FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Zhang, ZJ McCaffery, JM Spencer, RGS Francomano, CA AF Zhang, ZJ McCaffery, JM Spencer, RGS Francomano, CA TI Growth and integration of neocartilage with native cartilage in vitro SO JOURNAL OF ORTHOPAEDIC RESEARCH LA English DT Article DE cartilage; chondrocytes; integration; apoptosis ID ARTICULAR-CARTILAGE; CHONDROCYTE APOPTOSIS; HYALINE CARTILAGE; REPAIR; DEFECTS; CULTURE; PROTEOGLYCANS; OSTEOARTHRITIS; EXPRESSION; ADHESION AB Poor integration of neocartilage with recipient has been a major obstacle to articular cartilage restoration. An in vitro study was designed to provide insights regarding the integration process. Cartilage explants and chondrocytes were harvested from the distal sternum of 16-day-old chick embryos. Four million chondrocytes and one 1 mm(3) explant were centrifuged together in a 0.75 ml tube. In the constructs, consisting of cartilage explant and chondrocyte pellet, isolated chondrocytes attached to the surface of the explant at the beginning of the Culture, followed by significant chondrocyte death at the interface between chondrocyte pellet and explant. Chondrocyte apoptosis was seen almost exclusively at this interface. Meanwhile, the interface was a zone with active extracellular matrix deposition as demonstrated by immunohistochemistry. By two weeks, the junction of neocartilage and native cartilage explant had formed an acellular zone with collagen fibrils orientated parallel with the surface of the cartilage explant. In conclusion, chondrocyte death leads to acellularity and fibril network reorganization at the neocartilage/explant interface, and impacts the quality of cartilage repair as abnormal matrix remodeling implies. (c) 2004 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved. C1 NIA, Intramural Res Program, NIH, Genet Lab, Baltimore, MD 21224 USA. Johns Hopkins Univ, Integrated Imaging Ctr, Baltimore, MD USA. NIA, Intramural Res Program, INIH, Baltimore, MD 21224 USA. RP Zhang, ZJ (reprint author), NIA, Intramural Res Program, NIH, Genet Lab, 333 Cassell Dr,Suite 3000, Baltimore, MD 21224 USA. EM zhangzj@grc.nia.nih.gov NR 28 TC 26 Z9 31 U1 1 U2 4 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0736-0266 J9 J ORTHOP RES JI J. Orthop. Res. PD MAR PY 2005 VL 23 IS 2 BP 433 EP 439 DI 10.1016/j.orthres.2004.08.028 PG 7 WC Orthopedics SC Orthopedics GA 905KN UT WOS:000227567100029 PM 15734259 ER PT J AU Lee, A Davies, AJ Clear, A Calaminici, M Matthews, J Norton, A Wright, G Staudt, MLM Fitzgibbon, J Lister, TA Goff, LK AF Lee, A Davies, AJ Clear, A Calaminici, M Matthews, J Norton, A Wright, G Staudt, MLM Fitzgibbon, J Lister, TA Goff, LK TI Tissue microarray is a useful tool in the evaluation of genes implicated in transformation of follicular lymphoma SO JOURNAL OF PATHOLOGY LA English DT Meeting Abstract CT 187th Meeting of the Pathological-Society-of-Great-Britain-and-Ireland CY JAN 06-07, 2005 CL London, ENGLAND SP Patholog Soc Great Britain Ireland C1 St Bartholomews Hosp, Dept Histopathol, London, England. St Bartholomews Hosp, Dept Med Oncol, London, England. NCI, Lymphoid Malignancies Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0022-3417 J9 J PATHOL JI J. Pathol. PD MAR PY 2005 VL 205 SU S BP 11 EP 11 PG 1 WC Oncology; Pathology SC Oncology; Pathology GA 906AX UT WOS:000227614000043 ER PT J AU McCrae, RR Terracciano, A AF McCrae, RR Terracciano, A CA Personal Profiles Cultures Project TI Universal features of personality traits from the observer's perspective: Data from 50 cultures SO JOURNAL OF PERSONALITY AND SOCIAL PSYCHOLOGY LA English DT Article; Proceedings Paper CT 2nd World Congress on Womens Mental Health CY MAR 17-20, 2004 CL Washington, DC ID SEX-DIFFERENCES; AGE-DIFFERENCES; LIFE-SPAN; PSYCHOLOGY; DIMENSIONS; TESTS AB To test hypotheses about the universality of personality traits, college students in 50 cultures identified an adult or college-aged man or woman whom they knew well and rated the 11,985 targets using the 3rd-person version of the Revised NEO Personality Inventory. Factor analyses within cultures showed that the normative American self-report structure was clearly replicated in most cultures and was recognizable in all. Sex differences replicated earlier self-report results, with the most pronounced differences in Western cultures. Cross-sectional age differences for 3 factors followed the pattern identified in self-reports, with moderate rates of change during college age and slower changes after age 40. With a few exceptions, these data support the hypothesis that features of personality traits are common to all human groups. C1 NIA, Gerontol Res Ctr, NIH, US Dept HHS, Baltimore, MD 21224 USA. RP McCrae, RR (reprint author), NIA, Gerontol Res Ctr, NIH, US Dept HHS, Box 3,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mccraej@grc.nia.nih.gov RI terracciano, antonio/B-1884-2008; De Fruyt, Filip/A-3083-2009; Rossier, Jerome/A-3494-2009; Allik, Juri/D-5609-2009; Sanchez-Bernardos, Maria Luisa/C-6038-2011; Avia, Maria Dolores/C-7061-2011; Henrich, Joseph/A-2403-2009; Realo, Anu/M-9524-2016 OI Rossier, Jerome/0000-0002-9924-3672; Allik, Juri/0000-0002-8358-4747; Sanchez-Bernardos, Maria Luisa/0000-0003-4931-867X; FU Intramural NIH HHS [Z99 AG999999] NR 52 TC 410 Z9 422 U1 4 U2 74 PU AMER PSYCHOLOGICAL ASSOC/EDUCATIONAL PUBLISHING FOUNDATION PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-3514 J9 J PERS SOC PSYCHOL JI J. Pers. Soc. Psychol. PD MAR PY 2005 VL 88 IS 3 BP 547 EP 561 DI 10.1037/0022-3514.88.3.547 PG 15 WC Psychology, Social SC Psychology GA 901VO UT WOS:000227310400009 PM 15740445 ER PT J AU Le Foll, B Goldberg, SR AF Le Foll, B Goldberg, SR TI Cannabinoid CB1 receptor antagonists as promising new medications for drug dependence SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Review ID DOPAMINE D-3 RECEPTOR; CONDITIONED PLACE PREFERENCE; NUCLEUS-ACCUMBENS DOPAMINE; COCAINE-SEEKING BEHAVIOR; FREELY-MOVING RATS; 2ND-ORDER SCHEDULES; KNOCKOUT MICE; SQUIRREL-MONKEYS; DELTA(9)-TETRAHYDROCANNABINOL THC; ENDOCANNABINOID SYSTEM AB This review examines the development of cannabinoid CB1 receptor antagonists as a new class of therapeutic agents for drug addiction. Abused drugs [ alcohol, opiates, Delta(9)-tetrahydrocannabinol (Delta(9)-THC), and psychostimulants, including nicotine] elicit a variety of chronically relapsing disorders by interacting with endogenous neural pathways in the brain. In particular, they share the common property of activating mesolimbic dopamine brain reward systems, and virtually all abused drugs elevate dopamine levels in the nucleus accumbens. Cannabinoid CB1 receptors are expressed in this brain reward circuit and modulate the dopamine-releasing effects of Delta(9)-THC and nicotine. Rimonabant (SR141716), a CB1 receptor antagonist, blocks both the dopamine-releasing and discriminative and rewarding effects of Delta(9)-THC in animals. Blockade of CB1 receptor activity by genetic invalidation also decreases rewarding effects of opiates and alcohol in animals. Although CB1 receptor blockade is generally ineffective in reducing the self-administration of cocaine in rodents and primates, it reduces the reinstatement of extinguished cocaine-seeking behavior produced by cocaine-associated conditioned stimuli and cocaine-priming injections. Likewise, CB1 receptor blockade is effective in reducing nicotine-seeking behavior induced by re-exposure to nicotine-associated stimuli. Some of these findings have been recently validated in humans. In clinical trials, Rimonabant blocks the subjective effects of Delta(9)-THC in humans and prevents relapse to smoking in exsmokers. Findings from both clinical and preclinical studies suggest that ligands blocking CB1 receptors offer a novel approach for patients suffering from drug dependence that may be efficacious across different classes of abused drugs. C1 NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, NIH,Dept HHS, Baltimore, MD 21224 USA. RP Le Foll, B (reprint author), NIDA, Preclin Pharmacol Sect, Behav Neurosci Res Branch, NIH,Dept HHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM blefoll@intra.nida.nih.gov RI Le Foll, Bernard/K-2952-2014 OI Le Foll, Bernard/0000-0002-6406-4973 NR 116 TC 177 Z9 183 U1 1 U2 8 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAR PY 2005 VL 312 IS 3 BP 875 EP 883 DI 10.1124/jpet.104.077974 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 897MR UT WOS:000227008800001 PM 15525797 ER PT J AU Jutkiewicz, EM Walker, NP Folk, JE Rice, KC Portoghese, PS Woods, JH Traynor, JR AF Jutkiewicz, EM Walker, NP Folk, JE Rice, KC Portoghese, PS Woods, JH Traynor, JR TI Comparison of peptidic and nonpeptidic delta-opioid agonists on guanosine 5 '-O-(3-[S-35]thio)triphosphate ([S-35]GTP gamma S) binding in brain slices from Sprague-Dawley rats SO JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS LA English DT Article ID RECEPTOR KNOCKOUT MICE; G-PROTEIN ACTIVATION; RHESUS-MONKEYS; SQUIRREL-MONKEYS; MU; BW373U86; EFFICACY; ANTINOCICEPTION; AUTORADIOGRAPHY; ANTAGONISTS AB Previous studies have demonstrated that peptidic and nonpeptidic delta-opioid receptor agonists have different effects depending on the measure. For example, nonpeptidic delta-opioid agonists, but not peptidic agonists, produce convulsions in rats, and in vitro studies suggested that peptidic and nonpeptidic delta-opioid agonists might have differential mechanisms of receptor downregulation. The present study evaluated potential differences between peptidic and nonpeptidic delta-opioid agonists in their ability to activate G proteins using guanosine 5'-O-(3-[S-35] thio) triphosphate ([S-35] GTPgammaS) autoradiography experiments in rat brain slices. The peptidic agonist [D-Pen(2), D-Pen(5)]-enkephalin and the nonpeptidic agonist (+) BW373U86 [(+)-4-[alpha(R)-alpha- [(2S, 5R)-2,5-dimethyl- 4-(2-propenyl)-1-piperazinyl]-(3-hydroxyphenyl) methyl]-N, N-diethylbenzamide] demonstrated concentration-dependent increases in [S-35] GTPgammaS binding that were attenuated by the delta-opioid antagonist naltrindole. (+) BW373U86 was more potent and efficacious than the peptidic agonist, and this difference remained consistent across brain regions where significant stimulation was observed. In addition, multiple delta-opioid compounds were evaluated for their agonist activity in this assay. These data suggested that differences between peptidic and nonpeptidic delta-opioid agonists in behavioral studies were most likely caused by differences in agonist efficacy. Finally, these data also revealed that [S-35] GTPgammaS autoradiography could be used to compare efficacy differences among agonists across various brain regions in rat brain slices. C1 Univ Michigan, Sch Med, Dept Pharmacol, Ann Arbor, MI 48109 USA. NIDDKD, Med Chem Lab, NIH, Bethesda, MD 20892 USA. Univ Minnesota, Coll Pharm, Dept Med Chem, Minneapolis, MN 55455 USA. RP Traynor, JR (reprint author), Univ Michigan, Sch Med, Dept Pharmacol, 1301 Med Sci Res Bldg 3, Ann Arbor, MI 48109 USA. EM jtraynor@umich.edu FU NIDA NIH HHS [T32 DA007267, T32 DA07267, DA00254, P01 DA000254, P50 DA000254, K21 DA000254]; NIGMS NIH HHS [T32 GM07767, T32 GM007767] NR 39 TC 15 Z9 15 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0022-3565 J9 J PHARMACOL EXP THER JI J. Pharmacol. Exp. Ther. PD MAR PY 2005 VL 312 IS 3 BP 1314 EP 1320 DI 10.1124/jpet.104.078741 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 897MR UT WOS:000227008800052 PM 15574687 ER PT J AU Xu, M Geer, LY Bryant, SH Roth, JS Kowalak, JA Maynard, DM Markey, SP AF Xu, M Geer, LY Bryant, SH Roth, JS Kowalak, JA Maynard, DM Markey, SP TI Assessing data quality of peptide mass spectra obtained by quadrupole ion trap mass spectrometry SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE shotgun proteomics; mass spectral quality; pepticle sequence; CID; quadrupole ion trap mass spectrometry ID PROTEIN IDENTIFICATION; SEQUENCE DATABASES; SEARCH; MODEL; SYSTEM AB An algorithm is introduced to assess spectral quality for peptide CID spectra acquired by a quadrupole ion trap mass spectrometer. The method employs a quadratic discriminant function calibrated with manually classified 'bad' and 'good' quality spectra, producing a single 'spectral quality' score. Many spectra examined that do not have significant matches are assessed to have good spectral quality, indicating that advances in search methods may yield substantial improvements in results. C1 NIH, NCBI, Natl Lib Med, Bethesda, MD 20894 USA. NIMH, NIH, Bethesda, MD 20892 USA. RP Geer, LY (reprint author), NIH, NCBI, Natl Lib Med, 38a-5S512, Bethesda, MD 20894 USA. EM lewisg@mail.nih.gov RI Geer, Lewis/H-2714-2014 NR 17 TC 29 Z9 32 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD MAR-APR PY 2005 VL 4 IS 2 BP 300 EP 305 DI 10.1021/pr049844y PG 6 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 916YE UT WOS:000228421900011 PM 15822904 ER PT J AU DeGiorgis, JA Jaffe, H Moreira, JE Carlotti, CG Leite, JP Pant, HC Dosemeci, A AF DeGiorgis, JA Jaffe, H Moreira, JE Carlotti, CG Leite, JP Pant, HC Dosemeci, A TI Phosphoproteomic analysis of synaptosomes from human cerebral cortex SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE LC-MS/MS; IMAC; mass spectrometry; protein phosphorylation; phosphoproteomics; synaptosome; synaptic; synataxin; SNIP; GABA-B ID TANDEM MASS-SPECTROMETRY; CASEIN KINASE-II; PROTEIN-KINASE; SYNAPSIN-I; TYROSINE PHOSPHORYLATION; STIMULATE PHOSPHORYLATION; SYNAPTIC PLASTICITY; IDENTIFICATION; SITES; CELLS AB Protein phosphorylation is a crucial post-translational modification mechanism in the regulation of synaptic organization and function. Here, we analyzed synaptosome fractions from human cerebral cortex obtained during therapeutic surgery. To minimize changes in the phosphorylation state of proteins, the tissue was homogenized within two minutes of excision. Synaptosomal proteins were digested with trypsin and phosphopeptides were isolated by immobilized metal affinity chromatography and analyzed by liquid chromatography and tandem mass spectrometry. The method allowed the detection of residues on synaptic proteins that were presumably phosphorylated in the intact cell, including synapsin 1, syntaxin 1, and SNIP, PSD-93, NCAM, GABA-B receptor, chaperone molecules, and protein kinases. Some of the residues identified are the same or homologous to sites that had been previously described to be phosphorylated in mammals whereas others appear to be novel sites which, to our knowledge, have not been reported previously. The study shows that new phosphoproteomic strategies can be used to analyze subcellular fractions from small amounts of tissue for the identification of phosphorylated residues for research and potentially for diagnostic purposes. C1 NINDS, Neurobiol Lab, NIH, Bethesda, MD 20892 USA. NINDS, Prot & Peptide Sequencing Facil, NIH, Bethesda, MD 20892 USA. Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Cellular & Mol Biol, BR-14049 Ribeirao Preto, SP, Brazil. Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Surg, Div Neurosurg, Ribeirao Preto, SP, Brazil. Univ Sao Paulo, Ribeirao Preto Sch Med, Dept Neurol, Ribeirao Preto, SP, Brazil. NINDS, Neurochem Lab, Bethesda, MD 20892 USA. Marine Biol Lab, Woods Hole, MA 02543 USA. RP 9000 Rockville Pike,NIH Bldg 36,2A21, Bethesda, MD 20892 USA. EM dosemeca@mail.nih.gov RI Leite, Joao/B-9070-2012; Carlotti, Carlos/C-1608-2012 OI Leite, Joao/0000-0003-0558-3519; Carlotti, Carlos/0000-0002-7055-0564 NR 41 TC 37 Z9 44 U1 0 U2 2 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 EI 1535-3907 J9 J PROTEOME RES JI J. Proteome Res. PD MAR-APR PY 2005 VL 4 IS 2 BP 306 EP 315 DI 10.1021/pr0498436 PG 10 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 916YE UT WOS:000228421900012 PM 15822905 ER PT J AU Karsan, A Blonder, J Law, J Yaquian, E Lucas, DA Conrads, TP Veenstra, T AF Karsan, A Blonder, J Law, J Yaquian, E Lucas, DA Conrads, TP Veenstra, T TI Proteomic analysis of lipid microdomains from lipopolysaccharide-activated human endothelial cells SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE lipopolysaccharide; endothelium; caveolae; lipid rafts; lipid-rich microdomains; inflammation ID INNATE IMMUNE RECOGNITION; MASS-SPECTROMETRY; RAFTS; MEMBRANE; CAVEOLAE; PROTEIN; CD14; HETEROGENEITY; ENDOTOXIN; REVEALS AB The endothelium plays a critical role in orchestrating the inflammatory response seen during sepsis. Many of the inflammatory effects of Gram-negative sepsis are elicited by lipopolysaccharide (LPS), a glycolipid component of bacterial cell walls. Lipid-rich microdomains have been shown to concentrate components of the LPS signaling system. However, much remains to be learned about which proteins are constituents of lipid microdomains, and how these are regulated following cell activation. Progress in this area would be accelerated by employing global proteomic analyses, but the hydrophobicity of membrane proteins presents an analytical barrier to the effective application of such approaches. Herein, we describe a method to isolate detergent-resistant membranes from endothelial cells, and prepare these samples for proteomic analysis in a way that is compatible with subsequent separations and mass spectrometric (MS) analysis. In the application of these sample preparation and MS analyses, 358 proteins from the lipid-rich microdomains of LPS-activated endothelial cell membranes have been identified of which half are classified as membrane proteins by Gene Ontology. We also demonstrate that the sample preparation method used for solubilization and trypsin digestion of lipid-rich microdomains renders the membrane spanning sequences of transmembrane proteins accessible for endoproteolytic hydrolysis. This analysis sets the analytical foundation for an in-depth probing of LPS signaling in endothelial cells. C1 British Columbia Canc Agcy, Dept Med Biophy & Pathol & Lab Med, Vancouver, BC V5Z 1L3, Canada. Univ British Columbia, Dept Pathol & Lab Med, Vancouver, BC V5Z 1M9, Canada. Natl Canc Inst, Lab Proteom & Analyt Technol, SAIC Frederick Inc, Frederick, MD 21702 USA. RP Karsan, A (reprint author), British Columbia Canc Agcy, Dept Med Biophy & Pathol & Lab Med, Vancouver, BC V5Z 1L3, Canada. EM akarsan@bccrc.ca RI Tang, Macy/B-9798-2014; Karsan, Aly/K-2067-2015 FU NCI NIH HHS [N01-CO-12400] NR 48 TC 29 Z9 33 U1 0 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD MAR-APR PY 2005 VL 4 IS 2 BP 349 EP 357 DI 10.1021/pr049824w PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 916YE UT WOS:000228421900017 PM 15822910 ER PT J AU Blonder, J Hale, ML Chan, KC Yu, LR Lucas, DA Conrads, TP Zhou, M Popoff, MR Issaq, HJ Stiles, BG Veenstra, TD AF Blonder, J Hale, ML Chan, KC Yu, LR Lucas, DA Conrads, TP Zhou, M Popoff, MR Issaq, HJ Stiles, BG Veenstra, TD TI Quantitative profiling of the detergent-resistant membrane proteome of Iota-b toxin induced Vero cells SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE membrane proteins; quantitation; O-18/O-16 labeling; iota-b toxin ID CHROMATOGRAPHY-TANDEM MASS; LIPID RAFTS; BIOLOGICAL-ACTIVITY; PROTEINS; SPECTROMETRY; BINDING; RECEPTOR; CALNEXIN; O-18; IDENTIFICATION AB Enzyme-mediated O-18/O-16 differential labeling of proteome samples often suffers from incomplete exchange of the carboxy-terminus oxygen atoms, resulting in ambiguity in the measurable abundance differences. In this study, an O-18/O-16 labeling strategy was optimized for and applied to the solution-based cornparative analysis of the detergent-resistant membrane proteome (DRMP) of untreated and lota-b (lb)-induced Vero cells. Solubilization and tryptic digestion of the DRMP was conducted in a buffer containing 60% methanol. Unfortunately, the activity of trypsin is attenuated at this methanol concentration hampering the ability to obtain complete oxygen atom turnover. Therefore, the incorporation of the 110 atoms was decoupled from the protein digestion step by carrying out the trypsin-mediated heavy atom incorporation in a buffer containing 20% methanol; a concentration at which trypsin activity is enhanced compared to purely aqueous conditions. After isotopic labeling, the samples were combined, fractionated by strong cation exchange and analyzed by microcapillary reversed-phase liquid chromatography coupled on-line with electrospray ionization tandem mass spectrometry. In total, over 1400 unique peptides, corresponding to almost 600 proteins, were identified and quantitated, including all known caveolar and lipid raft marker proteins. The quantitative profiling of lb-induced DRMP from Vero cells revealed several proteins with altered expression levels suggesting their possible role in lb binding/uptake. C1 NCI, Lab Proteom & Analyt Technol, SAIC Frederick, Frederick, MD 21702 USA. USA, Med Res Inst Infect Dis, Div Toxicol, Dept Immunol & Mol Biol, Frederick, MD 21702 USA. Inst Pasteur, Anaerob Bacteria & Toxins Unit, F-75724 Paris, France. RP Veenstra, TD (reprint author), NCI, Lab Proteom & Analyt Technol, SAIC Frederick, PO Box B, Frederick, MD 21702 USA. EM veenstra@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 48 TC 49 Z9 53 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD MAR-APR PY 2005 VL 4 IS 2 BP 523 EP 531 DI 10.1021/pr049790s PG 9 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 916YE UT WOS:000228421900037 PM 15822930 ER PT J AU Wang, HYJ Taggi, AE Meinwald, J Wise, RA Woods, AS AF Wang, HYJ Taggi, AE Meinwald, J Wise, RA Woods, AS TI Study of the interaction of chlorisondamine and chlorisondamine analogues with an epitope of the alpha-2 neuronal acetylcholine nicotinic receptor subunit SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE ganglionic blockers; chlorisondamine analogues; molecular modeling ID CATION-PI INTERACTIONS; RAT-BRAIN; FOLDING PROBLEM; ADDICTION; MECHANISMS; PARAMETERS; AROMATICS; STACKING; BLOCKADE; GANGLION AB Chlorisondamine (CHL), a neuronal nicotinic ganglionic blocker, when injected in the cerebral ventricle of rats chronically blocks the increase in locomotion and rearing by subcutaneous nicotine injection. The blocking of the ion channel(s) prevents nicotine from exerting its rewarding effects on the CNS. When administered intraperitoneally, a dose 400-500 times the intracerebroventricular one is needed to cross the blood-brain barrier and to generate the same level of nicotine antagonism, resulting in severe side-effects, thus making it unlikely to be used as a therapeutical compound. Three CHL analogues, 2-(indolin-1-yl)-N,N,N-trimethylethanaminium iodide, 2-(1,3-dioxoisoindolin-2-yl)- N,N,N-trimethylethanaminium iodide, and 2-(1H-indole-3-carboxamido)-N,N,N-trimethylethanaminium iodide, were synthesized in the hope of circumventing the parent compound's shortcomings. They all share a modified indole ring, lack the four chlorines CHL carries, and have one tertiary amine and one quaternary amine. The CHL analogues form noncovalent complexes with an epitope of the alpha-2 nicotinic receptor subunit, GEREE(p)TEEEEEEEDEN, previously proposed as the possible site of CHL interaction. Complexes were analyzed using matrix-assisted laser desorption/ionization mass spectrometry for comparison with CHL. Overall, all three analogues showed better affinity than CHL for complex formation with both the nonphosphorylated and phosphorylated epitopes. C1 NIDA, Behav Neurosci Branch, IRP, NIH,DHHS, Baltimore, MD 21224 USA. Cornell Univ, Dept Chem & Biol Chem, Ithaca, NY 14853 USA. RP Woods, AS (reprint author), NIDA, Behav Neurosci Branch, IRP, NIH,DHHS, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM andrew.e.taggi@usa.dupont.com; awoods@intra.nida.nih.gov RI Wise, Roy/A-6465-2012 NR 27 TC 7 Z9 7 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD MAR-APR PY 2005 VL 4 IS 2 BP 532 EP 539 DI 10.1021/pr049786g PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 916YE UT WOS:000228421900038 PM 15822931 ER PT J AU Tempez, A Ugarov, M Egan, T Schultz, JA Novikov, A Della-Negra, S Lebeyec, Y Pautrat, M Caroff, M Smentkowski, VS Wang, HYJ Jackson, SN Woods, AS AF Tempez, A Ugarov, M Egan, T Schultz, JA Novikov, A Della-Negra, S Lebeyec, Y Pautrat, M Caroff, M Smentkowski, VS Wang, HYJ Jackson, SN Woods, AS TI Matrix implanted laser desorption ionization (MILDI) combined with ion mobility-mass spectrometry for bio-surface analysis SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE matrix implanted laser desorption ionization; mass spectrometry; gold; tissue; ion mobility ID GOLD CLUSTERS; MALDI; DESORPTION/IONIZATION; TOF AB The implantation of low velocity massive gold cluster ions allows homogeneous incorporation of a metallic matrix into the near-surface region of rat brain tissues. Subsequent analysis by laser desorption ionization mass spectrometry yields spectra exhibiting molecular ion peaks in the mass range up to 35 kDa similar to those observed by matrix-assisted LDI. Matrix-implanted LDI when combined with ion-mobility preseparation promises to be a useful technique for molecular imaging of biotissues with a laser microprobe. C1 NIDA, IRP, Baltimore, MD 21224 USA. Ionwerks Inc, Houston, TX 77005 USA. Inst Phys Nucl, CNRS, IN2P3, F-91406 Orsay, France. Univ Paris 11, CNRS, Equipe Endotoxines, UMR 8619,IBBMC, F-91405 Orsay, France. Gen Elect, Global Res, New York, NY 12309 USA. RP Woods, AS (reprint author), NIDA, IRP, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM awoods@intra.nida.nih.gov NR 14 TC 30 Z9 31 U1 0 U2 9 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD MAR-APR PY 2005 VL 4 IS 2 BP 540 EP 545 DI 10.1021/pr0497879 PG 6 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 916YE UT WOS:000228421900039 PM 15822932 ER PT J AU Chen, XL Cushman, SW Pannell, LK Hess, S AF Chen, XL Cushman, SW Pannell, LK Hess, S TI Quantitative proteomic analysis of the secretory proteins from rat adipose cells using a 2D liquid chromatography-MS/MS approach SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE comparative proteomics; proteolytic O-18 labeling; secreted proteome; adipose cell; electrospray-ionization mass spectrometry ID DESORPTION/IONIZATION MASS-SPECTROMETRY; IDENTIFICATION TECHNOLOGY; ADIPOCYTE DIFFERENTIATION; 3T3-L1 PREADIPOCYTES; YEAST PROTEOME; INSULIN; O-18; TISSUE; ELECTROSPRAY; ADIPONECTIN AB We have developed two-dimensional liquid chromatography-tandem mass spectrometry (2D-LC-MS/ MS) and O-18 proteolytic labeling strategies to identify and compare levels of secretory proteins with low abundance in the conditioned medium of rat adipose cells without or with insulin stimulation. Culture medium was concentrated and secreted proteins were separated on a RP-HPLC followed by LC-MS/MS analysis. For O-18 proteolytic labeling, O-16- to O-18-exchange in the digested peptides from eight individual fractions was carried out in parallel in H-2 O-16 and H-2 O-18 with immobilized trypsin, and the ratios of isotopically distinct peptides were measured by mass spectrometry. A total of 84 proteins was identified as secreted adipokines. This large number of secretory proteins comprise multiple functional categories. Comparative proteomics of O-18 proteolytic labeling allows the detection of different levels of many secreted proteins as exemplified here by the difference between basal and insulin treatment of adipose cells. Taken together, our proteomic approach is able to identify and quantify the comprehensive secretory proteome of adipose cells. Thus, our data support the endocrine role of adipose cells in pathophysiological states through the secretion of signaling molecules. C1 NIDDK, Bioorgan Chem Lab, Dept Hlth & Human Serv,Diabetes Branch & Proteom, NIH,Expt Diabetes Metab & Nutr Sect, Bethesda, MD 20892 USA. RP Hess, S (reprint author), NIH, Bldg 8,Rm,B2A19, Bethesda, MD 20892 USA. EM Sonja_Hess@nih.gov RI Hess, Sonja/K-4842-2013 OI Hess, Sonja/0000-0002-5904-9816 NR 44 TC 71 Z9 79 U1 0 U2 7 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD MAR-APR PY 2005 VL 4 IS 2 BP 570 EP 577 DI 10.1021/pr049772a PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 916YE UT WOS:000228421900043 PM 15822936 ER PT J AU Hathout, Y Flippin, J Fan, CG Liu, PH Csaky, K AF Hathout, Y Flippin, J Fan, CG Liu, PH Csaky, K TI Metabolic labeling of human primary retinal pigment epithelial cells for accurate comparative proteomics SO JOURNAL OF PROTEOME RESEARCH LA English DT Article DE metabolic labeling; SILAC; human RPE; comparative proteomics; MALDI-TOF-TOF; proliferating cells; resting cells ID BREAST-CANCER CELLS; CODED AFFINITY TAGS; PROTEIN EXPRESSION; MASS-SPECTROMETRY; AMINO-ACIDS; CULTURE SILAC; PHOSPHORYLATION; KINASE; ELECTROPHORESIS; IDENTIFICATION AB Metabolic labeling was evaluated, using both C-13(6)-Arg and C-13(6), N-15(2)-Lys amino acids, for a primary human retinal pigment epithelial cell (hRPE) culture prepared from an autopsy eye of an 81 year old donor. Satisfactory incorporation (> 90%) was achieved with both stable isotope labeled amino acids after four passages (roughly 7 population doublings). The degree of incorporation was found to be efficient with both amino acids as well as in different proteins. The presence of 10% whole serum in the culture medium did not interfere with the incorporation of the exogenous stable isotope labeled amino acids. Metabolic labeling of these human primary retinal pigment epithelial cells was further tested to quantify protein ratios between proliferating and resting cells using a combination of 2-DG and MALDI-TOF-TOF/MS analysis. Using computational data processing and analysis, we obtained accurate protein ratio measurement for every single identified protein (1156 proteins) in the 2-Dg array. Of these 156 proteins, 12 proteins were found significantly increased in dividing versus resting cells by at least a factor of 1.5 while 13 other proteins were found increased in resting versus dividing cells by at least the same fold. Most of these differentially expressed proteins are directly involved in cell proliferation, protein synthesis, and actin-remodeling and differentiation. C1 Childrens Natl Med Ctr, Ctr Genet Med, Washington, DC USA. NEI, NIH, Bethesda, MD 20892 USA. RP Hathout, Y (reprint author), Childrens Natl Med Ctr, Ctr Genet Med, Washington, DC USA. EM yhathout@cnmcresearch.org NR 34 TC 18 Z9 18 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1535-3893 J9 J PROTEOME RES JI J. Proteome Res. PD MAR-APR PY 2005 VL 4 IS 2 BP 620 EP 627 DI 10.1021/pr049749p PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 916YE UT WOS:000228421900050 PM 15822943 ER PT J AU Yabroff, KR Lawrence, WF King, JC Mangan, P Washington, KS Yi, B Kerner, JF Mandelblatt, JS AF Yabroff, KR Lawrence, WF King, JC Mangan, P Washington, KS Yi, B Kerner, JF Mandelblatt, JS TI Geographic disparities in cervical cancer mortality: What are the roles of risk factor prevalence, screening, and use of recommended treatment? SO JOURNAL OF RURAL HEALTH LA English DT Review ID HUMAN-PAPILLOMAVIRUS INFECTION; PREVENTIVE HEALTH-CARE; ABNORMAL PAPANICOLAOU SMEARS; RURAL AMERICAN-INDIANS; CORONARY HEART-DISEASE; UNITED-STATES; FOLLOW-UP; UTERINE CERVIX; NEW-MEXICO; INTRAEPITHELIAL NEOPLASIA AB Context: Despite advances in early detection and prevention of cervical cancer, women living in rural areas, and particularly in Appalachia, the rural South, the Texas/Mexico border, and the central valley of California, have had consistently higher rates of cervical cancer mortality than their counterparts in other areas during the past several decades. Methods: This paper reviews the published literature from 1966 to July 2002 to assess three potential pathways underlying this excess mortality-high human papilloma virus (HPV) prevalence, lack of or infrequent screening and advanced disease at diagnosis, and tinder-use of recommended treatment and shorter survival. Findings: Living in rural areas may impose barriers to cervical cancer control, including lack of transportation and medical care infrastructures. Population characteristics that place women at greater risk for developing and dying from cervical cancer, such as low income, lack of health insurance, and physician availability, are concentrated in rural areas. Published data, however, are insufficient to identify the key reasons for the observed mortality patterns. Conclusions: At this time, given the lack of definitive evidence in the published literature, decisions about priorities in areas with high rates of cervical cancer mortality will depend on knowledge of current levels of screening, incidence, and stage distribution; and service delivery infrastructures, resources, and acceptability of interventions to the target population. C1 NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Georgetown Univ, Canc Control Program, Vincent T Lombardi Canc Res Ctr, Sch Med, Washington, DC 20007 USA. Agcy Healthcare Res & Qual, Ctr Outcomes & Evidence, Rockville, MD USA. SUNY Stony Brook, Stony Brook, NY 11794 USA. RP Yabroff, KR (reprint author), NCI, Div Canc Control & Populat Sci, Execut Pl N,Room 4005,6130 Execut Blvd,MSC 7344, Bethesda, MD 20892 USA. EM yabroffr@mail.nih.gov OI Yabroff, K. Robin/0000-0003-0644-5572 FU NIA NIH HHS [R01-AG15340] NR 123 TC 79 Z9 79 U1 9 U2 21 PU NATL RURAL HEALTH ASSOC PI KANSAS CITY PA ONE WEST ARMOUR BLVD, STE 301, KANSAS CITY, MO 64111 USA SN 0890-765X J9 J RURAL HEALTH JI J. Rural Health PD SPR PY 2005 VL 21 IS 2 BP 149 EP 157 DI 10.1111/j.1748-0361.2005.tb00075.x PG 9 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 966JV UT WOS:000232016900007 PM 15859052 ER PT J AU Fox, SD Roman, JM Cizza, G Veenstra, TD Issaq, HJ AF Fox, SD Roman, JM Cizza, G Veenstra, TD Issaq, HJ TI Quantitative determination of antalarmin, a novel corticotropin-releasing hormone receptor-1 antagonist, in canine plasma by HPLC-MS SO JOURNAL OF SEPARATION SCIENCE LA English DT Article DE HPLC-MS; pharmacokinetics; antalarmin ID RESPONSES; ANXIETY; STRESS AB A simple and rapid method was developed for the quantitation of antalarmin from plasma using high performance liquid chromatography coupled with electrospray ionization mass spectrometry (ESI/MS). Separation of antalarmin from interfering compounds was achieved using reversed phase chromatography on a C-8 micro-column with an isocratic mobile phase comprised of 80% acetonitrile, 20% water, and 5 mM triethylamine. Detection by ESI/MS was accomplished in positive ion mode using single ion monitoring of the protonated molecular ions of antalarmin and its C-13(2)-isotopimer. The area ratio of the integrated peaks of interest in the extracted ion chromatogram was used for quantitation. The lower limit of detection was 1 picogram (pg) and the quantitation showed a linear response up to 4 nanograms loaded on column. To achieve acceptable accuracy at or around the limit of quantitation of 20 pg, a 1/x weighting was applied to the calibration data. Accuracy and precision variation for intra and inter-day validation were below the acceptable limit (15%) for pharmacokinetic studies. C1 NIMH, Clin Neuroendocrinol Branch, Bethesda, MD 20892 USA. NCI, SAIC Frederick Inc, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. RP Issaq, HJ (reprint author), NIDDKD, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. EM issaq@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 7 TC 2 Z9 2 U1 0 U2 1 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA BOSCHSTRASSE 12, D-69469 WEINHEIM, GERMANY SN 1615-9306 J9 J SEP SCI JI J. Sep. Sci. PD MAR PY 2005 VL 28 IS 4 BP 332 EP 336 DI 10.1002/jssc.200400048 PG 5 WC Chemistry, Analytical SC Chemistry GA 907SD UT WOS:000227737300003 PM 15792247 ER PT J AU Zheng, G Gastwirth, JL AF Zheng, G Gastwirth, JL TI Fisher information in randomly sampled sib pairs and extremely discordant sib pairs in genetic analysis for a quantitative trait locus SO JOURNAL OF STATISTICAL PLANNING AND INFERENCE LA English DT Article DE Haseman-Elston; maximum likelihood estimate; pseudo-likelihood; QTL; recombination fraction; selected sib pairs ID MAXIMUM-LIKELIHOOD-ESTIMATION; ASYMPTOTIC-DISTRIBUTION; ORDER-STATISTICS; LINKAGE ANALYSIS; HUMANS AB The conditional mixture likelihood method using the absolute difference of the trait values of a sib pair to estimate genetic parameters underlies commonly used method in linkage analysis. Here, the statistical properties of the model are examined. The marginal model with a pseudo-likelihood function based on a sample of the absolute difference of sib-traits is also studied. Both approaches are compared numerically. When genotyping is much more expensive than screening a quantitative trait. it is known that extremely discordant sib pairs provide more powerful link-age, tests than randomly sampled sib pairs. The Fisher information about genetic parameters contained in extremely discordant sib pairs is calculated using the marginal mixture model. Our results supplement current research showing that extremely discordant sib pairs are powerful for the linkage detection by demonstrating they also contain more information about other genetic parameters. (C) 2004 Elsevier B.V. All rights reserved. C1 NHLBI, Off Biostat Res, Bethesda, MD 20892 USA. George Washington Univ, Dept Stat, Washington, DC 20052 USA. NCI, Biostat Branch, Bethesda, MD 20892 USA. RP Gastwirth, JL (reprint author), NHLBI, Off Biostat Res, 6701 Rockledge Dr,Room 8223 Rockledge 2,MSC 7938, Bethesda, MD 20892 USA. EM zhengg@nhlbi.nih.gov; gastwirj@mail.nih.gov NR 16 TC 3 Z9 3 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-3758 J9 J STAT PLAN INFER JI J. Stat. Plan. Infer. PD MAR 1 PY 2005 VL 130 IS 1-2 BP 299 EP 315 DI 10.1016/j.jspi.2003.08.019 PG 17 WC Statistics & Probability SC Mathematics GA 892IZ UT WOS:000226645200018 ER PT J AU Unser, M Sorzano, COS Thevenaz, P Jonic, S El-Bez, C De Carlo, S Conway, JF Trus, BL AF Unser, M Sorzano, COS Thevenaz, P Jonic, S El-Bez, C De Carlo, S Conway, JF Trus, BL TI Spectral signal-to-noise ratio and resolution assessment of 3D reconstructions SO JOURNAL OF STRUCTURAL BIOLOGY LA English DT Article ID SYMMETRICAL VOLUME ELEMENTS; ELECTRON-MICROSCOPY; 3-DIMENSIONAL RECONSTRUCTION; CRYOELECTRON MICROSCOPY; BIOLOGICAL PARTICLES; CHAPERONIN GROEL; SINGLE PARTICLES; MACROMOLECULES; ORIENTATION; PROTEIN AB Measuring the quality of three-dimensional 3D reconstructed by transmission electron microscopy is still an open problem. In this article, we extend the applicability of the spectral signal-to-noise ratio (SSNR) to the evaluation of 3D volumes reconstructed with any reconstruction algorithm. The basis of the method is to measure the consistency between the data and a corresponding set of reprojections computed for the reconstructed 3D map. The idiosyncrasies of file recosntruction algorithm are taken explicity into account by performing a noise-only reconstruction. This results ill the definition of a 3D SSNR which provides all objective indicator of the quality of the 3D reconstruction. Furthermore, the information to build file SSNR call be Used to produce a volumetric SSNR (VSSNR). Our method overcomes file need to divide the data set in two. It also provides a direct measure of the performance of the reconstruction algorithm itself; this latter information is typically not available with the standard resolution methods which are primarily focused oil reproducibility alone. (C) 2004 Elsevier Inc. All rights reserved. C1 Swiss Fed Inst Technol, Biomed Imaging Grp, CH-1015 Lausanne VD, Switzerland. Univ San Pablo, CEU, Escuela Politecn Super, E-28668 Madrid, Spain. CSIC, Natl Ctr Biotechnol, Biocomputing Unit, Madrid 28047, Spain. Univ Lausanne, Lab Anal Ultrastruct, CH-1015 Lausanne VD, Switzerland. Univ Calif Berkeley, Dept Mol & Cell Biol, Howard Hughes Med Inst, Berkeley, CA 94720 USA. Inst Biol Struct, Lab Microscopie Elect Struct, F-38027 Grenoble 1, France. NIH, DHHS, Ctr Informat Technol, Imaging Sci Lab, Bethesda, MD 20892 USA. RP Sorzano, COS (reprint author), Swiss Fed Inst Technol, Biomed Imaging Grp, CH-1015 Lausanne VD, Switzerland. EM coss@cnb.uam.es RI Unser, Michael/A-1550-2008; S. Sorzano, Carlos Oscar/F-2639-2016; Conway, James/A-2296-2010; OI S. Sorzano, Carlos Oscar/0000-0002-9473-283X; Conway, James/0000-0002-6581-4748; Jonic, Slavica/0000-0001-5112-2743 FU CIT NIH HHS [Z01 CT000090-25]; NHLBI NIH HHS [1R01 HL 67465-01] NR 43 TC 35 Z9 35 U1 0 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1047-8477 J9 J STRUCT BIOL JI J. Struct. Biol. PD MAR PY 2005 VL 149 IS 3 BP 243 EP 255 DI 10.1016/j.jsb.2004.10.011 PG 13 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 902YY UT WOS:000227393800003 PM 15721578 ER PT J AU Magnusson, A Goransson, M Heilig, M AF Magnusson, A Goransson, M Heilig, M TI Unexpectedly high prevalence of alcohol use among pregnant Swedish women: Failed detection by antenatal care and simple tools that improve detection SO JOURNAL OF STUDIES ON ALCOHOL LA English DT Article ID GAMMA-GLUTAMYL-TRANSFERASE; MEAN CELL-VOLUME; CARBOHYDRATE-DEFICIENT TRANSFERRIN; IDENTIFICATION TEST AUDIT; USE DISORDERS; SCREENING INSTRUMENTS; CHILDBEARING AGE; BINGE DRINKING; CONSUMPTION; RISK AB Objective: We examined the use of alcohol during early pregnancy in urban Swedish women, the ability of Swedish antenatal care to identify alcohol-related risk pregnancies and the utility of some potential tools for improving its performance. Method: Women attending regular antenatal care were randomized to regular assessment only (control, n = 156) or intensified screening (intervention, n = 147). In the intervention group, alcohol use was determined using the Timeline Followback (TLFB) interview, alcohol use habits with the Alcohol Use Disorder Inventory Test (AUDIT), and biomarkers for alcohol use were analyzed. Data were typically obtained in pregnancy week 12. Results: In the intervention group as a whole, average absolute alcohol consumption during the first 6 weeks of pregnancy was low but highly variable (mean [SD] = 24.9 [50.5] g/week; 4.8 [6.0] episodes for the entire 6 week period); 22 women (15%) drank at levels exceeding 70 g/week during any 2 or more weeks and/or in a heavy episodic drinking pattern, 60 g/episode, on 2 or more episodes. The AUDIT had a moderate sensitivity (54%) to identify these subjects. Biomarkers identified subjects with somatic illness rather than high alcohol consumption. In the control group, only 4 (3%) were identified as using alcohol, indicating a probable underestimation of alcohol use by regular antenatal screening procedures (p = .0001). Conclusions: An unexpected proportion of pregnant women in urban Sweden consume alcohol at levels likely to produce adverse effects. Regular antenatal care did not identify most of these risk pregnancies. The TLFB identified pregnant women with risk use of alcohol during pregnancy who were only partly identified by analyzing prepregnancy alcohol use patterns with the AUDIT. Elevated laboratory markers likely indicated somatic illness rather than harmful drinking. C1 Karolinska Inst, NEUROTEC, Div Psychiat, S-14186 Huddinge, Sweden. RP Heilig, M (reprint author), NIAAA, Lab Clin & Translat Studies, 10 Ctr Dr,10-1E5330, Bethesda, MD 20892 USA. EM markus.heilig@mail.nih.gov NR 46 TC 13 Z9 13 U1 5 U2 6 PU ALCOHOL RES DOCUMENTATION INC CENT ALCOHOL STUD RUTGERS UNIV PI PISCATAWAY PA C/O DEIRDRE ENGLISH, 607 ALLISON RD, PISCATAWAY, NJ 08854-8001 USA SN 0096-882X J9 J STUD ALCOHOL JI J. Stud. Alcohol PD MAR PY 2005 VL 66 IS 2 BP 157 EP 164 PG 8 WC Substance Abuse; Psychology SC Substance Abuse; Psychology GA 925CC UT WOS:000229028100001 PM 15957666 ER PT J AU Martin, RCG Lan, Q Hughes, K Doll, MA Martini, BD Lissowska, J Zatonski, W Rothman, N Hein, DW AF Martin, RCG Lan, Q Hughes, K Doll, MA Martini, BD Lissowska, J Zatonski, W Rothman, N Hein, DW TI No apparent association between genetic polymorphisms (-102 C > T) and (-9 T > C) in the human manganese superoxide dismutase gene and gastric cancer SO JOURNAL OF SURGICAL RESEARCH LA English DT Article DE manganese superoxide dismutase; gastric cancer; epidemiology ID BREAST-CANCER; MONOCLONAL-ANTIBODY; MNSOD EXPRESSION; STOMACH-CANCER; CELLS; RISK; OVEREXPRESSION; ESOPHAGEAL; CHEMOSENSITIVITY; SUPPRESSION AB Background. Manganese superoxide dismutase (Mn-SOD) plays a critical role in the detoxification of mitochondrial reactive oxygen species, constituting a major cellular defense mechanism against agents that induce oxidative stress. A genetic polymorphism in the mitochondrial targeting sequence of this gene has been associated with increased cancer risk. This one base pair transition (-9 T > C) leads to a Val to Ala amino acid change in the mitochondrial targeting sequence. In addition, the MnSOD promoter contains an activator protein-2 (AP-2) binding site that modifies transcription of MnSOD. Mutations have been identified in the proximal region of the promoter in human tumor cell lines. One of these mutations (-102 C > T) has been shown to change the binding pattern of AP-2, leading to a reduction in transcriptional activity. The aim of our study was to investigate possible associations of the (-9 T > C) and (-102 C > T) polymorphisms with gastric cancer in a population-based case-control study conducted in Warsaw, Poland. Materials and methods. DNA was obtained from a population based case-control study of stomach cancer conducted in Warsaw, Poland, between 1994 and 1996. The MnSOD-9 T > C genotype was determined by PCR-RFLP assay. The MnSOD-102 C > T genotype was determined using a TaqMan allele discrimination assay. Results. The frequency of the -102 C > T polymorphism was 41% (38/91) in gastric cancer cases and 38% (50/130) in the controls (odds ratio [OR] 1.1, 95% confidence interval [CI] 0.6-2.1). The frequency of the -9 T > C polymorphism was 44% (202/464) in cases and 56% (262/464) in controls (OR 1.1; 95% CI 0.9-1.37). The lack of association was observed in both non-smokers (OR 1.5; 95% CI 0.7-2.34) and smokers (OR 1.1; 95% CI 0.7-1.7). Furthermore, the association was not significant when smokers were segregated by extent of smoking history. Conclusion. The association of the manganese superoxide dismutase polymorphisms at -102 C > T and the -9 T > C were not found to be associated with gastric cancer in a Polish case-control study. (c) 2004 Elsevier Inc. All rights reserved. C1 Univ Louisville, Sch Med, James Graham Brown Canc Ctr, Dept Surg, Louisville, KY 40292 USA. Univ Louisville, Sch Med, James Graham Brown Canc Ctr, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. Univ Louisville, Sch Med, James Graham Brown Canc Ctr, Louisville, KY 40292 USA. NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. Ctr Canc, Div Canc Epidemiol & Prevent, Warsaw, Poland. M Slodowska Curie Inst Oncol, Warsaw, Poland. RP Martin, RCG (reprint author), 315 E Broadway,Room 313, Louisville, KY 40202 USA. EM Robert.martin@louisville.edu RI Hein, David/A-9707-2008; OI Lissowska, Jolanta/0000-0003-2695-5799 FU NCI NIH HHS [CA34627, CA97942, R01 CA034627, R01 CA034627-19] NR 30 TC 22 Z9 23 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 0022-4804 J9 J SURG RES JI J. Surg. Res. PD MAR PY 2005 VL 124 IS 1 BP 92 EP 97 DI 10.1016/j.jss.204.09.009 PG 6 WC Surgery SC Surgery GA 906NY UT WOS:000227650100015 PM 15734485 ER PT J AU Dhingra, R Nam, BH Benjamin, EJ Wang, TJ Larson, MG D'Agostino, RB Levy, D Vasan, RS AF Dhingra, R Nam, BH Benjamin, EJ Wang, TJ Larson, MG D'Agostino, RB Levy, D Vasan, RS TI Cross-sectional relations of electrocardiographic QRS duration to left ventricular dimensions - The Framingham Heart Study SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID BUNDLE-BRANCH-BLOCK; HYPERTROPHY; ACTIVATION; ASYNCHRONY; CRITERIA; FAILURE; DISEASE AB OBJECTIVES The goal of this study was to assess the relations of electrocardiographic QRS duration to left ventricular (LV) measurements in individuals without heart failure (HF) or prior myocardial infarction (MI). BACKGROUND Increased electrocardiographic QRS duration ( greater than or equal to 120 ms) is a marker of ventricular dyssynchrony. METHODS We evaluated the relations of maximal electrocardiographic QRS duration to echocardiographic LV dimensions in 4,534 Framingham Heart study participants (mean age 54 years, 57% women) without prior HF or MI. QRS duration was analyzed as a continuous variable and as categories (< 100, 100 to 119, and greater than or equal to 120 ms). RESULTS In linear regression models, LV mass, end-diastolic dimension, and septal and posterior wall thicknesses were positively related to log-QRS duration, whereas fractional shortening (FS) was inversely related (p < 0.001). There was a significant trend for increasing LV mass and dimensions, and decreasing FS across categories of QRS duration (p < 0.001). Left bundle branch block was associated with higher LV mass and lower FS compared with a normal QRS duration (p < 0.001). CONCLUSIONS In our community-based sample of individuals free of HF and MI, increasing electrocardiographic QRS duration was positively related to LV mass and dimensions, and inversely associated with LV FS. Additional investigations are warranted to elucidate the mechanisms underlying the observed associations. (C) 2005 by the American College of Cardiology Foundation. C1 Framingham Heart Dis Epidemiol Study, Framingham, MA 01702 USA. Vet Affairs Boston Healthcare Syst, Boston, MA USA. NHLBI, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Boston Univ, Dept Math, Boston, MA 02215 USA. Boston Univ, Dept Epidemiol & Prevent Med, Sch Med, 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 Larson, Martin/0000-0002-9631-1254; Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [1R01HL67288, 2K24HL04334, K23HL74077, N01-HC-25195] NR 15 TC 47 Z9 51 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0735-1097 J9 J AM COLL CARDIOL JI J. Am. Coll. Cardiol. PD MAR 1 PY 2005 VL 45 IS 5 BP 685 EP 689 DI 10.1016/j.jacc.2004.11.046 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 901FP UT WOS:000227268700007 PM 15734611 ER PT J AU Cannick, GF Horowitz, A Drury, TF Reed, SG Day, TA AF Cannick, GF Horowitz, A Drury, TF Reed, SG Day, TA TI Assessing oral cancer knowledge among dental students in South Carolina SO JOURNAL OF THE AMERICAN DENTAL ASSOCIATION LA English DT Article DE oral cancer; dental students; dental education ID HYGIENISTS KNOWLEDGE; HUMAN-PAPILLOMAVIRUS; PHARYNGEAL CANCER; OPINIONS; DENTISTS; PREVENTION; HEALTH; ASSOCIATION; STATISTICS; RISK AB Background. Because South Carolina has the fourth highest mortality rate for oral cancer among the 50 states, dental students in the state must be knowledgeable about prevention and early detection of the disease. Methods. In 2002, the authors surveyed 163 students using a written questionnaire (response rate, 79.1 percent). The questionnaire included questions about oral cancer risk and nonrisk factors as well as oral cancer diagnostic signs, symptoms and examination procedures. The authors performed univariate and bivariate analyses (alpha <= .025). Results. At least 93 percent of the students replied that tobacco, alcohol and previous oral cancer lesions were risk factors. One hundred six students (65 percent) knew that the most likely site for oral cancer is the ventrolateral border of the tongue. Student differed in their overall knowledge of risk factors (P = .002), nonrisk factors (P < .001) and diagnostic procedures (P < .001). Conclusion. Although students' level of knowledge increased with academic year, educators and policy-makers need to place greater emphasis on oral cancer education and training in dental schools. Practice Implications. Morbidity and mortality are likely to be reduced if dentists know how to prevent and detect oral cancer. C1 Med Univ S Carolina, Coll Dent Med, Dept Biostat Bioinformat & Epidemiol, Charleston, SC USA. Med Univ S Carolina, Coll Dent Med, Dept Publ Hlth, Charleston, SC USA. Med Univ S Carolina, Coll Dent Med, Oral Epidemiol Sect, Charleston, SC USA. Med Univ S Carolina, Coll Med, Dept Otolaryngol Head & Neck Surg, Charleston, SC USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Horowitz, A (reprint author), Natl Inst Dent & Craniofacial Res, NIH, 45 Ctr Dr,Bldg 45,Room 4As 38A, Bethesda, MD 20892 USA. EM Alice.Horowitz@nih.gov NR 34 TC 25 Z9 26 U1 0 U2 0 PU AMER DENTAL ASSN PI CHICAGO PA 211 E CHICAGO AVE, CHICAGO, IL 60611 USA SN 0002-8177 J9 J AM DENT ASSOC JI J. Am. Dent. Assoc. PD MAR PY 2005 VL 136 IS 3 BP 373 EP 378 PG 6 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 907ZN UT WOS:000227756900027 PM 15819353 ER PT J AU Thompson, FE Midthune, D Subar, AF McNeel, T Berrigan, D Kipnis, V AF Thompson, FE Midthune, D Subar, AF McNeel, T Berrigan, D Kipnis, V TI Dietary intake estimates in the National Health Interview Survey, 2000: Methodology, results, and interpretation SO JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION LA English DT Article ID NUTRIENT INTAKE; PHYSICAL-ACTIVITY; FOOD; ADULTS; PATTERNS; TRENDS; NONSMOKERS; BEHAVIOR; SMOKERS; STATES AB Objectives To describe the implementation of the Multifactor Screener in the 2000 National Health Interview Survey (NHIS); to provide intake estimates for fruits and vegetables, fiber, and percentage of energy from fat by various demographic and behavioral characteristics; and to discuss the strengths and weaknesses of the method. Design/Subjects The 2000 NHIS was conducted in 38,632 households in a clustered sample representative of the 48 contiguous states in the United States. The Cancer Control Module was administered to adults (18 years and older) and included 17 dietary intake questions. Analyses After excluding individuals with missing data or unlikely values on the diet questions, we computed individual intake of servings of fruits and vegetables, percentage of energy from fat, and grams of fiber. We estimated median intakes and distributions of intakes using adjusted variance estimates. We present bivariate relationships between diet and demographics and diet and behavioral characteristics in almost 30,000 adults in the United States. Results In general, intakes of these dietary factors were closer to recommendations among well-educated individuals, those engaged in other healthful behaviors, and underweight and normal weight individuals. Latinos had higher intakes of fruits and vegetables (men: 6 servings; women: 4.8 servings) and fiber (men: 23 g; women: 17 g), and generally a lower percentage of energy intake from fat (men: 33.7%; women: 32.1%) than did non-Latino whites (men: 5.4 servings; women: 4.5 servings; men: 19 g; women: 14 g; men: 33.9%; women: 32.0%) and non-Latino blacks (men: 5.4 servings; women: 4.4 servings; men: 19 g; women: 13 g; men: 34.7%; women: 33.5%). The strengths and limitations of the short dietary assessment method are discussed. Conclusions The Multifactor Screener in NHIS, when used in conjunction with external reference data, provides reasonable estimates for three dietary factors and suggests relationships between intakes and other characteristics that are consistent with other data. Thus, these NHIS estimates could provide useful national benchmarks for local surveys using the same instrument. C1 NCI, Risk Factor Monitoring & Methods Brach, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Informat Management Serv Inc, Silver Spring, MD USA. RP Thompson, FE (reprint author), NCI, Risk Factor Monitoring & Methods Brach, Appl Res Program, Div Canc Control & Populat Sci, EPN 4016,6130 Execut Bvld,MSC 7344, Bethesda, MD 20892 USA. EM ThompsoF@mail.NIH.GOV NR 23 TC 55 Z9 57 U1 0 U2 9 PU AMER DIETETIC ASSOC PI CHICAGO PA 216 W JACKSON BLVD #800, CHICAGO, IL 60606-6995 USA SN 0002-8223 J9 J AM DIET ASSOC JI J. Am. Diet. Assoc. PD MAR PY 2005 VL 105 IS 3 BP 352 EP 363 DI 10.1016/j.jada.2004.12.032 PG 12 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 903YU UT WOS:000227462400011 PM 15746822 ER PT J AU Ble, A Volpato, S Zuliani, G Guralnik, JM Bandinelli, S Lauretani, F Bartali, B Maraldi, C Fellin, R Ferrucci, L AF Ble, A Volpato, S Zuliani, G Guralnik, JM Bandinelli, S Lauretani, F Bartali, B Maraldi, C Fellin, R Ferrucci, L TI Executive function correlates with walking speed in older persons: The InCHIANTI study SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE aging; cognitive function; executive function; lower extremity function; walking speed; InCHIANTI ID PHYSICAL PERFORMANCE; ATTENTIONAL DEMANDS; PARKINSONS-DISEASE; TRAIL; WOMEN; DECLINE; RISK AB OBJECTIVES: To study the association between performance on psychological tests of executive function and performance on lower extremity tasks with different attentional demands in a large sample of nondemented, older adults. DESIGN: Cross-sectional study. SETTING: Community-based. PARTICIPANTS: Nine hundred twenty-six persons aged 65 and older, without dementia, stroke, parkinsonism, visual impairment, or current treatment with neuroleptics, enrolled in a large epidemiological study. MEASUREMENTS: Trail Making Test (TMT) parts A and B and two performance-based measures of lower extremity function that require different executive/attentional-demanding skills: walking speed on a 4-m course at usual pace and walking speed on a 7-m obstacle course at fast pace. A difference score (Delta TMT), obtained by subtracting time to perform part A from time to perform part B of the TMT, was used as an indicator of executive function. Based on Delta TMT, subjects were divided into poor performance, intermediate performance, and good performance. RESULTS: After adjustment, no association between Delta TMT and 4-m course usual-pace walking speed was found. Participants with poor Delta TMT and with intermediate Delta TMT performance were more likely to be in the lowest tertile for 7-m obstacle course walking speed. CONCLUSION: In nondemented older persons, executive function is independently associated with tasks of lower extremity function that require high attentional demand. C1 NIA, Longitudinal Studies Sect, Clin Res Branch, NIH, Bethesda, MD 20892 USA. Univ Ferrara, Dept Clin & Expt Med, Sect Internal Med & Geriatr, I-44100 Ferrara, Italy. NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. Italian Natl Inst Res & Care Aging, Lab Clin Epidemiol, Florence, Italy. Cornell Univ, Div Nutr Sci, Ithaca, NY 14853 USA. RP Ferrucci, L (reprint author), NIA, NIH, Harbor Hosp, 3001 S Hanover St, Baltimore, MD 21225 USA. EM ferruccilu@grc.nia.nih.gov RI VOLPATO, STEFANO/H-2977-2014; Lauretani, Fulvio/K-5115-2016 OI VOLPATO, STEFANO/0000-0003-4335-6034; Lauretani, Fulvio/0000-0002-5287-9972 NR 30 TC 173 Z9 177 U1 3 U2 5 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAR PY 2005 VL 53 IS 3 BP 410 EP 415 DI 10.1111/j.1532-5415.2005.53157.x PG 6 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 900BG UT WOS:000227189800007 PM 15743282 ER PT J AU Sayers, SP Guralnik, JM Thombs, LA Fielding, RA AF Sayers, SP Guralnik, JM Thombs, LA Fielding, RA TI Effect of leg muscle contraction velocity on functional performance in older men and women SO JOURNAL OF THE AMERICAN GERIATRICS SOCIETY LA English DT Article DE disability; skeletal muscle strength; contraction velocity; aging; exercise ID LOWER-EXTREMITY FUNCTION; PHYSICAL PERFORMANCE; SKELETAL-MUSCLE; STRENGTH; POWER; DISABILITY; BATTERY; PEOPLE AB OBJECTIVES: To explore the relationship between impairment (skeletal muscle strength and contraction velocity) and function in community-dwelling older adults. DESIGN: Cross-sectional. SETTING: University-based human physiology laboratory. PARTICIPANTS: One hundred one men and women (aged 75-90). MEASUREMENTS: Muscle strength and contraction velocity during bilateral leg press (LP) were calculated during one-repetition maximum (1RM) and 40% 1RM. A short physical performance battery (SPPB) and gait speed (GS) from a 400-m self-paced walk assessed function. Sex differences in LP strength and contraction velocity (at 40% 1RM) were assessed. The relationship between these variables and function was also examined. RESULTS: Lower extremity strength and contraction velocity were significantly associated with GS (P=.02 and P=.005, respectively) and SPPB (P<.001 and P=.009, respectively) in men only. Contraction velocity, but not muscle strength, was significantly associated with GS (P<.001) and SPPB (P=.02) in women. CONCLUSION: Sex differences exist in the relationship between impairment (muscle strength and contraction velocity) and function. Older men and women may employ different strategies to achieve success on different functional tasks. These findings may have important implications for clinicians practicing geriatric rehabilitation. C1 Univ Missouri, Sch Hlth Profess, Dept Phys Therapy, Columbia, MO 65211 USA. Univ Missouri, Social Sci Stat Ctr, Dept Stat, Columbia, MO 65211 USA. Boston Univ, Sargent Coll Hlth & Rehabil Sci, Dept Hlth Sci, Human Physiol Lab, Boston, MA 02215 USA. NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. RP Sayers, SP (reprint author), Univ Missouri, Sch Hlth Profess, Dept Phys Therapy, 114 Lewis Hall, Columbia, MO 65211 USA. EM sayerss@missouri.edu FU NIA NIH HHS [R01-AG18844]; PHS HHS [P50-A11669, 263-MA-202876] NR 22 TC 45 Z9 47 U1 1 U2 5 PU BLACKWELL PUBLISHING INC PI MALDEN PA 350 MAIN ST, MALDEN, MA 02148 USA SN 0002-8614 J9 J AM GERIATR SOC JI J. Am. Geriatr. Soc. PD MAR PY 2005 VL 53 IS 3 BP 467 EP 471 DI 10.1111/j.1532-5415.2005.53166.x PG 5 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 900BG UT WOS:000227189800016 PM 15743291 ER PT J AU McCray, AT AF McCray, AT TI Promoting health literacy SO JOURNAL OF THE AMERICAN MEDICAL INFORMATICS ASSOCIATION LA English DT Review ID PATIENT EDUCATION MATERIALS; WORLD-WIDE-WEB; SPOKEN MEDICAL INSTRUCTIONS; RANDOMIZED CONTROLLED-TRIAL; CARE INFORMATION; READABILITY LEVELS; AFRICAN-AMERICANS; READING-ABILITY; PHYSICIAN COMMUNICATION; PATIENTS UNDERSTAND AB This report reviews some of the extensive literature in health literacy, much of it focused on the intersection of low literacy and the understanding of basic health care information. Several articles describe methods for assessing health literacy as well as methods for assessing the readability of texts, although generally these latter have not been developed with health materials in mind. Other studies have looked more closely at the mismatch between patients' literacy levels and the readability of materials intended for use by those patients. A number of studies have investigated the phenomenon of literacy from the perspective of patients' interactions in the health care setting, the disenfranchisement of some patients because of their low literacy skills, the difficulty some patients have in navigating the health care system, the quality of the communication between doctors and their patients including the cultural overlay of such exchanges, and ultimately the effect of low literacy on health outcomes. Finally, the impact of new information technologies has been studied by a number of investigators. There remain many opportunities for conducting further research to gain a better understanding of the complex interactions between general literacy, health literacy, information technologies, and the existing health care infrastructure. C1 Natl Lib Med, Bethesda, MD 20894 USA. RP McCray, AT (reprint author), Natl Lib Med, Bethesda, MD 20894 USA. EM mccray@nlm.nih.gov NR 202 TC 98 Z9 100 U1 7 U2 27 PU HANLEY & BELFUS INC PI PHILADELPHIA PA 210 S 13TH ST, PHILADELPHIA, PA 19107 USA SN 1067-5027 J9 J AM MED INFORM ASSN JI J. Am. Med. Inf. Assoc. PD MAR-APR PY 2005 VL 12 IS 2 BP 152 EP 163 DI 10.1197/jamia.M1687 PG 12 WC Computer Science, Information Systems; Computer Science, Interdisciplinary Applications; Information Science & Library Science; Medical Informatics SC Computer Science; Information Science & Library Science; Medical Informatics GA 909EC UT WOS:000227842000006 PM 15561782 ER PT J AU Rapp, BA Wheeler, DL AF Rapp, BA Wheeler, DL TI Bioinformatics resources from the national center for biotechnology information: An integrated foundation for discovery SO JOURNAL OF THE AMERICAN SOCIETY FOR INFORMATION SCIENCE AND TECHNOLOGY LA English DT Article ID DATA-BANK; DATABASE AB The National Center for Biotechnology Information (NCBI) provides access to more than 30 publicly available molecular biology resources, offering an effective discovery space through high levels of data integration among large-scale data repositories. The foundation for many services is GenBank(R), a public repository of DNA sequences from more than 133,000 different organisms. GenBank is accessible through the Entrez retrieval system, which integrates data from the major DNA and protein sequence databases, along with resources for taxonomy, genome maps, sequence variation, gene expression, gene function and phenotypes, protein structure and domain information, and the biomedical literature via PubMed(R). Computational tools allow scientists to analyze vast quantities of diverse data. The BLAST(R) sequence similarity programs are instrumental in identifying genes and genetic features. Other tools support mapping disease loci to the genome, identifying new genes, comparing genomes, and relating sequence data to model protein structures. A basic research program in computational molecular biology enhances the database and software tool development initiatives. Future plans include further data integration, enhanced genome annotation and protein classification, additional data types, and links to a wider range of resources. C1 Natl Lib Med, Bethesda, MD 20894 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Rapp, BA (reprint author), Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM RappB@mail.nih.gov; wheeler@ncbi.nlm.nih.gov NR 18 TC 4 Z9 4 U1 1 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1532-2882 J9 J AM SOC INF SCI TEC JI J. Am. Soc. Inf. Sci. Technol. PD MAR PY 2005 VL 56 IS 5 BP 538 EP 550 DI 10.1002/asi.20142 PG 13 WC Computer Science, Information Systems; Information Science & Library Science SC Computer Science; Information Science & Library Science GA 899NF UT WOS:000227150500011 ER PT J AU Bean, CA Corn, M AF Bean, CA Corn, M TI Extramural funding opportunities in bioinformatics from the National Library of Medicine SO JOURNAL OF THE AMERICAN SOCIETY FOR INFORMATION SCIENCE AND TECHNOLOGY LA English DT Article AB National Library of Medicine (NLM) extramural programs in bioinformatics are described in the context of National Institutes of Health (NIH) funding mechanisms and illustrated through a sampling of recently funded grants. The NIH application, evaluation, and funding process is described as used by the NLM. C1 NIH, Natl Ctr Res Resources, Div Biomed Technol & Res Resources, Bethesda, MD 20892 USA. NIH, Div Extramural Programs, Natl Lib Med, Bethesda, MD 20892 USA. RP Bean, CA (reprint author), NIH, Natl Ctr Res Resources, Div Biomed Technol & Res Resources, 6701 Democracy Blvd, Bethesda, MD 20892 USA. EM cabean@mail.nih.gov NR 0 TC 2 Z9 2 U1 1 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1532-2882 J9 J AM SOC INF SCI TEC JI J. Am. Soc. Inf. Sci. Technol. PD MAR PY 2005 VL 56 IS 5 BP 551 EP 556 DI 10.1002/asi.20143 PG 6 WC Computer Science, Information Systems; Information Science & Library Science SC Computer Science; Information Science & Library Science GA 899NF UT WOS:000227150500012 ER PT J AU Midthune, DN Fay, MP Clegg, LX Feuer, EJ AF Midthune, DN Fay, MP Clegg, LX Feuer, EJ TI Modeling reporting delays and reporting corrections in cancer registry data SO JOURNAL OF THE AMERICAN STATISTICAL ASSOCIATION LA English DT Article DE cancer surveillance; delay-adjusted rates; incurred but not reported; random effects; Surveillance, Epidemiology, and End Results program; truncated data ID TRUNCATED DATA; AIDS INCIDENCE; CLAIMS; RATES; SURVEILLANCE; PREDICTION; EVENTS; TRENDS AB The Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute is an authoritative source of cancer incidence statistics in the United States. The SEER program is a consortium of population-based cancer registries from different areas of the country. Each registry is charged with collecting data on all cancers that occur within its geographic area. As with any disease registry, there is a delay between the time that the disease (cancer) is first diagnosed and the time that it is reported to the registry. The SEER program has allowed for reporting delays of up to 19-months before releasing data for public use. Nevertheless, additional cases are discovered after the 19-month delay, and these cases are added in subsequent releases of the data. Further, any errors discovered are corrected in subsequent releases. Such reporting delays and corrections typically lead to underestimation of the cancer incidence rates in recent diagnosis years, making it difficult to monitor trends. In this article we study models that account for reporting delays and corrections in predicting eventual cancer counts for a diagnosis year from the preliminary counts. Previous models of this type have been studied, especially as applied to AIDS registries. We offer several additions to existing models. First, we explicitly model the reporting corrections. Second, we model the delay distribution with very general models, combining aspects of previous nonparametric-like models (i.e., models that have a separate parameter for each delay time) with more parametric models. Third, we allow random reporting-year effects in the model. Practical issues of model selection and how the data are classified are also discussed, particularly how the definition of a reporting correction may change depending on how subpopulations are defined. An example with SEER melanoma data is studied in detail. C1 NCI, Biometry Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. Natl Inst Allergy & Infect Dis, Biostat Res Branch, Bethesda, MD 20892 USA. Natl Canc Inst, Div Canc Control & Populat Sci, Stat Res & Appl Branch, Bethesda, MD 20892 USA. RP Midthune, DN (reprint author), NCI, Biometry Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. EM dm76q@nih.gov RI Fay, Michael/A-2974-2008; OI Fay, Michael P./0000-0002-8643-9625 NR 24 TC 16 Z9 16 U1 0 U2 2 PU AMER STATISTICAL ASSOC PI ALEXANDRIA PA 1429 DUKE ST, ALEXANDRIA, VA 22314 USA SN 0162-1459 J9 J AM STAT ASSOC JI J. Am. Stat. Assoc. PD MAR PY 2005 VL 100 IS 469 BP 61 EP 70 DI 10.1198/016214504000001899 PG 10 WC Statistics & Probability SC Mathematics GA 984NH UT WOS:000233311100007 ER PT J AU Doi, AM Irwin, RD Bucher, JR AF Doi, AM Irwin, RD Bucher, JR TI Influence of functional group substitutions on the carcinogenicity of anthraquinone in rats and mice: Analysis of long-term bioassays by the National Cancer Institute and the National Toxicology Program SO JOURNAL OF TOXICOLOGY AND ENVIRONMENTAL HEALTH-PART B-CRITICAL REVIEWS LA English DT Review ID URINARY-BLADDER; FREE-RADICALS; DNA-BINDING; METABOLISM; INDUCTION; NEOPLASMS; SULFOTRANSFERASE; DERIVATIVES; CHRYSAZIN; TUMORS AB The carcinogenic activities of anthraquinone and six derivatives were compared and contrasted. Studies included representatives of amino, alkyl, nitro, hydroxy, or halogen-containing anthraquinones, with the purpose of uncovering general structure-activity relationships. Anthraquinone, 2-aminoanthraquinone, 1-amino-2-methylanthraquinone, 2-methyl-1-nitroanthraquinone, 1-amino-2,4-dibromoanthraquinone, 1, 4,5,8-tetraaminoanthraquinone, and 1,3,8-trihydroxy-6-methylanthraquinone (of varying purities) were administered via feed to Fischer 344/N rats and B6C3F(1) mice. In rats, anthraquinone induced tumors in the liver, kidney, and urinary bladder. A 2-amino substitution narrowed the carcinogenicity to the liver, while multiple amino substitutions led to a carcinogenic response in the urinary bladder alone. A methyl substitution ortho to a I-amino group preserved the hepatic and renal neoplasms seen with the parent anthraquinone, but did not induce urinary bladder tumors; amino or bromo substitutions para to a 1-amino group were related to urinary bladder neoplasms. The intestine may have been a target organ for bromine-substituted anthraquinones. The presence of a nitro group altered the targets of carcinogenicity, and skin tumors may have been associated with this particular functional group in both rats and mice. Overall for mice, the findings were somewhat different and limited by the small number of common target organs. The parent anthraquinone was clearly carcinogenic only to the liver. There were no other effects of single amino substitutions, in the presence or absence of an additional methyl group, on the carcinogenicity or the site of carcinogenesis of anthraquinone in mice. Multiple amino substitutions diminished, while bromine substitutions enhanced the carcinogenicity induced by anthraquinone and extended the target organs to include forestomach and lung. C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Doi, AM (reprint author), NIEHS, POB 12233,MD EC-34, Res Triangle Pk, NC 27709 USA. EM doi@niehs.nih.gov NR 54 TC 13 Z9 13 U1 0 U2 2 PU TAYLOR & FRANCIS INC PI PHILADELPHIA PA 325 CHESTNUT ST, SUITE 800, PHILADELPHIA, PA 19106 USA SN 1093-7404 J9 J TOXICOL ENV HEAL B JI J. Toxicol. Env. Health-Pt b-Crit. Rev. PD MAR-APR PY 2005 VL 8 IS 2 BP 109 EP 126 DI 10.1080/10937400590909077 PG 18 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 903PQ UT WOS:000227438500003 PM 15804751 ER PT J AU Colfax, G Coates, TJ Husnik, MJ Huang, YJ Buchbinder, S Koblin, B Chesney, M Vittinghoff, E AF Colfax, G Coates, TJ Husnik, MJ Huang, YJ Buchbinder, S Koblin, B Chesney, M Vittinghoff, E CA EXPLORE Study Team TI Longitudinal patterns of methamphetamine, popper (Amyl nitrite), and cocaine use and high-risk sexual behavior among a cohort of San Francisco men who have sex with men SO JOURNAL OF URBAN HEALTH-BULLETIN OF THE NEW YORK ACADEMY OF MEDICINE LA English DT Article; Proceedings Paper CT Workshop on New Dynamics of HIV Risk Among Drug-Using Men Who Have Sex With Men CY MAR 01-02, 2004 CL Bethesda, MD SP NIDA DE drug use; HIV; men who have sex with men; sexual risk behavior ID SUBSTANCE USE; HIV RISK; UNITED-STATES; YOUNG MEN; GAY MEN; TRANSMISSION; PREVENTION; EXPLORE; HEALTH AB Most prior studies examining drug use among men who have sex with men (MSM) have been cross-sectional or retrospective and have not determined whether periods of increased drug use are associated with high-risk sexual behavior at the individual level. In this article, we describe patterns of use of methamphetamines, poppers, and sniffed cocaine and sexual risk behavior among 736 San Francisco MSM enrolled in the EXPLORE study and followed for up to 48 months. In longitudinal analysis, use of methamphetamines, poppers, and sniffed cocaine declined during follow-up. However, compared with older participants, younger participants were more likely to increase their drug use over time. Results of conditional logistic regression demonstrated that high-risk sexual behavior was more common during reporting periods characterized by increased methamphetamine, poppers, or sniffed cocaine use. This within-person analysis found that compared with periods of no drug use, periods of both light drug use (less than weekly use of drugs) and heavier drug use (at least weekly use of at least one drug) were significantly associated with increased risk of engaging in unprotected anal sex with an HIV-Positive or unknown-status partner. These results suggest that even intermittent, recreational use of these drugs may lead to high-risk sexual behavior, and that, to reduce and prevent risks of HIV, no level of use of these drugs should be considered "safe." HIV prevention interventions should target MSM who report either light or heavy use of methamphetamines, poppers, and sniffed cocaine. C1 San Francisco Dept Publ Hlth, HIV Res Branch, San Francisco, CA 94120 USA. Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Div Publ Hlth Sci, Seattle, WA 98104 USA. Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. New York Blood Ctr, New York, NY 10021 USA. Natl Ctr Complementary & Alternat Med, Bethesda, MD USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Colfax, G (reprint author), San Francisco Dept Publ Hlth, HIV Res Branch, 25 Van Ness Ave,Suite 500, San Francisco, CA 94120 USA. EM grant_colfax@sfdph.org FU NIAID NIH HHS [U01 AI47995, 5 U01 AI46749, N01 AI35176] NR 26 TC 84 Z9 90 U1 2 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1099-3460 J9 J URBAN HEALTH JI J. Urban Health PD MAR PY 2005 VL 82 IS 1 SU 1 BP I62 EP I70 DI 10.1093/jurban/jti025 PG 9 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 911OM UT WOS:000228013900008 PM 15738319 ER PT J AU Lambert, E Normand, J Stall, R Aral, S Vlahov, D AF Lambert, E Normand, J Stall, R Aral, S Vlahov, D TI Introduction: New dynamics of HIV risk among drug-using men who have sex with men SO JOURNAL OF URBAN HEALTH-BULLETIN OF THE NEW YORK ACADEMY OF MEDICINE LA English DT Editorial Material ID NEW-YORK-CITY; SAN-FRANCISCO; BISEXUAL MEN; METHAMPHETAMINE; GAY; BEHAVIOR; EPIDEMIC; PATTERNS; COHORT; ABUSE C1 Natl Inst Drug Abuse, DESPR, ERB, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Atlanta, GA USA. New York Acad Med, Ctr Urban Epidemiol Studies, New York, NY USA. RP Lambert, E (reprint author), Natl Inst Drug Abuse, DESPR, ERB, 6001 Execut Blvd,Room 5153,MSC 9589, Bethesda, MD 20892 USA. EM el46i@nih.gov NR 25 TC 4 Z9 6 U1 3 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1099-3460 J9 J URBAN HEALTH JI J. Urban Health PD MAR PY 2005 VL 82 IS 1 SU 1 BP I1 EP I8 DI 10.1093/jurban/jti018 PG 8 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 911OM UT WOS:000228013900001 PM 15738326 ER PT J AU Williams, RD AF Williams, RD TI Urologic diseases in America project SO JOURNAL OF UROLOGY LA English DT Editorial Material C1 Univ Iowa, Dept Urol, NIDDKD, UDA Project,External Consultant & Advisory Comm, Iowa City, IA USA. RP Williams, RD (reprint author), Univ Iowa, Dept Urol, NIDDKD, UDA Project,External Consultant & Advisory Comm, Iowa City, IA USA. NR 2 TC 3 Z9 3 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD MAR PY 2005 VL 173 IS 3 BP 679 EP 679 DI 10.1097/01.ju0000154031.18562.0c PG 1 WC Urology & Nephrology SC Urology & Nephrology GA 898KK UT WOS:000227075500002 PM 15711240 ER PT J AU Pinsky, PF Andriole, GL Kramer, BS Hayes, RB Prorok, PC Gohagan, JK AF Pinsky, PF Andriole, GL Kramer, BS Hayes, RB Prorok, PC Gohagan, JK CA Prostate Lung Colorectal Ovarina P TI Prostate biopsy following a positive screen in the prostate, lung, colorectal and ovarian cancer screening trial SO JOURNAL OF UROLOGY LA English DT Article DE prostate; prostatic neoplasms; biopsy; mass screening; prostate-specific antigen ID ANTIGEN; TRENDS AB Purpose: The benefit of prostate specific antigen (PSA) and digital rectal examination (DRE) screening for prostate cancer is under evaluation in the Prostate, Lung, Colorectal. and Ovarian (PLCO) Cancer Screening Trial. Followup of positive screens in PLCO is done by subject personal physicians and it is outside of trial control. We describe the pattern of prostate biopsy in men with positive screens in PLCO. Materials and Methods: We examined all men with positive baseline PSA or DRE screens and men with positive post-baseline screens occurring by December 2000. Results: Of 2,717 men with positive PSA (greater than 4 ng/ml) at baseline 41% and 64% underwent biopsy within 1 and 3 years, respectively. A screening PSA of 7 to 10 and greater than 10 ng/ml at baseline was associated with significantly higher biopsy rates (HR 1.9 and 2.6, respectively) compared to PSA 4 to 7 ng/ml. The 1,793 in men whom the first positive PSA was after baseline had a lower overall biopsy rate (50% within 3 years). Furthermore, PSA above 7 ng/ml were not associated with higher biopsy rates in this group. The 4,449 men with positive DRE screens and negative PSA had a 3-year biopsy rate of 27%. Men with positive DRE at diagnostic followup had a biopsy rate of around 90%. However, few men, even of those with positive DRE screens, had positive diagnostic DREs. Conclusions: These biopsy rates following positive PSA and DRE screens are likely to be representative of national rates. These results suggest that PLCO is evaluating the effects of screening in a contemporary and robust manner. C1 NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. NIH, Off Dis Prevent, Bethesda, MD USA. Washington Univ, Sch Med, St Louis, MO USA. RP Pinsky, PF (reprint author), NCI, Div Canc Prevent, 6130 Execut Blvd,EPN 3064, Bethesda, MD 20892 USA. EM pinskyp@mail.nih.gov NR 10 TC 47 Z9 50 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD MAR PY 2005 VL 173 IS 3 BP 746 EP 750 DI 10.1097/01.ju.000152697.25708.71 PG 5 WC Urology & Nephrology SC Urology & Nephrology GA 898KK UT WOS:000227075500018 PM 15711261 ER PT J AU Figg, WD Liu, Y Arlen, P Gulley, J Steinberg, SM Liewehr, DJ Cox, MC Zhai, SP Cremers, S Parr, A Yang, XW Chen, CC Jones, E Dahut, WL AF Figg, WD Liu, Y Arlen, P Gulley, J Steinberg, SM Liewehr, DJ Cox, MC Zhai, SP Cremers, S Parr, A Yang, XW Chen, CC Jones, E Dahut, WL TI A randomized, phase II trial of ketoconazole plus alendronate versus ketoconazole alone in patients with androgen independent prostate cancer and bone metastases SO JOURNAL OF UROLOGY LA English DT Article DE prostate; prostatic neoplasms; ketoconazole; alendronate; pharmacokinetics ID ZOLEDRONIC ACID; DOUBLE-BLIND; PAMIDRONATE; GUIDELINES; RESORPTION; MARKERS; EVENTS; URINE AB Purpose: Alendronate (AL), a potent oral bisphosphonate, blocks the secretion of matrix metalloproteinase-2 and the establishment of bone metastases in animal models. Ketoconazole (KT) has demonstrated activity in androgen independent prostate cancer (AIPC). In this study we determined whether KT plus AL produced acceptable disease responses compared with KT alone. As the experimental design, 72 patients with progressive AIPC metastatic to bone were randomized to receive KT (1,200 mg daily) plus hydrocortisone (H) (30 mg daily) with or without AL (40 mg daily). Prostate specific antigen (PSA) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decrease, time to progression and response duration. The pharmacokinetics of KT and AL were characterized and changes in circulating angiogenic factors were assessed. Results: At a median potential followup of 23.9 months the proportion of patients with a greater than 50% decrease in PSA was similar in the KT/H/AL and KT/H, groups (50% and 47%, respectively). The median duration of response was 8.9 and 6.3 months in the KT/H/AL and KT/H groups, respectively (p = 0.125). Median progression-free survival was not significantly prolonged in the KT/H/AL group (4.6 vs 3.8 months, p = 0.27). There was no significant difference in overall survival between the 2 treatment arms but there was a trend toward improved survival in the KT/H arm (p = 0.074). Toxicity in the 2 groups was mild and there were no clear associations between changes in circulating angiogenic factor levels and clinical outcomes in either treatment arm. Conclusions: There were no statistically significant differences in response rate, progression-free survival or overall survival between KT/H alone and KT/H plus AL treatment in patients with AIPC. The addition of AL to KT/H may increase the response duration with an acceptable safety profile compared with treatment with KT/H alone. However, the addition of AL offers no survival benefit in patients with AIPC. C1 NCI, Canc Res Ctr, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. NIH, Dept Diagnost Radiol, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. Leiden Univ, Med Ctr, Dept Clin Pharm & Toxicol, Leiden, Netherlands. RP Figg, WD (reprint author), NCI, Canc Res Ctr, 10 Ctr Dr,Bldg 10,Room 5A-01, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Gulley, James/K-4139-2016; Figg Sr, William/M-2411-2016 OI Gulley, James/0000-0002-6569-2912; NR 27 TC 51 Z9 52 U1 1 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD MAR PY 2005 VL 173 IS 3 BP 790 EP 796 DI 10.1097/01.ju.0000147013.09157.8e PG 7 WC Urology & Nephrology SC Urology & Nephrology GA 898KK UT WOS:000227075500032 PM 15711271 ER PT J AU Coleman, J Franks, ME Grubb, RL Wynberg, J Lee, CSD Behari, A Kim, CM Williams, C Linehan, WM AF Coleman, J Franks, ME Grubb, RL Wynberg, J Lee, CSD Behari, A Kim, CM Williams, C Linehan, WM TI Highlights from the Society of Urologic Oncology 4th Annual Meeting SO JOURNAL OF UROLOGY LA English DT Article DE societies, medical; prostatic neoplasms; kidney neoplasms; bladder neoplasms; testicular neoplasms ID ADVANCED BLADDER-CANCER; PROSTATE-CANCER; TESTICULAR CANCER; NEOADJUVANT CHEMOTHERAPY; CYSTECTOMY; MORTALITY; CISPLATIN; TOXICITY; BIOPSIES; RISK AB The 4th annual meeting of the Society of Urologic Oncology (SUO) was held December 5-6, 2003 in Bethesda, Maryland. The meeting was attended by urologists, medical and radiation oncologists, and researchers whose focus is genitourinary (GU) malignancies. More than 500 participants registered for the meeting. Materials and Methods: The agenda for the SUO meeting included more than 50 speakers and discussion panels, and addressed a broad range of topics in GU oncology. Transcripts of the proceedings and submitted slide presentations were reviewed for content following the meeting, and the highlights were summarized. These written materials can be accessed through the SUO web site at http://societyofurologiconcology.org. Results: Reviewed session topics included epidemiology of GU malignancies, biomarkers for GU malignancies, cancer genomics, bladder cancer, testis cancer, minimally invasive treatments for GU malignancies, molecular therapeutics and advanced prostate cancer. Significant advances in these fields have directly impacted clinical care and improved patient outcomes across the many disciplines associated with treatment of GU cancers. Conclusions: The SUO meeting is unique in its multidisciplinary forum and focus on urological oncology. The 2003 meeting highlighted recent advances in epidemiology, clinical management and emerging molecular approaches in the diagnosis and treatment of urological malignancies with several state-of-the-art presentations. C1 NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. RP Coleman, J (reprint author), NCI, Urol Oncol Branch, NIH, 9000 Rockville Pike,Bldg 10-2B47, Bethesda, MD 20892 USA. EM colemanj@mail.nih.gov OI Coleman, Jonathan/0000-0002-6428-7835 NR 18 TC 0 Z9 0 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0022-5347 J9 J UROLOGY JI J. Urol. PD MAR PY 2005 VL 173 IS 3 BP 938 EP 941 DI 10.1097/01.ju.0000152087.34485.43 PG 4 WC Urology & Nephrology SC Urology & Nephrology GA 898KK UT WOS:000227075500058 PM 15711343 ER PT J AU Neeman, Z Sarin, S Coleman, J Fojo, T Wood, BJ AF Neeman, Z Sarin, S Coleman, J Fojo, T Wood, BJ TI Radiofrequency ablation for tumor-related massive hematuria SO JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Article ID HEPATOCELLULAR-CARCINOMA; EMBOLIZATION; MANAGEMENT AB To determine whether radiofrequency (RF) ablation targeting the tumor-collecting system interface has a durable effect in patients with transfusion-dependent kidney tumor-related hematuria, four patients aged 61-71 years were successfully treated with RF ablation, with a mean follow up of 12 months. Baseline creatinine levels varied from 2.0 mg/dL to 3.7 mg/dL. All patients had received red blood cell transfusions in the days and hours before RF ablation. No subsequent surgical or interventional procedures were required for management of hematuria. Gross hematuria resolved in 24-48 hours in all four patients. Two of the patients are alive with stable renal function and two died of causes unrelated to treatment. RF ablation may be an effective therapeutic option for transfusion-dependent cancer-related hematuria in patients with renal insufficiency, solitary kidney, or comorbidities, or after failed conventional therapies in patients who are not candidates for surgery. C1 NIH, Dept Diagnost Radiol, Ctr Clin, Bethesda, MD 20892 USA. NIH, Dept Urol, Ctr Clin, Bethesda, MD 20892 USA. NEOUCOM, Aultman Hlth Fdn, Dept Diagnost Radiol, Canton, OH USA. RP Neeman, Z (reprint author), NIH, Dept Diagnost Radiol, Ctr Clin, Bldg 10,Room 1C 660,10 Ctr Dr, Bethesda, MD 20892 USA. EM zneeman@cc.nih.gov OI Coleman, Jonathan/0000-0002-6428-7835 FU Intramural NIH HHS [Z99 CL999999] NR 11 TC 7 Z9 7 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1051-0443 J9 J VASC INTERV RADIOL JI J. Vasc. Interv. Radiol. PD MAR PY 2005 VL 16 IS 3 BP 417 EP 421 DI 10.1097/01.RVI.0000147076.02176.13 PG 5 WC Radiology, Nuclear Medicine & Medical Imaging; Peripheral Vascular Disease SC Radiology, Nuclear Medicine & Medical Imaging; Cardiovascular System & Cardiology GA 907VE UT WOS:000227745300017 PM 15758142 ER PT J AU Kino, T Gragerov, A Valentin, A Tsopanomihalou, M Ilyina-Gragerova, G Erwin-Cohen, R Chrousos, GP Pavlakis, GN AF Kino, T Gragerov, A Valentin, A Tsopanomihalou, M Ilyina-Gragerova, G Erwin-Cohen, R Chrousos, GP Pavlakis, GN TI Vpr protein of human immunodeficiency virus type 1 binds to 14-3-3 proteins and facilitates complex formation with Cdc25C: Implications for cell cycle arrest SO JOURNAL OF VIROLOGY LA English DT Article ID YEAST SCHIZOSACCHAROMYCES-POMBE; DNA-DAMAGE; HIV-1 VPR; NUCLEAR-LOCALIZATION; GLUCOCORTICOID-RECEPTOR; MUTATIONAL ANALYSIS; IN-VIVO; CHECKPOINT; CHK1; PHOSPHORYLATION AB Vpr and selected mutants were used in a Saccharomyces cerevisiae two-hybrid screen to identify cellular interactors. We found Vpr interacted with 14-3-3 proteins, a family regulating a multitude of proteins in the cell. Vpr mutant R80A, which is inactive in cell cycle arrest, did not interact with 14-3-3. 14-3-3 proteins regulate the G(2)/M transition by inactivating Cdc25C phosphatase via binding to the phosphorylated serine residue at position 216 of Cdc25C. 14-3-3 overexpression in human cells synergized with Vpr in the arrest of cell cycle. Vpr did not arrest efficiently cells not expressing 14-3-3sigma. This indicated that a full complement of 14-3-3 proteins is necessary for optimal Vpr function on the cell cycle. Mutational analysis showed that the C-terminal portion of Vpr, known to harbor its cell cycle-arresting activity, bound directly to the C-terminal part of 14-3-3, outside of its phosphopeptide-binding pocket. Vpr expression shifted localization of the mutant Cdc25C S216A to the cytoplasm, indicating that Vpr promotes the association of 14-3-3 and Cdc25C, independently of the presence of serine 216. Immunoprecipitations of cell extracts indicated the presence of triple complexes (Vpr/14-3-3/Cdc25C). These results indicate that Vpr promotes cell cycle arrest at the G2/M phase by facilitating association of 14-3-3 and Cdc25C independently of the latter's phosphorylation status. C1 NCI, Human Retrovirus Sect, Ctr Canc Res, Frederick, MD 21702 USA. NICHHD, Pediat & Reprod Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Pavlakis, GN (reprint author), NCI, Human Retrovirus Sect, Ctr Canc Res, Bldg 535,Rm 210, Frederick, MD 21702 USA. EM pavlakis@ncifcrf.gov OI tsopanomichalou, maria/0000-0002-1886-2376 NR 53 TC 49 Z9 53 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2005 VL 79 IS 5 BP 2780 EP 2787 DI 10.1128/JVI.79.5.2780-2787.2005 PG 8 WC Virology SC Virology GA 898TF UT WOS:000227098400013 PM 15708996 ER PT J AU Buck, CB Thompson, CD Pang, YYS Lowy, DR Schiller, JT AF Buck, CB Thompson, CD Pang, YYS Lowy, DR Schiller, JT TI Maturation of papillomavirus capsids SO JOURNAL OF VIROLOGY LA English DT Article ID VIRUS-LIKE PARTICLES; L1; PROTEIN; EXPRESSION; DNA; PSEUDOVIRIONS; CYSTEINES; PATHWAY; HPV-16; BOVINE AB The papillomavirus capsid is a nonenveloped icosahedral shell formed by the viral major structural protein, L1. It is known that disulfide bonds between neighboring L1 molecules help to stabilize the capsid. However, the kinetics of inter-L1 disulfide bond formation during particle morphogenesis have not previously been examined. We have recently described a system for producing high-titer papillomavirus-based gene transfer vectors (also known as pseudoviruses) in mammalian cells. Here we show that papillomavirus capsids produced using this system undergo a maturation process in which the formation of inter-L1 disulfide bonds drives condensation and stabilization of the capsid. Fully mature capsids exhibit improved regularity and resistance to proteolytic digestion. Although capsid maturation for other virus types has been reported to occur in seconds or minutes, papillomavirus capsid maturation requires overnight incubation. Maturation of the capsids of human papillomavirus types 16 and 18 proceeds through an ordered accumulation of dimeric and trimeric L1 species, whereas the capsid of bovine papillomavirus type I matures into more extensively cross-linked forms. The presence of encapsidated DNA or the minor capsid protein, L2, did not have major effects on the kinetics or extent of capsid maturation. Immature capsids and capsids formed from L1 mutants with impaired disulfide bond formation are infectious but physically fragile. Consequently, capsid maturation is essential for efficient purification of papillomavirus-based gene transfer vectors. Despite their obvious morphological differences, mature and immature capsids are similarly neutralizable by various L1- and L2-specific antibodies. C1 NCI, Cellular Oncol Lab, Bethesda, MD 20892 USA. RP Schiller, JT (reprint author), NCI, Cellular Oncol Lab, Bldg 37,Room 4106,9000 Rockville Pike, Bethesda, MD 20892 USA. EM schillej@dc37a.nci.nih.gov OI Buck, Christopher/0000-0003-3165-8094 NR 39 TC 157 Z9 163 U1 3 U2 16 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2005 VL 79 IS 5 BP 2839 EP 2846 DI 10.1128/JVI.79.5.2839-2846.2005 PG 8 WC Virology SC Virology GA 898TF UT WOS:000227098400020 PM 15709003 ER PT J AU Seaman, MS Xu, L Beaudry, K Martin, KL Beddall, MH Miura, A Sambor, A Chakrabarti, BK Huang, Y Bailer, R Koup, RA Mascola, JR Nabel, GJ Letvin, NL AF Seaman, MS Xu, L Beaudry, K Martin, KL Beddall, MH Miura, A Sambor, A Chakrabarti, BK Huang, Y Bailer, R Koup, RA Mascola, JR Nabel, GJ Letvin, NL TI Multiclade human immunodeficiency virus type 1 envelope immunogens elicit broad cellular and humoral immunity in rhesus monkeys SO JOURNAL OF VIROLOGY LA English DT Article ID NEUTRALIZING ANTIBODIES; VACCINE DEVELOPMENT; HIV VACCINES; AIDS VACCINE; DNA VACCINES; IMMUNIZATION; PROTECTION; DIVERSITY; INFECTION; PLASMIDS AB The development of a human immunodeficiency virus type 1 (HIV-1) vaccine that elicits potent cellular and humoral immune responses recognizing divergent strains of HIV-1 will be critical for combating the global AIDS epidemic. The present studies were initiated to examine the magnitude and breadth of envelope (Env)specific T-lymphocyte and antibody responses generated by vaccines containing either a single or multiple genetically distant HIV-1 Env immunogens. Rhesus monkeys were immunized with DNA prime-recombinant adenovirus boost vaccines encoding a Gag-Pol-Nef polyprotein in combination with either a single Env or a mixture of clade-A, clade-B, and clade-C Envs. Monkeys receiving the multiclade Env immunization developed robust immune responses to all vaccine antigens and, importantly, a greater breadth of Env recognition than monkeys immunized with vaccines including a single Env immunogen. All groups of vaccinated monkeys demonstrated equivalent immune protection following challenge with the pathogenic simian-human immunodeficiency virus 89.6P. These data suggest that a multicomponent vaccine encoding Env proteins from multiple clades of HIV-1 can generate broad Env-specific T-lymphocyte and antibody responses without antigenic interference. This study demonstrates that it is possible to generate protective immune responses by vaccination with genetically diverse isolates of HIV-1. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Boston, MA 02215 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Letvin, NL (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, 330 Brookline Ave,RE-113, Boston, MA 02215 USA. EM nletvin@bidmc.harvard.edu FU NIAID NIH HHS [AI30033, N01AI30033] NR 26 TC 99 Z9 101 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2005 VL 79 IS 5 BP 2956 EP 2963 DI 10.1128/JVI.79.5.2956-2963.2005 PG 8 WC Virology SC Virology GA 898TF UT WOS:000227098400032 PM 15709015 ER PT J AU Sadagopal, S Amara, RR Montefiori, DC Wyatt, LS Staprans, SI Kozyr, NL McClure, HM Moss, B Robinson, HL AF Sadagopal, S Amara, RR Montefiori, DC Wyatt, LS Staprans, SI Kozyr, NL McClure, HM Moss, B Robinson, HL TI Signature for long-term vaccine-mediated control of a simian and human immunodeficiency virus 89.6P challenge: Stable low-breadth and low-frequency T-cell response capable of coproducing gamma interferon and interleukin-2 SO JOURNAL OF VIROLOGY LA English DT Article ID TYPE-1 GAG GENE; RHESUS-MONKEYS; HIV-1 INFECTION; AIDS VACCINE; VIRAL ESCAPE; IN-VIVO; LYMPHOCYTE ESCAPE; MUCOSAL CHALLENGE; DNA; REPLICATION AB In 2001, we reported 20 weeks of control of challenge with the virulent 89.6P chimera of simian and human immunodeficiency viruses (SHIV-89.6P) by a Gag-Pol-Env vaccine consisting of DNA priming and modified vaccinia virus Ankara boosting. Here we report that 22 out of 23 of these animals successfully controlled their viremia until their time of euthanasia at 200 weeks postchallenge. At euthanasia, all animals had low to undetectable viral loads and normal CD4 counts. During the long period of viral control, gamma interferon (IFN-gamma)-producing antiviral T cells were present at unexpectedly low breadths and frequencies. Most animals recognized two CD8 and one CD4 epitope and had frequencies of IFN-gamma-responding T cells from 0.01 to 0.3% of total CD8 or CD4 T cells. T-cell responses were remarkably stable over time and, unlike responses in most immunodeficiency virus infections, maintained good functional characteristics, as evidenced by coproduction of IFN-gamma and interleukin-2. Overall, high titers of binding and neutralizing antibody persisted throughout the postchallenge period. Encouragingly, long-term control was effective in macaques of diverse histocompatibility types. C1 Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA. Emory Univ, Emory Vaccine Ctr, Atlanta, GA 30329 USA. Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Dept Med, Div Infect Dis, Atlanta, GA 30322 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27706 USA. NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP Robinson, HL (reprint author), Emory Univ, Yerkes Natl Primate Res Ctr, 954 Gatewood Dr, Atlanta, GA 30329 USA. EM hrobins@rmy.emory.edu FU NCRR NIH HHS [P51 RR000165]; NIAID NIH HHS [P01 AI043045, P01-AI43045]; NIDA NIH HHS [P30 DA12121] NR 47 TC 25 Z9 25 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2005 VL 79 IS 6 BP 3243 EP 3253 DI 10.1128/JVI.79.6.3243-3253.2005 PG 11 WC Virology SC Virology GA 902OR UT WOS:000227366900002 PM 15731219 ER PT J AU Jang, MY Yarborough, OH Conyers, GB McPhie, P Owens, RA AF Jang, MY Yarborough, OH Conyers, GB McPhie, P Owens, RA TI Stable secondary structure near the nicking site for adeno-associated virus type 2 Rep proteins on human chromosome 19 SO JOURNAL OF VIROLOGY LA English DT Article ID DNA HELICASE ACTIVITY; HUMAN-CHROMOSOME 19; TERMINAL REPEATS; BIOCHEMICAL-CHARACTERIZATION; SEQUENCE REQUIREMENTS; TARGETED INTEGRATION; NUCLEOTIDE-SEQUENCE; ATPASE ACTIVITIES; BINDING-SITES; VIRAL-DNA AB Adeno-associated virus serotype 2 (AAV-2) can preferentially integrate its DNA into a 4-kb region of human chromosome 19, designated AAVS1. The nicking activity of AAV-2's Rep68 or Rep78 proteins is essential for preferential integration. These proteins nick at the viral origin of DNA replication and at a similar site within AAVS1. The current nicking model suggests that the strand containing the nicking site is separated from its complementary strand prior to nicking. In AAV serotypes 1 through 6, the nicking site is flanked by a sequence that is predicted to form a stem-loop with standard Watson-Crick base pairing. The region flanking the nicking site in AAVS1 (5'-GGCGGCGGT/TGGGGCTCG-3' [the slash indicates the nicking site]) lacks extensive potential for Watson-Crick base pairing. We therefore performed an empirical search for a stable secondary structure. By comparing the migration of radiolabeled oligonucleotides containing wild-type or mutated sequences from the AAVS1 nicking site to appropriate standards, on native and denaturing polyacrylamide gels, we have found evidence that this region forms a stable secondary structure. Further confirmation was provided by circular dichroism analyses. We identified six bases that appear to be important in forming this putative secondary structure. Mutation of five of these bases, within the context of a double-stranded nicking substrate, reduces the ability of the substrate to be nicked by Rep78 in vitro. Four of these five bases are outside the previously recognized GTTGG nicking site motif and include parts of the CTC motif that has been demonstrated to be important for integration targeting. C1 NIDDKD, Mol & Cellular Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIDDKD, Lab Biochem & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Owens, RA (reprint author), NIDDKD, Mol & Cellular Biol Lab, NIH, Dept Hlth & Human Serv, Bldg 8,Rm 310,8 Ctr Dr,MSC 0840, Bethesda, MD 20892 USA. EM ro6n@nih.gov NR 68 TC 11 Z9 11 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2005 VL 79 IS 6 BP 3544 EP 3556 DI 10.1128/JVI.79.6.3544-3556.2005 PG 13 WC Virology SC Virology GA 902OR UT WOS:000227366900032 PM 15731249 ER PT J AU Nakai, H Wu, XL Fuess, S Storm, TA Munroe, D Montini, E Burgess, SM Grompe, M Kay, MA AF Nakai, H Wu, XL Fuess, S Storm, TA Munroe, D Montini, E Burgess, SM Grompe, M Kay, MA TI Large-scale molecular characterization of adeno-associated virus vector integration in mouse liver SO JOURNAL OF VIROLOGY LA English DT Article ID GENE-THERAPY; IN-VIVO; EFFICIENT TRANSDUCTION; INTERGENIC SPACER; RIBOSOMAL DNA; HUMAN GENOME; AAV VECTOR; SITES; JUNCTIONS; MUSCLE AB Recombinant adeno-associated virus (rAAV) vector holds promise for gene therapy. Despite a low frequency of chromosomal integration of vector genomes, recent studies have raised concerns about the risk of rAAV integration because integration occurs preferentially in genes and accompanies chromosomal deletions, which may lead to loss-of-function insertional mutagenesis. Here, by analyzing 347 rAAV integrations in mice, we elucidate novel features of rAAV integration: the presence of hot spots for integration and a strong preference for integrating near gene regulatory sequences. The most prominent hot spot was a harmless chromosomal niche in the rRNA gene repeats, whereas nearly half of the integrations landed near transcription start sites or CpG islands, suggesting the possibility of activating flanking cellular disease genes by vector integration, similar to retroviral gain-of-function insertional mutagenesis. Possible cancer-related genes were hit by rAAV integration at a frequency of 3.5%. In addition, the information about chromosomal changes at 218 integration sites and 602 breakpoints of vector genomes have provided a clue to how vector terminal repeats and host chromosomal DNA are joined in the integration process. Thus, the present study provides new insights into the risk of rAAV-mediated insertional mutagenesis and the mechanisms of rAAV integration. C1 Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Genet, Stanford, CA 94305 USA. NCI, SAIC Frederick, Lab Mol Technol, Frederick, MD 21701 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. Oregon Hlth Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA. Oregon Hlth Sci Univ, Dept Pediat, Portland, OR 97201 USA. RP Nakai, H (reprint author), Stanford Univ, Sch Med, Dept Pediat, 300 Pasteur Dr,Grant Bldg,Rm S374, Stanford, CA 94305 USA. EM nakaih@stanford.edu OI Burgess, Shawn/0000-0003-1147-0596; Montini, Eugenio/0000-0003-1771-6067 FU NCI NIH HHS [N01-CO-12400, N01CO12400]; NHLBI NIH HHS [HL66948, U01 HL066948]; NIDDK NIH HHS [DK068636, DK18252, R21 DK068636] NR 32 TC 104 Z9 109 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2005 VL 79 IS 6 BP 3606 EP 3614 DI 10.1128/JVI.79.6.3606-3614.2005 PG 9 WC Virology SC Virology GA 902OR UT WOS:000227366900038 PM 15731255 ER PT J AU Casazza, JP Betts, MR Hill, BJ Brenchley, JM Price, DA Douek, DC Koup, RA AF Casazza, JP Betts, MR Hill, BJ Brenchley, JM Price, DA Douek, DC Koup, RA TI Immunologic pressure within class I-restricted cognate human immunodeficiency virus epitopes during highly active antiretroviral therapy SO JOURNAL OF VIROLOGY LA English DT Article ID CYTOTOXIC T-LYMPHOCYTES; PNEUMOCYSTIS-CARINII PNEUMONIA; PRIMARY IMMUNE-RESPONSE; CELL RESPONSES; REVERSE-TRANSCRIPTASE; COMBINATION THERAPY; DISEASE PROGRESSION; PRIMARY INFECTION; PERIPHERAL-BLOOD; TYPE-1 INFECTION AB Cytotoxic T lymphocytes (CTL) and highly active antiretroviral therapy (HAART) are known to exert strong evolutionary pressures on the virus population during human immunodeficiency virus (HIV) infection. However, it is not known whether CTL responses continue to substantially affect viral evolution during treatment. To study the effect of immunologic pressure on viral sequences during HAART, we identified 10 targeted HIV-specific CD8(+)-T-cell epitopes in five treatment-naive patients, sequenced each epitope in plasma-derived viruses, and then identified evidence of immunologic pressure at these epitopes by comparing the frequency of viral variants in plasma to the frequency of the CD8(+)-T-cell response for each variant identified. For one of the five patients, evidence of viral evolution was found during therapy. The sequence of the CTL-targeted epitope changed from an apparent escape variant prior to the initiation of therapy, to the sequence that is best recognized by the CTL response after the initiation of therapy, and then finally to a new escape variant during continued therapy. These data show that CTL-mediated pressure can continue to affect viral evolution after the initiation of HAART, even when treatment drives the viral load below detectable levels, and suggest that antiretroviral therapy may preferentially inhibit those virus variants that escape the CTL response. C1 NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NIAID, Human Immunol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Koup, RA (reprint author), NIAID, Immunol Lab, Vaccine Res Ctr, NIH, Bldg 40,Room 3502,40 Convent Dr, Bethesda, MD 20892 USA. EM rkoup@mail.nih.gov RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 FU Medical Research Council [G108/441]; NIAID NIH HHS [R01 AI047603, R0I-AI47603] NR 54 TC 16 Z9 17 U1 0 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0022-538X J9 J VIROL JI J. Virol. PD MAR PY 2005 VL 79 IS 6 BP 3653 EP 3663 DI 10.1128/JVI.79.6.3653-3663.2005 PG 11 WC Virology SC Virology GA 902OR UT WOS:000227366900042 PM 15731259 ER PT J AU Visser, M Goodpaster, BH Kritchevsky, SB Newman, AB Nevitt, M Rubin, SM Simonsick, EM Harris, TB AF Visser, M Goodpaster, BH Kritchevsky, SB Newman, AB Nevitt, M Rubin, SM Simonsick, EM Harris, TB CA Hlth ABC Study TI Muscle mass, muscle strength, and muscle fat infiltration as predictors of incident mobility limitations in well-functioning older persons SO JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES LA English DT Article ID SKELETAL-MUSCLE; BODY-COMPOSITION; COMPUTED-TOMOGRAPHY; ELDERLY-MEN; PHYSICAL PERFORMANCE; WOMEN; DISABILITY; SARCOPENIA; HEALTH; AGE AB Background. Lower muscle mass has been correlated with poor physical function: however, no studies have examined this relationship prospectively. This study aims to investigate whether low muscle mass, low muscle strength, and greater fat infiltration into the muscle predict incident mobility limitation. Methods. Our study cohort included 3075 well-functioning black and white men and women aged 70-79 years participating in the Health, Aging, and Body Composition study. Participants were followed for 2.5 years. Muscle cross-sectional area and muscle tissue attenuation (a measure of fat infiltration) were measured by computed tomography at the mid-thigh, and knee extensor strength by using a KinCom dynamometer. Incident mobility limitation was defined as two consecutive self-reports of any difficulty walking one-quarter mile or climbing 10 steps. Results. Mobility limitations were developed by 22.3% of the men and by 31.8% of the women. Cox's proportional hazards models, adjusting for demographic, lifestyle, and health factors, showed a hazard ratio of 1.90 [95% confidence interval (CI), 1.27-2.84] in men and 1.68 (95% CI, 1.23-2.31) in women for the lowest compared to the highest quartile of muscle area (p < .01 for trend). Results for muscle strength were 2.02 (95% CI, 1.39-2.94) and 1,91 (95% Cl. 1.41-2.58), p < .001 trend, and for muscle attenuation were 1.91 (95% CI, 1.31-2.83) and 1.69 (95% CI, 1.20-2,35), p < .01 for trend. When included in one model, only muscle attenuation and muscle strength independently predicted mobility limitation (p < .05). Among men and women, associations were similar for blacks and whites. Conclusion. Lower muscle mass (smaller cross-sectional thigh muscle area), greater fat infiltration into the muscle, and lower knee extensor muscle strength are associated with increased risk of mobility loss in older men and women, The association between low muscle mass and functional decline seems to be a function of underlying muscle strength. C1 Free Univ Amsterdam, Med Ctr, Inst Res Extramural Med, NL-1081 BT Amsterdam, Netherlands. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA 15260 USA. Wake Forest Univ, Sch Med, Stitch Ctr Aging, Winston Salem, NC USA. Univ Pittsburgh, Div Geriatr Med, Pittsburgh, PA 15260 USA. Univ Calif San Francisco, Prevent Sci Grp, San Francisco, CA 94143 USA. NIA, Gerontol Res Ctr, Baltimore, MD 21224 USA. RP Visser, M (reprint author), Free Univ Amsterdam, Med Ctr, Inst Res Extramural Med, Van der Boechorststr 7, NL-1081 BT Amsterdam, Netherlands. EM m.visser@vumc.nl RI CHEN, Jiangang/A-1549-2011; Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU NIA NIH HHS [N01-AG-6-2103, N01-AG-6-2101, N01-AG-6-2106] NR 36 TC 452 Z9 465 U1 4 U2 28 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5006 J9 J GERONTOL A-BIOL JI J. Gerontol. Ser. A-Biol. Sci. Med. Sci. PD MAR PY 2005 VL 60 IS 3 BP 324 EP 333 PG 10 WC Geriatrics & Gerontology; Gerontology SC Geriatrics & Gerontology GA 923AL UT WOS:000228880900010 PM 15860469 ER PT J AU Harris, JR AF Harris, JR TI Research on environmental effects in genetic studies of aging - Introduction SO JOURNALS OF GERONTOLOGY SERIES B-PSYCHOLOGICAL SCIENCES AND SOCIAL SCIENCES LA English DT Editorial Material 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, POB 4404,Nydalen, N-0403 Oslo, Norway. EM jennifer.harris@fhi.no NR 7 TC 2 Z9 2 U1 0 U2 1 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5014 J9 J GERONTOL B-PSYCHOL JI J. Gerontol. Ser. B-Psychol. Sci. Soc. Sci. PD MAR PY 2005 VL 60 SI 1 BP 5 EP 6 PG 2 WC Geriatrics & Gerontology; Gerontology; Psychology; Psychology, Multidisciplinary SC Geriatrics & Gerontology; Psychology GA 907UI UT WOS:000227743100001 PM 15863704 ER PT J AU Seeman, TE Huang, MH Bretsky, P Crimmins, E Launer, L Guralnik, JM AF Seeman, TE Huang, MH Bretsky, P Crimmins, E Launer, L Guralnik, JM TI Education and APOE-e4 in longitudinal cognitive decline: MacArthur studies of successful aging SO JOURNALS OF GERONTOLOGY SERIES B-PSYCHOLOGICAL SCIENCES AND SOCIAL SCIENCES LA English DT Article ID ALZHEIMERS-DISEASE; APOLIPOPROTEIN-E; OLDER PERSONS; DEMENTIA; POPULATION; ALLELE; RISK; ASSOCIATION; EPSILON-4; GENOTYPE AB Longitudinal data from the MacArthur Study of Successful Aging were used to test for interactions between education and apolipoprotein E (APOE) genotype with respect to time trends in cognitive performance. Interactions between education, APOE-e4 status, and time were found for overall cognitive function, and for subscales measuring memory and naming: The presence of the e4 allele was associated with steeper declines in cognition for those with a greater than eighth-grade education. For those with an eighth-grade education or less, time trends did not differ by APOE genotype. A measure of cognitive impairment (i.e., scores of less than or equal to 7 on the Short Portable Mental Status Questionnaire) yielded parallel though weaker evidence for a similar interaction with respect to risk of cognitive impairment. These findings suggest that the presence of at least one e4 allele appears to reduce the protective effects of education for those with at least a ninth-grade education or more, resulting in steeper cognitive declines with age. C1 Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. Univ So Calif, Dept Prevent Med, Los Angeles, CA 90089 USA. Univ So Calif, Ethel Percy Andrus Gerontol Ctr, Los Angeles, CA 90089 USA. NIA, NIH, Bethesda, MD 20892 USA. RP Seeman, TE (reprint author), Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90024 USA. FU NIA NIH HHS [AG-17056, AG-17055, AG-17265] NR 49 TC 22 Z9 22 U1 3 U2 9 PU GERONTOLOGICAL SOCIETY AMER PI WASHINGTON PA 1275 K STREET NW SUITE 350, WASHINGTON, DC 20005-4006 USA SN 1079-5014 J9 J GERONTOL B-PSYCHOL JI J. Gerontol. Ser. B-Psychol. Sci. Soc. Sci. PD MAR PY 2005 VL 60 IS 2 BP P74 EP P83 PG 10 WC Geriatrics & Gerontology; Gerontology; Psychology; Psychology, Multidisciplinary SC Geriatrics & Gerontology; Psychology GA 903ZY UT WOS:000227465900002 PM 15746021 ER PT J AU Zagzag, D Salnikow, K Chiriboga, L Yee, H Lan, L Ali, MA Garcia, R Demaria, S Newcomb, EW AF Zagzag, D Salnikow, K Chiriboga, L Yee, H Lan, L Ali, MA Garcia, R Demaria, S Newcomb, EW TI Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain SO LABORATORY INVESTIGATION LA English DT Article DE gene chip; gliomas; invasion; major histocompatibility complex; microarray analysis; laser capture microdissection ID HUMAN GLIOBLASTOMA CELLS; FOCAL ADHESION KINASE; GROWTH-FACTOR-BETA; CLASS-I ANTIGENS; MALIGNANT GLIOMA; GENE-EXPRESSION; EXTRACELLULAR-MATRIX; SUPPRESSOR FACTOR; MICROARRAY DATA; MESSENGER-RNA AB Invasion into surrounding brain tissue is a fundamental feature of gliomas and the major reason for treatment failure. The process of brain invasion in gliomas is not well understood. Differences in gene expression and/ or gene products between invading and noninvading glioma cells may identify potential targets for new therapies. To look for genes associated with glioma invasion, we first employed Affymetrix microarray Genechips(R) technology to identify genes differentially expressed in migrating glioma cells in vitro and in invading glioma cells in vivo using laser capture microdissection. We observed upregulation of a variety of genes, previously reported to be linked to glioma cell migration and invasion. Remarkably, major histocompatiblity complex ( MHC) class I and II genes were significantly downregulated in migrating cells in vitro and in invading cells in vivo. Decreased MHC expression was confirmed in migrating glioma cells in vitro using RT- PCR and in invading glioma cells in vivo by immunohistochemical staining of human and murine glioblastomas for beta2 microglobulin, a marker of MHC class I protein expression. To the best of our knowledge, this report is the first to describe the downregulation of MHC class I and II antigens in migrating and invading glioma cells, in vitro and in vivo, respectively. These results suggest that the very process of tumor invasion is associated with decreased expression of MHC antigens allowing glioma cells to invade the surrounding brain in a ' stealth'- like manner. C1 NYU Med Ctr, Sch Med, Dept Pathol, Div Neuropathol, New York, NY 10016 USA. NYU, Sch Med, Microvasc & Mol Neurooncol Lab, New York, NY USA. NYU, Sch Med, Dept Neurosurg, New York, NY USA. NYU, Sch Med, Inst Canc, New York, NY USA. NCI, NIH, Frederick, MD 21701 USA. RP Zagzag, D (reprint author), NYU Med Ctr, Sch Med, Dept Pathol, Div Neuropathol, 550 1st Ave, New York, NY 10016 USA. EM dz4@nyu.edu RI Demaria, Sandra/A-8959-2008; OI Demaria, Sandra/0000-0003-4426-0499; Chiriboga, Luis/0000-0002-2028-6873 FU NCI NIH HHS [R01 CA100426-01A1] NR 70 TC 62 Z9 65 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 0023-6837 J9 LAB INVEST JI Lab. Invest. PD MAR PY 2005 VL 85 IS 3 BP 328 EP 341 DI 10.1038/labinvest.3700233 PG 14 WC Medicine, Research & Experimental; Pathology SC Research & Experimental Medicine; Pathology GA 899TS UT WOS:000227168700004 PM 15716863 ER PT J AU Cutts, FT Zaman, SMA Enwere, G Jaffar, S Levine, OS Okoko, JB Oluwalana, C Vaughan, A Obaro, SK Leach, A McAdam, KP Biney, E Saaka, M Onwuchekwa, U Yallop, F Pierce, NF Greenwood, BM Adegbola, RA AF Cutts, FT Zaman, SMA Enwere, G Jaffar, S Levine, OS Okoko, JB Oluwalana, C Vaughan, A Obaro, SK Leach, A McAdam, KP Biney, E Saaka, M Onwuchekwa, U Yallop, F Pierce, NF Greenwood, BM Adegbola, RA CA Gambian Pneumococcal Vaccine Trial TI Efficacy of nine-valent pneumococcal conjugate vaccine against pneumonia and invasive pneumococcal disease in The Gambia: randomised, double-blind, placebo-controlled trial SO LANCET LA English DT Article ID INTEGRATED MANAGEMENT; CHILDHOOD ILLNESS; CHILDREN; SAFETY; IMMUNOGENICITY; INFECTIONS; PREVENTION; DIPHTHERIA; PERTUSSIS; TETANUS AB Background Pneumonia is estimated to cause 2 million deaths every year in children. Streptococcus pneumoniae is the most important cause of severe pneumonia. We aimed to assess the efficacy of a nine-valent pneumococcal conjugate vaccine in children. Methods We undertook a randomised, placebo-controlled, double-blind trial in eastern Gambia. Children age 6-51 weeks were randomly allocated three doses of either pneumococcal conjugate vaccine (n=8718) or placebo (8719), with intervals of at least 25 days between doses. Our primary outcome was first episode of radiological pneumonia. Secondary endpoints were clinical or severe clinical pneumonia, invasive pneumococcal disease, and all-cause admissions. Analyses were per protocol and intention to treat. Findings 529 children assigned vaccine and 568 allocated placebo were not included in the per-protocol analysis. Results of per-protocol and intention-to-treat analyses were similar. By per-protocol analysis, 333 of 8189 children given vaccine had an episode of radiological pneumonia compared with 513 of 8151 who received placebo. Pneumococcal vaccine efficacy was 37% (95% CI 27-45) against first episode of radiological pneumonia. First episodes of clinical pneumonia were reduced overall by 7% (95% CI 1-12). Efficacy of the conjugate vaccine was 77% (51-90) against invasive pneumococcal disease caused by vaccine serotypes, 50% (21-69) against disease caused by all serotypes, and 15% (7-21) against all-cause admissions. We also found an efficacy of 16% (3-28) against mortality. 110 serious adverse events arose in children given the pneumococcal vaccine compared with 131 in those who received placebo. Interpretation In this rural African setting, pneumococcal conjugate vaccine has high efficacy against radiological pneumonia and invasive pneumococcal disease, and can substantially reduce admissions and improve child survival. Pneumococcal conjugate vaccines should be made available to African infants. C1 MRC Labs, Banjul, Gambia. London Sch Hyg & Trop Med, London WC1, England. NIAID, NIH, Bethesda, MD 20892 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. RP Cutts, FT (reprint author), WHO, Initiat Vaccine Res, CH-1211 Geneva, Switzerland. EM cuttsf@who.int FU NIAID NIH HHS [N01-AI-25477] NR 29 TC 535 Z9 564 U1 4 U2 17 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD MAR-APR PY 2005 VL 365 IS 9465 BP 1139 EP 1146 DI 10.1016/S0140-6736(05)71876-6 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 910DD UT WOS:000227909500026 PM 15794968 ER PT J AU Lyon, GR AF Lyon, GR TI Why scientific research must guide educational policy and instructional practices in learning disabilities SO LEARNING DISABILITY QUARTERLY LA English DT Article C1 NICHHD, Child Dev & Behav Branch, Bethesda, MD 20892 USA. RP Lyon, GR (reprint author), NICHHD, Child Dev & Behav Branch, Bethesda, MD 20892 USA. NR 15 TC 5 Z9 5 U1 0 U2 0 PU COUNCIL LEARNING DISABILITIES PI LEESBURG PA PO BOX 4014, LEESBURG, VA 20177 USA SN 0731-9487 J9 LEARN DISABILITY Q JI Learn. Disabil. Q. PD SPR PY 2005 VL 28 IS 2 BP 140 EP 143 DI 10.2307/1593614 PG 4 WC Education, Special; Rehabilitation SC Education & Educational Research; Rehabilitation GA 991UG UT WOS:000233839000016 ER PT J AU Choi, IY Lee, SP Shen, J AF Choi, IY Lee, SP Shen, J TI Selective homonuclear Hartmann-Hahn transfer method for in vivo spectral editing in the human brain SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRS; Hartmann-Hahn transfer; GABA; human brain in vivo; spectral editing ID GAMMA-AMINOBUTYRIC-ACID; DOUBLE-QUANTUM FILTER; HUMAN CEREBRAL GABA; CORRELATION SPECTROSCOPY; COHERENCE TRANSFER; PULSES; POLARIZATION; GLUTATHIONE; MULTIPLETS; RESONANCES AB A novel selective homonuclear Hartmann-Hahn transfer method for in vivo spectral editing is proposed and applied to measurements of gamma-aminobutyric acid (GABA) in the human brain at 3 T. The proposed method utilizes a new concept for in vivo spectral editing, the spectral selectivity of which is not based on a conventional editing pulse but based on the stringent requirement of the doubly selective Hartmann-Hahn match. The sensitivity and spectral selectivity of GABA detection achieved by this doubly selective Hartmann-Hahn match scheme was superior to that achievable by conventional in vivo spectral editing techniques providing both sensitivity enhancement and excellent suppression of overlapping resonances in a single shot. Since double-quantum filtering gradients were not employed, singlets such as the NAA methyl group at 2.02 ppm and the creatine methylene group at 3.92 ppm were detected simultaneously. These singlets may serve as navigators for the spectral phase of GABA and for frequency shifts during measurements. The estimated concentration of GABA in the frontoparietal region of the human brain in vivo was 0.7 0.2ttmol/g (mean +/- SD,n = 12). C1 Nathan S Kline Inst Psychiat Res, Orangeburg, NY 10962 USA. NIMH, NIH, Bethesda, MD 20892 USA. RP Choi, IY (reprint author), Nathan S Kline Inst Psychiat Res, 140 Old Orangeburg Rd,Bldg 35, Orangeburg, NY 10962 USA. EM iychoi@nki.rfmh.org OI Lee, Phil/0000-0002-2087-8887 FU NIA NIH HHS [R03 AG 022193]; NIBIB NIH HHS [8R01 EB 00315] NR 32 TC 12 Z9 14 U1 0 U2 1 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD MAR PY 2005 VL 53 IS 3 BP 503 EP 510 DI 10.1002/mrm.20381 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 900PM UT WOS:000227226800002 PM 15723418 ER PT J AU Lee, JH Silva, AC Merkle, H Koretsky, AP AF Lee, JH Silva, AC Merkle, H Koretsky, AP TI Manganese-enhanced magnetic resonance imaging of mouse brain after systemic administration of MnCl2: Dose-dependent and temporal evolution of T-1 contrast SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE MRI; contrast agents; cortical layers; hippocampus; molecular imaging ID METAL-ION TRANSPORTER; IN-VIVO; 3D MRI; RAT; INJECTION; AGENTS; BLOOD; IRON; MN; CONNECTIONS AB Manganese is a useful contrast agent for MRI of animals. Previously, it has been shown that systemic doses of MnCl2, provide unique contrast in the rodent brain, enabling visualization of neuroarchitecture. The present work investigates the dose and temporal dependence of brain enhancement after i.v. administration of MnCl2 Varying doses of MnCl2 (9-175 mg/kg) were administered to mice from 0 to 24 h prior to T-1 -weighted manganese-enhanced MRI (MEMRI) at 11.7 T. Pre-MnCl2 T-1 values measured in different brain regions ranged from 1.17 +/- 0.03 to 1.76 +/- 0.01 s. Post-MnCl2 T-1 measured 24 hr after administration of MnCl2 were significantly decreased, even after the lowest dose of MnCl2. The largest decreases occurred in the pituitary gland, where post-MnCl2 T-1 ranged from 231 +/- 23 ms following the lowest dose to 143 +/- 43 ms after the highest dose, while the smallest decreases were observed in cortex (post-MnCl2 T-1 = 1060 +/- 5 ms for low dose and 637 +/- 5 ms for high dose). The contrast resulting after 14 hr did not change up to 24 hr. Enhancement first occurred in subarachnoid spaces, followed by ventricles and periventricular tissues, and finally reached the remainder of the brain. Cortical layers were detected at higher doses (>88 mg/kg) and olfactory bulb layers were detected with the lowest dose (9 mg/kg). Temporal evolution of the enhancement of the olfactory bulb layers was observed. In some regions of the brain, such as hippocampus and thalamus, the changes in contrast detected between 2 and 14 hr used very specific pathways. These results demonstrate that both the dose and the time after MnCl2 can be manipulated to optimize brain contrast in a region-specific manner. Published 2005 Wiley-Liss, Inc. C1 Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, Bethesda, MD 20892 USA. RP Koretsky, AP (reprint author), Natl Inst Neurol Disorders & Stroke, Lab Funct & Mol Imaging, NIH, 10 Ctr Dr,Bldg 10 Room B1D118, Bethesda, MD 20892 USA. EM KoretskyA@ninds.nih.gov RI Silva, Afonso/A-7129-2009; Koretsky, Alan/C-7940-2015 OI Koretsky, Alan/0000-0002-8085-4756 FU Intramural NIH HHS [Z01 NS002989-08] NR 40 TC 108 Z9 109 U1 0 U2 14 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD MAR PY 2005 VL 53 IS 3 BP 640 EP 648 DI 10.1002/mrm.20368 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 900PM UT WOS:000227226800018 PM 15723400 ER PT J AU St Lawrence, KS Frank, JA Bandettini, PA Ye, FQ AF St Lawrence, KS Frank, JA Bandettini, PA Ye, FQ TI Noise reduction in multi-slice arterial spin tagging imaging SO MAGNETIC RESONANCE IN MEDICINE LA English DT Article DE arterial spin tagging; arterial spin labeling; cerebral blood flow; blood oxygenation level dependant contrast; functional magnetic resonance imaging; physilogical noise ID CEREBRAL-BLOOD-FLOW; OXIDATIVE-METABOLISM; OXYGEN-CONSUMPTION; INDOMETHACIN; CORTEX; SIGNAL AB Attenuating the static signal in arterial spin tagging (ASSIST) was initially developed for 3D imaging of cerebral blood flow. To enable the simultaneous collection of cerebral blood flow and BOLD data, a multi-slice version of ASSIST is proposed. As with the 3D version, this sequence uses multiple inversion pulses during the tagging period to suppress the static signal. To maintain background suppression in all slices, the multi-slice sequence applies additional inversion pulses between slice acquisitions. The utility of the sequence was demonstrated by simultaneously acquiring ASSIST and BOLD data during a functional task and by collecting resting-state ASSIST data over a large number of slices. In addition, the temporal stability of the perfusion signal was found to be 60% greater at 3 T compared to 1.5 T, which was attributed to the insensitivity of ASSIST to physiologic noise. C1 NIH, Lab Diagnost Radiol Res, Ctr Clin, London, England. NIMH, Funct MRI Facil, Div Intramural Res Programs, NIH, Bethesda, MD USA. RP St Lawrence, KS (reprint author), St Josephs Hlth Care London, Lawson Hlth Res Inst, 268 Grosvenor St, London, ON N6A 4V2, Canada. EM kstlaw@lri.sjhc.london.on.ca RI Bandettini, Peter/F-5871-2012; St. Lawrence, Keith/B-5726-2015 NR 15 TC 76 Z9 76 U1 0 U2 0 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0740-3194 J9 MAGNET RESON MED JI Magn. Reson. Med. PD MAR PY 2005 VL 53 IS 3 BP 735 EP 738 DI 10.1002/mrm.20396 PG 4 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 900PM UT WOS:000227226800031 PM 15723412 ER PT J AU Ledin, KE Zeidner, NS Ribeiro, JMC Biggerstaff, BJ Dolan, MC Dietrich, G Vredevoe, L Piesman, J AF Ledin, KE Zeidner, NS Ribeiro, JMC Biggerstaff, BJ Dolan, MC Dietrich, G Vredevoe, L Piesman, J TI Borreliacidal activity of saliva of the tick Amblyomma americanum SO MEDICAL AND VETERINARY ENTOMOLOGY LA English DT Article DE Amblyomma americanum; Ixodes scapularis; borreliacidal effect; salivary glands; salivation; tick saliva ID LYME-DISEASE SPIROCHETE; WHITE-TAILED DEER; IXODES-SCAPULARIS; DERMACENTOR-VARIABILIS; UNITED-STATES; ACARINA-IXODIDAE; NORTH-CAROLINA; NEW-YORK; BURGDORFERI; TRANSMISSION AB Amblyomma americanum (Linneaus) (Acari: Ixodidae), an important tick vector of human and animal disease, is not a competent vector of the bacterial agent of Lyme disease, Borrelia burgdorferi, although its range overlaps the geographical distribution of Lyme disease within the United States. A possible mechanism that could prevent acquisition of B. burgdorferi spirochetes from infected hosts is the toxic effect of A. americanum saliva on B. burgdorferi. The data presented here indicate that after 24 and 48 h of exposure to A. americanum saliva, significantly fewer B. burgdorferi were alive compared to treatment controls as assessed by spirochete motility under dark-field microscopy and resistance to the dead stain, propidium iodide. After 48 h, fewer than 13% of saliva-exposed B. burgdorferi were alive. In contrast, significantly more B. burgdorferi exposed to Ixodes scapularis (Acari: Ixodidae) saliva survived after 24 or 48 h compared to A. americanum saliva or treatment controls. C1 Ctr Dis Control & Prevent, Div Vector Borne Infect Dis, Natl Ctr Infect Dis, Ft Collins, CO 80522 USA. NIAID, Lab Malaria & Vector Res, Sect Vector Biol, NIH, Bethesda, MD 20892 USA. California Polytech STate Univ San Luis Obispo, Dept Biol Sci, San Luis Obispo, CA USA. RP Zeidner, NS (reprint author), Ctr Dis Control & Prevent, Div Vector Borne Infect Dis, Natl Ctr Infect Dis, POB 2087, Ft Collins, CO 80522 USA. EM naz2@cdc.gov OI Ribeiro, Jose/0000-0002-9107-0818 NR 54 TC 21 Z9 21 U1 3 U2 11 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0269-283X J9 MED VET ENTOMOL JI Med. Vet. Entomol. PD MAR PY 2005 VL 19 IS 1 BP 90 EP 95 DI 10.1111/j.0269-283X.2005.00546.x PG 6 WC Entomology; Veterinary Sciences SC Entomology; Veterinary Sciences GA 902XN UT WOS:000227390100012 PM 15752182 ER PT J AU Shaw, JW Johnson, JA Coons, SJ AF Shaw, JW Johnson, JA Coons, SJ TI US valuation of the EQ-5D health states - Development and testing of the D1 valuation model SO MEDICAL CARE LA English DT Article; Proceedings Paper CT 5th Annual Workshop of the Drug-Information-Association CY JAN 21-23, 2004 CL Tucson, AZ SP Drug Info Assoc DE EQ-5D; health status; preference weights; time trade-off (TTO) ID CHI-SQUARED TESTS; GENERAL-POPULATION; SYSTEM; MULTIATTRIBUTE; PREFERENCES; EUROQOL; SAMPLE; TABLES; SF-12 AB Purpose: The EQ-5D is a brief, multiattribute, preference-based health status measure. This article describes the development of a statistical model for generating US population-based EQ-5D preference weights. Methods: A multistage probability sample was selected from the US adult civilian noninstitutional population. Respondents valued 13 of 243 EQ-5D health states using the time trade-off (TTO) method. Data for 12 states were used in econometric modeling. The TTO valuations were linearly transformed to lie on the interval [-1, 1]. Methods were investigated to account for interaction effects caused by having problems in multiple EQ-5D dimensions. Several alternative model specifications (eg, pooled least squares, random effects) also were considered. A modified split-sample approach was used to evaluate the predictive accuracy of the models. All statistical analyses took into account the clustering and disproportionate selection probabilities inherent in our sampling design. Results: Our D1 model for the EQ-5D included ordinal terms to capture the effect of departures from perfect health as well as interaction effects. A random effects specification of the D1 model yielded a good fit for the observed TTO data, with an overall R-2 of 0.38, a mean absolute error of 0.025, and 7 prediction errors exceeding 0.05 in absolute magnitude. Conclusions: The D1 model best predicts the values for observed health states. The resulting preference weight estimates represent a significant enhancement of the EQ-5D's utility for health status assessment and economic analysis in the US. C1 Univ Arizona, Coll Pharm, Ctr Hlth Outcomes & PharamcoEcon Res, Tucson, AZ 85721 USA. Univ Alberta, Edmonton, AB, Canada. Inst Hlth Econ, Edmonton, AB, Canada. NCI, Tobacco Control Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Coons, SJ (reprint author), Univ Arizona, Coll Pharm, Ctr Hlth Outcomes & PharamcoEcon Res, POB 210207, Tucson, AZ 85721 USA. EM coons@pharmacy.arizona.edu FU AHRQ HHS [5 R01 HS10243] NR 47 TC 624 Z9 634 U1 5 U2 37 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD MAR PY 2005 VL 43 IS 3 BP 203 EP 220 DI 10.1097/00005650-200503000-00003 PG 18 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 900WD UT WOS:000227244100003 PM 15725977 ER PT J AU Johnson, JA Luo, N Shaw, JW Kind, P Coons, SJ AF Johnson, JA Luo, N Shaw, JW Kind, P Coons, SJ TI Valuations of EQ-5D health states - Are the United States and United kingdom different? SO MEDICAL CARE LA English DT Article DE EQ-5D; health preference; health-related quality of life; population survey; time trade-off; valuation ID TRADE-OFF VALUES; GENERAL-POPULATION; EUROQOL; MULTIATTRIBUTE; UTILITIES; SYSTEM AB Purpose: We sought to compare directly elicited valuations for EQ-5D health states between the US and UK general adult populations. Methods: We analyzed data from 2 EQ-5D) valuation studies where, using similar time trade-off protocols, values for 42 common health states were elicited from representative samples of the US and UK general adult populations. First, US and UK population mean valuations were estimated and compared for each health state. Second, random-effect models were used to compare the US and UK valuations while adjusting for known predictors of EQ-5D valuations (ie, age, sex, health state descriptors) and to investigate whether and how the valuations differ. Results: Population mean valuations of the 42 health states ranged from -0.38 to 0.88 for the United States and from -0.54 to 0.88 for the United Kingdom, with the US mean scores being numerically higher than the UK for 39 health states (mean difference: 0. 