FN Thomson Reuters Web of Science™ VR 1.0 PT J AU Bailey, RC Moses, S Parker, CB Agot, K Maclean, I Krieger, JN Williams, CFM Campbell, RT Ninya-Achola, JO AF Bailey, Robert C. Moses, Stephen Parker, Corette B. Agot, Kawango Maclean, Ian Krieger, John N. Williams, Carolyn F. M. Campbell, Richard T. Ninya-Achola, Jeckoniah O. TI Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial SO LANCET LA English DT Article ID SEXUALLY-TRANSMITTED INFECTIONS; SUB-SAHARAN AFRICA; UNCIRCUMCISED MEN; TARGET-CELLS; RISK; UGANDA; SEROCONVERSION; COMPLICATIONS; METAANALYSIS; ASSOCIATION AB Background Male circumcision could provide substantial protection against acquisition of HIV-1 infection. Our aim was to determine whether male circumcision had a protective effect against HIV infection, and to assess safety and changes in sexual behaviour related to this intervention. Methods We did a randomised controlled trial of 2784 men aged 18-24 years in Kisumu, Kenya. Men were randomly assigned to an intervention group (circumcision; n=1391) or a control group (delayed circumcision, 1393), and assessed by HIV testing, medical examinations, and behavioural interviews during follow-ups at 1, 3, 6, 12, 18, and 24 months. HIV seroincidence was estimated in an intention-to-treat analysis. This trial is registered with ClinicalTrials.gov, with the number NCT00059371. Findings The trial was stopped early on December 12, 2006, after a third interim analysis reviewed by the data and safety monitoring board. The median length of follow-up was 24 months. Follow-up for HIV status was incomplete for 240 (8.6%) participants. 22 men in the intervention group and 47 in the control group had tested positive for HIV when the study was stopped. The 2-year HIV incidence was 2.1% (95% CI 1.2-3.0) in the circumcision group and 4.2% (3.0-5.4) in the control group (p=0.0065); the relative risk of HIV infection in circumcised men was 0.47 (0.28-0.78), which corresponds to a reduction in the risk of acquiring an HIV infection of 53% (22-72). Adjusting for non-adherence to treatment and excluding four men found to be seropositive at enrolment, the protective effect of circumcision was 60% (32-77). Adverse events related to the intervention (21 events in 1.5% of those circumcised) resolved quickly. No behavioural. risk compensation after circumcision was observed. Interpretation Male circumcision significantly reduces the risk of HIV acquisition in young men in Africa. Where appropriate, voluntary, safe, and affordable circumcision services should be integrated with other HIV preventive interventions and provided as expeditiously as possible. C1 Univ Illinois, Sch Publ Hlth, Div Epidemiol & Biostat, Chicago, IL 60612 USA. UNIM Project, Dept Med Microbiol, Kisumu, Kenya. Univ Manitoba, Dept Community Hlth Sci, Winnipeg, MB R3T 2N2, Canada. RTI Int, Res Triangle Pk, NC USA. Univ Washington, Sch Med, Dept Urol, Seattle, WA 98195 USA. NIAID, Div AIDS, NIH, Bethesda, MD 20892 USA. Univ Nairobi, Dept Med Microbiol, Nairobi, Kenya. RP Bailey, RC (reprint author), Univ Illinois, Sch Publ Hlth, Div Epidemiol & Biostat, 1603 W Taylor St, Chicago, IL 60612 USA. EM rcbailey@uic.edu FU NIAID NIH HHS [AI50440] NR 49 TC 1150 Z9 1207 U1 6 U2 86 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD FEB 24 PY 2007 VL 369 IS 9562 BP 643 EP 656 DI 10.1016/S0140-6736(07)60312-2 PG 14 WC Medicine, General & Internal SC General & Internal Medicine GA 141RO UT WOS:000244596600026 PM 17321310 ER PT J AU Gray, RH Kigozi, G Serwadda, D Makumbi, F Watya, S Nalugoda, F Kiwanuka, N Moulton, LH Chaudhary, MA Chen, MZ Sewankambo, NK Wabwire-Mangen, F Bacon, MC Williams, CFM Opendi, P Reynolds, SJ Laeyendecker, O Quinn, TC Wawer, MJ AF Gray, Ronald H. Kigozi, Godfrey Serwadda, David Makumbi, Frederick Watya, Stephen Nalugoda, Fred Kiwanuka, Noah Moulton, Lawrence H. Chaudhary, Mohammad A. Chen, Michael Z. Sewankambo, Nelson K. Wabwire-Mangen, Fred Bacon, Melanie C. Williams, Carolyn F. M. Opendi, Pius Reynolds, Steven J. Laeyendecker, Oliver Quinn, Thomas C. Wawer, Maria J. TI Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial SO LANCET LA English DT Article ID SEXUALLY-TRANSMITTED INFECTIONS; IMMUNODEFICIENCY-VIRUS TYPE-1; CLINICAL-TRIALS; TARGET-CELLS; RISK; METAANALYSIS; ACQUISITION; INDIA; DISEASES; COHORT AB Background Ecological and observational studies suggest that male circumcision reduces the risk of HIV acquisition in men. Our aim was to investigate the effect of male circumcision on HIV incidence in men. Methods 4996 uncircumcised, HIV-negative men aged 15-49 years who agreed to HIV testing and counselling were enrolled in this randomised trial in rural Rakai district, Uganda. Men were randomly assigned to receive immediate circumcision (n=2474) or circumcision delayed for 24 months (2522). HIV testing, physical examination, and interviews were repeated at 6, 12, and 24 month follow-up visits. The primary outcome was HIV incidence. Analyses were done on a modified intention-to-treat basis. This trial is registered with ClinicaITrials.gov, with the number NCT00425984. Findings Baseline characteristics of the men in the intervention and control groups were much the same at enrolment. Retention rates were much the same in the two groups, with 90-92% of participants retained at all time points. In the modified intention-to-treat analysis, HIV incidence over 24 months was 0.66 cases per 100 person-years in the intervention group and 1.33 cases per 100 person-years in the control group (estimated efficacy of intervention 51%, 95% Cl 16-72; p=0.006). The as-treated efficacy was 55% (95% CI 22-75; p=0.002); efficacy from the Kaplan-Meier time-to-HIV-detection as-treated analysis was 60% (30-77; p=0.003). HIV incidence was lower in the intervention group than it was in the control group in all sociodemographic, behavioural, and sexually transmitted disease symptom subgroups. Moderate or severe adverse events occurred in 84 (3.6%) circumcisions; all resolved with treatment. Behaviours were much the same in both groups during follow-up. Interpretation Male circumcision reduced HIV incidence in men without behavioural disinhibition. Circumcision can be recommended for HIV prevention in men. C1 Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Baltimore, MD 21215 USA. Rakai Hlth Sci Program, Entebbe, Uganda. Makerere Univ, Inst Publ Hlth, Kampala, Uganda. Makerere Univ, Mulago Hosp, Dept Surg, Urol Unit, Kampala, Uganda. Makerere Univ, Dept Med, Kampala, Uganda. NIAID, NIH, Bethesda, MD 20892 USA. Johns Hopkins Med Inst, Baltimore, MD 21205 USA. RP Gray, RH (reprint author), Johns Hopkins Univ, Bloomberg Sch Publ Hlth, Suite E4132,615 N Wolfe St, Baltimore, MD 21215 USA. EM rgray@jhsph.edu RI Quinn, Thomas/A-2494-2010; Laeyendecker, Oliver/B-9331-2009 OI Sewankambo, Nelson/0000-0001-9362-053X; Laeyendecker, Oliver/0000-0002-6429-4760; Moulton, Lawrence/0000-0001-7041-7387; FU FIC NIH HHS [D43 TW001508]; NIAID NIH HHS [U01 AI051171] NR 27 TC 1142 Z9 1194 U1 4 U2 45 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD FEB 24 PY 2007 VL 369 IS 9562 BP 657 EP 666 DI 10.1016/S0140-6736(07)60313-4 PG 10 WC Medicine, General & Internal SC General & Internal Medicine GA 141RO UT WOS:000244596600027 PM 17321311 ER PT J AU Oknianska, A Zmuda-Trzebiatowska, E Manganiello, V Degerman, E AF Oknianska, Alina Zmuda-Trzebiatowska, Emilia Manganiello, Vincent Degerman, Eva TI Long-term regulation of cyclic nucleotide phosphodiesterase type 3B and 4 in 3T3-L1 adipocytes SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE phosphodiesterase 3B; phosphodiesterase 4; adipocyte; insulin; isoproterenol ID ELEMENT-BINDING PROTEIN; FAT-CELLS; CAMP PHOSPHODIESTERASE; GENE-EXPRESSION; PDE4 EXPRESSION; ADIPOSE-TISSUE; MOUSE-BRAIN; INSULIN; LIPOLYSIS; AGENTS AB Phosphodiesterase 3B (PDE3B), is known to play an important role in acute insulin and cAMP-mediated regulation of lipid metabolism, and PDE4 are the main PDE types expressed in adipocytes. Here, we show that members of all PDE4 isoforms are expressed in 3T3-L1 and primary mouse adipocytes. Long-term treatment of 3T3-L1 adipocytes with insulin induced up-regulation of PDE3B and PDE4D in a phosphatidylinositol 3-kinase-dependent manner whereas long-term treatment with P-adrenergic agonists induced down-regulation of PDE3B and up-regulation of PDE4D. Thus, PDE3B and PDE4D can be added to the list of genes regulated by insulin and cAMP-increasing hormones. Altered expression of PDE3B and PDE4D in response to long-term treatment with insulin and catecholamines may contribute to altered regulation of metabolism in diabetes. (c) 2006 Elsevier Inc. All rights reserved. C1 Biomed Ctr, Dept Expt Med Sci, S-22184 Lund, Sweden. NHLB, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Zmuda-Trzebiatowska, E (reprint author), Biomed Ctr, Dept Expt Med Sci, C11, S-22184 Lund, Sweden. EM emilia.zmuda-trzebiatowska@med.lu.se NR 30 TC 6 Z9 6 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 23 PY 2007 VL 353 IS 4 BP 1080 EP 1085 DI 10.1016/j.bbrc.2006.12.141 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 131HL UT WOS:000243859600039 PM 17198676 ER PT J AU Bushel, PR Wolfinger, RD Gibson, G AF Bushel, Pierre R. Wolfinger, Russell D. Gibson, Greg TI Simultaneous clustering of gene expression data with clinical chemistry and pathological evaluations reveals phenotypic prototypes SO BMC SYSTEMS BIOLOGY LA English DT Article ID BREAST-CANCER; MICROARRAY DATA; PROFILES; ACETAMINOPHEN; RAT; TOXICOGENOMICS; DISCOVERY; PREDICTION; TOXICOLOGY; ONTOLOGY AB Background: Commonly employed clustering methods for analysis of gene expression data do not directly incorporate phenotypic data about the samples. Furthermore, clustering of samples with known phenotypes is typically performed in an informal fashion. The inability of clustering algorithms to incorporate biological data in the grouping process can limit proper interpretation of the data and its underlying biology. Results: We present a more formal approach, the modk-prototypes algorithm, for clustering biological samples based on simultaneously considering microarray gene expression data and classes of known phenotypic variables such as clinical chemistry evaluations and histopathologic observations. The strategy involves constructing an objective function with the sum of the squared Euclidean distances for numeric microarray and clinical chemistry data and simple matching for histopathology categorical values in order to measure dissimilarity of the samples. Separate weighting terms are used for microarray, clinical chemistry and histopathology measurements to control the influence of each data domain on the clustering of the samples. The dynamic validity index for numeric data was modified with a category utility measure for determining the number of clusters in the data sets. A cluster's prototype, formed from the mean of the values for numeric features and the mode of the categorical values of all the samples in the group, is representative of the phenotype of the cluster members. The approach is shown to work well with a simulated mixed data set and two real data examples containing numeric and categorical data types. One from a heart disease study and another from acetaminophen ( an analgesic) exposure in rat liver that causes centrilobular necrosis. Conclusion: The modk-prototypes algorithm partitioned the simulated data into clusters with samples in their respective class group and the heart disease samples into two groups ( sick and buff denoting samples having pain type representative of angina and non-angina respectively) with an accuracy of 79%. This is on par with, or better than, the assignment accuracy of the heart disease samples by several well-known and successful clustering algorithms. Following modk-prototypes clustering of the acetaminophen-exposed samples, informative genes from the cluster prototypes were identified that are descriptive of, and phenotypically anchored to, levels of necrosis of the centrilobular region of the rat liver. The biological processes cell growth and/or maintenance, amine metabolism, and stress response were shown to discern between no and moderate levels of acetaminophen-induced centrilobular necrosis. The use of well-known and traditional measurements directly in the clustering provides some guarantee that the resulting clusters will be meaningfully interpretable. C1 Natl Ctr Toxicogenom, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. SAS Inst, Cary, NC USA. N Carolina State Univ, Dept Genet, Raleigh, NC 27695 USA. N Carolina State Univ, Bioinformat Program, Raleigh, NC 27695 USA. RP Bushel, PR (reprint author), Natl Ctr Toxicogenom, Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. EM bushel@niehs.nih.gov; Russ.Wolfinger@sas.com; ggibson@ncsu.edu FU Intramural NIH HHS NR 47 TC 21 Z9 22 U1 0 U2 1 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1752-0509 J9 BMC SYST BIOL JI BMC Syst. Biol. PD FEB 23 PY 2007 VL 1 AR 15 DI 10.1186/1752-0509-1-15 PG 20 WC Mathematical & Computational Biology SC Mathematical & Computational Biology GA 218FS UT WOS:000250002000001 PM 17408499 ER PT J AU Radley, JJ Farb, CR He, Y Janssen, WGM Rodrigues, SM Johnson, LR Hof, PR LeDoux, JE Morrison, JH AF Radley, Jason J. Farb, Claudia R. He, Yong Janssen, William G. M. Rodrigues, Sarina M. Johnson, Luke R. Hof, Patrick R. LeDoux, Joseph E. Morrison, John H. TI Distribution of NMDA and AMPA receptor subunits at thalamo-amygdaloid dendritic spines SO BRAIN RESEARCH LA English DT Article DE GluR2; GluR3; excitatory amino acid; immunogold; NR1; NR2B; postembedding; immunohistochemistry; tracing; electron microscopy ID LONG-TERM POTENTIATION; LATERAL AMYGDALA; SYNAPTIC-TRANSMISSION; COMPUTER-PROGRAM; MEMORY FORMATION; RAT HIPPOCAMPUS; FEAR; PLASTICITY; NEURONS; ACQUISITION AB Synapses onto dendritic spines in the lateral amygdala formed by afferents from the auditory thalamus represent a site of plasticity in Pavlovian fear conditioning. Previous work has demonstrated that thalamic afferents synapse onto LA spines expressing glutamate receptor (GluR) subunits, but the GluR subunit distribution at the synapse and within the cytoplasm has not been characterized. Therefore, we performed a quantitative analysis for alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor subunits GluR2 and GluR3 and N-methyl-D-aspartate (NMDA) receptor subunits NR1 and NR2B by combining anterograde labeling of thalamo-amygdaloid afferents with postembedding immunoelectron microscopy for the GluRs in adult rats. A high percentage of thalamo-amygdaloid spines was immunoreactive for GluR2 (80%), GluR3 (83%), and NR1 (83%), while a smaller proportion of spines expressed NR2B (59%). To compare across the various subunits, the cytoplasmic to synaptic ratios of GluRs were measured within thalamo-amygdaloid spines. Analyses revealed that the cytoplasmic pool of GluR2 receptors was twice as large compared to the GluR3, NR1, and NR2B subunits. Our data also show that in the adult brain, the NR2B subunit is expressed in the majority of in thalamo-amygdaloid spines and that within these spines, the various GluRs are differentially distributed between synaptic and non-synaptic sites. The prevalence of the NR2B subunit in thalamo-amygdaloid spines provides morphological evidence supporting its role in the fear conditioning circuit