-Society-for-Clinical-Pharmacology-and-Therapeutics CY MAR 21-24, 2007 CL Anaheim, CA SP Amer Soc Clin Pharmacol & Therapeut C1 Univ Sydney, Sydney, NSW 2006, Australia. SUNY Buffalo, Buffalo, NY USA. NIA, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Univ Tennessee, Knoxville, TN 37996 USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2007 VL 81 SU 1 BP S10 EP S10 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 144FW UT WOS:000244782900027 ER PT J AU Lee, H Romkes, M Branch, R Backer, L Lan, Q Blount, B Nuckols, J Lyu, C Kieszak, S Brinkman, M Gordon, S Cantor, K AF Lee, H. Romkes, M. Branch, R. Backer, L. Lan, Q. Blount, B. Nuckols, J. Lyu, C. Kieszak, S. Brinkman, M. Gordon, S. Cantor, K. TI Glutathione-S-transferase theta 1 (GSTT1) and CYP2D6 null genotypes have a lower clearance for chloroform absorbed during a shower. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of American-Society-for-Clinical-Pharmacology-and-Therapeutics CY MAR 21-24, 2007 CL Anaheim, CA SP Amer Soc Clin Pharmacol & Therapeut C1 Univ Calif San Francisco, Ctr Drug Dev Sci, Ctr Clin Pharmacol, San Francisco, CA 94143 USA. Univ Pittsburgh, Natl Ctr Environm Hlth, Ctr Dis Control & Prevent, NCI,Dept Environm & Radiol Hlth Sci,Div Canc Epid, Pittsburgh, PA 15260 USA. Colorado State Univ, Battelle Ctr Publ Hlth Res & Evaluat, Natl Ctr Environm Hlth, Ctr Dis Control & Prevent, Washington, DC USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2007 VL 81 SU 1 BP S115 EP S116 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 144FW UT WOS:000244782900341 ER PT J AU Mager, DE Gronich, N Gowan, K Abernethy, DR AF Mager, D. E. Gronich, N. Gowan, K. Abernethy, D. R. TI Pharmacodynamic model of atropine effects on heart rate variability using a wavelet-based biomarker of vagal tone. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT 108th Annual Meeting of American-Society-for-Clinical-Pharmacology-and-Therapeutics CY MAR 21-24, 2007 CL Anaheim, CA SP Amer Soc Clin Pharmacol & Therapeut C1 SUNY Buffalo, NIA, Buffalo, NY USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2007 VL 81 SU 1 BP S70 EP S71 PG 2 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 144FW UT WOS:000244782900206 ER PT J AU Moaddel, R Ravichandran, S Bighi, F Yamaguchi, R Collins, J Wainer, IW AF Moaddel, R. Ravichandran, S. Bighi, F. Yamaguchi, R. Collins, J. Wainer, I. W. TI Pharmacophore of the stereoselective inhibitor binding site of the human organic cation transporter, hOCT1. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of American-Society-for-Clinical-Pharmacology-and-Therapeutics CY MAR 21-24, 2007 CL Anaheim, CA SP Amer Soc Clin Pharmacol & Therapeut C1 NIH, NIA, Baltimore, MD USA. NCI, SAIC, Baltimore, MD USA. NIH, NCI, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2007 VL 81 SU 1 BP S61 EP S61 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 144FW UT WOS:000244782900180 ER PT J AU Ramchandani, VA Kumar, SR Spero, DE Momenan, R Walker, JT Hommer, DW AF Ramchandani, V. A. Kumar, S. R. Spero, D. E. Momenan, R. Walker, J. T. Hommer, D. W. TI Influence of sex and age on ethanol elimination rates in social drinkers. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of American-Society-for-Clinical-Pharmacology-and-Therapeutics CY MAR 21-24, 2007 CL Anaheim, CA SP Amer Soc Clin Pharmacol & Therapeut C1 Natl Inst Alcohol Abuse & Alcoholism, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2007 VL 81 SU 1 BP S38 EP S38 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 144FW UT WOS:000244782900109 ER PT J AU Zhang, X Yasuno, F Zoghbi, S Liow, J Hong, J McCarron, J Pike, V Innis, R AF Zhang, X. Yasuno, F. Zoghbi, S. Liow, J. Hong, J. McCarron, J. Pike, V. Innis, R. TI Quantification of serotonin 5-HT1A receptors in humans with [11C](R)-(-)-RWAY: Radiometabolite(s) likely confound brain measurements. SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Meeting Abstract CT Annual Meeting of American-Society-for-Clinical-Pharmacology-and-Therapeutics CY MAR 21-24, 2007 CL Anaheim, CA SP Amer Soc Clin Pharmacol & Therapeut C1 NIH, NIMH, Mol Imaging Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD MAR PY 2007 VL 81 SU 1 BP S119 EP S119 PG 1 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 144FW UT WOS:000244782900351 ER PT J AU Hama, Y Koyama, Y Bernardo, M Choyke, PL Kobayashi, H AF Hama, Yukihiro Koyama, Yoshinori Bernardo, Marcelino Choyke, Peter L. Kobayashi, Hisataka TI Spectral near-infrared fluorescence imaging of curved surfaces using projection reconstruction algorithms SO CONTRAST MEDIA & MOLECULAR IMAGING LA English DT Article DE optical imaging; image acquisition; lymphangiography; projection image; near-infrared; quantum dot; deblurring ID INTENSITY PROJECTIONS; TOMOGRAPHY AB In vivo spectral fluorescence imaging has made it possible to non-invasively Visualize superficial curved structures as well as structures deep to the skin. However, the defocus created by blurring has been an obstacle to creating anatomically interpretable surface images. Herein we present a methodology to correct for blurring induced by curved structures during spectral fluorescence imaging using signal intensity projection algorithms. In a phantom and an animal model in which the lymphatic system was visualized after the interstitial injection of quantum dots with emission spectra in the near-infrared (NIR) range, the planes of focus were sequentially adjusted to obtain a z-stack of images which contains images acquired from multiple focal points. Maximum, minimum, median and average intensity projections were applied to the resulting images. Using the phantom, the minimum and the median intensity projection images demonstrated improved deblurring whereas during in vivo imaging the median intensity projection images more clearly visualized important structures than did the other projection techniques. Image stacking with subsequent application of appropriate projection techniques provides a simple method for deblurring in vivo optical images obtained from curved surfaces, thus improving their anatomic resolution. Copyright (c) 2007 John Wiley & Sons, Ltd. C1 NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NCI, SAIC, Frederick, MD 21701 USA. RP Kobayashi, H (reprint author), NCI, Mol Imaging Program, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. EM Kobayash@mail.nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 14 TC 4 Z9 5 U1 0 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1555-4309 J9 CONTRAST MEDIA MOL I JI Contrast Media Mol. Imaging PD MAR-APR PY 2007 VL 2 IS 2 BP 82 EP 87 DI 10.1002/cmmi.129 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 174IE UT WOS:000246934800003 PM 17451166 ER PT J AU Bassi, GL Curto, F Zanella, A Stylianou, M Kolobow, T AF Bassi, Gianluigi Li Curto, Francesco Zanella, Alberto Stylianou, Mario Kolobow, Theodor TI A 72-hour study to test the efficacy and safety of the "Mucus Slurper" in mechanically ventilated sheep SO CRITICAL CARE MEDICINE LA English DT Article DE artificial ventilation; intratracheal intubation; airway obstruction; bacterial pneumonia; intensive care; evaluation studies ID ENDOTRACHEAL-TUBE; BACTERIAL-COLONIZATION; MUCOCILIARY TRANSPORT; TEMPERATURE; HUMIDITY; SHAVER; SYSTEM; VOLUME; AIRWAY; GAS AB Objective: In patients intubated with endotracheal tubes (ETTs), suctioning is routinely performed to remove mucus from within the ETT and trachea. The Mucus Slurper is a novel ETT with built-in suction ports arranged radially at its tip. We evaluated the safety and efficacy of the Mucus Slurper, compared with conventional tracheal suction, to prevent airway obstruction in sheep with the ETT and trachea oriented below horizontal. Design: Prospective randomized animal study. Setting. Animal research facility at the National Institutes of Health. Subjects: Twelve healthy sheep. Interventions: Sheep were randomized to be intubated with either the Mucus Slurper (study group) or a Hi-Lo Tracheal Tube (Mallinckrodt, St. Louis, MO) (control group) and mechanically ventilated for 72 hrs. In the study group, automatic, timed tracheal aspiration lasted 0.3 secs, was repeated every 2 mins, and was synchronized with the early expiratory phase. In the control group, tracheal suction was performed every 6 hrs or as required. Measurements and Main Results: In the control group, tracheal secretions accumulated progressively within the ETT and the trachea. In the study group, all mucus that reached the tip of the Mucus Slurper was aspirated, keeping the lumen of the ETT, and proximal trachea, free from secretions, In the study group, expiratory water trap protein concentration, a crude index to measure mucus drainage through the ETT, was consistently less than the control group (p < .001). At autopsy, no macroscopic injury to the tracheal mucosa was found in either group. In the study group, the respiratory circuit was less colonized than in the control group. There were no statistically significant differences between the two groups in bacterial colonization of the lungs/bronchi. Conclusions. The Mucus Slurper, combined with orientation of the trachea below horizontal, prevents accumulation of secretions within the lumen of the ETT and trachea, without need for conventional tracheal suctioning. C1 NHLBI, Sect Pulm & Cardiac Assist Devices, Pulm & Crit Cre Med Branch, NIH,PCCMB, Bethesda, MD 20892 USA. NHLBI, Div Epidemiol & Clin Applicat, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Kolobow, T (reprint author), NHLBI, Sect Pulm & Cardiac Assist Devices, Pulm & Crit Cre Med Branch, NIH,PCCMB, 9000 Rockville Pike,Bldg 10,Rm 5D-07, Bethesda, MD 20892 USA. EM libassig@aim.com OI zanella, Alberto/0000-0002-2967-2527 NR 29 TC 9 Z9 9 U1 0 U2 1 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 MAR PY 2007 VL 35 IS 3 BP 906 EP 911 DI 10.1097/01.CCM.0000257332.62358.0E PG 6 WC Critical Care Medicine SC General & Internal Medicine GA 139ZE UT WOS:000244470800031 ER PT J AU Bassi, GL Berra, L Kolobow, T AF Bassi, Gianluigi Li Berra, Lorenzo Kolobow, Theodor TI Silver-coated endotracheal tubes: Is the bactericidal effect time limited? SO CRITICAL CARE MEDICINE LA English DT Letter ID MUCUS SHAVER; COLONIZATION; BURDEN; LUNGS C1 NHLBI, Sect Pulm & Cardiac Assist Devices, Pulm & Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Dept Anesthesia & Crit Care, Boston, MA 02114 USA. RP Bassi, GL (reprint author), NHLBI, Sect Pulm & Cardiac Assist Devices, Pulm & Crit Care Med Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 7 TC 1 Z9 1 U1 1 U2 1 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 MAR PY 2007 VL 35 IS 3 BP 986 EP 986 DI 10.1097/01.CCM.0000257477.44926.90 PG 1 WC Critical Care Medicine SC General & Internal Medicine GA 139ZE UT WOS:000244470800068 ER PT J AU Huang, HZ Shukla, HD Wu, C Saxena, S AF Huang, Hongzhan Shukla, Hem D. Wu, Cathy Saxena, Satya TI Challenges and solutions in proteomics SO CURRENT GENOMICS LA English DT Article DE proteomic profiling; high-throughput analysis; biomarkers; bioinformatic tools; iProXpress; sequence library; pathway discovery; stage specific proteins ID MASS-SPECTROMETRY; GENE-ONTOLOGY; PROTEIN IDENTIFICATION; STATISTICAL-MODEL; MICROARRAY DATA; DATABASE; CANCER; TRANSCRIPTOME; RESOURCE; SEARCH AB The accelerated growth of proteomics data presents both opportunities and challenges. Large-scale proteomic profiling of biological samples such as cells, organelles or biological fluids has led to discovery of numerous key and novel proteins involved in many biological/disease processes including cancers, as well as to the identification of novel disease biomarkers and potential therapeutic targets. While proteomic data analysis has been greatly assisted by the many bioinformatics tools developed in recent years, a careful analysis of the major steps and flow of data in a typical high-throughput analysis reveals a few gaps that still need to be filled to fully realize the value of the data. To facilitate functional and pathway discovery for large-scale proteomic data, we have developed an integrated proteomic expression analysis system, iProXpress, which facilitates protein identification using a comprehensive sequence library and functional interpretation using integrated data. With its modular design, iProXpress complements and can be integrated with other software in a proteornic data analysis pipeline. This novel approach to complex biological questions involves the interrogation of multiple data sources, thereby facilitating hypothesis generation and knowledge discovery from the genomic-scale studies and fostering disease diagnosis and drug development. C1 NIA, Proteom & Mass Spectrometry Unit, Res Resources Branch, NIH, Baltimore, MD 21224 USA. Georgetown Univ, Med Ctr, Dept Biochem & Mol & Cellular Biol, Washington, DC 20007 USA. RP Saxena, S (reprint author), NIA, Proteom & Mass Spectrometry Unit, Res Resources Branch, NIH, 333 Cassell Dr, Baltimore, MD 21224 USA. EM ssaxena@grc.nia.nih.gov RI Crozier, Laura/A-4821-2010 NR 34 TC 4 Z9 5 U1 0 U2 0 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y-2, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1389-2029 EI 1875-5488 J9 CURR GENOMICS JI Curr. Genomics PD MAR PY 2007 VL 8 IS 1 BP 21 EP 28 DI 10.2174/138920207780076910 PG 8 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 146HS UT WOS:000244925700002 ER PT J AU Lindwasser, OW Chaudhuri, R Bonifacino, JS AF Lindwasser, O. Wolf Chaudhuri, Rittik Bonifacino, Juan S. TI Mechanisms of CD4 downregulation by the Nef and Vpu proteins of primate immunodeficiency viruses SO CURRENT MOLECULAR MEDICINE LA English DT Review DE AIDS; HIV; CD4; Vpu; Nef; clathrin; ERAD; beta-TrCP ID CELL-SURFACE EXPRESSION; TRCP-UBIQUITIN LIGASE; CLASS-I MHC; LONG-TERM NONPROGRESSORS; CLATHRIN-COATED VESICLES; PIG-TAILED MACAQUES; BLOOD-BANK COHORT; AIDS-LIKE DISEASE; CASEIN KINASE-II; HIV-1 NEF AB Human immunodeficiency virus type 1 (HIV-1), human immunodeficiency virus type 2 (HIV-2), and simian immunodeficiency virus (SIV) are the etiological agents of acquired immunodeficiency syndrome (AIDS) in humans and a related disease in non-human primates. These viruses infect T cells and macrophages that express the surface glycoprotein, CD4, because this glycoprotein acts as a coreceptor for incoming virus particles. Once infection has occurred, however, the presence of CD4 poses problems for the virus life cycle, including the possibility of superinfection, premature binding of CD4 to nascent virus particles, and inhibition of virus release. Accordingly, primate immunodeficiency viruses have evolved at least two distinct mechanisms, mediated by the Nef and Vpu viral proteins, to "down regulate" CD4 in the host cells. Nef and Vpu are mainly expressed early and late, respectively, in the viral life cycle, ensuring continuous removal of CD4. Nef links mature CD4 to components of clathrin-dependent trafficking pathways at the plasma membrane, and perhaps in intracellular compartments, leading to internalization and delivery of CD4 to lysosomes for degradation. Vpu, on the other hand, interacts with newly-synthesized CD4 in the endoplasmic reticulum, linking CD4 