11; range: - 0.0 1 to 0.25). After adjusting for the main effects of known predictors, the average difference in valuations was 0.10 (P < 0.001). The magnitude of the difference in the US and UK valuations was not constant across EQ-5D) health states; greater differences in valuations were present in health states characterized by extreme problems. Conclusions: Meaningful differences exist in directly elicited TTO valuations of EQ-5D health states between the US and UK general populations. Therefore, EQ-5D index scores generated using valuations from the US general population should be used for studies aiming to reflect health state preferences of the US general public. C1 Univ Arizona, Coll Pharm, Ctr Hlth Outcomes & PharmacoEcon Res, Tucson, AZ 85721 USA. York Univ, Ctr Hlth Econ, York, N Yorkshire, England. NCI, Div Canc Control & Populat Sci, Behav Res Program, Tobacco Control Res Branch, Bethesda, MD 20892 USA. Univ Alberta, Edmonton, AB, Canada. Inst Hlth Econ, Edmonton, AB, Canada. RP Coons, SJ (reprint author), Univ Arizona, Coll Pharm, Ctr Hlth Outcomes & PharmacoEcon Res, POB 21207, Tucson, AZ 85721 USA. EM coons@pharmacy.arizona.edu RI Luo, Nan/G-1419-2014 FU AHRQ HHS [5 R01 HS10243] NR 22 TC 140 Z9 142 U1 2 U2 6 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0025-7079 J9 MED CARE JI Med. Care PD MAR PY 2005 VL 43 IS 3 BP 221 EP 228 DI 10.1097/00005650-200503000-00004 PG 8 WC Health Care Sciences & Services; Health Policy & Services; Public, Environmental & Occupational Health SC Health Care Sciences & Services; Public, Environmental & Occupational Health GA 900WD UT WOS:000227244100004 PM 15725978 ER PT J AU Yant, SR Wu, XL Huang, Y Garrison, B Burgess, SM Kay, MA AF Yant, SR Wu, XL Huang, Y Garrison, B Burgess, SM Kay, MA TI High-resolution genome-wide mapping of transposon integration in mammals SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID SLEEPING-BEAUTY TRANSPOSITION; TARGET SITE SELECTION; LONG-TERM EXPRESSION; IN-VIVO; GENE-EXPRESSION; CHROMOSOMAL TRANSPOSITION; INSERTIONAL MUTAGENESIS; CAENORHABDITIS-ELEGANS; TRANSGENE EXPRESSION; DIRECTS INTEGRATION AB The Sleeping Beauty (SB) transposon is an emerging tool for transgenesis, gene discovery, and therapeutic gene delivery in mammals. Here we studied 1,336 SB insertions in primary and cultured mammalian cells in order to better understand its target site preferences. We report that, although widely distributed, SB integration recurrently targets certain genomic regions and shows a small but significant bias toward genes and their upstream regulatory sequences. Compared to those of most integrating viruses, however, the regional preferences associated with SB-mediated integration were much less pronounced and were not significantly influenced by transcriptional activity. Insertions were also distinctly nonrandom with respect to intergenic sequences, including a strong bias toward microsatellite repeats, which are predominantly enriched in noncoding DNA. Although we detected a consensus sequence consistent with a twofold dyad symmetry at the target site, the most widely used sites did not match this consensus. In conjunction with an observed SB integration preference for bent DNA, these results suggest that physical properties may be the major determining factor in SB target site selection. These findings provide basic insights into the transposition process and reveal important distinctions between transposon- and virus-based integrating vectors. C1 Stanford Univ, Sch Med, Dept Pediat, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Genet, Stanford, CA USA. NCI, Lab Mol Technol, SAIC Frederick, Frederick, MD USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Kay, MA (reprint author), Stanford Univ, Sch Med, Dept Pediat, 300 Pasteur Dr,Room G-305, Stanford, CA 94305 USA. EM markay@stanford.edu OI Burgess, Shawn/0000-0003-1147-0596 FU NIAMS NIH HHS [AR44012, P01 AR044012] NR 63 TC 200 Z9 207 U1 0 U2 7 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAR PY 2005 VL 25 IS 6 BP 2085 EP 2094 DI 10.1128/MCB.25.6.2085-2094.2005 PG 10 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 904DC UT WOS:000227475300002 PM 15743807 ER PT J AU Kim, YS Nedospasov, SA Liu, ZG AF Kim, YS Nedospasov, SA Liu, ZG TI TRAF2 plays a key, nonredundant role in LIGHT-lymphotoxin beta receptor signaling SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID NF-KAPPA-B; HERPESVIRUS ENTRY MEDIATOR; DOMAIN KINASE RIP; CELL-DEATH; SPLENIC MICROARCHITECTURE; IMMUNE-RESPONSES; TNF SUPERFAMILY; IKK ACTIVATION; MAP KINASES; T-CELLS AB LIGHT is a member of the tumor necrosis factor (TNF) superfamily, and its function is mediated by at least two receptors, including lymphotoxin P receptor (LTbetaR) and herpes simplex virus entry mediator. However, the molecular mechanism of LIGHT signaling mediated by LTbetaR has not been clearly defined. In this report, we demonstrate that TRAF2 is critical for LIGHT- and LTbetaR-mediated activation of both the transcription factor NF-kappaB and the mitogen-activated protein kinase JNK. In HeLa cells, LIGHT induces NF-kappaB and JNK activation, which can be blocked by the dominant negative mutant of TRAF2. In these cells, LIGHT causes the recruitment of TRAF2, TRAF3, and IkappaB kinase into the LTbetaR complex. Importantly, while both NF-kappaB and JNK are activated by LIGHT in wild-type mouse embryonic fibroblasts, no activation of either of these two pathways is observed in TRAF2 null fibroblasts. However, LIGHT-induced NF-kappaB and JNK activation can be restored by ectopic expression of TRAF2 in TRAF(-/-) cells. Interestingly, in contrast to TNF signaling, the activation of both NF-kappaB and JNK by LIGHT was normal in RIP-/- and TRAF5(-/-) cells. Taken together, our data demonstrate that TRAF2, an important effector molecule of TNF signaling, plays a critical, nonredundant role in LIGHT-LTbetaR signaling. C1 NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. SAIC Frederick Inc, Basic Res Program, Frederick, MD USA. NCI, Mol Immunoregulat Lab, Frederick, MD 21701 USA. RP Liu, ZG (reprint author), NCI, Cell & Canc Biol Branch, Ctr Canc Res, NIH, Bldg 10,Rm 6N105,9000 Rockville Pike, Bethesda, MD 20892 USA. EM zgliu@helix.nih.gov RI Nedospasov, Sergei/J-5936-2013; Nedospasov, Sergei/L-1990-2015; Nedospasov, Sergei/Q-7319-2016 FU NCI NIH HHS [N01-CO-12400, N01CO12400] NR 56 TC 32 Z9 33 U1 0 U2 2 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAR PY 2005 VL 25 IS 6 BP 2130 EP 2137 DI 10.1128/MCB.25.6.2130-2137.2005 PG 8 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 904DC UT WOS:000227475300006 PM 15743811 ER PT J AU Rayasam, GV Elbi, C Walker, DA Wolford, R Fletcher, TM Edwards, DP Hager, GL AF Rayasam, GV Elbi, C Walker, DA Wolford, R Fletcher, TM Edwards, DP Hager, GL TI Ligand-specific dynamics of the progesterone receptor in living cells and during chromatin remodeling in vitro SO MOLECULAR AND CELLULAR BIOLOGY LA English DT Article ID GLUCOCORTICOID-RECEPTOR; NUCLEAR RECEPTORS; TRANSCRIPTION FACTORS; ESTROGEN-RECEPTOR; MOLECULAR CHAPERONES; GENE-EXPRESSION; BINDING; DNA; NUCLEOSOME; COMPLEXES AB Progesterone receptor (PR), a member of the nuclear receptor superfamily, is a key regulator of several processes in reproductive function. We have studied the dynamics of the interaction of PR with a natural target promoter in living cells through the use of fluorescence recovery after photobleaching (FRAP) analysis and also have characterized the dynamics of the interaction of PR with the mouse mammary tumor virus (MMTV) promoter reconstituted into chromatin in vitro. In photobleaching experiments, PR in the presence of the agonist R5020 exhibits rapid exchange with the MMTV promoter in living cells. Two PR antagonists, RU486 and ZK98299, have opposite effects on receptor dynamics in vivo. In the presence of RU486, PR binds to the promoter and is exchanged more slowly than the agonist-activated receptor. In contrast, PR bound to ZK98299 is not localized to the promoter and exhibits higher mobility in the nucleoplasm than the agonist-bound receptor. Significantly, PR bound to R5020 or RU486 can recruit the SWI/SNF chromatin remodeling complex to the promoter, but PR activated with ZK98299 cannot. Furthermore, we found ligand-specific active displacement of PR from the MMTV promoter during chromatin remodeling in vitro and conclude that the interaction of PR with chromatin is highly dynamic both in vivo and in vitro. We propose that factor displacement during chromatin remodeling is an important component of receptor mobility and that ligand-specific interactions with remodeling complexes can strongly influence receptor nuclear dynamics and rates of exchange with chromatin in living cells. C1 NCI, Lab Receptor Biol & Gene Express, NIH, Bethesda, MD 20892 USA. Univ Colorado, Sch Med, Dept Pathol, Denver, CO 80262 USA. Univ Colorado, Sch Med, Mol Biol Program, Denver, CO 80262 USA. RP Hager, GL (reprint author), NCI, Lab Receptor Biol & Gene Express, NIH, Bldg 41,B602,41 Library Dr, Bethesda, MD 20892 USA. EM hagerg@exchange.nih.gov NR 47 TC 82 Z9 85 U1 1 U2 1 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0270-7306 J9 MOL CELL BIOL JI Mol. Cell. Biol. PD MAR PY 2005 VL 25 IS 6 BP 2406 EP 2418 DI 10.1128/MCB.25.6.2406-2418.2005 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 904DC UT WOS:000227475300028 PM 15743833 ER PT J AU Sonntag, KC Simantov, R Bjorklund, L Cooper, O Pruszak, J Kowalke, F Gilmartin, J Ding, JX Hu, YP Shen, MM Isacson, O AF Sonntag, KC Simantov, R Bjorklund, L Cooper, O Pruszak, J Kowalke, F Gilmartin, J Ding, JX Hu, YP Shen, MM Isacson, O TI Context-dependent neuronal differentiation and germ layer induction of Smad4(-/-) and Cripto(-/-) embryonic stem cells SO MOLECULAR AND CELLULAR NEUROSCIENCE LA English DT Article ID DOPAMINERGIC-NEURONS; NEURAL INDUCTION; MOUSE EMBRYOS; PARKINSONS-DISEASE; FATE SPECIFICATION; IN-VITRO; GENE; TRANSPLANTATION; ORGANIZER; MIDBRAIN AB Activation of transforming growth factor-beta (TGF-beta) receptors typically elicits mesodermal development, whereas inhibition of this pathway induces neural fates. In vitro differentiated mouse embryonic stem (ES) cells with deletion of the TGF-beta pathway-related factors Smad4 or Cripto exhibited increased numbers of neurons. Cripto(-/-) ES cells developed into neuroecto-/epidermal cell types, while Smad4(-/-) cells also displayed mesodermal differentiation. ES cell differentiation into catecholaminergic neurons showed that these ES cells retained their ability to develop into dopaminergic and serotonergic neurons with typical expression patterns of midbrain and hindbrain genes. In vivo, transplanted ES cells to the mouse striatum became small neuronal grafts, or large grafts with cell types from all germ layers independent of their ES cell genotype. This demonstrates that Smad4(-/-) and Cripto(-/-) ES cells favor a neural fate in vitro, but also express the mesodermal phenotype, implying that deletion of either Smad4 or Cripto is not sufficient to block nonneuronal tissue formation. (c) 2004 Elsevier Inc. All rights reserved. C1 Harvard Univ, McLean Hosp, Neuroregenerat Labs, Sch Med, Belmont, MA 02478 USA. Harvard Univ, McLean Hosp, Udall Parkinsons Dis Res Ctr Excellence, Sch Med, Belmont, MA 02478 USA. Univ Louisville, Sch Dent, Birth Defects Res Ctr, Dept Mol Cellular & Craniofacial Biol, Louisville, KY 40202 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Ctr Adv Biotechnol & Med, Piscataway, NJ 08854 USA. Univ Med & Dent New Jersey, Robert Wood Johnson Med Sch, Dept Pediat, Piscataway, NJ 08854 USA. RP Isacson, O (reprint author), Harvard Univ, McLean Hosp, Neuroregenerat Labs, Sch Med, MRC 120,115 Mill St, Belmont, MA 02478 USA. EM isacson@hms.harvard.edu RI Shen, Michael/C-7546-2009; Pruszak, Jan/G-6972-2015; OI Shen, Michael/0000-0002-4042-1657; Pruszak, Jan/0000-0003-4297-4009; Cooper, Oliver/0000-0001-6567-7491 FU NCRR NIH HHS [P20-RR/DE17702]; NICHD NIH HHS [HD042837]; NIMH NIH HHS [MH48866]; NINDS NIH HHS [P50 NS039793-06A1]; PHS HHS [(P50)N539793] NR 45 TC 27 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 1044-7431 J9 MOL CELL NEUROSCI JI Mol. Cell. Neurosci. PD MAR PY 2005 VL 28 IS 3 BP 417 EP 429 DI 10.1016/j.mcn.2004.06.003 PG 13 WC Neurosciences SC Neurosciences & Neurology GA 906DK UT WOS:000227620500002 PM 15737733 ER PT J AU Niu, TK Pfeifer, AC Lippincott-Schwartz, J Jackson, CL AF Niu, TK Pfeifer, AC Lippincott-Schwartz, J Jackson, CL TI Dynamics of GBF1, a brefeldin A-sensitive Arf1 exchange factor at the Golgi SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID ADP-RIBOSYLATION FACTORS; LIVING CELLS; COPI COAT; NUCLEOTIDE; PROTEIN; MECHANISM; FAMILY; DOMAIN AB Trafficking through the Golgi apparatus requires members of the Arf family of GTPases, whose activation is regulated by guanine nucleotide exchange factors (GEFs). Once activated, Arf-GTP recruits effectors such as coat complexes and lipid-modifying enzymes to specific membrane sites, creating a domain competent for cargo concentration and transport. GBF1 is a peripherally associated Arf GEF involved in both endoplasmic reticulum-Golgi and intra-Golgi transport. The mechanism of GBF1 binding to membranes is unknown. As a first step to understanding the mechanism of membrane association, we constructed a yellow fluorescent protein-tagged version of GBF1 and performed fluorescence recovery after photobleaching analysis to determine its residence time on Golgi membranes. We find that GBF1 molecules are not stably associated with the Golgi but rather cycle rapidly on and off membranes. The drug brefeldin A (BFA), an uncompetitive inhibitor of the exchange reaction that binds to an Arf-GDP-Arf GEF complex, stabilizes GBF1 on Golgi membranes. Using an in vivo assay to monitor Arf1-GTP levels, we show that GBF1 exchange activity on Arf1 is inhibited by BFA in mammalian cells. These results suggest that an Arf1-GBF1-BFA complex is formed and has a longer residence time on Golgi membranes than GBF1 or Arf1 alone. C1 NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. RP Jackson, CL (reprint author), NICHHD, Cell Biol & Metab Branch, NIH, Bethesda, MD 20892 USA. EM cathyj@helix.nih.gov RI Jackson, Catherine/A-3421-2013 OI Jackson, Catherine/0000-0002-0843-145X NR 28 TC 123 Z9 127 U1 0 U2 3 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD MAR PY 2005 VL 16 IS 3 BP 1213 EP 1222 DI 10.1091/mbc.E04-07-0599 PG 10 WC Cell Biology SC Cell Biology GA 902SZ UT WOS:000227378100017 PM 15616190 ER PT J AU Balla, A Tuymetova, G Tsiomenko, A Varnai, P Balla, T AF Balla, A Tuymetova, G Tsiomenko, A Varnai, P Balla, T TI A plasma membrane pool of phosphatidylinositol 4-phosphate is generated by phosphatidylinositol 4-kinase type-III alpha: Studies with the PH domains of the oxysterol binding protein and FAPP1 SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID PLECKSTRIN HOMOLOGY DOMAINS; SACCHAROMYCES-CEREVISIAE; GOLGI; YEAST; LOCALIZATION; ASSOCIATION; REVEALS; PHOSPHOINOSITIDES; TRAFFICKING; SECRETION AB The PH domains of OSBP and FAPP1 fused to GFP were used to monitor PI(4)P distribution in COS-7 cells during manipulations of PI 4-kinase (PI4K) activities. Both domains were associated with the Golgi and small cytoplasmic vesicles, and a small fraction of OSBP-PH was found at the plasma membrane (PM). Inhibition of type-III PI4Ks with 10 muM wortmannin (Wm) significantly reduced but did not abolish Golgi localization of either PH domains. Down-regulation of PI4KIIalpha or PI4KIIIbeta by siRNA reduced the localization of the PH domains to the Golgi and in the former case any remaining Golgi localization was eliminated by Wm treatment. PLC activation by Ca2+ ionophores dissociated the domains from all membranes, but after Ca2+ chelation, they rapidly reassociated with the Golgi, the intracellular vesicles and with the PM. PM association of the domains was significantly higher after the Ca2+ transient and was abolished by Wm pretreatment. PM relocalization was not affected by down-regulation of PI4KIIIbeta or -IIalpha, but was inhibited by down-regulation of PI4KIIIalpha, or by 10 muM PAO, which also inhibits PI4KIIIalpha. Our data suggest that these PH domains detect PIMP formation in extra-Golgi compartments under dynamic conditions and that various PI4Ks regulate PI(4)P synthesis in distinct cellular compartments. C1 NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. Semmelweis Univ, Fac Med, Dept Physiol, H-1085 Budapest, Hungary. RP Balla, T (reprint author), NICHHD, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. EM tambal@box-t.nih.gov OI Balla, Tamas/0000-0002-9077-3335; Balla, Andras/0000-0002-6450-2793 NR 43 TC 128 Z9 131 U1 1 U2 6 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD MAR PY 2005 VL 16 IS 3 BP 1282 EP 1295 DI 10.1091/mbc.E04-07-0578 PG 14 WC Cell Biology SC Cell Biology GA 902SZ UT WOS:000227378100023 PM 15635101 ER PT J AU Hu, W Xu, RJ Zhang, GF Jin, JF Szulc, ZM Bielawski, J Hannun, YA Obeid, LM Mao, CG AF Hu, W Xu, RJ Zhang, GF Jin, JF Szulc, ZM Bielawski, J Hannun, YA Obeid, LM Mao, CG TI Golgi fragmentation is associated with ceramide-induced cellular effects SO MOLECULAR BIOLOGY OF THE CELL LA English DT Article ID ACTIN CYTOSKELETON; INDUCED APOPTOSIS; FOCAL ADHESION; CELLS; GLYCOSYLATION; FIBRONECTIN; METABOLISM; RECEPTOR; BETA-1-INTEGRINS; ORGANIZATION AB Ceramide has been shown to cause anoikis, a subtype of apoptosis due to inadequate cell adhesion. However, the underlying mechanism is unclear. Herein, we report that D-e-C-6-ceramide (D-e-Cer), via generating sphingosine, disrupts the Golgi complex (GC), which is associated with various cellular effects, including anoikis. Treatment of HeLa cells with D-e-Cer caused cell elongation, spreading inhibition, rounding, and detachment before apoptosis (anoikis). In D-e-Cer-treated cells, glycosylation of beta1 integrin in the GC was inhibited, thus its associated integrin receptors failed to translocate to the cell surface. Ceramide treatment also inhibited the reorganization of both microtubule and F-actin cytoskeletons, focal adhesions, and filopodia. These cellular effects were preceded by fragmentation of the Golgi complex. In contrast, L-e-C-6-ceramide (L-e-Cer), the enantiomer of D-e-Cer, failed to induce these cellular effects. Mass spectrometric analysis revealed that treatment HeLa cells with D-e-Cer but not L-e-Cer caused a >50-fold increase in the levels of sphingosine, a product of hydrolysis of ceramide. Treatment with D-e-sphingosine and its enantionter, L-e-sphingosine, caused massive perinuclear vacuolization, Golgi fragmentation, and cell rounding. Together, these results suggest that sphingosine generated from hydrolysis of ceramide causes the GC disruption, leading to various cellular effects. C1 Med Univ S Carolina, Dept Med & Biochem, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Mol Biol, Charleston, SC 29425 USA. NIH, Div Bioengn & Phys Sci, Bethesda, MD 20892 USA. Ralph H Johnson Vet Adm Hosp, Charleston, SC 29401 USA. RP Mao, CG (reprint author), Med Univ S Carolina, Dept Med & Biochem, Charleston, SC 29425 USA. EM maoc@musc.edu OI obeid, lina/0000-0002-0734-0847 FU NCI NIH HHS [R01 CA104834, P01 CA097132]; NCRR NIH HHS [P20 RR017677, P20RR017677] NR 45 TC 53 Z9 56 U1 0 U2 0 PU AMER SOC CELL BIOLOGY PI BETHESDA PA 8120 WOODMONT AVE, STE 750, BETHESDA, MD 20814-2755 USA SN 1059-1524 J9 MOL BIOL CELL JI Mol. Biol. Cell PD MAR PY 2005 VL 16 IS 3 BP 1555 EP 1567 DI 10.1091/mbc.E04-07-0594 PG 13 WC Cell Biology SC Cell Biology GA 902SZ UT WOS:000227378100046 PM 15647381 ER PT J AU Tsai, MH Yan, HL Chen, X Chandramouli, GVR Zhao, SP Coffin, D Coleman, CN Mitchell, JB Chuang, EY AF Tsai, MH Yan, HL Chen, X Chandramouli, GVR Zhao, SP Coffin, D Coleman, CN Mitchell, JB Chuang, EY TI Evaluation of hybridization conditions for spotted oligonucleotide-based DNA microarrays SO MOLECULAR BIOTECHNOLOGY LA English DT Article DE gene expression; hybridization conditions; oligonucleotide microarrays ID GENE-EXPRESSION; ATTACHMENT AB We compared different hybridization conditions of oligonucleotide-based DNA microarray to acquire optimized and reliable microarray data. Several parameters were evaluated at different hybridization conditions, including signal-to-background (S:B) ratios, signal dynamic range, usable spots, and reproducibility Statistical analysis showed that better results were obtained when spotted, presynthesized long oligonucleotide arrays were blocked with succinic anhydride and hybridized at 42&DEG; C in the presence of 50% formamide. C1 NCI, Radiat Oncol Sci Program, Radiat Oncol Branch, Biol Branch,Ctr Canc Res,NIH, Gaithersburg, MD 20878 USA. RP Chuang, EY (reprint author), NCI, Radiat Oncol Sci Program, Radiat Oncol Branch, Biol Branch,Ctr Canc Res,NIH, 8717 Grovemont Cr,Room 109J, Gaithersburg, MD 20878 USA. EM chuange@mail.nih.gov NR 8 TC 2 Z9 2 U1 0 U2 2 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 1073-6085 J9 MOL BIOTECHNOL JI Mol. Biotechnol. PD MAR PY 2005 VL 29 IS 3 BP 221 EP 224 DI 10.1385/MB:29:3:221 PG 4 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology GA 927CV UT WOS:000229170900004 PM 15767699 ER PT J AU Kim, JS Baek, SJ Sali, T Eling, TE AF Kim, JS Baek, SJ Sali, T Eling, TE TI The conventional nonsteroidal anti-inflammatory drug sulindac sulfide arrests ovarian cancer cell growth via the expression of NAG-1/MIC-1/GDF-15 SO MOLECULAR CANCER THERAPEUTICS LA English DT Article ID ACTIVATED GENE NAG-1; BETA SUPERFAMILY MEMBER; ORAL-CONTRACEPTIVES; CYCLIN D1; APOPTOSIS; P53; INHIBITORS; TUMORS; LINES; OVEREXPRESSION AB Although the chemopreventive and antitumorigenic activities of nonsteroidal anti-inflammatory drugs MAID) against colorectal cancer are well established, the molecular mechanisms responsible for these properties in ovarian cancer have not been elucidated. Therefore, there is an urgent need to develop mechanism-based approaches for the management of ovarian cancer. To this end, the effect of several NSAIDs on ovarian cancer cells was investigated as assessed by the induction of NAG-1/MIC-1/GDF-15, a proapoptotic gene belonging to the transforming growth factor-p superfamily. Sulindac sulfide was the most significant NSAID activated gene 1 (NAG-1) inducer and its expression was inversely associated with cell viability as determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)- 2-(4-sulfophenyl)-2H-tetrazolium assay. This growth suppression by sulindac sulfide was recovered by transfection of NAGA small interfering RNA. These results indicate that NAG-1 is one of the genes responsible for growth suppression by sulindac sulfide. Furthermore, we observed down-regulation of p21 WAF1/CIP1 by introduction of NAG-1 small interfering RNA into sulindac sulfide-treated cells. In addition, to elucidate other potential molecular mechanisms involved in sulindac sulfide treatment of ovarian cancer cells, we did a membrane-based microarray experiment. We found that cyclin D1, MMP-1, P13KR1, and uPA were down-regulated by sulindac sulfide. In conclusion, a novel molecular mechanism is proposed to explain the experimental results and provide a rationale for the chemopreventive activity of NSAIDs in ovarian cancer. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Tennessee, Lab Environm Carcinogenesis, Dept Pathobiol, Coll Vet Med, Knoxville, TN USA. RP Eling, TE (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, MD E4-09,POB 12233,111 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM eling@niehs.nih.gov OI Baek, Seung/0000-0001-7866-7778 NR 36 TC 50 Z9 51 U1 1 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1535-7163 J9 MOL CANCER THER JI Mol. Cancer Ther. PD MAR PY 2005 VL 4 IS 3 BP 487 EP 493 PG 7 WC Oncology SC Oncology GA 905SI UT WOS:000227589600016 PM 15767558 ER PT J AU Hewitt, SC Collins, J Grissom, S Deroo, B Korach, KS AF Hewitt, SC Collins, J Grissom, S Deroo, B Korach, KS TI Global uterine Genomics in vivo: Microarray evaluation of the estrogen receptor alpha-growth factor cross-talk mechanism SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID FACTOR BINDING-PROTEINS; RAT UTERUS; CELL-PROLIFERATION; SIGNALING PATHWAYS; GENE-EXPRESSION; MAPK ACTIVATION; BREAST-CANCER; C-FOS; ESTRADIOL; MOUSE AB Cross-talk between growth factor receptors and the estrogen receptor ( ER) has been proposed as a signaling mechanism in estrogen target tissues, with ERalpha as a direct target of growth factor receptor-activated signals, leading to regulation of estrogen target genes and estrogen-like biological responses to growth factors. We evaluated whether global genomic changes in the mouse uterus in response to epidermal growth factor or IGF-I mimic those of estradiol (E2), reflecting the cross-talk mechanism. Overlapping responses to growth factors and E2 were expected in the wild type (WT) whereas no response was expected in mice lacking ERalpha (ERalpha knockout). Surprisingly, although most of the E2 response in the WT also occurred after growth factor treatment, some genes were induced only by E2. Second, although E2 did not induce gene changes in the alphaER knockout, the growth factor response was almost indistinguishable from that of the WT. Differences in response of some genes to IGF-I or epidermal growth factor indicated selective regulation mechanisms, such as phosphatidylinositol 3-kinase or MAPK-dependent responses. The robust ERalpha-independent genomic response to growth factor observed here is surprising considering that the biological growth response is ERalpha dependent. We propose two mechanisms as alternatives to the cross-talk mechanism for uterine gene regulation. First, E2 increases uterine growth factors, which activate downstream signaling cascades, resulting in gene regulation. Second, growth factors and estrogen regulate similar genes. Our results suggest that the estrogen response in the uterus involves E2-specific ERalpha-mediated responses as well as responses resulting from convergence of growth factor and ER-initiated activities. C1 NIEHS, Receptor Biol Sect, Res Triangle Pk, NC 27709 USA. NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. NIEHS, Microarray Grp, Res Triangle Pk, NC 27709 USA. RP Hewitt, SC (reprint author), NIEHS, Receptor Biol Sect, POB 12233, Res Triangle Pk, NC 27709 USA. EM curtiss@niehs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X NR 49 TC 51 Z9 51 U1 0 U2 2 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD MAR PY 2005 VL 19 IS 3 BP 657 EP 668 DI 10.1210/me.2004-0142 PG 12 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 903XB UT WOS:000227457800009 PM 15528273 ER PT J AU Minn, AH Lan, H Rabaglia, ME Harlan, DM Peculis, BA Attie, AD Shalev, A AF Minn, AH Lan, H Rabaglia, ME Harlan, DM Peculis, BA Attie, AD Shalev, A TI Increased insulin translation from an insulin splice-variant overexpressed in diabetes, obesity, and insulin resistance SO MOLECULAR ENDOCRINOLOGY LA English DT Article ID PANCREATIC BETA-CELL; MESSENGER-RNA; PROINSULIN BIOSYNTHESIS; WHITE FAT; GLUCOSE; EXPRESSION; MICE; ELONGATION; MELLITUS; FAILURE AB Type 2 diabetes occurs when pancreatic beta-cells become unable to compensate for the underlying insulin resistance. Insulin secretion requires beta-cell insulin stores to be replenished by insulin biosynthesis, which is mainly regulated at the translational level. Such translational regulation often involves the 5'- untranslated region. Recently, we identified a human insulin splice- variant (SPV) altering only the 5'- untranslated region and conferring increased translation efficiency. We now describe a mouse SPV (mSPV) that is found in the cytoplasm and exhibits increased translation efficiency resulting in more normal ( prepro) insulin protein per RNA. The RNA stability of mSPV is not increased, but the predicted secondary RNA structure is altered, which may facilitate translation. To determine the role of mSPV in insulin resistance and diabetes, mSPV expression was measured by quantitative real-time RT-PCR in islets from three diabetic and/or insulin-resistant, obese and nonobese, mouse models (BTBRob/ob, C57BL/6ob/ob, and C57BL/6azip). Interestingly, mSPV expression was significantly higher in all diabetic/insulin-resistant mice compared with wild-type littermates and was dramatically induced in primary mouse islets incubated at high glucose. This raises the possibility that the mSPV may represent a compensatory beta-cell mechanism to enhance insulin biosynthesis when insulin requirements are elevated by hyperglycemia/insulin resistance. C1 Univ Wisconsin, Dept Med, Madison, WI 53792 USA. Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. NIDDKD, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Shalev, A (reprint author), Univ Wisconsin, Dept Med, H4-526 Clin Sci Ctr,600 Highland Ave, Madison, WI 53792 USA. EM as7@medicine.wisc.edu FU PHS HHS [58037-01] NR 30 TC 20 Z9 21 U1 0 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0888-8809 J9 MOL ENDOCRINOL JI Mol. Endocrinol. PD MAR PY 2005 VL 19 IS 3 BP 794 EP 803 DI 10.1210/me.2004-0119 PG 10 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 903XB UT WOS:000227457800020 PM 15550470 ER PT J AU Schiffmann, R AF Schiffmann, R TI Childhood ataxia with CNS hypomyelination (CACH)/vanishing white matter disease (VWM) is a common leukodystrophy caused by abnormal control of protein synthesis. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2005) CY MAR 06-09, 2005 CL Pacific Grove, CA SP Genzyme Corp, Mead Johnson Nutr, NIDDK, NIH, Off Rare Dis, Dept Hlth & Human Serv, Ucyclyd Pharma, Actelion Pharmaceut US Inc, Abbott Labs, Ross Prod Div, SHS N Amer, Appl Biosyst, Appl Nutr Corp, BioMarin Pharmaceut Inc, Milupa N Amer, Vitaflo, Biochrom Inc, Cambrooke Foods, Hitachi High Technologies Amer Inc, Natl Urea Cycle Defects Fdn, Pickering Labs Inc, Rare Dis Therapeut Inc, Sigma Tau Pharmaceut, Transkarot Therapies Inc C1 NINDS, 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2005 VL 84 IS 3 BP 198 EP 198 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 906NH UT WOS:000227648400007 ER PT J AU Helip-Wooley, A Dorward, H Westbroek, W Stanescu, H Hess, R Boissy, R Huizing, M Gahl, WA AF Helip-Wooley, A Dorward, H Westbroek, W Stanescu, H Hess, R Boissy, R Huizing, M Gahl, WA TI Unraveling lysosome-related organelle biogenesis through the cell biology of Hermansky-Pudlak syndrome. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2005) CY MAR 06-09, 2005 CL Pacific Grove, CA SP Genzyme Corp, Mead Johnson Nutr, NIDDK, NIH, Off Rare Dis, Dept Hlth & Human Serv, Ucyclyd Pharma, Actelion Pharmaceut US Inc, Abbott Labs, Ross Prod Div, SHS N Amer, Appl Biosyst, Appl Nutr Corp, BioMarin Pharmaceut Inc, Milupa N Amer, Vitaflo, Biochrom Inc, Cambrooke Foods, Hitachi High Technologies Amer Inc, Natl Urea Cycle Defects Fdn, Pickering Labs Inc, Rare Dis Therapeut Inc, Sigma Tau Pharmaceut, Transkarot Therapies Inc C1 NHGRI, NIH, Bethesda, MD 20892 USA. Univ Cincinnati, Cincinnati, OH 45221 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2005 VL 84 IS 3 BP 203 EP 203 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 906NH UT WOS:000227648400018 ER PT J AU Sparks, SE Ciccone, C Lalor, M Orvisky, E Krasnewich, D Sun, MS Dalakas, M Gahl, WA Huizing, M AF Sparks, SE Ciccone, C Lalor, M Orvisky, E Krasnewich, D Sun, MS Dalakas, M Gahl, WA Huizing, M TI Hereditary inclusion body myopathy is caused by defective sialic acid biosynthesis. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2005) CY MAR 06-09, 2005 CL Pacific Grove, CA SP Genzyme Corp, Mead Johnson Nutr, NIDDK, NIH, Off Rare Dis, Dept Hlth & Human Serv, Ucyclyd Pharma, Actelion Pharmaceut US Inc, Abbott Labs, Ross Prod Div, SHS N Amer, Appl Biosyst, Appl Nutr Corp, BioMarin Pharmaceut Inc, Milupa N Amer, Vitaflo, Biochrom Inc, Cambrooke Foods, Hitachi High Technologies Amer Inc, Natl Urea Cycle Defects Fdn, Pickering Labs Inc, Rare Dis Therapeut Inc, Sigma Tau Pharmaceut, Transkarot Therapies Inc C1 NHGRI, Sect Human Biochem Genet, MGB, NIH, Bethesda, MD 20892 USA. NIMH, NSB, NIH, Bethesda, MD 20892 USA. NINDS, 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2005 VL 84 IS 3 BP 203 EP 203 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 906NH UT WOS:000227648400019 ER PT J AU Suwannarat, P O'Brien, K Perry, M Gerber, L Bernardini, I Gahl, WA AF Suwannarat, P O'Brien, K Perry, M Gerber, L Bernardini, I Gahl, WA TI Natural history and therapy of alkaptonuria. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2005) CY MAR 06-09, 2005 CL Pacific Grove, CA SP Genzyme Corp, Mead Johnson Nutr, NIDDK, NIH, Off Rare Dis, Dept Hlth & Human Serv, Ucyclyd Pharma, Actelion Pharmaceut US Inc, Abbott Labs, Ross Prod Div, SHS N Amer, Appl Biosyst, Appl Nutr Corp, BioMarin Pharmaceut Inc, Milupa N Amer, Vitaflo, Biochrom Inc, Cambrooke Foods, Hitachi High Technologies Amer Inc, Natl Urea Cycle Defects Fdn, Pickering Labs Inc, Rare Dis Therapeut Inc, Sigma Tau Pharmaceut, Transkarot Therapies Inc C1 NIH, Dept Rehabil Med, Ctr Clin, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2005 VL 84 IS 3 BP 207 EP 207 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 906NH UT WOS:000227648400026 ER PT J AU Venditti, CP Chandler, R Tsai, M Wehrli, N Deering, R Kaestner, K Giaever, G Kazazian, H AF Venditti, CP Chandler, R Tsai, M Wehrli, N Deering, R Kaestner, K Giaever, G Kazazian, H TI Genetic and genomic systems to study methylmalonic acidemia. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2005) CY MAR 06-09, 2005 CL Pacific Grove, CA SP Genzyme Corp, Mead Johnson Nutr, NIDDK, NIH, Off Rare Dis, Dept Hlth & Human Serv, Ucyclyd Pharma, Actelion Pharmaceut US Inc, Abbott Labs, Ross Prod Div, SHS N Amer, Appl Biosyst, Appl Nutr Corp, BioMarin Pharmaceut Inc, Milupa N Amer, Vitaflo, Biochrom Inc, Cambrooke Foods, Hitachi High Technologies Amer Inc, Natl Urea Cycle Defects Fdn, Pickering Labs Inc, Rare Dis Therapeut Inc, Sigma Tau Pharmaceut, Transkarot Therapies Inc C1 NHGRI, GDRB, NIH, Bethesda, MD 20892 USA. Univ Penn, Philadelphia, PA 19104 USA. Stanford Genome Technol Ctr, Palo Alto, CA USA. Univ Penn, Philadelphia, PA 19104 USA. Stanford Genome Technol Ctr, Palo Alto, CA USA. NR 0 TC 2 Z9 2 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2005 VL 84 IS 3 BP 207 EP 208 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 906NH UT WOS:000227648400027 ER PT J AU Eblan, MJ Nguyen, J Stubblefield, B Goker-Alpan, O Hurtig, HI Trojanowski, JQ Giasson, B Sidransky, E AF Eblan, MJ Nguyen, J Stubblefield, B Goker-Alpan, O Hurtig, HI Trojanowski, JQ Giasson, B Sidransky, E TI Glucocerebrosidase mutations in brain samples from subjects with parkinsonism. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2005) CY MAR 06-09, 2005 CL Pacific Grove, CA SP Genzyme Corp, Mead Johnson Nutr, NIDDK, NIH, Off Rare Dis, Dept Hlth & Human Serv, Ucyclyd Pharma, Actelion Pharmaceut US Inc, Abbott Labs, Ross Prod Div, SHS N Amer, Appl Biosyst, Appl Nutr Corp, BioMarin Pharmaceut Inc, Milupa N Amer, Vitaflo, Biochrom Inc, Cambrooke Foods, Hitachi High Technologies Amer Inc, Natl Urea Cycle Defects Fdn, Pickering Labs Inc, Rare Dis Therapeut Inc, Sigma Tau Pharmaceut, Transkarot Therapies Inc C1 NIMH, Sect Mol Neurogenet, NHGRI, NIH, Bethesda, MD 20892 USA. Univ Penn, Dept Neurol, Philadelphia, PA 19104 USA. Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Univ Penn, Dept Pharmacol, Philadelphia, PA 19104 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2005 VL 84 IS 3 BP 217 EP 218 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 906NH UT WOS:000227648400041 ER PT J AU Goker-Alpan, O Stubblefield, B Hruska, K Sidransky, E AF Goker-Alpan, O Stubblefield, B Hruska, K Sidransky, E TI Temperature sensitive mutants indicate protein misfolding in Gaucher disease. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2005) CY MAR 06-09, 2005 CL Pacific Grove, CA SP Genzyme Corp, Mead Johnson Nutr, NIDDK, NIH, Off Rare Dis, Dept Hlth & Human Serv, Ucyclyd Pharma, Actelion Pharmaceut US Inc, Abbott Labs, Ross Prod Div, SHS N Amer, Appl Biosyst, Appl Nutr Corp, BioMarin Pharmaceut Inc, Milupa N Amer, Vitaflo, Biochrom Inc, Cambrooke Foods, Hitachi High Technologies Amer Inc, Natl Urea Cycle Defects Fdn, Pickering Labs Inc, Rare Dis Therapeut Inc, Sigma Tau Pharmaceut, Transkarot Therapies Inc C1 NIMHG, Sect Mol Neurogenet, NHGRI, NIH, 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2005 VL 84 IS 3 BP 220 EP 221 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 906NH UT WOS:000227648400049 ER PT J AU Gottlieb, E Ciccone, C Darvish, D Naiem, S Savelkoul, P Krasnewich, D Gahl, W Huizing, M AF Gottlieb, E Ciccone, C Darvish, D Naiem, S Savelkoul, P Krasnewich, D Gahl, W Huizing, M TI Correlation between the age of onsetiseverity of hereditary inclusion body myopathy and polymorphisms within the dystroglyean gene. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2005) CY MAR 06-09, 2005 CL Pacific Grove, CA SP Genzyme Corp, Mead Johnson Nutr, NIDDK, NIH, Off Rare Dis, Dept Hlth & Human Serv, Ucyclyd Pharma, Actelion Pharmaceut US Inc, Abbott Labs, Ross Prod Div, SHS N Amer, Appl Biosyst, Appl Nutr Corp, BioMarin Pharmaceut Inc, Milupa N Amer, Vitaflo, Biochrom Inc, Cambrooke Foods, Hitachi High Technologies Amer Inc, Natl Urea Cycle Defects Fdn, Pickering Labs Inc, Rare Dis Therapeut Inc, Sigma Tau Pharmaceut, Transkarot Therapies Inc C1 NHGRI, MGB, NIH, Bethesda, MD 20892 USA. HIBM Res Grp, Encino, CA 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2005 VL 84 IS 3 BP 221 EP 221 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 906NH UT WOS:000227648400050 ER PT J AU Hruska, KS LaMarca, ME Portnoy, ME Green, ED Sidransky, E AF Hruska, KS LaMarca, ME Portnoy, ME Green, ED Sidransky, E TI In silico investigation of regulatory elements in the glucocerebrosidase gene locus. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2005) CY MAR 06-09, 2005 CL Pacific Grove, CA SP Genzyme Corp, Mead Johnson Nutr, NIDDK, NIH, Off Rare Dis, Dept Hlth & Human Serv, Ucyclyd Pharma, Actelion Pharmaceut US Inc, Abbott Labs, Ross Prod Div, SHS N Amer, Appl Biosyst, Appl Nutr Corp, BioMarin Pharmaceut Inc, Milupa N Amer, Vitaflo, Biochrom Inc, Cambrooke Foods, Hitachi High Technologies Amer Inc, Natl Urea Cycle Defects Fdn, Pickering Labs Inc, Rare Dis Therapeut Inc, Sigma Tau Pharmaceut, Transkarot Therapies Inc C1 NIMH, Clin Neurosci Branch, NHGRI, Bethesda, MD 20892 USA. NHGRI, Med Genet Branch, Bethesda, MD 20892 USA. NHGRI, Genome Technol 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2005 VL 84 IS 3 BP 223 EP 223 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 906NH UT WOS:000227648400058 ER PT J AU Jeong, A Zarzour, W Suwannarat, P Gunay-Aygun, M Kleta, R Gahl, WA AF Jeong, A Zarzour, W Suwannarat, P Gunay-Aygun, M Kleta, R Gahl, WA TI Clinical and molecular findings in a patient with Chediak-Higashi syndrome. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2005) CY MAR 06-09, 2005 CL Pacific Grove, CA SP Genzyme Corp, Mead Johnson Nutr, NIDDK, NIH, Off Rare Dis, Dept Hlth & Human Serv, Ucyclyd Pharma, Actelion Pharmaceut US Inc, Abbott Labs, Ross Prod Div, SHS N Amer, Appl Biosyst, Appl Nutr Corp, BioMarin Pharmaceut Inc, Milupa N Amer, Vitaflo, Biochrom Inc, Cambrooke Foods, Hitachi High Technologies Amer Inc, Natl Urea Cycle Defects Fdn, Pickering Labs Inc, Rare Dis Therapeut Inc, Sigma Tau Pharmaceut, Transkarot Therapies Inc C1 NHGRI, Sect Human Biochem Genet, NIH, Bethesda, MD 20892 USA. NIH, ORD, Intramural Program, OD, 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2005 VL 84 IS 3 BP 225 EP 226 PG 2 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 906NH UT WOS:000227648400065 ER PT J AU Kleta, R Bernardini, I Arcos-Burgos, M Helip-Wooley, A Bockenhauer, D Skovby, F Lee, P Gahl, WA AF Kleta, R Bernardini, I Arcos-Burgos, M Helip-Wooley, A Bockenhauer, D Skovby, F Lee, P Gahl, WA TI Molecular basis of the Hartnup disorder. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2005) CY MAR 06-09, 2005 CL Pacific Grove, CA SP Genzyme Corp, Mead Johnson Nutr, NIDDK, NIH, Off Rare Dis, Dept Hlth & Human Serv, Ucyclyd Pharma, Actelion Pharmaceut US Inc, Abbott Labs, Ross Prod Div, SHS N Amer, Appl Biosyst, Appl Nutr Corp, BioMarin Pharmaceut Inc, Milupa N Amer, Vitaflo, Biochrom Inc, Cambrooke Foods, Hitachi High Technologies Amer Inc, Natl Urea Cycle Defects Fdn, Pickering Labs Inc, Rare Dis Therapeut Inc, Sigma Tau Pharmaceut, Transkarot Therapies Inc C1 NIH, Off Rare Sis, Intramural Program, Off Director, Bethesda, MD 20892 USA. Great Ormond St Hosp Children, NHS Trust, London, England. Rigshosp, Dept Clin Genet, Copenhagen, Denmark. RI Bockenhauer, Detlef/C-5951-2008 OI Bockenhauer, Detlef/0000-0001-5878-941X NR 0 TC 1 Z9 1 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2005 VL 84 IS 3 BP 226 EP 226 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 906NH UT WOS:000227648400066 ER PT J AU Krasnewich, D Sparks, S Orvisky, E LaMarca, M Andrews, D Tayebi, N Goker-Alpan, O Sidransky, E AF Krasnewich, D Sparks, S Orvisky, E LaMarca, M Andrews, D Tayebi, N Goker-Alpan, O Sidransky, E TI American patients with congenital disorders of glycosylation. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2005) CY MAR 06-09, 2005 CL Pacific Grove, CA SP Genzyme Corp, Mead Johnson Nutr, NIDDK, NIH, Off Rare Dis, Dept Hlth & Human Serv, Ucyclyd Pharma, Actelion Pharmaceut US Inc, Abbott Labs, Ross Prod Div, SHS N Amer, Appl Biosyst, Appl Nutr Corp, BioMarin Pharmaceut Inc, Milupa N Amer, Vitaflo, Biochrom Inc, Cambrooke Foods, Hitachi High Technologies Amer Inc, Natl Urea Cycle Defects Fdn, Pickering Labs Inc, Rare Dis Therapeut Inc, Sigma Tau Pharmaceut, Transkarot Therapies Inc C1 NIH, NHGRI, 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2005 VL 84 IS 3 BP 227 EP 227 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 906NH UT WOS:000227648400070 ER PT J AU Naviaux, RK Chan, SSL Nguyen, KV Copeland, WC AF Naviaux, RK Chan, SSL Nguyen, KV Copeland, WC TI A novel U-to-G mRNA editing event in POLG corrects a lethal stop codon in Alpers syndrome. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2005) CY MAR 06-09, 2005 CL Pacific Grove, CA SP Genzyme Corp, Mead Johnson Nutr, NIDDK, NIH, Off Rare Dis, Dept Hlth & Human Serv, Ucyclyd Pharma, Actelion Pharmaceut US Inc, Abbott Labs, Ross Prod Div, SHS N Amer, Appl Biosyst, Appl Nutr Corp, BioMarin Pharmaceut Inc, Milupa N Amer, Vitaflo, Biochrom Inc, Cambrooke Foods, Hitachi High Technologies Amer Inc, Natl Urea Cycle Defects Fdn, Pickering Labs Inc, Rare Dis Therapeut Inc, Sigma Tau Pharmaceut, Transkarot Therapies Inc C1 Univ Calif San Diego, Mitochondrial & Metab Dis Ctr, Dept Med, San Diego, CA 92103 USA. Univ Calif San Diego, Mitochondrial & Metab Dis Ctr, Dept Pediat, San Diego, CA 92103 USA. Natl Inst Environm Hlth Sci, Genet Mol Lab, NIH, Res Triangle Pk, NC 27709 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2005 VL 84 IS 3 BP 232 EP 232 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 906NH UT WOS:000227648400084 ER PT J AU Sun, MS Sparks, SE Klootwijk, ED Schwartzberg, PL Settara, C Gahl, WA Huizing, M AF Sun, MS Sparks, SE Klootwijk, ED Schwartzberg, PL Settara, C Gahl, WA Huizing, M TI Creation of a conditional knock-in/out mouse mutant of UDP-N-acetylglucosamine 2 epimerase/N-acetylmannosamine kinase to mimic human hereditary inclusion body myopathy. SO MOLECULAR GENETICS AND METABOLISM LA English DT Meeting Abstract CT Annual Meeting of the Society-for-Inherited-Metabolic-Disorders (SIMD 2005) CY MAR 06-09, 2005 CL Pacific Grove, CA SP Genzyme Corp, Mead Johnson Nutr, NIDDK, NIH, Off Rare Dis, Dept Hlth & Human Serv, Ucyclyd Pharma, Actelion Pharmaceut US Inc, Abbott Labs, Ross Prod Div, SHS N Amer, Appl Biosyst, Appl Nutr Corp, BioMarin Pharmaceut Inc, Milupa N Amer, Vitaflo, Biochrom Inc, Cambrooke Foods, Hitachi High Technologies Amer Inc, Natl Urea Cycle Defects Fdn, Pickering Labs Inc, Rare Dis Therapeut Inc, Sigma Tau Pharmaceut, Transkarot Therapies Inc C1 NHGRI, Sect Human Biochem Genet, SHBG, Med Genet Branch,NIH,DHHS, Bethesda, MD 20892 USA. NHGRI, Genome Technol Branch, NIH, DHHS, 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 1096-7192 J9 MOL GENET METAB JI Mol. Genet. Metab. PD MAR PY 2005 VL 84 IS 3 BP 237 EP 237 PG 1 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 906NH UT WOS:000227648400100 ER PT J AU Hiragun, T Peng, Z Beaven, MA AF Hiragun, T Peng, Z Beaven, MA TI Dexamethasone up-regulates the inhibitory adaptor protein Dok-1 and suppresses downstream activation of the mitogen-activated protein kinase pathway in antigen-stimulated RBL-2H3 mast cells SO MOLECULAR PHARMACOLOGY LA English DT Article ID FC-EPSILON-RI; NEGATIVE REGULATION; MAPK PHOSPHATASE-1; RASGAP-BINDING; P62(DOK); GLUCOCORTICOIDS; P38; TRANSCRIPTION; EXPRESSION; MEDIATOR AB The glucocorticoid dexamethasone suppresses antigen-induced degranulation, cytokine production, and intermediate signaling events in RBL-2H3 mast cells, although the exact mechanisms are uncertain. By microarray analysis, we discovered that expression of the inhibitory adaptor protein, downstream of tyrosine kinase (Dok)-1, was up-regulated 4-fold in dexamethasone-treated RBL-2H3 cells. The up-regulation was apparent with as little as 1 to 10 nM dexamethasone. Treatment with dexamethasone also enhanced tyrosine phosphorylation of Dok-1, augmented recruitment of Ras GTPase-activating protein (RasGAP) by Dok-1, and inhibited activation of the mitogen-activated protein (MAP) kinase pathway in antigen-stimulated cells. The same effects were obtained by transient overexpression of Dok-1 but not by overexpression of Dok-1 that was mutated in RasGAP-binding domain. The negative regulatory role of Dok-1 was further validated by the expression of small interfering RNA directed against Dok-1, which enhanced activation of MAP kinase and subsequent release of arachidonic acid and tumor necrosis factor-alpha. These findings identify Dok-1 as mediator of the antiallergic actions of dexamethasone and as a negative regulator of the MAP kinase pathway and downstream release of inflammatory mediators. C1 Natl Heart Lung & Blood Inst, Lab Mol Immunol, NIH, Bethesda, MD USA. RP Beaven, MA (reprint author), Hiroshima Univ, Fac Med, Dept Dermatol, Minami Ku, 1-2-3 Kasumi, Hiroshima, Japan. EM beavenm@mail.nih.gov NR 24 TC 29 Z9 29 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAR PY 2005 VL 67 IS 3 BP 598 EP 603 DI 10.1124/mol.104.008607 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 898JA UT WOS:000227071900004 PM 15608142 ER PT J AU Stauber, AJ Brown-Borg, H Liu, J Waalkes, MP Laughter, A Staben, RA Coley, JC Swanson, C Voss, KA Kopchick, JJ Corton, JC AF Stauber, AJ Brown-Borg, H Liu, J Waalkes, MP Laughter, A Staben, RA Coley, JC Swanson, C Voss, KA Kopchick, JJ Corton, JC TI Constitutive expression of peroxisome proliferator-activated receptor alpha-regulated genes in dwarf mice SO MOLECULAR PHARMACOLOGY LA English DT Article ID GROWTH-HORMONE; PPAR-ALPHA; RAT-LIVER; TRANSCRIPTIONAL ACTIVITY; IN-VIVO; TARGETED DISRUPTION; SIGNALING PATHWAYS; DOWN-REGULATION; BETA-OXIDATION; CROSS-TALK AB Defects in growth hormone secretion or signaling in mice are associated with decreased body weights (dwarfism), increased longevity, increased resistance to stress, and decreases in factors that contribute to cardiovascular disease and cancer. Peroxisome proliferators (PP) alter a subset of these changes in wild-type mice through activation of the nuclear receptor family member PP-activated receptor alpha (PPARalpha). We tested the hypothesis that an overlap in the transcriptional programs between untreated dwarf mice and PP-treated wild-type mice underlies these similarities. Using transcript profiling, we observed a statistically significant overlap in the expression of genes differentially regulated in control Snell dwarf mice (Pit-1(dw)) compared with phenotypically normal heterozygote (+/-dw) control mice and those altered by the PP 4-chloro-6-(2,3-xylidino)-2-pyrimidinyl) thioacetic acid (WY-14,643) in +/-dw mice. The genes included those involved in beta- and omega-oxidation of fatty acids (Acox1, Cyp4a10, Cyp4a14) and those involved in stress responses ( the chaperonin, T-complex protein1epsilon) and cardiovascular disease (fibrinogen). The levels of some of these gene products were also altered in other dwarf mouse models, including Ames, Little, and growth hormone receptor-null mice. The constitutive increases in PPARalpha-regulated genes may be partly caused by increased expression of PPARalpha mRNA and protein as observed in the livers of control Snell dwarf mice. These results indicate that some of the beneficial effects associated with the dwarf phenotype may be caused by constitutive activation of PPARalpha and regulated genes. C1 CIIT Ctr Hlth Res, Res Triangle Pk, NC USA. Univ N Dakota, Sch Med, Dept Pharmacol Physiol & Therapeut, Grand Forks, ND USA. NCI, Res Triangle Pk, NC USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. USDA ARS, Toxicol & Mycotoxin Res Unit, Athens, GA USA. Ohio Univ, Biotechnol Inst, Coll Osteopath Med & Edison, Dept Biomed Sci, Athens, OH USA. ToxicoGenom, Chapel Hill, NC USA. RP Corton, JC (reprint author), Eli Lilly Co, Greenfield, IN 46140 USA. EM ccorton@msn.com NR 40 TC 25 Z9 26 U1 0 U2 0 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAR PY 2005 VL 67 IS 3 BP 681 EP 694 DI 10.1124/mol.104.007278 PG 14 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 898JA UT WOS:000227071900014 PM 15576629 ER PT J AU Sugatani, J Nishitani, S Yamakawa, K Yoshinari, K Sueyoshi, T Negishi, M Miwa, M AF Sugatani, J Nishitani, S Yamakawa, K Yoshinari, K Sueyoshi, T Negishi, M Miwa, M TI Transcriptional regulation of human UGT1A1 gene expression: Activated glucocorticoid receptor enhances constitutive androstane receptor/pregnane X receptor-mediated UDP-glucuronosyltransferase 1A1 regulation with glucocorticoid receptor-interacting protein 1 SO MOLECULAR PHARMACOLOGY LA English DT Article ID RESPONSE ELEMENT; NUCLEAR RECEPTORS; HUMAN HEPATOCYTES; INDUCTION; CAR; CYP3A4; RAT; IDENTIFICATION; HORMONE; LIVER AB UDP-glucuronosyltransferase (UGT) 1A1 glucuronidates endogenous metabolites, such as bilirubin, and exogenous substances, and plays a critical role in their detoxification and excretion. In a previous article, we described the phenobarbital response activity to a 290-base pair ( bp) distal enhancer sequence (-3499/-3210) of the human UGT1A1 gene that is activated by the constitutive androstane receptor (CAR). Here, we show that dexamethasone at submicromolar concentrations enhances the pregnane X receptor (PXR) activator-mediated expression of the UGT1A1 gene and protein in HepG2 cells. We investigated the molecular mechanism of UGT1A1 induction by glucocorticoids at submicromolar concentrations and PXR activators and the functional cross-talk between the glucocorticoid receptor (GR) and CAR/PXR. The glucocorticoid-response element (GRE) was characterized by cotransfection experiments, site-directed mutagenesis, and electrophoretic mobility shift assays. Analysis of the human UGT1A1 promoter revealed GREs at -3404/-3389 and -3251/-3236 close to the CAR/PXR response element gtNR1 (-3382/-3367). Furthermore, in an in vitro reporter gene assay, dexamethasone effectively enhanced CAR/PXR-mediated transactivation of the 290-bp distal enhancer module in HepG2 cells and CV-1 cells in the presence of exogenously expressed GR and glucocorticoid receptor-interacting protein 1 (GRIP1). In glutathione S-transferase pull-down experiments, CAR and PXR interacted with GRIP1. Together, these results demonstrate a rational mechanistic basis for UGT1A1 induction by glucocorticoids and PXR activators, showing that activated GR enhances CAR/PXR-mediated UGT1A1 regulation with the transcriptional cofactor GRIP1 and that GR may be involved synergistically in the xenobiotic-responsive regulation of UGT1A1 by CAR/PXR. C1 Univ Shizuoka, Sch Pharmaceut Sci, Dept Pharmacobiochem, Shizuoka 4228526, Japan. Univ Shizuoka, Sch Pharmaceut Sci, COE 21, Shizuoka 4228526, Japan. NIEHS, NIH, Reprod & Dev Toxicol Lab, Pharmacogenet Sect, Res Triangle Pk, NC 27709 USA. RP Miwa, M (reprint author), Univ Shizuoka, Sch Pharmaceut Sci, Dept Pharmacobiochem, 52-1 Yada, Shizuoka 4228526, Japan. EM miwa@u-shizuoka-ken.ac.jp NR 39 TC 93 Z9 96 U1 0 U2 3 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0026-895X J9 MOL PHARMACOL JI Mol. Pharmacol. PD MAR PY 2005 VL 67 IS 3 BP 845 EP 855 DI 10.1124/mol.104.007161 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 898JA UT WOS:000227071900031 PM 15557560 ER PT J AU Postolache, TT Stiller, JW Herrell, R Goldstein, MA Shreeram, SS Zebrak, R Thrower, CM Volkov, J No, MJ Volkov, I Rohan, KJ Redditt, J Parmar, M Mohyuddin, F Olsen, C Moca, M Tonelli, LH Merikangas, K Komarow, HD AF Postolache, TT Stiller, JW Herrell, R Goldstein, MA Shreeram, SS Zebrak, R Thrower, CM Volkov, J No, MJ Volkov, I Rohan, KJ Redditt, J Parmar, M Mohyuddin, F Olsen, C Moca, M Tonelli, LH Merikangas, K Komarow, HD TI Tree pollen peaks are associated with increased nonviolent suicide in women SO MOLECULAR PSYCHIATRY LA English DT Letter ID DEPRESSION; CYTOKINES; FINLAND; STRESS; HUMANS C1 Univ Maryland, Sch Med, Dept Psychiat, Mood & Anxiety Disorder Program, Baltimore, MD 21201 USA. St Elizabeth Hosp, DC DMH, Psychiat Residency Training Program, Washington, DC USA. NIMH, Sect Dev Genet Epidemiol, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Med Psychol, Bethesda, MD 20814 USA. Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD 20814 USA. NIMH, Sect Neuroendocrine Immunol & Behav, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIAMSD, Genet & Genom Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Postolache, TT (reprint author), Univ Maryland, Sch Med, Dept Psychiat, Mood & Anxiety Disorder Program, 685 W Baltimore St,MSTF Bldg Room 502, Baltimore, MD 21201 USA. EM tpostolache@psych.umaryland.edu NR 10 TC 32 Z9 34 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAR PY 2005 VL 10 IS 3 BP 232 EP 235 DI 10.1038/sj.mp.4001620 PG 4 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 901QP UT WOS:000227297300003 PM 15599378 ER PT J AU Marques-Deak, A Cizza, G Sternberg, E AF Marques-Deak, A Cizza, G Sternberg, E TI Brain-immune interactions and disease susceptibility SO MOLECULAR PSYCHIATRY LA English DT Review DE neuroendocrine; depression; autoimmune disease; osteoporosis ID PITUITARY-ADRENAL AXIS; CORTICOTROPIN-RELEASING HORMONE; CHRONIC-FATIGUE-SYNDROME; GLUCOCORTICOID-RECEPTOR GENE; SYMPATHETIC-NERVOUS-SYSTEM; DEXAMETHASONE SUPPRESSION TEST; TUMOR-NECROSIS-FACTOR; DIAGNOSED RHEUMATOID-ARTHRITIS; TREATMENT-RESISTANT DEPRESSION; FACTOR-LIKE IMMUNOREACTIVITY AB Many studies have established the routes by which the immune and central nervous (CNS) systems communicate. This network of connections permits the CNS to regulate the immune system through both neuroendocrine and neuronal pathways. In turn, the immune system signals the CNS through neuronal and humoral routes, via immune mediators and cytokines. This regulatory system between the immune system and CNS plays an important role in susceptibility and resistance to autoimmune, inflammatory, infectious and allergic diseases. This review focuses on the regulation of the immune system via the neuroendocrine system, and underlines the link between neuroendocrine dysregulation and development of major depressive disorders, autoimmune diseases and osteoporosis. C1 NIMH, Sect Neuroendocrine Immunol & Behav, Integrat Neural Immune Program, NIH, Bethesda, MD 20892 USA. NIDDKD, Ctr Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Sternberg, E (reprint author), NIMH, Sect Neuroendocrine Immunol & Behav, Integrat Neural Immune Program, NIH, Bldg 36 1A23 MSC 4020, Bethesda, MD 20892 USA. EM ems@codon.nih.gov NR 242 TC 53 Z9 60 U1 3 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAR PY 2005 VL 10 IS 3 BP 239 EP 250 DI 10.1038/sj.mp.4001643 PG 12 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 901QP UT WOS:000227297300006 PM 15685252 ER PT J AU Aston, C Jiang, L Sokolov, BP AF Aston, C Jiang, L Sokolov, BP TI Transcriptional profiling reveals evidence for signaling and oligodendroglial abnormalities in the temporal cortex from patients with major depressive disorder SO MOLECULAR PSYCHIATRY LA English DT Article DE gene expression; myelin; synapse; signal transduction; microarray; white matter ID GENE-EXPRESSION PROFILE; POSTMORTEM HUMAN BRAIN; PSYCHIATRIC-DISORDERS; BIPOLAR DISORDER; FRONTAL-CORTEX; MESSENGER-RNA; MOLECULAR CHARACTERIZATION; N-ACETYLASPARTYLGLUTAMATE; NEUROPATHOLOGY CONSORTIUM; PROTEOLIPID PROTEIN AB Major depressive disorder is one of the most common and devastating psychiatric disorders. To identify candidate mechanisms for major depressive disorder, we compared gene expression in the temporal cortex from 12 patients with major depressive disorder and 14 matched controls using Affymetrix HgU95A microarrays. Significant expression changes were revealed in families of genes involved in neurodevelopment, signal transduction and cell communication. Among these, the expression of 17 genes related to oligodendrocyte function was significantly (P<0.05, fold change>1.4) decreased in patients with major depressive disorder. Eight of these 17 genes encode structural components of myelin (CNP, MAG, MAL, MOG, MOBP, PMP22, PLLP, PLP1). Five other genes encode enzymes involved in the synthesis of myelin constituents (ASPA, UGT8), or are essential in regulation of myelin formation (ENPP2, EDG2, TF, KLK6). One gene, that is, SOX10, encodes a transcription factor regulating other myelination-related genes. OLIG2 is a transcription factor present exclusively in oligodendrocytes and oligodendrocyte precursors. Another gene, ERBB3, is involved in oligodendrocyte differentiation. In addition to myelination-related genes, there were significant changes in multiple genes involved in axonal growth/synaptic function. These findings suggest that major depressive disorder may be associated with changes in cell communication and signal transduction mechanisms that contribute to abnormalities in oligodendroglia and synaptic function. Taken together with other studies, these findings indicate that major depressive disorder may share common oligodendroglial abnormalities with schizophrenia and bipolar disorder. C1 NIDA, Mol Neuropsychiat Branch, NIH, DHHS, Baltimore, MD 21224 USA. Wyeth Ayerst Res, Neurosci Discovery Res, Princeton, NJ 08543 USA. RP Sokolov, BP (reprint author), NIDA, Mol Neuropsychiat Branch, NIH, DHHS, 5500 Nathan Schock Dr, Baltimore, MD 21224 USA. EM Bsokolov@intra.nida.nih.gov NR 69 TC 190 Z9 198 U1 4 U2 8 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1359-4184 J9 MOL PSYCHIATR JI Mol. Psychiatr. PD MAR PY 2005 VL 10 IS 3 BP 309 EP 322 DI 10.1038/sj.mp.4001565 PG 14 WC Biochemistry & Molecular Biology; Neurosciences; Psychiatry SC Biochemistry & Molecular Biology; Neurosciences & Neurology; Psychiatry GA 901QP UT WOS:000227297300012 PM 15303102 ER PT J AU Shan, Z Li, J Zheng, C Liu, X Fan, Z Zhang, C Goldsmith, CM Wellner, RB Baum, BJ Wang, S AF Shan, Z Li, J Zheng, C Liu, X Fan, Z Zhang, C Goldsmith, CM Wellner, RB Baum, BJ Wang, S TI Increased fluid secretion after adenoviral-mediated transfer of the human aquaporin-1 cDNA to irradiated miniature pig parotid glands SO MOLECULAR THERAPY LA English DT Article DE salivary gland; irradiation; aquaporin-1; adenoviral vector; gene therapy ID GENE-TRANSFER VECTORS; SALIVARY-GLANDS; IN-VIVO; NECK RADIOTHERAPY; LOCAL-DELIVERY; ORAL-CAVITY; INDIVIDUALS; SPECTRUM; CHANNEL; PROTEIN AB The treatment of most head and neck cancer patients includes ionizing radiation (111). Salivary glands in the IR field suffer irreversible damage. Previously, we reported that adenoviral (Ad)mediated transfer of the human aquaporin-1 (hAQP1) cDNA to rat submandibular glands following IR restored salivary flow to near normal levels. It is unclear if this strategy is useful in larger animals. Herein, we evaluated AdhAQP1-mediated gene transfer after parotid gland IR (20 Cy) in the miniature pig. Sixteen weeks following IR, salivation from the targeted gland was decreased by > 80%. AdhAQP1 administration resulted in a dose-dependent increase in parotid salivary flow to similar to 80% of pre-IR levels on day 3. A control Ad vector was without significant effect. The effective AdhAQP1 dose was 2.5 x 105 pfu/mu l infusate, a dose that leads to comparable transgene expression in murine and minipig salivary glands. Three days after Ad vector administration little change was observed in clinical chemistry and hematology values. These findings demonstrate that localized delivery of AdhAQP1 to IR-damaged salivary glands increases salivary secretion, without significant general adverse events, in a large animal model. C1 Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, DHHS, Bethesda, MD 20892 USA. Capital Univ Med Sci, Salivary Gland Dis Ctr, Beijing 100050, Peoples R China. Capital Univ Med Sci, Mol Lab Gene Therapy, Fac Stomatol, Beijing 100050, Peoples R China. RP Baum, BJ (reprint author), Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, DHHS, Bldg 10,Room 1N113,MSC-1190, Bethesda, MD 20892 USA. EM bbaum@dir.nidcr.nih.gov; songlinwang@dentist.org.cn NR 24 TC 62 Z9 69 U1 1 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1525-0016 J9 MOL THER JI Mol. Ther. PD MAR PY 2005 VL 11 IS 3 BP 444 EP 451 DI 10.1016/j.ymthe.2004.11.007 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 906EL UT WOS:000227623200016 PM 15727941 ER PT J AU Zeuner, KE Shill, HA Sohn, YH Molloy, FM Thornton, BC Dambrosia, JM Hallett, M AF Zeuner, KE Shill, HA Sohn, YH Molloy, FM Thornton, BC Dambrosia, JM Hallett, M TI Motor training as treatment in focal hand dystonia SO MOVEMENT DISORDERS LA English DT Article DE focal hand dystonia; motor training; handwriting; TMS; EEG ID INDUCED MOVEMENT THERAPY; WRITERS CRAMP; BEHAVIORAL TREATMENT; CORTICAL POTENTIALS; MUSICIANS AB Focal hand dystonia may arise as a result of aberrant plasticity from excessive repetitive use. Improvement might be possible with appropriate motor training. Focusing on trying to decrease abnormal overflow of movement to fingers not involved in a task, we developed a motor training program for individualized finger movements. Ten patients with writer's cramp participated in the motor training program. Evaluation was done with the Fahn dystonia scale, kinematic analysis of handwriting, transcranial magnetic Stimulation (TMS), and electroencephalography (EEG). Clinical improvement of dystonia was significant using the Fahn dystonia scale, and 6 patients reported an improvement in writing. The handwriting analysis showed a trend for improvement after training in simple exercises. There were no changes in cortical excitability measured by TMS and EEG. Whereas this method of motor training for 4 weeks led to mild subjective improvement and some improvement in handwriting, it is not sufficient to reverse motor cortex abnormalities measured by TMS and EEG. (dagger)Published 2004 John Wiley F Sons. C1 NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. NIH, Occupat Therapy Rehabil Med Dept, Ctr Clin, Bethesda, MD 20892 USA. NINDS, Biostat Branch, NIH, Bethesda, MD 20892 USA. RP Hallett, M (reprint author), NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bldg 10,Room 5N226,10 Ctr Dr,MSC1428, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov NR 24 TC 57 Z9 57 U1 3 U2 10 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD MAR PY 2005 VL 20 IS 3 BP 335 EP 341 DI 10.1002/mds.20314 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 910EC UT WOS:000227912100008 PM 15486996 ER PT J AU Schild, LJ Phillips, DH Osborne, MR Hewer, A Beland, FA Churchwell, MI Brown, K Gaskell, M Wright, E Poirier, MC AF Schild, LJ Phillips, DH Osborne, MR Hewer, A Beland, FA Churchwell, MI Brown, K Gaskell, M Wright, E Poirier, MC TI Hepatic DNA adduct dosimetry in rats fed tamoxifen: a comparison of methods SO MUTAGENESIS LA English DT Article ID TANDEM MASS-SPECTROMETRY; BREAST-CANCER; ALPHA-HYDROXYTAMOXIFEN; HUMAN ENDOMETRIUM; IN-VITRO; N-DESMETHYLTAMOXIFEN; METABOLIC-ACTIVATION; LIVER CELLS; IDENTIFICATION; TRIALS AB Liver homogenates from rats fed tamoxifen (TAM) in the diet were shared among four different laboratories. TAM-DNA adducts were assayed by high pressure liquid chromatography-electrospray tandem mass spectrometry (HPLC-ES-MS/MS), TAM-DNA chemiluminescence immunoassay (TAM-DNA CIA), and P-32-postlabeling with either thin layer (P-32-P-TLC) or liquid chromatography (P-32-P-HPLC) separation. In the first study, rats were fed a diet containing 500 p.p.m. TAM for 2 months, and the values for measurements of the (E)-alpha-(deoxyguanosin-N-2-yl)-tamoxifen (dG-N-2-TAM) adduct in replicate rat livers varied by 3.5-fold when quantified using 'in house' TAM-DNA standards, or other approaches where appropriate. In the second study, rats were fed 0, 50, 250 or 500 p.p.m. TAM for 2 months, and TAM-DNA values were quantified using both 'in house' approaches as well as a newly synthesized [N-methyl-H-3]TAM-DNA standard that was shared among all the participating groups. In the second study, the total TAM-DNA adduct values varied by 2-fold, while values for the dG-N-2-TAM varied by 2.5-fold. Ratios of dG-N-2-TAM:(E)-alpha-(deoxyguanosin-N-2-yl)-N-desmethyltamoxifen (dG-N-2-N-desmethyl-TAM) in the second study were similar to 1:1 over the range of doses examined. The study demonstrated a remarkably good agreement for TAM-DNA adduct measurements among the diverse methods employed. C1 NCI, Carcinogen DNA Interact Sect, NIH, Bethesda, MD 20892 USA. Inst Canc Res, Sutton SM2 5NG, Surrey, England. Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. Univ Leicester, Bioctr, Canc Biomarkers & Prevent Grp, Leicester LE1 7RH, Leics, England. RP Poirier, MC (reprint author), NCI, Carcinogen DNA Interact Sect, NIH, Bldg 37,Room 4032m37 Convent Dr MSC-4255, Bethesda, MD 20892 USA. EM poirierm@exchange.nih.gov OI Phillips, David/0000-0001-8509-3485 NR 44 TC 14 Z9 14 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0267-8357 J9 MUTAGENESIS JI Mutagenesis PD MAR PY 2005 VL 20 IS 2 BP 115 EP 124 DI 10.1093/mutage/gei015 PG 10 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 919SB UT WOS:000228636800006 PM 15755801 ER PT J AU Olivero, OA Tejera, AM Fernandez, JJ Taylor, BJ Das, S Divi, RL Poirier, MC AF Olivero, OA Tejera, AM Fernandez, JJ Taylor, BJ Das, S Divi, RL Poirier, MC TI Zidovudine induces S-phase arrest and cell cycle gene expression changes in human cells SO MUTAGENESIS LA English DT Article ID 3'-AZIDO-2',3'-DIDEOXYTHYMIDINE AZT; DNA INCORPORATION; GENOTOXICITY; PROGRESSION; APOPTOSIS; DAMAGE; 3'-AZIDO-3'-DEOXYTHYMIDINE; INTERFERENCE; MONKEYS; MOUSE AB Antiretroviral therapy for the human immunodeficiency virus-1 (HIV-1) typically includes two nucleoside reverse transcriptase inhibitors (NRTIs). 3'-Azido-3'-deoxythymidine (AZT, Zidovudine) plus 2'-deoxy-3'-thiacytidine (3TC, Lamivudine) is a combination that is used frequently. The NRTIs are mutagenic nucleoside analogs that become incorporated into DNA and terminate replication. We therefore hypothesized that exposure to this class of drug may alter cell cycle parameters. We used flow cytometry to examine the cell cycle in human epithelioid carcinoma (HeLa) cells exposed to AZT and 3TC alone, as well as a series of AZT/3TC dose combinations: (A) 125.0 mu M AZT/12.5 mu M 3TC; (B) 250.0 mu M AZT/25.0 mu M 3TC; and (C) 500 mu M AZT/50 mu M 3TC. At 24 h, at all doses, there was a good cell viability (>= 68%), and incorporation of AZT into nuclear DNA. Using flow cytometry, a dose-related increase in the percentage of cells in S phase, from 9.5% with no drug, to 36.0% with dose C, was observed in cells exposed for 24 h (P = 0.001, ANOVA). A concomitant decrease in the percentage of cells in G(1) phase, from 82.6% with no drug to 58.5% with dose C, was observed in cells exposed for 24 h (P = 0.017, ANOVA). A similar S phase arrest was seen in cells exposed to 125, 250 and 500 mu M AZT alone, but there was no S phase alteration with 50 mu M 3TC alone, suggesting that AZT is responsible for the accumulation of cells in S phase. To elucidate the accumulation of cells in S phase and explore the cell cycle gene expression changes induced by AZT and 3TC, we used c-DNA microarray, Cell Cycle Super Array and real-time PCR. There was a strong upregulation of the DNA damage-inducible transcript 3 (DDIT3 or GADD153) in NRTI-exposed cells. In addition, AZT induced an upregulation of cyclin D1 accompanied by a downregulation of the cyclin D1-associated inhibitors P18 and P57, and the G(1)-S check point gene P21, the net effect of which would be to foster a cell progression into S phase. Cyclin A2 was down-regulated in cells exposed to AZT, suggesting a block in S-G(2)-M progression that would also be consistent with the accumulation of cells in S phase. Overall, the study demonstrates that AZT, but not 3TC, causes an arrest of cells in S phase with a consistent alteration in the expression of several cell cycle genes. C1 NCI, Carcinogen DNA Interact Sect, Lab Cellular Carcinogenesis & Tumor Promot, NIH, Bethesda, MD 20892 USA. Quilmes Natl Univ, Oncol Mol Lab, Bernal, Argentina. RP Olivero, OA (reprint author), NCI, Carcinogen DNA Interact Sect, Lab Cellular Carcinogenesis & Tumor Promot, NIH, Bldg 37,Room 4032B,37 Convent Dr,MSC-4255, Bethesda, MD 20892 USA. EM oliveroo@exchange.nih.gov RI Tejera, Agueda/L-1946-2015 NR 28 TC 38 Z9 39 U1 1 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0267-8357 J9 MUTAGENESIS JI Mutagenesis PD MAR PY 2005 VL 20 IS 2 BP 139 EP 146 DI 10.1093/mutage/gei019 PG 8 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 919SB UT WOS:000228636800009 PM 15784690 ER PT J AU Desai, SA AF Desai, Sanjay A. TI Open and closed states of the plasmodial surface anion channel SO NANOMEDICINE-NANOTECHNOLOGY BIOLOGY AND MEDICINE LA English DT Article DE Ion channels; Gating; Malaria; Plasmodium falciparum; Patch-clamp; Ion channel pharmacology AB Background: The malaria parasite, Plasmodium falciparum, causes most of its clinical sequelae through its intracellular growth and multiplication in human red blood cells (RBCs). During this intracellular cycle, the parasite markedly alters the membrane transport properties of the host RBC through the induction of an unusual ion channel known as the plasmodial surface anion channel (PSAC). In addition to its unusual selectivity and pharmacology, PSAC exhibits atypical voltage-dependent gating; single-channel recordings reveal fast-flickering behavior interspersed with periods of inactivity. Detailed study of its gating properties have been complicated by the technical difficulty of obtaining single PSAC recordings, its small conductance, and various sources of error important for fast-flickering channels. Methods: Here, we developed an automated algorithm to analyze large amounts of single-channel data with particular emphasis on these sources of error. This algorithm was evaluated with high-quality single-channel and multichannel recordings obtained in the presence and absence of furosemide, a well-known PSAC antagonist. Results and Conclusions: Our analysis reveals that the adequate description of PSAC gating requires only one exponentially decaying open state, but at least three closed channel states. This model was further supported by single-channel recordings in the presence of furosemide, which inhibits PSAC with moderate affinity through an allosteric mechanism. Published by Elsevier Inc. C1 [Desai, Sanjay A.] NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. RP Desai, SA (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM sdesai@niaid.nih.gov FU Intramural NIH HHS [Z01 AI000882-07] NR 22 TC 19 Z9 19 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1549-9634 EI 1549-9642 J9 NANOMED-NANOTECHNOL JI Nanomed.-Nanotechnol. Biol. Med. PD MAR PY 2005 VL 1 IS 1 BP 58 EP 66 DI 10.1016/j.nano.2004.11.001 PG 9 WC Nanoscience & Nanotechnology; Medicine, Research & Experimental SC Science & Technology - Other Topics; Research & Experimental Medicine GA V45LK UT WOS:000209817900009 PM 17292059 ER PT J AU Goldman, J AF Goldman, J TI Is imatinib a cost-effective treatment for newly diagnosed chronic myeloid leukemia patients? SO NATURE CLINICAL PRACTICE ONCOLOGY LA English DT Editorial Material DE chronic myeloid leukemia; cytarabine; imatinib; interferon-alpha; pharmacoeconomics C1 Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Hematol, London, England. RP Goldman, J (reprint author), NHLBI, NIH, 10 Ctr Dr, Bethesda, MD 20892 USA. EM goldmanj2@nhlbi.nih.gov NR 2 TC 4 Z9 4 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVENUE SOUTH, NEW YORK, NY 10010-1707 USA SN 1743-4254 J9 NAT CLIN PRACT ONCOL JI Nat. Clin. Pract. Oncol. PD MAR PY 2005 VL 2 IS 3 BP 126 EP 127 DI 10.1038/ncponc0110 PG 2 WC Oncology SC Oncology GA 926JH UT WOS:000229119000004 PM 16264901 ER PT J AU Wade, PA AF Wade, PA TI SWItching off methylated DNA SO NATURE GENETICS LA English DT Editorial Material ID REPRESSION; CHROMATIN; COMPLEX; MECP2 AB The mechanism by which cytosine methylation stably represses transcription is of great interest. A new study provides evidence associating DNA methylation, MeCP2 and the SWI/SNF chromatin-remodeling factor, implicating local chromatin architecture in DNA methylation-dependent transcriptional repression. C1 NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. RP Wade, PA (reprint author), NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. EM wadep2@niehs.nih.gov NR 8 TC 6 Z9 7 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1061-4036 J9 NAT GENET JI Nature Genet. PD MAR PY 2005 VL 37 IS 3 BP 212 EP 213 DI 10.1038/ng0305-212 PG 3 WC Genetics & Heredity SC Genetics & Heredity GA 901QU UT WOS:000227297800004 PM 15731752 ER PT J AU Barouch, DH Powers, J Truitt, DM Kishko, MG Arthur, JC Peyerl, FW Kuroda, MJ Gorgone, DA Lifton, MA Lord, CI Hirsch, VM Montefiori, DC Carville, A Mansfield, KG Kunstman, KJ Wolinsky, SM Letvin, NL AF Barouch, DH Powers, J Truitt, DM Kishko, MG Arthur, JC Peyerl, FW Kuroda, MJ Gorgone, DA Lifton, MA Lord, CI Hirsch, VM Montefiori, DC Carville, A Mansfield, KG Kunstman, KJ Wolinsky, SM Letvin, NL TI Dynamic immune responses maintain cytotoxic T lymphocyte epitope mutations in transmitted simian immunodeficiency virus variants SO NATURE IMMUNOLOGY LA English DT Article ID VACCINATED RHESUS-MONKEYS; VIRAL ESCAPE; DISEASE PROGRESSION; PRIMARY INFECTION; CELL RESPONSES; PATHOGENIC SIV; VIREMIA; AIDS; SELECTION; TRANSMISSION AB Viral escape from cytotoxic T lymphocytes (CTLs) can undermine immune control of human immunodeficiency virus 1. It is therefore important to assess the stability of viral mutations in CTL epitopes after transmission to naive hosts. Here we demonstrate the persistence of mutations in a dominant CTL epitope after transmission of simian immunodeficiency virus variants to major histocompatibility complex-matched rhesus monkeys. Transient reversions to wild-type sequences occurred and elicited CTLs specific for the wild-type epitope, resulting in immunological pressure that rapidly reselected the mutant viruses. These data suggest that mutations in dominant human immunodeficiency virus 1 CTL epitopes may accumulate in human populations with limited major histocompatibility complex heterogeneity by a mechanism involving dynamic CTL control of transiently reverted wild-type virus. C1 Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, Boston, MA 02215 USA. Northwestern Univ, Feinberg Sch Med, Dept Med, Chicago, IL 60611 USA. NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA. New England Primate Res Ctr, Southborough, MA 01772 USA. RP Barouch, DH (reprint author), Harvard Univ, Sch Med, Beth Israel Deaconess Med Ctr, Div Viral Pathogenesis, 330 Brookline Ave, Boston, MA 02215 USA. EM dbarouch@bidmc.harvard.edu RI Wolinsky, Steven/B-2893-2012; OI Arthur, Janelle/0000-0002-4796-0207; Wolinsky, Steven/0000-0002-9625-6697 FU NCRR NIH HHS [P51 RR-00168]; NIAID NIH HHS [AI-20729, AI-51223, AI-58727] NR 30 TC 50 Z9 51 U1 1 U2 2 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1529-2908 J9 NAT IMMUNOL JI Nat. Immunol. PD MAR PY 2005 VL 6 IS 3 BP 247 EP 252 DI 10.1038/ni1167 PG 6 WC Immunology SC Immunology GA 899AN UT WOS:000227117400016 PM 15685174 ER PT J AU Lane, HC Folkers, GK Fauci, AS AF Lane, HC Folkers, GK Fauci, AS TI Reports on nevirapine threaten public health SO NATURE MEDICINE LA English DT Letter C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Lane, HC (reprint author), NIAID, NIH, Bldg 31,Room 7AO3,9000 Rockville Pike, Bethesda, MD 20892 USA. NR 7 TC 1 Z9 1 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD MAR PY 2005 VL 11 IS 3 BP 245 EP 245 DI 10.1038/nm0305-245 PG 1 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 905BA UT WOS:000227541300012 PM 15746930 ER PT J AU Rescigno, M Chieppa, M AF Rescigno, M Chieppa, M TI Gut-level decisions in peace and war SO NATURE MEDICINE LA English DT Editorial Material ID CELLS; BACTERIA C1 European Inst Oncol, Dept Expt Oncol, Milan, Italy. NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Rescigno, M (reprint author), European Inst Oncol, Dept Expt Oncol, Milan, Italy. EM maria.rescigno@ifom-ieo-campus.it RI Chieppa, Marcello/K-4846-2012; Rescigno, Maria/J-9704-2012 OI Rescigno, Maria/0000-0002-6464-509X NR 11 TC 22 Z9 23 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD MAR PY 2005 VL 11 IS 3 BP 254 EP 255 DI 10.1038/nm0305-254 PG 2 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 905BA UT WOS:000227541300016 PM 15746935 ER PT J AU Nichols, KE Hom, J Gong, SY Ganguly, A Ma, CS Cannons, JL Tangye, SG Schwartzberg, PL Koretzky, GA Stein, PL AF Nichols, KE Hom, J Gong, SY Ganguly, A Ma, CS Cannons, JL Tangye, SG Schwartzberg, PL Koretzky, GA Stein, PL TI Regulation of NKT cell development by SAP, the protein defective in XLP SO NATURE MEDICINE LA English DT Article ID LINKED LYMPHOPROLIFERATIVE-DISEASE; CONTROLS T-CELL; SH2 DOMAIN; MICE DEFICIENT; ENCODING GENE; EBV INFECTION; CUTTING EDGE; MUTANT MICE; B-CELLS; DIFFERENTIATION AB The adaptor molecule SAP is expressed in T lymphocytes and natural killer (NK) cells, where it regulates cytokine production and cytotoxicity(1-3). Here, we show that SAP, encoded by the SH2D1A gene locus, also has a crucial role during the development of NKT cells, a lymphocyte subset with immunoregulatory functions in response to infection, cancer and autoimmune disease(4). Following stimulation with the NKT cell-specific agonist alpha-galactosyl ceramide (alpha GC), Sh2d1a(-/-) splenocytes did not produce cytokines or activate other lymphoid lineages in an NKT cell-dependent manner. While evaluating the abnormalities in alpha GC-induced immune responses, we observed that Sh2d1a(-/-) animals lacked NKT cells in the thymus and peripheral organs. The defect in NKT cell ontogeny was hematopoietic cell autonomous and could be rescued by reconstitution of SAP expression within Sh2d1a(-/-) bone marrow cells. Seventeen individuals with X-linked lymphoproliferative disease (XLP), who harbored germline mutations in SH2D1A, also lacked NKT cells. Furthermore, a female XLP carrier showed completely skewed X chromosome inactivation within NKT cells, but not T or B cells. Thus, SAP is a crucial regulator of NKT cell ontogeny in humans and in mice. The absence of NKT cells may contribute to the phenotypes of SAP deficiency, including abnormal antiviral and antitumor immunity and hypogammaglobulinemia. C1 Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA. Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Dermatol, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA. Centenary Inst Canc Med & Cell Biol, Newtown, NSW 2014, Australia. NHGRI, NIH, Bethesda, MD 20892 USA. RP Nichols, KE (reprint author), Childrens Hosp Philadelphia, 4th Floor,3615 Civic Ctr Blvd, Philadelphia, PA 19104 USA. EM nicholsk@email.chop.edu; p-stein2@northwestern.edu RI Ma, Cindy/B-2340-2012; Tangye, Stuart/H-4023-2014 NR 30 TC 247 Z9 252 U1 0 U2 4 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1078-8956 J9 NAT MED JI Nat. Med. PD MAR PY 2005 VL 11 IS 3 BP 340 EP 345 DI 10.1038/nm1189 PG 6 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 905BA UT WOS:000227541300031 PM 15711562 ER PT J AU Gales, C Rebois, RV Hogue, M Trieu, P Breit, A Hebert, TE Bouvier, M AF Gales, C Rebois, RV Hogue, M Trieu, P Breit, A Hebert, TE Bouvier, M TI Real-time monitoring of receptor and G-protein interactions in living cells SO NATURE METHODS LA English DT Article ID BETA-ADRENERGIC-RECEPTORS; HETEROTRIMERIC G-PROTEINS; RESONANCE ENERGY-TRANSFER; BETA(2)-ADRENERGIC RECEPTOR; SUBUNIT DISSOCIATION; COUPLED RECEPTORS; PLASMA-MEMBRANE; ACTIVATION; VISUALIZATION; G-ALPHA(S) AB G protein-coupled receptors (GPCRs) represent the largest family of proteins involved in signal transduction. Here we present a bioluminescence resonance energy transfer (BRET) assay that directly monitors in real time the early interactions between human GPCRs and their cognate G-protein subunits in living human cells. In addition to detecting basal precoupling of the receptors to Galpha-, Gbeta- and Ggamma-subunits, BRET measured very rapid ligand-induced increases in the interaction between receptor and Galphabetagamma-complexes (t(1/2) similar to 300 ms) followed by a slower (several minutes) decrease, reflecting receptor desensitization. The agonist-promoted increase in GPCR-Gbetagamma interaction was highly dependent on the identity of the Galpha-subunit present in the complex. Therefore, this G protein-activity biosensor provides a novel toot to directly probe the dynamics and selectivity of receptor-mediated, G-protein activation-deactivation cycles that could be advantageously used to identify ligands for orphan GPCRs. C1 Univ Montreal, Dept Biochem, Montreal, PQ H3C 3J7, Canada. Natl Inst Hlth, Lab Cellular Biol, Rockville, MD 20850 USA. Univ Montreal, Inst Cardiol Montreal, Montreal, PQ H1T 1C8, Canada. Univ Montreal, Dept Anesthesiol, Montreal, PQ H1T 1C8, Canada. RP Bouvier, M (reprint author), Univ Montreal, Dept Biochem, POB 6128,Down Town Stn, Montreal, PQ H3C 3J7, Canada. EM michel.bouvier@umontreal.ca RI Bouvier, Michel/H-2758-2014 OI Bouvier, Michel/0000-0003-1128-0100 NR 28 TC 218 Z9 224 U1 2 U2 25 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1548-7091 J9 NAT METHODS JI Nat. Methods PD MAR PY 2005 VL 2 IS 3 BP 177 EP 184 DI 10.1038/NMETH743 PG 8 WC Biochemical Research Methods SC Biochemistry & Molecular Biology GA 901NT UT WOS:000227289900015 PM 15782186 ER PT J AU Boemio, A Fromm, S Braun, A Poeppel, D AF Boemio, A Fromm, S Braun, A Poeppel, D TI Hierarchical and asymmetric temporal sensitivity in human auditory cortices SO NATURE NEUROSCIENCE LA English DT Article ID HUMAN BRAIN; SPEECH-PERCEPTION; CORTEX; SOUNDS; FMRI; REPRESENTATIONS; INTEGRATION; TIME; IDENTIFICATION; ORGANIZATION AB Lateralization of function in auditory cortex has remained a persistent puzzle. Previous studies using signals with differing spectrotemporal characteristics support a model in which the left hemisphere is more sensitive to temporal and the right more sensitive to spectral stimulus attributes. Here we use single-trial sparse-acquisition fMRI and a stimulus with parametrically varying segmental structure affecting primarily temporal properties. We show that both left and right auditory cortices are remarkably sensitive to temporal structure. Crucially, beyond bilateral sensitivity to timing information, we uncover two functionally significant interactions. First, local spectrotemporal signal structure is differentially processed in the superior temporal gyrus. Second, lateralized responses emerge in the higher-order superior temporal sulcus, where more slowly modulated signals preferentially drive the right hemisphere. The data support a model in which sounds are analyzed on two distinct timescales, 25-50 ms and 200-300 ms. C1 Univ Maryland, Dept Linguist, College Pk, MD 20742 USA. NIMH, Brain & Cognit Lab, NIH, Bethesda, MD 20892 USA. Natl Inst Deafness & Other Commun Disorders, NIH, Bethesda, MD 20892 USA. RP Poeppel, D (reprint author), Univ Maryland, Dept Linguist, College Pk, MD 20742 USA. EM dpoeppel@deans.umd.edu FU NIDCD NIH HHS [R01 DC05660] NR 39 TC 268 Z9 273 U1 1 U2 21 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1097-6256 J9 NAT NEUROSCI JI Nat. Neurosci. PD MAR PY 2005 VL 8 IS 3 BP 389 EP 395 DI 10.1038/nn1409 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 902KL UT WOS:000227354600025 PM 15723061 ER PT J AU Ferrari, M AF Ferrari, M TI Cancer nanotechnology: Opportunities and challenges SO NATURE REVIEWS CANCER LA English DT Review ID DIP-PEN NANOLITHOGRAPHY; ULTRASENSITIVE DNA DETECTION; SEMICONDUCTOR QUANTUM DOTS; SINGLE LIVING CELLS; BLOOD-BRAIN-BARRIER; DRUG-DELIVERY; IN-VIVO; BIOCONJUGATED NANOPARTICLES; VASCULAR-PERMEABILITY; PHOTODYNAMIC THERAPY AB Nanotechnology is a multidisciplinary field, which covers a vast and diverse array of devices derived from engineering, biology, physics and chemistry. These devices include nanovectors for the targeted delivery of anticancer drugs and imaging contrast agents. Nanowires and nanocantilever arrays are among the leading approaches under development for the early detection of precancerous and malignant lesions from biological fluids. These and other nanodevices can provide essential breakthroughs in the fight against cancer. C1 Ohio State Univ, Div Haematol & Oncol, Davis Heart & Lung Res Inst 110U, Columbus, OH 43210 USA. NCI, Bethesda, MD 20892 USA. RP Ferrari, M (reprint author), Ohio State Univ, Div Haematol & Oncol, Davis Heart & Lung Res Inst 110U, 473 W 12th Ave, Columbus, OH 43210 USA. EM ferrari.5@osu.edu NR 133 TC 2310 Z9 2359 U1 194 U2 1291 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD MAR PY 2005 VL 5 IS 3 BP 161 EP 171 DI 10.1038/nrc1566 PG 11 WC Oncology SC Oncology GA 901SR UT WOS:000227302700011 PM 15738981 ER PT J AU Green, JE Hudson, T AF Green, JE Hudson, T TI The promise of genetically engineered mice for cancer prevention studies SO NATURE REVIEWS CANCER LA English DT Review ID ANTIGEN-TRANSGENIC MICE; FAMILIAL ADENOMATOUS POLYPOSIS; MIN MOUSE MODEL; SPONTANEOUS INTESTINAL ADENOMAS; SPONTANEOUS MAMMARY-TUMORS; GENE-EXPRESSION PATTERNS; HUMAN BREAST-CANCER; COLON-CANCER; CYCLOOXYGENASE-2 INHIBITOR; PROTECTIVE IMMUNITY AB Sophisticated genetic technologies have led to the development of mouse models of human cancers that recapitulate important features of human oncogenesis. Many of these genetically engineered mouse models promise to be very relevant and relatively rapid systems for determining the efficacy of chemopreventive agents and their mechanisms of action. The validation of such models for chemoprevention will help the selection of appropriate agents for large-scale clinical trials and allow the testing of combination therapies. C1 NCI, Transgen Oncogenesis Grp, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Green, JE (reprint author), NCI, Transgen Oncogenesis Grp, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. EM jegreen@mail.nih.gov NR 134 TC 49 Z9 52 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-175X J9 NAT REV CANCER JI Nat. Rev. Cancer PD MAR PY 2005 VL 5 IS 3 BP 184 EP 198 DI 10.1038/nrc1565 PG 15 WC Oncology SC Oncology GA 901SR UT WOS:000227302700013 PM 15738982 ER PT J AU Pommier, Y Johnson, AA Marchand, C AF Pommier, Y Johnson, AA Marchand, C TI Integrase inhibitors to treat HIV/AIDS SO NATURE REVIEWS DRUG DISCOVERY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; TYPE-1 PREINTEGRATION COMPLEXES; PNEUMOCYSTIS-CARINII PNEUMONIA; METAL-DEPENDENT INHIBITION; HIV DNA INTEGRATION; AMINO-ACID-RESIDUES; BETA-DIKETO ACIDS; IN-VITRO; STYRYLQUINOLINE DERIVATIVES; CDNA INTEGRATION AB HIV integrase is a rational target for treating HIV infection and preventing AIDS. It took approximately 12 years to develop clinically usable inhibitors of integrase, and Phase I clinical trials of integrase inhibitors have just begun. This review focuses on the molecular basis and rationale for developing integrase inhibitors. The main classes of lead compounds are also described, as well as the concept of interfacial inhibitors of protein-nucleic-acid interactions that might apply to the clinically used strand-transfer inhibitors. C1 NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Pommier, Y (reprint author), NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bldg 37,Room 5068, Bethesda, MD 20892 USA. EM pommier@nih.gov RI Marchand, Christophe/D-8559-2016 NR 98 TC 463 Z9 496 U1 6 U2 61 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1776 J9 NAT REV DRUG DISCOV JI Nat. Rev. Drug Discov. PD MAR PY 2005 VL 4 IS 3 BP 236 EP 248 DI 10.1038/nrd1660 PG 13 WC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Pharmacology & Pharmacy GA 901SQ UT WOS:000227302600016 PM 15729361 ER PT J AU Rehermann, B Nascimbeni, M AF Rehermann, B Nascimbeni, M TI Immunology of hepatitis B virus and hepatitis C virus infection SO NATURE REVIEWS IMMUNOLOGY LA English DT Review ID CD8(+) T-CELLS; CELLULAR IMMUNE-RESPONSES; TRANSGENIC MOUSE MODEL; ACUTE VIRAL-HEPATITIS; HCV INFECTION; LYMPHOCYTE RESPONSE; ENVELOPE PROTEIN; DENDRITIC CELLS; IN-VIVO; NONSTRUCTURAL PROTEIN-3 AB More than 500 million people worldwide are persistently infected with the hepatitis B virus (HBV) and/or hepatitis C virus (HCV) and are at risk of developing chronic liver disease, cirrhosis and hepatocellular carcinoma. Despite many common features in the pathogenesis of HBV- and HCV-related liver disease, these viruses markedly differ in their virological properties and in their immune escape and survival strategies. This review assesses recent advances in our understanding of viral hepatitis, contrasts mechanisms of virus - host interaction in acute hepatitis B and hepatitis C, and outlines areas for future studies. C1 NIDDKD, Liver Res Branch, NIH, Bethesda, MD 20892 USA. RP Rehermann, B (reprint author), NIDDKD, Liver Res Branch, NIH, Bldg 10,Room 9B16,10 Ctr Dr, Bethesda, MD 20892 USA. EM Rehermann@nih.gov NR 131 TC 948 Z9 1059 U1 29 U2 158 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1474-1733 J9 NAT REV IMMUNOL JI Nat. Rev. Immunol. PD MAR PY 2005 VL 5 IS 3 BP 215 EP 229 DI 10.1038/nri1573 PG 15 WC Immunology SC Immunology GA 901SO UT WOS:000227302400012 PM 15738952 ER PT J AU Mayer, ML AF Mayer, ML TI Some assembly required SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Editorial Material ID LIGAND-BINDING CORE; GLUTAMATE-RECEPTOR; MECHANISMS; CHANNELS; DIMERS; DOMAIN AB Glutamate receptor ion channels are multidomain membrane proteins that mediate excitatory synaptic responses in the brain and spinal cord. Single-particle electron microscopy reveals their molecular envelope and how this changes during desensitization. C1 NICHHD, Bethesda, MD 20892 USA. RP Mayer, ML (reprint author), NICHHD, Bldg 35,Room 3B1002, Bethesda, MD 20892 USA. EM mlm@helix.nih.gov RI Mayer, Mark/H-5500-2013 NR 13 TC 0 Z9 0 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD MAR PY 2005 VL 12 IS 3 BP 208 EP 209 DI 10.1038/nsmb0305-208 PG 3 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 902HL UT WOS:000227345400003 PM 15744319 ER PT J AU Serganov, A Keiper, S Malinina, L Tereshko, V Skripkin, E Hobartner, C Polonskaia, A Phan, AT Wombacher, R Micura, R Dauter, Z Jaschke, A Patel, DJ AF Serganov, A Keiper, S Malinina, L Tereshko, V Skripkin, E Hobartner, C Polonskaia, A Phan, AT Wombacher, R Micura, R Dauter, Z Jaschke, A Patel, DJ TI Structural basis for Diels-Alder ribozyme-catalyzed carbon-carbon bond formation SO NATURE STRUCTURAL & MOLECULAR BIOLOGY LA English DT Article ID RNA-PROTEIN RECOGNITION; NUCLEIC-ACID APTAMERS; IN-VITRO SELECTION; CRYSTAL-STRUCTURE; MACROPHOMATE SYNTHASE; INDUCED FIT; ANTIBODY; REFINEMENT; SELENIUM; BINDING AB The majority of structural efforts addressing RNA's catalytic function have focused on natural ribozymes, which catalyze phosphodiester transfer reactions. By contrast, little is known about how RNA catalyzes other types of chemical reactions. We report here the crystal structures of a ribozyme that catalyzes enantioselective carbon- carbon bond formation by the Diels- Alder reaction in the unbound state and in complex with a reaction product. The RNA adopts a -shaped nested pseudoknot architecture whose preformed hydrophobic pocket is precisely complementary in shape to the reaction product. RNA folding and product binding are dictated by extensive stacking and hydrogen bonding, whereas stereoselection is governed by the shape of the catalytic pocket. Catalysis is apparently achieved by a combination of proximity, complementarity and electronic effects. We observe structural parallels in the independently evolved catalytic pocket architectures for ribozyme- and antibody-catalyzed Diels- Alder carbon- carbon bond-forming reactions. C1 Univ Heidelberg, Inst Pharm & Mol Biotechnol, D-69120 Heidelberg, Germany. Mem Sloan Kettering Canc Ctr, Struct Biol Program, New York, NY 10021 USA. Leopold Franzens Univ, Inst Organ Chem, Ctr Mol Biosci, A-6020 Innsbruck, Austria. Brookhaven Natl Lab, Synchrotron Radiat Res Sect, NCI, Upton, NY 11973 USA. RP Jaschke, A (reprint author), Univ Heidelberg, Inst Pharm & Mol Biotechnol, Bergheimer Str 58, D-69120 Heidelberg, Germany. EM jaeschke@uni-hd.de; pateld@mskcc.org RI Jaschke, Andres/F-1575-2010; Phan, Anh Tuan/A-3673-2010; Malinina, Lucy/B-8161-2013; Hobartner, Claudia/E-8462-2010; Wombacher, Richard/M-7117-2016 OI Jaschke, Andres/0000-0002-4625-2655; Phan, Anh Tuan/0000-0002-4970-3861; Hobartner, Claudia/0000-0002-4548-2299; Wombacher, Richard/0000-0002-3027-7778 FU NCI NIH HHS [P30 CA008748]; NIGMS NIH HHS [R01 GM034504] NR 51 TC 142 Z9 147 U1 0 U2 24 PU NATURE PUBLISHING GROUP PI NEW YORK PA 345 PARK AVE SOUTH, NEW YORK, NY 10010-1707 USA SN 1545-9985 J9 NAT STRUCT MOL BIOL JI Nat. Struct. Mol. Biol. PD MAR PY 2005 VL 12 IS 3 BP 218 EP 224 DI 10.1038/nsmb906 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 902HL UT WOS:000227345400012 PM 15723077 ER PT J AU Lei, B Morris, DP Smith, MP Svetkey, LP Newman, MF Rotter, JI Buchanan, TA Beckstrom-Sternberg, SM Green, ED Schwinn, DA AF Lei, B Morris, DP Smith, MP Svetkey, LP Newman, MF Rotter, JI Buchanan, TA Beckstrom-Sternberg, SM Green, ED Schwinn, DA TI Novel human alpha(1a)-adrenoceptor single nucleotide polymorphisms alter receptor pharmacology and biological function SO NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY LA English DT Article DE alpha(1a)-adrenoceptor; polymorphism; single nucleotide polymorphisms; signal transduction; inositol phosphate; receptor/G protein coupling; human ID CONGESTIVE-HEART-FAILURE; SUBTYPE MESSENGER-RNAS; ADRENERGIC-RECEPTOR; ALPHA(1B)-ADRENERGIC RECEPTOR; ALPHA(1)-ADRENERGIC RECEPTORS; BETA(2)-ADRENERGIC RECEPTOR; AGONIST BINDING; BETA(1)-ADRENERGIC RECEPTOR; ANTAGONIST BINDING; CARDIAC MYOCYTES AB We identified nine naturally-occurring human single nucleotide polymorphisms (SNPs) in the alpha(1a)-adrenoceptor (alpha(1a)AR) coding region, seven of which result in amino acid change. Utilizing rat-1 fibroblasts stably expressing wild type alpha(1a)AR or each SNP at both high and low levels, we investigated the effect of these SNPs on receptor function. Compared with wild type, two SNPs (R166K, V311I) cause a decrease in binding affinity for agonists norepinephrine, epinephrine, and phenylephrine, and also shift the dose-response curve for norepinephrine stimulation of inositol phosphate (IP) production to the right (reduced potency) without altering maximal IP activity. In addition, SNP V311I and I200S display altered antagonist binding. Interestingly, a receptor with SNP G247R (located in the third intracellular loop) displays increased maximal receptor IP activity and stimulates cell growth. The increased receptor signaling for alpha(1a)AR G247R is not mediated by altered ligand binding or a deficiency in agonist-mediated desensitization, but appears to be related to enhanced receptor-G protein coupling. In conclusion, four naturally-occurring human alpha(1a)AR SNPs induce altered receptor pharmacology and/or biological activity. This finding has potentially important implications in many areas of medicine and can be used to guide alpha(1a)AR SNP choice for future clinical studies. C1 Duke Univ, Med Ctr, Dept Anesthesiol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Pharmacol Canc Biol, Durham, NC USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Cedars Sinai Med Ctr, Dept Pediat, Los Angeles, CA 90048 USA. Cedars Sinai Med Ctr, Dept Human Genet, Los Angeles, CA 90048 USA. Univ So Calif, Dept Med, Los Angeles, CA USA. Translat Genom Res Inst, Phoenix, AZ USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA. RP Schwinn, DA (reprint author), Duke Univ, Med Ctr, Dept Anesthesiol, Box 3094, Durham, NC 27710 USA. EM schwi001@mc.duke.edu FU NHLBI NIH HHS [HL67974, R37 HL049103, R37 HL049103-12, R37 HL049103-13, R37 HL049103-11, R01 HL067974, HL55055]; NIA NIH HHS [AG17556] NR 48 TC 28 Z9 28 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0028-1298 J9 N-S ARCH PHARMACOL JI Naunyn-Schmiedebergs Arch. Pharmacol. PD MAR PY 2005 VL 371 IS 3 BP 229 EP 239 DI 10.1007/s00210-005-1019-9 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 927IW UT WOS:000229188600008 PM 15900517 ER PT J AU Launer, LJ AF Launer, LJ TI The epidemiologic study of dementia: a life-long quest? SO NEUROBIOLOGY OF AGING LA English DT Article; Proceedings Paper CT 33rd Annual Meeting of the Society-for-Neuroscience CY NOV 08-12, 2003 CL NEW ORLEANS, LA SP Soc Neurosci DE epidemiologic study; apolipoprotein E epsilon 4 allele; neurodegenerative brain ID CARDIOVASCULAR RISK-FACTORS; SYSTOLIC BLOOD-PRESSURE; WHITE-MATTER LESIONS; MILD COGNITIVE IMPAIRMENT; TOTAL CHOLESTEROL LEVEL; ALZHEIMERS-DISEASE; BRAIN-LESIONS; ELDERLY-MEN; MIDDLE-AGE; MALE TWINS AB Based on many experimental and observational studies we now understand that neurodegenerative brain changes begin by middle age. Characteristics of the risk factors for these brain changes may also change with age. A review is conducted of studies that report on the association of mid-life risk factors to late cognitive impairment and dementia. Issues related to the interpretation of the data are discussed. The studies suggest that mid-life cardiovascular risk factors, and in particular elevated levels of blood pressure, increase the risk for late-life cognitive impairment and dementia. Our understanding the contribution of cardiovascular risk factors to late age brain disease has been helped tremendously by prospective studies with long follow-up. To better understand which risk factors lead to disease initiation, progression and prognosis, a life course approach to the epidemiologic study of dementia is needed. (C) 2004 Elsevier Inc. All rights reserved. C1 NIA, Lab Epidemiol, NIH, Bethesda, MD 20892 USA. RP Launer, LJ (reprint author), NIA, Lab Epidemiol, NIH, Bethesda, MD 20892 USA. EM launerl@nia.nih.gov NR 54 TC 72 Z9 73 U1 1 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0197-4580 J9 NEUROBIOL AGING JI Neurobiol. Aging PD MAR PY 2005 VL 26 IS 3 SI SI BP 335 EP 340 DI 10.1016/j.neurobiolaging.2004.03.016 PG 6 WC Geriatrics & Gerontology; Neurosciences SC Geriatrics & Gerontology; Neurosciences & Neurology GA 889QA UT WOS:000226456300008 PM 15639311 ER PT J AU Engelstein, R Grigoriadis, N Greig, NH Ovadia, H Gabizon, R AF Engelstein, R Grigoriadis, N Greig, NH Ovadia, H Gabizon, R TI Inhibition of P53-related apoptosis had no effect on PrPsc accumulation and prion disease incubation time SO NEUROBIOLOGY OF DISEASE LA English DT Article DE prion; apoptosis; P53; pifitrin alpha; PrP ID CREUTZFELDT-JAKOB-DISEASE; BOVINE SPONGIFORM ENCEPHALOPATHY; EXPERIMENTAL SCRAPIE; HAMSTERS; DEATH AB Results from several laboratories indicate that apoptosis via the P53 pathway is involved in prion disease pathogenesis. Prion diseases, among them scrapie and BSE, are a group of fatal neurodegenerative disorders associated with the conversion of PrPC to PrPSc, its conformational abnormal isoform. In this work, we tested whether an established anti-apoptotic reagent, PFT, which has been shown in different systems to inhibit P53 activity, can delay the outbreak of prion disease in infected animals. Our findings indicate that although PFT efficiently reduced caspase 3 expression in brains from scrapie sick hamsters, as well as inhibited PrPSc accumulation in cell culture, it had no effect on disease incubation time or PrPSc accumulation in vivo. We conclude that the P53 dependent apoptosis may not be an obligatory mechanism for prion disease-induced cell death. (C) 2004 Elsevier Inc. All rights reserved. C1 Hadassah Univ Hosp, Dept Neurol, Agnes Ginges Ctr Human Neurogenet, IL-91120 Jerusalem, Israel. Aristotle Univ Thessaloniki, AHEPA, Dept Neurol, Thessaloniki, Greece. NIA, Neurosci Lab, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Gabizon, R (reprint author), Hadassah Univ Hosp, Dept Neurol, Agnes Ginges Ctr Human Neurogenet, IL-91120 Jerusalem, Israel. EM gabizonr@chadassah.org.il NR 17 TC 7 Z9 11 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 0969-9961 J9 NEUROBIOL DIS JI Neurobiol. Dis. PD MAR PY 2005 VL 18 IS 2 BP 282 EP 285 DI 10.1016/j.nbd.2004.10.008 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 896RC UT WOS:000226950200004 PM 15686956 ER PT J AU Garraux, G Hallett, M Talagala, SL AF Garraux, G Hallett, M Talagala, SL TI CASL fMRI of subcortico-cortical perfusion changes during memory-guided finger sequences SO NEUROIMAGE LA English DT Article DE cerebral blood flow; arterial spin labeling; fMRI; motor system; deactivation ID CEREBRAL-BLOOD-FLOW; PRIMARY MOTOR CORTEX; POSITRON EMISSION TOMOGRAPHY; BRAIN PERFUSION; ARTERIAL WATER; BASAL GANGLIA; 3.0 T; ACTIVATION; MRI; MOVEMENT AB Arterial spin labeling (ASL) perfusion functional magnetic resonance imaging (fMRI) is an attractive alternative to BOLD fMRI. Nevertheless, current ASL fMRI techniques are limited by several factors that hamper more routine applications in humans. One of these factors is restricted brain coverage so that whole-brain ASL fMRI studies have never been reported. The present study tested the ability of a multislice continuous ASL (CASL) fMRI approach using a small surface coil placed on the subject's neck to map changes in regional cerebral blood flow (rCBF) throughout the brain while healthy individuals (N = 15) performed memory-guided sequential finger movements at a mean rate of similar to0.5 Hz. As predicted by results from a large number of studies, reliable task-related increases in flow were detected across subjects not only in primary and associative cortical areas but also in subcortical brain regions. When normalized to baseline, rCBF increased 31% in the hand representation area (HRA) of left primary motor cortex (M1) 13% in the left supplementary motor area proper (SMA), 10% in the left dorsolateral prefrontal cortex (DLPFC), 10-18% in the bilateral intraparietal sulci, 6% in the HRA of left putamen, 10% in the left thalamus, and 17% in the right anterior cerebellum. In addition to these increases, 6% and 4% decreases in rCBF were detected in the HRA of the right M1 and the bilateral posterior cingulate sulci, respectively. These results demonstrate that perfusion-based fMRI using CASL with a separate labeling coil can now be used to characterize task-related flow changes in most of the brain volume with adequate accuracy and sensitivity, Published by Elsevier Inc. C1 NINDS, Human Motor Control Sect, NIH, Bethesda, MD 20892 USA. Univ Liege, Cyclotron Res Ctr, B-4000 Cointe Ougree, Belgium. Univ Liege, Dept Neurol, B-4000 Cointe Ougree, Belgium. Natl Inst Neurol Disorders & Stroke, NIH MRI Res Facil, NIH, Bethesda, MD 20892 USA. RP Garraux, G (reprint author), NINDS, Human Motor Control Sect, NIH, Bldg 10,Room 5N226,10 Ctr Dr,MSC 1428, Bethesda, MD 20892 USA. EM hallettm@ninds.nih.gov RI Garraux, Gaetan/G-9050-2011 NR 65 TC 32 Z9 32 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD MAR PY 2005 VL 25 IS 1 BP 122 EP 132 DI 10.1016/j.neuroimage.2004.11.004 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 902PS UT WOS:000227369600012 PM 15734349 ER PT J AU Greenwood, PM Lambert, C Sunderland, T Parasuraman, R AF Greenwood, PM Lambert, C Sunderland, T Parasuraman, R TI Effects of apolipoprotein E genotype on spatial attention, working memory, and their interaction in healthy, middle-aged adults: Results from the National Institute of Mental Health's BIOCARD study SO NEUROPSYCHOLOGY LA English DT Article DE attention; memory; APOE; phenotype ID MILD COGNITIVE IMPAIRMENT; E EPSILON-4 ALLELE; ALZHEIMERS-DISEASE; VISUAL-ATTENTION; VISUOSPATIAL ATTENTION; HIPPOCAMPAL VOLUME; EPISODIC MEMORY; GENETIC RISK; OLDER ADULTS; DEMENTIA AB The cognitive consequences of the apolipoprotein E-epsilon 4 (APOE-epsilon 4) allele were examined in middle age, before likely onset of symptoms of Alzheimer's disease. The authors identified 3 cognitive processes-visuospatial attention, spatial working memory, and the effect of visuospatial attention on working memory-and devised "behavioral assays" of the integrity of components of these processes. Redirecting visuospatial attention, retention of memory for location, and attentional modulation of memory of target location were affected by APOE genotype. Visuospatial attention showed additive effects of epsilon 4 gene dose; each additional epsilon 4 allele inherited further slowed disengagement from invalidly cued space. In contrast, working memory performance was affected only in epsilon 4 homozygotes. Effect sizes for the APOE gene were moderate to large, ranging from 14% to 24%. Effects of APOE genotype on component processes of cognition in healthy, middle-aged adults is consistent with the emergence in adulthood of an APOE-epsilon 4 cognitive phenotype. C1 Catholic Univ Amer, Washington, DC 20064 USA. NIMH, Bethesda, MD 20892 USA. RP Greenwood, PM (reprint author), George Mason Univ, Arch Lab, MSN 3F5,4400 Univ Dr, Fairfax, VA 22030 USA. EM pgreenw1@ginu.edu FU NIA NIH HHS [AG07569, AG12387, AG19653, R01 AG019653, U01 AG019653] NR 87 TC 91 Z9 93 U1 2 U2 5 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0894-4105 J9 NEUROPSYCHOLOGY JI Neuropsychology PD MAR PY 2005 VL 19 IS 2 BP 199 EP 211 DI 10.1037/0894-4105.19.2.199 PG 13 WC Psychology, Clinical; Neurosciences; Psychology SC Psychology; Neurosciences & Neurology GA 906DE UT WOS:000227619900007 PM 15769204 ER PT J AU Basselin, M Chang, L Seemann, R Bell, JM Rapoport, SI AF Basselin, M Chang, L Seemann, R Bell, JM Rapoport, SI TI Chronic lithium administration to rats selectively modifies 5-HT2A/2C receptor-mediated brain signaling via arachidonic acid SO NEUROPSYCHOPHARMACOLOGY LA English DT Review DE lithium; serotonin; arachidonic acid; phospholipase A(2); DOI; bipolar disorder ID PHOSPHOLIPASE A(2) ACTIVATION; BIPOLAR DISORDER PEDIGREES; HUMAN CEREBRAL METABOLISM; DRUG-INDUCED MANIA; WET-DOG SHAKES; PREFRONTAL CORTEX; G-PROTEINS; ANTIDEPRESSANT TREATMENTS; SUPERIOR COLLICULUS; 5-HT1B RECEPTORS AB The effects of chronic lithium administration on regional brain incorporation coefficients k* of arachidonic acid ( AA), a marker of phospholipase A(2) (PLA(2)) activation, were determined in unanesthetized rats administered i.p. saline or 1 mg/ kg i.p. (+/-)-1-(2,5-dimethoxy- 4-iodophenyl)-2-aminopropane hydrochloride (DOI), a 5-HT2A/2C receptor agonist. After injecting [1-C-14] AA intravenously, k* ( brain radioactivity/integrated plasma radioactivity) was measured in each of 94 brain regions by quantitative autoradiography. Studies were performed in rats fed a LiCl or a control diet for 6 weeks. In the control diet rats, DOI significantly increased k* in widespread brain areas containing 5-HT2A/2C receptors. In the LiCl-fed rats, the significant positive k* response to DOI did not differ from that in control diet rats in most brain regions, except in auditory and visual areas, where the response was absent. LiCl did not change the head turning response to DOI seen in control rats. In summary, LiCl feeding blocked PLA(2)-mediated signal involving AA in response to DOI in visual and auditory regions, but not generally elsewhere. These selective effects may be related to lithium's therapeutic efficacy in patients with bipolar disorder, particularly its ability to ameliorate hallucinations in that disease. C1 NIA, NIH, Brain Physiol & Metab Sect, Bethesda, MD 20892 USA. RP NIA, NIH, Brain Physiol & Metab Sect, Bldg 10,Room 6N202, Bethesda, MD 20892 USA. EM mirvasln@mail.nih.gov NR 126 TC 35 Z9 35 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X EI 1740-634X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2005 VL 30 IS 3 BP 461 EP 472 DI 10.1038/sj.npp.1300611 PG 12 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 900IE UT WOS:000227207800002 PM 15562295 ER PT J AU Baumann, MH Clark, RD Budzynski, AG Partilla, JS Blough, BE Rothman, RB AF Baumann, MH Clark, RD Budzynski, AG Partilla, JS Blough, BE Rothman, RB TI N-substituted piperazines abused by humans mimic the molecular mechanism of 3,4-methylenedioxymethamphetamine (MDMA, or 'Ecstasy') SO NEUROPSYCHOPHARMACOLOGY LA English DT Article DE dopamine; in vivo microdialysis; release; serotonin; transporters ID SEROTONIN-DOPAMINE INTERACTIONS; RAT NUCLEUS-ACCUMBENS; LOCOMOTOR-ACTIVITY; IN-VIVO; EXTRACELLULAR CONCENTRATIONS; M-CHLOROPHENYLPIPERAZINE; PREFRONTAL CORTEX; 5-HT2C RECEPTORS; DESIGNER DRUGS; H-3 DOPAMINE AB 3,4-Methylenedioxymethamphetamine (MDMA, or 'Ecstasy') is an illicit drug that stimulates the release of serotonin (5-HT) and dopamine (DA) from neurons. Recent evidence reveals that drug users are ingesting piperazine analogs, like 1-benzylpiperazine (BZP, or 'A2') and 1-(m-trifluoromethylphenyl) piperazine ( TFMPP, or 'Molly'), to mimic psychoactive effects of MDMA. In the present study, we compared the neurochemistry of MDMA, BZP, and TFMPP in rats. The effects of MDMA, BZP, and TFMPP on transporter-mediated efflux of [H-3] 5-HT and [H-3] MPP+ ( DA transporter substrate) were determined in synaptosomes. The effects of drugs on extracellular levels of 5-HT and DA were examined using in vivo microdialysis in conscious rats. MDMA evoked transporter-mediated release of [H-3] 5- HT and [H-3] MPP+. BZP released [H-3] MPP+, whereas TFMPP was a selective releaser of [H-3] 5-HT. MDMA ( 1 - 3 mg/kg, i.v.) increased dialysate 5- HT and DA in a dose-related fashion, with actions on 5- HT being predominant. BZP ( 3 - 10 mg/kg, i.v.) elevated dialysate DA and 5- HT, while TFMPP ( 3 - 10 mg/kg, i.v.) elevated 5- HT. Administration of BZP plus TFMPP at a 1: 1 ratio (BZP/TFMPP) produced parallel increases in dialysate 5- HT and DA; a 3 mg/kg dose of BZP/TFMPP mirrored the effects of MDMA. At a 10 mg/kg dose, BZP/TFMPP increased dialysate DA more than the summed effects of each drug alone, and some rats developed seizures. Our results show that BZP/TFMPP and MDMA share the ability to evoke monoamine release, but dangerous drug - drug synergism may occur when piperazines are coadministered at high doses. C1 NIDA, Clin Psychopharmacol Sect, IRP, NIH,Intramural Res Program, Baltimore, MD 21224 USA. Res Triangle Inst Int, Chem & Life Sci Grp, Res Triangle Pk, NC USA. RP Baumann, MH (reprint author), NIDA, Clin Psychopharmacol Sect, IRP, NIH,Intramural Res Program, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM mbaumann@intra.nida.nih.gov NR 69 TC 110 Z9 117 U1 1 U2 6 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0893-133X J9 NEUROPSYCHOPHARMACOL JI Neuropsychopharmacology PD MAR PY 2005 VL 30 IS 3 BP 550 EP 560 DI 10.1038/sj.npp.1300585 PG 11 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 900IE UT WOS:000227207800010 PM 15496938 ER PT J AU Hummel, F Cohen, LG AF Hummel, F Cohen, LG TI Improvement of motor function with noninvasive cortical stimulation in a patient with chronic stroke SO NEUROREHABILITATION AND NEURAL REPAIR LA English DT Article DE stroke; rehabilitation; stimulation; TMS; DCS; motor ID TRANSCRANIAL MAGNETIC STIMULATION; CORTEX STIMULATION; EXCITABILITY; PLASTICITY; MODULATION; RECOVERY; BRAIN; INFARCT; HAND AB This manuscript reports the effects of transcranial DC stimulation (tDCS), a technique that enhances cortical plasticity in healthy humans, on motor function in a patient with chronic subcortical ischemic stroke. tDCS but not sham applied in a double-blind protocol to motor region of the affected hemisphere led to improvements in pinch force, Jebsen-Taylor Hand Function Test, and simple reaction times in the paretic hand that outlasted the stimulation period for at least 40min. These changes were accompanied by increased corticomotor excitability identified by enhanced recrutiment curves and reduced intracortical inhibition to transcranical magnetic stimulation. These results document a beneficial effect of noninvasive brain stimulation on motor function in a human patient with stroke and raise the hypothesis of it potential application in neurorehabilitation. C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20817 USA. Univ Tubingen, Dept Neurol, Cort Physiol Res Grp, D-7400 Tubingen, Germany. Univ Tubingen, Hertie Inst Clin Brain Res, Tubingen, Germany. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20817 USA. EM cohenl@ninds.nih.gov NR 29 TC 128 Z9 132 U1 1 U2 22 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1545-9683 J9 NEUROREHAB NEURAL RE JI Neurorehabil. Neural Repair PD MAR PY 2005 VL 19 IS 1 BP 14 EP 19 DI 10.1177/1545968304272698 PG 6 WC Clinical Neurology; Rehabilitation SC Neurosciences & Neurology; Rehabilitation GA 902EX UT WOS:000227338200002 PM 15673839 ER PT J AU Kingman, A Albers, JW Arezzo, JC Garabrant, DH Michalek, JE AF Kingman, A Albers, JW Arezzo, JC Garabrant, DH Michalek, JE TI Amalgam exposure and neurological function SO NEUROTOXICOLOGY LA English DT Article DE amalgam exposure; mercury; neurological signs; peripheral neuropathy; epidemiology ID DENTAL AMALGAM; ELEMENTAL MERCURY; PERIPHERAL NEUROPATHY; FILLINGS; HEALTH; POLYNEUROPATHY; RELIABILITY; VETERANS; DENTISTS; BRAIN AB Concerns regarding the safety of silver-mercury amalgam fillings continue to be raised in the absence of any direct evidence of harm. The widespread population exposure to amalgam mandated that a thorough investigation be conducted of its potential effects on the nervous system. The National Institute of Dental and Craniofacial Research and U.S. Air Force investigators collaborated in the ongoing Air Force Health Study (AFHS) of Vietnam era veterans. The primary study question involved adverse health effects associated with exposure to herbicides or dioxin. Air assessment of exposure to dental amalgam fillings was added to the 1997-1998 health examination to investigate possible associations between amalgam exposure and neurological abnormalities. Our study population consisted of 1663 dentate AFHS participants, comprised of 986 AFHS controls and 677 Ranch Hand veterans who were exposed to dioxin in Vietnam. Two hundred and fifty-two of the participants had confirmed diabetes mellitus. Study outcomes included clinical neurological signs, vibrotactile thresholds, and summary variables for different levels of peripheral neuropathy. A limitation of our study is that our database did not include more sensitive continuous measures such as nerve conduction studies. No significant associations were found between amalgam exposure and clinical neurological signs of abnormal tremor, coordination, station or gait, strength, sensation, or muscle stretch reflexes or for any level of peripheral neuropathy among our study participants. A statistically significant association was detected between amalgam exposure and the continuous vibrotactile sensation response for the combined non-diabetic participants and separately for non-diabetic AFHS controls. No significant association in this measure was detectable for non-diabetic Ranch Hand veterans or among the combined diabetic participants,. The association is a sub-clinical finding that was not associated with symptoms, clinically evident signs of neuropathy, or any functional impairment. Overall, we found no association between amalgam exposure and neurological signs or clinically evident peripheral neuropathy. Our findings do not support the hypothesis that exposure to amalgam produces adverse, clinically evident neurological effects. (C) 2004 Elsevier Inc. All rights reserved. C1 Natl Inst Dent & Craniofacial Res, Div Clin Res & Hlth Promot, NIH, Bethesda, MD 20892 USA. Univ Michigan, Sch Med, Dept Neurol, Ann Arbor, MI 48109 USA. Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10467 USA. Univ Michigan, Sch Publ Hlth, Dept Environm Hlth Sci, Ann Arbor, MI 48109 USA. Univ Michigan, Sch Publ Hlth, Dept Epidemiol, Ann Arbor, MI 48109 USA. USAF, Res Lab, San Antonio, TX USA. RP Kingman, A (reprint author), Natl Inst Dent & Craniofacial Res, Div Clin Res & Hlth Promot, NIH, 45 Ctr Dr,Room 4As-25U, Bethesda, MD 20892 USA. EM Albert.Kingman@nih.gov NR 46 TC 38 Z9 39 U1 1 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0161-813X J9 NEUROTOXICOLOGY JI Neurotoxicology PD MAR PY 2005 VL 26 IS 2 BP 241 EP 255 DI 10.1016/j.neuro.2004.09.008 PG 15 WC Neurosciences; Pharmacology & Pharmacy; Toxicology SC Neurosciences & Neurology; Pharmacology & Pharmacy; Toxicology GA 904QT UT WOS:000227513500010 PM 15713345 ER PT J AU Miller-Loncar, C Lester, BM Seifer, R Lagasse, LL Bauer, CR Shankaran, S Bada, HS Wright, LL Smeriglio, VL Bigsby, R Liu, J AF Miller-Loncar, C Lester, BM Seifer, R Lagasse, LL Bauer, CR Shankaran, S Bada, HS Wright, LL Smeriglio, VL Bigsby, R Liu, J TI Predictors of motor development in children prenatally exposed to cocaine SO NEUROTOXICOLOGY AND TERATOLOGY LA English DT Article DE cocaine; pregnancy substance abuse; prenatal drug exposure; neurobehavior; NNNS; motor development; hierarchical linear modeling ID EARLY-CHILDHOOD; BIRTH-WEIGHT; DRUG-USE; INFANTS; ABUSE; PREGNANCY; GROWTH; MECHANISMS; MECONIUM; SMOKING AB The current study examined the pattern of motor development across the first 18 months of life in infants with in utero exposure to cocaine to determine how prenatal drug effects and level of exposure relates to motor development. Motor development was examined at 1, 4, 12, and 18 months of age (corrected for prematurity). Infants were divided into cocaine exposed (n=392) and comparison (n=776) groups. Exposure status was determined by meconium assay and maternal self-report with alcohol, marijuana, tobacco, and opiates present in both groups. Motor skills were assessed at 1 month using the NICU Network Neurobehavioral Scale (NNNS), at 4 months using the posture and fine motor assessment of infants (PFMAI), at 12 months using the Bayley Scales of Infant Development-Second Edition (BSID-II), and at 18 months using the Peabody Developmental Motor Scales (PDMS). Examiners masked to exposure status performed all assessments. Motor scores were converted to standard (z) scores, and hierarchical linear modeling (HLM) was used to examine the change in motor skills from 1 to 18 months of age. Infants with exposure to cocaine showed low motor skills at their initial status of 1 month but displayed significant increases over time. Both higher and lower levels of tobacco use related to poorer motor performance on average. Heavy cocaine use related to poorer motor performance as compared to no use, but there were no effects of level of cocaine use on change in motor skills. (c) 2004 Elsevier Inc. All rights reserved. C1 Women & Infants Hosp Rhode Isl, Infants Dev Ctr, Brown Med Sch, Providence, RI 02903 USA. EP Bradley Hosp, Providence, RI 02903 USA. Univ Miami, Sch Med, Miami, FL 33152 USA. Wayne State Univ, Sch Med, Detroit, MI USA. Univ Tennessee, Sch Med, Memphis, TN 38163 USA. NICHHD, Bethesda, MD 20892 USA. NIDA, Bethesda, MD 20892 USA. RP Miller-Loncar, C (reprint author), Women & Infants Hosp Rhode Isl, Infants Dev Ctr, Brown Med Sch, 101 Dudley St, Providence, RI 02903 USA. EM Cynthia_Loncar@brown.edu OI Seifer, Ronald/0000-0003-4879-2839 FU NICHD NIH HHS [N01-HD-2-3159, U10 HD 27904, U10 HD 27856, U10 HD 21385, U10 HD 21397]; NIDA NIH HHS [U10 DA024119] NR 41 TC 24 Z9 25 U1 1 U2 7 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0892-0362 J9 NEUROTOXICOL TERATOL JI Neurotoxicol. Teratol. PD MAR-APR PY 2005 VL 27 IS 2 BP 213 EP 220 DI 10.1016/j.ntt.2004.10.007 PG 8 WC Neurosciences; Toxicology SC Neurosciences & Neurology; Toxicology GA 905JC UT WOS:000227563400004 PM 15734272 ER PT J AU Qu, W Liu, J Fuquay, R Shimoda, R Sakurai, T Saavedra, JE Keefer, LK Waalkes, MP AF Qu, W Liu, J Fuquay, R Shimoda, R Sakurai, T Saavedra, JE Keefer, LK Waalkes, MP TI The nitric oxide prodrug, V-PYRRO/NO, protects against cadmium toxicity and apoptosis at the cellular level SO NITRIC OXIDE-BIOLOGY AND CHEMISTRY LA English DT Article DE V-PYRRO/NO; cadmium; apoptotic resistance; in vitro; liver cells ID INDUCED MALIGNANT-TRANSFORMATION; INDUCED HEPATOTOXICITY; GENE-EXPRESSION; KINASE JNK/SAPK; REGULATORY ROLE; METALLOTHIONEIN; ACTIVATION; DONOR; CELLS; MICE AB The liver is an important target tissue of cadmium. The compound O-2-vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2 diolate (V-PYRRO/NO) is a fiver-selective nitric oxide (NO) prodrug that is metabolized by hepatic P450 enzymes to release NO in hepatocytes. In vivo. V-PYRRO/NO call protect against the toxicity of various hepatotoxicants, including cadmium. Since NO is an effective vasodilator, whether this protective effect against cadmium toxicity is M the level of the hepatic vascular system or actually within the liver cells has not been defined. Thus, we studied the effects of V-PYRRO/NO pretreatment oil cadmium-induced toxicity and apoptosis in cultured rat liver epithelial (TRL 1215) cells. Cells were pretreated with V-PYRRO/NO at 500 or 1000 mu M for up to 24 h then exposed to cadmium (as CdCl2) for additional 24 h and cytotoxicity was measured. Cadmium was significantly less cytotoxic in V-PYRRO/NO (1000 mu M) pretreated cells (LC50 = 6.1 +/- 0.6 mu M) compared to control cells (LC50 = 3.5 +/- 0.4 mu M). TRL 1215 cells acted upon the prodrug to release NO. producing nitrite levels in the extracellular media after 24 It of exposure to 500 or 1000 mu M V-PYRRO/NO measured at 87.0 +/- 4.2 and 324 +/- 14.8 PM, respectively, compared to basal levels of 7.70 +/- 0.46 mu M. V-PYRRO/NO alone produced small increases in metallothionein (MT) a metal-binding, protein associated with cadmium tolerance. However, V-PYRRO/NO pretreatment greatly enhanced cadmium induction of MT. V-PYRRO/NO pretreatment also markedly reduced apoptotic cell death induced by cadmium (5 mu M) apparently by blocking cadmium-induced activation Or the c-Jun N-terminal kinase (JNK) pathway. Thus, the prodrug, V-PYRRO/NO, protects against the adverse effects of cadmium directly within rat liver cells apparently through generation of NO and, at least in part, by facilitation of cadmium-induced MT synthesis. Published by Elsevier Inc. C1 NCI, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. NCI, Chem Sect, Comparat Carcinogenesis Lab, Frederick, MD USA. RP Waalkes, MP (reprint author), NCI, Inorgan Carcinogenesis Sect, Comparat Carcinogenesis Lab, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. EM waalkes@niehs.nih.gov RI Keefer, Larry/N-3247-2014 OI Keefer, Larry/0000-0001-7489-9555 NR 33 TC 20 Z9 24 U1 0 U2 2 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1089-8603 J9 NITRIC OXIDE-BIOL CH JI Nitric Oxide-Biol. Chem. PD MAR PY 2005 VL 12 IS 2 BP 114 EP 120 DI 10.1016/j.niox.2005.01.005 PG 7 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 906DO UT WOS:000227620900007 PM 15740985 ER PT J AU Rudy, E Grady, P AF Rudy, E Grady, P TI Biological researchers: Building nursing science SO NURSING OUTLOOK LA English DT Article ID ANIMAL RESEARCH AB Nursing science addresses the individual from a multidimensional perspective, and the questions nurses generate from their practice are often grounded in basic biology. However, concern is frequently voiced as to whether there is adequate preparation and support for biological researchers within nursing. This study reports on a survey of nurse investigators funded by the National Institutes of Health who carry out biological research. All study participants were current faculty, and 48% had post-doctoral training. The majority worked with animal models. Research areas ranged from cell and molecular biology to delivery of health care. Some participants reported tension between their work and how others view "typical" nursing research. All participants had been awarded federal research funding, primarily from the National Institute of Nursing Research (NINR), and most reported receiving small grants from other funding organizations early in their careers. Self-identified factors influencing success included mentoring, flexibility, persistence, and hard work. C1 NINR, Off Sci Policy & Publ Liaison, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Nursing, Pittsburgh, PA 15261 USA. RP Rudy, E (reprint author), NINR, Off Sci Policy & Publ Liaison, 31 Ctr Dr,MSC-2178,Bldg 5B-10, Bethesda, MD 20892 USA. NR 11 TC 5 Z9 5 U1 1 U2 1 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0029-6554 J9 NURS OUTLOOK JI Nurs. Outlook PD MAR-APR PY 2005 VL 53 IS 2 BP 88 EP 94 DI 10.1016/j.outlook.2004.09.006 PG 7 WC Nursing SC Nursing GA 923ZA UT WOS:000228946900007 PM 15858527 ER PT J AU Zhu, M de Cabo, R Anson, RM Ingram, DK Lane, MA AF Zhu, M de Cabo, R Anson, RM Ingram, DK Lane, MA TI Caloric restriction modulates insulin receptor signaling in liver and skeletal muscle of rat SO NUTRITION LA English DT Article DE caloric restriction; tyrosine phosphorylation; insulin receptor; protein tyrosine phosphatase-1B ID PROTEIN-TYROSINE PHOSPHATASE-1B; COMPLEMENT-RELATED PROTEIN; LIFE-SPAN; CAENORHABDITIS-ELEGANS; METABOLIC SYNDROME; DIABETES-MELLITUS; ADIPOSE-TISSUE; RHESUS-MONKEYS; MICE LACKING; RESISTANCE AB Objective: We investigated how the insulin/insulin-like growth factor-1 signaling pathway is involved in the robust antiaging effects produced by caloric restriction. Methods: We subjected male rats to feeding ad libitum or calorie restriction, i.e., 60% of the ad libitum amount, for 2 and 25 mo and then assessed the effects of calorie restriction on insulin receptor (IR) signaling in liver and skeletal muscle. Results: The results indicated that aging was accompanied by a significant decrease in IR tyrosine phosphorylation after insulin stimulation in live and skeletal muscle, which was associated with a significant increase in the activity of protein tyrosine phosphatase-1B. However, these age-related alterations were attenuated by long-term calorie restriction. Expression profile of mRNA showed an increased expression of mRNAs for IR and insulin-like growth factor-1 receptor in both tissues of calorie-restricted rats, but increased expression of IR mRNA was dissociated with the IR gene product in rats maintained on long-term calorie-restricted diet. Conclusion: IR signaling may play an important role in aging and its retardation by calorie restriction, and normal function of IR in liver and skeletal muscle is required for healthy aging and extending lifespan in mammals. (C) 2005 Elsevier Inc. All rights reserved. C1 NIA, Lab Expt Gerontol, Gerontol Res Ctr, Intramural Res Program, Baltimore, MD 21224 USA. Merck & Co Inc, Rahway, NJ 07065 USA. RP Ingram, DK (reprint author), NIA, Lab Expt Gerontol, Gerontol Res Ctr, Intramural Res Program, Baltimore, MD 21224 USA. EM ingramd@grc.nia.nih.gov RI de Cabo, Rafael/E-7996-2010; de Cabo, Rafael/J-5230-2016; OI de Cabo, Rafael/0000-0002-3354-2442; , rafael/0000-0003-2830-5693 NR 58 TC 23 Z9 25 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0899-9007 J9 NUTRITION JI Nutrition PD MAR PY 2005 VL 21 IS 3 BP 378 EP 388 DI 10.1016/j.nut.2004.06.030 PG 11 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 915DH UT WOS:000228277400015 PM 15797682 ER PT J AU Ellsworth, DL Coady, SA Chen, W Srinivasan, SR Boerwinkle, E Berenson, GS AF Ellsworth, DL Coady, SA Chen, W Srinivasan, SR Boerwinkle, E Berenson, GS TI Interactive effects between polymorphisms in the beta-adrenergic receptors and longitudinal changes in obesity SO OBESITY RESEARCH LA English DT Article DE children; young adults; genetics; body weight gain ID TRP64ARG POLYMORPHISM; GENETIC-FACTORS; QUEBEC FAMILY; CHILDHOOD; PREVALENCE; ADIPOSITY; WEIGHT; BLOOD; GAIN; MEN AB We assessed interactions between polymorphisms in the beta-adrenergic receptor genes and longitudinal changes in obesity from childhood to adulthood using longitudinal data collected over a 24-year period from 1973 to 1996. Sex- and age-stratified analyses using random coefficients models were used to examine gene-gene interaction effects on obesity measures in 1179 African-American and white men and women (71% white, 57% women). Suggestive evidence for an interaction (p = 0.022) between the beta 1- and beta 2-adrenergic receptors was observed in men for longitudinal change in BMI. Men with Gly/Gly genotypes for both the beta l and beta 2 receptors showed significant increases (similar to 0.6%/yr) in BMI from childhood to adulthood. Women showed suggestive evidence for an interaction (p = 0.035) between the beta 1 - and beta 3-adrenergic receptors for change over time in BMI. Women with Gly/Gly genotypes at the beta 1-receptor and carrying at least one beta 3-Arg allele showed notable increases in BMI. The regulation of lipolysis and development of obesity differ markedly between men and women and may be influenced by genetic polymorphisms, which contribute to the efficiency of the beta-adrenergic receptors, and hormonal effects on adrenergic receptor activity. C1 Tulane Univ, Ctr Cardiovasc Hlth, Sch Publ Hlth & Trop Med, New Orleans, LA 70112 USA. Tulane Univ, Dept Epidemiol, Sch Publ Hlth & Trop Med, New Orleans, LA 70112 USA. Windber Res Inst, Cardiovasc Dis Res Program, Windber, PA USA. NHLBI, Div Epidemiol & Clin Applicat, NIH, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Ctr Human Genet, Houston, TX USA. Univ Texas, Hlth Sci Ctr, Inst Mol Med, Houston, TX USA. RP Berenson, GS (reprint author), Tulane Univ, Ctr Cardiovasc Hlth, Sch Publ Hlth & Trop Med, 1440 Canal St,Suite 2140, New Orleans, LA 70112 USA. EM berenson@mailhost.tcs.tulane.edu FU NHLBI NIH HHS [HL38844] NR 26 TC 28 Z9 32 U1 0 U2 0 PU NORTH AMER ASSOC STUDY OBESITY PI SILVER SPRING PA 8630 FENTON ST, SUITE 918, SILVER SPRING, MD 20910 USA SN 1071-7323 J9 OBES RES JI Obes. Res. PD MAR PY 2005 VL 13 IS 3 BP 519 EP 526 DI 10.1038/oby.2005.55 PG 8 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 919NT UT WOS:000228625500007 PM 15833937 ER PT J AU Simpkins, F Zahurak, M Armstrong, D Grumbine, F Bristow, R AF Simpkins, F Zahurak, M Armstrong, D Grumbine, F Bristow, R TI Ovarian malignancy in breast cancer patients with an adnexal mass SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID UNITED-STATES; WOMEN; CARE; CARCINOMA; PATTERNS AB OBJECTIVE: The objectives of this study were to estimate ovarian malignancy rate in breast cancer patients with an adnexal mass and to identify variables predictive of malignancy. METHODS: This was a review from 1990-2002 including women with breast cancer diagnosed with an adnexal mass who subsequently underwent oophorectomy. Ovarian pathology was classified as benign, primary malignancy, or metastatic breast cancer. Women with preoperative evidence of malignancy were excluded. RESULTS: Of 129 cases reviewed, benign ovarian cysts were found in 113 cases (88%) and malignant ovarian neoplasms were found in 16 cases (12%). Univariate logistic regression analyses were performed to determine predictors of malignancy. Complex masses were 29 times more likely to be malignant (P < .001). Women with estrogen-receptor-negative breast cancer had an increased risk for malignant adnexal masses (44%; OR 12.4, 95% confidence interval 2.4-65.1; P = .003). Patients with an elevated CA 125 had a 6.3-fold increased risk of malignancy, P = .02. Adnexal mass size greater than 5 cm also increased the risk of malignancy (18.8%; OR 4.6, 95% confidence interval 1.2-17.3; P = .02). Malignant adnexal masses had a greater likelihood of being primary ovarian cancer than metastatic breast cancer by 7:1. CONCLUSION: An isolated adnexal mass in the breast cancer patient is most commonly a benign ovarian cyst. Adnexal masses associated with an increased CA 125, complex architecture by ultrasonography, or size greater than 5cm are significant predictors of malignancy and are indications for referral to a gynecologic oncologist. (C) 2005 by The American College of Obstetricians and Gynecologists. C1 NCI, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Kelly Gynecol Oncol Serv, Dept Gynecol & Obstet, Baltimore, MD 21205 USA. Greater Baltimore Med Ctr, Dept Gynecol & Obstet, Div Gynecol Oncol, Baltimore, MD 21204 USA. RP Simpkins, F (reprint author), NCI, 10 Ctr Dr,Bldg 10,B1-B40, Bethesda, MD 20892 USA. EM simpkinf@mail.nih.gov NR 15 TC 7 Z9 8 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAR PY 2005 VL 105 IS 3 BP 507 EP 513 DI 10.1097/01.AOG.0000154162.51442.14 PG 7 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 900IZ UT WOS:000227209900010 PM 15738016 ER PT J AU Reddy, UM Branum, AM Klebanoff, MA AF Reddy, UM Branum, AM Klebanoff, MA TI Relationship of maternal body mass index and height to twinning SO OBSTETRICS AND GYNECOLOGY LA English DT Article ID RISKS CONFRONTING TWINS; RATES; US; PREGNANCIES; PREVALENCE; OBESITY; PARITY; ADULTS; BIRTHS; WOMEN AB OBJECTIVE: Increasing use of fertility drugs is considered the primary cause for the recent increase in dizygotic twinning in developed countries. However, dizygotic twinning has also been related to obesity in foreign populations. We sought to confirm this relationship in U.S. pregnancies, which predated widespread use of fertility drugs. METHODS: We analyzed 51,783 pregnancies (561 twin) in the Collaborative Perinatal Project, which took place at 12 hospitals in the United States from 1959 to 1966. The occurrence of twinning was compared according to maternal self-reported prepregnant body mass index (BMI) of less than 20, 20-24.99, 25-29.99, and 30 kg/m(2) or greater, before and after adjustment for confounding factors. RESULTS: There was a statistically significant trend for increased risk of total twinning with increasing BMI (P < .001). The odds of monozygous twinning were not significantly related to BMI, but the odds of dizygous twinning were significantly related to increased BMI. After adjusting for maternal race, age, parity, and height, the odds of dizygous twinning were still significantly elevated among women with a BMI of 30 or more, and the trend for increasing risk of dizygous twinning with increasing BMI was significant (P = .001). The trend for increased twinning with increasing height was also significant. Women in the tallest quartile of height had a significantly increased odds ratio for dizygous twin pregnancies, although not of die same magnitude as women with BMI over 30. CONCLUSION: We confirmed the association of maternal weight and height with dizygotic twinning in a U.S. population among which. fertility drugs were not a factor. (C) 2005 by T'he American College of Obstetricians and Gynecologists. C1 NICHHD, Pregnancy & Perinatol Branch, Bethesda, MD 20892 USA. NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Infant Child & Womens Hlth Stat Branch, Natl Ctr Hlth Stat, Atlanta, GA USA. RP Reddy, UM (reprint author), 6100 Execut Blvd,Room 4B03F, Bethesda, MD 20892 USA. EM reddyu@mail.nih.gov NR 31 TC 40 Z9 41 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0029-7844 J9 OBSTET GYNECOL JI Obstet. Gynecol. PD MAR PY 2005 VL 105 IS 3 BP 593 EP 597 DI 10.1097/01.AOG.0000153491.09525.dd PG 5 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 900IZ UT WOS:000227209900024 PM 15738030 ER PT J AU Galperin, MY Rigden, DJ AF Galperin, MY Rigden, DJ TI OMICS-related research in South America SO OMICS-A JOURNAL OF INTEGRATIVE BIOLOGY LA English DT Editorial Material C1 NIH, Bethesda, MD 20892 USA. Univ Liverpool, Liverpool L69 3BX, Merseyside, England. RP Galperin, MY (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 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 1536-2310 J9 OMICS JI OMICS PD MAR PY 2005 VL 9 IS 1 BP 1 EP 1 DI 10.1089/omi.2005.9.1 PG 1 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 919VO UT WOS:000228645900001 ER PT J AU Low, JA Schoenfeldt, M AF Low, JA Schoenfeldt, M TI Current clinical trials investigating 3-AP - Referral resource SO ONCOLOGY-NEW YORK LA English DT Editorial Material C1 NCI, Bethesda, MD 20892 USA. Emmes Corp, Rockville, MD USA. RP Low, JA (reprint author), NCI, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU P R R INC PI MELVILLE PA 48 SOUTH SERVICE RD, MELVILLE, NY 11747 USA SN 0890-9091 J9 ONCOLOGY-NY JI Oncology-NY PD MAR PY 2005 VL 19 IS 3 BP 354 EP 354 PG 1 WC Oncology SC Oncology GA 052ED UT WOS:000238213300016 PM 15828551 ER PT J AU Simpson, K Reardon, K Bevans, M AF Simpson, K Reardon, K Bevans, M TI The development of an algorithm managing acute delirium in patients undergoing allogenic stem cell transplant SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOCIETY PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD MAR PY 2005 VL 32 IS 2 MA 18 BP 427 EP 427 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 907XV UT WOS:000227752400044 ER PT J AU Schuver, B Woolery-Antill, M Carroll, E McKenzie, V Bahne, E AF Schuver, B Woolery-Antill, M Carroll, E McKenzie, V Bahne, E TI Adolescents through the looking glass: The look good feel better program for teens. SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Baltimore, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOCIETY PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD MAR PY 2005 VL 32 IS 2 MA 23 BP 428 EP 428 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 907XV UT WOS:000227752400049 ER PT J AU Steakley, C Sahin, S Wise, A Balis, F AF Steakley, C Sahin, S Wise, A Balis, F TI The impact of screening patients for clinical trials: Resources and costs. SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 NCI, Bethesda, MD 20892 USA. Orkand Harris Informat Corp, Falls Church, VA USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOCIETY PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD MAR PY 2005 VL 32 IS 2 MA 227 BP 486 EP 486 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 907XV UT WOS:000227752400252 ER PT J AU Woolery-Antill, M Carroll, E Wallen, G Jarosinski, P Corey, B Wieland, H Dagher, R AF Woolery-Antill, M Carroll, E Wallen, G Jarosinski, P Corey, B Wieland, H Dagher, R TI Navigating the potholes along the research highway: Implementing a research study. SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. US FDA, Rockville, MD 20857 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ONCOLOGY NURSING SOCIETY PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD MAR PY 2005 VL 32 IS 2 MA 225 BP 486 EP 486 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 907XV UT WOS:000227752400250 ER PT J AU Galgay, L Swift, S Cusack, G Jones-Wells, A Rivera, P Chisholm, L AF Galgay, L Swift, S Cusack, G Jones-Wells, A Rivera, P Chisholm, L TI Actualizing a wellness program and wellness room in the oncology setting: Getting a program through a large institution. SO ONCOLOGY NURSING FORUM LA English DT Meeting Abstract C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ONCOLOGY NURSING SOCIETY PI PITTSBURGH PA 125 ENTERPRISE DR, PITTSBURGH, PA 15275 USA SN 0190-535X J9 ONCOL NURS FORUM JI Oncol. Nurs. Forum PD MAR PY 2005 VL 32 IS 2 MA 254 BP 494 EP 494 PG 1 WC Oncology; Nursing SC Oncology; Nursing GA 907XV UT WOS:000227752400278 ER PT J AU Lass, JH Gal, RL Ruedy, KJ Benetz, BA Beck, RW Baratz, KH Holland, EJ Kalajian, A Kollman, C Manning, FJ Mannis, MJ McCoy, K Montoya, M Stulting, RD Xing, DY Densley, D Moke, PS Powe, A Edwards, S Karpinecz, L Rice, C Redford, M Cotch, MF AF Lass, JH Gal, RL Ruedy, KJ Benetz, BA Beck, RW Baratz, KH Holland, EJ Kalajian, A Kollman, C Manning, FJ Mannis, MJ McCoy, K Montoya, M Stulting, RD Xing, DY Densley, D Moke, PS Powe, A Edwards, S Karpinecz, L Rice, C Redford, M Cotch, MF CA Cornea Donor Study Grp TI An evaluation of image quality and accuracy of eye bank measurement of donor cornea endothelial cell density in the Specular Microscopy Ancillary Study SO OPHTHALMOLOGY LA English DT Article; Proceedings Paper CT Annual Meeting of the American-Academy-of-Ophthalmology CY OCT, 2004 CL New Orleans, LA SP Amer Acad Ophthalmol ID TRANSPLANTED HUMAN CORNEAS; LONG-TERM CHANGES; PENETRATING KERATOPLASTY; QUANTITATIVE-ANALYSIS; CHONDROITIN SULFATE; STORAGE MEDIUM; MORPHOMETRY; PRECISION; OPTISOL; REPRODUCIBILITY AB Purpose: The Specular Microscopy Ancillary Study was designed to examine donor corneal endothelial specular image quality, compare the central endothelial cell density determined by eye banks with the endothelial cell density determined by a central specular microscopy reading center, and evaluate donor factors that may have an impact on specular image quality and endothelial cell density accuracy. Design: Nonrandomized comparative trial. Participants: Endothelial specular images of donor corneas assigned in the Cornea Donor Study. Methods: Certified readers assessed donor image quality (analyzable from fair to excellent vs. unanalyzable) and determined the central endothelial cell density. Independent adjudication was performed if there was a difference in the quality of grading or if the endothelial cell density varied by greater than or equal to5.0% between readers. Average reading center-determined endothelial cell density was compared with the endothelial cell density determined by each eye bank. Main Outcome Measures: Evaluation of image quality and accuracy of endothelial cell density. Results: Of 688 donor endothelial images submitted by 23 eye banks, 663 (96%) were analyzable (excellent, 40 [6%]; good, 302 [44%]; fair, 321 [47%]), and 25 (4%) were unanalyzable by reading center standards. In situ retrieval and greater epithelial exposure correlated with a higher image quality grading. The eye bank-determined endothelial cell density of 434 of the 663 (65%) analyzable images were within 10% of the endothelial cell density determined by the reading center, whereas 185 (28%) were more than 10% higher and 44 (7%) were more than 10% lower. Greater variation in endothelial cell density between the eye banks and the reading center was observed with shorter time of death to preservation, presence of an epithelial defect, folds in Descemet's membrane, lower image quality, and the use of fixed-frame or center method endothelial cell density analysis. Conclusions: Overall, donor endothelial specular image quality and accuracy of endothelial cell density determination were good. However, the data suggest that factors that may affect image quality and contribute to variation in interpretation of the endothelial cell density should be addressed, because the donor endothelial cell density is an important parameter for assessing long-term corneal graft survival. (C) 2005 by the American Academy of Ophthalmology. C1 Jaeb Ctr Hlth Res, Cornea Donor Study Coordinating Ctr, Tampa, FL 33647 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Univ Hosp Cleveland, Cleveland, OH 44106 USA. NEI, Bethesda, MD 20892 USA. RP Lass, JH (reprint author), Jaeb Ctr Hlth Res, Cornea Donor Study Coordinating Ctr, 153120 Amberly Dr,Suite 350, Tampa, FL 33647 USA. EM cds@jaeb.org FU NEI NIH HHS [U10 EY12358, U10 EY12728] NR 63 TC 35 Z9 36 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0161-6420 J9 OPHTHALMOLOGY JI Ophthalmology PD MAR PY 2005 VL 112 IS 3 BP 431 EP 440 DI 10.1016/j.ophtha.2004.10.045 PG 10 WC Ophthalmology SC Ophthalmology GA 900IY UT WOS:000227209800011 PM 15745770 ER PT J AU Rosenbaum, PF Buck, GM Brecher, ML AF Rosenbaum, PF Buck, GM Brecher, ML TI Allergyand infectious disease histories and the risk of childhyood acute lymphoblastic leukaemia SO PAEDIATRIC AND PERINATAL EPIDEMIOLOGY LA English DT Article ID ACUTE LYMPHOCYTIC-LEUKEMIA; RESPIRATORY-TRACT ILLNESS; NON-HODGKINS-LYMPHOMA; CHILDHOOD LEUKEMIA; DAY-CARE; UNITED-STATES; MULTIPLE-MYELOMA; OTITIS-MEDIA; ETIOLOGIC FACTORS; ATOPIC DISEASES AB Infectious disease histories were evaluated in a population-based case-control study of childhood acute lymphoblastic leukaemia (ALL) as it has been hypothesised that delays in early infections are associated with an increased risk of disease. Allergy histories were also assessed as part of a broader evaluation of the role of immune factors in ALL. Cases (n = 255) were diagnosed between 1980 and 1991 at one of four referral centres in a 31-county area of New York State; controls (n = 760) were a random sample of live births from the same region, frequency matched to cases by sex, race and birth year. Data were collected by mailed questionnaire, completed by case and control parents in 1995. Allergy and infectious histories before the age at leukaemia diagnosis for cases and an equivalent age for controls were evaluated. The adjusted odds ratio and 95% confidence interval [CI] associated with a positive history of any allergy was 0.58 [95% Cl 0.38, 0.88] compared with a negative allergy history The occurrence of several common childhood illnesses before 25 months of age and ALL were assessed, with both weak positive and weak inverse associations observed. Overall, these analyses provide little support for the hypothesis that infection delay in early life is associated with an increased risk of ALL. Children with positive allergy histories reported significantly more infections than those with negative histories; however, effect modification of the infection-ALL associations by child allergy history was not observed. Nonetheless, these observations suggest the importance of assessing both allergy and infectious histories and their possible interactions when evaluating the association between these immune factors and childhood ALL. C1 SUNY Upstate Med Univ, Ctr Outcomes Res & Evaluat, Syracuse, NY 13210 USA. NICHHD, Div Epidemiol Stat & Prevent, Bethesda, MD 20892 USA. Roswell Pk Canc Inst, Dept Pediat, Buffalo, NY 14263 USA. RP Rosenbaum, PF (reprint author), SUNY Upstate Med Univ, Ctr Outcomes Res & Evaluat, IHP Room 4005A,505 Irving Ave, Syracuse, NY 13210 USA. EM rosenbap@upstate.edu OI Buck Louis, Germaine/0000-0002-1774-4490 NR 81 TC 42 Z9 42 U1 2 U2 4 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0269-5022 J9 PAEDIATR PERINAT EP JI Paediatr. Perinat. Epidemiol. PD MAR PY 2005 VL 19 IS 2 BP 152 EP 164 PG 13 WC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics SC Public, Environmental & Occupational Health; Obstetrics & Gynecology; Pediatrics GA 915IU UT WOS:000228298700010 PM 15787890 ER PT J AU Yakar, S Kim, H Zhao, H Toyoshima, Y Pennisi, P Gavrilova, O LeRoith, D AF Yakar, S Kim, H Zhao, H Toyoshima, Y Pennisi, P Gavrilova, O LeRoith, D TI The growth hormone-insulin like growth factor axis revisited: lessons from IGF-1 and IGF-1 receptor gene targeting SO PEDIATRIC NEPHROLOGY LA English DT Article; Proceedings Paper CT 7th Symposium on Growth and Development in Children with Chronic Kidney Disease CY APR 01-03, 2004 CL Heidelberg, GERMANY SP IPNA DE insulin-like growth factor-1; insulin-like growth factor-1 receptor; liver-specific igf1 deletion; transgenic overexpression; type 2 diabetes; mouse model; lipotoxicity ID FACTOR-I; SOMATOMEDIN; DELETION AB We have created a liver-specific igf1 gene-deletion mouse model (LID) with markedly reduced circulating IGF-I levels. They demonstrate that while they have normal growth and development they develop insulin resistance secondary to the elevation of circulating growth hormone. When mated with an acid-labile subunit (ALS) gene-deleted mouse they also show osteopenia suggesting that circulating IGF-I levels play a significant role in bone formation. In a separate transgenic mouse we created a model of severe insulin resistance and type 2 diabetes by the overexpression of a dominant-negative IGF-I receptor in skeletal muscle. In this model we show that lipotoxicity plays a major role in the progression of the disease and is affected by treatment with a fibrate, which reverses the insulin resistance and diabetic state. These models are therefore very useful in studying human physiology and disease states. C1 NIH, Diabet Branch, Bethesda, MD 20892 USA. RP LeRoith, D (reprint author), NIH, Diabet Branch, Room 8D12,Bldg 10,MSC 1758, Bethesda, MD 20892 USA. EM derek@helix.nih.gov NR 10 TC 32 Z9 32 U1 0 U2 3 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD MAR PY 2005 VL 20 IS 3 BP 251 EP 254 DI 10.1007/s00467-004-1613-y PG 4 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 907JS UT WOS:000227713600002 PM 15645308 ER PT J AU Nilsson, O Baron, J AF Nilsson, O Baron, J TI Impact of growth plate senescence on catch-up growth and epiphyseal fusion SO PEDIATRIC NEPHROLOGY LA English DT Article; Proceedings Paper CT 7th Symposium on Growth and Development in Children with Chronic Kidney Disease CY APR 01-03, 2004 CL Heidelberg, GERMANY SP IPNA DE longitudinal bone growth; growth plate; senescence; epiphyseal fusion; catch-up growth ID AROMATASE DEFICIENCY; RAT TIBIA; ESTROGEN; HORMONE; PUBERTY; TESTOSTERONE; OXANDROLONE; MATURATION; CARTILAGE; MUTATION AB In mammals, longitudinal bone growth occurs rapidly in prenatal and early postnatal life, but then slows and eventually ceases. This deceleration, which reflects a decline in chondrocyte proliferation, was previously attributed to a hormonal or other systemic mechanism. However, new evidence suggests that it is due to a local mechanism within the growth plate. In particular, recent findings suggest that growth plate chondrocytes have a finite proliferative capacity that is gradually exhausted, causing growth to slow and finally stop. This concept has provided insight into clinical phenomena including catch-up growth after transient growth inhibition, catch-down growth after transient estrogen exposure, and epiphyseal fusion. C1 NICHD, Nihon Univ, CRC, Bethesda, MD 20892 USA. NICHHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. RP Nilsson, O (reprint author), NICHD, Nihon Univ, CRC, Room 1-3330,10 Ctr Dr,MSC 1103, Bethesda, MD 20892 USA. EM ola.nilsson@nih.gov OI Nilsson, Ola/0000-0002-9986-8138 NR 27 TC 23 Z9 24 U1 0 U2 6 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0931-041X J9 PEDIATR NEPHROL JI Pediatr. Nephrol. PD MAR PY 2005 VL 20 IS 3 BP 319 EP 322 DI 10.1007/s00467-004-1689-4 PG 4 WC Pediatrics; Urology & Nephrology SC Pediatrics; Urology & Nephrology GA 907JS UT WOS:000227713600012 PM 15723267 ER PT J AU He, QC Lowrie, C Shelton, GD Castellani, RJ Menotti-Raymond, M Murphy, W O'Brien, SJ Swanson, WF Fyee, JC AF He, QC Lowrie, C Shelton, GD Castellani, RJ Menotti-Raymond, M Murphy, W O'Brien, SJ Swanson, WF Fyee, JC TI Inherited motor neuron disease in domestic cats: A model of spinal muscular atrophy SO PEDIATRIC RESEARCH LA English DT Article ID MOLECULAR-MECHANISMS; RADIATION HYBRID; DETERMINING GENE; SMN GENE; MICE; IDENTIFICATION; MAPS AB Juvenile-onset spinal muscular atrophy was observed in an extended family of purebred domestic cats as a fully penetrant, simple autosomal recessive trait. Affected kittens exhibited tremor, proximal muscle weakness, and muscle atrophy beginning at similar to4 mo of age. Apparent loss of function was rapid initially but progressed slowly after 7-8 mo of age, and variably disabled cats lived for at least 8 y. Electromyography and microscopic examination of muscle and nerve biopsies were consistent with denervation atrophy as a result of a central lesion. There was astrogliosis and dramatic loss of motor neurons in ventral but not dorsal horn gray matter of spinal cord and loss of axons in ventral horn nerve roots. These phenotypic findings were similar to mild forms (type III) of spinal muscular atrophy in humans caused by survival of motor neuron mutations, but molecular analysis excluded feline survival of motor neuron as the disease gene in this family. A breeding colony has been established for further investigation of this naturally occurring large-animal model of inherited motor neuron disease. C1 Michigan State Univ, Lab Comparat Med Genet, Coll Vet Med, E Lansing, MI 48824 USA. Michigan State Univ, Dept Microbiol & Mol Genet, Coll Vet Med, E Lansing, MI 48824 USA. Michigan State Univ, Coll Vet Med, Dept Small Anim Clin Sci, E Lansing, MI 48824 USA. Univ Calif San Diego, Sch Med, Dept Pathol, Comparat Neuromuscular Lab, La Jolla, CA 92093 USA. Michigan State Univ, Coll Human Med, Div Neuropathol, E Lansing, MI 48824 USA. NCI, Lab Genom Divers, Frederick, MD 21702 USA. Cincinnati Zoo & Bot Garden, Ctr Res Endangered Wildlife, Cincinnati, OH 45220 USA. RP Fyee, JC (reprint author), Michigan State Univ, Lab Comparat Med Genet, Coll Vet Med, 2209 Biomed Phys Sci, E Lansing, MI 48824 USA. EM fyfe@cvm.msu.edu RI Castellani, Rudy/A-9555-2009 FU NCRR NIH HHS [RR 15388]; NICHD NIH HHS [HD 39888] NR 30 TC 13 Z9 14 U1 0 U2 3 PU INT PEDIATRIC RESEARCH FOUNDATION, INC PI BALTIMORE PA 351 WEST CAMDEN ST, BALTIMORE, MD 21201-2436 USA SN 0031-3998 J9 PEDIATR RES JI Pediatr. Res. PD MAR PY 2005 VL 57 IS 3 BP 324 EP 330 DI 10.1203/01.PDR.0000153625.486892.6F PG 7 WC Pediatrics SC Pediatrics GA 899NU UT WOS:000227152100003 PM 15635053 ER PT J AU Hintz, SR Kendrick, DE Stoll, BJ Vohr, BR Fanaroff, AA Donovan, EF Poole, WK Blakely, ML Wright, L Higgins, R AF Hintz, SR Kendrick, DE Stoll, BJ Vohr, BR Fanaroff, AA Donovan, EF Poole, WK Blakely, ML Wright, L Higgins, R CA NICHD Neonatal Res Network TI Neurodevelopmental and growth outcomes of extremely low birth weight infants after necrotizing enterocolitis SO PEDIATRICS LA English DT Article DE necrotizing enterocolitis; extremely low birth weight; neurodevelopmental outcome; cerebral palsy; Bayley Scales of Infant Development; growth ID TERM-FOLLOW-UP; PLATELET-ACTIVATING FACTOR; NEONATAL RESEARCH NETWORK; GROSS MOTOR FUNCTION; NATIONAL INSTITUTE; CEREBRAL-PALSY; CHILD HEALTH; SCHOOL-AGE; SURGERY; COMPLICATIONS AB Objectives. Necrotizing enterocolitis (NEC) is a significant complication for the premature infant. However, subsequent neurodevelopmental and growth outcomes of extremely low birth weight (ELBW) infants with NEC have not been well described. We hypothesized that ELBW infants with surgically managed (SurgNEC) are at greater risk for poor neurodevelopmental and growth outcomes than infants with medically managed NEC (MedNEC) compared with infants without a history of NEC (NoNEC). The objective of this study was to compare growth, neurologic, and cognitive outcomes among ELBW survivors of SurgNEC and MedNEC with NoNEC at 18 to 22 months' corrected age. Methods. Multicenter, retrospective analysis was conducted of infants who were born between January 1, 1995, and December 31, 1998, and had a birth weight <1000 g in the National Institute of Child Health and Human Development Neonatal Research Network Registry. Neurodevelopment and growth were assessed at 18 to 22 months' postmenstrual age. chi(2), t test, and logistic regression analyses were used. Results. A total of 2948 infants were evaluated at 18 to 22 months, 124 of whom were SurgNEC and 121 of whom were MedNEC. Compared with NoNEC, both SurgNEC and MedNEC infants were of lower birth weight and had a greater incidence of late sepsis; SurgNEC but not MedNEC infants were more likely to have received a diagnosis of cystic periventricular leukomalacia and bronchopulmonary dysplasia and been treated with postnatal steroids. Weight, length, and head circumference <10 percentile at 18 to 22 months were significantly more likely among SurgNEC but not MedNEC compared with NoNEC infants. After correction for anthropometric measures at birth and adjusted age at follow-up, all growth parameters at 18 to 22 months for SurgNEC but not MedNEC infants were significantly less than for NoNEC infants. SurgNEC but not MedNEC was a significant independent risk factor for Mental Developmental Index <70 (odds ratio [OR]: 1.61; 95% confidence interval [CI]: 1.05-2.50), Psychomotor Developmental Index <70 (OR: 1.95; 95% CI: 1.25-3.04), and neurodevelopmental impairment (OR: 1.78; 95% CI: 1.172.73) compared with NoNEC. Conclusions. Among ELBW infants, SurgNEC is associated with significant growth delay and adverse neurodevelopmental outcomes at 18 to 22 months' corrected age compared with NoNEC. MedNEC does not seem to confer additional risk. SurgNEC is likely to be associated with greater severity of disease. C1 Stanford Univ, Sch Med, Dept Pediat, Div Neonatal & Dev Med, Palo Alto, CA 94304 USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Emory Univ, Dept Pediat, Atlanta, GA 30322 USA. Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. Case Western Reserve Univ, Dept Pediat, Cleveland, OH 44106 USA. Univ Cincinnati, Dept Pediat, Cincinnati, OH 45221 USA. Univ Texas, Dept Pediat Surg, Houston, TX USA. NICHHD, Washington, DC USA. RP Hintz, SR (reprint author), Stanford Univ, Sch Med, Dept Pediat, Div Neonatal & Dev Med, 750 Welch Rd,Suite 315, Palo Alto, CA 94304 USA. EM srhintz@stanford.edu FU NICHD NIH HHS [U01 HD36790, U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21415, U10 HD27851, U10 HD27853, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27881, U10 HD27904, U10 HD34167, U10 HD34216] NR 44 TC 266 Z9 276 U1 5 U2 18 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 MAR PY 2005 VL 115 IS 3 BP 696 EP 703 DI 10.1542/peds.2004-0569 PG 8 WC Pediatrics SC Pediatrics GA 905UV UT WOS:000227596900029 PM 15741374 ER PT J AU Loscalzo, ML Van, PL Ho, VB Bakalov, VK Rosing, DR Malone, CA Dietz, HC Bondy, CA AF Loscalzo, ML Van, PL Ho, VB Bakalov, VK Rosing, DR Malone, CA Dietz, HC Bondy, CA TI Association between fetal lymphedema and congenital cardiovascular defects in Turner syndrome SO PEDIATRICS LA English DT Article DE X-chromosome; aortic coarctation; bicuspid aortic valve; lymphedema ID NOONAN-SYNDROME; HEART-DISEASE; TRANSCRIPTION FACTOR; CYSTIC HYGROMA; MUTATIONS; FETUSES; WEB; MALFORMATIONS; PTPN11; MFH-1 AB Objectives. Turner syndrome (TS) is associated with congenital cardiovascular defects (CCVDs), most commonly bicuspid aortic valve (BAV) and aortic coarctation (COARC), congenital renal anomalies, and fetal lymphedema. It has been theorized that compressive or obstructive effects of fetal lymphedema may actually cause cardiovascular and renal dysmorphogenesis in TS. The objective of this study was to determine whether there is a specific association between a history of fetal lymphedema and CCVDs in monosomy X, or TS, independent of karyotype or general severity of the phenotype. Methods. This was a prospective study of 134 girls and women who have TS (mean age: 30 years) and were clinically evaluated for evidence of fetal lymphedema, classified as central (signified by the presence of neck webbing) or peripheral (current or perinatal, or dysplastic fingernails). The presence of BAV and/or COARC was detected by magnetic resonance imaging combined with echocardiography, and renal anomalies were determined by ultrasound. Results. There is a strong association between developmental central lymphedema, signified by neck webbing, and the presence of BAV (chi(2) = 10) and COARC (chi(2) = 8). The association between webbed neck and CCVDs was independent of karyotype. There was, in contrast, no significant association between renal anomalies and webbed neck or CCVDs. Conclusions. The strong, statistically significant association between neck webbing and the presence of BAV and COARC in TS suggests a pathogenetic connection between fetal lymphatic obstruction and defective aortic development. The presence of neck webbing in TS should alert the clinician to the possibility of congenital cardiovascular defects. C1 NICHD, Dev Endocrinol Branch, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. NIH, Dept Diagnost Radiol, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Radiol, Bethesda, MD 20814 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Bondy, CA (reprint author), NICHD, Dev Endocrinol Branch, NIH, Bldg 10-10N262,10 Ctr Dr, Bethesda, MD 20892 USA. EM bondyc@mail.nih.gov NR 20 TC 52 Z9 55 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 MAR PY 2005 VL 115 IS 3 BP 732 EP 735 DI 10.1542/peds.2004-1369 PG 4 WC Pediatrics SC Pediatrics GA 905UV UT WOS:000227596900034 PM 15741379 ER PT J AU Falkner, B Roccella, E Rosner, B AF Falkner, B Roccella, E Rosner, B CA Working Grp Natl High Blood Pressu TI Blood pressure tables - Reply SO PEDIATRICS LA English DT Letter C1 Thomas Jefferson Univ, Dept Med & Pediat, Philadelphia, PA 19107 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Harvard Univ, Sch Med, Dept Med, Channing Lab, Boston, MA 02115 USA. RP Falkner, B (reprint author), Thomas Jefferson Univ, Dept Med & Pediat, Philadelphia, PA 19107 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 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 MAR PY 2005 VL 115 IS 3 BP 827 EP 827 DI 10.1542/peds.2004-2733 PG 1 WC Pediatrics SC Pediatrics GA 905UV UT WOS:000227596900056 ER PT J AU Blackmon, LR Fanaroff, AA Raju, T AF Blackmon, LR Fanaroff, AA Raju, T TI Prevention of kernicterus: A lesson from the past - Reply SO PEDIATRICS LA English DT Letter C1 Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. Case Western Reserve Univ, Sch Med, Dept Pediat, Cleveland, OH 44106 USA. NICHHD, Pregnancy & Perinatol Branch, Bethesda, MD 20892 USA. RP Blackmon, LR (reprint author), Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD 21201 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 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 MAR PY 2005 VL 115 IS 3 BP 830 EP 830 DI 10.1542/peds.2004-2815 PG 1 WC Pediatrics SC Pediatrics GA 905UV UT WOS:000227596900062 ER PT J AU Walsh, MC AF Walsh, MC TI Physiologically redefining bronchopulmonary dysplasia - Reply SO PEDIATRICS LA English DT Letter C1 Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. NICHHD, Neonatal Res Network, Bethesda, MD USA. RP Walsh, MC (reprint author), Rainbow Babies & Childrens Hosp, Dept Pediat, Cleveland, OH 44106 USA. NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 EI 1098-4275 J9 PEDIATRICS JI Pediatrics PD MAR PY 2005 VL 115 IS 3 BP 831 EP 831 DI 10.1542/peds.2004-2846 PG 1 WC Pediatrics SC Pediatrics GA 905UV UT WOS:000227596900064 ER PT J AU Ambalavanan, N Tyson, JE Kennedy, KA Hansen, NI Vohr, BR Wright, LL Carlo, WA AF Ambalavanan, N Tyson, JE Kennedy, KA Hansen, NI Vohr, BR Wright, LL Carlo, WA CA Natl Inst Child Hlth Human Dev Neo TI Vitamin A supplementation for extremely low birth weight infants: Outcome at 18 to 22 months SO PEDIATRICS LA English DT Article DE vitamin A; retinol; follow-up studies; premature infant; outcomes assessment; bronchopulmonary dysplasia ID BRONCHOPULMONARY DYSPLASIA; TRIAL AB Background. A National Institute of Child Health and Human Development Neonatal Research Network randomized trial showed that vitamin A supplementation reduced bronchopulmonary dysplasia (O-2 at 36 weeks' postmenstrual age) or death in extremely low birth weight (ELBW) neonates (relative risk [RR]: 0.89). As with postnatal steroids or other interventions, it is important to ensure that there are no longer-term adverse effects that outweigh neonatal benefits. Primary Objective. To determine if vitamin A supplementation in ELBW infants during the first month after birth affects survival without neurodevelopmental impairment at a corrected age of 18 to 22 months. Design/Methods. Infants enrolled in the National Institute of Child Health and Human Development vitamin A trial were evaluated at 18 to 22 months by carefully standardized assessments: Bayley Mental Index (MDI) and Psychomotor Index (PDI), visual and hearing screens, and physical examination for cerebral palsy (CP). The medical history was also obtained. Neurodevelopmental impairment (NDI) was predefined as >= 1 of MDI <70, PDI <70, CP, blind in both eyes, or hearing aids in both ears. Results. Of 807 enrolled infants, 133 died before and 16 died after discharge. Five hundred seventy-nine (88%) of the 658 remaining infants were followed up. The primary outcome of NDI or death could be determined for 687 of 807 randomized infants (85%). Baseline characteristics and predischarge and postdischarge mortality were comparable in both study groups. NDI or death by 18 to 22 months occurred in 190 of 345 (55%) infants in the vitamin A group and in 204 of 342 (60%) of the control group (RR: 0.94; 95% confidence interval: 0.80-1.07). RRs for low MDI, low PDI, and CP were also <1.0. We found no evidence that neonatal vitamin A supplementation reduces hospitalizations or pulmonary problems after discharge. Conclusion. Vitamin A supplementation for ELBW infants reduces bronchopulmonary dysplasia without increasing mortality or neurodevelopmental impairment at 18 to 22 months. However, this study was not powered to evaluate small magnitudes of change in long-term outcomes. C1 Univ Alabama Birmingham, Dept Pediat, Birmingham, AL 35249 USA. Univ Texas, Sch Med, Dept Pediat, Houston, TX USA. Res Triangle Inst, Res Triangle Pk, NC 27709 USA. Brown Univ, Women & Infants Hosp, Dept Pediat, Providence, RI 02908 USA. NICHHD, Neonatal Res Network, Bethesda, MD 20892 USA. RP Ambalavanan, N (reprint author), Univ Alabama Birmingham, Dept Pediat, 525 New Hillman Bldg,619 S 20th St, Birmingham, AL 35249 USA. EM ambal@uab.edu OI Ambalavanan, Namasivayam/0000-0003-0731-9092 FU NCRR NIH HHS [M01 RR 00070, M01 RR 00750, M01 RR 00997, M01 RR 06022, M01 RR 08084]; NICHD NIH HHS [U10 HD27853, U01 HD36790, U10 HD19897, U10 HD21364, U10 HD21373, U10 HD21385, U10 HD21397, U10 HD21415, U10 HD27851, U10 HD27856, U10 HD27871, U10 HD27880, U10 HD27881, U10 HD27904, U10 HD34167, U10 HD34216] NR 26 TC 67 Z9 71 U1 0 U2 2 PU AMER ACAD PEDIATRICS PI ELK GROVE VILLAGE PA 141 NORTH-WEST POINT BLVD,, ELK GROVE VILLAGE, IL 60007-1098 USA SN 0031-4005 J9 PEDIATRICS JI Pediatrics PD MAR PY 2005 VL 115 IS 3 BP E249 EP E254 DI 10.1542/peds.2004-1812 PG 6 WC Pediatrics SC Pediatrics GA 905UV UT WOS:000227596900001 PM 15713907 ER PT J AU Ries, M Gupta, S Moore, DF Sachdev, V Quirk, JM Murray, GJ Rosing, DR Robinson, C Schaefer, E Gal, A Dambrosia, JM Garman, SC Brady, RO Schiffmann, R AF Ries, M Gupta, S Moore, DF Sachdev, V Quirk, JM Murray, GJ Rosing, DR Robinson, C Schaefer, E Gal, A Dambrosia, JM Garman, SC Brady, RO Schiffmann, R TI Pediatric Fabry disease SO PEDIATRICS LA English DT Article DE adolescence; child; human; Fabry disease; genetics; cornea verticillata; pain; acroparesthesia; diarrhea; heart; cardiomyopathy; echocardiogram; kidney; proteinuria; alpha-galactosidase A; quantitative sudomotor axon reflex test; sweating; quality of life ID ENZYME REPLACEMENT THERAPY; LEFT-VENTRICULAR MASS; HUMAN ALPHA-GALACTOSIDASE; CLINICAL MANIFESTATIONS; NATURAL-HISTORY; RENAL-DISEASE; BODY-SIZE; CHILDREN; INVOLVEMENT; OVERWEIGHT AB Background. Fabry disease is an under-diagnosed, treatable, X-linked, multisystem disorder. Objectives. To test the hypothesis that quality of life and sweating are decreased among pediatric patients with Fabry disease, compared with control subjects, and to provide quantitative natural history data and novel clinical end points for therapeutic trials. Design. Prospective, cross-sectional, observational study. Setting. Referral to the National Institutes of Health. Participants. Twenty-five male children with Fabry disease (mean age: 12.3 +/- 3.5 years) and 21 age-matched control subjects. Main Outcome Measures. Quality of life (measured with the Child Health Questionnaire) and sweating (assessed with the quantitative sudomotor axon reflex test). Results. Quality of life scores for pediatric patients <10 years of age with Fabry disease, compared with published normative values, were 55 +/- 17 vs 83 +/- 19 for bodily pain and 62 +/- 19 vs 80 +/- 13 for mental health. Bodily pain scores for patients >= 10 years of age were 54 +/- 22 vs 74 +/- 23. Sweat volume in the Fabry disease group was 0.41 +/- 0.46 mu L/mm(2), compared with 0.65 +/- 0.44 mu L/mm(2) in the control group. Renal function, urinary protein excretion, and cardiac function and structure were normal for the majority of patients. The 3 patients with residual alpha-galactosidase A activity >= 1.5% of normal values were free of cornea verticillata and had normal serum and urinary globotriaosylceramide levels. All other children had glycolipid levels comparable to those of adult patients with Fabry disease. Acroparesthesia and cardiac abnormalities were generally present before anhidrosis and proteinuria. Mapping of the missense mutations on the crystallographic structure of alpha-galactosidase A revealed that the mutations were partially surface-exposed and distal to the active site among individuals with residual enzyme activity. Mutations associated with left ventricular hypertrophy (defined as left ventricular mass index of >51 g/m(2.7)) were localized near the catalytic site of the enzyme. Conclusions. Despite the absence of major organ dysfunction, Fabry disease demonstrates significant morbidity already in childhood. We have identified important, potentially correctable or preventable, outcome measures for future therapeutic trials. Prevention of complications involving major organs should be the goal for long-term specific therapy. C1 NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Biostat Branch, NIH, Bethesda, MD 20892 USA. Temple Univ, Childrens Med Ctr, Dept Pediat, Philadelphia, PA 19122 USA. Univ Manitoba, Dept Internal Med, Neurol Sect, Winnipeg, MB, Canada. NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. Univ Hamburg, Univ Hosp Eppendorf, Inst Human Genet, Hamburg, Germany. Univ Massachusetts, Dept Biochem & Mol Biol, Amherst, MA 01003 USA. RP Ries, M (reprint author), NINDS, Dev & Metab Neurol Branch, NIH, Bldg 10,Room 3D03, Bethesda, MD 20892 USA. EM mr380t@nih.gov OI Ries, Markus/0000-0002-5054-5741 FU NINDS NIH HHS [NS002984-05] NR 51 TC 100 Z9 103 U1 0 U2 0 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 MAR PY 2005 VL 115 IS 3 BP E344 EP E355 DI 10.1542/peds.2004-1678 PG 12 WC Pediatrics SC Pediatrics GA 905UV UT WOS:000227596900015 PM 15713906 ER PT J AU Miller, FG AF Miller, FG TI William James, Faith, and the placebo effect SO PERSPECTIVES IN BIOLOGY AND MEDICINE LA English DT Article ID ANALGESIA; TRIALS AB Long considered a fact of medicine and of clinical investigation, the placebo effect has recently been challenged. The thought of the great American psychologist and philosopher William James, particularly his understanding of the practical value of faith, helps to illuminate the nature of the placebo effect and the implications of this puzzling phenomenon for understanding healing and the practice of medicine. C1 NIH, Dept Clin Bioeth, Ctr Clin, Bethesda, MD 20892 USA. RP Miller, FG (reprint author), NIH, Dept Clin Bioeth, Ctr Clin, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM fmiller@nih.gov NR 17 TC 5 Z9 5 U1 1 U2 1 PU JOHNS HOPKINS UNIV PRESS PI BALTIMORE PA JOURNALS PUBLISHING DIVISION, 2715 NORTH CHARLES ST, BALTIMORE, MD 21218-4363 USA SN 0031-5982 J9 PERSPECT BIOL MED JI Perspect. Biol. Med. PD SPR PY 2005 VL 48 IS 2 BP 273 EP 281 DI 10.1353/pbm.2005.0059 PG 9 WC History & Philosophy Of Science; Medicine, Research & Experimental SC History & Philosophy of Science; Research & Experimental Medicine GA 922AL UT WOS:000228807900011 PM 15834199 ER PT J AU Neumeister, A Charney, DS Belfer, I Geraci, M Holmes, C Sharabi, Y Alim, T Bonne, O Luckenbaugh, DA Manji, H Goldman, D Goldstein, DS AF Neumeister, A Charney, DS Belfer, I Geraci, M Holmes, C Sharabi, Y Alim, T Bonne, O Luckenbaugh, DA Manji, H Goldman, D Goldstein, DS TI Sympathoneural and adrenomedullary functional effects of alpha(2c)-adrenoreceptor gene polymorphism in healthy humans SO PHARMACOGENETICS AND GENOMICS LA English DT Article DE alpha(2)-adrenoceptor; genetic variant; noradrenaline and adrenaline spillover; yohimbine ID HEART-FAILURE PATIENTS; ADRENERGIC-RECEPTOR; PRESYNAPTIC RECEPTORS; AFRICAN-AMERICANS; SUBTYPE; IDENTIFICATION; DEPRESSION; DELETION AB Objectives α(2)-Adrenoreceptors restrain sympathetic nervous outflows and inhibit release of noradrenaline from sympathetic nerves. In-frame deletion of the α(2C)-adrenoreceptor subtype (α(2C)Del322-325) increases the risk of congestive heart failure. Increased delivery of catecholamines to cardiovascular receptors might explain this increased risk. Methods Twenty-nine healthy African-Americans genotyped for α(2)-adrenoreceptor subtype polymorphisms underwent H-3-noradrenaline and H-3-adrenaline intravenous infusion and arterial blood sampling for measurements of rates of entry of endogenous noradrenaline and adrenaline into arterial plasma (total body spillovers) by the tracer dilution technique. Eleven subjects were homozygotes for the α(2C)Del322-325 polymorphism, nine heterozygotes, and nine non-carriers. Subjects were studied during supine rest and during and after i.v. infusion of the α(2)-adrenoreceptor antagonist, yohimbine. Results At rest, homozygotes for the α(2C)Del322-325 polymorphism had higher total body noradrenaline spillover than did heterozygotes (t = 2.90, df = 18, P = 0.023) or non-carriers (t = 3.22, df = 18, P = 0.010). Adrenaline spillover was higher in homozygotes than non-carriers (t = 2.61, df = 18, P = 0.045). Administration of yohimbine produced larger, more sustained increments in noradrenaline spillover, heart rate, and anxiety in homozygotes than in the other groups. Conclusion In healthy people, α(2C)Del322-325 polymorphism is associated with increased sympathetic nervous and adrenomedullary hormonal activities, both during supine rest and during pharmacologically evoked catecholamine release. Polymorphisms of the α(2C)-adrenoreceptor may help explain individual differences in predisposition to a variety of disorders of catecholaminergic function, such as cardiovascular disorders, depression or anxiety disorders. Pharmacogenetics and Genomics 15:143-149 © 2005 Lippincott Williams & Wilkins. C1 Yale Univ, Sch Med, Dept Psychiat, Clin Neurosci Div,VA Connecticut Healthcare Syst, West Haven, CT 06516 USA. NIMH, Mood & Anxiety Disorders Program, Sect Expt Therapeut & Pathophysiol, NIH, Bethesda, MD 20892 USA. Mt Sinai Sch Med, New York, NY USA. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. Chaim Sheba Med Ctr, Dept Med, IL-52621 Tel Hashomer, Israel. Howard Univ, Coll Med, Dept Psychiat, Washington, DC USA. NIMH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. NIDCR, Pain & Neurosensory Mechanisms Branch, Bethesda, MD USA. RP Neumeister, A (reprint author), Yale Univ, Sch Med, Dept Psychiat, Clin Neurosci Div,VA Connecticut Healthcare Syst, 116-A,950 Campbell Ave,Room 9-174,MSC 151E, West Haven, CT 06516 USA. EM alexander.neumeister@yale.edu RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 31 TC 62 Z9 62 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1744-6872 J9 PHARMACOGENET GENOM JI Pharmacogenet. Genomics PD MAR PY 2005 VL 15 IS 3 BP 143 EP 149 DI 10.1097/01213011-200503000-00002 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy SC Biotechnology & Applied Microbiology; Genetics & Heredity; Pharmacology & Pharmacy GA 923IC UT WOS:000228902600002 PM 15861038 ER PT J AU Lepper, ER Nooter, K Verweij, J Acharya, M Figg, WD Sparreboom, A AF Lepper, ER Nooter, K Verweij, J Acharya, M Figg, WD Sparreboom, A TI Mechanisms of resistance to anticancer drugs: the role of the polymorphic ABC transporters ABCB1 and ABCG2 SO PHARMACOGENOMICS LA English DT Review DE ABC transporters; ABCB 1; ABCG2; BCRP; breast cancer resistance protein; chemotherapy; P-glycoprotein; pharmacogenetics; polymorphisms ID ATP-BINDING CASSETTE; SINGLE-NUCLEOTIDE POLYMORPHISMS; MEDIATED MULTIDRUG-RESISTANCE; RENAL-TRANSPLANT PATIENTS; MESSENGER-RNA EXPRESSION; MDR1 GENE POLYMORPHISMS; PERIPHERAL-BLOOD LYMPHOCYTES; ACUTE LYMPHOBLASTIC-LEUKEMIA; INTESTINAL P-GLYCOPROTEIN; HEALTHY JAPANESE SUBJECTS AB ATP-binding cassette (ABC) genes play a role in the resistance of malignant cells to anticancer agents. The ABC gene products, including ABCB1 (P-glycoprotein) and ABCG2 (breast cancer-resistance protein [BCRP], mitoxantrone-resistance protein [MXR], or ABC transporter in placenta [ABCP]), are also known to influence oral absorption and disposition of a wide variety of drugs. As a result, the expression levels of these proteins in humans have important consequences for an individual's susceptibility to certain drug-induced side effects, interactions, and treatment efficacy. Naturally occurring variants in ABC transporter genes have been identified that might affect the function and expression of the protein. This review focuses on recent advances in the pharmacogenetics of the ABC transporters ABCB1 and ABCG2, and discusses potential implications of genetic variants for the chemotherapeutic treatment of cancer. C1 NCI, Clin Pharmacol Res Core, Bethesda, MD 20892 USA. Erasmus Univ, Med Ctr, Dept Med Oncol, NL-3075 EA Rotterdam, Netherlands. RP Sparreboom, A (reprint author), NCI, Clin Pharmacol Res Core, Bldg 10,Room 5A01,9000 Rockville Pike, Bethesda, MD 20892 USA. EM sparreba@mail.nih.gov RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 NR 235 TC 73 Z9 76 U1 3 U2 10 PU FUTURE MEDICINE LTD PI LONDON PA UNITEC HOUSE, 3RD FLOOR, 2 ALBERT PLACE, FINCHLEY CENTRAL, LONDON, N3 1QB, ENGLAND SN 1462-2416 J9 PHARMACOGENOMICS JI Pharmacogenomics PD MAR PY 2005 VL 6 IS 2 BP 115 EP 138 DI 10.1517/14622416.6.2.115 PG 24 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 919WE UT WOS:000228647500006 PM 15882131 ER PT J AU Karlsson, RM Holmes, A Heilig, M Crawley, JN AF Karlsson, RM Holmes, A Heilig, M Crawley, JN TI Anxiolytic-like actions of centrally-administered neuropeptide Y, but not galanin, in C57BL/6J mice SO PHARMACOLOGY BIOCHEMISTRY AND BEHAVIOR LA English DT Article DE anxiety; mouse; neuropeptide Y; galanin; fear conditioning; stereotaxic; intraventricular; behavior; neuropeptides; stress; nociception ID CENTRAL-NERVOUS-SYSTEM; OVEREXPRESSING TRANSGENIC MICE; LOCUS-COERULEUS NEURONS; FORCED SWIMMING TEST; ELEVATED PLUS-MAZE; RECEPTOR SUBTYPES; ANXIETY MODELS; KNOCKOUT MICE; ACUTE STRESS; OPEN-FIELD AB Neuropeptide Y (NPY) and galanin (GAL) are densely localized in brain regions subserving stress, fear and anxiety. While previous research supports a role for both neuropeptides in the mediation of rodent emotional behaviors, there is currently a lack of information on the effects of central administration of NPY and GAL on fear- and anxiety-related behaviors in mice. In the present study, the effects of intracerebroventricularly administered NPY and GAL were assessed in C57BL/6J mice on a battery of tests for fear- and anxiety-related behavior. NPY (0.5, 1.0 nmol) produced clear anxiolytic-like effects in the elevated plus-maze and light <-> dark exploration test, whereas GAL (0.5, 1.0 nmol) was without effect. NPY (0.5 nmol) also increased locomotor activity in the open field test. In the fear conditioning paradigm, NPY administered prior to training reduced freezing to context (0.5, 1.0 nmol) and auditory cue (1.0 nmol). Pre-training GAL (0.5 nmol) treatment reduced freezing to context. Taken together, results demonstrate robust effects of centrally-administered NPY, but not GAL, on anxiety-like behaviors and fear conditioning in mice. These findings provide a basis for future studies of mice with targeted gene mutations, directed at delineating the anatomical regions and receptor subtypes mediating the effects of NPY and GAL on emotion. (c) 2004 Elsevier Inc. All rights reserved. C1 NIMH, Lab Behav Neurosci, Bethesda, MD 20892 USA. NIAAA, Clin Sci Lab, NIH, Bethesda, MD USA. Karolinska Inst, NEUROTEC, Div Psychiat, Stockholm, Sweden. RP Karlsson, RM (reprint author), NIMH, Lab Behav Neurosci, Bldg 10 Room 4D11, Bethesda, MD 20892 USA. EM rosemariekarlsson@mail.nih.gov OI Heilig, Markus/0000-0003-2706-2482 NR 59 TC 71 Z9 73 U1 1 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 MAR PY 2005 VL 80 IS 3 BP 427 EP 436 DI 10.1016/j.pbb.2004.12.009 PG 10 WC Behavioral Sciences; Neurosciences; Pharmacology & Pharmacy SC Behavioral Sciences; Neurosciences & Neurology; Pharmacology & Pharmacy GA 907QE UT WOS:000227732200009 PM 15740785 ER PT J AU Russell, CA Smith, DL Childs, JE Real, LA AF Russell, CA Smith, DL Childs, JE Real, LA TI Predictive spatial dynamics and strategic planning for raccoon rabies emergence in Ohio SO PLOS BIOLOGY LA English DT Article ID PUBLIC VETERINARY-MEDICINE; UNITED-STATES; MONOCLONAL-ANTIBODIES; RECOMBINANT VACCINE; HEALTH AB Rabies is an important public health concern in North America because of recent epidemics of a rabies virus variant associated with raccoons. The costs associated with surveillance, diagnostic testing, and post-exposure treatment of humans exposed to rabies have fostered coordinated efforts to control rabies spread by distributing an oral rabies vaccine to wild raccoons. Authorities have tried to contain westward expansion of the epidemic front of raccoon-associated rabies via a vaccine corridor established in counties of eastern Ohio, western Pennsylvania, and West Virginia. Although sporadic cases of rabies have been identified in Ohio since oral rabies vaccine distribution in 1998, the first evidence of a significant breach in this vaccine corridor was not detected until 2004 in Lake County, Ohio. Herein, we forecast the spatial spread of rabies in Ohio from this breach using a stochastic spatial model that was first developed for exploratory data analysis in Connecticut and next used to successfully hind-cast wave-front dynamics of rabies spread across New York. The projections, based on expansion from the Lake County breach, are strongly affected by the spread of rabies by rare, but unpredictable long-distance translocation of rabid raccoons; rabies may traverse central Ohio at a rate 2.5-fold greater than previously analyzed wildlife epidemics. Using prior estimates of the impact of local heterogeneities on wave-front propagation and of the time lag between surveillance-based detection of an initial rabies case to full-blown epidemic, specific regions within the state are identified for vaccine delivery and expanded surveillance effort. C1 Emory Univ, Dept Biol, Atlanta, GA 30322 USA. Emory Univ, Ctr Dis Ecol, Atlanta, GA 30322 USA. Univ Cambridge, Dept Zool, Cambridge CB2 1TN, England. Fogarty Int Ctr, Bethesda, MD USA. RP Real, LA (reprint author), Emory Univ, Dept Biol, Atlanta, GA 30322 USA. EM lreal@emory.edu RI Russell, Colin/B-2226-2008; Childs, James/B-4002-2012; Smith, David/L-8850-2013; OI Smith, David/0000-0003-4367-3849; Russell, Colin/0000-0002-2113-162X FU NIAID NIH HHS [R01 AI047498] NR 27 TC 50 Z9 54 U1 1 U2 14 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1544-9173 J9 PLOS BIOL JI PLoS. Biol. PD MAR PY 2005 VL 3 IS 3 BP 382 EP 388 AR e88 DI 10.1371/journal.pbio.0030088 PG 7 WC Biochemistry & Molecular Biology; Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics GA 911ED UT WOS:000227984000007 PM 15737065 ER PT J AU Gupta, V Carey, JL Kawakubo, H Muzikansky, A Green, JE Donahoe, PK MacLaughlin, DT Maheswaran, S AF Gupta, V Carey, JL Kawakubo, H Muzikansky, A Green, JE Donahoe, PK MacLaughlin, DT Maheswaran, S TI Mullerian inhibiting substance suppresses tumor growth in the C3(1)T antigen transgenic mouse mammary carcinoma model SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE proliferation; apoptosis; simian virus 40 large T antigen ID CANCER CELL-GROWTH; IN-VIVO; BREAST-CANCER; SEXUAL DEVELOPMENT; GENE-EXPRESSION; II RECEPTOR; T-ANTIGEN; HORMONE; PATHWAY; REGRESSION AB Mullerian inhibiting substance (MIS) inhibits breast cancer cell growth in vitro. To extend the use of MIS to treat breast cancer, it is essential to test the responsiveness of mammary tumor growth to MIS in vivo. Mammary tumors arising in the C3(1) T antigen mouse model expressed the MIS type II receptor, and MIS in vitro inhibited the growth of cells derived from tumors. Administration of MIS to mice was associated with a lower number of palpable mammary tumors compared with vehicle-treated mice (P = 0.048), and the mean mammary tumor weight in the MIS-treated group was significantly lower compared with the control group (P = 0.029). Analysis of proliferating cell nuclear antigen (PCNA) expression and caspase-3 cleavage in tumors revealed that exposure to MIS was associated with decreased proliferation and increased apoptosis, respectively, and was not caused by a decline in T antigen expression. The effect of MIS on tumor growth was also evaluated on xenografted human breast cancer cell line MDA-MB-468, which is estrogen receptor- and retinoblastoma-negative and expresses mutant p53, and thus complements the C3(1)Tag mouse mammary tumors that do not express estrogen receptor and have functional inactivation of retinoblastoma and p53. In agreement with results observed in the transgenic mice, MIS decreased the rate of MDA-MB-468 tumor growth and the gain in mean tumor volume in severe combined immunodeficient mice compared' with vehicle-treated controls (P = 0.004). These results suggest that MIS can suppress the growth of mammary tumors in vivo. C1 Massachusetts Gen Hosp, Dept Surg Oncol, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Biostat, Boston, MA 02114 USA. Massachusetts Gen Hosp, Pediat Surg Res Labs, Boston, MA 02114 USA. Harvard Univ, Sch Med, Boston, MA 02114 USA. NIH, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Maheswaran, S (reprint author), Massachusetts Gen Hosp, Dept Surg Oncol, Boston, MA 02114 USA. EM maheswaran@helix.mgh.harvard.edu FU NCI NIH HHS [CA089138-04, R01 CA089138, R01 CA017393, CA17393]; NICHD NIH HHS [HD32112, R01 HD032112] NR 30 TC 20 Z9 22 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 1 PY 2005 VL 102 IS 9 BP 3219 EP 3224 DI 10.1073/pnas.0409709102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 903KC UT WOS:000227423700012 PM 15728372 ER PT J AU Havlin, RH Tycko, R AF Havlin, RH Tycko, R TI Probing site-specific conformational distributions in protein folding with solid-state NMR SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE chemical denaturation; magnetic resonance; protein structure; two-state system; villin ID VILLIN HEADPIECE SUBDOMAIN; DIFFUSION-COLLISION MODEL; DENATURED STATE; CHEMICAL-SHIFTS; 2-DIMENSIONAL NMR; PEPTIDE; ENSEMBLE; ALPHA; SIMULATIONS; TEMPERATURE AB We demonstrate an experimental approach to structural studies of unfolded and partially folded proteins in which conformational distributions are probed at a site-specific level by 2D solid-state C-13 NMR spectroscopy of glassy frozen solutions. Experiments on chemical denaturation of the 35-residue villin headpiece subdomain, a model three-helix-bundle protein with a known folded structure, reveal that C-13-labeled residues in the three helical segments of the folded state have markedly different conformational distributions in the unfolded state. Moreover, the 2D solid-state NMR line shapes near the unfolding midpoint do not fit a simple two-state model, in which the conformational distributions of the unfolded component are assumed to be independent of denaturant concentration. Comparison with solid-state NMR spectra of peptides containing the individual helical segments suggests an alternative two-step description of conformational distributions in partially folded states of the helical villin headpiece subdomain, in which chemical denaturation is viewed as a disruption of tertiary contacts followed by equilibration of local secondary structure according to the intrinsic helical propensities of individual segments. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDKD, Chem Phys Lab, NIH, Bldg 5,Room 112, Bethesda, MD 20892 USA. EM robertt@niddk.nih.gov NR 40 TC 72 Z9 73 U1 1 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 1 PY 2005 VL 102 IS 9 BP 3284 EP 3289 DI 10.1073/pnas.0406130102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 903KC UT WOS:000227423700023 PM 15718283 ER PT J AU Yildirim, E Kawasaki, BT Birnbaumer, L AF Yildirim, E Kawasaki, BT Birnbaumer, L TI Molecular cloning of TRPC3a, an N-terminally extended, store-operated variant of the human C3 transient receptor potential channel SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE capacitative Ca entry; cation channel; store-operated Ca entry ID CAPACITATIVE CA2+ ENTRY; MUSCARINIC ACETYLCHOLINE-RECEPTOR; FUNCTIONAL EXPRESSION; CANDIDATE PROTEIN; DROSOPHILA TRP; CELLS; DEPLETION; INFLUX; CURRENTS; HOMOLOG AB AK032317 is the GenBank accession no. of a full-length RIKEN mouse cDNA. It encodes a putative variant of the C3-type TRPC (transient receptor potential channel) that differs from the previously cloned murine TRPC3 cDNA in that it has a 5' extension stemming from inclusion of an additional exon (exon 0). The extended cDNA adds 62 as to the sequence of the murine TRPC3. Here, we report the cloning of a cDNA encoding the human homologue of this extended TRPC3 having a highly homologous 73-aa N-terminal extension, referred to as hTRPC3a. A query of the GenBank genomic database predicts the existence of a similar gene product also in rats. Transient expression of the longer TRPC3a in human embryonic kidney (HEK) cells showed that it mediates Ca2+ entry in response to stimulation of the Gq-phospholipase C beta pathway, which is similar to that mediated by the shorter hTRPC3. However, after isolation of HEK cells expressing hTRPC3 in stable form, TRPC3a gave rise to Ca2+-entry channels that are not only activated by the Gq-phospholipase C beta pathway (receptor-activated Ca entry) but also by thapsigargin triggered store depletion. In conjunction with findings from our and other laboratories that TRPC1, TRPC2, TRPC4, TRPC5, and TRPC7, can each mediate store-depletion-activated Ca2+ entry in mammalian cells, our findings with hTRC3a support our previous proposal that TRPCs form capacitative Ca-entry channels. C1 NIEHS, Transmembrane Signaling Grp, Lab Signal Transduct, Div Intramural Res,NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Birnbaumer, L (reprint author), NIEHS, Bldg 101,Room A214,111 TW Alexander Dr, Res Triangle Pk, NC 27706 USA. EM birnbaul@niehs.nih.gov OI Yildirim, Eda/0000-0002-4796-3854 NR 31 TC 31 Z9 35 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 1 PY 2005 VL 102 IS 9 BP 3307 EP 3311 DI 10.1073/pnas.0409908102 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 903KC UT WOS:000227423700027 PM 15728370 ER PT J AU Margulies, EH Maduro, VVB Thomas, PJ Tomkins, JP Amemiya, CT Luo, MZ Green, ED AF Margulies, EH Maduro, VVB Thomas, PJ Tomkins, JP Amemiya, CT Luo, MZ Green, ED CA NISC Comparative Sequencing Progra TI Comparative sequencing provides insights about the structure and conservation of marsupial and monotreme genomes SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE comparative genomics; genome sequencing; genome analysis; phylogenetics; mammalian evolution ID MAMMALIAN EVOLUTION; MITOCHONDRIAL GENOMES; VERTEBRATE EVOLUTION; CORE-SINES; RATES; DNA; IDENTIFICATION; HYPOTHESIS; REGIONS; MOUSE AB Sequencing and comparative analyses of genomes from multiple vertebrates are providing insights about the genetic basis for biological diversity. To date, these efforts largely have focused on eutherian mammals, chicken, and fish. In this article, we describe the generation and study of genomic sequences from noneutherian mammals, a group of species occupying unusual phylogenetic positions. A large sequence data set (totaling >5 Mb) was generated for the same orthologous region in three marsupial (North American opossum, South American opossum, and Australian tammar wallaby) and one monotreme (platypus) genomes. These ancient mammalian genomes are characterized by unusual architectural features with respect to G + C and repeat content, as well as compression relative to human. Approximately 14% and 34% of the human sequence forms alignments with the orthologous sequence from platypus and the marsupials, respectively; these numbers are distinctly lower than that observed with nonprimate eutherian mammals (45-70%). The alignable sequences between human and each marsupial species are not completely overlapping (only 80% common to all three species) nor are the platypus-alignable sequences completely contained within the marsupial-alignable sequences. Phylogenetic analysis of synonymous coding positions reveals that platypus has a notably long branch length, with the human-platypus substitution rate being on average 55% greater than that seen with human-marsupial pairs. Finally, analyses of the major mammalian lineages reveal distinct patterns with respect to the common presence of evolutionarily conserved vertebrate sequences. Our results confirm that genomic sequence from noneutherian mammals can contribute uniquely to unraveling the functional and evolutionary histories of the mammalian genome. C1 NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, NISC, NIH, Bethesda, MD 20892 USA. Clemson Univ, Genom Inst, Dept Genet & Biochem & Life Sci Studies, Clemson, SC 29634 USA. Virginia Mason, Benaroya Res Inst, Seattle, WA 98101 USA. Univ Arizona, Dept Plant Sci, Arizona Genom Inst, Tucson, AZ 85721 USA. RP Green, ED (reprint author), NHGRI, Genome Technol Branch, NIH, 50 South Dr,Bldg 50,Room 5222, Bethesda, MD 20892 USA. EM egreen@nhgri.nih.gov FU NHLBI NIH HHS [HL66728] NR 37 TC 57 Z9 58 U1 2 U2 15 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 1 PY 2005 VL 102 IS 9 BP 3354 EP 3359 DI 10.1073/pnas.0408539102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 903KC UT WOS:000227423700035 PM 15718282 ER PT J AU Patino, WD Mian, OY Kang, JG Matoba, S Bartlett, LD Holbrook, B Trout, HH Kozloff, L Hwang, PM AF Patino, WD Mian, OY Kang, JG Matoba, S Bartlett, LD Holbrook, B Trout, HH Kozloff, L Hwang, PM TI Circulating transcriptome reveals markers of atherosclerosis SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE monocytes; serial analysis of gene expression; Finkel-Biskis-Jinkins osteosarcoma; 3-hydroxy-3-methyl-glutaryl CoA reductase inhibitor; high sensitivity C-reactive protein ID GENE-EXPRESSION; SERIAL ANALYSIS; C-FOS; HUMAN MONOCYTES; CELL-LINE; DIFFERENTIATION; MACROPHAGE; DISEASE; MICE; INFLAMMATION AB Circulating monocytes mediate inflammation in atherosclerosis and may serve as easily accessible reporters of disease. To search for markers of atherosclerosis, we compared the in vivo transcriptomes of monocytes purified from patients undergoing carotid endarterectomy and normal subjects by using the serial analysis of gene expression technique. We selected a subset of differentially expressed monocyte-specific genes and confirmed their expression levels. The Finkel-Biskis-Jinkins osteosarcoma (FOS) gene was significantly increased in patients, and the highest levels of FOS associated with patients who had previously undergone coronary revascularization. The correlation between coronary revascularization and FOS was higher than that compared with the cardiac risk marker high sensitivity C-reactive protein. In vitro inhibition of FOS using small interfering RNA and 3-hydroxy-3-methyl-glutaryl CoA reductase inhibitor simvastatin (statin) affected monocyte activation and suggested an important role in pathogenesis. Given the prominent role of FOS in inflammation and calcification, its association with atherosclerosis severity has clear pathophysiologic bases as well as clinical implications as a marker. Our results suggest that analysis of gene expression in circulating cells may provide biological and clinical insights into human atherosclerosis, and that this type of approach maybe applicable for studying other types of diseases. C1 NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. RP Hwang, PM (reprint author), NHLBI, Cardiovasc Branch, NIH, Bldg 10-CRC,5 E,Room 5-5330,10 Ctr Dr, Bethesda, MD 20892 USA. EM hwangp@mail.nih.gov OI Mian, Omar/0000-0002-8133-8120 NR 37 TC 57 Z9 61 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD MAR 1 PY 2005 VL 102 IS 9 BP 3423 EP 3428 DI 10.1073/pnas.0408032102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 903KC UT WOS:000227423700047 PM 15728378 ER PT J AU Mosca, TJ Carrillo, RA White, BH Keshishian, H AF Mosca, TJ Carrillo, RA White, BH Keshishian, H TI Dissection of synaptic excitability phenotypes by using a dominant-negative Shaker K+ channel subunit SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE activity; behavioral genetics; Drosophila ID DROSOPHILA NEUROMUSCULAR-JUNCTION; IDENTIFIED MOTOR TERMINALS; VOLTAGE-CLAMP ANALYSIS; POTASSIUM CHANNEL; MORPHOMETRIC DESCRIPTION; FUNCTIONAL COMPONENTS; TRANSMITTER RELEASE; WANDERING BEHAVIOR; GENETIC DISSECTION; RETROGRADE SIGNAL AB During nervous system development, synapses undergo morphological change as a function of electrical activity. In Drosophila, enhanced, activity results in the expansion of larval neuromuscular junctions. We have examined whether these structural changes involve the pre- or postsynaptic partner by selectively enhancing electrical excitability with a Shaker dominant-negative (SDN) potassium channel subunit. We find that the SDN enhances neurotransmitter release when expressed in motoneurons, postsynaptic potential broadening when expressed in muscles and neurons, and selectively suppresses fast-inactivating, Shaker-mediated I-A currents in muscles. SDN expression also phenocopies the canonical behavioral-phenotypes of the Sh mutation. At the neuromuscular junction, we find that activity-dependent changes in arbor size occur only when SDN is expressed presynaptically. This finding indicates that elevated postsynaptic membrane excitability is by itself insufficient to enhance presynaptic arbor growth. Such changes must minimally involve increased neuronal excitability. C1 Yale Univ, Dept Mol Cellular & Dev Biol, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Pharmacol, New Haven, CT 06520 USA. NIMH, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Keshishian, H (reprint author), Yale Univ, Dept Mol Cellular & Dev Biol, POB 208103, New Haven, CT 06520 USA. EM haig.keshishian@yale.edu OI Mosca, Timothy/0000-0003-3485-0719 FU NINDS NIH HHS [R01 NS031651, R01 NS31651] NR 63 TC 36 Z9 36 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 1 PY 2005 VL 102 IS 9 BP 3477 EP 3482 DI 10.1073/pnas.0406164102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 903KC UT WOS:000227423700056 PM 15728380 ER PT J AU Bai, Y Gao, YT Deng, J Sesterhenn, IA Fraumeni, JF Hsing, AW AF Bai, Y Gao, YT Deng, J Sesterhenn, IA Fraumeni, JF Hsing, AW TI Risk of prostate cancer and family history of cancer: a population based study in China SO PROSTATE CANCER AND PROSTATIC DISEASES LA English DT Article DE esophageal cancer; familial aggregation; prostate cancer ID ANDROGEN RECEPTOR GENE; ESOPHAGEAL CANCER; UNITED-STATES; REPEAT LENGTHS; BODY-SIZE; BLACKS; WHITES; COHORT; VEGETABLES; CARCINOMA AB We evaluated prostate cancer risk and family history of cancers using data from a case - control study in China. Cancer information among first-degree relatives was collected from 709 subjects ( 238 cases and 471 controls). None of the subjects reported a family history of prostate cancer. However, excess prostate cancer risk was associated with a family history of any cancer ( OR = 1.79, 95% CI: 1.21 - 2.63) and esophageal cancer ( OR = 2.39, 95% CI: 1.15 - 5.00). Nonsignificant risk was seen for family history of cancers of the stomach, lung, and female breast. Our results did not confirm the familial tendency toward prostate cancer but other cancers prevalent in China appeared to be aggregate, particularly esophageal cancer. Larger studies are needed to confirm these findings, and to clarify the genetic and lifestyle factors that may be involved. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Bethesda, MD 20892 USA. Shanghai Canc Inst, Shanghai, Peoples R China. Armed Forces Inst Pathol, Washington, DC 20306 USA. RP Bai, Y (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd,Room 7106,MSC 7236, Bethesda, MD 20892 USA. EM baiy@mail.nih.gov NR 34 TC 7 Z9 7 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1365-7852 J9 PROSTATE CANCER P D JI Prostate Cancer Prostatic Dis. PD MAR PY 2005 VL 8 IS 1 BP 60 EP 65 DI 10.1038/sj.pcan.4500775 PG 6 WC Oncology; Urology & Nephrology SC Oncology; Urology & Nephrology GA 918OF UT WOS:000228553700022 PM 15643451 ER PT J AU Maxwell, KL Wildes, D Zarrine-Afsar, A de los Rios, MA Brown, AG Friel, CT Hedberg, L Horng, JC Bona, D Miller, EJ Vallee-Belisle, A Main, ERG Bemporad, F Qiu, LL Teilum, K Vu, ND Edwards, AM Ruczinski, I Poulsen, FM Kragelund, BB Michnick, SW Chiti, F Bai, YW Hagen, SJ Serrano, L Oliveberg, M Raleigh, DP Wittung-Stafshede, P Radford, SE Jackson, SE Sosnick, TR Marqusee, S Davidson, AR Plaxco, KW AF Maxwell, KL Wildes, D Zarrine-Afsar, A de los Rios, MA Brown, AG Friel, CT Hedberg, L Horng, JC Bona, D Miller, EJ Vallee-Belisle, A Main, ERG Bemporad, F Qiu, LL Teilum, K Vu, ND Edwards, AM Ruczinski, I Poulsen, FM Kragelund, BB Michnick, SW Chiti, F Bai, YW Hagen, SJ Serrano, L Oliveberg, M Raleigh, DP Wittung-Stafshede, P Radford, SE Jackson, SE Sosnick, TR Marqusee, S Davidson, AR Plaxco, KW TI Protein folding: Defining a "standard" set of experimental conditions and a preliminary kinetic data set of two-state proteins SO PROTEIN SCIENCE LA English DT Article DE two-state; protein folding; kinetics; chevron plots; equilibrium ID PSEUDOMONAS-AERUGINOSA AZURIN; SINGLE-DOMAIN PROTEINS; TRANSITION-STATE; CONTACT-ORDER; MUSCLE ACYLPHOSPHATASE; TERMINAL DOMAIN; BINDING DOMAIN; STABILITY; MECHANISM; UBIQUITIN AB Recent years have seen the publication of both empirical and theoretical relationships predicting the rates with which proteins fold. Our ability to test and refine these relationships has been limited, however, by a variety of difficulties associated with the comparison of folding and unfolding rates, thermodynamics, and structure across diverse sets of proteins. These difficulties include the wide, potentially confounding range of experimental conditions and methods employed to date and the difficulty of obtaining correct and complete sequence and structural details for the characterized constructs. The lack of a single approach to data analysis and error estimation, or even of a common set of units and reporting standards, further hinders comparative studies of folding. In an effort to overcome these problems, we define here a "consensus" set of experimental conditions (25degreesC at pH 7.0, 50 mM buffer), data analysis methods, and data reporting standards that we hope will provide a benchmark for experimental studies. We take the first step in this initiative by describing the folding kinetics of 30 apparently two-state proteins or protein domains under the consensus conditions. The goal of our efforts is to set uniform standards for the experimental community and to initiate an accumulating, self-consistent data set that will aid ongoing efforts to understand the folding process. C1 Univ Calif Santa Barbara, Dept Chem & Biochem, Santa Barbara, CA 93106 USA. Ontario Canc Inst, Toronto, ON M4X 1K9, Canada. Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. Univ Toronto, Dept Biochem, Toronto, ON, Canada. Univ Toronto, Struct Genom Consortium, Toronto, ON, Canada. Univ Toronto, Dept Med Genet & Microbiol, Toronto, ON, Canada. Univ Calif Berkeley, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. Univ Cambridge, Dept Chem, Biochem Lab, Cambridge CB2 1EW, England. Univ Leeds, Sch Biochem & Microbiol, Leeds LS2 9JT, W Yorkshire, England. Univ Leeds, Astbury Ctr Struct Mol Biol, Leeds LS2 9JT, W Yorkshire, England. Umea Univ, Dept Biochem, S-90187 Umea, Sweden. SUNY Stony Brook, Dept Chem, Stony Brook, NY 11794 USA. Univ Montreal, Dept Biochim, Montreal, PQ H3C 3J7, Canada. Univ Florence, Dipartimento Sci Biochim, I-50134 Florence, Italy. Univ Florida, Dept Phys, Gainesville, FL 32611 USA. Dept Prot Chem, Inst Mol Biol, DK-1353 Copenhagen, Denmark. NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Biostat, Baltimore, MD 21205 USA. European Mol Biol Lab, D-69012 Heidelberg, Germany. Rice Univ, Dept Biochem & Cell Biol, Houston, TX 77251 USA. Rice Univ, Dept Chem, Houston, TX 77251 USA. Univ Chicago, Dept Biochem & Mol Biol, Inst Biophys Dynam, Chicago, IL 60637 USA. RP Plaxco, KW (reprint author), Univ Calif Santa Barbara, Dept Chem & Biochem, Santa Barbara, CA 93106 USA. EM kwp@chem.ucsb.edu RI Miller, Erik/B-4766-2008; Poulsen, Flemming/E-6848-2010; Plaxco, Kevin/O-1793-2013; Kragelund, Birthe/M-3927-2014; Hagen, Stephen/E-9737-2015; Serrano, Luis/B-3355-2013; Teilum, Kaare/K-4340-2014; OI Bemporad, Francesco/0000-0002-0643-6249; wittung-stafshede, pernilla/0000-0003-1058-1964; Plaxco, Kevin/0000-0003-4772-8771; Kragelund, Birthe/0000-0002-7454-1761; Hagen, Stephen/0000-0002-3373-5033; Serrano, Luis/0000-0002-5276-1392; Teilum, Kaare/0000-0001-6919-1982; Friel, Claire/0000-0001-8395-5301 FU NIGMS NIH HHS [GM59663, GM50945, GM55694, GM62868-01A2, GM70941, R01 GM050945, R01 GM055694, R01 GM059663, R01 GM062868, R01 GM070941, R29 GM055694] NR 47 TC 144 Z9 148 U1 2 U2 30 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 0961-8368 J9 PROTEIN SCI JI Protein Sci. PD MAR PY 2005 VL 14 IS 3 BP 602 EP 616 DI 10.1110/ps.041205405 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 899AD UT WOS:000227116400004 PM 15689503 ER PT J AU Gallardo, KA AF Gallardo, KA TI A psychiatric resident's reflections on the nonmedical use of - Prescription stimulants SO PSYCHIATRIC ANNALS LA English DT Editorial Material ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; DEFICIT HYPERACTIVITY DISORDER; INTRANASAL ABUSE; METHYLPHENIDATE; ADOLESCENTS; PREVALENCE; CONCERTA; CHILDREN; TRENDS C1 NIMH, Child Psychiat Branch, Bethesda, MD 20892 USA. RP Gallardo, KA (reprint author), NIMH, Child Psychiat Branch, Bldg 10,Room 3N202,10 Ctr Dr,MSC 1381, Bethesda, MD 20892 USA. EM gallardok@mail.nih.gov NR 15 TC 0 Z9 0 U1 0 U2 0 PU SLACK INC PI THOROFARE PA 6900 GROVE RD, THOROFARE, NJ 08086 USA SN 0048-5713 J9 PSYCHIAT ANN JI Psychiatr. Ann. PD MAR PY 2005 VL 35 IS 3 BP 264 EP + PG 5 WC Psychiatry SC Psychiatry GA 909IS UT WOS:000227854200015 ER PT J AU Kahng, SK Mowbray, CT AF Kahng, SK Mowbray, CT TI What affects self-esteem of persons with psychiatric disabilities: The role of causal attributions of mental illnesses SO PSYCHIATRIC REHABILITATION JOURNAL LA English DT Article ID SOCIAL COGNITION; STIGMA; CONSEQUENCES; METAANALYSIS; INDIVIDUALS; ATTITUDES; LIFE AB This study addresses the factors which affect the self-esteem of persons with psychiatric disabilities, with a specific focus on the role of causal attributions of mental illnesses. It is based on data collected from 461 persons with psychiatric disabilities (consumers) served through psychiatric rehabilitation agencies. The results of regression analyses revealed that household income, diagnosis, psychiatric symptoms, service satisfaction, perceived stigma, and perceptions of social roles were all related to self-esteem. Consumers' causal attributions did not have direct effects on self-esteem, but the effects of causal attributions on self-esteem were moderated by psychiatric symptoms and by perceptions of social roles, suggesting that self-esteem enhancement strategies should be tailored to consumers' psychiatric and cognitive characteristics. C1 Washington Univ, George Warren Brown Sch Social Work, St Louis, MO 63131 USA. Univ Michigan, NIMH, Ctr Res Poverty Risk Mental Hlth, Sch Social Work, Ann Arbor, MI USA. RP Kahng, SK (reprint author), Washington Univ, George Warren Brown Sch Social Work, Campus Box 1196, St Louis, MO 63131 USA. EM skahng@wustl.edu FU NIMH NIH HHS [1 R03 MH64317-01A1] NR 36 TC 16 Z9 16 U1 0 U2 2 PU CENTER PSYCHIATRIC REHABILITATION PI BOSTON PA BOSTON UNIV, 930 COMMONWEALTH AVE, BOSTON, MA 02215 USA SN 1095-158X J9 PSYCHIATR REHABIL J JI Psychiatr. Rehabil. J. PD SPR PY 2005 VL 28 IS 4 BP 354 EP 361 DI 10.2975/28.2005.354.360 PG 8 WC Psychiatry; Rehabilitation SC Psychiatry; Rehabilitation GA 916KB UT WOS:000228382700007 PM 15895919 ER PT J AU Weiss, A Costa, PT Karuza, J Duberstein, PR Friedman, B McCrae, RR AF Weiss, A Costa, PT Karuza, J Duberstein, PR Friedman, B McCrae, RR TI Cross-sectional age differences in personality among medicare patients aged 65 to 100 SO PSYCHOLOGY AND AGING LA English DT Article ID 5-FACTOR MODEL; PSYCHOLOGY; STABILITY; TRAITS; RISK AB 1,084 older Medicare recipients were orally administered the NEO Five-Factor Inventory (NEO-FFI; P. T. Costa 1 R. R. McCrae, 1992). Participants were assigned to groups based on gender and age (65-79 or 80-100). An analysis of covariance showed that women had significantly higher Neuroticism, Openness, and Agreeableness scores; that older participants were significantly higher in Agreeableness; and that age differences in Agreeableness were significantly greater in men than in women. With the exception of Agreeableness, this study provides no evidence for age differences among those in the last decades of life. C1 NIA, Lab Personal & Cognit, NIH, Dept Hlth & Human Serv, Baltimore, MD 21224 USA. Univ Rochester, Med Ctr, Finger Lakes Geriatr Educ Ctr, Rochester, NY 14642 USA. SUNY Coll Buffalo, Dept Psychol, Buffalo, NY 14222 USA. Univ Rochester, Med Ctr, Lab Personal & Dev, Dept Psychiat, Rochester, NY 14642 USA. Univ Rochester, Med Ctr, Ctr Canc, Rochester, NY 14642 USA. Univ Rochester, Med Ctr, Dept Community & Prevent Med, Rochester, NY 14642 USA. RP Weiss, A (reprint author), NIA, Lab Personal & Cognit, NIH, Dept Hlth & Human Serv, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM weissal@grc.nia.nih.gov OI Costa, Paul/0000-0003-4375-1712 FU NIMH NIH HHS [K01 MH64718-01] NR 24 TC 37 Z9 37 U1 0 U2 1 PU AMER PSYCHOLOGICAL ASSOC PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0882-7974 J9 PSYCHOL AGING JI Psychol. Aging PD MAR PY 2005 VL 20 IS 1 BP 182 EP 185 DI 10.1037/0882-7974.20.1.182 PG 4 WC Gerontology; Psychology, Developmental SC Geriatrics & Gerontology; Psychology GA 907PW UT WOS:000227731300014 PM 15769223 ER PT J AU Holmes, A Li, Q Koenig, EA Gold, E Stephenson, D Yang, RJ Dreiling, J Sullivan, T Crawley, JN AF Holmes, A Li, Q Koenig, EA Gold, E Stephenson, D Yang, RJ Dreiling, J Sullivan, T Crawley, JN TI Phenotypic assessment of galanin overexpressing and galanin receptor R1 knockout mice in the tail suspension test for depression-related behavior SO PSYCHOPHARMACOLOGY LA English DT Article DE galanin; antidepressant; stress; depression; mouse; knockout; autoradiography; serotonin; norepinephrine; behavior ID LOCUS-COERULEUS NEURONS; ANXIETY-LIKE BEHAVIOR; NULL MUTANT MICE; TRANSGENIC MICE; DORSAL RAPHE; SEROTONIN TRANSPORTER; DEPENDENT MODULATION; MESSENGER-RNA; IN-VIVO; RAT AB Rationale: Galanin and its receptors exert inhibitory neuromodulatory control over brain monoamines. Rat studies revealed that galanin expression is upregulated by exposure to stressors and that galanin manipulations modify neuroendocrine and behavioral responses to stress, leading to the hypothesis that galanin mediates depression-related behaviors. Methods: In the present study, we examined the role of galanin in modulating antidepressant-related behavior in galanin overexpressing transgenic (GAL-tg) mice and galanin receptor R1 knockout (GAL-R1 KO) mice, using the tail suspension test (TST). Quantitative autoradiography for 5-HT1A- R and serotonin transporter binding density tested for changes in these two major regulatory components of the 5-HT system in galanin mutant mice. Results: Baseline TST behavior was normal in GAL-tg and GAL-R1 KO mice, and intracerebroventricular administration of galanin failed toalter TST behavior in normal C57BL/6J mice. The TST anti-immobility effects of acute treatment with the serotonin reuptake inhibitor, fluoxetine ( 0-30 mg/kg), and the norepinephrine reuptake inhibitor, desipramine (0-30 mg/kg), wereunaltered in galanin mutant mice. Hippocampal 5-HT1A- R density was significantly elevated in GAL-tg and GAL-R1 KO mice, while hippocampal 5-HTTdensity was reduced in GAL-R1 KO mice, relative to controls. Conclusion: Neither pharmacological nor molecular genetic manipulations of galanin altered depression-related profiles in the TST. Possible functional alterations in hippocampal 5-HT neurotransmission may have contributed to these negative results. These preliminary findings provide evidence against the hypothesis that galaninplays a central role in mouse depression-related behaviors. It remains possible that galanin modulates depression-related responses in other experimental paradigms and species. C1 NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, Bethesda, MD 20892 USA. Univ Texas, Med Branch, Dept Psychiat & Behav Sci, Galveston, TX 77555 USA. NIMH, Lab Behav Neurosci, NIH, Bethesda, MD 20892 USA. RP Holmes, A (reprint author), NIAAA, Sect Behav Sci & Genet, Lab Integrat Neurosci, Bldg 10,Room 3C217, Bethesda, MD 20892 USA. EM holmesan@mail.nih.gov NR 44 TC 24 Z9 26 U1 1 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2005 VL 178 IS 2-3 BP 276 EP 285 DI 10.1007/s00213-004-1997-1 PG 10 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 899SY UT WOS:000227166500020 PM 15365683 ER PT J AU Anderson, GM Barr, CS Lindell, S Durham, AC Shifrovich, I Higley, JD AF Anderson, GM Barr, CS Lindell, S Durham, AC Shifrovich, I Higley, JD TI Time course of the effects of the serotonin-selective reuptake inhibitor sertraline on central and peripheral serotonin neurochemistry in the rhesus monkey SO PSYCHOPHARMACOLOGY LA English DT Article DE serotonin; cerebrospinal fluid; CSF; rhesus monkey; cisternal; sertraline; selective serotonin reuptake inhibitor; SSRI; 5-hydroxyindoleacetic acid ID RAT FRONTAL-CORTEX; PREMENSTRUAL DYSPHORIC DISORDER; CISTERNAL CEREBROSPINAL-FLUID; CSF MONOAMINE METABOLITE; IN-VIVO; EXTRACELLULAR SEROTONIN; 5-HT1A RECEPTORS; WHOLE-BLOOD; FLUOXETINE; BRAIN AB Rationale: Fundamental questions remain regarding the actions of the selectiveserotonin reuptake inhibitors (SSRIs). Objectives: To examine the time courseof central and peripheral neurochemical effects of sertraline (SER) in non-human primates. Methods: SER ( 20 mg/kg, p.o.) or placebo were administered daily for 4 weeks to two groups of six young adult male rhesus monkeys. Both groups received placebo during a 3-week baseline lead-in period and for 6 weeks after discontinuation. Blood and cisternal cerebrospinal fluid ( cCSF) samples were obtained on days -21, -14, -7, 0, +3, +7, +14, +21, +28, +35 and +70. Results: In animals receiving SER, mean (+/- SD) levels of cCSF serotonin (5-HT) increased from 38.6 +/- 9.0 pg/ml at baseline to 128 +/- 46.4 pg/ml during treatment (paired t= 4.17, P=0.014). Concentrations of cCSF 5-HT were 290% of baseline on day 0 (+ 3 h), ranged from 260% to 436% of baseline during treatment, and returned to baseline 7 days after discontinuation. Levels of cCSF 5-hydroxyindoleacetic acid declined to 51 +/- 2.0% of baseline by day + 3 and remained at similarly reduced levels during treatment. Plasma drug levels and decrements in platelet 5-HT were similar to those seen in patients. Conclusions: SER rapidly and substantially increases cCSF levels of 5-HT in primates, the extent of elevation is relatively constant during prolonged administration, and values return to baseline shortly after discontinuation. The results suggest that response latency for SSRIs in depression is not due to gradually increasing brain extracellular fluid 5-HT levels and tend not to support theories that positSSRI response latency as being due to autoreceptor desensitization, transporter downregulation, or drug accumulation. C1 Yale Univ, Sch Med, Dept Child Psychiat, New Haven, CT 06520 USA. Yale Univ, Sch Med, Dept Lab Med, New Haven, CT 06510 USA. NIAAA, Lab Clin Studies Primate Unit, Poolesville, MD USA. RP Anderson, GM (reprint author), Yale Univ, Sch Med, Dept Child Psychiat, 333 Cedar St, New Haven, CT 06520 USA. EM george.anderson@yale.edu NR 56 TC 24 Z9 24 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0033-3158 J9 PSYCHOPHARMACOLOGY JI Psychopharmacology PD MAR PY 2005 VL 178 IS 2-3 BP 339 EP 346 DI 10.1007/s00213-004-2011-7 PG 8 WC Neurosciences; Pharmacology & Pharmacy; Psychiatry SC Neurosciences & Neurology; Pharmacology & Pharmacy; Psychiatry GA 899SY UT WOS:000227166500027 PM 15452685 ER PT J AU Kerlikowske, K Smith-Bindman, R Abraham, LA Lehman, CD Yankaskas, BC Ballard-Barbash, R Barlow, WE Voeks, JH Geller, BM Carney, PA Sickles, EA AF Kerlikowske, K Smith-Bindman, R Abraham, LA Lehman, CD Yankaskas, BC Ballard-Barbash, R Barlow, WE Voeks, JH Geller, BM Carney, PA Sickles, EA TI Breast cancer yield for screening mammographic examinations with recommendation for short-interval follow-up SO RADIOLOGY LA English DT Article ID PROBABLY BENIGN LESIONS; PREDICTIVE-VALUE; MANAGEMENT; NODULES AB PURPOSE: To compare cancer yield for screening examinations with recommendation for short-interval follow-up after diagnostic imaging work-up versus after screening mammography only. MATERIALS AND METHODS: From January 1996 to December 1999, Breast Imaging Reporting and Data System assessments and recommendations were collected prospectively for 1171792 screening examinations in 758 015 women aged 40-89 years at seven mammography registries in Breast Cancer Surveillance Consortium. Registries obtained waiver of signed consent or collected signed consent in accordance with institutional review boards at each location. Diagnosis of invasive cancer or ductal carcinoma in situ within 24 months of screening examination and tumor stage and size for invasive cancer were determined through linkage to pathology database or tumor registry. chi(2) test was used to determine significant differences between groups. RESULTS: Overall, 5.2% of first and 1.7% of subsequent screens included recommendation for short-interval follow-up, which was similar to likelihood of recommendation for diagnostic evaluation (first screens, 4.6%; subsequent, 2.6%). Most recommendations for short-interval follow-up were based on screening mammography alone (86.2% of first screens, 77.5% of subsequent). Yield of cancer for screening examinations with probably benign finding (PBF) and recommendation for short-interval follow-up based on screening mammography alone tended to be lower than in those with PBF and recommendation for short-interval follow-up after additional work-up (first screens: 0.54% vs 0.96%, P = .10; subsequent: 1.50% vs 1.73%, P = .26). Proportion of stage 11 and higher disease tended to be higher for examinations with PBF and recommendation for short-interval follow-up based on screening mammography alone compared with those recommended for short-interval follow-up after additional work-up (first screens: 34.7% vs 24.4%, P = .43; subsequent: 27.5% vs 19.2%, P = .13). CONCLUSION: Many first screening examinations include recommendation for short-interval follow-up based on screening mammography alone. Cancer yield for these examinations is low and is lower than that with diagnostic work-up prior to short-interval follow-up recommendation. Absence of diagnostic work-up prior to short-interval follow-up recommendation may result in periodic surveillance of a high proportion of benign lesions. (C) RSNA, 2005. C1 Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94143 USA. Vet Affairs Med Ctr, Gen Internal Med Sect, San Francisco, CA 94121 USA. Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA 98101 USA. Univ Washington, Med Ctr, Dept Radiol, Seattle Canc Care Alliance, Seattle, WA 98195 USA. Univ N Carolina, Dept Radiol, Chapel Hill, NC USA. NCI, Appl Res Program, DCCPS, Bethesda, MD 20892 USA. Univ Washington, Dept Biostat, Seattle, WA 98195 USA. Canc Res & Biostat, Seattle, WA USA. Cooper Inst, Ctr Res Methods & Biometry, Denver, CO USA. Univ Vermont, Coll Med, Burlington, VT USA. Dartmouth Coll Sch Med, Dept Community & Family Med, Dartmouth Hitchcock Med Ctr, Norris Cotton Canc Ctr, Lebanon, NH USA. RP Kerlikowske, K (reprint author), Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. EM kerliko@itsa.ucsf.edu FU NCI NIH HHS [U01CA86082, R01 CA080888, U01 CA086082, U01CA63731, U01CA63736, U01CA63740, U01CA70013, U01CA70040, U01CA86076] NR 28 TC 39 Z9 39 U1 0 U2 1 PU RADIOLOGICAL SOC NORTH AMERICA PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523 USA SN 0033-8419 J9 RADIOLOGY JI Radiology PD MAR PY 2005 VL 234 IS 3 BP 684 EP 692 DI 10.1148/radiol.2343031976 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 899LM UT WOS:000227145900007 PM 15734926 ER PT J AU Zullo, SJ Parks, WT Chloupkova, M Wei, B Weiner, H Fenton, WA Eisenstadt, JM Merril, CR AF Zullo, SJ Parks, WT Chloupkova, M Wei, B Weiner, H Fenton, WA Eisenstadt, JM Merril, CR TI Stable transformation of CHO cells and human NARP cybrids confers oligomycin resistance (oli(r)) following transfer of a mitochondrial DNA-encoded oli(r) ATPase6 gene to the nuclear genome: A model system for mtDNA gene therapy SO REJUVENATION RESEARCH LA English DT Article ID KEARNS-SAYRE SYNDROME; CYTOCHROME-C-OXIDASE; HYDROPHOBIC PROTEINS; YEAST MITOCHONDRIA; SEQUENCE-ANALYSIS; POINT MUTATION; IN-VIVO; COENZYME-Q10; IMPORT; DEFICIENCY AB Point and deletion mutations and a general depletion of mammalian mitochondrial DNA (mtDNA) give rise to a wide variety of medical syndromes that are refractory to treatment, possibly including aging itself. While gene therapy directed at correcting such deficits in the mitochondrial genome may offer some therapeutic benefits, there are inherent problems associated with a direct approach. These problems are primarily due to the high mitochondrial genome copy number in each cell and the mitochondrial genome being "protected" inside the double-membrane mitochondrial organelle. In an alternative approach there is evidence that genes normally present in the mitochondrial genome can be incorporated into the nuclear genome. To extend such studies, we modified the Chinese Hamster Ovary (CHO) mtDNA-located ATPase6 gene (possessing a mutation which confers oligomycin resistanceoli(r)) by altering the mtDNA code to the universal code (U-code) to permit the correct translation of its mRNA in the cytoplasm. The U-code construct was inserted into the nuclear genome (nucDNA) of a wild type CHO cell. The expressed transgene products enabled the transformed CHO cell lines to grow in up to 1000 ng mL(-1) oligomycin, while untransformed sensitive CHO cells were eliminated in 1 ng mL-1 oligomycin. This approach, termed allotopic expression, provides a model that may make possible the transfer of all 13 mtDNA mammalian protein-encoding genes to the nucDNA, for treatments of mtDNA disorders. The CHO mtATPase6 protein is 85% identical to both the mouse and human mtATPase6 protein; these proteins are highly conserved in the region of the oligomycin resistance mutation. They are also well conserved in the regions of the oligomycin resistance mutation of the mouse, and in the region of a mutation found in Leigh's syndrome (T8993G), also called NARP (neurogenic weakness, ataxia, retinitis pigmentosum). It is likely that the CHO oli(r) mtATPase6 Ucode construct could impart oligomycin-resistance in human and mouse cells, as well as function in place of the mutant ATPase subunit in a NARP cell line. Preliminary experiments on human cybrids homoplasmic for the NARP mutation (kindly supplied by D.C. Wallace), transformed with our construct, display an increased oligomycin resistance that supports these suppositions. C1 NIMH, Biochim Genet Lab, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. Purdue Univ, Dept Biochem, W Lafayette, IN 47907 USA. RP Zullo, SJ (reprint author), 308 N Lee St, Falls Church, VA 22046 USA. EM szullo007@netscape.net NR 45 TC 31 Z9 34 U1 1 U2 5 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1549-1684 J9 REJUV RES JI Rejuv. Res. PD SPR PY 2005 VL 8 IS 1 BP 18 EP 28 DI 10.1089/rej.2005.8.18 PG 11 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 913QG UT WOS:000228167300006 PM 15798371 ER PT J AU Ko, MS AF Ko, MS TI Molecular biology of preimplantation embryos: primer for philosophical discussions SO REPRODUCTIVE BIOMEDICINE ONLINE LA English DT Article; Proceedings Paper CT International Conference on Ethics, Law and Moral Philosophy of Reproductive Biomedicine CY SEP 30-OCT 01, 2004 CL Royal Soc, London, ENGLAND HO Royal Soc DE embryo; embryogenomics; philosophy; preimplantation ID GENE-EXPRESSION PATTERNS; EQUALIZED CDNA LIBRARY; EARLY MOUSE EMBRYOS; STEM-CELL; HUMAN BLASTOCYSTS; GENOME-WIDE; CONSTRUCTION; MICROARRAY; OOCYTES; TRANSCRIPTOME AB This article is based on a presentation at the First International Conference on Ethics. Science and Moral Philosophy of Assisted Human Reproduction. The goal is to provide scientific background for the discussion of philosophic issues. Recent advances in the systematic molecular analysis of preimplantation embryos are summarized, including the molecular identification of nearly all genes involved in preimplantation development and their detailed expression patterns. Notwithstanding a quantum leap in molecular understanding, of p reimplantation embryos, molecular evidence seems to provide no decisive definition of a threshold for the beginning of human life during preimplantation development. C1 NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Bethesda, MD 21224 USA. RP Ko, MS (reprint author), NIA, Dev Genom & Aging Sect, Genet Lab, NIH, Bethesda, MD 21224 USA. EM kom@grc.nia.nih.gov RI Ko, Minoru/B-7969-2009 OI Ko, Minoru/0000-0002-3530-3015 NR 69 TC 5 Z9 5 U1 0 U2 2 PU REPRODUCTIVE HEALTHCARE LTD PI CAMBRIDGE PA DUCK END FARM, DRY DRAYTON, CAMBRIDGE, CB3 8DB, ENGLAND SN 1472-6483 J9 REPROD BIOMED ONLINE JI Reprod. Biomed. Online PD MAR PY 2005 VL 10 SU 1 BP 80 EP 87 PG 8 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 906NA UT WOS:000227647700019 PM 15820015 ER PT J AU Zakowicz, H Yang, HS Stark, C Wlodawer, A Laronde-Leblanc, N Colburn, NH AF Zakowicz, H Yang, HS Stark, C Wlodawer, A Laronde-Leblanc, N Colburn, NH TI Mutational analysis of the DEAD-box RNA helicase eIF4AII characterizes its interaction with transformation suppressor Pdcd4 and eIF4GI SO RNA-A PUBLICATION OF THE RNA SOCIETY LA English DT Article DE translation initiation; eIF4F; tumor suppressor; eIF4A homology model ID INITIATION-FACTOR 4A; FACTOR 4G EIF4G; TRANSLATION INITIATION; MAMMALIAN TRANSLATION; AP-1 TRANSACTIVATION; FACTOR EIF-4A; BINDING; CELLS; HYDROLYSIS; INDUCTION AB Eukaryotic initiation factor (eIF) 4A unwinds secondary and tertiary structures in the 5'-untranslated region of mRNA, permitting translation initiation. Programmed cell death 4 (Pdcd4) is a novel transformation suppressor and eIF4A-binding partner that inhibits eIF4A helicase activity and translation. To elucidate the regions of eIF4A that are functionally significant in binding to Pdcd4, we generated point mutations of eIF4A. Two-hybrid analysis revealed that five eIF4A mutants completely lost binding to Pdcd4 while four eIF4A mutants retained wild-type levels of binding. The residues that, when mutated, inactivated Pdcd4 binding specified ATP binding, ATP hydrolysis, or RNA binding. With the exception of the Q-motif mutant eIF4A(P56L), the eIF4A mutants inactivated for Pdcd4 binding were inactivated for binding to eIF4G (G(M), G(C), or both) and for enhancing translation. Several eIF4A mutants showing wild-type level binding to Pdcd4 were also inactivated for binding to eIF4G and for enhancing translation. Thus, significant dissociation of eIF4A's Pdcd4- and eIF4G-binding regions appears to occur. Because three of the four eIF4A mutants that retained Pdcd4 binding also suppressed translation activity in a dominant-negative manner, the structure that defines the Pdcd4-binding domain of eIF4A may be necessary but is insufficient for translation. A structural homology model of eiF4A shows regions important for binding to Pdcd4 and/or eIF4G lying on the perimeters of the hinge area of eIF4A. A competition experiment revealed that Pdcd4 competes with C-terminal eIF4G for binding to eIF4A. In summary, the Pdcd4-binding domains on eIF4A impact both binding to eIF4G and translation initiation in cells. C1 NCI, Lab Canc Prevent, Frederick, MD 21702 USA. George Washington Univ, Genet Program, Washington, DC 20037 USA. NCI, Macromol Crystallog Lab, Frederick, MD 21702 USA. RP Colburn, NH (reprint author), NCI, Lab Canc Prevent, Bldg 576,Rm 101, Frederick, MD 21702 USA. EM colburn@ncifcrf.gov RI Yang, Hsin-Sheng/A-6419-2008; LaRonde-LeBlanc, Nicole/C-3399-2009 OI LaRonde-LeBlanc, Nicole/0000-0002-2778-8358 NR 34 TC 43 Z9 45 U1 1 U2 3 PU COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT PI WOODBURY PA 500 SUNNYSIDE BLVD, WOODBURY, NY 11797-2924 USA SN 1355-8382 J9 RNA JI RNA-Publ. RNA Soc. PD MAR PY 2005 VL 11 IS 3 BP 261 EP 274 DI 10.1261/rna.7191905 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 900BI UT WOS:000227190000004 PM 15661843 ER PT J AU Reynolds, HY Gail, DB Kiley, JP AF Reynolds, HY Gail, DB Kiley, JP TI Interstitial lung diseases - where we started from and are now going SO SARCOIDOSIS VASCULITIS AND DIFFUSE LUNG DISEASES LA English DT Review DE pulmonary fibrosis; idiopathic pulmonary fibrosis; sarcoidosis; hypersensitivity pneumonitis ID IDIOPATHIC PULMONARY-FIBROSIS; HUMAN ALVEOLAR MACROPHAGES; NEUTROPHIL CHEMOTACTIC FACTOR; LOWER RESPIRATORY-TRACT; BRONCHOALVEOLAR LAVAGE; HYPERSENSITIVITY PNEUMONITIS; INTERFERON GAMMA-1B; PROGNOSTIC-SIGNIFICANCE; IMMUNOCOMPETENT CELLS; POTENTIAL MECHANISM AB Background and Aim. Research into mechanisms causing interstitial lung diseases (ILD) began 35 years ago with the advent of cellular immunology and techniques to sample airways for biologic materials. After an analysis of lung research programs by the then National Heart and Lung Institute in 1972 identified as a priority the study of fibrotic and immunologic lung diseases, this began in the Pulmonary Branch (1974) of the Institute's intramural program. The Division of Lung Diseases initiated extramural research support also. ILD research developed quickly at many centers in the US and throughout the world. This review focuses on idiopathic pulmonary fibrosis (IPF) and highlights some of the initial research from the Pulmonary Branch. Recent research paradigm. In the 1990s research emphasis changed from a focus on inflammation to alveolar epithelial injury, fibrogenesis in fibroblastic foci, myofibroblast function, cytokine secretion and disordered matrix remodeling. More precise classification of ILD was advocated, especially for IPF. New strategies for therapy of IPF followed, including anti-fibrotic agents and interferon gamma treatment. However, therapy is still not sufficiently effective. Much is still left to do. Future Directions. The NHLBI research support continues for ILD, especially IPF. Current programs include: searching for new molecular therapeutic targets; establishing of a clinical network for IPF patients to assess combinations of therapy and new agents as appropriate; identifying genomic and genetic susceptibility factors; and creating a repository for lung tissue and biologic samples to aid investigators. C1 US Dept HHS, Div Lung Dis, NHLBI, NIH, Bethesda, MD USA. RP Reynolds, HY (reprint author), 6701 Rockledge Dr,Suite 10018, Bethesda, MD 20817 USA. EM reynoldh@nhlbi.nih.gov NR 80 TC 11 Z9 12 U1 0 U2 3 PU FONDAZIONE PNEUMOLOGIA U I P ONLUS PI MILANO PA VIA FRUA 15, MILANO, ITALY SN 1124-0490 J9 SARCOIDOSIS VASC DIF JI Sarcoidosis Vasc. Diffus. Lung Dis. PD MAR PY 2005 VL 22 IS 1 BP 5 EP 12 PG 8 WC Respiratory System SC Respiratory System GA 910GJ UT WOS:000227918500001 PM 15881274 ER PT J AU Sporn, A Greenstein, D Gogtay, N Sailer, F Hommer, DW Rawlings, R Nicolson, R Egan, MF Lenane, M Gochman, P Weinberger, DR Rapoport, JL AF Sporn, A Greenstein, D Gogtay, N Sailer, F Hommer, DW Rawlings, R Nicolson, R Egan, MF Lenane, M Gochman, P Weinberger, DR Rapoport, JL TI Childhood-onset schizophrenia: smooth pursuit eye-tracking dysfunction in family members SO SCHIZOPHRENIA RESEARCH LA English DT Article DE COS; AOS; smooth pursuit eye-tracking dysfunction ID DIAGNOSTIC INTERVIEW; AFFECTIVE-DISORDERS; EARLY EXPRESSION; MOVEMENTS; RELATIVES; CHILDREN; SACCADES; AGE; ABNORMALITIES; IMPAIRMENT AB Background: Childhood-onset schizophrenia (COS), a severe form of the disorder, is of interest for etiologic studies. Smooth pursuit eye-tracking dysfunction (ETD) is a biological marker for schizophrenia. Aims: To compare familial eye-tracking abnormalities for COS and adult-onset schizophrenia (AOS). Method. Eye-tracking performance for 70 COS parents, 64 ADS parents and 20 COS siblings was compared to their respective age-matched control groups. Results: COS and AOS parents had higher rate of dichotomously rated eye-tracking dysfunction than their respective controls (16% vs. 1% and 22% vs. 4%, respectively). COS parents and siblings also differed from controls on several continuous measures. However, scores for COS, AOS and control groups overlapped extensively. Conclusions: Genetic factors underlying eye-tracking dysfunction appear more salient for COS. However, eye-tracking measures have to be used with caution for endophenotypic definition due to low predictive power. Declaration of interest: The study was done at the National Institutes of Health. (C) 2004 Elsevier B.V. All rights reserved. C1 NIMH, Child Psychiat Branch, NIH, Bethesda, MD 20892 USA. NIAAA, Clin Studies Lab, NIH, Bethesda, MD 20892 USA. NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. RP Sporn, A (reprint author), NIMH, Child Psychiat Branch, NIH, Bldg 10,Rm 3N202, Bethesda, MD 20892 USA. EM sporna@intra.nimh.nih.gov RI Gogtay, Nitin/A-3035-2008; Nicolson, Robert/E-4797-2011 NR 34 TC 17 Z9 17 U1 1 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0920-9964 J9 SCHIZOPHR RES JI Schizophr. Res. PD MAR 1 PY 2005 VL 73 IS 2-3 BP 243 EP 252 DI 10.1016/j.schres.2004.07.020 PG 10 WC Psychiatry SC Psychiatry GA 892OY UT WOS:000226661100012 PM 15653267 ER PT J AU Sevransky, J Vandivier, RW Gerstenberger, E Correa, R Ferantz, V Banks, SM Danner, RL Eichacker, PQ Natanson, C AF Sevransky, J Vandivier, RW Gerstenberger, E Correa, R Ferantz, V Banks, SM Danner, RL Eichacker, PQ Natanson, C TI Prophylactic high-dose N-omega-monomethyl-L-arginine prevents the late cardiac dysfunction associated with lethal tumor necrosis factor-alpha challenge in dogs SO SHOCK LA English DT Article DE nitric oxide; tumor necrosis factor; cardiac function; N-omega-monomethyl-L-arginine; nitric oxide synthase ID NITRIC-OXIDE SYNTHASE; SEPTIC SHOCK; CARDIOVASCULAR DYSFUNCTION; INHIBITION; CYTOKINES; BACTEREMIA; SURVIVAL; FAILURE; HUMANS AB We investigated nitric oxide (NO) as a possible cause of the cardiac dysfunction associated with high, lethal doses of tumor necrosis factor-a (TNF-alpha) in dogs. Eighty-seven awake, 2-year-old (10-12 kg), purpose-bred beagles were randomized to receive an infusion of saline or N-omega-monomethyl-L-arginine (L-NMMA), a nonselective NO synthase (NOS) inhibitor, as a 40 mg kg(-1) bolus followed by a 40 mg kg(-1) h(-1) infusion for 3 to 6 h 3 h before (prophylactic) or 3 h after (therapeutic) challenge with TNF-alpha (60 mug kg(-1)) or vehicle. Serial radionuclide-heart scans and thermodilution pulmonary artery catheter hemodynamic measurements were performed. The effects of prophylactic L-NMMA on TNF-alpha-induced cardiac dysfunction as measured by decreases in mean left ventricular (LV) ejection fraction and downward and rightward shifts of LV function plots (peak systolic pressure versus end systolic volume index and LV stroke work index versus end diastolic volume index) were significantly different comparing early (3-6 h) and delayed (24 h) time points (P = 0.02). Prophylactic L-NMMA therapy did not appear to fully prevent early (3-6 h) TNF-alpha-induced cardiac dysfunction, but at 24 h, complete protection was seen. Therapeutic L-NMMA did not appear to fully protect the heart from TNF-a-induced early or delayed cardiac dysfunction (P = NS). Similarly, L-NMMA given prophylactically, but not therapeutically, blocked TNF-alpha-induced increases in exhaled NO flow rates and plasma nitrite and nitrate concentrations (both P=0.02). These data suggest that TNF-a initiates two phases of cardiac injury: an early (3-6 h) phase that may be partially NO independent and a delayed (24 h) phase that is NO dependent. The delayed, more persistent dysfunction can be completely blocked by high doses of a nonselective NOS inhibitor administered before TNF-alpha. C1 NIH, Dept Crit Care Med, Bethesda, MD 20892 USA. RP Sevransky, J (reprint author), Johns Hopkins Univ, Div Pulm & Crit Care Med, Asthma & Allergy Bldg 4B-73,5501 Hopkins Bayview, Baltimore, MD 21224 USA. EM sevransj@jhmi.edu NR 34 TC 2 Z9 2 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1073-2322 J9 SHOCK JI Shock PD MAR PY 2005 VL 23 IS 3 BP 281 EP 288 DI 10.1097/01.shk.0000152973.78297.3b PG 8 WC Critical Care Medicine; Hematology; Surgery; Peripheral Vascular Disease SC General & Internal Medicine; Hematology; Surgery; Cardiovascular System & Cardiology GA 901PS UT WOS:000227295000015 PM 15718929 ER PT J AU Floel, A Cohen, LG AF Floel, A Cohen, LG TI Strategies in motor stroke rehabilitation SO STROKE LA English DT Letter C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. NINDS, Stroke Neurorehabil Clin, NIH, Bethesda, MD 20892 USA. RP Floel, A (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA. RI Floel, Agnes/A-9426-2017 NR 5 TC 3 Z9 3 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 MAR PY 2005 VL 36 IS 3 BP 530 EP 530 DI 10.1161/01.STR.0000154867.01422.76 PG 1 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 902QN UT WOS:000227371700009 PM 15738578 ER PT J AU Fox, ER Taylor, HA Benjamin, EJ Ding, JZ Liebson, PR Arnett, D Quin, EM Skelton, TN AF Fox, ER Taylor, HA Benjamin, EJ Ding, JZ Liebson, PR Arnett, D Quin, EM Skelton, TN TI Left ventricular mass indexed to height and prevalent MRI cerebrovascular disease in an African American cohort - The Atherosclerotic Risk in Communities Study SO STROKE LA English DT Article DE African American; cerebrovascular disorders; echocardiography; magnetic resonance imaging ID WHITE-MATTER LESIONS; MIDDLE-AGED ADULTS; CARDIOVASCULAR HEALTH; ELDERLY COHORT; ESSENTIAL-HYPERTENSION; CARDIAC-HYPERTROPHY; VASCULAR DEMENTIA; WALL THICKNESS; SILENT STROKE; PREDICTORS AB Background and Purpose-Previous studies have demonstrated that echocardiographic left ventricular mass (LVM) is an independent risk factor for stroke in whites. Despite the greater burden of stroke, the echocardiographic predictors of stroke in African Americans remain poorly understood. Methods-This investigation is a retrospective analysis of prospectively collected data from the Jackson, Miss (all African American), cohort of the Atherosclerotic Risk in the Communities study. Between 1993 and 1995, 2445 participants received an echocardiogram, and a random subset (n=778) received cerebral MRI evaluating presence of infarcts or white matter disease (WMD; >3 on a scale of 0 to 9). Compared with the entire Jackson cohort, the random subset was older, had a lower body mass index (BMI), and a higher systolic blood pressure (SBP). Logistic regression models examined the relations of LVM indexed by height (LVM/height) to MRI findings adjusted for age, gender, BMI, SBP, hypertensive medications, diabetes, total/high-density lipoprotein cholesterol, smoking status, and history of myocardial infarction. Results-The 667 participants (63% women; 62+/-4 years of age) had a high prevalence of hypertension (68%), obesity (46%), echocardiographic left ventricular hypertrophy (49%), MRI stroke (n=133), and WMD (n=92). Adjusted LVM/height was significantly associated with prevalent MRI stroke (odds ratio [OR], 1.3; 95% CI, 1.1 to 1.7; P=0.02) and WMD (OR, 1.5; 95% CI, 1.1 to 1.9; P=0.006; OR expressed per 1 SD LVM/height, 45 g/m). Conclusion-In this randomized subset of a population-based cohort of African American adults, LVM/height was related to MRI evidence of prevalent cerebrovascular disease. The current study supports the hypothesis that LVM/height is an important risk factor for stroke in multiple ethnicities. C1 Univ Mississippi, Med Ctr, Jackson, MS 39216 USA. NHLBI Jackson Heart Study, Jackson, MS USA. Boston Univ, Sch Med, Boston, MA 02215 USA. NHLBI FHS, Framingham, MA USA. Johns Hopkins Sch Publ Hlth, Baltimore, MD USA. Rush Univ, Med Ctr, Chicago, IL 60612 USA. Univ Minnesota, Minneapolis, MN USA. RP Fox, ER (reprint author), Univ Mississippi, Med Ctr, 2500 N State St, Jackson, MS 39216 USA. EM efox@medicine.umsmed.edu OI Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [N01-HC-55020, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55021, N01-HC-55022]; NINDS NIH HHS [5R01-NS 17950] NR 34 TC 10 Z9 11 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 MAR PY 2005 VL 36 IS 3 BP 546 EP 550 DI 10.1161/01.STR.0000154893.68957.55 PG 5 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 902QN UT WOS:000227371700016 PM 15662040 ER PT J AU Shen, H Chen, GJ Harvey, BK Bickford, PC Wang, Y AF Shen, H Chen, GJ Harvey, BK Bickford, PC Wang, Y TI Inosine reduces ischemic brain injury in rats SO STROKE LA English DT Article DE inosine, adenosine; neuroprotection; stroke ID A(3) ADENOSINE RECEPTOR; PC12 CELLS; CULTURES; NEURONS; ACTIVATION; STROKE AB Background and Purpose-Purinergic nucleoside inosine elicits protection and regeneration during various injuries. The purpose of this study was to examine the protective effects of inosine against cerebral ischemia. Methods-Adult Sprague-Dawley rats were anesthetized. Inosine, hypoxathine, or vehicle was administered intracerebroventricularly before transient right middle cerebral artery occlusion (MCAo). Animals were placed in behavioral chambers 2 days to 2 weeks after MCAo and then euthanized for tri-phenyl-tetrazolium chloride staining. Glutamate release was measured by microdialysis/high-performance liquid chromatography, and single-unit action potentials were recorded from neurons in the parietal cortex. Results-Stroke animals receiving inosine pretreatment demonstrated a higher level of locomotor activity and less cerebral infarction. Intracerebroventricular administration of the same dose of hypoxanthine did not confer protection. Coadministration of selective A3 receptor antagonist 3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1, 4-(+)-dihydropyridine-3,5-dicarboxylate (MRS1191) significantly reduced inosine-mediated protection. Inosine did not alter basal glutamate release, nor did it reduce ischemia-evoked glutamate overflow from cerebral cortex. However, inosine antagonized glutamate-induced electrophysiological excitation in cerebral cortical neurons. Conclusions-Inosine inhibits glutamate postsynaptic responses and reduces cerebral infarction. Its protective effect against ischemia/reperfusion-related insults may involve activation of adenosine A3 receptors. C1 NIDA, IRP, NIH, Baltimore, MD 21224 USA. Univ S Florida, Ctr Aging & Brain Repair, Tampa, FL USA. RP Wang, Y (reprint author), NIDA, IRP, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM ywang@intra.nida.nih.gov RI Bickford, Paula/J-5970-2012 OI Bickford, Paula/0000-0001-9657-7725 NR 22 TC 60 Z9 62 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0039-2499 J9 STROKE JI Stroke PD MAR PY 2005 VL 36 IS 3 BP 654 EP 659 DI 10.1161/01.STR.0000155747.15679.04 PG 6 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 902QN UT WOS:000227371700036 PM 15692110 ER PT J AU Morgenstern, LB Woodbury-Harris, K Marler, JR AF Morgenstern, LB Woodbury-Harris, K Marler, JR CA NINDS ICH Workshop Participants TI Priorities for clinical research in intracerebral hemorrhage - Report from a National Institute of Neurological Disorders and Stroke Workshop SO STROKE LA English DT Review DE acute care; brain edema; cerebral amyloid angiopathy; hematology; intracerebral hemorrhage; stroke, acute ID TISSUE-PLASMINOGEN-ACTIVATOR; BLOOD-BRAIN-BARRIER; FOCAL CEREBRAL-ISCHEMIA; ANEURYSMAL SUBARACHNOID HEMORRHAGE; PROSPECTIVE RANDOMIZED TRIAL; ACUTE MYOCARDIAL-INFARCTION; COMBINATION-DRUG THERAPY; CENTRAL-NERVOUS-SYSTEM; TUMOR-NECROSIS-FACTOR; EDEMA FORMATION AB Background and Purpose-Spontaneous intracerebral hemorrhage (ICH) is one of the most lethal stroke types. In December 2003, a National Institute of Neurological Disorders and Stroke (NINDS) workshop was convened to develop a consensus for ICH research priorities. The focus was clinical research aimed at acute ICH in patients. Methods-Workshop participants were divided into 6 groups: ( 1) current state of ICH research; ( 2) basic science; and ( 3) imaging, ( 4) medical, ( 5) surgical, and ( 6) clinical methodology. Each group formulated research priorities before the workshop. At the workshop, these were discussed and refined. Results-Recent progress in management of hemorrhage growth, intraventricular hemorrhage, and limitations in the benefit of open craniotomy were noted. The workshop identified the importance of developing animal models to reflect human ICH, as well as the phenomena of rebleeding. More human ICH pathology is needed. Real-time, high-field magnets and 3-dimensional imaging, as well as high-resolution tissue probes, are ICH imaging priorities. Trials of acute blood pressure-lowering in ICH and coagulopathy reversal are medical priorities. The exact role of edema in human ICH pathology and its treatment requires intensive study. Trials of minimally invasive surgical techniques including mechanical and chemical surgical adjuncts are critically important. The methodologic challenges include establishing research networks and a multi-specialty approach. Waiver of consent issues and standardizing care in trials are important issues. Encouragement of young investigators from varied backgrounds to enter the ICH research field is critical. Conclusions-Increasing ICH research is crucial. A collaborative approach is likely to yield therapies for this devastating form of brain injury. C1 Univ Michigan, Stroke Program, Ann Arbor, MI 48109 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. NINDS, Rockville, MD USA. Washington Univ, St Louis, MO USA. Univ Washington, Seattle, WA 98195 USA. Northwestern Univ, Chicago, IL 60611 USA. Scripps Res Inst, La Jolla, CA USA. Univ Texas, Houston, TX USA. Univ Cincinnati, Cincinnati, OH 45221 USA. Univ Med & Dent New Jersey, Newark, NJ 07103 USA. Columbia Univ, New York, NY USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. Newcastle Univ, Newcastle Upon Tyne NE1 7RU, Tyne & Wear, England. Univ Pittsburgh, Pittsburgh, PA 15260 USA. Univ Calif Los Angeles, Los Angeles, CA USA. Johns Hopkins, Baltimore, MD USA. Univ Chicago, Chicago, IL 60637 USA. RP Morgenstern, LB (reprint author), Univ Michigan, Stroke Program, 1500 E Med Ctr Dr,TC1920-0316, Ann Arbor, MI 48109 USA. EM lmorgens@umich.edu NR 228 TC 53 Z9 53 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA TWO COMMERCE SQ, 2001 MARKET ST, PHILADELPHIA, PA 19103 USA SN 0039-2499 EI 1524-4628 J9 STROKE JI Stroke PD MAR PY 2005 VL 36 IS 3 BP E23 EP E41 DI 10.1161/01.STR.0000155685.77775.4c PG 19 WC Clinical Neurology; Peripheral Vascular Disease SC Neurosciences & Neurology; Cardiovascular System & Cardiology GA 902QN UT WOS:000227371700048 ER PT J AU Quarrie, SA Steed, A Calestani, C Semikhodskii, A Lebreton, C Chinoy, C Steele, N Pljevljakusic, D Waterman, E Weyen, J Schondelmaier, J Habash, DZ Farmer, P Saker, L Clarkson, DT Abugalieva, A Yessimbekova, M Turuspekov, Y Abugalieva, S Tuberosa, R Sanguineti, MC Hollington, PA Aragues, R Royo, A Dodig, D AF Quarrie, SA Steed, A Calestani, C Semikhodskii, A Lebreton, C Chinoy, C Steele, N Pljevljakusic, D Waterman, E Weyen, J Schondelmaier, J Habash, DZ Farmer, P Saker, L Clarkson, DT Abugalieva, A Yessimbekova, M Turuspekov, Y Abugalieva, S Tuberosa, R Sanguineti, MC Hollington, PA Aragues, R Royo, A Dodig, D TI A high-density genetic map of hexaploid wheat (Triticum aestivum L.) from the cross Chinese Spring X SQ1 and its use to compare QTLs for grain yield across a range of environments SO THEORETICAL AND APPLIED GENETICS LA English DT Article ID QUANTITATIVE TRAIT LOCI; DISOMIC ADDITION LINES; L EM THELL; BREAD WHEAT; LINKAGE MAP; PROTEIN-CONTENT; SALT TOLERANCE; CHROMOSOMES; BARLEY; LOCATION AB A population of 96 doubled haploid lines (DHLs) was prepared from F-1 plants of the hexaploid wheat cross Chinese Spring x SQ1 (a high abscisic acid-expressing breeding line) and was mapped with 567 RFLP, AFLP, SSR, morphological and biochemical markers covering all 21 chromosomes, with a total map length of 3,522 cM. Although the map lengths for each genome were very similar, the D genome had only half the markers of the other two genomes. The map was used to identify quantitative trait loci (QTLs) for yield and yield components from a combination of 24 site x treatment x year combinations, including nutrient stress, drought stress and salt stress treatments. Although yield QTLs were widely distributed around the genome, 17 clusters of yield QTLs from five or more trials were identified: two on group 1 chromosomes, one each on group 2 and group 3, five on group 4, four on group 5, one on group 6 and three on group 7. The strongest yield QTL effects were on chromosomes 7AL and 7BL, due mainly to variation in grain numbers per ear. Three of the yield QTL clusters were largely site-specific, while four clusters were largely associated with one or other of the stress treatments. Three of the yield QTL clusters were coincident with the dwarfing gene Rht-B1 on 4BS and with the vernalisation genes Vrn-A1 on 5AL and Vrn-D1 on 5DL. Yields of each DHL were calculated for trial mean yields of 6 g plant(-1) and 2 g plant(-1) (equivalent to about 8 t ha(-1) and 2.5 t ha(-1), respectively), representing optimum and moderately stressed conditions. Analyses of these yield estimates using interval mapping confirmed the group-7 effects on yield and, at 2 g plant(-1), identified two additional major yield QTLs on chromosomes 1D and 5A. Many of the yield QTL clusters corresponded with QTLs already reported in wheat and, on the basis of comparative genetics, also in rice. The implications of these results for improving wheat yield stability are discussed. C1 John Innes Inst, Norwich NR4 7UH, Norfolk, England. SAATEN UNION Resistenzlabor GmbH, D-33818 Leopoldshohe, Germany. Rothamsted Res, CPI Div, Harpenden AL5 2JQ, Herts, England. Univ Bristol, Long Ashton Res Stn, IACR, Bristol BS18 9AF, Avon, England. Kazak Inst Agr, Almaty, Kazakhstan, Kazakhstan. Natl Biotechnol Ctr, Inst Plant Physiol Genet & Bioengn, Almaty 480090, Kazakhstan. Dept Agroenvironm Sci & Technol, I-40127 Bologna, Italy. Univ Wales, Ctr Arid Zone Studies, Bangor LL57 2UW, Gwynedd, Wales. SIA, DGA, Unidad Suelos & Riegos, Gobierno Aragon, Zaragoza, Spain. CATR, Agr Res Inst Serbia, YU-19000 Zajecar, Serbia Monteneg, Yugoslavia. RP Quarrie, SA (reprint author), John Innes Inst, Norwich Res Pk,Coloney Lane, Norwich NR4 7UH, Norfolk, England. EM quarrie@eunet.yu RI Mason, Richard/F-9865-2010; Aragues, Ramon/C-5872-2012; Turuspekov, Yerlan/C-3458-2011; Abugalieva, Saule/M-6690-2015; Tuberosa, Roberto/A-2781-2016; OI Abugalieva, Saule/0000-0002-9748-507X; Tuberosa, Roberto/0000-0001-9143-9569; Quarrie, Steve/0000-0002-8858-0251; Turuspekov, Yerlan/0000-0001-8590-1745 NR 63 TC 220 Z9 258 U1 4 U2 75 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0040-5752 J9 THEOR APPL GENET JI Theor. Appl. Genet. PD MAR PY 2005 VL 110 IS 5 BP 865 EP 880 DI 10.1007/s00122-004-1902-7 PG 16 WC Agronomy; Plant Sciences; Genetics & Heredity; Horticulture SC Agriculture; Plant Sciences; Genetics & Heredity GA 913KK UT WOS:000228150300009 PM 15719212 ER PT J AU Vidal, B Parra, M Jardi, M Saito, S Appella, E Munoz-Canoves, P AF Vidal, B Parra, M Jardi, M Saito, S Appella, E Munoz-Canoves, P TI The alkylating carcinogen N-methyl-N '-nitro-N-nitrosoguanidine activates the plasminogen activator inhibitor-I gene through sequential phosphorylation of p53 by ATM and ATR kinases SO THROMBOSIS AND HAEMOSTASIS LA English DT Article DE gene expression; proteases/inhibitors; signal transduction ID DEPENDENT PROTEIN-KINASE; DNA-DAMAGE; RADIOSENSITIZING AGENT; IONIZING-RADIATION; GENOTOXIC STRESS; CELLS; PATHWAY; NITROSOUREA; MECHANISMS; INDUCTION AB The alkylating agent MNNG is an environmental carcinogen that causes DNA lesions leading to cell death. We previously demonstrated that MNNG induced the transcriptional activity of the plasminogen activator inhibitor-1 (PAI-1) gene in a p53-dependent manner. However the mechanism(s) linking external MNNG stimulation and PAI-1 gene induction remained to be elucidated. Here, we show that ATM and ATR kinases, but not DNA-PK, which participate in DNA damage-activated checkpoints, regulate the phosphorylation of p53 at serine 15 in response to MNNG cell treatment. Using ATM-deficient cells, ATM was shown to be required for early phosphorylation of serine is in response to MNNG, whereas catalytically inactive ATR selectively interfered with late phase serine 15 phosphorylation. In contrast, DNA-PK-deficient cells showed no change in the MNNG-induced serine 15 phosphorylation pattern. In agreement with this,sequential activation of ATM and ATR kinases was also required for adequate induction of the endogenous PAI-1 gene by MNNG. Finally, we showed that cells derived from PAI-1-deficient mice were more resistant to MNNG-induced cell death than normal cells, suggesting that p53-dependent PAI-1 expression partially mediated this effect. Since PAI-1 is involved in the control of tumor invasiveness, our finding that MNNG induces PAI-1 gene expression via ATM/ATR-mediated phosphorylation of p53 sheds new insight on the role of these DNA damage-induced cell cycle checkpoint kinases. C1 Ctr Genom Regulat, Program Differentiat & Canc, E-08003 Barcelona, Spain. NCI, NIH, Bethesda, MD 20892 USA. RP Munoz-Canoves, P (reprint author), Ctr Genom Regulat, Program Differentiat & Canc, Barcelona Passeig Maritim,37-49, E-08003 Barcelona, Spain. EM pura.munoz@crg.es RI Munoz-Canoves, Pura/B-3889-2015; M, Jardi/I-1201-2015 OI Munoz-Canoves, Pura/0000-0002-7533-9047; M, Jardi/0000-0002-2058-6606 NR 44 TC 5 Z9 6 U1 0 U2 3 PU SCHATTAUER GMBH-VERLAG MEDIZIN NATURWISSENSCHAFTEN PI STUTTGART PA HOLDERLINSTRASSE 3, D-70174 STUTTGART, GERMANY SN 0340-6245 J9 THROMB HAEMOSTASIS JI Thromb. Haemost. PD MAR PY 2005 VL 93 IS 3 BP 584 EP 591 DI 10.1160/TH04-10-0644 PG 8 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 908RT UT WOS:000227808200030 PM 15735814 ER PT J AU Close, NC Hering, B Eggerman, TL AF Close, NC Hering, B Eggerman, TL TI Results from the inaugural year of the collaborative islet transplant registry SO TRANSPLANTATION PROCEEDINGS LA English DT Article; Proceedings Paper CT 20th International Congress of the Transplantion-Society CY SEP 05-10, 2004 CL Vienna, AUSTRIA SP Transplant Soc AB The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) established the Collaborative Islet Transplant Registry (CITR) in September 2001. In its inaugural year, CITR represents the efforts of 12 collaborating North American islet transplant centers reporting 86 islet transplant recipients' data (1999-2003) and 173 processed pancreata leading to 158 infusion procedures. Recipient median age was 42.2 years, duration of diabetes was 30 years, and over 66% of the recipients were female. Twenty-eight patients received a total of 1 islet infusion, 44 patients received 2 islet infusions, and 14 patients received 3 islet infusions. The median age of the deceased donor was 44 years and body mass index was 28.2. Median time from cross clamp to pancreas recovery was 27 minutes, while duration of cold ischemia was 7 hours. Over 77% of the processing facilities used a density gradient for islet purification. For recipients of only 1 infusion, approximately 8665 total islet equivalents/kg were infused; recipients of 2 infusions received 14,102 islet equivalents/kg, and recipients of 3 infusions received 22,922 islet equivalents/kg. At 6 months after the last infusion, 61.1% of the recipients were reported to be insulin independent; at 12 months, 57.9% were reported to be insulin independent. There have been no deaths reported to CITR; 45 serious adverse events were reported. Through its collaboration with the islet transplant community and its interaction with professional societies and federal agencies, CITR is positioned to provide current and comprehensive information on clinically significant outcome measures in islet transplantation. C1 EMMES Corp, Rockville, MD 20850 USA. Univ Minnesota, Diabet Inst Immunol & Transplantat, Minneapolis, MN USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Close, NC (reprint author), EMMES Corp, 401 N Washington St,Suite 700, Rockville, MD 20850 USA. EM nclose@emmes.com NR 0 TC 13 Z9 13 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0041-1345 J9 TRANSPLANT P JI Transplant. Proc. PD MAR PY 2005 VL 37 IS 2 BP 1305 EP 1308 DI 10.1016/j.transproceed.2004.12.117 PG 4 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 918SW UT WOS:000228568900256 PM 15848704 ER PT J AU Morris, RW Bean, CA Farber, GK Gallahan, D Jakobsson, E Liu, Y Lyster, PM Peng, GCY Roberts, FS Twery, M Whitmarsh, J Skinner, K AF Morris, RW Bean, CA Farber, GK Gallahan, D Jakobsson, E Liu, Y Lyster, PM Peng, GCY Roberts, FS Twery, M Whitmarsh, J Skinner, K TI Digital biology: an emerging and promising discipline SO TRENDS IN BIOTECHNOLOGY LA English DT Editorial Material ID RESOURCE AB This article examines the role of computation and quantitative methods in modern biomedical research to identify emerging scientific, technical, policy and organizational trends. It identifies common concerns and practices in the emerging community of computationally-oriented bio-scientists by reviewing a national symposium, Digital Biology: the Emerging Paradigm, held at the National Institutes of Health in Bethesda, Maryland, November 6(th) and 7(th) 2003. This meeting showed how biomedical computing promises scientific breakthroughs that will yield significant health benefits. Three key areas that define the emerging discipline of digital biology are: scientific data integration, multiscale modeling and networked science. Each area faces unique technical challenges and information policy issues that must be addressed as the field matures. Here we summarize the emergent challenges and offer suggestions to academia, industry and government on how best to expand the role of computation in their scientific activities. C1 NIH, Bethesda, MD 20892 USA. Rutgers State Univ, Ctr Discrete Math & Theoret Comp Sci, Piscataway, NJ 08855 USA. RP Morris, RW (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM rmorris@niaid.nih.gov NR 11 TC 8 Z9 8 U1 1 U2 1 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0167-7799 J9 TRENDS BIOTECHNOL JI Trends Biotechnol. PD MAR PY 2005 VL 23 IS 3 BP 113 EP 117 DI 10.1016/j.tibtech.2005.01.005 PG 5 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 906FB UT WOS:000227624800002 PM 15734552 ER PT J AU Ilias, L Shulkin, B Pacak, K AF Ilias, L Shulkin, B Pacak, K TI New functional imaging modalities for chromaffin tumors, neuroblastomas and ganglioneuromas SO TRENDS IN ENDOCRINOLOGY AND METABOLISM LA English DT Review ID POSITRON-EMISSION-TOMOGRAPHY; SOMATOSTATIN RECEPTOR SCINTIGRAPHY; CYCLASE-ACTIVATING PEPTIDE; WHOLE-BODY PET; OCTREOTIDE SCINTIGRAPHY; METAIODOBENZYLGUANIDINE SCINTIGRAPHY; I-123 METAIODOBENZYLGUANIDINE; MALIGNANT PHEOCHROMOCYTOMA; PEDIATRIC NEUROBLASTOMA; NEUROENDOCRINE TUMORS AB Nuclear medicine modalities use radiolabeled ligands that either follow metabolic pathways or act on cellular receptors. Thus, they permit functional imaging of physiological processes and help to localize sites such as tumors that harbor pathological events. The application of positron emission tomography (PET) ligands to the specific pathways of synthesis, metabolism and inactivation of catecholamines found in chromaffin tumors, neuroblastomas and ganglioneuromas can be used to provide a more thorough localization of these types of tumor. Recent advances have been made in functional imaging to localize pheochromocytomas, paragangliomas, neuroblastomas and ganglioneuromas, including approaches based on PET with [F-18]fluorodopamine, [F-18]fluorohydroxyphenylalanine, [C-11]epinephrine or [C-11]hydroxyephedrine. Such functional imaging can complement computed tomography or magnetic resonance imaging and, other scintigraphic techniques to localize these tumors before surgical or medical therapeutic approaches are considered. C1 NICHHD, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. Univ Patras, Sch Med, Dept Pharmacol, GR-26504 Rion, Greece. St Jude Childrens Res Hosp, Div Nucl Med, Dept Radiol Sci, Memphis, TN 38105 USA. RP Pacak, K (reprint author), NICHHD, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. EM karel@mail.nih.gov NR 68 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1043-2760 J9 TRENDS ENDOCRIN MET JI Trends Endocrinol. Metab. PD MAR PY 2005 VL 16 IS 2 BP 66 EP 72 PG 7 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 909NA UT WOS:000227865400006 ER PT J AU Rivera, J AF Rivera, J TI NTAL/LAB and LAT: a balancing act in mast-cell activation and function SO TRENDS IN IMMUNOLOGY LA English DT Article ID FC-EPSILON-RI; NEGATIVE REGULATION; ALLERGIC RESPONSE; DISTAL TYROSINES; LINKER; DEGRANULATION; MEMBRANE; ADAPTERS; KINASE AB The absence of the linker for activation of T cells (LAT) causes partial inhibition of mast-cell responses. The LAT homolog, non-T-cell activation linker (NTAL), also termed linker for activation of B cells (LAB), might compensate in the absence of LAT. Recent studies reveal that NTAL/LAB-deficiency causes enhanced LAT function and augments mast-cell responses. However, deletion of both of these lipid raft-associated transmembrane adaptor proteins inhibits mast-cell responsiveness to a greater extent than deletion of LAT alone. The new findings reveal a dual function for NTAL/LAB, which might manifest on mast-cell activation. C1 NIAMSD, Mol Inflammat Sect, Mol Immunol & Inflammat Branch, NIH, Bethesda, MD 20892 USA. RP Rivera, J (reprint author), NIAMSD, Mol Inflammat Sect, Mol Immunol & Inflammat Branch, NIH, Bldg 10,Room 9N228, Bethesda, MD 20892 USA. EM juan_rivera@nib.gov NR 21 TC 34 Z9 34 U1 0 U2 0 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4906 J9 TRENDS IMMUNOL JI Trends Immunol. PD MAR PY 2005 VL 26 IS 3 BP 119 EP 122 DI 10.1016/j.it.2005.01.001 PG 4 WC Immunology SC Immunology GA 909NE UT WOS:000227865800001 PM 15745852 ER PT J AU Stetler-Stevenson, WG Seo, DW AF Stetler-Stevenson, WG Seo, DW TI TIMP-2: an endogenous inhibitor of angiogenesis SO TRENDS IN MOLECULAR MEDICINE LA English DT Article ID ERYTHROID-POTENTIATING ACTIVITY; HUMAN-TISSUE INHIBITOR; METALLOPROTEINASE-2 TIMP-2; MATRIX METALLOPROTEINASES; EXTRACELLULAR-MATRIX; GELATINASE-A; IN-VITRO; ACTIVATION; GROWTH; CANCER AB Remodeling of the extracellular matrix - regulated by the matrix metalloproteinases (MMPs) and their endogenous inhibitors - is an important component of disease progression in many chronic disease states. Unchecked MMP activity can result in significant tissue damage, facilitate disease progression and is associated with host responses to pathologic injury, such as angiogenesis. The tissue inhibitors of metalloproteinases (TIMPs) have been shown to regulate MMP activity. However, recent findings demonstrate that an MMP-independent effect of TIMP-2 inhibits the mitogenic response of human microvascular endothelial cells to growth factors. This is the first demonstration of a cellsurface signaling receptor for a member of the TIMP family and suggests that TIMP-2 functions to regulate cellular responses to growth factors. These new findings are integrated in a comprehensive model of TIMP-2 function in tissue homeostasis. C1 NCI, Cell & Canc Biol Branch, Vasc Biol Fac, CCR,NIH, Bethesda, MD 20892 USA. RP Stetler-Stevenson, WG (reprint author), NCI, Cell & Canc Biol Branch, Vasc Biol Fac, CCR,NIH, Bldg 10,Room 2A33,MSC 1500,10 Ctr Dr, Bethesda, MD 20892 USA. EM sstevenw@mail.nih.gov RI Stetler-Stevenson, William/H-6956-2012; OI Stetler-Stevenson, William/0000-0002-5500-5808; Seo, Dong-Wan/0000-0003-4971-834X NR 46 TC 94 Z9 102 U1 0 U2 5 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4914 J9 TRENDS MOL MED JI Trends Mol. Med PD MAR PY 2005 VL 11 IS 3 BP 97 EP 103 DI 10.1016/j.molmed.2005.01.007 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Cell Biology; Research & Experimental Medicine GA 910LI UT WOS:000227932500002 PM 15760767 ER PT J AU Dionne, RA Bartoshuk, L Mogil, J Witter, J AF Dionne, RA Bartoshuk, L Mogil, J Witter, J TI Individual responder analyses for pain: does one pain scale fit all? SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Editorial Material ID RHEUMATOID-ARTHRITIS; CLINICAL PAIN; RECEPTOR GENE; INTENSITY; HUMANS; TARGET AB The outcomes of clinical trials are based on the mean responses of large numbers of subjects but fail to address inter-individual differences. The molecular mechanisms that underlie pain vary among individuals over time and among different types of pain to produce wide inter-individual variations in pain perception and response. Gender, ethnicity, temperament and genetic factors also contribute to individual variation in pain sensitivity and responses to analgesics. Pain measurement scales can be used differently across individuals based on the past pain experiences of individuals. We propose that individual responder analyses could be used in clinical trials to better detect analgesic activity across patient groups and within sub-groups, and to identify molecular-genetic mechanisms that contribute to individual variation. C1 NIDCR, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, New Haven, CT 06520 USA. McGill Univ, Dept Psychol, Montreal, PQ H3A 1B1, Canada. McGill Univ, Ctr Res Pain, Montreal, PQ H3A 1B1, Canada. US FDA, Rockville, MD 20850 USA. RP Dionne, RA (reprint author), NIDCR, NIH, 10 Ctr Dr,Room 1N-103, Bethesda, MD 20892 USA. EM raymond.dionne@nih.gov NR 33 TC 63 Z9 65 U1 1 U2 6 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD MAR PY 2005 VL 26 IS 3 BP 125 EP 130 DI 10.1016/j.tips.2005.01.009 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 910LR UT WOS:000227933400004 PM 15749157 ER PT J AU Pommier, Y Cherfils, J AF Pommier, Y Cherfils, J TI Interfacial inhibition of macromolecular interactions: nature's paradigm for drug discovery SO TRENDS IN PHARMACOLOGICAL SCIENCES LA English DT Review ID GUANINE-NUCLEOTIDE-EXCHANGE; SMALL-MOLECULE INHIBITORS; DNA TOPOISOMERASE-I; BREFELDIN-A; CRYSTAL-STRUCTURE; STRUCTURAL BASIS; HUMAN CALCINEURIN; ADENYLYL-CYCLASE; QUINOLONE ACTION; SEC7 DOMAIN AB One of nature's strategies for interfering with molecular interactions is to trap macromolecules in transition states with their partners in dead-end complexes that are unable to complete their biological function. This type of inhibition, which we refer to as 'interfacial inhibition', is illustrated by two natural inhibitors, brefeldin A (BFA) and camptothecin (CPT), whose modes of action have been elucidated fully in structural studies. Interfacial inhibition occurs at the protein-protein interface in the case of BFA and at the protein-DNA interface in the case of CPT. In both systems, the drugs take advantage of transient structural and energetic conditions created by the macromolecular complex, which give rise to 'hot-spots' for drug binding. In addition to these examples, several natural compounds such as forskolin, tubulin inhibitors and immunophilins target protein interfaces. We propose that interfacial inhibition is a paradigm for the discovery of drugs that interfere with macromolecular complexes. C1 NCI, Ctr Canc Res, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. CNRS, Lab Enzymol & Biochim Struct, Gif Sur Yvette, France. RP Pommier, Y (reprint author), NCI, Ctr Canc Res, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA. EM Pommier@nih.gov; Cherfils@lebs.cnrs-gif.fr NR 60 TC 109 Z9 114 U1 0 U2 3 PU ELSEVIER SCIENCE LONDON PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0165-6147 J9 TRENDS PHARMACOL SCI JI Trends Pharmacol. Sci. PD MAR PY 2005 VL 26 IS 3 BP 138 EP 145 DI 10.1016/j.tips.2005.01.008 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 910LR UT WOS:000227933400006 PM 15749159 ER PT J AU Hanley, KA Goddard, LB Gilmore, LE Scott, TW Speicher, J Murphy, BR Pletnev, AG AF Hanley, KA Goddard, LB Gilmore, LE Scott, TW Speicher, J Murphy, BR Pletnev, AG TI Infectivity of west Nile/Dengue chimeric viruses for West Nile and dengue mosquito vectors SO VECTOR-BORNE AND ZOONOTIC DISEASES LA English DT Article DE Dengue virus; West Nile virus; mosquito ID SIZED RNA SEGMENT; AEDES-AEGYPTI; VACCINE CANDIDATE; MOLECULAR-BASIS; RHESUS-MONKEYS; OS INFECTION; TYPE-4; COMPETENCE; LIVE; SUSCEPTIBILITY AB West Nile virus (WN), an agent of significant human and veterinary disease, is endemic in the Old World and rapidly spreading throughout the Americas. Vaccines are needed to halt the geographic expansion of this virus and prevent disease where it is established. However, to preclude introduction of a vaccine virus into the environment, a live attenuated WN vaccine should have low potential for transmission by mosquitoes. A chimeric WN vaccine candidate was previously generated by replacing the membrane and envelope structural protein genes of recombinant dengue type 4 virus (rDEN4) with those of WN; a derivative of this virus, WN/DEN4-3'Delta 30, contains a 30-nucleotide deletion in the 3' untranslated region. To assess the potential for transmission by mosquitoes of these vaccine candidates, the ability of each chimeric virus to infect the mosquito midgut, disseminate to the head, and pass into the saliva was compared to that of their wild-type parental WN and DEN4 viruses in three vector species. The WN/DEN4 chimeric viruses were significantly attenuated in both Culex tarsalis, a vector able to transmit WN but not dengue, and in Ae. aegypti, a vector able to transmit dengue but not WN. However, the chimeric viruses were as infectious as either wild-type virus for Ae. albopictus, a vector able to transmit both dengue and WN. These results indicate that chimerization caused a contraction in vector host range rather than universal attenuation for mosquitoes per se. This restriction in potential vectors renders it less likely that WN/DEN4 and WN/DEN4-3'Delta 30 would be transmitted from vaccinees to mosquitoes. C1 New Mexico State Univ, Dept Biol, Las Cruces, NM 88003 USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD USA. Univ Calif Davis, Dept Entomol, Davis, CA 95616 USA. Walter Reed Army Inst Res, Dept Entomol, Silver Spring, MD USA. RP Hanley, KA (reprint author), New Mexico State Univ, Dept Biol, Las Cruces, NM 88003 USA. EM khanley@nmsu.edu NR 38 TC 24 Z9 24 U1 1 U2 6 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1530-3667 J9 VECTOR-BORNE ZOONOT JI Vector-Borne Zoonotic Dis. PD SPR PY 2005 VL 5 IS 1 BP 1 EP 10 DI 10.1089/vbz.2005.5.1 PG 10 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 916KY UT WOS:000228385000001 PM 15815144 ER PT J AU Stoppini, R Gilger, BC Malarkey, DE Ratto, A Brigati, G AF Stoppini, R Gilger, BC Malarkey, DE Ratto, A Brigati, G TI Bilateral nodular lymphocytic conjunctivitis in a horse SO VETERINARY OPHTHALMOLOGY LA English DT Article DE conjunctival mass; horse; nodular lymphoid hyperplasia ID B-CELL LYMPHOMA; OCULAR ANGIOSARCOMA; LYMPHOSARCOMA; MASTOCYTOSIS AB A Russian jumper horse presented because of an ocular perilimbal conjunctival mass and, on clinical examination, two bilateral conjunctival masses were found, of different size and conformation. Attempts at complete excision of the left eye mass and excisional biopsy of the right eye mass were performed. The left eye mass recurred rapidly, but resolved completely after topical corticosteroid therapy. The two lesions had similar histopathologic features, characterized by focal, chronic, primarily lymphocytic conjunctivitis with follicular lymphoid hyperplasia. Special histopathologic staining techniques (Gomori methenamine silver and acid fast stains) and immunohistochemistry (for CD3, BLA36 and lysozyme) failed to reveal any etiologic agents and indicated an inflammatory lesion composed of a heterogeneous population of lymphocytes and macrophages (nodular lymphocytic conjunctivitis). The lesions were indistinguishable, clinically and behaviorally, from what has been reported as 'conjunctival pseudotumor' in the horse. Equine conjunctival pseudotumor/nodular lymphocytic conjunctivitis has been reported to be unilateral and have a good prognosis after partial or complete surgical excision. This is the first reported case of bilateral nodular lymphocytic conjunctivitis in a horse and for which surgical excision alone was not curative. C1 Solo Practitioner, I-25122 Brescia, Italy. N Carolina State Univ, Dept Clin Sci, Raleigh, NC 27606 USA. NIEHS, Lab Expt Pathol, Res Triangle Pk, NC 27709 USA. Ist Zooprofilatt Sperimentale Piemonte Liguria &, Genoa, Italy. Studio Vet Cristella, S Daniele Po, CR, Italy. RP Stoppini, R (reprint author), Solo Practitioner, Via Pace 24, I-25122 Brescia, Italy. EM stopric@tin.it OI Ratto, Alessandra/0000-0003-0445-2306 NR 44 TC 6 Z9 6 U1 0 U2 3 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1463-5216 J9 VET OPHTHALMOL JI Vet. Ophthalmol. PD MAR-APR PY 2005 VL 8 IS 2 BP 129 EP 134 DI 10.1111/j.1463-5224.2005.00349.x PG 6 WC Veterinary Sciences SC Veterinary Sciences GA 904XS UT WOS:000227532500008 PM 15762926 ER PT J AU Shtrasburg, S Gal, R Gruys, E Perl, S Martin, BM Kaplan, B Koren, R Nyska, A Pras, M Livneh, A AF Shtrasburg, S Gal, R Gruys, E Perl, S Martin, BM Kaplan, B Koren, R Nyska, A Pras, M Livneh, A TI An ancillary tool for the diagnosis of amyloid A amyloidosis in a variety of domestic and wild animals SO VETERINARY PATHOLOGY LA English DT Article DE AA amyloidosis; amyloid A; amyloid-enhancing factor; animal model; N-terminal sequence analysis; reactive amyloidosis; the Shtrasburg method ID AMINO-ACID-SEQUENCE; PARAFFIN-EMBEDDED TISSUES; REACTIVE AMYLOIDOSIS; ENHANCING FACTOR; SYSTEMIC AMYLOIDOSIS; ACINONYX-JUBATUS; PROTEIN-AA; DEPOSITION; CLASSIFICATION; IDENTIFICATION AB Immunohistochemistry, the standard method for diagnosing amyloid A (AA) amyloidosis, is limited in animals because it requires a large array of animal-specific anti-AA antibodies, not commercially available. The Shtrasburg method (SH method) is a highly specific and sensitive technique, helping in the diagnosis and determination of AA amyloidosis in humans. The aim of this study is to determine whether the SH method is applicable in the diagnosis of AA amyloidosis in a variety of animals. Tissue samples were obtained from animals suffering from spontaneous or experimentally induced AA amyloidosis (mice, hamsters, guinea pigs, cheetahs, cats, cows, ducks, a dog, a goose, a chicken, and a turaco). Detection of the amyloid and quantitative evaluation were performed using Congo red staining, and specific AA typing was performed by the potassium permangoanate technique. The studied tissues were subjected to the SH method, which confirmed the AA nature of the amyloid deposit, by displaying in polyacrylamide gel electrophoresis protein bands consistent with the molecular weight of the species-specific AA, in all the animals examined, except mice, hamsters, and guinea pigs. N-terminal analysis of these bands corroborated their AA origin. We conclude that the SH method may be used as an ancillary simple tool for the diagnosis of AA amyloidosis in a large number of domestic and wild animals. Moreover, our findings further increase the feasibility of applying this method in humans. C1 Chaim Sheba Med Ctr, Heller Inst Med Res, IL-52621 Tel Hashomer, Israel. Rabin Med Ctr, Dept Pathol, Petah Tiqwa, Israel. Univ Utrecht, Dept Vet Pathol, NL-3508 TC Utrecht, Netherlands. Kimron Vet Inst, Bet Dagan, Israel. NIMH, Toxicol Lab, NIH, Bethesda, MD 20892 USA. Natl Inst Environm Hlth & Sci, Lab Expt Pathol, Res Triangle Pk, NC USA. Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel. RP Shtrasburg, S (reprint author), Chaim Sheba Med Ctr, Heller Inst Med Res, IL-52621 Tel Hashomer, Israel. EM shmuels@sheba.health.gov.il NR 53 TC 10 Z9 10 U1 1 U2 3 PU AMER COLL VET PATHOLOGIST PI LAWRENCE PA 810 EAST 10TH STREET, LAWRENCE, KS 66044 USA SN 0300-9858 J9 VET PATHOL JI Vet. Pathol. PD MAR PY 2005 VL 42 IS 2 BP 132 EP 139 DI 10.1354/vp.42-2-132 PG 8 WC Pathology; Veterinary Sciences SC Pathology; Veterinary Sciences GA 901RU UT WOS:000227300400003 PM 15753466 ER PT J AU Pinczewski, J Zhao, J Malkevitch, N Patterson, LJ Aldrich, K Alvord, WG Robert-Guroff, M AF Pinczewski, J Zhao, J Malkevitch, N Patterson, LJ Aldrich, K Alvord, WG Robert-Guroff, M TI Enhanced immunity and protective efficacy against SIVmac251 intrarectal challenge following Ad-SIV priming by multiple mucosal routes and gp120 boosting in MPL-SE SO VIRAL IMMUNOLOGY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; DEPENDENT CELLULAR CYTOTOXICITY; RHESUS MACAQUES; SYSTEMIC IMMUNITY; VACCINE; INDUCTION; INTRANASAL; RESPONSES; ANTIBODIES; ADJUVANT AB Previously, 39% of rhesus macaques primed orally, intranasally, and intratracheally with adenovirus (Ad)-simian immunodeficiency virus (SIV) recombinants and boosted with gp120 in monophosphoryl lipid A-stable emulsion (MPL-SE) remained aviremic or cleared or controlled viremia at the threshold of detection following SIVmac251 intrarectal challenge (Study B). In contrast, no macaques primed orally and intranasally with Ad-SIV recombinants and boosted with gp120 in Quillaja Saponaria-21 exhibited undetectable viremia post-challenge (Study A). We conducted a detailed comparison of the studies to elucidate the effect of different vaccine regimens on induced immunity associated with the different challenge outcomes. Quantitative viral load comparisons were statistically analyzed. All immune responses were assessed at identical timepoints post-immunization, and cellular immunity was re-evaluated on cryopreserved cells from Study B macaques to match Study A data acquired with frozen cells. Study B exhibited greater protective efficacy, increased levels of p11C and p54m tetramer positive cells and a trend toward enhanced interferon-gamma secreting cells in response to Env and Gag peptides, modestly enhanced serum neutralizing antibodies, and greater positivity in anti-gp120 rectal IgA and IgG antibodies. Study A macaques exhibited greater positivity in salivary IgA anti-gp120 antibodies. Thus, the vaccine regimen using oral-intranasal-intratracheal priming and protein boosting in MPL-SE was superior, eliciting greater protective efficacy against pathogenic SIVmac25, and enhanced SIV-specific immunity, systemically and at rectal sites. The mechanism(s) by which binding antibodies, lacking neutralizing activity against the primary challenge virus, may contribute to protection requires further study. C1 NCI, Vaccine Branch, NIH, Bethesda, MD 20892 USA. NCI, Data Management Serv, Frederick, MD 21702 USA. RP Robert-Guroff, M (reprint author), NCI, Vaccine Branch, NIH, 41 Medlars Dr,Bldg 41,Room D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov NR 18 TC 13 Z9 14 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 0882-8245 J9 VIRAL IMMUNOL JI Viral Immunol. PD SPR PY 2005 VL 18 IS 1 BP 236 EP 243 DI 10.1089/vim.2005.18.236 PG 8 WC Immunology; Virology SC Immunology; Virology GA 915EW UT WOS:000228281800023 PM 15802969 ER PT J AU Boyer, JD Robinson, TM Maciag, PC Peng, XH Johnson, RS Pavlakis, G Lewis, MG Shen, AD Siliciano, R Browne, CR Weiner, DB Paterson, Y AF Boyer, JD Robinson, TM Maciag, PC Peng, XH Johnson, RS Pavlakis, G Lewis, MG Shen, AD Siliciano, R Browne, CR Weiner, DB Paterson, Y TI DNA prime Listeria boost induces a cellular immune response to SIV antigens in the rhesus macaque model that is capable of limited suppression of SIV239 viral replication SO VIROLOGY LA English DT Article DE HIV/SIV vaccine; prime/boost; Listeria monocytogenes; DNA vaccine ID CYTOTOXIC T-LYMPHOCYTES; MONOCYTOGENES VACCINE; PROTECTS MICE; HIV-INFECTION; GAG PROTEIN; VIRUS; CHALLENGE; INDUCTION; CELLS; VIREMIA AB DNA vaccines and recombinant Listeria monocytogenes that express and secrete SIV Gag and Env antigens were combined in a nonhuman primate prime-boost immunogenicity study followed by a challenge with SIV239. We report that recombinant DNA vaccine delivered intramuscularly, and recombinant L. monocytogenes delivered orally each individually have the ability to induce CD8(+) and CD4(+) T cell immune responses in a nonhuman primate. Four rhesus monkeys were immunized at weeks 0, 4, 8, and 12 with the pCSIVgag and pCSIVenv DNA plasmids and boosted with SIV expressing L. monocytogenes vaccines at weeks 16, 20, and 28. Four rhesus monkeys received only the L. monocytogenes vaccines at weeks 16, 20, and 28. A final group of monkeys served as a control group. Blood samples were taken before vaccination and 2 weeks post each injection and analyzed by ELISPOT for CD4(+) and CD8(+) T cell responses. Moderate vaccine induced SIV-specific cellular immune responses were observed following immunization with either DNA or L. monocytogenes vectors. However, the SIV antigen-specific immune responses were significantly increased when Rhesus macaques were primed with SIV DNA vaccines and boosted with the SIV expressing L. monocytogenes vectors. In addition, the combined vaccine was able to impact SIV239 viral replication following an intrarectal challenge. This study demonstrates for the first time that oral L. monocytogenes can induce a cellular immune response in a nonhuman primate and is able to enhance the efficacy of a DNA vaccine as well as provide modest protection against SIV239 challenge. (C) 2005 Elsevier Inc. All rights reserved. C1 Univ Penn, Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA. Dept Pathol & Lab Med, Philadelphia, PA USA. NCI, Bethesda, MD 20892 USA. So Res Inst, Frederick, MD USA. Johns Hopkins Univ, Baltimore, MD 21218 USA. RP Paterson, Y (reprint author), Univ Penn, Sch Med, Dept Microbiol, 323 Johnson Pavil,36th St & Hamilton Walk, Philadelphia, PA 19104 USA. EM yvonne@mail.med.upenn.edu RI Weiner, David/H-8579-2014 FU NIAID NIH HHS [R01 AI36657] NR 43 TC 32 Z9 34 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD MAR 1 PY 2005 VL 333 IS 1 BP 88 EP 101 DI 10.1016/j.virol.2004.12.026 PG 14 WC Virology SC Virology GA 899BD UT WOS:000227119000009 PM 15708595 ER PT J AU Moniuszko, M Bogdan, D Pal, R Venzon, D Stevceva, L Nacsa, J Tryniszewska, E Edghill-Smith, Y Wolinsky, SM Franchini, G AF Moniuszko, M Bogdan, D Pal, R Venzon, D Stevceva, L Nacsa, J Tryniszewska, E Edghill-Smith, Y Wolinsky, SM Franchini, G TI Correlation between viral RNA levels but not immune responses in plasma and tissues of macaques with long-standing SIVmac251 infection SO VIROLOGY LA English DT Article DE immune escape; macaque model; simian immunodeficiency virus ID IMMUNODEFICIENCY VIRUS-INFECTION; CYTOTOXIC T-LYMPHOCYTES; CLASS-I MOLECULE; RHESUS-MONKEYS; CELL RESPONSES; ANTIRETROVIRAL TREATMENT; CD8(+) LYMPHOCYTES; NASBA TECHNOLOGY; ACUTE-PHASE; SIV AB Plasma virus in human immunodeficiency virus type 1/simian immunodeficiency virus (HIV-1/SIV) infection most likely results from the combination of viruses produced in different tissues. As immunological pressure may be higher in effector sites than secondary lymphoid tissues, we investigated quantitative and qualitative changes in viral RNA in blood and tissues of 10 Mamu-A*01-positive SIV-infected macaques in parallel with the frequency of CD8+ T cells recognizing the dominant Gag 181-189 CM9 epitope. The plasma virus level in these macaques directly correlated with the viral RNA levels in lymph nodes, spleen, lungs, colon, and jejunum. In contrast, the frequency of the Gag 181-189 CM9 tetramer did not correlate with SIV RNA levels in any compartment. We investigated the presence of viral immune escape in RNA from several tissues. The complete substitution of wild-type genotype with viral immune-escape variant within the Gag 181-189 CM9 epitope was associated with low tetramer response in all tissues and blood of two macaques. In one macaque, the replacement of wild type with an immune-escape mutant was asynchronous. While the mutant virus was prevalent in blood and effector tissues (lungs, jejunum, and colon), secondary lymphoid organs such as spleen and lymph nodes still retained 80% and 40%, respectively, of the wild-type virus. These results may imply that there are differences in the immunological pressure exerted by cytotoxic T lymphocytes (CTLs) in tissue compartments of SlVmac251-infected macaques. Published by Elsevier Inc. C1 NCI, Anim Models & Retroviral Vaccines Sect, Bethesda, MD 20892 USA. Med Univ Bialystok, Dept Allergol & Internal Dis, PL-15276 Bialystok, Poland. Northwestern Univ, Feinberg Med Sch, Div Infect Dis, Chicago, IL 60611 USA. Adv Biosci Labs, Kensington, MD 20895 USA. NCI, Biostat & Data Management Sect, Bethesda, MD 20892 USA. Med Univ Bialystok, Dept Pediat 3, PL-15274 Bialystok, Poland. RP Franchini, G (reprint author), NCI, Anim Models & Retroviral Vaccines Sect, 41-D804, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov RI Venzon, David/B-3078-2008; Wolinsky, Steven/B-2893-2012; OI Stevceva, Liljana/0000-0002-3761-2460; Wolinsky, Steven/0000-0002-9625-6697 NR 42 TC 12 Z9 12 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 0042-6822 J9 VIROLOGY JI Virology PD MAR 1 PY 2005 VL 333 IS 1 BP 159 EP 168 DI 10.1016/j.virol.2005.01.003 PG 10 WC Virology SC Virology GA 899BD UT WOS:000227119000015 PM 15708601 ER PT J AU Krempl, CD Lamirande, EW Collins, PL AF Krempl, CD Lamirande, EW Collins, PL TI Complete sequence of the RNA genome of pneumonia virus of mice (PVM) SO VIRUS GENES LA English DT Article DE mouse virus; paramyxovirus; pneumovirus; RNA virus; viral transcription; viral virulence ID RESPIRATORY SYNCYTIAL VIRUS; AMINO-ACID-SEQUENCE; NONSTRUCTURAL PROTEINS NS1; AVIAN PNEUMOVIRUS ISOLATE; SITE-SPECIFIC ATTENUATION; POLYMERASE L-GENE; NUCLEOTIDE-SEQUENCES; VIRAL POLYMERASE; TISSUE-CULTURE; HUMAN RSV AB Pneumonia virus of mice (PVM) is an enveloped RNA-containing virus of Family Paramyxoviridae. Sequences had been determined previously for a number of PVM genes, although these represented cloned cDNAs rather than consensus sequences. Sequences were not available for the 3'- leader and 50 trailer regions that constitute the genome termini or for the large polymerase L gene that accounts for 43% of the genome. Also, the available sequences were from an attenuated variant of strain 15, whereas the present study analyzed the version of strain 15 that is available from the American Type Culture Collection ( ATCC) and is highly virulent in mice. Analysis of unclosed RT-PCR products yielded a complete consensus sequence of 14,886 nt ( GenBank accession number AY729016). Of the regions for which sequences had been previously reported for the non-pathogenic strain, there were 13 nucleotide differences and 10 amino acid differences compared to the present consensus sequence for the virulent isolate. The various genes of PVM shared 29 - 62% nucleotide sequence identity and 10 - 60% amino acid sequence identity with human or bovine respiratory syncytial virus ( HRSV and BRSV), its closest relatives. C1 NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. Univ Freiburg, Inst Med Microbiol & Hyg, Dept Virol, Freiburg, Germany. RP Collins, PL (reprint author), NIAID, Infect Dis Lab, Bethesda, MD 20892 USA. EM collins@niaid.nih.gov RI Krempl, Christine/O-2081-2015 NR 48 TC 24 Z9 28 U1 0 U2 2 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0920-8569 J9 VIRUS GENES JI Virus Genes PD MAR PY 2005 VL 30 IS 2 BP 237 EP 249 DI 10.1007/s11262-004-5631-4 PG 13 WC Genetics & Heredity; Virology SC Genetics & Heredity; Virology GA 903MZ UT WOS:000227431400009 PM 15744580 ER PT J AU Cheng, WH Sakamoto, S Fox, JT Komatsu, K Carney, J Bohr, VA AF Cheng, WH Sakamoto, S Fox, JT Komatsu, K Carney, J Bohr, VA TI Werner syndrome protein associates with gamma H2AX in a manner that depends upon Nbs1 SO FEBS LETTERS LA English DT Article DE WRN; Nbs1; H2AX; aging; DNA repair ID DOUBLE-STRAND BREAKS; DNA-DAMAGE; MRE11 COMPLEX; HISTONE H2AX; HOMOLOGOUS RECOMBINATION; PHYSICAL INTERACTION; REPLICATION ARREST; ATM ACTIVATION; SYNDROME CELLS; WRN HELICASE AB The WRN protein is mutated in the chromosomally unstable Werner syndrome (WS) and the Nbsl protein is mutated in Nijmegen breakage syndrome (NBS). The NbsI protein is an integral component of the M/R/N complex. Although WRN is known to interact with this complex in response to gamma-irradiation, the mechanism of action is unclear. Here, we show that WRN co-localizes and associates with gammaH2AX, a marker protein of DNA double strand breaks (DSBs), after cellular exposure to gamma-irradiation. While the DNA damage-inducible Nbsl foci formation is normal in WS cells, WRN focus formation is defective in NBS cells. Consistent with this, gammaH2AX colocalizes with NbsI in WS cells but not with WRN in NBS cells. The defective WRN-yH2AX association in NBS cells can be complemented with wild-type NbsI, but not with an Nbsl S343A point mutant that lacks an ATM phosphorylation site. WRN associates with H2AX in a manner dependent upon the M/R/N complex. Our results suggest a novel pathway in which Nbsl may recruit WRN to the site of DNA DSBs in an ATM-dependent manner. (C) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. Kyoto Univ, Ctr Radiat Biol, Dept Genome Repair Dynam, Kyoto 6068501, Japan. Univ Maryland, Sch Med, Radiat Oncol Lab, Baltimore, MD 21201 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM vbohr@nih.gov NR 42 TC 22 Z9 23 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD FEB 28 PY 2005 VL 579 IS 6 BP 1350 EP 1356 DI 10.1016/j.febslet.2005.01.028 PG 7 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 902YX UT WOS:000227393700006 PM 15733840 ER PT J AU Rimondini, R Thorsell, A Heilig, M AF Rimondini, R Thorsell, A Heilig, M TI Suppression of ethanol self-administration by the neuropeptide Y (NPY) Y2 receptor antagonist BIIE0246: evidence for sensitization in rats with a history of dependence SO NEUROSCIENCE LETTERS LA English DT Article DE NPYY2 antagonist; intermittent exposure; alcoholism; operant self-administration; rat; history of dependence ID NONPREFERRING RATS; RESTRAINT STRESS; PEPTIDE YY; ALCOHOL; CONSUMPTION; AMYGDALA; ANXIETY; BEHAVIOR; EXPRESSION; INCREASES AB Evidence from genetically modified mice suggests a role for NPY in regulation of ethanol intake, but results of pharmacological studies have been more variable. We have previously shown that potentiation of NPY signaling through antagonism at NPY-Y2 receptors decreases operant responding for ethanol in Wistar rats without a history of dependence. Here, we examined the effects of Y2-antagonism in animals with a history of dependence induced by long-term intermittent exposure to ethanol vapor. The Y2-receptor antagonist BIIE0246 suppressed operant responding for ethanol (approximately 50%, p = 0.01), at a dose (0.5 nmol i.c.v.) which was ineffective in subjects without a history of dependence. Responding for the ethanol-free control solution was unaffected. These data confirm that antagonism at central NPY-Y2 receptors selectively suppresses motivation to self-administer ethanol, and indicate that the NPY system is sensitized in animals with a history of dependence. This may render the NPY system, and Y2 receptors in particular, an attractive target for treatment of alcohol dependence. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 Huddinge Univ Hosp, Karolinska Inst, NEUROTEC, SE-14186 Huddinge, Sweden. NIAAA, NIH, Clin Studies Lab, Bethesda, MD 20892 USA. RP Rimondini, R (reprint author), Huddinge Univ Hosp, Karolinska Inst, NEUROTEC, M57, SE-14186 Huddinge, Sweden. EM roberto.rimondini@neurotec.ki.se RI Rimondini, Roberto/B-2500-2010; OI Rimondini, Roberto/0000-0003-4099-513X; Heilig, Markus/0000-0003-2706-2482; Thorsell, Annika/0000-0003-3535-3845 NR 37 TC 59 Z9 60 U1 1 U2 3 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD FEB 28 PY 2005 VL 375 IS 2 BP 129 EP 133 DI 10.1016/j.neulet.2004.10.084 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 897OI UT WOS:000227014100012 PM 15670655 ER PT J AU Kafadar, K Prorok, C AF Kafadar, K Prorok, C TI Computational methods in medical decision making: to screen or not to screen? SO STATISTICS IN MEDICINE LA English DT Article; Proceedings Paper CT Symposium on Statistical Methods -Study Design and Decision-Making in Public Health CY JAN 27-29, 2003 CL Atlanta, GA SP US Ctr Dis Control & Prevent, Agcy Toxic Substances & Dis Registry DE randomized screening trial; disease progression model; lead time; length-biased sampling; preclinical duration; sojourn time; survival function; discrete event simulation ID BREAST-CANCER DETECTION; BENEFIT TIME; DEATH RATES; LEAD TIME; TRIALS; MORTALITY; NEOPLASMS; GROWTH; LUNG; BIAS AB Screening for a disease such as cancer is often regarded as a beneficial and successful strategy for reducing mortality. However, as with any clinical treatment or intervention. benefit cannot be assumed, and screening can entail both costs and harms, so the screening as a 'treatment' must undergo evaluation. An evaluation requires a definition of the treatment 'benefit', design of studies to measure that benefit with as little bias and variance as possible, and the development of methods for estimating the potential benefit. In screening studies, the factors most central to the evaluation are unobservable (e.g. earliest point in time at which disease becomes detectable, or 'preclinical'; time at which disease might have been detected in the absence of screening; test sensitivity). Thus, screening programs should be evaluated on scenarios in which these factors are varied, to ensure the robustness of the estimated benefit under a variety of circumstances. This article describes the importance of computational methods and simulations to assess the benefit of screening programs, particularly for cancer, based on randomized screening trials, with special attention to benefit time, lead time, and bias due to length-biased sampling. Copyright (C) 2005 John Wiley Sons, Ltd. C1 Univ Colorado, Dept Math, Denver, CO 80217 USA. NCI, Biometry Res Grp, Bethesda, MD 20982 USA. RP Kafadar, K (reprint author), Univ Colorado, Dept Math, POB 173364,Campus Box 170, Denver, CO 80217 USA. EM kk@math.cudenver.edu NR 29 TC 5 Z9 5 U1 1 U2 3 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD FEB 28 PY 2005 VL 24 IS 4 BP 569 EP 581 DI 10.1002/sim.2037 PG 13 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 893SP UT WOS:000226739800009 PM 15678410 ER PT J AU Borkowf, CB Albert, PS AF Borkowf, CB Albert, PS TI Efficient estimation of the risk of a disease by quantile-categories of a key predictor variable using generalized additive models SO STATISTICS IN MEDICINE LA English DT Article; Proceedings Paper CT Symposium on Statistical Methods -Study Design and Decision-Making in Public Health CY JAN 27-29, 2003 CL Atlanta, GA SP US Ctr Dis Control & Prevent, Agcy Toxic Substances & Dis Registry DE cancer; bootstrap; epidemiology; generalized additive model; permutation test; quantile-category ID MARGINAL DISTRIBUTIONS; EMPIRICAL QUANTILES; REGRESSION AB Suppose that one wishes to make inference to the risk of a disease by the population quartile-categories of a key continuous predictor variable. When one collects data on a prospective cohort, the standard method is simply to categorize the key predictor variable by the empirical quartiles. One may then include indicator variables for these empirical quartile-categories as predictors, along with other covariates, in a generalized linear model (GLM), with the observed health status of each subject as the response. The standard GLM method, however, is relatively inefficient, because it treats all observations that fall in the same quartile-category of the predictor variable identically, regardless of whether they lie in the centre or near the boundaries of that category. Alternatively, one may include the key predictor variable, along with other covariates, in a generalized additive model (GAM), again with the observed health status of each subject as the response. The alternative GAM method non-parametrically estimates the functional relationship between the key predictor variable and the response. One may then compute statistics of interest, such as proportions and odds ratios. from the fitted GAM equation using the empirical quartile-categories. Simulations show that both the GLM and GAM methods are nearly unbiased, but the latter method produces smaller variances and narrower bootstrap confidence intervals. An example from nutritional epidemiology illustrates the use of these methods. Published in 2005 by John Wiley Sons, Ltd. C1 Ctr Dis Control & Prevent, Natl Ctr Infect Dis, Div Viral & Rickettsial Dis, Influenza Branch,Epidemiol Sect, Atlanta, GA 30333 USA. NCI, Biomet Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. RP Borkowf, CB (reprint author), Ctr Dis Control & Prevent, Natl Ctr Infect Dis, Div Viral & Rickettsial Dis, Influenza Branch,Epidemiol Sect, Mail Stop A32,1600 Clifton Rd NE, Atlanta, GA 30333 USA. EM CBorkowf@cdc.gov NR 14 TC 0 Z9 0 U1 0 U2 1 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD FEB 28 PY 2005 VL 24 IS 4 BP 623 EP 645 DI 10.1002/sim.2041 PG 23 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 893SP UT WOS:000226739800013 PM 15678439 ER PT J AU Farhadi, M Tahmasebi, Z Merat, S Kamangar, F Nasrollahzadeh, D Malekzadeh, R AF Farhadi, Mohammad Tahmasebi, Zahra Merat, Shahin Kamangar, Farin Nasrollahzadeh, Dariush Malekzadeh, Reza TI Human papillomavirus in squamous cell carcinoma of esophagus in a high-risk population SO WORLD JOURNAL OF GASTROENTEROLOGY LA English DT Article DE Papillomavirus; Squamous cell carcinoma of esophagus; Population AB AIM: To investigate the relation of human papillomavirus (HPV) and esophageal squamous cell carcinoma (ESCC) in Iranian patients as compared to normal controls. METHODS: Using MY09/MY11 consensus primers, we compared the prevalence of a HPV L1 gene in tumor tissues from 38 ESCC cases and biopsied tissues from 38 endoscopically normal Iranian individuals. We also compared the presence of HPV16 and HPV18 in the same samples using type-specific E6/E7 primers. RESULTS: Fourteen (36.8%) of the 38 ESCC samples but only 5 (13.2%) of the 38 control samples were positive for the HPV L1 gene (P = 0.02). Five (13.2%) of the ESCC samples but none of the control samples were positive for the HPV16 E6/E7 gene (P = 0.05). Three (7.9%) of the ESCC samples and 5 (13.2%) of the control samples were positive for the HPV18 E6/E7 gene (P = 0.71). CONCLUSION: Our data are consistent with HPV DNA studies conducted in other high-risk areas for ESCC. HPV should be considered as a potential factor contributing to the high incidence of ESCC in Iran and other high-incidence areas of the world. (C) 2005 The WJG Press and Elsevier Inc. All rights reserved. C1 [Farhadi, Mohammad; Merat, Shahin; Nasrollahzadeh, Dariush; Malekzadeh, Reza] Univ Tehran Med Sci, Digest Dis Res Ctr, Tehran, Iran. [Tahmasebi, Zahra] Khatam Postgrad Fac, Dept Mol Biol, Tehran, Iran. [Kamangar, Farin] US Natl Canc Inst, Canc Prevent Studies Branch, Bethesda, MD USA. RP Malekzadeh, R (reprint author), Shariati Hosp, Digest Dis Res Ctr, N Kargar Ave, Tehran 14114, Iran. EM malek@ams.ac.ir OI Malekzadeh, Reza/0000-0003-1043-3814 FU Digestive Disease Research Center, Tehran University of Medical Sciences FX Supported by the Digestive Disease Research Center, Tehran University of Medical Sciences NR 24 TC 56 Z9 62 U1 0 U2 2 PU BAISHIDENG PUBL GRP CO LTD PI BEIJING PA RM 903, BLDG D, OCEAN INTERNATIONAL CTR, NO 62 DONGSIHUAN ZHONGLU, BEIJING, CHAOYANG DISTRICT 100025, PEOPLES R CHINA SN 1007-9327 J9 WORLD J GASTROENTERO JI World J. Gastroenterol. PD FEB 28 PY 2005 VL 11 IS 8 BP 1200 EP 1203 PG 4 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA V19VX UT WOS:000208101000019 PM 15754405 ER PT J AU Balaban, RS Nemoto, S Finkel, T AF Balaban, RS Nemoto, S Finkel, T TI Mitochondria, oxidants, and aging SO CELL LA English DT Review ID NEMATODE CAENORHABDITIS-ELEGANS; ELECTRON-TRANSPORT CHAIN; EXTENDS LIFE-SPAN; OXIDATIVE STRESS; REACTIVE OXYGEN; DROSOPHILA-MELANOGASTER; SUPEROXIDE-DISMUTASE; CYTOCHROME-C; UNCOUPLING PROTEINS; HEART-MITOCHONDRIA AB The free radical theory of aging postulates that the production of intracellular reactive oxygen species Is the major determinant of life span. Numerous cell culture, invertebrate, and mammalian models exist that lend support to this half-century-old hypothesis. Here we review the evidence that both supports and conflicts with the free radical theory and examine the growing link between mitochondrial metabolism, oxidant formation, and the biology of aging. C1 NIH, Cardiovasc Branch, Bethesda, MD 20892 USA. NIH, Cardiac Energet Lab, Bethesda, MD 20892 USA. RP Finkel, T (reprint author), NIH, Cardiovasc Branch, Bldg 10, Bethesda, MD 20892 USA. EM finkelt@nih.gov RI Balaban, Robert/A-7459-2009 OI Balaban, Robert/0000-0003-4086-0948 NR 107 TC 1848 Z9 1922 U1 50 U2 370 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD FEB 25 PY 2005 VL 120 IS 4 BP 483 EP 495 DI 10.1016/j.cell.2005.02.001 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 901GR UT WOS:000227271500006 PM 15734681 ER PT J AU Hadley, EC Lakatta, EG Morrison-Bogorad, M Warner, HR Hodes, RJ AF Hadley, EC Lakatta, EG Morrison-Bogorad, M Warner, HR Hodes, RJ TI The future of aging therapies SO CELL LA English DT Review ID CARDIOVASCULAR-DISEASE ENTERPRISES; MILD COGNITIVE IMPAIRMENT; CONTROLS OXIDATIVE STRESS; AMES DWARF MICE; LIFE-SPAN; CAENORHABDITIS-ELEGANS; ALZHEIMERS-DISEASE; CALORIE RESTRICTION; TRANSGENIC MICE; C-ELEGANS AB Advances in understanding aging processes and their consequences are leading to the development of therapies to slow or reverse adverse changes formerly considered to be "normal" aging and processes that underlie multiple age-related conditions. Estimating the effectiveness of candidate aging therapies, whose effects on human aging may require many years to determine, is a particular challenge. Strategies for identifying candidate interventions can be developed through multiple approaches, including the screening of molecular targets and pathways in vitro and in animal models, informed as well by evidence from human genetic and epidemiologic data. A number of recently established programs and networks can serve as resources for such research. For all these research approaches, from in vitro molecular studies to clinical trials, contributions of cell and molecular biology are crucial and offer the prospect of therapeutic advances that address fundamental biological processes as well as the clinically important challenges of aging. C1 NIA, NIH, Bethesda, MD 20892 USA. RP Hadley, EC (reprint author), NIA, NIH, Bethesda, MD 20892 USA. EM ehadley@nih.gov NR 93 TC 56 Z9 58 U1 1 U2 5 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD FEB 25 PY 2005 VL 120 IS 4 BP 557 EP 567 DI 10.1016/j.cell.2005.01.030 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 901GR UT WOS:000227271500012 PM 15734687 ER PT J AU Burkhart, BA Hebbar, PB Trotter, KW Archer, TK AF Burkhart, BA Hebbar, PB Trotter, KW Archer, TK TI Chromatin-dependent E1A activity modulates NF-kappa B RelA-mediated repression of glucocorticoid receptor-dependent transcription SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TUMOR VIRUS PROMOTER; HISTONE ACETYLTRANSFERASE ACTIVITY; THYROID-HORMONE RECEPTOR; CREB-BINDING-PROTEIN; HUMAN BREAST-CANCER; CELL-CYCLE ARREST; IN-VIVO; COREPRESSOR CTBP; MMTV PROMOTER; CROSS-TALK AB The role of chromatin-dependent regulatory mechanisms in the repression of glucocorticoid-dependent transcription from the murine mammary tumor virus (MMTV) promoter by p65 and E1A was investigated by using chromatin and transiently transfected reporters. The p65 RelA subunit of NF-kappaB represses MMTV expression on either transient or integrated reporters. In contrast, the viral oncoprotein E1A represses a transient but not an integrated MMTV. E1A repression is attenuated by chromatin, suggesting p65 but not E1A manipulates chromatin appropriately to inhibit the GR. Coexpression of p65 and E1A additively represses the transient NMTV but restores the transcriptional activation of the chromatin MMTV in response to glucocorticoids. This indicates that E1A has a dominant chromatin-dependent activity that attenuates repression by p65. E1A, p65, and GR bind the MMTV promoter, and chromatin remodeling enhances binding on both repressed and activated promoters. In addition, p65 requires Brg for repression of the integrated NMTV. This suggests that neither p65 repression nor E1A attenuation of repression results from an inhibition of remodeling that prevents transcription factor binding. Furthermore, p300/CBP is also required for both repression and attenuation by p65 and E1A. E1A and p65 mutants that do not bind p300/CBP are inactive, indicative of a requirement for p300/CBP-dependent complex formation for both repression and attenuation with chromatin. These data suggest that both the p65-dependent repression and the E1A-mediated attenuation of repression require the Brg1 dependent chromatin remodeling function and p300/CBP-dependent complex formation at a promoter assembled within chromatin. C1 NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Archer, TK (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, Res Triangle Pk, NC 27709 USA. EM archer1@niehs.nih.gov NR 75 TC 18 Z9 18 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 FEB 25 PY 2005 VL 280 IS 8 BP 6349 EP 6358 DI 10.1074/jbc.M411147200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 902DT UT WOS:000227332700015 PM 15556937 ER PT J AU Hepp, G Puri, N Hohenstein, AC Crawford, GL Whiteheart, SW Roche, PA AF Hepp, G Puri, N Hohenstein, AC Crawford, GL Whiteheart, SW Roche, PA TI Phosphorylation of SNAP-23 regulates exocytosis from mast cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PROTEIN-KINASE-C; SYNAPTOSOME-ASSOCIATED PROTEIN; ACTIVATED HUMAN PLATELETS; SNARE-COMPLEX; GRANULE EXOCYTOSIS; MEMBRANE-FUSION; SYNTAXIN 4; DIFFERENTIAL PHOSPHORYLATION; NEUROTRANSMITTER RELEASE; POSSIBLE INVOLVEMENT AB Regulated exocytosis is a process in which a physiological trigger initiates the translocation, docking, and fusion of secretory granules with the plasma membrane. A class of proteins termed SNAREs (including SNAP-23, syntaxins, and VAMPs) are known regulators of secretory granule/plasma membrane fusion events. We have investigated the molecular mechanisms of regulated exocytosis in mast cells and find that SNAP-23 is phosphorylated when rat basophilic leukemia mast cells are triggered to degranulate. The kinetics of SNAP-23 phosphorylation mirror the kinetics of exocytosis. We have identified amino acid residues Ser(95) and Ser(120) as the major phosphorylation sites in SNAP-23 in rodent mast cells. Quantitative analysis revealed that similar to10% of SNAP-23 was phosphorylated when mast cell degranulation was induced. These same residues were phosphorylated when mouse platelet degranulation was induced with thrombin, demonstrating that phosphorylation of SNAP-23 Ser(95) and Ser(120) is not restricted to mast cells. Although triggering exocytosis did not alter the absolute amount of SNAP-23 bound to SNAREs, after stimulation essentially all of the SNAP-23 bound to the plasma membrane SNARE syntaxin 4 and the vesicle SNARE VAMP-2 was phosphorylated. Regulated exocytosis studies revealed that overexpression of SNAP-23 phosphorylation mutants inhibited exocytosis from rat basophilic leukemia mast cells, demonstrating that phosphorylation of SNAP-23 on Ser(120) and Ser(95) modulates regulated exocytosis by mast cells. C1 Univ Kentucky, Coll Med, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA. RP Roche, PA (reprint author), NCI, Expt Immunol Branch, NIH, Bldg 10,Rm 4B36, Bethesda, MD 20892 USA. EM paul.roche@nih.gov OI Whiteheart, Sidney/0000-0001-5577-0473 NR 42 TC 4 Z9 4 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 FEB 25 PY 2005 VL 280 IS 8 BP 6610 EP 6620 DI 10.1074/jbc.M412126200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 902DT UT WOS:000227332700046 ER PT J AU Bouamr, F Cornilescu, CC Goff, SP Tjandra, N Carter, CA AF Bouamr, F Cornilescu, CC Goff, SP Tjandra, N Carter, CA TI Structural and dynamics studies of the D54A mutant of human T cell leukemia virus-1 capsid protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID BACKBONE DYNAMICS; NMR-SPECTROSCOPY; RELAXATION; DOMAIN; RESONANCES; DIMERS; AMIDE; H2O AB The human T cell leukemia virus and the human immunodeficiency virus share a highly conserved, predominantly helical two-domain mature capsid (CA) protein structure with an N-terminal beta-hairpin. Despite overall structural similarity, differences exist in the backbone dynamic properties of the CA N-terminal domain. Since studies with other retroviruses suggest that the beta-hairpin is critical for formation of a CA-CA interface, we investigated the functional role of the human T cell leukemia virus beta-hairpin by disrupting the salt bridge between Prol and Asp 54 that stabilizes the beta-hairpin. NMR N-15 relaxation data were used to characterize the backbone dynamics of the D54A mutant in the context of the N-terminal domains, compared with the wildtype counterpart. Moreover, the effect of the mutation on proteolytic processing and release of virus-like particles (VLPs) from human cells in culture was determined. Conformational and dynamic changes resulting from the mutation were detected by NMR spectroscopy. The mutation also altered the conformation of mature CA in cells and VLPs, as reflected by differential antibody recognition of the wild-type and mutated CA proteins. In contrast, the mutation did not detectably affect antibody recognition of the CA protein precursor or release of VLPs assembled by the precursor, consistent with the fact that the hairpin cannot form in the precursor molecule. The particle morphology and size were not detectably affected. The results indicate that the beta-hairpin contributes to the overall structure of the mature CA protein and suggest that differences in the backbone dynamics of the beta-hairpin contribute to mature CA structure, possibly introducing flexibility into interface formation during proteolytic maturation. C1 Howard Hughes Med Inst, New York, NY USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. Columbia Univ, Coll Phys & Surg, Dept Biochem & Mol Biophys, New York, NY 10027 USA. Columbia Univ, Coll Phys & Surg, Dept Microbiol, New York, NY 10027 USA. SUNY Stony Brook, Dept Mol Genet & Microbiol, Stony Brook, NY 11794 USA. RP Tjandra, N (reprint author), Howard Hughes Med Inst, New York, NY USA. EM nico@heliz.nih.gov; ccater@ms.c.sunysb.edu RI Cornilescu, Claudia/H-1959-2012; Goff, Stephen/K-6337-2014; Cornilescu, Claudia/K-1981-2015 OI Goff, Stephen/0000-0003-0693-5547; Cornilescu, Claudia/0000-0002-2401-7806 FU NIAID NIH HHS [P30 AI 42848]; NIGMS NIH HHS [GM 48294] NR 35 TC 9 Z9 9 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 25 PY 2005 VL 280 IS 8 BP 6792 EP 6801 DI 10.1074/jbc.M408119200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 902DT UT WOS:000227332700068 PM 15569685 ER PT J AU Heymann, JB Iwasaki, K Yim, YI Cheng, NQ Belnap, DM Greene, LE Eisenberg, E Steven, AC AF Heymann, JB Iwasaki, K Yim, YI Cheng, NQ Belnap, DM Greene, LE Eisenberg, E Steven, AC TI Visualization of the binding of Hsc70 ATPase to clathrin baskets - Implications for an uncoating mechanism SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID COATED VESICLES; BIOLOGICAL MACROMOLECULES; BETA-PROPELLER; AUXILIN; ENDOCYTOSIS; DOMAIN; PROTEIN; MICROSCOPY; RESOLUTION; LOCATION AB Clathrin assembly into coated pits and vesicles is promoted by accessory proteins such as auxilin and AP180, and disassembly is effected by the Hsc70 ATPase. These interactions may be mimicked in vitro by the assembly and disassembly of clathrin "baskets." The chimera C58J is a minimal construct capable of supporting both reactions; it consists of the C58 moiety of AP180, which facilitates clathrin assembly, fused with the J domain of auxilin, which recruits Hsc70 to baskets. We studied the process of disassembly by using cryo-electron microscopy to identify the initial binding site of Hsc70 on clathrin-C58J baskets at pH 6, under which conditions disassembly does not proceed further. Hsc70 interactions involve two sites: (i) its major interaction is with the sides of spars of the clathrin lattice, close to the triskelion hubs and GO there is another interaction at a site at the N-terminal hooks of the clathrin heavy chains, presumably via the J domain of C58J. We propose that individual triskelions may be extricated from the clathrin lattice by the concerted action of up to six Hsc70 molecules, which intercalate between clathrin leg segments, prying them apart. Three Hsc70s remain bound to the dissociated triskelion, close to its trimerization hub. C1 NHLBI, Struct Biol Lab, NIAMS, NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Cell Biol Lab, Bethesda, MD 20892 USA. Osaka Univ, Res Ctr Ultra High Voltage Electron Microscopy, Osaka 5670047, Japan. RP Steven, AC (reprint author), NHLBI, Struct Biol Lab, NIAMS, NIH, Bldg 50,Rm 1517,50 South Dr,MSC 8025, Bethesda, MD 20892 USA. EM Alasdair_Steven@nih.gov RI Heymann, Bernard/F-6825-2011; OI Heymann, Bernard/0000-0002-8872-5326 NR 37 TC 20 Z9 22 U1 0 U2 3 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 25 PY 2005 VL 280 IS 8 BP 7156 EP 7161 DI 10.1074/jbc.M411712200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 902DT UT WOS:000227332700106 PM 15596443 ER PT J AU Zheng, WJ Brooks, B AF Zheng, WJ Brooks, B TI Identification of dynamical correlations within the myosin motor domain by the normal mode analysis of an elastic network model SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE normal mode analysis; elastic network model; dynamical correlation; power-stroke; myosin ID CONFORMATIONAL-CHANGE; MOTIONS; PROTEINS; FLEXIBILITY; NUCLEOTIDE; RESOLUTION; MECHANICS; RELEASE; STATES; S1 AB In order to systematically analyze functionally relevant dynamical correlations within macromolecular complexes, we have developed computational methods based on the normal mode analysis of an elastic network model. First, we define two types of dynamical correlations (fluctuation-based And density-based), which are computed by summing up contributions from all low-frequency normal modes up to a given cutoff. Then we use them to select dynamically important "hinge residues" whose elastic distortion affects the fluctuations of a large number of residues. Second, in order to clarify long-range dynamical correlations, we decompose the dynamical correlations to individual normal modes to identify the most relevant modes. We have applied these methods to the analysis of the motor domain of Dictyostelium myosin and have obtained the following three interesting results that shed light on its mechanism of force generation: first, we find the hinge residues are distributed over several key inter-subdomain joints (including the nucleotide-binding pocket, the relay helix, the SH1 helix, the strut between the upper 50 kDa. and the lower 50 kDa subdomains), which is consistent with their hypothesized roles in modulating functionally relevant inter-subdomain conformational changes; second, a single mode 7 (for structure 1VOM) is found to dominate the fluctuation-based correlations between the converter/strut and the nucleotide-binding pocket, revealing a surprising simplicity for their intriguing roles in the force generation mechanism; finally, we find a negative density-based correlation between the strut and the nucleotide-binding pocket, which is consistent with the hypothesized signaling pathway that links the actin-binding site's opening/closing with the nucleotide-binding pocket's closing/opening. Published by Elsevier Ltd. C1 NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP Zheng, WJ (reprint author), NHLBI, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. EM zhengwj@helix.nih.gov NR 23 TC 84 Z9 84 U1 0 U2 6 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD FEB 25 PY 2005 VL 346 IS 3 BP 745 EP 759 DI 10.1016/j.jmb.2004.12.020 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 897EM UT WOS:000226986800007 PM 15713460 ER PT J AU Loftus, BJ Fung, E Roncaglia, P Rowley, D Amedeo, P Bruno, D Vamathevan, J Miranda, M Anderson, IJ Fraser, JA Allen, JE Bosdet, IE Brent, MR Chiu, R Doering, TL Dontin, MJ D'Souza, CA Fox, DS Grinberg, V Fu, JM Fukushima, M Haas, BJ Huang, JC Janbon, G Jones, SJM Koo, HL Krzywinski, MI Kwon-Chung, JK Lengeler, KB Maiti, R Marra, MA Marra, RE Mathewson, CA Mitchell, TG Pertea, M Riggs, FR Salzberg, SL Schein, JE Shvartsbeyn, A Shin, H Shumway, M Specht, CA Suh, BB Tenney, A Utterback, TR Wickes, BL Wortman, JR Wye, NH Kronstad, JW Lodge, JK Heitman, J Davis, RW Fraser, CM Hyman, RW AF Loftus, BJ Fung, E Roncaglia, P Rowley, D Amedeo, P Bruno, D Vamathevan, J Miranda, M Anderson, IJ Fraser, JA Allen, JE Bosdet, IE Brent, MR Chiu, R Doering, TL Dontin, MJ D'Souza, CA Fox, DS Grinberg, V Fu, JM Fukushima, M Haas, BJ Huang, JC Janbon, G Jones, SJM Koo, HL Krzywinski, MI Kwon-Chung, JK Lengeler, KB Maiti, R Marra, MA Marra, RE Mathewson, CA Mitchell, TG Pertea, M Riggs, FR Salzberg, SL Schein, JE Shvartsbeyn, A Shin, H Shumway, M Specht, CA Suh, BB Tenney, A Utterback, TR Wickes, BL Wortman, JR Wye, NH Kronstad, JW Lodge, JK Heitman, J Davis, RW Fraser, CM Hyman, RW TI The genome of the basidiomycetous yeast and human pathogen Cryptococcus neoformans SO SCIENCE LA English DT Article ID SACCHAROMYCES-CEREVISIAE; EVOLUTION; SEQUENCE AB Cryptococcus neoformans is a basidionnycetous yeast ubiquitous in the environment, a model for fungal pathogenesis, and an opportunistic human pathogen of global importance. We have sequenced its similar to20-megabase genome, which contains similar to6500 intron-rich gene structures and encodes a transcriptome abundant in alternatively spliced and antisense messages. The genome is rich in transposons, many of which cluster at candidate centromeric regions. The presence of these transposons may drive karyotype instability and phenotypic variation. C. neoformans encodes unique genes that may contribute to its unusual virulence properties, and comparison of two phenotypically distinct strains reveals variation in gene content in addition to sequence polymorphisms between the genomes. C1 Inst Genom Res, Rockville, MD 20850 USA. Stanford Univ, Stanford Genome Technol Ctr, Palo Alto, CA 94304 USA. Scuola Int Super Studi Avanzati, SISSA, I-34014 Trieste, Italy. Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada. Washington Univ, Lab Computat Genom, St Louis, MO 63130 USA. Washington Univ, Sch Med, Dept Mol Microbiol, St Louis, MO 63110 USA. St Louis Univ, Sch Med, Dept Biochem & Mol Biol, St Louis, MO 63104 USA. Univ British Columbia, Michael Smith Labs, Vancouver, BC V6T 1Z4, Canada. Childrens Hosp, Louisiana State Hlth Sci Ctr, Dept Pediat, New Orleans, LA 70118 USA. Childrens Hosp, Louisiana State Hlth Sci Ctr, Res Inst Children, New Orleans, LA 70118 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX 78229 USA. Inst Pasteur, Unite Mycol Mol, Paris 15, France. NIAID, Mol Microbiol Sect, Clin Invest Lab, NIH, Bethesda, MD 20892 USA. Univ Dusseldorf, Inst Mikrobiol, D-4000 Dusseldorf, Germany. Connecticut Agr Expt Stn, New Haven, CT 06511 USA. Boston Univ, Dept Med, Boston, MA 02118 USA. Univ Calif Santa Cruz, Dept Biomol Engn, Santa Cruz, CA 95064 USA. J Craig Venter Fdn, Joint Technol Ctr, Rockville, MD 20850 USA. RP Loftus, BJ (reprint author), Inst Genom Res, 9712 Med Ctr Dr, Rockville, MD 20850 USA. EM bjloftus@tigr.org RI Mitchell, Thomas/A-2356-2008; Fraser, James/B-4918-2012; Tang, Macy/B-9798-2014; Schein, Jacquie/G-3674-2015; Jones, Steven/C-3621-2009; Marra, Marco/B-5987-2008; Salzberg, Steven/F-6162-2011; OI Janbon, Guilhem/0000-0002-4788-1154; Vamathevan, Jessica/0000-0003-2016-9754; loftus, brendan/0000-0001-8871-8356; Fraser, James/0000-0001-5724-5285; Salzberg, Steven/0000-0002-8859-7432; Wortman, Jennifer/0000-0002-8713-1227; Roncaglia, Paola/0000-0002-2825-0621; Fraser, Claire/0000-0003-1462-2428 FU NHLBI NIH HHS [R01 HL088905, R01 HL088905-04A2]; NIAID NIH HHS [AI47087, AI48594, R01 AI050184, R01 AI050184-05] NR 13 TC 411 Z9 1152 U1 10 U2 58 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD FEB 25 PY 2005 VL 307 IS 5713 BP 1321 EP 1324 DI 10.1126/science.1103773 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 901WP UT WOS:000227313200062 PM 15653466 ER PT J AU Luo, WM Yu, QS Zhan, M Parrish, D Deschamps, JR Kulkarni, SS Holloway, HW Alley, GM Lahiri, DK Brossi, A Greig, NH AF Luo, WM Yu, QS Zhan, M Parrish, D Deschamps, JR Kulkarni, SS Holloway, HW Alley, GM Lahiri, DK Brossi, A Greig, NH TI Novel anticholinesterases based on the molecular skeletons of furobenzofuran and methanobenzodioxepine SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID CARBAMATE ANALOGS; HUMAN ACETYLCHOLINESTERASE; TORPEDO-CALIFORNICA; ALZHEIMERS-DISEASE; BACK DOOR; INHIBITORS; BUTYRYLCHOLINESTERASE; PHENSERINE; BINDING; PROTEIN AB Reductive cyclization of 5-hydroxy-3-methyl-3-methoxycarbonylmethylenebenzofuran-2(3H)-one (4) gave 5-hydroxy-3a-methyl-2,3,3a,8a-tatrahydrofuro[2,3-blbenzofuran (5) and the rearrangement product 7-hydroxy-4,5-dihydro-2,5-methano-1,3-benzodioxepine (6). Reaction of compounds 5 and 6 with different isocyanates provided two series novel carbamates (7-12) whose structures were confirmed by X-ray crystallography. These were assessed for anticholinesterase action against freshly prepared human enzyme and proved to be potent inhibitors of either acetyl- (AChE) or butyrylcholinesterase (BChE) with specific compounds exhibiting remarkable selectivity. Because the two series of carbamates (7-12) differ in their phenolic moieties, their respective potency and selectivity for AChE versus BChE was governed by their N-substituted groups. This same characteristic was also present in a series of physovenine analogues (1, 13, 15, 17) and physostigmine analogues (2, 14, 16, 18). These structure-activity relations proved valuable in elucidating the mechanisms underpinning the interaction between carbamate-based cholinesterase inhibitors and their enzyme target. In addition, because physostigmine analogues have demonstrated activity in lowering the Alzheimer's disease protein, amyloid precursor protein (APP), examples of the two new series of carbamates were characterized in culture assays of quantifying cell viability and synthesis of APP. C1 NIA, Gerontol Res Ctr, NIH,Res Resources Branch, Drug Design & Dev Sect,Lab Neurosci, Baltimore, MD 21224 USA. NIA, Gerontol Res Ctr, NIH,Res Resources Branch, Bioinformat Unit, Baltimore, MD 21224 USA. USN, Res Lab, Struct Matter Lab, Dept Navy, Washington, DC 20375 USA. NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Indiana Univ, Sch Med, Indianapolis, IN 46202 USA. Univ N Carolina, Sch Pharm, Chapel Hill, NC 27599 USA. RP Greig, NH (reprint author), NIA, Gerontol Res Ctr, NIH,Res Resources Branch, Drug Design & Dev Sect,Lab Neurosci, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM Greign@grc.nia.nih.gov OI Deschamps, Jeffrey/0000-0001-5845-0010 NR 47 TC 31 Z9 32 U1 0 U2 4 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD FEB 24 PY 2005 VL 48 IS 4 BP 986 EP 994 DI 10.1021/jm049309+ PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 898ZU UT WOS:000227115500012 PM 15715468 ER PT J AU Kwong, PD AF Kwong, PD TI Human immunodeficiency virus - Refolding the envelope SO NATURE LA English DT Editorial Material ID RECEPTOR-BINDING; CD4 RECEPTOR; HIV-1; ANTIBODY; NEUTRALIZATION; GLYCOPROTEIN; TYPE-1 C1 NIH, Vaccine Res Ctr, Bethesda, MD 20892 USA. RP Kwong, PD (reprint author), NIH, Vaccine Res Ctr, 40 Convent Dr, Bethesda, MD 20892 USA. EM pdkwong@nih.gov NR 13 TC 27 Z9 29 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 24 PY 2005 VL 433 IS 7028 BP 815 EP 816 DI 10.1038/433815a PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 899VT UT WOS:000227174600028 PM 15729327 ER PT J AU Lucas, MES Deen, JL von Seidlein, L Wang, XY Ampuero, J Puri, M Ali, M Ansaruzzaman, M Amos, J Macuamule, A Cavailler, P Guerin, PJ Mahoudeau, C Kahozi-Sangwa, P Chaignat, C Barreto, A Songane, FF Clemens, JD AF Lucas, MES Deen, JL von Seidlein, L Wang, XY Ampuero, J Puri, M Ali, M Ansaruzzaman, M Amos, J Macuamule, A Cavailler, P Guerin, PJ Mahoudeau, C Kahozi-Sangwa, P Chaignat, C Barreto, A Songane, FF Clemens, JD TI Effectiveness of mass oral cholera vaccination in Beira, Mozambique SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID B-SUBUNIT; FIELD TRIAL; VACCINES; EFFICACY; BANGLADESH; DIARRHEA AB BACKGROUND: New-generation, orally administered cholera vaccines offer the promise of improved control of cholera in sub-Saharan Africa. However, the high prevalence of human immunodeficiency virus (HIV) infection in many cholera-affected African populations has raised doubts about the level of protection possible with vaccination. We evaluated a mass immunization program with recombinant cholera-toxin B subunit, killed whole-cell (rBS-WC) oral cholera vaccine in Beira, Mozambique, a city where the seroprevalence of HIV is 20 to 30 percent. METHODS: From December 2003 to January 2004, we undertook mass immunization of nonpregnant persons at least two years of age, using a two-dose regimen of rBS-WC vaccine in Esturro, Beira (population 21,818). We then assessed vaccine protection in a case-control study during an outbreak of El Tor Ogawa cholera in Beira between January and May 2004. To estimate the level of vaccine protection, antecedent rates of vaccination were compared between persons with culture-confirmed cholera severe enough to have prompted them to seek treatment and age- and sex-matched neighborhood controls without treated diarrhea. RESULTS: We assessed the effectiveness of the vaccine in 43 persons with cholera and 172 controls. Receipt of one or more doses of rBS-WC vaccine was associated with 78 percent protection (95 percent confidence interval, 39 to 92 percent; P=0.004). The vaccine was equally effective in children younger than five years of age and in older persons. A concurrently conducted case-control study designed to detect bias compared persons with treated, noncholeraic diarrhea and controls without diarrhea in the same population and found no protection associated with receipt of the rBS-WC vaccine. CONCLUSIONS: The rBS-WC vaccine was highly effective against clinically significant cholera in an urban sub-Saharan African population with a high prevalence of HIV infection. C1 Int Vaccine Inst, Seoul 151600, South Korea. Minist Hlth, Maputo, Mozambique. Ctr Hlth & Populat Res, Dhaka, Bangladesh. Epicentre, Paris, France. Med Sans Frontieres, Geneva, Switzerland. WHO, Maputo, Mozambique. NICHHD, Bethesda, MD 20892 USA. RP Deen, JL (reprint author), Int Vaccine Inst, POB 14, Seoul 151600, South Korea. EM jdeen@ivi.int RI Ali, Mohammad/E-2365-2017 OI Ali, Mohammad/0000-0003-1410-388X NR 23 TC 137 Z9 147 U1 0 U2 14 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 24 PY 2005 VL 352 IS 8 BP 757 EP 767 DI 10.1056/NEJMoa043323 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 899MC UT WOS:000227147500005 PM 15728808 ER PT J AU Krasnoselsky, AL Whiteford, CC Wei, JS Bilke, S Westermann, F Chen, QR Khan, J AF Krasnoselsky, AL Whiteford, CC Wei, JS Bilke, S Westermann, F Chen, QR Khan, J TI Altered expression of cell cycle genes distinguishes aggressive neuroblastoma SO ONCOGENE LA English DT Article DE cDNA microarray; gene expression; principal component analysis; neuroblastoma; MYCN; gene ontology ID ARTIFICIAL NEURAL-NETWORKS; PROLIFERATIVE ACTIVITY; MYCN; AMPLIFICATION; DIFFERENTIATION; IDENTIFICATION; PREDICTION; INDUCTION; SURVIVIN; BIOLOGY AB In this study, gene expression pro. ling was performed on 103 neuroblastoma (NB) tumors, stages 1-4 with and without MYCN amplification, using cDNA microarrays containing 42578 elements. Using principal component analysis (PCA) to analyse the relationships among these samples, we confirm that the global patterns of gene expression reflect the phenotype of the tumors. To explore the biological processes that may contribute to increasing aggressive phenotype of the tumors, we utilized a statistical approach based on PCA. We identified a specific subset of the cell cycle and/or chromosome segregation genes that distinguish stage 4 NB tumors from all lower stage tumors, including stage 3. Furthermore, the control of the kinetochore assembly emerges from the Gene Ontology analysis as one of the key biological processes associated with an aggressive NB phenotype. Finally, we establish that these genes are further upregulated in the most aggressive MYCN-amplified tumors. C1 Natl Canc Inst, Oncogenom Sect, Pediat Oncol Branch, Ctr Adv Technol, Gaithersburg, MD 20877 USA. German Canc Res Ctr, Dept Tumour Genet B030, D-69120 Heidelberg, Germany. RP Khan, J (reprint author), Natl Canc Inst, Oncogenom Sect, Pediat Oncol Branch, Ctr Adv Technol, Room 134E,8717 Grovemont Circle, Gaithersburg, MD 20877 USA. EM khanjav@mail.nih.gov RI Khan, Javed/P-9157-2014 OI Khan, Javed/0000-0002-5858-0488 NR 32 TC 38 Z9 40 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 FEB 24 PY 2005 VL 24 IS 9 BP 1533 EP 1541 DI 10.1038/sj.onc.1208341 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 900ME UT WOS:000227218200006 PM 15592497 ER PT J AU Stoll, BJ Hansen, N AF Stoll, BJ Hansen, N TI Neurodevelopmental impairment and neonatal infections - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 Emory Univ, Sch Med, Atlanta, GA 30322 USA. Res Triangle Inst, NICHHD, Neonatal Res Network, Res Triangle Pk, NC 27709 USA. RP Stoll, BJ (reprint author), Emory Univ, Sch Med, Atlanta, GA 30322 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 23 PY 2005 VL 293 IS 8 BP 932 EP 932 DI 10.1001/jama.293.8.932-b PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 899LR UT WOS:000227146400013 ER PT J AU Desai, RI Kopajtic, TA Koffarnus, M Newman, AH Katz, JL AF Desai, RI Kopajtic, TA Koffarnus, M Newman, AH Katz, JL TI Identification of a dopamine transporter ligand that blocks the stimulant effects of cocaine SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cocaine abuse; cocaine antagonist; dopamine transporter; ex vivo binding; JHW007; benztropine analogs ID BENZTROPINE ANALOGS; NONHUMAN-PRIMATES; UPTAKE INHIBITORS; BINDING; OCCUPANCY; COMBINATION; ANTAGONIST; RECEPTORS; DISCOVERY; MONKEYS AB There is a large unmet medical need for cocaine addiction treatments. Studies have indicated that the dopamine transporter ( DAT) is the primary biological target of cocaine, and most drugs that have DAT affinity have behavioral effects like those of cocaine. However, analogs of benztropine have high DAT affinity and behavioral effects that show varying degrees of similarity to cocaine. We now report the discovery that a benztropine analog, JHW007, with high affinity for theDATdoes not have cocaine- like behavioral effects and antagonizes the effects of cocaine. JHW007 occupied the DAT in vivo more slowly than did cocaine and had not reached an apparent plateau up to 270 min after injection. The in vivo binding of cocaine to the DAT suggested rate of DAT occupancy as an important contributor to its behavioral effects, and the slow association with the DAT may provide an explanation for JHW007 being relatively devoid of cocaine- like behavioral effects. The antagonism of cocaine suggests that DAT ligands with reduced cocaine- like activity can function as cocaine antagonists and suggests JHW007 as a lead for discovery of cocaine- abuse pharmacotherapeutics. C1 NIH, Intramural Res Program, Psychobiol Sect,Dept Hlth & Human Serv, Med Discovery Res Branch,Natl Inst Drug Abuse, Baltimore, MD 21224 USA. NIH, Intramural Res Program, Med Chem Sect,Dept Hlth & Human Serv, Med Discovery Res Branch,Natl Inst Drug Abuse, Baltimore, MD 21224 USA. RP Katz, JL (reprint author), NIH, Intramural Res Program, Psychobiol Sect,Dept Hlth & Human Serv, Med Discovery Res Branch,Natl Inst Drug Abuse, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM jkatz@intra.nida.nih.gov OI Katz, Jonathan/0000-0002-1068-1159 NR 34 TC 69 Z9 70 U1 1 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 23 PY 2005 VL 25 IS 8 BP 1889 EP 1893 DI 10.1523/JNEUROSCI.477/8-04.2005 PG 5 WC Neurosciences SC Neurosciences & Neurology GA 900JK UT WOS:000227211000002 PM 15728828 ER PT J AU Harries, D Rau, DC Parsegian, VA AF Harries, D Rau, DC Parsegian, VA TI Solutes probe hydration in specific association of cyclodextrin and adamantane SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID ENTHALPY-ENTROPY COMPENSATION; AQUEOUS-ELECTROLYTE SOLUTIONS; PROTEIN-WATER INTERACTIONS; HEAT-CAPACITY CHANGES; BETA-CYCLODEXTRIN; INCLUSION COMPLEXES; ALPHA-CYCLODEXTRIN; SURFACE-TENSION; THERMODYNAMIC QUANTITIES; PREFERENTIAL HYDRATION AB Using microcalorimetry, we follow changes in the association free energy of beta-cyclodextrin (CD) with the hydrophobic part of adamantane carboxylate (AD) due to added salt or polar (net-neutral) solutes that are excluded from the molecular interacting surfaces. Changes in binding constants with solution osmotic pressure (water activity) translate into changes in the preferential hydration upon complex formation. We find that these changes correspond to a release of 15-25 solute-excluding waters upon CD/AD association. Reflecting the preferential interaction of solute with reactants versus products, we find that changes in hydration depend on the type of solute used. All solutes used here result in a large change in the enthalpy of the CD-AD binding reaction. In one class of solutes, the corresponding entropy change is much smaller, while in the other class, the entropy change almost fully compensates the solute-specific enthalpy. For many of the solutes, the number of waters released correlates well with their effect on air-water surface tensions. We corroborate these results using vapor pressure osmometry to probe individually the hydration of reactants and products of association, and we discuss the possible interactions and forces between cosolute and hydrophobic surfaces responsible for different kinds of solute exclusion. C1 NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Harries, D (reprint author), NICHHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. EM harries@helix.nih.gov RI Harries, Daniel/F-7016-2012 OI Harries, Daniel/0000-0002-3057-9485 NR 86 TC 110 Z9 114 U1 1 U2 70 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD FEB 23 PY 2005 VL 127 IS 7 BP 2184 EP 2190 DI 10.1021/ja045541t PG 7 WC Chemistry, Multidisciplinary SC Chemistry GA 898TP UT WOS:000227099400038 PM 15713096 ER PT J AU Huang, W Osman, R Gershengorn, MC AF Huang, W Osman, R Gershengorn, MC TI Agonist-induced corformational changes in thyrotropin-releasing hormone receptor type I: Disulfide cross-linking and molecular modeling approaches SO BIOCHEMISTRY LA English DT Article ID PROTEIN-COUPLED RECEPTOR; BETA(2) ADRENERGIC-RECEPTOR; 3RD INTRACELLULAR LOOP; RANDOM SATURATION MUTAGENESIS; CONFORMATIONAL-CHANGES; TRANSMEMBRANE HELICES; DYNAMICS SIMULATIONS; AMINO-ACID; TERTIARY INTERACTIONS; PHOSPHOLIPASE-C AB The conformational changes at the cytoplasmic ends of transmembrane helices 5 and 6 (TMH5 and TMH6) of thyrotropin- releasing hormone (TRH) receptor type I (TRH-R1) during activation were analyzed by cysteine-scanning mutagenesis followed by disulfide cross-linking and molecular modeling. Sixteen double cysteine mutants were constructed by substitution of one residue at the cytoplasmic end of TMH5 and the other at that of TNIH6. The cross-linking experiments indicate that four mutants, Q263C/ G212C, Q263C/Y211C, T265C/G212C, and T265C/Y211C, exhibited disulfide bond formation that was sensitive to TRH occupancy. We refined our previous TRH-R1 models by embedding them into a hydrated explicit lipid bilayer. Molecular dynamics simulations of the models, as well as in silico double cysteine models, generated trajectories that were in agreement with experimental results. Our findings suggest that TRH binding induces a separation of the cytoplasmic ends of TMH5 and TMH6 and a rotation of TNIH6. These changes likely increase the surface accessible area at the juxtamembrane region of intracellular loop 3 that could promote interactions between G proteins and key residues within the receptor. C1 NIDDK, NIH, Clin Endocrinol Branch, Bethesda, MD 20892 USA. Cornell Univ, Grad Sch Med Sci, Grad Program Physiol Biophys & Mol Med, New York, NY 10021 USA. Mt Sinai Sch Med, Dept Phys & Biophys, New York, NY 10029 USA. RP Gershengorn, MC (reprint author), NIDDK, NIH, Clin Endocrinol Branch, 9000 Rockville Pike,50 South Dr,Bldg 50-4134, Bethesda, MD 20892 USA. EM marving@intra.niddk.nih.gov NR 68 TC 20 Z9 20 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 22 PY 2005 VL 44 IS 7 BP 2419 EP 2431 DI 10.1021/bi048808+ PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 898KH UT WOS:000227075200020 PM 15709754 ER PT J AU Blinova, K Carroll, S Bose, S Smirnov, AV Harvey, JJ Knutson, JR Balaban, RS AF Blinova, K Carroll, S Bose, S Smirnov, AV Harvey, JJ Knutson, JR Balaban, RS TI Distribution of mitochondrial NADH fluorescence lifetimes: Steady-state kinetics of matrix NADH interactions SO BIOCHEMISTRY LA English DT Article ID NICOTINAMIDE ADENINE-DINUCLEOTIDE; REDUCED PYRIDINE NUCLEOTIDE; OXIDATIVE-PHOSPHORYLATION; MALATE-DEHYDROGENASE; COMPLEX-I; ALCOHOL-DEHYDROGENASE; OXYGEN-CONSUMPTION; RAT-HEART; BINDING; DECAY AB The lifetimes of fluorescent components of matrix NADH in isolated porcine heart mitochondria were investigated using time-resolved fluorescence spectroscopy. Three distinct lifetimes of fluorescence were resolved: 0.4 (63%), 1.8 (30%), and 5.7 (7%) ns (% total NADH). The 0.4 ns lifetime and the emission wavelength of the short component were consistent with free NADH. In addition to their longer lifetimes, the remaining pools also had a blue-shifted emission spectrum consistent with immobilized NADH. On the basis of emission frequency and lifetime data, the immobilized pools contributed >80% of NADH fluorescence. The steady-state kinetics of NADH entering the immobilized pools was measured in intact mitochondria and in isolated mitochondrial membranes. The apparent binding constants (K(D)s) for NADH in intact mitochondria, 2.8 mM (1.9 ns pool) and >3 mM (5.7 ns pool), were on the order of the estimated matrix [NADH] (similar to3.5 mM). The affinities and fluorescence lifetimes resulted in an essentially linear relationship between matrix [NADH] and NADH fluorescence intensity. Mitochondrial membranes had shorter emission lifetimes in the immobilized pools [1 ns (34%) and 4.1 ns (8%)] with much higher apparent K(D)s of 100 muM and 20 muM, respectively. The source of the stronger NADH binding affinity in membranes is unknown but could be related to high order structure or other cofactors that are diluted out in the membrane preparation. In both preparations, the rate of NADH oxidation was proportional to the amount of NADH in the long lifetime pools, suggesting that a significant fraction of the bound NADH might be associated with oxidative phosphorylation, potentially in complex 1. C1 Natl Heart Lung & Blood Inst, Lab Cardiac Energet, NIH, Bethesda, MD 20892 USA. Natl Heart Lung & Blood Inst, Lab Biophys Chem, NIH, Bethesda, MD 20892 USA. RP Blinova, K (reprint author), Natl Heart Lung & Blood Inst, Lab Cardiac Energet, NIH, Bethesda, MD 20892 USA. EM blinovak@nhlbi.nih.gov RI Balaban, Robert/A-7459-2009 OI Balaban, Robert/0000-0003-4086-0948 NR 50 TC 74 Z9 75 U1 1 U2 12 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 22 PY 2005 VL 44 IS 7 BP 2585 EP 2594 DI 10.1021/bi0485124 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 898KH UT WOS:000227075200037 PM 15709771 ER PT J AU Goldstein, DS Eldadah, B Holmes, C Pechnik, S Moak, J Sharabi, Y AF Goldstein, DS Eldadah, B Holmes, C Pechnik, S Moak, J Sharabi, Y TI Neurocirculatory abnormalities in chronic orthostatic intolerance SO CIRCULATION LA English DT Article DE syncope; nervous system, sympathetic; tachycardia; norepinephrine; epinephrine ID POSTURAL TACHYCARDIA SYNDROME; NEURALLY-MEDIATED SYNCOPE; CHRONIC-FATIGUE-SYNDROME; NEUROCARDIOGENIC SYNCOPE; NOREPINEPHRINE KINETICS; VENOUS INNERVATION; VASOVAGAL SYNCOPE; SYNDROME POTS; HUMAN-HEART; BLOOD-FLOW AB Background - Chronic orthostatic intolerance (COI) occurs in postural tachycardia syndrome (POTS) and in some individuals with repeated neurocardiogenic syncope/presyncope (NCS), without POTS. This study addressed whether patients with COI and POTS or NCS have neurocirculatory abnormalities during supine rest. Methods and Results - Adult patients referred for COI who had POTS (n = 90, mean +/- SEM age 40 +/- 1 years, 86% women) or NCS (n = 36, 41 +/- 2 years old, 78% women) underwent measurements of plasma levels of catecholamines and forearm hemodynamics. Comparison data were obtained from 32 age- and gender-matched normal volunteers (39 +/- 2 years old, 81% women). The POTS group had a relatively fast mean heart rate (79 +/- 2 bpm) during supine rest compared with the NCS group (69 +/- 1.6 bpm, P = 0.03) and normal volunteers (66 +/- 3 bpm, P = 0.0004). The POTS group also had higher mean arterial norepinephrine (1.61 +/- 0.11 nmol/L, n = 37) and epinephrine (0.39 +/- 0.03 nmol/L, n = 37) concentrations than the NCS group (1.03 +/- 0.12 nmol/L, n = 20, P = 0.0012; 0.21 +/- 0.03 nmol/L, n = 20, P = 0.0005) and normal volunteers (1.13 +/- 0.11 nmol/L, n = 20, P = 0.006; 0.17 +/- 0.03 nmol/L, n = 15, P = 0.0001). The NCS group had higher mean forearm vascular resistance (52 +/- 6 U) than the POTS group (36 +/- 2 U, P = 0.003). Conclusions - Overall, POTS features increased heart rate and sympathetic nervous and adrenomedullary hormonal system outflows during supine rest. Increased sympathetic outflow may contribute to the relative tachycardia in POTS. NCS features forearm vasoconstriction during supine rest but not sympathoneural or adrenomedullary activation. C1 NINDS, Clin Neurocardiol Sect, NIH, Bethesda, MD 20892 USA. RP Goldstein, DS (reprint author), Bldg 10,Room 6N252,10 Ctr Dr,MSC-1620, Bethesda, MD 20892 USA. EM goldsteind@ninds.nih.gov NR 41 TC 19 Z9 22 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 FEB 22 PY 2005 VL 111 IS 7 BP 839 EP 845 DI 10.1161/01.CIR.0000155613.20376.CA PG 7 WC Cardiac & Cardiovascular Systems; Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 899AP UT WOS:000227117600004 PM 15699262 ER PT J AU Bufe, B Breslin, PAS Kuhn, C Reed, DR Tharp, CD Slack, JP Kim, UK Drayna, D Meyerhof, W AF Bufe, B Breslin, PAS Kuhn, C Reed, DR Tharp, CD Slack, JP Kim, UK Drayna, D Meyerhof, W TI The molecular basis of individual differences in phenylthiocarbamide and propylthiouracil bitterness perception SO CURRENT BIOLOGY LA English DT Article ID TASTE RECEPTOR GENES; IDENTIFICATION; SACCHARIN AB Individual differences in perception are ubiquitous within the chemical senses: taste, smell, and chemical somesthesis [1-4]. A hypothesis of this fact states that polymorphisms in human sensory receptor genes could alter perception by coding for functionally distinct receptor types [1, 5-8]. We have previously reported evidence that sequence variants in a presumptive bitter receptor gene (hTAS2R38) correlate with differences in bitterness recognition of phenylthiocarbamide (PTC) [9-11]. Here, we map individual psychogenomic pathways for bitter taste by testing people with a variety of psychophysical tasks and linking their individual perceptions of the compounds PTC and propylthiouracil (PROP) to the in vitro responses of their TAS2R38 receptor variants. Functional expression studies demonstrate that five different haplotypes from the hTAS2R38 gene code for operatively distinct receptors. The responses of the three haplotypes we also tested in vivo correlate strongly with individuals' psychophysical bitter sensitivities to a family of compounds. These data provide a direct molecular link between heritable variability in bitter taste perception to functional variations of a single G protein coupled receptor that responds to compounds such as PTC and PROP that contain the N-C=S moiety. The molecular mechanisms of perceived bitterness variability have therapeutic implications, such as helping patients to consume beneficial bitter-tasting compounds-for example, pharmaceuticals and selected phytochemicals. C1 German Inst Human Nutr, D-14558 Nuthetal, Germany. Monell Chem Senses Ctr, Philadelphia, PA 19104 USA. Givaudan Flavors Corp, Cincinnati, OH 45216 USA. Natl Inst Deafness & Commun Disorders, NIH, Rockville, MD 20850 USA. RP Breslin, PAS (reprint author), German Inst Human Nutr, Arthur Scheunert Allee 114-116, D-14558 Nuthetal, Germany. EM breslin@monell.org; meyerhof@mail.dife.de RI Marion-Poll, Frederic/D-8882-2011; OI Marion-Poll, Frederic/0000-0001-6824-0180; Reed, Danielle/0000-0002-4374-6107 FU NIDCD NIH HHS [R01 DC004698, DC0004698, DC02995, R01 DC002995, R03 DC003509, R29 DC002995] NR 21 TC 314 Z9 320 U1 29 U2 165 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0960-9822 J9 CURR BIOL JI Curr. Biol. PD FEB 22 PY 2005 VL 15 IS 4 BP 322 EP 327 DI 10.1016/j.cub.2005.01.047 PG 6 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 901FC UT WOS:000227267400021 PM 15723792 ER PT J AU Scher, AI Terwindt, GM Picavet, HSJ Verschuren, WMM Ferrari, MD Launer, LJ AF Scher, AI Terwindt, GM Picavet, HSJ Verschuren, WMM Ferrari, MD Launer, LJ TI Cardiovascular risk factors and migraine - The GEM population-based study SO NEUROLOGY LA English DT Article; Proceedings Paper CT 55th Annual Meeting of the American-Academy-of-Neurology CY MAR 29-APR 05, 2003 CL HONOLULU, HI SP Amer Acad Neurol ID METHYLENETETRAHYDROFOLATE REDUCTASE GENE; QUALITY-OF-LIFE; ISCHEMIC STROKE; BLOOD-PRESSURE; YOUNG-WOMEN; CEREBRAL-ISCHEMIA; SUBSEQUENT RISK; UNITED-STATES; HYPERTENSION; HEADACHE AB Background: Migraine, particularly with aura, is a risk factor for early-onset ischemic stroke. The underlying mechanisms are unknown, but may in part be due to migraineurs having an increased risk profile for cardiovascular disease. In this study, the authors compare the cardiovascular risk profile of adult migraineurs to that of nonmigraineurs. Methods: Participants (n = 5,755, 48% men, age 20 to 65 years) are from the Genetic Epidemiology of Migraine (GEM) study, a population-based study in the Netherlands. A total of 620 current migraineurs were identified: 31% with aura (MA), 64% without aura (MO), and 5% unclassified. Controls were 5,135 individuals without lifetime migraine. Measured cardiovascular risk factors included blood pressure (BP), serum total and high-density lipoprotein cholesterol (TC, HDL), smoking, oral contraceptive use, and the Framingham risk score for myocardial infarction or coronary heart disease (CHD) death. Results: Compared to controls, migraineurs were more likely to smoke (OR = 1.43 [1.1 to 1.8]), less likely to consume alcohol (OR = 0.58 [0.5 to 0.7]), and more likely to report a parental history of early myocardial infarction. Migraineurs with aura were more likely to have an unfavorable cholesterol profile (TC greater than or equal to 240 mg/dL [OR = 1.43 (0.97 to 2.1)], TC: HDL ratio > 5.0 [OR = 1.64 (1.1 to 2.4)]), have elevated BP (systolic BP > 140 mm Hg or diastolic BP > 90 mm Hg [OR = 1.76 (1.04 to 3.0)]), and report a history of early onset CHD or stroke (OR = 3.96 [1.1 to 14.3]); female migraineurs with aura were more likely to be using oral contraceptives (OR = 2.06 [1.05 to 4.0]). The odds of having an elevated Framingham risk score for CHD were approximately doubled for the migraineurs with aura. Conclusions: Migraineurs, particularly with aura, have a higher cardiovascular risk profile than individuals without migraine. C1 NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD USA. Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands. Ctr Prevent & Hlth Serv Res, Natl Inst Publ Hlth & Environm, Bilthoven, Netherlands. RP Scher, AI (reprint author), Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM ascher@usuhs.mil NR 42 TC 260 Z9 263 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 FEB 22 PY 2005 VL 64 IS 4 BP 614 EP 620 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 900HU UT WOS:000227206800009 PM 15728281 ER PT J AU Yamashita, T Wu, YP Sandhoff, R Werth, N Mizukami, H Ellis, JM Dupree, JL Geyer, R Sandhoff, K Proia, RL AF Yamashita, T Wu, YP Sandhoff, R Werth, N Mizukami, H Ellis, JM Dupree, JL Geyer, R Sandhoff, K Proia, RL TI Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon-glial interactions SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE glycosphingolipid; neurodegeneration; glycosyltransferase ID MYELIN-ASSOCIATED GLYCOPROTEIN; LUNG-CARCINOMA CELLS; COMPLEX GANGLIOSIDES; BRAIN GANGLIOSIDES; MICE; SYNTHASE; GM3; APOPTOSIS; LIGANDS; LACTOSYLCERAMIDE AB Gangliosides, which are sialylated glycosphingolipids, are the major class of glycoconjugates on neurons and carry the majority of the sialic acid within the central nervous system (CNS). To determine the role of ganglioside synthesis within the CNS, mice carrying null mutations in two critical ganglioside-specific glycosyltransferase genes, Siat9 (encoding GM3 synthase) and Galgt1 (encoding GM2 synthase), were generated. These double-null mice were unable to synthesize gangliosides of the ganglio-series of glycosphingolipids, which are the major ganglioside class in the CNS. Soon after weaning, viable mice developed a severe neurodegenerative disease that resulted in death. Histopathological examination revealed striking vacuolar pathology in the white matter regions of the CNS with axonal degeneration and perturbed axon-glia interactions. These results indicate that ganglioside synthesis is essential for the development of a stable CNS, possibly by means of the promotion of interactions between axon and glia. C1 NIDDKD, Genet Dev & Dis Branch, NIH, Bethesda, MD 20892 USA. German Canc Res Ctr, Dept Cellular & Mol Pathol, D-69120 Heidelberg, Germany. Univ Giessen, Fachbereich Humanmed, Inst Biochem, D-35392 Giessen, Germany. Virginia Commonwealth Univ, Dept Anat & Neurobiol, Richmond, VA 23298 USA. Univ Bonn, Kekule Inst Organ Chem & Biochem, D-53121 Bonn, Germany. RP Yamashita, T (reprint author), Inst Med Sci, Dept Cell Proc, Minato Ku, Shirokanedai 4-6-1, Tokyo 1088639, Japan. EM ty10104@ims.u-tokyo.ac.jp; proia@nih.gov RI Proia, Richard/A-7908-2012 NR 35 TC 118 Z9 121 U1 2 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 22 PY 2005 VL 102 IS 8 BP 2725 EP 2730 DI 10.1073/pnas.0407785102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 900RQ UT WOS:000227232400013 PM 15710896 ER PT J AU Schuler, B Lipman, EA Steinbach, PJ Kumke, M Eaton, WA AF Schuler, B Lipman, EA Steinbach, PJ Kumke, M Eaton, WA TI Polyproline and the "spectroscopic ruler" revisited with single-molecule fluorescence SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Forster resonance energy transfer; molecular dynamics; polypeptide; FRET ID RESONANCE ENERGY-TRANSFER; TRANSFER CONFOCAL MICROSCOPY; POLY-L-PROLINE; CONFORMATIONAL-CHANGES; PROTEIN; DYNAMICS; ORIENTATION; DISTANCE; FRET; DNA AB To determine whether Forster resonance energy transfer (FRET) measurements can provide quantitative distance information in single-molecule fluorescence experiments on polypeptides, we measured FRET efficiency distributions for donor and acceptor dyes attached to the ends of freely diffusing polyproline molecules of various lengths. The observed mean FRET efficiencies agree with those determined from ensemble lifetime measurements but differ considerably from the values expected from Forster theory, with polyproline treated as a rigid rod. At donor-acceptor distances much less than the Forster radius R-o, the observed efficiencies are lower than predicted, whereas at distances comparable to and greater than R-0, they are much higher. Two possible contributions to the former are incomplete orientational averaging during the donor lifetime and, because of the large size of the dyes, breakdown of the point-dipole approximation assumed in Forster theory. End-to-end distance distributions and correlation times obtained from Langevin molecular dynamics simulations suggest that the differences for the longer polyproline peptides can be explained by chain bending, which considerably shortens the donor-acceptor distances. C1 NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NIH, Ctr Mol Modeling, Ctr Informat Technol, Bethesda, MD 20892 USA. Univ Potsdam, Inst Chem, D-14476 Potsdam, Germany. RP Schuler, B (reprint author), Univ Zurich, Inst Biochem, CH-8057 Zurich, Switzerland. EM schuler@bioc.unizh.ch; eaton@helix.nih.gov RI Lipman, Everett/D-1696-2009; Schuler, Benjamin/E-7342-2011 OI Schuler, Benjamin/0000-0002-5970-4251 NR 48 TC 269 Z9 273 U1 5 U2 71 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 22 PY 2005 VL 102 IS 8 BP 2754 EP 2759 DI 10.1073/pnas.0408164102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 900RQ UT WOS:000227232400018 PM 15699337 ER PT J AU Xu, KF Shen, XY Li, HW Pacheco-Rodriguez, G Moss, J Vaughan, M AF Xu, KF Shen, XY Li, HW Pacheco-Rodriguez, G Moss, J Vaughan, M TI Interaction of BIG2, a brefeldin A-inhibited guanine nucleotide-exchange protein, with exocyst protein Exo70 SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE microtubule-organizing center; vesicular trafficking; centrosome; Golgi; ADP-ribosylation factor ID ADP-RIBOSYLATION FACTORS; PLASMA-MEMBRANE; COMPLEX; VESICLE; LOCALIZATION; MICROTUBULES; EXOCYTOSIS; TRAFFICKING; CENTROSOME; EXPRESSION AB Guanine nucleotide-exchange proteins activate ADP-ribosylation factors by accelerating the replacement of bound GDP with GTP. Mammalian brefeldin A-inhibited guanine nucleotide-exchange proteins, BIG1 and BIG2, are important activators of ADP-ribosylation factors for vesicular trafficking. To identify proteins that interact with BIG2, we used cDNA constructs encoding BIG2 sequences in a yeast two-hybrid screen of a human heart library. Clone p2-5-3, encoding a form of human exocyst protein Exo70, interacted with BIG2 amino acids 1-643 and 1-832, but not 644832, which was confirmed by coimmunoprecipitation of in vitro-translated BIG2 N-terminal segments and 2-5-3. By immunofluorescence microscopy, endogenous BIG2 and Exo70 in HepG2 cells were visualized at Golgi membranes and apparently at the microtubule-organizing center (MTOC). Both were identified in purified centrosomes. Immunoreactive Exo70 and BIG2 partially or completely overlapped with gamma-tubulin at the MTOC in cells inspected by confocal microscopy. In cells incubated with brefeldin A, most of the BIG2, Exo70, and trans-Golgi protein p230 were widely dispersed from their perinuclear concentrations, but small amounts always remained, apparently at the MTOC. After disruption of microtubules with nococlazole, BIG2 and Exo70 were widely distributed in cells and remained only partially colocalized with p230, BIG2 more so than Exo70. We conclude that in HepG2 cells BIG2 and Exo70 interact in trans-Golgi network and centrosomes, as well as in exocyst structures or complexes that move along microtubules to the plasma membrane, consistent with a functional association in both early and late stages of vesicular trafficking. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Vaughan, M (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10, Bethesda, MD 20892 USA. EM vaughanm@nih.gov NR 26 TC 37 Z9 40 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 FEB 22 PY 2005 VL 102 IS 8 BP 2784 EP 2789 DI 10.1073/pnas.0409871102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 900RQ UT WOS:000227232400023 PM 15705715 ER PT J AU Das, N Valjavec-Gratian, M Basuray, AN Fekete, RA Papp, PP Paulsson, J Chattoraj, DK AF Das, N Valjavec-Gratian, M Basuray, AN Fekete, RA Papp, PP Paulsson, J Chattoraj, DK TI Multiple homeostatic mechanisms in the control of P1 plasmid replication SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE autorepression; DNA replication control; homeostatic control; plasmid copy number control ID COPY-NUMBER CONTROL; SHOCK PROTEINS DNAJ; ESCHERICHIA-COLI; NEGATIVE CONTROL; INITIATOR-BINDING; RK2 REPLICATION; F-PLASMID; ORIGIN; REPA; AUTOREGULATION AB Many organisms control initiation of DNA replication by limiting supply or activity of initiator proteins. in plasmids, such as P1, initiators are limited primarily by transcription and dimerization. However, the relevance of initiator limitation to plasmid copy number control has appeared doubtful, because initiator oversupply increases the copy number only marginally. Copy number control instead has been attributed to initiator-mediated plasmid pairing ("handcuffing"), because initiator mutations to handcuffing deficiency elevates the copy number significantly. Here, we present genetic evidence of a role for initiator limitation in plasmid copy number control by showing that autorepression-defective initiator mutants also can elevate the plasmid copy number. We further show, by quantitative modeling, that initiator dimerization is a homeostatic mechanism that dampens active monomer increase when the protein is oversupplied. This finding implies that oversupplied initiator proteins are largely dimeric, partly accounting for their limited ability to increase copy number. A combination of autorepression, dimerization, and handcuffing appears to account fully for control of P1 plasmid copy number. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Univ Cambridge, Dept Appl Math & Theoret Phys, Cambridge CB3 0WA, England. RP Chattoraj, DK (reprint author), NCI, Biochem Lab, NIH, 37-6044, Bethesda, MD 20892 USA. EM chattoraj@nih.gov RI Papp, Peter/A-6907-2013 NR 44 TC 29 Z9 29 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 FEB 22 PY 2005 VL 102 IS 8 BP 2856 EP 2861 DI 10.1073/pnas.0409790102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 900RQ UT WOS:000227232400035 PM 15708977 ER PT J AU Mohamadzadeh, M Olson, S Kalina, WV Ruthel, G Demmin, GL Warfield, KL Bavari, S Klaenhammer, TR AF Mohamadzadeh, M Olson, S Kalina, WV Ruthel, G Demmin, GL Warfield, KL Bavari, S Klaenhammer, TR TI Lactobacilli activate human dendritic cells that skew T cells toward T helper 1 polarization SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID LACTIC-ACID BACTERIA; IMMUNE-SYSTEM; PROBIOTICS; MATURATION; RESPONSES; ANTIGEN; EXPRESSION; RHAMNOSUS; INDUCTION; CYTOKINES AB Professional antigen-presenting dendritic cells (DCs) are critical in regulating T cell immune responses at both systemic and mucosal sites. Many Lactobacillus species are normal members of the human gut microflora and most are regarded as safe when administered as probiotics. Because DCs can naturally or therapeutically encounter lactobacilli, we investigated the effects of several well defined strains, representing three species of Lactobacillus on human myeloid DCs (MDCs) and found that they modulated the phenotype and functions of human MDCs. Lactobacillus-ex posed MDCs up-regulated HLA-DR, CD83, CD40, CD80, and CD86 and secreted high levels of IL-12 and IL-18, but not IL-10. IL-12 was sustained in MDCs exposed to all three Lactobacillus species in the presence of LPS from Escherichia coli, whereas LPS-induced IL-10 was greatly inhibited. MDCs activated with lactobacilli clearly skewed CD4(+) and CID8(+) T cells to T helper 1 and Tc1 polarization, as evidenced by secretion of IFN-gamma, but not IL-4 or IL-13. These results emphasize a potentially important role for lactobacilli in modulating immunological functions of DCs and suggest that certain strains could be particularly advantageous as vaccine adjuvants, by promoting DCs to regulate T cell responses toward T helper 1 and Tc1 pathways. C1 NCI, Frederick, MD 21702 USA. Louisiana State Univ, Dept Microbiol, New Orleans, LA 70112 USA. Tulane Univ, Ctr Gene Therapy, New Orleans, LA 70112 USA. USA, Med Res Inst Infect Dis, Frederick, MD 21702 USA. N Carolina State Univ, Dept Food Sci, Raleigh, NC 27695 USA. RP Mohamadzadeh, M (reprint author), NCI, Frederick, MD 21702 USA. EM mzadeh@ncifcrf.gov FU NCRR NIH HHS [P51 RR000164, RR00164]; NIAID NIH HHS [AI 59590-01, R21 AI059590] NR 40 TC 264 Z9 282 U1 0 U2 10 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 22 PY 2005 VL 102 IS 8 BP 2880 EP 2885 DI 10.1073/pnas.0500098102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 900RQ UT WOS:000227232400039 PM 15710900 ER PT J AU Mavilio, D Lombardo, G Benjamin, J Kim, D Follman, D Marcenaro, E O'Shea, MA Kinter, A Kovacs, C Moretta, A Fauci, AS AF Mavilio, D Lombardo, G Benjamin, J Kim, D Follman, D Marcenaro, E O'Shea, MA Kinter, A Kovacs, C Moretta, A Fauci, AS TI Characterization of CD56(-)/CD16(+) natural killer (NK) cells: A highly dysfunctional NK subset expanded in HIV-infected viremic individuals SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cytokines; cytotoxicity; inhibitory NK receptors; killer immunoglobulin-like receptors; natural cytotoxicity receptors ID IMMUNODEFICIENCY-VIRUS-INFECTION; CLASS-I MOLECULES; DENDRITIC CELLS; ANTIRETROVIRAL THERAPY; ACTIVATING RECEPTORS; INNATE IMMUNITY; T-CELLS; EXPRESSION; DISEASE; IL-10 AB Natural killer (NK) cells are an important component of the innate immune response against viral infections. INK cell-mediated cytolytic activity is defective in HIV-infected individuals with high levels of viral replication. In the present study, we examined the phenotypic and functional characteristics of an unusual CD56(-)/CD16(+) (CD56(-)) NK subset that is greatly expanded in HIV-viremic individuals. The higher level of expression of inhibitory INK receptors and the lower level of expression of natural cytotoxicity receptors observed in the CD56- INK fraction compared with that of CD56(+) NK cells was associated with extremely poor in vitro cytotoxic function of this subset. in addition, the secretion of certain cytokines known to be important in initiating antiviral immune responses was markedly reduced in the CD56-, as compared with the CD56+ NK cell subset. These data suggest that the expansion of this highly dysfunctional CD56- NK cell subset in HIV-viremic individuals largely accounts for the impaired function of the total INK cell population. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NIAID, Biostat Res Branch, NIH, Bethesda, MD 20892 USA. Univ Genoa, Dipartimento Med Sperimentale, I-16132 Genoa, Italy. Univ Toronto, Dept Med, Toronto, ON M5S 1A1, Canada. RP Mavilio, D (reprint author), NIAID, Immunoregulat Lab, NIH, 10 Ctr Dr,Bldg 10,Room 6A08A,MSC 1576, Bethesda, MD 20892 USA. EM dmavillo@niaid.nih.gov OI Mavilio, Domenico/0000-0001-6147-0952 NR 41 TC 240 Z9 246 U1 0 U2 11 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 22 PY 2005 VL 102 IS 8 BP 2886 EP 2891 DI 10.1073/pnas.0409872102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 900RQ UT WOS:000227232400040 PM 15699323 ER PT J AU Ostedgaard, LS Rokhlina, T Karp, PH Lashmit, P Afione, S Schmidt, M Zabner, J Stinski, MF Chiorini, JA Welsh, MJ AF Ostedgaard, LS Rokhlina, T Karp, PH Lashmit, P Afione, S Schmidt, M Zabner, J Stinski, MF Chiorini, JA Welsh, MJ TI A shortened adeno-associated virus expression cassette for CFTR gene transfer to cystic fibrosis airway epithelia SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE CMV; promoter; gene therapy ID TRANSMEMBRANE CONDUCTANCE REGULATOR; AAV VECTORS; IN-VIVO; EFFICIENT TRANSDUCTION; QUANTITATIVE-ANALYSIS; SIALIC-ACID; THERAPY; CELLS; PROMOTER; CLONING AB Adeno-associated viruses (AAVs) such as AAV5 that transduce airway epithelia from the apical surface are attractive vectors for gene transfer in cystic fibrosis (CF). However, their utility in CF has been limited because packaging of the insert becomes inefficient when its length exceeds approximate to4,900-5,000 bp. To partially circumvent this size constraint, we previously developed a CIF transmembrane conductance regulator (CFTR) transgene that deleted a portion of the R domain (CFTRDeltaR). In this study, we focused on shortening the other elements in the AAV expression cassette. We found that portions of the CMV immediate/early (CMVie) enhancer/promoter could be deleted without abolishing activity. We also tested various intervening sequences, poly(A) signals, and an intron to develop an expression cassette that meets the size restrictions imposed by AAV. We then packaged these shortened elements with the CFTRDeltaR transgene into AAV5 and applied them to the apical surface of differentiated CF airway epithelia. Two to 4 weeks later, the AAV5 vectors partially corrected the CF Cl- transport defect. These results demonstrate that a single AAV vector can complement the CF defect in differentiated airway epithelia and thereby further the development of effective CF gene transfer. C1 Univ Iowa, Roy J & Lucille A Carver Coll Med, Howard Hughes Med Inst, Iowa City, IA 52242 USA. Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Internal Med, Iowa City, IA 52242 USA. Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Microbiol, Iowa City, IA 52242 USA. Univ Iowa, Roy J & Lucille A Carver Coll Med, Dept Physiol & Biophys, Iowa City, IA 52242 USA. Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. RP Welsh, MJ (reprint author), Univ Iowa, Roy J & Lucille A Carver Coll Med, Howard Hughes Med Inst, 500 EMRB, Iowa City, IA 52242 USA. EM michael-welsh@uiowa.edu FU NHLBI NIH HHS [HL51670, P01 HL051670]; NIAID NIH HHS [AI-13562, R21 AI013562, R01 AI013562]; NIDDK NIH HHS [P30 DK054759, DK54759] NR 46 TC 46 Z9 50 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 22 PY 2005 VL 102 IS 8 BP 2952 EP 2957 DI 10.1073/pnas.0409845102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 900RQ UT WOS:000227232400051 PM 15703296 ER PT J AU Roschke, AV Lababidi, S Tonon, G Gehlhaus, KS Bussey, K Weinstein, JN Kirsch, IR AF Roschke, AV Lababidi, S Tonon, G Gehlhaus, KS Bussey, K Weinstein, JN Kirsch, IR TI Karyotypic "state" as a potential determinant for anticancer drug discovery SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE cancer; chromosome; karyotypic complexity; NCI-60 ID CLINICOPATHOLOGICAL FEATURES; MOLECULAR PHARMACOLOGY; CANCER; ELLIPTICINE; TUMOR; BINDING; AGENT; DNA; ADENOCARCINOMAS; CYTOCHALASIN AB Cancer is a genetic disease caused by genomic instability. In many cancers, this instability is manifested by chromosomal reconfigurations and karyotypic complexity. These features are particular hallmarks of the epithelial cancers that are some of the malignancies most resistant to long term control by current chemotherapeutic agents. We have asked whether we could use karyotypic complexity and instability as determinants for the screening of potential anticancer compounds. Using a panel of well characterized cancer cell lines, we have been able to identify specific groups of chemical compounds that are more cytotoxic toward the relatively more karyotypically complex and unstable panel members. Thus, we delineate an approach for the identification of "lead compounds" for anticancer drug discovery complementary to those that are focused at the outset on a given gene or pathway. C1 NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. NCI, Mol Pharmacol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Kirsch, IR (reprint author), NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. EM kirschi@exchange.nih.gov OI Bussey, Kimberly/0000-0003-1001-8207 NR 33 TC 19 Z9 20 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 22 PY 2005 VL 102 IS 8 BP 2964 EP 2969 DI 10.1073/pnas.0405578102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 900RQ UT WOS:000227232400053 PM 15703300 ER PT J AU Brannon, AR Maresca, JA Boeke, JD Basrai, MA McBride, AA AF Brannon, AR Maresca, JA Boeke, JD Basrai, MA McBride, AA TI Reconstitution of papillomavirus E2-mediated plasmid maintenance in Saccharomyces cerevisiae by the Brd4 bromodomain protein SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE replication; yeast; segregation; bovine papillomavirus; human papillomavirus ID TYPE-1 E2 PROTEIN; MITOTIC CHROMOSOMES; EPISOMAL MAINTENANCE; HOST CHROMOSOMES; NUCLEAR ANTIGEN; YEAST; DNA; CHROMATIN; BINDING; GENE AB The papillomavirus E2 protein functions in viral transcriptional regulation, DNA replication, and episomal genome maintenance. Viral genomes are maintained in dividing cells by attachment to mitotic chromosomes by means of the E2 protein. To investigate the chromosomal tethering function of E2, plasmid stability assays were developed in Saccharomyces cerevisiae to determine whether the E2 protein could maintain plasmids containing the yeast autonomous replication sequence replication element but with the centromeric element replaced by E2-binding sites. E2 expression was not sufficient to maintain such plasmids, but plasmid stability could be rescued by expression of the mammalian protein Brd4. In the presence of both Brd4 and E2 proteins, plasmids with multiple E2-binding sites were stable without selection. S. cerevisiae encodes a homolog of Brd4 named Bdf1 that does not contain the C-terminal domain that interacts with the E2 protein. A fusion protein of Bdf1 and the Brd4 C-terminal "tail" could support E2-mediated plasmid maintenance in yeast. Using a panel of mutated E2 proteins, we determined that plasmid stability required the ability of E2 to bind DNA and to interact with Brd4 and mammalian mitotic chromosomes but did not require its replication initiation and transactivation functions. The S. cerevisiae-based plasmid maintenance assays described here are invaluable tools for dissecting mechanisms of episomal viral genome replication and screening for additional host protein factors involved in plasmid maintenance. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA. NCI, Genet Branch, NIH, Bethesda, MD 20889 USA. RP McBride, AA (reprint author), NIAID, Viral Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM amcbride@nih.gov OI Boeke, Jef/0000-0001-5322-4946; Maresca, Julia/0000-0002-3955-1585; McBride, Alison/0000-0001-5607-5157 NR 28 TC 35 Z9 36 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 FEB 22 PY 2005 VL 102 IS 8 BP 2998 EP 3003 DI 10.1073/pnas.0407818102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 900RQ UT WOS:000227232400059 PM 15710895 ER PT J AU Brochet, DXP Yang, DM Di Maio, A Lederer, WJ Franzini-Armstrong, C Cheng, HP AF Brochet, DXP Yang, DM Di Maio, A Lederer, WJ Franzini-Armstrong, C Cheng, HP TI Ca2+ blinks: Rapid nanoscopic store calcium signaling SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE calcium-induced calcium release; calcium spark; cardiac myocytes; endoplasmic reticulum; sarcoplasmic reticulum ID SARCOPLASMIC-RETICULUM CALCIUM; SKELETAL-MUSCLE; ENDOPLASMIC-RETICULUM; CARDIAC-MUSCLE; RYANODINE RECEPTORS; ELEMENTARY EVENTS; HEART-MUSCLE; 2 MECHANISMS; RELEASE; SPARKS AB Luminal Ca2+ in the endoplasmic and sarcoplasmic reticulum (ER/ SR) plays an important role in regulating vital biological processes, including store-operated capacitative Ca2+ entry, Ca2+-induced Ca2+ release, and ER/SR stress-mediated cell death. We report rapid and substantial decreases in luminal [Ca2+], called "Ca2+ blinks," within nanometer-sized stores (the junctional cisternae of the SIR) during elementary Ca2+ release events in heart cells. Blinks mirror small local increases in cytoplasmic Ca2+, or Ca2+ sparks, but changes of [Ca2+] in the connected free SIR network were below detection. Store microanatomy suggests that diffusional strictures may account for this paradox. Surprisingly, the nadir of the store depletion trails the peak of the spark by about 10 ms, and the refilling of local store occurs with a rate constant of 35 s(-1), which is approximate to6-fold faster than the recovery of local Ca2+ release after a spark. These data suggest that both local store depletion and some time-dependent inhibitory mechanism contribute to spark termination and refractoriness. Visualization of local store Ca2+ signaling thus broadens our understanding of cardiac store Ca2+ regulation and function and opens the possibility for local regulation of diverse store-dependent functions. C1 NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. Univ Penn, Dept Cell & Dev Biol, Philadelphia, PA 19104 USA. Univ Maryland, Inst Biotechnol, Ctr Med Biotechnol, Baltimore, MD 21201 USA. Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. Peking Univ, Natl Lab Biomembrane & Membrane Biotechnol, Beijing 100871, Peoples R China. RP Yang, DM (reprint author), NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. EM yangd1@grc.nia.nih.gov; chengp@grc.nia.nih.gov RI Lederer, William/B-1285-2010 NR 39 TC 133 Z9 135 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 22 PY 2005 VL 102 IS 8 BP 3099 EP 3104 DI 10.1073/pnas.0500059102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 900RQ UT WOS:000227232400076 PM 15710901 ER PT J AU Smith, DL Levin, SA Laxminarayan, R AF Smith, DL Levin, SA Laxminarayan, R TI Strategic interactions in multi-institutional epidemics of antibiotic resistance SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE game theory; nosocomial infections; infection control; optimal control; transmission dynamics ID HEALTH-CARE FACILITIES; STAPHYLOCOCCUS-AUREUS; TRANSMISSION DYNAMICS; ENTEROCOCCUS-FAECIUM; ACTIVE SURVEILLANCE; COLONIZED PATIENTS; GROWTH PROMOTERS; FOOD ANIMALS; HOSPITALS; SPREAD AB The increasing frequency of antibiotic resistance in hospital-acquired infections is a major public health concern that has both biological and economic causes. Here we develop conceptual mathematical models that couple the economic incentives and population biology of hospital infection control (HIC). We show that the optimal investment by a hospital for HIC changes with the proportion of patients already colonized with anti biotic-resistant bacteria (ARB) at the time of admission. As that proportion increases, the optimal behavior of a hospital is to increase spending to control ARB with low transmissibility and decrease spending on those with high transmissibility. In some cases, the global optimum investment in HIC can shift discontinuously from one that contains transmission to a do-nothing policy once the proportion already colonized at the time of admission becomes too great. We also show that investments in HIC are determined by a strategic game when several hospitals share patients. Hospitals acting selfishly and rationally will free-ride on the investments of other hospitals, and the level of free-riding should increase with the number of other hospitals in the area. Thus, in areas with many hospitals, the rational strategy for each hospital is to spend less than in areas with few hospitals. Thus, we predict that transmission rates and the prevalence of ARB should be higher in urban hospitals, for instance, compared with rural hospitals. We conclude that regional coordination and planning for HIC is an essential element of public health planning for hospital-acquired infections. C1 NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. Princeton Univ, Princeton, NJ 08544 USA. Resources Future Inc, Washington, DC 20036 USA. RP Smith, DL (reprint author), NIH, Fogarty Int Ctr, Bldg 10, Bethesda, MD 20892 USA. EM smitdave@helix.nih.gov RI Smith, David/L-8850-2013 OI Smith, David/0000-0003-4367-3849 NR 32 TC 60 Z9 60 U1 1 U2 13 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 22 PY 2005 VL 102 IS 8 BP 3153 EP 3158 DI 10.1073/pnas.0409523102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 900RQ UT WOS:000227232400085 PM 15677330 ER PT J AU Kaufmann, G Jeang, KT AF Kaufmann, G Jeang, KT TI Jacov Tal (1940-2005): remembrances of a friend SO RETROVIROLOGY LA English DT Biographical-Item AB An obituary commemorates the life and works of Jacov Tal. C1 NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. Tel Aviv Univ, Dept Biochem, IL-69978 Tel Aviv, Israel. RP Jeang, KT (reprint author), NIAID, Mol Microbiol Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM GabiKa@tauex.tau.ac.il; kj7e@nih.gov RI Jeang, Kuan-Teh/A-2424-2008 NR 0 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD FEB 22 PY 2005 VL 2 AR 12 DI 10.1186/1742-4690-2-12 PG 2 WC Virology SC Virology GA 032QZ UT WOS:000236790800002 PM 15725354 ER PT J AU Luo, DL Sun, H Xiao, RP Han, Q AF Luo, DL Sun, H Xiao, RP Han, Q TI Caffeine induced Ca2+ release and capacitative Ca2+ entry in human embryonic kidney (HEK293) cells SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE ryanodine receptor; HEK293 cells; Ca2+ release; capacitative Ca2+ entry ID RYANODINE RECEPTOR; SIGNALING PATHWAYS; HEK-293 CELLS; EXPRESSION; STORE; CALCIUM; SPECIFICITY; CHANNELS; ISOFORMS AB The potential role of endogenous ryanodine receptor (RyR) in modulating Ca2+ handling in HEK293 cells is controversial. Using Fura2/AM, here we provide evidence that caffeine can induce Ca2+ release from inositol 1,4,5-trisphosphate receptor-sensitive stores and Ca2+ entry in early passage numbers of HEK293 cells, but not in late passage ones. Ryanodine blocks caffeine-mediated effect, whereas 4-chloro-m-cresol can mimic these effects. In contrast, an increase in cyclic AMP or activation of voltage-dependent Ca2+ channels does not induce detectable alteration in intracellular Ca2+. Importantly, inummoblotting and staining have revealed that endogenous RyR expression is more abundant in the early than in the late passage cells. Additionally, similar to carbachol, Ca2+ entry in response to caffeine is blocked by capacitative Ca2+ entry inhibitors. These results indicate that the endogenous RyR in HEK293 cells can function as Ca2+ release channels and mediate capacitative Ca2+ entry, but they may be reduced due to cell passage. (C) 2005 Elsevier B.V. All rights reserved. C1 Peking Univ, Hlth Sci Ctr, Inst Cardiovasc Sci, Beijing 100083, Peoples R China. NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Luo, DL (reprint author), Peking Univ, Hlth Sci Ctr, Inst Cardiovasc Sci, Beijing 100083, Peoples R China. EM luodl@bjmu.edu.cn NR 25 TC 15 Z9 15 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD FEB 21 PY 2005 VL 509 IS 2-3 BP 109 EP 115 DI 10.1016/j.ejphar.2004.12.038 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 904AA UT WOS:000227466100003 PM 15733545 ER PT J AU Casciola-Rosen, L Nagaraju, K Plotz, P Wang, K Levine, S Gabrielson, E Corse, A Rosen, A AF Casciola-Rosen, L Nagaraju, K Plotz, P Wang, K Levine, S Gabrielson, E Corse, A Rosen, A TI Enhanced autoantigen expression in regenerating muscle cells in idiopathic inflammatory myopathy SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID MYOSITIS-SPECIFIC AUTOANTIBODIES; SYSTEMIC-LUPUS-ERYTHEMATOSUS; DEPENDENT PROTEIN-KINASE; MHC CLASS-I; SJOGRENS-SYNDROME; NUCLEOLAR PHOSPHOPROTEIN; IMMUNE-RESPONSES; EPITHELIAL-CELLS; TOPOISOMERASE-I; SKELETAL-MUSCLE AB Unique autoantibody specificities are strongly associated with distinct clinical phenotypes, making autoantibodies useful for diagnosis and prognosis. To investigate the mechanisms underlying this striking association, we examined autoantigen expression in normal muscle and in muscle from patients with autoimmune myositis. Although myositis autoantigens are expressed at very low levels in control muscle, they are found at high levels in myositis muscle. Furthermore, increased autoantigen expression correlates with differentiation state, such that myositis autoantigen expression is increased in cells that have features of regenerating muscle cells. Consistent with this, we found that cultured myoblasts express high levels of autoantigens, which are strikingly down-regulated as cells differentiate into myotubes in vitro. These data strongly implicate regenerating muscle cells rather than mature myotubes as the source of ongoing antigen supply in autoimmune myositis. Myositis autoantigen expression is also markedly increased in several cancers known to be associated with autoimmune myositis, but not in their related normal tissues, demonstrating that tumor cells and undifferentiated myoblasts are antigenically similar. We propose that in cancer-associated myositis, an autoimmune response directed against cancer cross-reacts with regenerating muscle cells, enabling a feed-forward loop of tissue damage and antigen selection. Regulating pathways of antigen expression may provide unrecognized therapeutic opportunities in autoimmune diseases. C1 Johns Hopkins Univ, Sch Med, Dept Med, Div Rheumatol, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Dermatol, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Cell Biol & Anat, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurol, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21224 USA. NIAMSD, Arthrit & Rheumatism Branch, Bethesda, MD 20892 USA. Armed Forces Inst Pathol, Dept Neuropathol, Washington, DC 20306 USA. RP Casciola-Rosen, L (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, Div Rheumatol, Baltimore, MD 21224 USA. EM lcr@jhmi.edu FU NCI NIH HHS [P50 CA088843, P50 CA058184, P50CA058184, P50CA088843]; NIAMS NIH HHS [AR-44684, R01 AR044684]; NIDCR NIH HHS [DE-12354, R01 DE012354, R37 DE012354] NR 59 TC 164 Z9 174 U1 0 U2 0 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD FEB 21 PY 2005 VL 201 IS 4 BP 591 EP 601 DI 10.1016/jem.20041367 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 901UH UT WOS:000227306900014 PM 15728237 ER PT J AU Wilson, TM Vaisman, A Martorno, SA Sullivan, P Lan, L Hanaoka, F Yasui, A Woodgate, R Gearhart, PJ AF Wilson, TM Vaisman, A Martorno, SA Sullivan, P Lan, L Hanaoka, F Yasui, A Woodgate, R Gearhart, PJ TI MSH2-MSH6 stimulates DNA polymerase eta, suggesting a role for A : T mutations in antibody genes SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CLASS-SWITCH RECOMBINATION; MISMATCH REPAIR PROTEIN; SINGLE-STRANDED-DNA; IMMUNOGLOBULIN VARIABLE GENES; CYTIDINE DEAMINASE AID; SOMATIC HYPERMUTATION; MICE DEFICIENT; MAMMALIAN-CELLS; ATPASE ACTIVITY; CUTTING EDGE AB Activation-induced cytidine deaminase deaminates cytosine to uracil (dU) in DNA, which leads to mutations at C:G basepairs in immunoglobulin genes during somatic hypermutation. The mechanism that generates mutations at A:T basepairs, however, remains unclear. It appears to require the MSH2-MSH6 mismatch repair heterodimer and DNA polymerase (pol) eta, as mutations of A:T are decreased in mice and humans lacking these proteins. Here, we demonstrate that these proteins interact physically and functionally. First, we show that MSH2-MSH6 binds to a U:G mismatch but not to other DNA intermediates produced during base excision repair of dUs, including an abasic site and a deoxyribose phosphate group. Second, MSH2 binds to pol eta in solution, and endogenous MSH2 associates with the pol in cell extracts. Third, MSH2-MSH6 stimulates the catalytic activity of pol eta in vitro. These observations suggest that the interaction between MSH2-MSH6 and DNA pol eta stimulates synthesis of mutations at bases located downstream of the initial dU lesion, including A:T pairs. C1 NIA, Lab Mol Gerontol, Bethesda, MD 20892 USA. Univ Maryland, Dept Radiat Oncol, Radiat Oncol Res Lab, Baltimore, MD 21201 USA. NICHHD, Sect DNA Replicat Repair & Mutagenesis, Lab Genom Integr, NIH, Bethesda, MD 20892 USA. Tohoku Univ, Inst Dev Aging & Canc, Dept Mol Genet, Sendai, Miyagi 9808575, Japan. Osaka Univ, Grad Frontier Biosci, Suita, Osaka 5650871, Japan. RP Gearhart, PJ (reprint author), NIA, Lab Mol Gerontol, Bethesda, MD 20892 USA. EM gearhartp@grc.nih.gov RI Vaisman, Alexandra/C-3766-2013 OI Vaisman, Alexandra/0000-0002-2521-1467 FU NCI NIH HHS [CA96590] NR 62 TC 116 Z9 116 U1 0 U2 3 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD FEB 21 PY 2005 VL 201 IS 4 BP 637 EP 645 DI 10.1084/jem.20042066 PG 9 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 901UH UT WOS:000227306900018 PM 15710654 ER PT J AU Miller, DW Crawley, A Gwinn-Hardy, K Lopez, G Nussbaum, R Cookson, MR Singleton, AB Hardy, J Dogu, O AF Miller, DW Crawley, A Gwinn-Hardy, K Lopez, G Nussbaum, R Cookson, MR Singleton, AB Hardy, J Dogu, O TI Unaltered alpha-synuclein blood levels in juvenile Parkinsonism with a parkin exon 4 deletion SO NEUROSCIENCE LETTERS LA English DT Article DE alpha-synuclein; autosomal recessive juvenile Parkinsonism; Lewy body; Parkin; proteasome ID DISEASE; GENE; ASSOCIATION; MUTATIONS; FAMILIES; NEURONS; BRAIN AB We recently reported here that SNCA triplication results in a doubling in the amount of a-synuclein protein in blood from cases with hereditary Lewy body disease. This observation shows that alpha-synuclein levels in blood accurately reflect gene dosage, which we assume drives pathogenesis in these individuals. A previous report has suggested that parkin can affect a-synuclein metabolism in human brain. Here we have tested whether there is also an increase of a-synuclein in autosomal recessive juvenile Parkinsonism (ARJP). We find there is not and discuss this result in terms of the putative relationships between alpha-synuclein and parkin. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Lab Genet Dis, NIH, Bethesda, MD 20892 USA. Mersin Univ, Fac Med, Dept Neurol, Mersin, Turkey. RP Miller, DW (reprint author), NIA, Neurogenet Lab, NIH, Bldg 35,Rm 1A-100,35 Convent Dr, Bethesda, MD 20892 USA. EM millerda@mail.nih.gov RI Gwinn, Katrina/C-2508-2009; Dogu, Okan/A-2045-2010; Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; OI Gwinn, Katrina/0000-0002-8277-651X NR 17 TC 9 Z9 10 U1 0 U2 0 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD FEB 21 PY 2005 VL 374 IS 3 BP 189 EP 191 DI 10.1016/j.neulet.2004.10.053 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 895XE UT WOS:000226896700008 PM 15663960 ER PT J AU Miller, DW Wilson, CR Kaleem, MA Blackinton, J Cookson, MR AF Miller, DW Wilson, CR Kaleem, MA Blackinton, J Cookson, MR TI Identification of the epitope of a monoclonal antibody to DJ-1 SO NEUROSCIENCE LETTERS LA English DT Article DE DJ-1; early onset parkinsonism; epitope map; PARK7; Parkinson's disease ID PARKINSONS-DISEASE; PROTEIN DJ-1; LOCALIZATION; INHIBITION; EXPRESSION; MUTATIONS; SYSTEM; PARK7 AB Mutations in DJ-1 can cause early onset parkinsonism. Various antibodies have been generated to detect this protein, one of which is a commonly used monoclonal antibody (clone 3E8). Since results of in situ examinations of DJ-1 expression with this antibody have differed from analyses with species-specific antibodies (e.g. rat), it would be useful to know the epitope for this antibody. Using GFP-tagged deletion constructs of human DJ-1, we have localized the epitope region for this antibody to within residues 56-78 of human DJ-1. Mapping this region to the published three-dimensional structure of DJ-1 indicates that this is a solvent-accessible surface epitope. Immunonegativity of E64D mutant DJ-1 with the monoclonal antibody suggests that glutamate 64 of human DJ-1 contributes to the epitope recognized by this antibody. Moreover, the loss of immunoreactivity due to such a small substitution demonstrates the remarkable sensitivity of the monoclonal antibody 3E8 to DJ-1. Published by Elsevier Ireland Ltd. C1 NIA, Neurogenet Lab, Bethesda, MD 20892 USA. RP Miller, DW (reprint author), NIA, Neurogenet Lab, Bldg 35,Rm 1A-1002,35 Convent Dr, Bethesda, MD 20892 USA. EM millerda@mail.nih.gov NR 15 TC 3 Z9 3 U1 0 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD FEB 21 PY 2005 VL 374 IS 3 BP 203 EP 206 DI 10.1016/j.neulet.2004.10.088 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 895XE UT WOS:000226896700011 PM 15663963 ER PT J AU Rollison, DEM Utaipat, U Ryschkewitsch, C Hou, J Goldthwaite, P Daniel, R Helzlsouer, KJ Burger, PC Shah, KV Major, EO AF Rollison, DEM Utaipat, U Ryschkewitsch, C Hou, J Goldthwaite, P Daniel, R Helzlsouer, KJ Burger, PC Shah, KV Major, EO TI Investigation of human brain tumors for the presence of polyomavirus genome sequences by two independent laboratories SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article ID HUMAN NEUROTROPIC POLYOMAVIRUS; CENTRAL-NERVOUS-SYSTEM; VIRUS-DNA SEQUENCE; LARGE T-ANTIGEN; JC VIRUS; BK VIRUS; GLIOBLASTOMA-MULTIFORME; ONCOGENIC PROTEIN; SIMIAN VIRUS-40; SV40 AB JC virus (JCV), BK virus (BKV) and simian virus 40 (SV40) may be associated with human brain tumors. These polyomaviruses have been shown to induce brain tumors in experimentally infected animals. Several studies have found polyomavirus genomic sequences in human brain tumor tissues by using polymerase chain reaction (PCR), while others have not. Inconsistencies in previous findings may be due in part to small sample sizes and differences in underlying patient populations, laboratory techniques and quality control measures. To assess the role of polyomaviruses in human brain tumors and address inconsistencies of previous reports, we investigated the prevalence of viral sequences in a series of 225 brain tumor tissue specimens in 2 independent laboratories. PCR followed by Southern hybridization was performed at the National Institute of Neurological Disorders and Stroke (NINDS). Real-time quantitative PCR was performed on the same tissues at Johns Hopkins University (JHU). Only those tumors with amplifiable DNA were tested further for polyomavirus sequences. Positive and negative control tissues were included, and all specimens were masked. Amplifiable DNA was detected in 225/225 (100%) tumors at NINDS, 9 (4%) of which contained polyomavirus sequences (3 JCV-positive, 3 BKV-positive and 3 SV40-positive). The JHU laboratory amplified DNA from 165/225 (73%) tumors, of which 1 tumor tested positive (for SV40). No tumors tested positive in both laboratories. Results for masked quality control tissues were concordant between laboratories. Nucleotide sequences for JCV, BKV and SV40 are rarely present in a large series of adult and pediatric brain tumors. (C) 2004 Wiley-Liss, Inc. C1 NINDS, Mol Med & Virol Sect, Lab Mol Med & Neurosci, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Dept Epidemiol, Bloomberg Sch Publ Hlth, Baltimore, MD USA. Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Dept Mol Microbiol & Immunol, Baltimore, MD USA. RP Major, EO (reprint author), NINDS, Mol Med & Virol Sect, Lab Mol Med & Neurosci, Bldg 36,Room 5W21,36 Convent Dr,MSC 4164, Bethesda, MD 20892 USA. EM majorg@ninds.nih.gov NR 39 TC 48 Z9 52 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 20 PY 2005 VL 113 IS 5 BP 769 EP 774 DI 10.1002/ijc.20641 PG 6 WC Oncology SC Oncology GA 887HE UT WOS:000226295700011 PM 15499616 ER PT J AU Raju, J Swamy, MV Cooma, I Patlolla, JMR Pittman, B Reddy, BS Steele, VE Rao, CV AF Raju, J Swamy, MV Cooma, I Patlolla, JMR Pittman, B Reddy, BS Steele, VE Rao, CV TI Low doses of beta-carotene and lutein inhibit AOM-induced rat colonic ACF formation but high doses augment ACF incidence SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE colon cancer; aberrant crypt foci; chemoprevention; beta-carotene; lutein ID ABERRANT CRYPT FOCI; LUNG-CANCER; DIETARY CAROTENOIDS; CARDIOVASCULAR-DISEASE; BIOLOGICAL ACTIONS; COLORECTAL-CANCER; SERUM CAROTENOIDS; BREAST-CANCER; VITAMIN-A; RISK AB Epidemiological studies suggest that carotenoids such as beta-carotene and lutein play an important role in reducing the risk for several cancers. However, in colon cancer there is ambiguity with regard to the role of these compounds in that both preventive effects and tumor promotion have been observed. In the present study we observed that male F344 rats were able to tolerate up to 2,500 ppm of beta-carotene as well as of lutein. We have then assessed the chemopreventive efficacy of beta-carotene and lutein at dose levels of similar to4 and 8% of the 2,500 ppm tolerated dose (TD) and also similar to40 and 80% of the TD on azoxymethane (AOM)-induced colon carcinogenesis, using aberrant crypt foci (ACF) as a surrogate biomarker for colon cancer. Throughout the experiments, 5-week-old male F344 rats were fed the control diet (modified AIN-76A) or experimental diets containing 100 or 200 ppm (similar to4 or 8% of the 2,500 ppm TD), or 1,000 or 2,000 ppm (similar to40 or 80% of the 2,500 ppm TD) of beta-carotene and lutein (n=10 rats/group). After 2 weeks on the experimental or control diets, all animals were injected with AOM (15 mg/kg body wt., once weekly for 2 weeks). At 14 weeks of age, all rats were killed, and their colons were evaluated for ACF. Administration of 100 or 200 ppm of beta-carotene inhibited AOM-induced total colonic ACF formation by 24% (p<0.01) and 36% (p<0.001), respectively, whereas lutein at 200 ppm produced a 27% inhibition (p<0.01) yet had no significant effect at the 100 ppm dose level. Surprisingly, administration of 1,000 or 2,000 ppm of beta-carotene and lutein increased colonic ACF formation in a dose-dependent manner, i.e., to 124% and 144% for the former and 110% and 159% for the latter. These results clearly suggest that further studies are warranted to determine whether the increase in ACF incidence by high doses of beta-carotene and lutein will also lead to an increase in tumor outcome. Taken together these data indicate that the chemopreventive activity of beta-carotene and lutein against colon carcinogenesis depends on the dose level. (C) 2004 Wiley-Liss, Inc. C1 Amer Hlth Fdn, Ctr Canc, Inst Canc Prevent, Chemoprevent Program, Valhalla, NY 10595 USA. Amer Hlth Fdn, Ctr Canc, Inst Canc Prevent, Biostat Facil, Valhalla, NY 10595 USA. NCI, Div Canc Prevent & Control, Bethesda, MD 20892 USA. RP Rao, CV (reprint author), Univ Oklahoma, Hlth Sci Ctr, Dept Med, Heam Onc Sect, POB 26901,920 Stanton L Yound Blvd, Oklahoma City, OK 73104 USA. RI Chinthalapally, Rao/B-3633-2010 FU NCI NIH HHS [CA65108] NR 57 TC 19 Z9 20 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 20 PY 2005 VL 113 IS 5 BP 798 EP 802 DI 10.1002/ijc.20640 PG 5 WC Oncology SC Oncology GA 887HE UT WOS:000226295700015 PM 15499611 ER PT J AU Weil, RJ Lonser, RR AF Weil, RJ Lonser, RR TI Selective excision of metastatic brain tumors originating in the motor cortex with preservation of function SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Article ID PARTITIONING ANALYSIS RPA; GAMMA-KNIFE RADIOSURGERY; RANDOMIZED-TRIAL; PROGNOSTIC-FACTORS; SINGLE METASTASES; RADIATION-THERAPY; AWAKE CRANIOTOMY; ELOQUENT BRAIN; RADIOTHERAPY; SURGERY AB Purpose Brain metastases are common in patients with cancer and can cause considerable morbidity or death. Metastasis in eloquent areas of the brain, particularly the primary motor cortex, may present significant treatment challenges. Patients and Methods Seventeen consecutive patients with metastasis within the primary motor cortex underwent selective microsurgical tumor resection. Operative, hospital, neuroimaging, and follow-up information was reviewed. Results There were 10 women and seven men (mean age, 54.3 years) who underwent 17 operations for symptomatic brain metastases. Motor cortex was identified and tumor (mean volume, 10.2 cm(3)) was completely resected in all patients. Three patients had transient or reversible complications, Karnofsky performance scores improved in 16 of 17 patients at 4 weeks postoperatively, with a mean improvement of 1.8 grades compared with preoperative scores (P < .05). Overall survival of 16 patients with distant follow-up > 6 months or until death) averaged 10.6 +/- 4.4 months, with nine of 16 (56%) assessable patients surviving 1 year or longer. Survival of these 16 patients, by recursive partitioning analysis (RPA), was 11.2, 13.3, and 6.7 months for RPA classes I, II, and III, respectively. The cause of death in 14 of 15 patients who have died was progressive systemic disease; in one patient it was a combination of systemic and distant CNS disease progression. There were no local CNS recurrences. Conclusion Complete microsurgical resection of metastatic tumors in the primary motor cortex is feasible and efficacious, results in a sustained improvement in performance outcomes, and permits satisfactory long-term survival. C1 Cleveland Clin Fdn, Brain Tumor Inst, Taussig Canc Ctr, Cleveland, OH 44195 USA. Vanderbilt Univ, Sch Med, Dept Neurosurg, Nashville, TN USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD USA. RP Weil, RJ (reprint author), Cleveland Clin Fdn, Brain Tumor Inst, Taussig Canc Ctr, 9500 Euclid Ave,Desk R-20, Cleveland, OH 44195 USA. EM weilr@ccf.org NR 37 TC 14 Z9 15 U1 0 U2 1 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2005 VL 23 IS 6 BP 1209 EP 1217 DI 10.1200/JCO.2005.04.124 PG 9 WC Oncology SC Oncology GA 898ZP UT WOS:000227115000022 PM 15718318 ER PT J AU Gupta, N Arthos, J Khazanie, P Steenbeke, TD Censoplano, NM Chung, EA Cruz, CC Chaikin, MA Daucher, M Kottilil, S Mavilio, D Schuck, P Sun, PD Rabin, RL Radaev, S Van Ryk, D Cicala, C Fauci, AS AF Gupta, N Arthos, J Khazanie, P Steenbeke, TD Censoplano, NM Chung, EA Cruz, CC Chaikin, MA Daucher, M Kottilil, S Mavilio, D Schuck, P Sun, PD Rabin, RL Radaev, S Van Ryk, D Cicala, C Fauci, AS TI Targeted lysis of HIV-infected cells by natural killer cells armed and triggered by a recombinant immunoglobulin fusion protein: implications for immunotherapy SO VIROLOGY LA English DT Article DE natural killer cell; antibody dependent cellular cytotoxicity; immunotherapy; HIV; CD16; recombinant antibody ID DEPENDENT CELLULAR CYTOTOXICITY; SEROPOSITIVE INDIVIDUALS; ANTIBODY; RECEPTOR; NEUTRALIZATION; GLYCOPROTEIN; EPITOPE; INVIVO; SIGNAL; SITES AB Natural killer (NK) cells play an important role in both innate and adaptive antiviral immune responses. The adaptive response typically requires that virus-specific antibodies decorate infected cells which then direct NK cell lysis through a CD16 mediated process termed antibody-dependent cellular cytotoxicity (ADCC). In this report, we employ a highly polymerized chimeric IgG1/IgA immunoglobulin (Ig) fusion protein that, by virtue of its capacity to extensively crosslink CD16, activates NK cells while directing the lysis of infected target cells. We employ HIV as a model system, and demonstrate that freshly isolated NK cells preloaded with an HIV gp120-specific chimeric IgG1/IgA fusion protein efficiently lyse HIV-infected target cells at picomolar concentrations. NK cells pre-armed in this manner retain the capacity to kill targets over an extended period of time. This strategy may have application to other disease states including various viral infections and cancers. Published by Elsevier Inc. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. NIH, Prot Biophys Resource, DPBS, ORS, Bethesda, MD 20892 USA. NIAID, Immunogenet Lab, NIH, Bethesda, MD 20892 USA. US FDA, Div Bacterial Parasit & Allergen Prod, CBER, Bethesda, MD 20892 USA. RP Arthos, J (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10 6A08,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jarthos@niaid.nih.gov OI Schuck, Peter/0000-0002-8859-6966; Mavilio, Domenico/0000-0001-6147-0952 NR 26 TC 21 Z9 24 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 0042-6822 J9 VIROLOGY JI Virology PD FEB 20 PY 2005 VL 332 IS 2 BP 491 EP 497 DI 10.1016/j.virol.2004.12.018 PG 7 WC Virology SC Virology GA 896EU UT WOS:000226918200003 PM 15680414 ER PT J AU Ravitsky, V AF Ravitsky, V TI Timers on ventilators SO BRITISH MEDICAL JOURNAL LA English DT Article C1 NIH, Warren G Magnuson Clin Ctr, Dept Clin Bioeth, Bethesda, MD 20892 USA. NHGRI, Social & Behav Res Branch, Bethesda, MD 20892 USA. RP Ravitsky, V (reprint author), NIH, Warren G Magnuson Clin Ctr, Dept Clin Bioeth, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM vravitsky@mail.mih.gov NR 11 TC 41 Z9 41 U1 0 U2 0 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 FEB 19 PY 2005 VL 330 IS 7488 BP 415 EP 417 DI 10.1136/bmj.330.7488.415 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 900NA UT WOS:000227220400026 PM 15718544 ER PT J AU Reichelt, ME Willems, L Molina, JG Sun, CX Noble, JC Ashton, KJ Schnermann, J Blackburn, MR Headrick, JP AF Reichelt, ME Willems, L Molina, JG Sun, CX Noble, JC Ashton, KJ Schnermann, J Blackburn, MR Headrick, JP TI Genetic deletion of the A(1) adenosine receptor limits myocardial ischemic tolerance SO CIRCULATION RESEARCH LA English DT Article DE adenosine; A(1) adenosine receptor; gene knockout; ischemia; reperfusion ID INFARCT SIZE-REDUCTION; ENDOGENOUS ADENOSINE; MOUSE HEART; DEPENDENT MECHANISMS; CARDIAC FIBROBLASTS; REPERFUSION INJURY; A(2B) RECEPTORS; RAT-HEART; CARDIOPROTECTION; STIMULATION AB Adenosine receptors may be important determinants of intrinsic ischemic tolerance. Genetically modified mice were used to examine effects of global A(1) adenosine receptor (A(1)AR) knockout (KO) on function and ischemic tolerance in perfused mouse hearts. Baseline contractile function and heart rate were unaltered by A(1)AR KO, which was shown to abolish the negative chronotropic effects of 2-chloroadenosine (A(1)AR-mediated) without altering A(2) adenosine receptor-mediated coronary dilation. Tolerance to 25 minutes global normothermic ischemia (followed by 45 minutes reperfusion) was significantly limited by A(1)AR KO, with impaired contractile recovery (reduced by approximate to25%) and enhanced lactate dehydrogenase (LDH) efflux (increased by approximate to100%). Functional effects of A(1)AR KO involved worsened systolic pressure development with little to no change in diastolic dysfunction. In contrast, cardiac specific A(1)AR overexpression enhanced ischemic tolerance with a primary action on diastolic dysfunction. Nonselective receptor agonism (10 mumol/L 2-chloroadenosine) protected wild-type and also A(1)AR KO hearts (albeit to a lesser extent), implicating protection via subtypes additional to A(1)ARs. However, A(1)AR KO abrogated effects of 2-chloroadenosine on ischemic contracture and diastolic dysfunction. These data are the first demonstrating global deletion of the A(1)AR limits intrinsic myocardial resistance to ischemia. Data indicate the function of intrinsically activated A(1)ARs appears primarily to be enhancement of postischemic contractility and limitation of cell death. C1 Griffith Univ, Heart Fdn Res Ctr, Southport, Qld 4217, Australia. Univ Texas, Hlth Sci Ctr, Dept Biochem & Mol Biol, Houston, TX USA. NIDDKD, NIH, Bethesda, MD 20892 USA. RP Headrick, JP (reprint author), Griffith Univ, Heart Fdn Res Ctr, Southport, Qld 4217, Australia. EM J.Headrick@griffith.edu.au RI Willems, Laura/B-6259-2009; Reichelt, Melissa/C-9579-2014; Ashton, Kevin/R-2147-2016; OI Reichelt, Melissa/0000-0002-5059-2046; Ashton, Kevin/0000-0001-6106-3425; Blackburn, Michael/0000-0002-1394-9966 FU NIAID NIH HHS [AI-43572] NR 42 TC 45 Z9 45 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0009-7330 J9 CIRC RES JI Circ.Res. PD FEB 18 PY 2005 VL 96 IS 3 BP 363 EP 367 DI 10.1161/01.RES.0000156075.00127.C3 PG 5 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 898PG UT WOS:000227088100014 PM 15653569 ER PT J AU Corpe, CP Lee, JH Kwon, O Eck, P Narayanan, J Kirk, KL Levine, M AF Corpe, CP Lee, JH Kwon, O Eck, P Narayanan, J Kirk, KL Levine, M TI 6-bromo-6-deoxy-L-ascorbic acid - An ascorbate analog specific for Na+-dependent vitamin C transporter but not glucose transporter pathways SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RECOMMENDED DIETARY ALLOWANCE; DEHYDROASCORBIC ACID; HUMAN-NEUTROPHILS; XENOPUS OOCYTES; ACCUMULATION; CELLS; CLONING; BRAIN AB Vitamin C intracellular accumulation is mediated by Na+-dependent vitamin C transporters SVCT1 and -2 and dehydroascorbic acid transporters GLUT1 and -3. It is unclear which pathways dominate in vivo. As a new step to resolve this issue, we identified and tested 6-bromo-6-deoxy-L-ascorbic acid as a specific candidate for SVCTs. In high performance liquid chromatography and electron paramagnetic resonance analyses, the reduced compounds ascorbic acid and 6-bromo-6-deoxy-L-ascorbic acid were similar. The oxidized products 6-bromo-6-deoxy dehydroascorbic acid (BrDHA) and dehydroascorbic acid (DHA) had comparable stabilities, based on reduction recoveries. Upon expression of GLUT1 or GLUT3 in Xenopus oocytes, BrDHA was neither transported nor bound, in contrast to robust transport of DHA. The findings were not explained by differences in the oocyte reduction of DHA and BrDHA because lysed oocytes reduced both compounds equally. Further, there was no transport of the reduced compound, 6-bromo-6-deoxy-L-ascorbic acid, by GLUT1 or GLUT3. As a prerequisite for investigating 6-bromo-6-deoxy-L-ascorbic acid transported by SVCTs, SVCT2 transport activity in oocytes was enhanced 14-fold by construction and use of a vector that added a fixed poly(A) tail to the 3' end of cRNA. For SVCT1 and SVCT2 expressed in oocytes, similar K-m and V.. values were observed for ascorbic acid and 6-bromo-6-deoxy-L-ascorbic acid. In human fibroblasts, predicted to have SVCT-mediated ascorbate accumulation, K-m and V-max values were again comparable for ascorbic acid and 6-bromo-6-deoxy-L-ascorbic acid. Using activated human neutrophils, predicted to have ascorbate accumulation mediated predominantly by DHA and GLUT transporters, 6-bromo-6-deoxy-L-ascorbic acid accumulation was <1% of accumulation when compared with ascorbic acid. We conclude that 6-bromo-6-deoxy-L-ascorbic acid is the first transport substrate identified as completely specific for SVCTs, but not GLUTs, and provide a new strategy to determine the contribution of each pathway to ascorbate accumulation. C1 NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Levine, M (reprint author), NIDDK, Mol & Clin Nutr Sect, Digest Dis Branch, NIH, Bldg 10,Rm 4D52,MSC 1372, Bethesda, MD 20892 USA. EM markl@intra.niddk.nih.gov OI Eck, Peter/0000-0003-2371-9774 NR 33 TC 50 Z9 51 U1 3 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 18 PY 2005 VL 280 IS 7 BP 5211 EP 5220 DI 10.1074/jbc.M412925200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 900LT UT WOS:000227217100014 PM 15590689 ER PT J AU Sharma, S Hoskins, JR Wickner, S AF Sharma, S Hoskins, JR Wickner, S TI Binding and degradation of heterodimeric substrates by ClpAP and ClpXP SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HEAT-SHOCK PROTEIN; ESCHERICHIA-COLI; MOLECULAR CHAPERONE; CRYSTAL-STRUCTURE; DEPENDENT PROTEASES; HSP100 CHAPERONE; TAGGING SYSTEM; MU-TRANSPOSASE; MACHINE; COMPLEX AB CIpA and CIpX function both as molecular chaperones and as the regulatory components of CIpAP and CIpXP proteases, respectively. CIpA and ClpX bind substrate proteins through specific recognition signals, catalyze ATP-dependent protein unfolding of the substrate, and when in complexes with ClpP translocate the unfolded polypeptide into the cavity of the CIpP peptidase for degradation. To examine the mechanism of interaction of CIpAP with dimeric substrates, single round binding and degradation experiments were performed, revealing that CIpAP degraded both subunits of a RepA homodimer in one cycle of binding. Furthermore, CIpAP was able to degrade both protomers of a RepA heterodimer in which only one subunit contained the CIpA recognition signal. In contrast, ClpXP degraded both subunits of a dimeric substrate only when both protomers contained a recognition signal. These data suggest that CIpAP and ClpXP may recognize and bind substrates in significantly different ways. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Wickner, S (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37,Rm 5144,37 Convent Dr, Bethesda, MD 20892 USA. EM suewick@helix.nih.gov NR 48 TC 11 Z9 11 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 18 PY 2005 VL 280 IS 7 BP 5449 EP 5455 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 900LT UT WOS:000227217100042 PM 15591068 ER PT J AU Carlson, BA Xu, XM Gladyshev, VN Hatfield, DL AF Carlson, BA Xu, XM Gladyshev, VN Hatfield, DL TI Selective rescue of selenoprotein expression in mice lacking a highly specialized methyl group in selenocysteine tRNA SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TARGETED DISRUPTION; SELENIUM DEFICIENCY; MESSENGER-RNAS; KNOCKOUT MICE; GPX2 GENES; MOUSE; CANCER; TRANSLATION; PROTEIN; TRSP AB Selenocysteine (Sec) is the 21st amino acid in the genetic code. Its tRNA is variably methylated on the 2'-0hydroxyl site of the ribosyl moiety at position 34 (Um34). Herein, we identified a role of Um34 in regulating the expression of some, but not all, selenoproteins. A strain of knock-out transgenic mice was generated, wherein the Sec tRNA gene was replaced with either wild type or mutant Sec tRNA transgenes. The mutant transgene yielded a tRNA that lacked two base modifications, Nisopentenyladenosine at position 37 (i(6) A37) and Um34. Several selenoproteins, including glutathione peroxidases 1 and 3, SeIR, and SelT, were not detected in mice rescued with the mutant transgene, whereas other selenoproteins, including thioredoxin reductases 1 and 3 and glutathione peroxidase 4, were expressed in normal or reduced levels. Northern blot analysis suggested that other selenoproteins (e.g. SeIW) were also poorly expressed. This novel regulation of protein expression occurred at the level of translation and manifested a tissue-specific pattern. The available data suggest that the Um34 modification has greater influence than the VA37 modification in regulating the expression of various mammalian selenoproteins and Um34 is required for synthesis of several members of this protein class. Many proteins that were poorly rescued appear to be involved in responses to stress, and their expression is also highly dependent on selenium in the diet. Furthermore, their mRNA levels are regulated by selenium and are subject to nonsense-mediated decay. Overall, this study described a novel mechanism of regulation of protein expression by tRNA modification that is in turn regulated by levels of the trace element, selenium. C1 NCI, Canc Res Ctr, Lab Canc Prevent, Mol Biol Selnium Sect,NIH, Bethesda, MD 20892 USA. Univ Nebraska, Dept Biochem, Lincoln, NE 68588 USA. RP Hatfield, DL (reprint author), NCI, Canc Res Ctr, Lab Canc Prevent, Mol Biol Selnium Sect,NIH, Bldg 37,Rm 6032A, Bethesda, MD 20892 USA. EM hatfield@dc37a.nci.nih.gov RI Gladyshev, Vadim/A-9894-2013 FU NIGMS NIH HHS [GM061603] NR 45 TC 82 Z9 85 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 18 PY 2005 VL 280 IS 7 BP 5542 EP 5548 DI 10.1074/jbc.M411725200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 900LT UT WOS:000227217100054 PM 15611090 ER PT J AU Li, B Nowak, NM Kim, SK Jacobson, KA Bagheri, A Schmidt, C Wess, J AF Li, B Nowak, NM Kim, SK Jacobson, KA Bagheri, A Schmidt, C Wess, J TI Random mutagenesis of the M-3 muscarinic acetylcholine receptor expressed in yeast - Identification of second-site mutations that restore function to a coupling-deficient mutant M-3 receptor SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SITE-DIRECTED MUTAGENESIS; CONSERVED ASPARTATE RESIDUE; 2ND TRANSMEMBRANE DOMAIN; 3RD CYTOPLASMIC LOOP; G-PROTEIN; LIGAND-BINDING; PHOSPHOLIPASE-C; HUMAN GENOME; AMINO-ACIDS; 7-TRANSMEMBRANE RECEPTORS AB The M, muscarinic receptor is a prototypical member of the class A family of G protein-coupled receptors (GPCRs). To gain insight into the structural mechanisms governing agonist-mediated M, receptor activation, we recently developed a genetically modified yeast strain (Saccharomyces cerevisiae) which allows the efficient screening of large libraries of mutant M-3 receptors to identify mutant receptors with altered/novel functional properties. Class A GPCRs contain a highly conserved Asp residue located in transmembrane domain II (TM II; corresponding to Asp-113 in the rat M-3 muscarinic receptor) which is of fundamental importance for receptor activation. As observed previously with other GPCRs analyzed in mammalian expression systems, the D113N point mutation abolished agonist-induced receptor/protein coupling in yeast. We then subjected the D113N mutant M, receptor to PCR-based random mutagenesis followed by a yeast genetic screen to recover point mutations that can restore G protein coupling to the D113N mutant receptor. A large scale screening effort led to the identification of three such second-site suppressor mutations, R165W, R165M, and Y250D. When expressed in the wild-type receptor background, these three point mutations did not lead to an increase in basal activity and reduced the efficiency of receptor/G protein coupling. Similar results were obtained when the various mutant receptors were expressed and analyzed in transfected mammalian cells (COS-7 cells). Interestingly, like Asp-113, Arg-165 and Tyr-250, which are located at the cytoplasmic ends of TM III and TM V, respectively, are also highly conserved among class A GPCRs. Our data suggest a conformational link between the highly conserved Asp-113, Arg-165, and Tyr-250 residues which is critical for receptor activation. C1 NIDDK, Dept Mol Signaling, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. NIDDK, Dept Mol Recognit, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP NIDDK, Dept Mol Signaling, Bioorgan Chem Lab, NIH, Bldg 8A,Rm B1A-05,8 Ctr Dr,MSC 0810, Bethesda, MD 20892 USA. EM jwess@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 NR 70 TC 28 Z9 28 U1 0 U2 1 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 18 PY 2005 VL 280 IS 7 BP 5664 EP 5675 DI 10.1074/jbc.M4116223200 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 900LT UT WOS:000227217100068 PM 15572356 ER PT J AU Ye, L Mishina, Y Chen, D Huang, HY Dallas, SL Dallas, MR Sivakumar, P Kunieda, T Tsutsui, TW Boskey, A Bonewald, LF Feng, JQ AF Ye, L Mishina, Y Chen, D Huang, HY Dallas, SL Dallas, MR Sivakumar, P Kunieda, T Tsutsui, TW Boskey, A Bonewald, LF Feng, JQ TI Dmp1-deficient mice display severe defects in cartilage formation responsible for a chondrodysplasia-like phenotype SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DENTIN MATRIX PROTEIN-1; BONE-FORMATION; IN-VIVO; ACIDIC PHOSPHOPROTEIN; GROWTH-PLATE; GENE; CBFA1; DIFFERENTIATION; ANGIOGENESIS; CHONDROCYTES AB Understanding the molecular mechanisms by which cartilage formation is regulated is essential toward understanding the physiology of both embryonic bone development and postnatal bone growth. Although much is known about growth factor signaling in cartilage formation, the regulatory role of noncollagenous matrix proteins in this process are still largely unknown. In the present studies, we present evidence for a critical role of DMP1 (dentin matrix protein 1) in postnatal chondrogenesis. The Dmp1 gene was originally identified from a rat incisor cDNA library and has been shown to play an important role in late stage dentinogenesis. Whereas no apparent abnormalities were observed in prenatal bone development, Dmp1-deficient (Dmp1(-I-)) mice unexpectedly develop a severe defect in cartilage formation during postnatal chondrogenesis. Vertebrae and long bones in Dmp1-deficient (Dmp1(-I-)) mice are shorter and wider with delayed and malformed secondary ossification centers and an irregular and highly expanded growth plate, results of both a highly expanded proliferation and a highly expanded hypertrophic zone creating a phenotype resembling dwarfism with chondrodysplasia. This phenotype appears to be due to increased cell proliferation in the proliferating zone and reduced apoptosis in the hypertrophic zone. In addition, blood vessel invasion is impaired in the epiphyses of Dmp1(-I-) mice. These findings show that DMP1 is essential for normal postnatal chondrogenesis and subsequent osteogenesis. C1 Univ Missouri, Sch Dent, Dept Oral Biol, Kansas City, MO 64108 USA. NIEHS, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Rochester, Sch Med & Dent, Dept Orthopaed, Rochester, NY 14642 USA. Third Mil Med Univ, Daping Hosp, Dept Orthopaed Surg, Chongqing 400042, Peoples R China. Hosp Special Surg, Dept Biochem, New York, NY 10021 USA. RP Feng, JQ (reprint author), Univ Missouri, Sch Dent, Dept Oral Biol, 650 E 25th St, Kansas City, MO 64108 USA. EM fengj@umkc.edu OI Boskey, Adele/0000-0002-6181-2219 FU NIAMS NIH HHS [AR46798, AR51587, P01 AR046798, P30 AR046121, R01 AR051189, R01 AR051189-01, R01 AR051587, R03 AR048920, R03 AR048920-02]; NIDCR NIH HHS [DE00455, DE13480, K02 DE000455, R29 DE013480] NR 34 TC 116 Z9 126 U1 1 U2 8 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 18 PY 2005 VL 280 IS 7 BP 6197 EP 6203 DI 10.1074/jbc.M412911200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 900LT UT WOS:000227217100126 PM 15590631 ER PT J AU Ito, Y AF Ito, Y TI Golden rules and pitfalls in selecting optimum conditions for high-speed counter-current chromatography SO JOURNAL OF CHROMATOGRAPHY A LA English DT Review DE high-speed counter-current chromatography; pH-zone-refining counter-current chromatography; type-J multilayer coil planet centrifuge; partition coefficient; on-line monitoring; retention of stationary ID LIQUID PARTITION CHROMATOGRAPHY; 2-PHASE SOLVENT SYSTEMS; COIL PLANET CENTRIFUGE; SOLID SUPPORT AB This paper aims to be an aid to those chemists who are interested in utilizing high-speed counter-current chromatography (HSCCC), which is free of irreversible adsorption and offers high resolution comparable to column chromatography. It explains the selection of HSCCC conditions step by step including the selection of two-phase solvent systems, determination of partition coefficient (K) of analytes, preparation of twophase solvent system and sample solution, selection of elution mode, flow rate, rotation speed, and on-line monitoring of the eluate. The paper covers both standard HSCCC and pH-zone-refining CCC techniques. Technical terms (italic) unfamiliar to the beginner are comprehensively explained in Glossary. Various examples of two-phase solvent systems used in HSCCC are listed in Appendices A and B. The commercial sources of HSCCC and other CCC instruments are described in detail in the study edited by Berthod. Published by Elsevier B.V. All rights reserved. C1 NHLBI, Ctr Biochem & Biophys, NIH, Bethesda, MD 20892 USA. RP Ito, Y (reprint author), NHLBI, Ctr Biochem & Biophys, NIH, Bldg 50,Room 3334,50 S Dr,MSC 8014, Bethesda, MD 20892 USA. EM itoy2@mail.nih.gov NR 37 TC 721 Z9 793 U1 19 U2 164 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD FEB 18 PY 2005 VL 1065 IS 2 BP 145 EP 168 DI 10.1016/j.chroma.2004.12.044 PG 24 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 900OR UT WOS:000227224700001 PM 15782961 ER PT J AU Kuzmin, I Geil, L Gibson, L Cavinato, T Loukinov, D Lobanenkov, V Lerman, MI AF Kuzmin, I Geil, L Gibson, L Cavinato, T Loukinov, D Lobanenkov, V Lerman, MI TI Transcriptional regulator CTCF controls human interleukin 1 receptor-associated kinase 2 promoter SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE CTCF; IRAK2; Yersinia ID ENHANCER-BLOCKING ACTIVITY; INNATE IMMUNE-RESPONSE; TOLL-LIKE RECEPTORS; KAPPA-B ACTIVATION; C-MYC GENE; ZINC FINGERS; PROTEIN CTCF; IRAK FAMILY; METHYLATION; INSULATOR AB Immune responses to invading pathogens are mediated largely through a family of transmembrane Toll-like receptors and modulated by a number of downstream effectors. In particular, a family of four interleukin 1 receptor-associated kinases (IRAK) regulates responsiveness to bacterial endotoxins. Pharmacological targeting of particular IRAK components may be beneficial for treatment of bacterial infections. Here, we studied transcriptional regulation of the human IRAK2 gene. Analysis of the IRAK2 promoter region reveals putative binding sites for several transcriptional factors, including ZIP (EGR1 and SP1), CTCF and AP-2beta. Deletion of the ZIP or AP-2 sites did not significantly affect IRAK2 promoter activity in naive and endotoxin-treated mononuclear cells, in dormant and activated Jurkat T-cells, in lung and kidney cells. In contrast, we found that CTCF plays a major role in IRAK2 transcription. An electrophoretic mobility shift assay of the DNA fragments containing the IRAK2 CpG island, revealed a single high-affinity binding site for the transcriptional regulator and a chromatin insulator protein, CTCF. This assay revealed a CTCF-binding site within the mouse Irak2 promoter. The presence of the CTCF protein in human IRAK2 promoter was confirmed by chromatin immunoprecipitation assay. Specific residues that interacted with the CTCF protein, were identified by methylation interference assay. In all cell lines analyzed, including cells of lung, renal, monocytic and T-cell origin, the IRAK2 luciferase reporter construct, containing an intact CTCF-binding site, showed strong promoter activity. However, IRAK2 promoter activity was decreased dramatically for the constructs with a mutated CTCF-binding site. (C) 2004 Elsevier Ltd. All rights reserved. C1 SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. NCI, Immunobiol Lab, Frederick, MD 21702 USA. NIAID, Sect Mol Pathol, LIP, NIH, Rockville, MD 20852 USA. RP Kuzmin, I (reprint author), SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. EM kuzmin@mail.ncifcrf.gov OI Lobanenkov, Victor/0000-0001-6665-3635 FU NCI NIH HHS [N01-CO-56000, N01-CO-12400] NR 43 TC 10 Z9 10 U1 0 U2 3 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD FEB 18 PY 2005 VL 346 IS 2 BP 411 EP 422 DI 10.1016/j.jmb.2004.11.066 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 896FA UT WOS:000226918800004 PM 15670593 ER PT J AU Varrot, A Yip, VLY Li, YS Rajan, SS Yang, XJ Anderson, WF Thompson, J Withers, SG Davies, GJ AF Varrot, A Yip, VLY Li, YS Rajan, SS Yang, XJ Anderson, WF Thompson, J Withers, SG Davies, GJ TI NAD(+) and metal-ion dependent hydrolysis by family 4 glycosidases: Structural insight into specificity for phospho-beta-D-glucosides SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE glycosidase; enzyme; mechanism; lyase ID BINDING CASSETTE TRANSPORTERS; CHONDROITIN AC LYASE; THERMOTOGA-MARITIMA; ALPHA-GLUCOSIDASE; BACILLUS-SUBTILIS; CRYSTAL-STRUCTURE; PHOSPHOTRANSFERASE SYSTEM; MACROMOLECULAR STRUCTURES; FUSOBACTERIUM-MORTIFERUM; ALPHA-1,4-GLUCAN LYASE AB The import of disaccharides by many bacteria is achieved through their simultaneous translocation and phosphorylation by the phosphoenolpyruvate-dependent phosphotransferase system (PEP-PTS). The imported phospho-disaccharides are, in some cases, subsequently hydrolyzed by members of the unusual glycoside hydrolase family GH4. The GH4 enzymes, occasionally found also in bacteria such as Thermotoga maritima that do not utilise a PEP-PTS system, require both NAD(+) and Mn(2+) for catalysis. A further curiosity of this family is that closely related enzymes may show specificity for either alpha-D- or beta-D-glycosides. Here, we present, for the first time, the three-dimensional structure (using single-wavelength anomalous dispersion methods, harnessing extensive non-crystallographic symmetry) of the 6-phospho-beta-glycosidase, BglT, from T maritima in native and complexed (NAD(+) and Glc6P) forms. Comparison of the active-center structure with that of the 6-phospho-alpha-glucosidase GlvA from Bacillus subtilis reveals a striking degree of structural similarity that, in light of previous kinetic isotope effect data, allows the postulation of a common reaction mechanism for both alpha and beta-glycosidases. Given that the "chemistry" occurs primarily on the glycone sugar and features no nucleophilic attack on the intact disaccharide substrate, modulation of anomeric specificity for alpha and beta-linkages is accommodated through comparatively minor structural changes. (C) 2004 Elsevier Ltd. All rights reserved. C1 Univ York, Dept Chem, York Struct Biol Lab, York YO10 5YW, N Yorkshire, England. Univ British Columbia, Dept Chem, Vancouver, BC V6T 1Z1, Canada. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. NIDCR, Microbial Biochem & Genet Unit, Oral Infect & Immun Branch, Bethesda, MD 20892 USA. RP Davies, GJ (reprint author), Univ York, Dept Chem, York Struct Biol Lab, York YO10 5YW, N Yorkshire, England. EM davies@ysbl.york.ac.uk OI Varrot, Annabelle/0000-0001-6667-8162 NR 50 TC 38 Z9 42 U1 0 U2 10 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD FEB 18 PY 2005 VL 346 IS 2 BP 423 EP 435 DI 10.1016/j.jmb.2004.11.058 PG 13 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 896FA UT WOS:000226918800005 PM 15670594 ER PT J AU Mandavilli, BS Boldogh, I Van Houten, B AF Mandavilli, BS Boldogh, I Van Houten, B TI 3-Nitropropionic acid-induced hydrogen peroxide, mitochondrial DNA damage, and cell death are attenuated by Bcl-2 overexpression in PC12 cells SO MOLECULAR BRAIN RESEARCH LA English DT Article DE 3-nitropropionic acid; bcl-2; PC12 cells; neurotoxicity; Huntington's disease; mitochondrial DNA ID SUCCINATE-DEHYDROGENASE; HUNTINGTONS-DISEASE; OXIDATIVE DAMAGE; CYTOCHROME-C; INHIBITOR MALONATE; TRANSGENIC MOUSE; RAT STRIATUM; APOPTOSIS; EXPRESSION; NMDA AB 3-Nitropropionic acid (3-NPA), a complex II inhibitor of the electron transport chain, causes Huntington disease-like symptoms after administration into animals. However, primary mechanisms of cell death are not clearly understood. This study tested the hypothesis that 3-NPA leads to the generation of reactive oxygen species (ROS), initochondrial DNA damage, and loss of mitochondrial function. Amplex red and horseradish peroxidase were used to accurately measure the amount of H2O2, and showed that PC12 cells treated with 3-NPA (4 mM) lead to the production of hydrogen peroxide (1 nmol/10(6) cells/h). This amount of 3-NPA also leads to a rapid decline of ATP levels. There was time- and dose-dependent mitochondrial DNA damage following 3-NPA treatment. Overexpression of the proto-oncogene bcl-2 protects cells from apoptosis induced by various Stimuli. Overexpression of Bcl-2 leads to almost threefold higher levels of ATP and also decreased the 3-NPA-mediated induction of hydrogen peroxide by over 50%. Bcl-2-overexpressing PC12 cells were also protected from mitochondrial DNA damage. These data show that ROS production followed by mitochondrial DNA damage is the primary event in 3-NPA toxicity, and Bcl-2 protects PC12 cells from 3-NPA toxicity by preventing mitochondrial DNA damage. Published by Elsevier B.V. C1 NIH, Genet Mol Lab, NIEHS, Res Triangle Pk, NC 27709 USA. Univ Texas, Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. RP Van Houten, B (reprint author), NIH, Genet Mol Lab, NIEHS, 111 Alexander Dr,POB 12233, Res Triangle Pk, NC 27709 USA. EM vanhout1@niehs.nih.gov NR 70 TC 55 Z9 55 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0169-328X J9 MOL BRAIN RES JI Mol. Brain Res. PD FEB 18 PY 2005 VL 133 IS 2 BP 215 EP 223 DI 10.1016/j.molbrainres.2004.10.033 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 904LC UT WOS:000227498500006 ER PT J AU Schlacher, K Leslie, K Wyman, C Woodgate, R Cox, MM Goodman, MF AF Schlacher, K Leslie, K Wyman, C Woodgate, R Cox, MM Goodman, MF TI DNA polymerase V and RecA protein, a minimal mutasome SO MOLECULAR CELL LA English DT Article ID SINGLE-STRANDED-DNA; ESCHERICHIA-COLI; TRANSLESION SYNTHESIS; MUTAGENESIS PROTEIN; POL-V; BIOCHEMICAL BASIS; SOS MUTAGENESIS; UMUDC COMPLEX; BETA-CLAMP; IN-VIVO AB A hallmark of the Escherichia coli SOS response is the large increase in mutations caused by translesion synthesis (TLS). TLS requires DNA polymerase V (UmuD'C-2) and RecA. Here, we show that pol V and RecA interact by two distinct mechanisms. First, pol V binds to RecA in the absence of DNA and ATP and second, through its UmuD' subunit, requiring DNA and ATP without ATP hydrolysis. TLS occurs in the absence of a RecA nucleoprotein filament but is inhibited in its presence. Therefore, a RecA nucleoprotein filament is unlikely to be required for SOS mutagenesis. Pol V activity is severely diminished in the absence of RecA or in the presence of RecA1730, a mutant defective for pol V mutagenesis in vivo. Pol V activity is strongly enhanced with RecA mutants constitutive for mutagenesis in vivo, suggesting that RecA is an obligate accessory factor that activates pol V for SOS mutagenesis. C1 Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. Erasmus MC, Dept Radiat Oncol, NL-3000 DR Rotterdam, Netherlands. Erasmus MC, Dept Cell Biol, NL-3000 DR Rotterdam, Netherlands. Erasmus MC, Dept Genet, NL-3000 DR Rotterdam, Netherlands. NIH, Sect DNA Replicat Repair & Mutagenesis, Bethesda, MD 20892 USA. Univ Wisconsin, Dept Biochem, Madison, WI 53706 USA. RP Goodman, MF (reprint author), Univ So Calif, Dept Biol Sci, Los Angeles, CA 90089 USA. EM mgoodman@usc.edu FU NIEHS NIH HHS [ES012259]; NIGMS NIH HHS [GM21422, GM52725] NR 45 TC 61 Z9 63 U1 0 U2 2 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB 18 PY 2005 VL 17 IS 4 BP 561 EP 572 DI 10.1016/j.molcel.2005.01.006 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 899KN UT WOS:000227143400012 PM 15721259 ER PT J AU Mayer, ML AF Mayer, ML TI Crystal structures of the GluR5 and GluR6 ligand binding cores: Molecular mechanisms underlying kainate receptor selectivity SO NEURON LA English DT Article ID MOSSY-FIBER SYNAPSES; HIGH-AFFINITY LIGAND; AMINO-ACID-RESIDUES; GLUTAMATE-RECEPTOR; ION CHANNELS; MACROMOLECULAR STRUCTURES; SYNAPTIC-TRANSMISSION; SYM 2081; ACTIVATION; AGONIST AB Little is known about the molecular mechanisms underlying differences in the ligand binding properties of AMPA, kainate, and NMDA subtype glutamate receptors. Crystal structures of the GluR5 and GluR6 kainate receptor ligand binding cores in complexes with glutamate, 2S,4R-4-methylglutamate, kainate, and quisqualate have now been solved. The structures reveal that the ligand binding cavities are 40% (GIuR5) and 16% (GluR6) larger than for GluR2. The binding of AMPA- and GluR5-selective agonists to GluR6 is prevented by steric occlusion, which also interferes with the high-affinity binding of 2S,4R-4-methylglutamate to AMPA receptors. Strikingly, the extent of domain closure produced by the GluR6 partial agonist kainate is only 3degrees less than for glutamate and 11degrees greater than for the GluR2 kainate complex. This, together with extensive interdomain contacts between domains 1 and 2 of GluR5 and GluR6, absent from AMPA receptors, likely contributes to the high stability of GluR5 and GluR6 kainate complexes. 