while the differential distribution of the GluR subtypes may reflect distinct roles for their involvement in this circuitry and synaptic plasticity. (c) 2006 Elsevier B.V. All rights reserved. C1 CUNY Mt Sinai Sch Med, Dept Neurosci, New York, NY 10029 USA. CUNY Mt Sinai Sch Med, Dept Geriatr & Adult Dev, New York, NY 10029 USA. NYU, Ctr Neural Sci, New York, NY 10003 USA. NIMH, Ctr Neurobiol Fear & Anxiety, New York, NY USA. RP Radley, JJ (reprint author), Salk Inst Biol Studies, Neuronal Struct & Funct Lab, 10010 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM radley@salk.edu RI Morrison, John/F-9229-2012 FU NIMH NIH HHS [MH58911, P50 MH058911] NR 59 TC 37 Z9 41 U1 2 U2 5 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD FEB 23 PY 2007 VL 1134 IS 1 BP 87 EP 94 DI 10.1016/j.brainres.2006.11.045 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 142GZ UT WOS:000244638700011 PM 17207780 ER PT J AU Misteli, T AF Misteli, Tom TI Beyond the sequence: Cellular organization of genome function SO CELL LA English DT Review ID DOUBLE-STRAND BREAKS; CHROMOSOME TERRITORIES; CHROMATIN DOMAINS; IN-VIVO; NUCLEAR-ORGANIZATION; LIVING CELLS; SPATIAL-ORGANIZATION; INTERPHASE NUCLEI; GENE DENSITY; DYNAMIC EQUILIBRIUM C1 NCI, NIH, Bethesda, MD 20892 USA. RP Misteli, T (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM mistelit@mail.nih.gov FU Intramural NIH HHS NR 120 TC 624 Z9 641 U1 6 U2 46 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 0092-8674 J9 CELL JI Cell PD FEB 23 PY 2007 VL 128 IS 4 BP 787 EP 800 DI 10.1016/j.cell.2007.01.028 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 148TX UT WOS:000245098600019 PM 17320514 ER PT J AU Reuter, M Jeste, N Klein, T Hennig, J Goldman, D Enoch, MA Oroszi, G AF Reuter, Martin Jeste, Neelum Klein, Thomas Hennig, Juergen Goldman, David Enoch, Mary-Anne Oroszi, Gabor TI Association of THR105Ile, a functional polymorphism of histamine N-methyltransferase (HNMT), with alcoholism in German Caucasians SO DRUG AND ALCOHOL DEPENDENCE LA English DT Article DE histamine; HNMT Thr105Ile; alcoholism; family history of alcoholism ID SINGLE NUCLEOTIDE POLYMORPHISM; BRAIN HISTAMINE; PHARMACOGENETICS; ASTHMA; POPULATION; MODEL; GENE; STIMULATION; TEMPERAMENT; ACTIVATION AB Background: CNS histamine has been shown to have an inhibitory effect on reward and it is implicated in the etiology of addiction and stress. Histamine N-methyltransferase (HNMT) is believed to be the sole pathway for termination of the neurotransmitter action of histamine in mammalian brain. A common, functional polymorphism, a C314T transition in the HNMT gene, results in a Thr105Ile substitution of the protein encoded. A recent study has shown that the frequency of the Ile105 allele was significantly lower in alcoholics compared to that in non-alcoholics in Finns and Plains American Indians. Following up these results, we tested whether the Thr105Ile polymorphism was associated with alcoholism in German Caucasians. Methods: Thr105Ile was genotyped in n=366 psychiatrically interviewed German Caucasian ICD-10 lifetime alcoholics, along with n=200 ethnically matched controls. Results: No significant difference was found in the frequency of the Ile105 allele between alcoholics (0.11) and controls (0.10) (chi(2) = 0.21, d.f. = 1, p = 0.647). Likewise, genotype distributions did not differ significantly. However, the frequency of the Ile105 allele was significantly lower in male alcoholics with a family history of alcoholism compared to that in male alcoholics without a family history of alcoholism (chi(2) = 4.07, d.f. = 1, p = 0.044). Conclusions: In German Caucasians the association of the HNMT Thr105Ile polymorphism with alcoholism was not replicated per se, but a congruent association was found between the Ile105 allele and family history of alcoholism supporting the protective role of the Ile105 allele against alcoholism. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 Univ Giessen, Dept Psychol, D-35394 Giessen, Germany. NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Clin Treatment Alcohol Abuse & Alcoholism Eschenb, D-35713 Eschenburg Wissenbach, Germany. RP Reuter, M (reprint author), Univ Giessen, Dept Psychol, Otto Behaghel Str 10F, D-35394 Giessen, Germany. EM martin.reuter@psychol.uni-giessen.de RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural NIH HHS NR 36 TC 9 Z9 9 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0376-8716 J9 DRUG ALCOHOL DEPEN JI Drug Alcohol Depend. PD FEB 23 PY 2007 VL 87 IS 1 BP 69 EP 75 DI 10.1016/j.drugalcdep.2006.08.006 PG 7 WC Substance Abuse; Psychiatry SC Substance Abuse; Psychiatry GA 132UK UT WOS:000243967600009 PM 16950574 ER PT J AU Ray, K Adipietro, KA Chen, C Northup, JK AF Ray, Kausik Adipietro, Kaylin A. Chen, Claudia Northup, John K. TI Elucidation of the role of peptide linker in calcium-sensing receptor activation process SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN CA2+ RECEPTOR; METABOTROPIC GLUTAMATE-RECEPTOR; CALCIMIMETIC COMPOUND; TRANSMEMBRANE DOMAIN; SIGNAL-TRANSDUCTION; CHIMERIC RECEPTORS; DIMERIZATION; RECOGNITION; EXPRESSION; MUTATIONS AB Family 3 G-protein-coupled receptors (GPCRs), which includes metabotropic glutamate receptors (mGluRs), sweet and "umami" taste receptors (T1Rs), and the extracellular calcium-sensing receptor (CaR), represent a distinct group among the superfamily of GPCRs characterized by large amino-terminal extracellular ligand-binding domains (ECD) with homology to bacterial periplasmic amino acid-binding proteins that are responsible for signal detection and receptor activation through as yet unresolved mechanism(s) via the seven-transmembrane helical domain (7TMD) common to all GPCRs. To address the mechanism(s) by which ligand-induced conformational changes are conveyed from the ECD to the 7TMD for G-protein activation, we altered the length and composition of a 14-amino acid linker segment common to all family 3 GPCRs except GABA(B) receptor, in the CaR by insertion, deletion, and site-directed mutagenesis of specific highly conserved residues. Small alterations in the length and composition of the linker impaired cell surface expression and abrogated signaling of the chimeric receptors. The exchange of nine amino acids within the linker of CaR with the homologous sequence of mGluR1, however, preserved receptor function. Ala substitution for the four highly conserved residues within this amino acid sequence identified a Len at position 606 of the CaR critical for cell surface expression and signaling. Substitution of Leu(606) for Ala resulted in impaired cell surface expression. However, Ile and Val substitutions displayed strong activating phenotypes. Disruption of the linker by insertion of nine amino acids of a random-coiled structure uncoupled the ECD from regulating the 7TMD. These data are consistent with a model of receptor activation in which the peptide linker, and particularly Leu(606), provides a critical interaction for the CaR signal transmission, a finding likely to be relevant for all family 3 GPCRs containing this conserved motif. C1 NIDCD, Lab Cellular Biol, NIH, Bethesda, MD 20892 USA. RP Ray, K (reprint author), 5 Res Ct,Rm 2A11, Rockville, MD 20850 USA. EM rayk@nidcd.nih.gov FU Intramural NIH HHS NR 21 TC 13 Z9 13 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 23 PY 2007 VL 282 IS 8 BP 5310 EP 5317 DI 10.1074/jbc.M609610200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 140CZ UT WOS:000244482300026 PM 17189274 ER PT J AU Sen, A Baxa, U Simon, MN Wall, JS Sabate, R Saupe, SJ Steven, AC AF Sen, Anindito Baxa, Ulrich Simon, Martha N. Wall, Joseph S. Sabate, Raimon Saupe, Sven J. Steven, Alasdair C. TI Mass analysis by scanning transmission electron microscopy and electron diffraction validate predictions of stacked beta-solenoid model of HET-s prion fibrils SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID FUNGUS PODOSPORA-ANSERINA; SACCHAROMYCES-CEREVISIAE; IN-VITRO; HETEROKARYON INCOMPATIBILITY; HYDROGEN/DEUTERIUM EXCHANGE; AMYLOID FIBRILS; CORE STRUCTURE; PROTEIN; DOMAIN; URE2P AB Fungal prions are infectious filamentous polymers of proteins that are soluble in uninfected cells. In its prion form, the HET-s protein of Podospora anserina participates in a fungal self/nonself recognition phenomenon called heterokaryon incompatibility. Like other prion proteins, HET-s has a so-called "prion domain" (its C-terminal region, HET-s-(218-289)) that is responsible for induction and propagation of the prion in vivo and for fibril formation in vitro. Prion fibrils are thought to have amyloid backbones of polymerized prion domains. A relatively detailed model has been proposed for prion domain fibrils of HET-s based on a variety of experimental constraints (Ritter, C., Maddelein, M. L., Siemer, A. B., Luhrs, T., Ernst, M., Meier, B. H., Saupe, S. J., and Riek, R. (2005) Nature 435, 844 - 848). To test specific predictions of this model, which envisages axial stacking of beta-solenoids with two coils per subunit, we examined fibrils by electron microscopy. Electron diffraction gave a prominent meridional reflection at (0.47 nm)(-1), indicative of cross-P structure, as predicted. STEM (scanning transmission electron microscopy) mass-per-unit-length measurements yielded 1.02 +/- 0.16 subunits per 0.94 nm, in agreement with the model prediction (I subunit per 0.94 nm). This is half the packing density of similar to I subunit per 0.47 nm previously obtained for fibrils of the yeast prion proteins, Ure2p and Sup35p, whence it follows that the respective amyloid architectures are basically different. C1 NIH, Struct Biol Lab, Bethesda, MD 20892 USA. NIH, NIAMSD, Bethesda, MD 20892 USA. Brookhaven Natl Lab, Dept Biol, Upton, NY 11973 USA. Univ Bordeaux 2, CNRS, UMR 5095,Inst Biochim & Genet Cellulaire, Lab Genet Mol Champignons, F-33077 Bordeaux, France. RP Steven, AC (reprint author), NIH, Struct Biol Lab, Bldg 50,Rm 1517,50 S Dr MSC 8025, Bethesda, MD 20892 USA. EM Alasdair_Steven@nih.gov OI saupe, sven/0000-0002-5589-721X; sabate, raimon/0000-0003-3894-2362 FU Intramural NIH HHS; NIBIB NIH HHS [5 P41 EB2181] NR 41 TC 57 Z9 57 U1 1 U2 7 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 23 PY 2007 VL 282 IS 8 BP 5545 EP 5550 DI 10.1074/jbc.M611464200 PG 6 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 140CZ UT WOS:000244482300050 PM 17178708 ER PT J AU Dror, N Rave-Harel, N Burchert, A Azriel, A Tamura, T Tailor, P Neubauer, A Ozato, K Levi, BZ AF Dror, Natalie Rave-Harel, Naama Burchert, Andreas Azriel, Aviva Tamura, Tomohiko Tailor, Prafullakumar Neubauer, Andreas Ozato, Keiko Levi, Ben-Zion TI Interferon regulatory factor-8 is indispensable for the expression of promyelocytic leukemia and the formation of nuclear bodies in myeloid cells SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID SEQUENCE-BINDING-PROTEIN; PML-RAR-ALPHA; TRANSCRIPTION FACTOR; PROGENITOR CELLS; ACTIVATED MACROPHAGES; PREMATURE SENESCENCE; PROMOTER ACTIVITY; DENDRITIC CELLS; ANTIBODY PG-M3; TARGET GENES AB Interferon (IFN) regulatory factor-8 (IRF-8), previously known as ICSBP, is a myeloid cell essential transcription factor. Mice with null mutation in IRF-8 are defective in the ability of myeloid progenitor cells to mature toward macrophage lineage. Accordingly, these mice develop chronic myelogenous leukemia (CML). We demonstrate here that IRF-8 is an obligatory regulator of the promyelocytic leukemia (PML) gene in activated macrophages, leading to the expression of the PML-I isoform. This regulation is most effective together with two other transcription factors, IRF-1 and PU.1. PML is a tumor suppressor gene that serves as a scaffold protein for nuclear bodies. IRF-8 is not only essential for the IFN-gamma-induced expression of PML in activated macrophages but also for the formation of nuclear bodies. Reduced IRF-8 transcript levels were reported in CML patients, and a recovery to normal levels was observed in patients in remission following treatment with IFN-alpha. We demonstrate a significant correlation between the levels of IRF-8 and PML in these CML patients. Together, our results indicate that some of the myeloleukemia suppressor activities of IRF-8 are mediated through the regulation of PML. When IRF-8 levels are compromised, the reduced PML expression may lead to genome instability and eventually to the leukemic phenotype. C1 Technion Israel Inst Technol, Dept Food Engn & Biotechnol, IL-32000 Haifa, Israel. Univ Klinikum Marburg & Giessen, Standort Marburg, Klin Hamatol Onkol, D-35033 Marburg, Germany. NICHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Levi, BZ (reprint author), Technion Israel Inst Technol, Dept Food Engn & Biotechnol, IL-32000 Haifa, Israel. EM blevi@technion.ac.il NR 65 TC 25 Z9 25 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 23 PY 2007 VL 282 IS 8 BP 5633 EP 5640 DI 10.1074/jbc.M607825200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 140CZ UT WOS:000244482300060 PM 17189268 ER PT J AU Ghosh, M Meiss, G Pingoud, AM London, RE Pedersen, LC AF Ghosh, Mahua Meiss, Gregor Pingoud, Alfred M. London, Robert E. Pedersen, Lars C. TI The nuclease A-inhibitor complex is characterized by a novel metal ion bridge SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID NEUTROPHIL EXTRACELLULAR TRAPS; TORSION ANGLE DYNAMICS; DNA-BINDING; STREPTOCOCCUS-PNEUMONIAE; SERRATIA-MARCESCENS; ENZYME-INHIBITORS; CRYSTAL-STRUCTURE; ACTIVE-SITE; PROTEIN; MECHANISM AB Nonspecific, extracellular nucleases have received enhanced attention recently as a consequence of the critical role that these enzymes can play in infectivity by overcoming the host neutrophil defense system. The activity of the cyanobacterial nuclease NucA, a member of the beta beta alpha Me superfamily, is controlled by the specific nuclease inhibitor, NuiA. Here we report the 2.3-angstrom resolution crystal structure of the NucA-NuiA complex, showing that NucA inhibition by NuiA involves an unusual divalent metal ion bridge that connects the nuclease with its inhibitor. The C-terminal Thr-135(NuiA) hydroxyl oxygen is directly coordinated with the catalytic Mg2+ of the nuclease active site, and Glu-24(NuiA) also extends into the active site, mimicking the charge of a scissile phosphate. NuiA residues Asp-75 and Trp-76 form a second interaction site, contributing to the strength and specificity of the interaction. The crystallographically defined interface is shown to be consistent with results of studies using site-directed NuiA mutants. This mode of inhibition differs dramatically from the exosite mechanism of inhibition seen with the DNase colicins E7/E9 and from other nuclease-inhibitor complexes that have been studied. The structure of this complex provides valuable insights for the development of inhibitors for related nonspecific nucleases that share the DRGH active site motif such as the Streptococcus pneumoniae nuclease EndA, which mediates infectivity of this pathogen, and mitochondrial EndoG, which is involved in recombination and apoptosis. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. Univ Giessen, Inst Biochem FB08, D-35392 Giessen, Germany. RP London, RE (reprint author), NIEHS, Struct Biol Lab, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM london@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 48 TC 19 Z9 20 U1 0 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 23 PY 2007 VL 282 IS 8 BP 5682 EP 5690 DI 10.1074/jbc.M605986200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 140CZ UT WOS:000244482300065 PM 17138564 ER PT J AU Abdelmohsen, K Pullmann, R Lai, A Kim, HH Galban, S Yang, XL Blethrow, JD Walker, M Shubert, J Gillespie, DA Furneaux, H Gorospe, M AF Abdelmohsen, Kotb Pullmann, Rudolf, Jr. Lai, Ashish Kim, Hyeon Ho Galban, Stefanie Yang, Xiaoling Blethrow, Justin D. Walker, Mark Shubert, Jonathan Gillespie, David A. Furneaux, Henry Gorospe, Myriam TI Phosphorylation of HuR by Chk2 regulates SIRT1 expression SO MOLECULAR CELL LA English DT Article ID RNA-BINDING PROTEIN; CHECKPOINT KINASE CHK2; MESSENGER-RNA; CALORIE RESTRICTION; GENE-EXPRESSION; REPLICATIVE SENESCENCE; TRANSCRIPTION FACTORS; GENOTOXIC STRESS; CELL-SURVIVAL; LIFE-SPAN AB The RNA binding protein HuR regulates the stability of many target mRNAs. Here, we report that HuR associated with the 3' untranslated region of the mRNA encoding the longevity and stress-response protein SIRT1, stabilized the SIRT1 mRNA, and increased SIRT1 expression levels. Unexpectedly, oxidative stress triggered the dissociation of the [HuR-SIRT1 mRNA] complex, in turn promoting SIRT1 mRNA decay, reducing SIRT1 abundance, and lowering cell survival. The cell cycle checkpoint kinase Chk2 was activated by H2O2, interacted with HuR, and was predicted to phosphorylate HuR at residues S88, S100, and T118. Mutation of these residues revealed a complex pattern of HuR binding, with S100 appearing to be important for [HuR-SIRT1 mRNA] dissociation after H2O2. Our findings demonstrate that HuR regulates SIRT1 expression, underscore functional links between the two stress-response proteins, and implicate Chk2 in these processes. C1 NIA, Lab Cellular & Mol Biol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Univ Calif San Francisco, Dept Cellular & Mol Pharmacol, San Francisco, CA 94143 USA. Canc Res UK Beatson Labs, Beatson Inst Canc Res, Glasgow G61 1BD, Lanark, Scotland. Univ Connecticut, Sch Med, Dept Mol Microbial & Struct Biol, Farmington, CT 06030 USA. RP Gorospe, M (reprint author), NIA, Lab Cellular & Mol Biol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM myriam-gorospe@nih.gov OI abdelmohsen, Kotb/0000-0001-6240-5810 FU Intramural NIH HHS [Z01 AG000511-10] NR 54 TC 315 Z9 325 U1 1 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB 23 PY 2007 VL 25 IS 4 BP 543 EP 557 DI 10.1016/ju.molcel.2007.01.011 PG 15 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 140WZ UT WOS:000244538800008 PM 17317627 ER PT J AU Chen, XJ Levine, JD AF Chen, Xiaojie Levine, Jon D. TI Mechanically-evoked C-fiber activity in painful alcohol and AIDS therapy neuropathy in the rat SO MOLECULAR PAIN LA English DT Article ID STREPTOZOTOCIN-DIABETIC RAT; ALTERED TEMPORAL PATTERN; PROTEIN-KINASE-C; PERIPHERAL NEUROPATHY; SENSORY NEURONS; IN-VITRO; INCREASED RESPONSIVENESS; ELECTRICAL-STIMULATION; INFLAMMATORY PAIN; SPINAL-CORD AB While altered activities in sensory neurons were noticed in neuropathic pain, caused by highly diverse insults to the peripheral nervous system, such as diabetes, alcohol ingestion, cancer chemotherapy and drugs used to treat AIDS, other infections and autoimmune diseases, as well as trauma, our understanding of how these various peripheral neuropathies manifest as altered neuronal activity is still rudimentary. The recent development of models of several of those neuropathies has, however, now made it possible to address their impact on primary afferent nociceptor function. We compared changes in mechanically-evoked C-fiber activity, in models of painful peripheral neuropathy induced by drinking ethanol ( alcohol) or administering 2 ', 3 '-dideoxycytidine (ddC), a nucleoside reverse transcriptase inhibitor for AIDS therapy, two comorbid conditions in which pain is thought to be mediated by different second messenger signaling pathways. In C-fiber afferents, ddC decreased conduction velocity. In contrast, alcohol but not ddC caused enhanced response to mechanical stimulation (i.e., decrease in threshold and increase in response to sustained threshold and supra-threshold stimulation) and changes in pattern of evoked activity (interspike interval and action potential variability analyses). These marked differences in primary afferent nociceptor function, in two different forms of neuropathy that produce mechanical hyperalgesia of similar magnitude, suggest that optimal treatment of neuropathic pain may differ depending on the nature of the causative insult to the peripheral nervous system, and emphasize the value of studying co-morbid conditions that produce painful peripheral neuropathy by different mechanisms. C1 Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA. Univ Calif San Francisco, Dept Oral & Maxillofacial Surg, Div Neurosci, NIH Pain Ctr, San Francisco, CA 94143 USA. RP Chen, XJ (reprint author), Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA. EM xiaojie.chen@ucsf.edu; jon.levine@ucsf.edu FU NINDS NIH HHS [NS21647] NR 61 TC 23 Z9 23 U1 1 U2 3 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1744-8069 J9 MOL PAIN JI Mol. Pain PD FEB 23 PY 2007 VL 3 AR 5 DI 10.1186/1744-8069-3-5 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 166CA UT WOS:000246353600001 PM 17319957 ER PT J AU Goldstein, RZ Tomasi, D Rajaram, S Cottone, LA Zhang, L Maloney, T Telang, F Alia-Klein, N Volkow, ND AF Goldstein, R. Z. Tomasi, D. Rajaram, S. Cottone, L. A. Zhang, L. Maloney, T. Telang, F. Alia-Klein, N. Volkow, N. D. TI Role of the anterior cingulate and medial orbitofrontal cortex in processing drug cues in cocaine addiction SO NEUROSCIENCE LA English DT Article DE emotional Stroop interference; inhibitory control; cognitive conflict; attention bias; drug addiction; fMRI BOLD ID ATTENTIONAL BIAS; STROOP PARADIGM; NEURAL SYSTEMS; ACTIVATION; DYSFUNCTION; ALCOHOL; USERS; STIMULI; ABUSERS; TASK AB Our goal in the current report was to design a new functional magnetic resonance imaging (fMRI) task to probe the role of the anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC) in processing of salient symptom-related cues during the simultaneous performance of an unrelated task in drug-addicted persons. We used a novel fMRI color-word drug Stroop task in 14 individuals with cocaine use disorders; subjects had to press for color of drug vs. matched neutral words. Although there were no accuracy or speed differences between the drug and neutral conditions in the current sample of subjects, drug words were more negatively valenced than the matched neutral words. Further, consistent with prior reports in individuals with other psychopathologies using different Stroop fMRI paradigms, our more classical color-word Stroop design revealed bilateral activations in the caudal-dorsal anterior cingulate cortex (cdACC) and hypoactivations in the rostro-ventral anterior cingulate cortex/medial orbitofrontal cortex (rACC/mOFC). A trend for larger rACC/mOFC hypoactivations to the drug than neutral words did not survive whole-brain corrections. Nevertheless, correlation analyses indicated that (1) the more the cdACC drug-related activation, the more negative the valence attributed to the drug words (r=-0.86, P < 0.0001) but not neutral words; and (2) the more the rACC/mOFC hypoactivation to drug minus neutral words, the more the errors committed specifically to the drug minus neutral words (r=0.85, P < 0.0001). Taken together, results suggest that this newly developed drug Stroop fMRI task may be a sensitive biobehavioral assay of the functions recruited for the regulation of responses to salient symptom-related stimuli in drug-addicted individuals. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved. C1 Brookhaven Natl Lab, Upton, NY 11973 USA. SUNY Stony Brook, Stony Brook, NY 11794 USA. NIDA, Bethesda, MD 20892 USA. RP Goldstein, RZ (reprint author), Brookhaven Natl Lab, POB 5000, Upton, NY 11973 USA. EM rgoldstein@bnl.gov RI Tomasi, Dardo/J-2127-2015 FU NCRR NIH HHS [5M01 RR 10710, M01 RR010710]; NIDA NIH HHS [1K23 DA 15517-01, K23 DA015517, R03 DA 017070-01, R03 DA017070] NR 36 TC 140 Z9 151 U1 4 U2 17 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD FEB 23 PY 2007 VL 144 IS 4 BP 1153 EP 1159 DI 10.1016/j.neuroscience.2006.11.024 PG 7 WC Neurosciences SC Neurosciences & Neurology GA 137SS UT WOS:000244313100001 PM 17197102 ER PT J AU Restif, O Grenfell, BT AF Restif, Olivier Grenfell, Bryan T. TI Vaccination and the dynamics of immune evasion SO JOURNAL OF THE ROYAL SOCIETY INTERFACE LA English DT Article DE cross-immunity; antigenic diversity; Bordetella pertussis ID HEPATITIS-B-VIRUS; ANTIGENICALLY DIVERSE PATHOGENS; INVASIVE HAEMOPHILUS-INFLUENZAE; EXACT STOCHASTIC SIMULATION; BORDETELLA-PERTUSSIS; CROSS-IMMUNITY; EVOLUTIONARY DYNAMICS; TRANSMISSION DYNAMICS; POPULATION-STRUCTURE; CHILDHOOD DISEASES AB Vaccines exert strong selective pressures on pathogens, favouring the spread of antigenic variants. We propose a simple mathematical model to investigate the dynamics of a novel pathogenic strain that emerges in a population where a previous strain is maintained at low endemic level by a vaccine. We compare three methods to assess the ability of the novel strain to invade and persist: algebraic rate of invasion; deterministic dynamics; and stochastic dynamics. These three techniques provide complementary predictions on the fate of the system. In particular, we emphasize the importance of stochastic simulations, which account for the possibility of extinctions of either strain. More specifically, our model suggests that the probability of persistence of an invasive strain (i) can be minimized for intermediate levels of vaccine cross-protection (i.e. immune protection against the novel strain) and (ii) is lower if cross-immunity acts through a reduced infectious period rather than through reduced susceptibility. C1 Univ Cambridge, Dept Vet Med, Cambridge Infect Dis Consortium, Cambridge CB3 0ES, England. Penn State Univ, Dept Biol, Ctr Infect Dis Dynam, University Pk, PA 16802 USA. NIH, Fogarty Int Ctr, Bethesda, MD 20892 USA. RP Restif, O (reprint author), Univ Cambridge, Dept Vet Med, Cambridge Infect Dis Consortium, Madingley Rd, Cambridge CB3 0ES, England. EM or226@cam.ac.uk OI Restif, Olivier/0000-0001-9158-853X NR 58 TC 21 Z9 23 U1 1 U2 13 PU ROYAL SOC PI LONDON PA 6-9 CARLTON HOUSE TERRACE, LONDON SW1Y 5AG, ENGLAND SN 1742-5689 J9 J R SOC INTERFACE JI J. R. Soc. Interface PD FEB 22 PY 2007 VL 4 IS 12 BP 143 EP 153 DI 10.1098/rsif.2006.0167 PG 11 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 124PS UT WOS:000243382600017 PM 17210532 ER PT J AU Kiley, JP Nabel, EG AF Kiley, James P. Nabel, Elizabeth G. TI Treating COPD SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NHLBI, Bethesda, MD 20892 USA. RP Kiley, JP (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM kileyj@nhlbi.nih.gov NR 2 TC 2 Z9 2 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 22 PY 2007 VL 356 IS 8 BP 867 EP 867 DI 10.1056/NEJMc076025 PG 1 WC Medicine, General & Internal SC General & Internal Medicine GA 137XQ UT WOS:000244326700017 PM 17314349 ER PT J AU Wang, Z Wade, P Mandell, KJ Akyildiz, A Parkos, CA Mrsny, RJ Nusrat, A AF Wang, Z. Wade, P. Mandell, K. J. Akyildiz, A. Parkos, C. A. Mrsny, R. J. Nusrat, A. TI Raf 1 represses expression of the tight junction protein occludin via activation of the zinc-finger transcription factor Slug SO ONCOGENE LA English DT Article DE TJ; occluding; Slug; Raf 1 ID EPITHELIAL-MESENCHYMAL TRANSITIONS; MEMBRANE-PROTEIN; DOWN-REGULATION; FACTOR SNAIL; TUMOR-CELLS; CANCER; KINASE; BREAST; RAS; DIFFERENTIATION AB Although dysregulation of tight junction (TJ) proteins is observed in epithelial malignancy, their participation in epithelial transformation is poorly understood. Recently we demonstrated that expression of oncogenic Raf 1 in Pa4 epithelial cells disrupts TJs and induces an oncogenic phenotype by downregulating expression of the TJ protein, occludin. Here we report the mechanism by which Raf 1 regulates occludin expression. Raf 1 inhibited occludin transcription by repressing a minimal segment of the occludin promoter in concert with upregulation of the transcriptional repressor, Slug without influencing the well-documented transcriptional repressor, Snail. Overexpression of Slug in Pa4 cells recapitulated the effect of Raf 1 on occludin expression, and depletion of Slug by small interfering RNA abrogated the effect of Raf 1 on occludin. Finally, chromatin immunoprecipitation assays and site- directed mutagenesis demonstrated a direct interaction between Slug and an E-box within the minimal Raf 1-responsive segment of the occludin promoter. These findings support a role of Slug in mediating Raf 1-induced transcriptional repression of occludin and subsequent epithelial to mesenchymal transition. C1 Emory Univ, Dept Pathol, Epithelial Pathobiol Res Unit, Atlanta, GA 30322 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. Unity Pharmaceut, Los Altos Hills, CA USA. RP Nusrat, A (reprint author), Emory Univ, Sch Med, Dept Pathol & Lab Med, Epithelial Pathobiol Res Unit, 615 Michael St,Room 105E, Atlanta, GA 30322 USA. EM anusrat@emory.edu RI Nusrat, Asma/B-3887-2009; Parkos, Charles/B-3896-2009 FU Intramural NIH HHS; NIDDK NIH HHS [DK 59888, DK 61379] NR 37 TC 35 Z9 41 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 22 PY 2007 VL 26 IS 8 BP 1222 EP 1230 DI 10.1038/sj.onc.1209902 PG 9 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 139BG UT WOS:000244406400012 PM 16924233 ER PT J AU Leon, SA Fontelo, P Green, L Ackerman, M Liu, F AF Leon, Sergio A. Fontelo, Paul Green, Linda Ackerman, Michael Liu, Fang TI Evidence-based medicine among internal medicine residents in a community hospital program using smart phones SO BMC MEDICAL INFORMATICS AND DECISION MAKING LA English DT Article ID HAND-HELD COMPUTERS; CLINICAL-PRACTICE; CARE; PHYSICIANS AB Background: This study implemented and evaluated a point-of-care, wireless Internet access using smart phones for information retrieval during daily clinical rounds and academic activities of internal medicine residents in a community hospital. We did the project to assess the feasibility of using smart phones as an alternative to reach online medical resources because we were unable to find previous studies of this type. In addition, we wanted to learn what Web-based information resources internal medicine residents were using and whether providing bedside, real-time access to medical information would be perceived useful for patient care and academic activities. Methods: We equipped the medical teams in the hospital wards with smart phones (mobile phone/PDA hybrid devices) to provide immediate access to evidence-based resources developed at the National Library of Medicine as well as to other medical Websites. The emphasis of this project was to measure the convenience and feasibility of real-time access to current medical literature using smart phones. Results: The smart phones provided real-time mobile access to medical literature during daily rounds and clinical activities in the hospital. Physicians found these devices easy to use. A post-study survey showed that the information retrieved was perceived to be useful for patient care and academic activities. Conclusion: In community hospitals and ambulatory clinics without