to the SCF ubiquitin ligase and facilitating the entry of CD4 into the endoplasmic-reticulum-associated degradation pathway. These two mechanisms lead to a dramatic reduction of CD4 expression in infected cells and are essential for efficient virus replication and disease progression. C1 Natl Inst Child Hlth & Human Dev, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Bonifacino, JS (reprint author), Natl Inst Child Hlth & Human Dev, Cell Biol & Metab Branch, NIH, Bldg 18T Room 101, Bethesda, MD 20892 USA. EM juan@helix.nih.gov FU Intramural NIH HHS NR 180 TC 67 Z9 70 U1 1 U2 7 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1566-5240 J9 CURR MOL MED JI Curr. Mol. Med. PD MAR PY 2007 VL 7 IS 2 BP 171 EP 184 PG 14 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 135PD UT WOS:000244164600003 PM 17346169 ER PT J AU Kingston, DGI Newman, DJ AF Kingston, David G. I. Newman, David J. TI Taxoids: Cancer-fighting compounds from nature SO CURRENT OPINION IN DRUG DISCOVERY & DEVELOPMENT LA English DT Review DE biosynthesis; clinical studies; drug targeting; medicinal chemistry; structure-activity relationship; tubulin ID ELECTRON CRYSTALLOGRAPHIC DENSITY; BOUND PACLITAXEL CONFORMATION; CELL LUNG-CANCER; BETA-TUBULIN; MULTIDRUG-RESISTANCE; IN-VITRO; T-TAXOL; BIOLOGICAL-ACTIVITY; MACROCYCLIC TAXOIDS; MEDICINAL CHEMISTRY AB This review covers advances in the discovery, preclinical and clinical development of potential anticancer agents based upon the diterpenoid taxane skeleton. The anticancer properties of approved clinical agents of this class are not discussed, but the review documents how, 13 years post-approval of paclitaxel (Taxol.), the base taxane structure is still utilized as the starting skeleton for molecules with improved pharmacological and toxicological properties. Paclitaxel may in fact be the first example of a 'tunable' anticancer agent. In addition, paclitaxel, and perhaps other taxanes in due course, has activities beyond the known antitumor indications, with an example being the use of paclitaxel-coated stents in cardiovascular therapies. C1 Virginia Polytech Inst & State Univ, Dept Chem, Blacksburg, VA 24061 USA. NCI, Frederick Nat Prod Branch, Frederick, MD 21702 USA. RP Kingston, DGI (reprint author), Virginia Polytech Inst & State Univ, Dept Chem, MC 0212, Blacksburg, VA 24061 USA. EM dkingston@vt.edu; newmand@mail.nih.gov OI Kingston, David/0000-0001-8944-246X NR 108 TC 89 Z9 91 U1 2 U2 11 PU THOMSON SCIENTIFIC PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND STREET, LONDON, W1T 4JE, ENGLAND SN 1367-6733 J9 CURR OPIN DRUG DISC JI Curr. Opin. Drug Discov. Dev. PD MAR PY 2007 VL 10 IS 2 BP 130 EP 144 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 145IL UT WOS:000244858400003 PM 17436548 ER PT J AU Sethi, AA Amar, M Shamburek, RD Remaley, AT AF Sethi, Amar A. Amar, Marcelo Shamburek, Robert D. Remaley, Alan T. TI Apolipoprotein AI mimetic peptides: Possible new agents for the treatment of atherosclerosis SO CURRENT OPINION IN INVESTIGATIONAL DRUGS LA English DT Review DE acute HDL therapy; apolipoprotein AI; atherosclerosis; coronary heart disease; HDL; LDL; mimetic peptide ID HIGH-DENSITY-LIPOPROTEIN; REVERSE CHOLESTEROL TRANSPORT; E-NULL MICE; DRAMATICALLY REDUCES ATHEROSCLEROSIS; RESTORES ENDOTHELIAL FUNCTION; I-MILANO; CELLULAR CHOLESTEROL; AMPHIPATHIC HELIX; CORONARY ATHEROSCLEROSIS; SYNTHETIC PEPTIDES AB There is increasing evidence that therapeutic agents for raising HDL would be a useful addition to the current treatment approach for preventing coronary heart disease (CHD), especially considering the fact that therapies for lowering LDLs are not fully adequate for preventing CHD. The recent unraveling of some of the complexities of HDL metabolism has led to the identification of new key proteins involved in HDL metabolism, thus giving new hope and ideas for drug targets. This review focuses on apolipoprotein AI mimetic peptides, which are currently being explored as therapeutic agents for a new treatment strategy known as acute HDL therapy. C1 NHLBI, NIH, Lipoprot Metab Sect, Vasc Med Branch, Bethesda, MD 20892 USA. RP Remaley, AT (reprint author), NHLBI, NIH, Lipoprot Metab Sect, Vasc Med Branch, Bldg 10,Room 7N-115,10 Ctr Dr, Bethesda, MD 20892 USA. EM aremaley@cc.nih.gov NR 91 TC 39 Z9 40 U1 0 U2 3 PU THOMSON SCIENTIFIC PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND STREET, LONDON, W1T 4JE, ENGLAND SN 1472-4472 J9 CURR OPIN INVESTIG D JI Curr. Opin. Investig. Drugs PD MAR PY 2007 VL 8 IS 3 BP 201 EP 212 PG 12 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 141HV UT WOS:000244570300003 PM 17408115 ER PT J AU Pira, GL Kern, F Gratama, J Roederer, M Manca, F AF Pira, Giuseppina Li Kern, Florian Gratama, Jan Roederer, Mario Manca, Fabrizio TI Measurement of antigen specific immune responses: 2006 update SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Review DE specific T cell; T cell activation; antigen presentation; cytokine production; flow cytometry ID T-CELL RESPONSES; MYCOBACTERIUM-TUBERCULOSIS; MEDIATED CYTOTOXICITY; DENDRITIC CELLS; FLOW-CYTOMETRY; HIV-INFECTION; RECEPTOR; LYMPHOCYTES; VACCINE; DISEASE AB Measuring antigen-specific immune responses (MASIR) is essential for basic immunological research and in the clinical setting. Numerous techniques have been used and the recent years have witnessed a flourishing of flow cytometry based methods for the identification of antigen specific T cells, in addition to other methodologies. The second MASIR conference held in Santorini, Greece, from 14 to 18 June 2006 has been a forum for the discussion of methodological issues and for research or clinical applications of these techniques, as reviewed here. In addition to flow cytometry based techniques, other emerging techniques with different degrees of complexity can be applied. These novel methods are highly promising in numerous conditions to look for correlates of protection, to test responses to natural infections or to vaccination trials, to evaluate the immune status of immunocompromised patients and to monitor persistence and function of specific T cells administered as adaptive therapy. C1 Adv Biotechnol Ctr, I-16132 Genoa, Italy. Univ Med Berlin, Charite, Berlin, Germany. Erasmus MC, Dept Med Oncol, Rotterdam, Netherlands. NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. G Gaslini Inst Children, Genoa, Italy. RP Pira, GL (reprint author), Adv Biotechnol Ctr, Largo Benzi 10, I-16132 Genoa, Italy. EM lipira@email.it RI Li Pira, Giuseppina/H-1973-2012 NR 48 TC 8 Z9 8 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD MAR PY 2007 VL 72B IS 2 BP 77 EP 85 DI 10.1002/cyto.b.20186 PG 9 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 146PR UT WOS:000244947200001 ER PT J AU Marti, G Orfao, A Goolsby, CL AF Marti, Gerald Orfao, Alberto Goolsby, Charles L. TI ZAP70 editorial: A follow-up to the special issue SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Editorial Material ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ZAP-70 EXPRESSION; CD38 EXPRESSION; FLOW-CYTOMETRY; B-CLL; CLINICAL-SIGNIFICANCE; DISEASE PROGRESSION; MUTATION STATUS; PREDICTOR; GENE C1 Univ Salamanca, Gen Cytometry Serv, Canc Res Ctr, E-37008 Salamanca, Spain. Univ Salamanca, Dept Med, E-37008 Salamanca, Spain. Northwestern Univ, Sch Med, Dept Pathol, Chicago, IL 60611 USA. RP Marti, G (reprint author), NIH Bldg 29B,Room 2NN08,9000 Rockville Pike, Bethesda, MD 20892 USA. EM gemarti@helix.nih.gov NR 15 TC 5 Z9 6 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD MAR PY 2007 VL 72B IS 2 BP 94 EP 95 DI 10.1002/cyto.b.20184 PG 2 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 146PR UT WOS:000244947200003 PM 17285625 ER PT J AU Holden, JT Kluin-Nelemans, JC Stetler-Stevenson, MA AF Holden, J. T. Kluin-Nelemans, J. C. Stetler-Stevenson, M. A. TI Flow cytometric staging in B-non Hodgkin's lymphoma (NHL): Clinically useful or not? SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Meeting Abstract CT 6th Euroconference on Clinical Cell Analysis CY SEP 14-16, 2006 CL Stresa, ITALY SP European Soc Clin Cell Anal C1 Emory Univ, Sch Med, Dept Pathol & Lab Med, Atlanta, GA 30322 USA. Univ Groningen, Med Ctr, Dept Hematol, Groningen, Netherlands. NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD MAR PY 2007 VL 72B IS 2 MA 20 BP 122 EP 122 PG 1 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 146PR UT WOS:000244947200027 ER PT J AU Marti, G AF Marti, G. TI Prognostic factors for B-CLL still a long way to go SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Meeting Abstract CT 6th Euroconference on Clinical Cell Analysis CY SEP 14-16, 2006 CL Stresa, ITALY SP European Soc Clin Cell Anal ID CHRONIC LYMPHOCYTIC-LEUKEMIA; ZAP-70; CYTOMETRY; GENE C1 NIH, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD MAR PY 2007 VL 72B IS 2 MA 26 BP 125 EP 126 PG 2 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 146PR UT WOS:000244947200033 ER PT J AU Fischer, R Lugar, P Lipsky, P Grammer, A AF Fischer, R. Lugar, P. Lipsky, P. Grammer, A. TI Translating research to the clinic-polychromatic flow cytometry in the identification of potential B cell biomarkers in systemic lupus erythematosus SO CYTOMETRY PART B-CLINICAL CYTOMETRY LA English DT Meeting Abstract CT 6th Euroconference on Clinical Cell Analysis CY SEP 14-16, 2006 CL Stresa, ITALY SP European Soc Clin Cell Anal C1 NIAMS, Cell Biol Grp B, Bethesda, MD USA. NIAMS, Repetoire Anal Grp, Autoimmun Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4949 J9 CYTOM PART B-CLIN CY JI Cytom. Part B-Clin. Cytom. PD MAR PY 2007 VL 72B IS 2 MA 48 BP 136 EP 136 PG 1 WC Medical Laboratory Technology; Pathology SC Medical Laboratory Technology; Pathology GA 146PR UT WOS:000244947200055 ER PT J AU Baibakov, B Gauthier, L Talbot, P Rankin, TL Dean, J AF Baibakov, Boris Gauthier, Lyn Talbot, Prue Rankin, Tracy L. Dean, Jurrien TI Sperm binding to the zona pellucida is not sufficient to induce acrosome exocytosis SO DEVELOPMENT LA English DT Article DE molecular mechanisms of mouse fertilization; sperm acrosome exocytosis; mechanosensory signal transduction; zona pellucida matrix; sperm-egg recognition; postfertilization block to polyspermy ID GAMETES IN-VITRO; MOUSE SPERM; CONTACT INTERACTIONS; PLASMA-MEMBRANE; EGG RECOGNITION; MACAQUE SPERM; KNOCKOUT MICE; HUMAN ZP3; FERTILIZATION; SPERMATOZOA AB At fertilization, spermatozoa bind to the zona pellucida (ZP1, ZP2, ZP3) surrounding ovulated mouse eggs, undergo acrosome exocytosis and penetrate the zona matrix before gamete fusion. Following fertilization, ZP2 is proteolytically cleaved and sperm no longer bind to embryos. We assessed Acr3-EGFP sperm binding to wild-type and huZP2 rescue eggs in which human ZP2 replaces mouse ZP2 but remains uncleaved after fertilization. The observed de novo binding of Acr3-EGFP sperm to embryos derived from huZP2 rescue mice supports a 'zona scaffold' model of sperm-egg recognition in which intact ZP2 dictates a three-dimensional structure supportive of sperm binding, independent of fertilization and cortical granule exocytosis. Surprisingly, the acrosomes of the bound sperm remain intact for at least 24 hours in the presence of uncleaved human ZP2 regardless of whether sperm are added before or after fertilization. The persistence of intact acrosomes indicates that sperm binding to the zona pellucida is not sufficient to induce acrosome exocytosis. A filter penetration assay suggests an alternative mechanism in which penetration into the zona matrix initiates a mechanosensory signal transduction necessary to trigger the acrosome reaction. C1 NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Calif Riverside, Dept Cell Biol & Neurosci, Riverside, CA 92521 USA. RP Baibakov, B (reprint author), NIDDK, Cellular & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. EM borisb@mail.nih.gov FU Intramural NIH HHS NR 79 TC 67 Z9 70 U1 0 U2 3 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD MAR 1 PY 2007 VL 134 IS 5 BP 933 EP 943 DI 10.1242/dev.02752 PG 11 WC Developmental Biology SC Developmental Biology GA 144XX UT WOS:000244830900013 PM 17293534 ER PT J AU Sullivan, JC Ryan, JF Mullikin, JC Finnerty, JR AF Sullivan, James C. Ryan, Joseph F. Mullikin, James C. Finnerty, John R. TI Conserved and novel Wnt clusters in the basal eumetazoan Nematostella vectensis SO DEVELOPMENT GENES AND EVOLUTION LA English DT Article DE Wnt; gene clusters; evolution; development; evo-devo ID SEA-ANEMONE; CNIDARIANS; COMPLEXITY; EVOLUTION AB Evolutionarily conserved gene clusters are interesting for two reasons: (1) they may illuminate ancient events in genome evolution and (2) they may reveal ongoing stabilizing selection; that is, the conservation of gene clusters may have functional significance. To test if the Wnt family of signaling factors exhibits conserved clustering in basal metazoans and if those clusters are of functional importance, we searched the genomic sequence of the sea anemone Nematostella vectensis for Wnt clusters and correlated the clustering we observed with published expression patterns. Our results indicate that the Wnt1-Wnt6-Wnt10 cluster observed in Drosophila melanogaster is partially conserved in the cnidarian lineage; Wnt6 and Wnt10 are separated by less than 4,500 nucleotides in Nematostella. A novel cluster comprised of Wnt5-Wnt7/Wnt7b was observed in Nematostella. Clustered Wnt genes do not exhibit Hox-like colinearity nor is the expression of linked Wnt genes more similar than the expression of nonlinked Wnt genes. Wnt6 and Wnt10 are not expressed in a spatially or temporally contiguous manner, and Wnt5 and Wnt7 are expressed in different germ layers. C1 Boston Univ, Dept Biol, Boston, MA 02215 USA. Boston Univ, Bioinformat Program, Boston, MA 02215 USA. NHGRI, Bethesda, MD 20892 USA. RP Finnerty, JR (reprint author), Boston Univ, Dept Biol, 5 Cummington St, Boston, MA 02215 USA. EM jrf3@bu.edu FU Intramural NIH HHS NR 17 TC 14 Z9 15 U1 0 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0949-944X J9 DEV GENES EVOL JI Dev. Genes Evol. PD MAR PY 2007 VL 217 IS 3 BP 235 EP 239 DI 10.1007/s00427-007-0136-5 PG 5 WC Cell Biology; Evolutionary Biology; Developmental Biology SC Cell Biology; Evolutionary Biology; Developmental Biology GA 140DH UT WOS:000244483300007 PM 17310352 ER PT J AU Dernburg, AF Misteli, T AF Dernburg, Abby F. Misteli, Tom TI Nuclear architecture - An island no more SO DEVELOPMENTAL CELL LA English DT Editorial Material ID CHROMATIN-STRUCTURE; ORGANIZATION; LOCALIZATION; CHROMOSOMES; TRANSPORT; DYNAMICS; ENVELOPE; EXCHANGE; DEFECTS; ALPHA AB The eukaryotic nucleus has been the neglected child of cell biology. The "International Symposium on Functional Organization of the Nucleus" held in January on Awaji Island, Japan, highlighted recent work on nuclear organization and function. Emerging from this conference was a holistic view in which diverse chemical and physical signals link the nuclear and cytoplasmic compartments of cells. C1 NCI, NIH, Bethesda, MD 20892 USA. Lawrence Berkeley Natl Lab, Berkeley, CA 94720 USA. Univ Calif Berkeley, Berkeley, CA 94720 USA. RP Dernburg, AF (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM afdernburg@lbl.gov; mistelit@mail.nih.gov OI Dernburg, Abby/0000-0001-8037-1079 NR 27 TC 9 Z9 9 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD MAR PY 2007 VL 12 IS 3 BP 329 EP 334 DI 10.1016/j.devcel.2007.02.014 PG 6 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 151LI UT WOS:000245291400006 PM 17336900 ER PT J AU Grego-Bessa, J Luna-Zurita, L del Monte, G Bolos, V Melgar, P Arandilla, A Garratt, AN Zang, H Mukouyama, YS Chen, HY Shou, WN Ballestar, E Esteller, M Rojas, A Perez-Pomares, JM de la Pompa, JL AF Grego-Bessa, Joaquin Luna-Zurita, Luis del Monte, Gonzalo Bolos, Victoria Melgar, Pedro Arandilla, Alejandro Garratt, Alistair N. Zang, Heesuk Mukouyama, Yoh-suke Chen, Hanying Shou, Weinian Ballestar, Esteban Esteller, Manel Rojas, Ana Perez-Pomares, Jose Maria de la Pompa, Jose Luis TI Notch signaling is essential for ventricular chamber development SO DEVELOPMENTAL CELL LA English DT Article ID RBP-J-KAPPA; CARDIAC DEVELOPMENT; TRANSCRIPTION FACTOR; NEUREGULIN RECEPTOR; ALAGILLE-SYNDROME; HEART; MOUSE; MICE; EXPRESSION; MORPHOGENESIS AB Ventricular chamber morphogenesis, first manifested by trabeculae formation, is crucial for cardiac function and embryonic viability and depends on cellular interactions between the endocardium and myocardium. We show that ventricular Notch1 activity is highest at presumptive trabecular endocardium. RBPJk and Notch1 mutants show impaired trabeculation and marker expression, attenuated EphrinB2, NRG1, and BMP10 expression and signaling, and decreased myocardial proliferation. Functional and molecular analyses show that Notch inhibition prevents EphrinB2 expression, and that EphrinB2 is a direct Notch target acting upstream of NRG1 in the ventricles. However, BMP10 levels are found to be independent of both EphrinB2 and NRG1 during trabeculation. Accordingly, exogenous BMP10 rescues the myocardial proliferative defect of in vitro-cultured RBPJk mutants, while exogenous NRG1 rescues differentiation in parallel. We suggest that during trabeculation Notch independently regulates cardiomyocyte, proliferation and differentiation, two exquisitely balanced processes whose perturbation may result in congenital heart disease. C1 CSIC, Ctr Nal Biotecnol, Dept Inmunol & Oncol, E-28049 Madrid, Spain. Max Delbruck Ctr Mol Med, D-10178 Berlin, Germany. NHLBI, Lab Dev Biol, NIH, Bethesda, MD USA. Indiana Univ, Sch Med, Dept Pediat, Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA. Ctr Nacl Invest Oncol, Programa Patol Mol, Struct Bioinformat Grp, E-28029 Madrid, Spain. Univ Malaga, Fac Ciencias, Dept Anim Biol, E-29071 Malaga, Spain. RP de la Pompa, JL (reprint author), CSIC, Ctr Nal Biotecnol, Dept Inmunol & Oncol, Darwin 3 Campus Cantoblanco, E-28049 Madrid, Spain. EM jlpompa@cnb.uam.es RI Rojas, Ana/C-3022-2008; Grego-Bessa, Joaquim/F-4398-2010; Garratt, Alistair/D-9893-2013; De La Pompa Minguez, Jose Luis/F-9719-2014; Rojas, Ana /D-5777-2011; Perez-Pomares, Jose/G-7885-2015; Esteller, Manel/L-5956-2014; Luna Zurita, Luis/F-3718-2016; IBIS, BIOINFORMATICA/O-1882-2015; OI Ballestar, Esteban/0000-0002-1400-2440; Grego-Bessa, Joaquim/0000-0002-0938-2346; Garratt, Alistair/0000-0001-9631-3041; De La Pompa Minguez, Jose Luis/0000-0001-6761-7265; Rojas, Ana /0000-0003-0750-9099; Perez-Pomares, Jose/0000-0001-5487-7252; Esteller, Manel/0000-0003-4490-6093; Luna Zurita, Luis/0000-0001-7515-1645; del Monte Nieto, Gonzalo/0000-0003-3830-2226 FU NHLBI NIH HHS [P01 HL085098, P01 HL085098-01A10003, R01 HL081092, R01 HL081092-01A2] NR 50 TC 195 Z9 203 U1 2 U2 21 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1534-5807 J9 DEV CELL JI Dev. Cell PD MAR PY 2007 VL 12 IS 3 BP 415 EP 429 DI 10.1016/j.devcel.2006.12.011 PG 15 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 151LI UT WOS:000245291400013 PM 17336907 ER PT J AU Robinson, GW Pacher-Zavisin, M Zhu, BM Yoshimura, A Hennighausen, L AF Robinson, Gertraud W. Pacher-Zavisin, Margit Zhu, Bing Mei Yoshimura, Alkihiko Hennighausen, Lothar TI Socs 3 modulates the activity of the transcription factor Stat3 in mammary tissue and controls alveolar homeostasis SO DEVELOPMENTAL DYNAMICS LA English DT Article DE cytokine signaling; mammary epithelial cells; programmed cell death ID GLAND DEVELOPMENT; TRANSGENIC MICE; EPITHELIAL-CELLS; DIFFERENTIATION; INVOLUTION; PROLACTIN; APOPTOSIS; GENE; SUPPRESSION; EXPRESSION AB Signal transducer and activator of transcription 5 and 3 (Stat5 and Stat3) control pregnancy-mediated mammary development and involution-dependent remodeling, respectively. Suppressor of cytokine signaling 3 (Socs3) has been implicated in the modulation of both Stat3 and Stat5 activity. To explore the biology of Socs3 in mammary tissue, the gene was deleted using Cre-mediated recombination. Deletion of the Socs3 gene from mammary stem or early progenitor cells did not grossly alter pregnancy-mediated mammary development but resulted in impaired lactation due to attenuated proliferation. Loss of Socs3 from differentiated luminal cells did not interfere with glandular function during lactation, but resulted in accelerated tissue remodeling upon weaning. Loss of Socs3 led to enhanced and precocious Stat3 activation. Thus, Socs3 serves as a modulator of Stat3 activity to ensure controlled proliferation and apoptosis in pregnancy and involution, respectively. C1 NIDDKD, Lab Genet & Physiol, NIH, Bethesda, MD 20892 USA. Med Univ Vienna, Dept Obstet & Gynecol, Vienna, Austria. Kyushu Univ, Div Mol & Cellular Immunol, Fukuoka 812, Japan. RP Robinson, GW (reprint author), NIDDKD, Lab Genet & Physiol, NIH, Bldg 8,Rm 101,8 Ctr Dr,MSC 0822, Bethesda, MD 20892 USA. EM traudl@nih.gov RI Robinson, Gertraud/I-2136-2012; Yoshimura, Akihiko/K-5515-2013 FU Intramural NIH HHS NR 27 TC 14 Z9 15 U1 0 U2 3 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD MAR PY 2007 VL 236 IS 3 BP 654 EP 661 DI 10.1002/dvdy.21058 PG 8 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 152WY UT WOS:000245394200003 PM 17205581 ER PT J AU Maestripieri, D Lindell, SG Higley, JD AF Maestripieri, Dario Lindell, Stephen G. Higley, J. Dee TI Intergenerational transmission of maternal behavior in rhesus macaques and its underlying mechanisms SO DEVELOPMENTAL PSYCHOBIOLOGY LA English DT Article DE maternal behavior; intergenerational transmission; crossfostering; early experience; serotonin; primates ID INDIVIDUAL-DIFFERENCES; EARLY EXPERIENCE; MACACA-MULATTA; MONKEYS; CARE; RAT; GENERATIONS; CHARACTERS; RESPONSES; EVOLUTION AB Thirteen group-living rhesus macaque females that were crossfostered shortly after birth were followed longitudinally until they gave birth for the first time. Their maternal behavior was compared to the behavior of both their foster and their biological mothers, and analyzed in relation to the cerebrospinal fluid (CSF) concentrations of serotonin, dopamine, and norepinephrine metabolites (5-HIAA, HVA, and MHPG) measured in their second year of life. Crossfostered females were similar to their,foster mothers in their rates of maternal rejection and grooming, whereas their contact-making behavior was more similar to that of their biological mothers. Crossfostered females with lower CSF concentrations of 5-HIAA exhibited higher rates of maternal rejection than females with higher CSF 5-HIAA. In a related article (Maestripieri et al., 2006), we reported that rhesus infants reared by highly rejecting mothers had lower CSF 5-HIAA in their first 3 years of life. Taken together, these findings suggest that early social experience and experience-related long-term changes in serotonergic function may play a role in the intergenerational transmission of maternal rejection from mothers to daughters. (c) 2007 Wiley Periodicals, Inc. Dev Psychobiol 49: 165-171, 2007. C1 Univ Chicago, Dept Comparat Human Dev, Chicago, IL 60637 USA. Emory Univ, Yerkes Natl Primate Res Ctr, Lawrenceville, GA 30043 USA. NIAAA, Sect Study Primate Models Psychopathol, LCTS, Poolesville, MD 20837 USA. RP Maestripieri, D (reprint author), Univ Chicago, Dept Comparat Human Dev, Chicago, IL 60637 USA. EM dario@uchicago.edu FU NCRR NIH HHS [RR-00165]; NIMH NIH HHS [K02-MH63097, R01-MH57249, R01-MH62577] NR 27 TC 43 Z9 44 U1 0 U2 8 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0012-1630 J9 DEV PSYCHOBIOL JI Dev. Psychobiol. PD MAR PY 2007 VL 49 IS 2 BP 165 EP 171 DI 10.1002/dev.20200 PG 7 WC Developmental Biology; Psychology SC Developmental Biology; Psychology GA 141OP UT WOS:000244588600006 PM 17299788 ER PT J AU Atouf, F Park, CH Pechhold, K Ta, M Choi, Y Lumelsky, NL AF Atouf, Fouad Park, Cheol Hong Pechhold, Klaus Ta, Malancha Choi, Yong Lumelsky, Nadya L. TI No evidence for mouse pancreatic beta-cell epithelial-mesenchymal transition in vitro SO DIABETES LA English DT Article ID STEM-CELLS; ISLET; GENERATION; EXPRESSION; NESTIN; MICE AB We used cre/loxP-based genetic lineage tracing analysis to test a previously proposed hypothesis that in vitro cultured adult pancreatic P-cells undergo epithelial-mesenchymal transition (EMT) to generate a highly proliferative, differentiation-competent population of mesenchymal islet "procrenitor" cells. Our results in the mouse that are likely to be directly relevant to the human system show that adult mouse beta-cells do not undergo EMT in vitro and that the mesenchymal cells that arise in cultures of adult pancreas are not derived from P-cells. We argue that these cells most likely originate from expansion of mesenchymal cells integral to the heterogeneous pancreatic islet preparations. As such, these mesenchymal "progenitors" might not represent the best possible source for generation of physiologically competent beta-cells for treatment of diabetes. C1 NIDDK, Diabet Branch, NIH, Bethesda, MD USA. RP Lumelsky, NL (reprint author), Natl Inst Dent & Craniofacial Res, Ctr Biotechnol & Innovat, NIH, 45 Ctr Dr,Room 4An,24J, Bethesda, MD 20892 USA. EM nadyal@nider.nih.gov FU Intramural NIH HHS NR 15 TC 57 Z9 57 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAR PY 2007 VL 56 IS 3 BP 699 EP 702 DI 10.2337/db06-1446 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 144WQ UT WOS:000244827500017 PM 17327438 ER PT J AU Chu, WS Das, SK Wang, H Chan, JC Deloukas, P Froguel, P Baier, LJ Jia, WP McCarthy, MI Ng, MCY Damcott, C Shuldiner, AR Zeggini, E Elbein, SC AF Chu, Winston S. Das, Swapan Kumar Wang, Hua Chan, Juliana C. Deloukas, Panos Froguel, Philippe Baier, Leslie J. Jia, Weiping McCarthy, Mark I. Ng, Maggie C. Y. Damcott, Coleen Shuldiner, Alan R. Zeggini, Eleftheria Elbein, Steven C. TI Activating transcription factor 6 (ATF6) sequence polymorphisms in type 2 diabetes and pre-diabetic traits SO DIABETES LA English DT Article ID UNFOLDED PROTEIN RESPONSE; 1Q21 LINKAGE PEAK; ENDOPLASMIC-RETICULUM; INSULIN SENSITIVITY; GENE; STRESS; SUSCEPTIBILITY; ASSOCIATION; CAUCASIANS; VARIANTS AB Activating transcription factor 6 (ATF6) is located within the region of linkage to type 2 diabetes on chromosome 1q21-q23 and is a key activator of the endoplasmic reticulum stress response. We evaluated 78 single nucleotide polymorphisms (SNPs) spanning > 213 kb in 95 people, from which we selected 64 SNPs for evaluation in 191 Caucasian case subjects from Utah and between 165 and 188 control subjects. Six SNPs showed nominal associations with type 2 diabetes (P = 0.001-0.04), including the nonsynonymous SNP rs1058405 (M67V) in exon 3 and rs11579627 in the 3' flanking region. Only rs1159627 remained significant on permutation testing. The associations were not replicated in 353 African-American case subjects and 182 control subjects, nor were ATF6 SNPs associated with altered insulin secretion or insulin sensitivity in nondiabetic Caucasian individuals. No association with type 2 diabetes was found in a subset of 44 SNPs in Caucasian (a = 2,099), Pima Indian (n = 293), and Chinese (n = 287) samples. Allelic expression imbalance was found in transformed lymphocyte cDNA for 3' untranslated region variants, thus suggesting cis-acting regulatory variants. ATF6 does not appear to play a major role in type 2 diabetes, but further work is required to identify the cause of the allelic expression imbalance. C1 Univ Arkansas Med Sci, Dept Med, Div Endocrinol, Little Rock, AR 72205 USA. Cent Arkansas Vet Healthcare Syst, Little Rock, AR USA. Chinese Univ Hong Kong, Dept Med & Therapeut, Shatin, Hong Kong, Peoples R China. Wellcome Trust Sanger Inst, Hinxton, England. Inst Biol Lille, Lille, France. Univ London Imperial Coll Sci Technol & Med, Fac Life Sci, London, England. NIDDKD, Phoenix Epidemiol & Clin Res Sect, Phoenix, AZ USA. Shanghai Jiao Tong Univ, Shanghai Diabet Inst, Dept Endocrinol & Metab, Shanghai 200030, Peoples R China. Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. Univ Chicago, Dept Med, Chicago, IL 60637 USA. Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. RP Elbein, SC (reprint author), Univ Arkansas Med Sci, McClellan Mem Vet Hosp, Endocrinol 111J-1-LR,4700 W 7th St, Little Rock, AR 72205 USA. EM elbeinstevenc@uams.edu RI Deloukas, Panos/B-2922-2013; Chan, Juliana /B-7918-2016; OI Deloukas, Panos/0000-0001-9251-070X; Chan, Juliana /0000-0003-1325-1194; Zeggini, Eleftheria/0000-0003-4238-659X FU NCRR NIH HHS [M01 RR014288]; NIDDK NIH HHS [K23 DK059311, R01 DK039311, R01 DK039311-24, R01 DK073490, U01 DK058026]; Wellcome Trust [076113, 079557] NR 24 TC 23 Z9 24 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAR PY 2007 VL 56 IS 3 BP 856 EP 862 DI 10.2337/db06-1305 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 144WQ UT WOS:000244827500036 PM 17327457 ER PT J AU Owen, KR Groves, CJ Hanson, RL Knowler, WC Shuldiner, AR Elbein, SC Mitchell, BD Froguel, P Ng, MCY Chan, JC Jia, WP Deloukas, P Hitman, GA Walker, M Frayling, TM Hattersley, AT Zeggini, E McCarthy, MI AF Owen, Katharine R. Groves, Christopher J. Hanson, Robert L. Knowler, William C. Shuldiner, Alan R. Elbein, Steven C. Mitchell, Braxton D. Froguel, Philippe Ng, Maggie C. Y. Chan, Juliana C. Jia, Weiping Deloukas, Panos Hitman, Graham A. Walker, Mark Frayling, Timothy M. Hattersley, Andrew T. Zeggini, Eleftheria McCarthy, Mark I. CA Int Type 2 Diabetes 1q Consortium TI Common variation in the LMNA gene (encoding lamin A/C) and type 2 diabetes - Association analyses in 9,518 subjects SO DIABETES LA English DT Article ID PIMA-INDIANS; PARTIAL LIPODYSTROPHY; INSULIN-RESISTANCE; SUSCEPTIBILITY; LINKAGE; DISEQUILIBRIUM; LAMINOPATHIES; HAPLOTYPES; CANDIDATE; OBESITY AB Mutations in the LMNA gene (encoding lamin A/C) underlie familial partial lipodystrophy, a syndrome of monogenic insulin resistance and diabetes. LMNA maps to the well-replicated diabetes-linkage region on chromosome 1q, and there are reported associations between LMNA single nucleotide polymorphisms (SNPs) (particularly rs4641; H566H) and metabolic syndrome components. We examined the relationship between LMNA variation and type 2 diabetes (using six tag SNPs capturing > 90% of common variation) in several large datasets. Analysis of 2,490 U.K. diabetic case and 2,556 control subjects revealed no significant associations at either genotype or haplotype level: the minor allele at rs4641 was no more frequent in case subjects (allelic odds ratio [OR] 1.07 [95% CI 0.98-1.17], P = 0.15). In 390 U.K. trios, family-based association analyses revealed nominally significant overtransmission of the major allele at rs12063564 (P = 0.01), which was not corroborated in other samples. Finally, genotypes for 2,817 additional subjects from the International 1q Consortium revealed no consistent case-control or family-based associations with LMNA variants. Across all our data, the OR for the rs4641 minor allele approached but did not attain significance (1.07 [0.99-1.15], P = 0.08). Our data do not therefore support a major effect of LMNA variation on diabetes risk. However, in a meta-analysis including other available data, there is evidence that rs4641 has a modest effect on diabetes susceptibility (1.10 [1.04-1.16], P = 0.001). C1 Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England. NIDDKD, Phoenix Epidemiol & Clin Res Sect, Phoenix, AZ USA. Univ Maryland, Sch Med, Div Endocrinol Diabet & Nutr, Baltimore, MD 21201 USA. Cent Arkansas Vet Healthcare Syst, Med Serv, Endocrinol Sect, Little Rock, AR USA. Univ Arkansas Med Sci, Coll Med, Dept Internal Med, Div Endocrinol & Metab, Little Rock, AR 72205 USA. CNRS, UMR 8090, Inst Biol Lille, Lille, France. Univ London Imperial Coll Sci Technol & Med, Fac Life Sci, London, England. Univ Chicago, Dept Med, Chicago, IL 60637 USA. Chinese Univ Hong Kong, Dept Med & Therapeut, Shatin, Hong Kong, Peoples R China. Shanghai Jiao Tong Univ, Shanghai Diabet Inst, Dept Endocrinol & Metab, Peoples Hosp 6, Shanghai 200030, Peoples R China. Wellcome Trust Sanger Inst, Hinxton, England. Barts & London Queen Marys Sch Med & Dent, Ctr Diabet & Metab Med, London, England. Univ Newcastle, Dept Med, Newcastle Upon Tyne, Tyne & Wear, England. Peninsula Med Sch, Inst Clin & Biomed Sci, Exeter, Devon, England. Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England. RP Owen, KR (reprint author), Univ Oxford, Churchill Hosp, Oxford Ctr Diabet Endocrinol & Metab, Old Rd, Oxford OX3 7LJ, England. EM katherine.owen@drl.ox.ac.uk RI Deloukas, Panos/B-2922-2013; Hanson, Robert/O-3238-2015; Chan, Juliana /B-7918-2016; OI Deloukas, Panos/0000-0001-9251-070X; Hanson, Robert/0000-0002-4252-7068; Chan, Juliana /0000-0003-1325-1194; Zeggini, Eleftheria/0000-0003-4238-659X; Mitchell, Braxton/0000-0003-4920-4744 FU Intramural NIH HHS; Medical Research Council [G0500070]; NIA NIH HHS [T32 AG 00219, T32 AG000219]; NIDDK NIH HHS [U01 DK 58026, K24 DK 2673, R01 DK 073490, R01 DK 39311, R01 DK 54261, R01 DK039311, R01 DK054261, R01 DK073490, U01 DK058026]; Wellcome Trust [076113, 079557] NR 25 TC 21 Z9 23 U1 0 U2 1 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAR PY 2007 VL 56 IS 3 BP 879 EP 883 DI 10.2337/db06-0930 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 144WQ UT WOS:000244827500039 PM 17327460 ER PT J AU Malhotra, A Elbein, SC Ng, MCY Duggirala, R Arya, R Imperatore, G Adeyemo, A Pollin, TI Hsueh, WC Chan, JCN Rotimi, C Hanson, RL Hasstedt, SJ Wolford, JK AF Malhotra, Alka Elbein, Steven C. Ng, Maggie C. Y. Duggirala, Ravindranath Arya, Rector Imperatore, Giuseppina Adeyemo, Adebowale Pollin, Toni I. Hsueh, Wen-Chi Chan, Juliana C. N. Rotimi, Charles Hanson, Robert L. Hasstedt, Sandra J. Wolford, Johanna K. CA Amer Diabetes Ass GENNID Study Grp TI Meta-analysis of genome-wide linkage studies of quantitative lipid traits in families ascertained for type 2 diabetes SO DIABETES LA English DT Article ID CORONARY-HEART-DISEASE; CHOLESTEROL CONCENTRATIONS; SUSCEPTIBILITY LOCUS; MEXICAN-AMERICANS; AFRICAN-AMERICANS; SERUM-CHOLESTEROL; LDL CHOLESTEROL; SCAN; TRIGLYCERIDE; POPULATION AB Dyslipidemia is a major risk factor for coronary heart disease, which is the predominant cause of mortality in individuals with type 2 diabetes. To date, nine linkage studies for quantitative lipid traits have been performed in families ascertained for type 2 diabetes, individually yielding linkage results that were largely nonoverlapping. Discrepancies in linkage findings are not uncommon and are typically due to limited sample size and heterogeneity. To address these issues and increase the power to detect linkage, we performed a meta-analysis of all published genome scans for quantitative lipid traits conducted in families ascertained for type 2 diabetes. Statistically significant evidence (i.e., P < 0.00043) for linkage was observed for total cholesterol on 7q32.3-q36.3 (152.43-182 cM; P = 0.00004), 19p13.3-p12 (6.57-38.05 cM; P = 0.00026), 19p12-q13.13 (38.05-69.53 cM; P = 0.00001), and 19q13.13-q13.43 (69.53-101.1 cM; P = 0.00033), as well as LDL on 19p13.3-p12 (P = 0.00041). Suggestive evidence (i.e., P < 0.00860) for linkage was also observed for LDL on 19p12q13.13, triglycerides on 7p11-q21.11 (63.72-93.29 cM), trlglyceride/HDL on 7p11-q21.11 and 19p12-q13.13, and LDL/HDL on 16q11.2-q24.3 (65.2-130.4 cM) and 19p12-q13.13. Linkage for lipid traits has been previously observed on both chromosomes 7 and 19 in several unrelated studies and, together with the results of this meta-analysis, provide compelling evidence that these regions harbor important determinants of lipid levels in individuals with type 2 diabetes. C1 Translat Genom Res Inst, Genet Basis Human Dis, Diabet & Obes Res Unit, Phoenix, AZ 85004 USA. Univ Arkansas, Endocrinol Sect, Fayetteville, AR 72701 USA. Chinese Univ Hong Kong, Dept Med & Therapeut, Sha Tin, Hong Kong, Peoples R China. SW Fdn Biomed Res, Dept Genet, San Antonio, TX USA. Univ Texas, Hlth Sci Ctr, Div Clin Epidemiol, San Antonio, TX 78285 USA. Ctr Dis Control & Prevent, Div Biabet Translat, Atlanta, GA USA. Howard Univ, Natl Human Genome Ctr, Washington, DC 20059 USA. Univ Maryland, Div Endocrinol Diabet & Nutr, College Pk, MD 20742 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. NIDDKD, Diabetes & Arthritis Epidemiol Sect, Phoenix, AZ 85016 USA. Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA. RP Malhotra, A (reprint author), Translat Genom Res Inst, Genet Basis Human Dis, Diabet & Obes Res Unit, 445 N 5th St, Phoenix, AZ 85004 USA. EM amalhotra@tgen.org RI Hanson, Robert/O-3238-2015; Chan, Juliana /B-7918-2016; OI Hanson, Robert/0000-0002-4252-7068; Chan, Juliana /0000-0003-1325-1194; Adeyemo, Adebowale/0000-0002-3105-3231; Kahn, Steven/0000-0001-7307-9002 FU FIC NIH HHS [3T37 TW 00041-03S2]; Intramural NIH HHS; NHGRI NIH HHS [N01 HG 65403]; NIDDK NIH HHS [DK 42273, DK 39311, DK 47482, DK 53889, DK 54001] NR 23 TC 25 Z9 27 U1 0 U2 2 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD MAR PY 2007 VL 56 IS 3 BP 890 EP 896 DI 10.2337/db06-1057 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 144WQ UT WOS:000244827500041 PM 17327462 ER PT J AU Saldana, TM Basso, O Hoppin, JA Baird, DD Knott, C Blair, A Alavanja, MCR Sandler, DP AF Saldana, Tina M. Basso, Olga Hoppin, Jane A. Baird, Donna D. Knott, Charles Blair, Aaron Alavanja, Michael C. R. Sandler, Dale P. TI Pesticide exposure and self-reported gestational diabetes mellitus in the agricultural health study SO DIABETES CARE LA English DT Article ID SUBCHRONIC EXPOSURE; GLUCOSE-INTOLERANCE; SERUM DIOXIN; ORGANOPHOSPHATE; EPIDEMIOLOGY; APPLICATORS; 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN; MALATHION; VETERANS; PATTERNS AB OBJECTIVE - To examine the association between pesticide use during pregnancy and gestational diabetes mellitus (GDM) among wives of licensed pesticide applicators. RESEARCH DESIGN AND METHODS - Using data from the Agricultural Health Study (AHS), we estimated the association between self-reported pesticide-related activities during the first trimester of the most recent pregnancy and GDM among 11,273 women whose pregnancy occurred within 25 years of enrollment. RESULTS - A total of 506 (4.5%) women reported having had GDM. Women who reported agricultural pesticide exposure (mixing or applying pesticides to crops or repairing pesticide application equipment) during pregnancy were more likely to report GDM (odds ratio [OR] 2.2 [95% CI 1.5-3.3]). We saw no association between residential pesticide exposure (applying pesticides in the home and garden during pregnancy) and GDM (1.0 [0.8-1.3]). Among women who reported agricultural exposure during pregnancy, risk of GDM was associated with ever-use of four herbicides (2,4,5-T 2,4,5-TP; atrazine or butylate) and three insecticides (diazinon, phorate, or carbofuran). CONCLUSIONS - These findings suggest that activities involving exposure to agricultural pesticides during the first trimester of pregnancy may increase the risk of GDM. C1 Natl Inst Environm Hlth Sci, Epidemiol Branch, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. Battelle Mem Inst, Ctr Publ Hlth Res & Evaluat, Durham, NC USA. NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM saldana@niehs.nih.gov RI Basso, Olga/E-5384-2010; Baird, Donna/D-5214-2017; OI Basso, Olga/0000-0001-9298-4921; Baird, Donna/0000-0002-5544-2653; Sandler, Dale/0000-0002-6776-0018 FU Intramural NIH HHS [Z01 ES049030-11] NR 34 TC 76 Z9 77 U1 2 U2 9 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 MAR PY 2007 VL 30 IS 3 BP 529 EP 534 DI 10.2337/dc06-1832 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 146NM UT WOS:000244941200012 PM 17327316 ER PT J AU Otu, HH Can, H Spentzos, D Nelson, RG Hanson, RL Looker, HC Knowler, WC Monroy, M Libermann, TA Karumanchi, SA Thadhani, R AF Otu, Hasan H. Can, Handan Spentzos, Dimitrios Nelson, Robert G. Hanson, Robert L. Looker, Helen C. Knowler, William C. Monroy, Manuel Libermann, Towia A. Karumanchi, S. Ananth Thadhani, Ravi TI Prediction of diabetic nephropathy using urine proteomic profiling 10 years prior to development of nephropathy SO DIABETES CARE LA English DT Article ID PROSTATE-CANCER; PIMA-INDIANS; ALBUMIN EXCRETION; OVARIAN-CANCER; SERUM; MICROALBUMINURIA; MELLITUS; BENIGN; NIDDM; IDENTIFICATION AB OBJECTIVE - We examined whether proteomic technologies identify novel urine proteins associated with subsequent development of diabetic nephropathy in subjects with type 2 diabetes before evidence of microalbuminuria. RESEACH DESIGN AND METHODS - in a nested case-control study of Pima Indians with type 2 diabetes, baseline (serum creatinine < 1.2 mg/dl and urine albumin excretion < 30 mg/g) and 10-year urine samples were examined. Case subjects (n = 31) developed diabetic nephropathy (urinary albumin-to-creatinine ratio > 300 mg/g) over 10 years. Control subjects (n = 3 1) were matched to case subjects (1: 1) according to diabetes duration, age, sex, and BMI but remained normoalbuminuric (albumin-to-creatinine ratio < 30 mg/g) over the same 10 years. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) was performed on baseline urine samples, and training (14 cases:14 controls) and validation (17:17) sets were tested. RESULTS - At baseline, A1C levels differed between case and control subjects. SELDI-TOF MS detected 714 unique urine protein peaks. Of these, a 12-peak proteomic signature correctly predicted 89% of cases of diabetic nepropathy (93% sensitivity, 86% specificity) in the training set. Applying this same signature to the independent validation set yielded an accuracy rate of 74% (71% sensitivity, 76% specificity). In multivariate analyses, the 12-peak signature was independently associated with subsequent diabetic nephropathy when applied to the validation set (odds ratio [OR] 7.9 [95% CI 1.5-43.5], P = 0.017) and the entire dataset (14.5 [3.7-55.6], P = 0.001), and A1C levels were no longer significant. CONCLUSIONS - Urine proteomic, profiling identifies normoalbuminuric subjects with type 2 diabetes who subsequently develop diabetic nephropathy. Further studies are needed to characterize the specific proteins involved in this early prediction. C1 Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Massachusetts Gen Hosp, Renal Unit, Boston, MA 02114 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Genom Ctr, Boston, MA 02114 USA. Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, DF HCC Canc Prote Core, Boston, MA 02114 USA. Yeditepe Univ, Dept Genet & Bioengn, Istanbul, Turkey. NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, Phoenix, AZ USA. Beth Israel Deaconess Med Ctr, Div Nephrol, Dept Med, Boston, MA 02215 USA. RP Thadhani, R (reprint author), Harvard Univ, Sch Med, Massachusetts Gen Hosp, Dept Med, Bullfinch 127,55 Fruit St, Boston, MA 02114 USA. EM thadhani.r@mgh.harvard.edu RI Libermann, Towia/F-9866-2010; Nelson, Robert/B-1470-2012; Hanson, Robert/O-3238-2015; OI Hanson, Robert/0000-0002-4252-7068; Libermann, Towia/0000-0002-4006-8179; Otu, Hasan/0000-0002-9253-8152 FU NIDDK NIH HHS [DK 068465] NR 30 TC 74 Z9 84 U1 0 U2 1 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 MAR PY 2007 VL 30 IS 3 BP 638 EP 643 DI 10.2337/dc06-1656 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 146NM UT WOS:000244941200029 PM 17327333 ER PT J AU Looker, HC Fagot-Campagna, A Gunter, EW Pfeiffer, CM Sievers, ML Bennett, PH Nelson, RG Hanson, RL Knowler, WC AF Looker, Helen C. Fagot-Campagna, Anne Gunter, Elaine W. Pfeiffer, Christine M. Sievers, Maurice L. Bennett, Peter H. Nelson, Robert G. Hanson, Robert L. Knowler, William C. TI Homocysteine and vitamin B-12 concentrations and mortatity rates in type 2 diabetes SO DIABETES-METABOLISM RESEARCH AND REVIEWS LA English DT Article DE diabetes mellitus; mortality; homocysteine ID PLASMA TOTAL HOMOCYSTEINE; CORONARY-HEART-DISEASE; STAGE RENAL-DISEASE; C-REACTIVE PROTEIN; NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; PIMA-INDIANS; CARDIOVASCULAR-DISEASE; FOLIC-ACID; MYOCARDIAL-INFARCTION AB Objective To assess the role of homocysteine as a risk factor for mortality in diabetic subjects. Methods Homocysteine, vitamin B-12, and folate concentrations were measured in stored sera of 396 diabetic Pima Indians aged >= 40 years when examined between 1982 and 1985. Vital status was assessed through 2001. Results and Conclusions Over a median follow-up of 15.7 years, there were 221 deaths -76 were due to cardiovascular disease (CVD), 36 to diabetes/nephropathy and 34 to infections. Homocysteine was positively associated with mortality from all causes (hazard rate ratio (HRR) for highest versus lowest tertile of homocysteine = 1.70, 95% confidence interval (CI) 1.18-2.46), from diabetes/nephropathy (HRR = 2.39, 95% Cl 0.94-6.11) and from infectious diseases (HRR = 3.39, 95% CI 1.19-9.70), but not from CVD (HRR = 1.16, 95% CI 0.62-2.17) after adjustment for age, sex and diabetes duration. Homocysteine correlated with serum creatinine (r = 0.50), and the relationships with mortality rates were not significant after adjustment for creatinine. Vitamin B-12 was positively associated with all-cause mortality (HRR for 100 pg/mL difference adjusted for age, sex and diabetes duration = 1.15, 95% Cl 1.08-1.22) and death from diabetes/nephropathy (HRR = 1.27, 95% Cl 1.10-1.46). The association between homocysteine and mortality in type 2 diabetes is not causal, but is confounded by renal disease in Pima Indians. Copyright (c) 2006 John Wiley & Sons, Ltd. C1 Natl Inst Diabet & Digest & Kidney Dis, Phoenix, AZ USA. Ctr Dis Control & Prevent, Atlanta, GA USA. RP Looker, HC (reprint