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 NR 52 TC 196 Z9 204 U1 0 U2 6 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD FEB 17 PY 2005 VL 45 IS 4 BP 539 EP 552 DI 10.1016/j.neuron.2005.01.031 PG 14 WC Neurosciences SC Neurosciences & Neurology GA 898TS UT WOS:000227099700010 PM 15721240 ER PT J AU Dave, SS Staudt, LM AF Dave, SS Staudt, LM TI Lymphoma-infiltrating immune cells - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. RP Dave, SS (reprint author), NCI, Bethesda, MD 20892 USA. EM lstaudt@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 17 PY 2005 VL 352 IS 7 BP 725 EP 725 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 897UO UT WOS:000227031100019 ER PT J AU Eblan, MJ Walker, JM Sidransky, E AF Eblan, MJ Walker, JM Sidransky, E TI The glucocerebrosidase gene and Parkinson's disease in Ashkenazi Jews SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter ID MUTATIONS C1 NIH, Bethesda, MD 20892 USA. RP Eblan, MJ (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM sidranse@irp.nimh.nih.gov NR 3 TC 31 Z9 31 U1 0 U2 0 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 17 PY 2005 VL 352 IS 7 BP 728 EP 729 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 897UO UT WOS:000227031100027 PM 15716572 ER PT J AU Guttmacher, AE Collins, FS Carmona, RH AF Guttmacher, AE Collins, FS Carmona, RH TI Family history - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NHGRI, Bethesda, MD 20892 USA. Off Surg Gen, Rockville, MD 20857 USA. RP Guttmacher, AE (reprint author), NHGRI, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU MASSACHUSETTS MEDICAL SOC PI WALTHAM PA WALTHAM WOODS CENTER, 860 WINTER ST,, WALTHAM, MA 02451-1413 USA SN 0028-4793 J9 NEW ENGL J MED JI N. Engl. J. Med. PD FEB 17 PY 2005 VL 352 IS 7 BP 732 EP 733 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 897UO UT WOS:000227031100035 ER PT J AU Lui, WO Foukakis, T Liden, J Thoppe, SR Dwight, T Hoog, A Zedenius, J Wallin, G Reimers, M Larsson, C AF Lui, WO Foukakis, T Liden, J Thoppe, SR Dwight, T Hoog, A Zedenius, J Wallin, G Reimers, M Larsson, C TI Expression profiling reveals a distinct transcription signature in follicular thyroid carcinomas with a PAX8-PPAR gamma fusion oncogene SO ONCOGENE LA English DT Article DE follicular thyroid carcinomas; fusion oncogene; PAX8-PPAR gamma; expression array ID ACTIVATED-RECEPTOR-GAMMA; TRANSLATIONAL CONTROL; BRAF MUTATIONS; PPAR-GAMMA; CANCER; GENE; TUMORS; REARRANGEMENTS; GROWTH; DIFFERENTIATION AB The demonstration of the PAX8-PPARgamma fusion oneogene in a subset of follicular thyroid tumors provides a new and promising starting point to dissect the molecular genetic events involved in the development of this tumor form. In the present study, we compared the gene expression profiles of follicular thyroid carcinomas (FTCs) bearing a PAX8-PPAR7 fusion against FTCs that lack this fusion. Using unsupervised clustering and multidimensional sealing analyses, we show that FTCs possessing a PAX8-wPPARgamma fusion have a highly uniform and distinct gene expression signature that clearly distinguishes them from FTCs without the fusion. The PAX8-PPARgamma(+) FTCs grouped in a defined cluster, where highly ranked genes were mostly associated with signal transduction, cell growth and translation control. Notably, a large number of ribosomal protein and translation-associated genes were concurrently underexpressed in the FTCs with the fusion. Taken together, our findings further support that follicular carcinomas with a PAX8-PPAR7 rearrangement constitute a distinct biological entity. The current data represent one step to elucidate the molecular pathways in the development of FTCs with the specific PAX8-PPARgamma fusion. C1 Karolinska Univ Hosp, Dept Mol Med, SE-17176 Stockholm, Sweden. Karolinska Univ Hosp, Surg Sci Ctr, SE-14186 Huddinge, Sweden. Karolinska Univ Hosp, Dept Surg Sci, SE-17176 Stockholm, Sweden. Novum, Dept Biosci, SE-14157 Huddinge, Sweden. Karolinska Univ Hosp, Dept Oncol Pathol, SE-17176 Stockholm, Sweden. NCI, Mol Pharmacol Lab, Bethesda, MD 20892 USA. RP Lui, WO (reprint author), Stanford Univ, Sch Med, Dept Pathol, 300 Pasteur Dr,Lane Bldg,L313, Stanford, CA 94305 USA. EM weng-onn.lui@cmm.ki.se RI Lui, Weng-Onn/G-6703-2013; OI Lui, Weng-Onn/0000-0003-4717-4473; Foukakis, Theodoros/0000-0001-8952-9987 NR 39 TC 43 Z9 45 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 FEB 17 PY 2005 VL 24 IS 8 BP 1467 EP 1476 DI 10.1038/sj.onc.1208135 PG 10 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 898QZ UT WOS:000227092600017 PM 15608688 ER PT J AU Casey, G Lindor, NM Papadopoulos, N Thibodeau, SN Moskow, J Steelman, S Buzin, CH Sommer, SS Collins, CE Butz, M Aronson, M Gallinger, S Barker, MA Young, JP Jass, JR Hopper, JL Diep, A Bapat, B Salem, M Seminara, D Haile, R AF Casey, G Lindor, NM Papadopoulos, N Thibodeau, SN Moskow, J Steelman, S Buzin, CH Sommer, SS Collins, CE Butz, M Aronson, M Gallinger, S Barker, MA Young, JP Jass, JR Hopper, JL Diep, A Bapat, B Salem, M Seminara, D Haile, R CA Colon Canc Family Registry TI Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID MICROSATELLITE INSTABILITY; GENOMIC DELETIONS; UNITED-STATES; FAMILIES; GENE AB Context The accurate identification and interpretation of germline mutations in mismatch repair genes in colorectal cancer cases is critical for clinical management. Current data suggest that mismatch repair mutations are highly heterogeneous and that many mutations are not detected when conventional DNA sequencing alone is used. Objective To evaluate the potential of conversion analysis compared with DNA sequencing alone to detect heterogeneous germline mutations in MLH1, MSH2, and MSH6 in colorectal cancer patients. Design, Setting, and Participants Multicenter study with patients who participate in the Colon Cancer Family Registry. Mutation analyses were performed in participant samples determined to have a high probability of carrying mismatch repair germline mutations. Samples from a total of 64 hereditary nonpolyposis colorectal cancer cases, 8 hereditary nonpolyposis colorectal cancer-like cases, and 17 cases diagnosed prior to age 50 years were analyzed from June 2002 to June 2003. Main Outcome Measures Classification of family members as carriers or noncarriers of germline mutations in MLH1, MSH2, or MSH6; mutation data from conversion analysis compared with genomic DNA sequencing. Results Genomic DNA sequencing identified 28 likely deleterious exon mutations, 4 in-frame deletion mutations, 16 missense changes, and 22 putative splice site mutations. Conversion analysis identified all mutations detected by genomic DNA sequencing-plus an additional exon mutation, 12 large genomic deletions, and 1 exon duplication mutation-yielding an increase of 33% (14/42) in diagnostic yield of deleterious mutations. Conversion analysis also showed that 4 of 16 missense changes resulted in exon skipping in transcripts and that 17 of 22 putative splice site mutations affected splicing or mRNA transcript stability. Conversion analysis provided an increase of 56% (35/63) in the diagnostic yield of genetic testing compared with genomic DNA sequencing alone. Conclusions The data confirm the heterogeneity of mismatch repair mutations and reveal that many mutations in colorectal cancer cases would be missed using conventional genomic DNA sequencing alone. Conversion analysis substantially increases the diagnostic yield of genetic testing for mismatch repair mutations in patients diagnosed as having colorectal cancer. C1 Cleveland Clin, Lerner Coll Med, Dept Canc Biol, Cleveland, OH 44195 USA. Mayo Clin & Mayo Fdn, Dept Med Genet, Rochester, MN 55905 USA. Mayo Clin & Mayo Fdn, Dept Lab Med & Pathol, Rochester, MN 55905 USA. GMP Genet, Waltham, MA USA. City Hope Natl Med Ctr, Clin Mol Diagnost Lab, Duarte, CA 91010 USA. Mt Sinai Hosp, Dept Surg, Toronto, ON M5G 1X5, Canada. Mt Sinai Hosp, Dept Pathol, Toronto, ON M5G 1X5, Canada. Bancroft Ctr, Cojoint Gastroenterol Lab, Herston, Qld, Australia. McGill Univ, Dept Pathol, Montreal, PQ, Canada. Univ Melbourne, Ctr Genet Epidemiol, Melbourne, Vic, Australia. Univ So Calif, Norris Canc Ctr, Dept Prevent Med, Los Angeles, CA USA. NCI, NIH, Bethesda, MD 20892 USA. RP Casey, G (reprint author), Cleveland Clin, Lerner Coll Med, Dept Canc Biol, ND50,9500 Euclid Ave, Cleveland, OH 44195 USA. EM caseyg@ccf.org RI Papadopoulos, Nickolas/K-7272-2012; Gallinger, Steven/E-4575-2013; Bapat, Bharati/B-5839-2014 FU NCI NIH HHS [UO1 CA074783, CA-95-011, U01 CA074783, U01 CA074794, U01 CA074799, U01 CA074800, U01 CA074800-06, U01 CA074806, U01 CA078296, U01 CA097735, U01 CA74800, UO1 CA074794, UO1 CA074799, UO1 CA074800, UO1 CA074806, UO1 CA078296, UO1 CA097735] NR 20 TC 62 Z9 68 U1 1 U2 4 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 16 PY 2005 VL 293 IS 7 BP 799 EP 809 DI 10.1001/jama.293.7.799 PG 11 WC Medicine, General & Internal SC General & Internal Medicine GA 897DQ UT WOS:000226984600021 PM 15713769 ER PT J AU Nettles, RE Kieffer, TL Kwon, P Monie, D Han, YF Parsons, T Cofrancesco, J Gallant, JE Quinn, TC Jackson, B Flexner, C Carson, K Ray, S Persaud, D Siliciano, RF AF Nettles, RE Kieffer, TL Kwon, P Monie, D Han, YF Parsons, T Cofrancesco, J Gallant, JE Quinn, TC Jackson, B Flexner, C Carson, K Ray, S Persaud, D Siliciano, RF TI Intermittent HIV-1 viremia (blips) and drug resistance in patients receiving HAART SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; ACTIVE ANTIRETROVIRAL THERAPY; UNDETECTABLE VIRAL LOADS; CELLS IN-VIVO; RNA LEVELS; HIV-1-INFECTED PATIENTS; COMBINATION THERAPY; INFLUENZA VACCINATION; VIROLOGICAL FAILURE; GENOTYPIC ANALYSIS AB Context Many patients infected with human immunodeficiency virus type 1 (HIV-1) and receiving highly active antiretroviral therapy experience intermittent episodes of detectable viremia ("blips"), which may raise concerns about drug resistance, lead to costly repeat measurements of viral RNA, and sometimes trigger alterations in therapy. Objective To test the hypothesis that blips represent random biological and statistical variation around mean steady-state HIV-1 RNA levels slightly below 50 copies/mL rather than biologically significant elevations in viremia. Design, Setting, and Patients Between June 19, 2003, and February 9, 2004, patients receiving therapy underwent intensive sampling (every 2-3 days) over 3 to 4 months to define the frequency, magnitude, and duration of blips and their association with drug levels and other clinical variables. Blips were defined as HIV-1 RNA measurements greater than or equal to 50 copies/mL preceded and followed by measurements less than 50 copies/mL without a change in treatment. To-determine whether blips result from or lead to drug resistance, an ultrasensitive genotyping assay was used to detect drug resistance mutations before, during, and after blips. Patients were 10 HIV-1-infected asymptomatic adults recruited by clinicians and followed up in the Moore Clinic at the Johns Hopkins Hospital. Patients had suppression of viremia to below 50 copies/mL while receiving a stable antiretroviral regimen for 6 months or longer. Main Outcome Measures At each time point, plasma HIV-1 RNA levels were measured in 2 independent laboratories and drug resistance mutations were analyzed by clonal sequencing. Results With the intensive sampling, blips were detected in 9 of 10 patients. Statistical analysis was consistent with random assay variation around a mean viral load below 50 copies/mL. Blips were not concordant on independent testing and had a short duration (median, <3 days) and low magnitude (median, 79 copies/mL). Blip frequency was not associated with demographic, clinical, or treatment variables. Blips did not occur in relation to illness, vaccination, or directly measured antiretroviral drug concentrations. Blips were marginally associated (P=.08) with reported episodes of nonadherence. Most importantly, in approximately 1000 independent clones sequenced for both protease and reverse transcriptase, no new resistance mutations were seen before, during, or shortly after blips. Conclusion Most blips in this population appear to represent random biological and statistical variation around mean HIV-1 levels below 50 copies/mL rather than clinically significant elevations in viremia. C1 Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. NIAID, NIH, Bethesda, MD 20892 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Howard Hughes Med Inst, Baltimore, MD 21205 USA. RP Siliciano, RF (reprint author), Johns Hopkins Univ, Sch Med, Dept Med, 879 Broadway Res Bldg,733 N Broadway, Baltimore, MD 21205 USA. EM rsiliciano@jhmi.edu RI Quinn, Thomas/A-2494-2010; Ray, Stuart/B-7527-2008 OI Ray, Stuart/0000-0002-1051-7260 FU NCRR NIH HHS [M01-RR00052]; NIAID NIH HHS [AI51178, AI43222, F32 AI056696, K08 AI060367] NR 59 TC 228 Z9 231 U1 0 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 16 PY 2005 VL 293 IS 7 BP 817 EP 829 DI 10.1001/jama.293.7.817 PG 13 WC Medicine, General & Internal SC General & Internal Medicine GA 897DQ UT WOS:000226984600023 PM 15713771 ER PT J AU Chakravarty, S Herkenham, M AF Chakravarty, S Herkenham, M TI Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines SO JOURNAL OF NEUROSCIENCE LA English DT Article DE inflammation; neuroimmunology; lipopolysaccharide; rodent; blood-brain; corticosterone ID MESSENGER-RNA EXPRESSION; HUMAN ENDOTHELIAL-CELLS; CENTRAL-NERVOUS-SYSTEM; IN-SITU HYBRIDIZATION; MARROW-DERIVED CELLS; KAPPA-B-ALPHA; MOUSE-BRAIN; RAT-BRAIN; BACTERIAL LIPOPOLYSACCHARIDE; GENE-EXPRESSION AB Inflammatory agonists such as lipopolysaccharide (LPS) induce robust systemic as well as CNS responses after peripheral administration. Responses in the innate immune system require triggering of toll-like receptor 4 (TLR4), but the origin of CNS sequelas has been controversial. We demonstrate expression of TLR4 transcripts in mouse brain in the meninges, ventricular ependyma, circumventricular organs, along the vasculature, and in parenchymal microglia. The contribution of TLR4 expressed in CNS resident versus hematopoietic cells to the development of CNS inflammation was examined using chimeric mice. Reciprocal bone marrow chimeras between wild-type and TLR4 mutant mice show that TLR4 on CNS resident cells is critically required for sustained inflammation in the brain after systemic LPS administration. Hematopoietic TLR4 alone supported the systemic release of acute phase cytokines, but transcription of proinflammatory genes in the CNS was reduced in duration. In contrast, TLR4 function in radiation-resistant cells was sufficient for inflammatory progression in the brains of chimeric mice, despite the striking absence of cytokine elevations in serum. Surprisingly, a temporal rise in serum corticosterone was also dependent on TLR4 signaling in nonhematopoietic cells. Our findings demonstrate a requirement for TLR4 function in CNS-resident cells, independent of systemic cytokine effects, for sustained CNS-specific inflammation and corticosterone rise during endotoxemia. C1 NIMH, Funct Neuroanat Sect, NIH, Bethesda, MD 20892 USA. RP Herkenham, M (reprint author), NIMH, Funct Neuroanat Sect, NIH, Bldg 35,Room 1C913,35 Convent Dr, Bethesda, MD 20892 USA. EM herkenh@mail.nih.gov OI Herkenham, Miles/0000-0003-2228-4238 NR 30 TC 235 Z9 246 U1 3 U2 14 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 16 PY 2005 VL 25 IS 7 BP 1788 EP 1796 DI 10.1523/jneurosci.4268-04.2005 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 898GG UT WOS:000227064000020 PM 15716415 ER PT J AU Goedert, JJ AF Goedert, JJ TI Preventing infection-associated cancer: From bench to hillside SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID HEPATITIS-B-VIRUS; HEPATOCELLULAR-CARCINOMA; TAIWAN; ANTIGEN; VACCINATION; GENOTYPES C1 NCI, Viral Epidemiol Branch, Bethesda, MD 20892 USA. RP Goedert, JJ (reprint author), NCI, Viral Epidemiol Branch, 6120 Execut Blvd,Rm 8012, Bethesda, MD 20892 USA. EM goedertj@mail.nih.gov NR 20 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 FEB 16 PY 2005 VL 97 IS 4 BP 245 EP 246 DI 10.1093/jnci/dji059 PG 2 WC Oncology SC Oncology GA 898WW UT WOS:000227107900002 PM 15713953 ER PT J AU Abnet, CC Lai, B Qiao, YL Vogt, S Luo, XM Taylor, PR Dong, ZW Mark, SD Dawsey, SM AF Abnet, CC Lai, B Qiao, YL Vogt, S Luo, XM Taylor, PR Dong, ZW Mark, SD Dawsey, SM TI Zinc concentration in esophageal biopsy specimens measured by x-ray fluorescence and esophageal cancer risk SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CELL-PROLIFERATION; GASTRIC CANCERS; DEFICIENT RATS; DIETARY ZINC; INDUCTION AB Background. In rodents, zinc deficiency potentiates the effects of certain nitrosamines that act as esophageal carcinogens. Studies of the association between zinc and esophageal squamous cell carcinoma in humans have been hampered by plasmazinchomeostasis, which obscures individual differences in total zinc stores, and by the uncertainty regarding zinc bioavailability when estimating dietary zinc intake because phytate from whole grains effectively prohibits zinc absorption. By using baseline tissue biopsy specimens collected in a prospective observational study, we determined the association between incident esophageal squamous cell carcinoma and baseline element concentrations in tissue sections from residents of Linzhou, China, participating in a nutrition intervention trial. Methods: We used x-ray fluorescence spectroscopy to measure zinc, copper, iron, nickel, and sulfur concentrations in single 5-mum-thick sections from formalin-fixed, paraffin-embedded esophageal biopsy specimens collected in 1985 from 60 eventual case and 72 control subjects. Subjects were matched on baseline histology and followed for 16 years. We used Cox proportional hazards models to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between each element and risk of incident esophageal cancer. All statistical tests were two-sided. Results: The risk of developing esophageal cancer was much lower for subjects in the highest quartile of esophageal tissue zinc concentration compared with those in the lowest quartile (HR = 0.21, 95% CI = 0.065 to 0.68). The association was statistically significant across quartiles (P-trend =.015). Individuals in the highest quartile of sulfur concentration had a lower risk of esophageal cancer than individuals in the lowest quartile (HR = 0.29, 95% CI = 0.095 to 0.85), but the association across quartiles was not statistically significant (P-trend = .081). There was no association between copper, iron, or nickel concentrations and risk of esophageal cancer. Conclusion: High tissue zinc concentration was strongly associated with a reduced risk of developing esophageal squamous cell carcinoma. X-ray fluorescence spectroscopy can be used to assess relationships among concentrations of both nutritional and toxic elements and disease risk in banked tissue specimens. C1 NCI, NIH, Canc Prevent Studies Branch, Canc Res Ctr, Bethesda, MD 20892 USA. Argonne Natl Lab, Expt Facil Div, Argonne, IL 60439 USA. Chinese Acad Med Sci, Dept Canc Epidemiol, Beijing 100037, Peoples R China. NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Abnet, CC (reprint author), NCI, NIH, Canc Prevent Studies Branch, Canc Res Ctr, 6116 Execut Blvd,Rm 705, Bethesda, MD 20892 USA. EM qiaoy@public.bta.net.cn RI Abnet, Christian/C-4111-2015; Vogt, Stefan/B-9547-2009; Vogt, Stefan/J-7937-2013; Qiao, You-Lin/B-4139-2012 OI Abnet, Christian/0000-0002-3008-7843; Vogt, Stefan/0000-0002-8034-5513; Vogt, Stefan/0000-0002-8034-5513; Qiao, You-Lin/0000-0001-6380-0871 FU NCI NIH HHS [N01-CP-40540, N01-SC-91030]; PHS HHS [263-MQ-822420, 263-MQ-731789] NR 26 TC 80 Z9 82 U1 1 U2 9 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 16 PY 2005 VL 97 IS 4 BP 301 EP 306 DI 10.1093/jnci/dji042 PG 6 WC Oncology SC Oncology GA 898WW UT WOS:000227107900013 PM 15713965 ER PT J AU Liotta, LA Lowenthal, M Mehta, A Conrads, TP Veenstra, TD Fishman, DA Petricoin, EF AF Liotta, LA Lowenthal, M Mehta, A Conrads, TP Veenstra, TD Fishman, DA Petricoin, EF TI Importance of communication between producers and consumers of publicly available experimental data SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Editorial Material ID FLIGHT MASS-SPECTROMETRY; PROSTATE-CANCER; OVARIAN-CANCER; LASER DESORPTION/IONIZATION; RAPID IDENTIFICATION; PROTEOMIC PATTERNS; SERUM; BIOMARKERS; RESOLUTION AB The application of mass spectrometry to discover new cancer biomarkers is in its infancy. Many of these new markers are low-abundance proteins that exist as fragments associated with carrier proteins. Although reproducibility is key to the use of mass spectrometry for ion fingerprint analysis, the scientific community has yet to establish a common platform or standardized operating procedures that are necessary for intra- and inter-laboratory comparison. In an effort to assist others who are perfecting mass spectrometry platforms for profiling, ongoing experimental data were posted for public consumption. An unintended consequence of unrestricted access to experimental data is the risk of inappropriate conclusions drawn and publicly disseminated that could have been avoided by communication between the producers and consumers of the data. Such disputes, however, should not divert us from the validation of this promising new approach. C1 NCI, US FDA, Clin Proteom Program, Off Cell Therapy & Gene Therapy,CBER, Bethesda, MD 20892 USA. NCI, US FDA, Clin Proteom Program, Lab Pathol,CCR, Bethesda, MD 20892 USA. NCI, Inst Biomed Proteom Program, Lab Proteom & Analyt Technol, SAIC Frederick Inc, Frederick, MD 21701 USA. NYU, Natl Ovarian Canc Early Detect Program, New York, NY USA. RP Petricoin, EF (reprint author), NCI, US FDA, Clin Proteom Program, Off Cell Therapy & Gene Therapy,CBER, Bethesda, MD 20892 USA. EM petricoin@cber.fda.gov NR 24 TC 58 Z9 62 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 16 PY 2005 VL 97 IS 4 BP 310 EP 314 DI 10.1093/jnci/dji053 PG 5 WC Oncology SC Oncology GA 898WW UT WOS:000227107900015 PM 15713967 ER PT J AU Zezula, J Hudlicky, T AF Zezula, J Hudlicky, T TI Recent progress in the synthesis of morphine alkaloids SO SYNLETT LA English DT Article DE morphine; total synthesis; alkaloids; approaches to morphine skeleton; morphine analogs and mimics ID RECEPTOR-MEDIATED PHENOMENA; BRIDGED PHENYLMORPHAN ISOMERS; FORMAL TOTAL-SYNTHESIS; ENANTIOSELECTIVE SYNTHESIS; CLAISEN REARRANGEMENT; ASYMMETRIC-SYNTHESIS; PRACTICAL SYNTHESIS; OPIUM-ALKALOIDS; CONCISE ROUTE; CHEMOENZYMATIC SYNTHESIS AB Recent accomplishments in the field of total synthesis of morphine alkaloids are reviewed. Approaches to the skeleton of morphine are included as are various efforts towards related medicinally important agents. The literature coverage begins after the publication of our last update in 2000 and continues mid-way through 2004. C1 Brock Univ, Dept Chem, St Catharines, ON L2S 3A1, Canada. NIDDK, NIH, Bethesda, MD 20892 USA. RP Hudlicky, T (reprint author), Brock Univ, Dept Chem, 500 Glenridge Ave, St Catharines, ON L2S 3A1, Canada. EM thudlicky@brocku.ca NR 98 TC 62 Z9 62 U1 4 U2 20 PU GEORG THIEME VERLAG KG PI STUTTGART PA RUDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0936-5214 J9 SYNLETT JI Synlett PD FEB 16 PY 2005 IS 3 BP 388 EP 405 DI 10.1055/s-2005-862383 PG 18 WC Chemistry, Organic SC Chemistry GA 901PQ UT WOS:000227294800002 ER PT J AU Breslow, RA Smothers, BA AF Breslow, RA Smothers, BA TI Drinking patterns and body mass index in never smokers - National Health Interview Survey, 1997-2001 SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE alcohol drinking; body mass index; cross-sectional studies; health surveys; obesity ID UNITED-STATES ADULTS; MIDDLE-AGED MEN; WEIGHT-GAIN; ALCOHOL INTAKE; FOOD-INTAKE; PHYSICAL-ACTIVITY; WINE CONSUMPTION; US ADULTS; OBESITY; SMOKING AB Alcohol could contribute to obesity. The authors examined the relation between drinking patterns and body mass index (BMI) (weight (kg)/height (m)(2)) by pooling cross-sectional data from the 1997-2001 National Health Interview Surveys. Weighted analyses included 45,896 adult never smokers who were current alcohol drinkers. Height and weight were self-reported. In adjusted analyses, alcohol quantity and frequency had opposite associations with BMI. As quantity increased from 1 drink/drinking day to greater than or equal to 4 drinks/drinking day, BMI significantly increased; in men, it increased from 26.5 (95% confidence interval (Cl): 26.3, 26.6) to 27.5 (95% Cl: 27.4, 27.7), and in women, it increased from 25.1 (95% Cl: 25.0, 25.2) to 25.9 (95% Cl: 25.5, 26.3). As frequency increased from low quintiles of drinking days/year to high quintiles, BMI significantly decreased; in men, it decreased from 27.4 (95% Cl: 27.2, 27.6) to 26.3 (95% Cl: 26.2, 26.5), and in women, it decreased from 26.2 (95% Cl: 26.0, 26.5) to 24.3 (95% Cl: 24.2, 24.5). In stratified analyses of frequency trends within quantity categories, BMI declines were more pronounced in women than in men, but all linear trends were inverse and significant (p trend < 0.001). In all respondents combined, persons who consumed the smallest quantity the most frequently were leanest, and those who consumed the greatest quantity the least frequently were heaviest. Alcohol may contribute to excess body weight among certain drinkers. C1 NIAAA, Div Epidemiol & Prevent Res, Bethesda, MD 20892 USA. RP Breslow, RA (reprint author), NIAAA, Div Epidemiol & Prevent Res, 5635 Fishers Lane,Room 2081, Bethesda, MD 20892 USA. EM rbreslow@mail.nih.gov NR 50 TC 85 Z9 85 U1 2 U2 7 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 15 PY 2005 VL 161 IS 4 BP 368 EP 376 DI 10.1093/aje/kwi061 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 899LI UT WOS:000227145500009 PM 15692081 ER PT J AU Arimoto, T Kadiiska, MB Sato, K Corbett, J Mason, RP AF Arimoto, T Kadiiska, MB Sato, K Corbett, J Mason, RP TI Synergistic production of lung free radicals by diesel exhaust particles and endotoxin SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE diesel exhaust particles; ESR spin trapping; free radicals; lipopolysaccharide; xanthine oxidase ID XANTHINE-OXIDASE ACTIVITY; IN-VIVO EVIDENCE; GENE-EXPRESSION; AIR-POLLUTION; NADPH OXIDASE; RAT LUNG; INFLAMMATORY RESPONSE; BACTERIAL-ENDOTOXIN; ENDOTHELIAL-CELLS; CHEMICAL-ANALYSIS AB The present study tested the hypothesis that free radicals were involved in the pathogenesis of lung injury caused by diesel exhaust particles (DEP) and bacterial lipopolysaccharides (LPS). Intratracheal coinstillation of DEP and LIPS in rat lungs resulted in synergistic enhancement of free radical generation in the lungs. The radical metabolites were characterized as lipid-derived by electron spin resonance (ESR). The free radical generation was paralleled by a synergistic increase in total protein and by infiltration of neutrophils in the bronchoalveolar lavage (BAL) fluid of the lungs. Experiments with NADP-reduced (NADPH) oxidase and iNOS knockout mice showed that NADPH oxidase and iNOS did not contribute to free radical generation. However, pretreatment with the macrophage toxicant GdCl3, the xanthine oxidase (XO) inhibitor allopurinol, and the Fe-III chelator Desferal resulted in a marked decrease in free radical generation, lung inflammation, and lung injury. These effects were concomitant with the inhibition of XO activity in BAL, suggesting that the activated macrophages and the activity of XO contributed to the generation of free radicals caused by DEP and LPS. This is the first demonstration that DEP and LPS work synergistically to enhance free radical generation in lungs, mediated by the activation of local XO. C1 NIEHS, Lab Pharmacol & Chem, NIH, Free Rad Metab Sect, Res Triangle Pk, NC 27709 USA. RP Mason, RP (reprint author), NIEHS, Lab Pharmacol & Chem, NIH, Free Rad Metab Sect, POB 12233, Res Triangle Pk, NC 27709 USA. EM mason4@niehs.nih.gov NR 64 TC 37 Z9 37 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1073-449X J9 AM J RESP CRIT CARE JI Am. J. Respir. Crit. Care Med. PD FEB 15 PY 2005 VL 171 IS 4 BP 379 EP 387 DI 10.1164/rccm.200402-248OC PG 9 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 895SA UT WOS:000226882200014 PM 15477498 ER PT J AU Lee, BC Lee, YK Lee, HJ Stadtman, ER Lee, KH Chung, N AF Lee, BC Lee, YK Lee, HJ Stadtman, ER Lee, KH Chung, N TI Cloning and characterization of antioxidant enzyme methionine sulfoxide-S-reductase from Caenorhabditis elegans SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE catalytic efficiency; Caenorhabditis elegans; MsrA; methionine sulfoxide; methionine-S-sulfoxide reductase ID CATALYTIC MECHANISM; PROTEIN OXIDATION; STRESS; RESIDUES; DEFENSE; GENE; ZINC; SITE AB Methionine (Met) residues in proteins are susceptible to oxidation. The resulting methionine sulfoxide can be reduced back to methionine by methionine, sulfoxide-S-reductase (MsrA). The MsrA gene, isolated front Caenorhabditis elegans was cloned and expressed in Escherichia coli. The resultant enzyme Was able to revert both free Met and Met in proteins in the presence of either NADPH or dithiothreitol (DTT). However, approximately seven times higher enzyme activity was observed in the presence of DTT than of NADPH. The enzyme had an absolute specificity for the reduction Of L-methionine-S-sulfoxide but no specificity for the R isomer. K-m and k(cat) values for the enzyme were similar to1.18 mM and 3.64 min(-1), respectively. Other kinetics properties of the enzyme were also evaluated. (C) 2004 Elsevier Inc. All rights reserved. C1 Korea Univ, Coll Life & Environm Sci, Seoul 136701, South Korea. NHLBI, NIH, Bethesda, MD 20892 USA. Catholic Univ Korea, Coll Med, Seoul 137701, South Korea. RP Chung, N (reprint author), Korea Univ, Coll Life & Environm Sci, Seoul 136701, South Korea. EM nchung@korea.ac.kr NR 28 TC 9 Z9 11 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 FEB 15 PY 2005 VL 434 IS 2 BP 275 EP 281 DI 10.1016/j.abb.2004.11.012 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 887OV UT WOS:000226316300007 PM 15639227 ER PT J AU Oz, M Alptekin, A Tchugunova, Y Dinc, M AF Oz, M Alptekin, A Tchugunova, Y Dinc, M TI Effects of saturated long-chain N-acylethanolamines on voltage-dependent Ca2+ fluxes in rabbit T-tubule membranes SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE N-acylethanolamines; calcium channels; endocannabinoids ID PERMANENTLY CHARGED 1,4-DIHYDROPYRIDINES; RECEPTOR-MEDIATED RESPONSES; XENOPUS-LAEVIS OOCYTES; BOVINE SERUM-ALBUMIN; SKELETAL-MUSCLE; CALCIUM CHANNELS; SYNTHETIC CANNABINOIDS; ACYL-ETHANOLAMINES; BINDING; ANANDAMIDE AB The effects of saturated long-chain (C: 16-22) N-acylethanolamines and a series of saturated fatty acids with the same length of carbon chains were investigated on depolarization-induced Ca-45(2+) fluxes mediated by voltage-dependent Ca2+ channels in transverse tubule membrane vesicles from rabbit skeletal muscle. Vesicles were loaded with Ca-45(2+) and membrane potentials were generated by establishing potassium gradients across the vesicle using the ionophore valinomycin. Arachidonoylethanolamide and docosaenoylethanolamide but not palmitoylethanolamide and stearoylethanolamide (all 10 muM) caused a significant inhibition of depolarization-induced Ca-45(2+) fluxes and specific binding of [H-3]Isradipine to transverse tubule membranes. On the other hand. Saturated fatty acids including palmitic, stearic, arachidic, and docosanoic acids (all 10 muM) were ineffective in functional and radioligand binding experiments. Additional experiments using endocannabinoid metabolites suggested that whereas ethanolamine and arachidic acids were ineffective, arachidonoylethanolamide inhibited Ca2+ effluxes and specific binding of [H-3]Isradipine. Further studies indicated that only those fatty acids containing ethanolamine as a head group and having a chain length of more than 18 carbons were effective in inhibiting depolarization-induced Ca2+ effluxes and specific binding of [H-3]Isradipine. In conclusion, results indicate that depending on the chain length and the head group of fatty acid, N-acylethanolamines have differential effects on the function of voltage-dependent Ca2+ channels and on the specific binding of [H-3]Isradipine in skeletal Muscle membranes. (C) 2004 Elsevier Inc. All rights reserved. C1 Natl Inst Drug Abuse, Cellular Neurobiol Sect, Baltimore, MD 21224 USA. SSK Training Hosp, Dept Anesthesiol, TR-06472 Ankara, Turkey. Oncol Training Hosp, Dept Pulm Disorders, TR-06514 Ankara, Turkey. RP Oz, M (reprint author), Natl Inst Drug Abuse, Cellular Neurobiol Sect, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM rnoz@intra.nida.nih.gov RI Oz, Murat/E-2148-2012 NR 36 TC 15 Z9 15 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD FEB 15 PY 2005 VL 434 IS 2 BP 344 EP 351 DI 10.1016/j.abb.2004.11.010 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 887OV UT WOS:000226316300015 PM 15639235 ER PT J AU Smith, JA Thompson, DJS Whitcup, SM Suhler, E Clarke, G Smith, S Robinson, M Kim, J Barron, KS AF Smith, JA Thompson, DJS Whitcup, SM Suhler, E Clarke, G Smith, S Robinson, M Kim, J Barron, KS TI A randomized, placebo-controlled, double-masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis SO ARTHRITIS & RHEUMATISM-ARTHRITIS CARE & RESEARCH LA English DT Article DE uveitis; juvenile idiopathic arthritis; etanercept; tumor necrosis factor alpha inhibitor ID EXPERIMENTAL AUTOIMMUNE UVEORETINITIS; RHEUMATOID-ARTHRITIS; METHOTREXATE; THERAPY; CHILDREN; IRIDOCYCLITIS; CYTOKINES; ONSET; ALPHA AB Objective. To investigate the safety and efficacy of etanercept in the treatment of uveitis associated with juvenile idiopathic arthritis (IIA). Methods. Children who met the American College of Rheumatology diagnostic criteria for JIA with active uveitis, who had anterior chamber cells of greater than or equal to1 + or requiring topical corticosteroid greater than or equal to3 times daily, and who were on a stable regimen for arthritis treatment were eligible. Study participants received etanercept (0.4 mg/kg) or placebo administered subcutaneously twice weekly for 6 months. All participants received open-label etanercept for an additional 6 months. Results. Five patients received placebo and 7 received etanercept. Three of the 7 patients treated with etanercept and 2 of the 5 placebo-treated patients were considered ophthalmic successes (P = 1.0). One patient in each treatment group was considered a treatment failure. Three of the 7 etanercept-treated and 2 of the 5 placebo-treated patients were neither successes nor failures by our definition. There were no serious adverse events for any patient during the entire study period. Reports of minor infections were comparable in each treatment group, 71% for etanercept and 60% for placebo (P = 0.58). Conclusion. In this small pilot study there was no apparent difference in the anterior segment inflammation between patients treated with etanercept and placebo. The stringent criteria used to measure ophthalmic success of treatment and the small patient population limit the implications of our findings. C1 NEI, NIH, Bethesda, MD 20892 USA. EMMES Corp, Rockville, MD USA. NIAID, NIH, Bethesda, MD 20892 USA. RP Smith, JA (reprint author), NEI, NIH, 10 Ctr Dr,MSC 1863, Bethesda, MD 20892 USA. EM smithj@nei.nih.gov NR 26 TC 141 Z9 152 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRIT RHEUM-ARTHR JI Arthritis Rheum-Arthritis Care Res. PD FEB 15 PY 2005 VL 53 IS 1 BP 18 EP 23 DI 10.1002/art.20904 PG 6 WC Rheumatology SC Rheumatology GA 895IL UT WOS:000226854300005 PM 15696578 ER PT J AU Nakagawa, T Hocart, SJ Schumann, M Tapia, JA Mantey, SA Coy, DH Tokita, K Katsuno, T Jensen, RT AF Nakagawa, T Hocart, SJ Schumann, M Tapia, JA Mantey, SA Coy, DH Tokita, K Katsuno, T Jensen, RT TI Identification of key amino acids in the gastrin-releasing peptide receptor (GRPR) responsible for high affinity binding of gastrin-releasing peptide (GRP) SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE gastrin-releasing peptide; neuromedin B; bombesin; bombesin receptor; gastrin-releasing peptide receptor; BRS-3 ID PROTEIN-COUPLED RECEPTOR; NEUROMEDIN-B RECEPTOR; SUBTYPE-SELECTIVE LIGANDS; 5TH TRANSMEMBRANE DOMAIN; HUMAN ORPHAN RECEPTOR; LUNG-CARCINOMA CELLS; MOLECULAR-BASIS; BOMBESIN RECEPTORS; AGONIST BINDING; STRUCTURAL REQUIREMENTS AB The bombesin (Bn) receptor family includes the gastrin-releasing peptide (GRPR) and neuromedin B (NMBR) receptors, Bn receptor subtype 3 (BRS-3) and Bn receptor subtype 4 (13134). They share 50% homology, yet their affinities for gastrin-releasing peptide (GRP) differ. The determinants of GRP high affinity for GRPR and 13134, and low affinity for BRS-3 are largely unknown. To address this question we made an analysis of structural homologies in Bn receptor members correlated with their affinities for GRP to develop criteria to identify amino acids important for GRP selectivity. Fourteen differences were identified and each was mutated singly in GRPR to that found in hBRS-3. Eleven mutants had a loss of GRP affinity. Furthermore, three of four amino acids in the GRPR selected used a similar approach and previously reported to be important for high affinity Bn binding, were important for GRP affinity. Some GRPR mutants containing combinations of these mutations had greater decreases in GRP affinity than any single mutation. Particularly important for GRP selectivity were K101, Q121, A198, P199, S293, R288, T297 in GRPR. These results were confirmed by making the reverse mutations in BRS-3 to make GRP gain of affinity mutants. Modeling studies demonstrated a number of the important amino acids had side-chains oriented inward and within 6 A of the binding pocket. These results demonstrated this approach could identify amino acids needed for GRP affinity and complemented results from chimera/mutagenesis studies by identifying which differences in the extracellular domains of Bn receptors were important for GRP affinity. Published by Elsevier Inc. C1 NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. Tulane Hlth Sci Ctr, Dept Med, Peptide Res Labs, New Orleans, LA 70112 USA. RP Jensen, RT (reprint author), NIDDKD, Digest Dis Branch, NIH, Bethesda, MD 20892 USA. EM robertj@bdg10.niddk.nih.gov RI Tapia, Jose/C-5181-2008; Schumann, Michael/K-6426-2013 OI Tapia, Jose/0000-0002-3614-6867; Schumann, Michael/0000-0001-6391-9979 NR 59 TC 13 Z9 13 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0006-2952 J9 BIOCHEM PHARMACOL JI Biochem. Pharmacol. PD FEB 15 PY 2005 VL 69 IS 4 BP 579 EP 593 DI 10.1016/j.bcp.2004.11.003 PG 15 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 896KX UT WOS:000226934100005 PM 15670577 ER PT J AU Bruder, GE Tenke, CE Warner, V Nomura, Y Grillon, C Hille, J Leite, P Weissman, MM AF Bruder, GE Tenke, CE Warner, V Nomura, Y Grillon, C Hille, J Leite, P Weissman, MM TI Electroencephalographic measures of regional hemispheric activity in offspring at risk for depressive disorders SO BIOLOGICAL PSYCHIATRY LA English DT Article DE alpha power; EEG; hemispheric asymmetry; high risk; major depressive disorder ID FRONTAL BRAIN ACTIVITY; EEG ALPHA ASYMMETRY; MAJOR DEPRESSION; INDIVIDUAL-DIFFERENCES; PSYCHIATRIC-DISORDER; CEREBRAL ASYMMETRY; ANXIETY DISORDERS; ONSET DEPRESSION; QUANTITATIVE EEG; FAMILY HISTORY AB Background: Electroencephalographic (EEG) studies have found abnormal regional hemispheric asymmetries in depressive disorders which have been hypothesized to be vulnerability markers for depression, In a longitudinal high-risk study, resting EEG was measured in primarily adult offspring of depressed or nondepressed probands. Methods:. Electroencephalograms from 12 homologous sites over each hemisphere (digitally linked-ears reference) were analyzed in right-handed offspring for whom both parents (n = 18), one parent (n = 40), or neither parent (n = 29) had a major depressive disorder (MDD). Results: Offspring with both parents having MDD showed greater alpha asymmetry at medial sites, with relatively less activity (more offspring having one or no parent with MDD. Relatively less left frontal alpha) over fight central and parietal regions, compared with of activity at lateral sites was associated with lifetime MDD in offspring but not with parental MDD. Offspring with both parents having a MDD also showed markedly greater anterior-to-posterior increase in alpha with eyes closed compared with those with one or no parent with a MDD. Conclusions: Alpha asymmetry indicative of right parietotemporal hypoactivity, previously reported fir depressed adolescents and adults, and heightened anterior-to-posterior gradient of alpha are present in high-risk offspring having parents concordant for MDD. C1 New York State Psychiat Inst & Hosp, Dept Biopsychol, New York, NY 10032 USA. Columbia Univ Coll Phys & Surg, Dept Psychiat, New York, NY 10032 USA. New York State Psychiat Inst & Hosp, Dept Clin & Genet Epidemiol, New York, NY 10032 USA. NIMH, Anxiety Disorders Res Program, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Dept Psychiat, New Haven, CT USA. RP Bruder, GE (reprint author), New York State Psychiat Inst & Hosp, Dept Biopsychol, 1051 Riverside Dr, New York, NY 10032 USA. EM bruderg@pi.cpmc.columbia.edu OI Tenke, Craig/0000-0002-0924-4314; Weissman, Myrna/0000-0003-3490-3075 FU NIMH NIH HHS [MH36197, MH36295, R01 MH036295] NR 55 TC 59 Z9 60 U1 6 U2 11 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 2005 VL 57 IS 4 BP 328 EP 335 DI 10.1016/j.biopsych.2004.11.015 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 898KJ UT WOS:000227075400002 PM 15705347 ER PT J AU Sanchez, MM Noble, PM Lyon, CK Plotsky, PM Davis, M Nemeroff, CB Winslow, JT AF Sanchez, MM Noble, PM Lyon, CK Plotsky, PM Davis, M Nemeroff, CB Winslow, JT TI Alterations in diurnal cortisol rhythm and acoustic startle response in nonhuman primates with adverse rearing SO BIOLOGICAL PSYCHIATRY LA English DT Article DE HPA axis; fear; rhesus monkeys; maternal separation; amygdala; behavioral inhibition ID POSTTRAUMATIC-STRESS-DISORDER; CORTICOTROPIN-RELEASING-FACTOR; CORTICOSTEROID RECEPTOR BALANCE; FEAR-POTENTIATED STARTLE; RHESUS-MONKEYS; SALIVARY CORTISOL; MATERNAL SEPARATION; ANXIETY DISORDERS; ADRENOCORTICAL ACTIVITY; PREPULSE INHIBITION AB Background: Early adverse experiences represent risk factors for the development of anxiety and mood disorders. Studies in nonhuman primates have largely focused on the impact of protracted maternal and social deprivation, but such intense manipulations also result in severe social and emotional deficits very difficult to remediate, This study attempts to model more subtle deficits associated with developmental perturbations that may increase the vulnerability for anxiety/mood disorders but lack the severe de motherless rearing. Methods: We investigated the consequences of repeated maternal separations between 3 to 6 months of age on rhesus monkeys hypothalamic-pituitary-adrenal (HPA) axis function and acoustic startle reactivity. Results: Repetitive maternal separation led to increased cortisol reactivity to the separation protocol in female infants and alterations in mother-infant interaction. It also resulted in a flattened diurnal rhythm of cortisol secretion and increased acoustic startle reactivity at later ages. Conclusions: Macaques with adverse rearing exhibited short-term and long-term alterations in HPA axis function and increased acoustic startle response comparable with changes associated with mood/anxiety disorders. The magnitude of HPA axis reactivity to the separations and the alterations in mother-infant relationship detected during the separation protocol predicted some of the alterations in HPA axis and emotionality exhibited later in lift. C1 Emory Univ, Sch Med, Dept Psychiat & Behav Sci, Atlanta, GA 30322 USA. Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. Emory Univ, Ctr Behav Neurosci, Atlanta, GA 30322 USA. NIMH, IRP Neurobiol Primate Corp, NIH, Bethesda, MD 20892 USA. RP Sanchez, MM (reprint author), Emory Univ, Sch Med, Dept Psychiat & Behav Sci, 101 Woodruff Circle,WMRB SUite 4000, Atlanta, GA 30322 USA. EM sanchez@rmy.emory.edu FU NIMH NIH HHS [MH01005, MH42088, MH57704, MH58922] NR 64 TC 103 Z9 108 U1 2 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 FEB 15 PY 2005 VL 57 IS 4 BP 373 EP 381 DI 10.1016/j.biopsych.2004.11.032 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 898KJ UT WOS:000227075400008 PM 15705353 ER PT J AU Zarate, CA Quiroz, JA Singh, JB Denicoff, KD De Jesus, G Luckenbaugh, DA Charney, DS Manji, HK AF Zarate, CA Quiroz, JA Singh, JB Denicoff, KD De Jesus, G Luckenbaugh, DA Charney, DS Manji, HK TI An open-label trial of the glutamate-modulating agent riluzole in combination with lithium for the treatment of bipolar depression SO BIOLOGICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 59th Annual Meeting of the Society-of-Biological-Psychiatry CY APR 29-MAY 01, 2004 CL NEW YORK, NY SP Soc Biol Psychiat DE antidepressant; bipolar disorder; depression; glutamatergic; riluzole ID AMYOTROPHIC-LATERAL-SCLEROSIS; SCALE AB Background: Preclinical and clinical evidence indicate that the glutamatergic system might play a role in the pathophysiology of mood disorders. This study was conducted to determine the efficacy and safety of riluzole, a glutamate-modulating agent, in bipolar depression. Methods: This was an 8-week add-on study of riluzole in combination with lithium in acutely depressed bipolar patients aged 18 years and older. After open treatment with lithium for a minimum period of 4 weeks, subjects who continued to have a Montgomery-Asberg Depression Rating Scale (MADRS) score of greater than or equal to20 received riluzole (50-200 mg/day) for 8 weeks. Results. Fourteen bipolar depressed patients entered the study. The linear mixed models for total MADRS score showed a significant treatment effect. No switch into hypomania or mania was observed. Overall, riluzole was well tolerated. Conclusions. Although preliminary, these results suggest that riluzole might indeed have antidepressant efficacy in subjects with bipolar depression. C1 NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. NIMH, Mol Pathophysiol Lab, Bethesda, MD 20892 USA. RP Zarate, CA (reprint author), NIMH, Mood & Anxiety Disorders Program, 9000 Rockville Pike,Bldg 10,Unit 3,Room 3s250, Bethesda, MD 20892 USA. EM zaratec@mail.nih.gov NR 18 TC 155 Z9 162 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 2005 VL 57 IS 4 BP 430 EP 432 DI 10.1016/j.biopsych.2004.11.023 PG 3 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 898KJ UT WOS:000227075400015 PM 15705360 ER PT J AU Van Rompaey, P Jacobson, KA Gross, AS Gao, ZG Van Calenbergh, S AF Van Rompaey, P Jacobson, KA Gross, AS Gao, ZG Van Calenbergh, S TI Exploring human adenosine A(3) receptor complementarity and activity for adenosine analogues modified in the ribose and purine moiety SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE adenosine receptors; nucleoside analogues; binding; efficacy ID CL-IB-MECA; MOLECULAR-CLONING; STRUCTURAL DETERMINANTS; SPECIES-DIFFERENCES; INTRINSIC EFFICACY; CEREBRAL-ISCHEMIA; CELL-GROWTH; MAST-CELLS; LIGANDS; ACTIVATION AB In this paper we investigated the influence on affinity, selectivity and intrinsic activity upon modification of the adenosine agonist scaffold at the 3- and 5'-positions of the ribofuranosyl moiety and the 2- and N-6-positions of the purine base. This resulted in the synthesis of various analogues, that is, 3-12 and 24-33, with good hA(3)AR selectivity and moderate-to-high affinities (as in 32, K-i = 27 nM). Interesting was the ability to tune the intrinsic activity depending on the substituent introduced at the 3'-position. (C) 2004 Elsevier Ltd. All rights reserved. C1 NIDDKD, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. State Univ Ghent, Fac Pharmaceut Sci, Med Chem Lab, B-9000 Ghent, Belgium. RP Van Calenbergh, S (reprint author), NIDDKD, Bioorgan Chem Lab, Mol Recognit Sect, NIH, Bethesda, MD 20892 USA. EM serge.vancalenbergh@ugent.be RI Van Calenbergh, Serge/A-3167-2008; Jacobson, Kenneth/A-1530-2009 OI Van Calenbergh, Serge/0000-0002-4201-1264; Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [Z01 DK031115-24] NR 53 TC 17 Z9 17 U1 0 U2 1 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 FEB 15 PY 2005 VL 13 IS 4 BP 973 EP 983 DI 10.1016/j.bmc.2004.11.044 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 896XN UT WOS:000226967900004 PM 15670905 ER PT J AU Esslinger, CS Cybulski, KA Rhoderick, JF AF Esslinger, CS Cybulski, KA Rhoderick, JF TI N-gamma-Aryl glutamine analogues as probes of the ASCT2 neutral amino acid transporter binding site SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE pharmacophore; modeling; inhibition; H-bonding ID C6 GLIOMA-CELLS; SYSTEM; INHIBITION; METABOLISM; ASTROCYTES; EXPRESSION; SUGGESTS; NEURONS; CLONING; EFFLUX AB Analogues of L-glutamine were designed and synthesized to test a hydrogen-bond hypothesis between ligand and neutral amino acid transporter ASCT2. The key design feature contains a substituted phenyl ring on the amide nitrogen that contains electron withdrawing and electron donating groups that alter the pK(a) of the amide NH. Through this study a preliminary binding site map has been developed, and a potent commercially available competitive inhibitor of the ASCT2 transporter has been identified. (C) 2004 Elsevier Ltd. All rights reserved. C1 Univ Montana, NIH, COBRE, Ctr Ctruct & FUnct Neurosci,Dept Biomed & Pharmac, Missoula, MT 59812 USA. RP Esslinger, CS (reprint author), Univ Montana, NIH, COBRE, Ctr Ctruct & FUnct Neurosci,Dept Biomed & Pharmac, Missoula, MT 59812 USA. EM christopher.esslinger@umontana.edu FU NCRR NIH HHS [P20 RR15583] NR 31 TC 34 Z9 37 U1 0 U2 4 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 FEB 15 PY 2005 VL 13 IS 4 BP 1111 EP 1118 DI 10.1016/j.bmc.2004.11.028 PG 8 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 896XN UT WOS:000226967900018 PM 15670919 ER PT J AU Alagille, D Baldwin, RM Roth, BL Wroblewski, JT Grajkowska, E Tamagnan, GD AF Alagille, D Baldwin, RM Roth, BL Wroblewski, JT Grajkowska, E Tamagnan, GD TI Functionalization at position 3 of the phenyl ring of the potent mGluR5 noncompetitive antagonists MPEP SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE metabotropic; mGluR5; MPEP; antagonist ID GLUTAMATE-RECEPTOR SUBTYPE-5; COCAINE; CELLS AB We described the synthesis and biological evaluation of MPEP analogs functionalized at the position 3 of the phenyl ring. The results point out the limitation in the choice of a functional group at this position; the only substituents leading to retention of activity are NO2 (IC50 = 13 nM) and CN (IC50 = 8 nM). (C) 2004 Elsevier Ltd. All rights reserved. C1 Yale Univ, Dept Psychiat, West Haven, CT 06516 USA. VA Connecticut 116A2, West Haven, CT 06516 USA. Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, NIMH, Psychoact Drug Screening Program, Cleveland, OH 44106 USA. Georgetown Univ, Med Ctr, Dept Pharmacol, Washington, DC 20007 USA. Inst Neurodegenerat Disorders, New Haven, CT 06510 USA. RP Tamagnan, GD (reprint author), Yale Univ, Dept Psychiat, 950 Campbell Ave, West Haven, CT 06516 USA. EM gtamagnan@indd.org RI Roth, Bryan/F-3928-2010 FU NIDA NIH HHS [DA16180-01]; NIMH NIH HHS [N01MH80005, KO2MH01366] NR 10 TC 25 Z9 25 U1 0 U2 3 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 15 PY 2005 VL 15 IS 4 BP 945 EP 949 DI 10.1016/j.bmcl.2004.12.047 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 899HL UT WOS:000227135400016 PM 15686891 ER PT J AU Fitch, RW Kaneko, Y Klaperski, P Daly, JW Seitz, G Gundisch, D AF Fitch, RW Kaneko, Y Klaperski, P Daly, JW Seitz, G Gundisch, D TI Halogenated and isosteric cytisine derivatives with increased affinity and functional activity at nicotinic acetylcholine receptors SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE nicotinic receptors; cytisine; acetylcholine; structure-activity relationships ID CHOLINERGIC RECEPTORS; NACHR LIGANDS; BINDING; BRAIN; LINE; RAT AB A series of pyridone ring-modified derivatives of (7R,9S)-(-)-cytisine were evaluated for affinity and functional activity at neuromuscular alpha1beta1gammadelta, ganglionic alpha3beta4, and central neuronal alpha4beta2 subtypes of nicotinic receptors. Halogenation at the 3-position improved affinity and functional activity, while substitution at the 5-position led to modest decreases in both, and disubstitution led to near abolition of functional activities and could be correlated with the electron-withdrawing ability of the halogen. Subtype selectivities of the halogenated derivatives were altered relative to cytisine in a substitution-dependent manner. Caulophylline methiodide was less potent than cytisine, but retained significant activity. Thiocytisine was relatively weak in potency and efficacy, but was significantly selective for the alpha4beta2 subtype. (C) 2004 Elsevier Ltd. All rights reserved. C1 NIDDKD, Bioorgan Chem Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Univ Marburg, Dept Pharmaceut Chem, D-35032 Marburg, Germany. Univ Bonn, Dept Pharmaceut Chem, D-53115 Bonn, Germany. RP Daly, JW (reprint author), NIDDKD, Bioorgan Chem Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM jdaly@nih.gov NR 19 TC 27 Z9 27 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 15 PY 2005 VL 15 IS 4 BP 1221 EP 1224 DI 10.1016/j.bmcl.2004.11.073 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 899HL UT WOS:000227135400071 PM 15686946 ER PT J AU Oh, H Loberiza, FR Zhang, MJ Ringden, O Akiyama, H Asai, T Miyawaki, S Okamoto, S Horowitz, MM Antin, JH Bashey, A Bird, JM Carabasi, MH Fay, JW Gale, RP Giller, RH Goldman, JM Hale, GA Harris, RE Henslee-Downey, J Kolb, HJ Litzow, MR McCarthy, PL Neudorf, SM Serna, DS Socie, G Tiberghien, P Barrett, AJ AF Oh, H Loberiza, FR Zhang, MJ Ringden, O Akiyama, H Asai, T Miyawaki, S Okamoto, S Horowitz, MM Antin, JH Bashey, A Bird, JM Carabasi, MH Fay, JW Gale, RP Giller, RH Goldman, JM Hale, GA Harris, RE Henslee-Downey, J Kolb, HJ Litzow, MR McCarthy, PL Neudorf, SM Serna, DS Socie, G Tiberghien, P Barrett, AJ TI Comparison of graft-versus-host-disease and survival after HLA-identical sibling bone marrow transplantation in ethnic populations SO BLOOD LA English DT Article ID STEM-CELL TRANSPLANTATION; CHRONIC MYELOID-LEUKEMIA; RISK-FACTORS; JAPANESE; ANTIGEN; ASSOCIATION AB The association of ethnicity with the incidence of graft-versus-host disease (GVHD) and other clinical outcomes after transplantation is controversial. We compared the results of HLA-identical sibling bone marrow transplantations for leukemia, performed between 1990 and 1999, among different ethnic populations, including 562 Japanese, 829 white Americans, 71 African Americans, 195 Scandinavians, and 95 Irish. Results for adults and children were analyzed separately. Multivariate analyses of adult patients showed that white Americans, African Americans, and Irish cohorts were at significantly higher risk for acute GVHD than Japanese or Scandinavian cohorts (relative risk [RR] = 1.77, P < .001; RR = 1.84, P < .006; R R = 2.22, P < .001, respectively). White Americans, African Americans, and Irish, but not Scandinavians, were at significantly higher risk for early (within 3 months of transplantation) transplant-related mortality (TRM) compared with Japanese (RR = 2.99, P < .001; RR = 5.88, P < .001; RR = 2.66, P < .009, respectively). No differences in the risk for chronic GVHD, relapse, and overall survival were noted. In the pediatric cohort (limited to Japanese and white Americans), white Americans were at significantly higher risk for acute (RR = 1.93; P = .04) and chronic (RR = 3.16; P = .002) GVHD. No differences in other clinical outcomes were noted. Our findings suggest that ethnicity may influence the risk for GVHD, though overall survival rates after transplantation remain similar. (C) 2005 by The American Society of Hematology. C1 INOUE Mem Hosp, Chuo Ku, Chiba 2600027, Japan. Med Coll Wisconsin, Hlth Policy Inst, IBMTR, GVHD Imune Reconstitut Working Comm, Milwaukee, WI 53226 USA. Huddinge Univ Hosp, S-14186 Huddinge, Sweden. Tokyo Metropolitan Komagome Hosp, Japan Adult Leukemia Study Grp, Tokyo, Japan. Chiba Uiv Hosp, Chuo Ku, Chiba, Japan. Saiseikai Maebashi Hosp, Maebashi, Gumma, Japan. Keio Univ, Sch Med, Tokyo, Japan. Dana Farber Canc Inst, Boston, MA 02115 USA. Univ Calif San Diego, La Jolla, CA 92093 USA. Southmead Gen Hosp, Bristol, Avon, England. Univ So Calif, Norris Cotton Canc Ctr, Los Angeles, CA USA. Baylor Univ, Med Ctr, Dallas, TX USA. Ctr Adv Studies Leukemia, Los Angeles, CA USA. Childrens Hosp, Denver, CO 80218 USA. Hammersmith Hosp, London, England. St Jude Childrens Res Hosp, Memphis, TN 38105 USA. Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Mayo Clin & Mayo Fdn, Rochester, MN 55905 USA. Roswell Pk Canc Inst, Buffalo, NY 14263 USA. Childrens Hosp Orange Cty, Orange, CA 92668 USA. Hop St Louis, Paris, France. INSERM, U645, Estab Francais Sang, Besancon, France. RP Oh, H (reprint author), INOUE Mem Hosp, Chuo Ku, 1-16,Shindencho, Chiba 2600027, Japan. EM hakumei@chive.ocn.ne.jp FU NCI NIH HHS [U24-CA76518] NR 23 TC 86 Z9 88 U1 1 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 15 PY 2005 VL 105 IS 4 BP 1408 EP 1416 DI 10.1182/blood-2004-06-2385 PG 9 WC Hematology SC Hematology GA 896YP UT WOS:000226970800016 PM 15486071 ER PT J AU Boasso, A Herbeuval, JP Hardy, AW Winkler, C Shearer, GM AF Boasso, A Herbeuval, JP Hardy, AW Winkler, C Shearer, GM TI Regulation of indoleamine 2,3-dioxygenase and tryptophanyl-tRNA-synthetase by CTLA-4-Fc in human CD4(+) T cells SO BLOOD LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; DENDRITIC CELLS; FETAL REJECTION; INTERFERON; CATABOLISM; ACTIVATION; AUTOIMMUNITY; EXPRESSION; INDUCTION; TOLERANCE AB Indoleamine-2,3-dioxygenase (IDO) and tryptophanyl-tRNA-synthetase (TTS) are interferon-gamma (IFN-gamma)-inducible enzymes that are responsible for tryptophan degradation and for its use in protein synthesis, respectively. IFN-gamma-induced IDO has immunomodulatory properties in murine and human models. A concomitant increase of TTS has been postulated to protect the IDO-expressing cells from tryptophan catabolism. IDO can be induced in dendritic cells (DCs) by recombinant soluble cytotoxic T lymphocyte antigen-4 (CTLA-4-Fc). We investigated the effects of CTLA-4-Fc on IDO and TTS mRNA expression in human peripheral blood mononuclear cells (PBMCs) and isolated leukocyte subsets. CTLA-4-Fc exposure induced increased IDO and TTS expression in unseparated PBMCs, as well as in monocyte-derived mature Ms. CD4(+) T cells isolated from CTLA-4-Fc-treated PBMCs showed increased IDO and TTS compared with untreated cells. CD8(+) T cells from CTLA-4-Fc-treated PBMCs expressed increased levels of TTS but not IDO. Pretreatment of PBMCs with CTLA-4-Fc inhibited the activation of CD4(+) T cells induced by influenza A virus (Flu) or phytohemagglutinin A (PHA), but had no effect on CD8(+) T cells. This is the first report of IDO and TTS regulation by the CTLA-4-B7 system in human CD4(+) and CD8(+) T cells, and raises the possibility that these 2 tryptophan-modulating enzymes provide an important mechanism for regulating immune responses. (C) 2005 by The American Society of Hematology. C1 NCI, NIH, EIB, CCR, Bethesda, MD 20892 USA. Innsbruck Med Univ, Inst Med Chem & Biochem, Innsbruck, Austria. Ludwig Boltzmann Inst AIDS Res, Innsbruck, Austria. RP Shearer, GM (reprint author), NCI, NIH, EIB, CCR, 9000 Rockville Pike,Bldg 10,Rm 4B36, Bethesda, MD 20892 USA. EM shearerg@mail.nih.gov OI Boasso, Adriano/0000-0001-9673-6319 NR 53 TC 108 Z9 119 U1 2 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 15 PY 2005 VL 105 IS 4 BP 1574 EP 1581 DI 10.1082/blood-2004-06-2089 PG 8 WC Hematology SC Hematology GA 896YP UT WOS:000226970800038 PM 15466932 ER PT J AU Guedez, L Martinez, A Zhao, SM Vivero, A Pittaluga, S Stetler-Stevenson, M Raffeld, M Stetler-Stevenson, WG AF Guedez, L Martinez, A Zhao, SM Vivero, A Pittaluga, S Stetler-Stevenson, M Raffeld, M Stetler-Stevenson, WG TI Tissue inhibitor of metalloproteinase 1 (TIMP-1) promotes plasmablastic differentiation of a Burkitt lymphoma cell line: implications in the pathogenesis of plasmacytic/plasmablastic tumors SO BLOOD LA English DT Article ID TRANSCRIPTION FACTOR XBP-1; UNFOLDED PROTEIN RESPONSE; MARROW PLASMA-CELLS; MULTIPLE-MYELOMA; GENE-EXPRESSION; UNDETERMINED SIGNIFICANCE; TERMINAL DIFFERENTIATION; GERMINAL CENTER; B-LYMPHOCYTES; IN-VITRO AB Tissue inhibitor of metalloproteinase 1 (TIMP-1) is a stromal factor with multiple functions. Overexpression of TIMP-1 correlates with aggressive clinical behavior of a spectrum of tumors. Here, for the first time, we address the role of TIMP-1 in the pathogenesis of B-cell lymphomas. An Epstein-Barr virus (EBV)-negative Burkitt lymphoma cell line with ectopic TIMP-1 expression (TIMP-1JD38) was used to identify genes induced/repressed by TIMP-1. Differentially expressed genes were analyzed by cDNA microarray, and they were validated by immunohistochemistry, flow cytometry, and Western blotting. Analysis revealed changes of genes coding for B-cell growth/differentiation, transcription, and cell cycle regulators. TIMP-1 repressed expression of germinal center (GC) markers CD10, Bcl-6, PAX-5 and up-regulated plasma cell-associated antigens CD138, MUM-1/IRF-4, XBP-1, and CD44, suggesting a plasma cell differentiation. This is accompanied by activation of signal transducer and activator of transcription 3 (STAT-3) and switch to cyclin D2 expression. However, TIMP-1JD38 cells expressed an inactive form of XBP-1, lacking antibody production/secretion. This incomplete plasmacytic differentiation occurs without altering cell proliferation, and despite c-Myc deregulation, indicating an arrested plasmacytic/plasmablastic stage of differentiation. Further validation in human lymphoma cell lines and in primary B-cell tumors demonstrated a predominant TIMP-1 expression in tumors with plasmacytic/plasmablastic phenotypes, including multiple myelomas. These findings strongly support TIMP-1 as an important factor in the pathogenesis of plasmacytic/plasmablastic tumors. (C) 2005 by The American Society of Hematology. C1 Natl Canc Inst, Cell & Canc Biol Branch, Pathol Lab, Canc Res Ctr, Bethesda, MD USA. Natl Canc Inst, Hematopathol Sect, Pathol Lab, Canc Res Ctr, Bethesda, MD USA. Hosp del Mar, Dept Pathol, Barcelona, Spain. EM lquedezm@mail.nih.gov RI Martinez, Antonio/D-8188-2012; Stetler-Stevenson, William/H-6956-2012; Guedez, Liliana/H-4951-2012 OI Martinez, Antonio/0000-0003-0790-9017; Stetler-Stevenson, William/0000-0002-5500-5808; NR 43 TC 31 Z9 32 U1 0 U2 3 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 15 PY 2005 VL 105 IS 4 BP 1660 EP 1668 DI 10.1182/blood-2004-04-1385 PG 9 WC Hematology SC Hematology GA 896YP UT WOS:000226970800049 PM 15479729 ER PT J AU Kim, KT Baird, K Ahn, JY Meltzer, P Lilly, M Levis, M Small, D AF Kim, KT Baird, K Ahn, JY Meltzer, P Lilly, M Levis, M Small, D TI Pim-1 is up-regulated by constitutively activated FLT3 and plays a role in FLT3-mediated cell survival SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; INTERNAL TANDEM DUPLICATION; TYROSINE KINASE INHIBITOR; TRANSGENIC MICE; C-MYC; HEMATOPOIETIC-CELLS; SIGNALING PATHWAY; 32D CELLS; IN-VITRO; EXPRESSION AB Constitutively activating internal tandem duplication (ITD) mutations of the receptor tyrosine kinase FLT3 (Fms-like tyrosine kinase 3) play an important role in leukemogenesis, and their presence is associated with poor prognosis in acute myeloid leukemia (AML). To better understand FLT3 signaling in leukemogenesis, we have examined the changes in gene expression induced by FLT3/ITD or constitutively activated wild-type FLT3 expression. Microarrays were used with RNA harvested before and after inhibition of FLT3 signaling. Pim-1 was found to be one of the most significantly down-regulated genes upon FLT3 inhibition. Pim-1 is a proto-oncogene and is known to be up-regulated by signal transducer and activator of transcription 5 (STAT5), which itself is a downstream target of FLT3 signaling. Quantitative polymerase chain reaction (QPCR) confirmed the microarray results and demonstrated approximately 10-fold decreases in Pim-1 expression in response to FLT3 inhibition. Pim-1 protein also decreased rapidly in parallel with decreasing autophosphorylation activity of FLT3. Enforced expression of either the 44-kDa or 33-kDa Pim-1 isotypes resulted in increased resistance to FLT3 inhibition-mediated cytotoxicity and apoptosis. In contrast, expression of a dominant-negative Pim-1 construct accelerated cytotoxicity in response to FLT3 inhibition and inhibited colony growth of FLT3/ITD-transformed BaF3 cells. These findings demonstrate that constitutively activated FLT3 signaling up-regulates Pim-1 expression in leukemia cells. This up-regulation contributes to the proliferative and antiapoptotic pathways induced by FLT3 signaling. (C) 2005 by The American Society of Hematology. C1 Johns Hopkins Univ, Sch Med, Dept Oncol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Baltimore, MD 21205 USA. NHGRI, NIH, Canc Genet Branch, Bethesda, MD 20892 USA. Loma Linda Univ, Sch Med, Dept Med, Loma Linda, CA 92354 USA. RP Small, D (reprint author), CRB 251,1650 Orleans St, Baltimore, MD 21231 USA. EM donsmall@jhmi.edu FU NCI NIH HHS [CA100632, CA70970CA91177, CA90668] NR 54 TC 126 Z9 126 U1 1 U2 6 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 15 PY 2005 VL 105 IS 4 BP 1759 EP 1767 DI 10.1182/blood-2004-05-2006 PG 9 WC Hematology SC Hematology GA 896YP UT WOS:000226970800061 PM 15498859 ER PT J AU Sommers, JA Sharma, S Doherty, KM Karmakar, P Yang, Q Kenny, MK Harris, CC Brosh, RM AF Sommers, JA Sharma, S Doherty, KM Karmakar, P Yang, Q Kenny, MK Harris, CC Brosh, RM TI P53 Modulates RPA-dependent and RPA-independent WRN helicase activity SO CANCER RESEARCH LA English DT Article ID WERNER-SYNDROME PROTEIN; DNA-REPLICATION; SYNDROME CELLS; FLAP ENDONUCLEASE-1; HOLLIDAY JUNCTIONS; GROWTH-CONTROL; T-ANTIGEN; TRANSCRIPTION; EXONUCLEASE; INTERACTS AB Werner syndrome is a hereditary disorder characterized by the early onset of age-related symptoms, including cancer. The absence of a p53-WRN helicase interaction may disrupt the signal to direct S-phase cells into apoptosis for programmed cell death and contribute to the pronounced genomic instability and cancer predisposition in Werner syndrome cells. Results from coimmunoprecipitation studies indicate that WRN is associated with replication protein A (RPA) and p53 in vivo before and after treatment with the replication inhibitor hydroxyurea or gamma-irradiation that introduces DNA strand breaks. Analysis of the protein interactions among purified recombinant WRN, RPA, and p53 proteins indicate that all three protein pairs bind with similar affinity in the low nanomolar range. In vitro studies show that p53 inhibits RPA-stimulated WRN helicase activity on an 849-bp M13 partial duplex substrate. p53 also inhibited WRN unwinding of a short (19-bp) forked duplex substrate in the absence of RPA. WRN unwinding of the forked duplex substrate was specific, because helicase inhibition mediated by p53 was retained in the presence of excess competitor DNA and was significantly reduced or absent in helicase reactions catalyzed by a WRN helicase domain fragment lacking the p53 binding site or the human RECQ1 DNA helicase, respectively. p53 effectively inhibited WRN helicase activity on model DNA substrate intermediates of replication/repair, a 5' ssDNA flap structure and a synthetic replication fork. Regulation of WRN helicase activity by p53 is likely to play an important role in genomic integrity surveillance, a vital function in the prevention of tumor progression. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. NCI, Human Carcinogenesis Lab, NIH, Baltimore, MD 21224 USA. Montefiore Med Ctr, Dept Radiat Oncol, Bronx, NY 10467 USA. Albert Einstein Canc Ctr, Bronx, NY USA. RP Brosh, RM (reprint author), NIA, Lab Mol Gerontol, NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM BroshR@grc.nia.nih.gov OI Sharma, Sudha/0000-0003-2765-2482 NR 53 TC 38 Z9 40 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2005 VL 65 IS 4 BP 1223 EP 1233 DI 10.1158/0008-5472.CAN-03-0231 PG 11 WC Oncology SC Oncology GA 897IR UT WOS:000226997800015 PM 15735006 ER PT J AU Park, SS Kim, JS Tessarollo, L Owens, JD Peng, LP Han, SS Chung, ST Torrey, TA Cheung, WC Polakiewicz, RD McNeil, N Ried, T Mushinski, JF Morse, HC Janz, S AF Park, SS Kim, JS Tessarollo, L Owens, JD Peng, LP Han, SS Chung, ST Torrey, TA Cheung, WC Polakiewicz, RD McNeil, N Ried, T Mushinski, JF Morse, HC Janz, S TI Insertion of c-Myc into Igh induces B-cell and plasma-cell neoplasms in mice SO CANCER RESEARCH LA English DT Article ID EPSTEIN-BARR-VIRUS; BURKITTS-LYMPHOMA CELLS; HEAVY-CHAIN LOCUS; TRANSGENIC MICE; CHROMOSOMAL TRANSLOCATIONS; INDUCED APOPTOSIS; GENE; ENHANCER; REGION; RECOMBINATIONS AB We used gene targeting in mice to insert a His(6)-tagged mouse c-Myc cDNA, Myc(His), head to head into the mouse immuno-globulin heavy-chain locus, Igh, just 5' of the intronic enhancer, Emu. The insertion of Myc(His) mimicked both the human t(8;14)(q24;q32) translocation that results in the activation of MYC in human endemic Burkitt lymphomas and the homologous mouse T(12;15) translocation that deregulates Myc in certain mouse plasmacytomas. Beginning at the age of 6 months, Myc(His) transgenic mice developed B-cell and plasma neoplasms, such as IgM(+) lymphoblastic B-cell lymphomas, Bcl-6(+) diffuse large B-cell lymphomas, and CD138(+) plasmacytomas, with an overall incidence of 68% by 21 months. Molecular studies of lymphoblastic B-cell lymphoma, the most prevalent neoplasm (50% of all tumors), showed that the lymphomas were clonal, overexpressed Myc(His), and exhibited the P2 to P1 promoter shift in Myc expression, a hallmark of MYC/Myc deregulation in human endemic Burkitt lymphoma and mouse plasmacytoma. Only 1 (6.3%) of 16 lymphoblastic B-cell lymphomas contained a BL-typical point mutation in the amino-terminal transactivation domain of MYCHis, suggesting that most of these tumors are derived from naive, pregerminal center B cells. Twelve (46%) of 26 lymphoblastic B-cell lymphomas exhibited changes in the p19(Arf)- Mdm2-p53 tumor suppressor axis, an important pathway for Myc-dependent apoptosis. We conclude that Myc(His) insertion into Igh predictably induces B-cell and plasma-cell tumors in mice, providing a valuable mouse model for understanding the transformation-inducing consequences of the MYC/Myc-activating endemic Burkitt lymphoma t(8;14)/plasmacytoma T(12;15) translocation. C1 NCI, Genet Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Genet Branch, Canc Res Ctr, Bethesda, MD 20892 USA. NIAID, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. NCI, Lab Neural Dev, Ctr Canc Res, Bethesda, MD 20892 USA. Cell Signaling Technol, Beverly, MA USA. RP Janz, S (reprint author), NCI, Genet Lab, Canc Res Ctr, NIH, Bldg 37,Room 3130A, Bethesda, MD 20892 USA. EM sj4s@nih.gov OI Morse, Herbert/0000-0002-9331-3705 NR 56 TC 73 Z9 76 U1 1 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 FEB 15 PY 2005 VL 65 IS 4 BP 1306 EP 1315 DI 10.1158/0008-5472.CAN-04-0268 PG 10 WC Oncology SC Oncology GA 897IR UT WOS:000226997800025 PM 15735016 ER PT J AU Sun, RH Gao, P Chen, L Ma, DL Wang, JM Oppenheim, JJ Zhang, N AF Sun, RH Gao, P Chen, L Ma, DL Wang, JM Oppenheim, JJ Zhang, N TI Protein kinase C zeta is required for epidermal growth factor-induced chemotaxis of human breast cancer cells SO CANCER RESEARCH LA English DT Article ID CHEMOKINE RECEPTORS; ACTIN POLYMERIZATION; LEADING-EDGE; MOTILITY; ACTIVATION; POLARITY; CDC42; MIGRATION; INTEGRIN; 3-KINASE AB Chemotaxis plays an important role in cancer cell metastasis. In this study, we showed that epidermal growth factor (EGF) was a more potent chemoattractant than chemokine SDF-1alpha/CXCL12 for human breast cancer cell MDA-MB-231. Different inhibitors were used to evaluate the involvement of 12 protein kinase C (PKC) isotypes in the chemotactic signaling pathway. Chelerythrine chloride, an inhibitor of all PKC isotypes, blocked chemotaxis, whereas inhibitors of classic and novel PKC, such as Go6976, Go6850, or calphostin C, only impaired EGF-induced chemotaxis to a minor extent by not greater than32% inhibition. These data suggested that atypical PKC were involved. The ligand-induced actin polymerization and cell adhesion were also similarly dependent on atypical PKC. Immunofluorescent staining showed an EGF-induced, LY294002- sensitive translocation of PKCzeta from the cytosol to the plasma membrane, indicating that EGF was capable of activating PKCzeta, probably via phosphoinositide 3 kinases. A myristoylated PKCzeta pseudosubstrate blocked the chemotaxis with an IC50 of 20 mumol/L. To expand our investigation, we further showed that in MCF-7 and T47D, two additional human breast cancer cell lines, EGF-activated PKCzeta and the PKCzeta pseudosubstrate, inhibited chemotaxis. Taken together, our data suggest that PKCzeta is an essential component of the EGF-stimulated chemotactic signaling pathway in human breast cancer cells. C1 Peking Univ, Dept Biol Chem, Beijing 100871, Peoples R China. Peking Univ, State Key Lab Mol Dynam & Stable Struct, Coll Chem, Beijing 100871, Peoples R China. Peking Univ, Lab Med Immunol, Sch Basic Med Sci, Beijing 100871, Peoples R China. NCI, Mol Immunoregulat Lab, Ctr Canc Res, Intramural Res Support Program, Frederick, MD 21701 USA. RP Zhang, N (reprint author), Peking Univ, Dept Biol Chem, Beijing 100871, Peoples R China. EM zhangnz@pku.edu.cn NR 44 TC 108 Z9 123 U1 2 U2 11 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 EI 1538-7445 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2005 VL 65 IS 4 BP 1433 EP 1441 DI 10.1158/0008-5472.CAN-04-1163 PG 9 WC Oncology SC Oncology GA 897IR UT WOS:000226997800040 PM 15735031 ER PT J AU Bang, S Nagata, S Onda, M Kreitman, RJ Pastan, I AF Bang, S Nagata, S Onda, M Kreitman, RJ Pastan, I TI HA22 (R490A) is a recombinant immunotoxin with increased antitumor activity without an increase in animal toxicity SO CLINICAL CANCER RESEARCH LA English DT Article ID PSEUDOMONAS EXOTOXIN; CYTOTOXIC ACTIVITY; ENDOTHELIAL-CELLS; NUDE-MICE; RFB4(DSFV)-PE38; MALIGNANCIES; XENOGRAFTS; AERUGINOSA; LEUKEMIA; PLASMIN AB Purpose: RFB4 (dsFv)-PE38 (BL22) is a recombinant immunotoxin containing an anti-CD22 (Fv) fused to truncated Pseudomonas exotoxin A, which induces a high complete remission rate in patients with purine analogue-resistant hairy cell leukemia. HA22 is a mutant of BL22 with mutations in heavy-chain CDR3 resulting in increased cytotoxic activity. Our goal was to improve the activity of HA22. Experimental Design: Arg, which is located in the catalytic domain (111) of the immunotoxin HA22, was mutated to alanine. Purified immunotoxins were produced and tested for cytotoxic activity in cell culture and for antitumor activity and nonspecific toxicity in mice. ADP-ribosylation activity was also measured. Results: HA22 (R490A) is similar to2-fold more cytotoxic than HA22 on several CD22-positive cell lines. When injected i.v., HA22 (R490A) has more potent antitumor activity than HA22 against CA46 tumors in mice. HA22 and HA22 (R490A) have similar LD50S (similar to1.3 mg/kg) and similar plasma half-lives. The R490A mutation also improved the cytotoxicity of the antimesothelin recombinant immunotoxin SS1 (dsFv)-PE38 (SS1P). In vitro ADP-ribosylation assays show that HA22 R490A has increased activity. Increased cytotoxic activity is probably related to this increase in ADP-ribosylation activity. Conclusion: Protein engineering can be used to increase the efficacy of recombinant immunotoxins. Because HA22 (R490A) has increased antitumor activity without increased animal toxicity, immunotoxins with this mutation are candidates for clinical development. C1 NCI, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, NIH, Bldg 37,Room 5106,37 Convent Dr,MSC 4264, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov NR 20 TC 59 Z9 64 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2005 VL 11 IS 4 BP 1545 EP 1550 DI 10.1158/1078-0432.CCR-04-1939 PG 6 WC Oncology SC Oncology GA 901EU UT WOS:000227266600029 PM 15746059 ER PT J AU Tsang, KY Palena, C Yokokawa, J Arlen, PM Gulley, JL Mazzara, GP Gritz, L Yafal, AG Ogueta, S Greenhalgh, P Manson, K Panicali, D Schlom, J AF Tsang, KY Palena, C Yokokawa, J Arlen, PM Gulley, JL Mazzara, GP Gritz, L Yafal, AG Ogueta, S Greenhalgh, P Manson, K Panicali, D Schlom, J TI Analyses of recombinant vaccinia and fowlpox vaccine vectors expressing transgenes for two human tumor antigens and three human costimulatory molecules SO CLINICAL CANCER RESEARCH LA English DT Article ID HUMAN CARCINOEMBRYONIC ANTIGEN; CYTOTOXIC T-LYMPHOCYTE; COLONY-STIMULATING FACTOR; HUMAN DENDRITIC CELLS; RESTRICTED CTL EPITOPES; TANDEM REPEAT SEQUENCE; CANCER-PATIENTS; BREAST-CANCER; PHASE-I; MONOCLONAL-ANTIBODY AB Purpose: The poor immunogenicity of tumor antigens and the antigenic heterogeneity of tumors call for vaccine strategies to enhance T-cell responses to multiple antigens. Two antigens expressed noncoordinately on most human carcinomas are carcinoembryonic antigen (CEA) and MUC-1. We report here the construction and characterization of two viral vector vaccines to address these issues. Experimental Design: The two viral vectors analyzed are the replication-competent recombinant vaccinia virus (rV-) and the avipox vector, fowlpox (rF-), which is replication incompetent in mammalian cells. Each vector encodes the transgenes for three human costimulatory molecules (B7-1, ICAM-1, and LFA-3, designated TRICOM) and the CEA and MUC-1 transgenes (which also contain agonist epitopes). The vectors are designated rV-CEA/MUC/ TRICOM and rF-CEA/MUC/TRICOM. Results: Each of the vectors is shown to be capable of faithfully expressing all five transgenes in human dendritic cells (DC). DCs infected with either vector are shown to activate both CEA- and MUC-1-specific T-cell lines to the same level as DCs infected with CEA-TRICOM or MUG 1-TRICOM vectors. Thus, no evidence of antigenic competition between CEA and MUC-1 was observed. Human DCs infected with rV-CEA/MUC/TRICOM or rF-CEA/MUC/TRICOM are also shown to be capable of generating both MUC-1- and CEA-specific T-cell lines; these T-cell lines are in turn shown to be capable of lysing targets pulsed with MUC-1 or CEA peptides as well as human tumor cells endogenously expressing MUC-1 and/or CEA. Conclusion: These studies provide the rationale for the clinical evaluation of these multigene vectors in patients with a range of carcinomas expressing MUC-1 and/or CEA. C1 NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Therion Biol Corp, Cambridge, MD USA. RP Schlom, J (reprint author), NCI, Lab Tumor Immunol & Biol, Ctr Canc Res, NIH, 10 Ctr Dr,Room 8B09,MSC 1750, Bethesda, MD 20892 USA. EM js141c@nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 NR 60 TC 33 Z9 35 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2005 VL 11 IS 4 BP 1597 EP 1607 DI 10.1158/1078-0432.CCR-04-1609 PG 11 WC Oncology SC Oncology GA 901EU UT WOS:000227266600035 PM 15746065 ER PT J AU Jacobs, SS Fox, E Dennie, C Morgan, LB McCully, CL Balis, FM AF Jacobs, SS Fox, E Dennie, C Morgan, LB McCully, CL Balis, FM TI Plasma and cerebrospinal fluid pharmacokineties of intravenous oxaliplatin, cisplatin, and carboplatin in nonhuman primates SO CLINICAL CANCER RESEARCH LA English DT Article ID CLINICAL PHARMACOKINETICS; CANCER; PATIENT; DRUGS AB Purpose: Describe and compare the central nervous system pharmacology of the platinum analogues, cisplatin, carboplatin, and oxaliplatin and develop a pharmacokinetic model to distinguish the disposition of active drug from inert platinum species. Experimental Design: Oxaliplatin (7 or 5 mg/kg), cisplatin (2 mg/kg), or carboplatin (10 mg/kg) was given i.v. Serial plasma and cerebrospinal fluid (CSF) samples were collected over 24 hours. Plasma ultrafiltrates were prepared immediately. Platinum concentrations were measured using atomic absorption spectrometry. Areas under the concentration x time curve were derived using the linear trapezoidal method. CSF penetration was defined as the CSF AUC(0.24)/plasma ultrafiltrate AUC(0.24) ratio. A four-compartment model with first-order rate constants was fit to the data to distinguish active drug from inactive metabolites. Results: The mean +/- SD AUCs in plasma ultrafiltrate for oxaliplatin, cisplatin, and carboplatin were 61 22, 18 +/- 6, and 211 +/- 64 mumol/L hour, respectively. The AUCs in CSF were 1.2 +/- 0.4 mumol/L hour for oxaliplatin, 0.56 +/- 0.08 mumol/L hour for cisplatin, and 8 +/- 2.2 mumol/L hour for carboplatin, and CSF penetration was 2.0 %, 3.6 %, and 3.8 %, respectively. For oxaliplatin, cisplatin, and carboplatin, the pharmacokinetic model estimated that active drug accounted for 29 %, 79 %, and 81 % of platinum in plasma ultrafiltrate, respectively, and 25 %, 89 %, and 56 % of platinum in CSF, respectively. The CSF penetration of active drug was 1.6 % for oxaliplatin, 3.7 % for cisplatin, and 2.6 % for carboplatin. Conclusions: The CSF penetration of the platinum analogues is limited. The pharmacokinetic model distinguished between active drug and their inactive (inert) metabolites in plasma and CSF. C1 NCI, Childrens Natl Med Ctr, Pediat Oncol Branch, Pharmacol & Expt Therapeut Sect, Bethesda, MD 20815 USA. RP Jacobs, SS (reprint author), NCI, Childrens Natl Med Ctr, Pediat Oncol Branch, Pharmacol & Expt Therapeut Sect, 10 Ctr Dr,Bldg 10,Room 13C 108, Bethesda, MD 20815 USA. EM Jacobss@mail.nih.gov NR 22 TC 37 Z9 38 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2005 VL 11 IS 4 BP 1669 EP 1674 DI 10.1158/1078-0432.CCR-04-1807 PG 6 WC Oncology SC Oncology GA 901EU UT WOS:000227266600042 PM 15746072 ER PT J AU Tao, YG Xing, S Deng, XY Xie, DX Lee, LM Liu, YP Wei, L Li, LL Lin, D Qiao, W Gong, JP Ya, C AF Tao, YG Xing, S Deng, XY Xie, DX Lee, LM Liu, YP Wei, L Li, LL Lin, D Qiao, W Gong, JP Ya, C TI Nuclear accumulation of epidermal growth factor receptor and acceleration of G1/S stage by Epstein-Barr-encoded oncoprotein latent membrane protein 1 SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Epstein-Bar virus; latent membrane protein 1; epidermal growth factor receptor; nuclear accumulation; cylinD1; cyclinE; G1/S transition ID NF-KAPPA-B; MEMBRANE-PROTEIN 1; CELL-CYCLE PROGRESSION; TRAF-BINDING-SITE; EGF RECEPTOR; INFECTION MEMBRANE-PROTEIN-1; MEDIATES ACTIVATION; SIGNAL-TRANSDUCTION; S PHASE; VIRUS AB Epstein-Barr virus (EBV)-encoded latent membrane protein 1 (LMP1) is considered to be the major oncogenic protein of EBV-encoded proteins and has always been the core of the oncogenic mechanism of EBV. Advanced studies oil nuclear translocation of the epidermal growth factor receptor (EGFR) family have greatly improved our knowledge of the biological function of cell surface receptors. In this study, we used the Tet-on LMP1 HNE2 cell line as a cell model, which is a dual-stable LMP1-integrated nasopharyngeal carcinoma (NPC) cell line and the expression of LMP1 which could be regulated by the Tet system. We found that LMP1 could regulate the nuclear accumulation of EGFR in a dose-dependent manner quantitatively and qualitatively. We also demonstrated that the nuclear localization sequence of EGFR played some roles in the location of the protein within the nucleus under LMP1 regulation and EGFR ill the nucleus Could bind to the promoters of cyclinD1 and cyclinE, respectively. We further demonstrated that EGFR is involved in the acceleration of the G1/S phase transition by LMP1 through binding to cyclinD1 and cyclinE directly. These findings provided a novel view that the acceleration of LMP1 on the G1/S transition via the nuclear accumulation of EGFR was critical in the process of nasopharyngeal carcinoma. (C) 2004 Elsevier Inc. All rights reserved. C1 Cent S Univ, Inst Canc Res, Xiangya Sch Med, Changsha 410078, Hunan, Peoples R China. Tongji Med Univ, Tongji Hosp, Mol Med Ctr, Wuhan 430030, Peoples R China. SAIC Frederick, Natl Canc Inst, Lab Mol Technol, Frederick, MD 21702 USA. Xiamen Univ, Key Lab, Minist Educ Cell Biol & Tumor Cell Engn, Sch Life Sci, Xiamen 361005, Peoples R China. RP Ya, C (reprint author), Cent S Univ, Inst Canc Res, Xiangya Sch Med, 110,Xiangya Rd, Changsha 410078, Hunan, Peoples R China. EM ycao98@public.cs.hn.cn RI Cao, Ya/C-6801-2008 NR 45 TC 49 Z9 57 U1 1 U2 5 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495, UNITED STATES SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD FEB 15 PY 2005 VL 303 IS 2 BP 240 EP 251 DI 10.1016/j.yexcr.2004.09.030 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 891HL UT WOS:000226571800004 PM 15652339 ER PT J AU Musio, A Montagna, C Mariani, T Tilenni, M Focarelli, ML Brait, L Indino, E Benedetti, PA Chessa, L Albertini, A Ried, T Vezzoni, P AF Musio, A Montagna, C Mariani, T Tilenni, M Focarelli, ML Brait, L Indino, E Benedetti, PA Chessa, L Albertini, A Ried, T Vezzoni, P TI SMC1 involvement in fragile site expression SO HUMAN MOLECULAR GENETICS LA English DT Article ID DNA-POLYMERASE-ALPHA; DOUBLE-STRAND BREAKS; S-PHASE CHECKPOINT; HUMAN-CHROMOSOMES; STRUCTURAL MAINTENANCE; HISTONE H2AX; REPLICATION; INSTABILITY; RECOMBINATION; PROTEIN AB Common fragile sites have been involved in neoplastic transformation, although their molecular basis is still poorly understood. Here, we demonstrate that inhibition of the SMC1 by RNAi is sufficient to induce fragile site expression. By investigating normal, ATM- and ATR-deficient cell lines, we provide evidence that the contribution of SMC1 in preventing the collapse of stalled replication fork is an Atr-dependent pathway. Using a fluorescent antibody specific for gamma-H2AX, we show that very rare discrete nuclear foci appear 1 and 2 h after exposure to aphidicolin and/or RNAi-SMC1, but became more numerous and distinct after longer treatment times. In this context, fragile sites might be viewed as an in vitro phenomenon originating from double-strand breaks formed because of a stalled DNA replication that lasted too long to be managed by physiological rescue acting through the Atr/Smc1 axis. We propose that in vivo, following an extreme replication block, rare cells could escape checkpoint mechanisms and enter mitosis with a defect in genome assembly, eventually leading to neoplastic transformation. C1 CNR, Ist Tecnol Biomed, I-20090 Milan, Italy. NCI, Genet Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. CNR, Ist Proc Chim Fis, I-56124 Pisa, Italy. Ist Nazl Neurol Carlo Besta, Milan, Italy. Ist Zooprofilatt Sperimentale Reg Lazio & Toscana, Dipartimento Interprov Pisa, I-56100 Pisa, Italy. Univ Roma La Sapienza, Dipartimento Med Sperimentale & Patol, I-00185 Rome, Italy. RP Musio, A (reprint author), CNR, Ist Tecnol Biomed, Via Fratelli Cervi 93, I-20090 Milan, Italy. EM antonio.musio@itb.cnr.it OI albertini, alberto/0000-0002-7989-649X FU Telethon [C.35] NR 46 TC 68 Z9 69 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0964-6906 J9 HUM MOL GENET JI Hum. Mol. Genet. PD FEB 15 PY 2005 VL 14 IS 4 BP 525 EP 533 DI 10.1093/hmg/ddi049 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 897XK UT WOS:000227040000007 PM 15640246 ER PT J AU Chiba, Y Srisodsai, A Supavilai, P Kimura, S AF Chiba, Y Srisodsai, A Supavilai, P Kimura, S TI Interleukin-5 reduces the expression of uteroglobin-related protein (UGRP) 1 gene in allergic airway inflammation SO IMMUNOLOGY LETTERS LA English DT Article DE uteroglobin-related protein 1 (UGRP 1); interleukin-5 (IL-5); airway inflammation; allergic asthma ID COLONY-STIMULATING FACTOR; EOSINOPHIL FUNCTION; BRONCHIAL-ASTHMA; BONE-MARROW; GUINEA-PIGS; RECEPTOR; MOUSE; IL-5; HYPERRESPONSIVENESS; MICE AB Airway inflammation is thought to play a major role in the pathogenesis of bronchial asthma. The precise role of individual inflammatory cells, mediator and asthma related genes in allergic lung diseases is not completely understood. The uteroglobin-related protein (UGRP) I was proposed to be an asthma candidate gene and play a role in regulating lung inflammation, however its precise function in the airways remains obscure. In this investigation, we used a mouse model of allergic airway inflammation to establish a relationship between UGRP I and IL-5 in airway inflammation. Ovalbumin (OVA) challenged mice demonstrate eosinophilia in airway tissues and high levels of IL-5 in bronchoalveolar lavage (BAL) fluid analogous to that found in bronchial asthma. Interestingly, these "OVA-challenged" mice show down-regulation of Ugrp1 expression as compared with the control group. Regression analysis further demonstrates a significant negative correlation between Ugrp1 mRNA expression in the lung and IL-5 levels in BAL fluid with r = 0.948 and P < 0.0001 when IL-5 levels were normalized by log transformation. Intranasal instillation of IL-5 to mice revealed an inhibitory effect of IL-5 on the expression of Ugrp1 mRNA. Together, these results indicate an involvement of IL-5 in the down-regulation of Ugrp1 expression in airway inflammation such as allergic asthma disease. Published by Elsevier B.V. C1 NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. Hoshi Univ, Dept Pharmacol, Tokyo 1428501, Japan. Mahidol Univ, Fac Sci, Dept Pharmacol, Bangkok 10400, Thailand. RP Kimura, S (reprint author), NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. EM shioko@helix.nih.gov FU Intramural NIH HHS [Z99 CA999999, Z01 BC010449-06] NR 40 TC 22 Z9 26 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2478 J9 IMMUNOL LETT JI Immunol. Lett. PD FEB 15 PY 2005 VL 97 IS 1 BP 123 EP 129 DI 10.1016/j.imlet.2004.10.013 PG 7 WC Immunology SC Immunology GA 891HD UT WOS:000226571000015 PM 15626484 ER PT J AU Jang, SI Kalinin, A Takahashi, K Marekov, LN Steinert, PM AF Jang, SI Kalinin, A Takahashi, K Marekov, LN Steinert, PM TI Characterization of human epiplakin: RNAi-mediated epiplakin depletion leads to the disruption of keratin and vimentin IF networks SO JOURNAL OF CELL SCIENCE LA English DT Article DE epiplakin; intermediate filaments; keratinocyte ID INTERMEDIATE-FILAMENT NETWORKS; BULLOUS-PEMPHIGOID ANTIGEN-1; CYTOSKELETAL LINKER PROTEIN; HUMAN EPIDERMAL AUTOANTIGEN; PLAKIN FAMILY; CORNIFIED ENVELOPE; DESMOSOMAL PLAQUE; CULTURED-CELLS; COOH TERMINUS; DESMOPLAKIN AB Epiplakin is a member of the plakin family with multiple copies of the plakin repeat domain (PRD). We studied the subcellular distribution and interactions of human epiplakin by immunostaining, overlay assays and RNAi knockdown. Epiplakin decorated the keratin intermediate filaments (IF) network and partially that of vimentin. In the binding assays, the repeat unit (PRD plus linker) showed strong binding and preferentially associated with assembled IF over keratin monomers. Epiplakin knockdown revealed disruption of IF networks in simple epithelial but not in epidermal cells. In rescue experiments, the repeat unit was necessary to prevent the collapse of IF networks in transient knockdown; however, it could only partially restore the keratin but not the vimentin IF network in stably knocked down HeLa cells. We suggest that epiplakin is a cytolinker involved in maintaining the integrity of IF networks in simple epithelial cells. Furthermore, we observed an increase of epiplakin expression in keratinocytes after the calcium switch, suggesting the involvement of epiplakin in the process of keratinocyte differentiation. C1 NIAMS, Skin Biol Lab, NIH, Bethesda, MD 20892 USA. RP Jang, SI (reprint author), NIDCR, Human Craniofacial Genet Sect, CRC, NIH,DHHS, Bldg 10,Room 5N102,10 Ctr Dr, Bethesda, MD 20892 USA. EM jangs@mail.nih.gov NR 54 TC 29 Z9 29 U1 0 U2 0 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0021-9533 J9 J CELL SCI JI J. Cell Sci. PD FEB 15 PY 2005 VL 118 IS 4 BP 781 EP 793 DI 10.1242/jcs.01647 PG 13 WC Cell Biology SC Cell Biology GA 907TS UT WOS:000227741500014 PM 15671067 ER PT J AU Havlin, RH Walls, JD Pines, A AF Havlin, RH Walls, JD Pines, A TI Isotropic proton-detected local-field nuclear magnetic resonance in solids SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID STATE NMR; DIPOLAR COUPLINGS; ROTATING SOLIDS; MAGIC-ANGLE; SECONDARY STRUCTURE; QUADRUPOLAR NUCLEI; PULSE SEQUENCES; CHEMICAL-SHIFT; SPECTROSCOPY; SPECTRA AB A nuclear magnetic resonance method is presented which produces linear, isotropic proton-detected local-field spectra for INS spin systems in powdered samples. The method, heteronuclear isotropic evolution (HETIE), refocuses the anisotropic portion of the heteronuclear dipolar coupling frequencies by evolving the system under a series of specially designed Hamiltonians and evolution pathways. The theory behind HETIE is presented along with experimental studies conducted on a powdered sample of ferrocene, demonstrating the methodology outlined in this paper. Applications of HETIE for use in structure determination in the solid state are discussed. (C) 2005 American Institute of Physics. C1 Univ Calif Berkeley, Lawrence Berkeley Lab, Div Mat Sci, Berkeley, CA 94720 USA. Univ Calif Berkeley, Dept Chem, Berkeley, CA 94720 USA. Harvard Univ, Dept Chem & Biol Chem, Cambridge, MA 02138 USA. NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Pines, A (reprint author), Univ Calif Berkeley, Lawrence Berkeley Lab, Div Mat Sci, Berkeley, CA 94720 USA. EM pines@cchem.berkeley.edu NR 31 TC 1 Z9 1 U1 0 U2 3 PU AMER INST PHYSICS PI MELVILLE PA CIRCULATION & FULFILLMENT DIV, 2 HUNTINGTON QUADRANGLE, STE 1 N O 1, MELVILLE, NY 11747-4501 USA SN 0021-9606 J9 J CHEM PHYS JI J. Chem. Phys. PD FEB 15 PY 2005 VL 122 IS 7 AR 074507 DI 10.1063/1.1844296 PG 12 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 899JF UT WOS:000227140000043 PM 15743254 ER PT J AU Nacsa, J Edghill-Smith, Y Tsai, WP Venzon, D Tryniszewska, E Hryniewicz, A Moniuszko, M Kinter, A Smith, KA Franchini, G AF Nacsa, J Edghill-Smith, Y Tsai, WP Venzon, D Tryniszewska, E Hryniewicz, A Moniuszko, M Kinter, A Smith, KA Franchini, G TI Contrasting effects of low-dose IL-2 on vaccine-boosted simian immunodeficiency virus (SIV)-specific CD4(+) and CD8(+) T cells in macaques chronically infected with SIVmac251 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; IMMUNOLOGICAL SELF-TOLERANCE; RANDOMIZED CONTROLLED-TRIAL; PHASE-II TRIAL; SUBCUTANEOUS INTERLEUKIN-2; IN-VITRO; REGULATORY CELLS; INTRAVENOUS INTERLEUKIN-2; IMMUNE-RESPONSES; LYMPHOCYTES AB IL-2, the first cytolkine discovered with T cell growth factor activity, is now known to have pleiotropic effects on T cells. For example, it can promote growth, survival, and differentiation of Ag-selected cells, or facilitate Ag-induced cell death of T cells when Ag persists, and in vivo, it is thought to contribute to the regulation of the size of adaptive T cell response. IL-2 is deficient in HIV-1 infection and has been used in the management of HIV-1-infected individuals undergoing antiretroviral therapy. In this study, we investigated how continuous low-dose IL-2 affected the CD4(+) and CD8(+) T cell response induced by two inoculations of a canarypox recombinant SIV-based vaccine candidate in healthy macaques chronically infected with SIVmac251. These macaques had normal levels of CD4(+) T cells at the beginning of antiretroviral therapy treatment. Vaccination in the presence of ILL-2 significantly augmented Gag-specific CD8(+) T cell responses, but actually reduced Gag-specific CD4(+) T cell responses. Although IL-2 at low doses did not change the overall concentration of circulating CD4(+) or CD8(+) T cells, it expanded the frequency of CD4(+)CD25(+) T cells. Depletion of the CD4(+)CD25(+) T cells in vitro, however, did not result in a reconstitution of Gag-specific CD4(+) responses or augmentation of SIV-specific CD8(+) T cell responses. Thus, we conclude that the decrease in virus-specific CD4(+) T cell response may be due to IL-2-promoted redistribution of cells from the circulation, or due to Ag-induced cell death, rather than suppression by a T regulatory population. C1 Natl Canc Inst, Anim Models & Retrociral Vaccines Sect, NIAID, Bethesda, MD 20892 USA. Natl Canc Inst, Biostat & Data Management Sect, NIAID, Bethesda, MD 20892 USA. Natl Canc Inst, Immunoregulat Lab, NIAID, Bethesda, MD 20892 USA. Med Univ Bialystok, Dept Pediat 3, Bialystok, Poland. Med Univ Bialystok, Dept Allergol & Internal Dis, Bialystok, Poland. Cornell Univ, Weill Med Coll, Dept Med, Div Immunol, New York, NY 10021 USA. RP Franchini, G (reprint author), Natl Canc Inst, Anim Models & Retrociral Vaccines Sect, NIAID, 41-D804, Bethesda, MD 20892 USA. EM franchig@mail.nih.gov RI Venzon, David/B-3078-2008 NR 66 TC 25 Z9 27 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2005 VL 174 IS 4 BP 1913 EP 1921 PG 9 WC Immunology SC Immunology GA 897EL UT WOS:000226986700017 PM 15699118 ER PT J AU Ellmerich, S Mycko, M Takacs, K Waldner, H Wahid, FN Boyton, RJ King, RHM Smith, PA Amor, S Herlihy, AH Hewitt, RE Jutton, M Price, DA Hafler, DA Kuchroo, VK Altmann, DM AF Ellmerich, S Mycko, M Takacs, K Waldner, H Wahid, FN Boyton, RJ King, RHM Smith, PA Amor, S Herlihy, AH Hewitt, RE Jutton, M Price, DA Hafler, DA Kuchroo, VK Altmann, DM TI High incidence of spontaneous disease in an HLA-DR15 and TCR transgenic multiple sclerosis model SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MYELIN BASIC-PROTEIN; T-CELL-RECEPTOR; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; ALPHA-B-CRYSTALLIN; EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS; EPITOPE SPREAD; MICE; CD4; IMMUNOTHERAPY; DEMYELINATION AB Multiple sclerosis (MS) is thought to involve CD4T cell recognition of self myelin, many studies focusing on a pathogenic role for anti-myelin, HLA-DR15-restricted T cells. In experimental allergic encephalomyelitis, it is known which epitopes trigger disease and that disease is associated with determinant spread of T cell reactivity. Characterization of these events in human MS is critical for the development of peptide immunotherapies, but it has been difficult to define the role of determinant spread or define which epitopes might be involved. In this study, we report humanized transgenic mice, strongly expressing HLA-DR15 with an MS-derived TCR; even on a RAG-2 wild-type background, mice spontaneously develop paralysis. Disease, involving demyelination and axonal degeneration, correlates with inter- and intramolecular spread of the T-cell response to HLA-DR15-restricted epitopes of myelin basic protein, myelin oligodendrocyte glycoprotein, and alphaB-crystallin. Spread is reproducible and progressive, with two of the epitopes commonly described in responses of HLA-DR15 patients. The fact that this pattern is reiterated as a consequence of CNS tissue damage in mice demonstrates the value of the transgenic model in supplying an in vivo disease context for the human responses. This model, encompassing pathologically relevant, spontaneous disease with the presentation of myelin epitopes in the context of HLA-DR15, should offer new insights and predictions about T cell responses during MS as well as a more stringent test bed for immunotherapies. C1 Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Infect Dis, Human Dis Immunogenet Grp, London W12 ONN, England. Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Transplantat Biol Grp, Med Res Council,Clin Sci Ctr, London W12 ONN, England. Univ London Imperial Coll Sci Technol & Med, Dept Neuroinflammat, Div Neurosci, Rijswijk, Netherlands. Biomed Primate Res Ctr, Dept Immunobiol, Rijswijk, Netherlands. Univ London Imperial Coll Sci Technol & Med, Biol Imaging Ctr, MRC, Ctr Clin Sci, London, England. Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. UCL Royal Free & Univ Coll Med Sch, Dept Clin Neurosci, London, England. Univ Oxford, Oxford, England. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Altmann, DM (reprint author), Univ London Imperial Coll Sci Technol & Med, Hammersmith Hosp, Dept Infect Dis, Human Dis Immunogenet Grp, Du Cane Rd, London W12 ONN, England. EM d.altmann@ic.ac.uk RI Price, David/C-7876-2013; Mycko, Marcin Przemyslaw/S-9386-2016; OI Price, David/0000-0001-9416-2737; Hewitt, Rachel/0000-0002-2367-1822 FU Biotechnology and Biological Sciences Research Council [S20114]; Medical Research Council [G108/441]; Multiple Sclerosis Society [589] NR 36 TC 47 Z9 48 U1 0 U2 3 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2005 VL 174 IS 4 BP 1938 EP 1946 PG 9 WC Immunology SC Immunology GA 897EL UT WOS:000226986700020 PM 15699121 ER PT J AU Lyakh, LA Sanford, M Chekol, S Young, HA Roberts, AB AF Lyakh, LA Sanford, M Chekol, S Young, HA Roberts, AB TI TGF-beta and vitamin D-3 utilize distinct pathways to suppress IL-12 production and modulate rapid differentiation of human monocytes into CD83(+) dendritic cells SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; NF-KAPPA-B; SERUM-FREE CONDITIONS; ACTIVATED PROTEIN-KINASE; IN-VITRO DEVELOPMENT; TRANS-RETINOIC ACID; 1-ALPHA,25-DIHYDROXYVITAMIN D-3; 1,25-DIHYDROXYVITAMIN D-3; LANGERHANS CELLS; CD14(+) MONOCYTES AB We previously demonstrated that agents known to signal infection or inflammation can rapidly and directly drive differentiation of human CD14(+) monocytes into CD83(+) dendritic cells (DCs) when introduced to cells under serum-free conditions. In this study, we evaluated the effects of TGF-beta and vitamin D-3 (VitD(3)) on the proportion and function of monocytes that adopt DC characteristics. TGF-beta significantly decreased the proportion of cells that rapidly adopted stable DC characteristics in response to LPS, but had little or no effect on calcium ionophore-induced differentiation. In contrast, VitD3 showed no such pathway specificity and dramatically suppressed differentiation of monocytes into DCs in response to these agents. Both TGF-beta and VitD(3) altered cytokine and chemokine production in LPS-treated monocytes, inhibited IL-12 and IL-10 secretion, and decreased the functional capacity of DCs. Despite the similar effects of TGF-beta and VitD(3), there are significant differences in the signaling pathways used by these agents, as evidenced by their distinct effects on LPS- and calcium ionophore-induced DC differentiation, on LPS-induced secretion of IL-10, and on two members of the NF-kappaB family of transcription factors, ROB and cRel. These studies identify TGF-beta and VitD(3) as potent regulatory factors that use distinct pathways to suppress both the differentiation of DCs as well as their capacity to secrete the Th1-polarizing cytokine IL-12. Because these agents are present in serum and negatively affect DC differentiation at physiological concentrations, our findings are likely to have significance regarding the in vivo role of TGF-beta and VitD(3) in determining the type of immune responses. C1 NCI, Lab Cell Regulat & Carinogenesis, Bethesda, MD 20892 USA. NCI, Expt Immunol Lab, Frederick, MD 21702 USA. RP Roberts, AB (reprint author), NCI, Lab Cell Regulat & Carinogenesis, 41 Library Dr,MSC 5055, Bethesda, MD 20892 USA. EM Robertsa@dce41.nci.nih.gov NR 79 TC 71 Z9 75 U1 0 U2 4 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2005 VL 174 IS 4 BP 2061 EP 2070 PG 10 WC Immunology SC Immunology GA 897EL UT WOS:000226986700035 PM 15699136 ER PT J AU McKarns, SC Schwartz, RH AF McKarns, SC Schwartz, RH TI Distinct effects of TGF-beta 1 on CD4(+) and CD8(+) T cell survival, division, and IL-2 production: A role for T cell intrinsic Smad3 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID GROWTH-FACTOR-BETA; TGF-BETA; IN-VIVO; TRANSFORMING GROWTH-FACTOR-BETA-1; INFLAMMATORY RESPONSE; TARGETED DISRUPTION; CDK INHIBITOR; CYCLE ARREST; FAS LIGAND; ACTIVATION AB TGF-beta1 is critical for maintaining T cell homeostasis. Smad3 has been implicated in this regulatory process, yet the cellular targets and molecular details remain poorly understood. In this study, we report that TGF-beta1 impairs the entry of CD4(+) and CD8(+) T cells into the cell cycle as well as their progression through subsequent rounds of division, and show that Smad3 is essential for TGF-beta1 to inhibit TCR-induced division of only CD4(+) and not CD8(+) T cells. Both CD8(+) and CD4(+) T cells from Smad3(-/-) mice were refractory to TGF-beta1-induced inhibition of IL-2 production, thus demonstrating that not all CD8+ T cell responses to TGF-beta1 are Smad3 independent. These TGF-beta1 effects were all T cell intrinsic, as they were reproduced in purified CD4(+) and CD8(+) T cells. Finally, we found that Smad3 was critical for the survival of CD8(+), but not CD4(+) T cells following activation ex vivo. The TCR-induced death of Smad3(-/-) CD8(+) T cells was not dependent upon TNF-alpha production. Exogenous TGF-beta1 partially rescued the CD8(+) T cells by signaling through a Smad3-independent pathway. TGF-beta1 also enhanced survival of TCR-stimulated CD4(+) CD44(high) T cells in a Smad3-independent manner. Collectively, these findings firmly establish for the first time that TGF-beta1 discriminately regulates CD4(+) and CD8(+) T cell expansion by signaling through distinct intracellular pathways. C1 NIH, NIAID, Cellular & Mol Immunol Lab, Bethesda, MD 20892 USA. RP McKarns, SC (reprint author), NIH, NIAID, Cellular & Mol Immunol Lab, Bldg 4,Room 111,MSC-0420,4 Ctr Dr, Bethesda, MD 20892 USA. EM smckarns@niaid.nih.gov NR 53 TC 53 Z9 68 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 FEB 15 PY 2005 VL 174 IS 4 BP 2071 EP 2083 PG 13 WC Immunology SC Immunology GA 897EL UT WOS:000226986700036 PM 15699137 ER PT J AU Howcroft, TK Weissman, JD Gegonne, A Singer, DS AF Howcroft, TK Weissman, JD Gegonne, A Singer, DS TI A T lymphocyte-specific transcription complex containing RUNX1 activates MHC class I expression SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NF-KAPPA-B; SYSTEMIC-LUPUS-ERYTHEMATOSUS; STIMULATED RESPONSE ELEMENT; MATRIX TARGETING SIGNAL; ALPHA ENHANCER FUNCTION; GENE-EXPRESSION; NUCLEAR-FACTOR; ACUTE-LEUKEMIA; BINDING-SITES; THYROID-CELLS AB MHC class I expression is subject to both tissue-specific and hormonal regulatory mechanisms. Consequently, levels of expression vary widely among tissues, with the highest levels of class I occurring in the lymphoid compartment, in T cells and B cells. Although the high class I expression in B cells is known to involve the B cell enhanceosome, the molecular basis for high constitutive class I expression in T cells has not been explored. T cell-specific genes, such as TCR genes, are regulated by a T cell enhanceosome consisting of RUNX1, CBFbeta, LEF1, and Aly. In this report, we demonstrate that MHC class I gene expression is enhanced by the T cell enhanceosome and results from a direct interaction of the RUNX1-containing complex with the class I gene in vivo. T cell enhanceosome activation of class I transcription is synergistic with CIITA-mediated activation and targets response elements distinct from those targeted by CIITA. These findings provide a molecular basis for the high levels of MHC class I in T cells. C1 NCI, NIH, Expt Immunol Branch, Bethesda, MD 20892 USA. RP Singer, DS (reprint author), NCI, NIH, Expt Immunol Branch, Bldg 10,Room 4B-36,10 Ctr Dr,MSC 1360, Bethesda, MD 20892 USA. EM dinah.singer@nih.gov NR 95 TC 18 Z9 18 U1 0 U2 0 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2005 VL 174 IS 4 BP 2106 EP 2115 PG 10 WC Immunology SC Immunology GA 897EL UT WOS:000226986700040 PM 15699141 ER PT J AU Marusina, AI Kim, DK Lieto, LD Borrego, F Coligan, JE AF Marusina, AI Kim, DK Lieto, LD Borrego, F Coligan, JE TI GATA-3 is an important transcription factor for regulating human NKG2A gene expression SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NK-CELL RECEPTORS; HUMAN T-LYMPHOCYTES; IFN-GAMMA PRODUCTION; INHIBITORY RECEPTORS; CUTTING EDGE; HEMATOPOIETIC-CELLS; ENDOTHELIAL-CELLS; PHYSICAL MAP; HLA-E; CD94/NKG2A AB CD94/NKG2A is an inhibitory receptor expressed by most human NK cells and a subset of T cells that recognizes HLA-E on potential target cells. To study the transcriptional regulation of the human NKG2A gene, we cloned a 3.9-kb genomic fragment that contains a 1.65-kb region upstream of the exon 1, as well as exon 1 (untranslated), intron 1 and exon 2. Using deletion mutants, we identified a region immediately upstream from the most upstream transcriptional initiation site that led to increased transcriptional activity from a luciferase reporter construct in YT-Indy (NKG2A positive) cells relative to Jurkat and K562 (both NKG2A negative) cells. We also localized a DNase I hypersensitivity site to this region. Within this 80-bp segment, we identified two GATA binding sites. Mutation of GATA binding site II (-2302 bp) but not GATA binding site I (-2332 bp) led to decreased transcriptional activity. Pull-down assays revealed that GATA-3 could bind oligonuclecifide probes containing the wild type but not a mutated GATA site II. Using chromatin immunoprecipitation assays, we showed that GATA-3 specifically binds to the NKG2A promoter in situ in NKL and primary NK cells, but not in Jurkat T cells. Moreover, coexpression of human GATA-3 with an NKG2A promoter construct in K562 cells led to enhanced promoter activity, and transfection of NKL cells with small interfering RNA specific for GATA-3 reduced NKG2A cell surface expression. Taken together, our data indicate that GATA-3 is an important transcription factor for regulating NKG2A gene expression. C1 NIAID, NIH, Receptor Cell Biol Sect, Lab Allerg Dis, Rockville, MD 20852 USA. RP Coligan, JE (reprint author), NIAID, NIH, Receptor Cell Biol Sect, Lab Allerg Dis, Twinbrook 2,Room 205,12441 Parklawn Dr, Rockville, MD 20852 USA. EM jcoligan@niaid.nih.gov NR 67 TC 30 Z9 33 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 FEB 15 PY 2005 VL 174 IS 4 BP 2152 EP 2159 PG 8 WC Immunology SC Immunology GA 897EL UT WOS:000226986700045 PM 15699146 ER PT J AU Gomez-Roman, VR Patterson, LJ Venzon, D Liewehr, D Aldrich, K Florese, R Robert-Guroff, M AF Gomez-Roman, VR Patterson, LJ Venzon, D Liewehr, D Aldrich, K Florese, R Robert-Guroff, M TI Vaccine-elicited antibodies mediate antibody-dependent cellular cytotoxicity correlated with significantly reduced acute viremia in rhesus macaques challenged with SIVmac251 SO JOURNAL OF IMMUNOLOGY LA English DT Article ID SIMIAN-IMMUNODEFICIENCY-VIRUS; IMMUNE-RESPONSES; MONOCLONAL-ANTIBODIES; PROTECTIVE IMMUNITY; BOOSTING REGIMEN; INFECTED-CELLS; HIV-INFECTION; MONKEYS; AIDS; ADCC AB Effector cells armed with Abs can eliminate virus-infected target cells by Ab-dependent cellular cytotoxicity (ADCC), an immune mechanism that has been largely overlooked in HIV vaccine development. Here, we show that a prime/boost AIDS vaccine approach elicits potent ADCC activity correlating with protection against SIV in rhesus macaques (Macacca mulatta). Priming with replicating adenovirus type 5 host range mutant-SIV recombinants, followed by boosting with SIV gp120, elicited Abs with ADCC activity against SIVmac251-infected cells. In vitro ADCC activity correlated with in vivo reduced acute viremia after a mucosal challenge with pathogenic SIV. Our findings expose ADCC activity as an immune correlate that may be relevant in the rational design of an efficacious vaccine against HIV. C1 NCI, NIH, Vaccine Branch, Bethesda, MD 20892 USA. NCI, NIH, Biostat & Data Management Sect, Bethesda, MD 20892 USA. RP Robert-Guroff, M (reprint author), NCI, NIH, Vaccine Branch, 41 Medlars Dr,Room D804, Bethesda, MD 20892 USA. EM guroffm@mail.nih.gov RI Venzon, David/B-3078-2008 NR 42 TC 170 Z9 173 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 FEB 15 PY 2005 VL 174 IS 4 BP 2185 EP 2189 PG 5 WC Immunology SC Immunology GA 897EL UT WOS:000226986700049 PM 15699150 ER PT J AU Greenough, TC Babcock, GJ Roberts, A Hernandez, HJ Thomas, WD Coccia, JA Graziano, RF Srinivasan, M Lowy, I Finberg, RW Subbarao, K Vogel, L Somasundaran, M Luzuriaga, K Sullivan, JL Ambrosino, DM AF Greenough, TC Babcock, GJ Roberts, A Hernandez, HJ Thomas, WD Coccia, JA Graziano, RF Srinivasan, M Lowy, I Finberg, RW Subbarao, K Vogel, L Somasundaran, M Luzuriaga, K Sullivan, JL Ambrosino, DM TI Development and characterization of a severe acute respiratory syndrome-associated coronavirus-neutralizing human monoclonal antibody that provides effective immunoprophylaxis in mice SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 17th International Conference on Antiviral Research CY MAY 02-06, 2004 CL Tucson, AZ SP Int Soc Antiviral Res, Hilton El Conquistador Hotel ID ANGIOTENSIN-CONVERTING ENZYME-2; SARS CORONAVIRUS; SPIKE PROTEIN; MOLECULAR EPIDEMIOLOGY; RECEPTOR; PREVENTION; IDENTIFICATION; GLYCOPROTEIN; EVOLUTION; INFECTION AB Background. Severe acute respiratory syndrome (SARS) remains a significant public health concern after the epidemic in 2003. Human monoclonal antibodies (MAbs) that neutralize SARS-associated coronavirus (SARS-CoV) could provide protection for exposed individuals. Methods. Transgenic mice with human immunoglobulin genes were immunized with the recombinant major surface (S) glycoprotein ectodomain of SARS-CoV. Epitopes of 2 neutralizing MAbs derived from these mice were mapped and evaluated in a murine model of SARS-CoV infection. Results. Both MAbs bound to S glycoprotein expressed on transfected cells but differed in their ability to block binding of S glycoprotein to Vero E6 cells. Immunoprecipitation analysis revealed 2 antibody-binding epitopes: one MAb ( 201) bound within the receptor-binding domain at aa 490-510, and the other MAb ( 68) bound externally to the domain at aa 130-150. Mice that received 40 mg/kg of either MAb prior to challenge with SARS-CoV were completely protected from virus replication in the lungs, and doses as low as 1.6 mg/kg offered significant protection. Conclusions. Two neutralizing epitopes were defined for MAbs to SARS-CoV S glycoprotein. Antibodies to both epitopes protected mice against SARS-CoV challenge. Clinical trials are planned to test MAb 201, a fully human MAb specific for the epitope within the receptor-binding region. C1 Univ Massachusetts, Sch Med, Dept Pediat, Program Mol Med, Worcester, MA USA. Univ Massachusetts, Sch Med, Dept Med, Program Mol Med, Worcester, MA USA. NIAID, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Medarex Inc, Bloomsbury, NJ USA. RP Ambrosino, DM (reprint author), Univ Massachusetts, Sch Med, Massachusetts Biol Labs, 305 South St, Jamaica Plain, MA 02130 USA. EM donna.ambrosino@umassmed.edu FU NIAID NIH HHS [N01-AI65315, P30-AI042845] NR 25 TC 77 Z9 86 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 15 PY 2005 VL 191 IS 4 BP 507 EP 514 DI 10.1086/427242 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 888ZM UT WOS:000226413100005 PM 15655773 ER PT J AU Rao, MR Wierzba, TF Savarino, SJ Abu-Elyazeed, R El-Ghoreb, N Hall, ER Naficy, A Abdel-Messih, I Frenck, RW Svennerholm, AM Clemens, JD AF Rao, MR Wierzba, TF Savarino, SJ Abu-Elyazeed, R El-Ghoreb, N Hall, ER Naficy, A Abdel-Messih, I Frenck, RW Svennerholm, AM Clemens, JD TI Serologic correlates of protection against enterotoxigenic Escherichia coli diarrhea SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID COLONIZATION FACTOR ANTIGENS; CELL CHOLERA VACCINE; HEAT-LABILE TOXIN; SERUM ANTIBODY; B-SUBUNIT; SEROEPIDEMIOLOGIC EVALUATION; MONOCLONAL-ANTIBODIES; IMMUNOSORBENT-ASSAY; TRAVELERS DIARRHEA; RURAL BANGLADESH AB Background. We conducted a nested case-control study in 397 rural Egyptian children <36 months of age to assess the correlation between serum levels of antibodies against toxin and colonization factors (CFs) and the risk of homologous enterotoxigenic Escherichia coli ( ETEC) diarrhea. Methods. Active case detection was performed via semiweekly home visits, and blood was obtained at 3-month intervals. After each serosurvey, case subjects were selected from children experiencing a CF antigen (CFA)/I-, CFA/II-, CFA/IV-, or heat-labile enterotoxin (LT)-ETEC diarrheal episode during the subsequent 3 months. Up to 5 control subjects per case subject were selected from children who did not experience an ETEC diarrheal episode during the corresponding interval. Serum titers of immunoglobulin G antibodies against CFA/I, coli surface antigen (CS) 3, CS6, and LT were measured by enzyme-linked immunosorbant assay. Results. The distribution of serum titers of LT, CS3, and CS6 antibodies did not differ between the case and control subjects. For children <18 months of age, serum titers of CFA/I antibody were inversely related to the risk of CFA/I-ETEC diarrhea; reciprocal serum titers of CFA/I antibody greater than or equal to76 were associated with a 77% reduction in the odds of CFA/I-ETEC diarrhea. Conclusion. Induction of reciprocal serum titers of antibodies against CFA/I within or above the 76-186 range should be further evaluated as a predictor for assessment of the ability of candidate vaccines to protect against CFA/I-ETEC diarrhea. C1 USN, Med Res Ctr, Silver Spring, MD 20910 USA. NICHHD, Div Epidemiol Stat & Prevent Res, Bethesda, MD 20892 USA. USN, Med Res Unit 3, Cairo, Egypt. Univ Gothenburg, Dept Med Microbiol & Immunol, Gothenburg, Sweden. Int Vaccine Inst, Seoul, South Korea. RP Savarino, SJ (reprint author), USN, Med Res Ctr, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. EM savarinos@nmrc.navy.mil NR 36 TC 30 Z9 32 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 15 PY 2005 VL 191 IS 4 BP 562 EP 570 DI 10.1086/427662 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 888ZM UT WOS:000226413100012 PM 15655780 ER PT J AU Porto, AF Santos, SB Muniz, AL Basilio, V Rodrigues, W Neva, FA Dutra, WO Gollob, KJ Jacobson, S Carvalho, EM AF Porto, AF Santos, SB Muniz, AL Basilio, V Rodrigues, W Neva, FA Dutra, WO Gollob, KJ Jacobson, S Carvalho, EM TI Helminthic infection down-regulates type 1 immune responses in human T cell lymphotropic virus type 1 (HTLV-1) carriers and is more prevalent in HTLV-1 carriers than in patients with HTLV-1-associated myelopathy/tropical spastic paraparesis SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 40th Congress of the Sociedade-Brasileria-de-Medicina-Tropical CY MAR 07-11, 2004 CL Aracaju, BRAZIL SP Soc Brasileria Med Trop ID I-ASSOCIATED MYELOPATHY; STRONGYLOIDES-STERCORALIS; INTERFERON-GAMMA; PROVIRAL LOAD; SCHISTOSOMIASIS; SERUM; LYMPHOCYTES; EXPRESSION; LEUKEMIA; HAM/TSP AB Human T cell lymphotropic virus type 1 (HTLV-1) infection is associated with an exacerbated type 1 immune response and secretion of high levels of proinflammatory cytokines. In contrast, helminthic infection induces a type 2 immune response. In the present study, the cytokine profile in HTLV-1 carriers coinfected with helminths (Strongyloides stercoralis and/or Schistosoma mansoni) was compared with that in HTLV-1 carriers not coinfected with helminths. Levels of interferon (IFN)-gamma were higher in HTLV-1 carriers not coinfected with helminths than in HTLV-1 carriers coinfected with helminths (P<.05). The overall frequency of IFN-γ expressing CD8(+) and CD4(+) cells was decreased in HTLV- 1 carriers coinfected with helminths (P<.05). The percentage of interleukin (IL)-5- and IL-10-expressing T cells in HTLV-1 carriers coinfected with helminths was higher than that in HTLV-1 carriers not coinfected with helminths (P<.05). Moreover, we found that the prevalence of helminthic infection was 7-fold higher in HTLV-1 carriers than in patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (P<.05). These data show that helminthic infection decreases activation of type 1 cells, which may influence the clinical outcome of HTLV-1 infection. C1 Univ Fed Bahia, Hosp Univ Prof Edgard Santos, Serv Imunol, Lab Imunol, BR-40110160 Salvador, BA, Brazil. Univ Fed Minas Gerais, Dept Morfol, Belo Horizonte, MG, Brazil. Univ Fed Minas Gerais, Dept Bioquim Imunol, Belo Horizonte, MG, Brazil. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. RP Carvalho, EM (reprint author), Univ Fed Bahia, Hosp Univ Prof Edgard Santos, Serv Imunol, Lab Imunol, 5 Andar,Rua joao Botas S-N, BR-40110160 Salvador, BA, Brazil. EM edgar@ufba.br RI Gollob, Kenneth/C-1341-2008 OI Gollob, Kenneth/0000-0003-4184-3867 NR 34 TC 18 Z9 19 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 15 PY 2005 VL 191 IS 4 BP 612 EP 618 DI 10.1086/427560 PG 7 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 888ZM UT WOS:000226413100018 PM 15655786 ER PT J AU Hashimoto, M Nitta, A Fukumitsu, H Nomoto, H Shen, L Furukawa, S AF Hashimoto, M Nitta, A Fukumitsu, H Nomoto, H Shen, L Furukawa, S TI Involvement of glial cell line-derived neurotrophic factor in activation processes of rodent macrophages SO JOURNAL OF NEUROSCIENCE RESEARCH LA English DT Article DE macrophages; phagocytic activity; spinal cord; glial cell line-derived neurotrophic factor; GDNF monocyte chemoattractant protein-1; MCP-1 ID RAT SPINAL-CORD; NERVE GROWTH-FACTOR; INFLAMMATORY RESPONSE; CHEMOKINE EXPRESSION; CONTUSION INJURY; GDNF; SYSTEM; ACCUMULATION; RECEPTORS; ISCHEMIA AB The physiological roles of glial cell line-derived neurotrophic factor (GDNF) expressed in the microglia/macrophages of the injured spinal cord have not yet been clarified. mRNA expression of chemokines, including monocyte chemoattractant protein (MCP)-1, was evoked within 1 hr after transection of the spinal cord, and GDNF mRNA expression was similarly up-regulated. Immunohistochemical analysis showed that GDNF was coexpressed with MCP-1 in the CD1 1 b-positive cells. Therefore, we examined further the effects of GDNF on cultured rat peritoneal macrophages. GDNF enhanced the phagocytic activity of the macrophages via GFRalpha-1, glycosylphosphatidylinositol-anchored specific binding site of GDNF, in a c-Ret-independent manner. The influence of autocrine and/or paracrine GDNF synthesis was evaluated by performing activation experiments using macrophages cultured from heterozygous (+/-) GDNF gene-deficient mice or wild-type (+/+) mice. There were no morphological differences dependent on genetic types or stimulators. However, the GDNF mRNA level, but not the MCP-1 or GFRalpha-1 mRNA level, was substantially lower in the mutant macrophages than in the +/+ cells irrespective of stimulation with MCP-1 or lipopolysaccharide (LPS). The phagocytic activity enhanced by MCP-1 or LPS was significantly lower in the mutant cells (+/-) than in the +/+ ones, demonstrating the involvement of endogenous GDNF in the activation processes of macrophages in vitro and suggesting that not only neuroprotective function but also activation of macrophages is effected by the GDNF produced after a spinal cord injury. (C) 2005 Wiley-Liss, Inc. C1 Gifu Pharmaceut Univ, Mol Biol Lab, Gifu 5028585, Japan. Nagoya Univ, Grad Sch Med, Dept Neuropsychopharmacol & Hosp Pharm, Nagoya, Aichi, Japan. NIH, Lab Mammalian Genes & Dev, Bethesda, MD USA. RP Furukawa, S (reprint author), Gifu Pharmaceut Univ, Mol Biol Lab, 5-6-1 Mitahora Higashi, Gifu 5028585, Japan. EM furukawa@gifu-pu.ac.jp NR 34 TC 36 Z9 39 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0360-4012 J9 J NEUROSCI RES JI J. Neurosci. Res. PD FEB 15 PY 2005 VL 79 IS 4 BP 476 EP 487 DI 10.1002/jnr.20368 PG 12 WC Neurosciences SC Neurosciences & Neurology GA 892VD UT WOS:000226677200007 PM 15635609 ER PT J AU Quarles, RH AF Quarles, RH TI Comparison of CNS and PNS myelin proteins in the pathology of myelin disorders SO JOURNAL OF THE NEUROLOGICAL SCIENCES LA English DT Article; Proceedings Paper CT Symposium of the Society-for-Experimental-Neuropathol CY OCT 03, 2004 CL Toronto, CANADA SP Soc Expt Neuropathol, Amer Neurol Assoc ID MULTIPLE-SCLEROSIS; NEUROPATHIES; DEGENERATION; DISEASE C1 NINDS, Mol & Cellular Neurobiol Lab, NIH, Bethesda, MD 20892 USA. RP Quarles, RH (reprint author), NINDS, Mol & Cellular Neurobiol Lab, NIH, Bldg 49,Room 2A28,49 Convent Dr,MSC 4440, Bethesda, MD 20892 USA. EM quarlesr@ninds.nih.gov NR 25 TC 7 Z9 7 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0022-510X J9 J NEUROL SCI JI J. Neurol. Sci. PD FEB 15 PY 2005 VL 228 IS 2 BP 187 EP 189 DI 10.1016/j.jns.2004.10.005 PG 3 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 898VL UT WOS:000227104200011 PM 15694201 ER PT J AU Sabatinelli, D Bradley, MM Fitzsimmons, JR Lang, PJ AF Sabatinelli, D Bradley, MM Fitzsimmons, JR Lang, PJ TI Parallel amygdala and inferotemporal activation reflect emotional intensity and fear relevance SO NEUROIMAGE LA English DT Article DE emotion; attention; functional imaging; visual cortex; amygdala; human ID FACIAL EXPRESSIONS; TEMPORAL CORTEX; FUNCTIONAL MRI; VISUAL-CORTEX; PHOBIC FEAR; HUMAN FACES; BRAIN; STARTLE; FMRI; PSYCHOPHYSIOLOGY AB Much research demonstrates that emotional stimuli prompt increased amygdala and visual cortical activation. Here we measure functional activity in the visual cortex and amygdala with fMRI while selected fearful and control participants view a range of neutral, emotionally arousing, and fear-relevant pictures. BOLD signal in the amygdala and inferotemporal visual cortex closely covaried during emotional picture viewing, increasing systematically with rated picture arousal. Furthermore, fearful individuals reacting to specific fear cues show parallel, heightened activation in these two structures compared with non-fearful controls. The findings suggest an individually-sensitive, positive linear relationship between the arousing quality of visual stimuli and activation in amygdala and ventral visual cortex, supporting the hypothesized functional connectivity described in the animal model. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Florida, NIMH, Ctr Study Emot & Attent, Gainesville, FL 32610 USA. Univ Florida, Dept Radiol, Gainesville, FL 32610 USA. RP Sabatinelli, D (reprint author), Univ Florida, NIMH, Ctr Study Emot & Attent, POB 100165 HSC, Gainesville, FL 32610 USA. EM sabat@ufl.edu RI Frank, David/E-8213-2012; OI sabatinelli, dean/0000-0001-7409-8504 FU NIDCR NIH HHS [DE13956]; NIMH NIH HHS [P50-MH52384]; PHS HHS [P41-16105] NR 45 TC 269 Z9 272 U1 1 U2 16 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2005 VL 24 IS 4 BP 1265 EP 1270 DI 10.1016/j.neuroimage.2004.12.015 PG 6 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 894JT UT WOS:000226788100037 PM 15670706 ER PT J AU Soltis, J Wegner, FH Newman, JD AF Soltis, J Wegner, FH Newman, JD TI Urinary prolactin is correlated with mothering and allo-mothering in squirrel monkeys SO PHYSIOLOGY & BEHAVIOR LA English DT Article DE communal breeding; allomothering; parenting; salivary prolactin; primates ID SAIMIRI-BOLIVIENSIS-BOLIVIENSIS; MARMOSET CALLITHRIX-JACCHUS; COTTON-TOP TAMARINS; NEW-WORLD PRIMATE; SAGUINUS-OEDIPUS; COMMON MARMOSETS; LACTATION; HORMONE; RESPONSIVENESS; PREGNANCY AB The hormone prolactin is implicated in infant care-giving by parents and allo-parents in a variety of species. Adult female squirrel monkeys (Saimiri spp.) engage in allo-mothering behavior, which includes carrying and nursing infants, but communal care of offspring has not been investigated from an endocrine standpoint in this taxon. We attempted to fill this gap by examining prolactin levels in squirrel monkeys (Saimiri sciureus) as a function of parental responsiveness. Subjects were housed at the National Institutes of Health Animal Center and assays were performed at the Wisconsin National Primate Research Center. To test for the presence of prolactin in squirrel monkey, saliva, blood and saliva were simultaneously collected from anesthetized subjects during routine health examinations. Prolactin was detectable in serum but not in saliva samples. In the core investigation, behavioral data were collected by focal animal sampling on three 1-male multi-female groups, and individually identified urine was collected non-invasively from foil containers underneath group cages on a daily basis throughout the behavioral study. Changes in urinary prolactin over time reflected changes in the reproductive state of a female who was pregnant, gave birth and lactated during the study. Mean urinary prolactin levels in non-lactating females and a male housed with infants in one group were higher than in adults from 2 groups without infants. In the group with infants, mean urinary prolactin levels in adults increased with the amount of infant contact and care-giving. The squirrel monkey may represent a new primate model for investigating the endocrinology of infant care-giving. Published by Elsevier Inc. C1 NICHHD, Comparat Ethol Lab, Dept Hlth & Human Serv, NIH, Poolesville, MD 20837 USA. Univ Wisconsin, Wisconsin Natl Primate Res Ctr, Madison, WI 53715 USA. RP Newman, JD (reprint author), NICHHD, Comparat Ethol Lab, Dept Hlth & Human Serv, NIH, POB 529, Poolesville, MD 20837 USA. EM jdnewman@helix.nih.gov NR 38 TC 10 Z9 10 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0031-9384 J9 PHYSIOL BEHAV JI Physiol. Behav. PD FEB 15 PY 2005 VL 84 IS 2 BP 295 EP 301 DI 10.1016/j.physbeh.2004.12.006 PG 7 WC Psychology, Biological; Behavioral Sciences SC Psychology; Behavioral Sciences GA 902MW UT WOS:000227362200013 PM 15708781 ER PT J AU Oubrahim, H Wang, J Stadtman, ER Chock, PB AF Oubrahim, H Wang, J Stadtman, ER Chock, PB TI Molecular cloning and characterization of murine caspase-12 gene promoter SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE apoptosis; endoplasmic reticulum; genome walking; RACE; reporter gene ID OXIDE INHIBITS APOPTOSIS; UBIQUITIN-PROTEIN LIGASE; CELL-DEATH; EXPRESSION; ACTIVATION; FAMILY; PHOSPHORYLATION; IDENTIFICATION; INJURY AB The activation of caspase-12 is involved in endoplasmic reticulum-mediated apoptosis. To investigate how caspase-12 is transcriptionally and translationally regulated, we isolated and sequenced the 5'-flanking region of mouse caspase-12 gene by a PCR-mediated chromosome-walking technique, using mouse genomic DNA as a template. Two DNA fragments of 3,221 and 800 bp were isolated and cloned into pGL3 promoterless vector upstream of the luciferase gene. The small DNA fragment contains the first intron sequence located downstream of the first exon and 27 bp from the second exon, whereas the large fragment contains the small fragment and the 5'-flanking region. Reporter constructs generated from these DNA fragments showed a substantial promoter activity in mouse NIH 3T3 or human embryonic kidney 293 cells grown in the presence of 10% serum. In the absence of serum, the luciferase activity was drastically reduced. However, the luciferase mRNA was higher in serum-starved cells than in control cells, suggesting that translation of luciferase mRNA was drastically inhibited. However, Western blot analysis revealed that the quantity of procaspase-12 is actually higher in serum-starved cells relative to that cultured in the presence of 10% serum. Progressive deletion analysis of the 3,221-bp sequence revealed that the highest luciferase activity was observed with the construct containing 700 bp upstream of ATG. The transcriptional initiation site was identified by 5' RACE techniques using total RNA from NIH 3T3 cells. Our results should facilitate studies on the mechanism regulating the expression of this important gene. C1 NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Oubrahim, H (reprint author), NHLBI, Biochem Lab, NIH, Bldg 50,Room 2144,50 South Dr,MSC-8012, Bethesda, MD 20892 USA. EM oubrahih@nhlbi.nih.gov NR 31 TC 8 Z9 10 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 15 PY 2005 VL 102 IS 7 BP 2322 EP 2327 DI 10.1073/pnas.0409874102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 898JM UT WOS:000227073100015 PM 15701691 ER PT J AU Prag, G Lee, SH Mattera, R Arighi, CN Beach, BM Bonifacino, JS Hurley, JH AF Prag, G Lee, SH Mattera, R Arighi, CN Beach, BM Bonifacino, JS Hurley, JH TI Structural mechanism for ubiquitinated-cargo recognition by the Golgi-localized, gamma-ear-containing, ADP-ribosylation-factor-binding proteins SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE protein-protein interactions; structural biology; trafficking ID GGA1 GAT DOMAIN; MOLECULAR REPLACEMENT; CRYSTAL-STRUCTURE; ALPHA-APPENDAGE; COMPLEX; CLATHRIN; TOM1; MONOUBIQUITIN; ENDOCYTOSIS; TRANSPORT AB The Golgi-localized, gamma-ear-containing, Arf (ADP-ribosylation factor)-binding (GGA) proteins are clathrin adaptors that mediate the sorting of transmembrane-cargo molecules at the trans-Golgi network and endosomes. Cargo proteins can be directed into the GGA pathway by at least two different types of sorting signals: acidic cluster-dileucine motifs and covalent modification by ubiquitin. The latter modification is recognized by the GGAs through binding to their GAT [GGA and TOM (target of Myb)] domain. Here we report the crystal structure of the GAT domain of human GGA3 in a 1:1 complex with ubiquitin at 2.8-Angstrom resolution. Ubiquitin binds to a hydrophobic and acidic patch on helices alpha1 and alpha2 of the GAT three-helix bundle that includes Asn-223, Leu-227, Glu-230, Met-231, Asp-244, Glu-246, Leu-247, Glu-250, and Leu-251. The GAT-binding surface on ubiquitin is a hydrophobic patch centered on Ile-44 that is also responsible for binding most other ubiquitin effectors. The ubiquitin-binding site observed in the crystal is distinct from the Rabaptin-5-binding site on helices alpha2 and alpha3 of the GAT domain. Mutational analysis and modeling of the ubiquitin-Rabaptin-5-GAT ternary complex indicates that ubiquitin and Rabaptin-5 can bind to the GAT domain at two different sites without any steric conflict. This ability highlights the GAT domain as a hub for interactions with multiple partners in trafficking. C1 NIDDKD, Mol Biol Lab, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NICHHD, Cell Biol & Metab Branch, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Hurley, JH (reprint author), NIDDKD, Mol Biol Lab, NIH, US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM hurley@helix.nih.gov OI Arighi, Cecilia/0000-0002-0803-4817 NR 37 TC 43 Z9 44 U1 0 U2 4 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 15 PY 2005 VL 102 IS 7 BP 2334 EP 2339 DI 10.1073/pnas.0500118102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 898JM UT WOS:000227073100017 PM 15701688 ER PT J AU Heller, T Saito, S Auerbach, J Williams, T Moreen, TR Jazwinski, A Cruz, B Jeurkar, N Sapp, R Luo, GX Liang, TJ AF Heller, T Saito, S Auerbach, J Williams, T Moreen, TR Jazwinski, A Cruz, B Jeurkar, N Sapp, R Luo, GX Liang, TJ TI An in vitro model of hepatitis C virion production SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE assembly; cell culture; infection; ribozyme; viral replication ID VIRUS-LIKE PARTICLES; NEUTRALIZING ANTIBODY; STRUCTURAL PROTEINS; RNA REPLICATION; PLUS RIBAVIRIN; CDNA-CLONE; CELL LINE; HCV RNA; GENOME; MUTATIONS AB The hepatitis C virus (HCV) is a major cause of liver disease worldwide. The understanding of the viral life cycle has been hampered by the lack of a satisfactory cell culture system. The development of the HCV replicon system has been a major advance, but the system does not produce virions. In this study, we constructed an infectious HCV genotype 1b cDNA between two ribozymes that are designed to generate the exact 5' and 3' ends of HCV. A second construct with a mutation in the active site of the viral RNA-dependent RNA polymerase (RdRp) was generated as a control. The HCV-ribozyme expression construct was transfected into Huh7 cells. Both HCV structural and nonstructural proteins were detected by immunofluorescence and Western blot. RNase protection assays showed positive- and negative-strand HCV RNA. Sequence analysis of the 5' and 3' ends provided further evidence of viral replication. Sucrose density gradient centrifugation of the culture medium revealed colocalization of HCV RNA and structural proteins in a fraction with the density of 1.16 g/ml, the putative density of HCV virions. Electron microscopy showed viral particles of approximate to 50 nm in diameter. The level of HCV RNA in the culture medium was as high as 10 million copies per milliliter. The HCV-ribozyme construct with the inactivating mutation in the RdRp did not show evidence of viral replication, assembly, and release. This system supports the production and secretion of high-level HCV virions and extends the repertoire of tools available for the study of HCV biology. C1 NIDDKD, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. Univ Kentucky, Coll Med, Lexington, KY 40506 USA. RP Liang, TJ (reprint author), NIDDKD, Liver Dis Branch, NIH, Bldg 10,Room 9B16,10 Ctr Dr MSC 1800, Bethesda, MD 20892 USA. EM jliang@nih.gov FU NCI NIH HHS [R01 CA093712]; NIAID NIH HHS [R01 AI051592] NR 29 TC 84 Z9 93 U1 1 U2 3 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 15 PY 2005 VL 102 IS 7 BP 2579 EP 2583 DI 10.1073/pnas.0409666102 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 898JM UT WOS:000227073100060 PM 15701697 ER PT J AU Maitournam, A Simon, R AF Maitournam, A Simon, R TI On the efficiency of targeted clinical trials SO STATISTICS IN MEDICINE LA English DT Article DE genomics; clinical trials; molecularly targeted therapeutics pharmacogenomics; sample size; normal mixture ID B-CELL LYMPHOMA; SAMPLE-SIZE; RUN-IN; DISCOVERY; SURVIVAL; TUMORS AB The development of genomics-based technologies is demonstrating that many common diseases are heterogeneous collections of molecularly distinct entities. Molecularly targeted therapeutics is often effective only for some subsets patients with a conventionally defined disease. We consider the problem of design of phase III randomized clinical trials for the evaluation of a molecularly targeted treatment when there is an assay predictive of which patients will be more responsive to the experimental treatment than to the control regimen. We compare the conventional randomized clinical trial design to a design based on randomizing only patients predicted to preferentially benefit from the new treatment. Trial designs are compared based on the required number of randomized patients and the expected number of patients screened for randomization eligibility. Relative efficiency depends upon the distribution of treatment effect across patient subsets.. prevalence of the subset of patients who respond preferentially to the experimental treatment, and assay performance. Copyright (C) 2004 John Wiley Sons. Ltd. C1 NCI, Biomet Res Branch, Bethesda, MD 20892 USA. RP Simon, R (reprint author), NCI, Biomet Res Branch, 9000 Rockville Pike,MSC 7434, Bethesda, MD 20892 USA. EM rsimon@mail.nih.gov NR 24 TC 104 Z9 109 U1 2 U2 7 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD FEB 15 PY 2005 VL 24 IS 3 BP 329 EP 339 DI 10.1002/sim.1975 PG 11 WC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Medicine, Research & Experimental; Statistics & Probability SC Mathematical & Computational Biology; Public, Environmental & Occupational Health; Medical Informatics; Research & Experimental Medicine; Mathematics GA 892OE UT WOS:000226659100001 PM 15551403 ER PT J AU Kerns, W Schwartz, L Blanchard, K Burchiel, S Essayan, D Fung, E Johnson, R Lawton, M Louden, C MacGregor, J Miller, F Nagarkatti, P Robertson, D Sistare, F Snyder, P Thomas, H Wagner, B Ward, A Zhang, J AF Kerns, W Schwartz, L Blanchard, K Burchiel, S Essayan, D Fung, E Johnson, R Lawton, M Louden, C MacGregor, J Miller, F Nagarkatti, P Robertson, D Sistare, F Snyder, P Thomas, H Wagner, B Ward, A Zhang, J CA Expert Working Grp Drug-Induced Vasc TI Drug-induced vascular injury - a quest for biomarkers SO TOXICOLOGY AND APPLIED PHARMACOLOGY LA English DT Review ID CIRCULATING ENDOTHELIAL-CELLS; C-REACTIVE PROTEIN; CORONARY ARTERIAL LESIONS; ACUTE CARDIOVASCULAR TOXICITY; SOLUBLE ADHESION MOLECULES; VON-WILLEBRAND-FACTOR; ACUTE-PHASE PROTEINS; IN-VIVO; RECEPTOR ANTAGONIST; ADENOSINE AGONIST C1 Univ New Mexico, Albuquerque, NM 87131 USA. CBER, FDA, Rockville, MD 20857 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Virginia Commonwealth Univ, Richmond, VA 23284 USA. Purdue Univ, W Lafayette, IN 47907 USA. NYU, Med Ctr, New York, NY 10016 USA. OI Miller, Frederick/0000-0003-2831-9593 NR 153 TC 49 Z9 50 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 0041-008X J9 TOXICOL APPL PHARM JI Toxicol. Appl. Pharmacol. PD FEB 15 PY 2005 VL 203 IS 1 BP 62 EP 87 DI 10.1016/j.taap.2004.08.001 PG 26 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 903ED UT WOS:000227407400008 PM 15694465 ER PT J AU Abbott, KC Koff, J Bohen, EM Oglesby, RJ Agodoa, LYC Lentine, KL Schnitzler, MA AF Abbott, KC Koff, J Bohen, EM Oglesby, RJ Agodoa, LYC Lentine, KL Schnitzler, MA TI Maintenance immunosuppression use and the associated risk of avascular necrosis after kidney transplantation in the United States SO TRANSPLANTATION LA English DT Article DE avascular necrosis; medicare claim; renal transplant; female; peritoneal dialysis; cyclosporine A; tacrolimus; US renal database system ID BONE-MARROW EDEMA; RENAL-TRANSPLANTATION; FEMORAL-HEAD; THROMBOTIC MICROANGIOPATHY; MYCOPHENOLATE-MOFETIL; DIABETES-MELLITUS; GRAFT-SURVIVAL; PAIN SYNDROME; SINGLE-CENTER; OSTEONECROSIS AB Background. Avascular necrosis (AVN) after renal transplantation has been largely attributed to the use of corticosteroids. However, other risk factors such as microvascular thrombosis and hyperlipidemia have been well described and may be of increased importance in the era of early steroid cessation and avoidance. We hypothesized that maintenance immunosuppressive medications known to be associated with these risk factors for AVN would also be associated with a higher risk of AVN. Methods. By using the U.S. Renal Data System database, we studied 27,772 primary patients on Medicare who received a solitary kidney transplant between January 1, 1996, and July 31, 2000. Cox proportional hazards regression models were used to calculate adjusted hazard ratios (AHRs) for patient- and transplant-related factors (including allograft rejection) with Medicare claims for AVN. The intensity and duration of corticosteroid use could not be assessed. Results. Among patients who were prescribed sirolimus at discharge, 3.5% of patients who received the combination of sirolimus-cyclosporine A (CsA) demonstrated AVN, compared with 1.4% of patients who received the combination of siroli-mus-tacrolimus (P=0.06 by chi(2)). In Cox regression, CsA use (vs. tacrolimus) (AHR 1.36, 95% confidence interval, 1.09-1.71) was independently associated with an increased risk of AVN. Sirolimus use showed a trend toward significance (AHR 1.59, 95% confidence interval, 0.99-2.56), with no significant interaction with CsA. Conclusions. Compared with other maintenance immunosuppression, AVN was significantly more common after use of CsA prescribed at the time of discharge for renal transplantation. Whether this increased risk of AVN was directly attributable to hyperlipidemia, microvascular thrombosis, or differences in corticosteroid dosing could not be determined. C1 Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. Walter Reed Army Med Ctr, Serv Gastroenterol, Washington, DC 20307 USA. Walter Reed Army Med Ctr, Rheumatol Serv, Washington, DC 20307 USA. NIDDK, NIH, Bethesda, MD USA. St Louis Univ, Sch Med, Ctr Outcomes Res, St Louis, MO USA. RP Abbott, KC (reprint author), Walter Reed Army Med Ctr, Serv Nephrol, Washington, DC 20307 USA. EM kevin.abbott@na.amedd.army.mil RI ieong, bee/C-5840-2012; OI Abbott, Kevin/0000-0003-2111-7112 NR 46 TC 12 Z9 13 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0041-1337 J9 TRANSPLANTATION JI Transplantation PD FEB 15 PY 2005 VL 79 IS 3 BP 330 EP 336 DI 10.1097/01.TP.0000149894.95435.7F PG 7 WC Immunology; Surgery; Transplantation SC Immunology; Surgery; Transplantation GA 898NH UT WOS:000227083000011 PM 15699764 ER PT J AU Simonsen, L Reichert, TA Viboud, C Blackwelder, WC Taylor, RJ Miller, MA AF Simonsen, L Reichert, TA Viboud, C Blackwelder, WC Taylor, RJ Miller, MA TI Impact of influenza vaccination on seasonal mortality in the US elderly population SO ARCHIVES OF INTERNAL MEDICINE LA English DT Article ID CONTROLLED-TRIAL; UNITED-STATES; HOSPITALIZATIONS; INDIVIDUALS; COMMUNITY; EFFICACY; MANITOBA; DEATHS; VIRUS; OLDER AB Background: observational studies report that influenza vaccination reduces winter mortality risk from any cause by 50% among the elderly. Influenza vaccination coverage among elderly persons ( greater than or equal to65 years) in the United States increased from between 15% and 20% before 1980 to 65% in 2001. Unexpectedly, estimates of influenza-related mortality in this age group also increased during this period. We tried to reconcile these conflicting findings by adjusting excess mortality estimates for aging and increased circulation of influenza A(H3N2) viruses. Methods: We used a cyclical regression model to generate seasonal estimates of national influenza-related mortality (excess mortality) among the elderly in both pneumonia and influenza and all-cause deaths for the 33 seasons from 1968 to 2001. We stratified the data by 5-year age group and separated seasons dominated by A(H3N2) viruses from other seasons. Results: For people aged 65 to 74 years, excess mortality rates in A(H3N2)-dominated seasons fell between 1968 and the early 1980s but remained approximately constant thereafter. For persons 85 years or older, the mortality rate remained flat throughout. Excess mortality in A(H1N1) and B seasons did not change. All-cause excess mortality for persons 65 years or older never exceeded 10% of all winter deaths. Conclusions: We attribute the decline in influenza-related mortality among people aged 65 to 74 years in the decade after the 1968 pandemic to the acquisition of immunity to the emerging A(H3N2) virus. We could not correlate increasing vaccination coverage after 1980 with declining mortality rates in any age group. Because fewer than 10% of all winter deaths were attributable to influenza in any season, we conclude that observational studies substantially overestimate vaccination benefit. C1 NIAID, Off Global Affairs, NIH, Bethesda, MD 20892 USA. Natl Inst Hlth, Fogarty Int Ctr, Bethesda, MD USA. Entropy Res Inst, Boston, MA USA. RP Simonsen, L (reprint author), NIAID, Off Global Affairs, NIH, 6610 Rockledge Dr,Room 2033, Bethesda, MD 20892 USA. EM Lsimonsen@niaid.nih.gov OI Simonsen, Lone/0000-0003-1535-8526 NR 38 TC 328 Z9 340 U1 2 U2 22 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60654-0946 USA SN 0003-9926 J9 ARCH INTERN MED JI Arch. Intern. Med. PD FEB 14 PY 2005 VL 165 IS 3 BP 265 EP 272 DI 10.1001/archinte.165.3.265 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 896RY UT WOS:000226952400002 PM 15710788 ER PT J AU Dawson, DA Grant, BF Stinson, FS Chou, PS AF Dawson, DA Grant, BF Stinson, FS Chou, PS TI Psychopathology associated with drinking and alcohol use disorders in the college and general adult populations SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE drinking; alcohol use disorders; psychopathology ID SUBSTANCE USE DISORDERS; NATIONAL EPIDEMIOLOGIC SURVEY; AXIS-II COMORBIDITY; PERSONALITY-DISORDERS; MENTAL-HEALTH; ANXIETY DISORDERS; CONSUMPTION PATTERNS; FAMILY-HISTORY; BINGE DRINKING; UNITED-STATES AB This paper examines the associations between past-year drinking status and the prevalence of 15 different past-year anxiety, mood and personality disorders, using a large (n = 43,093) nationally representative sample of the U.S. population. The prevalence of these disorders and their associations with drinking are compared for college students 18-29 years of age, other youth 18-29 years of age, and adults 30 years of age and older. After adjusting for sociodemographic characteristics and past-year tobacco and illicit drug use, only drinkers with alcohol dependence experienced an excess risk of a mood or anxiety disorder among college students 18-29 years of age, OR = 2.4. In contrast, the excess risk of any mood or anxiety disorder associated with drinking status among non-college youth varied from an OR of 1.8 for non-binge drinkers to 4.7 for drinkers with alcohol dependence. Among persons 30 years of age and older, the degree of excess risk was slightly lower but still higher than those for college students, OR = 1.5-3.8. Similarly, the excess odds of any personality disorder associated with drinking varied from 1.6 to 5.0 for the younger, non-college group and from 1.5 to 3.8 for the older adults, with no significant effect observed among college students. Factors that may help explain the weaker association of psychopathology and drinking in the college population include selectivity and greater availability of social and treatment resources that serve as alternatives to self-medicating the symptoms of psychological distress with alcohol. (C) 2004 Published by Elsevier Ireland Ltd. C1 NIAAA, US Dept Hlth & Human Serv, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res,NIH,DBE, Bethesda, MD 20892 USA. RP Dawson, DA (reprint author), NIAAA, US Dept Hlth & Human Serv, Lab Epidemiol & Biometry, Div Intramural Clin & Biol Res,NIH,DBE, Willco Bldg,Suite 514,600 Execut Blvd,MSC 7003, Bethesda, MD 20892 USA. EM ddawson@wqillco.niaaa.nih.gov NR 56 TC 81 Z9 83 U1 6 U2 14 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD FEB 14 PY 2005 VL 77 IS 2 BP 139 EP 150 DI 10.1016/j.drugalcdep.2004.07.012 PG 12 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 898QW UT WOS:000227092300004 PM 15664715 ER PT J AU Weiss, RD Griffin, ML Gallop, RJ Najavits, LM Frank, A Crits-Christoph, P Thase, ME Blaine, J Gastfriend, DR Daley, D Luborsky, L AF Weiss, RD Griffin, ML Gallop, RJ Najavits, LM Frank, A Crits-Christoph, P Thase, ME Blaine, J Gastfriend, DR Daley, D Luborsky, L TI The effect of 12-step self-help group attendance and participation on drug use outcomes among cocaine-dependent patients SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article; Proceedings Paper CT 63rd Annual Meeting of the College-on-Problems-of-Drug-Dependence CY JUN 16-21, 2001 CL SCOTTSDALE, AZ SP Coll Problems Drug Dependence DE cocaine; treatment; Alcoholics Anonymous; self-help; addiction; substance abuse ID SUBSTANCE-ABUSE TREATMENT; OUTPATIENT TREATMENT; INVOLVEMENT; PSYCHOTHERAPY; AFFILIATION; PROGRAM; CARE AB Objective: Although cocaine-dependent patients are frequently referred to 12-step self-help groups, little research has examined the benefits of 12-step group attendance in this population. Moreover, the distinction between attending meetings and actively participating in 12-step activities has not typically been examined. Method: In the National Institute on Drug Abuse Collaborative Cocaine Treatment Study, 487 cocaine-dependent outpatients were recruited at five sites for a randomized controlled trial of 24-week behavioral treatments. Study data were examined to see whether self-help attendance or active participation were related to subsequent drug use. Results: Twelve-step group attendance did not predict subsequent drug use. However, active 12-step participation in a given month predicted less cocaine use in the next month. Moreover, patients who increased their 12-step participation during the first 3 months of treatment had significantly less cocaine use and lower ASI Drug Use Composite scores in the subsequent 3 months. Finally, Individual Drug Counseling, based on a 12-step model, and increasing levels of 12-step participation each offered discrete benefits. Conclusions: Results suggest that active 12-step participation by cocaine-dependent patients is more important than meeting attendance, and that a combination of Individual Drug Counseling and active 12-step participation is effective for these patients. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. McLean Hosp, Belmont, MA 02478 USA. Univ Penn, Dept Psychiat, Ctr Psychotherapy Res, Dept Psychiat, Philadelphia, PA 19104 USA. Univ Miami, Sch Med, Dept Epidemiol & Publ Hlth, Miami, FL 33136 USA. Univ Pittsburgh, Dept Psychiat, Pittsburgh, PA 15260 USA. Western Psychiat Inst & Clin, Pittsburgh, PA 15260 USA. Natl Inst Drug Abuse, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Boston, MA 02115 USA. RP Weiss, RD (reprint author), Harvard Univ, Sch Med, Dept Psychiat, Boston, MA 02115 USA. EM rweiss@mclean.harvard.edu FU NIDA NIH HHS [K02-DA 00326, K05-DA00168, R01 DA012249, U01-DA07085, U01-DA07090, U01-DA07663, U01-DA07673, U01-DA07693, U18 DA007090]; NIMH NIH HHS [K02-MH00756, P30-MH-45178] NR 41 TC 64 Z9 66 U1 7 U2 13 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD FEB 14 PY 2005 VL 77 IS 2 BP 177 EP 184 DI 10.1016/j.drugalcdep.2004.08.012 PG 8 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 898QW UT WOS:000227092300008 PM 15664719 ER PT J AU Zi, ZK Cho, KH Sung, MH Xia, XF Zheng, JS Sun, ZR AF Zi, ZK Cho, KH Sung, MH Xia, XF Zheng, JS Sun, ZR TI In silico identification of the key components and steps in IFN-gamma induced JAK-STAT signaling pathway SO FEBS LETTERS LA English DT Article DE Janus kinase-signal transducers and activators of transcription; interferon gamma; robustness analysis; multi-parametric sensitivity analysis; systems biology ID INTERFERON-GAMMA; TRANSDUCTION PATHWAY; SYSTEMS BIOLOGY; KINASE CASCADE; ACTIVATION; INHIBITOR; MECHANISM; NETWORKS; CYTOKINE; DYNAMICS AB Systems biology efforts are increasingly adopting quantitative, mechanistic modeling to study cellular signal transduction pathways and other networks. However, it is uncertain whether the particular set of kinetic parameter values of the model closely approximates the corresponding biological system. We propose that the parameters be assigned statistical distributions that reflect the degree of uncertainty for a comprehensive simulation analysis. From this analysis, we globally identify the key components and steps in signal transduction networks at a systems level. We investigated a recent mathematical model of interferon gamma induced Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway by applying multi-parametric sensitivity analysis that is based on simultaneous variation of the parameter values. We find that suppressor of cytokine signaling-1, nuclear phosphatases, cytoplasmic STAT1, and the corresponding reaction steps are sensitive perturbation points of this pathway. (C) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 Seoul Natl Univ, Coll Med, Seoul 110799, South Korea. Tsing Hua Univ, Inst Bioinformat, Dept Biol Sci & Biotechnol, MOE Key Lab Bioinformat, Beijing 100084, Peoples R China. Seoul Natl Univ, Korea Bio MAX Inst, Seoul 151818, South Korea. NCI, NIH, Biometr Res Brach, Bethesda, MD 20892 USA. RP Cho, KH (reprint author), Seoul Natl Univ, Coll Med, Seoul 110799, South Korea. EM ckh-sb@snu.ac.kr; sunzhr@mail.tsinghua.edu.cn RI Cho, Kwang-Hyun/C-1684-2011; Zheng, Jiashun/A-3098-2012; Zi, Zhike/B-4185-2012; OI Zi, Zhike/0000-0002-7601-915X NR 35 TC 73 Z9 77 U1 2 U2 8 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD FEB 14 PY 2005 VL 579 IS 5 BP 1101 EP 1108 DI 10.1016/j.febslet.2005.01.009 PG 8 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 900JG UT WOS:000227210600022 PM 15710397 ER PT J AU Durkin, ME Avner, MR Huh, CG Yuan, BZ Thorgeirsson, SS Popescu, NC AF Durkin, ME Avner, MR Huh, CG Yuan, BZ Thorgeirsson, SS Popescu, NC TI DLC-1, a Rho GTPase-activating protein with tumor suppressor function, is essential for embryonic development SO FEBS LETTERS LA English DT Article DE Rho GTPase-activating protein; knock-out mouse; embryonic lethal ID HEPATOCELLULAR-CARCINOMA; FOCAL ADHESIONS; GENE; DOMAIN; MICE; ARHGAP7; CLONING; GROWTH AB DLC-1 (deleted in liver cancer 1) is a Rho GTPase-activating protein that is able to inhibit cell growth and suppress tumorigenesis. We have used homologous recombination to inactivate the mouse DLC-1 gene (Arhgap7). Mice heterozygous for the targeted allele were phenotypically normal, but homozygous mutant embryos did not survive beyond 10.5 days post coitum. Histological analysis revealed that DLC-1(-/-) embryos had defects in the neural tube, brain, heart, and placenta. Cultured fibroblasts from DLC-1-deficient embryos displayed alterations in the organization of actin filaments and focal adhesions. (C) 2005 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. NCI, SAIC Frederick, Pathol Histotechnol Lab, Vet Pathol Sect, Ft Detrick, MD 21702 USA. RP Durkin, ME (reprint author), NCI, Expt Carcinogenesis Lab, NIH, 37 Convent Dr, Bethesda, MD 20892 USA. EM marian_durkin@nih.gov; popescun@mail.nih.gov NR 28 TC 64 Z9 68 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD FEB 14 PY 2005 VL 579 IS 5 BP 1191 EP 1196 DI 10.1016/j.febslet.2004.12.090 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 900JG UT WOS:000227210600037 PM 15710412 ER PT J AU Landi, MT Bergen, AW Baccarelli, A Patterson, DG Grassman, J Ter-Minassian, M Mocarelli, P Caporaso, N Masten, SA Pesatori, AC Pittman, GS Bell, DA AF Landi, MT Bergen, AW Baccarelli, A Patterson, DG Grassman, J Ter-Minassian, M Mocarelli, P Caporaso, N Masten, SA Pesatori, AC Pittman, GS Bell, DA TI CYP1A1 and CYP1B1 genotypes, haplotypes, and TCDD-induced gene expression in subjects from seveso, Italy SO TOXICOLOGY LA English DT Article DE 2,3,7,8-tetrachlorodibenzo-p-dioxin; CYP1A1; CYP1B1; genotypes; haplotypes; gene expression ID CYTOCHROME P4501B1 VARIANTS; PRIMARY CONGENITAL GLAUCOMA; LUNG-CANCER RISK; HYDROCARBON RECEPTOR; FUNCTIONAL-ANALYSIS; DIOXIN EXPOSURE; POOLED ANALYSIS; POLYMORPHISMS; POPULATION; ASSOCIATION AB 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is highly toxic in experimental animals, and is known to induce cytochrome P450 (CYP) gene expression. We investigated the effect of CYP1A1 and CYP1B1 variant genotypes and haplotypes on CYP1A1 and CYP1B1 mRNA expression and ethoxyresorufin-O-deethylase (EROD) activity in lymphocytes from 121 subjects from the Seveso population, Italy, accidentally exposed to TCDD in 1976. The 3'UTR 3801T>C and 1462V variants of CYP1A1 were present in 16% and 6% of the subjects, respectively. The frequency of CYP1B1 variants was 85.2% for L432V, 49.6% for R48G and A119S, and 28.7% for N453S. There was complete linkage disequilibrium (LD) among the CYP1B1 variant loci (D' = -1) and high LD among the CYP1A1 loci (D' = 0.86). Gene expression measured by RT-PCR did not vary by CYP1B1 genotype in uncultured lymphocytes. However, when lymphocytes were treated in vitro with 10 nM TODD, CYP1B1 and CYP1A1 mRNA expression was strongly induced and modified by CYP variant alleles. Specifically, the CYP1B1*3 haplotype (L432V) was associated with increased CYP1B1 mRNA expression (P = 0.03), following an additive model; the CYP1A1 1462V polymorphism was positively, although not significantly, associated with CYP1A1 expression. The CYP1B1*3 variant may have affected CYP1B1 expression in subjects highly and acutely exposed to dioxin at the time of the accident. Although based on small number of subjects, a slight increase in eczema (P = 0.05, n = 8) and urticaria (P = 0.02, n = 2) was observed 20 years after the accident in subjects carrying the CYP1B1*3 allele. Genetic variation in cytochrome P450 induction may identify subjects with variable responsiveness to TCDD and potentially increased risk of disease. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, EPS,NIH, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Toxicol Branch, Atlanta, GA USA. CUNY Brooklyn Coll, Brooklyn, NY 11210 USA. Univ Milan Bicocca, Hosp Desio, Dept Lab Med, Desio, Italy. Natl Inst Environm Hlth Sci, Environm Toxicol Program, Res Triangle Pk, NC USA. Univ Milan, Epidemiol Res Ctr, EPOCA, Milan, Italy. Natl Inst Environm Hlth Sci, Lab Computat Biol & Risk Anal, Res Triangle Pk, NC USA. RP Landi, MT (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, EPS,NIH, 6120 Execut Blvd, Bethesda, MD 20892 USA. EM Iandim@mail.nih.gov RI masten, scott/R-1403-2016; OI masten, scott/0000-0002-7847-181X; Baccarelli, Andrea/0000-0002-3436-0640; Bergen, Andrew/0000-0002-1237-7644; pesatori, angela/0000-0002-0261-3252 NR 61 TC 50 Z9 52 U1 0 U2 4 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD FEB 14 PY 2005 VL 207 IS 2 BP 191 EP 202 DI 10.1016/j.tox.2004.08.021 PG 12 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 892JB UT WOS:000226645500003 PM 15596250 ER PT J AU White, KL Germolec, DR Booker, CD Hernendez, DM McCay, JA Delclos, KB Newbold, RR Weis, C Guo, TL AF White, KL Germolec, DR Booker, CD Hernendez, DM McCay, JA Delclos, KB Newbold, RR Weis, C Guo, TL TI Dietary methoxychlor exposure modulates splenic natural killer cell activity, antibody-forming cell response and phenotypic marker expression in F-0 and F-1 generations of Sprague Dawley rats SO TOXICOLOGY LA English DT Article DE methoxychlor; developmental exposure; immunomodulation; rat; endocrine disrupter ID ESTROGEN-RECEPTOR; INUTERO EXPOSURE; MICE; DIETHYLSTILBESTROL; IMMUNE; BETA; METABOLITES; ACTIVATION; TOXICOLOGY; CHEMICALS AB Methoxychlor, a chlorinated hydrocarbon pesticide, is a persistent environmental contaminant that has been identified in human reproductive tissues. Methoxychlor has been shown to be estrogenic in both in vivo and in vitro studies. As an endocrine disrupter, it may have the potential to adversely affect endocrine, reproductive, and immune systems in animals. The present study evaluated methoxychlor's immunotoxic potential in F-0 (dams) and F-1 generations of Sprague Dawley rats exposed to an isoflavone-free diet containing methoxychlor at concentrations of 10, 100, and 1000 ppm. In dams, exposure to methoxychlor from gestation day 7 to postpartum day 51 (65 days total exposure) produced a significant increase in the NK activity (1000 ppm) and the percentages of T cells (1000 ppm), helper T cells (1000 ppm) and macrophages (100 and 1000 ppm). In contrast, a decrease in the numbers of splenocytes and B cells was observed at the 100 and 1000 ppm concentrations. In F-1 males, exposure to methoxychlor gestationally, lactationally and through feed from postnatal day 22-64 (78 days total exposure) produced an increase in the spleen IgM antibody-forming cell response to sheep red blood cells (100 and 1000 ppm) and the activity of NK cells (1000 ppm). However, there was a decrease in the terminal body weight (1000ppm), spleen weight (1000 ppm), thymus weight (100 and 1000ppm), and the numbers of splenocytes (1000ppm), B cells (100 and 1000ppm), cytotoxic T cells (1000ppm) and NK cells (100 and 1000ppm). In F-1 females, exposure to methoxychlor produced a decrease in the terminal body weight (1000 ppm) and the percentages of cytotoxic T cells (10, 100 and 1000 ppm). These results demonstrate that developmental and adult dietary exposure to methoxychlor modulates immune responses in Sprague Dawley rats. Immunological changes were more pronounced in the F-1 generation male rats that were exposed during gestation and postpartum, when compared to the F-0 and F-1 generation females. Increases in antibody-forming cell response and NK cell activity, and altered spleen cell subpopulation numbers were observed in the F-1 generation male rats, without similar changes to the F-1 generation females. (C) 2004 Elsevier Ireland Ltd. All rights reserved. C1 Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. NIEHS, Mol Toxicol Lab, Res Triangle Pk, NC 27709 USA. US FDA, Natl Ctr Toxicol Res, Div Biochem Toxicol, Jefferson, AR 72079 USA. RP Guo, TL (reprint author), Virginia Commonwealth Univ, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA. EM tlguo@hsc.vcu.edu FU NIEHS NIH HHS [ES 55094]; PHS HHS [224-93-0001] NR 42 TC 19 Z9 21 U1 1 U2 1 PU ELSEVIER SCI IRELAND LTD PI CLARE PA CUSTOMER RELATIONS MANAGER, BAY 15, SHANNON INDUSTRIAL ESTATE CO, CLARE, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD FEB 14 PY 2005 VL 207 IS 2 BP 271 EP 281 DI 10.1016/j.tox.2004.09.011 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 892JB UT WOS:000226645500010 PM 15596257 ER PT J AU Zhao, YD Li, MC Simon, R AF Zhao, YD Li, MC Simon, R TI An adaptive method for cDNA microarray normalization SO BMC BIOINFORMATICS LA English DT Article ID SINGLE AB Background: Normalization is a critical step in analysis of gene expression profiles. For dual-labeled arrays, global normalization assumes that the majority of the genes on the array are non-differentially expressed between the two channels and that the number of over-expressed genes approximately equals the number of under-expressed genes. These assumptions can be inappropriate for custom arrays or arrays in which the reference RNA is very different from the experimental samples. Results: We propose a mixture model based normalization method that adaptively identifies non-differentially expressed genes and thereby substantially improves normalization for dual-labeled arrays in settings where the assumptions of global normalization are problematic. The new method is evaluated using both simulated and real data. Conclusions: The new normalization method is effective for general microarray platforms when samples with very different expression profile are co-hybridized and for custom arrays where the majority of genes are likely to be differentially expressed. C1 NCI, Biometr Res Branch, NIH, Rockville, MD USA. EMMES Corp, Rockville, MD USA. RP Zhao, YD (reprint author), NCI, Biometr Res Branch, NIH, Rockville, MD USA. EM zhaoy@helix.nih.gov; mli@emmes.com; rsimon@mail.nih.gov NR 13 TC 23 Z9 24 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 FEB 11 PY 2005 VL 6 AR 28 DI 10.1176/1471-2105-6-28 PG 10 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Mathematical & Computational Biology SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Mathematical & Computational Biology GA 903UZ UT WOS:000227452400002 PM 15707486 ER PT J AU Weinstein, BM AF Weinstein, BM TI Vessels and nerves: Marching to the same tune SO CELL LA English DT Review ID ANGIOGENIC FACTOR; AXON GUIDANCE; SEMAPHORIN; RECEPTOR; NEUROPILIN-1; MORPHOGENESIS; NETRIN-1; PATTERN; GROWTH; VEINS AB The patterning of the nervous system is achieved through coordinated action of a variety of repulsive or attractive neuronal guidance factors that direct the growth of growing axons to specific pathways. Recent studies suggest that the same or similar sets of factors also guide migration of endothelial cells, helping to direct the stereotypical embryonic patterning of the developing vertebrate vascular system. C1 NICHHD, Genet Mol Lab, NIH, Bethesda, MD 20892 USA. RP Weinstein, BM (reprint author), NICHHD, Genet Mol Lab, NIH, 6 Ctr Dr, Bethesda, MD 20892 USA. EM flyingfish@nih.gov NR 20 TC 95 Z9 100 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD FEB 11 PY 2005 VL 120 IS 3 BP 299 EP 302 DI 10.1016/j.cell.2005.01.010 PG 4 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 897TS UT WOS:000227028900006 PM 15707889 ER PT J AU Pengt, B Hodge, DR Thomas, SB Cherry, JM Munroe, DJ Pompeia, C Xiao, WH Farrar, WL AF Pengt, B Hodge, DR Thomas, SB Cherry, JM Munroe, DJ Pompeia, C Xiao, WH Farrar, WL TI Epigenetic silencing of the human nucleotide excision repair gene, hHR23B, in interleukin-6-responsive multiple myeloma KAS-6/1 cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID DNA METHYLATION; REPRESSES TRANSCRIPTION; XERODERMA-PIGMENTOSUM; P53 GENE; PROMOTER; CANCER; DAMAGE; METHYLTRANSFERASE; CARCINOGENESIS; EXPRESSION AB During tumorigenesis, selective proliferative advantage in certain cell subsets is associated with accumulation of multiple genetic alterations. For instance, multiple myeloma is characterized by frequent karyotypic instability at the earliest stage, progressing to extreme genetic abnormalities as the disease progresses. These successive genetic alterations can be attributed, in part, to defects in DNA repair pathways, perhaps based on epigenetic gene silencing of proteins involved in DNA damage repair. Here we report epigenetic hypermethylation of the hHR23B gene, a key component of the nucleotide excision repair in response to DNA damage, in interleukin-6 (IL-6)-responsive myeloma KAS-6/1 cells. This hypermethylation was significantly abated by Zebularine, a potent demethylating agent, with a consequent increase in the hHR23B mRNA level. Subsequent removal of this drug and supplementation with IL-6 in the culture medium re-established DNA hypermethylation of the hHR23B gene and silencing of mRNA expression levels. The inclination of DNA to be remethylated, at least within the hHR23B gene promoter region, reflects an epigenetic driving force by the cytogenetic/ tumorigenic status of KAS-6/1 myeloma. The IL-6 response of V.AS-6/1 myeloma also raises a question of whether the proneoplastic growth factor, such as IL-6, supports the epigenetic silencing of important DNA repair genes via promoter hypermethylation during the development of multiple myeloma. C1 NCI, Frederick Canc Res & Dev Ctr, Cytokine Mol Mech Sect, Mol Immunoregulat Lab, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Intramural Res Support Program, Sci Applicat Int Corp, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Lab Mol Technol, Frederick, MD 21702 USA. NCI, Frederick Canc Res & Dev Ctr, Gene Express Lab, Frederick, MD 21702 USA. RP Farrar, WL (reprint author), NCI, Frederick Canc Res & Dev Ctr, Cytokine Mol Mech Sect, Mol Immunoregulat Lab, 1050 Boyles St,Bldg 560,Rm 31-68, Frederick, MD 21702 USA. EM farrar@mail.ncifcrf.gov RI Xiao, Weihua/N-2775-2013 OI Xiao, Weihua/0000-0001-9102-6326 FU NCI NIH HHS [N01-CO-5600] NR 32 TC 27 Z9 28 U1 1 U2 5 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 11 PY 2005 VL 280 IS 6 BP 4182 EP 4187 DI 10.1074/jbc.M412566200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 898SN UT WOS:000227096600024 PM 15550378 ER PT J AU Hu, JX McLarnon, SJ Mora, S Jiang, J Thomas, C Jacobson, KA Spiegel, AM AF Hu, JX McLarnon, SJ Mora, S Jiang, J Thomas, C Jacobson, KA Spiegel, AM TI A region in the seven-transmembrane domain of the human Ca2+ receptor critical for response to Ca2+ SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CALCIUM-SENSING RECEPTOR; AUTOSOMAL-DOMINANT HYPOCALCEMIA; PROTEIN-COUPLED RECEPTORS; TRANSMEMBRANE DOMAIN; HYPOCALCIURIC HYPERCALCEMIA; CA2+-SENSING RECEPTOR; ACTIVATING MUTATIONS; IDENTIFICATION; RHODOPSIN; EXPRESSION AB Of 12 naturally occurring, activating mutations in the seven-transmembrane MM) domain of the human Ca2+ receptor (CaR) identified previously in subjects with autosomal dominant hypocalcemia (ADII), five appear at the junction of TM helices 6 and 7 between residue Ile(819) and Glu(837). After identifying a sixth activating mutation in this region, V836L, in an ADH patient, we studied the remaining residues in this region to determine whether they are potential sites for activating mutations. Alanine-scanning mutagenesis revealed five additional residues in this region that when substituted by alanine led to CaR activation. We also found that, whereas E837A did not activate the receptor, E837D and E837K mutations did. Thus, region Ile(819)-Glu(837) of the 7TM domain represents a "hot spot" for naturally occurring, activating mutations of the receptor, and most of the residues in this region apparently maintain the 7TM domain in its inactive configuration. Unique among the residues in this region, Pro(823), which is highly conserved in family 3 of the G protein-coupled receptors, when mutated to either alanine or glycine, despite good expression severely impaired CaR activation by Ca2+. Both the P823A mutation and NPS 2143, a negative allosteric modulator that acts on the 7TM through a critical interaction with Glu(837), blocked activation of the CaR by various ADII mutations. These results suggest that the 7TM domain region Ile(819)-Glu(837) plays a key role in CaR activation by Ca2+. The implications of our finding that NPS 2143 corrects the molecular defect of ADH mutations for treatment of this disease are also discussed. C1 NIDCD, Mol Pathophysiol Sect, NIH, Bethesda, MD 20892 USA. Sci Inst H San Raffaele, Lab Pediat Endocrinol, I-20132 Milan, Italy. Sci Inst H San Raffaele, Dept Pediat, I-20132 Milan, Italy. NIDDK, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Hu, JX (reprint author), NIDCD, Mol Pathophysiol Sect, NIH, Bldg 10,Rm 8C-101,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jianxinh@intra.niddk.nih.gov RI Jacobson, Kenneth/A-1530-2009; Mora, Sefano/B-2143-2013 OI Jacobson, Kenneth/0000-0001-8104-1493; NR 27 TC 53 Z9 57 U1 0 U2 2 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 11 PY 2005 VL 280 IS 6 BP 5113 EP 5120 DI 10.1074/jbc.M413403200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 898SN UT WOS:000227096600133 PM 15591042 ER PT J AU Lim, YP Josic, D Callanan, H Brown, J Hixson, DC AF Lim, YP Josic, D Callanan, H Brown, J Hixson, DC TI Affinity purification and enzymatic cleavage of inter-alpha inhibitor proteins using antibody and elastase immobilized on CIM monolithic disks SO JOURNAL OF CHROMATOGRAPHY A LA English DT Article; Proceedings Paper CT 1st Monolith Summer School CY JUN 06-09, 2004 CL Portoroz, SLOVENIA DE inter-alpha inhibitors; bikunin; preparative cleavage; enzyme immobilization; monolithic chromatographic supports; epitope mapping ID HIGH-MOLECULAR MASSES; TRYPSIN INHIBITOR; HEAVY-CHAIN; CHROMATOGRAPHY; HYALURONAN; SEPSIS; PLASMA; FAMILY AB Epoxy-activated monolithic CIM disks seem to be excellent supports for immobilization of protein ligands. The potential use of enzymes, immobilized on monolithic disks for rapid preparative cleavage proteins in solution was investigated. Digestion of complex plasma proteins was demonstrated by using inter-alpha inhibitors with elastase, immobilized on epoxy-activated CIM disks. Recently, a monoclonal antibody against human inter-alpha inhibitor proteins (MAb 69.34) was developed. MAb 69.31 blocks the inhibitory activity of inter-alpha inhibitor proteins to serine proteases. These results suggest that the epitope defined by this antibody is located within or proximal to the active site of the inhibitor molecule. This antibody, immobilized on monolithic disk, was used for very rapid isolation of inter-alpha proteins. The isolated complex protein was used for enzymatic digestion and isolation of cleavage products, especially from inter-alpha inhibitor light chain to elucidate precisely the target sequence for MAb 69.31 by N-terminal amino acid sequencing. Bovine pancreatic elastase immobilized on monolithic disk cleaves inter-alpha inhibitor protein complex into small fragments which are still reactive with MAb 69.31. One of these proteolytic fragments was isolated and partially sequenced. It could be shown that this sequence is located at the beginning of two proteinase inhibitor domains of the inter-alpha inhibitor light chain (bikunin). Elastase immobilized on monolithic disk offers a simple and rapid method for preparative isolation of protease cleavage fragments. The immobilized enzyme is stable and still active after repeated runs. A partial or complete digestion can be achieved by varying the flow rate. (C) 2004 Elsevier B.V. All rights reserved. C1 Rhode Isl Hosp, Brown Med Sch, Div Hematol Oncol, Dept Med, Providence, RI 02903 USA. ProThera Biol, E Providence, RI USA. Rhode Isl Hosp, COBRE, Ctr Canc Res Dev, Providence, RI USA. RP Lim, YP (reprint author), Rhode Isl Hosp, Brown Med Sch, Div Hematol Oncol, Dept Med, 593 Eddy St, Providence, RI 02903 USA. EM yow_pin.lim_md@brown.edu NR 18 TC 20 Z9 21 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0021-9673 J9 J CHROMATOGR A JI J. Chromatogr. A PD FEB 11 PY 2005 VL 1065 IS 1 BP 39 EP 43 DI 10.1016/j.chroma.2004.11.006 PG 5 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 900ZW UT WOS:000227253800006 PM 15782948 ER PT J AU Feng, HQ Vu, ND Bai, YW AF Feng, HQ Vu, ND Bai, YW TI Detection of a hidden folding intermediate of the third domain of PDZ SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE protein folding; hydrogen exchange; PDZ domain; hidden intermediate ID STATE HYDROGEN-EXCHANGE; NATIVE-STATE; CYTOCHROME-C; TRANSITION-STATE; PROTEIN; PATHWAYS; MECHANISM; ENSEMBLE AB The folding pathway of the third domain of PDZ from the synaptic protein PSD-95 was characterized using kinetic and equilibrium methods by monitoring the fluorescence signal from a Trp residue that is incorporated at a near-surface position. Kinetic folding of this domain showed multiple exponential phases, whereas unfolding showed a single exponential phase. The slow kinetic phases were attributed to isomerization of proline residues, since there are five proline residues in this domain. We found that the logarithms of the rate constants for the fast phase of folding and unfolding are linearly dependent on the concentrations of denaturant. The unfolding free energy derived from these rate constants at zero denaturant was close to the value measured using the equilibrium method, suggesting the absence of detectable sub-millisecond folding intermediates. However, native-state hydrogen exchange experiments detected a partially unfolded intermediate under native conditions. It was further confirmed by a protein engineering study. These data suggest that a hidden intermediate exists after the rate-limiting step in the folding of the third domain of PDZ. Published by Elsevier Ltd. C1 NCI, Biochem Lab, NIH, Bethesda, MD 20892 USA. RP Bai, YW (reprint author), NCI, Biochem Lab, NIH, Bldg 37,Room 6114E, Bethesda, MD 20892 USA. EM yawen@helix.nih.gov NR 39 TC 33 Z9 33 U1 1 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD FEB 11 PY 2005 VL 346 IS 1 BP 345 EP 353 DI 10.1016/j.jmb.2004.11.040 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 892UG UT WOS:000226674900028 PM 15663949 ER PT J AU Borlongan, CV Yu, GL Matsukawa, N Xu, L Hess, DC Sanberg, PR Wang, Y AF Borlongan, CV Yu, GL Matsukawa, N Xu, L Hess, DC Sanberg, PR Wang, Y TI Acute functional effects of cyclosporine-A and methylprednisolone treatment in adult rats exposed to transient ischemic stroke SO LIFE SCIENCES LA English DT Article DE immunosuppression; inflammation; neuroprotection; cerebral ischemia; brain infarct; cognitive tasks ID CEREBRAL-ISCHEMIA; CELLS; TRANSPLANTATION; PROTECTS; RECOVERY; SURVIVAL; THERAPY AB The present study examined the neuroprotective effects of immunosuppressant cyclosporine-A (CsA) and anti-inflammatory methylprednisolone (MP) in a stroke model. Adult Sprague-Dawley rats were initially subjected to transient middle cerebral artery occlusion (MCAo) then randomly assigned to one of the following treatment conditions: low dose CsA, MP, low dose CsA plus MP, high dose CsA, or vehicle. Ischemic animals that received low dose CsA, NIP or vehicle exhibited significant cognitive impairments, as revealed by passive avoidance and Morris water maze tasks, at days 1-3 after stroke. In contrast, ischemic animals that received high dose CsA exhibited near normal cognitive performance throughout the test period. Ischemic animals that received low dose CsA plus MP also showed significantly less cognitive deficits but such attenuation of stroke-induced behavioral impairments was only consistently reflected in the passive avoidance task, while performance in the Morris water maze task deteriorated over time. Histological analysis at 3 days post-stroke revealed that only those ischemic animals treated with high dose CsA had significantly reduced cerebral infarcts. These observations suggest that despite overt cerebral damage, alterations in simple, but not complex, cognitive tasks produced by MCAo could be ameliorated by low dose CsA when combined with MP. (C) 2004 Elsevier Inc. All rights reserved. C1 Med Coll Georgia, Dept Neurol, Augusta VAMC, Augusta, GA 30912 USA. Med Coll Georgia, Inst Mol Med & Genet, Augusta VAMC, Augusta, GA 30912 USA. Augusta VAMC, Res & Affiliat Serv Line, Augusta, GA 30912 USA. Univ S Florida, Dept Neurosurg, Tampa, FL 33612 USA. NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Borlongan, CV (reprint author), Med Coll Georgia, Dept Neurol, Augusta VAMC, BI-3080,1120 15th St, Augusta, GA 30912 USA. EM cborlongan@mail.mcg.edu OI Borlongan, Cesar/0000-0002-2966-9782 NR 23 TC 21 Z9 22 U1 0 U2 1 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0024-3205 J9 LIFE SCI JI Life Sci. PD FEB 11 PY 2005 VL 76 IS 13 BP 1503 EP 1512 DI 10.1016/j.lfs.2004.09.022 PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 895GC UT WOS:000226847900007 PM 15680314 ER PT J AU Jinsmaa, Y Fujita, Y Shiotani, K Miyazaki, A Li, TY Tsuda, Y Okada, Y Ambo, A Sasaki, Y Bryant, SD Lazarus, LH AF Jinsmaa, Y Fujita, Y Shiotani, K Miyazaki, A Li, TY Tsuda, Y Okada, Y Ambo, A Sasaki, Y Bryant, SD Lazarus, LH TI Differentiation of opioid receptor preference by [Dmt(1)]endomorphin-2-mediated antinociception in the mouse SO EUROPEAN JOURNAL OF PHARMACOLOGY LA English DT Article DE dint (2 ',6 '-dimethyl-L-tyrosine); endomorphin; antinociception; spinal; supraspinal; antagonist ID DMT-TIC PHARMACOPHORE; MEDIATED ANALGESIA; OPIATE RECEPTORS; BINDING ACTIVITY; PYRAZINONE RING; MU-RECEPTOR; AMIDE BOND; ANALOGS; POTENT; ANTAGONIST AB The potent opioid [Dmt(1)]endomorphin-2 (Dmt-Pro-Phe-Phe-NH2) differentiated between the opioid receptor subtypes responsible for the antinociception elicited by endomorphin-2 in mice. Antinociception, induced by the intracerebroventricular administration of [Dmt(1)]endomorphin-2 and inhibited by various opioid receptor antagonists [naloxone, naltrindole, beta-funaltrexamine, naloxonazine], was determined by the tail-flick (spinal effect) and hot-plate (supraspinal effect) tests. The opioid receptor subtypes involved in [Dmt(1)] endomorphin-2-induced antinociception differed between these in vivo model paradigms: naloxone (non-specific opioid receptor antagonist) and beta-funaltrexamine (irreversible mu(1)/mu(2)-opioid receptor antagonist) blocked antinociception in both tests, although stronger inhibition occurred in the hot-plate than the tail-flick test suggesting involvement of other opioid receptors. Consequently, we applied naloxonazine (mu(1)-opioid receptor antagonist) that significantly blocked the effect in the hot-plate test and naltrindole (delta-opioid receptor antagonist), which was only effective in the tail-flick test. The data indicated that [Dmt(1)]endomorphin-2-induced spinal antinociception was primarily mediated by both mu(2)- and delta-opioid receptors, while a supraspinal mechanism involved only mu(1)/mu(2)-subtypes. (C) 2004 Elsevier B.V. All rights reserved. C1 Natl Inst Environm Hlth Sci, Med Chem Grp, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. Kobe Gakuin Univ, Grad Sch Food & Med Sci, Nishi Ku, Kobe, Hyogo 65121, Japan. Kobe Gakuin Univ, Dept Med Chem, Fac Pharmaceut Sci, Nishi Ku, Kobe, Hyogo 6512180, Japan. Kobe Gakuin Univ, High Technol Res Ctr, Nishi Ku, Kobe, Hyogo 6512180, Japan. Tohoku Pharmaceut Univ, Dept Biochem, Aoba Ku, Sendai, Miyagi 9818558, Japan. RP Jinsmaa, Y (reprint author), Natl Inst Environm Hlth Sci, Med Chem Grp, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. EM yunden@niehs.nih.gov NR 37 TC 20 Z9 21 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-2999 J9 EUR J PHARMACOL JI Eur. J. Pharmacol. PD FEB 10 PY 2005 VL 509 IS 1 BP 37 EP 42 DI 10.1016/j.ejphar.2004.12.015 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 901AO UT WOS:000227255600005 PM 15713427 ER PT J AU Simoni, D Grisolia, G Giannini, G Roberti, M Rondanin, R Piccagli, L Baruchello, R Rossi, M Romagnoli, R Invidiata, FP Grimaudo, S Jung, MK Hamel, E Gebbia, N Crosta, L Abbadessa, V Di Cristina, A Dusonchet, L Meli, M Tolomeo, M AF Simoni, D Grisolia, G Giannini, G Roberti, M Rondanin, R Piccagli, L Baruchello, R Rossi, M Romagnoli, R Invidiata, FP Grimaudo, S Jung, MK Hamel, E Gebbia, N Crosta, L Abbadessa, V Di Cristina, A Dusonchet, L Meli, M Tolomeo, M TI Heterocyclic and phenyl double-bond-locked combretastatin analogues possessing potent apoptosis-inducing activity in HL60 and in MDR cell lines SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID ANTIMITOTIC ANTITUMOR AGENTS; SOLID TUMOR-THERAPY; ANTINEOPLASTIC AGENTS; BIOLOGICAL EVALUATION; A-4 ANALOGS; TUBULIN; COLCHICINE; DEATH; MULTIDRUG; DISCOVERY AB Two new series of combretastatin (CA-4) analogues have been prepared. The alkenyl motif of CA-4 was replaced either by a five-membered heterocyclic (isoxazoline or isoxazole) or by a six-membered ring (pyridine or benzene). The new compounds have been evaluated for their effects on tubulin assembly and for cytotoxic and apoptotic activities. Five compounds (18b, 20a, 21a, 34b, and 35b) demonstrated an attractive profile of cytotoxicity (IC50 < 1 muM) and apoptosis-inducing activity but poor antitubulin activity. The isoxazoline derivatives 18b, 20a, and 21a, demonstrated potent apoptotic activity different from that of natural CA-4. Their ability to block most cells in the G2 phase suggests that these compounds could act on targets different from the mitotic spindle. This would indicate activation of both the intrinsic and the extrinsic apoptotic pathways. The data suggest unambiguously that structural alteration of the stilbene motif of CA-4 can be extremely effective in producing potent apoptosis-inducing agents. C1 Univ Ferrara, Dipartimento Sci Farmaceut, I-44100 Ferrara, Italy. Univ Bologna, Dipartimento Sci Farmaceut, I-40126 Bologna, Italy. R&D Sigma Tau, Pomezia, Italy. Univ Palermo, Dipartimento Farmacochim Tossicol & Biol, I-90133 Palermo, Italy. Policlin Palermo, Cattedra Ematol & Serv AIDS, Palermo, Italy. SAIC Frederick Inc, Frederick, MD 21702 USA. NCI, Screening Technol Branch, Dev Therapeut Program, Div Canc Treatment & Diag,Natl Inst Hlth, Frederick, MD 21702 USA. Univ Palermo, Dipartimento Sci Farmacol, I-90133 Palermo, Italy. RP Simoni, D (reprint author), Univ Ferrara, Dipartimento Sci Farmaceut, Via Fossato Mortara 17-19, I-44100 Ferrara, Italy. EM smd@dns.unife.it RI antonietta, di cristina/I-9251-2012; Meli, Maria/F-7027-2013; Romagnoli, Romeo/G-9887-2015; OI Grimaudo, Stefania/0000-0003-3225-4112 FU NCI NIH HHS [N01-CO-12400] NR 44 TC 91 Z9 92 U1 2 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD FEB 10 PY 2005 VL 48 IS 3 BP 723 EP 736 DI 10.1021/jm049622b PG 14 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 895RR UT WOS:000226881300009 PM 15689156 ER PT J AU Oishi, S Karki, RG Kang, SU Wang, XZ Worthy, KM Bindu, LK Nicklaus, MC Fisher, RJ Burke, TR AF Oishi, S Karki, RG Kang, SU Wang, XZ Worthy, KM Bindu, LK Nicklaus, MC Fisher, RJ Burke, TR TI Design and synthesis of conformationally constrained Grb2 SH2 domain binding peptides employing alpha-methylphenylalanyl based phosphotyrosyl mimetics SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID HUMAN BREAST-CANCER; TYROSINE KINASE; AFFINITY; LIGANDS; MACROCYCLIZATION; INHIBITORS; SRC; PATHWAYS; PROTEIN AB Previous work has shown that incorporation of either I-aminocyclohexanecarboxylic acid (Ac(6)c) or alpha-methyl-p-phosphonophenylalanine ((alpha-Me)Ppp) in the phosphotyrosyl (pTyr) C-proximal position (pY + 1 residue) of Grb2 SH2 domain binding peptides confers high affinity. The tetralin-based (S)-2-amino-6-phosphonotetralin-2-carboxylic acid (Atc(6-(POH2)-H-3)) simultaneously presents structural features of both (a-Me)Ppp and Ac(6)c residues. The current study compares the affinity of this tetralin hybrid Atc(6-PO3H2) versus Ac(6)c and (alpha-Me)Ppp residues when incorporated into the pY + I position of a high-affinity Grb2 SH2 domain binding tripeptide platform. The highest binding affinity (K-D = 14.8 nM) was exhibited by the (alpha-Me)Ppp-containing parent, with the corresponding Ac(6)c-containing peptide being nearly 2-fold less potent (K-D = 23.8 nM). The lower KD value was attributable primarily to a 50% increase in off-rate. Replacement of the Ac(6)c residue with the tetralin-based hybrid resulted in a further 4-fold decrease in binding affnity (K-D = 97.8 nM), which was the result of a further 6-fold increase in off-rate, offset by an approximate 45% increase in on-rate. Therefore, by incorporation of the key structural components found in (alpha-Me)Ppp into the Ac(6)c residue, the tetralin hybrid does enhance binding on-rate. However, net binding affinity is decreased due to an associated increase in binding off-rate. Alternatively, global conformational constraint of an ((alpha-Me)Ppp-containing peptide by beta-macrocyclization did result in pronounced elevation of binding affinity, which was achieved primarily through a decrease in the binding off-rate. Mathematical fitting using a simple model that assumed a single binding site yielded an effective KD of 2.28 nM. However this did not closely approximate the data obtained. Rather, use of a complex model that assumed two binding sites resulted in a very close fit of data and provided KD values of 97 pM and 72 nM for the separate sites, respectively. Therefore, although local conformational constraint in the pY + 1 residue proved to be deleterious, global conformational constraint through beta-macrocyclization achieved higher affinity. Similar beta-macrocyclization may potentially be extended to SH2 domain systems other than Grb2, where bend geometries are required. C1 NCI, CCR, Med Chem Lab, NIH, Frederick, MD 21702 USA. Sci Applicat Int Corp, Prot Chem Lab, Frederick, MD 21702 USA. RP Burke, TR (reprint author), NCI, CCR, Med Chem Lab, NIH, POB B,Bldg 376 Boyles St, Frederick, MD 21702 USA. EM tburke@helix.nih.gov RI Fisher, Robert/B-1431-2009; Nicklaus, Marc/N-4183-2014; Burke, Terrence/N-2601-2014; Oishi, Shinya/C-1350-2011; OI Oishi, Shinya/0000-0002-2833-2539; Nicklaus, Marc/0000-0002-4775-7030 NR 28 TC 20 Z9 20 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD FEB 10 PY 2005 VL 48 IS 3 BP 764 EP 772 DI 10.1021/jm0492709 PG 9 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 895RR UT WOS:000226881300013 PM 15689160 ER PT J AU Grundt, P Carlson, EE Cao, JJ Bennett, CJ McElveen, E Taylor, M Luedtke, RR Newman, AH AF Grundt, P Carlson, EE Cao, JJ Bennett, CJ McElveen, E Taylor, M Luedtke, RR Newman, AH TI Novel heterocyclic trans olefin analogues of N-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl}arylcarboxamides as selective probes with high affinity for the dopamine D3 receptor SO JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article ID COCAINE-SEEKING; LIGANDS; POTENT; ANTAGONIST; DESIGN; INHIBITION; AGONIST; AGENTS AB Dopamine D3 receptor subtypes have been hypothesized to play a pivotal role in modulating the reinforcing and drug-seeking effects induced by cocaine. However, definitive pharmacological investigations have been hampered by the lack of highly D3 receptor selective compounds that can be used in vivo. To address this problem, the potent and D3-receptor-selective antagonist NGB 2904 (1, 9H-fluorene-2-carboxylic acid {4-[(2,3-dichlorophenyl)-piperazin-1-yl]-butyl} amide, K-i (hD3) = 2.0 nM, K-i (hD2(L)) = 112 nM, D2/D3 selectivity ratio of 56) was chosen as a lead structure for chemical modification in an attempt to reduce its high lipophilicity (c log D = 6.94) while optimizing D3 receptor binding affinity and D2/D3 selectivity. A series of >30 novel analogues were synthesized, and their binding affinities were evaluated in competition binding assays in HEK 293 cells transfected with either D2(L), D3, or D4 human dopamine receptors using the high affinity, selective D2-like receptor antagonist I-125-IABN. Structural diversity in the aryl amide end of the molecule Was found to have a major influence on (sub)nanomolar D3 receptor affinity and D2/D3 selectivity, which was optimized using a more rigid trans-butenyl linker between the aryl amide and the piperazine. Several analogues demonstrated superior D3 receptor binding affinities and selectivities as compared to the parent ligand. Compound 29 (N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine- 2-yl-benzamide) displayed the most promising pharmacological profile (K-i (hD3) = 0.7 nM, K-i (hD2(L)) = 93.3 nM, D2/D3 selectivity ratio of 133). In addition, this ligand inhibited quinpirole stimulation of mitogenesis at human dopamine D3 receptors transfected into Chinese hamster ovary (CHO) cells, with an EC50 value of 3.0 nM. Compound 29 was a nearly 5 times more potent antagonist at the D3 receptor than 1 (EC50 = 14.4 nM). Moreover, a decrease in c log D value of similar to2 orders of magnitude was determined for this novel D3-receptor-preferring ligand, compared to 1. In summary, chemical modification of 1 has resulted in compounds with high affinity and selectivity for D3 receptors. The most promising candidate, compound 29, is currently being evaluated in animal models of cocaine abuse and will provide an important tool with which to elucidate the role of D3 receptors in drug reinforcement in vivo. C1 NIDA, Med Chem Sect, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Univ N Texas, Hlth Sci Ctr, Dept Pharmacol & Neurosci, Ft Worth, TX 76107 USA. RP Newman, AH (reprint author), NIDA, Med Chem Sect, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM anewman@intra.nida.nih.gov FU NIDA NIH HHS [1 DA 13584] NR 23 TC 99 Z9 99 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0022-2623 J9 J MED CHEM JI J. Med. Chem. PD FEB 10 PY 2005 VL 48 IS 3 BP 839 EP 848 DI 10.1021/jm049465g PG 10 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 895RR UT WOS:000226881300021 PM 15689168 ER PT J AU Jordan, IK Kondrashov, FA Adzhubei, IA Wolf, YI Koonin, EV Kondrashov, AS Sunyaev, S AF Jordan, IK Kondrashov, FA Adzhubei, IA Wolf, YI Koonin, EV Kondrashov, AS Sunyaev, S TI A universal trend of amino acid gain and loss in protein evolution SO NATURE LA English DT Article ID SEQUENCE EVOLUTION; BASE COMPOSITION; FREQUENCIES; DROSOPHILA; ALIGNMENT; BACTERIA; GENOME; GENE; CODE AB Amino acid composition of proteins varies substantially between taxa and, thus, can evolve. For example, proteins from organisms with ( G+C)- rich ( or ( A+T)- rich) genomes contain more ( or fewer) amino acids encoded by ( G+C)- rich codons(1 - 4). However, no universal trends in ongoing changes of amino acid frequencies have been reported. We compared sets of orthologous proteins encoded by triplets of closely related genomes from 15 taxa representing all three domains of life ( Bacteria, Archaea and Eukaryota), and used phylogenies to polarize amino acid substitutions. Cys, Met, His, Ser and Phe accrue in at least 14 taxa, whereas Pro, Ala, Glu and Gly are consistently lost. The same nine amino acids are currently accrued or lost in human proteins, as shown by analysis of non- synonymous single-nucleotide polymorphisms. All amino acids with declining frequencies are thought to be among the first incorporated into the genetic code; conversely, all amino acids with increasing frequencies, except Ser, were probably recruited late(5 - 7). Thus, expansion of initially under- represented amino acids, which began over 3,400 million years ago(8,9), apparently continues to this day. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Univ Calif Davis, Sect Evolut & Ecol, Davis, CA 95616 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Dept Med,Div Genet, Boston, MA 02115 USA. RP Kondrashov, AS (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM kondrashov@ncbi.nlm.nih.gov; ssunyaev@rics.bwh.harvard.edu RI Kondrashov, Fyodor Alexeevich/H-6331-2015 OI Kondrashov, Fyodor Alexeevich/0000-0001-8243-4694 NR 30 TC 147 Z9 152 U1 1 U2 18 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0028-0836 J9 NATURE JI Nature PD FEB 10 PY 2005 VL 433 IS 7026 BP 633 EP 638 DI 10.1038/nature03306 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 895KX UT WOS:000226862000045 PM 15660107 ER PT J AU Mannon, PJ Fuss, IJ Strober, W AF Mannon, PJ Fuss, IJ Strober, W TI Anti-interleukin-12 antibody for active Crohn's disease - Reply SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NIAID, Bethesda, MD 20892 USA. RP Mannon, PJ (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pmannon@niaid.nih.gov NR 1 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 FEB 10 PY 2005 VL 352 IS 6 BP 628 EP 628 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 895KY UT WOS:000226862100025 ER PT J AU Hentges, KE Weiser, KC Schountz, T Woodward, LS Morse, HC Justice, MJ AF Hentges, KE Weiser, KC Schountz, T Woodward, LS Morse, HC Justice, MJ TI Evi3, a zinc-finger protein related to EBFAZ, regulates EBF activity in B-cell leukemia SO ONCOGENE LA English DT Article DE Evi3; EBF; Pax-5; mb-1; B29; B-cell leukemia ID INBRED MOUSE STRAINS; ANTIGEN RECEPTOR; FUNCTIONAL-CHARACTERIZATION; RETROVIRAL INTEGRATION; LYMPHOCYTE DEVELOPMENT; NEURONAL DEVELOPMENT; GENE-EXPRESSION; TARGET GENES; CHAIN GENES; LYMPHOMAS AB Retroviral insertions that activate proto-oncogenes are a primary cause of tumors in certain strains of mice. The AKXD recombinant inbred mice are predisposed to a variety of leukemias and lymphomas as a result of viral integration. One common insertion site, the ecotropic viral insertion site 3 ( Evi3), has been implicated in most B-cell tumors in the AKXD-27 strain. The Evi3 gene encodes a zinc-finger protein with sequence similarity to the Early B-cell Factor-Associated Zinc-finger gene (EBFAZ). We show that the Evi3 gene is overexpressed in several tumors with viral insertions at Evi3, which results in the upregulation of Early B-cell Factor (EBF)-target gene expression, suggesting that Evi3 modulates EBF activity. Reconstitution of primary leukemia cells showed that these tumors express high densities of the B-cell surface proteins CD19 and CD38, which are EBF targets. Using a transactivation assay, we show that the terminal six zinc-fingers of Evi3 are required for modi. cation of EBF activity. This is the first evidence that Evi3 expression in tumors alters the level of EBF target genes, and the first characterization of the Evi3 protein domains required for modulation of EBF activity. Further, these data imply that Evi3 misexpression initiates tumorigenesis by perturbing B-cell development via an interaction with EBF. C1 Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA. Baylor Coll Med, Interdepartmental Program Cell & Mol Biol, Houston, TX 77030 USA. NIAID, Immunopathol Lab, NIH, Rockville, MD USA. RP Justice, MJ (reprint author), Baylor Coll Med, Dept Mol & Human Genet, Room S413,1 Baylor Plaza, Houston, TX 77030 USA. EM mjustice@bcm.tmc.edu OI Morse, Herbert/0000-0002-9331-3705 FU NCI NIH HHS [R01 CA63229]; NICHD NIH HHS [F32 HD42436] NR 39 TC 26 Z9 27 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 10 PY 2005 VL 24 IS 7 BP 1220 EP 1230 DI 10.1038/sj.onc.1208243 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 895XV UT WOS:000226898700009 PM 15580294 ER PT J AU Woodard, GE Lin, L Zhang, JH Agarwal, SK Marx, SJ Simonds, WF AF Woodard, GE Lin, L Zhang, JH Agarwal, SK Marx, SJ Simonds, WF TI Parafibromin, product of the hyperparathyroidism-jaw tumor syndrome gene HRPT2, regulates cyclin D1/PRAD1 expression SO ONCOGENE LA English DT Article DE parathyroid; parafibromin; tumor suppressor; hyperparathyroidism; jaw tumor syndrome; parathyroid carcinoma; cyclin D1 ID FAMILIAL ISOLATED HYPERPARATHYROIDISM; HEREDITARY HYPERPARATHYROIDISM; PARATHYROID CARCINOMA; ADENOMAS; MUTATIONS; FIBROMAS; 1Q21-Q32; MAPS AB Parafibromin is the 531-amino-acid protein product encoded by HRPT2, a putative tumor suppressor gene recently implicated in the autosomal dominant hyperparathyroidism-jaw tumor familial cancer syndrome, sporadic parathyroid cancer, and a minority of families with isolated hyperparathyroidism. Parafibromin contains no identified functional domains but bears sequence homology to Cdc73p, a budding yeast protein component of the RNA polymerase II-associated Paf1 complex. This study addressed the expression and functional properties of human parabromin. A survey of human and mouse tissues analysed with polyclonal antibodies to parabromin showed specific immunoreactivity in adrenal and parathyroid glands, kidney, heart, and skeletal muscle. Subcellular fractionation and laser confocal microscopy of normal human parathyroid gland demonstrated expression of parafibromin in both the cytoplasmic and nuclear compartments. Parafibromin was expressed in four parathyroid adenomas but was absent from two parathyroid carcinomas. Transient overexpression of wild-type parafibromin, but not its Leu64Pro missense mutant implicated in parathyroid cancer and familial isolated hyperparathyroidism, inhibited cell proliferation, and blocked expression of cyclin D1, a key cell cycle regulator previously implicated in parathyroid neoplasia. These results demonstrate that human parafibromin is a nucleocytoplasmic protein with functions consistent with its postulated role as a tumor suppressor protein. C1 NIDDKD, Metab Dis Branch, NIH, Bethesda, MD 20892 USA. RP Simonds, WF (reprint author), NIDDKD, Metab Dis Branch, NIH, Bldg 10,Room 8C-101,10 Ctr DR MSC 1752, Bethesda, MD 20892 USA. EM wfs@helix.nih.gov RI Woodard, Geoffrey/A-8608-2009; Agarwal, Sunita/D-1428-2016 OI Agarwal, Sunita/0000-0002-7557-3191 NR 33 TC 86 Z9 92 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0950-9232 J9 ONCOGENE JI Oncogene PD FEB 10 PY 2005 VL 24 IS 7 BP 1272 EP 1276 DI 10.1038/sj.onc.1208274 PG 5 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 895XV UT WOS:000226898700014 PM 15580289 ER PT J AU Pospisil, R Obiakor, H Newman, BA Alexander, C Mage, RG AF Pospisil, R Obiakor, H Newman, BA Alexander, C Mage, RG TI Stable expression of the extracellular domains of rabbit recombinant CD5: development and characterization of polyclonal and monoclonal antibodies SO VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY LA English DT Article DE rabbit; CD5; monoclonal antibodies; scavenger receptor cysteme-rich domains; B cells ID CELL SURFACE-IMMUNOGLOBULIN; POTENTIAL SELECTING LIGAND; B-LYMPHOCYTES; SUPERANTIGENS; RECEPTOR; DIFFERENTIATION; EXPANSION; APPENDIX AB Previous studies in our laboratory suggested that there was positive selection of B cells during early development in the appendix of normal and V-H mutant (ali/ali) rabbits. Preferential expansion and survival of B lymphocytes was affected by the Ig V-H frameworks 1 and 3 sequences expressed on the cell surface. We demonstrated a specific interaction between rabbit CD5 and the V region of rabbit heavy chains and suggested that CD5 is a potential selecting ligand for B-cell surface immunoglobulin framework region sequences. To further investigate the role of CD5 in rabbit B-cell selection and survival we prepared recombinant constructs and obtained stable expression of the three scavenger receptor cysteine-rich (SRCR) extracellular domains of rabbit CD5. Here we describe the production and purification of this expressed recombinant CD5 protein, polyclonal antibody obtained by immunization of a goat and initial production and characterization of specific mAbs against peptides selected from each sequenced SRCR domain. Published by Elsevier B.V. C1 NIAID, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Mage, RG (reprint author), NIAID, Immunol Lab, NIH, Bldg 10,Room 11N311,10 Ctr Dr MSC 1892, Bethesda, MD 20892 USA. EM rmage@niaid.nih.gov RI Pospisil, Richard/B-7467-2012 NR 14 TC 6 Z9 6 U1 1 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-2427 J9 VET IMMUNOL IMMUNOP JI Vet. Immunol. Immunopathol. PD FEB 10 PY 2005 VL 103 IS 3-4 BP 257 EP 267 DI 10.1016/j.vetimm.2004.09.030 PG 11 WC Immunology; Veterinary Sciences SC Immunology; Veterinary Sciences GA 888YC UT WOS:000226409100011 PM 15621311 ER PT J AU Harlan, DM McBride, MA AF Harlan, DM McBride, MA TI Survival after pancreas transplantation - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter ID TYPE-1; NEPHROPATHY C1 NIDDKD, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. United Network Organ Sharing, Richmond, VA USA. RP Harlan, DM (reprint author), NIDDKD, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM davidmh@intra.niddk.nih.gov NR 5 TC 0 Z9 0 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 9 PY 2005 VL 293 IS 6 BP 675 EP 676 DI 10.1001/jama.293.6.675-b PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 895DX UT WOS:000226842200017 ER PT J AU Scherer, SS Xu, YT Messing, A Willecke, K Fischbeck, KH Jeng, LJB AF Scherer, SS Xu, YT Messing, A Willecke, K Fischbeck, KH Jeng, LJB TI Transgenic expression of human connexin32 in myelinating Schwann cells prevents demyelination in connexin32-null mice SO JOURNAL OF NEUROSCIENCE LA English DT Article DE axon-Schwann cell interactions; Charcot-Marie-Tooth disease; CMT; myelin; Schwann cells; gap junctions; Cx32 ID MARIE-TOOTH-DISEASE; GAP-JUNCTION PROTEIN; NERVE-CONDUCTION VELOCITIES; PERIPHERAL-NERVE; SENSORY NEUROPATHY; HEREDITARY MOTOR; MEMBRANE INSERTION; SCIATIC-NERVE; ADULT-RATS; MUTATIONS AB Mutations in Gap Junction beta1 ( GJB1), the gene encoding the gap junction protein connexin32 ( Cx32), cause the X-linked form of Charcot-Marie-Tooth disease ( CMT1X), an inherited demyelinating neuropathy. We investigated the possibility that the expression of mutant Cx32 in other cells besides myelinating Schwann cells contributes to the development of demyelination. Human Cx32 was expressed in transgenic mice using a rat myelin protein zero (Mpz) promoter, which is exclusively expressed by myelinating Schwann cells. Male mice expressing the human transgene were crossed with female Gjb1/cx32-null mice; the resulting male offspring were all cx32-null (on the X chromosome), and one-half were transgene positive. In these transgenic mice, all of the Cx32 was derived from the expression of the transgene and was found in the sciatic nerve but not in the spinal cord or the liver. Furthermore, the Cx32 protein was properly localized ( within incisures and paranodes) in myelinating Schwann cells. Finally, the expression of human Cx32 protein "rescued" the phenotype of cx32-null mice, because the transgenic mice have significantly fewer demyelinated or remyelinated axons than their nontransgenic littermates. These results indicate that the loss of Schwann-cell-autonomous expression of Cx32 is sufficient to account for demyelination in CMT1X. C1 Univ Penn, Med Ctr, Dept Neurol, Philadelphia, PA 19104 USA. Univ Penn, Med Ctr, Cell & Mol Biol Grad Grp, Philadelphia, PA 19104 USA. Univ Bonn, Genet Inst, Abt Mol Genet, D-53117 Bonn, Germany. Univ Wisconsin, Sch Vet Med, Dept Pathobiol Sci, Madison, WI 53706 USA. NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. RP Scherer, SS (reprint author), Univ Penn, Med Ctr, Dept Neurol, 464 Stemmler Hall,36th St & Hamilton Walk, Philadelphia, PA 19104 USA. EM sscherer@mail.med.upenn.edu FU NINDS NIH HHS [R01 NS08075, R01 NS42878] NR 59 TC 37 Z9 39 U1 0 U2 2 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 9 PY 2005 VL 25 IS 6 BP 1550 EP 1559 DI 10.1523/JNEUROSCI.3082-04.2005 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 895XP UT WOS:000226898100025 PM 15703409 ER PT J AU Rajamoorthi, K Petrache, HI McIntosh, TJ Brown, MF AF Rajamoorthi, K Petrache, HI McIntosh, TJ Brown, MF TI Packing and viscoelasticity of polyunsaturated omega-3 and omega-6 lipid bilayers as seen by H-2 NMR and X-ray diffraction SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Review ID SPIN-LATTICE RELAXATION; MOLECULAR-DYNAMICS SIMULATIONS; NUCLEAR-MAGNETIC-RESONANCE; STATISTICAL MECHANICAL TREATMENT; ACYL CHAIN ORDER; DOCOSAHEXAENOIC ACID; FATTY-ACIDS; PHOSPHOLIPID-BILAYERS; C-13 NMR; UNSATURATED PHOSPHATIDYLCHOLINES AB Polyunsaturated phospholipids of the omega-3 and omega-6 classes play key roles in cellular functions, yet their mechanisms of biological action are still a matter of debate. Using deuterium (H-2) NMR spectroscopy and small-angle X-ray diffraction, we show how membrane properties are modified by docosahexaenoic (DHA; 22:6) and arachidonic (AA; 20:4) acyl chains of the omega-3 and the omega-6 families, respectively. Structural and dynamical differences due to polyunsaturation are evident in both the ordered and disordered phases of mixed-chain (16:0)(22:6)PC and (16:0)(20:4)PC bilayers. Due to the lower chain melting temperature, the omega-6 AA bilayer is more disordered in the fluid (Lalpha) state than the omega-3 DHA bilayer; it is thinner with a larger area per lipid. The thermal hysteresis observed for the DHA bilayer may represent the influences of angle-iron conformers in the gel state and back-bended, hairpinlike conformers in the fluid state, consistent with molecular dynamics studies. Interpretation of the H-2 NMR order profiles of (16:0-d(31))(22:6)PC and (16:0-d(31))(20:4)PC together with X-ray electron density profiles reveals an uneven distribution of mass; i.e., the sn-1 saturated chain is displaced toward the membrane center, whereas the sn-2 polyunsaturated chain is shifted toward the bilayer aqueous interface. Moreover, the H-2 NMR relaxation rates are increased by the presence of omega-6 AA chains compared to omega-3 DHA chains. When evaluated at the same amplitude of motion, relaxation parameters give a naturally calibrated scale for comparison of fluid lipid bilayers. Within this framework, polyunsaturated bilayers are relatively soft to bending and area fluctuations on the mesoscale approaching molecular dimensions. Significant differences are evident in the viscoelastic properties of the omega-3 and omega-6 bilayers, a possibly biologically relevant feature that distinguishes between the two phospholipid classes. C1 Univ Arizona, Dept Chem, Tucson, AZ 85721 USA. Univ Arizona, Dept Phys, Tucson, AZ 85721 USA. NICHD, Lab Phys & Stuct Biol, NIH, Bethesda, MD 20892 USA. Duke Univ, Dept Cell Biol, Sch Med, Durham, NC 27708 USA. RP Brown, MF (reprint author), Univ Arizona, Dept Chem, Tucson, AZ 85721 USA. EM mfbrown@u.arizona.edu FU NEI NIH HHS [R01 EY012049, EY12049]; NIGMS NIH HHS [GM27278] NR 102 TC 70 Z9 71 U1 2 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 FEB 9 PY 2005 VL 127 IS 5 BP 1576 EP 1588 DI 10.1021/ja046453b PG 13 WC Chemistry, Multidisciplinary SC Chemistry GA 895EO UT WOS:000226843900051 PM 15686391 ER PT J AU Pan, YP Ma, BY Venkataraghavan, RB Levine, AJ Nussinov, R AF Pan, YP Ma, BY Venkataraghavan, RB Levine, AJ Nussinov, R TI In the quest for stable rescuing mutants of p53: Computational mutagenesis of flexible loop L1 SO BIOCHEMISTRY LA English DT Article ID TUMOR-SUPPRESSOR P53; HOT-SPOT MUTANT; CORE DOMAIN; DNA-BINDING; WILD-TYPE; STRUCTURAL ASPECTS; CRYSTAL-STRUCTURE; GENE EVOLUTION; MUTATIONS; PROTEIN AB p53 is a protein with marginal stability. Its transcriptional functions are often inactivated by single missense mutations, shown to be associated with half of all human cancers. Here, we aim to design stable functional p53 mutants. We target loop L1, one of the most mobile structural motifs in the p53 core domain (p53C). Specifically, we selected Ser116 in the middle of loop L1 and mutated it to 14 other amino acids. All resulting mutants were subjected to molecular dynamics simulations, revealing a wide spectrum of stabilities. Among these, mutant S116M displayed a remarkable stability, with a structural deviation comparable to that of the experimental quadruple mutant M133L/V203A/N239Y/N268D that is thermodynamically more stable than that of the wild type by 2.6 kcal/mol. Structural analysis showed that the high stability of the S116M mutant was indeed due to the preservation of the p53C loop L I conformation and the reduction of mobility in that region. The differential stabilities conferred by the single mutations are rationalized based on the geometries and chemical properties of the side chains introduced into this site. Linearity (i.e., nonbranched), moderate size, and balanced hydrophobic and hydrophilic properties of the side chain are crucial to the stabilizing effect of the residue substitutions. C1 NCI, SAIC Frederick, Basic Res Program, Lab Expt & Computat Biol, Frederick, MD 21702 USA. Inst Adv Study, Princeton, NJ 08540 USA. Tel Aviv Univ, Sackler Sch Med, Sackler InstMol Med, Dept Human Genet & Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, SAIC Frederick, Basic Res Program, Lab Expt & Computat Biol, Bldg 469,Room 151, Frederick, MD 21702 USA. EM ruthn@ncifcrf.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU NCI NIH HHS [N01-CO-12400] NR 36 TC 17 Z9 17 U1 0 U2 1 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 8 PY 2005 VL 44 IS 5 BP 1423 EP 1432 DI 10.1021/bi047845y PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 894OR UT WOS:000226802000006 PM 15683227 ER PT J AU Herning, RI Better, WE Tate, K Cadet, JL AF Herning, RI Better, WE Tate, K Cadet, JL TI Cerebrovascular perfusion in marijuana users during a month of monitored abstinence SO NEUROLOGY LA English DT Article ID TRANSCRANIAL DOPPLER SONOGRAPHY; CEREBRAL-BLOOD-FLOW; PULSATILITY INDEXES; DISEASE; HEMODYNAMICS; ARTERY; BRAIN AB Objective: To determine possible effects of prolonged marijuana use on the cerebrovascular system during a month of monitored abstinence and to assess how the intensity of current use might have influenced cerebrovascular perfusion in these marijuana users. Method: The authors recorded blood flow velocity in the anterior and middle cerebral arteries using transcranial Doppler sonography in three groups of marijuana users who differed in the intensity of recent use (light: n = 11; moderate: n = 23; and heavy: n = 20) and in control subjects (n = 18) to assess the nature and duration of any potential abnormalities. Blood flow velocity was recorded within 3 days of admission and 28 to 30 days of monitored abstinence on an inpatient research unit in order to evaluate subacute effects of the drug and any abstinence-generated changes. Results: Pulsatility index, a measure of cerebrovascular resistance, and systolic velocity were significantly increased in the marijuana users vs control subjects. These increases persisted in the heavy marijuana users after a month of monitored abstinence. Conclusions: Chronic marijuana use is associated with increased cerebrovascular resistance through changes mediated, in part, in blood vessels or in the brain parenchyma. These findings might provide a partial explanation for the cognitive deficits observed in a similar group of marijuana users. C1 NIDA, Mol Neuropsychiat Branch, NIH, Baltimore, MD 21224 USA. RP Herning, RI (reprint author), NIDA, Mol Neuropsychiat Branch, NIH, POB 5180, Baltimore, MD 21224 USA. EM rherning@intra.nida.nih.gov NR 24 TC 47 Z9 48 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD FEB 8 PY 2005 VL 64 IS 3 BP 488 EP 493 PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 895GD UT WOS:000226848000019 PM 15699380 ER PT J AU Hashimoto, M Nitta, A Fukumitsu, H Nomoto, H Shen, LY Furukawa, S AF Hashimoto, M Nitta, A Fukumitsu, H Nomoto, H Shen, LY Furukawa, S TI Inflammation-induced GDNF improves locomotor function after spinal cord injury SO NEUROREPORT LA English DT Article DE glial cell line-derived neurotrophic factor (GDNF); inducible NO synthase (iNOS); lipopolysaccharide (LPS); inflammation; microglia/macrophages; spinal cord injury ID NEUROTROPHIC FACTOR; RAT; NEUROPROTECTION; CHEMOKINES; MACROPHAGE; REPAIR AB Activation of microglia/macrophages after injury occurs limitedly in the CNS, which finding may explain unsuccessful axonal regeneration. Therefore, the relationship between lipopolysaccharide (LPS)-induced inflammation and recovery of locomotor function of rats after spinal cord injury was examined. High-dose LIPS improved locomotor function greater than low-dose LIPS, being consistent with the expression of neurotrophic factor (GDNF) in microglia/macrophages. Experiments using GDNF gene mutant mice confirmed that the increase in the GDNF mRNA level, rather than the reduction in the mRNA level of inducible NO synthase, could be correlated with the restoration activity of locomotor function. These results suggest that a higher degree of inflammation leads to a higher degree of repair of CNS injuries through GDNF produced by activated microglia/macrophages. (C) 2005 Lippincott Williams Wilkins. C1 Gifu Pharmaceut Univ, Mol Biol Lab, Gifu 5028585, Japan. Nagoya Univ, Grad Sch Med, Dept Neuropsychopharmacol & Hosp Pharm, Showa Ku, Nagoya, Aichi 4668560, Japan. NIH, Lab Mammalian Genes & Dev, Bethesda, MD 20983 USA. RP Furukawa, S (reprint author), Gifu Pharmaceut Univ, Mol Biol Lab, 5-6-1 Mitahora Higashi, Gifu 5028585, Japan. EM furukawa@gifu-pu.ac.jp NR 22 TC 52 Z9 58 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD FEB 8 PY 2005 VL 16 IS 2 BP 99 EP 102 DI 10.1097/00001756-200502080-00004 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 899NN UT WOS:000227151400004 PM 15671854 ER PT J AU Le Foll, B Diaz, J Sokoloff, P AF Le Foll, B Diaz, J Sokoloff, P TI A single cocaine exposure increases BDNF and D-3 receptor expression: implications for drug-conditioning SO NEUROREPORT LA English DT Article DE drug conditioning; methamphetamine; morphine; nicotine; prefrontal cortex; quantitative in situ hybridization; ventral tegmental area ID NEUROTROPHIC FACTOR; BEHAVIORAL SENSITIZATION; SEEKING BEHAVIOR; DOPAMINE; BRAIN; REWARD; WITHDRAWAL; MICE; INCUBATION; ADDICTION AB Environmental stimuli associated with a single cocaine exposure acquire long-lasting motivational properties that are able to induce relapse. We measured Brain-derived neurotrophic factor (BDNF) and dopamine D-3 receptor (Drd3) expressions in rat brain regions that have been involved in drug-conditioning. Acute cocaine produced a transient increase in BDNF mRNA in the prefrontal cortex, associated with a long-lasting increase in drd3 mRNA, and a delayed and long-lasting increase in Drd3 protein in the nucleus accumbens. Methamphetamine and morphine, two drugs known to easily induce drug-conditioning, also markedly elevated BDNF mRNA. Nicotine had more limited effects. Abused drugs increase acutely BDNF expression, which leads to subsequent long-lasting elevation of Drd3 in the nucleus accumbens that may facilitate responding to drug-associated stimuli. NeuroReport 16:175-178 (C) 2005 Lippincott Williams Wilkins. C1 Univ Paris 05, Physiol Lab, F-75006 Paris, France. Ctr Paul Broca, INSERM, U573, F-75014 Paris, France. RP Le Foll, B (reprint author), NIDA, Preclin Pharmacol Sect, NIH, Nathan Shock Dr, Baltimore, MD USA. EM blefoll@intra.nida.nih.gov RI Le Foll, Bernard/K-2952-2014 OI Le Foll, Bernard/0000-0002-6406-4973 FU NIDA NIH HHS [R01-DA11534] NR 25 TC 120 Z9 121 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4965 J9 NEUROREPORT JI Neuroreport PD FEB 8 PY 2005 VL 16 IS 2 BP 175 EP 178 DI 10.1097/00001756-200502080-00022 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 899NN UT WOS:000227151400022 PM 15671872 ER PT J AU Shears, SB AF Shears, SB TI Telomere maintenance by intracellular signals: New kid on the block? SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Editorial Material ID SACCHAROMYCES-CEREVISIAE; KINASES; STRESS; FAMILY; PENTAKISPHOSPHATE; TETRAKISPHOSPHATE; POLYPHOSPHATES; PROTEINS; BINDING; CELLS C1 NIEHS, Inositol Signaling Grp, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. RP Shears, SB (reprint author), NIEHS, Inositol Signaling Grp, Dept Hlth & Human Serv, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM shears@niehs.nih.gov NR 20 TC 2 Z9 2 U1 0 U2 0 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 8 PY 2005 VL 102 IS 6 BP 1811 EP 1812 DI 10.1073/pnas.0409801102 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 898JK UT WOS:000227072900001 PM 15684046 ER PT J AU Gonzalez, JM Velez, M Jimenez, M Alfonso, C Schuck, P Mingorance, J Vicente, M Minton, AP Rivas, G AF Gonzalez, JM Velez, M Jimenez, M Alfonso, C Schuck, P Mingorance, J Vicente, M Minton, AP Rivas, G TI Cooperative behavior of Escherichia coli cell-division protein FtsZ assembly involves the preferential cyclization of long single-stranded fibrils SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE analytical ultracentrifugation; sedimentation velocity; polymerization; septation; Z-ring ID SELF-ASSOCIATION; GTP HYDROLYSIS; TUBULIN; POLYMERIZATION; POLYMERS; ULTRACENTRIFUGATION; MACROMOLECULES; STABILITY; MONOMER AB A mechanism of noncooperative (isodesmic) assembly coupled with preferential cyclization of long polymers is proposed to explain the previously posed question of how a single-stranded filament of the bacterial cell-division protein FtsZ can assemble in an apparently cooperative manner. This proposal is based on results of GTP-mediated assembly of FtsZ from Escherichia coli that was studied under physiologically relevant steady-state solution conditions by a combination of methods including measurement of sedimentation velocity, atomic force and electron microscopy, and precipitation assays. Sedimentation-velocity experiments carried out at multiple protein concentrations reveal an essentially bimodal distribution of slowly sedimenting species and a relatively narrow distribution of rapidly sedimenting species that appears only above an apparent "critical concentration" of protein. In a precipitation assay, the amount of protein that pellets, which correlates with the fraction of rapidly sedimenting species observed in sedimentation-velocity experiments, increases linearly with the total concentration of protein in excess of the critical concentration. Sedimentation coefficients of the rapidly sedimenting fraction are qualitatively consistent with the presence of single-stranded cyclic oligomers with a size range of approximate to50-150 protomers, similar to polymeric single-stranded rings observed in atomic force and electron micrographs. The proposed model is in accord with the results obtained from our experimental observations. C1 CSIC, Ctr Invest Biol, Madrid 28040, Spain. Ctr Nacl Biotecnol, Ctr Invest Biol, Madrid 28040, Spain. Univ Autonoma Madrid, Fac Ciencias, Inst Nicolas Cabrera, E-28049 Madrid, Spain. NIDDK, Prot Biophys Resource,Off Director, Div Bioengn & Phys Sci,Off Res Serv, NIH, Bethesda, MD 20892 USA. NIDDK, Sect Phys Biochem, Lab Biochem & Genet, NIH, Bethesda, MD 20892 USA. RP Rivas, G (reprint author), CSIC, Ctr Invest Biol, Velazquez 144, Madrid 28040, Spain. EM grivas@cib.csic.es RI Mingorance, Jesus/B-7562-2009; Velez, Marisela/F-2900-2013; Jimenez Sarmiento, Mercedes/K-2691-2014; Alfonso, Carlos/K-1316-2014; OI Mingorance, Jesus/0000-0001-6173-5711; Minton, Allen/0000-0001-8459-1247; Rivas, German/0000-0003-3450-7478; Jimenez Sarmiento, Mercedes/0000-0003-2006-1903; Alfonso, Carlos/0000-0001-7165-4800; Schuck, Peter/0000-0002-8859-6966 NR 32 TC 68 Z9 68 U1 1 U2 5 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 8 PY 2005 VL 102 IS 6 BP 1895 EP 1900 DI 10.1073/pnas.0409517102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 898JK UT WOS:000227072900019 PM 15684053 ER PT J AU Vichi, A Payne, DM Pacheco-Rodriguez, G Moss, J Vaughan, M AF Vichi, A Payne, DM Pacheco-Rodriguez, G Moss, J Vaughan, M TI E3 ubiquitin liqase activity of the trifunctional ARD1 (ADP-riblosylation factor domain protein 1) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE RBCC; TRIM protein; ARF; ARF-GAP ID RIBOSYLATION FACTOR DOMAIN; RING FINGER PROTEIN; CONJUGATING ENZYME; LIGASE; MOTIF; INTERACTS; BINDING; FAMILY; ARF; POLYUBIQUITIN AB Protein ubiquitinylation plays a key role in many important cellular processes. Ubiquitinylation requires the Ell ubiquitin-activating enzyme, an E2 ubiquitin-conjugating enzyme, and, frequently, a substrate-specific E3 ubiquitin-protein ligase. In one class of E3 ubiquitin ligases, the catalytic domain contains a zinc-binding RING finger motif. ARD1 (ADP-ribosylation factor domain protein 1), with a RING finger domain in the N-terminal region, two predicted B-Boxes, and a coiled-coil protein interaction motif immediately preceding an ADP-ribosylation factor domain at the C terminus, belongs to the TRIM (Tripartite motif) or RBCC (RING, B-Box, coiled-coil) family. The region containing the B-Boxes and the coiled-coil motif acts as a GTPase-activating protein for the ADP-ribosylation factor domain of ARD1. We report here that full-length ARD1 or the RING finger domain (residues 1-110) produced polyubiquitinylated proteins in vitro in the presence of mammalian El, an E2 enzyme (UbcH6 or UbcH5a, -5b, or -5c), ATP, and ubiquitin. Deletion of the RING region or point mutations within the RING sequence abolished ARD1 E3 ligase activity. All data are consistent with a potential function for ARD1 as an E3 ubiquitin ligase in cells. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Vichi, A (reprint author), 9000 Rockville Pike,Bldg 10,Room 5N 307, Bethesda, MD 20892 USA. EM vichia@nhlbi.nih.gov NR 47 TC 30 Z9 31 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 FEB 8 PY 2005 VL 102 IS 6 BP 1945 EP 1950 DI 10.1073/pnas.0409800102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 898JK UT WOS:000227072900028 PM 15684077 ER PT J AU Wei, B Velazquez, P Turovskaya, O Spricher, K Aranda, R Kronenberg, M Birnbaumer, L Braun, J AF Wei, B Velazquez, P Turovskaya, O Spricher, K Aranda, R Kronenberg, M Birnbaumer, L Braun, J TI Mesenteric B cells centrally inhibit CD4(+) T cell colitis through interaction with regulatory T cell subsets SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE inflammatory bowel disease; G proteins; immune regulation; NKT cells; CD8 alpha alpha(+) T cells ID INDUCED AIRWAY HYPERREACTIVITY; ULCERATIVE-COLITIS; INTRAEPITHELIAL LYMPHOCYTES; AUTOIMMUNE-DISEASE; CROHNS-DISEASE; DEFICIENT MICE; MARGINAL ZONE; CUTTING EDGE; MEMORY; INFLAMMATION AB Inflammatory bowel disease reflects an aberrant mucosal CD4(+) T cell response to commensal enteric bacteria. In addition to regulatory T cell subsets, recent studies have revealed a protective role of B cells in murine CD4+ T cell colitis, but the relationship of their action to T cell immunoregulation is unknown. Here we report that mesenteric lymph node (MLN) B cells protect mice from colitis induced by Galphai2(-/-)CD4(+) T cells. Protection required the transfer of both B cells and CD8alpha(+) T cells; neither cell type alone was sufficient to inhibit CD4+ T cell-mediated colitis. Similar results were also observed in colitis induced by CD4(+)CD45RB(hi) T cells. Immunoregulation was associated with localization of B cells and expansion of CD4(-)CD8(-) CD3(+)NK1.1(+) T cells in the secondary lymphoid compartment, as well as expansion of CD4(+)CD8alpha(+) T cells in the intestinal intraepithelial compartment. MLN B cells from Galphai2(-/-) mice were deficient in a phenotypic subset and failed to provide cotransfer colitis protection. These findings indicate that protective action of B cells is a selective trait of MLN B cells acquired through a Galphai2-dependent developmental process and link B cells with the formation of regulatory T cells associated with mucosal immune homeostasis. C1 Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA. Univ Calif Los Angeles, Inst Mol Biol, Los Angeles, CA 90095 USA. La Jolla Inst Allergy & Immunol, San Diego, CA 92121 USA. Univ Dusseldorf, Inst Biochem & Mol Biol 2, D-40225 Dusseldorf, Germany. Bristol Myers Squibb Co, Princeton, NJ 08540 USA. NIEHS, Res Triangle Pk, NC 27709 USA. RP Braun, J (reprint author), Univ Calif Los Angeles, David Geffen Sch Med, Dept Pathol & Lab Med, CHS 13-222, Los Angeles, CA 90095 USA. EM jbraun@mednet.ucla.edu FU NCI NIH HHS [CA-16042, P30 CA016042]; NIAID NIH HHS [P30 AI028697, AI-28697, F31 AI058919, AI058919]; NIDDK NIH HHS [R01 DK069434, DK19318, DK46763, DK69434, P01 DK046763] NR 50 TC 121 Z9 124 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 FEB 8 PY 2005 VL 102 IS 6 BP 2010 EP 2015 DI 10.1073/pnas.0409449102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 898JK UT WOS:000227072900039 PM 15684084 ER PT J AU Nikolenko, GN Palmer, S Maldarelli, F Mellors, JW Coffin, JM Pathak, VK AF Nikolenko, GN Palmer, S Maldarelli, F Mellors, JW Coffin, JM Pathak, VK TI Mechanism for nucleoside analog-mediated abrogation of HIV-1 replication: Balance between RNase H activity and nucleotide excision SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE drug resistance; recombination; NRTI; reverse transcriptase; dynamic copy choice ID IMMUNODEFICIENCY-VIRUS TYPE-1; DEPENDENT PRIMER UNBLOCKING; HEAVILY TREATED PATIENTS; I REVERSE-TRANSCRIPTASE; AMINO-ACID-RESIDUES; DRUG-RESISTANCE; RIBONUCLEASE-H; 3'-AZIDO-3'-DEOXYTHYMIDINE AZT; MUTATION-RATE; INHIBITORS AB Understanding the mechanisms of HIV-1 drug resistance is critical for developing more effective antiretroviral agents and therapies. Based on our previously described dynamic copy-choice mechanism for retroviral recombination and our observations that nucleciside reverse transcriptase inhibitors (NRTIs) increase the frequency of reverse transcriptase template switching, we propose that an equilibrium exists between (i) NRTI incorporation, NRTI excision, and resumption of DNA synthesis and (it) degradation of the RNA template by RNase H activity, leading to dissociation of the template-primer and abrogation of HIV-1 replication. As predicted by this model, mutations in the RNase H domain that reduced the rate of RNA degradation conferred high-level resistance to 3'-azido-3'-deoxythymidine and 2,3-didehydro-2,3-dideoxythymidine by as much as 180- and 10-fold, respectively, by increasing the time available for excision of incorporated NRTIs from terminated primers. These results provide insights into the mechanism by which NRTIs inhibit HIV-1 replication and imply that mutations in RNase H could significantly contribute to drug resistance either alone or in combination with NRTI-resistance mutations in reverse transcriptase. C1 NCI, HIV Drug Resistance Program, Viral Mutat Sect, Frederick, MD 21702 USA. NCI, HIV Drug Resistance Program, Host Virus Interact Unit, Frederick, MD 21702 USA. Univ Pittsburgh, Sch Med, Div Infect Dis, Pittsburgh, PA 15260 USA. RP Pathak, VK (reprint author), NCI, HIV Drug Resistance Program, Viral Mutat Sect, Bldg 535,Room 334, Frederick, MD 21702 USA. EM vpathak@ncifcrf.gov NR 34 TC 103 Z9 108 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 FEB 8 PY 2005 VL 102 IS 6 BP 2093 EP 2098 DI 10.1073/pnas.0409823102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 898JK UT WOS:000227072900053 PM 15684061 ER PT J AU Kolker, E Picone, AF Galperin, MY Romine, MF Higdon, R Makarova, KS Kolker, N Anderson, GA Qiu, XY Auberry, KJ Babnigg, G Beliaev, AS Edlefsen, P Elias, DA Gorby, YA Holzman, T Klappenbach, JA Konstantinidis, KT Land, ML Lipton, MS McCue, LA Monroe, M Pasa-Tolic, L Pinchuk, G Purvine, S Serres, MH Tsapin, S Zakrajsek, BA Zhou, JH Larimer, FW Lawrence, CE Riley, M Collart, FR Yates, JR Smith, RD Giometti, CS Nealson, KH Fredrickson, JK Tiedje, JM AF Kolker, E Picone, AF Galperin, MY Romine, MF Higdon, R Makarova, KS Kolker, N Anderson, GA Qiu, XY Auberry, KJ Babnigg, G Beliaev, AS Edlefsen, P Elias, DA Gorby, YA Holzman, T Klappenbach, JA Konstantinidis, KT Land, ML Lipton, MS McCue, LA Monroe, M Pasa-Tolic, L Pinchuk, G Purvine, S Serres, MH Tsapin, S Zakrajsek, BA Zhou, JH Larimer, FW Lawrence, CE Riley, M Collart, FR Yates, JR Smith, RD Giometti, CS Nealson, KH Fredrickson, JK Tiedje, JM TI Global profiling of Shewanella oneidensis MR-1: Expression of hypothetical genes and improved functional annotations SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE computational biology; expression analysis; microarrays; proteomics; integrative microbiology ID TANDEM MASS-SPECTROMETRY; ACCURATE MASS; HAEMOPHILUS-INFLUENZAE; GENOMIC PERSPECTIVE; PROTEOME ANALYSIS; YEAST PROTEOME; IDENTIFICATION; DATABASE; PROTEINS; SEQUENCE AB The gamma-proteobacterium Shewanella oneidensis strain MR-1 is a metabolically versatile organism that can reduce a wide range of organic compounds, metal ions, and radionuclides. Similar to most other sequenced organisms, approximate to40% of the predicted ORFs in the S. oneidensis genome were annotated as uncharacterized "hypothetical" genes. We implemented an integrative approach by using experimental and computational analyses to provide more detailed insight into gene function. Global expression profiles were determined for cells after UV irradiation and under aerobic and suboxic growth conditions. Transcriptomic and proteomic analyses confidently identified 538 hypothetical genes as expressed in S. oneidensis cells both as mRNAs and proteins (33% of all predicted hypothetical proteins). Publicly available analysis tools and databases and the expression data were applied to improve the annotation of these genes. The annotation results were scored by using a seven-category schema that ranked both confidence and precision of the functional assignment. We were able to identify homologs for nearly all of these hypothetical proteins (97%), but could confidently assign exact biochemical functions for only 16 proteins (category 1; 3%). Altogether, computational and experimental evidence provided functional assignments or insights for 240 more genes (categories 2-5; 45%). These functional annotations advance our understanding of genes involved in vital cellular processes, including energy conversion, ion transport, secondary metabolism, and signal transduction. We propose that this integrative approach offers a valuable means to undertake the enormous challenge of characterizing the rapidly growing number of hypothetical proteins with each newly sequenced genome. C1 BIATECH, Bothell, WA 98011 USA. NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Pacific NW Natl Lab, Div Biol Sci, Richland, WA 99352 USA. Pacific NW Natl Lab, Environm Mol Sci Lab, Richland, WA 99352 USA. Michigan State Univ, Ctr Microbial Ecol, E Lansing, MI 48824 USA. Argonne Natl Lab, Biosci Div, Argonne, IL 60439 USA. Oak Ridge Natl Lab, Genome Anal Grp, Oak Ridge, TN 37831 USA. Oak Ridge Natl Lab, Div Environm Sci, Oak Ridge, TN 37831 USA. Wadsworth Ctr, Albany, NY 12201 USA. Marine Biol Lab, Ctr Comparat Mol Biol & Evolut, Woods Hole, MA 02543 USA. Univ So Calif, Dept Earth Sci, Los Angeles, CA 90089 USA. Scripps Res Inst, Dept Cell Biol, La Jolla, CA 92037 USA. RP Kolker, E (reprint author), BIATECH, 19310 N Creek Pkwy,Suite 115, Bothell, WA 98011 USA. EM ekolker@biatech.org RI Land, Miriam/A-6200-2011; Elias, Dwayne/B-5190-2011; Smith, Richard/J-3664-2012; Kolker, Eugene/C-6711-2008; Galperin, Michael/B-5859-2013; Beliaev, Alexander/E-8798-2016; OI Collart, Frank/0000-0001-6942-4483; Land, Miriam/0000-0001-7102-0031; Elias, Dwayne/0000-0002-4469-6391; Smith, Richard/0000-0002-2381-2349; Galperin, Michael/0000-0002-2265-5572; Beliaev, Alexander/0000-0002-6766-4632; Romine, Margaret/0000-0002-0968-7641; McCue, Lee Ann/0000-0003-4456-517X FU Intramural NIH HHS [Z99 LM999999] NR 44 TC 88 Z9 91 U1 1 U2 24 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 8 PY 2005 VL 102 IS 6 BP 2099 EP 2104 DI 10.1073/pnas.0409111102 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 898JK UT WOS:000227072900054 PM 15684069 ER PT J AU Turchi, J Saunders, RC Mishkin, M AF Turchi, J Saunders, RC Mishkin, M TI Effects of cholinergic deafferentation of the rhinal cortex on visual recognition memory in monkeys SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE entorhinal cortex; medial temporal lobe; perirhinal cortex; visual memory; non-human primate ID IBOTENIC-ACID LESIONS; BASAL FOREBRAIN; NUCLEUS BASALIS; RHESUS-MONKEYS; OBJECT RECOGNITION; NEUROTOXIC LESIONS; PERIRHINAL CORTEX; NGF RECEPTOR; SCOPOLAMINE; PHYSOSTIGMINE AB Excitotoxic lesion studies have confirmed that the rhinal cortex is essential for visual recognition ability in monkeys. To evaluate the mnemonic role of cholinergic inputs to this cortical region, we compared the visual recognition performance of monkeys given rhinal cortex infusions of a selective cholinergic immunotoxin, ME20.4-SAP, with the performance of monkeys given control infusions into this same tissue. The immunotoxin, which leads to selective cholinergic deafferentation of the infused cortex, yielded recognition deficits of the same magnitude as those produced by excitotoxic lesions of this region, providing the most direct demonstration to date that cholinergic activation of the rhinal cortex is essential for storing the representations of new visual stimuli and thereby enabling their later recognition. C1 NIMH, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. RP Turchi, J (reprint author), NIMH, Neurophysiol Lab, NIH, Bldg 49,Room 1B80, Bethesda, MD 20892 USA. EM turchij@mail.nih.gov NR 27 TC 50 Z9 51 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 FEB 8 PY 2005 VL 102 IS 6 BP 2158 EP 2161 DI 10.1073/pnas.0409708102 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 898JK UT WOS:000227072900064 PM 15684066 ER PT J AU Yang, W AF Yang, W TI Portraits of a Y-family DNA polymerase SO FEBS LETTERS LA English DT Article; Proceedings Paper CT 130th Nobel Symposium on Molecular Mechanisms in Biological Processes CY SEP 10-15, 2004 CL Tallberg, SWEDEN DE structure; mechanism; Y-family polymerase; mutagenesis; translesion (CPD, BPDE, AP) ID SYN THYMINE DIMER; ESCHERICHIA-COLI; CRYSTAL-STRUCTURE; ERROR-PRONE; SULFOLOBUS-SOLFATARICUS; XERODERMA-PIGMENTOSUM; TRANSLESION REPLICATION; MUTAGENESIS PROTEIN; REV1 PROTEIN; GENE ENCODES AB Members of the Y-family of DNA polymerases catalyze template-dependent DNA synthesis but share no sequence homology with other known DNA polymerases. Y-family polymerases exhibit high error rates and low processivity when copying normal DNA but are able to synthesize DNA opposite damaged templates. In the past three years, much has been learned about this family of polymerases including determination of more than a dozen crystal structures with various substrates. In this short review, I will summarize the biochemical properties and structural features of Y-family DNA polymerases. (C) 2004 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. C1 NIDDKD, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. RP Yang, W (reprint author), NIDDKD, Lab Mol Biol, NIH, Bethesda, MD 20892 USA. EM Wei.Yang@nih.gov NR 42 TC 54 Z9 55 U1 1 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0014-5793 J9 FEBS LETT JI FEBS Lett. PD FEB 7 PY 2005 VL 579 IS 4 SI SI BP 868 EP 872 DI 10.1016/j.febslet.2004.11.047 PG 5 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 895PB UT WOS:000226874300006 PM 15680965 ER PT J AU McKenzie, FE Bossert, WH AF McKenzie, FE Bossert, WH TI An integrated model of Plasmodium falciparum dynamics SO JOURNAL OF THEORETICAL BIOLOGY LA English DT Article DE malaria; Plasmodium; parasite; host; vector ID BLOOD-STAGE DYNAMICS; MALARIA TRANSMISSION; ANOPHELES-GAMBIAE; POPULATION-DYNAMICS; GENETIC DIVERSITY; INFECTIONS; IMMUNITY; DISEASE; AREA; MICROSATELLITE AB The within-host and between-host dynamics of malaria are linked in myriad ways, but most obviously by gametocytes, the parasite blood forms transmissible from human to mosquito. Gametocyte dynamics depend on those of non-transmissible blood forms, which stimulate immune responses, impeding transmission as well as within-host parasite densities. These dynamics can, in turn, influence antigenic diversity and recombination between genetically distinct parasites. Here, we embed a differential-equation model of parasite-immune system interactions within each of the individual humans represented in a discrete-event model of Plasmodium falciparum transmission, and examine the effects of human population turnover, parasite antigenic diversity, recombination, and gametocyte production on the dynamics of malaria. Our results indicate that the local persistence of P. falciparum increases with turnover in the human population and antigenic diversity in the parasite, particularly in combination, and that antigenic diversity arising from meiotic recombination in the parasite has complex differential effects on the persistence of founder and progeny genotypes. We also find that reductions in the duration of individual human infectivity to mosquitoes, even if universal, produce population-level effects only if near-absolute, and that, in competition, the persistence and prevalence of parasite genotypes with gametocyte production concordant with data exceed those of genotypes with higher gametocyte production. This new, integrated approach provides a framework for investigating relation ships between pathogen dynamics within ail individual host and pathogen dynamics within interacting host and vector populations. (C) 2004 Elsevier Ltd. All rights reserved. C1 Harvard Univ, Div Engn & Appl Sci, Dept Organism & Evolutionary Biol, Cambridge, MA 02138 USA. RP McKenzie, FE (reprint author), Forgarty Int Ctr, NIH, Room 306,Bldg 16, Bethesda, MD 20892 USA. EM mckenzel@mail.nih.gov FU Intramural NIH HHS [NIH0010951158]; PHS HHS [NIH0010951158] NR 57 TC 35 Z9 37 U1 0 U2 6 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-5193 EI 1095-8541 J9 J THEOR BIOL JI J. Theor. Biol. PD FEB 7 PY 2005 VL 232 IS 3 BP 411 EP 426 DI 10.1016/j.jtbi.2004.08.021 PG 16 WC Biology; Mathematical & Computational Biology SC Life Sciences & Biomedicine - Other Topics; Mathematical & Computational Biology GA 887FQ UT WOS:000226291400011 PM 15572065 ER PT J AU Favor, J Shelby, MD AF Favor, J Shelby, MD TI Transmitted mutational events induced in mouse germ cells following acrylamide or glycidamide exposure SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Review DE acrylamide; glycidamide; heritable translocation test; specific-locus test; transmitted germ line mutations; mouse ID UNSCHEDULED DNA-SYNTHESIS; MALE-MICE; HERITABLE TRANSLOCATIONS; LOCUS MUTATIONS; ADDUCT FORMATION; INDUCTION; METABOLISM; INTRAPERITONEAL; SPERMATOGONIA; SPERMATIDS AB An increase in the germ line mutation rate in humans will result in an increase in the incidence of genetically determined diseases in subsequent generations. Thus, it is important to identify those agents that are mutagenic in mammalian germ cells. Acrylamide is water soluble, absorbed and distributed in the body, chemically reactive with nucleophilic sites, and there are known sources of human exposure. Here we review all seven published studies that assessed the effectiveness of acrylamide or its active metabolite, glycidamide, in inducing transmitted reciprocal translocations or gene mutations in the mouse. Major conclusions were (a) acrylamide is mutagenic in spermatozoa and spermatid stages of the male germ line; (b) in these spermatogenic stages acrylamide is mainly or exclusively a clastogen; (c) per unit dose, i.p. exposure is more effective than dermal exposure; and (d) per unit dose, glycidamide is more effective than acrylamide. Since stem cell spermatogonia persist and may accumulate mutations throughout the reproductive life of males, assessment of induced mutations in this germ cell stage is critical for the assessment of genetic risk associated with exposure to a mutagen. The two specific-locus mutation experiments which studied the stem cell spermatogonial stage yielded conflicting results. This discrepancy should be resolved. Finally, it is noted that no experiments have studied the mutagenic potential of acrylamide to increase the frequency of transmitted mutational events following exposure in the female germ line. (C) 2004 Elsevier B.V. All rights reserved. C1 GSF, Natl Res Ctr Environm & Hlth, Inst Human Genet, D-85764 Neuherberg, Germany. Natl Inst Environm Hlth Sci, NTP, CERHR, Res Triangle Pk, NC USA. RP Favor, J (reprint author), GSF, Natl Res Ctr Environm & Hlth, Inst Human Genet, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany. EM favor@gsf.de NR 32 TC 13 Z9 13 U1 0 U2 2 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 FEB 7 PY 2005 VL 580 IS 1-2 BP 21 EP 30 DI 10.1016/j.mrgentox.2004.09.010 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 898DI UT WOS:000227055900003 PM 15668104 ER PT J AU Ferraren, DO Liu, C Badner, JA Corona, W Rezvani, A Monje, VD Gershon, ES Bonner, TI Detera-Wadleigh, SD AF Ferraren, DO Liu, C Badner, JA Corona, W Rezvani, A Monje, VD Gershon, ES Bonner, TI Detera-Wadleigh, SD TI Linkage disequilibrium analysis in the LOC93081-KDELC1-BIVM region on 13q in bipolar disorder SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE SNP; TDT; linkage; association ID SUSCEPTIBILITY LOCUS; CHROMOSOME 13Q32; PEDIGREE SERIES; POTENTIAL LOCI; GENOME SCREEN; SCHIZOPHRENIA; GENE; SCAN; METAANALYSIS; FAMILIES AB Genome-wide scans in bipolar disorder and a meta analysis on published data have provided evidence for linkage to chromosome 13q, although the reported peaks from various studies have not converged in a narrow region. Recently, single nucleotide polymorphisms (SNPs) at the G72/G30 locus have been shown to be associated with bipolar disorder suggesting its potential role in increasing disease risk. The proposed linkage region on 13q extends over a wide span, and could provide a clue to the existence of other susceptibility variants. In the present study, SNPs in the LOC93081-KDELC1-BIVM, a region proximal to G72, were interrogated in two bipolar family series. KDELC1 has a predicted filamin domain and BIVM contains an immunoglobulin-like motif. The small pedigree series yielded a nominally significant global P-value due to under-transmission of a rare haplotype but this finding was not supported by results from the larger series and in the case-control study that compared 278 cases and 277 controls. (C) 2005 Wiley-Liss, Inc. C1 NIMH, Genet Lab, Intramural Res Program, NIH, Bethesda, MD 20892 USA. NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. Univ Philippines, Natl Inst Mol Biol & Biotechnol, Quezon City 1101, Philippines. RP Detera-Wadleigh, SD (reprint author), NIMH, Genet Lab, Intramural Res Program, NIH, 35 Convent Dr,Bldg 35,Room 1A205, Bethesda, MD 20892 USA. EM sevilladetera@nih.gov RI Liu, Chunyu/G-7561-2012 OI Liu, Chunyu/0000-0002-5986-4415 NR 35 TC 2 Z9 2 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD FEB 5 PY 2005 VL 133B IS 1 BP 12 EP 17 DI 10.1002/ajmg.b.30121 PG 6 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 891ZN UT WOS:000226619600003 PM 15635705 ER PT J AU Feng, JN Chen, JS Yan, J Jones, IR Craddock, N Cook, EH Goldman, D Heston, LL Sommer, SS AF Feng, JN Chen, JS Yan, J Jones, IR Craddock, N Cook, EH Goldman, D Heston, LL Sommer, SS TI Structural variants in the retinoid receptor genes in patients with schizophrenia and other psychiatric diseases SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE schizophrenia; retinoic acid receptors (RARs); retinoid X receptors (RXRs); NURR1 gene; mutation detection ID ALPHA GENES; NGFI-B; NURR1; EXPRESSION; MUTATIONS; SYSTEM; ACID; BETA AB Retinoid receptors (RARs and RXRs) regulate brain morphogenesis and function. Defects in these receptors may contribute to schizophrenia or other psychiatric diseases. To test the hypothesis that genetic variants of the retinoid receptor genes may predispose to schizophrenia and other psychiatric diseases, the six RAR and RXR genes and a heterodimer partner, the NURR1 gene, were scanned in 100 schizophrenia patients, along with pilot studies in 20-24 patients with bipolar disorder (BPD), attention-deficit hyperactivity disorder (ADHD), autism, or alcoholism. A total of 5.4 megabases of genomic sequence was scanned. No variants affecting protein structure or expression (VAPSEs) were found in four of the genes. One uncommon missense variant was found in each of the RARbeta, RARgamma, and RXRgamma genes. We conclude that structural variants in the RAR/RXR and NURR1 genes do not play a major role in the etiology of schizophrenia. (C) 2005 Wiley-Liss, Inc. C1 City Hope Natl Med Ctr, Dept Mol Genet, Duarte, CA 91010 USA. City Hope Natl Med Ctr, Dept Mol Diag, Duarte, CA 91010 USA. Univ Wales Coll Med, Dept Psychol Med, Cardiff CF4 4XN, S Glam, Wales. Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. NIAAA, Dept Psychiat, NIH, Bethesda, MD USA. Univ Washington, Dept Psychiat, Seattle, WA 98195 USA. RP Sommer, SS (reprint author), City Hope Natl Med Ctr, Dept Mol Genet, 1500 E Duarte Rd, Duarte, CA 91010 USA. EM sommerlab@coh.org RI Jones, Ian/B-4925-2009; turton, miranda/F-4682-2011; Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 NR 16 TC 8 Z9 8 U1 0 U2 5 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD FEB 5 PY 2005 VL 133B IS 1 BP 50 EP 53 DI 10.1002/ajmg.b.30113 PG 4 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 891ZN UT WOS:000226619600009 PM 15635645 ER PT J AU Herman, AI Kaiss, KM Ma, R Philbeck, JW Hasan, A Dasti, H DePetrillo, PB AF Herman, AI Kaiss, KM Ma, R Philbeck, JW Hasan, A Dasti, H DePetrillo, PB TI Serotonin transporter promoter polymorphism and monoamine oxidase type a VNTR allelic variants together influence alcohol binge drinking risk in young women SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE pharmacogenetics; polymorphism (genetics); alcohol drinking ID COLLEGE ALCOHOL; HARVARD SCHOOL; GENE PROMOTER; ETHANOL; REGION; DRINKERS; BEHAVIOR; RATS; MICE; MAOA AB The short allelic variant of the serotonin transporter protein promoter polymorphism. (5HTTLPR) appears to influence binge drinking in college students. Both monoamine oxidase type A (MAOA) and the serotonin transporter protein are involved in the processing of serotonin, and allelic variants are both associated with differences in the efficiency of expression. We hypothesized that a significant gene x gene interaction would further stratify the risk of binge drinking in this population. Participants were college students (n = 412) who completed the College Alcohol Study, used to measure binge drinking behaviors. Genomic DNA was extracted from saliva for PCR based genotyping. The risk function for binge drinking was modeled using logistic regression, with final model fit P < 0.0005. This model was valid only for Caucasian females (n = 223), but the power to detect sex and ethnic effects was small. Young Caucasian women carrying higher expression MAOA VNTR alleles homozygous for the short allelic variant of the 5HTTLPR demonstrated the highest rate of binge drinking by self-report, odds ratio (genotype odds: population odds) and 95% confidence intervals, 3.11 (1.14-18.10). Individuals carrying higher expression MAOA VNTR alleles carrying at least one long 5HTTLPR allelic variant had the lowest risk of binge drinking 0.46 (0.28-0.71). These results support the hypothesis that binge drinking behavior in young adulthood may be influenced by neurobiological differences in serotonergic function conferred by functional polymorphisms in genes involved in serotonin processing. (C) 2005 Wiley-Liss, Inc. C1 NIAAA, Intramural Res Program, Clin Studies Lab, Unit Clin & Biochem Pharmacol,NIH, Bethesda, MD USA. George Washington Univ, Dept Psychol, Washington, DC 20052 USA. RP DePetrillo, PB (reprint author), Wake Forest Univ, Sch Med, Friedburg Campus,2105 Welf Rd, Winston Salem, NC 27127 USA. EM pd@apgs.org NR 19 TC 26 Z9 28 U1 0 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD FEB 5 PY 2005 VL 133B IS 1 BP 74 EP 78 DI 10.1002/ajmg.b.30135 PG 5 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 891ZN UT WOS:000226619600014 PM 15635592 ER PT J AU Clarimon, J Johnson, J Dogu, O Horta, W Khan, N Lees, AJ Hardy, J Singleton, A AF Clarimon, J Johnson, J Dogu, O Horta, W Khan, N Lees, AJ Hardy, J Singleton, A TI Defining the ends of Parkin Exon 4 deletions in two different families with Parkinson's disease SO AMERICAN JOURNAL OF MEDICAL GENETICS PART B-NEUROPSYCHIATRIC GENETICS LA English DT Article DE recessive juvenile Parkinson's disease; mutation; genetics; PARK2 ID RECESSIVE JUVENILE PARKINSONISM; EARLY-ONSET; MUTATIONS; GENE; CANCER; EUROPE AB Autosomal recessive juvenile parkinsonism (AR-JP, PARK2) is characterized by an early onset parkinsonism, often presenting with dystonia as an early feature. Mutations in Parkin are a relatively common cause of AR-JP and are estimated to be present in similar to30% of familial young onset Parkinson disease (PD) [Abbas et al. (1999); Hum Mol Genet 8:567-574]. These mutations include exon rearrangements (deletions and duplications), point mutations, and small deletions. Similar genomic mutations have been described in unrelated patients, thereby indicating independent mutational events or ancient founder effects. We have identified homozygous deletion mutations of exon 4 in Parkin in two unrelated families, one from Brazil and the other from Turkey [Dogu et al. (2004); Mov Dis 9:812-816; Khan et al., Mov Dis, in press]. We have performed molecular analysis of the deletion breakpoints and this data indicates these mutations originated independently. We present here data demonstrating that the mutation responsible for disease in the Brazilian kindred consists of two separate deletions (1,069 and 1,750 bp) surrounding and including exon 4. The deletion removing parkin exon 4 identified in the Turkish family extended 156,203 bp. In addition to demonstrating that disease in these families is not caused by a single founder mutation, these data show that there is no common fragile site between these mutational events. (C) 2005 Wiley-Liss, Inc. C1 NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Mersin Univ, Fac Med, Movement Disorders Unit, Dept Neurol, Mersin, Turkey. Univ Hosp, Walter Cantidio & Movement Disorder Serv UFC, Fortaleza, Ceara, Brazil. Inst Neurol, Dept Mol Neurosci, London, England. UCL, Reta Lila Weston Inst Neurol Studies, Windeyer Med Inst, London, England. RP Clarimon, J (reprint author), NIA, Mol Genet Sect, Neurogenet Lab, NIH, Bldg 35,Room 1A1002,MSC 3707,35 Lincoln Dr, Bethesda, MD 20892 USA. EM clarimon@mail.nih.gov RI Dogu, Okan/A-2045-2010; Johnson, Janel/A-7136-2010; Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; Lees, Andrew/A-6605-2009; OI Clarimon, Jordi/0000-0002-6824-6942 NR 14 TC 12 Z9 13 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1552-4841 J9 AM J MED GENET B JI Am. J. Med. Genet. B PD FEB 5 PY 2005 VL 133B IS 1 BP 120 EP 123 DI 10.1002/ajmg.b.30119 PG 4 WC Genetics & Heredity; Psychiatry SC Genetics & Heredity; Psychiatry GA 891ZN UT WOS:000226619600024 PM 15635662 ER PT J AU Baxter, MK McBride, AA AF Baxter, MK McBride, AA TI An acidic amphipathic helix in the Bovine Papillomavirus E2 protein is critical for DNA replication and interaction with the E1 protein SO VIROLOGY LA English DT Article DE papillomavirus; BPV; DNA replication; E1; E2; protein structure ID E2 PROTEIN; TRANSCRIPTIONAL ACTIVATION; TRANSACTIVATION DOMAIN; AMINO-ACIDS; IN-VITRO; ORIGIN; BINDING; TYPE-1; IDENTIFICATION; COMPLEX AB The papillomavirus E2 proteins function in viral transcriptional regulation, and genome replication and episomal maintenance. The transactivation domain is essential for these activities. To identify functional regions, a structural model of the BPV1 E2 transactivation domain was used to target surface residues for mutation. Mutation of several previously uncharacterized regions yielded proteins specifically disrupted in the replication activity of E2. Mutations in an amino-terminal acidic amphipathic helix disrupted the interaction of the El and E2 proteins and a peptide derived from this helix blocked cooperative origin binding of El and E2. Mutation of clusters of charged residues, R47, K48, K49, R58, and H61 or R172, D175, E176, and R179, or residue R68 in the previously described putative El interaction region, specifically disrupted replication while retaining the ability to bind to the E I protein. Thus, this approach has identified novel regions that are required for the replication function of E2. Published by Elsevier Inc. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. RP McBride, AA (reprint author), NIAID, Viral Dis Lab, NIH, Bldg 4,Room 137,4 Ctr Dr MSC 0455, Bethesda, MD 20892 USA. EM amcbride@nih.gov OI McBride, Alison/0000-0001-5607-5157 NR 25 TC 17 Z9 17 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 FEB 5 PY 2005 VL 332 IS 1 BP 78 EP 88 DI 10.1016/j.virol.2004.11.036 PG 11 WC Virology SC Virology GA 892ZM UT WOS:000226688500009 PM 15661142 ER PT J AU Pancera, M Wyatt, R AF Pancera, M Wyatt, R TI Selective recognition of oligomeric HIV-1 primary isolate envelope glycoprotelins by potently neutralizing ligands requires efficient precursor cleavage SO VIROLOGY LA English DT Article DE HIV-1; glycoproteins; precursor cleavage ID HUMAN-IMMUNODEFICIENCY-VIRUS; HUMAN MONOCLONAL-ANTIBODY; SEMLIKI-FOREST-VIRUS; CD4 BINDING-SITE; NONNEUTRALIZING ANTIBODIES; TYPE-1 NEUTRALIZATION; PARTIAL DELETION; MEMBRANE-FUSION; GP120; PROTEIN AB A critical component of an effective HIV vaccine will be the induction of broadly neutralizing antibodies. Comprising the HIV spike, the exterior envelope glycoprotein gp120 and the transmembrane glycoprotein gp41 mediate receptor binding, viral entry, and are the targets for neutralizing antibodies. The gp120 and gp41 glycoproteins are derived from the gp160 precursor glycoprotein and following gp160 glycosylation, oligomerization and cleavage in the endoplasmic reticulum and Golgi, remain as non-covalently associated trimers of heterodimers. Previously, using cell-surface envelope glycoproteins derived from infection of a laboratory-adapted HIV-1 strain, a correlation had been established between the binding of gp120-directed antibodies to the viral glycoprotein and the ability of the antibodies to neutralize laboratory-adapted isolates. However, this has been more difficult to demonstrate for glycoproteins derived from primary patient isolates. Here, using a FACS-based method, we report that only gp120-directed neutralizing antibodies and the neutralizing ligand soluble CD4 efficiently bind to glycoproteins derived from the JR-FL primary isolate provided that the gp160 precursor protein is efficiently cleaved. Precursor cleavage was demonstrated by cell-surface biotinylation and Western blotting. In stark contrast, both non-neutralizing and neutralizing antibodies bind non-cleaved envelope glycoproteins from JR-FL and YU2 isolates. These data imply that significant changes in Env spike structure are dependent upon precursor gp160 cleavage and are consistent with a restricted-binding-to-Env model of neutralization. The data also have implications in regards to the use and design of non-cleaved envelope glycoprotein trimeric immunogens as a means to selectively and preferentially present neutralizing epitopes to the host immune system. Published by Elsevier Inc. C1 NIAID, Struct Virol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Wyatt, R (reprint author), NIAID, Struct Virol Sect, Vaccine Res Ctr, NIH, 40 Convent Dr,Bldg 40,Room 4512, Bethesda, MD 20892 USA. EM richardwyatt@nih.gov NR 63 TC 92 Z9 92 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB 5 PY 2005 VL 332 IS 1 BP 145 EP 156 DI 10.1016/j.virol.2004.10.042 PG 12 WC Virology SC Virology GA 892ZM UT WOS:000226688500014 PM 15661147 ER PT J AU Hoshino, Y Honma, S Jones, RW Ross, J Santos, N Gentsch, JR Kapikian, AZ Hesse, RA AF Hoshino, Y Honma, S Jones, RW Ross, J Santos, N Gentsch, JR Kapikian, AZ Hesse, RA TI A porcine G9 rotavirus strain shares neutralization and VP7 phylogenetic sequence lineage 3 characteristics with contemporary human G9 rotavirus strains SO VIROLOGY LA English DT Article DE rotavirus; porcine rotavirus; serotype G9; neutralization characterization ID POLYMERASE CHAIN-REACTION; SEROTYPE G9; GENOMIC CHARACTERIZATION; MOLECULAR CHARACTERIZATION; MONOCLONAL-ANTIBODIES; GEL-ELECTROPHORESIS; VACCINE CANDIDATES; UNITED-STATES; REASSORTANT ROTAVIRUSES; ANTIGENIC RELATIONSHIPS AB Of five globally important VP7 (G) serotypes (G1-4 and 9) of group A rotaviruses (the single most important etiologic agents of infantile diarrhea worldwide), G9 continues to attract considerable attention because of its unique natural history. Serotype G9 rotavirus was isolated from a child with diarrhea first in the United States in 1983 and subsequently in Japan in 1985. Curiously, soon after their detection, G9 rotaviruses were not detected for about a decade in both countries and then reemerged in both countries in the mid-1990s. Unexpectedly, however, such reemerged (39 strains were distinct genetically and molecularly from those isolated in the 1980s. Thus, the origin of the reemerged G9 viruses remains an enigma. Sequence analysis has demonstrated that the G9 rotavirus VP7 gene belongs to one of at least three phylogenetic lineages: lineage 1 (strains isolated in the 1980s in the United States and Japan), lineage 2 (strains first isolated in 1986 and exclusively in India thus far), and lineage 3 (strains that emerged/reemerged in the mid-1990s). Currently, lineage 3 G9 viruses are the most frequently detected G9 strains globally. We characterized a porcine rotavirus (A2 strain) isolated in the United States that was known to belong to the P[7] genotype but had not been serotyped by neutralization. The A2 strain was found to bear serotype G9 and P9 specificities as well as NSP4 [B] and subgroup I characteristics. By VP7-specific neutralization, the porcine G9 strain was more closely related to lineage 3 viruses than to lineage 1 or 2 viruses. Furthermore, by sequence analysis, the A2 VP7 was shown to belong to lineage 3 G9. These findings raise intriguing questions regarding possible explanations for the emergence of variations among the G9 strains. Published by Elsevier Inc. C1 NIAID, Epidemiol Sect, Infect Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Fed Rio de Janeiro, Inst Microbiol, BR-21941 Rio De Janeiro, Brazil. Ctr Dis Control & Prevent, Viral Gastroenteritis Sect, Div Viral & Rickettsial Dis, Atlanta, GA 30333 USA. Intervet Inc, DeSoto, KS 66018 USA. RP Hoshino, Y (reprint author), NIAID, Epidemiol Sect, Infect Dis Lab, NIH, Bldg 50,Room 6308,50 S Dr,MSC 8026, Bethesda, MD 20892 USA. EM thoshino@niaid.nih.gov; shonma@niaid.nih.gov; rjones@niaid.nih.gov; jross@niaid.nih.gov; nsantos@niaid.nih.gov; jrg4@cdc.gov; akapikian@niaid.nih.gov; Dick.Hesse@intervet.com RI Santos, Norma/H-6986-2015 OI Santos, Norma/0000-0002-5123-9172 NR 87 TC 31 Z9 31 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB 5 PY 2005 VL 332 IS 1 BP 177 EP 188 DI 10.1016/j.virol.2004.11.006 PG 12 WC Virology SC Virology GA 892ZM UT WOS:000226688500017 PM 15661150 ER PT J AU Cho, EG Schwartz, RH Kim, MG AF Cho, EG Schwartz, RH Kim, MG TI Shedding of membrane epithin is blocked without LDLRA4 and its protease activation site SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE epithin; epithin(Delta); isoform; type II; transmembrane; serine protease; N-terminal processing; shedding ID THYMIC STROMAL CELLS; SERINE-PROTEASE; SPLICE SITES; IDENTIFICATION; MATRIPTASE-2; RECEPTOR; CLONING; CDNA AB Epithin, a mouse type II transmembrane serine protease, is processed at Gly(149) and released from the membrane. Here, we report the identification of an epithin isoform, epithin(Delta), containing a 66 amino acid deletion from the full-length epithin, which is missing the 4th LDLRA domain and the protease activation sequence. This truncated isoform showed the same characteristic N-terminal processing at Gly149 as the full-length form, however, no protease activity was detected. The N-terminal processed epithin(Delta) short form (Epi(Delta)-S) was not released into the medium under conditions in which the processed epithin short form (Epi-S) is released. This type of epithin shedding was also prevented when serine protease inhibitors were added to cells expressing the full-length form. These results strongly suggest that the serine protease activity is involved in the shedding process. The presence of epithin(Delta) message was detected in multiple tissues and its significance is discussed. Published by Elsevier Inc. C1 NIAID, Lab Cellular & Mol Immunol, NIH, Bethesda, MD 20892 USA. Korea Univ, Sch Life Sci & Biotechnol, Natl Creat Res Initiat Ctr Cell Death, Seoul 136701, South Korea. RP Kim, MG (reprint author), NIAID, Lab Cellular & Mol Immunol, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM mkim@niaid.nih.gov NR 17 TC 10 Z9 10 U1 0 U2 3 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 4 PY 2005 VL 327 IS 1 BP 328 EP 334 DI 10.1016/j.bbrc.2004.12.014 PG 7 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 888AA UT WOS:000226345400047 PM 15629466 ER PT J AU Woo, HA Jeong, WJ Chang, TS Park, KJ Park, SJ Yang, JS Rhee, SG AF Woo, HA Jeong, WJ Chang, TS Park, KJ Park, SJ Yang, JS Rhee, SG TI Reduction of cysteine sulfinic acid by sulfiredoxin is specific to 2-Cys peroxiredoxins SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID THIOL-SPECIFIC ANTIOXIDANT; TYROSINE-PHOSPHATASE 1B; NECROSIS-FACTOR-ALPHA; MAMMALIAN PEROXIREDOXIN; SACCHAROMYCES-CEREVISIAE; REVERSIBLE INACTIVATION; THIOREDOXIN PEROXIDASE; SITE CYSTEINE; ACTIVE-SITE; PROTEIN AB Cysteine residues of certain peroxiredoxins (Prxs) undergo reversible oxidation to sulfinic acid (Cys-SO2H) and the reduction reaction is catalyzed by sulfiredoxin (Srx). Specific Cys residues of various other proteins are also oxidized to sulfinic acid, suggesting that formation Of Cys-SO2H might be a novel posttranslational. modification that contributes to regulation of protein function. To examine the susceptibility of sulfinic forms of proteins to reduction by Srx, we prepared such forms of all six mammalian Prx isoforms and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Purified sulfiredoxin reduced the sulfinic forms of the four 2-Cys members (Prx I to Prx IV) of the Prx family in vitro, but it did not affect those of Prx V, Prx VI, or GAPDH. Furthermore, Srx bound specifically to the four 2-Cys Prxs in vitro and in cells. Sulfinic forms of Prx I and Prx II, but not of Prx VI or GAPDH, present in H2O2-treated A549 cells were gradually reduced after removal of H2O2; overexpression of Srx increased the rate of the reduction of Prx I and Prx II but did not induce that of Prx VI or GAPDH. These results suggest that reduction of Cys-SO2H by Srx is specific to 2-Cys Prx isoforms. For proteins such as Prx VI and GAPDH, sulfinic acid formation might be an irreversible process that causes protein damage. C1 NHLBI, Lab Cell Signaling, NIH, Bethesda, MD 20892 USA. NHLBI, Biophys Chem Lab, NIH, Bethesda, MD 20892 USA. Ewha Womans Univ, Ctr Cell Signaling Res, Seoul 120750, South Korea. Ewha Womans Univ, Div Mol Life Sci, Seoul 120750, South Korea. RP Rhee, SG (reprint author), Bldg 50,Rm 3523,South Dr,MSC 8015, Bethesda, MD 20892 USA. EM sgrhee@nih.gov NR 32 TC 172 Z9 181 U1 0 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 EI 1083-351X J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 4 PY 2005 VL 280 IS 5 BP 3125 EP 3128 PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 897DJ UT WOS:000226983900002 PM 15590625 ER PT J AU Swales, K Kakizaki, S Yamamoto, Y Inoue, K Kobayashi, K Negishi, M AF Swales, K Kakizaki, S Yamamoto, Y Inoue, K Kobayashi, K Negishi, M TI Novel CAR-mediated mechanism for synergistic activation of two distinct elements within the human cytochrome P4502B6 gene in HepG2 cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NUCLEAR RECEPTOR CAR; PROTEIN PHOSPHATASE 2A; HELIX-LOOP-HELIX; TRANSCRIPTION FACTOR; CYP2B1/B2 GENE; XENOBIOTIC INDUCTION; PRIMARY HEPATOCYTES; ENHANCER MODULE; DNA-BINDING; RAT-LIVER AB The constitutive active receptor (CAR) regulates the induction of the cytochrome P450 2B6 (CYP2B6) gene by phenobarbital-type inducers, such as 1,4 bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) via the distal phenobarbital-responsive enhancer module (PBREM, at -1732/-1685 bp). Activation of the PBREM by TCPOBOP generated a 10-fold induction of CYP2B6 mRNA in HepG2 cells stably expressing mouse CAR (Ym17). Co-treatment with the protein phosphatase inhibitor okadaic acid (OA) synergistically increased this induction over 100-fold without directly activating CAR or the PBREM. Although OA synergy required the presence of PBREM, deletion assays delineated the OA-responsive activity to a proximal 24-bp (-256/-233) sequence (OARE) in the CYP2B6 promoter. CAR did not directly bind to the OARE in electrophoretic mobility shift assays. However, both DNA affinity and chromatin immunoprecipitation assays showed a significant increase in CAR association with the OARE after co-treatment with TCPOBOP and OA, indicating the indirect binding of CAR to the OARE. The two cis-acting elements, the distal PBREM and the proximal OARE, within the chromatin structure are both regulated by CAR in response to TCPOBOP and OA, respectively, to maximally induce the CYP2B6 promoter. This functional interaction between the two sites expands the current understanding of the mechanism of CAR-mediated inducible transcription. C1 NIEHS, NIH, Reprod & Dev Toxicol Lab, Pharmacogenet Sect, Res Triangle Pk, NC 27709 USA. RP Negishi, M (reprint author), NIEHS, NIH, Reprod & Dev Toxicol Lab, Pharmacogenet Sect, POB 12233, Res Triangle Pk, NC 27709 USA. EM negishi@niehs.nih.gov NR 48 TC 45 Z9 47 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 FEB 4 PY 2005 VL 280 IS 5 BP 3458 EP 3466 DI 10.1074/jbc.M411318200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 897DJ UT WOS:000226983900041 PM 15563456 ER PT J AU Sidhaye, V Hoffert, JD King, LS AF Sidhaye, V Hoffert, JD King, LS TI cAMP has distinct acute and chronic effects on Aquaporin-5 in lung epithelial cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID APICAL PLASMA-MEMBRANE; RESPIRATORY-TRACT CELLS; CILIARY BEAT FREQUENCY; PAROTID ACINAR-CELLS; NA+-K+-ATPASE; WATER CHANNELS; TRANSGENIC MICE; CYCLIC-AMP; GLANDULAR TISSUES; SJOGRENS-SYNDROME AB Aquaporin-5 (AQP5) is present on the apical membrane of epithelial cells in various secretory glands as well as on the apical membrane of the airway epithelium, airway submucosal glands, and type 1 pneumocytes, where it can participate in respiratory tract water homeostasis. We examined the effects of cAMP on AQP5 distribution and abundance. When AQP5-expressing mouse lung epithelial cells were treated with cAMP or the beta-adrenergic agonist terbutaline, a biphasic AQP5 response was observed. Short term (minutes) exposure to cAMP produced internalization of AQP5 off of the membrane and a decrease in protein abundance. Both of these responses were blocked by inhibition of protein kinase A and the decrease in abundance was blocked by chloroquine, indicating lysosome-mediated degradation. Sustained cAMP exposure (hours) produced an increase in membrane localization and increased abundance; these effects were also blocked by protein kinase A inhibition. The beta-adrenergic agonist terbutaline produced changes in AQP5 abundance in mouse trachea and lung, consistent with our findings in cultured epithelial cells. Purified AQP5 protein was phosphorylated by protein kinase A but not protein kinase C or casein kinase II, and aquaporin-5 was phosphorylated in cultured cells after long term (but not short term) exposure to cAMP. These studies indicate that cAMP and beta-adrenergic agonists produce distinct short and long term effects on AQP5 distribution and abundance that may contribute to regulation of lung water homeostasis. C1 Johns Hopkins Univ, Sch Med, Dept Med, Div Pulm & Crit Care Med, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Biol Chem, Baltimore, MD 21224 USA. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP King, LS (reprint author), Johns Hopkins Asthma & Allergy Ctr, 4B-64,5501 Hopkins Bayview Circle, Baltimore, MD 21224 USA. EM lsking@jhmi.edu FU NHLBI NIH HHS [F32 HL074515, R01-HL70217, F32-HL074515] NR 50 TC 68 Z9 72 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 FEB 4 PY 2005 VL 280 IS 5 BP 3590 EP 3596 DI 10.1074/jbc.M411038200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 897DJ UT WOS:000226983900057 PM 15536076 ER PT J AU Liu, Y Beard, WA Shock, DD Prasad, R Hou, EW Wilson, SH AF Liu, Y Beard, WA Shock, DD Prasad, R Hou, EW Wilson, SH TI DNA polymerase beta and flap endonuclease 1 enzymatic specificities sustain DNA synthesis for long patch base excision repair SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PURIFIED HUMAN PROTEINS; POLY(ADP-RIBOSE) POLYMERASE-1; MAMMALIAN-CELLS; AP ENDONUCLEASE-1; SITE REPAIR; LIGASE-I; RECONSTITUTION; REPLICATION; RESIDUES; HOMOLOG AB DNA polymerase beta (pol beta) and flap endonuclease 1 (FEN1) are key players in pol beta-mediated long-patch base excision repair (LP-BER). It was proposed that this type of LP-BER is accomplished through FEN1 removal of a 2- to 11-nucleotide flap created by pol beta strand displacement DNA synthesis. To understand how these enzymes might cooperate during LP-BER, we characterized purified human pol beta DNA synthesis by utilizing various BER intermediates, including single-nucleotide-gapped DNA, nicked DNA, and nicked DNA with various lengths of flaps all with a 5'-terminal tetrahydrofuran (THF) residue. We observed that nicked DNA and nicked-THF flap DNA were poor substrates for pol beta-mediated DNA synthesis; yet, DNA synthesis was strongly stimulated by purified human FEN1. FEN1 did not improve pol beta substrate binding. FEN1 cleavage activity was required for the stimulation, suggesting that FEN1 removed a barrier to pol beta DNA synthesis. In addition, FEN1 cleavage on both nicked and nicked-THF flap DNA resulted in a one-nucleotide gapped DNA molecule that was an ideal substrate for pol beta. This study demonstrates that pol beta cooperates with FEN1 to remove DNA damage via a "Hit and Run" mechanism, involving alternating short gap production by FEN1 and gap filling by pol beta, rather than through coordinated formation and removal of a strand-displaced flap. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233,111 TW Alexander Dr,MD B2-06, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov NR 67 TC 90 Z9 95 U1 1 U2 6 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 4 PY 2005 VL 280 IS 5 BP 3665 EP 3674 DI 10.1074/jbc.M412922200 PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 897DJ UT WOS:000226983900066 PM 15561706 ER PT J AU Joshi, MB Rogers, ME Shakarian, AM Yamage, M Al-Harthi, SA Bates, PA Dwyer, DM AF Joshi, MB Rogers, ME Shakarian, AM Yamage, M Al-Harthi, SA Bates, PA Dwyer, DM TI Molecular characterization, expression, and in vivo analysis of LmexCht1 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID PLASMA CHITOTRIOSIDASE ACTIVITY; PATHOGEN LEISHMANIA-DONOVANI; ACIDIC MAMMALIAN CHITINASE; EUKARYOTIC HUMAN PATHOGENS; BACILLUS-CIRCULANS WL-12; CRYSTAL-STRUCTURE; INDUCIBLE EXPRESSION; FUNCTIONAL DOMAINS; MEMBRANE-PROTEINS; SANDFLY VECTOR AB Chitinases have been implicated to be of importance in the life cycle development and transmission of a variety of parasitic organisms.. Using a molecular approach, we identified and characterized the structure of a single copy LmexCht1-chitinase gene from the primitive trypanosomatid pathogen of humans, Leishmania mexicana. The LmexCht1 encodes an similar to50 kDa protein, with well conserved substrate binding and catalytic domains characteristic of members of the chitinase-18 protein family. Further, we showed that LmexCht1 mRNA is constitutively expressed by both the insect vector (i.e. promastigote) and mammalian (i.e. amastigote) life cycle developmental forms of this protozoan parasite. Interestingly, however, amastigotes were found to secrete/release similar to>2-4-fold higher levels of chitinase activity during their growth in vitro than promastigotes. Moreover, a homologous episomal expression system was devised and used to express an epitope-tagged LmexCht1 chimeric construct in these parasites. Expression of the LrnexCht1 chimera was verified in these transfectants by, reverse transcription-PCR, Western blots, and indirect immunofluorescence analyses. Further, results of coupled immunoprecipitation/enzyme activity experiments demonstrated that the LntexCht1 chimeric protein was secreted/released by these transfected L mexicana parasites and that it possessed functional chitinase enzyme activity. Such transfectants were also evaluated for their infectivity both in human macrophages in vitro and in two different strains of mice. Results of those experiments demonstrated that the LmexCht1 transfectants survived significantly better in human macrophages and also produced significantly larger lesions in mice than control parasites. Taken together, our results indicate that the LmexCht1-chimera afforded a definitive survival advantage to the parasite within these mammalian hosts. Thus, the LniexCht1 could potentially represent a new virulence determinant in the mammalian phase of this important human pathogen. C1 NIAID, Cell Biol Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Univ Liverpool, Liverpool Sch Trop Med, Mol & Biochem Parasitol Grp, Liverpool L3 5QA, Merseyside, England. RP Dwyer, DM (reprint author), NIAID, Cell Biol Sect, Parasit Dis Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM ddwyer@niaid.nih.gov OI Bates, Paul/0000-0001-6861-5421 FU Wellcome Trust [064945] NR 70 TC 19 Z9 20 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 FEB 4 PY 2005 VL 280 IS 5 BP 3847 EP 3861 DI 10.1074/jbc.M412299200 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 897DJ UT WOS:000226983900088 PM 15561707 ER PT J AU Wilson, DM AF Wilson, DM TI Ape1 abasic endonuclease activity is regulated by magnesium and potassium concentrations and is robust on alternative DNA structures SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE Ape1; Apex1; abasic (AP) endonuclease; exonuclease; base excision repair ID HUMAN APURINIC/APYRIMIDINIC ENDONUCLEASE; HUMAN APURINIC ENDONUCLEASE; SITE-DIRECTED MUTAGENESIS; INCISION REPAIR PATHWAY; COLI EXONUCLEASE-III; MAJOR HUMAN; SUBSTRATE; BINDING; DAMAGE; DETERMINANTS AB Abasic lesions are common mutagenic or cytotoxic DNA damages. Apel is the major human apurinic/apyrimidinic (AP) endonuclease and initiates repair of abasic sites by catalyzing strand cleavage at the lesion. I show here that Apel single-stranded (ss) AP site incision activity) prefers 0.5 mM or 2 mM MgCl2 and low concentrations (less than or equal to 50 mM) of KCl, whereas its double-stranded (ds) activity favors 10 n-mM MgCl2, and 50 mM KCl or 2 mM MgCl2 and 200 mM KCl. Both activities favor a pH between 7.0 and 7.5, suggesting a common catalytic mechanism. In conditions designed to mimic the intracellular environment (pH 7.2; 100 mM KCl; I mM,l MgCl2), Apel ssAP site incision activity is either about fivefold more active or similar to 20-fold less efficient than its ds activity, depending on the oligonucleotide employed. Secondary structure predictions suggest a role for the DNA conformational state in determining the effectiveness of Apel. Apel complex stability in the presence of EDTA (non-incising conditions) is significantly weaker for ssDNA than dsDNA, regardless of the AP substrate. Duplexes where the AP site is positioned opposite the 3' terminus of a complementary primer strand are incised with an efficiency similar (less than twofold difference) to that of the ssAP substrate alone. Moreover, Apel cleaved AP sites in fork-like and bubble DNA structures with an efficiency that is identical or up to seven-fold higher than ssAP-DNA. The findings here suggest that Apel ssAP and dsAP endonuclease activities are regulated by sequence context and the relative concentrations of certain chemical elements in vivo, and that Apel incision activity occurs on complex replication, recombination, and/or transcription DNA intermediates. (C) 2004, Elsevier Ltd. All rights reserved. C1 NIA, Lab Mol Gerontol, GRC, IRP,NIH, Baltimore, MD 21224 USA. RP Wilson, DM (reprint author), NIA, Lab Mol Gerontol, GRC, IRP,NIH, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM wilsonda@grc.nia.nih.gov NR 57 TC 28 Z9 32 U1 0 U2 7 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD FEB 4 PY 2005 VL 345 IS 5 BP 1003 EP 1014 DI 10.1016/j.jmb.2004.11.028 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 890SP UT WOS:000226531400005 PM 15644200 ER PT J AU Haspel, N Zanuy, D Ma, BY Wolfson, H Nussinov, R AF Haspel, N Zanuy, D Ma, BY Wolfson, H Nussinov, R TI A comparative study of amyloid fibril formation by residues 15-19 of the human calcitonin hormone: A single beta-sheet model with a small hydrophobic core SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE amyloid conformation; beta-sheet; calcitonin; network of interactions; hydrophobic core ID MOLECULAR-DYNAMICS; PEPTIDE; SEQUENCE; DISEASE; SIMULATIONS; OLIGOMERS; FRAGMENT; STATE; NMR AB Experimentally, the human calcitonin hormone (hCT) can form highly stable amyloid protofibrils. Further, a peptide consisting of hCT residues 15-19, DFNKF, was shown to create highly ordered fibrils, similar to those formed by the entire hormone sequence. However, there are limited experimental data regarding the detailed 30 arrangement of either of these fibrils. We have modeled the DFNKF protofibril, using molecular dynamics simulations. We tested the stabilities of single sheet and of various multi sheet models. Remarkably, our most ordered and stable model consists of a parallel-stranded, single P-sheet with a relatively insignificant hydrophobic core. We investigate the chemical and physical interactions responsible for the high structural organization of this single beta-sheet amyloid fibril. We observe that the most important chemical interactions contributing to the stability of the DFNKF organization are electrostatic, specifically between the Lys and the C terminus, between the Asp and N terminus, and a hydrogen bond network between the Asn side-chains of adjacent strands. Additionally, we observe hydrophobic and aromatic pi stacking interactions. We further simulated truncated filaments, FNKF and DFNK. Our tetra-peptide mutant simulations assume models similar to the penta-peptide. Experimentally, the FNKF does not create fibrils while DFNK does, albeit short and less ordered than DFNKF. In the simulations, the FNKF system was less stable than the DFNK and DFNKF. DFNK also lost many of its original interactions becoming less organized, however, many contacts were maintained. Thus, our results emphasize the role played by specific amino acid interactions. To further study specific interactions, we have mutated the penta-peptide, simulating DANK, DFNKA and EFNKF. Here we describe the model, its relationship to experiment and its implications to amyloid organization. (C) 2004 Elsevier Ltd. All rights reserved. C1 SAIC Frederick Inc, Lab Expt & Computat Biol, Basic Res Program, NCI, Ft Detrick, MD 21702 USA. Tel Aviv Univ, Sackler Inst Mol Med, Sackler Fac Med, Dept Human Genet, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), SAIC Frederick Inc, Lab Expt & Computat Biol, Basic Res Program, NCI, Bldg 469,Rm 151, Ft Detrick, MD 21702 USA. EM ruthn@ncifcrf.gov RI Wolfson, Haim/A-1837-2011; Ma, Buyong/F-9491-2011; Zanuy, David/G-3930-2014; Haspel, Nurit/D-1961-2017 OI Ma, Buyong/0000-0002-7383-719X; Zanuy, David/0000-0001-7704-2178; FU NCI NIH HHS [N01-CO-12400] NR 33 TC 58 Z9 61 U1 0 U2 7 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD FEB 4 PY 2005 VL 345 IS 5 BP 1213 EP 1227 DI 10.1016/j.jmb.2004.11.002 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 890SP UT WOS:000226531400021 PM 15644216 ER PT J AU Keskin, O Ma, BY Nussinov, R AF Keskin, O Ma, BY Nussinov, R TI Hot regions in protein-protein interactions: The organization and contribution of structurally conserved hot spot residues SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE protein-protein interactions; hot spots; residue conservation; residue cooparativity; residue networks ID INTERACTION SITES; RECOGNITION SITES; NEURAL-NETWORKS; BINDING-ENERGY; INTERFACES; COMPLEXES; PREDICTION; SEQUENCE; POTENTIALS; PRINCIPLES AB Structurally conserved residues at protein-protein interfaces correlate with the experimental alanine-scanning hot spots. Here, we investigate the organization of these conserved, computational hot spots and their contribution to the stability of protein associations. We find that computational hot spots are not homogeneously distributed along the protein interfaces; rather they are clustered within locally tightly packed regions. Within the dense clusters, they form a network of interactions and consequently their contributions to the stability of the complex are cooperative; however the contributions of independent clusters are additive. This suggests that the binding free energy is not a simple summation of the single hot spot residue contributions. As expected, around the hot spot residues we observe moderately conserved residues, further highlighting the crucial role of the conserved interactions in the local densely packed environment. The conserved occurrence of these organizations suggests that they are advantageous for protein-protein associations. Interestingly, the total number of hydrogen bonds and salt bridges contributed by hot spots is as expected. Thus, H-bond forming residues may use a "hot spot for water exclusion" mechanism. Since conserved residues are located within highly packed regions, water molecules are easily removed upon binding, strengthening electrostatic contributions of charge-charge interactions. Hence, the picture that emerges is that protein-protein associations are optimized locally, with the clustered, networked, highly packed structurally conserved residues contributing dominantly and cooperatively to the stability of the complex. When addressing the crucial question of "what are the preferred ways of proteins to associate", these findings point toward a critical involvement of hot regions in protein-protein interactions. (C) 2004 Elsevier Ltd. All rights reserved. C1 Koc Univ, Ctr Computat Biol & Bioinformat, TR-34450 Istanbul, Turkey. Koc Univ, Coll Engn, TR-34450 Istanbul, Turkey. SAIC Frederick Inc, Basic Res Program, Lab Expt & Computat Biol, NCI, Ft Detrick, MD 21702 USA. Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Keskin, O (reprint author), Koc Univ, Ctr Computat Biol & Bioinformat, TR-34450 Istanbul, Turkey. EM okeskin@ku.edu.tr; ruthn@ncifcrf.gov RI Ma, Buyong/F-9491-2011 OI Ma, Buyong/0000-0002-7383-719X FU NCI NIH HHS [N01-CO-12400] NR 67 TC 292 Z9 299 U1 0 U2 30 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD FEB 4 PY 2005 VL 345 IS 5 BP 1281 EP 1294 DI 10.1016/j.jmb.2004.10.077 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 890SP UT WOS:000226531400026 PM 15644221 ER PT J AU Neighbors, JD Beutler, JA Wiemer, DF AF Neighbors, JD Beutler, JA Wiemer, DF TI Synthesis of nonracemic 3-deoxyschweinfurthin B SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID ENANTIOSELECTIVE TOTAL-SYNTHESIS; CATIONIC POLYENE CYCLIZATIONS; BETA-AMYRIN; ASYMMETRIC DIHYDROXYLATION; MACARANGA-SCHWEINFURTHII; PENTACYCLIC TRITERPENES; O-METHYLMANDELATE; SYN ELIMINATION; INHIBITOR; SQUALENE AB Synthesis of nonracemic 3-deoxyschweinfurthin B has been accomplished through a synthetic sequence including a key cascade cyclization of an epoxy olefin. The intermediate epoxide could be prepared as a single enantiomer through an AD-mix-alpha (or AD-mix-beta) oxidation, and the stereochemistry of the epoxide has been shown to control formation of the two additional stereogenic centers created through the cyclization. Synthetic 3-deoxyschweinfurthin B was found to have potent differential activity in the National Cancer Institute's 60 cell line anticancer assay. This represents the first synthesis of the tetracyclic schweinfurthin skeleton, validating our overall synthetic strategy and providing the first schweinfurthin analogue with activity slightly greater than those of the natural products. C1 Univ Iowa, Dept Chem, Iowa City, IA 52242 USA. NCI, Ctr Canc Res, Mol Targets Dev Program, Frederick, MD 21702 USA. RP Wiemer, DF (reprint author), Univ Iowa, Dept Chem, Iowa City, IA 52242 USA. EM david-wiemer@uiowa.edu RI Beutler, John/B-1141-2009 OI Beutler, John/0000-0002-4646-1924 NR 44 TC 44 Z9 45 U1 0 U2 14 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 FEB 4 PY 2005 VL 70 IS 3 BP 925 EP 931 DI 10.1021/jo048444r PG 7 WC Chemistry, Organic SC Chemistry GA 894FW UT WOS:000226777100021 PM 15675850 ER PT J AU Panchenko, AR Madej, T AF Panchenko, AR Madej, T TI Structural similarity of loops in protein families: toward the understanding of protein evolution SO BMC EVOLUTIONARY BIOLOGY LA English DT Article ID CONSERVED DOMAIN ALIGNMENTS; HOMOLOGY; DATABASE; CLASSIFICATION; SUPERFAMILY; INSERTIONS; DELETIONS; TAXONOMY; RNASE; CDD AB Background: Protein evolution and protein classification are usually inferred by comparing protein cores in their conserved aligned parts. Structurally aligned protein regions are separated by less conserved loop regions, where sequence and structure locally deviate from each other and do not superimpose well. Results: Our results indicate that even longer protein loops can not be viewed as "random coils" and for the majority of protein families in our test set there exists a linear correlation between the measures of sequence similarity and loop structural similarity. Results suggest that distance matrices derived from the loop (dis)similarity measure may produce in some cases more reliable cluster trees compared to the distance matrices based on the conventional measures of sequence and structural (dis)similarity. Conclusions: We show that by considering "dissimilar" loop regions rather than only conserved core regions it is possible to improve our understanding of protein evolution. C1 NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Panchenko, AR (reprint author), NIH, Computat Biol Branch, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM panch@ncbi.nlm.nih.gov; madej@ncbi.nlm.nih.gov NR 25 TC 26 Z9 27 U1 0 U2 2 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1471-2148 J9 BMC EVOL BIOL JI BMC Evol. Biol. PD FEB 3 PY 2005 VL 5 AR 10 DI 10.1186/1471-2148-5-10 PG 8 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 900VV UT WOS:000227243300002 PM 15691378 ER PT J AU Karthikeyan, G Resnick, MA AF Karthikeyan, G Resnick, MA TI Impact of mitochondria on nuclear genome stability SO DNA REPAIR LA English DT Review ID CAUSES INCREASED ESCAPE; DNA-POLYMERASE-GAMMA; SACCHAROMYCES-CEREVISIAE; SUPEROXIDE-DISMUTASE; FRIEDREICH ATAXIA; IRON ACCUMULATION; OXIDATIVE STRESS; DILATED CARDIOMYOPATHY; TRIPLET REPEAT; HUMAN-CELLS C1 NIEHS, Mol Genet Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Resnick, MA (reprint author), NIEHS, Mol Genet Lab, NIH, 111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM resnick@niehs.nih.gov NR 84 TC 6 Z9 6 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 FEB 3 PY 2005 VL 4 IS 2 BP 141 EP 148 DI 10.1016/j.dnarep.2004.07.004 PG 8 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 887AV UT WOS:000226275600001 PM 15590322 ER PT J AU Beard, BC Stevenson, JJ Wilson, SH Smerdon, MJ AF Beard, BC Stevenson, JJ Wilson, SH Smerdon, MJ TI Base excision repair in nucleosomes lacking histone tails SO DNA REPAIR LA English DT Article DE chromatin; glycosylase; DNA polymerase beta; tailless histones; AP endonuclease ID DNA-POLYMERASE-BETA; GLUCOCORTICOID RESPONSE ELEMENT; CORE PARTICLES; POSITIONING SEQUENCES; ANGSTROM RESOLUTION; WERNER-SYNDROME; TARGET SITES; CHROMATIN; PROTEIN; ACCESSIBILITY AB Recently, we developed an in vitro system using human uracil DNA glycosylase (UDG), AP endonuclease (APE), DNA polymerase beta (pol beta) and rotationally positioned DNA containing a single uracil associated with a 'designed' nucleosome, to test short-patch base excision repair (BER) in chromatin. We found that UDG and APE carry out their catalytic activities with reduced efficiency on nucleosome substrates, showing a distinction between uracil facing 'out' or 'in' from the histone surface, while DNA polymerase beta (pol beta) is completely inhibited by nucleosome formation. In this report, we tested the inhibition of BER enzymes by the N-terminal 'tails' of core histones that take part in both inter- and intra-nucleosome interactions, and contain sites of post-translational modifications. Histone tails were removed by limited trypsin digestion of 'donor' nucleosome core particles and histone octamers were exchanged onto a nucleosome-positioning DNA sequence containing a single G:U mismatch. The data indicate that UDG and APE activities are not significantly enhanced with tailless nucleosomes, and the distinction between rotational settings of uracil on the histone surface is unaffected. More importantly, the inhibition of pol beta activity is not relieved by removal of the histone tails, even though these tails interact with DNA in the G:U mismatch region. Finally, inclusion of X-ray cross complement group protein 1 (XRCC1) or Werner syndrome protein (WRN) had no effect on the BER reactions. Thus, additional activities may be required in cells for efficient BER of at least some structural domains in chromatin. (C) 2004 Elsevier B.V. All rights reserved. C1 Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. Fred Hutchinson Canc Res Ctr, Div Clin Res, Transplantat Biol Program, Seattle, WA 98109 USA. Univ Washington, Sch Med, Seattle, WA 98195 USA. NIEHS, Struct Biol Lab, Res Triangle Pk, NC 27709 USA. RP Smerdon, MJ (reprint author), Washington State Univ, Sch Mol Biosci, Pullman, WA 99164 USA. EM smerdon@mail.wsu.edu FU NIEHS NIH HHS [ES04106] NR 50 TC 18 Z9 18 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 FEB 3 PY 2005 VL 4 IS 2 BP 203 EP 209 DI 10.1016/j.dnarep.2004.09.011 PG 7 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 887AV UT WOS:000226275600007 PM 15590328 ER PT J AU Yoo, S McKee, BD AF Yoo, S McKee, BD TI Functional analysis of the Drosophila Rad5l gene (spn-A) in repair of DNA damage and meiotic chromosome segregation SO DNA REPAIR LA English DT Article DE rad51; recombination; DNA repair; nondisjunction ID ESCHERICHIA-COLI RECA; SACCHAROMYCES-CEREVISIAE; PAIRING SITES; RECOMBINATIONAL REPAIR; HOMOLOGOUS RECOMBINATION; SYNAPTONEMAL COMPLEXES; IONIZING-RADIATION; MELANOGASTER; PROTEIN; MEIOSIS AB Rad51 is a crucial enzyme in DNA repair, mediating the strand invasion and strand exchange steps of homologous recombination (HR). Mutations in the Drosophila Rad51 gene (spn-A) disrupt somatic as well as meiotic double-strand break (DSB) repair, similar to fungal Rad51 genes. However, the sterility of spn-A mutant females prevented a thorough analysis of the role of Rad51 in meiosis. In this study, we generated transgenic animals that express spn-A dsRNA under control of an inducible promoter, and examined the effects of inhibiting expression of spn-A on DNA repair, meiotic recombination and meiotic chromosome pairing and segregation. We found that depletion of spn-A mRNA had no effect on the viability of non-mutagen-treated transgenic animals but greatly reduced the survival of larvae that were exposed to the radiomimetic drug MMS, in agreement with the MMS and X-ray sensitivity of spn-A mutant animals. We also found that increases in dose of spn-A gene enhanced larval resistance to MMS exposure, suggesting that at high damage levels, Rad51 protein levels may be limiting for DNA repair. spn-A RNAi strongly stimulated X-X nondisjunction and decreased recombination along the X in female meiosis, consistent with a requirement of Rad51 in meiotic recombination. However, neither RNAi directed against the spn-A mRNA nor homozygosity for a spn-A null mutation had any effect on male fertility or on X-Y segregation in male meiosis, indicating that Rad51 likely plays no role in male meiotic chromosome pairing. Our results support a central role for Rad51 in HR in both somatic and meiotic DSB repair, but indicate that Rad51 in Drosophila is dispensable for meiotic chromosome pairing. Our results also provide the first demonstration that RNAi can be used to inhibit the functions of meiotic genes in Drosophila. (C) 2004 Elsevier B.V. All rights reserved. C1 Univ Tennessee, Dept Biochem & Cellular & Mol Biol, Knoxville, TN 37996 USA. NHLBI, Lab Biochem Genet, NIH, Bethesda, MD 20892 USA. RP McKee, BD (reprint author), Univ Tennessee, Dept Biochem & Cellular & Mol Biol, 1414 Cumberland Ave,M407 Walters Life Sci Bldg, Knoxville, TN 37996 USA. EM bdmckee@utk.edu FU NIGMS NIH HHS [R01 GM40489] NR 60 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1568-7864 J9 DNA REPAIR JI DNA Repair PD FEB 3 PY 2005 VL 4 IS 2 BP 231 EP 242 DI 10.1016/j.dnarep.2004.09.009 PG 12 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 887AV UT WOS:000226275600010 PM 15590331 ER PT J AU Bohr, VA Sander, M Kraemer, KH AF Bohr, VA Sander, M Kraemer, KH TI Rare diseases provide rare insights into DNA repair pathways, TFIIH, aging and cancer SO DNA REPAIR LA English DT Editorial Material DE DNA repair; cancer; aging; nucleotide excision repair; transcription; base excision repair; xeroderma pigmentosum; trichothiodystrophy; cockayne syndrome ID COCKAYNE-SYNDROME; TRICHOTHIODYSTROPHY; TRANSCRIPTION AB The study of rare human diseases has been instrumental in the development of our understanding of human DNA repair processes. This meeting focused on three disorders of DNA repair and transcription: Cockayne syndrome (CS), xeroderma pigmentosum (XP) and trichothiodystrophy (TTD). For the first time, clinicians, basic researchers and patient advocates met together, shared information and discussed their needs and goals. Cancer susceptibility varies greatly from more than 1000-fold increase in XP to normal in CS and TTD. Some patients with CS, XP or TTD have progressive neurological degeneration. The clinical diagnosis of these disorders involves evaluation by several specialties including neurology, dermatology, radiology, pathology and genetics. There is a pressing need for a laboratory to perform clinically certified diagnostic testing in the US. These diseases are quite complex and overlap syndromes have been found. Each can arise from mutations in more than one gene and conversely, different mutations in one gene can give rise to more than one clinical disease. Some of the proteins that are defective in these disorders function in both DNA repair and transcription. They respond to UV and oxidative DNA damage and involve varied functions such as DNA unwinding, transcription initiation, protein ubiquitination, nuclear receptor phosphorylation, promoter release and myc homeostasis. Mouse models offer the possibility of exploring the effects of complex interactions among these genes. These issues were all discussed at a recent workshop. C1 NIA, Lab Mol Gerontol, NIH, Baltimore, MD 21224 USA. NCI, Basic Res Lab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Bohr, VA (reprint author), NIA, Lab Mol Gerontol, NIH, GRC,Box 01,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM vbohr@nih.gov FU Intramural NIH HHS [Z01 BC004517-31] NR 8 TC 18 Z9 19 U1 2 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 FEB 3 PY 2005 VL 4 IS 2 BP 293 EP 302 DI 10.1016/j.dnarep.2004.09.010 PG 10 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 887AV UT WOS:000226275600018 PM 15678607 ER PT J AU Pelkey, KA McBain, CJ AF Pelkey, KA McBain, CJ TI How to dismantle a detonator synapse SO NEURON LA English DT Editorial Material ID MOSSY FIBER BOUTONS; RAT HIPPOCAMPUS; TARGETS; CELLS AB Direct electrophysiological evaluation of ion channels in vertebrate presynaptic nerve terminals has been limited to synapses such as the neuromuscular junction and the giant calyx of Held. In this issue of Neuron, Engel and Jonas demonstrate that mossy fiber boutons have specialized voltage-gated Na+ channels that critically impact upon presynaptic Ca2+ influx by amplifying terminal invading action potentials. C1 NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, Bethesda, MD 20892 USA. RP Pelkey, KA (reprint author), NICHHD, Lab Cellular & Synapt Neurophysiol, NIH, Bldg 35, Bethesda, MD 20892 USA. NR 15 TC 2 Z9 2 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0896-6273 J9 NEURON JI Neuron PD FEB 3 PY 2005 VL 45 IS 3 BP 327 EP 329 DI 10.1016/j.neuron.2005.01.018 PG 3 WC Neurosciences SC Neurosciences & Neurology GA 894JP UT WOS:000226787700002 PM 15694316 ER PT J AU Kidwell, CS Chalela, J Saver, JL Hill, MD Demchuk, A Butman, J Warach, S AF Kidwell, CS Chalela, J Saver, JL Hill, MD Demchuk, A Butman, J Warach, S TI Comparison of MRI and CT for detection of acute intracerebral hemorrhage - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 Washington Hosp Ctr, Dept Neurol, Washington, DC 20010 USA. UCLA Med Ctr, UCLA Stroke Ctr, Los Angeles, CA USA. Univ Calgary, Foothills Hosp, Dept Clin Neurosci, Calgary Stroke Program, Calgary, AB, Canada. NINDS, NIH, Bethesda, MD 20892 USA. RP Kidwell, CS (reprint author), Washington Hosp Ctr, Dept Neurol, Washington, DC 20010 USA. EM Chelsea.Kidwell@Medstar.Net RI Butman, John/A-2694-2008; Demchuk, Andrew/E-1103-2012 OI Demchuk, Andrew/0000-0002-4930-7789 NR 0 TC 0 Z9 0 U1 1 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 2 PY 2005 VL 293 IS 5 BP 550 EP 551 DI 10.1001/jama.293.5.550-b PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 893BL UT WOS:000226694200008 ER PT J AU Fauci, AS AF Fauci, AS TI Emerging infectious diseases - Reply SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Letter C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM afauci@niaid.nih.gov NR 1 TC 0 Z9 0 U1 0 U2 1 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 2 PY 2005 VL 293 IS 5 BP 554 EP 554 DI 10.1001/jama.293.5.554-b PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 893BL UT WOS:000226694200016 ER PT J AU Kramer, BS AF Kramer, BS TI In memoriam: Daniel C. Ihde SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Biographical-Item C1 Journal Natl Canc Inst, Bethesda, MD 20814 USA. RP Kramer, BS (reprint author), Journal Natl Canc Inst, 8120 Woodmont Ave,Suite 500, Bethesda, MD 20814 USA. EM kate.travis@oupjournals.org NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 2 PY 2005 VL 97 IS 3 BP 158 EP 159 PG 2 WC Oncology SC Oncology GA 893VK UT WOS:000226748200001 ER PT J AU Baker, SG AF Baker, SG TI Re: The central role of receiver operating characteristic (ROC) curves in evaluating tests for the early detection of cancer - Response SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. RP Baker, SG (reprint author), NCI, EPN 3131,6130 Execut Blvd,MSC 7354, Bethesda, MD 20892 USA. EM sb16i@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0027-8874 J9 J NATL CANCER I JI J. Natl. Cancer Inst. PD FEB 2 PY 2005 VL 97 IS 3 BP 235 EP 235 PG 1 WC Oncology SC Oncology GA 893VK UT WOS:000226748200018 ER PT J AU Iordanescu, G Pickhardt, PJ Choi, JR Summers, RM AF Iordanescu, G Pickhardt, PJ Choi, JR Summers, RM TI Automated seed placement for colon segmentation in computed tomography colonography SO ACADEMIC RADIOLOGY LA English DT Article; Proceedings Paper CT Medical Imaging 2004 Conference CY FEB 17-19, 2004 CL San Diego, CA SP SPIE, Amer Assoc Phys Med, Amer Physiol Soc, Ctr Devices & Radiol Hlth, Soc Imaging Sci & Technol, Natl Elect Mfg Assoc, Diagnost Imaging & Therapy Syst Div, Radiol Soc N Amer, Soc Comp Applicat Radiol DE computer-aided detection; image processing ID CT COLONOGRAPHY; VIRTUAL COLONOSCOPY; POLYPS; FEASIBILITY; WALLS AB Rationale and Objective. To present an algorithm to automatically locate seeds for colon segmentation in computed tomography colonography (CTC). Materials and Methods. The algorithm automatically locates two points (seeds) inside the colon lumen. Because of their high distention and fixed anatomic position, we focus on the cecum and rectum for automatic seed placement. We use two-dimensional morphological operators that find pockets of colonic air of sufficient size. For the rectum, we search within an inferiorly and centrally located CT slice. For the cecum, we search in a group of CT slices in the middle of the scanned volume on the patient's right side. We applied our automated algorithm to segment the colon in 292 consecutive cases of CTC (146 prone, 146 supine). Results. After automated seed placement, 83.2% (243 of 292) of the colons were segmented completely and 9.6% (28 of 292) were segmented partially. The unsegmented colon parts were present in datasets where the colon was collapsed in more than one place or because seeds could not be placed in regions filled with fluid. In the remaining 7.2% (21 of 292) of cases, the automatic segmentation leaked outside the colon because of a limitation of the contrast-enhanced fluid detection algorithm. Conclusion. Fully automatic seed placement for colonic segmentation is feasible in the majority of cases without seeding of undesired extracolonic air. C1 NIH, Dept Radiol, Bethesda, MD 20892 USA. Univ Wisconsin, Sch Med, Dept Radiol, Madison, WI USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Summers, RM (reprint author), NIH, Dept Radiol, Blg 10,Room 1C660,10 Ctr Dr MSC 1182, Bethesda, MD 20892 USA. EM rms@nih.gov NR 20 TC 21 Z9 21 U1 0 U2 0 PU ASSOC UNIV RADIOLOGISTS PI OAK BROOK PA 820 JORIE BLVD, OAK BROOK, IL 60523-2251 USA SN 1076-6332 J9 ACAD RADIOL JI Acad. Radiol. PD FEB PY 2005 VL 12 IS 2 BP 182 EP 190 DI 10.1016/j.acra.2004.11.013 PG 9 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 900OY UT WOS:000227225400008 PM 15721595 ER PT J AU Gordon, CM Forsyth, AD Stall, R Cheever, LW AF Gordon, CM Forsyth, AD Stall, R Cheever, LW TI Prevention interventions with persons living with HIV/AIDS: State of the science and future directions SO AIDS EDUCATION AND PREVENTION LA English DT Article ID RISK REDUCTION INTERVENTION; SEXUALLY-TRANSMITTED-DISEASES; RANDOMIZED CONTROLLED-TRIAL; INJECTION-DRUG USERS; SAFER-SEX; HIV; EFFICACY; CARE; MEN; OPPORTUNITIES AB The National Institutes of Health (NIH/NIMH), the Centers for Disease Control and Prevention (CDC), and the HIV/AIDS Bureau of the Health Resources and Services Administration (HRSA) support the CDC's Serostatus Approach to Fighting the HIV Epidemic (SAFE; Janssen et al., 2001). One aim of the strategy is to help individuals living with HIV (and their partners) adopt and sustain HIV and STD risk reduction, treatment adherence, and effective strategies for coping with HIV/AIDS. Efficacious interventions are needed by community organizations and clinics that provide evidence-based services. To expedite translation from research to practice, we convened scientist-practitioners, HIV treatment and prevention providers, and community/consumer members. In this article, we include an overview of prevention trials with HIV-positive persons presented at the meeting, discuss strengths and limitations, recommendations for future research, and discuss sponsoring agencies' plans for advancing prevention tailored for persons living with HIV. C1 NIMH, Ctr Mental Hlth Res AIDS, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Behav Intervent Res Branch, Atlanta, GA USA. HIV AIDS Bur, HRSA, Rockville, MD USA. RP Gordon, CM (reprint author), NIMH, Ctr Mental Hlth Res AIDS, 6001 Execut Blvd,Room 6204, Bethesda, MD 20892 USA. EM cgordon1@mail.nih.gov NR 22 TC 33 Z9 33 U1 2 U2 4 PU GUILFORD PUBLICATIONS INC PI NEW YORK PA 72 SPRING STREET, NEW YORK, NY 10012 USA SN 0899-9546 J9 AIDS EDUC PREV JI Aids Educ. Prev. PD FEB PY 2005 VL 17 IS 1 SU A BP 6 EP 20 DI 10.1521/aeap.17.2.6.58697 PG 15 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA 902CF UT WOS:000227328200002 PM 15843114 ER PT J AU Smith, JM Amara, RR Wyatt, LS Ellenberger, DL Li, B Herndon, JG Patel, M Sharma, S Chennareddi, L Butera, S McNicholl, J McClure, HM Moss, B Robinson, HL AF Smith, JM Amara, RR Wyatt, LS Ellenberger, DL Li, B Herndon, JG Patel, M Sharma, S Chennareddi, L Butera, S McNicholl, J McClure, HM Moss, B Robinson, HL TI Studies in macaques on cross-clade T cell responses elicited by a DNA/MVA AIDS vaccine, better conservation of CD8 than CD4 T cell responses SO AIDS RESEARCH AND HUMAN RETROVIRUSES LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV TYPE-1; INFECTION; DNA; IMMUNOGENICITY; CONSTRUCTION; LYMPHOCYTES; EXPRESSION; DEPLETION; PROTEINS AB One of the unknowns faced by an HIV/AIDS vaccine is the ability of a single clade vaccine to protect against the multiple genetic subtypes and recombinant forms of HIV- I present in the current pandemic. Here, we use a macaque model to investigate the ability of our clade B vaccine that consists of DNA priming and modified vaccinia Ankara (MVA) virus boosting to elicit T cell responses that recognize an A/G recombinant of HIV-1. To test for cross-reactive T cells, intracellular cytokine staining was conducted using five pools of Gag and six pools of Env peptides representing B or A/G sequences. Studies using the peptide pools revealed essentially complete conservation of the CD8 response but only similar to 50% conservation of the CD4 response. Thus, the ability of an HIV vaccine for one clade to protect against other clades may be more limited by the ability to provide CD4 T cell help than the ability to elicit CD8 effector functions. C1 Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30329 USA. Emory Univ, Sch Med, Dept Microbiol & Immunol, Atlanta, GA 30322 USA. NIAID, Viral Dis Lab, Bethesda, MD 20892 USA. Ctr Dis Control & Prevent, HIV & Retrovirol Branch, Atlanta, GA 30333 USA. RP Robinson, HL (reprint author), Emory Univ, Yerkes Natl Primate Res Ctr, 954 Gatewood Rd, Atlanta, GA 30322 USA. EM hrobins@rmy.emory.edu FU NCRR NIH HHS [RR-00165]; NIAID NIH HHS [P01 AI49364]; NIDA NIH HHS [P30 DA 12121] NR 26 TC 8 Z9 8 U1 0 U2 0 PU MARY ANN LIEBERT INC PI LARCHMONT PA 2 MADISON AVENUE, LARCHMONT, NY 10538 USA SN 0889-2229 J9 AIDS RES HUM RETROV JI Aids Res. Hum. Retrovir. PD FEB PY 2005 VL 21 IS 2 BP 140 EP 144 DI 10.1089/aid.2005.21.140 PG 5 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 902KR UT WOS:000227355500004 PM 15725752 ER PT J AU Quertemont, E Grant, KA Correa, M Arizzi, MN Salamone, JD Tambour, S Aragon, CMG McBride, WJ Rodd, ZA Goldstein, A Zaffaroni, A Li, TK Pisano, M Diana, M AF Quertemont, E Grant, KA Correa, M Arizzi, MN Salamone, JD Tambour, S Aragon, CMG McBride, WJ Rodd, ZA Goldstein, A Zaffaroni, A Li, TK Pisano, M Diana, M TI The role of acetaldehyde in the central effects of ethanol SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article; Proceedings Paper CT 27th Annual Meeting of the Research-Society-on-Alcoholism CY JUN 26-30, 2004 CL Vancouver, CANADA SP Res Soc Alcoholism DE acetaldehyde; ethanol; brain; catalase; self-administration; dopamine ID BRAIN CATALASE ACTIVITY; VENTRAL TEGMENTAL AREA; INDUCED LOCOMOTOR-ACTIVITY; NIGRA PARS RETICULATA; ALCOHOL-PREFERRING RATS; FREELY MOVING RATS; DOPAMINE NEURONS; WISTAR RATS; INTRAVENTRICULAR-INJECTIONS; DISULFIRAM TREATMENT AB This article represents the proceedings of a symposium at the 2004 annual meeting of the Research Society on Alcoholism in Vancouver, Canada. The symposium was organized by Etienne Quertemont and chaired by Kathleen A. Grant. The presentations were (1) Behavioral stimulant effects of intracranial injections of ethanol and acetaldehyde in rats, by Merc Correa, Maria N. Arizzi and John D. Salamone; (2) Behavioral characterization of acetaldehyde in mice, by Etienne Quertemont and Sophie Tambour; (3) Role of brain catalase and central formed acetaldehyde in ethanol's behavioral effects, by Carlos M.G. Aragon; (4) Contrasting the reinforcing actions of acetaldehyde and ethanol within the ventral tegmental area (VTA) of alcohol-preferring (P) rats, by William J. McBride, Zachary A. Rodd, Avram Goldstein, Alejandro Zaffaroni and Ting-Kai Li; and (5) Acetaldehyde increases dopaminergic transmission in the limbic system, by Milena Pisano and Marco Diana. C1 Univ Liege, B-4000 Liege, Belgium. Wake Forest Univ, Bowman Gray Sch Med, Dept Physiol & Pharmacol, Winston Salem, NC 27103 USA. Univ Connecticut, Dept Psychol, Storrs, CT USA. Univ Jaume 1, Area Psicobiol, Castellon de La Plana, Spain. Indiana Univ, Sch Med, Dept Psychiat, Inst Psychiat Res, Indianapolis, IN 46202 USA. Stanford Univ, Stanford, CA 94305 USA. Technofyn Associates, Palo Alto, CA USA. NIAAA, Bethesda, MD USA. Univ Sassari, Dept Drug Sci, Cognit Neurosci Lab, I-07100 Sassari, Italy. RP Quertemont, E (reprint author), Univ Liege, Blvd Rectorat 5-B32, B-4000 Liege, Belgium. EM equertemont@ulg.ac.be RI Diana, Marco/D-1475-2011; Salamone, John/H-8165-2015; CORREA, MERCE/G-6125-2011; Rodd, Zachary/L-1580-2015 OI Diana, Marco/0000-0002-6561-5642; Salamone, John/0000-0001-6435-9635; CORREA, MERCE/0000-0002-9868-3131; Rodd, Zachary/0000-0002-8105-1920 FU NIAAA NIH HHS [AA07611, AA12262, AA14437] NR 80 TC 45 Z9 46 U1 1 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD FEB PY 2005 VL 29 IS 2 BP 221 EP 234 DI 10.1097/01.ALC.0000156185.39073.D2 PG 14 WC Substance Abuse SC Substance Abuse GA 900NN UT WOS:000227221700006 PM 15714045 ER PT J AU Lavigne, JA Baer, DJ Wimbrow, HH Albert, PS Brown, ED Judd, JT Campbell, WS Giffen, CA Dorgan, JF Hartman, TJ Barrett, JC Hursting, SD Taylor, PR AF Lavigne, JA Baer, DJ Wimbrow, HH Albert, PS Brown, ED Judd, JT Campbell, WS Giffen, CA Dorgan, JF Hartman, TJ Barrett, JC Hursting, SD Taylor, PR TI Effects of alcohol on insulin-like growth factor I and insulin-like growth factor binding protein 3 in postmenopausal women SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE alcohol; insulin-like growth factor I; insulin-like growth factor binding protein 3; postmenopausal women; controlled feeding study ID FACTOR-BINDING PROTEIN-3; BREAST-CANCER RISK; IGF-I; COLORECTAL-CANCER; LUNG-CANCER; PLASMA-LEVELS; BODY-COMPOSITION; C-PEPTIDE; SERUM; MEN AB Background: Increased circulating insulin-like growth factor I (IGF-I) concentrations, frequently adjusted for IGI, binding protein 3 (IGFBP-3), have been associated with increased risk of several types of cancer, including colon, prostate, and breast. Studies have suggested that alcohol may affect IGF-I or IGFBP-3; however, controlled feeding studies to assess alcohol's effects on IGF-I or IGFBP-3 have not been conducted. Objective: To determine whether chronic, moderate alcohol intake affects serum IGF-I or IGFBP-3 concentrations, we performed a controlled, crossover feeding study. Design: Fifty-three postmenopausal women were randomly assigned to consume 0 g (control), 15 g (one drink), or 30 g (2 drinks) alcohol daily for 8 wk and were rotated through the other 2 intake levels in random order. All foods and beverages were provided during the intervention. Individuals were monitored and calories adjusted to maintain constant weight, and serum was collected at the end of each diet period. Results: Compared with the effects of 0 g alcohol/d, IGF-I concentrations were nearly unchanged by 15 g alcohol/d (0.8%; 95% CI: -3.2%, 3.5%) but decreased significantly by 4.9% (95% CI: -8.0%, -1.6%) with 30 g alcohol/d. IGFBP-3 concentrations significantly increased by 3.0% (95% CI: 0.4%, 5.6%) with 15 g alcohol/d but did not increase significantly with 30 g/d (1.8%; 95% CI: -0.9%, 4.5%). Conclusions: To our knowledge, this is the first published controlled diet study to find that in postmenopausal women, when weight is kept constant, alcohol consumption reduces the amount of serum IGF-I potentially available for receptor binding. These findings suggest that the effect of alcohol intake should be considered in studies of IGF-I, IGFBP-3, and cancer in postmenopausal women. C1 NCI, Canc Res Ctr, Bethesda, MD 20892 USA. USDA ARS, Beltsville Human Nutr Res Ctr, Beltsville, MD USA. Informat Management Serv Inc, Silver Spring, MD USA. Fox Chase Canc Ctr, Philadelphia, PA 19111 USA. Penn State Univ, University Pk, PA 16802 USA. RP Lavigne, JA (reprint author), NCI, Canc Res Ctr, 9000 Rockville Pike,Bldg 37,Room 5046, Bethesda, MD 20892 USA. EM lavignej@mail.nih.gov FU NCI NIH HHS [Y1-SC-8012] NR 52 TC 17 Z9 17 U1 0 U2 1 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD FEB PY 2005 VL 81 IS 2 BP 503 EP 507 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 896OJ UT WOS:000226943100024 PM 15699241 ER PT J AU Rastogi, T Reddy, KS Vaz, M Spiegelman, D Prabhakaran, D Willett, WC Stanpfer, MJ Ascherio, A AF Rastogi, T Reddy, KS Vaz, M Spiegelman, D Prabhakaran, D Willett, WC Stanpfer, MJ Ascherio, A TI Diet and risk of ischemic heart disease in India - Reply SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Letter C1 NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD 20852 USA. RP Rastogi, T (reprint author), NCI, Nutr Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,DHHS, 6120 Execut Blvd,EPS,Room 3030, Rockville, MD 20852 USA. EM trastogi@post.harvard.edu NR 1 TC 0 Z9 0 U1 0 U2 0 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD FEB PY 2005 VL 81 IS 2 BP 537 EP 537 PG 1 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 896OJ UT WOS:000226943100033 ER PT J AU Castle, PE Garcia-Meijide, M Holladay, EB Chuke, R Payne, J Long, A Siefers, H Demuth, F Lorincz, AT AF Castle, PE Garcia-Meijide, M Holladay, EB Chuke, R Payne, J Long, A Siefers, H Demuth, F Lorincz, AT TI A novel filtration-based processing method of liquid cytology specimens for human papillomavirus DNA testing by hybrid capture II SO AMERICAN JOURNAL OF CLINICAL PATHOLOGY LA English DT Article DE human papillomavirus; HPV; hybrid capture II; PreservCyt ID SQUAMOUS INTRAEPITHELIAL LESIONS; CERVICAL-CANCER; RANDOMIZED-TRIAL; HIGH-RISK; UNDETERMINED SIGNIFICANCE; MANAGEMENT STRATEGIES; WOMEN; WORLDWIDE; NEOPLASIA; CELLS AB We evaluated a more efficient method of processing liquid-based cervical cytology specimens for human papillomavirus (HPV) DNA testing by Hybrid Capture II (HCII). Aliquots were made from 701 specimens in the following sequence: 4.0, 2.0, 1.0, 0.5, and 1.5 mL. The 4.0-mL aliquot was processed by the standard method (STP), and half of the processed material was tested by HCH. Other aliquots were processed with a new, filtration-based processing method (NPM). The 2.0-mL NPM aliquot had HCH test Performance most similar to the STP ie, similar HCH positivity (P = .4) and good test agreement (kappa = 0.85, 95% confidence interval [CI], 0.80-0.89). The 194 cytologic negatives had greater positivity by STP (P = .04) compared with the 2.0-mL aliquot processed by NPM; between-method agreement was modest (K = 0.54, 95% CI, 0.36-0.72). A lower positive cut point for the 2.0-mL NPM aliquot partially abrogated this minor difference. In 241 specimens diagnosed as low-grade and 31 as high-grade squamous intraepithelial lesions, there were no significant differences in HPV positivity (>85% and 90%, respectively) between STP and NPM. NPM reduces specimen handling and decreases total testing time by approximately 33% without significant losses in HCH test performance. C1 NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Digene, Gaithersburg, MD USA. Med Univ S Carolina, Charleston, SC 29425 USA. BBI Biotech Res Labs, Silver Spring, MD USA. Informat Management Serv Inc, Silver Spring, MD USA. RP Castle, PE (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, 6120 Execut Blvd,MSC 7234, Bethesda, MD 20892 USA. NR 17 TC 1 Z9 1 U1 0 U2 0 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 FEB PY 2005 VL 123 IS 2 BP 250 EP 255 DI 10.1309/MEPB1TAMAD6Q13G3 PG 6 WC Pathology SC Pathology GA 893XM UT WOS:000226754400012 PM 15842050 ER PT J AU Promislow, JHE Gladen, BC Sandler, DP AF Promislow, JHE Gladen, BC Sandler, DP TI Maternal recall of breastfeeding duration by elderly women SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE bias (epidemiology); breast feeding; epidemiologic methods; mental recall; reproductive history; validation studies ID REPRODUCTIVE FACTORS; ADULT INTELLIGENCE; MEASUREMENT-ERROR; REDUCED RISK; CANCER RISK; LACTATION; LIFE; RELIABILITY; MOTHERS; CHILDREN AB Studies of long-term effects of breastfeeding on the health of both infants and mothers often rely on maternal recall of breastfeeding duration after several decades. The authors evaluated this recall by 140 college-educated, US women 69-79 years of age who breastfed a child in 1940-1956 and recorded the duration both prospectively in a diary for the Menstruation and Reproductive History Study and retrospectively in a questionnaire in 1990-1991. Mean prospective breastfeeding duration was 5.6 months (range, 1-12 months). Mean reporting difference, questionnaire minus diary duration, was 0.0 months, with a standard deviation of 2.7 months; women who recorded short durations tended to overreport, while women who noted long durations underreported. The weighted kappa statistic for reporting agreement was 0.55 (95% confidence interval: 0.42, 0.67), with better recall observed for women in the youngest quintile at recall, firstborns, and infants with more siblings. Ever having breastfed was recalled by 94% of women. For categories of 1-3, 4-6, 7-9, and 10-12 months, recalled breastfeeding duration was correctly classified by 54% of women and was classified within +/-1 category by 89%. The observed misclassification, if nondifferential with respect to outcome, would appreciably attenuate estimates of dose-response associations between breastfeeding duration and later health. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. NIEHS, Biostat Branch, Res Triangle Pk, NC 27709 USA. RP Promislow, JHE (reprint author), NIEHS, Epidemiol Branch, POB 12233,MD A3-05, Res Triangle Pk, NC 27709 USA. EM promisl1@niehs.nih.gov OI Sandler, Dale/0000-0002-6776-0018 NR 42 TC 55 Z9 56 U1 0 U2 4 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 1 PY 2005 VL 161 IS 3 BP 289 EP 296 DI 10.1093/aje/kwi044 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 891TW UT WOS:000226604900010 PM 15671261 ER PT J AU Nussbaum, RL AF Nussbaum, RL TI 2004 ASHG presidential address - What is special about the "human" in "human genetics"? SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Editorial Material C1 NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Nussbaum, RL (reprint author), NHGRI, Genet Dis Res Branch, NIH, 49-4A72,49 Convent Dr MSC4472, Bethesda, MD 20892 USA. EM rlnuss@nhgri.nih.gov NR 0 TC 1 Z9 1 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0002-9297 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB PY 2005 VL 76 IS 2 BP 198 EP 202 DI 10.1086/427894 PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 886GO UT WOS:000226215100001 PM 15714685 ER PT J AU Hoopes, RR Shrimpton, AE Knohl, SJ Hueber, P Hoppe, B Matyus, J Simckes, A Tasic, V Toenshoff, B Suchy, SF Nussbaum, RL Scheinman, SJ AF Hoopes, RR Shrimpton, AE Knohl, SJ Hueber, P Hoppe, B Matyus, J Simckes, A Tasic, V Toenshoff, B Suchy, SF Nussbaum, RL Scheinman, SJ TI Dent disease with mutations in OCRL1 SO AMERICAN JOURNAL OF HUMAN GENETICS LA English DT Article ID OCULOCEREBRORENAL SYNDROME; CHLORIDE CHANNEL; RENAL-FAILURE; LOWE-SYNDROME; IMPAIRS ENDOCYTOSIS; EPITHELIAL-CELLS; NEPHROLITHIASIS; 5-PHOSPHATASE; DEFICIENCY; ACTIN AB Dent disease is an X-linked renal proximal tubulopathy associated with mutations in the chloride channel gene CLCN5. Lowe syndrome, a multisystem disease characterized by renal tubulopathy, congenital cataracts, and mental retardation, is associated with mutations in the gene OCRL1, which encodes a phosphatidylinositol 4,5-bisphosphate (PIP2) 5-phosphatase. Genetic heterogeneity has been suspected in Dent disease, but no other gene for Dent disease has been reported. We studied male probands in 13 families, all of whom met strict criteria for Dent disease but lacked mutations in CLCN5. Linkage analysis in the one large family localized the gene to a candidate region at Xq25-Xq27.1. Sequencing of candidate genes revealed a mutation in the OCRL1 gene. Of the 13 families studied, OCRL1 mutations were found in 5. PIP2 5-phosphatase activity was markedly reduced in skin fibroblasts cultured from the probands of these five families, and protein expression, measured by western blotting, was reduced or absent. Slit-lamp examinations performed in childhood or adulthood for all five probands showed normal results. Unlike patients with typical Lowe syndrome, none of these patients had metabolic acidosis. Three of the five probands had mild mental retardation, whereas two had no developmental delay or behavioral disturbance. These findings demonstrate that mutations in OCRL1 can occur with the isolated renal phenotype of Dent disease in patients lacking the cataracts, renal tubular acidosis, and neurological abnormalities that are characteristic of Lowe syndrome. This observation confirms genetic heterogeneity in Dent disease and demonstrates more-extensive phenotypic heterogeneity in Lowe syndrome than was previously appreciated. It establishes that the diagnostic criteria for disorders resulting from mutations in the Lowe syndrome gene OCRL1 need to be revised. C1 SUNY Upstate Med Univ, Dept Med, Syracuse, NY 13210 USA. SUNY Upstate Med Univ, Dept Pathol, Syracuse, NY 13210 USA. Univ Cologne, Cologne, Germany. Univ Debrecen, Sch Med, H-4012 Debrecen, Hungary. Childrens Mercy Hosp, Kansas City, MO 64108 USA. Univ Childrens Hosp, Skopje, Macedonia. Univ Childrens Hosp, Heidelberg, Germany. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Scheinman, SJ (reprint author), SUNY Upstate Med Univ, Dept Med, 1257 Weiskotten Hall,750 E Adams St, Syracuse, NY 13210 USA. EM scheinms@upstate.edu FU NIDDK NIH HHS [DK063936, R21 DK063936] NR 24 TC 160 Z9 164 U1 1 U2 7 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0002-9297 EI 1537-6605 J9 AM J HUM GENET JI Am. J. Hum. Genet. PD FEB PY 2005 VL 76 IS 2 BP 260 EP 267 DI 10.1086/427887 PG 8 WC Genetics & Heredity SC Genetics & Heredity GA 886GO UT WOS:000226215100011 PM 15627218 ER PT J AU Parle-McDermott, A Mills, JL Kirke, PN Cox, C Signore, CC Kirke, S Molloy, AM O'Leary, VB Pangilinan, FJ O'Herlihy, C Brody, LC Scott, JM AF Parle-McDermott, A Mills, JL Kirke, PN Cox, C Signore, CC Kirke, S Molloy, AM O'Leary, VB Pangilinan, FJ O'Herlihy, C Brody, LC Scott, JM TI MTHFD1 R653Q polymorphism is a maternal genetic risk factor for severe abruptio placentae SO AMERICAN JOURNAL OF MEDICAL GENETICS PART A LA English DT Article DE abruptio placentae; placental abruption; MTHFD1; MTHFR; C1 synthase; folate ID NEURAL-TUBE DEFECTS; METHYLENETETRAHYDROFOLATE REDUCTASE; COMMON MUTATION; PLASMA HOMOCYSTEINE; FOLIC-ACID; PREGNANCY; PREECLAMPSIA; HETEROZYGOSITY; SYNTHETASE AB This study examined the relationship between folate/homocysteine-related genetic polymorphisms: MTHFD1 1958G-->A (R653Q), MTHFR 677C-->T (A222V), MTHFR 1298A-->C (E429A), and risk of severe abruptio placentae. We genotyped 62 women with a pregnancy history complicated by severe abruptio placentae and 184 control pregnancies. Analysis of the MTHFD1 1958G-->A (R653Q) polymorphism, showed increased frequency of the 'QQ' homozygote genotype in pregnancies affected by severe abruptio placentae compared to control pregnancies (odds ratio 2.85 (1.47-5.53), P = 0.002). In contrast to previous reports, the MTHFR polymorphisms 677C-->T (A222V) and 1298A-->C (E429A) were not associated with abruptio placentae risk in our cohort, when analyzed either independently or in combination. We conclude that women who are 'QQ' homozygote for the MTHFD1 1258G-->A (R653Q) polymorphism are almost three times more likely to develop severe abruptio placentae during their pregnancy than women who are 'RQ' or 'RR.' Published 2005 Wiley-Liss, Inc.(dagger). C1 NHGRI, Mol Pathogenesis Sect, Genome Technol Branch, Bethesda, MD 20892 USA. Trinity Coll Dublin, Dept Biochem, Dublin, Ireland. NICHHD, Div Epidemiol Stat & Prevent Res, US Dept HHS, NIH, Bethesda, MD 20892 USA. Hlth Res Board, Child Hlth Epidemiol Div, Dublin, Ireland. Univ Coll Dublin, Natl Matern Hosp, Dept Obstet & Gynaecol, Dublin 2, Ireland. Trinity Coll Dublin, Dept Clin Med, Dublin, Ireland. RP Brody, LC (reprint author), NHGRI, Mol Pathogenesis Sect, Genome Technol Branch, Bldg 50,Room 5306,50 South Dr,MSC 8004, Bethesda, MD 20892 USA. EM lbrody@helix.nih.gov OI Molloy, Anne/0000-0002-1688-9049; O'Leary, Valerie/0000-0003-1171-9830 NR 29 TC 36 Z9 40 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1552-4825 J9 AM J MED GENET A JI Am. J. Med. Genet. A PD FEB 1 PY 2005 VL 132A IS 4 BP 365 EP 368 DI 10.1002/ajmg.a.30354 PG 4 WC Genetics & Heredity SC Genetics & Heredity GA 893HO UT WOS:000226710100005 PM 15633187 ER PT J AU Gomez, R Santolaya, J AF Gomez, R Santolaya, J TI Being mothers too early SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Editorial Material C1 Pontificia Univ Catolica Chile, Hosp Dr Sotero del Rio, CEDIP, Puente Alto, Chile. NICHHD, Perinatol Res Branch, DHHS, NIH, Bethesda, MD 20892 USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. RP Gomez, R (reprint author), Pontificia Univ Catolica Chile, Hosp Dr Sotero del Rio, CEDIP, Puente Alto, Chile. NR 8 TC 3 Z9 3 U1 0 U2 0 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD FEB PY 2005 VL 192 IS 2 BP 340 EP 341 DI 10.1016/j.ajog.2004.10.594 PG 2 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 897FI UT WOS:000226989000005 PM 15695969 ER PT J AU Gomez, R Romero, R Medina, L Nien, JK Chaiworapongsa, T Carstens, M Gonzalez, R Espinoza, J Iams, JD Edwin, S Rojas, I AF Gomez, R Romero, R Medina, L Nien, JK Chaiworapongsa, T Carstens, M Gonzalez, R Espinoza, J Iams, JD Edwin, S Rojas, I TI Cervicovaginal fibronectin improves the prediction of preterm delivery based on sonographic cervical length in patients with preterm uterine contractions and intact membranes SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article; Proceedings Paper CT 23rd Annual Meeting of the Society-for-Maternal-Fetal-Medicine CY FEB 03-08, 2003 CL SAN FRANCISCO, CA SP Soc Maternal Fetal Med DE uterine cervix; ultrasound; fetal fibronectin; preterm delivery; prediction ID FETAL FIBRONECTIN; ULTRASONOGRAPHIC EXAMINATION; VAGINAL SECRETIONS; PREMATURE DELIVERY; LABOR; BIRTH; RISK; ACCURACY; SYMPTOMS AB Objective: The Purpose of this study was to examine the diagnostic performance of ultrasonographic measurement of the cervical length and vaginal fetal fibronectin determination in the prediction of preterm delivery in patients with preterm uterine contractions and intact membranes. Study design: Ultrasound examination of the cervical length and fetal fibronectin determination in vaginal secretions were performed in 215 patients admitted with preterm uterine contractions (22-35 weeks) and cervical dilatation of less than or equal to 3 cm. Outcome variables were the occurrence of preterm delivery within 48 hours, 7 days, and 14 days of admission, delivery less than or equal to 32 and :less than or equal to 35 weeks, as well as the admission-to-delivery interval. Statistical analysis included chi-square test, receiver-operator characteristic (ROC) curve analysis, logistic regression, and survival analysis. Results: The overall prevalence of preterm delivery less than or equal to 35 weeks was 20% (43/215). The prevalence of spontaneous preterm delivery within 48 hours, 7 days, and 14 days of admission, and delivery less than or equal to 32 and less than or equal to 35 weeks were 7.9% (17/215), 13.0% (28/215), 15.8% (34/215), 8.9% (9/101), and 15.8% (34/215), respectively. ROC curve analysis and contingency tables showed a significant relationship between the occurrence of preterm, delivery and both cervical length and fetal fibronectin results (P < .01 for each). Both tests performed comparably in the prediction of spontaneous preterm delivery. However, when fetal fibronectin results were added to those of cervical length (< 30 mm), a significant improvement in the prediction of preterm delivery was achieved. Conclusion: Fetal fibronectin adds prognostic information to that provided by sonographic measurement of the cervical length in patients with preterm uterine contractions and intact membranes. (C) 2005 Elsevier Inc. All rights reserved. C1 Pontificia Univ Catolica Chile, CEDIP, Hosp Dr Sotero del Rio, Puente Alto, Chile. NICHHD, Perinatol Res Branch, DHHS, NIH, Bethesda, MD USA. NICHHD, Perinatol Res Branch, DHHS, NIH, Detroit, MI USA. Wayne State Univ, Sch Med, Dept Obstet & Gynecol, Detroit, MI 48201 USA. Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. RP Gomez, R (reprint author), Pontificia Univ Catolica Chile, CEDIP, Hosp Dr Sotero del Rio, Puente Alto, Chile. NR 33 TC 102 Z9 110 U1 1 U2 4 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD FEB PY 2005 VL 192 IS 2 BP 350 EP 359 DI 10.1016/j.ajog.2004.09.034 PG 10 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 897FI UT WOS:000226989000007 PM 15695971 ER PT J AU Klebanoff, MA Hillier, SL Nugent, RP MacPherson, CA Hauth, JC Carey, JC Harper, M Wapner, RJ Trout, W Moawad, A Leveno, KJ Miodovnik, M Sibai, BM VanDorsten, JP Dombrowski, MP O'Sullivan, MJ Varner, M Langer, O AF Klebanoff, MA Hillier, SL Nugent, RP MacPherson, CA Hauth, JC Carey, JC Harper, M Wapner, RJ Trout, W Moawad, A Leveno, KJ Miodovnik, M Sibai, BM VanDorsten, JP Dombrowski, MP O'Sullivan, MJ Varner, M Langer, O CA Natl Inst Child Hlth Human Dev Mat TI Is bacterial vaginosis a stronger risk factor for preterm birth when it is diagnosed earlier in gestation? SO AMERICAN JOURNAL OF OBSTETRICS AND GYNECOLOGY LA English DT Article DE bacterial vaginosis; preterm birth; gram stain ID EARLY-PREGNANCY; DELIVERY; WOMEN; METRONIDAZOLE; COLONIZATION; ASSOCIATION; INFECTION AB Objective: It is stated commonly that the earlier in pregnancy bacterial vaginosis is diagnosed, the greater is the increase in risk of preterm birth compared with women without bacterial vaginosis. However, this contention is based on small numbers of women. Study design: In this analysis of 12,937 women who were screened for bacterial vaginosis as part of a previously conducted clinical trial, the odds ratio of preterm birth (<7 weeks of gestation) for asymptomatic bacterial vaginosis-positive versus bacterial vaginosis-negative women was evaluated among women who were screened from 8 to 22 weeks of gestation. Results: The odds ratio of preterm birth among bacterial vaginosis-positive versus bacterial vaginosis-negative women ranged from 1.1 to 1.6 and did not vary significantly according to the gestational age at which bacterial vaginosis was screened. The odds ratio for preterm birth did not vary significantly by gestational age at diagnosis when bacterial vaginosis was subdivided into Gram stain score 7 to 8 or 9 to 10. Conclusion: Although bacterial vaginosis was associated with an increased risk of preterm birth, the gestational age at which bacterial vaginosis was screened for and diagnosed did not influence the increase. (C) 2005 Elsevier Inc. All rights reserved. C1 NICHHD, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Obstet Gynecol & Reprod Sci, Pittsburgh, PA USA. George Washington Univ, Ctr Biostat, Rockville, MD USA. Univ Alabama, Dept Obstet & Gynecol, Birmingham, AL USA. Univ Oklahoma, Dept Obstet & Gynecol, Oklahoma City, OK 73190 USA. Wake Forest Univ, Dept Obstet & Gynecol, Winston Salem, NC 27109 USA. Thomas Jefferson Univ, Dept Obstet & Gynecol, Philadelphia, PA 19107 USA. Ohio State Univ, Dept Obstet & Gynecol, Columbus, OH 43210 USA. Univ Chicago, Dept Obstet & Gynecol, Chicago, IL 60637 USA. Univ Texas, SW Med Ctr, Dept Obstet & Gynecol, Dallas, TX 75235 USA. Univ Cincinnati, Dept Obstet & Gynecol, Cincinnati, OH 45267 USA. Univ Tennessee, Dept Obstet & Gynecol, Memphis, TN 38103 USA. Med Univ S Carolina, Dept Obstet & Gynecol, Charleston, SC 29425 USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI USA. Univ Miami, Sch Med, Dept Obstet & Gynecol, Miami, FL 33101 USA. Univ Utah, Dept Obstet & Gynecol, Salt Lake City, UT USA. Univ Texas, Dept Obstet & Gynecol, San Antonio, TX 78284 USA. RP Klebanoff, MA (reprint author), NICHD, DESPR, NIH, Bldg 6100,Room 7B05, Bethesda, MD 20892 USA. EM mk90h@nih.gov RI Varner, Michael/K-9890-2013 OI Varner, Michael/0000-0001-9455-3973 FU NIAID NIH HHS [AI 38514]; NICHD NIH HHS [U10 HD27883, U01 HD36801, U10 HD21410, U10 HD21414, U10 HD27860, U10 HD27861, U10 HD27869, U10 HD27889, U10 HD27905, U10 HD27915, U10 HD27917, U10 HD34116, U10 HD34122, U10 HD34136, U10 HD34208, U10 HD34210] NR 22 TC 52 Z9 60 U1 0 U2 2 PU MOSBY, INC PI ST LOUIS PA 11830 WESTLINE INDUSTRIAL DR, ST LOUIS, MO 63146-3318 USA SN 0002-9378 J9 AM J OBSTET GYNECOL JI Am. J. Obstet. Gynecol. PD FEB PY 2005 VL 192 IS 2 BP 470 EP 477 DI 10.1016/j.ajog.2004.07.017 PG 8 WC Obstetrics & Gynecology SC Obstetrics & Gynecology GA 897FI UT WOS:000226989000025 PM 15695989 ER PT J AU Graham, MR Virtaneva, K Porcella, SF Barry, WT Gowen, BB Johnson, CR Wright, FA Musser, JM AF Graham, MR Virtaneva, K Porcella, SF Barry, WT Gowen, BB Johnson, CR Wright, FA Musser, JM TI Group A Streptococcus transcriptome dynamics during growth in human blood reveals bacterial adaptive and survival strategies SO AMERICAN JOURNAL OF PATHOLOGY LA English DT Article ID HYALURONIC-ACID CAPSULE; 2-COMPONENT REGULATORY SYSTEM; TOXIC-SHOCK-SYNDROME; VIRULENCE FACTORS; GENE-EXPRESSION; M-PROTEIN; IN-VIVO; MOLECULAR CHARACTERIZATION; PYOGENES; IDENTIFICATION AB The molecular basis for bacterial responses to host signals during natural infections is poorly understood. The gram-positive bacterial pathogen group A Streptococcus (GAS) causes human mucosal, skin, and life-threatening systemic infections. During the transition from a throat or skin infection to an invasive infection, GAS must adapt to changing environments and host factors. To better understand how GAS adapts, we used transcript profiling and functional analysis to investigate the transcriptome of a wild-type serotype M1 GAS strain in human blood. Global changes in GAS gene expression occur rapidly in response to human blood exposure. increased transcription was observed for many genes that likely enhance bacterial survival, including those encoding superantigens and host-evasion proteins regulated by a multiple gene activator called Mga. GAS also coordinately expressed genes involved in proteolysis, transport, and catabolism of oligopeptides to obtain amino acids in this protein-rich host environment. Comparison of the transcriptome of the wild-type strain to that of an isogenic deletion mutant (DeltacovR) mutated in the two-component regulatory system designated CovR-CovS reinforced the hypothesis that CovR-CovS has an important role linking key biosynthetic, catabolic, and virulence functions during transcriptome restructuring. Taken together, the data provide crucial insights into strategies used by pathogenic bacte-ria for thwarting host defenses and surviving in human blood. C1 Baylor Coll Med, Dept Pathol, Ctr Human Bacterial Pathogenesis, Houston, TX 77030 USA. NIAID, Rocky Mt Lab, Lab Human Bacterial Pathogenesis, Hamilton, MT 59840 USA. Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. RP Musser, JM (reprint author), Baylor Coll Med, Dept Pathol, Ctr Human Bacterial Pathogenesis, 1 Baylor Pl, Houston, TX 77030 USA. EM musser@bcm.tmc.edu FU NIAID NIH HHS [U01 AI060595, U01 AI 60595]; NIEHS NIH HHS [T32 ES 07018, T32 ES007018] NR 58 TC 91 Z9 93 U1 0 U2 4 PU AMER SOC INVESTIGATIVE PATHOLOGY, INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3993 USA SN 0002-9440 J9 AM J PATHOL JI Am. J. Pathol. PD FEB PY 2005 VL 166 IS 2 BP 455 EP 465 DI 10.1016/S0002-9440(10)62268-7 PG 11 WC Pathology SC Pathology GA 893TU UT WOS:000226743000012 PM 15681829 ER PT J AU Manini, TM Cook, SB Ordway, NR Ploutz-Snyder, RJ Ploutz-Snyder, LL AF Manini, TM Cook, SB Ordway, NR Ploutz-Snyder, RJ Ploutz-Snyder, LL TI Knee extensor isometric unsteadiness does not predict functional limitation in older adults SO AMERICAN JOURNAL OF PHYSICAL MEDICINE & REHABILITATION LA English DT Article DE steadiness; elderly; aging; function; muscle strength ID OUTPUT VARIABILITY; STAIR DESCENT; FORCE CONTROL; MOTOR OUTPUT; CHAIR-RISE; STRENGTH; CONTRACTIONS; MUSCLE; GAIT; AGE AB Objective: To determine how knee extensor steadiness is related to age and difficulty performing everyday tasks. Design: In this cross-sectional study performed at a research laboratory, 50 older adults (age range, (56-95 yrs) performed steadiness testing at 50% of maximum strength and were timed and rated on four tasks of daily living: chair rise, stair ascent and descent, and walk. The independent variables of age, steadiness, and strength-to-weight ratio were entered into regression models with the ratings and time to complete the four everyday tasks as dependent variables. Results: The strength-to-weight ratio was the only significant predictor in the multiple regression models, explaining 29%, 33%, 14%, and 14% of the variance in gait speed and time to complete a chair rise, stair ascent, and stair descent, respectively. Similar results were seen with task ratings. Age was not correlated with steadiness (r = 0.25, P = 0.07). Conclusion: This study suggests that knee extensor isometric steadiness performance does not carry over to tasks of everyday living, and older subjects, regardless of age, have similar steadiness values. Because the strength-to-weight ratio predicted the most variance in functional performance, it is recommended that muscle strength be improved to increase function in older adults. C1 Syracuse Univ, Dept Exercise Sci, Syracuse, NY USA. Upstate Med Univ, Ctr Outcomes Res & Evaluat, Syracuse, NY USA. Upstate Med Univ, Dept Phys Med & Rehabil, Syracuse, NY USA. RP Manini, TM (reprint author), NIA, Lab Epidemiol Demog & Biometry, Gateway Bldg,Suite 3C-309,7201 Wisconsin Ave,MSC, Bethesda, MD 20892 USA. NR 44 TC 9 Z9 11 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0894-9115 J9 AM J PHYS MED REHAB JI Am. J. Phys. Med. Rehabil. PD FEB PY 2005 VL 84 IS 2 BP 112 EP 121 DI 10.1097/01.PHM.0000151940.47912.DF PG 10 WC Rehabilitation; Sport Sciences SC Rehabilitation; Sport Sciences GA 889RX UT WOS:000226461200006 PM 15668559 ER PT J AU Shearer, J Fueger, PT Rottman, JN Bracy, DP Binas, B Wasserman, DH AF Shearer, J Fueger, PT Rottman, JN Bracy, DP Binas, B Wasserman, DH TI Heart-type fatty acid-binding protein reciprocally regulates glucose and fatty acid utilization during exercise SO AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM LA English DT Article DE skeletal muscle; metabolism; substrate balance; 2-deoxyglucose; 15-(p-iodophenyl)-3-R,S-methylpentadecanoic acid ID SKELETAL-MUSCLE; MICE; INSULIN; TRANSPORT; FABP; GENE; METABOLISM; MUTATION; RATS; DIET AB The role of heart-type cytosolic fatty acid-binding protein (H-FABP) in mediating whole body and muscle-specific long-chain fatty acid (LCFA) and glucose utilization was examined using exercise as a phenotyping tool. Catheters were chronically implanted in a carotid artery and jugular vein of wild-type (WT, n = 8), heterozygous (H-FABP(+/-), n = 8), and null (H-FABP(-/-), n = 7) chow-fed C57BL/6J mice, and mice were allowed to recover for 7 days. After a 5-h fast, conscious, unrestrained mice were studied during 30 min of treadmill exercise (0.6 mph). A bolus of [I-125]-15( p-iodophenyl)-3-R, S- methylpentadecanoic acid and 2-deoxy[ H-3] glucose was administered to obtain rates of whole body metabolic clearance (MCR) and indexes of muscle LCFA (R-f) and glucose (R-g) utilization. Fasting, nonesterified fatty acids (mM) were elevated in H- FABP(-/-) mice (2.2 +/- 0.9 vs. 1.3 +/- 0.1 and 1.3 +/- 0.2 for WT and H- FABP(+/-)). During exercise, blood glucose (mM) increased in WT (11.7 +/- 0.8) and H-FABP(+/-) (12.6 +/- 0.9) mice, whereas H- FABP(-/-) mice developed overt hypoglycemia (4.8 +/- 0.8). Examination of tissue- specific and whole body glucose and LCFA utilization demonstrated a dependency on H- FABP with exercise in all tissues examined. Reductions in H- FABP led to decreasing exercise-stimulated R-f and increasing R-g with the most pronounced effects in heart and soleus muscle. Similar results were seen for MCR with decreasing LCFA and increasing glucose clearance with declining levels of H- FABP. These results show that, in vivo, H- FABP has reciprocal effects on glucose and LCFA utilization and whole body fuel homeostasis when metabolic demands are elevated by exercise. C1 Vanderbilt Univ, Dept Mol Physiol & Biophys, Nashville, TN 37232 USA. Vanderbilt Univ, Dept Cardiol, Nashville, TN 37232 USA. Vanderbilt Univ, Mouse Metab Phenotyping Ctr, Nashville, TN 37232 USA. Texas A&M Univ, Coll Vet Med, Dept Pathobiol, College Stn, TX 77843 USA. RP Wasserman, DH (reprint author), Vanderbilt Univ, Dept Mol Physiol & Biophys, 823 Light Hall, Nashville, TN 37232 USA. EM david.wasserman@vanderbilt.edu FU NIDDK NIH HHS [DK 54902, U24 DK 59637] NR 23 TC 17 Z9 17 U1 1 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1849 J9 AM J PHYSIOL-ENDOC M JI Am. J. Physiol.-Endocrinol. Metab. PD FEB PY 2005 VL 288 IS 2 BP E292 EP E297 DI 10.1152/ajpendo.00287.2004 PG 6 WC Endocrinology & Metabolism; Physiology SC Endocrinology & Metabolism; Physiology GA 888LH UT WOS:000226375100002 PM 15454399 ER PT J AU Skavdahl, M Steenbergen, C Clark, J Myers, P Demianenko, T Mao, L Rockman, HA Korach, KS Murphy, E AF Skavdahl, M Steenbergen, C Clark, J Myers, P Demianenko, T Mao, L Rockman, HA Korach, KS Murphy, E TI Estrogen receptor-beta mediates male-female differences in the development of pressure overload hypertrophy SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE lipoprotein lipase; heart ID LEFT-VENTRICULAR MASS; LIPOPROTEIN-LIPASE; HEART-FAILURE; CARDIOVASCULAR-SYSTEM; CARDIAC-HYPERTROPHY; GENDER-DIFFERENCES; GENE-EXPRESSION; RISK-FACTORS; MOUSE MODEL; ER-ALPHA AB The goal of this study was to determine the role of estrogen receptor subtypes in the development of pressure overload hypertrophy in mice. Epidemiological studies have suggested gender differences in the development of hypertrophy and heart disease, but the mechanism and the role of estrogen receptor subtypes are not established. We performed transverse aortic constriction (TAC) and sham operations in male and female wild-type (WT) mice and mice lacking functional estrogen receptor-alpha [alpha-estrogen receptor knockout (alpha-ERKO)] and mice lacking estrogen receptor-beta (beta-ERKO). Body, heart, and lung weights were measured 2 wk postsurgery. WT male mice subjected to TAC showed a 64% increase in the heart weight-to-body weight ratio (HW/BW) compared with sham, and WT males have increased lung weight at 2 wk. WT female mice subjected to TAC showed a 31% increase in HW/BW compared with sham, which was significantly less than their male counterparts and with no evidence of heart failure. alpha-ERKO females developed HW/BW nearly identical to that seen in WT littermate females in response to TAC, indicating that estrogen receptor-alpha is not essential for the attenuation of hypertrophy observed in WT females. In contrast, beta-ERKO females responded to TAC with a significantly greater increase in HW/BW than WT littermate females. beta-ERKO females have lower expression of lipoprotein lipase at baseline than WT or alpha-ERKO females. These data suggest an important role for estrogen receptor-beta in attenuating the hypertrophic response to pressure overload in females. C1 NIEHS, Lab Signal Transduct, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Comparat Med, Res Triangle Pk, NC 27709 USA. NIEHS, Reprod & Dev Toxicol Lab, Res Triangle Pk, NC 27709 USA. Duke Univ, Sch Med, Dept Pathol, Durham, NC 27706 USA. Duke Univ, Sch Med, Dept Med, Durham, NC 27706 USA. RP Murphy, E (reprint author), NIEHS, Lab Signal Transduct, MD-D2-03,POB 12233, Res Triangle Pk, NC 27709 USA. OI Korach, Kenneth/0000-0002-7765-418X FU NHLBI NIH HHS [HL-56687, R01 HL039752, R01-HL-39752] NR 34 TC 93 Z9 94 U1 1 U2 4 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6135 J9 AM J PHYSIOL-HEART C JI Am. J. Physiol.-Heart Circul. Physiol. PD FEB PY 2005 VL 288 IS 2 BP H469 EP H476 DI 10.1152/ajpheart.00723.2004 PG 8 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 888FE UT WOS:000226358800003 PM 15374829 ER PT J AU Bilukha, O Hahn, RA Crosby, A Fullilove, MT Liberman, A Moscicki, E Snyder, S Tuma, F Corso, P Schofield, A Briss, PA AF Bilukha, O Hahn, RA Crosby, A Fullilove, MT Liberman, A Moscicki, E Snyder, S Tuma, F Corso, P Schofield, A Briss, PA CA Task Force on Community Preventive TI The effectiveness of early childhood home visitation in preventing violence - A systematic review SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review ID RANDOMIZED CONTROLLED-TRIAL; HEALTHY START PROGRAM; BIRTH-WEIGHT INFANTS; 15-YEAR FOLLOW-UP; ABUSE PREVENTION; ANTISOCIAL-BEHAVIOR; AT-RISK; SERVICES; OUTCOMES; NEGLECT C1 CDCP, Community Guide Branch, Epidemiol Program Off, Atlanta, GA 30333 USA. CDCP, Natl Ctr Injury Prevention, Atlanta, GA 30333 USA. Columbia Univ, Dept Psychiat & Publ Hlth, New York, NY USA. Natl Inst Justice, Washington, DC USA. NIMH, Bethesda, MD 20892 USA. RP Hahn, RA (reprint author), CDCP, Community Guide Branch, Epidemiol Program Off, 1600 Clifton Rd,MS E-90, Atlanta, GA 30333 USA. EM RHahn@cdc.gov NR 75 TC 72 Z9 77 U1 2 U2 13 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD FEB PY 2005 VL 28 IS 2 SU 1 BP 11 EP 39 DI 10.1016/j.amepre.2004.10.004 PG 29 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 898DY UT WOS:000227057600004 PM 15698746 ER PT J AU Hahn, RA Bilukha, O Crosby, A Fullilove, MT Liberman, A Moscicki, E Snyder, S Tuma, F Briss, PA AF Hahn, RA Bilukha, O Crosby, A Fullilove, MT Liberman, A Moscicki, E Snyder, S Tuma, F Briss, PA CA Task Force on Community Preventive TI Firearms laws and the reduction of violence - A systematic review SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review ID COMMUNITY-PREVENTIVE-SERVICES; CARRY CONCEALED HANDGUNS; DISTRICT-OF-COLUMBIA; GUN-CONTROL LAWS; UNITED-STATES; SUICIDE RATES; HOMICIDE; CRIME; IMPACT; CANADA C1 CDCP, Community Guide Branch, Epidemiol Program Off, Violence Prevent Rev, Atlanta, GA 30333 USA. CDCP, Natl Ctr Injury Prevent & Control, Atlanta, GA 30333 USA. Columbia Univ, Dept Psychiat & Publ Hlth, New York, NY USA. Natl Inst Justice, Washington, DC USA. NIMH, Bethesda, MD 20892 USA. RP Hahn, RA (reprint author), CDCP, Community Guide Branch, Epidemiol Program Off, Violence Prevent Rev, 1600 Clifton Rd,MS E-90, Atlanta, GA 30333 USA. EM RHahn@cdc.gov NR 120 TC 52 Z9 54 U1 2 U2 52 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD FEB PY 2005 VL 28 IS 2 SU 1 BP 40 EP 71 DI 10.1016/j.amepre.2004.10.005 PG 32 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 898DY UT WOS:000227057600005 PM 15698747 ER PT J AU Hahn, RA Bilukha, O Lowy, J Crosby, A Fullilove, MT Liberman, A Moscicki, E Snyder, S Tuma, F Corso, P Schofield, A AF Hahn, RA Bilukha, O Lowy, J Crosby, A Fullilove, MT Liberman, A Moscicki, E Snyder, S Tuma, F Corso, P Schofield, A CA Task Force on Community Preventive TI The effectiveness of therapeutic foster care for the prevention of violence - A systematic review SO AMERICAN JOURNAL OF PREVENTIVE MEDICINE LA English DT Review ID SERVICES; OFFENDERS; CHILDREN; ADOLESCENTS; BEHAVIOR C1 CDCP, Community Guide Branch, Epidemiol Program Off, Atlanta, GA 30333 USA. CDCP, Natl Ctr Injury Prevent & Control, Atlanta, GA 30333 USA. Columbia Univ, Natl Ctr Hlth Marketing, Div Sci Commun, New York, NY USA. Natl Inst Justice, Washington, DC USA. NIMH, Bethesda, MD 20892 USA. RP Hahn, RA (reprint author), CDCP, Community Guide Branch, Epidemiol Program Off, 1600 Clifton Rd,MS E-90, Atlanta, GA 30333 USA. EM Rhahn@cdc.gov NR 50 TC 18 Z9 18 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0749-3797 J9 AM J PREV MED JI Am. J. Prev. Med. PD FEB PY 2005 VL 28 IS 2 SU 1 BP 72 EP 90 DI 10.1016/j.ampre.2004.10.007 PG 19 WC Public, Environmental & Occupational Health; Medicine, General & Internal SC Public, Environmental & Occupational Health; General & Internal Medicine GA 898DY UT WOS:000227057600006 PM 15698748 ER PT J AU Pine, DS Mogg, K Bradley, BP Montgomery, L Monk, CS McClure, E Guyer, AE Ernst, M Charney, DS Kaufman, J AF Pine, DS Mogg, K Bradley, BP Montgomery, L Monk, CS McClure, E Guyer, AE Ernst, M Charney, DS Kaufman, J TI Attention bias to threat in maltreated children: Implications for vulnerability to stress-related psychopathology SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID GENERALIZED ANXIETY DISORDER; SELECTIVE ATTENTION; DEPRESSIVE-DISORDERS; FACIAL EXPRESSIONS; EARLY EXPERIENCE; EMOTIONAL FACES; ADOLESCENTS; STIMULI; TASK; RECOGNITION AB Objective: Previous research in adults implicates attention bias in posttraumatic stress disorder ( PTSD). To study attention bias in children, the authors used picture-based versions of the visual-probe attention bias task previously used with adults. They tested the hypothesis that attention bias to threatening facial photographs is associated with maltreatment and PTSD. Method: A visual-probe task that manipulated threat levels was used to test 34 children who had been maltreated and 21 children who had not been maltreated. The visual-probe task involved showing photographs of actors with faces depicting neutral, angry/threatening, or happy expressions for 500 msec each. Results: Attention bias away from threat was associated with severity of physical abuse and diagnosis of PTSD. This association reflected the tendency for high levels of abuse or PTSD to predict attention avoidance of threatening faces. Conclusions: Previous studies examined the engagement of specific brain regions associated with attention orientation to angry/threatening faces. The current study used similar methods to document associations between attention bias and maltreatment in children. This sets the stage for studies examining relationships in children among perturbed brain function, psychopathology, attention bias, and maltreatment. C1 NIMH, Sect Dev & Affect Neurosci, Bethesda, MD 20817 USA. NIMH, Sect Expt Therapeut, Intramural Res Program, Bethesda, MD 20817 USA. Yale Univ, Sch Med, Dept Psychiat, Child & Adolescent Res & Educ Program, New Haven, CT USA. Vet Adm, Natl Ctr Posttraumat Stress Disorders, West Haven, CT USA. Univ Southampton, Sch Psychol, Southampton SO9 5NH, Hants, England. RP Pine, DS (reprint author), NIMH, Sect Dev & Affect Neurosci, Bldg 15-K,Rm 110,MSC-2670, Bethesda, MD 20817 USA. EM daniel.pine@nih.gov RI Mogg, Karin/C-1181-2008; Bradley, Brendan/B-9724-2008; Monk, Christopher/J-1805-2014; OI Mogg, Karin/0000-0002-2738-7378; Bradley, Brendan/0000-0003-2801-4271 NR 40 TC 154 Z9 159 U1 6 U2 27 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD FEB PY 2005 VL 162 IS 2 BP 291 EP 296 DI 10.1176/appi.ajp.162.2.291 PG 6 WC Psychiatry SC Psychiatry GA 900JI UT WOS:000227210800014 PM 15677593 ER PT J AU Bonne, O Bain, E Neumeister, A Nugent, AC Vythilingam, M Carson, RE Luckenbaugh, DA Eckelman, W Herscovitch, P Drevets, WC Charney, DS AF Bonne, O Bain, E Neumeister, A Nugent, AC Vythilingam, M Carson, RE Luckenbaugh, DA Eckelman, W Herscovitch, P Drevets, WC Charney, DS TI No change in serotonin type 1A receptor binding in patients with posttraumatic stress disorder SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article; Proceedings Paper CT 42nd Meeting of the American-College-of-Neuropsychopharmacology CY DEC 07-11, 2003 CL San Juan, PR SP Amer Coll Neuropsychopharmacol ID POSITRON-EMISSION-TOMOGRAPHY; ANXIETY; DEPRESSION; STATES AB Objective: Serotonin type 1A receptors (5HT1ARs) have been shown to be affected by stress in experimental animals and related to anxiety and depression in humans. In the present study, the authors sought an association between 5HT1AR binding and posttraumatic stress disorder ( PTSD). Method: Using positron emission tomography and the radioligand [F-18] FCWAY, the authors compared 5HT1AR binding between patients with PTSD and healthy subjects. Results: No significant differences in 5HT1AR distribution volume, binding potential, or tracer delivery were found. Conclusions: 5HT1AR expression may not be altered in patients with PTSD. C1 NIMH, Sect Neuroimanging Mood & Anxiety Disorders, Mood & Anxiety Disorders Program, Bethesda, MD USA. NIMH, Sect Expt Therapeut, Mood & Anxiety Disorders Program, Bethesda, MD USA. NIH, PET Imaging Ctr, Bethesda, MD 20892 USA. RP Bonne, O (reprint author), NIMH, NIH, Mood & Anxiety Disorders Program, North Dr,Bldg 15K,Room 200, Bethesda, MD 20892 USA. EM bonneo@intra.nimh.nih.gov RI Carson, Richard/H-3250-2011; OI Carson, Richard/0000-0002-9338-7966; Nugent, Allison/0000-0003-2569-2480 NR 12 TC 44 Z9 52 U1 0 U2 0 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD FEB PY 2005 VL 162 IS 2 BP 383 EP 385 DI 10.1176/appi.ajp.162.2.383 PG 3 WC Psychiatry SC Psychiatry GA 900JI UT WOS:000227210800027 PM 15677606 ER PT J AU Avila, NA Dwyer, AJ Murphy-Johnson, DV Brooks, P Moss, J AF Avila, NA Dwyer, AJ Murphy-Johnson, DV Brooks, P Moss, J TI Sonography of lymphangioleiomyoma in lymphangioleiomyomatosis: Demonstration of diurnal variation in lesion size SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article AB OBJECTIVE. Our aims were to define the sonographic features of abdominal and pelvic lymphangioleiomyomas in lymphangioleiomyomatosis (LAM) and to evaluate the utility of sonography in visualizing diurnal change in the size of the masses. MATERIALS AND METHODS. Forty-four patients with LAM and abdominal and pelvic lymphangioleiomyomas found on screening CT underwent sonography. Twenty-two patients had two studies on the same day, one in the morning and the other late in the aftemoon. RESULTS. Forty-nine masses were scanned in the 44 patients. The anatomic distribution of the masses was the following: retroperitoneal (29/44 patients, 66%), pelvic (10/44, 23%), and both retroperitoneal and pelvic (5/44, 11%). Of the 49 masses, 12 (24%) were cystic, 16 (33%) were solid, and 21 (43%) were complex. Twenty-two patients underwent sonography in the morning and afternoon. The masses increased in size between the two studies in all 21 patients in whom the masses were visualized in both studies. In three of 21 patients, the echotexture of the masses changed between the morning and afternoon studies: In two the echotexture changed from solid to complex, and in the other, it changed from hyperechoic to isoechoic relative to the liver. CONCLUSION. The sonographic characteristics of lymphangioleiomyomas are similar to some neoplasms such as lymphoma and ovarian cancer (a similarity that sometimes prompts biopsy). After a mass is shown in a patient with LAM, repeat sonography in the morning and afternoon is useful to depict diurnal variation in size and echotexture and to confirm the diagnosis of lymphangioleiomyoma and avoid biopsy. C1 NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, Bethesda, MD 20892 USA. NHLBI, NIH, Pulmonary Crit Care Med Branch, Bethesda, MD 20892 USA. RP Avila, NA (reprint author), NIH, Warren Grant Magnuson Clin Ctr, Dept Diagnost Radiol, 10 Ctr Dr,MSC 1182,Bldg 10,Rm 1C-658, Bethesda, MD 20892 USA. NR 6 TC 14 Z9 16 U1 0 U2 0 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD FEB PY 2005 VL 184 IS 2 BP 459 EP 464 PG 6 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 895MV UT WOS:000226868300020 PM 15671364 ER PT J AU Andersen, EM Cruz-Saldarriaga, M Llanos-Cuentas, A Luz-Cjuno, M Echevarria, J Miranda-Verastegui, C Colina, O Berman, JD AF Andersen, EM Cruz-Saldarriaga, M Llanos-Cuentas, A Luz-Cjuno, M Echevarria, J Miranda-Verastegui, C Colina, O Berman, JD TI Comparison of meglumine antimoniate and pentamidine for Peruvian cutaneous leishmaniasis SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID SODIUM STIBOGLUCONATE; AGENTS AB Pentamidine was compared with meglumine antimoniate (Glucantime) for 80 patients with cutaneous leishmaniasis due to LEishmania braziliensis in Peru. Of the 40 patients administered Glucantime (20 mg of antimony [Sb]/kg,/day intravenously for 20 days), 31 cured (78%), 6 failed (15%), of which 5 were due to relapse, and 3 were lost to follow-up (7%). Of the 40 patients administered pentamidine (2 mg/kg every other day for seven injections), 14 were cured (35%), 23 failed (58%), and 3 were lost to follow-up (7%). Five pentamidine failures were due to relapse, and 14 failures were due to the presence of parasites two weeks after therapy. Both regimens were well tolerated. Gastrointestinal. musculoskeletal, and total adverse events were not statistically different in either group. Elevations in levels of liver enzymes and pancreatic enzymes were statistically higher in the Glucantime group, but no patient terminated therapy prematurely. In this study, Glucantime was more effective than pentamidine for treatment of L. braziliensis cutaneous leishmaniasis in Peru based on parasitologic as well as clinical criteria. C1 USN, Environm & Prevent Med Unit 5, Naval Stn, San Diego, CA 92136 USA. Hosp Inst Peruano Seguro Social, Cuzco, Peru. Univ Peruana Cayetano Heredia, Lima, Peru. NIH, Natl Ctr Complementary & Alternat Med, Bethesda, MD 20892 USA. RP Andersen, EM (reprint author), USN, Environm & Prevent Med Unit 5, Naval Stn, 3235 Albacore Alley, San Diego, CA 92136 USA. EM eandersen@nepmu5.med.navy.mil NR 13 TC 54 Z9 58 U1 0 U2 2 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD FEB PY 2005 VL 72 IS 2 BP 133 EP 137 PG 5 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 903CE UT WOS:000227402200005 PM 15741547 ER PT J AU Harrington, LC Scott, TW Lerdthusnee, K Coleman, RC Costero, A Clark, GG Jones, JJ Kitthawee, S Kittayapong, P Sithiprasasna, R Edman, JD AF Harrington, LC Scott, TW Lerdthusnee, K Coleman, RC Costero, A Clark, GG Jones, JJ Kitthawee, S Kittayapong, P Sithiprasasna, R Edman, JD TI Dispersal of the dengue vector Aedes aegypti within and between rural communities SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID MARK-RELEASE-RECAPTURE; PUERTO-RICO; DIPTERA-CULICIDAE; STICKY OVITRAPS; POPULATION-SIZE; VILLAGE; MOVEMENT; SURVIVAL; THAILAND; BLOOD AB Knowledge of mosquito dispersal is critical for vector-borne disease control and prevention strategies and for understanding population structure and pathogen dissemination. We determined Aedes aegypti flight range and dispersal patterns from 21 mark-release-recapture experiments conducted over 11 years (1991-2002) in Puerto Rico and Thailand. Dispersal was compared by release location, sex, age, season, and village. For all experiments, the majority of mosquitoes were collected from their release house or adjacent house. Inter-village movement was detected rarely, with a few mosquitoes moving a maximum of 512 meters from one Thai village to the next. Average dispersal distances were similar for males and females and females released indoors versus outdoors. The movement of Ae. aegypti was not influenced by season or age, but differed by village. Results demonstrate that adult Ae. aegypti disperse relatively short distances. suggesting that people rather than mosquitoes are the primary mode of dengue virus dissemination within and among communities. C1 Cornell Univ, Dept Entomol, Ithaca, NY 14850 USA. Univ Calif Davis, Dept Entomol, Davis, CA USA. Armed Forces Res Inst Med Sci, Dept Entomol, Bangkok, Thailand. NIAID, Entomol Sect, Parasit Dis Lab, NIH, Bethesda, MD USA. Ctr Dis Control & Prevent, Dengue Branch, San Juan, PR USA. Mahidol Univ, Fac Sci, Dept Biol, Bangkok, Thailand. Mahidol Univ, Ctr Vectors & Vector Borne Dis, Bangkok, Thailand. RP Harrington, LC (reprint author), Cornell Univ, Dept Entomol, Ithaca, NY 14850 USA. EM lch27@cornell.edu; twscott@ucdqavis.edu; Colemanre@amedd.army.mil; acostero@niaid.hih.gov; ggc1@cdc.gov; james.jones@afrims.org; grskt@mucc.mahidol.ac.th; grpkt@mucc.mahidol.ac.th; ratanas@afrims.org; jdedman@ucdavis.edu FU NIAID NIH HHS [AI-22119] NR 36 TC 241 Z9 246 U1 3 U2 37 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD FEB PY 2005 VL 72 IS 2 BP 209 EP 220 PG 12 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 903CE UT WOS:000227402200017 PM 15741559 ER PT J AU Sturup, S Hayes, RB Peters, U AF Sturup, S Hayes, RB Peters, U TI Development and application of a simple routine method for the determination of selenium in serum by octopole reaction system ICPMS SO ANALYTICAL AND BIOANALYTICAL CHEMISTRY LA English DT Article DE ICPMS; selenium; serum; octopole reaction system; signal-to-noise optimization; interferences ID PLASMA-MASS-SPECTROMETRY; HEXAPOLE COLLISION CELL; CANCER SCREENING TRIAL; BIOLOGICAL-MATERIALS; TOENAIL SELENIUM; MS; PROSTATE; PREVENTION; ELEMENTS; RISK AB The aim of the study was to develop an inductively coupled plasma mass spectrometry (ICPMS) method for robust and simple routine determination of selenium in serum. Polyatomic interferences on Se-76, Se-77, and Se-78 were removed by applying an octopole reaction system ICPMS with the reaction cell pressurized with H-2 gas. We developed a novel simple optimization routine for the H-2 gas flow based on a signal-to-noise ratio (SNR) calculation of the selenium signal measured in a single selenium standard. The optimum H-2 flow was 2.9 mL min(-1). The selenium content in serum was determined after a 50-fold dilution with 0.16 M HNO3 and quantified by using addition calibration and gallium as an internal standard. The method detection limit was 0.10 mu g L-1 for Se-76 and Se-78 and 0.13 mu g L-1 for Se-77. Human serum samples from a case-control study investigating if selenium was associated with risk of colorectal adenoma were analyzed. The average selenium concentration for the control group (n=768) was 137.1 mu g L-1 and the range was 73.4-305.5 mu g L-1. The within-batch repeatability (a batch is ten samples) estimated from 182 replicate analyses was 6.3% coefficient of variation (CV), whereas the between-batch repeatability was 7.4% CV estimated from 361 replicates between batches. The method accuracy was evaluated by analysis of a human serum certified reference material (Seronorm Serum level II, Sero A/S, Norway). There was a fairly good agreement between the measured average of 145 +/- 3 mu g L-1 (n=36) and the certified value of 136 +/- 9 mu g L-1. In addition the method was successfully applied for analysis of zinc serum concentrations without further optimization. For the Seronorm certified reference material a value of 911 +/- 75 mu g L-1 (n=31) for zinc was obtained, which corresponds well to the certified zinc value of 920 +/- 60 mu g L-1. C1 Dartmouth Coll, Dept Earth Sci, Dartmouth Trace Element Anal Core Facil, Hanover, NH 03755 USA. Dartmouth Coll, Dept Chem, Dartmouth Trace Element Anal Core Facil, Hanover, NH 03755 USA. NCI, Div Canc Epidemiol & Genet, NIH, Dept Health & Human Serv, Rockville, MD 20852 USA. RP Sturup, S (reprint author), Dartmouth Coll, Dept Earth Sci, Dartmouth Trace Element Anal Core Facil, 6105 Sherman Fairchild Hall, Hanover, NH 03755 USA. EM Stefan.sturup@dartmouth.edu OI Hayes, Richard/0000-0002-0918-661X NR 37 TC 22 Z9 22 U1 0 U2 7 PU SPRINGER HEIDELBERG PI HEIDELBERG PA TIERGARTENSTRASSE 17, D-69121 HEIDELBERG, GERMANY SN 1618-2642 J9 ANAL BIOANAL CHEM JI Anal. Bioanal. Chem. PD FEB PY 2005 VL 381 IS 3 BP 686 EP 694 DI 10.1007/s00216-004-2946-x PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 907EE UT WOS:000227697400022 PM 15702311 ER PT J AU Attri, AK Minton, AP AF Attri, AK Minton, AP TI New methods for measuring macromolecular interactions in solution via static light scattering: basic methodolog, and application to nonassociating and self-associating proteins SO ANALYTICAL BIOCHEMISTRY LA English DT Article ID SIZE-EXCLUSION CHROMATOGRAPHY; SEDIMENTATION EQUILIBRIUM; HEMOGLOBIN; DETECTORS AB A method for rapid detection and characterization of reversible associations of macromolecules in solution is presented. A programmable dual-syringe infusion pump is used to introduce a solution of time-varying composition into parallel flow cells for concurrent measurement of laser light scattering at multiple angles and ultraviolet-visible absorbance. An experiment lasting less than 15 min produces a large and information-rich set of data, consisting of several thousand values of the Rayleigh ratio as a function of solute concentration(s) and scattering angle. Using a novel treatment of the data, the entire data set may be equally rapidly analyzed in the context of models for self-association. Validation experiments conducted on previously characterized nonassociating and self-associating proteins yielded robust values for molecular weights in the range 10-330 kDa and equilibrium association constants for dimer formation in the range 2 x 10(3)-6 x 10(5) M-1. (C) 2004 Elsevier Inc. All rights reserved. C1 NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Minton, AP (reprint author), NIDDKD, Sect Phys Biochem, Lab Biochem & Genet, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NR 30 TC 50 Z9 50 U1 1 U2 17 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD FEB 1 PY 2005 VL 337 IS 1 BP 103 EP 110 DI 10.1016/j.ab.2004.09.045 PG 8 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 891ZH UT WOS:000226619000013 PM 15649382 ER PT J AU Poeppl, AG Murray, GJ Medin, JA AF Poeppl, AG Murray, GJ Medin, JA TI Enhanced filter paper enzyme assay for high-throughput population screening for Fabry disease SO ANALYTICAL BIOCHEMISTRY LA English DT Editorial Material ID REPLACEMENT THERAPY; GENE-THERAPY; VARIANT; MICE C1 Ontario Canc Inst, Div Expt Therapeut, Toronto, ON, Canada. Toronto Gen Res Inst, Div Expt Therapeut, Toronto, ON, Canada. Univ Toronto, Dept Med Biophys, Toronto, ON, Canada. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Medin, JA (reprint author), Ontario Canc Inst, Div Expt Therapeut, Toronto, ON, Canada. EM jmedin@uhnres.utoronto.ca NR 10 TC 5 Z9 5 U1 1 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0003-2697 J9 ANAL BIOCHEM JI Anal. Biochem. PD FEB 1 PY 2005 VL 337 IS 1 BP 161 EP 163 DI 10.1016/j.ab.2004.10.007 PG 3 WC Biochemical Research Methods; Biochemistry & Molecular Biology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 891ZH UT WOS:000226619000021 PM 15649390 ER PT J AU Guzman, NA Phillips, TM AF Guzman, NA Phillips, TM TI Immunoaffinity CE for proteomics studies SO ANALYTICAL CHEMISTRY LA English DT Article ID AFFINITY CAPILLARY-ELECTROPHORESIS; INDUCED FLUORESCENCE DETECTION; MASS-SPECTROMETRY; PROTEIN INTERACTIONS; CHROMATOGRAPHY; PRECONCENTRATION; RECOGNITION; BINDING; TOOL C1 NIH, UAIR, ORS, OD, Bethesda, MD 20892 USA. RP Guzman, NA (reprint author), Bioanalyt Drug Metab, JJPRDUS-B356,1000 Route 202,Box 300, Raritan, NJ 08869 USA. EM nguzman@prdus.jnj.com; phillipt@ors.od.nih.gov NR 44 TC 29 Z9 29 U1 0 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD FEB 1 PY 2005 VL 77 IS 3 BP 60A EP 67A DI 10.1021/ac053325c PG 8 WC Chemistry, Analytical SC Chemistry GA 893ZG UT WOS:000226759000007 ER PT J AU Moaddel, R Jozwiak, K Whittington, K Wainer, IW AF Moaddel, R Jozwiak, K Whittington, K Wainer, IW TI Conformational mobility of immobilized alpha 3 beta 2, alpha 3 beta 4, alpha 4 beta 2, and alpha 4 beta 4 nicotinic acetylcholine receptors SO ANALYTICAL CHEMISTRY LA English DT Article ID BINDING-SITES; STATIONARY-PHASE; NONCOMPETITIVE INHIBITORS; TORPEDO-CALIFORNICA; LIGAND-BINDING; HEK293 CELLS; SUBTYPES; FLUORESCENCE; PHARMACOLOGY; ANTAGONISTS AB Four affinity chromatography stationary phases have been developed based upon immobilized nicotinic acetylcholine receptor (nAChR) subtypes, the alpha3beta2, alpha3beta4, alpha4beta2, and alpha4beta4 nAChRs. The stationary phases were created using membranes from cell lines expressing the subtypes and an immobilized artificial membrane stationary phase. The immobilized nAChRs were characterized using frontal chromatography with the agonist epibatidine as the marker. The observed binding affinities for the agonists; epibatidine, nicotine, and cytisine were consistent with reported values, indicating that the nAChRs retained their ability to bind agonists. The noncompetitive inhibitors (NCIs) of the nAChR (R)- and (S)-mecamylamine, phencylcidine, dextromethoprphan, and levomethorphan were also chromatographed on the columns using nonlinear chromatography techniques. The studies were carried out before and after exposure of the columns to epibatidine. The NO retention times increased after exposure to epibtatidine as did the enantioselective separation of mecamylamine and methorphan. The results indicate that the immobilized nAChRs retained their ability to undergo agonist-induced conformational change from the resting to the desensitized states. The columns provide a unique ability to study the interactions of NCIs with both of these conformational. states. C1 NIA, Gerontol Res Ctr, NIH, Baltimore, MD 21224 USA. RP Wainer, IW (reprint author), NIA, Gerontol Res Ctr, NIH, 4940 Eastern Ave, Baltimore, MD 21224 USA. EM Wainerir@grc.nia.nih.gov NR 35 TC 34 Z9 36 U1 0 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD FEB 1 PY 2005 VL 77 IS 3 BP 895 EP 901 DI 10.1021/ac048826x PG 7 WC Chemistry, Analytical SC Chemistry GA 893ZG UT WOS:000226759000031 PM 15679359 ER PT J AU Kim, H Lizak, MJ Tansey, G Csaky, KG Robinson, MR Yuan, P Wang, NS Lutz, RJ AF Kim, H Lizak, MJ Tansey, G Csaky, KG Robinson, MR Yuan, P Wang, NS Lutz, RJ TI Study of ocular transport of drugs released from an intravitreal implant using magnetic resonance imaging SO ANNALS OF BIOMEDICAL ENGINEERING LA English DT Article DE T-1-weighted magnetic resonance imaging; PVA-based implant; Gd-DTPA; finite element eye model; ocular drug delivery ID CYTOMEGALOVIRUS RETINITIS; PHARMACOKINETIC MODEL; SUSTAINED-RELEASE; VITREOUS-HUMOR; RABBIT EYE; COMPUTER-SIMULATION; GANCICLOVIR IMPLANT; VITRO CORRELATION; CONTRAST AGENT; DELIVERY AB Ensuring optimum delivery of therapeutic agents in the eye requires detailed information about the transport mechanisms and elimination pathways available. This knowledge can guide the development of new drug delivery devices. In this study, we investigated the movement of a drug surrogate, Gd-DTPA( Magnevist((R))) released from a polymer-based implant in rabbit vitreous using T-1-weighted magnetic resonance imaging (MRI). Intensity values in the MRI data were converted to concentration by comparison with calibration samples. Concentration profiles approaching pseudosteady state showed gradients from the implant toward the retinal surface, suggesting that diffusion was occurring into the retinal-choroidal-scleral (RCS) membrane. Gd-DTPA concentration varied from high values near the implant to lower values distal to the implant. Such regional concentration differences throughout the vitreous may have clinical significance when attempting to treat ubiquitous eye diseases using a single positional implant. We developed a finite element mathematical model of the rabbit eye and compared the MRI experimental concentration data with simulation concentration profiles. The model utilized a diffusion coefficient of Gd-DTPA in the vitreous of 2.8 x 10(-6) cm(2) s(-1) and yielded a diffusion coefficient for Gd-DTPA through the simulated composite posterior membrane ( representing the retina-choroid sclera membrane) of 6.0 x 10(-8) cm(2) s(-1). Since the model membrane was 0.03-cm thick, this resulted in an effective membrane permeability of 2.0 x 10(-6) cm s(-1). Convective movement of Gd-DTPA was shown to have minimal effect on the concentration profiles since the Peclet number was 0.09 for this system. C1 NIH, Drug Delivery & Kinet Resource, Div Bioengn & Phys Sci ORS, Bethesda, MD 20892 USA. NINDS, NIH, Bethesda, MD 20892 USA. NEI, NIH, Bethesda, MD 20892 USA. NIH, Dept Pharm, Bethesda, MD 20892 USA. Univ Maryland, Dept Chem Engn, College Pk, MD 20742 USA. Univ Maryland, Bioengn Program, College Pk, MD 20742 USA. RP Lutz, RJ (reprint author), NIH, Drug Delivery & Kinet Resource, Div Bioengn & Phys Sci ORS, Bldg 13,Room N17,9000 Rockville Pike, Bethesda, MD 20892 USA. EM rjlutz@mail.nih.gov RI Wang, Nam Sun/E-4253-2016 NR 44 TC 44 Z9 45 U1 1 U2 10 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0090-6964 J9 ANN BIOMED ENG JI Ann. Biomed. Eng. PD FEB PY 2005 VL 33 IS 2 BP 150 EP 164 DI 10.1007/s10439-005-8974-7 PG 15 WC Engineering, Biomedical SC Engineering GA 899RO UT WOS:000227162700004 PM 15771269 ER PT J AU Macaluso, M Wang, XQ Brill, I Fleenor, M Robey, L Kelaghan, J Johnson, C AF Macaluso, M Wang, XQ Brill, I Fleenor, M Robey, L Kelaghan, J Johnson, C TI Participation and retention in a study of female condom use among women at high STD risk SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE epidemiologic methods; sociodemographic factors; high-risk behavior ID SEXUALLY-TRANSMITTED-DISEASE; INTERVENTION; CLINICS; PREVENTION; DESIGN AB PURPOSE: Differential participation and retention can bias the findings of a follow-up study. This problem was evaluated in a study of barrier contraception among women at high STD risk. The goal of this study was to identify predictors of participation and retention and determine whether they could influence study results. METHODS: Six-month follow-up study of women attending STD clinics. Determinants of participation and retention were evaluated using logistic and proportional hazards models. RESULTS: Agreement to participate was associated with young age, black race, low education and income, older age at first intercourse, the number of lifetime partners, and STD history. Early attrition was associated with young age, non-black race, higher income, lack of interest/commitment to using the female condom, high coital frequency, no STD history, not using a birth control method at baseline, and with inconsistent condom use, high coital frequency, and pregnancy during follow up. CONCLUSIONS: There was little evidence that differential participation influenced the validity of the study. Differential attrition may have biased behavioral measures of intervention effectiveness, but not necessarily measures of condom use effectiveness. (C) 2004 Elsevier Inc. All rights reserved. C1 Ctr Dis Control & Prevent, Natl Ctr Hlth Promot & Dis Prevent, Div Reprod Hlth, Atlanta, GA 30341 USA. Univ Alabama, Sch Publ Hlth, Dept Epidemiol, Birmingham, AL 35294 USA. Jefferson Cty Dept Hlth, Birmingham, AL USA. Madison Cty Hlth Dept, Huntsville, AL USA. NICHHD, Contracept & Reprod Hlth Branch, Bethesda, MD 20892 USA. RP Macaluso, M (reprint author), Ctr Dis Control & Prevent, Natl Ctr Hlth Promot & Dis Prevent, Div Reprod Hlth, 4770 Buford Highway,Mail Stop K-34, Atlanta, GA 30341 USA. EM mmacaluso@cdc.gov RI Macaluso, Maurizio/J-2076-2015 OI Macaluso, Maurizio/0000-0002-2977-9690 FU NICHD NIH HHS [N01-HD-1-3135]; ODCDC CDC HHS [U48/CCU409679-02] NR 13 TC 4 Z9 4 U1 1 U2 1 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 FEB PY 2005 VL 15 IS 2 BP 105 EP 111 DI 10.1016/j.annepidem.2004.05.005 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 894IR UT WOS:000226785100004 PM 15652715 ER PT J AU Rao, RS Sigurdson, AJ Doody, MM Graubard, BI AF Rao, RS Sigurdson, AJ Doody, MM Graubard, BI TI An application of a weighting method to adjust for nonresponse in standardized incidence ratio analysis of cohort studies SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE nonresponse; cohort; weighting ID RADIOLOGIC TECHNOLOGISTS; UNITED-STATES; MORTALITY; CANCER; HEALTH; TRENDS AB PURPOSE: Cohort studies often conduct periodic follow-up interviews (or waves) to determine disease incidence since the previous follow-up and to update measures of exposure and confounders. The common practice of excluding nonrespondents from standardized incidence ratio (SIR) analyses of these cohorts can bias the estimates of interest if nonrespondents and respondents differ on important characteristics related to outcomes of interest. We propose an analytic approach to reduce the impact of nonresponse in the analyses of SIRs. METHODS: Logistic regression models controlling baseline information are used to estimate the propensity, or the probability of response; the reciprocals of these propensities are used as weights in the analysis of risk. This is illustrated in the analysis of 15 years of follow-up of a cohort of US radiologic technologists after an initial interview to assess the risk at several cancer sites from occupational radiation exposure. We use information from the baseline survey and certification records to compute the propensity of responding to the second survey. SIRs are computed using Surveillance, Epidemiology, and End Results (SEER) cancer incidence rates. Variances of the SIRs are estimated by a jackknife method that accounts for additional variability resulting from estimation of the weights. RESULTS: We find that, in this application, weighting alters point estimates and confidence limits only to a small degree, thus providing reassurance that the results are robust to nonresponse. This indicates that results from the analyses excluding the missing data may be slightly biased and weighting helps in reducing the nonresponse bias. CONCLUSION: This method is flexible, practical, easy to use with existing software, and is applicable to missing data from cohorts with baseline information on all subjects. (C) 2004 Elsevier Inc. All rights reserved. C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, Bethesda, MD 20892 USA. NCI, Radiat Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, Bethesda, MD 20892 USA. RP Rao, RS (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,US Dept HHS, 6120 Execut Blvd,EpS 8047,MSC 7244, Bethesda, MD 20892 USA. EM raos@mail.nih.gov NR 33 TC 32 Z9 32 U1 0 U2 1 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 FEB PY 2005 VL 15 IS 2 BP 129 EP 136 DI 10.1016/j.annepidem.2004.05.007 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 894IR UT WOS:000226785100007 PM 15652718 ER PT J AU Chen, YX Kittles, R Zhou, J Chen, GJ Adeyemo, A Panguluri, RK Chen, WD Amoah, A Opoku, V Acheampong, J Agyenim-Boateng, K Eghan, BA Nyantaki, A Oli, J Okafor, G Ofoegbu, E Osotimehin, B Abbiyesuku, F Johnson, T Fasanmade, O Rufus, T Furbert-Harris, P Daniel, HI Berg, KA Collins, FS Dunston, GM Rotimi, CN AF Chen, YX Kittles, R Zhou, J Chen, GJ Adeyemo, A Panguluri, RK Chen, WD Amoah, A Opoku, V Acheampong, J Agyenim-Boateng, K Eghan, BA Nyantaki, A Oli, J Okafor, G Ofoegbu, E Osotimehin, B Abbiyesuku, F Johnson, T Fasanmade, O Rufus, T Furbert-Harris, P Daniel, HI Berg, KA Collins, FS Dunston, GM Rotimi, CN TI Calpain-10 gene polymorphisms and type 2 diabetes in West Africans: The Africa America Diabetes Mellitus (AADM) Study SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE calpain-10; SNP-43; insulin; type 2 diabetes; West Africa ID SUSCEPTIBILITY GENES; INDEPENDENT REPLICATION; GENOMEWIDE SEARCH; POPULATION; CAPN10; LOCUS; ASSOCIATION; VARIANTS; LOCATION; LINKAGE AB PURPOSE: To investigate whether the three single nucleotide polymorphisms (SNPs), SNP-43, -56, and -63 of CAPN10 were associated with type 2 diabetes in a West African cohort. METHODS: A total of 347 diabetic subjects and 148 unaffected controls from four ethnic groups in two West African countries were enrolled in this study. After genotyping three SNPs of CAPN10 and one SNP from CYP19, the allele, genotype, and haplotype frequencies as well as the odds ratios were calculated to test their association with type 2 diabetes. RESULTS: None of the alleles or genotypes was associated with type 2 diabetes. Although statistical analysis indicated that haplotype 221 was associated with type 2 diabetes (OR, 3.765; 95% CI, 1.577-8.989) in the two ethnic groups of Nigeria, the same haplotype did not show any association with type 2 diabetes in the two ethnic groups in Ghana (OR, 0.906; 95% CI, 0.322-2.552). CONCLUSION: Considering the relatively low frequency of haplotype 221 and that none of the haplotypes including 221 was associated with any of the diabetes-related quantitative traits tested, it is concluded that SNP-43,-56, and -63 of the CAPN10 gene variants may play a limited role in the risk of type 2 diabetes risks in this cohort of West Africans. (C) 2004 Elsevier Inc. All rights reserved. C1 Howard Univ, Coll Med, Natl Human Genome Ctr, Washington, DC 20059 USA. Univ Ghana, Sch Med, Dept Med, Accra, Ghana. Univ Sci & Technol Kumasi, Dept Med, Kumasi, Ghana. Univ Nigeria, Teaching Hosp, Dept Med, Enugu, Nigeria. Univ Coll Ibadan Hosp, Dept Chem Pathol, Ibadan, Nigeria. Univ Lagos, Coll Med, Endocrine & Metab Unit, Lagos, Nigeria. NHGRI, NIH, Bethesda, MD 20892 USA. RP Rotimi, CN (reprint author), Howard Univ, Coll Med, Natl Human Genome Ctr, 2216 6th St NW, Washington, DC 20059 USA. EM crotimi@howard.edu OI Adeyemo, Adebowale/0000-0002-3105-3231 NR 26 TC 18 Z9 20 U1 0 U2 4 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 FEB PY 2005 VL 15 IS 2 BP 153 EP 159 DI 10.1016/j.annepidem.2004.05.014 PG 7 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 894IR UT WOS:000226785100010 PM 15652721 ER PT J AU Kern, LM Powe, NR Levine, MA Fitzpatrick, AL Harris, TB Robbins, J Fried, LP AF Kern, LM Powe, NR Levine, MA Fitzpatrick, AL Harris, TB Robbins, J Fried, LP TI Association between screening for osteoporosis and the incidence of hip fracture SO ANNALS OF INTERNAL MEDICINE LA English DT Article; Proceedings Paper CT 25th Annual Meeting of the Society-of-General-Internal-Medicine CY MAY 01-05, 2002 CL ATLANTA, GA SP Soc Gen Internal Med ID SERVICES-TASK-FORCE; POSTMENOPAUSAL OSTEOPOROSIS; BONE-DENSITY; VITAMIN-D; NONVERTEBRAL FRACTURES; VERTEBRAL FRACTURES; OLDER ADULTS; RISK; WOMEN; ALENDRONATE AB Background: Because direct evidence for the effectiveness of screening is lacking, guidelines disagree on whether people should be screened for osteoporosis. Objective: To determine whether population-based screening for osteoporosis in older adults is associated with fewer incident hip fractures than usual medical care. Design: Nonconcurrent cohort study. Setting: Population-based cohort enrolled in the Cardiovascular Health Study (CHS) from 4 states (California, Pennsylvania, Maryland, and North Carolina). Patients: 3107 adults 65 years of age and older who attended their CHS study visits in 1994-1995. Measurements: 31 participant characteristics (including demographic characteristics, medical histories, medications, and physical examination findings) and incident hip fractures over 6 years of follow-up. Intervention: Bone density scans (dual-energy x-ray absorptiometry [DEXA] at the hip) for participants in California and Pennsylvania (n = 1422) and usual care for participants in Maryland and North Carolina (n = 1685). Results: The incidence of hip fractures per 1000 person-years was 4.8 in the screened group and 8.2 in the usual care group. Screening was associated with a statistically significant lower hazard of hip fracture than usual care after adjustment for sex and propensity to be screened (Cox proportional hazard ratio, 0.64 [95% CI, 0.41 to 0.99]). Limitations: The mechanism of the association was unclear. A small unmeasured confounder that decreased the hazard of hip fracture could diminish or erase the observed association. Conclusions: Use of hip DEXA scans to screen for osteoporosis in older adults was associated with 36% fewer incident hip fractures over 6 years compared with usual medical care. Further research is needed to explore the mechanism of this association. C1 Johns Hopkins Bloomberg Sch Publ Hlth, Sch Med, Robert Wood Johnson Clin Scholars Program, Baltimore, MD USA. Univ Washington, Seattle, WA 98195 USA. Univ Calif Davis, Sacramento, CA 95817 USA. NIA, Bethesda, MD 20892 USA. RP Kern, LM (reprint author), Cornell Univ, Weill Med Coll, Dept Publ Hlth, 411 E 69th St,Room KB-311, New York, NY 10021 USA. EM lmk2003@med.cornell.edu OI Levine, Michael/0000-0003-0036-7809 FU NHLBI NIH HHS [N01-HC-85081, 1-Y02-HC-40205, N01-HC-15103, N01-HC-35129, N01-HC-85079, N01-HC-85080, N01-HC-85082, N01-HC-85083, N01-HC-85084, N01-HC-85085, N01-HC-85086]; NIA NIH HHS [Y02-AG-4-0251]; NIDDK NIH HHS [K24DK02643] NR 42 TC 54 Z9 55 U1 0 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD FEB 1 PY 2005 VL 142 IS 3 BP 173 EP 181 PG 9 WC Medicine, General & Internal SC General & Internal Medicine GA 900UH UT WOS:000227239300003 PM 15684205 ER PT J AU Hoover, SE Fischer, SH Shaffer, R Steinberg, BM Lucey, DR AF Hoover, SE Fischer, SH Shaffer, R Steinberg, BM Lucey, DR TI Endocarditis due to a novel Cardiobacterium species SO ANNALS OF INTERNAL MEDICINE LA English DT Letter ID HOMINIS C1 NIH, Bethesda, MD 20892 USA. Washington Hosp Ctr, Washington, DC 20010 USA. RP Hoover, SE (reprint author), NIH, Bethesda, MD 20892 USA. RI Hoover, Susan/F-8580-2015 NR 4 TC 11 Z9 11 U1 0 U2 2 PU AMER COLL PHYSICIANS PI PHILADELPHIA PA INDEPENDENCE MALL WEST 6TH AND RACE ST, PHILADELPHIA, PA 19106-1572 USA SN 0003-4819 J9 ANN INTERN MED JI Ann. Intern. Med. PD FEB 1 PY 2005 VL 142 IS 3 BP 229 EP 230 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 900UH UT WOS:000227239300023 PM 15684222 ER PT J AU Elm, JJ Goetz, CG Ravina, B Shannon, K Wooten, GF Tanner, CM Palesch, YY Huang, P Guimaraes, P Kamp, C Tilley, BC Kieburtz, K AF Elm, JJ Goetz, CG Ravina, B Shannon, K Wooten, GF Tanner, CM Palesch, YY Huang, P Guimaraes, P Kamp, C Tilley, BC Kieburtz, K CA NET-PD Investigators TI A responsive outcome for Parkinson's disease neuroprotection futility studies SO ANNALS OF NEUROLOGY LA English DT Article ID CLINICAL-TRIALS; RATING-SCALE; PROGRESSION; LEVODOPA; DATATOP; SELEGILINE AB Futility studies are designed to test new treatments over a short period in a small number of subjects to determine if those treatments are worthy of larger and longer term studies, or if they should be abandoned. An appropriate outcome measure for a neuroprotection futility study in Parkinson's disease (sensitive to tracking disease progression in the short-term) has not been determined. Data sets from three clinical trials were used to compare Parkinsons disease outcome measures. Total Unified Parkinson's Disease Rating Scale (UPDRS; Mentation + Activities of Daily Living + Motor) change and Motor plus Activities of Daily Living UPDRS change, measured in untreated patients, required the smallest sample sizes of all the outcome measures explored. Other outcomes (UPDRS Motor, UPDRS Activities of Daily Living, and time to need levodopa) required somewhat larger sample sizes. Futility designs in Parkinsons disease are feasible in terms of short duration. and small sample size requirements, and this design is being applied in two ongoing 14 Parkinson's disease studies to select agents for future larger and longer term neuroprotection studies. C1 Med Univ S Carolina, Dept Biostat Bioinformat & Epidemiol, Charleston, SC 29425 USA. Rush Presbyterian St Lukes Med Ctr, Dept Neurol Sci, Chicago, IL 60612 USA. Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. Univ Virginia, Ctr Hlth Sci, Dept Neurol, Charlottesville, VA USA. Parkinsons Inst, Sunnyvale, CA USA. Univ Rochester, Clin Trials Coordinat Ctr, Dept Neurol, Rochester, NY USA. RP Elm, JJ (reprint author), Med Univ S Carolina, Dept Biostat Bioinformat & Epidemiol, 135 Cannon St,Suite 303, Charleston, SC 29425 USA. EM elm@musc.edu RI Guimaraes, Paulo/A-7085-2008 OI Guimaraes, Paulo/0000-0002-2992-1028 FU NINDS NIH HHS [U01NS43128, U01NS043127] NR 28 TC 50 Z9 50 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0364-5134 J9 ANN NEUROL JI Ann. Neurol. PD FEB PY 2005 VL 57 IS 2 BP 197 EP 203 DI 10.1002/ana.20361 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 892EW UT WOS:000226633800007 PM 15668964 ER PT J AU Alexander, HR Libutti, SK Pingpank, JF Bartlett, DL Helsabeck, C Beresneva, T AF Alexander, HR Libutti, SK Pingpank, JF Bartlett, DL Helsabeck, C Beresneva, T TI Isolated hepatic perfusion for the treatment of patients with colorectal cancer liver metastases after irinotecan-based therapy SO ANNALS OF SURGICAL ONCOLOGY LA English DT Article DE metastatic colorectal cancer; isolated hepatic perfusion; liver metastases; melphalan; hyperthermia ID TUMOR-NECROSIS-FACTOR; 1ST-LINE TREATMENT; ARTERIAL INFUSION; PHASE-I; FLUOROURACIL; OXALIPLATIN; LEUCOVORIN; MELPHALAN; FLOXURIDINE; TRIAL AB Background: Irinotecan given With 5-fluorouracil and leucovorin is currently used as firstline therapy for patients with metastatic colorectal cancer (CRC). However, the response duration is <1 year, and second-line systemic chemotherapy has limited efficacy. We analyzed the efficacy of isolated hepatic perfusion (IHP) for patients with progressive CRC liver metastases after irinotecan. Methods: Between March 1993 and February 2003, 124 patients with CRC liver rnetastascs underwent IHP on institutional review board-approved protocols. The overall treatment mortality was 4% (5 of 124). Twenty-five patients (10 women and 15 men, mean age, 53 years) were identified who had progressive liver metastases by carcinoembryonic antigen, imaging studies, or both after irinotecan. A 1-hour hyperthermic IHP (mean hepatic temperature, 40.0degreesC) with melphalan 1.5 mg/kg (mean total dose. 100 mg) was administered via laparotomy. Perfusion with an oxygenated extracorporeal circuit Was established with inflow via a cannula in the gastroduodenal artery and common hepatic artery inflow occlusion. Outflow was via a cannula in in isolated segment of the inferior vena cava. During IHP, portal and inferior vena caval flow were shunted to the axillary vein. Patients were assessed for radiographical response, recurrence pattern, and survival. Results: The mean number of prior irinotecan cycles in 25 patients was 6 (range, 2-14), and it was given primarily Lis second-line therapy. The median number of liver metastases before IHP was 10 (ranged 1-50), and the median percentage of hepatic replacement by tumor was 25%. The mean operative time was 9 hours (range, 6-12 hours), and the median hospital stay was I I days (range, 8-76 days). There was 1 complete response and there were 14 partial responses in 25 patients (60%), with a median duration of 12 months (range, 5-35 months). Disease progressed systemically in 13 of 25 patients at a median of 5 months (range, 3-16 months). The median overall survival was 12 months (range, 1-47 months), and the 2-year survival was 28%. Conclusions: For patients with progressive CRC liver metastases after irinotecan, IHP has good efficacy in terms of response rate and duration. Continued evaluation of IHP with melphalan as second-line therapy in this clinical setting is justified. C1 NCI, Surg Branch, Surg Metab Sect, Canc Res Ctr, Bethesda, MD 20892 USA. RP Alexander, HR (reprint author), NCI, Surg Branch, Surg Metab Sect, Canc Res Ctr, 10 Ctr Dr,Bldg 10,Room 4W-5940, Bethesda, MD 20892 USA. EM richard_alexander@nih.gov NR 20 TC 32 Z9 32 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2005 VL 12 IS 2 BP 138 EP 144 DI 10.1245/ASO.2005.05.003 PG 7 WC Oncology; Surgery SC Oncology; Surgery GA 898TJ UT WOS:000227098800011 PM 15827794 ER PT J AU Belluco, C Calvert, V Mammano, E Espina, VE Wulfkuhle, JD Nitti, D Lise, M Liotta, LA Petricoin, EF AF Belluco, C Calvert, V Mammano, E Espina, VE Wulfkuhle, JD Nitti, D Lise, M Liotta, LA Petricoin, EF TI Kinase substrate protein microarray analysis reveals a specific signaling pathway profile in colorectal cancer liver metastasis SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 58th Annual Cancer Symposium CY MAR 03-06, 2005 CL Atlanta, GA SP Soc Surg Oncol C1 Univ Padua, Dept Oncol & Surg Sci, Padua, Italy. US FDA, CBER, Bethesda, MD 20014 USA. NCI, CCR, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2005 VL 12 IS 2 SU S BP S78 EP S78 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 895FU UT WOS:000226847100226 ER PT J AU Cole, GW Alleva, AM Ziauddin, MF Zuo, J Schrump, DS Nguyen, DM AF Cole, GW Alleva, AM Ziauddin, MF Zuo, J Schrump, DS Nguyen, DM TI Suppression of prometastasis phenotype expression in malignant pleural mesothelioma cells by the selective PI3K inhibitor LV294002 or the MEK inhibitor UO126 SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 58th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 03-06, 2005 CL Atlanta, GA SP Soc Surg Oncol C1 NIH, Surg Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2005 VL 12 IS 2 SU S BP S100 EP S100 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 895FU UT WOS:000226847100296 ER PT J AU Cox, DD Pingpank, JF Schrump, DS Nguyen, D Bakke, S Alexander, HR Libutti, SK Fojo, T AF Cox, DD Pingpank, JF Schrump, DS Nguyen, D Bakke, S Alexander, HR Libutti, SK Fojo, T TI Role of surgical resection and combination chemotherapy for selected patients with metastatic adrenocortical carcinoma (ACC) SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 58th Annual Cancer Symposium CY MAR 03-06, 2005 CL Atlanta, GA SP Soc Surg Oncol C1 NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2005 VL 12 IS 2 SU S BP S26 EP S26 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 895FU UT WOS:000226847100059 ER PT J AU Farma, JM Puhlmann, M Weinreich, DM Alexander, HR AF Farma, JM Puhlmann, M Weinreich, DM Alexander, HR TI Direct evidence for rapid and selective induction of tumor neovascular permeability by tumor necrosis factor (TNF) using in vivo videornicroscopy (IVVM) SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 58th Annual Cancer Symposium CY MAR 03-06, 2005 CL Atlanta, GA SP Soc Surg Oncol C1 NCI, Surg Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2005 VL 12 IS 2 SU S BP S47 EP S47 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 895FU UT WOS:000226847100121 ER PT J AU Farma, JM Pingpank, JF Libutti, SK Chang, R Wood, BJ Neeman, Z Kam, A Seidel, G Beresneva, T Alexander, HR AF Farma, JM Pingpank, JF Libutti, SK Chang, R Wood, BJ Neeman, Z Kam, A Seidel, G Beresneva, T Alexander, HR TI Percutaneous hepatic perfusion (PHP) with melphalan for patients with metastatic melanoma (MM) to the liver SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 58th Annual Cancer Symposium CY MAR 03-06, 2005 CL Atlanta, GA SP Soc Surg Oncol C1 NCI, Surg Branch, Bethesda, MD 20892 USA. NIH, Ctr Clin, Dept Radiol, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2005 VL 12 IS 2 SU S BP S20 EP S20 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 895FU UT WOS:000226847100039 ER PT J AU Feldman, E Weinreich, DM Carroll, NM Burness, MB Feldman, AL Turner, E Xu, H Alexander, HR AF Feldman, E Weinreich, DM Carroll, NM Burness, MB Feldman, AL Turner, E Xu, H Alexander, HR TI Interferon-gamma-inducible protein 10 (IP-10) selectively inhibits proliferation and induces apoptosis in endothelial cells SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 58th Annual Cancer Symposium CY MAR 03-06, 2005 CL Atlanta, GA SP Soc Surg Oncol C1 NCI, Surg Branch, Bethesda, MD 20892 USA. RI Feldman, Andrew/D-5028-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2005 VL 12 IS 2 SU S BP S24 EP S24 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 895FU UT WOS:000226847100051 ER PT J AU Maker, AV Phan, GQ Attia, P Rosenberg, SA AF Maker, AV Phan, GQ Attia, P Rosenberg, SA TI Tumor regression and autoimmunity in metastatic melanoma patients treated with cytotoxic T lymphocyte associated antigen 4 blockade and interleukin-2 SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 58th Annual Cancer Symposium CY MAR 03-06, 2005 CL Atlanta, GA SP Soc Surg Oncol C1 NCI, NIH, Surg Branch, Bethesda, MD 20892 USA. NR 0 TC 16 Z9 16 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2005 VL 12 IS 2 SU S BP S18 EP S18 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 895FU UT WOS:000226847100034 ER PT J AU Reddy, RM Alleva, A Tsai, WS Maxhimer, JB Cole, GW Zuo, J Ziauddin, MF Schrump, DS Nguyen, DM AF Reddy, RM Alleva, A Tsai, WS Maxhimer, JB Cole, GW Zuo, J Ziauddin, MF Schrump, DS Nguyen, DM TI HDAC inhibitor trichostatin A(TSA) profoundly enhances APO2L/TRAIL mediated cytotoxicity in a mitochondria dependent manner in malignant pleural mesothelioma(MPM) SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 58th Annual Cancer Symposium CY MAR 03-06, 2005 CL Atlanta, GA SP Soc Surg Oncol C1 NCI, NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2005 VL 12 IS 2 SU S BP S25 EP S25 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 895FU UT WOS:000226847100056 ER PT J AU Ziauddin, MF Maxhimer, JB Baras, A Chua, A Reddy, RM Zuo, J Schrump, DS Nguyen, DM AF Ziauddin, MF Maxhimer, JB Baras, A Chua, A Reddy, RM Zuo, J Schrump, DS Nguyen, DM TI Potentiation of the cytotoxic effect of valproic acid, an antiepileptic drug with histone deacetylase inhibitory activity, on cultured thoracic cancer cells by UCN-01 SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 58th Annual Cancer Symposium CY MAR 03-06, 2005 CL Atlanta, GA SP Soc Surg Oncol C1 NIH, Surg Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2005 VL 12 IS 2 SU S BP S37 EP S37 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 895FU UT WOS:000226847100097 ER PT J AU Girschick, HJ Raab, P Surbaum, S Trusen, A Kirschner, S Schneider, P Papadopoulos, T Muller-Hermelink, HK Lipsky, PE AF Girschick, HJ Raab, P Surbaum, S Trusen, A Kirschner, S Schneider, P Papadopoulos, T Muller-Hermelink, HK Lipsky, PE TI Chronic non-bacterial osteomyelitis in children SO ANNALS OF THE RHEUMATIC DISEASES LA English DT Article ID RECURRENT MULTIFOCAL OSTEOMYELITIS; CHRONIC SCLEROSING OSTEOMYELITIS; SPONDYLARTHROPATHY-STUDY-GROUP; SAPHO SYNDROME; PUSTULOTIC ARTHROOSTEITIS; DIAGNOSTIC-VALUE; LONG-TERM; FOLLOW-UP; OSTEITIS; HYPEROSTOSIS AB Background: Chronic recurrent multifocal osteomyelitis (CRMO) in children is a chronic non-suppurative inflammation involving multiple sites. Some children affected by chronic non-bacterial osteomyelitis (CNO) do not have multiple lesions or a recurrent course. Objective: To characterise the long term outcome of children with the full spectrum of CNO. Methods: 30 children diagnosed with CNO were followed up for a mean of 5.6 years and their disease assessed using a clinical score, multiple imaging, and a diagnostic biopsy, including extensive microbial analysis. Results: 9 patients had unifocal non-relapsing disease, 3 unifocal lesions with relapses, 9 multifocal lesions without relapses, and 9 multifocal lesions with relapses (CRMO). Granulocytes were present significantly more often in CRMO than in unifocal and non-recurrent lesions. Pustulosis was more common in multifocal cases regardless of recurrence. Mean duration of treatment in 15 children with a single occurrence was 9.2 months. Naproxen treatment was generally effective. Naproxen treatment in 12 patients with relapses lasted 25 months. However, 7 of these were not effectively treated with naproxen alone. Five were treated with oral glucocorticoids for 27 days in addition to naproxen, which induced remission in four, lasting for at least 1.5 years. Longitudinal growth of affected bones was not altered, except for the development of hyperostosis. Conclusion: CNO is a spectrum of inflammatory conditions, with CRMO being the most severe. Most children with CNO have a favourable outcome of the disease. Oral glucocorticoids may be necessary in severe recurrent cases. C1 Univ Wurzburg, Dept Paediat, D-97070 Wurzburg, Germany. Univ Wurzburg, Sect Paediat Orthopaed, D-97070 Wurzburg, Germany. Univ Wurzburg, Dept Microbiol, D-97070 Wurzburg, Germany. Univ Wurzburg, Dept Radiol, Sect Paediat Radiol, D-97070 Wurzburg, Germany. Univ Wurzburg, Clin Nucl Med, D-97070 Wurzburg, Germany. Univ Erlangen Nurnberg, Dept Pathol, D-8520 Erlangen, Germany. NIAMS, NIH, Bethesda, MD USA. RP Girschick, HJ (reprint author), Univ Wurzburg, Childrens Hosp, Sect Paediat Rheumatol, Josef Schneider Str 2, D-97080 Wurzburg, Germany. EM Hermann.Girschick@mail.uni-wuerzburg.de NR 55 TC 91 Z9 96 U1 2 U2 4 PU B M J PUBLISHING GROUP PI LONDON PA BRITISH MED ASSOC HOUSE, TAVISTOCK SQUARE, LONDON WC1H 9JR, ENGLAND SN 0003-4967 J9 ANN RHEUM DIS JI Ann. Rheum. Dis. PD FEB PY 2005 VL 64 IS 2 BP 279 EP 285 DI 10.1136/ard.2004.023838 PG 7 WC Rheumatology SC Rheumatology GA 887CE UT WOS:000226279200023 PM 15647436 ER PT J AU Brantley, E Patel, V Stinson, SF Trapani, V Hose, CD Ciolino, HP Yeh, GC Gutkind, JS Sausville, EA Loaiza-Perez, AI AF Brantley, E Patel, V Stinson, SF Trapani, V Hose, CD Ciolino, HP Yeh, GC Gutkind, JS Sausville, EA Loaiza-Perez, AI TI The antitumor drug candidate 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole induces NF-kappa B activity in drug-sensitive MCF-7 cells SO ANTI-CANCER DRUGS LA English DT Article DE 5F 203; aryl hydrocarbon receptor; breast cancer; interleukin-6; NF-kappa B ID CANCER-CELLS; IN-VITRO; TRANSCRIPTIONAL ACTIVATION; TUMOR-CELLS; DNA-BINDING; 2-(4-AMINOPHENYL)BENZOTHIAZOLES; BENZOTHIAZOLES; APOPTOSIS; INHIBITOR; INDUCTION AB 2-(4-Amino-3-methylphenyl)-5-fluoro-benzothiazole (5F 203) potently inhibits MCF-7 breast cancer cell growth in part by activating the aryl hydrocarbon receptor (AhR) signaling pathway. Ligands for the AhR (i.e. dioxin) have also been shown to modulate the NF-kappaB signaling cascade, affecting physiological processes such as cellular immunity, inflammation, proliferation and survival. The objective of this study was to investigate the effect of 5F 203 treatment on the NF-kappaB signaling pathway in breast cancer cells. Exposure of MCF-7 cells to 5F 203 increased protein-DNA complex formation on the NF-kappaB-responsive element as determined by electrophoretic mobility shift assay, but this effect was eliminated in MDA-MB-435 cells, which are resistant to the antiproliferative effects of 5F 203. An increase in NF-kappaB-dependent transcriptional activity was confirmed by a significant increase in NF-kappaB-dependent reporter activity in sensitive MCF-7 cells, which was absent in resistant MDA-MB-435 cells and AhR-deficient subclones of MCF-7 cells. Inhibition of NF-kappaB activation enhanced the increase in xenobiotic response element-dependent reporter activity in MCF-7 cells when treated with 5F 203. The drug candidate 5F 203 also induced mRNA levels of IL-6, an NF-kappaB-responsive gene, in MCF-7 cells, but not in MDA-MB-435 cells, as determined by quantitative RT-PCR. These findings suggest that 5F 203 activation of the NF-kappaB signaling cascade may contribute to 5F 203-mediated anticancer activity in human breast cancer MCF-7 cells. (C) 2005 Lippincott Williams Wilkins. C1 NCI, Dev Therapeut Program, Div Canc Treatment & Diag, NIH, Frederick, MD 21701 USA. Natl Inst Dent & Craniofacial Res, Pharyngeal Canc Res, Bethesda, MD USA. Univ Nottingham, Canc Res Labs, Sch Pharmaceut Sci, Nottingham NG7 2RD, England. NCI, SAIC Frederick, Dev Therapeut Program, STB Funct Genomics Lab, Frederick, MD 21701 USA. NCI, Cellular Def & Carcinogenesis Sect, Lab Metab, Ctr Canc Res, Frederick, MD 21701 USA. Div Canc Treatment & Diag, Dev Therapeut Program, Bethesda, MD USA. RP Sausville, EA (reprint author), Univ Maryland, Greenebaum Canc Ctr, 22 S Greene St, Baltimore, MD 21201 USA. EM esausville@umm.edu RI Gutkind, J. Silvio/A-1053-2009 NR 24 TC 32 Z9 32 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4973 J9 ANTI-CANCER DRUG JI Anti-Cancer Drugs PD FEB PY 2005 VL 16 IS 2 BP 137 EP 143 DI 10.1097/00001813-200502000-00004 PG 7 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 898TT UT WOS:000227099800004 PM 15655410 ER PT J AU Moreau, P Holbeck, S Prudhomme, M Sausville, EA AF Moreau, P Holbeck, S Prudhomme, M Sausville, EA TI Cytotoxicities of three rebeccamycin derivatives in the National Cancer Institute screening of 60 human tumor cell lines SO ANTI-CANCER DRUGS LA English DT Article DE COMPARE analysis; cytotoxicity; DNA binding; indolocarbazoles; topoisomerase I; inhibition ID TOPOISOMERASE-I INHIBITORS; BIOLOGICAL-ACTIVITIES; ANALOGS; ANTITUMOR; INDOLOCARBAZOLES; KINASES AB Among the biologically active indolocarbazoles, rebeccamycin, a microbial metabolite produced by Saccharothrix aerocolonigenes, is a well-known topoisomerase (Topo) I poison. In the course of structure-activity relationship studies on rebeccamycin analogs, we have prepared a large number of indolocarbazole derivatives and have shown that, depending on the structural modifications, the cytotoxic effects may be, or not, directly correlated to DNA binding and Topo I inhibition. This suggests that if DNA binding and Topo I play a part in the biological activity of these compounds, other cellular targets might be involved. This paper reports the results of the antiproliferative activities (evaluated in the National Cancer Institute's in vitro panel of 60 tumor cell lines) and the results of a COMPARE analysis run with rebeccamycin derivatives to identify other potential biological targets for these compounds. (C) 2005 Lippincott Williams Wilkins. C1 Univ Clermont Ferrand, Lab SEESIB, UMR 6504, CNRS, F-63177 Clermont Ferrand, France. NCI, Dev Therapeut Program, Informat Technol Branch, Rockville, MD USA. RP Prudhomme, M (reprint author), Univ Clermont Ferrand, Lab SEESIB, UMR 6504, CNRS, 24 Rue Landais, F-63177 Clermont Ferrand, France. EM mprud@chimie.univ-bpclermont.fr RI Moreau, Pascale/M-9020-2016 NR 18 TC 8 Z9 8 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0959-4973 J9 ANTI-CANCER DRUG JI Anti-Cancer Drugs PD FEB PY 2005 VL 16 IS 2 BP 145 EP 150 DI 10.1097/00001813-200502000-00005 PG 6 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 898TT UT WOS:000227099800005 PM 15655411 ER PT J AU Ma, ZL Wang, XB Hockman, S Snow, EC Hersh, LB AF Ma, ZL Wang, XB Hockman, S Snow, EC Hersh, LB TI Subcellular localization of nardilysin during mouse oocyte maturation SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Article DE nardilysin; oocyte; nuclear localization; meiosis; maturation ID ARGININE DIBASIC CONVERTASE; GERMINAL VESICLE BREAKDOWN; NRD CONVERTASE; GROWTH-FACTOR; BINDING; KINASE; METALLOENDOPEPTIDASE; ISOFORMS; DOMAIN; SITES AB We have previously shown that the peptidase, nardilysin, contains a bipartite nuclear localization signal that permits the enzyme to cycle between the nucleus and cytoplasm. In the present study, we report that nardilysin accumulates in the nucleus of an oocyte as a function of its maturation. Nardilysin is predominantly localized in the cytoplasm of an oocyte when initially placed into culture. The enzyme starts to accumulate in the nucleus within 30 min of in vitro culture. After 3 h, nardilysin is found as a spherical structure surrounded by condensed chromosomal DNA. After IS h of in vitro culture, it co-localizes with beta-tubulin at the spindle apparatus. Cilostamide, a phosphodiesterase 3A inhibitor that inhibits meiosis, blocks accumulation of nuclear nardilysin. This finding demonstrates that the nuclear entry of nardilysin is tightly controlled in the oocyte. Taken together, these experiments strongly suggest a role for nardilysin in meiosis through its dynamic translocation from cytosol to nucleus, and then to the spindle apparatus. (C) 2004 Elsevier Inc. All rights reserved. C1 Univ Kentucky, Med Ctr, Dept Microbiol Immunol & Mol Genet, Lexington, KY 40536 USA. Univ Kentucky, Med Ctr, Dept Mol & Cellular Biochem, Lexington, KY 40536 USA. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Ma, ZL (reprint author), Univ Kentucky, Med Ctr, Dept Microbiol Immunol & Mol Genet, 800 Rose St, Lexington, KY 40536 USA. EM maz@uky.edu NR 27 TC 6 Z9 6 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD FEB 1 PY 2005 VL 434 IS 1 BP 187 EP 194 DI 10.1016/j.abb.2004.10.027 PG 8 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 889QO UT WOS:000226457700022 PM 15629122 ER PT J AU Hariri, AR Drabant, EM Munoz, KE Kolachana, LS Mattay, VS Egan, MF Weinberger, DR AF Hariri, AR Drabant, EM Munoz, KE Kolachana, LS Mattay, VS Egan, MF Weinberger, DR TI A susceptibility gene for affective disorders and the response of the human amygdala SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID TRANSPORTER PROMOTER POLYMORPHISM; STRUCTURED CLINICAL INTERVIEW; ANXIETY-RELATED TRAITS; PREFRONTAL CORTEX; ALLELIC VARIATION; SOCIAL PHOBIA; SEROTONIN; ASSOCIATION; BRAIN; 5-HTTLPR AB Background: A common regulatory variant (5-HTTLPR) in the human serotonin transporter gene (SLC6A4), resulting in altered transcription and transporter availability, has been associated with vulnerability for affective disorders, including anxiety and depression. A recent functional magnetic resonance imaging study suggested that this association may be mediated by 5-HTTLPR effects on the response bias of the human amygdala-a brain region critical for emotional and social behavior-to environmental threat. Objectives and Design: To examine the effects of 5-HTTLPR genotype on the reactivity of the human amygdala to salient environmental cues with functional magnetic resonance imaging in a large (N = 92) cohort of volunteers carefully screened for past and present medical or psychiatric illness, and to explore the effects of 5-HTTLPR genotype as well as amygdala reactivity on harm avoidance, a putative personality measure related to trait anxiety. Results: We now confirm the finding of 5-HTTLPR short allele-driven amygdala hyperreactivity in a large independent cohort of healthy subjects with no history of psychiatric illness or treatment. Furthermore, we demonstrate that these genotype effects on amygdala function are consistent with a dominant short allele effect and are equally prominent in men and women. However, neither 5-HTTLPR genotype, amygdala reactivity, nor genotype-driven Variability in this reactivity was reflected in harm avoidance scores. Conclusions: Our results reveal a potent modulatory effect of the 5-HTTLPR on amygdala reactivity to environmental threat. Since this genetically driven effect exists in healthy subjects, it does not, in and of itself, predict dimensions of mood or temperament. As such, the 5-HTTLPR may represent a classic susceptibility factor for affective disorders by biasing the functional reactivity of the human amygdala in the context of stressful life experiences and/or deficient cortical regulatory input. C1 NIMH, Genes Cognit & Psychosis Program, Intramural Res Program, NIH,US Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Weinberger, DR (reprint author), NIMH, Genes Cognit & Psychosis Program, Intramural Res Program, NIH,US Dept Hlth & Human Serv, Room 4S-235,10 Ctr Dr, Bethesda, MD 20892 USA. EM weinberd@intra.nimh.nih.gov RI Hariri, Ahmad/D-5761-2011 NR 45 TC 552 Z9 568 U1 8 U2 42 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD FEB PY 2005 VL 62 IS 2 BP 146 EP 152 DI 10.1001/archpsyc.62.2.146 PG 7 WC Psychiatry SC Psychiatry GA 893TN UT WOS:000226742300004 PM 15699291 ER PT J AU Schmidt, PJ Daly, RC Bloch, M Smith, MJ Danaceau, MA St Clair, LS Murphy, JH Haq, N Rubinow, DR AF Schmidt, PJ Daly, RC Bloch, M Smith, MJ Danaceau, MA St Clair, LS Murphy, JH Haq, N Rubinow, DR TI Dehydroepiandrosterone monotherapy in midlife-onset major and minor depression SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID METHYL-D-ASPARTATE; ORAL DEHYDROEPIANDROSTERONE; DOUBLE-BLIND; PERIMENOPAUSAL WOMEN; SIGMA-RECEPTORS; DHEA TREATMENT; ELDERLY-WOMEN; RATING-SCALE; SEX STEROIDS; OLDER MEN AB Context: Alternative and over-the-counter medicines have become increasingly popular choices for many patients who prefer not to take traditional antidepressants. The adrenal androgen and neurosteroid dehydroepiandrosterone (DHEA) is available as over-the counter hormonal therapy and previously has been reported to have antidepressant-like effects. Objective: To evaluate the efficacy of DHEA as a mono-therapy treatment for midlife-onset depression. Design: A double-blind, randomized, placebo controlled, crossover treatment study was performed from January 4, 1996, through August 31, 2002. Settings: The National Institute of Mental Health Midlife Outpatient Clinic in the National Institutes of Health Clinical Center, Bethesda, Md. Patients: Men (n = 23) and women (n = 23) aged 45 to 65 years with midlife-onset major or minor depression participated in this study. None of the subjects received concurrent antidepressant medications. Intervention: Six weeks of DHEA therapy, 90 mg/d for 3 weeks and 450 mg/d for 3 weeks, and 6 weeks of placebo. Main Outcome Measures: The 17-Item Hamilton Depression Rating Scale and Center for Epidermologic Studies Depression Scale. Additional measures included the Derogatis Interview for Sexual Functioning. Results were analyzed by means of repeated-measures analysis of variance and post hoc Bonferroni t tests. Results: Six weeks of DHEA administration was associated with a significant improvement in the 17-Item Hamilton Depression Rating Scale and the Center for Epidemiologic Studies Depression Scale ratings compared with both baseline (P<.01) and 6 weeks of placebo treatment (P<.01). A 50% or greater reduction in baseline Hamilton Depression Rating Scale scores was observed in 23 subjects after DHEA and in 13 subjects after placebo treatments. Six weeks of DHEA treatment also was associated with significant improvements in Derogatis Interview for Sexual Functioning scores relative to baseline and placebo conditions. Conclusion: We find DHEA to be an effective treatment for midlife-onset major and minor depression. C1 NIMH, Behav Endocrinol Branch, Rockville, MD 20857 USA. NIH, Clin Ctr Nursing Dept, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Schmidt, PJ (reprint author), NIMH, Bldg 10,Room 3N238,10 Ctr Dr,MSC 1276, Bethesda, MD 20892 USA. EM PeterSchmidt@mail.nih.gov NR 65 TC 145 Z9 152 U1 3 U2 7 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD FEB PY 2005 VL 62 IS 2 BP 154 EP 162 DI 10.1001/archpsyc.62.2.154 PG 9 WC Psychiatry SC Psychiatry GA 893TN UT WOS:000226742300005 PM 15699292 ER PT J AU Andersen, JF Gudderra, NP Francischetti, IMB Ribeiro, JMC AF Andersen, JF Gudderra, NP Francischetti, IMB Ribeiro, JMC TI The role of salivary lipocalins in blood feeding by Rhodnius prolixus SO ARCHIVES OF INSECT BIOCHEMISTRY AND PHYSIOLOGY LA English DT Article; Proceedings Paper CT Symposim on Insect Saliva held at the 51st Annual Meeting of the Entomological-Society-of-America CY OCT, 2003 CL Cincinnati, OH SP Entomol Soc Amer ID NITRIC-OXIDE-BINDING; BLOODSUCKING BUG; HEME PROTEIN; PLATELET-AGGREGATION; HIGH-AFFINITY; ANTIHEMOSTATIC PROTEIN; TRANSPORT PROTEIN; CRYSTAL-STRUCTURE; NITROPHORIN 4; INSECT AB In order to overcome host mechanisms that prevent blood loss, the blood-sucking bug Rhodnius prolixus has evolved a complex salivary secretion containing dozens of different proteins. A number of these have been characterized and found to have roles in inhibiting various hemostatic or inflammatory systems. Interestingly, many of these biologically active salivary proteins belong to the lipocalin protein family. A proliferation of lipocalin genes has occurred via gene duplication and subsequent divergence. Functional genomic, proteomic, and functional studies have been performed to probe the role of salivary lipocalins in blood feeding. In the course of these investigations, anticoagulant, antiplatelet, antiinflammatory, and vasodilatory molecules have been described. Published 2005 Wiley-Liss, Inc.(t). C1 NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. RP Andersen, JF (reprint author), NIAID, Lab Malaria & Vector Res, NIH, Twinbrook 3 Bldg,12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM jandersen@niaid.nih.gov RI Marion-Poll, Frederic/D-8882-2011; OI Marion-Poll, Frederic/0000-0001-6824-0180; Ribeiro, Jose/0000-0002-9107-0818 FU Intramural NIH HHS [Z01 AI000810-11, Z99 AI999999] NR 32 TC 61 Z9 62 U1 0 U2 1 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0739-4462 J9 ARCH INSECT BIOCHEM JI Arch. Insect Biochem. Physiol. PD FEB PY 2005 VL 58 IS 2 BP 97 EP 105 DI 10.1002/arch.20032 PG 9 WC Biochemistry & Molecular Biology; Entomology; Physiology SC Biochemistry & Molecular Biology; Entomology; Physiology GA 893GB UT WOS:000226706200005 PM 15660358 ER PT J AU Li, PY Tessler, A Han, SSW Fischer, I Rao, MS Selzer, ME AF Li, PY Tessler, A Han, SSW Fischer, I Rao, MS Selzer, ME TI Fate of immortalized human neuronal progenitor cells transplanted in rat spinal cord SO ARCHIVES OF NEUROLOGY LA English DT Article ID PORCINE NEURAL XENOGRAFTS; EMBRYONIC STEM-CELLS; ADULT-RAT; IN-VITRO; DIFFERENTIATION; MOTONEURONS; APOPTOSIS; SURVIVAL; LINEAGE; BRAIN AB Background: Replacement of neurons and glia by transplantation has been proposed as a therapy for neurodegenerative diseases, including amyotrophic lateral sclerosis. This strategy requires using human motor neuronal progenitor cells or xenografts of animal cells, but there is little evidence that xenografted neuronal cells can survive in spinal cord despite immunosuppression. Objective: To clarify the mechanisms responsible for the death of xenografted neurons in spinal cord. Methods: Cells from an immortalized, neuronally committed, human embryonic spinal cord-derived cell line (HSPI) that expresses motor neuronal properties in vitro were transplanted into adult rat spinal cord. The rats were killed at intervals up to 8 weeks and serial sections through the graft sites were processed for immunofluorescence using primary antibodies against human nuclear and mitochondrial antigens, microtubule-associated protein 2, TUJ1, CD5, natural killer cells, and activated microglia-macrophages, caspase-3 and caspase-9. Results: Grafted cells did not migrate and underwent partial differentiation along a neuronal pathway. They were rejected after 4 weeks despite cyclosporine immunosuppression. Cells died by apoptosis via the cytochrome c/caspase-9/caspase-3 pathway. The host response included natural killer cells and activated microglia-macrophages but few T cells. Conclusions: Intraspinal neuronal xenotransplantation failed because of apoptotic cell death. Neither T cells nor the spinal cord environment, which favors gliogenesis, are likely to have been responsible, but natural killer cells may have been involved. C1 Univ Penn, Ctr Med, Dept Neurol, Philadelphia, PA 19104 USA. Univ Penn, Ctr Med, David Mahoney Inst Neurol Sci, Philadelphia, PA 19104 USA. Drexel Univ, Coll Med, Dept Neurobiol & Anat, Drexel, Germany. NIA, Lab Neurosci, Gerontol Res Ctr, Baltimore, MD USA. RP Selzer, ME (reprint author), Univ Penn, Ctr Med, Dept Neurol, 3400 Spruce St, Philadelphia, PA 19104 USA. EM selzerm@mail.med.upenn.edu RI Fischer, Itzhak/D-1080-2012 OI Fischer, Itzhak/0000-0003-3187-8740 FU NINDS NIH HHS [NS24707, R01-NS14837, R01-NS38537] NR 20 TC 26 Z9 33 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD FEB PY 2005 VL 62 IS 2 BP 223 EP 229 DI 10.1001/archneur.62.2.223 PG 7 WC Clinical Neurology SC Neurosciences & Neurology GA 895FY UT WOS:000226847500006 PM 15710850 ER PT J AU Lim, WK Nussenblatt, RB Chan, CC AF Lim, WK Nussenblatt, RB Chan, CC TI Immunopathologic features of inflammatory coats disease SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article C1 NEI, NIH, Bethesda, MD 20892 USA. RP Chan, CC (reprint author), NEI, NIH, 10 Ctr Dr,Bldg 10,Room 10N103, Bethesda, MD 20892 USA. EM chanc@nei.nih.gov NR 5 TC 3 Z9 3 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD FEB PY 2005 VL 123 IS 2 BP 279 EP 281 DI 10.1001/archopht.123.2.279 PG 3 WC Ophthalmology SC Ophthalmology GA 893XS UT WOS:000226755000028 PM 15710836 ER PT J AU Opsahl, S Septier, D Aubin, I Guenet, JL Sreenath, T Kulkarni, A Vermelin, L Goldberg, M AF Opsahl, S Septier, D Aubin, I Guenet, JL Sreenath, T Kulkarni, A Vermelin, L Goldberg, M TI Is the lingual forming part of the incisor a structural entity? Evidences from the fragilitas ossium (fro/fro) mouse mutation and the TGF beta 1 overexpressing transgenic strain SO ARCHIVES OF ORAL BIOLOGY LA English DT Article; Proceedings Paper CT 8th International Conference on Tooth Morphogenesis and Differentiation CY JUL, 2004 CL York, ENGLAND DE fro/fro; TGF beta 1 overexpression; incisor; mouse; cell proliferation; mineralisation ID CASEIN KINASE INHIBITOR; INOSITOL HEXASULPHATE; TOOTH GERMS; PROTEINS; DENTIN; TEETH; EXPRESSION; MODEL AB Our objective was to study the teeth of a mutant mice fro/fro that display severe forms of osteogenesis imperfecta. One day and 8 week-old fro/fro and +/fro heterozygote mice (wild type, WT) were processed for light and scanning electron microscopy. The genetic defect, shown to be located on chromosome 8, induced alveolar bone and teeth hypomineralisation. Due to defective cell proliferation in the fro/fro, the distal growth of the mandibular incisors was impaired. Immunolabelling revealed an increase of chondroitin/dermatan sulphate, whereas no difference was detected in dental tissues for decorin and biglycan. Amelogenin expression was decreased in the incisor and enhanced in the molar. Dentin sialoprotein was below the level of detection in the fro/fro, whereas osteonectin and osteopontin were unchanged. The main target of the mutation was seen in the lingual part of the incisor near the apex where dentine formation was delayed. In the molars, bulbous roots with obliteration of the pulp chamber were seen. In the TGF beta 1 overexpressing mice, the lingual root-analogue part of the incisor was missing. In the molar, short roots, circumpulpal dentine of the osteodentine type and pulp obliteration were seen. It may be noted that, although the mutant and transgenic strains mutations are two different genetic alterations not related to the same defective gene, in both cases the expression of the dentin sialoprotein is altered. Altogether, the present data suggest that the lingual forming part of the incisor seems to be an anatomical entity bearing its own biological specificities. (c) 2004 Elsevier Ltd. All rights reserved. C1 Univ Paris 05, Fac Chirurg Dent, Grp Matrices Extracellulaires & Biomineralista, EA 2496, F-92190 Meudon, France. Inst Pasteur, Unite Genet Mammiferes, F-75724 Paris, France. NIDCR, Funct Genom Sect, Craniofacial Dev Biol & Rergenerat Branch, NIH, Bethesda, MD 20892 USA. RP Goldberg, M (reprint author), Univ Paris 05, Fac Chirurg Dent, Grp Matrices Extracellulaires & Biomineralista, EA 2496, 1 Rue Maurice Arnoux, F-92190 Meudon, France. EM mgoldod@aol.com NR 15 TC 12 Z9 12 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0003-9969 J9 ARCH ORAL BIOL JI Arch. Oral Biol. PD FEB PY 2005 VL 50 IS 2 BP 279 EP 286 DI 10.1016/j.archoralbio.2004.09.009 PG 8 WC Dentistry, Oral Surgery & Medicine SC Dentistry, Oral Surgery & Medicine GA 905KW UT WOS:000227568000030 PM 15721162 ER PT J AU Powell, TM Paul, JD Hill, JM Thompson, M Benjamin, M Rodrigo, M McCoy, JP Read, EJ Khuu, HM Leitman, SF Finkel, T Cannon, RO AF Powell, TM Paul, JD Hill, JM Thompson, M Benjamin, M Rodrigo, M McCoy, JP Read, EJ Khuu, HM Leitman, SF Finkel, T Cannon, RO TI Granulocyte colony-stimulating factor mobilizes functional endothelial progenitor cells in patients with coronary artery disease SO ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY LA English DT Article DE coronary disease; atherosclerosis; angiogenesis; cell adhesion molecules; cells ID NEOVASCULARIZATION; BLOOD; STEM; AC133; HEART; RISK AB Objective - Endothelial progenitor cells ( EPCs) that may repair vascular injury are reduced in patients with coronary artery disease ( CAD). We reasoned that EPC number and function may be increased by granulocyte colony- stimulating factor ( G- CSF) used to mobilize hematopoietic progenitor cells in healthy donors. Methods and Results - Sixteen CAD patients had reduced CD34(+)/CD133(+) ( 0.0224 +/- 0.0063% versus 0.121 +/- 0.038% mononuclear cells [ MNCs], P < 0.01) and CD133(+)/ VEGFR-2(+) cells, consistent with EPC phenotype ( 0.00033 +/- 0.00015% versus 0.0017 +/- 0.0006% MNCs, P < 0.01), compared with 7 healthy controls. Patients also had fewer clusters of cells in culture, with out- growth consistent with mature endothelial phenotype ( 2 +/- 1/ well) compared with 16 healthy subjects at high risk ( 13 +/- 4/ well, P < 0.05) or 14 at low risk ( 22 +/- 3/ well, P < 0.001) for CAD. G- CSF 10 mug/ kg per day for 5 days increased CD34(+)/ CD133(+) cells from 0.5 +/- 0.2/muL to 59.5 +/- 10.6/muL and CD133(+)/ VEGFR-2(+) cells from 0.007 +/- 0.004/muL to 1.9 +/- 0.6/muL ( both P < 0.001). Also increased were CD133(+) cells that coexpressed the homing receptor CXCR4 ( 30.4 +/- 8.3/μL, P < 0.05). Endothelial cell- forming clusters in 10 patients increased to 27 +/- 9/ well after treatment ( P < 0.05), with a decline to 9 +/- 4/ well at 2 weeks ( P = 0.06). Conclusions - Despite reduced EPCs compared with healthy controls, patients with CAD respond to G- CSF with increases in EPC number and homing receptor expression in the circulation and endothelial out- growth in culture. C1 NIH, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. NHLBI, Cardiovasc Branch, Bethesda, MD 20892 USA. RP Cannon, RO (reprint author), NIH, Dept Transfus Med, Ctr Clin, Bldg 10 Room 7B15,10 Ctr Dr MSC 1650, Bethesda, MD 20892 USA. EM cannonr@nih.gov NR 23 TC 169 Z9 194 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1079-5642 J9 ARTERIOSCL THROM VAS JI Arterioscler. Thromb. Vasc. Biol. PD FEB PY 2005 VL 25 IS 2 BP 296 EP 301 DI 10.1161/01.ATV.00000151690.43777.e4 PG 6 WC Hematology; Peripheral Vascular Disease SC Hematology; Cardiovascular System & Cardiology GA 891PW UT WOS:000226594000008 PM 15569821 ER PT J AU van Lent, PLEM Nabbe, KCAM Holthuysen, AEM Kolls, JK Holland, SM van den Berg, WB AF van Lent, P. L. E. M. Nabbe, K. C. A. M. Holthuysen, A. E. M. Kolls, J. K. Holland, S. M. van den Berg, W. B. TI Oxygen radical production determines chondrocyte death and regulates matrix metalloproteinase-mediated matrix degradation during interferon gamma-accelerated immune complex arthritis SO ARTHRITIS RESEARCH & THERAPY LA English DT Meeting Abstract CT 25th European Workshop for Rheumatology Research CY FEB 24-27, 2005 CL Glasgow, SCOTLAND SP Abbott Immunol, Britol-Myers Squibb Co, Wyeth, MSD, AstraZeneca, AMGEN C1 UMCN Nijmegen, Dept Rheumatol, Nijmegen, Netherlands. Univ Pittsburgh, Dept Pediat, Pittsburgh, PA 15260 USA. NIAID, Bethesda, MD 20892 USA. RI van Lent, Peter/A-4269-2014; van Lent, Peter/A-4047-2014; Berg, W.B./H-8010-2014 NR 1 TC 0 Z9 0 U1 0 U2 0 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1478-6354 J9 ARTHRITIS RES THER JI Arthritis Res. Ther. PD FEB PY 2005 VL 7 SU 1 BP S15 EP S15 DI 10.1186/ar1553 PG 1 WC Rheumatology SC Rheumatology GA 061DT UT WOS:000238852100046 ER PT J AU Doyon, J Carrier, J Simard, A Tahar, AH Morin, A Benali, H Ungerleider, LG AF Doyon, J Carrier, J Simard, A Tahar, AH Morin, A Benali, H Ungerleider, LG TI Motor memory: Consolidation-based enhancement effect revisited SO BEHAVIORAL AND BRAIN SCIENCES LA English DT Editorial Material ID TIME-COURSE; SKILL; SLEEP; IMPROVEMENT; CORTEX AB Following Karni's seminal work, Walker and other researchers have recently provided gradually convincing evidence that sleep is critical for the consolidation-based enhancement (CBE) of motor sequence learning. Studies in our laboratory using a motor adaptation paradigm, however, show that CBE can also occur after the simple passage of time, suggesting that sleep effects on memory consolidation are task-related, and possibly dependent on anatomically dissociable circuits. C1 Univ Montreal, Dept Psychol, Montreal, PQ H3C 3J7, Canada. CHU Pitie Salpetriere, INSERM, Unite 494, F-75634 Paris, France. NIMH, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Doyon, J (reprint author), Univ Montreal, Dept Psychol, CP 6128, Montreal, PQ H3C 3J7, Canada. EM julien.doyon@umontreal.ca; J-Carrier@CRHSC.UMontreal.CA; asimard002@sympatico.ca; amzoughi@yahoo.com; amelie.morin@umontreal.ca; Habib.Benali@imed.jussieu.fr; lesile_ungerleider@nih.gov NR 16 TC 1 Z9 1 U1 0 U2 0 PU CAMBRIDGE UNIV PRESS PI NEW YORK PA 40 WEST 20TH ST, NEW YORK, NY 10011-4211 USA SN 0140-525X J9 BEHAV BRAIN SCI JI Behav. Brain Sci. PD FEB PY 2005 VL 28 IS 1 BP 68 EP + PG 10 WC Psychology, Biological; Behavioral Sciences; Neurosciences SC Psychology; Behavioral Sciences; Neurosciences & Neurology GA 937RV UT WOS:000229944100033 ER PT J AU McGlynn, KA London, WT AF McGlynn, KA London, WT TI Epidemiology and natural history of hepatocellular carcinoma SO BEST PRACTICE & RESEARCH IN CLINICAL GASTROENTEROLOGY LA English DT Review DE hepatocellular carcinoma; incidence; hepatitis B virus; hepatitis C virus; aflatoxin B-I ID HEPATITIS-B-VIRUS; PRIMARY LIVER-CANCER; PORPHYRIA-CUTANEA-TARDA; TERM-FOLLOW-UP; NONALCOHOLIC STEATOHEPATITIS; C VIRUS; CRYPTOGENIC CIRRHOSIS; ALPHA-1-ANTITRYPSIN DEFICIENCY; DIABETES-MELLITUS; RISK-FACTOR AB Hepatocellular carcinoma (HCC) is a major contributor to cancer incidence and mortality. There is a wide variation, however, in the global distribution of HCC. Eighty percent of the burden is borne by countries in Asia and sub-Saharan Africa. In most high-risk countries, principal risk factors include infection with hepatitis B virus and dietary exposure to aflatoxin B-1. In contrast, hepatitis C virus and alcohol consumption are more important risk factors in low-risk countries. In recent years, the incidence of HCC has decreased in some high-risk countries and increased in some low-risk countries. Reasons for both trends are not completely understood, but are likely related to public health efforts in Asia and the increase in hepatitis C virus infection in low-risk countries. Vaccination programs against hepatitis B virus will likely decrease the HCC rate even further in decades to come. C1 NCI, HREB DCEG, Rockville, MD 20892 USA. Fox Chase Canc Ctr, Div Populat Sci, Philadelphia, PA 19111 USA. RP McGlynn, KA (reprint author), NCI, HREB DCEG, EPS-7060,6120 Execut Blvd, Rockville, MD 20892 USA. EM mcglynnk@mail.nih.gov; wt_london@fccc.edu NR 130 TC 185 Z9 197 U1 1 U2 8 PU BAILLIERE TINDALL PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1521-6918 J9 BEST PRACT RES CL GA JI Best Pract. Res. Clin. Gastroenterol. PD FEB PY 2005 VL 19 IS 1 BP 3 EP 23 DI 10.1016/j.bpg.2004.10.004 PG 21 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 911HW UT WOS:000227994200002 PM 15757802 ER PT J AU Nishimura, K Murozumi, K Shirahata, A Park, MH Kashiwagi, K Igarashi, K AF Nishimura, K Murozumi, K Shirahata, A Park, MH Kashiwagi, K Igarashi, K TI Independent roles of eIF5A and polyarnines in cell proliferation SO BIOCHEMICAL JOURNAL LA English DT Article DE biosynthetic inhibitor; cell proliferation; deoxyhypusine synthase; eukaryotic translation initiation factor 5A (eIF5A); hypusine; polyamine ID INITIATION-FACTOR 5A; YEAST SACCHAROMYCES-CEREVISIAE; POLYAMINE-REQUIRING MUTANTS; 30-S RIBOSOMAL-SUBUNITS; HAMSTER OVARY CELLS; DEOXYHYPUSINE SYNTHASE; SPERMINE SYNTHASE; PROTEIN-SYNTHESIS; ESCHERICHIA-COLI; MESSENGER-RNA AB To exam ne the roles of active hypusinated eIF5A (eukaryotic translation initiation factor 5A) and polyamines in cell proliferation, mouse mammary carcinoma FM3A cells were treated with an inhibitor of deoxyhypusine synthase, GC(7) (N-1-guanyl-1, 7-diaminoheptane), or with an inhibitor of ornithine decarboxylase, DFMO (alpha-difluoromethylomithine), or with DFMO plus an inhibitor of spermine synthase, APCHA [N'-(3-aminopropyl)cyclohex ylamine]. Treatment with GC(7) decreased the level of active eIF5/. on day I without affecting cellular polyamine content, and inhibition of cell growth occurred from day 2. This delay reflects the fact that eIF5A was present in excess and was very stable in these cells. Treatment with DFMO or with DFMO plus APCHA inhibited cell growth on day 1. DFMO considerably decreased the levels of putrescine and spermidine, and the formation of active eIF5A began to decrease when the level of spermidine fell below 8 nmol/mg of protein after 12 h of incubation with DFMO. The combination of DFMO and APCHA markedly decreased the levels of putrescine and spermine and significantly decreased the level of spermidine, but did not affect the level of active eIF5A until day 3 when spermidine level decreased to 7 nmol/mg of protein. The results show that a decrease in either active eIF5A or polyamines inhibits cell growth, indicating that elF5A and polyamines are independently involved in cell growth. C1 Chiba Univ, Grad Sch Pharmaceut Sci, Chuo Ku, Chiba 2608675, Japan. Josai Univ, Fac Pharmaceut Sci, Sakado, Saitama 3500248, Japan. Natl Inst Dental & Craniofacial Res, NIH, Oral & Pharyngeal Canc Branch, Bethesda, MD 20892 USA. RP Igarashi, K (reprint author), Chiba Univ, Grad Sch Pharmaceut Sci, Chuo Ku, 1-8-1 Inohana, Chiba 2608675, Japan. EM iga16077@p.chiba-u.ac.jp FU Intramural NIH HHS [Z01 DE000608-14, Z99 DE999999] NR 40 TC 79 Z9 85 U1 1 U2 5 PU PORTLAND PRESS LTD PI LONDON PA 59 PORTLAND PLACE, LONDON W1B 1QW, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD FEB 1 PY 2005 VL 385 BP 779 EP 785 PN 3 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 895JW UT WOS:000226858300018 PM 15377278 ER PT J AU Polgar, O Bates, SE AF Polgar, O Bates, SE TI ABC transporters in the balance: is there a role in multidrug resistance? SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT International Symposium on Membrane Transport and Transporters CY SEP 02-05, 2004 CL Selwyn Coll, Cambridge, ENGLAND HO Selwyn Coll DE ABC (ATP-binding cassette) transporter; ABCG2; multidrug resistance; multidrug resistance protein (MRP); Pgp ID ACUTE MYELOID-LEUKEMIA; CELL LUNG-CANCER; P-GLYCOPROTEIN EXPRESSION; TYROSINE KINASE INHIBITOR; SOUTHWEST-ONCOLOGY-GROUP; OVARIAN-CANCER; HALF-TRANSPORTER; DRUG-RESISTANCE; PHASE-II; IN-VIVO AB Drug resistance can occur at several levels and is the major cause of treatment failure in oncology. The ABC (ATP-binding cassette) transporters, beginning with the discovery of P-gylcoprotein (Pgp) almost 30 years ago, have been intensively studied as potential mediators of drug resistance. Although we understand that drug resistance is almost certainly multifactorial, investigators have attempted to link anticancer drug resistance to overexpression of ABC transporters and the consequent reduction in drug accumulation. A body of evidence implicated Pgp as being important in clinical outcome; however, critical studies aimed at proving the hypothesis using Pgp inhibitors in clinical trials have to date failed. identification of the MRP (multidrug resistance protein)/ABCC subfamily expanded the possible mechanisms of reduced drug accumulation, and the discovery of ABCG2 added a new chapter in these investigations. Correlative studies examining ABCG2 and the ABCC subfamily members in clinical drug resistance have been less avidly pursued, while basic molecular studies of structure and function have proceeded briskly. Recently, studies have focused on how single nucleotide polymorphism in multidrug transporters might affect the pharmacokinetics and pharmacodynamics of anticancer agents. These studies suggest an important role for ABC transporters in pharmacology, independent of the ultimate determination of their role in multidrug resistance. C1 NCI, Canc Therapeut Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Bates, SE (reprint author), NCI, Canc Therapeut Branch, Ctr Canc Res, NIH, 9000 Rockville Pike,Bldg 10,Rm 12C103, Bethesda, MD 20892 USA. EM sebates@helix.nih.gov NR 38 TC 53 Z9 60 U1 1 U2 10 PU PORTLAND PRESS LTD PI LONDON PA 59 PORTLAND PLACE, LONDON W1B 1QW, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD FEB PY 2005 VL 33 BP 241 EP 245 PN 1 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 901GA UT WOS:000227269800070 PM 15667317 ER PT J AU Prieto, JH Benitez, BAS Melacini, G Johnson, DA Wood, MJ Komives, EA AF Prieto, JH Benitez, BAS Melacini, G Johnson, DA Wood, MJ Komives, EA TI Dynamics of the fragment of thrombomodulin containing the fourth and fifth epidermal growth factor-like domains correlate with function SO BIOCHEMISTRY LA English DT Article ID N-15 NMR RELAXATION; BACKBONE DYNAMICS; ROTATIONAL DIFFUSION; LIGAND-BINDING; PROTEIN; THROMBIN; ANISOTROPY; MOTIONS; COMPLEX; REVEAL AB Thrombomodulin (TM) forms a 1:1 complex with thrombin. Whereas thrombin alone cleaves fibrinogen to make the fibrin clot, the thrombin-TM complex cleaves protein C to initiate the anticoagulant pathway. The fourth and fifth EGF-like domains of TM together form the minimal fragment with anticoagulant cofactor activity. A short linker connects the fourth and fifth EGF-like domains of TM, and Met 388 in the middle of the linker interacts with both domains. Several different structures of TMEGF45 variants are now available, and these show that mutation of Met 388 alters the structure of the fifth domain, as well as the connectivity of the two domains. To probe this phenomenon more thoroughly, NMR backbone dynamics experiments have been carried out on the individual fourth and fifth domains as well as on the wild type, the Met 388 Leu mutant, and the variant in which Met 388 is oxidized. The results presented here show that changes at Met 388 cause significant changes in backbone dynamics in both the fourth and fifth EGF-like domains of TM. Backbone dynamics within the small loop of the fourth domain Tyr 358 correlate with anticoagulant cofactor activity. Backbone dynamics of the thrombin-binding residues Tyr 413 and Ile 414 are inversely correlated with thrombin binding. The preordering of the backbone of Tyr 413 and Ile 414 only occurs in the two-domain fragments, revealing a role for the fourth domain in thrombin binding as well as in anticoagulant cofactor activity. C1 Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. Marymt Manhattan Coll, Dept Nat Sci, New York, NY 10021 USA. Marymt Manhattan Coll, Dept Math, New York, NY 10021 USA. McMaster Univ, Dept Chem, Hamilton, ON L8S 4M1, Canada. Univ Calif Riverside, Riverside, CA 92521 USA. NICHHD, Cell Biol & Metab Branch, Bethesda, MD 20892 USA. RP Komives, EA (reprint author), Univ Calif San Diego, Dept Chem & Biochem, La Jolla, CA 92093 USA. EM ekomives@ucsd.edu FU NHLBI NIH HHS [R01-HL070999, R01 HL047463]; NIDDK NIH HHS [T32 DK007233] NR 37 TC 5 Z9 5 U1 0 U2 0 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 1 PY 2005 VL 44 IS 4 BP 1225 EP 1233 DI 10.1021/bi0478852 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 891QE UT WOS:000226594800015 PM 15667216 ER PT J AU Polozova, A Li, XG Shangguan, T Meers, P Schuette, DR Ando, N Gruner, SM Perkins, WR AF Polozova, A Li, XG Shangguan, T Meers, P Schuette, DR Ando, N Gruner, SM Perkins, WR TI Formation of homogeneous unilamellar liposomes from an interdigitated matrix SO BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES LA English DT Article DE homogeneous; liposome; matrix ID EFFICIENT ENCAPSULATION; LIPID VESICLES; FUSION; ETHANOL; HYDRATION; PHASE AB Phospholipid-ethanol-aqueous mixtures containing bilayer-fonning lipids and 20-50 wt.