wireless networks where the majority of physicians work, real-time access to current medical literature may be achieved through smart phones. Immediate availability of reliable and updated information obtained from authoritative sources on the Web makes evidence-based practice in a community hospital a reality. C1 NIH, Off High Performance Comp & Commun, Natl Lib Med, Bethesda, MD 20894 USA. Prince Georges Hosp, Internal Med Residency Program, Landover, MD 20785 USA. RP Leon, SA (reprint author), NIH, Off High Performance Comp & Commun, Natl Lib Med, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM sleon@mail.nih.gov; fontelo@nlm.nih.gov; green_linda@hotmail.com; ackerman@nlm.nih.gov; fliu@mail.nih.gov FU Intramural NIH HHS NR 17 TC 30 Z9 31 U1 0 U2 12 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1472-6947 J9 BMC MED INFORM DECIS JI BMC Med. Inform. Decis. Mak. PD FEB 21 PY 2007 VL 7 AR 5 DI 10.1186/1472-6947-7-5 PG 11 WC Medical Informatics SC Medical Informatics GA 168ID UT WOS:000246516400001 PM 17313680 ER PT J AU Orlova, VV Choi, EY Xie, CP Chavakis, E Bierhaus, A Ihanus, E Ballantyne, CM Gahmberg, CG Bianchi, ME Nawroth, PP Chavakis, T AF Orlova, Valeria V. Choi, Eun Young Xie, Changping Chavakis, Emmanouil Bierhaus, Angelika Ihanus, Eveliina Ballantyne, Christie M. Gahmberg, Carl G. Bianchi, Marco E. Nawroth, Peter P. Chavakis, Triantafyllos TI A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-integrin SO EMBO JOURNAL LA English DT Article DE adhesion; inflammation; integrins; neutrophils ID GLYCATION END-PRODUCTS; GROUP BOX-1 PROTEIN; LEUKOCYTE INTEGRIN MAC-1; FACTOR-KAPPA-B; IN-VIVO; BETA(2) INTEGRINS; TRANSENDOTHELIAL MIGRATION; NEUTROPHIL ADHESION; UROKINASE RECEPTOR; HUMAN MONOCYTES AB High-mobility group box 1 (HMGB1) is released extra-cellularly upon cell necrosis acting as a mediator in tissue injury and inflammation. However, the molecular mechanisms for the proinflammatory effect of HMGB1 are poorly understood. Here, we define a novel function of HMGB1 in promoting Mac-1-dependent neutrophil recruitment. HMGB1 administration induced rapid neutrophil recruitment in vivo. HMGB1-mediated recruitment was prevented in mice deficient in the beta 2-integrin Mac-1 but not in those deficient in LFA-1. As observed by bone marrow chimera experiments, Mac-1-dependent neutrophil recruitment induced by HMGB1 required the presence of receptor for advanced glycation end products ( RAGE) on neutrophils but not on endothelial cells. In vitro, HMGB1 enhanced the interaction between Mac-1 and RAGE. Consistently, HMGB1 activated Mac-1 as well as Mac-1-mediated adhesive and migratory functions of neutrophils in a RAGE-dependent manner. Moreover, HMGB1-induced activation of nuclear factor-kappa B in neutrophils required both Mac-1 and RAGE. Together, a novel HMGB1-dependent pathway for inflammatory cell recruitment and activation that requires the functional interplay between Mac-1 and RAGE is described here. C1 NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. Univ Heidelberg, Dept Internal Med 1, D-6900 Heidelberg, Germany. Univ Frankfurt, Dept Internal Med 3, D-6000 Frankfurt, Germany. Univ Helsinki, Fac Biosci, Div Biochem, FIN-00014 Helsinki, Finland. Baylor Coll Med, Dept Med, Sect Atherosclerosis & Lipoprot Res, Houston, TX 77030 USA. Methodist DeBakey Heart Ctr, Ctr Cardiovasc Dis Prevent, Houston, TX USA. San Raffaele Univ, Fac Med, Milan, Italy. RP Chavakis, T (reprint author), NCI, Expt Immunol Branch, NIH, 10 Ctr Dr,RM 4B17, Bethesda, MD 20892 USA. EM chavakist@mail.nih.gov RI Orlova, Valeria/C-6065-2014; OI Orlova, Valeria/0000-0002-1169-2802; Gahmberg, Carl/0000-0001-9892-9296; Bianchi, Marco Emilio/0000-0002-5329-6445 FU Intramural NIH HHS NR 53 TC 212 Z9 234 U1 1 U2 10 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0261-4189 J9 EMBO J JI Embo J. PD FEB 21 PY 2007 VL 26 IS 4 BP 1129 EP 1139 DI 10.1038/sj.emboj.7601552 PG 11 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 138TZ UT WOS:000244387500020 PM 17268551 ER PT J AU Mitchell, GF Vasan, RS Keyes, MJ Parise, H Wang, TJ Larson, MG D'Agostino, RB Kannel, WB Levy, D Benjamin, EJ AF Mitchell, Gary F. Vasan, Ramachandran S. Keyes, Michelle J. Parise, Helen Wang, Thomas J. Larson, Martin G. D'Agostino, Ralph B., Sr. Kannel, William B. Levy, Daniel Benjamin, Emelia J. TI Pulse pressure and risk of new-onset atrial fibrillation SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Article ID NATRIURETIC PEPTIDE LEVELS; SYSTOLIC HYPERTENSION; DIASTOLIC DYSFUNCTION; BLOOD-PRESSURE; HEART-FAILURE; HEALTHY-MEN; FRAMINGHAM; POPULATION; ADULTS; AGE AB Context Atrial fibrillation (AF) is responsible for considerable morbidity and mortality, making identification of modifiable risk factors a priority. Increased pulse pressure, a reflection of aortic stiffness, increases cardiac load and may increase AF risk. Objective To examine relations between pulse pressure and incident AF. Design, Setting, and Participants Prospective, community-based observational cohort in Framingham, Mass, including 5331 Framingham Heart Study participants aged 35 years and older and initially free from AF (median age, 57 years; 55% women). Main Outcome Measures Incident AF. Results AF developed in 698 participants (13.1%) a median of 12 years after pulse pressure assessment. Cumulative 20-year AF incidence rates were 5.6% for pulse pressure of 40 mm Hg or less (25th percentile) and 23.3% for pulse pressure greater than 61 mm Hg (75th percentile). In models adjusted for age, sex, baseline and time-dependent change in mean arterial pressure, and clinical risk factors for AF (body mass index, smoking, valvular disease, diabetes, electrocardiographic left ventricular hypertrophy, hypertension treatment, and prevalent myocardial infarction or heart failure), pulse pressure was associated with increased risk for AF (adjusted hazard ratio [HR], 1.26 per 20-mm Hg increment; 95% confidence interval [CI], 1.12-1.43; P < .001). In contrast, mean arterial pressure was unrelated to incident AF (adjusted HR, 0.96 per 10-mm Hg increment; 95% CI, 0.88-1.05; P = .39). Systolic pressure was related to AF (HR, 1.14 per 20-mm Hg increment; 95% CI, 1.04-1.25; P = .006); however, if diastolic pressure was added, model fit improved and the diastolic relation was inverse (adjusted HR, 0.87 per 10-mm Hg increment; 95% CI, 0.78-0.96; P = .01), consistent with a pulse pressure effect. Among patients with interpretable echocardiographic images, the association between pulse pressure and AF persisted in models that adjusted for baseline left atrial dimension, left ventricular mass, and left ventricular fractional shortening (adjusted HR, 1.23; 95% CI, 1.09-1.39; P = .001). Conclusion Pulse pressure is an important risk factor for incident AF in a community-based sample. Further research is needed to determine whether interventions that reduce pulse pressure will limit the growing incidence of AF. C1 Cardiovasc Engn Inc, Waltham, MA 02453 USA. Boston Univ, Sch Med, Evans Dept Med, Boston, MA 02118 USA. Boston Univ, Sch Med, Whitaker Cardiovasc Inst, Boston, MA 02118 USA. Boston Univ, Sch Med, Sect Prevent Med, Boston, MA 02118 USA. Boston Univ, Dept Math & Stat, Boston, MA 02215 USA. Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA. Natl Heart Lung & Blood Inst Framingham Study, Framingham, MA USA. NHLBI, Bethesda, MD 20892 USA. RP Mitchell, GF (reprint author), Cardiovasc Engn Inc, 51 Sawyer Rd,Suite 100, Waltham, MA 02453 USA. EM garyfmitchell@mindspring.com OI Ramachandran, Vasan/0000-0001-7357-5970; Benjamin, Emelia/0000-0003-4076-2336 FU NHLBI NIH HHS [K24-HL-04334, N01-HC-25195, R01-HL60040, R01-HL70100] NR 42 TC 154 Z9 160 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 21 PY 2007 VL 297 IS 7 BP 709 EP 715 DI 10.1001/jama.297.7.709 PG 7 WC Medicine, General & Internal SC General & Internal Medicine GA 137KI UT WOS:000244291100022 PM 17312290 ER PT J AU Sieving, PA Collins, FS AF Sieving, Paul A. Collins, Francis S. TI Genetic ophthalmology and the era of clinical care SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID FACTOR-H POLYMORPHISM; MACULAR DEGENERATION; CHILDHOOD BLINDNESS; CIGARETTE-SMOKING; UNITED-STATES; CANINE MODEL; RPE65; RISK; SUSCEPTIBILITY; PREVALENCE C1 NEI, NIH, Bethesda, MD 20892 USA. NHGRI, NIH, Bethesda, MD 20892 USA. RP Sieving, PA (reprint author), NEI, NIH, Bldg 31,Room 6A03,31 Ctr Dr,MSC 2510, Bethesda, MD 20892 USA. EM pas@nei.nih.gov NR 47 TC 13 Z9 14 U1 0 U2 3 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 21 PY 2007 VL 297 IS 7 BP 733 EP 736 DI 10.1001/jama.297.7.733 PG 4 WC Medicine, General & Internal SC General & Internal Medicine GA 137KI UT WOS:000244291100025 PM 17315303 ER PT J AU Maric, D Pla, AF Chang, YH Barker, JL AF Maric, Dragan Pla, Alessandra Fiorio Chang, Yoong Hee Barker, Jeffery L. TI Self-renewing and differentiating properties of cortical neural stem cells are selectively regulated by basic fibroblast growth factor (FGF) signaling via specific FGF receptors SO JOURNAL OF NEUROSCIENCE LA English DT Article DE rat; cortical; development; neural stem cells; progenitors; flow cytometry ID EMBRYONIC RAT NEOCORTEX; CENTRAL-NERVOUS-SYSTEM; PROGENITOR CELLS; CEREBRAL-CORTEX; RADIAL GLIA; NEUROGENESIS; NEURONS; LINEAGE; PROLIFERATION; APOPTOSIS AB Developmental processes mediating the initiation of lineage commitment from self-renewing neural stem cells (NSCs) remain mostly unclear because of the persisting ambiguity in identifying true NSCs from proliferative lineage-restricted progenitors (LRPs), which are directly or indirectly derived from NSCs. Our multilineage immunohistochemical analyses of early embryonic rat telencephalon at the onset of neurogenesis revealed clear dorsoventral gradients in the emergence of two types of neuronal progenitors (NPs) from multilineage-negative NSCs. Enumeration of NSCs using comprehensive flow cytometric analysis demonstrated that their precipitous decline in vivo involved both active differentiation into NPs and an increased propensity toward apoptosis. Both processes paralleled the dorsoventral changes in fibroblast growth factor receptor (FGFR) expressions. NSCs residing in the dorsal telencephalon coexpressed FGFR1 and FGFR3, whereas those residing in the ventral telencephalon also expressed FGFR2. NSCs exposed to basic fibroblast growth factor (bFGF) in vitro generated four stereotypical clonal expansion states: efficiently self-renewing, inefficiently self-renewing limited by apoptosis, exclusively neurogenic, and multipotential, generating up to five types of LRPs. The plasticity among these expansion states depended on ambient [bFGF], telencephalic developmental stage, and differential activation/inactivation of specific FGFRs. Coactivation of FGFR1 and FGFR3 promoted symmetrical divisions of NSCs (self-renewal), whereas inactivation of either triggered asymmetrical divisions and neurogenesis from these cells. Developmental upregulation of FGFR2 expression correlated with a shift of NSCs into a multipotential state or apoptosis. These results provide new insights regarding the roles of FGFRs in diversification of NSC properties and initiation of neural lineage-restricted differentiation. C1 Natl Inst Neurol Disorders & Stroke, Neurophysiol Lab, NIH, Bethesda, MD 20892 USA. Univ Turin, Dept Human & Anim Biol, Physiol Lab, I-10123 Turin, Italy. Nanostruct Interfaces & Surfaces Ctr Excellence, I-10125 Turin, Italy. RP Maric, D (reprint author), Natl Inst Neurol Disorders & Stroke, Neurophysiol Lab, NIH, Bldg 49,Room 2B-3, Bethesda, MD 20892 USA. EM maricd@ninds.nih.gov RI Fiorio Pla, Alessandra/B-6646-2012 OI Fiorio Pla, Alessandra/0000-0003-4576-1594 FU Intramural NIH HHS NR 32 TC 82 Z9 91 U1 0 U2 6 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 21 PY 2007 VL 27 IS 8 BP 1836 EP 1852 DI 10.1523/JNEUROSCI.5141-06.2007 PG 17 WC Neurosciences SC Neurosciences & Neurology GA 138SA UT WOS:000244381400006 PM 17314281 ER PT J AU Hope, BT Nagarkar, D Leonard, S Wise, RA AF Hope, Bruce T. Nagarkar, Deepti Leonard, Sherry Wise, Roy A. TI Long-term upregulation of protein kinase a and adenylate cyclase levels in human smokers SO JOURNAL OF NEUROSCIENCE LA English DT Article DE cAMP; nicotine; nucleus accumbens; addiction; neuroadaptations; PKA ID VENTRAL TEGMENTAL AREA; MESOLIMBIC DOPAMINE SYSTEM; DEPRESSED SUICIDE VICTIMS; INDUCED BEHAVIORAL SENSITIZATION; COCAINE-SEEKING BEHAVIOR; POSTMORTEM HUMAN BRAINS; MESSENGER-RNA LEVELS; NUCLEUS-ACCUMBENS; MOLECULAR-MECHANISMS; NICOTINIC RECEPTORS AB Repeated injections of cocaine and morphine in laboratory rats cause a variety of molecular neuroadaptations in the cAMP signaling pathway in nucleus accumbens and ventral tegmental area. Here we report similar neuroadaptations in postmortem tissue from the brains of human smokers and former smokers. Activity levels of two major components of cAMP signaling, cAMP-dependent protein kinase A(PKA) and adenylate cyclase, were abnormally elevated in nucleus accumbens of smokers and in ventral midbrain dopaminergic region of both smokers and former smokers. Protein levels of the catalytic subunit of PKA were correspondingly higher in the ventral midbrain dopaminergic region of both smokers and former smokers. Protein levels of other candidate neuroadaptations, including glutamate receptor subunits, tyrosine hydroxylase, and other protein kinases, were within normal range. These findings extend our understanding of addiction-related neuroadaptations of cAMP signaling to tobacco smoking in human subjects and suggest that smoking-induced brain neuroadaptations can persist for significant periods in former smokers. C1 NIDA, Behav Neurosci Branch, Intramural Res Program, Dept Hlth & Human Serv,NIH, Baltimore, MD 21224 USA. Univ Colorado, Dept Psychiat, Aurora, CO 80045 USA. Univ Colorado, Ctr Hlth Sci, Aurora, CO 80045 USA. RP Hope, BT (reprint author), NIDA, Behav Neurosci Branch, Intramural Res Program, Dept Hlth & Human Serv,NIH, 5500 Nathan Shock Dr,Bldg C, Baltimore, MD 21224 USA. EM bhope@intra.nida.nih.gov RI Hope, Bruce/A-9223-2010; Wise, Roy/A-6465-2012 OI Hope, Bruce/0000-0001-5804-7061; FU Intramural NIH HHS; NIDA NIH HHS [R01 DA009457, R01 DA009457-09] NR 86 TC 19 Z9 19 U1 0 U2 1 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 21 PY 2007 VL 27 IS 8 BP 1964 EP 1972 DI 10.1523/JNEUROSCI.3661-06.2007 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 138SA UT WOS:000244381400017 PM 17314292 ER PT J AU Deonarine, K Panelli, MC Stashower, ME Jin, P Smith, K Slade, HB Norwood, C Wang, E Marincola, FM Stroncek, DF AF Deonarine, Kavita Panelli, Monica C. Stashower, Mitchell E. Jin, Ping Smith, Kina Slade, Herbert B. Norwood, Christopher Wang, Ena Marincola, Francesco M. Stroncek, David F. TI Gene expression profiling of cutaneous wound healing SO JOURNAL OF TRANSLATIONAL MEDICINE LA English DT Article ID ANGIOGENESIS; POLARIZATION; PATTERNS; DIFFERENTIATION; PROGRANULIN; INTEGRINS; GROWTH AB Background: Although the sequence of events leading to wound repair has been described at the cellular and, to a limited extent, at the protein level this process has yet to be fully elucidated. Genome wide transcriptional analysis tools promise to further define the global picture of this complex progression of events. Study Design: This study was part of a placebo-controlled double-blind clinical trial in which basal cell carcinomas were treated topically with an immunomodifier - toll-like receptor 7 agonist: imiquimod. The fourteen patients with basal cell carcinoma in the placebo arm of the trial received placebo treatment consisting solely of vehicle cream. A skin punch biopsy was obtained immediately before treatment and at the end of the placebo treatment ( after 2, 4 or 8 days). 