author), 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM hlooker@mail.nih.gov RI Nelson, Robert/B-1470-2012; Hanson, Robert/O-3238-2015 OI Hanson, Robert/0000-0002-4252-7068 FU Intramural NIH HHS NR 46 TC 8 Z9 8 U1 0 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 1520-7552 J9 DIABETES-METAB RES JI Diabetes-Metab. Res. Rev. PD MAR PY 2007 VL 23 IS 3 BP 193 EP 201 DI 10.1002/dmrr.660 PG 9 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 149KW UT WOS:000245146800003 PM 16845688 ER PT J AU Perl, S Hirshberg, B Harlan, DM Tisdale, JF AF Perl, S. Hirshberg, B. Harlan, D. M. Tisdale, J. F. TI How much insulin is enough? A quantitative assessment of the transdifferentiaton potential of liver SO DIABETOLOGIA LA English DT Letter ID STREPTOZOTOCIN C1 NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. NIDDKD, Islet & Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Perl, S (reprint author), NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. EM perls@niddk.nih.gov FU Intramural NIH HHS NR 6 TC 3 Z9 3 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 MAR PY 2007 VL 50 IS 3 BP 690 EP 692 DI 10.1007/s00125-006-0549-0 PG 3 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 133PT UT WOS:000244025500027 PM 17221213 ER PT J AU Sonoda, E Zhao, GY Kohzaki, M Dhar, PK Kikuchi, K Redon, C Pilch, DR Bonner, WM Nakano, A Watanabe, M Nakayama, T Takeda, S Takami, Y AF Sonoda, Eiichiro Zhao, Guang Yu Kohzaki, Masaoki Dhar, Pawan Kumar Kikuchi, Koji Redon, Christophe Pilch, Duane R. Bonner, William M. Nakano, Atsushi Watanabe, Masami Nakayama, Tatsuo Takeda, Shunichi Takami, Yasunari TI Collaborative roles of gamma H2AX and the Rad51 paralog Xrcc3 in homologous recombinational repair SO DNA REPAIR LA English DT Article DE gamma H2AX; Rad51 paralog; homologous recombination; genome stability; double-strand break repair ID STRAND BREAK REPAIR; SISTER-CHROMATID COHESION; DNA-DAMAGE CHECKPOINT; B-LYMPHOCYTE LINE; ATAXIA-TELANGIECTASIA; HISTONE H2AX; VERTEBRATE CELLS; IONIZING-RADIATION; POSTREPLICATION REPAIR; CHROMOSOMAL INTEGRITY AB One of the earliest events in the signal transduction cascade that initiates a DNA damage checkpoint is the phosphorylation on serine 139 of histone H2AX (gamma H2AX) at DNA double-strand breaks (DSBs). However, the role of gamma H2AX in DNA repair is poorly understood. To address this question, we generated chicken DT40 cells carrying a serine to alanine mutation at position 139 of H2AX (H2AX(-/S139A)) and examined their DNA repair capacity. H2AX(-/S139A) cells exhibited defective homologous recombinational repair (HR) as manifested by delayed Rad51 focus formation following ionizing radiation (IR) and hypersensitivity to the topoisomerase I inhibitor, camptothecin (CPT), which causes DSBs at replication blockage. Deletion of the Rad51 paralog gene, XRCC3, also delays Rad51 focus formation. To test the interaction of Xrcc3 and gamma H2AX, we disrupted XRCC3 in H2AX(-/S139A) cells. XRCC3(-/-)/H2AX(-/S139A) mutants were not viable, although this synthetic lethality was reversed by inserting a transgene that conditionally expresses wild-type H2AX. Upon repression of the wild-type H2AX transgene, XRCC3(-/-)/H2AX(-/S139A) cells failed to form Rad51 foci and exhibited markedly increased levels of chromosomal aberrations after CPT treatment. These results indicate that H2AX and XRCC3 act in separate arms of a branched pathway to facilitate Rad51 assembly. (c) 2006 Elsevier B.V. All rights reserved. C1 Miyazaki Univ, Miyazaki Med Coll, Dept Med Sci, Sect Biochem & Mol Biol, Kiyotake, Miyazaki 8891692, Japan. Miyazaki Univ, Miyazaki Med Coll, Frontier Res Ctr, Dept Life Sci, Kiyotake, Miyazaki 8891692, Japan. Kyoto Univ, Grad Sch Med, Dept Radiat Genet, CREST Lab, Kyoto 6068501, Japan. Nagasaki Univ, Grad Sch Biomed Sci, Dept Radiol & Radiat Biol, Nagasaki 8528521, Japan. NCI, NIH, CCR, LMP, Bethesda, MD 20892 USA. Kyoto Univ, Grad Sch Med, Dept Cardiovasc Med, Kyoto 6068501, Japan. RP Takami, Y (reprint author), Miyazaki Univ, Miyazaki Med Coll, Dept Med Sci, Sect Biochem & Mol Biol, 5200 Kihara, Kiyotake, Miyazaki 8891692, Japan. EM ytakami@med.miyazaki-u.ac.jp NR 57 TC 31 Z9 31 U1 0 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD MAR 1 PY 2007 VL 6 IS 3 BP 280 EP 292 DI 10.1016/j.dnarep.2006.10.025 PG 13 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 147GL UT WOS:000244991300003 PM 17123873 ER PT J AU Holmes, SF Scarpinato, KD McCulloch, SD Schaaper, RM Kunkel, TA AF Holmes, Shannon F. Scarpinato, Karin Drotschmann McCulloch, Scott D. Schaaper, Roel M. Kunkel, Thomas A. TI Specialized mismatch repair function of Glu339 in the Phe-X-Glu motif of yeast Msh6 SO DNA REPAIR LA English DT Article DE mismatch repair; oxidative damage; Muts; Msh6 ID STATE KINETIC-ANALYSIS; ESCHERICHIA-COLI; DNA MISMATCH; SACCHAROMYCES-CEREVISIAE; 8-OXODEOXYGUANOSINE TRIPHOSPHATE; REPLICATION FIDELITY; MUTATOR PHENOTYPES; MUTS HOMOLOGS; PROTEIN MUTS; STEADY-STATE AB The major eukaryotic mismatch repair (MMR) pathway requires Msh2-Msh6, which, like Escherichia coli MutS, binds to and participates in repair of the two most common replication errors, single base-base and single base insertion-deletion mismatches. For both types of mismatches, the side chain of E. coli Glu38 in a conserved Phe-X-Glu motif interacts with a mismatched base. The O epsilon of Glu38 forms a hydrogen bond with either the N7 of purines or the N3 of pyrimidines. We show here that changing E. coli Glu38 to alanine results in nearly complete loss of repair of both single base-base and single base deletion mismatches. In contrast, a yeast strain with alanine replacing homologous Glu339 in Msh6 has nearly normal repair for insertion-deletion and most base-base mismatches, but is defective in repairing base-base mismatches characteristic of oxidative stress, e.g. 8-oxo-G-A mismatches. The results suggest that bacterial MutS and yeast Msh2-Msh6 differ in how they recognize and/or process replication errors involving undamaged bases, and that Glu339 in Msh6 may have a specialized role in repairing mismatches containing oxidized bases. (c) 2006 Elsevier B.V. All rights reserved. C1 NIEHS, Lab Mol Genet, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Struct Biol, Res Triangle Pk, NC 27709 USA. Wake Forest Univ, Sch Med, Dept Canc Biol, Winston Salem, NC 27157 USA. RP Kunkel, TA (reprint author), NIEHS, NIH, POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov FU Intramural NIH HHS; NIEHS NIH HHS [Z01 ES065089-09]; NIGMS NIH HHS [F32 GM069100, 5 F32 GM069100-03] NR 50 TC 9 Z9 10 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD MAR 1 PY 2007 VL 6 IS 3 BP 293 EP 303 DI 10.1016/j.dnarep.2006.10.023 PG 11 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 147GL UT WOS:000244991300004 PM 17141577 ER PT J AU Barone, F McCulloch, SD Macpherson, P Maga, G Yamada, M Nohmi, T Minoprio, A Mazzei, F Kunkel, TA Karran, P Bignami, M AF Barone, Flavia McCulloch, Scott D. Macpherson, Peter Maga, Giovanni Yamada, Masami Nohmi, Takehiko Minoprio, Anna Mazzei, Filomena Kunkel, Thomas A. Karran, Peter Bignami, Margherita TI Replication of 2-hydroxyadenine-containing DNA and recognition by human MutS alpha SO DNA REPAIR LA English DT Article DE 2-Hydroxyadenine; mismatch repair; replication; Y family polymerases ID MISMATCH REPAIR PATHWAY; POLYMERASE-ETA; Y-FAMILY; CRYSTAL-STRUCTURE; ESCHERICHIA-COLI; BASE-PAIRS; FIDELITY; SPECIFICITY; TRIPHOSPHATE; MUTATIONS AB 2-Hydroxyadenine (2-OH-A), a product of DNA oxidation, is a potential source of mutations. We investigated how representative DNA polymerases from the A, B and Y families dealt with 2-OH-A in primer extension experiments. A template 2-OH-A reduced the rate of incorporation by DNA polymerase alpha (Pol alpha) and Klenow fragment (Kf(exo-)). Two Y family DNA polymerases, human polymerase eta (Pol eta) and the archeal Dpo4 polymerase were affected differently. Bypass by Pol eta was very inefficient whereas Dpo4 efficiently replicated 2-OH-A. Replication of a template 2-OH-A by both enzymes was mutagenic and caused base substitutions. Dpo4 additionally introduced single base deletions. Thermodynamic analysis showed that 2-OH-A forms stable base pairs with T, C and G, and to a lesser extent with A. Oligonucleotides containing 2-OH-A base pairs, including the preferred 2-OH-A:T, were recognized by the human MutS alpha mismatch repair (MMR). MutS alpha also recognized 2-OH-A located in a repeat sequence that mimics a frameshift intermediate. (c) 2006 Elsevier B.V. All rights reserved. C1 Ist Super Sanita, Dept Environm & Primary Prevent, Unit Expt Carcinogenesis, I-00161 Rome, Italy. Natl Inst Environm Sci, Lab Mol Genet & Struct Biol, NIH, DHHS, Res Triangle Pk, NC 27709 USA. Clare Hall Labs, Canc Res UK London Res Inst, Potters Bar EN6 3LD, Herts, England. CNR, IGM, CNR, Ist Genet Mol, I-27100 Pavia, Italy. Natl Inst Hlth Sci, Div Genet & Mutagenesis, Setagaya Ku, Tokyo 1588501, Japan. RP Bignami, M (reprint author), Ist Super Sanita, Dept Environm & Primary Prevent, Unit Expt Carcinogenesis, Viale Regina Elena 299, I-00161 Rome, Italy. EM bignami@iss.it RI Maga, Giovanni/C-5409-2009 OI Maga, Giovanni/0000-0001-8092-1552 FU Intramural NIH HHS [Z01 ES065070-17] NR 41 TC 16 Z9 16 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD MAR 1 PY 2007 VL 6 IS 3 BP 355 EP 366 DI 10.1016/j.dnarep.2006.11.002 PG 12 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 147GL UT WOS:000244991300009 PM 17188944 ER PT J AU Schwan, TG Raffel, SJ Schrumpf, ME Porcella, SF AF Schwan, Tom G. Raffel, Sandra J. Schrumpf, Merry E. Porcella, Stephen F. TI Diversity and distribution of Borrelia hermsii SO EMERGING INFECTIOUS DISEASES LA English DT Article ID BORNE RELAPSING FEVER; NORTH-AMERICA; LYME BORRELIOSIS; BURGDORFERI; CALIFORNIA; PROTEIN; EUROPE; BIRDS AB Borrelia hermsii is the most common cause of tick-borne relapsing fever in North America. DNA sequences of the 16S-23S rDNA noncoding intergenic spacer (IGS) region were determined for 37 isolates of this spirochete. These sequences distinguished the 2 genomic groups of B. hermsii identified previously with other loci. Multiple IGS genotypes were identified among isolates from an island, which suggested that birds might play a role in dispersing these spirochetes in nature. In support of this theory, all stages of the tick vector Ornithodoros hermsi fed successfully on birds in the laboratory and advanced in their life cycle. B. hermsii produced a detectable spirochetmia in 1 chicken inoculated subcutaneously. Additional work is warranted to explore the role of birds as enzootic hosts for this relapsing fever spirochete. C1 NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, Hamilton, MT 59840 USA. RP Schwan, TG (reprint author), NIAID, Lab Zoonot Pathogens, Rocky Mt Labs, 903 S 4th St, Hamilton, MT 59840 USA. EM tschwan@niaid.nih.gov FU Intramural NIH HHS NR 28 TC 34 Z9 35 U1 1 U2 5 PU CENTER DISEASE CONTROL PI ATLANTA PA ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD MAR PY 2007 VL 13 IS 3 BP 436 EP 442 PG 7 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 144MQ UT WOS:000244800900010 PM 17552097 ER PT J AU Geli, J Kiss, N Lanner, F Foukakis, T Natalishvili, N Larsson, O Kogner, P Hoog, A Clark, GJ Ekstrom, TJ Backdahl, M Farnebo, F Larsson, C AF Geli, Janos Kiss, Nimrod Lanner, Fredrik Foukakis, Theodoros Natalishvili, Natalia Larsson, Olle Kogner, Per Hoog, Anders Clark, Geoffrey J. Ekstrom, Tomas J. Backdahl, Martin Farnebo, Filip Larsson, Catharina TI The Ras effectors NORE1A and RASSF1A are frequently inactivated in pheochromocytoma and abdominal paraganglioma SO ENDOCRINE-RELATED CANCER LA English DT Article ID TUMOR-SUPPRESSOR GENE; ABERRANT PROMOTER HYPERMETHYLATION; HUMAN-CHROMOSOME 3P21.3; EPIGENETIC INACTIVATION; NASOPHARYNGEAL CARCINOMA; BREAST CANCERS; CPG ISLAND; GROWTH; LUNG; IDENTIFICATION AB NORE1A (RASSF5) and RASSF1A are newly described Ras effectors with tumour suppressor functions. Both molecules are frequently inactivated in various cancers. In this study, we aimed to explore the potential involvement of NORE1A and RASSF1A in pheochromocytorna and abdominal paraganglioma tumorigenesis. A panel of 54 primary tumours was analysed for NORE1A and RASSF1A mRNA expression by TaqMan quantitative RT-PCR. Furthermore, NORE1A and RASSF1A promoter methylation was assessed by combined bisulphite restriction endonuclease assay and methylation-sensitive Pyrosequencing respectively. The anti-tumorigenic role of NORE1A was functionally investigated in Nore1A-transfected PC12 rat pheochromocytoma cells by fluorescent inhibition of caspase activity and soft agar assays. Significantly suppressed NORE1A and RASSF1A mRNA levels were detected in primary tumours compared with normal adrenal medulla (P < 0.001). Methylation of the NORE1A promoter was not observed in primary tumours. On the other hand, 9% (5/54) of the primary tumours examined showed RASSF1A promoter methylation greater than 20% as detected by Pyrosequencing. Methylation of the RASSF1A promoter was significantly associated with malignant behaviour (P < 0.05). Transient expression of Nore1a resulted in enhanced apoptosis and impaired colony formation in soft agar. Our study provides evidence that NORE1A and RASSF1A are frequently suppressed in pheochromocytorna and abdominal paraganglioma. Silencing of NORE1A contributes to the transformed phenotype in these tumours. C1 Karolinska Univ Hosp Solna, Karolinska Inst, Dept Mol Med & Surg, SE-17176 Stockholm, Sweden. Karolinska Inst, Dept Cell & Mol Biol, SE-17177 Stockholm, Sweden. Karolinska Univ Hosp Solna, Karolinska Inst, Dept Oncol Pathol, SE-17176 Stockholm, Sweden. Karolinska Univ Hosp Solna, Karolinska Inst, Dept Woman & Child Hlth, SE-17176 Stockholm, Sweden. NCI, Dept Cell & Canc Biol, Rockville, MD USA. Karolinska Univ Hosp Solna, Karolinska Inst, Dept Clin Neurosci, SE-17176 Stockholm, Sweden. RP Geli, J (reprint author), Karolinska Univ Hosp Solna, Karolinska Inst, Dept Mol Med & Surg, CMM L8 01, SE-17176 Stockholm, Sweden. EM janos.geli@ki.se OI Lanner, Fredrik/0000-0002-2771-7445; Foukakis, Theodoros/0000-0001-8952-9987; Kogner, Per/0000-0002-2202-9694 NR 33 TC 24 Z9 27 U1 0 U2 0 PU SOC ENDOCRINOLOGY PI BRISTOL PA 22 APEX COURT, WOODLANDS, BRADLEY STOKE, BRISTOL BS32 4JT, ENGLAND SN 1351-0088 J9 ENDOCR-RELAT CANCER JI Endocr.