% of water form viscous gels. Further hydration of these gels results in the formation of liposomes whose morphology depends upon the lipid type. Upon hydration of gels containing mixtures of the lipids 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) and 1-palmitoyl-2-oleoyl-phosphatidylglyceroI (POPG), small homogeneous and unilamellar liposomes were produced. In contrast, hydration of gels containing only POPC resulted in formation of large multilamellar liposomes. Likewise, mulitlamellar liposomes resulted when this method was applied to form highly fusogenic liposomes comprised of the novel negatively charged N-acyl-phosphatidylethanolamine (NAPE) mixed with di-oleoyl-phosphatidylcholine (DOPC) (7:3) [T. Shangguan, C.C. Pak, S. Ali, A.S. Janoff, P. Meers, Cation-dependent fusogenicity of an N-acyl phosphatidylethanolamine, Biochim. Biophys. Acta 1368 (1998) 171-183]. In all cases, the measured aqueous entrapment efficiencies were relatively high. To better understand how the molecular organization of these various gels affects liposome morphology, we examined samples by freeze-fracture transmission electron microscopy and X-ray diffraction. We found that phospholipid-ethanol-water gels are comprised of highly organized stacks of lamellae. A distinct feature of the gel samples that result in small unilamellar liposomes is the combination of acyl chain interdigitation and net electrostatic charge. We speculate that the mechanism of unilamellar liposome formation proceeds via formation of stalk contacts between neighboring layers similar to membrane hemifusion intermediates, and the high aqueous entrapment efficiencies make this liposome formation process attractive for use in drug delivery applications. (C) 2004 Elsevier B.V. All rights reserved. C1 Elan Drug Delivery, Princeton, NJ 08540 USA. Cornell Univ, Dept Phys, Ithaca, NY 14853 USA. RP Polozova, A (reprint author), NIAAA, NIH, 5625 Fishers Lane,Room 3N-07, Bethesda, MD 20892 USA. EM apolozva@mail.nih.gov RI Gruner, Sol/G-2924-2010 OI Gruner, Sol/0000-0002-1171-4426 NR 23 TC 11 Z9 11 U1 2 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0005-2736 J9 BBA-BIOMEMBRANES JI Biochim. Biophys. Acta-Biomembr. PD FEB 1 PY 2005 VL 1668 IS 1 BP 117 EP 125 DI 10.1016/j.bbamem.2004.11.012 PG 9 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 895ID UT WOS:000226853400013 PM 15670737 ER PT J AU Little, JT Ketter, TA Kimbrell, TA Dunn, RT Benson, BE Willis, MW Luckenbaugh, DA Post, RM AF Little, JT Ketter, TA Kimbrell, TA Dunn, RT Benson, BE Willis, MW Luckenbaugh, DA Post, RM TI Bupropion and venlafaxine responders differ in pretreatment regional cerebral metabolism in unipolar depression SO BIOLOGICAL PSYCHIATRY LA English DT Article DE bupropion; depression; positron emission tomography; treatment response; unipolar; venlafaxine ID COGNITIVE-AFFECTIVE SYNDROME; GLUCOSE-UTILIZATION; SLEEP-DEPRIVATION; NUCLEUS-ACCUMBENS; MAJOR DEPRESSION; BLOOD-FLOW; DISORDER; SCALE; HYPOMETABOLISM; MICRODIALYSIS AB Background. Pretreatment,functional brain imaging was examined for never-hospitalized outpatients with unipolar depression compared with control subjects in a crossover treatment trial involving bupropion or venlafaxine monotherapy. Methods. Patients (n = 20) with unipolar depression received baseline (medication-free) fluorine-18 deoxyglucose (FDG) positron emission tomography (PET) scan and then at least 6 weeks of bupropion or venlafaxine monotherapy in a single-blind crossover trial. Age-matched healthy control subjects (n = 20) also received baseline FDG PET scans. For each medication PET data from patients compared with control subjects was analyzed as a function of treatment response (defined as moderate to marked improvement on the Clinical Global Impression Scale). Results. Treatment response rates were similar for buproprion (32%) and venlafaxine (33010 Compared with control subjects, responders but not nonresponders, to both drugs demonstrated frontal and left temporal hypometabolism. Selectively, compared with control subjects bupropion responders (n = 6) also bad cerebellar hypermetabolism, whereas venlafaxine responders (n = 7) showed bilateral temporal and basal ganglia hypometabolism. Conclusions. These data suggest that pretreatment frontal and left temporal hypometabolism in never-hospitalized depressed outpatients compared with control subjects is linked to positive antidepressant response and that additional alterations in regional metabolism may be linked to differential responsivity to bupropion and venlafaxine monotherapy. C1 NIMH, Biol Psychiat Branch, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sch Med, Div Psychiat Neuroimaging, Baltimore, MD USA. Johns Hopkins Univ, Sch Med, Dept Psychiat & Behav Sci, Baltimore, MD USA. Stanford Univ, Sch Med, Stanford, CA 94305 USA. Vet Adm Med Ctr, N Little Rock, AR USA. RP Post, RM (reprint author), NIMH, Biol Psychiat Branch, Bldg 10,Rm 3N212,10 Ctr Dr,MSC 1272, Bethesda, MD 20892 USA. EM Robert.Post@NIH.gov FU NIMH NIH HHS [K23 MH01914] NR 51 TC 55 Z9 55 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 1 PY 2005 VL 57 IS 3 BP 220 EP 228 DI 10.1016/j.biopsysch.2004.10.033 PG 9 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 895TL UT WOS:000226886400003 PM 15691522 ER PT J AU Uthus, EO Davis, C AF Uthus, EO Davis, C TI Dietary arsenic affects dimethylhydrazine-induced aberrant crypt formation and hepatic global DNA methylation and DNA methyltransferase activity in rats SO BIOLOGICAL TRACE ELEMENT RESEARCH LA English DT Article DE arsenic; cancer; animal model; dimethylhydrazine; aberrant crypt; methylation ID INDUCED MALIGNANT-TRANSFORMATION; ADENOSYL-L-METHIONINE; S-ADENOSYLMETHIONINE; FOLATE-DEFICIENCY; BLADDER-CANCER; DRINKING-WATER; MESSENGER-RNA; ANIMAL-MODEL; FEMALE RATS; IN-VIVO AB Cell culture studies have suggested that arsenic exposure results in decreased S-adenosylmethionine (SAM), causing DNA hypomethylation. Previously, we have shown that hepatic SAM is decreased and/or S-adenosylhomocysteine increased in arsenic-deprived rats; these rats tended to have hypomethylated DNA. To determine the effect of dietary arsenic on dimethylhydrazine (DMH)-induced aberrant crypt formation in the colon, Fisher 344 weanling male rats were fed diets containing 0, 0.5, or 50 μ g As (as NaAsO2)/g. After 12 wk, dietary arsenic affected the number of aberrant crypts (p< 0.02) and aberrant crypt foci (p< 0.007) in the colon and the amount of global DNA methylation (p< 0.04) and activity of DNA methyltransferase (DNMT) (p< 0.003) in the liver. In each case, there were more aberrant crypts and aberrant crypt foci, a relative DNA hypomethylation, and increased activity of DNMT in the rats fed 50 μ g As/g compared to those fed 0.5 μ g As/g. The same phenomenon, an increased number of aberrant crypts and aberrant crypt foci, DNA hypomethylation, and increased DNMT tended to hold when comparing rats fed the diet containing no supplemental arsenic compared to rats fed 0.5 μ g As/g. The data suggest that there is a threshold for As toxicity and that possibly too little dietary As could also be detrimental. C1 USDA ARS, Grand Forks Human Nutr Res Ctr, Grand Forks, ND 58202 USA. NCI, Div canc Prevent, Nutr Sci Res Dept, US DHHS,NIH, Bethesda, MD 20892 USA. RP Uthus, EO (reprint author), USDA ARS, Grand Forks Human Nutr Res Ctr, Grand Forks, ND 58202 USA. NR 44 TC 12 Z9 14 U1 1 U2 1 PU HUMANA PRESS INC PI TOTOWA PA 999 RIVERVIEW DRIVE SUITE 208, TOTOWA, NJ 07512 USA SN 0163-4984 J9 BIOL TRACE ELEM RES JI Biol. Trace Elem. Res. PD FEB PY 2005 VL 103 IS 2 BP 133 EP 145 DI 10.1385/BTER:103:2:133 PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 924EJ UT WOS:000228961300004 PM 15772437 ER PT J AU Fowler, DH Foley, J Jung, U AF Fowler, DH Foley, J Jung, U TI In vitro rapamycin and costimulation generates Th1/Tc1 or Th2/Tc2 central memory effectors: Differential regulation by in vivo rapamycin after allogeneic BMT SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Joint Meeting of the American-Society-for-Blood-and-Marrow-Transplantation/Center-for-Interna tional-Blood-and-Marrow-Transplant-Research CY FEB 10-14, 2005 CL Keystone, CO SP Amer Soc Blood Marrow Transplantation, Ctr Int Blood Marrow Transplantation C1 NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2005 VL 11 IS 2 SU 1 MA 33 BP 12 EP 12 DI 10.1016/j.bbmt.2004.12.034 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 902CM UT WOS:000227329000034 ER PT J AU Hardy, NM Steinberg, SM Krumlauf, M Cvitkovic, R Castro, K Hakim, F Carter, C Read, EJ Leitman, S Gress, R Bishop, MR AF Hardy, NM Steinberg, SM Krumlauf, M Cvitkovic, R Castro, K Hakim, F Carter, C Read, EJ Leitman, S Gress, R Bishop, MR TI Development of graft-versus-host disease depends upon establishment of complete donor T cell chimerism after T cell depleted, reduced intensity hematopoietic stem cell transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Joint Meeting of the American-Society-for-Blood-and-Marrow-Transplantation/Center-for-Interna tional-Blood-and-Marrow-Transplant-Research CY FEB 10-14, 2005 CL Keystone, CO SP Amer Soc Blood Marrow Transplantation, Ctr Int Blood Marrow Transplantation C1 NCI, NIH, Inst Expt Transplantat, Bethesda, MD 20892 USA. NCI, NIH, Immunol Branch, Bethesda, MD 20892 USA. NCI, NIH, Biostat & Data Management Sect, Bethesda, MD 20892 USA. Brigham Young Univ, Provo, UT 84602 USA. NIH, Ctr Clin, Dept Transfus Med, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 2 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2005 VL 11 IS 2 SU 1 MA 112 BP 39 EP 39 DI 10.1016/j.bbmt.2004.12.113 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 902CM UT WOS:000227329000112 ER PT J AU Donohue, T Gorak, E McGettigan, C Morgan, T Fadell, A Srinivasan, R Childs, R AF Donohue, T Gorak, E McGettigan, C Morgan, T Fadell, A Srinivasan, R Childs, R TI Significant decline in pulmonary engraftment syndrome after nonmyeloablative allogeneic hematopoietic cell transplantation associated with less amphotericin use for febrile neutropenia SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Joint Meeting of the American-Society-for-Blood-and-Marrow-Transplantation/Center-for-Interna tional-Blood-and-Marrow-Transplant-Research CY FEB 10-14, 2005 CL Keystone, CO SP Amer Soc Blood Marrow Transplantation, Ctr Int Blood Marrow Transplantation C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. Walter Reed Army Med Ctr, Washington, DC 20307 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2005 VL 11 IS 2 SU 1 MA 115 BP 40 EP 40 DI 10.1016/j.bbmt.2004.12.116 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 902CM UT WOS:000227329000115 ER PT J AU Rezvani, K Tawab, A Kilical, Y Sconocchia, G Li, J Hensel, N Kurlander, R Barrett, J AF Rezvani, K Tawab, A Kilical, Y Sconocchia, G Li, J Hensel, N Kurlander, R Barrett, J TI PRAME-specific CD8(+) T cells are spontaneously present in a large proportion of healthy donors and leukemic HLA-A0201 patients SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Joint Meeting of the American-Society-for-Blood-and-Marrow-Transplantation/Center-for-Interna tional-Blood-and-Marrow-Transplant-Research CY FEB 10-14, 2005 CL Keystone, CO SP Amer Soc Blood Marrow Transplantation, Ctr Int Blood Marrow Transplantation C1 NIH, Stem Cell Allotransplantat Sect, Hematol Branch, Bethesda, MD 20892 USA. NIH, Dept Lab Med, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2005 VL 11 IS 2 SU 1 MA 129 BP 44 EP 44 DI 10.1016/j.bbmt.2004.12.130 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 902CM UT WOS:000227329000129 ER PT J AU Dean, RM Fowler, DH Odom, J Castro, KM Kasten-Sportes, C Wilson, WH Gress, RE Bishop, MR AF Dean, RM Fowler, DH Odom, J Castro, KM Kasten-Sportes, C Wilson, WH Gress, RE Bishop, MR TI Methotrexate alters hematopoietic recovery and engraftment kinetics when added to cyclosporine for acute GVHD prophylaxis after reduced-intensity stem cell transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Joint Meeting of the American-Society-for-Blood-and-Marrow-Transplantation/Center-for-Interna tional-Blood-and-Marrow-Transplant-Research CY FEB 10-14, 2005 CL Keystone, CO SP Amer Soc Blood Marrow Transplantation, Ctr Int Blood Marrow Transplantation C1 NCI, Ctr Canc Res, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2005 VL 11 IS 2 SU 1 MA 149 BP 51 EP 51 DI 10.1016/j.bbmt.2004.12.150 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 902CM UT WOS:000227329000149 ER PT J AU Sokolic, RA Burkholder, T Tuschong, LM Bacher, J Hai, M Gu, YC Bauer, TR Hickstein, DD AF Sokolic, RA Burkholder, T Tuschong, LM Bacher, J Hai, M Gu, YC Bauer, TR Hickstein, DD TI Nonmyeloablative conditioning with 200 cGy total body irradiation (TBI) prior to matched littermate allogeneic hematopoietic stem cell transplantation (HSCT) in dogs with canine leukocyte adhesion deficiency results in higher levels of engraftment and donor chimerism compared to busulfan alone SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Joint Meeting of the American-Society-for-Blood-and-Marrow-Transplantation/Center-for-Interna tional-Blood-and-Marrow-Transplant-Research CY FEB 10-14, 2005 CL Keystone, CO SP Amer Soc Blood Marrow Transplantation, Ctr Int Blood Marrow Transplantation C1 NCI, Expt Transplantat & Immunol Branch, Bethesda, MD 20892 USA. NIH, Div Vet Resources, Bethesda, MD 20892 USA. RI Sokolic, Robert/I-6072-2012 NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2005 VL 11 IS 2 SU 1 MA 238 BP 80 EP 81 DI 10.1016/j.bbmt.2004.12.238 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 902CM UT WOS:000227329000237 ER PT J AU Galgay, L Swift, S Cusak, G Jones-Wells, A Rivera, P Chisholm, L AF Galgay, L Swift, S Cusak, G Jones-Wells, A Rivera, P Chisholm, L TI Actualizing a wellness program and wellness room in the oncology setting: Getting a program through a large institution SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Joint Meeting of the American-Society-for-Blood-and-Marrow-Transplantation/Center-for-Interna tional-Blood-and-Marrow-Transplant-Research CY FEB 10-14, 2005 CL Keystone, CO SP Amer Soc Blood Marrow Transplantation, Ctr Int Blood Marrow Transplantation C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2005 VL 11 IS 2 SU 1 MA 259 BP 88 EP 88 DI 10.1016/j.bbmt.2004.12.259 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 902CM UT WOS:000227329000258 ER PT J AU Ramos, C Cook, L Shelburne, N Bevans, M AF Ramos, C Cook, L Shelburne, N Bevans, M TI The nurse's role as coordinator in the safe and effective management of patients with comorbidities undergoing allogeneic stem cell transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Joint Meeting of the American-Society-for-Blood-and-Marrow-Transplantation/Center-for-Interna tional-Blood-and-Marrow-Transplant-Research CY FEB 10-14, 2005 CL Keystone, CO SP Amer Soc Blood Marrow Transplantation, Ctr Int Blood Marrow Transplantation C1 NIH, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU CARDEN JENNINGS PUBL CO LTD PI CHARLOTTESVILLE PA BLAKE CTR, STE 200, 1224 W MAIN ST, CHARLOTTESVILLE, VA 22903 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2005 VL 11 IS 2 SU 1 MA 309 BP 103 EP 103 DI 10.1016/j.bbmt.2004.12.309 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 902CM UT WOS:000227329000308 ER PT J AU Huang, ZH Somanath, PR Chakrabarti, R Eddy, EM Vijayaraghavan, S AF Huang, ZH Somanath, PR Chakrabarti, R Eddy, EM Vijayaraghavan, S TI Changes in intracellular distribution and activity of protein phosphatase PP1 gamma 2 and its regulating proteins in spermatozoa lacking AKAP4 SO BIOLOGY OF REPRODUCTION LA English DT Article DE Akap4 gene knockout; epididymis; GSK-3; phosphatases; PP1 gamma 2; SP17; sperm; sperm motility and transport; testis ID GLYCOGEN-SYNTHASE KINASE-3; ZONA-PELLUCIDA BINDING; FIBROUS SHEATH; ANCHORING PROTEINS; MOUSE SPERM; SIGNAL-TRANSDUCTION; PHOSPHORYLATION; MOTILITY; LOCALIZATION; SUBUNITS AB The second messenger cAMP mediates its intracellular effects in spermatozoa through cAMP-dependent kinase (PKA, formally known as PRKACA). The intracellular organization of PKA in spermatozoa is controlled through its association with A-kinase-anchoring proteins (AKAPs). AKAP4 (A kinase [PRKA] anchor protein 4; also called fibrous sheath component 1 or AKAP 82) is sperm specific and the major fibrous sheath protein of the principal piece of the sperm flagellum. Presumably, AKAP4 recruits PKA to the fibrous sheath and facilitates local phosphorylation to regulate flagellar function. It is also proposed to act as a scaffolding protein for signaling proteins and proteins involved in metabolism. Akap4 gene knockout mice are infertile due to the lack of sperm motility. The fibrous sheath is disrupted in spermatozoa from mutant mice. In this article, we used A 4 gene knockout mice to study the effect of fibrous sheath disruption on the presence, subcellular distribution, and/or activity changes of PKA catalytic and regulatory subunits, sperm flagellum proteins PP1gamma2 (protein phosphatase 1, catalytic subunit, gamma isoform, formally known as PPP1CC), GSK-3 (glycogen synthase kinase-3), SP17 (sperm autoantigenic protein 17, formally known as SPA17), and other signaling proteins. There were no changes in the presence and subcellular distribution for PP1gamma2, GSK-3, hsp90 (heat shock protein 1, alpha, formally known as HSPCA), sds22 (protein phosphatase 1, regulatory [inhibitor] subunit 7, formally known as PPP1R7), 14-3-3 protein (tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein), and PKB (thymoma viral proto-oncogene, also known as AKT) in mutant mice. However, the subcellular distributions for PKA catalytic subunit and regulatory subunits, PI 3-kinase (phosphatidylinositol 3-kinase), and SP17 were disrupted in mutant mice. Furthermore, there was a significant change in the activity and phosphorylation of PP1gamma2 in mutant compared with wild-type spermatozoa. These studies have identified potentially significant new roles for the fibrous sheath in regulating the activity and function of key signaling enzymes. C1 Kent State Univ, Dept Biol Sci, Kent, OH 44242 USA. Cleveland Clin Fdn, Dept Mol Cardiol, Ctr Thrombosis & Vasc Biol, Lerner Res Inst, Cleveland, OH 44195 USA. NIEHS, Gamete Biol Sect, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Huang, ZH (reprint author), Kent State Univ, Dept Biol Sci, Kent, OH 44242 USA. EM zhuang1@kent.edu FU NICHD NIH HHS [R01 HD38520] NR 44 TC 25 Z9 26 U1 1 U2 2 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 FEB PY 2005 VL 72 IS 2 BP 384 EP 392 DI 10.1095/biolreprod.104.034140 PG 9 WC Reproductive Biology SC Reproductive Biology GA 890SZ UT WOS:000226532400015 PM 15385410 ER PT J AU Hovey, RC Asai-Sato, M Warri, A Terry-Koroma, B Colyn, N Ginsburg, E Vonderhaar, BK AF Hovey, RC Asai-Sato, M Warri, A Terry-Koroma, B Colyn, N Ginsburg, E Vonderhaar, BK TI Effects of neonatal exposure to diethylstilbestrol, tamoxifen, and toremifene on the BALB/c mouse mammary gland SO BIOLOGY OF REPRODUCTION LA English DT Article DE estradiol; lactation; mammary glands; prolactin; puberty ID HUMAN-BREAST-CANCER; ESTROGEN-RECEPTOR MODULATORS; PROGESTERONE-RECEPTOR; MESSENGER-RNA; FEMALE BALB-CFC3H; EPITHELIAL-CELLS; GROWTH-HORMONE; ADULT MICE; IN-UTERO; FAT PAD AB In this study, we compared the long-term effects of neonatal exposure to diethylstilbestrol (DES, 0.0125-50 mug), tamoxifen (TAM, 0.0125-50 mug), and toremifene (TOR, 53 mug) on mammary gland development and differentiation. Allometric growth of the mammary ducts was stimulated by neonatal DES exposure (112.5 mug) and impaired by exposure to TAM (25 mug). Neonatal treatment with high doses of DES resulted in mammary ducts that displayed extensive dilatation and precocious lactogenesis in postpubertal, nulliparous females. Initiation of this precocious differentiation coincided with the absence of corpora lutea, increased levels of serum prolactin (PRL), and the induction of Prl mRNA expression within the mammary glands. Neonatal exposure to 1.25 mug TAM increased alveolar development in postpubertal, nulliparous females similar to that recorded in females treated with low doses of DES. Lower doses of TAM did not affect alveolar development, whereas branching morphogenesis and alveolar development were impaired by higher doses. increased alveolar development in females exposed to 1.25 jig TAM was associated with elevated serum progesterone (P) and increased alveolar development in response to exogenous P. Taken together, our findings demonstrate that neonatal exposure to both DES and TAM exerts long-lasting effects on the proliferation and differentiation of the mammary glands in female BALB/c, primarily as the result of endocrine disruption. C1 NCI, Mol & Cellular Endocrinol Sect, Mammary Biol & Tumorigenesis Lab, NIH, Bethesda, MD 20892 USA. RP Hovey, RC (reprint author), Univ Vermont, Dept Anim Sci, Lactat & Mammary Gland Biol Grp, 121 Terril Hall,570 Main St, Burlington, VT 05405 USA. NR 65 TC 26 Z9 28 U1 0 U2 3 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 FEB PY 2005 VL 72 IS 2 BP 423 EP 435 DI 10.1095/biolreprod.104.029769 PG 13 WC Reproductive Biology SC Reproductive Biology GA 890SZ UT WOS:000226532400020 PM 15470002 ER PT J AU Li, WJ Tuli, R Okafor, C Derfoul, A Danielson, KG Hall, DJ Tuan, RS AF Li, WJ Tuli, R Okafor, C Derfoul, A Danielson, KG Hall, DJ Tuan, RS TI A three-dimensional nanofibrous scaffold for cartilage tissue engineering using human mesenchymal stem cells SO BIOMATERIALS LA English DT Article DE electrospinning; nanofiber; mesenchymal stein cello; cartilage tissue engineering; transforming growth factor-beta1 ID MARROW STROMAL CELLS; IN-VITRO CHONDROGENESIS; HUMAN TRABECULAR BONE; PROGENITOR CELLS; GROWTH-FACTORS; DIFFERENTIATION; MATRIX; REPAIR; CHONDROCYTES; EXPRESSION AB The utilization of adult stem cells in tissue engineering is a promising solution to the problem of tissue or organ shortage. Adult bone marrow derived mesenchymal stem cells (MSCs) are undifferentiated, multipotential cells which are capable of giving rise to chondrocytes when maintained in a three-diniensional culture and treated with members of the transforming growth factor-beta (TGF-beta) family of growth factors. In this study, we fabricated a nanofibrous scaffold (NFS) made of a synthetic biodegradable polymer, poly(epsilon-caprolactoile) (PCL), and examined its ability to support in vitro chondrogenesis of MSCs. The electrospun PCL porous scaffold was constructed of uniform, randomly oriented nanofibers with a diameter of 700 nm, and structural integrity of this scaffold was maintained over a 21-day culture period. MSCs cultured in NFSs in the presence of TGF-beta1 differentiated to a chondrocytic phenotype, as evidenced by chondrocyte-specific gene expression and synthesis of cartilage-associated extracellular matrix (ECM) proteins. The level of chondrogenesis observed in MSCs seeded within NFSs was comparable to that observed for MSCs maintained as cell aggregates or pellets, a widely used culture protocol for studying chondrogenesis of MSCs in vitro. Due to the physical nature and improved mechanical properties of NFSs, particularly in comparison to cell pellets, the findings reported here suggest that the PCL NFS is a practical carrier for MSC transplantation, and represents a candidate scaffold for cell-based tissue engineering approaches to cartilage repair. (C) 2004 Elsevier Ltd. All rights reserved. C1 NIAMSD, Dept Hlth & Human Serv, Cartilage Biol & Orthpaed Branch, NIH, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Cell & Tissue Engn Grad Program, Philadelphia, PA 19107 USA. RP Tuan, RS (reprint author), NIAMSD, Dept Hlth & Human Serv, Cartilage Biol & Orthpaed Branch, NIH, 50 Room 1503,50 South Dr,MSC 8022, Bethesda, MD 20892 USA. EM tuanr@mail.nih.gov RI Li, Wan-Ju/A-7002-2008 FU NIAMS NIH HHS [Z01AR41131] NR 52 TC 561 Z9 606 U1 23 U2 269 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0142-9612 J9 BIOMATERIALS JI Biomaterials PD FEB PY 2005 VL 26 IS 6 BP 599 EP 609 DI 10.1016/j.biomaterials.2004.03.005 PG 11 WC Engineering, Biomedical; Materials Science, Biomaterials SC Engineering; Materials Science GA 857RK UT WOS:000224135800003 PM 15282138 ER PT J AU Marchais-Oberwinkler, S Nowicki, B Pike, VW Halldin, C Sandell, J Chou, YH Gulyas, B Brennum, LT Farde, L Wikstrom, HV AF Marchais-Oberwinkler, S Nowicki, B Pike, VW Halldin, C Sandell, J Chou, YH Gulyas, B Brennum, LT Farde, L Wikstrom, HV TI N-Oxide analogs of WAY-100635: new high affinity 5-HT1A receptor antagonists SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE WAY-100635 5-HT1A receptor antagonist; high affinity; pyridinyl N-oxide; PET; aromatic nucleophilic substitution ID MASS-SPECTROMETRY IDENTIFICATION; IN-VIVO; RAT HEPATOCYTES; HUMAN BRAIN; PET; METABOLITES; RADIOLIGAND; C-11; DERIVATIVES; CLOZAPINE AB WAY-100635 [N-(2-(1-(4-(2-methoxyphenyl)piperazinyl)ethyl))-N-(2-pyridinyl)cyclohexanecarboxamide] 1 and its O-des-methyl derivative DWAY 2 are well-known high affinity 5-HT1A receptor antagonists. which when labeled with carbon-II (beta(+): t(1/2) 20.4min) in the carbonyl group are effective radioligands for imaging brain receptors with positron emission tomography (PET). In a search for new 5-HT1A antagonists with different pharmacokinetic and metabolic properties, the pyridinyl X-oxide moiety was incorporated into analogs of 1 and 2. NOWAY 3, in which the pyridinyl ring of I was oxidized to the pyridinyl X-oxide. was prepared via nucleophilic substitution of 2-[4-(2-methoxyphenyl)piperazin-1-yl]ethylamine on 2-chloropyridine-N-oxide followed by acylation with cyclohexanecarbonyl chloride. 6Cl-NOWAY 4. a more lipophilic (pyridinyl-6)-chloro derivative of 3. was prepared by treating 1-(2-methoxyphenyl)-4-(2-(2 -(6-bromo)aminopyridinyl-N-oxide)ethyl)piperazine with cyclohexanecarbonyl chloride for acylation and concomitant chloro for bromo substitution. NEWWAY 5. in which the 2-hydroxy-phenyl group of 2 is replaced with a 2-pyridinyl N-oxide group with the intention of mimicking the topology of 2. was prepared in five steps from 2-(chloroacetylamino)pyridine. AI-Oxides 3-5 were found to be high affinity antagonists at 5-HT1A receptors, with 3 having the highest affinity and a K-i value (0.22 nM) comparable to that of 1 (0.17 nM). By calculation the lipophilicity of 3 (Log,P = 1.87) is lower than that of 1 by 1.25 Log P units while TLC and reverse phase H PLC indicate that 3 has slightly lower lipophilicity than 1. On the basis of these encouraging findings, the N-oxide 3 was selected for labeling with carbon-l I in its carbonyl group and for evaluation as a radioligand with PET. After intravenous injection of [carbonyl-C-11 ]3 into cynomolgus monkey there was very low uptake of radioactivity into brain and no PET image of brain 5-HT1A receptors was obtained. Either 3 inadequately penetrates the blood-brain barrier or it is excluded from brain by an active efflux mechanism. Rapid deacylation or 3 was not apparent in vivo: in cynomolgus monkey plasma radioactive metabolites of [carbonyl-C-11]3 appeared less rapidly than from the radioligands [carbonyl-C-11]1 and [carbonyl-C-11]2, which are known to be primarily metabolized by deacylation. Ligand 3 may have value as a new pharmacological tool, but not as a radioligand for brain imaging. (C) 2004 Elsevier Ltd. All rights reserved. C1 Univ Groningen, Ctr Pharm, Dept Med Chem, NL-9713 AV Groningen, Netherlands. NIMH, PET Radiopharmaceut Sci, Mol Imaging Branch, NIH, Bethesda, MD 20892 USA. Karolinska Hosp, Karolinska Inst, Dept Clin Neurosci, Psychiat Sect, S-17176 Stockholm, Sweden. H Lundbeck & Co AS, Dept Mol Pharmacol, DK-2500 Valby, Denmark. RP Marchais-Oberwinkler, S (reprint author), Univ Saarland, Postfach 151150, D-66041 Saarbrucken, Germany. EM s.marchais@mx.uni-saarland.de RI Gulyas, Balazs/F-9508-2015 NR 49 TC 15 Z9 15 U1 0 U2 6 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 FEB 1 PY 2005 VL 13 IS 3 BP 883 EP 893 DI 10.1016/j.bmc.2004.10.033 PG 11 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 892UZ UT WOS:000226676800029 PM 15653354 ER PT J AU Fujita, Y Tsuda, Y Motoyama, T Li, TY Miyazaki, A Yokoi, T Sasaki, Y Ambo, A Niizuma, H Jinsmaa, Y Bryant, SD Lazarus, LH Okada, Y AF Fujita, Y Tsuda, Y Motoyama, T Li, TY Miyazaki, A Yokoi, T Sasaki, Y Ambo, A Niizuma, H Jinsmaa, Y Bryant, SD Lazarus, LH Okada, Y TI Studies on the structure-activity relationship of 2 ',6 '-dimethyl-L-tyrosine (Dmt) derivatives: bioactivity profile of H-Dmt-NH-CH3 SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Dmt; mu-opioid agonist; structure-activity relationship ID OPIOID RECEPTOR AGONISTS; HIGH-AFFINITY; TIC PHARMACOPHORE; AMPHIBIAN SKIN; ENDOGENOUS AGONIST; MEDIATED ANALGESIA; POTENT; PEPTIDES; SELECTIVITY; DERMORPHIN AB The 2',6'-dimethyl-L-tyrosine (Dmt) enhances receptor affinity, functional bioactivity and in vivo analgesia of opioid peptides. To further investigate its direct influence on these opioid parameters, we developed a series of compounds (H-Dmt-NH-X). Among them, H-Dmt-NH-CH3 showed the highest affinity (K(i)mu = 7.45 nM) equal to that of morphine, partial mu-opioid agonism (E-max = 66.6%) in vitro and a moderate antinociception in mice. (C) 2004 Elsevier Ltd. All rights reserved. C1 Kobe Gakuin Univ, Grad Sch Food & Med Sci, Nishi Ku, Kobe, Hyogo 6512180, Japan. Kobe Gakuin Univ, Fac Pharmaceut Sci, Dept Med Chem, Nishi Ku, Kobe, Hyogo 6512180, Japan. Kobe Gakuin Univ, High Technol Res Ctr, Nishi Ku, Kobe, Hyogo 6512180, Japan. Tohoku Pharmaceut Univ, Dept Biochem, Aoba Ku, Sendai, Miyagi 9818558, Japan. NIEHS, Med Chem Grp, LCBRA, Res Triangle Pk, NC 27709 USA. RP Okada, Y (reprint author), Kobe Gakuin Univ, Grad Sch Food & Med Sci, Nishi Ku, Kobe, Hyogo 6512180, Japan. EM okada@pharm.kobegakuin.ac.jp NR 36 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 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 1 PY 2005 VL 15 IS 3 BP 599 EP 602 DI 10.1016/j.bmcl.2004.11.040 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 896LN UT WOS:000226935700021 PM 15664820 ER PT J AU Jiang, JK Thomas, CJ Neumann, S Lu, XP Rice, KC Gershengorn, MC AF Jiang, JK Thomas, CJ Neumann, S Lu, XP Rice, KC Gershengorn, MC TI 1-(Phenyl)isoquinoline carboxamides: a novel class of subtype selective inhibitors of thyrotropin-releasing hormone (TRH) receptors SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE TRH; TRH receptors; PK 11195 ID BINDING AB We report the synthesis of and binding to the two subtypes of mouse thyrotropin -releasing hormone (TRH) receptors, TRH-R1 and TRH-R2, of several 1-(phenyl)isoquinoline carboxamide analogues. These analogues showed a degree of selectivity for binding at TRH-R2. These are the first ligands reported that show selective binding to these receptors. Published by Elsevier Ltd. C1 NIDDK, Clin Endocrinol Branch, NIH, Bethesda, MD 20892 USA. NIDDK, Clin Endocrinol Branch, Chem Biol Core Facility, Bethesda, MD 20892 USA. NIDDK, Clin Endocrinol Branch, Med Chem Lab, Bethesda, MD 20892 USA. RP Gershengorn, MC (reprint author), NIDDK, Clin Endocrinol Branch, NIH, Bldg 10,Room 9N-222, Bethesda, MD 20892 USA. EM marving@intra.niddk.nih.gov FU Intramural NIH HHS [Z01 DK070005-04] NR 10 TC 5 Z9 5 U1 0 U2 0 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 1 PY 2005 VL 15 IS 3 BP 733 EP 736 DI 10.1016/j.bmcl.2004.11.017 PG 4 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 896LN UT WOS:000226935700048 PM 15664847 ER PT J AU Sun, HY Nikolovska-Coleska, Z Chen, JY Yang, CY Tomita, Y Pan, HG Yoshioka, Y Krajewski, K Roller, PP Wang, SM AF Sun, HY Nikolovska-Coleska, Z Chen, JY Yang, CY Tomita, Y Pan, HG Yoshioka, Y Krajewski, K Roller, PP Wang, SM TI Structure-based design, synthesis and biochemical testing of novel and potent Smac peptido-mimetics SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE Smac; peptido-mimetics; XIAP ID PROMOTES APOPTOSIS; IAP PROTEINS; BIR DOMAIN; XIAP; SMAC/DIABLO; INHIBITOR; CASPASE; BINDING; DIABLO; CANCER AB Structure-based design, chemical synthesis and biochemical testing of a series of novel Smac peptido-mimetics as inhibitors of XIAP protein are described. The most potent compound, 6j, has a binding affinity (K-i value) of 24 nM to XIAP BIR3 protein and is 24 times more potent than the native Smac AVPI peptide. Further optimization of these potent Smac mimetics may ultimately lead to the development of a novel class of anticancer drugs for the treatment of human cancer by overcoming apoptosis-resistance of cancer cells through targeting the inhibitor of apoptosis proteins. (C) 2004 Elsevier Ltd. All rights reserved. C1 Univ Michigan, Ctr Comprehens Canc, Dept Internal Med, Ann Arbor, MI 48109 USA. Univ Michigan, Ctr Comprehens Canc, Dept Med Chem, Ann Arbor, MI 48109 USA. Georgetown Univ, Med Ctr, Vincent T Lombardi Canc Res Ctr, Washington, DC 20057 USA. NCI, Frederick Canc Res & Dev Ctr, Med Chem Lab, Frederick, MD 21702 USA. RP Wang, SM (reprint author), Univ Michigan, Ctr Comprehens Canc, Dept Internal Med, 1500 E Med Ctr Dr, Ann Arbor, MI 48109 USA. EM shaomeng@umich.edu FU NCI NIH HHS [1R01CA109025] NR 21 TC 45 Z9 49 U1 1 U2 5 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 1 PY 2005 VL 15 IS 3 BP 793 EP 797 DI 10.1016/j.bmcl.2004.11.008 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 896LN UT WOS:000226935700060 PM 15664859 ER PT J AU Minton, AP AF Minton, AP TI Models for excluded volume interaction between an unfolded protein and rigid macromolecular cosolutes: Macromolecular crowding and protein stability revisited SO BIOPHYSICAL JOURNAL LA English DT Article ID POROUS NETWORKS; POLYMER-CHAINS; 3 DIMENSIONS; EXCLUSION; DEXTRAN; POLYSACCHARIDES; CONSEQUENCES; EQUILIBRIUM; SOLUBILITY; SIMULATION AB Statistical-thermodynamic models for the excluded volume interaction between an unfolded polypeptide chain and a hard sphere or hard rod cosolute are presented, permitting estimation of the free energy of transfer of a polypeptide chain with fixed radius of gyration from a dilute (ideal) solution to a solution containing volume fraction phi of either cosolute. Also presented is a general thermodynamic description of the equilibrium between a unique native state and a manifold of unfolded or partially unfolded states of a protein distinguished by their respective radii of gyration. Together with results of a Monte Carlo calculation of the distribution of radii of gyration of four different unfolded proteins published by Goldenberg in 2003, these models are used to estimate the effect of intermolecular excluded volume upon an experimentally measurable apparent two-state constant for equilibrium between native and nonnative conformations of each of the four proteins, and upon the experimentally measurable root mean-square radius of gyration of the unfolded protein. Model calculations predict that addition of inert cosolutes at volume fractions exceeding 0.1 stabilizes the native state relative to unfolded states by an amount that increases strongly with phi and with the size of the native protein relative to the size of inert cosolute, and results in significant compaction of the manifold of unfolded states. Predicted effects are in qualitative and/or semiquantitative accord with the results of several published experimental studies. C1 NIDDKD, NIH, US Dept Hlth & Human Serv, Lab Biochem & Genet,Sect Phys Biochem, Bethesda, MD 20892 USA. RP Minton, AP (reprint author), NIDDKD, NIH, US Dept Hlth & Human Serv, Lab Biochem & Genet,Sect Phys Biochem, Bldg 8,Rm 226, Bethesda, MD 20892 USA. EM minton@helix.nih.gov OI Minton, Allen/0000-0001-8459-1247 NR 33 TC 175 Z9 177 U1 5 U2 43 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD FEB PY 2005 VL 88 IS 2 BP 971 EP 985 DI 10.1529/biophysj.104.050351 PG 15 WC Biophysics SC Biophysics GA 893WI UT WOS:000226750800020 PM 15596487 ER PT J AU Kuzmin, PI Akimov, SA Chizmadzhev, YA Zimmerberg, J Cohen, FS AF Kuzmin, PI Akimov, SA Chizmadzhev, YA Zimmerberg, J Cohen, FS TI Line tension and interaction energies of membrane rafts calculated from lipid splay and tilt SO BIOPHYSICAL JOURNAL LA English DT Article ID ATOMIC-FORCE MICROSCOPY; PROTEIN INTERACTION; BENDING ELASTICITY; MODEL MEMBRANES; CELL-MEMBRANES; PHOSPHOLIPID-MEMBRANES; CYLINDRICAL INCLUSIONS; BILAYER DEFORMATIONS; PHASE-EQUILIBRIA; FLUID MEMBRANES AB Membrane domains known as rafts are rich in cholesterol and sphingolipids, and are thought to be thicker than the surrounding membrane. If so, monolayers should elastically deform so as to avoid exposure of hydrophobic surfaces to water at the raft boundary. We calculated the energy of splay and tilt deformations necessary to avoid such hydrophobic exposure. The derived value of energy per unit length, the line tension gamma, depends on the elastic moduli of the raft and the surrounding membrane; it increases quadratically with the initial difference in thickness between the raft and surround; and it is reduced by differences, either positive or negative, in spontaneous curvature between the two. For zero spontaneous curvature, gamma is similar to1 pN for a monolayer height mismatch of similar to0.3 nm, in agreement with experimental measurement. Our model reveals conditions that could prevent rafts from forming, and a mechanism that can cause rafts to remain small. Prevention of raft formation is based on our finding that the calculated line tension is negative if the difference in spontaneous curvature for a raft and the surround is sufficiently large: rafts cannot form if gamma<0 unless molecular interactions ( ignored in the model) are strong enough to make the total line tension positive. Control of size is based on our finding that the height profile from raft to surround does not decrease monotonically, but rather exhibits a damped, oscillatory behavior. As an important consequence, the calculated energy of interaction between rafts also oscillates as it decreases with distance of separation, creating energy barriers between closely apposed rafts. The height of the primary barrier is a complex function of the spontaneous curvatures of the raft and the surround. This barrier can kinetically stabilize the rafts against merger. Our physical theory thus quantifies conditions that allow rafts to form, and further, defines the parameters that control raft merger. C1 Rush Univ, Sch Med, Dept Mol Biophys & Physiol, Chicago, IL 60612 USA. Russian Acad Sci, Fumkin Inst Electrochem, Lab Bioelectrochem, Moscow 119071, Russia. NICHHD, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Cohen, FS (reprint author), Rush Univ, Sch Med, Dept Mol Biophys & Physiol, Chicago, IL 60612 USA. EM fcohen@rush.edu RI Wunder, Stephanie/B-5066-2012; Chizmadzhev, Yuri/L-1984-2013; Akimov, Sergey/L-2001-2013; Zdilla, Michael/B-4145-2011; Akimov, Sergey/I-6432-2015 FU NIGMS NIH HHS [R01 GM066837] NR 59 TC 171 Z9 172 U1 8 U2 45 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD FEB PY 2005 VL 88 IS 2 BP 1120 EP 1133 DI 10.1529/biophysj.104.048223 PG 14 WC Biophysics SC Biophysics GA 893WI UT WOS:000226750800032 PM 15542550 ER PT J AU Christoph, GW Hofrichter, J Eaton, WA AF Christoph, GW Hofrichter, J Eaton, WA TI Understanding the shape of sickled red cells SO BIOPHYSICAL JOURNAL LA English DT Article ID HEMOGLOBIN-S FIBERS; HOMOGENEOUS NUCLEATION; HYDROXYUREA THERAPY; DOMAIN FORMATION; POLYMERIZATION; KINETICS; GELATION; DISEASE; MECHANISM; ANEMIA AB To understand the physical basis of the wide variety of shapes of deoxygenated red cells from patients with sickle cell anemia, we have measured the formation rate and volume distribution of the birefringent domains of hemoglobin S fibers. We find that the domain formation rate depends on the similar to80th power of the protein concentration, compared to similar to40th power for the concentration dependence of the reciprocal of the delay time that precedes fiber formation. These remarkably high concentration dependences, as well as the exponential distribution of domain volumes, can be explained by the previously proposed double nucleation model in which homogeneous nucleation of a single fiber triggers the formation of an entire domain via heterogeneous nucleation and growth. The enormous sensitivity of the domain formation rate to intracellular hemoglobin S concentration explains the variable cell morphology and why rapid polymerization results in cells that do not appear sickled at all. C1 NIDDKD, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Eaton, WA (reprint author), NIDDKD, Phys Chem Lab, NIH, Bldg 5,Rm 104, Bethesda, MD 20892 USA. EM eaton@helix.nih.gov NR 40 TC 33 Z9 35 U1 1 U2 8 PU BIOPHYSICAL SOCIETY PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0006-3495 J9 BIOPHYS J JI Biophys. J. PD FEB PY 2005 VL 88 IS 2 BP 1371 EP 1376 DI 10.1529/biophysj.104.051250 PG 6 WC Biophysics SC Biophysics GA 893WI UT WOS:000226750800054 PM 15542552 ER PT J AU Calvo, KR Liotta, LA Petricoin, EF AF Calvo, KR Liotta, LA Petricoin, EF TI Clinical proteomics: From biomarker discovery and cell signaling profiles to individualized personal therapy SO BIOSCIENCE REPORTS LA English DT Article DE Clinical Proteomics; mass spectroscopy; protein microarrays; combinatory theraphy; oncology; pathology; microdissection ID LASER CAPTURE MICRODISSECTION; HUMAN BREAST-CANCER; PHASE PROTEIN MICROARRAYS; PROSTATE-CANCER; GENE-EXPRESSION; TISSUE PROTEOMICS; OVARIAN-CANCER; POTENTIAL BIOMARKERS; PATTERN DIAGNOSTICS; MASS-SPECTROMETRY AB The discovery of new highly sensitive and specific biomarkers for early disease detection and risk stratification coupled with the development of personalized "designer" therapies holds the key to future treatment of complex diseases such as cancer. Mounting evidence confirms that the low molecular weight (LMW) range of the circulatory proteome contains a rich source of information that may be able to detect early stage disease and stratify risk. Current mass spectrometry (MS) platforms can generate a rapid and high resolution portrait of the LMW proteome. Emerging novel nanotechnology strategies to amplify and harvest these LMW biomarkers in vivo or ex vivo will greatly enhance our ability to discover and characterize molecules for early disease detection, subclassification and prognostic capability of current proteomics modalities. Ultimately genetic mutations giving rise to disease are played out and manifested on a protein level, involving derangements in protein function and information flow within diseased cells and the interconnected tissue microenvironment. Newly developed highly sensitive, specific and linearly dynamic reverse phase protein microarray systems are now able to generate circuit maps of information flow through phosphoprotein networks of pure populations of microdissected tumor cells obtained from patient biopsies. We postulate that this type of enabling technology will provide the foundation for the development of individualized combinatorial therapies of molecular inhibitors to target tumor-specific deranged pathways regulating key biologic processes including proliferation, differentiation, apoptosis, immunity and metastasis. Hence future therapies will be tailored to the specific deranged molecular circuitry of an individual patient's disease. The successful transition of these groundbreaking proteomic technologies from research tools to integrated clinical diagnostic platforms will require ongoing continued development, and optimization with rigorous standardization development and quality control procedures. C1 NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. US FDA, Off Cell Therapies & Gene Therapies, Ctr Biol Evaluat & Res, Rockville, MD 20852 USA. RP Calvo, KR (reprint author), NCI, Pathol Lab, NIH, Bldg 10, Bethesda, MD 20892 USA. EM calvok@mail.nih.gov RI Calvo, Katherine/A-8109-2009; OI Calvo, Katherine/0000-0002-0771-4191 NR 76 TC 91 Z9 96 U1 0 U2 14 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0144-8463 J9 BIOSCIENCE REP JI Biosci. Rep. PD FEB PY 2005 VL 25 IS 1-2 BP 107 EP 125 DI 10.1007/s10540-005-2851-3 PG 19 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 973ZH UT WOS:000232560600009 PM 16222423 ER PT J AU Chen, KG Gottesman, MM AF Chen, KG Gottesman, MM TI Useful tool to generate unidirectional deletion vectors by utilizing the star activity of BamHI in an NcoI-BamHI-XhoI cassette SO BIOTECHNIQUES LA English DT Article ID RECOGNITION; ENDONUCLEASE; SEQUENCE C1 NCI, Cell Biol Lab, NIH, Bethesda, MD 20892 USA. RP Gottesman, MM (reprint author), NCI, Cell Biol Lab, NIH, 37 Convent Dr,Room 2108, Bethesda, MD 20892 USA. EM mgottesman@nih.gov RI Chen, Kevin/D-6769-2011 OI Chen, Kevin/0000-0003-2983-6330 FU Intramural NIH HHS [Z99 NS999999] NR 6 TC 2 Z9 2 U1 0 U2 0 PU EATON PUBLISHING CO PI WESTBOROUGH PA ONE RESEARCH DRIVE, SUITE 400A, PO BOX 1070, WESTBOROUGH, MA 01581-6070 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD FEB PY 2005 VL 38 IS 2 BP 198 EP + DI 10.2144/05382BM05 PG 4 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 897IC UT WOS:000226996200007 PM 15727125 ER PT J AU Linask, KL Lo, CW AF Linask, KL Lo, CW TI High-throughput mouse genotyping using robotics automation SO BIOTECHNIQUES LA English DT Article ID DNA AB The use of mouse models is rapidly expanding in biomedical research. This has dictated the need for the rapid genotyping of mutant mouse colonies for more efficient utilization of animal holding space. We have established a high-throughput protocol for mouse genotyping using two robotics workstations: a liquid-handling robot to assemble PCR and a microfluidics electrophoresis robot for PCR product analysis. This dual-robotics setup incurs lower start-up costs than a fully automated system while still minimizing human intervention. Essential to this automation scheme is the construction of a database containing customized scripts for programming the robotics workstations. Using these scripts and the robotics systems, multiple combinations of genotyping reactions can be assembled simultaneously, allowing even complex genotyping data to be generated rapidly with consistency and accuracy. A detailed protocol, database, scripts, and additional background information are available at http://dir.nhlbi.nih.gov/labs/ldb-chd/autogene/. C1 NHLBI, Dev Biol Lab, NIH, Bethesda, MD 20816 USA. RP Lo, CW (reprint author), NHLBI, Dev Biol Lab, NIH, Bethesda, MD 20816 USA. EM loc@nhlbi.nih.gov FU NHLBI NIH HHS [Z01-HL005701] NR 5 TC 4 Z9 4 U1 0 U2 2 PU EATON PUBLISHING CO PI WESTBOROUGH PA ONE RESEARCH DRIVE, SUITE 400A, PO BOX 1070, WESTBOROUGH, MA 01581-6070 USA SN 0736-6205 J9 BIOTECHNIQUES JI Biotechniques PD FEB PY 2005 VL 38 IS 2 BP 219 EP 223 DI 10.2144/05382ST02 PG 5 WC Biochemical Research Methods; Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 897IC UT WOS:000226996200010 PM 15727128 ER PT J AU Jahnke, GD Iannucci, AR Scialli, AR Shelby, MD AF Jahnke, GD Iannucci, AR Scialli, AR Shelby, MD TI Center for the Evaluation of Risks to Human Reproduction - The first five years SO BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY LA English DT Article DE reproduction; fertility; development; birth defects; panel review ID DEVELOPMENTAL TOXICITY; PHTHALATE; PREGNANCY; HEALTH AB The National Toxicology Program (NTP) Center for the Evaluation of Risks to Human Reproduction (NTP-CERHR) was established by the NTP and the National Institute of Environmental Health Sciences (NIEHS) in 1998 to address the impact of chemical exposures on human reproductive and developmental health and to serve as an environmental and reproductive health resource for government agencies and the general public. The purpose of this report is to provide an overview of the Center activities and a summary of NTP conclusions on chemicals evaluated during this time period. CERHR evaluations involve the critical review of reproductive, developmental, and other relevant toxicity data by independent panels of scientists. The products of these evaluations are expert panel reports. The public has opportunities to provide oral comments at the panel meeting and written comments on draft and final expert panel reports. The NTP evaluates these comments, the conclusions of the expert panel, and any new data not available at the time of the panel meeting, and prepares an NTP brief that describes in plain language the NTP's conclusions on the reproductive and developmental hazard from specified chemical exposures. The NTP brief, expert panel report, and public comments comprise the NTP monograph on the chemical. Monographs are sent to federal regulatory agencies, the NTP Executive Committee, and the NTP Board of Scientific Counselors, and are publicly available. Over the last five years, CERHR conducted expert panel evaluations on 14 chemicals. At this time, 13 panel reports have been published and 12 NTP-CERHR monographs have been issued. Additionally, CERHR conducted a 2-day workshop on the role of thyroid hormones in reproductive and developmental health. Birth Defects Res B 74:1-8, 2005. Published 2005 Wiley-Liss, Inc. C1 NIEHS, Res Triangle Pk, NC 27709 USA. Sci Int Inc, Res Triangle Pk, NC USA. Sci Int Inc, Alexandria, VA USA. RP Jahnke, GD (reprint author), NIEHS, EC-32,79 TW Alexander Dr, Res Triangle Pk, NC 27709 USA. EM jahnke@niehs.nih.gov FU NIEHS NIH HHS [N01-ES-35503] NR 29 TC 11 Z9 12 U1 1 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-9733 J9 BIRTH DEFECTS RES B JI Birth Defects Res. Part B-Dev. Reprod. Toxicol. PD FEB PY 2005 VL 74 IS 1 BP 1 EP 8 DI 10.1002/bdrb.20028 PG 8 WC Oncology; Genetics & Heredity; Toxicology SC Oncology; Genetics & Heredity; Toxicology GA 905ZY UT WOS:000227611500001 PM 15729732 ER PT J AU Shelby, MD AF Shelby, MD TI National toxicology program center for the evaluation of risks to human reproduction: Guidelines for CERHR expert panel members SO BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY LA English DT Article C1 NIEHS, Res Triangle Pk, NC 27709 USA. RP Shelby, MD (reprint author), NIEHS, EC-32,POB 12233, Res Triangle Pk, NC 27709 USA. EM Shelby@niehs.nih.gov NR 4 TC 7 Z9 7 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-9733 J9 BIRTH DEFECTS RES B JI Birth Defects Res. Part B-Dev. Reprod. Toxicol. PD FEB PY 2005 VL 74 IS 1 BP 9 EP 16 DI 10.1002/bdrb.20029 PG 8 WC Oncology; Genetics & Heredity; Toxicology SC Oncology; Genetics & Heredity; Toxicology GA 905ZY UT WOS:000227611500002 PM 15729730 ER PT J AU Manson, J Brabec, MJ Buelke-Sam, J Carlson, GP Chapin, RE Favor, JB Fischer, LJ Hattis, D Lees, PSJ Perreault-Darney, S Rutledge, J Smith, TJ Tice, RR Working, P AF Manson, J Brabec, MJ Buelke-Sam, J Carlson, GP Chapin, RE Favor, JB Fischer, LJ Hattis, D Lees, PSJ Perreault-Darney, S Rutledge, J Smith, TJ Tice, RR Working, P TI NTP-CERHR expert panel report on the reproductive and developmental toxicity of acrylamide SO BIRTH DEFECTS RESEARCH PART B-DEVELOPMENTAL AND REPRODUCTIVE TOXICOLOGY LA English DT Review ID MALE GERM-CELLS; EPOXIDE METABOLITE GLYCIDAMIDE; MALE-MICE; HEMOGLOBIN ADDUCTS; DOMINANT LETHAL; HERITABLE TRANSLOCATIONS; DRINKING-WATER; MORTALITY PATTERNS; LOCUS MUTATIONS; MINIATURE PIGS C1 Univ Penn, Philadelphia, PA 19104 USA. Eastern Michigan Univ, Ypsilanti, MI 48197 USA. Toxicol Serv, Greenfield, IN USA. Purdue Univ, W Lafayette, IN 47907 USA. Pfizer Inc, Groton, CT 06340 USA. GSF, Natl Res Ctr Environm & Hlth, Neuherberg, Germany. Michigan State Univ, Lansing, MI USA. Clark Univ, Worcester, MA 01610 USA. Johns Hopkins Univ, Baltimore, MD USA. US EPA, Res Triangle Pk, NC 27711 USA. Childrens Hosp, Seattle, WA USA. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Integrated Lab Syst Inc, Res Triangle Pk, NC USA. Cell Genesys Inc, San Francisco, CA USA. RP Manson, J (reprint author), NIEHS, EC-32,POB 12233, Res Triangle Pk, NC 27709 USA. EM shelby@niehs.nih.gov OI Chapin, Robert/0000-0002-5997-1261 NR 129 TC 19 Z9 20 U1 3 U2 10 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1542-9733 J9 BIRTH DEFECTS RES B JI Birth Defects Res. Part B-Dev. Reprod. Toxicol. PD FEB PY 2005 VL 74 IS 1 BP 17 EP 113 DI 10.1002/bdrb.20030 PG 97 WC Oncology; Genetics & Heredity; Toxicology SC Oncology; Genetics & Heredity; Toxicology GA 905ZY UT WOS:000227611500003 PM 15729727 ER PT J AU Weatherall, D Hofman, K Rodgers, G Ruffin, J Hrynkow, S AF Weatherall, D Hofman, K Rodgers, G Ruffin, J Hrynkow, S TI A case for developing North-South partnerships for research in sickle cell disease SO BLOOD LA English DT Article ID GLOBAL HEALTH; CHILDREN; ANEMIA; MALARIA; TIME AB For a better understanding of the pathophysiology and mechanisms of phenotypic diversity of sickle cell disease, and for the improvement of its management globally, there is a strong case for developing sustainable research partnerships between rich and poor countries. (C) 2005 by The American Society of Hematology. C1 Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Oxford OX3 9DS, England. Fogarty Int Ctr, Natl Inst Hlth, Bethesda, MD USA. NIDDKD, Mol & Clin Hematol Branch, NIH, Bethesda, MD 20892 USA. Natl Ctr Minor Hlth & Hlth Dispar, NIH, Bethesda, MD USA. RP Weatherall, D (reprint author), Univ Oxford, John Radcliffe Hosp, Weatherall Inst Mol Med, Oxford OX3 9DS, England. NR 29 TC 35 Z9 37 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 FEB 1 PY 2005 VL 105 IS 3 BP 921 EP 923 DI 10.1182/blood-2004-06-2404 PG 3 WC Hematology SC Hematology GA 891QX UT WOS:000226596700011 PM 15466925 ER PT J AU Byrd, JC Marcucci, G Parthun, MR Xiao, JJ Klisovic, RB Moran, M Lin, TS Liu, SJ Sklenar, AR Davis, ME Lucas, DM Fischer, B Shank, R Tejaswi, SL Binkley, P Wright, J Chan, KK Grever, MR AF Byrd, JC Marcucci, G Parthun, MR Xiao, JJ Klisovic, RB Moran, M Lin, TS Liu, SJ Sklenar, AR Davis, ME Lucas, DM Fischer, B Shank, R Tejaswi, SL Binkley, P Wright, J Chan, KK Grever, MR TI A phase 1 and pharmacodynamic study of depsipeptide (FK228) in chronic lymphocytic leukemia and acute myeloid leukemia SO BLOOD LA English DT Article ID HISTONE DEACETYLASE INHIBITOR; T-CELL LYMPHOMA; MYELODYSPLASTIC SYNDROMES; SODIUM PHENYLBUTYRATE; METHYLATION TARGETS; GENE-TRANSCRIPTION; DOSE-ESCALATION; DOWN-REGULATION; TRICHOSTATIN-A; UP-REGULATION AB Preclinical studies with the histone deacetylase (HDAC) inhibitor depsipeptide (FK228) in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) have demonstrated that it effectively induces apoptosis at concentrations at which HDAC inhibition occurs. We initiated a minimum effective pharmacologic dose study of depsipeptide, targeting an in vivo dose at which acetylation of histone proteins H3 and H4 increased by 100% or more in vitro. Ten patients with CLL and 10 patients with AML were treated with 13 mg/m(2) depsipeptide intravenously days 1, 8, and 15 of therapy. Neither life-threatening toxicities nor cardiac toxicities were noted, although the majority of patients experienced progressive fatigue, nausea, and other constitutional symptoms that prevented repeated dosing. Several patients had evidence of antitumor activity following treatment, but no partial or complete responses were noted by National Cancer Institute criteria. HDAC inhibition and histone acetylation increases of at least 100% were noted, as well as increases in p21 promoter H4 acetylation, p2l protein, and 1D10 antigen expression. We conclude that depsipeptide effectively inhibits HDAC in vivo in patients with CLL and AML, but its use in the current schedule of administration is limited by progressive constitutional symptoms. Future studies with depsipeptide should examine alternative administration schedules. (C) 2005 by The American Society of Hematology. C1 Ohio State Univ, Div Hematol Oncol, Columbus, OH 43210 USA. Ohio State Univ, Dept Internal Med, Columbus, OH 43210 USA. Ohio State Univ, Dept Mol & Cellular Biochem, Columbus, OH 43210 USA. Ohio State Univ, Coll Pharm, Columbus, OH 43210 USA. Ohio State Univ, Div Human Canc Genet, Columbus, OH 43210 USA. Ohio State Univ, Dept Med, Columbus, OH 43210 USA. Ohio State Univ, Div Cardiol, Columbus, OH 43210 USA. Natl Canc Inst, Canc Therapy Evaluat Program, Washington, DC USA. RP Byrd, JC (reprint author), Ohio State Univ, Div Hematol Oncol, Starling Loving Hall,Rm 302, Columbus, OH 43210 USA. EM byrd-3@medctr.osu.edu RI Klisovic, Rebecca/E-3401-2011; Lucas, David/E-3555-2011 FU NCI NIH HHS [K08 CA90469, P01 CA81534, R21 CA096323]; NHLBI NIH HHS [K24-HLO 4208] NR 58 TC 310 Z9 326 U1 1 U2 8 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 1 PY 2005 VL 105 IS 3 BP 959 EP 967 DI 10.1182/blood-2004-05-1693 PG 9 WC Hematology SC Hematology GA 891QX UT WOS:000226596700017 PM 15466934 ER PT J AU Laukkanen, MO Kuramoto, K Calmels, B Takatoku, M von Kalle, C Donahue, RE Dunbar, CE AF Laukkanen, MO Kuramoto, K Calmels, B Takatoku, M von Kalle, C Donahue, RE Dunbar, CE TI Low-dose total body irradiation causes clonal fluctuation of primate hematopoietic stem and progenitor cells SO BLOOD LA English DT Article ID MEDIATED GENE-TRANSFER; NONHUMAN-PRIMATES; IN-VIVO; ENGRAFTMENT; THERAPY; TRANSPLANTATION; MARKING; MODEL AB Due to high frequency of side effects caused by high-dose total body irradiation (TBI) the nonmyeloablative regimen together with cytotoxic agents is currently used especially for elderly patients. However, immediate and long-term effects of low-dose irradiation used in allogeneic transplantation on stem cells is less well known. We have studied the effect of low-dose 3 Gy TBI on the number of hematopoietic stem cell (HSC) clones contributing simultaneously to granulocyte production in rhesus macaque. The number of clones after 3 Gy TBI decreased markedly by 2 to 3 weeks after 3 Gy TBI, followed by a period of clonal instability, and recovery to almost pre-3 Gy TBI clonal diversity. The clones accounting for this recovery contributed before 3 Gy TBI, suggesting the profound initial impact of TBI was on a pool of progenitor cells, whereas most of the more primitive HSCs remained unaffected and were able to again contribute to hematopoiesis after recovery. Clonal fluctuation may indirectly suggest the presence of short-term/long-term HSC populations in rhesus macaque bone marrow as reported in a mouse model. The results indicate that even low-dose irradiation affects hernatopoietic clonal dynamics and have implications for design of conditioning regimens for transplantation purposes. (C) 2005 by The American Society of Hematology. C1 NHLBI, Mol Hematopoiesis Sect, Hematol Branch, Bethesda, MD 20892 USA. Cincinnati Childrens Hosp, Ctr Med, Childrens Res Fdn, Div Expt Hematol, Cincinnati, OH USA. RP Dunbar, CE (reprint author), NHLBI, Mol Hematopoiesis Sect, Hematol Branch, Bldg 10,Rm 7C103,9000 Rockville Pike, Bethesda, MD 20892 USA. EM dunbarc@nhlbi.nih.gov RI calmels, boris/R-2538-2016 NR 24 TC 19 Z9 21 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 1 PY 2005 VL 105 IS 3 BP 1010 EP 1015 DI 10.1182/blood-2004-04-1498 PG 6 WC Hematology SC Hematology GA 891QX UT WOS:000226596700025 PM 15383461 ER PT J AU Zhang, ML Zhang, Z Goldman, CK Janik, J Waldmann, TA AF Zhang, ML Zhang, Z Goldman, CK Janik, J Waldmann, TA TI Combination therapy for adult T-cell leukemia-xenografted mice: flavopiridol and anti-CD25 monoclonal antibody SO BLOOD LA English DT Article ID DEPENDENT KINASE INHIBITOR; METASTATIC BREAST-CANCER; MURINE MODEL; INTERLEUKIN-2 RECEPTOR; FC-RECEPTORS; ANTITUMOR-ACTIVITY; PHASE-I; LYMPHOMA; APOPTOSIS; TAC AB Adult T-cell leukemia (ATL) develops in a small proportion of individuals infected with human T-cell lymphotrophic virus-1. The leukemia consists of an overabundance of activated T cells, which express CD25 on their cell surfaces. Presently, there is no accepted curative therapy for ATL. Flavopiriclol, an inhibitor of cyclin-dependent kinases, has potent antiproliferative effects and antitumor activity. We investigated the therapeutic efficacy of flavopiridol alone and in combination with humanized anti-Tac antibody (HAT), which recognizes CD25, in a murine model of human ATL. The ATL model was established by intraperitoneal injection of MET-1 leukemic cells into nonobese diabetic/severe combined immunodeficient mice. Either flavopiridol, given 2.5 mg/kg body weight daily for 5 days, or HAT, given 100 mug weekly for 4 weeks, inhibited tumor growth as monitored by serum levels of human beta-2-microglobulin (beta2mu; P <.01), and prolonged survival of the leukemia-bearing mice (P <.05) as compared with the control group. Combination of the 2 agents dramatically enhanced the antitumor effect, as shown by both beta2mu levels and survival of the mice, when compared with those in the flavopiridol or HAT alone group (P <.01). The significantly improved therapeutic efficacy by combining flavopiridol with HAT provides support for a clinical trial in the treatment of ATL.(C) 2005 by The American Society of Hematology. C1 NCI, NIH, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Waldmann, TA (reprint author), NCI, NIH, Metab Branch, Ctr Canc Res, Bldg 10, Rm 4N115,10 Ctr Dr, Bethesda, MD 20892 USA. EM tawald@helix.nih.gov NR 32 TC 26 Z9 26 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 1 PY 2005 VL 105 IS 3 BP 1231 EP 1236 DI 10.1182/blood-2004-05-1709 PG 6 WC Hematology SC Hematology GA 891QX UT WOS:000226596700054 PM 15383455 ER PT J AU Crowder, C Dahle, O Davis, RE Gabrielsen, OS Rudikoff, S AF Crowder, C Dahle, O Davis, RE Gabrielsen, OS Rudikoff, S TI PML mediates IFN-alpha-induced apoptosis in myeloma by regulating TRAIL induction SO BLOOD LA English DT Article ID ACUTE PROMYELOCYTIC LEUKEMIA; PROTEIN-KINASE PATHWAY; MULTIPLE-MYELOMA; INTERFERON-ALPHA; TUMOR SUPPRESSION; NUCLEAR-BODIES; CELL-GROWTH; LIGAND; GENES; DAXX AB Interferon (IFN) induces expression of proapoptotic genes and has been used in the clinical treatment of multiple myeloma. The promyelocytic leukemia (PML) gene is an IFN-induced target that encodes a tumor suppressor protein. PML protein is typically localized within discrete speckled nuclear structures termed PML nuclear bodies (NBs). Multiple myeloma cells demonstrate differential responses to IFN treatment, the mechanism of which is largely unknown. Herein, we show that growth inhibition effects of IFN-alpha in myeloma cells correlate with PML NBs and tumor necrosis factor (TNF)related apoptosis-inducing ligand (TRAIL) induction, whereas known IFN targets including signal transducer and activator of transcription-1 (STAT1), STAT3, p38, and Daxx cannot account for these differential responses. RNAi silencing of PML blocks IFN-alpha-induced apoptosis in myeloma cells and correspondingly down-regulates TRAIL expression. Similarly, stable expression of a dominant negative TRAIL receptor DR5 partially blocks IFN-induced cell death. These results demonstrate that PML and TRAIL play important roles in IFN-induced apoptosis and identify TRAIL as a novel downstream transcriptional target of PML. Identification of PML and PML NBs as effectors of IFN responses provides insights into mechanisms by which tumor cells exhibit resistance to this class of agents and may prove useful in assessing treatment. (C) 2005 by The American Society of Hematology. C1 NCI, NIH, Cellular & Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. Univ Oslo, Dept Mol Biosci, Oslo, Norway. NCI, NIH, Metab Branch, Bethesda, MD 20892 USA. RP Rudikoff, S (reprint author), NCI, NIH, Cellular & Mol Biol Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM rudikoff@helix.nih.gov NR 48 TC 34 Z9 34 U1 0 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 2021 L ST NW, SUITE 900, WASHINGTON, DC 20036 USA SN 0006-4971 EI 1528-0020 J9 BLOOD JI Blood PD FEB 1 PY 2005 VL 105 IS 3 BP 1280 EP 1287 DI 10.1182/blood-2004-04-1614 PG 8 WC Hematology SC Hematology GA 891QX UT WOS:000226596700060 PM 15459016 ER PT J AU Verbeek, DS Knight, MA Harmison, GG Fischbeck, KH Howell, BW AF Verbeek, DS Knight, MA Harmison, GG Fischbeck, KH Howell, BW TI Protein kinase C gamma mutations in spinocerebellar ataxia 14 increase kinase activity and alter membrane targeting SO BRAIN LA English DT Article DE SCA14; spinocerebellar ataxia; PKC gamma; Purkinje cells ID LONG-TERM DEPRESSION; DOMAIN-CONTAINING PROTEINS; GREEN FLUORESCENT PROTEIN; PURKINJE-CELLS; PKC-GAMMA; CEREBELLAR-ATAXIA; SLICE CULTURES; LIVING CELLS; MUTANT MICE; PHOSPHORYLATION AB The protein kinase C gamma (PKCgamma) gene is mutated in spinocerebellar ataxia type 14 (SCA14). In this study, we investigated the effects of two SCA14 missense mutations, G118D and C150F, on PKCgamma function. We found that these mutations increase the intrinsic activity of PKCgamma. Direct visualization of labelled PKCgamma in living cells demonstrates that the mutant protein translocates more rapidly to selected regions of the plasma membrane in response to Ca2+ influx. These results point to specific alterations in mutant PKCgamma function that could lead to the selective neuronal degeneration of SCA14. C1 NINDS, Neurogenet Branch, NIH, Bethesda, MD 20892 USA. Univ Med Ctr Utrecht, Dept Med Genet, Utrecht, Netherlands. RP Howell, BW (reprint author), NINDS, Neurogenet Branch, NIH, 35 Convent Dr,Bldg 35 Rm 2A116, Bethesda, MD 20892 USA. EM howellb@ninds.nih.gov OI Howell, Brian/0000-0002-0204-0773 NR 35 TC 41 Z9 43 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD FEB PY 2005 VL 128 BP 436 EP 442 DI 10.1093/brain/awh378 PN 2 PG 7 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 891UF UT WOS:000226605800023 PM 15618281 ER PT J AU Simon, MS Korczak, JF Yee, CL Daling, JR Malone, KE Bernstein, L Marchbanks, PA Folger, SG McDonald, JA Norman, SA Strom, BL Deapen, D Ursin, G Burkman, RT Press, MF Schwartz, AG Spirtas, R AF Simon, MS Korczak, JF Yee, CL Daling, JR Malone, KE Bernstein, L Marchbanks, PA Folger, SG McDonald, JA Norman, SA Strom, BL Deapen, D Ursin, G Burkman, RT Press, MF Schwartz, AG Spirtas, R TI Racial differences in the familial aggregation of breast cancer and other female cancers SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE African-American; case-control study; Caucasian; epidemiology; familial clustering; familial risk; gynecological cancers ID UTAH POPULATION DATABASE; SOCIOECONOMIC-STATUS; RISK; HISTORY; ONSET; BRCA1; VALIDATION; RELATIVES; SURVIVAL; WOMEN AB Although breast cancer familial aggregation has been studied in Caucasians, information for African-Americans is scant. We used family cancer history from the Women's Contraceptive and Reproductive Experiences study to assess the aggregation of breast and gynecological cancers in African-American and Caucasian families. Information was available on 41,825 first and second-degree relatives of Caucasian and 28,956 relatives of African American participants. We used a cohort approach in which the relative's cancer status was the outcome in unconditional logistic regression and adjusted for correlated data using generalized estimating equations. Race-specific models included a family history indicator, the relative's age, and type. Relative risk (RR) estimates for breast cancer were highest for first-degree relatives, and the overall RR for breast cancer among case relatives was 1.96 (95% CI = 1.68-2.30) for Caucasian and 1.78 (95% CI = 1.41-2.25) for African-Americans. The effect of CARE participants' reference age on their relatives' breast cancer risk was greatest among first-degree relatives of African-American patients with RRs (95% CI) for ages <45 and greater than or equal to45 of 2.97 (1.86-4.74) and 1.48 (1.14-1.92), respectively. Among Caucasians, first-degree relatives of case subjects were at greater risk for ovarian cancer, particularly relatives younger than 45 years (RR (95% CI) = 2.06 (1.02-4.12)), whereas African-American first-degree relatives of case subjects were at increased cervical cancer risk (RR (95% CI) = 2.17 (1.22-3.85). In conclusion, these racially distinct aggregation patterns may reflect different modes of inheritance and/or environmental factors that impact cancer risk. C1 Wayne State Univ, Barbara Ann Karmanos Canc Inst, Div Hematol & Oncol, Detroit, MI 48201 USA. Wayne State Univ, Karmanos Canc Inst, Div Epidemiol, Detroit, MI 48202 USA. Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA. Univ Washington, Sch Publ Hlth & Community Med, Dept Epidemiol, Seattle, WA 98195 USA. Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA USA. Ctr Dis Control & Prevent, Div Reprod Hlth, Atlanta, GA USA. Univ Penn, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Penn, Dept Biostat & Epidemiol, Philadelphia, PA 19104 USA. Baystate Med Ctr, Dept Obstet & Gynecol, Springfield, MA USA. NICHHD, Contracept & Reprod Hlth Branch, Populat Res Ctr, Bethesda, MD 20892 USA. RP Simon, MS (reprint author), Wayne State Univ, Barbara Ann Karmanos Canc Inst, Div Hematol & Oncol, 4100 John R,4221 Hudson,Weber Canc Res Bldg, Detroit, MI 48201 USA. EM Simonm@karmanos.org FU NCI NIH HHS [CN65064]; NICHD NIH HHS [Y01-HD-7022, N01-HD-3-3176, N01-HD-3-3175, N01-HD-3-3174, N01-HD-2-3166, N01-HD-3-3168] NR 29 TC 7 Z9 7 U1 1 U2 1 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD FEB PY 2005 VL 89 IS 3 BP 227 EP 235 DI 10.1007/s10549-004-2046-9 PG 9 WC Oncology SC Oncology GA 904RC UT WOS:000227514400003 PM 15754120 ER PT J AU Achiron, A Barak, Y Gail, M Mandel, M Pee, D Ayyagari, R Rotstein, Z AF Achiron, A Barak, Y Gail, M Mandel, M Pee, D Ayyagari, R Rotstein, Z TI Cancer incidence in multiple sclerosis and effects of immunomodulatory treatments SO BREAST CANCER RESEARCH AND TREATMENT LA English DT Article DE breast cancer; cancer; immunomodulatory drugs; multiple sclerosis ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; RHEUMATOID-ARTHRITIS; DANISH PATIENTS; DEATH; MALIGNANCY; MORTALITY; DISEASE; AUTOIMMUNITY; GUIDELINES; SERIES AB Multiple sclerosis ( MS) has been linked to reduced rates of cancer prior to the era of immunomodulating treatments. We assessed the incidence of cancer in a cohort of 1338 MS patients and evaluated the effect of exposure to immunomodulatory treatment. Cancer incidence in the MS population was compared with the expected age- and gender-matched incidence rates in the Israeli population for the period 1960-2003. Time-dependant Cox model analysis was used to estimate hazard ratios for glatiramer acetate, beta-interferons (1a and 1-b) and intravenous immunoglobulins (IVIg). Among 892 female MS patients, 15 (1.7%) developed breast cancer, and 31 (3.5%) developed cancers of any type. Seventeen of 446 (3.8%) male MS patients developed cancer. The standardized incidence ratios (SIRs) computed until the time of first immunomodulatory treatment were 0.60 (95% CI, 0.38-0.92, p = 0.02) for all female cancer, and 1.11 (95% CI, 0.64-1.91) for all male cancer. Time-dependent covariate analyses for female breast cancer yielded a relative risk for glatiramer acetate of 3.10 ( 95% CI, 0.86-11.1) and 0.52 ( 95% CI, 0.07-4.05) for beta-interferons. For IVIg, the analyses were uninformative. Our findings indicate that cancer incidence is significantly lower in female MS patients than in the general population. Female MS patients treated with glatiramer acetate showed an elevated rate of breast cancer and all MS patients treated with beta-interferons showed an elevated risk of non-breast cancers though not statistically significant ( p = 0.122 and 0.072, respectively). Further study is needed to assess possible associations between long-term exposure to the novel immunomodulatory treatments in MS and rate of caner. C1 Chaim Sheba Med Ctr, Multiple Sclerosis Ctr, IL-52621 Tel Hashomer, Israel. Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. NCI, Biostat Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Informat Management Serv Inc, Rockville, MD USA. RP Achiron, A (reprint author), Chaim Sheba Med Ctr, Multiple Sclerosis Ctr, IL-52621 Tel Hashomer, Israel. EM achiron@post.tau.ac.il NR 29 TC 44 Z9 45 U1 0 U2 2 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0167-6806 J9 BREAST CANCER RES TR JI Breast Cancer Res. Treat. PD FEB PY 2005 VL 89 IS 3 BP 265 EP 270 DI 10.1007/s10549-004-2229-4 PG 6 WC Oncology SC Oncology GA 904RC UT WOS:000227514400008 PM 15754125 ER PT J AU Dickinson, JD Smith, LM Sanger, WG Zhou, GM Townley, P Lynch, JC Pavletic, ZS Bierman, PJ Joshi, SS AF Dickinson, JD Smith, LM Sanger, WG Zhou, GM Townley, P Lynch, JC Pavletic, ZS Bierman, PJ Joshi, SS TI Unique gene expression and clinical characteristics are associated with the 11q23 deletion in chronic lymphocytic leukaemia SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE chromosome 11q; chronic lymphocytic leukaemia; CLL fish; gene arrays ID IN-SITU HYBRIDIZATION; NON-HODGKINS-LYMPHOMA; MANTLE CELL LYMPHOMA; GENOMIC ABERRATIONS; MUTATION STATUS; CD38 EXPRESSION; CYTOGENETIC ABNORMALITIES; CLINICOBIOLOGIC FEATURES; SURVIVAL; CDC2 AB Chromosome abnormalities influence prognosis and tumour progression in B-cell Chronic Lymphocytic Leukaemia (CLL). This study sought to determine whether these different disease subgroups were associated with unique gene expression patterns. Thirty-four cases of CLL were screened for the 11q23, 13q14, 17p13 deletions, and trisomy 12 by fluorescence in situ hybridization (FISH). Expression of 205 cell signalling and apoptosis genes were compared by cDNA array among cases with different chromosome abnormalities. A majority of the statistically differentially expressed genes were present in the 11q23 deletion group by hierarchical clustering. CDC2, a serine/threonine kinase, was overexpressed in the 11q23 deletion group (P = 0.0004) and confirmed by Taqman(TM) real-time polymerase chain reaction. Several other genes associated with cell signalling were overexpressed in the 11q23 deletion group. A strong overall correlation existed between the presence of different chromosome abnormalities and a number of prognostic factors including immunoglobulin heavy chain variable region mutation status (P = 0.011), time to treatment (P = 0.025) and lymphocyte doubling time (P = 0.034). This study confirmed the prognostic impact of chromosome abnormalities identified by FISH in CLL, particularly the 11q23 deletion and trisomy 12. In addition, the 11q23 deletion group was associated with a unique gene expression pattern involving cell signalling and apoptosis genes. C1 Univ Nebraska, Med Ctr, Dept Genet Cell Biol & Anat, Omaha, NE 68198 USA. Univ Nebraska, Med Ctr, Dept Prevent & Societal Med, Omaha, NE 68198 USA. Univ Nebraska, Med Ctr, Dept Human Genet, Omaha, NE 68198 USA. Univ Nebraska, Med Ctr, Dept Pathol & Microbiol, Omaha, NE 68198 USA. Methodist Hlth Care Syst, NE Oncol, Omaha, NE USA. NCI, NIH, Bethesda, MD 20892 USA. Univ Nebraska, Med Ctr, Hematol Oncol Sect, Omaha, NE 68198 USA. RP Joshi, SS (reprint author), Univ Nebraska, Med Ctr, Dept Genet Cell Biol & Anat, 986395 Nebraskia Med Ctr, Omaha, NE 68198 USA. EM ssjoshi@unmc.edu NR 41 TC 16 Z9 17 U1 0 U2 0 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD FEB PY 2005 VL 128 IS 4 BP 460 EP 471 DI 10.1111/j.1365-2141.2004.05344.x PG 12 WC Hematology SC Hematology GA 895YE UT WOS:000226899700003 PM 15686453 ER PT J AU Stanford, SJ Hislop, AA Oltmanns, U Nabel, EG Sang, H Haworth, SG Mitchell, JA AF Stanford, SJ Hislop, AA Oltmanns, U Nabel, EG Sang, H Haworth, SG Mitchell, JA TI Transition from placental to air breathing stimulates haem-oxygenase-1 expression without functional consequence for pulmonary vascular adaptation in pigs and mice SO BRITISH JOURNAL OF PHARMACOLOGY LA English DT Article DE vascular remodelling; haem-oxygenase; cGMP; development; vasodilation ID NITRIC-OXIDE SYNTHASE; CARBON-MONOXIDE; HEME OXYGENASE; SMOOTH-MUSCLE; RAT LUNG; HYPERTENSION; CIRCULATION; INHIBITOR; HYPOXIA AB 1 In systemic vessels, haem-oxygenase (HO) is induced during oxidative stress and known to modulate vasodilatation and vascular remodelling. At birth, with the transition from placental to air breathing, the pulmonary vessels are exposed to oxidative stress and undergo well-documented remodelling processes. Thus, we investigated the role of HO in the lung during adaptation to extrauterine life using a pig and mouse model. In addition to the novel data presented with regard to one isoform, HO-1, this study is among the first to describe the pulmonary vascular remodelling in the mouse after birth. 2 We show, for the first time, that another isoform, HO-2, is present constitutively at birth and HO-1 protein is induced in the porcine and murine lung after birth in vascular and airway structures, peaking at 14 days in the pig and at about 4 days in the mouse. Furthermore, we show that HO-1 mRNA declines after birth in the mouse lung. 3 Inhibitors of HO did not modify vasodilator responses in vessels from 14-day-old pigs. 4 Moreover, lungs from HO-1-deficient mice developed normally after birth. 5 HO-1 is induced at birth but plays no role in the development of vasodilator responses or remodelling that occurs at this time. These data suggest that HO-1 expression at birth is a redundant response to oxidative stress in the lungs of healthy mammals. However, it remains possible that this pathway protects if complications occur during or after birth. C1 Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, UCCM, Royal Brompton & Harefield NHS Trust, London SW3 9L6, England. Inst Child Hlth, London WC1N 1EH, England. NHLBI, Vasc Biol Branch, Bethesda, MD 20892 USA. RP Mitchell, JA (reprint author), Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, UCCM, Royal Brompton & Harefield NHS Trust, Dovehouse St,Sydney St, London SW3 9L6, England. EM j.a.mitchell@ic.ac.uk RI Mitchell, Jane/A-1991-2009 NR 29 TC 8 Z9 8 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-1188 J9 BRIT J PHARMACOL JI Br. J. Pharmacol. PD FEB PY 2005 VL 144 IS 4 BP 467 EP 476 DI 10.1038/sj.bjp.0705988 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 902DC UT WOS:000227330600003 PM 15655535 ER PT J AU Hira, E Ono, T Dhar, DK El-Assal, ON Hishikawa, Y Yamanoi, A Nagasue, N AF Hira, E Ono, T Dhar, DK El-Assal, ON Hishikawa, Y Yamanoi, A Nagasue, N TI Overexpression of macrophage migration inhibitory factor induces angiogenesis and deteriorates prognosis after radical resection for hepatocellular carcinoma SO CANCER LA English DT Article DE hypoxia; recurrence; endothelial cell; hepatoma cell line; microvessel density ID CELL LUNG-CANCER; FACTOR MIF; MICROVESSEL DENSITY; GROWTH-FACTOR; CLINICAL-SIGNIFICANCE; REGULATORY ROLE; MELANOMA-CELLS; FACTOR GENE; EXPRESSION; CYTOKINE AB BACKGROUND. Macrophage migration inhibitory factor (MIF) is a pivotal cytokine that regulates inflammatory and immune responses. Recently, many investigators reported that MIF is expressed highly in several tumors, including hepatocellular carcinoma (HCC). However, the role of MIF in tumor angiogenesis and patient prognosis has not been examined in patients with HCC. METHODS. The authors evaluated MIF expression in 56 samples of HCC by Western blot analysis, and the results were correlated with clinicopathologic factors and patient prognosis. MIF localization was determined by immunohistochemical methods, and the results were compared with tumor microvessel density (MVD), as assessed by anti-CD34 antibody. Furthermore, to validate the role of MIF in angiogenesis, both MIF expression during culture of HCC cells (using the Hep3B, HepG2, and Huh7 cell lines) under hypoxic condition and the angiogenic potential of recombinant MIF in an in vitro angiogenic model were examined. RESULTS. Tumors with high MIF expression had high alpha-fetoprotein levels (P = 0.049) and frequent intrahepatic recurrence (P = 0.043). Immunohistochemical MIF scores had a significant correlation with MVD (P = 0.007). Patients who had tumors with high MIF expression levels had a significantly worse (P = 0.025) disease-free survival, and this finding remained significant as an independent prognostic factor in the multivariate analysis. Hep3B cells had high expression of MIF at 6 hours and 12 hours after hypoxic stress and exogenous MIF stimulated endothelial tube formation in in vitro angiogenesis. CONCLUSIONS. The current findings suggest that MIF expression may play a pivotal role in the dismal prognosis of patients with HCC that may be attributable to the modulation of angiogenesis. (C) 2004 American Cancer Society. C1 Shimane Univ, Fac Med, Dept Digest & Gen Surg, Izumo, Shimane 6938501, Japan. NIAAA, Sect Liver Biol, Lab Physiol Studies, NIH, Bethesda, MD USA. Nagasaki Univ, Sch Med, Dept Histol & Cell Biol, Nagasaki 852, Japan. RP Hira, E (reprint author), Shimane Univ, Fac Med, Dept Digest & Gen Surg, Izumo, Shimane 6938501, Japan. EM ehira130@go3.enjoy.ne.jp NR 43 TC 62 Z9 74 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD FEB 1 PY 2005 VL 103 IS 3 BP 588 EP 598 DI 10.1002/cncr.20818 PG 11 WC Oncology SC Oncology GA 889YZ UT WOS:000226480100021 PM 15612021 ER PT J AU Chau, CH Figg, WD AF Chau, CH Figg, WD TI Molecular and phenotypic heterogeneity of metastatic prostate cancer SO CANCER BIOLOGY & THERAPY LA English DT Article DE prostate; cancer; metastasis; heterogeneity; phenotype ID PROGRESSION; EXPRESSION; AUTOPSY AB Metastatic prostate cancer remains a prevalent disease in the United States that requires detailed characterization of its pathobiology. In the December 2004 issue of Cancer Research, a comprehensive study by Shah et al. demonstrated that metastatic androgen-independent prostate cancer is a collective group of diseases even within the same patient. Understanding the molecular and phenotypic determinants of this heterogeneity is essential in assessing therapeutic outcomes in the management of prostate cancer progression. C1 NCI, Mol Pharmacol Sect, Canc Therapeut Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Figg, WD (reprint author), NCI, Mol Pharmacol Sect, Canc Therapeut Branch, Ctr Canc Res, Bldg 10,Rm 5A01,MSC 1910,9000 Rockville Pike, Bethesda, MD 20892 USA. EM wdfigg@helix.nih.gov RI Figg Sr, William/M-2411-2016 NR 10 TC 3 Z9 3 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 FEB PY 2005 VL 4 IS 2 BP 166 EP 167 PG 2 WC Oncology SC Oncology GA 957GX UT WOS:000231359400005 PM 15738648 ER PT J AU Bandyopadhyay, A Elkahloun, A Baysa, SJ Wang, L Sun, LZ AF Bandyopadhyay, A Elkahloun, A Baysa, SJ Wang, L Sun, LZ TI Development and gene expression profiling of a metastatic variant of the human breast cancer MDA-MB-435 cells SO CANCER BIOLOGY & THERAPY LA English DT Article DE bone metastasis; breast cancer; green fluorescence protein; cDNA-microarray ID GREEN FLUORESCENT PROTEIN; TUMOR-CELLS; BONE; MUTATIONS; STATISTICS; PATTERNS; MODEL AB We have developed a model system of late stage metastatic progression by isolating a highly malignant variant of human breast cancer cells from the parental MDA-MB-435 cell line. These cells, isolated from early lung metastasis, displayed increased anchorage independent growth in vitro and when transplanted ortho-topically into nude mice showed accelerated tumor growth rate and early lung spontaneous metastasis when compared to its parental counterpart. These cells, designated as MDA-MB-435-F-L, also showed intense wide spread early skeletal metastasis in vertebrae, mandible, femur, tibia and skull as detected by fluorescence imaging in an experimental bone metastasis model. Gene expression profiles from cDNA microarray showed up or downregulation of the expression of several significant genes regulating angiogenesis, apoptosis, ECM remodeling and metastasis in the MDA-MB-435-F-L cells in comparison to the parental cells. Among the up or downregulated genes, some have also been implicated in the survival of breast cancer patients. As such, the candidate genes selected in this breast cancer progression model system may serve as biomarkers of metastatic progression and also as potential tumor targets for breast cancer therapy. C1 Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, San Antonio, TX 78229 USA. NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA. RP Sun, LZ (reprint author), Univ Texas, Hlth Sci Ctr, Dept Cellular & Struct Biol, 7703 Floyd Curl Dr,Mail Code 7762, San Antonio, TX 78229 USA. EM sunl@uthscsa.edu FU NCI NIH HHS [CA79683, CA75253] NR 28 TC 16 Z9 19 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 FEB PY 2005 VL 4 IS 2 BP 168 EP 174 PG 7 WC Oncology SC Oncology GA 957GX UT WOS:000231359400006 PM 15655343 ER PT J AU Robey, RW Steadman, K Polgar, O Bates, SE AF Robey, RW Steadman, K Polgar, O Bates, SE TI ABCG2-mediated transport of photosensitizers - Potential impact on photodynamic therapy SO CANCER BIOLOGY & THERAPY LA English DT Article DE photodynamic therapy; ABCG2; drug-resistance; photosensitizer; chlorin; porphyrin ID CANCER RESISTANCE PROTEIN; MULTIDRUG-RESISTANCE; IN-VIVO; SUBSTRATE-SPECIFICITY; HALF-TRANSPORTER; DRUG-RESISTANCE; CELL CARCINOMA; CHLORIN E6; ABCG2; GENE AB In photodynamic therapy (PDT), a tumor-selective photosensitizer is administered followed by activation of the photosensitizer by exposure to a light source of a given wavelength. This, in turn, generates reactive oxygen species that induce cellular apoptosis and necrosis in tumor tissue. Based on our earlier finding that the photosensitizer pheophorbide a is an ABCG2 substrate, we explored the ability of ABCG2 to transport photosensitizers with a structure similar to that of pheophorbide a. ABCG2-overexpressing NCI-H1650 MX50 bronchoalveolar carcinoma cells were found to have reduced intracellular accumulation of pyropheophorbide a methyl ester and chlorin e6 compared to parental cells as measured by flow cytometry. The ABCG2 inhibitor fumitremorgin C was found to abrogate ABCG2-mediated transport. Intracellular fluorescence of hematoporphyrin IX, meso-tetra(3-hydroxyphenyl)porphyrin, and meso-tetra(3-hydroxyphenyl)chlorin was not substantially affected by ABCG2. ABCG2-overexpressing cells also displayed decreased intracellular fluorescence of protoporphyrin IX generated by exogenous application of 5-aminolevulinic acid. Mutations at amino acid 482 in the ABCG2 protein known to affect substrate specificity were not found to impact transport of the photosensitizers. In cytotoxicity assays, ABCG2-transfected HEK-293 cells were 11-fold, 30-fold, 4-fold, and >7-fold resistant to PDT with pheophorbide a, pyropheophorbide a methyl ester, chlorin e6, and 5-aminolevulinic acid, respectively. ABCG2-transfected cells were not resistant to PDT with meso-tetra(3-hydroxyphenyl) chlorin. Neither multidrug resistance-associated protein 1 expression nor P-glycoprotein expression appreciably decreased the intracellular fluorescence of any of the photosensitizers examined as determined by flow cytometry. The results presented here implicate ABCG2 as a possible cause for cellular resistance to photodynamic therapy. C1 NIH, Canc Therapeut Branch, Ctr Canc Res, Bethesda, MD 20892 USA. RP Robey, RW (reprint author), 9000 Rockville Pike,Bldg 10,Rm 12C103, Bethesda, MD 20892 USA. EM robeyr@mail.nih.gov RI Steadman, Kenneth/J-3883-2013 NR 46 TC 93 Z9 100 U1 0 U2 8 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 FEB PY 2005 VL 4 IS 2 BP 187 EP 194 PG 8 WC Oncology SC Oncology GA 957GX UT WOS:000231359400009 PM 15684613 ER PT J AU Garimella, TS Ross, DD Eiseman, JL Mondick, JT Joseph, E Nakanishi, T Bates, SE Bauer, KS AF Garimella, TS Ross, DD Eiseman, JL Mondick, JT Joseph, E Nakanishi, T Bates, SE Bauer, KS TI Plasma pharmacokinetics and tissue distribution of the breast cancer resistance protein (BCRP/ABCG2) inhibitor fumitremorgin C in SCID mice bearing T8 tumors SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE fumitremorgin C; breast cancer resistance protein; multidrug resistance ID MULTIDRUG-RESISTANCE; CELL-LINE; OVEREXPRESSION; TRANSPORTER; TOPOTECAN; GENE; LOCALIZATION; FLAVOPIRIDOL; MITOXANTRONE AB Multidrug resistance (MDR) remains a major obstacle in the treatment of human cancers. The recently discovered breast cancer resistance protein (BCRP/ ABCG2) has been found to be an important mediator of chemotherapeutic MDR. Fumitremorgin C (FTC) is a selective and potent inhibitor of BCRP that completely inhibits and reverses BCRP-mediated resistance at micromolar concentrations. We report a study of the pharmacokinetics and tissue distribution of FTC when administered intravenously (IV) at a dose of 25 mg/kg to female SCID mice bearing the BCRP-overexpressing human ovarian xenograft Igrov1/T8 tumors. Plasma pharmacokinetics and tissue distribution of FTC in various organs and tissues were studied. In addition, the effect of FTC administration on the expression of BCRP in T8 tumors was also assessed by RT-PCR. Administration of a single FTC IV dose did not appear to cause any major toxicities. The resulting pharmacokinetic data were fit to a two-compartment model using NONMEM and the FTC clearance was determined to be 0.55 ml/min (25.0 ml/ min/kg) with a 56% inter-animal variability. Area under the plasma concentration time curve was determined by Bailer's method and was calculated to be 1128 +/- 111 mug min/ml. FTC was widely distributed in all tissues assayed with highest concentrations found in lungs, liver and kidney in decreasing order, respectively. FTC did not appear to have any effect on the expression of BCRP in T8 tumors. Less than 2% of the administered dose was recovered in the urine and feces after 24 h, suggesting hepatic metabolism as a primary mechanism of elimination. The current study can be used as a basis for future animal or in vivo studies with FTC designed to further understand the impact of BCRP on drug resistance. C1 Univ Maryland, Dept Pharmaceut Sci, Baltimore, MD 21201 USA. Univ Maryland, Sch Med, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. Baltimore Vet Affairs Med Ctr, Baltimore, MD USA. Univ Pittsburgh, Pittsburgh Canc Inst, Pittsburgh, PA USA. Univ Pittsburgh, Sch Med, Dept Pharmacol, Pittsburgh, PA 15261 USA. Natl Canc Inst, Canc Therapeut Branch, Ctr Canc Res, Bethesda, MD USA. RP Bauer, KS (reprint author), Univ Maryland, Sch Pharm, Dept Pharm Practice & Sci, Baltimore, MD 21201 USA. EM kbauer@rx-umaryland.edu RI Nakanishi, Takeo/C-3891-2015 OI Nakanishi, Takeo/0000-0002-6561-7138 NR 21 TC 13 Z9 15 U1 0 U2 4 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0344-5704 J9 CANCER CHEMOTH PHARM JI Cancer Chemother. Pharmacol. PD FEB PY 2005 VL 55 IS 2 BP 101 EP 109 DI 10.1007/s00280-004-0866-2 PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 877WR UT WOS:000225606200001 PM 15580504 ER PT J AU Hawk, E Viner, JL AF Hawk, E Viner, JL TI The critical role of risk-benefit assessments in cancer prevention SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material C1 NCI, Div Canc Prevent, Gastrointestinal & Other Canc Res Grp, Bethesda, MD 20892 USA. RP Hawk, E (reprint author), NCI, Div Canc Prevent, Gastrointestinal & Other Canc Res Grp, Bethesda, MD 20892 USA. NR 0 TC 5 Z9 5 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2005 VL 14 IS 2 BP 297 EP 298 DI 10.1158/1055-9965.EPI-14-2-EDA PG 2 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 898ZD UT WOS:000227113800002 PM 15734949 ER PT J AU Brewer, MA Ranger-Moore, J Baruche, A Alberts, DS Greene, M Thompson, D Liu, Y Davis, J Bartels, PH AF Brewer, MA Ranger-Moore, J Baruche, A Alberts, DS Greene, M Thompson, D Liu, Y Davis, J Bartels, PH TI Exploratory study of ovarian intraepithelial neoplasia SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID PROPHYLACTIC OOPHORECTOMY SPECIMENS; MALIGNANCY-ASSOCIATED CHANGES; CHROMATIN TEXTURE; MUTATION CARRIERS; CANCER; BRCA1; BREAST; LESIONS; NUCLEI; EPITHELIUM AB Purpose: This was an exploratory study to test two hypotheses related to potential epithelial precursors to ovarian cancer: (a) histologically normal ovarian surface epithelium exhibited changes in the nuclear chromatin pattern, which indicate an ovarian abnormality, and (b) such changes were detectable in the ovarian surface epithelium of cancer-free subjects who were at high risk for ovarian cancer. Experimental Design: Ovaries were carefully collected to avoid damage to the surface epithelium. Five-micron-thick histologic sections were cut and stained with H&E. High-resolution images were recorded from the ovarian surface epithelium and from the underlying stroma of ovaries from normal women (10 cases), women at high risk of developing ovarian cancer (7 cases), and histologically normal areas adjacent to ovarian cancer (3 cases). Karyometric features and measurements of nuclear abnormality were computed for 3,390 epithelial nuclei. Discriminant function analyses and unsupervised learning algorithms were employed to define deviations from normal and to identify the sub-populations of nuclei exhibiting these changes. Results: Epithelium from ovaries harboring a malignant lesion had changes in the nuclear chromatin pattern consistent with a second phenotype, which were not visually detected with histopathologic surveillance. This phenotype was also present in the ovaries obtained from women at increased risk of ovarian cancer, suggesting that it may represent a premalignant abnormality. These changes were statistically significant. Conclusion: The observed changes in karyometric features were sufficiently distinct to warrant further study as both diagnostic and prognostic biomarkers for early detection and prevention of ovarian cancer. C1 Univ Arizona, Arizona Canc Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Tucson, AZ 85724 USA. Univ Arizona, Arizona Canc Ctr, Dept Pathol, Div Epidemiol & Biostat, Tucson, AZ 85724 USA. Univ Arizona, Arizona Canc Ctr, Dept Med, Div Epidemiol & Biostat, Tucson, AZ 85724 USA. Univ Arizona, Arizona Canc Ctr, Dept Pharmacol, Div Epidemiol & Biostat, Tucson, AZ 85724 USA. Univ Arizona, Arizona Canc Ctr, Dept Publ Hlth, Div Epidemiol & Biostat, Tucson, AZ 85724 USA. Univ Arizona, Arizona Canc Ctr, Natl Canc Inst, Tucson, AZ 85724 USA. Univ Arizona, Arizona Canc Ctr, Ctr Opt Sci, Tucson, AZ 85724 USA. RP Brewer, MA (reprint author), Univ Arizona, Arizona Canc Ctr, Dept Obstet & Gynecol, Div Gynecol Oncol, Room 1968G,1515 N Campbell Ave, Tucson, AZ 85724 USA. EM mbrewer@azcc.arizona.edu FU NCI NIH HHS [CA 53877] NR 24 TC 10 Z9 11 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2005 VL 14 IS 2 BP 299 EP 305 DI 10.1158/1055-9965.EPI-04-0212 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 898ZD UT WOS:000227113800003 PM 15734950 ER PT J AU Kirk, GD Turner, PC Gong, YY Lesi, OA Mendy, M Goedert, JJ Halls, AJ Whittle, H Hainaut, P Montesano, R Wild, CP AF Kirk, GD Turner, PC Gong, YY Lesi, OA Mendy, M Goedert, JJ Halls, AJ Whittle, H Hainaut, P Montesano, R Wild, CP TI Hepatocellular carcinoma and polymorphisms in carcinogen-metabolizing and DNA repair enzymes in a population with aflatoxin exposure and hepatitis B virus endemicity SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID GLUTATHIONE-S-TRANSFERASE; MICROSOMAL EPOXIDE HYDROLASE; GENETIC POLYMORPHISMS; GAMBIAN CHILDREN; LIVER-CANCER; ALBUMIN ADDUCTS; NULL GENOTYPES; PUBLIC-HEALTH; WEST-AFRICA; RISK AB High rates of hepatocellular carcinoma (HCC) in The Gambia, West Africa, are primarily due to a high prevalence of chronic hepatitis B virus infection and heavy aflatoxin exposure via groundnut consumption. We investigated genetic polymorphisms in carcinogen-metabolizing (GSTM1, GSTT1, HYL1*2) and DNA repair (XRCC1) enzymes in a hospital-based case-control study. Incident HCC cases (n = 216) were compared with frequency-matched controls (n = 408) with no clinically apparent liver disease. Although the prevalence of variant genotypes was generally low, in multivariable analysis (adjusting for demographic factors, hepatitis B virus, hepatitis C virus, and TP53 status), the GSTM1-null genotype [odds ratio (OR), 2.45; 95% confidence interval (95% CI), 1.21-4.95] and the heterozygote XRCC1-399 AG genotype (OR, 3.18; 95% CI, 1.35-7.51) were significantly associated with HCC. A weak association of the HYL1*2 polymorphism with HCC was observed but did not reach statistical significance. GSTT1 was not associated with HCC. The risk for HCC with null GSTM1 was most prominent among those with the highest groundnut consumption (OR, 4.67; 95% CI, 1.45-15.1) and was not evident among those with less than the mean groundnut intake (OR, 0.64; 95% Cl, 0.20-2.02). Among participants who had all three suspected aflatoxin-related high-risk genotypes [GSTM1 null, HLY1*2 (HY/HH), and XRCC1 (AG/GG)], a significant 15-fold increased risk of HCC was observed albeit with imprecise estimates (OR, 14.7; 95% CI, 1.27-169). Our findings suggest that genetic modulation of carcinogen metabolism and DNA repair can alter susceptibility to HCC and that these effects may be modified by environmental factors. C1 NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept HHS, Bethesda, MD 20892 USA. Gambia Hepatisis Intervent Study, IARC, Banjul, Gambia. MRC Labs, Banjul, Gambia. Univ Leeds, Mol Epidemiol Unit, Acad Unit Epidemiol & Hlth Serv Res, Leeds, W Yorkshire, England. London Sch Hyg & Trop Med, Infect Dis Epidemiol Unit, London WC1, England. IARC, Lyon, France. RP Kirk, GD (reprint author), NCI, Viral Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept HHS, 6120 Execut Blvd,EPS-8003,MSC-7248, Bethesda, MD 20892 USA. EM kirkg@mail.nih.gov RI Kirk, Gregory/A-8484-2009; Turner, Paul/A-6152-2011; Hainaut, Pierre /B-6018-2012; Gong, Yun Yun/L-7094-2016; Turner, Paul/B-8131-2013 OI Hainaut, Pierre /0000-0002-1303-1610; Gong, Yun Yun/0000-0003-4927-5526; NR 47 TC 63 Z9 72 U1 1 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2005 VL 14 IS 2 BP 373 EP 379 DI 10.1158/1055-9965.EPI-04-0161 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 898ZD UT WOS:000227113800013 PM 15734960 ER PT J AU Platz, EA Rohrmann, S Pearson, JD Corrada, MM Watson, DJ De Marzo, AM Landis, PK Metter, EJ Carter, HB AF Platz, EA Rohrmann, S Pearson, JD Corrada, MM Watson, DJ De Marzo, AM Landis, PK Metter, EJ Carter, HB TI Nonsteroidal anti-inflammatory drugs and risk of prostate cancer in the Baltimore Longitudinal Study of Aging SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID PROLIFERATIVE INFLAMMATORY ATROPHY; ASPIRIN USE; INVERSE ASSOCIATION; OVER-EXPRESSION; CYCLOOXYGENASE-2; CARCINOMA; HYPERPLASIA; CARCINOGENESIS; ADENOCARCINOMA; ACETAMINOPHEN AB Background: Laboratory and epidemiologic studies suggest that aspirin and nonaspirin nonsteroidal anti-inflammatory drugs (NSAID) reduce the risk of cancer, possibly via inhibition of the cyclooxygenase enzymes. We evaluated the association of aspirin and nonaspirin NSAIDs with subsequent prostate cancer in a prospective study. We also assessed whether use of these drugs influences serum prostate-specific antigen (PSA) concentration. Methods: Participants were 1,244 male members of the Baltimore Longitudinal Study of Aging. Use of prescription and over-the-counter drugs was collected by questionnaire and interview at multiple study visits. One hundred forty-one prostate cancer cases diagnosed between 1980 and May 2004 were confirmed by medical record review. We used Cox proportional hazards regression to estimate the rate ratio (RR) of prostate cancer updating drug use over time and taking into account age and year. We used generalized estimating equations to calculate age-adjusted geometric mean PSA concentration by aspirin or nonaspirin NSAIDs use among 933 of the men without prostate cancer, for whom 3,749 PSA measurements in archived sera had been done previously. Results: On 46.0% and 21.5% of the visits, current use of aspirin or nonaspirin NSAIDs (mostly ibuprofen) was reported, respectively. The RRs of prostate cancer comparing ever to never use were 0.76 [95% confidence interval (95% CI), 0.54-1.07] for aspirin, 0.79 (95% CI, 0.54-1.16) for nonaspirin NSAIDs, and 0.71 (95% CI, 0.49-1.02) for either medication. The association for ever use of either aspirin or nonaspirin NSAIDs was suggestively more pronounced in men <70 years (RR, 0.54; 95% CI, 0.27-1.03) than in men greater than or equal to70 years (RR, 0.78; 95% CI, 0.50-1.22; P-interaction = 0.73). The RR for current use of either drug was attenuated relative to ever use. Mean PSA concentration did not differ between users and nonusers of either aspirin or nonaspirin NSAIDs (1.01 versus 0.98 ng/mL, P = 0.56). Conclusion: In this prospective study, men, in particular younger men, who had ever used aspirin or nonaspirin NSAIDs had a modest nonstatistically significant lower risk of prostate cancer. The modest inverse association was unlikely due to detection bias that might have resulted if anti-inflammatory drugs had influenced serum PSA concentration. C1 Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, James Buchanan Brady Urol Inst, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA. NIA, Clin Res Branch, Intramural Res Program, Baltimore, MD 21224 USA. Merck & Co Inc, Dept Epidemiol, Blue Bell, PA USA. Univ Calif Irvine, Dept Neurol, Clin Aging Res & Educ, Irvine, CA 92717 USA. RP Platz, EA (reprint author), Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Room E6138,615 N Wolfe St, Baltimore, MD 21205 USA. EM eplatz@jhsph.edu RI Rohrmann, Sabine/D-2113-2012; OI corrada, maria/0000-0002-8168-8593 NR 37 TC 57 Z9 59 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2005 VL 14 IS 2 BP 390 EP 396 DI 10.1158/1055-9965.EPI-04-0532 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 898ZD UT WOS:000227113800016 PM 15734963 ER PT J AU You, WC Hong, JY Zhang, L Pan, KF Pee, D Li, JY Ma, JL Rothman, N Caporaso, N Fraumeni, JF Xu, GW Gail, MH AF You, WC Hong, JY Zhang, L Pan, KF Pee, D Li, JY Ma, JL Rothman, N Caporaso, N Fraumeni, JF Xu, GW Gail, MH TI Genetic polymorphisms of CYP2E1, GSTT1, GSTP1, GSTM1, ALDH2, and ODC and the risk of advanced precancerous gastric lesions in a chinese population SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SAMPLE-SIZE CALCULATIONS; N-NITROSO COMPOUNDS; ORNITHINE-DECARBOXYLASE; HELICOBACTER-PYLORI; STOMACH-CANCER; ALDEHYDE DEHYDROGENASE-2; JAPANESE ALCOHOLICS; SUSCEPTIBILITY; ESOPHAGEAL; GENOTYPES AB There have been few studies of the associations of genetic polymorphisms with precancerous gastric lesions. We conducted a cross-sectional study to compare the prevalences of several genetic polymorphisms in 302 subjects with mild chronic atrophic gastritis with prevalences in 606 subjects with deep intestinal metaplasia or dysplasia. This stratified random sample of 908 subjects was selected and analyzed for genetic polymorphisms from 2,628 individuals who had gastric biopsies with histopathology in 1989 in Linqu County, Shandong Province, China. In subjects with mild chronic atrophic gastritis, the frequencies of the variant (less common) alleles of CYP2E1 RsaI, CYP2E1 DraI, GSTP1, ALDH2, and ODC were, respectively, 0.156, 0.201, 0.189, 0.190, and 0.428. The frequencies of the null genotypes of GSTM1 and GSTT1 in the mild chronic atrophic gastritis group were 0.509 and 0.565, respectively. Comparing mild chronic atrophic gastritis with deep intestinal metaplasia or any degree of dysplasia, we found no statistically significant associations with any genotype from these loci for dominant, additive, or recessive inheritance models. There was no statistically significant evidence of multiplicative interactions between any pair of genotypes based on CYP2E1 RsaI, CYP2E1 DraI, GSTP1, GSTM1, or GSTT1; nor between Helicobacter pylori status and any of these five loci; nor between smoking status and GSTP1, GSTM1, or GSTT1; nor between alcohol consumption and ALDH2. Statistically significant interactions were noted between salt consumption and GSTP1 and between sour pancake consumption and CYP2E1 RsaI. There was, moreover, a statistically significant interaction (odds ratio, 1.78; 95% confidence interval, 1.03-3.08) between CYP2E1 DraI and smoking at least one cigarette per day. A positive but not statistically significant interaction was also seen between CYP2E1 RsaI and smoking status. These polymorphisms do not seem to govern progression from mild chronic atrophic gastritis to advanced precancerous gastric lesions, but the effects of smoking may be accentuated in individuals carrying variants of CYP2E1. C1 Peking Univ, Sch Oncol, Beijing Canc Hosp, Beijing 100036, Peoples R China. Inst Canc Res, Beijing 100036, Peoples R China. Univ Med & Dent New Jersey, Sch Publ Hlth, Piscataway, NJ 08854 USA. Natl Canc Inst, Div Canc Epidemiol & Genet, Bethesda, MD USA. Informat Management Serv Inc, Rockville, MD USA. RP You, WC (reprint author), Peking Univ, Sch Oncol, Beijing Canc Hosp, 52 Fu Cheng Rd,Haidian Dist, Beijing 100036, Peoples R China. EM weichengyou@yahoo.com FU NCI NIH HHS [N0I-CP-15620, N0I-CP-21009, N0I-CP-05613, N0I-CP-33041] NR 57 TC 25 Z9 32 U1 0 U2 6 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2005 VL 14 IS 2 BP 451 EP 458 DI 10.1158/1055-9965.EPI-04-0311 PG 8 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 898ZD UT WOS:000227113800025 PM 15734972 ER PT J AU Kreimer, AR Clifford, GM Boyle, P Franceschi, S AF Kreimer, AR Clifford, GM Boyle, P Franceschi, S TI Human papillomavirus types in head and neck squamous cell carcinomas worldwide: A systematic review SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Review ID CERVICAL-CANCER WORLDWIDE; ORAL-CANCER; SEXUAL-BEHAVIOR; RISK FACTOR; INFECTION; IDENTIFICATION; AMPLIFICATION; METAANALYSIS; ASSOCIATION; MULTICENTER AB Mucosal human papillomaviruses (HPV) are the cause of cervical cancer and likely a subset of head and neck squamous cell carcinomas (HNSCC), yet the global prevalence and type distribution of HPV in HNSCC remains unclear. We systematically reviewed published studies of HNSCC biopsies that employed PCR-based methods to detect and genotype HPV to describe the prevalence and type distribution of HPV by anatomic cancer site. Geographic location and study size were investigated as possible sources of variability. In the 5,046 HNSCC cancer specimens from 60 studies, the overall HPV prevalence was 25.9% [95% confidence interval (95% CI), 24.7-27.2]. HPV prevalence was significantly higher in oropharyngeal SCCs (35.6% of 969; 95% CI, 32.6-38.7) than oral SCCs (23.5% of 2,642; 95% CI, 21.9-25.1) or laryngeal SCCs (24.0% of 1,435; 95% CI, 21.8-26.3). HPV16 accounted for a larger majority of HPV-positive oropharyngeal SCCs (86.7%; 95% CI, 82.6-90.1) compared with HPV-positive oral SCCs (68.2%; 95% CI, 64.4-71.9) and laryngeal SCCs (69.2%; 95% CI, 64.0-74.0). Conversely, HPV18 was rare in HPV-positive oropharyngeal SCCs (2.8%; 95% CI, 1.3-5.3) compared with other head and neck sites [34.1% (95% CI, 30.4-38.0) of oral SCCs and 17.0% (95% CI, 13.0-21.6) of laryngeal SCCs]. Aside from HPV16 and HPV18, other oncogenic HPVs were rarely detected in HNSCC. Tumor site-specific HPV prevalence was higher among studies from North America compared with Europe and Asia. The high HPV16 prevalence and the lack of HPV18 in oropharyngeal compared with other HNSCCs may point to specific virus-tissue interactions. Small sample size and publication bias complicate the assessment of the prevalence of HPV in head and neck sites beyond the oropharynx. C1 NCI, Div Canc Prevent, Canc Prevent Fellowship Program, Bethesda, MD 20892 USA. Int Agcy Res Canc, F-69372 Lyon, France. RP Kreimer, AR (reprint author), NCI, Div Canc Prevent, Canc Prevent Fellowship Program, 6130 Execut Blvd,Suite 2131, Bethesda, MD 20892 USA. EM kreimera@mail.nih.gov RI Boyle, Peter/A-4380-2014; Kreimer, Aimee/H-1687-2015 OI Boyle, Peter/0000-0001-6251-0610; NR 31 TC 917 Z9 957 U1 10 U2 73 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2005 VL 14 IS 2 BP 467 EP 475 DI 10.1158/1055-9965.EPI-04-0551 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 898ZD UT WOS:000227113800027 PM 15734974 ER PT J AU Engels, EA Chen, JB Hartge, P Cerhan, JR Davis, S Severson, RK Cozen, W Viscidi, RP AF Engels, EA Chen, JB Hartge, P Cerhan, JR Davis, S Severson, RK Cozen, W Viscidi, RP TI Antibody responses to simian virus 40 T antigen: A case-control study of non-Hodgkin lymphoma SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SIMIAN VIRUS 40; LYMPHOPROLIFERATIVE DISORDERS; JC VIRUS; BK VIRUS; CELLS; ASSOCIATION; SEQUENCES; SV40; POLYOMAVIRUSES; EXPOSURE AB A possible role for SV40, a macaque polyomavirus, in nonHodgkin lymphoma (NHL) in humans was raised recently by the reported detection of SV40 DNA in tumor tissue. Animals with SV40-induced tumors frequently produce high-level antibodies against T antigen, the SV40 oncoprotein. In this study, we assessed whether SV40 T antibody measured in humans supported a relationship between SV40 and NHL. Subjects were sampled from a U.S. population-based case-control study of NHL, according to presence of antibodies against capsids of SV40 and BK, a related human polyomavirus (n = 85 cases, n = 95 controls). T antibody was measured by enzyme immunoassay. We also evaluated serum specimens from SV40-infected and SV40-uninfected macaques (n = 19 and n = 8, respectively), SV40-uninfected hamsters (n = 5), and hamsters with SV40-induced tumors (n = 10). Hamsters with SV40-induced tumors all produced robust SV40 T antibody (median absorbance, 0.99), whereas SV40-uninfected hamsters and macaques had much lower levels (median absorbance, 0.05 and 0.04, respectively). NHL cases, controls, and SV40-infected macaques resembled these latter two groups, generally showing only low-level T antibody (median absorbance, 0.03, 0.04, and 0.04, respectively). Overall, only five cases (6%) and five controls (5%) had T antibody responses classified as seropositive (odds ratio, 1.2; 95% confidence interval, 0.3-4.6). Interestingly, all 10 humans with T antibody responses also showed antibody responses to BK capsid. We found no association between the presence of T antibody-and NHL, arguing against SV40 as a cause of NHL. Infrequent and low-level T antibody responses among humans could represent cross-reactivity to BK virus T antigen. C1 NCI, Div Canc Epidemiol & Genet, Viral Epidemiol Branch, Dept HHS, Bethesda, MD 20892 USA. Mayo Clin, Coll Med, Rochester, MN USA. Fred Hutchinson Canc Res Ctr, Seattle, WA 98104 USA. Wayne State Univ, Karmanos Canc Inst, Detroit, MI USA. Univ So Calif, Los Angeles, CA USA. Johns Hopkins Univ, Sch Med, Baltimore, MD USA. RP Engels, EA (reprint author), NCI, Div Canc Epidemiol & Genet, Viral Epidemiol Branch, Dept HHS, 6120 Execut Blvd,EPS 8010, Bethesda, MD 20892 USA. EM engelse@exchange.nih.gov FU NCI NIH HHS [N01-PC-67010, N01-PC-67008, N01-PC-67009, N01-PC-65064, N02-PC-71105] NR 25 TC 12 Z9 13 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2005 VL 14 IS 2 BP 521 EP 524 DI 10.1158/1055-9965.EPI-04-0441 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 898ZD UT WOS:000227113800034 PM 15734981 ER PT J AU Wang, SS Schiffman, M AF Wang, SS Schiffman, M CA ALTS Grp TI Medication use, medical conditions, and the risk of human papillomavirus infection and subsequent cervical intraepithelial neoplasia 3 among women with mild cytologic abnormalities SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material ID NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ASCUS-LSIL TRIAGE; CANCER C1 NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. RP Wang, SS (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. EM wangso@mail.nih.gov FU NCI NIH HHS [CN-55156, CN-55159, CN-55154, CN-55153, CN-55158, CN-55155, CN-55157, CN-55105] NR 11 TC 1 Z9 1 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2005 VL 14 IS 2 BP 542 EP 545 DI 10.1158/1055-9965.EPI-04-0642 PG 4 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 898ZD UT WOS:000227113800040 PM 15734987 ER PT J AU Marcus, PM Miedzinksi, M AF Marcus, PM Miedzinksi, M TI Measuring the impact of HIPAA in the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Meeting Abstract CT 29th Annual Meeting of the American-Society-of-Preventive-Oncology CY MAR 13-15, 2005 CL San Francisco, CA SP Amer Soc Preventive Oncol C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. NR 0 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 FEB PY 2005 VL 14 IS 2 BP 549 EP 549 PG 1 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 898ZD UT WOS:000227113800054 ER PT J AU Liu, YQ Xia, DJ Li, F Zheng, CY Xiang, J AF Liu, YQ Xia, DJ Li, F Zheng, CY Xiang, J TI Intratumoral administration of immature dendritic cells following the adenovirus vector encoding CD40 ligand elicits significant regression of established myeloma SO CANCER GENE THERAPY LA English DT Article DE CD40 ligand; immature dendritic cells; adenoviral vector; apoptosis; antitumor immunotherapy ID ANTIGEN-PRESENTING CELLS; CYTOTOXIC T-LYMPHOCYTES; IN-VIVO; B-CELLS; TRANSGENIC EXPRESSION; ANTITUMOR IMMUNITY; APOPTOTIC CELLS; TUMOR-CELLS; ACTIVATION; RESPONSES AB Our previous study showed that J558 myeloma cells engineered CD40L lost their tumorigenicity in syngeneic mice, and the inoculation of J558/CD40L tumor cells further led to the protective immunity against wild tumors. In the present study, we investigated whether the vaccine can exert more efficient antitumor immunity by combination with adenovirus mediated CD40L gene therapy and immature dendritic cells (iDCs). The results demonstrated that intratumoral administration of iDCs 2 days after AdVCD40L injection, not only significantly suppressed the tumor growth, but also eradiated the established tumors in 40% of the mice. The potent antitumor effect produced by the combination therapy correlated with high expression of MHC, costimulatory and Fas molecules on J558 cells, which was derived from CD40L transgene expression. In addition, transgene CD40L expression could dramatically induce J558 cell apoptosis. Effectively capturing apoptotic bodies by iDCs in vivo could induce DC maturation, prime tumor-specific CTLs and tend to Th1-type immune response. Finally, in vivo depletion experimentation suggested both CD4(+) and CD8(+) T cells were involved in mediating the antitumor immune responses of combined treatment of AdVCD40L and iDCs, with CD8(+) T cells being the major effector. These findings could be beneficial for designing strategies of DCs vaccine and CD40L for anticancer immunotherapy. C1 Univ Saskatchewan, Coll Med, Dept Microbiol, Saskatoon, SK S7N 0W0, Canada. Univ Saskatchewan, Coll Med, Dept Immunol & Oncol, Saskatoon, SK S7N 0W0, Canada. Univ Saskatchewan, Saskatchewan Canc Agcy, Res Unit, Saskatoon, SK S7N 0W0, Canada. NIDR, Gene Therapy Branch, NIH, Bethesda, MD 20892 USA. RP Xiang, J (reprint author), Saskatchewan Canc Agcy, Canc Res Unit, 20 Campus Dr, Saskatoon, SK S7N 4H4, Canada. EM JXiang@scf.sk.ca NR 35 TC 19 Z9 22 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0929-1903 J9 CANCER GENE THER JI Cancer Gene Ther. PD FEB PY 2005 VL 12 IS 2 BP 122 EP 132 DI 10.1038/sj.cgt.7700757 PG 11 WC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Oncology; Genetics & Heredity; Research & Experimental Medicine GA 888HY UT WOS:000226366000003 PM 15565183 ER PT J AU Popkov, M Jendreyko, N McGavern, DB Rader, C Barbas, CF AF Popkov, M Jendreyko, N McGavern, DB Rader, C Barbas, CF TI Targeting tumor angiogenesis with adenovirus-delivered anti-Tie-2 intrabody SO CANCER RESEARCH LA English DT Article ID RECEPTOR TYROSINE KINASES; BLOOD-VESSEL FORMATION; SINGLE-CHAIN ANTIBODY; TIE2 RECEPTOR; INTRACELLULAR IMMUNIZATION; EMBRYONIC ANGIOGENESIS; PHAGE DISPLAY; GENE-THERAPY; IN-VIVO; EXPRESSION AB Inhibition of tumor angiogenesis is a promising approach for cancer therapy. As an endothelial cell-specific receptor kinase expressed almost exclusively on the surface of vascular endothelium, Tie-2 has an important role in tumor angiogenesis. To explore the therapeutic potential of blocking Tie-2 receptor-interaction pathway, an adenoviral vector was used to deliver a recombinant single-chain antibody fragment rabbit intrabody (pAd-2S03) capable of inhibition of both mouse and human Tie-2 surface expression. pAd-2S03 was given to mice with well-established primary tumors, either a human Kaposi's sarcoma (SLK) or a human colon carcinoma (SW1222). The intrabody significantly inhibited growth of both tumors (75% and 63%, respectively) when compared with pAd-GFP control-treated tumors (P < 0.01). Histopathologic analysis of cryosections taken from mice treated with pAd-2SO3 revealed a marked decrease in vessel density, which was reduced by >87% in both tumor models when compared with control-treated tumors (P < 0.01). In contrast, human Tie-2-monospecific pAd-1S05 intrabody did not affect the growth of tumors, indicating that the antitumor effect of pAd-2SO3 was due to the inhibition of tumor angiogenesis in these murine models. Our results show that the Tie-2 receptor pathway is essential for both SLK sarcoma and SW1222 colon carcinoma xenograft growth. The present study shows the potential utility of antiangiogenic agents that target the endothelium-specific receptor Tie-2 for down-regulation or genetic deletion. C1 Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. Scripps Res Inst, Skaggs Inst Chem Biol, La Jolla, CA 92037 USA. Scripps Res Inst, Dept Neuropharmacol, La Jolla, CA 92037 USA. NCI, Expt Transplantat & Immunol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Barbas, CF (reprint author), Scripps Res Inst, Dept Mol Biol, BCC-550,10550 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM carlos@scripps.edu FU NCI NIH HHS [R01 CA 086258] NR 45 TC 51 Z9 57 U1 0 U2 2 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2005 VL 65 IS 3 BP 972 EP 981 PG 10 WC Oncology SC Oncology GA 893SN UT WOS:000226739600041 PM 15705898 ER PT J AU Liu, KB Caldwell, SA Abrams, SI AF Liu, KB Caldwell, SA Abrams, SI TI Cooperative disengagement of Fas and intercellular adhesion molecule-1 function in neoplastic cells confers enhanced colonization efficiency SO CANCER RESEARCH LA English DT Article ID COLON-CARCINOMA CELLS; ALPHA-INDUCED INFLAMMATION; FLICE-INHIBITORY PROTEIN; RENAL-CANCER CELLS; ICAM-1 EXPRESSION; IMMUNE ESCAPE; IN-VIVO; PULMONARY METASTASES; LIGAND INTERACTIONS; TUMOR PROGRESSION AB Understanding the mechanisms of tumor progression is crucial toward the development of therapeutic interventions. Although the loss of sensitivity to cell death is a hallmark of neoplastic progression, it is likely one of several essential features that underlie a malignantly proficient or aggressive tumorigenic phenotype. Here, we identified intercellular adhesion molecule-1 (ICAM-1) as a molecule with expression coordinately regulated with Fas and inversely correlated with malignant phenotype between matched pairs of differentially aggressive malignant subpopulations in three mouse models. To determine whether coordinate expression of Fas and ICAM-1 regulated malignant behavior, tumor sublines were produced that expressed either lower levels of both Fas and ICAM-1, lower levels of Fas, or lower levels of ICAM-1 and then assessed for metastatic lung tumor growth. Tumor sublines rendered both Fas incompetent and ICAM-1 incompetent displayed significantly higher numbers of tumor nodules compared with tumor sublines separately expressing low levels of Fas or ICAM-1. However, all tumor sublines regardless of their Fas and ICAM-1 levels comparably infiltrated the lung, suggesting that Fas- and ICAM-1-based interactions ultimately influenced lung colonization efficiency. Overall, these data suggested that both Fas and ICAM-1 pathways cooperated to regulate tumor progression and that the coordinate down-regulation of Fas and ICAM-1 intensified malignant progression at the level of colonization. Thus, a Fas(lo)ICAM-1(lo) phenotype may be characteristic of at least certain advancing, immune-resistant neoplastic subpopulations. C1 NCI, Ctr Canc Res, Lab Tumor Immunol & Biol, NIH, Bethesda, MD 20892 USA. RP Abrams, SI (reprint author), NCI, Ctr Canc Res, Lab Tumor Immunol & Biol, NIH, Bldg 10 Room 5B46,10 Ctr Dr, Bethesda, MD 20892 USA. EM sa47z@nih.gov OI Liu, Kebin/0000-0003-1965-7240 NR 48 TC 15 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 FEB 1 PY 2005 VL 65 IS 3 BP 1045 EP 1054 PG 10 WC Oncology SC Oncology GA 893SN UT WOS:000226739600049 PM 15705906 ER PT J AU Zhou, XZ Jun, DY Thomas, AM Huang, X Huang, LQ Mautner, J Mo, W Robbins, PF Pardoll, DM Jaffee, EM AF Zhou, XZ Jun, DY Thomas, AM Huang, X Huang, LQ Mautner, J Mo, W Robbins, PF Pardoll, DM Jaffee, EM TI Diverse CD8(+) T-cell responses to renal cell carcinoma antigens in patients treated with an autologous granulocyte-macrophage colony-stimulating factor gene-transduced renal tumor cell vaccine SO CANCER RESEARCH LA English DT Article ID OPEN READING FRAME; HLA CLASS-I; ANTITUMOR IMMUNITY; METASTATIC MELANOMA; PEPTIDE-BINDING; PANCREATIC-CANCER; LYMPHOCYTES; IDENTIFICATION; TRIAL; MOLECULES AB A phase I clinical trial with granulocyte-macrophage colony-stimulating factor tumor cell vaccines in patients with metastatic renal cell carcinoma (RCC) showed immune cell infiltration at vaccine sites and delayed-type hypersensitivity (DTH) responses to autologous tumor cells indicative of T-cell immunity. To further characterize RCC T-cell responses and identify relevant RCC-associated antigens, we did a detailed analysis of CD8(+) T-cell responses in two vaccinated RCC patients who generated the greatest magnitude of DTH response and also displayed a strong clinical response to vaccination (>90% reduction in metastatic tumor volume). Three separate CD8(+) T-cell lines (and subsequent derived clones) derived from patient 24 recognized distinct RCC-associated antigens. One recognized a shared HLA-A*0201-restricted antigen expressed by both renal cancer cells and normal kidney cells. This recognition pattern correlated with a positive DTH test to normal kidney cells despite no evidence of impairment of renal function by the patient's remaining kidney after vaccination. A second line recognized a shared HLA-C7-restrieted antigen that was IFN-gamma inducible. A third line recognized a unique HLA-A*0101-restricted RCC antigen derived from a mutated KIAA1440 gene specific to the tumor. In addition, two independent CTL lines and three clones were also generated from patient 26 and they recognized autologous tumor cells restricted through HLA-A*0205, HLA-A/B/C, and HLA-B/C. These results show that paracrine granulocyte-macrophage colony-stimulating factor tumor vaccines may generate a diverse repertoire of tumor-reactive CD8(+) T-cell responses and emphasize the importance of polyvalency in the design of cancer immunotherapies. C1 Sidney Kimmel Comprehens Canc Ctr, Div Immunl & Hematopoiesis, Baltimore, MD USA. NCI, Surg Branch, NIH, Bethesda, MD USA. RP Zhou, XZ (reprint author), Univ Minnesota, Ctr Canc, Dept Pediat, MMC 366,420 Delaware St, Minneapolis, MN 55455 USA. EM zhoux058@umn.edu FU NCI NIH HHS [R01 CA 79685] NR 41 TC 31 Z9 32 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 FEB 1 PY 2005 VL 65 IS 3 BP 1079 EP 1088 PG 10 WC Oncology SC Oncology GA 893SN UT WOS:000226739600053 PM 15705910 ER PT J AU Keohavong, P Lan, Q Gao, WM Zheng, KC Mady, HH Melhem, MF Mumford, JL AF Keohavong, P Lan, Q Gao, WM Zheng, KC Mady, HH Melhem, MF Mumford, JL TI Detection of p53 and K-ras mutations in sputum of individuals exposed to smoky coal emissions in Xuan Wei County, China SO CARCINOGENESIS LA English DT Article ID BRONCHOALVEOLAR LAVAGE FLUID; LUNG-CANCER MORTALITY; COMBUSTION EMISSIONS; ONCOGENE MUTATIONS; FORMER SMOKERS; HIGH-FREQUENCY; RISK-FACTORS; INDOOR COAL; TP53; CARCINOMAS AB Lung cancer mortality rates in the Xuan Wei County population are among the highest in China and are associated with exposure to indoor emissions from the burning of smoky coal. Previous studies of lung tumors from both non-smoking women and smoking men in this region showed high frequencies of mutations, consisting mostly of G-->T transversions in the p53 tumor suppressor gene and K-ras oncogene, suggesting that these mutations were caused primarily by polycyclic aromatic hydrocarbons. In this study sputum samples from 92 individuals with no evidence of lung cancer from Xuan Wei County were screened for p53 and K-ras mutations. Sputum cells were collected on glass slides by sputum cytocentrifugation, stained and cytopathologically analyzed. Cytologically non-malignant epithelial cells were taken from each sputum sample using a laser capture microdissection microscope and molecularly analyzed. Cells taken from the sputum of 15 (16.3%) individuals were mutation positive, including 13 (14.1%) individuals each with a p53 mutation, 1 (1.1%) individual with a K-ras mutation and 1 (1.1%) individual with a p53 and a K-ras mutation. p53 mutations were found in both the sputum of individuals with evidence of chronic bronchitis (3 of 46 or 6.5%) and those without evidence of this disease (11 of 46 or 23.9%). Therefore, mutations in the p53 gene and, to a lesser extent, the K-ras gene were frequent in non-malignant epithelial cells taken from the sputum of individuals without evidence of lung cancer who were exposed to smoky coal emissions in Xuan Wei County and were at a high risk for developing the disease. C1 Univ Pittsburgh, Grad Sch Publ Hlth, Dept Environm & Occupat Hlth, Pittsburgh, PA 15260 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15260 USA. NCI, Div Canc Epidemiol & Genet, NIH, DHHS, Bethesda, MD 20892 USA. Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15240 USA. Vet Adm Hlth Care Syst, Pittsburgh, PA 15240 USA. US EPA, Natl Hlth & Environm Effects Lab, Res Triangle Pk, NC 27711 USA. RP Keohavong, P (reprint author), Univ Pittsburgh, Grad Sch Publ Hlth, Dept Environm & Occupat Hlth, 3343 Forbes Ave, Pittsburgh, PA 15260 USA. EM pho1@pitt.edu OI Keohavong, Phouthone/0000-0001-7812-4925 NR 30 TC 17 Z9 19 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 FEB PY 2005 VL 26 IS 2 BP 303 EP 308 DI 10.1093/carcin/bgh328 PG 6 WC Oncology SC Oncology GA 891VU UT WOS:000226609900005 PM 15564291 ER PT J AU Lubet, RA Christov, K Nunez, NP Hursting, SD Steele, VE Juliana, MM Eto, I Grubbs, CJ AF Lubet, RA Christov, K Nunez, NP Hursting, SD Steele, VE Juliana, MM Eto, I Grubbs, CJ TI Efficacy of Targretin on methylnitrosourea-induced mammary cancers: prevention and therapy dose-response curves and effects on proliferation and apoptosis SO CARCINOGENESIS LA English DT Article ID RETINOID-X-RECEPTOR; GROWTH-FACTOR-I; BREAST-CANCER; LGD1069 TARGRETIN; SELECTIVE LIGAND; TARGET GENES; TAMOXIFEN; CARCINOGENESIS; INHIBITION; COMBINATION AB Various aspects of the chemopreventive and chemotherapeutic properties of the RXR receptor agonist Targretin (LGD 1069) were examined in the methylnitrosourea (MNU)-induced model of mammary cancer. The administration of Targretin at dose levels of 60, 20 or 6.7 mg/kg body wt/day by gavage decreased the number of mammary tumors by 96, 85 and 78%, respectively. When Targretin was administered in the diet at 92 and 275 mg/kg diet cancer multiplicities were reduced by 78 and 92%, respectively. A wider range of dietary doses of Targretin at 15, 50 and 150 mg/kg diet reduced the number of mammary tumors by 38, 55 and 70%, respectively. Treatment of rats with different regimens of Targretin (250 mg/kg diet) yielded cancer multiplicities of 4.3 for non-treated rats, 0.5 for rats treated continuously with Targretin, 2.1 for rats treated with Targretin for 8 weeks followed by 10 weeks of the control diet and 1.6 for rats treated with Targretin alternating 3 days on and 4 days off. Targretin was also examined as a therapeutic agent by treating rats with at least one palpable mammary tumor for 5 weeks. A high dose of Targretin (272 mg/kg diet) caused partial or complete regression of similar to65% of the cancers over this time period. In contrast, in animals treated with 15 mg Targretin/kg diet only 1 of 12 cancers showed significant regression. Finally, the effect of a limited exposure to Targretin (7 days) on cell proliferation and apoptosis in small mammary tumors was determined. Targretin at 150 mg/kg diet strongly decreased proliferation (75%) and increased apoptosis (300%), while a lower dose of Targretin (15 mg/kg diet, which still prevented 30% of cancers) had no effect on apoptosis but did decrease cell proliferation. Determination of serum IGF1 levels showed that treatment of rats with highly effective doses of Targretin at 272 mg/kg diet or at 60 or 20 mg/kg body wt/day by gavage caused significantly decreased serum IGF1 levels. C1 NCI, Div Canc Prevent, Rockville, MD 20852 USA. Univ Illinois, Dept Surg Oncol, Chicago, IL USA. Univ Alabama, Dept Genet, Birmingham, AL USA. Univ Alabama, Dept Nutr Sci, Birmingham, AL 35294 USA. Univ Alabama, Dept Surg, Birmingham, AL 35294 USA. RP Lubet, RA (reprint author), NCI, Div Canc Prevent, Execut Plaza N,Suite 2110,6130 Execut Blvd, Rockville, MD 20852 USA. EM lubetr@mail.nih.gov NR 32 TC 28 Z9 28 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 FEB PY 2005 VL 26 IS 2 BP 441 EP 448 DI 10.1093/carcin/bgh338 PG 8 WC Oncology SC Oncology GA 891VU UT WOS:000226609900020 PM 15591091 ER PT J AU Shan, L Yu, MS Snyderwine, EG AF Shan, L Yu, MS Snyderwine, EG TI Gene expression profiling of chemically induced rat mammary gland cancer SO CARCINOGENESIS LA English DT Article ID SPRAGUE-DAWLEY RATS; BREAST-CANCER; HETEROCYCLIC AMINE; EPITHELIAL-CELLS; DNA-ADDUCTS; CARCINOGENESIS; 2-AMINO-1-METHYL-6-PHENYLIMIDAZO<4,5-B>PYRIDINE; CARCINOMAS; PATTERNS; TUMORS AB Exposure to carcinogens through diet, the atmosphere and other means is generally regarded as influencing human cancer risk, but the impact of specific environmental carcinogens on human breast cancer incidence is still unknown. We examined whether distinct chemical carcinogens induce a unique transcriptional profile in mammary gland cancer that is characteristic of the etiologic agent. Rat mammary gland cancers (n = 34) were generated by various carcinogens, including the food-derived heterocyclic amines 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, 7,12-dimethylbenz[a]anthracene, N-nitrosomethylurea and 4-aminobiphenyl. The histopathology of the carcinomas was graded using a modified Scarff-Bloom-Richardson scheme and the gene expression profiles in the carcinomas were evaluated on a 10K cDNA microarray. Unsupervised hierarchical clustering analysis revealed two major clusters of carcinomas irrespective of the carcinogenic agent that distinguished two groups with different histopathological parameters (degree of differentiation, nuclear grade, mitotic activity, epithelial cell growth pattern and necrosis). Using class comparison analysis and hierarchical clustering of all carcinomas irrespective of histopathology, gene expression profiles were further shown to be statistically differentially expressed according to the carcinogenic agent. These findings indicate that the transcriptional program in carcinomas is unique to the etiologic agent and can be observed among a diverse set of carcinogens despite variations in carcinoma histopathology. The ability to use microarray analysis to discern an etiology-specific profile among a pathologically heterogeneous group of breast carcinomas may ultimately be valuable in determining the role of environmental chemical carcinogens in human breast cancer risk. C1 NCI, Chem Carcinogenesis Sect, Expt Carcinogenesis Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Snyderwine, EG (reprint author), NCI, Chem Carcinogenesis Sect, Expt Carcinogenesis Lab, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. EM elizabeth_snyderwine@nih.gov NR 32 TC 18 Z9 18 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0143-3334 J9 CARCINOGENESIS JI Carcinogenesis PD FEB PY 2005 VL 26 IS 2 BP 503 EP 509 DI 10.1093/carcin/bgh330 PG 7 WC Oncology SC Oncology GA 891VU UT WOS:000226609900028 PM 15528215 ER PT J AU Wang, LH Yang, XY Zhang, XH Farrar, WL AF Wang, LH Yang, XY Zhang, XH Farrar, WL TI Nuclear receptors as negative modulators of STAT3 in multiple myeloma SO CELL CYCLE LA English DT Article DE STAT3; PPAR gamma; ER; multiple myeloma; nuclear receptor; crosstalk; interleukin-6 ID ESTROGEN-RECEPTOR; SIGNAL-TRANSDUCTION; CROSS-TALK; CELLS; ACTIVATION; HETERODIMERS; PROVIDES; TARGETS; BIOLOGY; EVENTS AB Multiple myeloma (MM) remains largely incurable despite conventional and high-dose therapies. Therefore, novel biologically based treatment approaches are urgently required. Particularly, STAT3 activated by IL-6 has a key role in preventing apoptosis and stimulating growth of multiple myeloma cells. Nuclear receptors, a distinct class of ligand-activated transcriptional factors, can interact and modify the function of transcriptional factors intrinsic to the cytokine signal transduction pathways. We have investigated regulation of two nuclear receptors, peroxisome proliferator-activated receptor g (PPAR g) and estrogen receptor (ER), and their crosstalk with STAT3 in multiple myeloma. These results indicate that ligand-activated nuclear receptors can function as negative modulators of STAT3 through direct mechanisms, or in turn, by facilitating coregulators such as PIAS or SMRT. Therefore, different classes of nuclear receptors affect suppression of STAT3 functions through diverse mechanisms resulting in downregulating IL-6-mediated cell growth and gene expression. Given the importance of IL-6 in multiple myeloma, the estrogen receptor-STAT3 or PPAR gamma-STAT3 interaction may have significant therapeutic implications in multiple myeloma. C1 NCI, Cytokine Mol Mech Sect, Mol Immunoregulat Lab, Div Basic Sci, Frederick, MD 21701 USA. NCI, Basic Res Program, SAIC Frederick, Frederick, MD 21701 USA. RP Wang, LH (reprint author), 1050 Boyles St, Frederick, MD 21702 USA. EM lhwang@ncifcrf.gov; farrar@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 28 TC 17 Z9 17 U1 0 U2 0 PU LANDES BIOSCIENCE PI AUSTIN PA 1806 RIO GRANDE ST, AUSTIN, TX 78702 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD FEB PY 2005 VL 4 IS 2 BP 242 EP 245 PG 4 WC Cell Biology SC Cell Biology GA 928WN UT WOS:000229302500013 PM 15655377 ER PT J AU Gonzalez, FJ AF Gonzalez, FJ TI Getting fat: Two new players in molecular adipogenesis SO CELL METABOLISM LA English DT Editorial Material ID PPAR-GAMMA; METABOLISM; ADIPOCYTE; REGULATOR AB A transcription factor cascade drives adipogenesis. Two new members of this cascade have been uncovered-Kruppel-like factor 5 (KLF5), which is induced by C/EBP beta and delta and acts in concert with C/EBP alpha, beta, and delta to activate PPAR gamma 2 expression, and Krox20, which is upstream of C/EBP beta expression and one of the earliest factors induced during adipogenesis. C1 NCI, Metab Lab, NIH, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NCI, Metab Lab, NIH, Bldg 37,Room 3106, Bethesda, MD 20892 USA. NR 11 TC 16 Z9 18 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1550-4131 J9 CELL METAB JI Cell Metab. PD FEB PY 2005 VL 1 IS 2 BP 85 EP 86 DI 10.1016/j.cmet.2005.01.004 PG 2 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 922IL UT WOS:000228830500001 PM 16054047 ER PT J AU Ivanova, AV Ivanov, SV Lerman, ML AF Ivanova, AV Ivanov, SV Lerman, ML TI Association, mutual stabilization, and transcriptional activity of the STRA13 and MSP58 proteins SO CELLULAR AND MOLECULAR LIFE SCIENCES LA English DT Article DE STRA13; MSP58; bHLH domain; FHA domain; mutual stabilization; phosphorylation; synergistic repression; cell cycle ID 58-KDA MICROSPHERULE PROTEIN; GENE-EXPRESSION; HYPOXIA; CELLS; DEC1; DIFFERENTIATION; DEGRADATION; INTERACTS; PATHWAY; ENHANCER AB STRA13 is a hypoxia-inducible bHLH transcription factor implicated in the pVHL/HIF, TGF-beta, and Jak/STAT pathways. To further characterize the STRA13 protein-interacting network and mechanisms of STRA13-dependent transcription, we utilized yeast two-hybrid screening. Here we report on STRA13 interaction with the cell cycle-associated transcription factor MSP58. We demonstrated that the basic domain of STRA13 and the FHA domain of MSP58 are essential for this association. We performed phospho-peptide mapping of both MSP58 and STRA13 and showed that their association was modulated by the STRA13 phosphorylation status. STRA13/MSP58 complex formation protected both proteins from the proteasome-mediated degradation, extending their half-lives considerably. STRA13 and MSP58 synergistically co-operated in the STRA13 promoter-driven transcription repression. Both proteins were co-localized in the nucleus and showed transcript accumulation during the S phase of the cell cycle. Thus, we characterize a novel STRA13-associated transcription repression complex and provide a link between cell cycle regulation and STRA13 activity. C1 SAIC Frederick Inc, Basic Res Program, Immunobiol Lab, NCI, Frederick, MD 21702 USA. NCI, Immunobiol Lab, Frederick, MD 21702 USA. RP Ivanova, AV (reprint author), SAIC Frederick Inc, Basic Res Program, Immunobiol Lab, NCI, Frederick, MD 21702 USA. EM ivanova@mail.ncifcrf.gov OI Ivanov, Sergey/0000-0001-9770-7237 FU NCI NIH HHS [N01 CO 56000] NR 32 TC 25 Z9 25 U1 1 U2 1 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 FEB PY 2005 VL 62 IS 4 BP 471 EP 484 DI 10.1007/s00018-004-4423-2 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 899RZ UT WOS:000227163800007 PM 15719173 ER PT J AU Danielli, A Barillas-Mury, C Kumar, S Kafatos, FC Loukeris, TG AF Danielli, A Barillas-Mury, C Kumar, S Kafatos, FC Loukeris, TG TI Overexpression and altered nucleocytoplasmic distribution of Anopheles ovalbumin-like SRPN10 serpins in Plasmodium-infected midgut cells SO CELLULAR MICROBIOLOGY LA English DT Article ID IMMUNE-RESPONSE; GENOME SEQUENCE; GAMBIAE; MOSQUITO; DROSOPHILA; INVASION; MECHANISM; GENES; SUPERFAMILY; ACTIVATION AB The design of effective, vector-based malaria transmission blocking strategies relies on a thorough understanding of the molecular and cellular interactions that occur during the parasite sporogonic cycle in the mosquito. During Plasmodium berghei invasion, transcription from the SRPN10 locus, encoding four serine protease inhibitors of the ovalbumin family, is strongly induced in the mosquito midgut. Herein we demonstrate that intense induction as well as redistribution of SRPN10 occurs specifically in the parasite-invaded midgut epithelial cells. Quantitative analysis establishes that in response to epithelial invasion, SRPN10 translocates from the nucleus to the cytoplasm and this is followed by strong SRPN10 overexpression. The invaded cells exhibit signs of apoptosis, suggesting a link between this type of intracellular serpin and epithelial damage. The SRPN10 gene products constitute a novel, robust and cell-autonomous marker of midgut invasion by ookinetes. The SRPN10 dynamics at the subcellular level confirm and further elaborate the 'time bomb' model of P. berghei invasion in both Anopheles stephensi and Anopheles gambiae. In contrast, this syndrome of responses is not elicited by mutant P. berghei ookinetes lacking the major ookinete surface proteins, P28 and P25. Molecular markers with defined expression patterns, in combination with mutant parasite strains, will facilitate dissection of the molecular mechanisms underlying vector competence and development of effective transmission blocking strategies. C1 European Mol Biol Lab, D-69117 Heidelberg, Germany. Univ Bologna, Dipartimento Biol Evoluzionist Sperimentale, I-40126 Bologna, Italy. Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. NIH, Lab Malaria & Vector Res, Bethesda, MD 20892 USA. Inst Mol Biol & Biotechnol, FORTH, GR-71110 Iraklion, Greece. RP Kafatos, FC (reprint author), European Mol Biol Lab, Meyerhofstr 1, D-69117 Heidelberg, Germany. EM dg-office@embl.de; loukeris@mailhost.imbb.forth.gr OI DANIELLI, ALBERTO/0000-0002-9414-9898 NR 29 TC 36 Z9 40 U1 0 U2 1 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 1462-5814 EI 1462-5822 J9 CELL MICROBIOL JI Cell Microbiol. PD FEB PY 2005 VL 7 IS 2 BP 181 EP 190 DI 10.1111/j.1462-5822.2004.00445.x PG 10 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 889XD UT WOS:000226475200003 PM 15659062 ER PT J AU de Bernard, M Cappon, A Pancotto, L Ruggiero, P Rivera, J Del Giudice, G Montecucco, C AF de Bernard, M Cappon, A Pancotto, L Ruggiero, P Rivera, J Del Giudice, G Montecucco, C TI The Helicobacter pylori VacA cytotoxin activates RBL-2H3 cells by inducing cytosolic calcium oscillations SO CELLULAR MICROBIOLOGY LA English DT Article ID MAST-CELLS; VACUOLATING CYTOTOXIN; PLASMA-MEMBRANE; TOXIN VACA; INFECTION; ACID; ALPHA; CA2+; RECRUITMENT; NEUTROPHILS AB Helicobacter pylori causes an acute inflammatory response followed by chronic infection of the human gastric mucosa. Identification of the bacterial molecules endowed with a pro-inflammatory activity is essential to a molecular understanding of the pathogenesis of H. pylori associated diseases. The vacuolating cytotoxin A (VacA) induces mast cells to release pro-inflammatory cytokines. Here, we show that VacA activates the mast cell line RBL-2H3 by rapidly inducing an oscillation of the level of cytosolic calcium with exocytosis of secretory granules. Cytosolic calcium derives mainly from intracellular stores. VacA also stimulates a calcium-dependent production of pro-inflammatory cytokines, including tumour necrosis factor alpha (TNF-alpha). These observations indicate that VacA may act as a pro-inflammatory factor of H. pylori at very early stages of the innate immune response. C1 Univ Padua, Dipartimento Biol, Padua, Italy. Univ Padua, Dipartimento Sci Biomed Sperimentali, Padua, Italy. Ist Veneto Med Mol, Padua, Italy. IRIS CHIRON SpA, Siena, Italy. NIAMSD, NIH, Bethesda, MD 20892 USA. RP de Bernard, M (reprint author), Univ Padua, Dipartimento Biol, Via G Colombo 3, Padua, Italy. EM marina.debernard@unipd.it NR 44 TC 31 Z9 34 U1 0 U2 2 PU BLACKWELL PUBLISHING LTD PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DG, OXON, ENGLAND SN 1462-5814 J9 CELL MICROBIOL JI Cell Microbiol. PD FEB PY 2005 VL 7 IS 2 BP 191 EP 198 DI 10.1111/j.1462-5822.2004.00446.x PG 8 WC Cell Biology; Microbiology SC Cell Biology; Microbiology GA 889XD UT WOS:000226475200004 PM 15659063 ER PT J AU Kim, WH Hong, F Jaruga, B Zhang, ZS Fan, SJ Liang, TJ Gao, B AF Kim, Won-Ho Hong, Feng Jaruga, Barbara Zhang, Zhengsheng Fan, Saijun Liang, T. Jake Gao, Bin TI Hepatitis B Virus X Protein Sensitizes Primary Mouse Hepatocytes to Ethanol- and TNF-alpha-Induced Apoptosis by a Caspase-3-Dependent Mechanism SO CELLULAR & MOLECULAR IMMUNOLOGY LA English DT Article DE HBV X protein; ethanol; apoptosis; TNF-alpha; caspase-3 AB It is well-documented that alcohol drinking together with hepatitis viral infection accelerates liver injury; however the underlying mechanisms remain unknown. In this paper, we demonstrated that primary hepatocytes from transgenic mice overexpressing hepatitis B virus X protein (HBX) were more susceptible to ethanol-and TNF-alpha induced apoptotic killing. Compared to normal control mouse hepatocytes, ethanol and/or TNF-a treatment led to a significant increase in reactive oxygen species, mitochondrial permeability transition, cytochrome C release, caspase-3 activity, and poly (ADP-ribose) polymerase degradation in hepatocytes from HBX transgenic mice. Blocking caspase-3 activity antagonized ethanol-and TNF-alpha-induced apoptosis in primary hepatocytes from HBX transgenic mice. Taken together, our findings suggest that HBX sensitizes primary mouse hepatocytes to ethanol-and TNF-alpha-induced apoptosis by a caspase-3-dependent mechanism, which may partly explain the synergistic effects of alcohol consumption and hepatitis B virus infection on liver injury. C1 [Kim, Won-Ho; Hong, Feng; Jaruga, Barbara; Gao, Bin] NIAAA, Lab Physiol Studies, Sect Liver Biol, NIH, Bethesda, MD 20892 USA. [Zhang, Zhengsheng; Liang, T. Jake] NIDDK, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. [Fan, Saijun] Georgetown Univ, Lombardi Canc Ctr, Dept Oncol, Washington, DC 20057 USA. RP Kim, WH (reprint author), NIH, Div Metab Dis, 5 Nokbun Dong, Seoul 122701, South Korea. EM jhkwh@hanmail.net NR 46 TC 24 Z9 25 U1 0 U2 1 PU CHIN SOCIETY IMMUNOLOGY PI BEING PA 5 DONGDAN SANTIAO, DONGCHEN DISTRICT, BEING, 100005, PEOPLES R CHINA SN 1672-7681 EI 2042-0226 J9 CELL MOL IMMUNOL JI Cell. Mol. Immunol. PD FEB PY 2005 VL 2 IS 1 BP 40 EP 48 PG 9 WC Immunology SC Immunology GA V32AS UT WOS:000208924700006 PM 16212910 ER PT J AU Spengler, ML Kennett, SB Moorefield, KS Simmons, SO Brattain, MG Horowitz, JM AF Spengler, ML Kennett, SB Moorefield, KS Simmons, SO Brattain, MG Horowitz, JM TI Sumoylation of internally initiated Sp3 isoforms regulates transcriptional repression via a Trichostatin A-insensitive mechanism SO CELLULAR SIGNALLING LA English DT Article DE sumoylation; trichostatin A; SP3; PML; transcriptional regulation; trans-activation; trans-repression ID SUMO-1 MODIFICATION; SP-FAMILY; COVALENT MODIFICATION; HISTONE DEACETYLASE; CYCLE REGULATION; NUCLEAR-BODIES; PROTEIN SUMO-1; GENE PROMOTER; DNA-BINDING; FACTOR AP-2 AB Sp3 is a ubiquitously expressed member of the Sp family of transcription factors that encodes three proteins, Sp3, M1 and M2, with differing capacities to stimulate or repress transcription. As part of ongoing efforts to study the functions of Sp3 isoforms, we employed a yeast ''two-hybrid" screen to identify Sp3-binding proteins. This screen resulted in the identification of Ubc9, a SUMO-1 conjugating enzyme, as an M2-binding protein, and consistent with these results sequence analyses identified consensus sumoylation motifs within several Sp family members. Western blots probed with anti-Sp3 detected a high molecular weight Sp3 isoform that is stabilized by a SUMO1 hydrolase inhibitor, and this protein is also bound by anti-SUMO-1 antiserum. Transient transfection assays with epitope-tagged-SUMO-1 and GFP-SUMO-1 fusion proteins confirmed that Sp3, M1 and M2 proteins are sumoylated in vivo. Substitution of arginine for lysine at one putative site of sumoylation, lysine(551), blocked sumoylation of all Sp3 isoforms in vivo and led to a marginal increase in Sp3-mediated trans-activation in insect and mammalian cells. In contrast, introduction of this amino acid substitution within M1 converted it into a potent transcriptional trans-activator. We conclude that Sp3 isoforms are sumoylated in vivo and this post-translational modification plays an important role in the regulation of Sp3-mediated transcription. (C) 2004 Elsevier Inc. All rights reserved. C1 N Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, Raleigh, NC 27606 USA. NIEHS, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Roswell Pk Canc Inst, Dept Pharmacol & Therapeut, Buffalo, NY 14263 USA. RP Horowitz, JM (reprint author), N Carolina State Univ, Coll Vet Med, Dept Mol Biomed Sci, 4700 Hillsborough St, Raleigh, NC 27606 USA. EM jon_horowitz@ncsu.edu OI Simmons, Steven/0000-0001-9079-1069 FU NCI NIH HHS [CA53248, CA72001, CA86500]; NIEHS NIH HHS [ES07046]; NIGMS NIH HHS [GM065405] NR 56 TC 25 Z9 26 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0898-6568 EI 1873-3913 J9 CELL SIGNAL JI Cell. Signal. PD FEB PY 2005 VL 17 IS 2 BP 153 EP 166 DI 10.1016/j.cellsig.2004.06.007 PG 14 WC Cell Biology SC Cell Biology GA 868RF UT WOS:000224930000003 PM 15494207 ER EF