17.5K cDNA microarrays were utilized to profile the biopsy material. Results: Four gene signatures whose expression changed relative to baseline ( before wound induction by the pre-treatment biopsy) were identified. The largest group was comprised predominantly of inflammatory genes whose expression was increased throughout the study. Two additional signatures were observed which included preferentially pro-inflammatory genes in the early post-treatment biopsies ( 2 days after pre-treatment biopsies) and repair and angiogenesis genes in the later ( 4 to 8 days) biopsies. The fourth and smallest set of genes was down-regulated throughout the study. Early in wound healing the expression of markers of both M1 and M2 macrophages were increased, but later M2 markers predominated. Conclusion: The initial response to a cutaneous wound induces powerful transcriptional activation of pro-inflammatory stimuli which may alert the host defense. Subsequently and in the absence of infection, inflammation subsides and it is replaced by angiogenesis and remodeling. Understanding this transition which may be driven by a change from a mixed macrophage population to predominately M2 macrophages, may help the interpretation of the cellular and molecular events occurring in the microenvironment of serially biopsied tissues. C1 NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. Clin Skin Ctr No Virginia, Fairfax, VA 22033 USA. DFB Pharmaceut, Ft Worth, TX 76107 USA. RP Stroncek, DF (reprint author), NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. EM kavitasoleil@yahoo.com; MPanelli@cc.nih.gov; mjstash.home@verizon.net; PJin@cc.nih.gov; ksmith2@cc.nih.gov; Bert.Slade@healthpoint.com; cnorwood@grovehill.com; EWang@cc.nih.gov; FMarincola@cc.nih.gov; dstroncek@cc.nih.gov NR 30 TC 91 Z9 95 U1 0 U2 9 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1479-5876 J9 J TRANSL MED JI J. Transl. Med. PD FEB 21 PY 2007 VL 5 AR 11 DI 10.1186/1479-5876-5-11 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 143RU UT WOS:000244742800001 PM 17313672 ER PT J AU Le Foll, B Wertheim, C Goldberg, SR AF Le Foll, Bernard Wertheim, Carrie Goldberg, Steven R. TI High Reinforcing Efficacy of Nicotine in Non-Human Primates SO PLOS ONE LA English DT Article AB Although tobacco appears highly addictive in humans, there has been persistent controversy about the ability of its psychoactive ingredient nicotine to induce self-administration behavior in laboratory animals, bringing into question nicotine's role in reinforcing tobacco smoking. Because of ethical difficulties in inducing nicotine dependence in naive human subjects, we explored reinforcing effects of nicotine in experimentally-naive non-human primates given access to nicotine for periods of time up to two years. Five squirrel monkeys with no experimental history were allowed to intravenously self-administer nicotine by pressing one of two levers. The number of presses on the active lever needed to obtain each injection was fixed (fixed-ratio schedule) or increased progressively with successive injections during the session (progressive-ratio schedule), allowing evaluation of both reinforcing and motivational effects of nicotine under conditions of increasing response cost. Over time, a progressive shift toward high rates of responding on the active lever, but not the inactive lever, developed. The monkeys' behavior was clearly directed toward nicotine self-administration, rather than presentation of environmental stimuli associated with nicotine injection. Both schedules of reinforcement revealed a high motivation to self-administer nicotine, with monkeys continuing to press the lever when up to 600 lever-presses were needed for each injection of nicotine. Thus, nicotine, by itself, in the absence of behavioral or drug-exposure history, is a robust and highly effective reinforcer of drug-taking behavior in a non-human primate model predictive of human behavior. This supports the use of nicotinic ligands for the treatment of smokers, and this novel preclinical model offers opportunities to test future medications for the treatment of nicotine dependence. C1 [Le Foll, Bernard; Wertheim, Carrie; Goldberg, Steven R.] NIDA, Preclin Pharmacol Sect, NIH, Dept Hlth & Human Serv, Baltimore, MD 20892 USA. [Le Foll, Bernard] Ctr Addict & Mental Hlth, Translat Addict Res Lab, Toronto, ON, Canada. [Le Foll, Bernard] Univ Toronto, Toronto, ON, Canada. RP Le Foll, B (reprint author), NIDA, Preclin Pharmacol Sect, NIH, Dept Hlth & Human Serv, Baltimore, MD 20892 USA. EM bernard_lefoll@camh.net RI Le Foll, Bernard/K-2952-2014 OI Le Foll, Bernard/0000-0002-6406-4973 FU Intramural Research Program of the National Institute on Drug Abuse; National Institutes of Health; Department of Health and Human Services FX This study was supported by the Intramural Research Program of the National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services. NR 62 TC 36 Z9 36 U1 1 U2 4 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 21 PY 2007 VL 2 IS 2 AR e230 DI 10.1371/journal.pone.0000230 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10DK UT WOS:000207444500011 PM 17311094 ER PT J AU Turingan, RS Liu, CH Hawkins, ME Martin, CT AF Turingan, Rosemary S. Liu, Cuihua Hawkins, Mary E. Martin, Craig T. TI Structural confirmation of a bent and open model for the initiation complex of T7 RNA polymerase SO BIOCHEMISTRY LA English DT Article ID 3.3 ANGSTROM RESOLUTION; PROMOTER DNA; TRANSCRIPTION INITIATION; CONFORMATIONAL-CHANGES; ELONGATION COMPLEX; CRYSTAL-STRUCTURE; START SITE; FLUORESCENCE; BINDING; IDENTIFICATION AB T7 RNA polymerase is known to induce bending of its promoter DNA upon binding, as evidenced by gel-shift assays and by recent end-to-end fluorescence energy transfer distance measurements. Crystal structures of promoter-bound and initially transcribing complexes, however, lack downstream DNA, providing no information on the overall path of the DNA through the protein. Crystal structures of the elongation complex do include downstream DNA and provide valuable guidance in the design of models for the complete melted bubble structure at initiation. In the current study, we test a specific structural model for the initiation complex, obtained by alignment of the C-terminal regions of the protein structures from both initiation and elongation and then simple transferal of the downstream DNA from the elongation complex onto the initiation complex. Fluorescence resonance energy transfer measurement of distances from a point upstream on the promoter DNA to various points along the downstream helix reproduce the expected helical periodicity in the distances and support the model's orientation and phasing of the downstream DNA. The model also makes predictions about the extent of melting downstream of the active site. By monitoring fluorescent base analogues incorporated at various positions in the DNA, we have mapped the downstream edge of the bubble, confirming the model. The initially melted bubble, in the absence of substrate, encompasses 7-8 bases and is sufficient to allow synthesis of a three base transcript before further melting is required. The results demonstrate that despite massive changes in the N-terminal portion of the protein and in the DNA upstream of the active site, the DNA downstream of the active site is virtually identical in both initiation and elongation complexes. C1 Univ Massachusetts, Dept Chem, Amherst, MA 01003 USA. NCI, Pediat Oncol Branch, Bethesda, MD 20892 USA. RP Martin, CT (reprint author), Univ Massachusetts, Dept Chem, Amherst, MA 01003 USA. EM cmartin@chem.umass.edu FU NIGMS NIH HHS [R01 GM055002-08, R01 GM055002-08S1, 1R01GM55002, R01 GM055002] NR 49 TC 12 Z9 13 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 20 PY 2007 VL 46 IS 7 BP 1714 EP 1723 DI 10.1021/bi061905d PG 10 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 135OC UT WOS:000244161900002 PM 17253774 ER PT J AU Huang, KP Huang, FL Shetty, PK Yergey, AL AF Huang, Kuo-Ping Huang, Freesia L. Shetty, Pavan K. Yergey, Alfred L. TI Modification of protein by disulfide S-monoxide and disulfide S-dioxide: Distinctive effects on PKC SO BIOCHEMISTRY LA English DT Article ID METHYL METHANE THIOSULFONATE; KINASE-C; HYDROGEN-PEROXIDE; RAT-BRAIN; OXIDATIVE MODIFICATION; DIALLYL DISULFIDE; REGULATORY DOMAIN; RADICAL FORMATION; MOLECULAR-OXYGEN; FENTON REACTION AB Disulfide S-monoxide (DSMO) and disulfide S-dioxide (DSDO) have been proposed as proximal mediators for the oxidant-mediated modification of proteins. These disulfide S-oxides (DSOs) derived from glutathione (GSH) and captopril (CPSH) were synthesized by iron- or methyltrioxorhenium (VII)-catalyzed oxidation of the thiols with H2O2. Treatment of mouse hippocampal extracts with [S-35]GS-DSOs revealed that a large number of proteins were susceptible to thionylation; however, only a limited number of the them were detectable by the commonly used antibody against GS-associated proteins. Using protein kinase C (PKC) as a model, we found that DSOs derived from different thiols modified this kinase with different efficacy and specificity; for example, the inhibitory potency of the kinase was glutathione disulfide S-dioxide (GS-DSDO) (IC50, similar to 30 mu M) > captopril disulfide S-dioxide (CPS-DSDO) (IC50, similar to 450 mu M) > glutathione disulfide S-monoxide (GS-DSMO) and captopril disulfide S-monoxide (CPS-DSMO). The stoichiometries of thionylation of PKC beta mediated by [S-35]GS-DSMO and [S-35]GS-DSDO were approximately 1 and 5 mol/mol, respectively, and at least four glutathionylation sites were identified in the GS-DSDO-treated kinase. Modification of PKC by GS-DSDO and CPS-DSDO rendered the kinase very susceptible to limited proteolysis; the former preferentially caused the degradation of the catalytic and the latter the regulatory domain of the kinase. Furthermore, CPS-DSDO-mediated modification of PKC increased the autonomous kinase activity; this was not the case for GS-DSDO-mediated modification. Since DSOs of different oxidative states as well as those derived from different thiols exert different effects on a target protein, these molecules could cause distinct cellular responses if derived from endogenous cellular reactions or even if they arise from exogenous sources. C1 Natl Inst Child Hlth & Human Dev, Metab Regulat Sect, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Child Hlth & Human Dev, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Huang, KP (reprint author), Natl Inst Child Hlth & Human Dev, Metab Regulat Sect, Endocrinol & Reprod Res Branch, NIH, Bethesda, MD 20892 USA. EM huangk@mail.nih.gov RI SHETTY, PAVAN/B-9804-2012 FU Intramural NIH HHS NR 51 TC 14 Z9 14 U1 0 U2 3 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 20 PY 2007 VL 46 IS 7 BP 1961 EP 1971 DI 10.1021/bi061955i PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 135OC UT WOS:000244161900026 PM 17249696 ER PT J AU Mitra, P Maceyka, M Payne, SG Lamour, N Milstien, S Chalfant, CE Spiegel, S AF Mitra, Poularal Maceyka, Michael Payne, Shawn G. Lamour, Nadia Milstien, Sheldon Chalfant, Charles E. Spiegel, Sarah TI Ceramide kinase regulates growth and survival of A549 human lung adenocarcinoma cells SO FEBS LETTERS LA English DT Article DE ceramide; ceramide-1-phosphate; ceramide kinase; apoptosis; proliferation ID DNA-SYNTHESIS; CANCER CELLS; 1-PHOSPHATE; SPHINGOLIPIDS; APOPTOSIS; SPHINGOSINE-1-PHOSPHATE; SPHINGOMYELINASE; ACTIVATION; MIGRATION; DIVISION AB Ceramide- I -phosphate (CIP) is emerging as a new addition to the family of bioactive sphingolipid metabolites. At low concentrations, 6P enhanced survival of NIH 3T3 fibroblasts and A549 lung cancer cells, while at high concentrations, it reduced survival and induced apoptosis. Apoptosis correlated with degradation of C1P to pro-apoptotic ceramide. To examine the role of endogenous C1P, expression of ceramide kinase, the enzyme that produces C1P, was downregulated, which reduced cellular proliferation, progression into S phase and enhanced apoptosis induced by serum starvation. Our results suggest that ceramide kinase determines the balance between pro-apoptotic ceramide and anti-apoptotic CIP to regulate cell fate, reminiscent of its function in plants. (c) 2007 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies. C1 Virginia Commonwealth Univ, Sch Med, Dept Biochem, Richmond, VA 23298 USA. Virginia Commonwealth Univ, Massey Canc Ctr, Sch Med, Richmond, VA 23298 USA. NIMH, NIH, Bethesda, MD 20892 USA. Hunter Holmes McGuire Vet Adm Med Ctr, Res Serv, Richmond, VA 23249 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Biochem, 2-011 Sanger Hall,1101 E Marshall St, Richmond, VA 23298 USA. EM sspiegel@vcu.edu RI Maceyka, Michael/B-9277-2008 FU Intramural NIH HHS; NCI NIH HHS [P30 CA16059, 5T32 CA085159-04]; NHLBI NIH HHS [HL072925]; NIGMS NIH HHS [GM069338, R37 GM043880] NR 25 TC 56 Z9 58 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 20 PY 2007 VL 581 IS 4 BP 735 EP 740 DI 10.1016/j.febstet.2007.01.041 PG 6 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 141IP UT WOS:000244572300025 PM 17274985 ER PT J AU Howard, RA Inskip, PD Travis, LB AF Howard, Regan A. Inskip, Peter D. Travis, Lois B. TI Suicide after childhood cancer SO JOURNAL OF CLINICAL ONCOLOGY LA English DT Letter ID ADOLESCENT CANCER; LATE MORTALITY; SURVIVORS; REGISTER; RISK C1 NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Howard, RA (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NR 9 TC 3 Z9 3 U1 0 U2 0 PU AMER SOC CLINICAL ONCOLOGY PI ALEXANDRIA PA 330 JOHN CARLYLE ST, STE 300, ALEXANDRIA, VA 22314 USA SN 0732-183X J9 J CLIN ONCOL JI J. Clin. Oncol. PD FEB 20 PY 2007 VL 25 IS 6 BP 731 EP 731 DI 10.1200/JCO.2006.09.2056 PG 1 WC Oncology SC Oncology GA 138SY UT WOS:000244384000023 PM 17308281 ER PT J AU Abbott, RD Launer, LJ Rodriguez, BL Ross, GW Wilson, PWF Masaki, KH Strozyk, D Curb, JD Yano, K Popper, JS Petrovitch, H AF Abbott, R. D. Launer, L. J. Rodriguez, B. L. Ross, G. W. Wilson, P. W. F. Masaki, K. H. Strozyk, D. Curb, J. D. Yano, K. Popper, J. S. Petrovitch, H. TI Serum estradiol and risk of stroke in elderly men SO NEUROLOGY LA English DT Article ID CORONARY-HEART-DISEASE; ENDOGENOUS SEX-HORMONES; DENSITY-LIPOPROTEIN CHOLESTEROL; JAPANESE-AMERICAN MEN; CARDIOVASCULAR-DISEASE; TESTOSTERONE; PROGRAM; ASSOCIATION; ESTROGEN; BRAIN AB Objective: To determine if levels of serum estradiol and testosterone can predict stroke in a population-based sample of elderly men. Methods: Serum 17 beta estradiol and testosterone were measured in 2,197 men aged 71 to 93 years who participated in the Honolulu-Asia Aging Study from 1991 to 1993. All were free of prevalent stroke, coronary heart disease, and cancer. Participants were followed to the end of 1998 for thromboembolic and hemorrhagic events. Results: During the course of follow-up, 124 men developed a stroke (9.1/1,000 person-years). After age adjustment, men in the top quintile of serum estradiol (>= 125 mu mol/L [34.1 pg/mL]) experienced a twofold excess risk of stroke vs men whose estradiol levels were lower (14.8 vs 7.3/1,000 person-years, p < 0.001). Among the lower quintiles, there were little differences in the risk of stroke. Findings were also significant and comparable for bioavailable estradiol and for thromboembolic and hemorrhagic events. After additional adjustment for hypertension, diabetes, adiposity, cholesterol concentrations, atrial fibrillation, and other characteristics, men in the top quintile of serum estradiol continued to have a higher risk of stroke vs those whose estradiol levels were lower (relative hazards = 2.2; 95% CI = 1.5 to 3.4, p < 0.001). Testosterone was not related to the risk of stroke. Conclusions: High levels of serum estradiol may be associated with an elevated risk of stroke in elderly men. C1 Univ Virginia, Hlth Syst, Dept Publ Hlth Sci, Sch Med,Div Biostat & Epidemiol, Charlottesville, VA 22908 USA. Shiga Univ Med Sci, Dept Hlth Sci, Otsu, Shiga 52021, Japan. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Pacific Hlth Res Inst, Honolulu, HI USA. Emory Univ, Sch Med, Dept Med, Atlanta, GA 30322 USA. Albert Einstein Coll Med, Dept Neurol, Bronx, NY 10467 USA. Vet Affairs Pacific Isl Hlth Care Syst, Honolulu, HI USA. Univ Hawaii, John A Burns Sch Med, Dept Geriatr Med, Honolulu, HI 96822 USA. Univ Hawaii, John A Burns Sch Med, Dept Med, Honolulu, HI 96822 USA. RP Abbott, RD (reprint author), Univ Virginia, Hlth Syst, Dept Publ Hlth Sci, Sch Med,Div Biostat & Epidemiol, POB 800717, Charlottesville, VA 22908 USA. EM rda3e@virginia.edu FU NHLBI NIH HHS [N01-HC-05102]; NIA NIH HHS [N01-AG-4-2149, 1-R01-AG17155-01A1]; NINDS NIH HHS [1-R01-NS41265-01] NR 42 TC 65 Z9 66 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD FEB 20 PY 2007 VL 68 IS 8 BP 563 EP 568 DI 10.1212/01.wnl.0000254473.88647.ca PG 6 WC Clinical Neurology SC Neurosciences & Neurology GA 137DT UT WOS:000244273900006 PM 17310026 ER PT J AU Li, Y Hough, RB Piatigorsky, J AF Li, Yan Hough, R. Barry Piatigorsky, Joram TI Tissue-specific activity of the blind mole rat and the two nucleotide-mutated mouse alpha B-crystallin promoter in transgenic mice SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE evolution; gene expression; lens; muscle ID SHOCK-PROTEIN GENE; CHICKEN DELTA-1-CRYSTALLIN GENE; SPALAX-EHRENBERGI; A-CRYSTALLIN; LENS CRYSTALLINS; TRANSCRIPTIONAL REGULATION; CONTROL ELEMENTS; CIRCADIAN GENES; PAIRED DOMAIN; DNA-BINDING AB The alpha B-crystallin and HspB2 genes are located approximate to 0.9 kb apart in a head-to-head arrangement in mammals. Previous experiments have shown that a truncated -668/+45 alpha B-crystallin enhancer/promoter fragment from blind mole rats (Spalax ehrenbergi), which have nonfunctional lenses, lacks lens activity and has enhanced muscle activity in transgenic mice. Here we show that the full-length mole rat alpha B-crystallin intergenic region behaves similarly in transgenic mice. A two-nucleotide mutation ((-273)CA -> G) in the mouse aB-crystallin enhancer/promoter fragment mimicking the wild-type mole rat sequence functionally converted the mouse promoter fragment to that of the wild-type mole rat promoter when tested in transgenic mice. The reciprocal mutation in the mole rat promoter fragment ((-272)G -> CA) did not affect its activity. Oligonucleotides from the wild-type mouse and mole rat alpha B-crystallin promoter region under study formed distinct complexes with nuclear proteins from cultured cells. The mouse mutant sequence lost binding ability, whereas the mutated mole rat sequence gained the ability to form a complex similar in size to that of the wild-type mouse oligonucleotide. Our data support the idea that blind mole rats' alpha B-crystallin promoter activity was modified during the evolution of subterranean life and shows that tissue-specific promoter activity can be modulated by changing as few as two apparently neutral nucleotides in the mouse alpha B-crystallin enhancer region, implying the importance of the context of regulatory sequences for promoter activity. C1 NEI, Mol & Dev Biol Lab, NIH, Bethesda, MD 20892 USA. RP Piatigorsky, J (reprint author), NEI, Mol & Dev Biol Lab, NIH, 7 Mem Dr Bldg 7,Room 100, Bethesda, MD 20892 USA. EM joramp@nei.nih.gov NR 52 TC 4 Z9 4 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 20 PY 2007 VL 104 IS 8 BP 2608 EP 2613 DI 10.1073/pnas.0611684104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 140NC UT WOS:000244511200011 PM 17293452 ER PT J AU Nettels, D Gopich, IV Hoffmann, A Schuler, B AF Nettels, Daniel Gopich, Irina V. Hoffmann, Armin Schuler, Benjamin TI Ultrafast dynamics of protein collapse from single-molecule photon statistics SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE correlation; fluorescence; Hanbury Brown and Twiss; photon bunching; protein folding ID COLD-SHOCK PROTEIN; INTRAMOLECULAR CONTACT FORMATION; UNFOLDED POLYPEPTIDE-CHAINS; RESONANCE ENERGY-TRANSFER; SPEED LIMIT; FOLDING KINETICS; BROWNIAN-MOTION; DOMAIN PROTEINS; FLUORESCENCE; DIFFUSION AB We use the statistics of photon emission from single molecules to probe the ultrafast dynamics of an unfolded protein via Forster resonance energy transfer. Global reconfiguration of the chain occurs on a time scale of approximate to 50 ns and slows down concomitant with chain collapse under folding conditions. These diffusive dynamics provide a missing link between the phenomenological chemical kinetics commonly used in protein folding and a physical description in terms of quantitative free energy surfaces. The experiments demonstrate the potential of single-molecule methods in accessing the biologically important nanosecond time scales even in heterogeneous populations. C1 Univ Zurich, Inst Biochem, CH-8057 Zurich, Switzerland. NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. RP Schuler, B (reprint author), Univ Zurich, Inst Biochem, Winterthurer Str 190, CH-8057 Zurich, Switzerland. EM schuler@bioc.unizh.ch RI Schuler, Benjamin/E-7342-2011 OI Schuler, Benjamin/0000-0002-5970-4251 FU Intramural NIH HHS NR 72 TC 197 Z9 198 U1 6 U2 38 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 20 PY 2007 VL 104 IS 8 BP 2655 EP 2660 DI 10.1073/pnas.0611093104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 140NC UT WOS:000244511200019 PM 17301233 ER PT J AU Moore, DF Krokhin, OV Beavis, RC Ries, M Robinson, C Goldin, E Brady, RO Wilkins, JA Schiffmann, R AF Moore, David F. Krokhin, Oleg V. Beavis, Ronald C. Ries, Markus Robinson, Chevalia Goldin, Ehud Brady, Roscoe O. Wilkins, John A. Schiffmann, Raphael TI Proteomics of specific treatment-related alterations in Fabry disease: A strategy to identify biological abnormalities SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE disease-specific alteration; enzyme replacement; vasculopathy ID ENZYME-REPLACEMENT THERAPY; D-BINDING PROTEIN; VASCULAR CALCIFICATION; CARDIOVASCULAR-DISEASES; CEREBRAL HYPERPERFUSION; ALPHA-GALACTOSIDASE; AGALSIDASE-ALPHA; CELLS; COAGULATION; MIXTURES AB Fabry disease is inherited as an X-linked disorder secondary to deficiency of alpha-galactosidase A, resulting in abnormal metabolism of substances containing a-D-galactosyl moieties. As a consequence, a multisystem disorder develops, culminating in strokes, progressive renal, and cardiac dysfunction. Signs and symptoms of Fabry disease become manifest in childhood, but diagnosis is often delayed. Thirteen children with Fabry disease (age range, 6.5-17 years) were studied as part of a 6-month open-label study of enzyme replacement therapy (ERT) with agalsidase alfa. Paired serum samples were drawn at the start of the study and after 6 months of ERT. Global protein changes in paired samples were compared by using differential stable isotope labeling of peptide lysine residues with O-methylisourea and subsequent nanoHPLC-tandem MS. Statistically significant decreases were observed for five proteins following ERT: alpha(2)-HS glycoprotein, vitamin D-binding protein, transferrin, Ig-alpha-2 C chain, and alpha-2-antiplasmin. The presence of low levels of a-2-antiplasmin and plasminogen was confirmed by alternate means in 34 consecutive patients, including four of five ERT-naive subjects. Decreased alpha-2-antiplasmin was associated with a parallel increase in circulating VEGF. Soluble VEGF receptor-2 was significantly elevated in plasma of patients compared with pediatric controls and decreased with ERT. These results suggest previously unknown abnormalities of fibrinolysis and angiogenesis factors in Fabry disease. We demonstrated the feasibility of identifying treatment-specific alterations in a small number of subjects that point to previously unsuspected disease-related biological abnormalities. C1 NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. Univ Manitoba, Sect Neurol, Winnipeg, MB R3C 4J5, Canada. Univ Manitoba, Sect Proteom & Syst Biol, Winnipeg, MB R3C 4J5, Canada. Univ Manitoba, Manitoba Ctr Proteom & Syst Biol, Winnipeg, MB R3C 4J5, Canada. RP Schiffmann, R (reprint author), NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. EM rs4e@nih.gov OI Ries, Markus/0000-0002-5054-5741 FU Intramural NIH HHS NR 46 TC 24 Z9 24 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 20 PY 2007 VL 104 IS 8 BP 2873 EP 2878 DI 10.1073/pnas.0611315104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 140NC UT WOS:000244511200056 PM 17301227 ER PT J AU Derse, D Hill, SA Princler, G Lloyd, P Heidecker, G AF Derse, David Hill, Shawn A. Princler, Gerald Lloyd, Patricia Heidecker, Gisela TI Resistance of human T cell leukemia virus type 1 to APOBEC3G restriction is mediated by elements in nucleocapsid SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE retrovirus ID VIF PROTEIN; ANTIVIRAL ACTIVITY; HIV-1 VIRIONS; ANTIRETROVIRAL DEFENSE; ENZYME APOBEC3G; INFECTION; DNA; DEGRADATION; GAG; HYPERMUTATION AB Human T cell leukemia virus type 1 (HTLV-1) has evolved a remarkable strategy to thwart the antiviral effects of the cellular cytidine deaminase APOBEC3G (hA3G). HTLV-1 infects T lymphocytes in vivo, where, like HIV-1, it is likely to encounter hA3G. HIV-1 counteracts the innate antiviral activity of hA3G by producing an accessory protein, Vif, which hastens the degradation of hA3G. In contrast, HTLV-1 does not encode a Vif homologue; instead, HTLV-1 has evolved a cis-acting mechanism to prevent hA3G restriction. We demonstrate here that a peptide motif in the C terminus of the HTLV-1 nucleocapsid (NC) domain inhibits hA3G packaging into nascent virions. Mutation of amino acids within this region resulted in increased levels of hA3G incorporation into virions and increased susceptibility to hA3G restriction. Elements within the C-terminal extension of the NC domain are highly conserved among the primate T cell leukemia viruses, but this extension is absent in all other retroviral NC proteins. C1 Natl Canc Inst, HIV Drug Resistance Program, Ft Detrick, MD 21702 USA. RP Derse, D (reprint author), Natl Canc Inst, HIV Drug Resistance Program, Ft Detrick, MD 21702 USA. EM derse@ncifcrf.gov NR 36 TC 79 Z9 79 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 20 PY 2007 VL 104 IS 8 BP 2915 EP 2920 DI 10.1073/pnas.0609444104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 140NC UT WOS:000244511200063 PM 17299050 ER PT J AU Gohla, A Klement, K Piekorz, RP Pexa, K vom Dahl, S Spicher, K Dreval, V Haussinger, D Birnbaumer, L Nurnberg, B AF Gohla, Antje Klement, Karinna Piekorz, Roland P. Pexa, Katja vom Dahl, Stephan Spicher, Karsten Dreval, Vladyslav Haeussinger, Dieter Birnbaumer, Lutz Nuernberg, Bernd TI An obligatory requirement for the heterotrimeric G protein G(i3) in the antiautophagic action of insulin in the liver SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE anticatabolic actions; autophagy; mouse knockout; pertussis toxin-sensitive G proteins ID SIGNALING PATHWAYS; ADENYLYL-CYCLASE; ALPHA-SUBUNITS; RAT-LIVER; AUTOPHAGY; CELLS; MICE; DISEASE; HEALTH; FAMILY AB Heterotrimeric G proteins of the G(i) class have been implicated in signaling pathways regulating growth and metabolism under physiological and pathophysiological conditions. Knockout mice carrying inactivating mutations in both of the widely expressed G alpha(i) class genes, G alpha(i2) and G alpha(i3), demonstrate shared as well as gene-specific functions. The presence of a single active allele of G alpha(i3) is sufficient for embryonic development, whereas at least one allele of G alpha(i2) is required for extrauterine life. Mice lacking both G alpha(i2) and G alpha(i3) are massively growth-retarded and die in utero. We have used biochemical and cell biological methods together with in situ liver perfusion experiments to study Gai isoform-specific functions in G alpha(i2)- and G alpha(i3)-deficient mice. The subcellular localization of G alpha(i3) in isolated mouse hepatocytes depends on the cellular metabolic status. G alpha(i3) localizes to autophagosomes upon starvation-induced autophagy and distributes to the plasma membrane upon insulin stimulation. Analysis of autophagic proteolysis in perfused mouse livers showed that mice lacking G alpha(i3) are deficient in the inhibitory action of insulin. These data indicate that G alpha(i3) is crucial for the antiautophagic action of insulin and suggest an as-yet-unrecognized function for G alpha(i3) on autophagosomal membranes. C1 NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. Klinikum Heinrich Heine Univ, Inst Biochem & Mol Biol 2, D-40225 Dusseldorf, Germany. Klinikum Heinrich Heine Univ, Klin Gastroenterol Hepatol & Infektiol, D-40225 Dusseldorf, Germany. Charite Univ Med Berlin, Inst Pharmakol, D-14195 Berlin, Germany. RP Birnbaumer, L (reprint author), NIEHS, Lab Signal Transduct, NIH, Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. EM birnbau1@niehs.nih.gov; bernd.nuernberg@uni-duesseldorf.de FU NIDDK NIH HHS [DK 19318] NR 36 TC 61 Z9 63 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 20 PY 2007 VL 104 IS 8 BP 3003 EP 3008 DI 10.1073/pnas.0611434104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 140NC UT WOS:000244511200078 PM 17296938 ER PT J AU Trinchieri, G AF Trinchieri, Giorgio TI Interleukin-10 production by effector T cells: Th1 cells show self control SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID PLASMACYTOID DENDRITIC CELLS; INTERFERON-GAMMA; GENE-EXPRESSION; IN-VIVO; INFLAMMATORY RESPONSE; RECEPTOR ANTIBODY; REGULATORY-CELLS; LEISHMANIA-MAJOR; IL-10 LOCUS; IFN-GAMMA AB Interleukin (IL)-10 is a cytokine that modulates both innate and adaptive immunity, primarily by exerting anti inflammatory effects. IL-10 was originally thought to be produced only by T helper (Th)2 cells, but is now known to be made by a variety of cell types. During many infections, CD4(+) T cells produce both interferon (IFN)-gamma, the signature Th1 cytokine, and IL-10. New data now show that the IL-10 produced by effector Th1 cells helps limit the collateral damage caused by exaggerated inflammation. But this control may also limit the effectiveness of the immune response, resulting in a failure to fully eliminate pathogens. C1 NCI, Ctr Canc Res, Canc & Inflammat Program, Frederick, MD 21702 USA. RP Trinchieri, G (reprint author), NCI, Ctr Canc Res, Canc & Inflammat Program, Frederick, MD 21702 USA. EM trinchig@mail.nih.gov NR 32 TC 155 Z9 163 U1 