-Relat. Cancer PD MAR PY 2007 VL 14 IS 1 BP 125 EP 134 DI 10.1677/ERC-06-0031 PG 10 WC Oncology; Endocrinology & Metabolism SC Oncology; Endocrinology & Metabolism GA 194KV UT WOS:000248344200011 PM 17395981 ER PT J AU Huh, JI Qiu, TH Chandramouli, GVR Charles, R Wiench, M Hager, GL Catena, R Calvo, A LaVallee, TM Desprez, PY Green, JE AF Huh, Jung-Im Qiu, Ting Hu Chandramouli, Gadisetti V. R. Charles, Rhonda Wiench, Malgorzata Hager, Gordon L. Catena, Raul Calvo, Alfonso LaVallee, Theresa M. Desprez, Pierre-Yves Green, Jeffrey E. TI 2-Methoxyestradiol induces mammary gland differentiation through amphiregulin-epithelial growth factor receptor-mediated signaling: Molecular distinctions from the mammary gland of pregnant mice SO ENDOCRINOLOGY LA English DT Article ID BREAST-CANCER; GENE-EXPRESSION; CELLS; ID-1; ANGIOGENESIS; PROTEINS; ESTROGEN; REVEALS; REPRESSION; LIGAND AB Levels of 2-methoxyestradiol ( 2ME(2)), an endogenous metabolite of estradiol, are highly elevated during late stages of pregnancy when mammary glands have differentiated with the formation of alveolar structures producing milk proteins. Based upon our previous demonstration that 2ME(2) induces mammary ductal dilation associated with expression of mammary differentiation markers when administered to transgenic mice that spontaneously develop mammary cancer, we studied the effects of 2ME(2) on normal mammary gland development. The results of this study demonstrate that 2ME(2) can induce a partial differentiation of normal mammary glands in virgin mice, as evidenced by the appearance of limited numbers of alveolar cells and significantly increased expression of the differentiation markers beta-casein and whey acidic protein. 2ME(2)-induced differentiation is associated with inhibition of expression of inhibitor of differentiation 1 ( Id-1) in normal mammary epithelial cells through elements in the 5'-flanking region of the Id-1 gene. Microarray analysis revealed that 2ME(2)-induced differentiation of the mammary gland shares some significant similarities in gene expression with that of mammary glands from late-stage pregnancy, including elevated expression of many milk protein differentiation markers. However, several genes are differentially regulated between 2ME(2)-treated mammary glands and differentiated mammary glands through pregnancy. Significantly, amphiregulin, ATF3, serpine2, and SOX6 were up-regulated in 2ME(2)-treated mammary glands but not in mammary glands from pregnant mice. Using the SCp2 differentiation cell line system, we demonstrate that 2ME(2) induces differentiation through the down-regulation of Id-1 and up-regulation of amphiregulin. Administration of amphiregulin to SCp2 cells induced differentiation, whereas inhibition of 2ME(2)-induced expression of amphiregulin by small interfering RNA blocked differentiation. Estrogen receptor-negative SCp2 cells differentiate in response to 2ME(2), but not estradiol, suggesting that 2ME(2) operates through an estrogen receptor-independent mechanism. These data demonstrate that 2ME(2) can induce a partial differentiation of the mammary gland through mechanisms that differ from those normally used during pregnancy. C1 NCI, Lab Vell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. NCI, Lab Biosyst & Canc, NIH, Bethesda, MD 20892 USA. NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. Univ Navarra, Div Oncol, E-31080 Pamplona, Spain. Univ Navarra, Ctr Appl Med Res, E-31080 Pamplona, Spain. Univ Navarra, Dept Histol & Pathol, E-31080 Pamplona, Spain. EntreMed Inc, Rockville, MD 20850 USA. Canc Res Inst, Calif Pacific Med Ctr, San Francisco, CA 94143 USA. RP Green, JE (reprint author), NCI, Lab Vell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. EM jegreen@nih.gov NR 27 TC 7 Z9 8 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAR PY 2007 VL 148 IS 3 BP 1266 EP 1277 DI 10.1210/en.2006-0964 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 137FJ UT WOS:000244278100037 PM 17158205 ER PT J AU Kim, CS Furuya, F Ying, H Kato, Y Hanover, JA Cheng, SY AF Kim, Caroline S. Furuya, Fumihiko Ying, Hao Kato, Yasuhito Hanover, John A. Cheng, Sheue-yann TI Gelsolin: A novel thyroid hormone receptor-beta interacting protein that modulates tumor progression in a mouse model of follicular thyroid cancer SO ENDOCRINOLOGY LA English DT Article ID TRANSCRIPTIONAL ACTIVITY; LIGAND-BINDING; CARCINOMA; EXPRESSION; RESISTANCE; CARCINOGENESIS; GENE; SUPPRESSOR; MUTATION; FAMILY AB Follicular thyroid cancer ( FTC) is known to metastasize to distant sites via hematogenous spread; however, the underlying pathways that contribute to metastasis remain unknown. Recent creation of a knockin mutant mouse that expresses a mutant thyroid hormone receptor-beta ( TR beta(PV/PV) mouse) that spontaneously develops thyroid cancer with metastasis similar to humans has provided new opportunities to study contributors to FTC metastasis. This study evaluates the role of gelsolin, an actin-regulatory protein, in modulating the metastatic potential of FTC. Gelsolin was previously found by cDNA microarray analysis to be down-regulated in TR beta(PV/PV) mice as compared with wild-type mice. This study found an age-dependent reduction of gelsolin protein abundance in TR beta(PV/PV) mice as tumorigenesis progressed. Knockdown of gelsolin by small interfering RNA resulted in increased tumor cell motility and increased gelsolin expression by histone deacetylase inhibitor ( trichostatin A) led to decreased cell motility. Additional biochemical analyses demonstrated that gelsolin physically interacted with TR beta 1 or PV in vivo and in vitro. The interaction regions were mapped to the C terminus of gelsolin and the DNA binding domain of TR. The physical interaction of gelsolin with PV reduced its binding to actin, leading to disarrayed cytoskeletal architectures. These results suggest that PV-induced alteration of the actin/gelsolin cytoskeleton contributes to increased cell motility. Thus, the present study uncovered a novel PV-mediated oncogenic pathway that could contribute to the local tumor progression and metastatic potential of thyroid carcinogenesis. C1 NIDDKD, Mol Biol Lab, Bethesda, MD 20892 USA. NIDDKD, Ctr Canc Res, NCI, Bethesda, MD 20892 USA. NIDDKD, Lab Cellular Biochem & Biol, Bethesda, MD 20892 USA. RP Cheng, SY (reprint author), NIDDKD, Mol Biol Lab, Bethesda, MD 20892 USA. EM chengs@mail.nih.gov FU Intramural NIH HHS NR 27 TC 17 Z9 19 U1 0 U2 3 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD MAR PY 2007 VL 148 IS 3 BP 1306 EP 1312 DI 10.1210/en.2006-0923 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 137FJ UT WOS:000244278100041 PM 17170101 ER PT J AU Wyrobek, AJ Mulvihill, JJ Wassom, JS Malling, HV Shelby, MD Lewis, SE Witt, KL Preston, RJ Perreault, SD Allen, JW DeMarini, DM Woychik, RP Bishop, JB AF Wyrobek, Andrew J. Mulvihill, John J. Wassom, John S. Malling, Heinrich V. Shelby, Michael D. Lewis, Susan E. Witt, Kristine L. Preston, R. Julian Perreault, Sally D. Allen, James W. DeMarini, David M. Woychik, Richard P. Bishop, Jack B. TI Assessing human germ-cell mutagenesis in the postgenome era: A celebration of the legacy of William Lawson (Bill) Russell SO ENVIRONMENTAL AND MOLECULAR MUTAGENESIS LA English DT Review DE inherited disease; mutation detection; molecular genetic analysis; human genetic risk ID EPIGENETIC TRANSGENERATIONAL ACTIONS; MINISATELLITE MUTATION-RATE; CHILDHOOD-CANCER SURVIVORS; SIGNATURE SEQUENCING MPSS; INDUCED SPECIFIC-LOCUS; LONG-TERM SURVIVORS; GENE-TOX PROGRAM; CHROMOSOMAL-ABNORMALITIES; ADOLESCENT CANCER; MEIOTIC RECOMBINATION AB Birth defects, de novo genetic diseases, and chromosomal abnormality syndromes occur in similar to 5% of all live births, and affected children suffer from a broad range of lifelong health consequences. Despite the social and medical impact of these defects, and the 8 decades of research in animal systems that have identified numerous germ-cell mutagens, no human germ-cell mutagen has been confirmed to date. There is now a growing consensus that the inability to detect human germ-cell mutagens is due to technological limitations in the detection of random mutations rather than biological differences between animal and human susceptibility. A multidisciplinary workshop responding to this challenge convened at The Jackson Laboratory in Bar Harbor, Maine. The purpose of the workshop was to assess the applicability of an emerging repertoire of genomic technologies to studies of human germ-cell mutagenesis. Workshop participants recommended large-scale human germ-cell mutation studies be conducted using samples from donors with high-dose exposures, such as cancer survivors. Within this high-risk cohort, parents and children could be evaluated for heritable changes in (a) DNA sequence and chromosomal structure, (b) repeat sequences and minisatellites, and (c) global gene expression profiles and pathways. Participants also advocated the establishment of a bio-bank of human tissue samples from donors with well-characterized exposure, including medical and reproductive histories. This mutational resource could support large-scale, multiple-endpoint studies. Additional studies could involve the examination of transgenerational effects associated with changes in imprinting and methylation patterns, nucleotide repeats, and mitochondrial DNA mutations. The further development of animal models and the integration of these with human studies are necessary to provide molecular insights into the mechanisms of germ-cell mutations and to identify prevention strategies. Furthermore, scientific specialty groups should be convened to review and prioritize the evidence for germ-cell mutagenicity from common environmental, occupational, medical, and lifestyle exposures. Workshop attendees agreed on the need for a full-scale assault to address key fundamental questions in human germ-cell environmental mutagenesis. These include, but are not limited to, the following: Do human germ-cell mutagens exist? What are the risks to future generations? Are some parents at higher risk than others for acquiring and transmitting germ-cell mutations? Obtaining answers to these, and other critical questions, will require strong support from relevant funding agencies, in addition to the engagement of scientists outside the fields of genomics and germ-cell mutagenesis. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Lawrence Berkeley Lab, Berkeley, CA USA. Univ Oklahoma, Hlth Sci Ctr, Oklahoma City, OK USA. YAHSGS LLC, Richland, WA USA. Oak Ridge Natl Lab, Oak Ridge, TN USA. US EPA, Res Triangle Pk, NC 27711 USA. Jackson Lab, Bar Harbor, ME 04609 USA. RP Bishop, JB (reprint author), NIEHS, POB 12233,EC-01, Res Triangle Pk, NC 27709 USA. EM bishop@niehs.nih.gov OI Dubrova, Yuri/0000-0001-5281-7539; Marchetti, Francesco/0000-0002-9435-4867 FU Intramural NIH HHS [Z99 ES999999]; NCI NIH HHS [R01 CA104666, R01 CA104666-03]; NICHD NIH HHS [R13 HD040151, R01 HD040151, R13 HD048151, R13 HD048151-01] NR 105 TC 35 Z9 35 U1 2 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0893-6692 J9 ENVIRON MOL MUTAGEN JI Environ. Mol. Mutagen. PD MAR PY 2007 VL 48 IS 2 BP 71 EP 95 DI 10.1002/em.20284 PG 25 WC Environmental Sciences; Genetics & Heredity; Toxicology SC Environmental Sciences & Ecology; Genetics & Heredity; Toxicology GA 142MF UT WOS:000244653300001 PM 17295306 ER PT J AU Hu, H Shih, R Rothenberg, S Schwartz, BS AF Hu, Howard Shih, Regina Rothenberg, Stephen Schwartz, Brian S. TI The epidemiology of lead toxicity in adults: Measuring dose and consideration of other methodologic issues SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Review DE biomarkers; epidemiologic methods; epidemiology; lead; toxicity ID X-RAY-FLUORESCENCE; NEUROBEHAVIORAL TEST-SCORES; BLOOD LEAD; BONE LEAD; RENAL-FUNCTION; COGNITIVE FUNCTION; ELDERLY MEN; TIBIA LEAD; CUMULATIVE EXPOSURE; INORGANIC LEAD AB We review several issues of broad relevance to the interpretation of epidemiologic evidence concerning the toxicity of lead in adults, particularly regarding cognitive function and the cardiovascular system, which are the subjects of two systematic reviews that are also part of this mini-monograph. Chief among the recent developments in methodologic advances has been the refinement of concepts and methods for measuring individual lead dose in terms of appreciating distinctions between recent versus cumulative doses and the use of biological markers to measure these parameters in epidemiologic studies of chronic disease. Attention is focused particularly on bone lead levels measured by K-shell X-ray fluorescence as a relatively new biological marker of cumulative dose that has been used in many recent epidemiologic studies to generate insights into lead's impact on cognition and risk of hypertension, as well as the alternative method of estimating cumulative dose using available repeated measures of blood lead to calculate an individual's cumulative blood lead index. We review the relevance and interpretation of these lead biomarkers in the context of the toxicokinetics of lead. In addition, we also discuss methodologic challenges that arise in studies of occupationally and environmentally exposed subjects and those concerning race/ethnicity and socioeconomic status and other important covariates. C1 Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Channing Lab, Boston, MA 02115 USA. Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Rockville, MD USA. IPN, Ctr Invest & Estudios Avanzados, Dept Ecol Humana, Unidad Merida, Merida, Yucatan, Mexico. Inst Nacl Salud Publ, Ctr Invest Salud Poblac, Cuernavaca, Morelos, Mexico. Johns Hopkins Sch Med, Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci & Epidemiol, Baltimore, MD USA. Johns Hopkins Sch Med, Dept Med, Baltimore, MD USA. RP Hu, H (reprint author), Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Rm 1518 Vaughan Bldg,SPH-1,109 S Observ St, Ann Arbor, MI 48109 USA. EM howardhu@umich.edu RI Rothenberg, Stephen/A-1313-2008; Rothenberg, Stephen/A-2147-2009 FU Intramural NIH HHS; NIA NIH HHS [R01 AG010785, R01 AG019604, R01-AG10785, R01-AG19604]; NIEHS NIH HHS [R01 ES005257, P30 ES000002, P30-ES00002, P42 ES005947, P42-ES05947, R01 ES007821, R01 ES010798, R01-ES05257, R01-ES07821, R01-ES10798] NR 109 TC 115 Z9 117 U1 4 U2 16 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD MAR PY 2007 VL 115 IS 3 BP 455 EP 462 DI 10.1289/ehp.9783 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 142LN UT WOS:000244651500042 PM 17431499 ER PT J AU Shih, RA Hu, H Weisskopf, MG Schwartz, BS AF Shih, Regina A. Hu, Howard Weisskopf, Marc G. Schwartz, Brian S. TI Cumulative lead dose and cognitive function in adults: A review of studies that measured both blood lead and bone lead SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE adults; blood; bone; cognitive function; lead; neurobehavior ID NEUROBEHAVIORAL TEST-PERFORMANCE; ALZHEIMERS-DISEASE; INORGANIC LEAD; OLDER-ADULTS; YOUNG-ADULTS; RISK-FACTORS; LONGITUDINAL DECLINE; HOMOCYSTEINE LEVELS; CHELATABLE LEAD; AGE-DIFFERENCES AB OBJECTIVE: We review empirical evidence for the relations of recent and cumulative lead dose with cog,nitive function in adults. DATA SOURCES: A systematic search of electronic databases resulted in 21 environmental and occupational studies from 1996 to 2006 that examined and compared associations of recent (in blood) and cumulative (in bone) lead doses with neurobehavioral outcomes. DATA EXTRACTION: Data were abstracted after consideration of exclusion criteria and quality assessment, and then compiled into summary tables. CONCLUSIONS: At exposure levels encountered after environmental exposure, associations with biomarkers of cumulative dose (mainly lead in tibia) were stronger and more consistent than associations with blood lead levels. Similarly, in studies of former workers with past occupational lead exposure, associations were also stronger and more consistent with cumulative dose than with recent dose (in blood). In contrast, studies of currently exposed workers generally found associations that were more apparent with blood lead levels; we speculate that the acute effects of high, recent dose may mask the chronic effects of cumulative dose. There is moderate evidence for an association between psychiatric symptoms and lead dose but only at high levels of current occupational lead exposure or with cumulative dose in environmentally exposed adults. C1 Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, Baltimore, MD 21205 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Rockville, MD USA. Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Channing Lab, Boston, MA 02115 USA. Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. RP Schwartz, BS (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Environm Hlth Sci, 615 N Wolfe St,Rm W7041, Baltimore, MD 21205 USA. EM bschwart@jhsph.edu FU Intramural NIH HHS; NIA NIH HHS [R01 AG010785, R01 AG019604, R01-AG10785, R01-AG19604]; NIEHS NIH HHS [K01 ES012653, K01 ES012653-05, K01-ES012653, P30 ES000002, P30-ES00002, P42 ES005947, P42-ES05947, R01 ES005257, R01 ES005257-15, R01 ES007198, R01 ES010798, R01-ES05257, R01-ES07198, R01-ES10798] NR 86 TC 101 Z9 105 U1 1 U2 13 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD MAR PY 2007 VL 115 IS 3 BP 483 EP 492 DI 10.1289/ehp.9786 PG 10 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 142LN UT WOS:000244651500045 PM 17431502 ER PT J AU Portier, CJ Suk, WA Schwartz, DA AF Portier, Christopher J. Suk, William A. Schwartz, David A. TI Filling the translation-policy gap SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 NIEHS, Res Triangle Pk, NC 27709 USA. EM david.schwartz@niehs.nih.gov RI Portier, Christopher/A-3160-2010 OI Portier, Christopher/0000-0002-0954-0279 NR 0 TC 0 Z9 0 U1 0 U2 0 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD MAR PY 2007 VL 115 IS 3 BP A125 EP A125 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 142LN UT WOS:000244651500002 ER PT J AU Kan, HD London, SJ Chen, HL Song, GX Chen, GH Jiang, LL Zhao, NQ Zhang, YH Chen, BH AF Kan, Haidong London, Stephanie J. Chen, Honglei Song, Guixiang Chen, Guohai Jiang, Lili Zhao, Naiqing Zhang, Yunhui Chen, Bingheng TI Diurnal temperature range and daily mortality in Shanghai, China SO ENVIRONMENTAL RESEARCH LA English DT Article DE climate change; diurnal temperature range; air pollution; mortality; time-series ID TIME-SERIES; AIR-POLLUTION; US CITIES; CARDIOVASCULAR DEATHS; UNITED-STATES; WEATHER; HEALTH; ASSOCIATION; CLIMATE AB Although the relationship between temperature level and mortality outcomes has been well established, it is still unknown whether within-day variation in temperature, e.g. diurnal temperature range (DTR), is a risk factor for death independent of the corresponding temperature. Moreover, DTR is a meteorological indicator associated with global climate change which may be related to a variety of health outcomes. We hypothesized that large diurnal temperature change might be a source of additional environmental stress and therefore a risk factor for death. We used daily weather and mortality data from Shanghai, China to test this hypothesis. We conducted a time-series study to examine the association between DTR and mortality outcomes from 2001 to 2004. A semi-parametric generalized additive model (GAM) was used to assess the acute effect of DTR on mortality after controlling for covariates including time trend, day of the week (DOW), temperature, humidity, and outdoor air pollution. We found a strong association between DTR and daily mortality after adjustment for those potential confounders. A 1 degrees C increment of the 3-day moving average of DTR corresponded to a 1.37% (95% Cl 1.08-1.65%) increase in total non-accidental mortality, a 1.86% (95% CI 1.40-2.32%) increase in cardiovascular mortality, and a 1.29% (95% Cl 0.49-2.09%) increase in respiratory mortality. The effects of DTR on total non-accidental and cardiovascular mortality were significant on both "cold" (below 23 degrees C) and "warm" (at least 23 degrees C) days, although respiratory mortality was only significantly associated with DTR on "cold" days. This study suggests within-day variation in temperature may be a novel risk factor for death. (c) 2006 Elsevier Inc. All rights reserved. C1 Fudan Univ, Sch Publ Hlth, Dept Environm Hlth, Shanghai 200032, Peoples R China. NIEHS, Dept Hlth & Human Serv, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. Shanghai Municipal Ctr Dis Control & Prevent, Shanghai 200336, Peoples R China. Shanghai Environm Monitoring Ctr, Shanghai 200030, Peoples R China. Fudan Univ, Dept Hlth Sci, Shanghai 200032, Peoples R China. RP Kan, HD (reprint author), NIEHS, Dept Hlth & Human Serv, Epidemiol Branch, NIH, POB 12233,Mail Drop A3-05, Res Triangle Pk, NC 27709 USA. EM kanh@niehs.nih.gov OI Chen, Honglei/0000-0003-3446-7779; London, Stephanie/0000-0003-4911-5290 FU Intramural NIH HHS NR 27 TC 71 Z9 80 U1 2 U2 18 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0013-9351 J9 ENVIRON RES JI Environ. Res. PD MAR PY 2007 VL 103 IS 3 BP 424 EP 431 DI 10.1016/j.envres.2006.11.009 PG 8 WC Environmental Sciences; Public, Environmental & Occupational Health SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health GA 145ZB UT WOS:000244903200018 PM 17234178 ER PT J AU Yin, XB Sun, LG Zhu, RB Liu, XD Ruan, DY Wang, YH AF Yin, Xuebin Sun, Liguang Zhu, Renbin Liu, Xiaodong Ruan, Diyun Wang, Yuhong TI Mercury-selenium association in antarctic seal hairs and animal excrements over the past 1,500 years SO ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY LA English DT Article DE Se-Hg association; Antarctica; seal hair; penguin excrement; lake sediment ID KING-GEORGE-ISLAND; INORGANIC MERCURY; PENGUIN DROPPINGS; MARINE MAMMALS; FOOD-WEB; METHYLMERCURY; DETOXIFICATION; SEDIMENTS; EXPOSURE; SEABIRDS AB Strong positive correlations between selenium (Se) and total mercury (Hg-T) contents in the liver of marine mammals and mercury mine workers in modern times have been documented in numerous investigations. Herein, we report a positive correlation between Se and HgT concentrations over the past 1,500 years in the seal hairs and in the lake sediments amended by seal or penguin excrements on King George Island (63 degrees 23'S, 57 degrees 00'W), West Antarctica. Because the changes in the input of Se and Hg into the marine environments of the studied sites do not seem to be synchronous, this striking correlation indicates a self-protection mechanism in Antarctic seals and penguins: Every time there is heavier Hg burden, more Se is accumulated to reduce the toxicity of Hg. This positive correlation between Hg and Se contents in the seal hairs and excrement sediments, however, becomes insignificant in the recent 50 years for unknown reasons. C1 Univ Sci & Technol China, Inst Polar Environm, Hefei 230026, Anhui, Peoples R China. Chinese Acad Sci, Nanjing Inst Soil Sci, State Key Lab Soil & Sustainable Agr, Soil & Environm Bioremediat Res Ctr, Nanjing 210008, Peoples R China. Univ Sci & Technol China, Sch Earth & Space Sci, Chinese Acad Sci, Key Lab Crust Mantle Mat & Environm, Anhua 230026, Peoples R China. Univ Sci & Technol China, Sch Life Sci, Hefei 230027, Anhui, Peoples R China. NIH, Bethesda, MD 20892 USA. RP Sun, LG (reprint author), Univ Sci & Technol China, Inst Polar Environm, Hefei 230026, Anhui, Peoples R China. EM slg@ustc.edu.cn NR 40 TC 10 Z9 12 U1 1 U2 16 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0730-7268 EI 1552-8618 J9 ENVIRON TOXICOL CHEM JI Environ. Toxicol. Chem. PD MAR PY 2007 VL 26 IS 3 BP 381 EP 386 DI 10.1897/06-128.1 PG 6 WC Environmental Sciences; Toxicology SC Environmental Sciences & Ecology; Toxicology GA 136RK UT WOS:000244241600001 PM 17373500 ER PT J AU Basso, O AF Basso, Olga TI Right or wrong? On the difficult relationship between epidemiologists and handedness SO EPIDEMIOLOGY LA English DT Editorial Material ID LANGUAGE LATERALIZATION; BREAST-CANCER; ASSOCIATION; ULTRASOUND; HANDERS; AUTISM; RISK AB The declining prevalence of left-handers with age has resulted in the hypothesis that sinistrality, being the result of a developmental insult, may be associated with a reduced life span. While it is plausible that some individuals become left-handed as a consequence of neurologic impairment, the literature on handedness itself appears to suffer from a number of problems. These include the ease with which information on handedness can be collected in the absence of prior hypotheses, the failure to address heterogeneity among left-handers, and the selective publication of positive results. Even if individual contributions, including one published in this issue of EPIDEMIOLOGY, are of reasonable quality, all the above problems conspire to lower the credibility of this area of research. C1 NIEHS, Epidemiol Branch, NIH, HHS, Res Triangle Pk, NC 27709 USA. RP Basso, O (reprint author), NIEHS, Epidemiol Branch, NIH, HHS, POB 12233,111 TW Alexander Dr,MD A3-05, Res Triangle Pk, NC 27709 USA. EM bassoo2@niehs.nih.gov RI Basso, Olga/E-5384-2010 OI Basso, Olga/0000-0001-9298-4921 FU Intramural NIH HHS NR 21 TC 13 Z9 13 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD MAR PY 2007 VL 18 IS 2 BP 191 EP 193 DI 10.1097/01.ede.0000254698.17800.e8 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 139HD UT WOS:000244422000002 PM 17301704 ER PT J AU MacLehose, RF Dunson, DB Herring, AH Hoppin, JA AF MacLehose, Richard F. Dunson, David B. Herring, Amy H. Hoppin, Jane A. TI Bayesian methods for highly correlated exposure data SO EPIDEMIOLOGY LA English DT Article ID EMPIRICAL-BAYES; HIERARCHICAL REGRESSION; CYTOKINE POLYMORPHISMS; EPIDEMIOLOGIC ANALYSES; NONORTHOGONAL PROBLEMS; AGRICULTURAL HEALTH; MULTIPLE EXPOSURES; MODEL UNCERTAINTY; RIDGE REGRESSION; INFERENCE AB Studies that include individuals with multiple highly correlated exposures are common in epidemiology. Because standard maximum likelihood techniques often fail to converge in such instances, hierarchical regression methods have seen increasing use. Bayesian hierarchical regression places prior distributions on exposure-specific regression coefficients to stabilize estimation and incorporate prior knowledge, if available. A common parametric approach in epidemiology is to treat the prior mean and variance as fixed constants. An alternative parametric approach is to place distributions on the prior mean and variance to allow the data to help inform their values. As a more flexible semiparametric option, one can place an unknown distribution on the coefficients that simultaneously clusters exposures into groups using a Dirichlet process prior. We also present a semiparametric model with a variableselection prior to allow clustering of coefficients at 0. We compare these 4 hierarchical regression methods and demonstrate their application in an example estimating the association of herbicides with retinal degeneration among wives of pesticide applicators. C1 Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. NIEHS, Biostat Branch, NIH, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. Univ N Carolina, Carolina Populat Ctr, Chapel Hill, NC USA. NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP MacLehose, RF (reprint author), POB 12233,MD A3-03, Res Triangle Pk, NC 27709 USA. EM maclehoser@niehs.nih.gov FU Intramural NIH HHS; NICHD NIH HHS [R03HD045780] NR 33 TC 46 Z9 46 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1044-3983 J9 EPIDEMIOLOGY JI Epidemiology PD MAR PY 2007 VL 18 IS 2 BP 199 EP 207 DI 10.1097/01.ede.0000256320.30737.c0 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 139HD UT WOS:000244422000005 PM 17272963 ER PT J AU Bodnar, LM Catov, JM Klebanoff, MA Ness, RB Roberts, JM AF Bodnar, Lisa M. Catov, Janet M. Klebanoff, Mark A. Ness, Roberta B. Roberts, James M. TI Prepregnancy body mass index and the occurrence of severe hypertensive disorders of pregnancy SO EPIDEMIOLOGY LA English DT Article ID RISK-FACTORS; UNITED-STATES; GESTATIONAL HYPERTENSION; SEVERE PREECLAMPSIA; PERINATAL OUTCOMES; NULLIPAROUS WOMEN; AFRICAN-AMERICAN; BLOOD-PRESSURE; DOSE-RESPONSE; US ADULTS AB Background: Prepregnancy overweight is a risk factor for mild preeclampsia and mild transient hypertension of pregnancy. Its association with severe subtypes of these disorders has received less attention. Methods: To assess the association of prepregnancy body mass index (BMI) with severe and mild preeclampsia and transient hypertension of pregnancy, we used data from a 1958-1964 prospective cohort study of 38,188 pregnant women receiving care at 12 U.S. hospitals. Results: There was a monotonic, dose-response relation between prepregnancy BMI and risk of both severe and mild preeclampsia, as well as the risk of severe and mild transient hypertension of pregnancy. Compared with white women with a BMI of 20, the odds ratios for severe preeclampsia at BMI values of 25 and 30 in white women were 1.7 (95% confidence interval = 1.1-2.5) and 3.4 (2.1-5.6), respectively, and 2.1 (1.4-3.2) and 3.2 (2.1-5.0) in black women. The effect of BMI on risk of severe preeclampsia was similar to its effect on mild disease. Compared with the same referent, odds ratios for severe transient hypertension of pregnancy at BMI values of 25 and 30 in white women were 3.6 (2.0-6.5) and 8.8 (4.4-18), respectively, and 3.0 (1.6-5.8) and 4.9 (2.5-9.6) in black women. Overweight was a stronger risk factor for severe than for mild transient hypertension. Conclusions: Incidence of both mild and severe hypertensive disorders of pregnancy rises with increasing BMI. Escalating obesity rates may increase pregnancy hypertensive disorders and ensuing perinatal morbidity. C1 Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Sch Med, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. Magee Womens Res Inst, Pittsburgh, PA USA. NICHHD, Epidemiol Branch, NIH, Bethesda, MD 20892 USA. RP Bodnar, LM (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, A742 Crabtree Hall,130 DeSoto St, Pittsburgh, PA 15261 USA. EM bodnar@edc.pitt.edu FU Intramural NIH HHS; NIMH NIH HHS [K01 MH074092] NR 43 TC 112 Z9 122 U1 1 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 1044-3983 EI 1531-5487 J9 EPIDEMIOLOGY JI Epidemiology PD MAR PY 2007 VL 18 IS 2 BP 234 EP 239 DI 10.1097/01.ede.0000254119.99600.e7 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 139HD UT WOS:000244422000010 PM 17237733 ER PT J AU Bagic, A Boudreau, EA Greenfield, J Sato, S AF Bagic, Anto Boudreau, Eilis A. Greenfield, Jacquelyn Sato, Susumu TI Electro-clinical evolution of refractory non-convulsive status epilepticus caused by West Nile virus encephalitis SO EPILEPTIC DISORDERS LA English DT Article DE West Nile virus (WNV); seizure; status epilepticus; encephalitis; arbovirus; chronic lymphocytic leukemia; nonconvulsive status epilepticus ID PROPOFOL INFUSION SYNDROME; ST-LOUIS ENCEPHALITIS; INFECTION; EPIDEMIC; CHILDREN; EEG; PATHOPHYSIOLOGY; PATHOGENESIS; ACIDOSIS; OUTBREAK AB West Nile virus (WNV) has re-emerged with a much wider geographic distribution and a higher incidence than ever. In