0 U2 4 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 19 PY 2007 VL 204 IS 2 BP 239 EP 243 DI 10.1084/jem.20070104 PG 5 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 140KP UT WOS:000244504100003 PM 17296790 ER PT J AU Jenkinson, SR Intlekofer, AM Sun, G Feigenbaum, L Reiner, SL Bosselut, R AF Jenkinson, S. Rhiannon Intlekofer, Andrew M. Sun, Guangping Feigenbaum, Lionel Reiner, Steven L. Bosselut, Remy TI Expression of the transcription factor cKrox in peripheral CD8 T cells reveals substantial postthymic plasticity in CD4-CD8 lineage differentiation SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID DNA METHYLATION; POSITIVE SELECTION; GENE-EXPRESSION; EFFECTOR; THYMOCYTES; COMMITMENT; BET; EOMESODERMIN; CHROMATIN; DOMAINS AB Most T cells belong to either of two lineages defined by the mutually exclusive expression of CD4 and CD8 coreceptors: CD4 T cells are major histocompatibility complex (MHC) II restricted and have helper function, whereas CD8 T cells are MHC I restricted and have cytotoxic function. The divergence between these two lineages occurs during intrathymic selection and is thought to be irreversible in mature T cells. It is, however, unclear whether the CD4-CD8 differentiation of postthymic T cells retains some level of plasticity or is stably maintained by mechanisms distinct from those that set lineage choice in the thymus. To address this issue, we examined if coreceptor or effector gene expression in mature CD8 T cells remains sensitive to the zinc finger transcription factor cKrox, which promotes CD4 and inhibits CD8 differentiation when expressed in thymocytes. We show that cKrox transduction into CD8 T cells inhibits their expression of CD8 and cytotoxic effector genes and impairs their cytotoxic activity, and that it promotes expression of helper-specific genes, although not of CD4 itself. These observations reveal a persistent degree of plasticity in CD4-CD8 differentiation in mature T cells. C1 NCI, Lab Immune Cell Biol, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Univ Penn, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA. Univ Penn, Dept Med, Philadelphia, PA 19104 USA. NCI, Frederick Canc Res & Dev Ctr, SAIC Frederick, Frederick, MD 21702 USA. RP Bosselut, R (reprint author), Walter Reed Army Inst Res, Dept Immunol, CD&I, Silver Spring, MD 20910 USA. EM remy@helix.nih.gov FU Intramural NIH HHS; NIAID NIH HHS [AI053827, R01 AI053827] NR 29 TC 44 Z9 46 U1 0 U2 1 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0022-1007 J9 J EXP MED JI J. Exp. Med. PD FEB 19 PY 2007 VL 204 IS 2 BP 267 EP 272 DI 10.1084/jem.20061982 PG 6 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 140KP UT WOS:000244504100007 PM 17296789 ER PT J AU Jankovic, D Kullberg, MC Feng, CG Goldszmid, RS Collazo, CM Wilson, M Wynn, TA Kamanaka, M Flavell, RA Sheri, A AF Jankovic, Dragana Kullberg, Marika C. Feng, Carl G. Goldszmid, Romina S. Collazo, Carmen M. Wilson, Mark Wynn, Thomas A. Kamanaka, Masahito Flavell, Richard A. Sheri, Alan TI Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID CD4(+) T-CELLS; INHIBITS CYTOKINE PRODUCTION; IFN-GAMMA PRODUCTION; TOXOPLASMA-GONDII; IN-VIVO; DENDRITIC CELLS; INTERLEUKIN-10-DEFICIENT MICE; ACTIVATED MACROPHAGES; RECEPTOR ANTIBODY; LEISHMANIA-MAJOR AB Although interferon gamma (IFN-gamma) secretion is essential for control of most intracellular pathogens, host survival often also depends on the expression of interleukin 10 (IL-10), a cytokine known to counteract IFN-gamma effector functions. We analyzed the source of regulatory IL-10 in mice infected with the protozoan parasite Toxoplasma gondii. Unexpectedly, IFN-gamma-secreting T-bet(+)Foxp3(-) T helper type 1 (Th1) cells were found to be the major producers of IL-10 in these animals. Further analysis revealed that the same IL-10(+)IFN-gamma(+) population displayed potent effector function against the parasite while, paradoxically, also inducing profound suppression of IL-12 production by antigen-presenting cells. Although at any given time point only a fraction of the cells appeared to simultaneously produce IL-10 and IFN-gamma, IL-10 production could be stimulated in IL-10(-)IFN-gamma(+) cells by further activation in vitro. In addition, experiments with T gondii-specific IL-10(+)IFN-gamma(+) CD4 clones revealed that although IFN-gamma expression is imprinted and triggered with similar kinetics regardless of the state of Th1 cell activation, IL-10 secretion is induced more rapidly from recently activated than from resting cells. These findings indicate that IL-10 production by CD4(+) T lymphocytes need not involve a distinct regulatory Th cell subset but can be generated in Th1 cells as part of the effector response to intracellular pathogens. C1 NIAID, Immunobiol Sect, NIH, Bethesda, MD 20892 USA. NIAID, Immunopathogenesis Sect, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Yale Univ, Sch Med, Immunobiol Sect, New Haven, CT 06520 USA. RP Jankovic, D (reprint author), NIAID, Immunobiol Sect, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM DJankovic@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 FU Intramural NIH HHS NR 64 TC 357 Z9 368 U1 0 U2 17 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 19 PY 2007 VL 204 IS 2 BP 273 EP 283 DI 10.1084/jem.20062175 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 140KP UT WOS:000244504100008 PM 17283209 ER PT J AU Anderson, CF Oukka, M Kuchroo, VJ Sacks, D AF Anderson, Charles F. Oukka, Mohammed Kuchroo, Vijay J. Sacks, David TI CD4(+)CD25(-)Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID REGULATORY T-CELLS; AZAR DERMAL LEISHMANIASIS; IFN-GAMMA; KALA-AZAR; INTERFERON-GAMMA; MAJOR INFECTION; DENDRITIC CELLS; INTERLEUKIN-10 PRODUCTION; VISCERAL LEISHMANIASIS; PLASMODIUM-FALCIPARUM AB Nonhealing forms of leishmaniasis in humans are commonly associated with elevated levels of the deactivating cytokine IL-10, and in the mouse, normally chronic infections can be cleared in the absence of IL-10. Using a Leishmania major strain that produces nonhealing dermal lesions in a T helper type 1 (Th1) cell-polarized setting, we have analyzed the cellular sources of IL-10 and their relative contribution to immune suppression. IL-10 was produced by innate cells, as well as CD4(+)CD25(+)Foxp3(+) and CD4(+)CD25(-)Foxp3- T cells in the chronic lesion. Nonetheless, only IL-10 production by antigen-specific CD4+CD25-Foxp3- T cells, the majority of which also produced IFN-gamma, was necessary for suppression of acquired immunity in Rag(-/-) reconstituted mice. Surprisingly, Rag(-/-) mice reconstituted with naive CD4(+) T cells depleted of natural T regulatory cells developed more severe infections, associated with elevated levels of IL-10 and, especially, Th2 cytokines in the site. The data demonstrate that IL-10-producing Th1 cells, activated early in a strong inflammatory setting as a mechanism of feedback control, are the principal mediators of T cell-derived IL-10-dependent immune suppression in a chronic intracellular infection. C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Neurol Dis, Boston, MA 02115 USA. RP Sacks, D (reprint author), NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. EM dsacks@niaid.nih.gov NR 62 TC 348 Z9 358 U1 1 U2 5 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 19 PY 2007 VL 204 IS 2 BP 285 EP 297 DI 10.1084/jem.20061886 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 140KP UT WOS:000244504100009 PM 17283207 ER PT J AU Smith, AL Ganesh, L Leung, K Jongstra-Bilen, J Jongstra, J Nabel, GJ AF Smith, Alvin L. Ganesh, Lakshmanan Leung, Kwanyee Jongstra-Bilen, Jenny Jongstra, Jan Nabel, Gary J. TI Leukocyte-specific protein 1 interacts with DC-SIGN and mediates transport of HIV to the proteasome in dendritic cells SO JOURNAL OF EXPERIMENTAL MEDICINE LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; LYMPHOCYTE-SPECIFIC PROTEIN-1; C-TYPE LECTIN; T-CELLS; ANTIGEN PRESENTATION; IN-VITRO; F-ACTIN; RECEPTORS; INFECTION; BINDING AB Dendritic cells (DCs) capture and internalize human immunodeficiency virus (HIV)-1 through C-type lectins, including DC-SIGN. These cells mediate efficient infection of T cells by concentrating the delivery of virus through the infectious synapse, a process dependent on the cytoplasmic domain of DC-SIGN. Here, we identify a cellular protein that binds specifically to the cytoplasmic region of DC-SIGN and directs internalized virus to the proteasome. This cellular protein, leukocyte-specific protein 1 (LSP1), was defined biochemically by immunoprecipitation and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. LSP1 is an F-actin binding protein involved in leukocyte motility and found on the cytoplasmic surface of the plasma membrane. LSP1 interacted specifically with DC-SIGN and other C-type lectins, but not the inactive mutant DC-SIGN Delta 35, which lacks a cytoplasmic domain and shows altered virus transport in DCs. LSP1 diverts HIV-1 to the proteasome. Down-regulation of LSP1 with specific small interfering RNAs in human DCs enhanced HIV-1 transfer to T cells, and bone marrow DCs from Isp1(-/-) mice also showed an increase in transfer of HIV-1(BaL) to a human T cell line. Proteasome inhibitors increased retention of viral proteins in Isp1(+/+) DCs, and substantial colocalization of virus to the proteasome was observed in wild-type compared with LSP1-deficient cells. Collectively, these data suggest that LSP1 protein facilitates virus transport into the proteasome after its interaction with DC-SIGN through its interaction with cytoskeletal proteins. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Howard Univ, Coll Med, Dept Microbiol, Washington, DC 20059 USA. Univ Toronto, Toronto Gen Res Inst, Hlth Network, Toronto, ON M5G 2C4, Canada. Univ Toronto, Toronto Western Res Inst, Hlth Network, Toronto, ON M5G 2C4, Canada. Univ Toronto, Dept Immunol, Toronto, ON M5S 1A8, Canada. RP Nabel, GJ (reprint author), NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. EM gnabel@nih.gov FU Intramural NIH HHS NR 45 TC 39 Z9 40 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 19 PY 2007 VL 204 IS 2 BP 421 EP 430 DI 10.1084/jem.20061604 PG 10 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 140KP UT WOS:000244504100020 PM 17296787 ER PT J AU Hibbeln, JR Davis, JM Steer, C Emmett, P Rogers, I Williams, C Golding, J AF Hibbeln, Joseph R. Davis, John M. Steer, Colin Emmett, Pauline Rogers, Imogen Williams, Cathy Golding, Jean TI Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (ALSPAC study): an observational cohort study SO LANCET LA English DT Article ID POLYUNSATURATED FATTY-ACIDS; DIFFICULTIES QUESTIONNAIRE; DOCOSAHEXAENOIC ACID; UNITED-KINGDOM; BIRTH-WEIGHT; FISH INTAKE; SOUTH-WEST; POPULATION; STRENGTHS; CHILDREN AB Background Seafood is the predominant source of omega-3 fatty acids, which are essential for optimum neural development. However, in the USA, women are advised to limit their seafood intake during pregnancy to 340 g per week. We used the Avon Longitudinal Study of Parents and Children (ALSPAC) to assess the possible benefits and hazards to a child's development of different levels of maternal seafood intake during pregnancy. Methods 11875 pregnant women completed a food frequency questionnaire assessing seafood consumption at 32 weeks' gestation. Multivariable logistic regression models including 28 potential confounders assessing social disadvantage, perinatal, and dietary items were used to compare developmental, behavioural, and cognitive outcomes of the children from age 6 months to 8 years in women consuming none, some (1-340 g per week), and >340 g per week. Findings After adjustment, maternal seafood intake during pregnancy of less than 340 g per week was associated with increased risk of their children being in the lowest quartile for verbal intelligence quotient (IQ) (no seafood consumption, odds ratio [OR] 1.48, 95% Cl 1.16-1.90; some, 1.09, 0.92-1.29; overall trend, p=0.004), compared with mothers who consumed more than 340 g per week. Low maternal seafood intake was also associated with increased risk of suboptimum outcomes for prosocial behaviour, fine motor, communication, and social development scores. For each outcome measure, the lower the intake of seafood during pregnancy, the higher the risk of suboptimum developmental outcome. Interpretation Maternal seafood consumption of less than 340 g per week in pregnancy did not protect children from adverse outcomes; rather, we recorded beneficial effects on child development with maternal seafood intakes of more than 340 g per week, suggesting that advice to limit seafood consumption could actually be detrimental. These results show that risks from the loss of nutrients were greater than the risks of harm from exposure to trace contaminants in 340 g seafood eaten weekly. C1 US Natl Inst Alcohol Abuse & Alcoholism, Lab Membrane Biophys & Biochem, US Natl Inst Hlth, Bethesda, MD 20952 USA. Univ Illinois, Chicago, IL USA. Univ Bristol, Dept Community Based Med, Bristol BS8 1TH, Avon, England. RP Hibbeln, JR (reprint author), US Natl Inst Alcohol Abuse & Alcoholism, Lab Membrane Biophys & Biochem, US Natl Inst Hlth, 31 Ctr Dr Rm 31,1B58,MSC 2088, Bethesda, MD 20952 USA. EM jhibbeln@mail.nih.gov OI Emmett, Pauline/0000-0003-1076-4779 FU Intramural NIH HHS; Medical Research Council [G9815508]; NIMH NIH HHS [1 P01MH68580-01]; Wellcome Trust NR 41 TC 437 Z9 465 U1 8 U2 85 PU LANCET LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0140-6736 J9 LANCET JI Lancet PD FEB 17 PY 2007 VL 369 IS 9561 BP 578 EP 585 DI 10.1016/S0140-6736(07)60277-3 PG 8 WC Medicine, General & Internal SC General & Internal Medicine GA 138MZ UT WOS:000244368000031 PM 17307104 ER PT J AU Shin, SY Choi, HY Ahn, BH Min, DS Son, SW Lee, YH AF Shin, Soon Young Choi, Ha Young Ahn, Bong-Hyun Min, Do Sik Son, Sang Wook Lee, Young Han TI Phospholipase C gamma 1 stimulates transcriptional activation of the matrix metalloproteinase-3 gene via the protein kinase C/Raf/ERK cascade SO BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS LA English DT Article DE PLC gamma 1; MMP-3; protein kinase C; MAPK ID EPIDERMAL-GROWTH-FACTOR; FACTOR RECEPTOR; CELL MOTILITY; OVEREXPRESSION; C-GAMMA-1; TRANSFORMATION; FIBROBLASTS; EXPRESSION; INVASION; EGR-1 AB The phospholipid hydrolase phospholipase C71 (PLC gamma 1) plays a major role in regulation of cell proliferation, development, and cell motility. Overexpression of PLC gamma 1 is associated with tumor development, and it is overexpressed in some tumors. Matrix metalloproteinase-3 (MMP-3) is a protein involved in tumor invasion and metastasis. Here, we demonstrate that overexpression of PLC gamma 1 stimulates MMP-3 expression at the transcriptional level via the PKC-mediated Raf/MEK1/ERK signaling cascade. We propose that modulation of PLC gamma 1 activity might be of value in controlling the activity of MMPs, which are important regulators of invasion and metastasis in malignant tumors. (c) 2006 Elsevier Inc. All rights reserved. C1 Hanyang Univ, Div Mol & Life Sci, Coll Sci & Technol, Dept Bionano Technol, Ansan 426791, Gyeonggi Do, South Korea. Hanyang Univ, Inst Nat Sci & Technol, Ansan 426791, Gyeonggi Do, South Korea. NHLBI, Cardiovasc Branch, NIH, Bethesda, MD 20892 USA. Pusan Natl Univ, Coll Nat Sci, Dept Mol Biol, Pusan, South Korea. Korea Univ, Coll Med, Dept Dermatol, Seoul 