spite of some recent reports on the neurological manifestations and EEG changes caused by WNV encephalitis, there are few data on the incidence of seizures, status epilepticus or post-encephalitic epilepsy. There is also no systematic review of EEG changes caused by WNV encephalitis that is based on a large series of patients. Here, we review the pertinent literature, and report the electroclinical evolution and therapeutic complexity of a patient with WNV encephalitis who developed refractory, non-convulsive status epilepticus. C1 NINDS, EEG Stn, NIH, Bethesda, MD 20892 USA. Portland VA Med Ctr, HSRDP, Portland, OR USA. RP Bagic, A (reprint author), Univ Pittsburgh, Sch Med, Dept Neurol, Suite 811,Kaufmann Med Bldg,3471 5th Ave, Pittsburgh, PA 15213 USA. EM bagica@upmc.edu NR 33 TC 7 Z9 7 U1 1 U2 1 PU JOHN LIBBEY EUROTEXT LTD PI MONTROUGE PA 127 AVE DE LA REPUBLIQUE, 92120 MONTROUGE, FRANCE SN 1294-9361 J9 EPILEPTIC DISORD JI Epileptic Disord. PD MAR PY 2007 VL 9 IS 1 BP 98 EP 103 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 145IG UT WOS:000244857900015 PM 17307720 ER PT J AU Armstrong, A Maddox, YT AF Armstrong, Alicia Maddox, Yvonne T. TI Health disparities and women's reproductive health SO ETHNICITY & DISEASE LA English DT Article; Proceedings Paper CT 6th Annual Primary Care and Prevention Conference/11th Annual HeLa Womens Health Conference CY SEP 11-13, 2006 CL Atlanta, GA DE health disparities; women's reproductive health; leiomyoma; birth outcomes; infant mortality; sudden infant death syndrome (SIDS); leiomyomata uteri ID UTERINE LEIOMYOMAS; OUTCOMES; TECHNOLOGY; RACE AB The National Institute of Child Health and Human Development (NICHD) is the institute within the National Institutes of Health that has played a great role in the conduct and support of research in women's reproductive health. In this position, the NICHD is advancing the health and well-being of women and girls in many areas, including research on uterine fibroids, birth outcomes, and community interventions that can improve health. This paper provides a general overview of the NICHD-sponsored women's reproductive health research portfolio, with emphasis on the challenges associated with eliminating racial/ethnic disparities in leiomyomata uteri and infant mortality. In addition, opportunities for community partnerships in reducing health disparities are described. C1 NICHHD, NIH, Bethesda, MD 20892 USA. RP Maddox, YT (reprint author), NICHHD, NIH, 31 Ctr Dr,MSC 2425, Bethesda, MD 20892 USA. EM Maddoxy16x@nih.gov NR 18 TC 0 Z9 0 U1 0 U2 2 PU INT SOC HYPERTENSION BLACKS-ISHIB PI ATLANTA PA 100 AUBURN AVE NE STE 401, ATLANTA, GA 30303-2527 USA SN 1049-510X J9 ETHNIC DIS JI Ethn. Dis. PD SPR PY 2007 VL 17 IS 2 BP S4 EP S7 PG 4 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 189SV UT WOS:000248009700034 ER PT J AU Vailbracht, S Jessen, B Mrusek, S Collins, PL Krempl, C Ehl, S AF Vailbracht, Simone Jessen, Birthe Mrusek, Sonja Collins, Peter L. Krempl, Christine Ehl, Stephan TI A single viral epitope determines T cell response and strain-specific disease susceptibility after RSV infection in the mouse SO EUROPEAN JOURNAL OF PEDIATRICS LA English DT Meeting Abstract C1 Univ Freiburg, Zentrum Kinderheilkunde & Jugendmed, D-7800 Freiburg, Germany. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Freiburg, Abt Virol, Inst Med Mikrobiol & Hyg, D-7800 Freiburg, Germany. 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 0340-6199 J9 EUR J PEDIATR JI Eur. J. Pediatr. PD MAR PY 2007 VL 166 IS 3 BP 288 EP 288 PG 1 WC Pediatrics SC Pediatrics GA 142JH UT WOS:000244645100061 ER PT J AU Maron, E Yuan, P Toru, I Vasar, V Neumeister, A Shlik, J Manji, H AF Maron, E. Yuan, P. Toru, I. Vasar, V. Neumeister, A. Shlik, J. Manji, H. TI Associations between plasma BDNF and CCK-4 challenge in healthy subjects SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT ECNP Workshop on Neuropsychopharmacology for Young Scientists in Europe CY MAR 08-11, 2007 CL Nice, FRANCE SP European Coll Neuropsychopharmacol ID NEUROTROPHIC FACTOR; EXPRESSION C1 Univ Tartu, Dept Psychiat, EE-50090 Tartu, Estonia. NIMH, Mood & Anxiety Disorders Progams, Bethesda, MD 20892 USA. NR 4 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD MAR PY 2007 VL 17 SU 1 BP S8 EP S9 DI 10.1016/S0924-977X(07)70009-3 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 151HF UT WOS:000245280400010 ER PT J AU Swedo, S AF Swedo, S. TI Challenges and achievements in childhood neuropsychopharmacology SO EUROPEAN NEUROPSYCHOPHARMACOLOGY LA English DT Meeting Abstract CT ECNP Workshop on Neuropsychopharmacology for Young Scientists in Europe CY MAR 08-11, 2007 CL Nice, FRANCE SP European Coll Neuropsychopharmacol C1 NIMH, Pediat & Dev Neuropsychiat Branch, Bethesda, MD 20892 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0924-977X J9 EUR NEUROPSYCHOPHARM JI Eur. Neuropsychopharmacol. PD MAR PY 2007 VL 17 SU 1 BP S89 EP S90 DI 10.1016/S0924-977X(07)70104-9 PG 2 WC Clinical Neurology; Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 151HF UT WOS:000245280400105 ER PT J AU Zalsman, G Huang, YY Oquendo, MA Burke, AK Hu, X Brent, DA Ellis, SP Goldman, D Mann, JJ AF Zalsman, G. Huang, Y. Y. Oquendo, M. A. Burke, A. K. Hu, X. Brent, D. A. Ellis, S. P. Goldman, D. Mann, J. J. TI A triallelic serotonin transporter gene, life events and depression SO EUROPEAN PSYCHIATRY LA English DT Meeting Abstract C1 Geha Mental Hlth Ctr, Petah Tiqwa, Israel. Columbia Univ, New York, NY USA. NIH, NIMH, Bethesda, MD 20892 USA. Univ Pittsburgh, Pittsburgh, PA USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0924-9338 J9 EUR PSYCHIAT JI Eur. Psychiat. PD MAR PY 2007 VL 22 SU 1 BP S25 EP S26 DI 10.1016/j.eurpsy.2007.01.101 PG 2 WC Psychiatry SC Psychiatry GA 153YC UT WOS:000245473000092 ER PT J AU Mullerad, M Issaq, H Kravtsov, A Waybright, T Luke, B Veenstra, T Issaq, E Nativ, O AF Mullerad, M. Issaq, H. Kravtsov, A. Waybright, T. Luke, B. Veenstra, T. Issaq, E. Nativ, O. TI Detection of bladder cancer by metabolomic profiling of urine samples using high performance liquid chromatography coupled with mass spectrometry SO EUROPEAN UROLOGY SUPPLEMENTS LA English DT Meeting Abstract C1 Bnai Zion Med Ctr, Haifa, Israel. NCI, Lab Prot & Analytical Technol, Res Technol Program, Frederick, MD 21701 USA. NCI, SAIC Inc, Adv Biomed Comp Ctr, Frederick, MD 21701 USA. NR 0 TC 0 Z9 0 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1569-9056 J9 EUR UROL SUPPL JI Eur. Urol. Suppl. PD MAR PY 2007 VL 6 IS 2 BP 117 EP 117 DI 10.1016/S1569-9056(07)60379-0 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 139HJ UT WOS:000244422600381 ER PT J AU Cullen, I Foley, R Woodson, K Fitzpatrick, J Lynch, T Watson, W Lawler, M AF Cullen, I. Foley, R. Woodson, K. Fitzpatrick, J. Lynch, T. Watson, W. Lawler, M. CA Prostate Cancer Res Consortium TI The C1772T single nucleotide polymorphism in the HIF-1A alpha gene is over-represented in the primary prostate cancer population SO EUROPEAN UROLOGY SUPPLEMENTS LA English DT Meeting Abstract C1 Inst Mol Med, Prostate Res Grp, Dublin, Ireland. NCI, Bethesda, MD 20892 USA. Univ Coll Dublin, Dublin 2, Ireland. St James Hosp, Dublin 8, Ireland. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1569-9056 J9 EUR UROL SUPPL JI Eur. Urol. Suppl. PD MAR PY 2007 VL 6 IS 2 BP 190 EP 190 DI 10.1016/S1569-9056(07)60665-4 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 139HJ UT WOS:000244422600667 ER PT J AU Perrv, A Loftus, B Moroose, R Lynch, T Hollywood, D Watson, RWG Woodson, K Lawler, M AF Perrv, A. Loftus, B. Moroose, R. Lynch, T. Hollywood, D. Watson, R. W. G. Woodson, K. Lawler, M. TI Promoter hypermethylation of IGFBP3 is an early event in prostate carcinogenesis SO EUROPEAN UROLOGY SUPPLEMENTS LA English DT Meeting Abstract C1 Trinity Coll Dublin, Dept Haematol, Acad Unit Clin & Mol Oncol, Dublin, Ireland. Adelaide & Meath Inc, Natl Childrens Hosp, Dublin, Ireland. Florida Hosp Canc Ctr, Orlando, FL USA. St James Hosp, Dublin 8, Ireland. Univ Coll Dublin, Dublin 2, Ireland. Natl Canc Inst, Bethesda, MD USA. 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 1569-9056 J9 EUR UROL SUPPL JI Eur. Urol. Suppl. PD MAR PY 2007 VL 6 IS 2 BP 191 EP 191 DI 10.1016/S1569-9056(07)60670-8 PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 139HJ UT WOS:000244422600673 ER PT J AU Passeron, T Coelho, SG Miyamura, Y Takahashi, K Hearing, VJ AF Passeron, Thierry Coelho, Sergio G. Miyamura, Yoshinori Takahashi, Kaoruko Hearing, Vincent J. TI Immunohistochemistry and in situ hybridization in the study of human skin melanocytes SO EXPERIMENTAL DERMATOLOGY LA English DT Review DE immunohistochemistry; melanocytes; tissue in situ hybridization ID MESENCHYMAL-EPITHELIAL INTERACTIONS; CUTANEOUS MALIGNANT-MELANOMA; ANTIGEN RETRIEVAL TECHNIQUES; OUTER ROOT SHEATH; MESSENGER-RNA; HUMAN HAIR; EXPRESSION; TYROSINASE; GROWTH; LOCALIZATION AB Although keratinocytes are the most numerous type of cell in the skin, melanocytes are also key players as they produce and distribute melanin that protects the skin from ultraviolet (UV) radiation. In vitro experiments on melanocytic cell lines are useful to study melanogenesis and their progression towards melanoma. However, interactions of melanocytes with keratinocytes and with other types of cells in the skin, such as fibroblasts and Langerhans cells, are also crucial. We describe two techniques, immunohistochemistry (IHC) and tissue in situ hybridization (TISH), that can be used to identify and study melanocytes in the skin and their responses to UV or other stimuli in situ. We describe a practical method to localize melanocytic antigens on formalin-fixed, paraffin-embedded tissue sections and in frozen sections using indirect immunofluorescence with conjugated secondary antibodies. In addition, we detail the use of TISH and its combination with IHC to study mRNA levels of genes expressed in the skin at cellular resolution. This methodology, along with relevant tips and troubleshooting items, are important tools to identify and study melanocytes in the skin. Although keratinocytes are the most numerous type of cell in the skin, melanocytes are also key players as they produce and distribute melanin that protects the skin from ultraviolet (UV) radiation. In vitro experiments on melanocytic cell lines are useful to study melanogenesis and their progression towards melanoma. However, interactions of melanocytes with keratinocytes and with other types of cells in the skin, such as fibroblasts and Langerhans cells, are also crucial. We describe two techniques, immunohistochemistry (IHC) and tissue in situ hybridization (TISH), that can be used to identify and study melanocytes in the skin and their responses to UV or other stimuli in situ. We describe a practical method to localize melanocytic antigens on formalin-fixed, paraffin-embedded tissue sections and in frozen sections using indirect immunofluorescence with conjugated secondary antibodies. In addition, we detail the use of TISH and its combination with IHC to study mRNA levels of genes expressed in the skin at cellular resolution. This methodology, along with relevant tips and troubleshooting items, are important tools to identify and study melanocytes in the skin. C1 NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Hearing, VJ (reprint author), NCI, Pigment Cell Biol Sect, Cell Biol Lab, NIH, Bldg 37,Room 2132,MSC 4256, Bethesda, MD 20892 USA. EM hearingv@nih.gov OI Passeron, Thierry/0000-0002-0797-6570 FU Intramural NIH HHS NR 46 TC 10 Z9 10 U1 1 U2 7 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0906-6705 J9 EXP DERMATOL JI Exp. Dermatol. PD MAR PY 2007 VL 16 IS 3 BP 162 EP 170 DI 10.1111/j.1600-0625.2006.00538.x PG 9 WC Dermatology SC Dermatology GA 134BC UT WOS:000244056600002 PM 17286807 ER PT J AU Aufenvenne, K Oji, V Walker, T Ahvazi, B Hennies, H Traupe, H AF Aufenvenne, K. Oji, V. Walker, T. Ahvazi, B. Hennies, H. Traupe, H. TI TGM1 mutations in bathing suit ichthyosis: a functional understanding SO EXPERIMENTAL DERMATOLOGY LA English DT Meeting Abstract CT 34th Annual Meeting of the Arbeitsgemeinschaft-Dermatologische-Forschung CY MAR 08, 2004-MAR 10, 2007 CL Freiburg, GERMANY SP Arbeitsgermeinsch Dermatolog Forschung C1 Univ Munster, Dept Dermatol, D-4400 Munster, Germany. NIH, Off Sci Technol, Bethesda, MD 20892 USA. Univ Cologne, Ctr Genom, Div Dermatogenet, Cologne, Germany. 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 0906-6705 J9 EXP DERMATOL JI Exp. Dermatol. PD MAR PY 2007 VL 16 IS 3 BP 206 EP 206 PG 1 WC Dermatology SC Dermatology GA 134BC UT WOS:000244056600046 ER PT J AU Dinges, S Lopez-Kostka, S Knop, J Iwakura, Y Udey, MC von Stebut, E AF Dinges, S. Lopez-Kostka, S. Knop, J. Iwakura, Y. Udey, M. C. von Stebut, E. TI Progressive disease in L-major-infected IL-1 receptor antagonist (RA) deficient mice SO EXPERIMENTAL DERMATOLOGY LA English DT Meeting Abstract CT 34th Annual Meeting of the Arbeitsgemeinschaft-Dermatologische-Forschung CY MAR 08, 2004-MAR 10, 2007 CL Freiburg, GERMANY SP Arbeitsgermeinsch Dermatolog Forschung C1 Univ Mainz, Dermatol Klin, D-6500 Mainz, Germany. Univ Tokyo, Ctr Med Expt, Tokyo, Japan. NIH, Natl Canc Inst, Dermatol Branch, Bethesda, MD 20892 USA. RI Iwakura, Yoichiro/E-5457-2011 OI Iwakura, Yoichiro/0000-0002-9934-5775 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 0906-6705 J9 EXP DERMATOL JI Exp. Dermatol. PD MAR PY 2007 VL 16 IS 3 BP 236 EP 236 PG 1 WC Dermatology SC Dermatology GA 134BC UT WOS:000244056600140 ER PT J AU Hugel, R Schwarz, A Tuxen, N Velasco, P Lange-Asschenfeldt, B Schwarz, T AF Huegel, R. Schwarz, A. Tuxen, N. Velasco, P. Lange-Asschenfeldt, B. Schwarz, T. TI Ultraviolet-B irradiation induces vascular hyperpermeability in the skin of SKH1 mice SO EXPERIMENTAL DERMATOLOGY LA English DT Meeting Abstract CT 34th Annual Meeting of the Arbeitsgemeinschaft-Dermatologische-Forschung CY MAR 08, 2004-MAR 10, 2007 CL Freiburg, GERMANY SP Arbeitsgermeinsch Dermatolog Forschung C1 Univ Hosp Schleswig Holstein, Dept Dermatol, Kiel, 20892, Germany. NCI, Natl Inst Hlth, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0906-6705 J9 EXP DERMATOL JI Exp. Dermatol. PD MAR PY 2007 VL 16 IS 3 BP 248 EP 248 PG 1 WC Dermatology SC Dermatology GA 134BC UT WOS:000244056600177 ER PT J AU Gaffal, E Landsberg, J Kohlmeyer, J Tormo, D Wenzel, J Merlino, G Tuting, T AF Gaffal, E. Landsberg, J. Kohlmeyer, J. Tormo, D. Wenzel, J. Merlino, G. Tueting, T. TI Mutant CDK4 increases the penetrance and decreases the latency of UV-induced, pigmented, metastasizing melanoma in the skin of C57BL/6 HGF mice SO EXPERIMENTAL DERMATOLOGY LA English DT Meeting Abstract CT 34th Annual Meeting of the Arbeitsgemeinschaft-Dermatologische-Forschung CY MAR 08, 2004-MAR 10, 2007 CL Freiburg, GERMANY SP Arbeitsgermeinsch Dermatolog Forschung C1 Univ Bonn, Dept Dermatol, Lab Expt Dermatol, D-5300 Bonn, Germany. Natl Canc Inst, Lab Cell Regulat & Carcinogenesis, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0906-6705 J9 EXP DERMATOL JI Exp. Dermatol. PD MAR PY 2007 VL 16 IS 3 BP 262 EP 262 PG 1 WC Dermatology SC Dermatology GA 134BC UT WOS:000244056600220 ER EF