136701, South Korea. RP Lee, YH (reprint author), Hanyang Univ, Div Mol & Life Sci, Coll Sci & Technol, Dept Bionano Technol, Ansan 426791, Gyeonggi Do, South Korea. EM younghan@hanyang.ac.kr NR 27 TC 2 Z9 4 U1 0 U2 0 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0006-291X J9 BIOCHEM BIOPH RES CO JI Biochem. Biophys. Res. Commun. PD FEB 16 PY 2007 VL 353 IS 3 BP 611 EP 616 DI 10.1016/j.bbrc.2006.12.064 PG 6 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 127FF UT WOS:000243570000014 PM 17196935 ER PT J AU af Bjerken, S Boger, HA Nelson, M Hoffer, BJ Granholm, AC Stromberg, I AF af Bjerken, Sara Boger, Heather A. Nelson, Matthew Hoffer, Barry J. Granholm, Ann-Charlotte Stromberg, Ingrid TI Effects of glial cell line-derived neurotrophic factor deletion on ventral mesencephalic organotypic tissue cultures SO BRAIN RESEARCH LA English DT Article DE GDNF; knockout; organotypic culture; ventral mesencephalon; dopamine; neural plasticity; astroglia; Parkinson's disease ID MICE LACKING GDNF; FACTOR IMPROVES SURVIVAL; DOPAMINERGIC-NEURONS; IN-VIVO; PARKINSONS-DISEASE; RAT MODEL; FUNCTIONAL RECOVERY; SUBSTANTIA-NIGRA; GRAFT-SURVIVAL; TIME-COURSE AB Glial cell line-derived neurotrophic factor (GDNF) is potent for survival and promotion of nerve fibers from midbrain dopamine neurons. It is also known to exert different effects on specific subpopulations of dopamine neurons. In organotypic tissue cultures, dopamine neurons form two diverse nerve fiber growth patterns, targeting the striatum differently. The aim of this study was to investigate the effect of GDNF on the formation of dopamine nerve fibers. Organotypic tissue cultures of ventral mesencephalon of qdnf gene-deleted mice were studied. The results revealed that dopamine neurons survive in the absence of GDNF. Tyrosine hydroxylase immunoreactivity demonstrated, in gdnf knockout and wildtype cultures, nerve fiber formation with two separate morphologies occurring either in the absence or the presence of astrocytes. The outgrowth that occurred in the absence of astrocytes was unaffected by qdnf deletion, whereas nerve fibers guided by the presence of astrocytes were affected in that they reached significantly shorter distances from the gdnf gene-deleted tissue slice, compared to those measured in wildtype cultures. Treatment with GDNF reversed this effect and increased nerve fiber density independent of genotype. Furthermore, migration of astrocytes reached significantly shorter distances from the tissue slice in GDNF knockout compared to wildtype cultures. Exogenous GDNF increased astrocytic migration in qdnf gene-deleted tissue cultures, comparable to lengths observed in wildtype tissue cultures. In conclusion, cultured midbrain dopamine neurons survive in the absence of GDNF, and the addition ofGDNF improved dopamine nerve fiber formation possibly as an indirect effect of astrocytic stimulation. (c) 2006 Elsevier B.V. All rights reserved. C1 Umea Univ, Dept Integrat Med Biol, S-90187 Umea, Sweden. Med Univ S Carolina, Dept Physiol & Neurosci, Charleston, SC 29425 USA. Med Univ S Carolina, Ctr Aging, Charleston, SC 29425 USA. NIDA, NIH, Baltimore, MD 21224 USA. RP Stromberg, I (reprint author), Umea Univ, Dept Integrat Med Biol, S-90187 Umea, Sweden. EM ingrid.stromberg@histocel.umu.se OI af Bjerken, Sara/0000-0002-2148-7714 FU NIA NIH HHS [P01 AG023630-01A2, 1P01AG 023630-01A2, P01 AG023630] NR 51 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD FEB 16 PY 2007 VL 1133 IS 1 BP 10 EP 19 DI 10.1016/j.brainres.2006.11.052 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 138NA UT WOS:000244368100002 PM 17184739 ER PT J AU Yang, DM Zhu, WZ Xiao, BL Brochet, DXP Chen, SRW Lakatta, EG Xiao, RP Cheng, HP AF Yang, Dongmei Zhu, Wei-Zhong Xiao, Bailong Brochet, Didier X. P. Chen, S. R. Wayne Lakatta, Edward G. Xiao, Rui-Ping Cheng, Heping TI Ca2+/calmodulin kinase II-dependent phosphorylation of ryanodine receptors suppresses Ca2+ sparks and Ca2+ waves in cardiac myocytes SO CIRCULATION RESEARCH LA English DT Article DE Ca2+/calmodulin-dependent protein kinase II; ryanodine receptor; Ca2+ sparks; Ca2+ waves; Ca2+-induced Ca2+ release ID CALCIUM-RELEASE CHANNEL; SARCOPLASMIC-RETICULUM; HEART-FAILURE; BETA(1)-ADRENERGIC STIMULATION; PHOSPHOLAMBAN PHOSPHORYLATION; VENTRICULAR MYOCYTES; CALMODULIN KINASE; A PHOSPHORYLATION; FAILING HEARTS; MUSCLE AB The multifunctional Ca2+/calmodulin-dependent protein kinase II delta(C) ( CaMKII delta(C)) is found in the macromolecular complex of type 2 ryanodine receptor (RyR2) Ca2+ release channels in the heart. However, the functional role of CaMKII-dependent phosphorylation of RyR2 is highly controversial. To address this issue, we expressed wild-type, constitutively active, or dominant-negative CaMKII delta(C) via adenoviral gene transfer in cultured adult rat ventricular myocytes. CaMKII-mediated phosphorylation of RyR2 was reduced, enhanced, or unaltered by dominant-negative, constitutively active, or wild-type CaMKII delta(C) expression, whereas phosphorylation of phospholamban at Thr17, an endogenous indicator of CaMKII activity, was at 73%, 161%, or 115% of the control group expressing beta-galactosidase (beta-gal), respectively. In parallel with the phospholamban phosphorylation, the decay kinetics of global Ca2+ transients was slowed, accelerated, or unchanged, whereas spontaneous Ca2+ spark activity was hyperactive, depressed, or unchanged in dominant-negative, constitutively active, or wild-type CaMKII delta(C) groups, respectively. When challenged by high extracellular Ca2+, both wild-type and constitutively active CaMKII delta(C) protected the cells from store overload-induced Ca2+ release, manifested by a approximate to 60% suppression of Ca2+ waves ( at 2 to 20 mmol/L extracellular Ca2+) in spite of an elevated sarcoplasmic reticulum Ca2+ content, whereas dominant-negative CaMKII delta(C) promoted Ca2+ wave production (at 20 mmol/L Ca2+) with significantly depleted sarcoplasmic reticulum Ca2+. Taken together, our data support the notion that CaMKII delta(C) negatively regulates RyR2 activity and spontaneous sarcoplasmic reticulum Ca2+ release, thereby affording a negative feedback that stabilizes local and global Ca2+-induced Ca2+-release in the heart. C1 Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. NIA, Lab Cardiovasc Sci, NIH, Baltimore, MD 21224 USA. Univ Calgary, Cardiovasc Res Grp, Dept Physiol & Biophys, Calgary, AB T2N 1N4, Canada. RP Zhu, WZ (reprint author), Peking Univ, Inst Mol Med, Beijing 100871, Peoples R China. EM zhuw@grc.nia.nih.gov; chengp@pku.edu.cn RI Xiao, Bailong/B-6187-2012 FU Intramural NIH HHS NR 41 TC 64 Z9 65 U1 0 U2 11 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 16 PY 2007 VL 100 IS 3 BP 399 EP 407 DI 10.1161/01.RES.0000258022.13090.55 PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 137DU UT WOS:000244274000014 PM 17234969 ER PT J AU Klein, DC AF Klein, David C. TI Arylalkylamine N-acetyltransferase: "the timezyme" SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Review ID MELATONIN RHYTHM ENZYME; PROTEIN-KINASE-C; HYDROXYINDOLE-O-METHYLTRANSFERASE; BETA-ADRENERGIC STIMULATION; RETINAL PHOTORECEPTOR CELLS; MAMMALIAN PINEAL-GLAND; OTX2 HOMEOBOX GENE; RAT PINEALOCYTES; EC 2.3.1.87; E-BOX AB Arylalkylamine N-acetyltransferase controls daily changes in melatonin production by the pineal gland and thereby plays a unique role in biological timing in vertebrates. Arylalkylamine N-acetyltransferase is also expressed in the retina, where it may play other roles in addition to signaling, including neurotransmission and detoxification. Large changes in activity reflect cyclic 3,5'-adenosine monophosphate-dependent phosphorylation of arylalkylamine N-acetyltransferase, leading to formation of a regulatory complex with 14-3-3 proteins. This activates the enzyme and prevents proteosomal. proteolysis. The conserved features of regulatory systems that control arylalkylamine N-acetyltransferase are a circadian clock and environmental lighting. C1 NICHD, Off Sci Director, Sect Neuroendocrinol, NIH, Bethesda, MD 20892 USA. RP Klein, DC (reprint author), NICHD, Off Sci Director, Sect Neuroendocrinol, NIH, Bethesda, MD 20892 USA. EM kleind@mail.nih.gov FU Intramural NIH HHS NR 89 TC 175 Z9 178 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 16 PY 2007 VL 282 IS 7 BP 4233 EP 4237 DI 10.1074/jbc.R600036200 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 140CX UT WOS:000244482000002 PM 17164235 ER PT J AU Burkhart, BA Kennett, SB Archer, TK AF Burkhart, Barbara A. Kennett, Sarah B. Archer, Trevor K. TI Osmotic stress-dependent repression is mediated by histone H3 phosphorylation and chromatin structure SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID ACTIVATED PROTEIN-KINASE; TRANSFORMED MOUSE FIBROBLASTS; B-INDUCED PHOSPHORYLATION; GLUCOCORTICOID-RECEPTOR; CHROMOSOME CONDENSATION; MITOTIC PHOSPHORYLATION; SER-10 PHOSPHORYLATION; BETAINE TRANSPORTER; KIDNEY-CELLS; IN-VIVO AB Histone H3 phosphorylation has been linked to various environmental stress responses and specific chromatin structure. The role of H3 phosphorylation in the osmotic stress response was investigated on the mouse mammary tumor virus (MMTV) promoter in different chromatin configurations. Hormone-dependent transcription from the MMTV promoter is repressed by osmotic stress when the promoter is integrated and has a normal chromatin structure. However, when the MMTV promoter is transiently transfected, the chromatin structure is less organized, and hormone induction is not affected by osmotic stress. On the integrated MMTV promoter, phosphorylation of histone H3 serine 10 and 28 increases in response to osmotic stress, but the transient promoter shows no change. Hormone-dependent glucocorticoid receptor binding is reduced on the repressed promoter, and elevated H3 phosphorylation is temporally correlated with maximal MMTV repression Additionally, the protein kinase C inhibitor rottlerin, but not other kinase inhibitors, blocks both histone H3 phosphorylation and osmotic repression of MMTV transcription. Glucocorticoid receptor binding is inversely correlated with H3 phosphorylation, suggesting that displacement of the glucocorticoid receptor from the promoter is due to H3 phosphorylation and is the mechanism for the osmotic repression of hormone-dependent transcription. C1 Interagcy Oncol Task Force Food & Drug Adm, Ctr Biol Evaluat & Res, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NIEHS, Lab Mol Carcinogenesis, NIH, Res Triangle Pk, NC 27709 USA. RP Archer, TK (reprint author), Interagcy Oncol Task Force Food & Drug Adm, Ctr Biol Evaluat & Res, NIH, Bethesda, MD 20892 USA. EM archer1@niehs.nih.gov FU Intramural NIH HHS NR 44 TC 8 Z9 8 U1 0 U2 0 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 16 PY 2007 VL 282 IS 7 BP 4400 EP 4407 DI 10.1074/jbc.M609041200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 140CX UT WOS:000244482000020 PM 17158874 ER PT J AU Galkin, A Kulakova, L Melamud, E Li, L Wu, C Mariano, P Dunaway-Mariano, D Nash, TE Herzberg, O AF Galkin, Andrey Kulakova, Liudmila Melamud, Eugene Li, Ling Wu, Chun Mariano, Patrick Dunaway-Mariano, Debra Nash, Theodore E. Herzberg, Osnat TI Characterization, kinetics, and crystal structures of fructose-1,6-bisphosphate aldolase from the human parasite, Giardia lamblia SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID CLASS-II ALDOLASES; ESCHERICHIA-COLI; ENERGY-METABOLISM; FUNCTIONAL-ROLE; MECHANISM; DATABASE; BINDING; PHOSPHOGLYCOLOHYDROXAMATE; DISCRIMINATION; SPECIFICITY AB Class I and class II fructose-1,6-bisphosphate aldolases (FBPA), glycolytic pathway enzymes, exhibit no amino acid sequence homology and utilize two different catalytic mechanisms. The mammalian class I FBPA employs a Schiff base mechanism, whereas the human parasitic protozoan Giardia lamblia class II FBPA is a zinc-dependent enzyme. In this study, we have explored the potential exploitation of the Giardia FBPA as a drug target. First, synthesis of FBPA was demonstrated in Giardia trophozoites by using an antibody-based fluorescence assay. Second, inhibition of FBPA gene transcription in Giardia trophozoites suggested that the enzyme is necessary for the survival of the organism under optimal laboratory growth conditions. Third, two crystal structures of FBPA in complex with the transition state analog phosphoglycolohydroxamate (PGH) show that the enzyme is homodimeric and that its active site contains a zinc ion. In one crystal form, each subunit contains PGH, which is coordinated to the zinc ion through the hydroxamic acid hydroxyl and carbonyl oxygen atoms. The second crystal form contains PGH only in one subunit and the active site of the second subunit is unoccupied. Inspection of the two states of the enzyme revealed that it undergoes a conformational transition upon ligand binding. The enzyme cleaves D-fructose-1,6-bisphosphate but not D-tagatose-1,6-bisphosphate, which is a tight binding competitive inhibitor. The essential role of the active site residue Asp-83 in catalysis was demonstrated by amino acid replacement. Determinants of catalysis and substrate recognition, derived from comparison of the G. lamblia FBPA structure with Escherichia coli FBPA and with a closely related enzyme, E. coli tagatose-1,6-bisphosphate aldolase (TBPA), are described. C1 Univ Maryland, Maryland Biotechnol Inst, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. Univ New Mexico, Dept Chem, Albuquerque, NM 87131 USA. NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. RP Herzberg, O (reprint author), Univ Maryland, Maryland Biotechnol Inst, Ctr Adv Res Biotechnol, Rockville, MD 20850 USA. EM osnat@carb.nist.gov FU NIAID NIH HHS [R01 AI059733] NR 42 TC 25 Z9 29 U1 6 U2 17 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 16 PY 2007 VL 282 IS 7 BP 4859 EP 4867 DI 10.1074/jbc.M609534200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 140CX UT WOS:000244482000068 PM 17166851 ER PT J AU Jia, YP Buehler, PW Boykins, RA Venable, RM Alayash, AI AF Jia, Yiping Buehler, Paul W. Boykins, Robert A. Venable, Richard M. Alayash, Abdu I. TI Structural basis of peroxide-mediated changes in human hemoglobin - A novel oxidative pathway SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID RECOMBINANT HUMAN ALPHA-1-ANTITRYPSIN; CROSS-LINKED HEMOGLOBIN; HEME PROSTHETIC GROUP; HYDROGEN-PEROXIDE; METHIONINE OXIDATION; CIRCULAR-DICHROISM; FREE-RADICALS; IN-VITRO; PROTEIN; MYOGLOBIN AB Hydrogen peroxide (H2O2) triggers a redox cycle between ferric and ferryl hemoglobin (Hb) leading to the formation of a transient protein radical and a covalent hemeprotein cross-link. Addition of H2O2 to highly purified human hemoglobin (HbA(0)) induced structural changes that primarily resided within beta subunits followed by the internalization of the heme moiety within a subunits. These modifications were observed when an equal molar concentration of H2O2 was added to HbA(0) yet became more abundant with greater concentrations of H2O2. Mass spectrometric and amino acid analysis revealed for the first time that beta Cys-93 and beta Cys-112 were oxidized extensively and irreversibly to cysteic acid when HbA(0) was treated with H2O2. Oxidation of further amino acids in HbA(0) exclusive to the beta-globin chain included modification of beta Trp-15 to oxyindolyl and kynureninyl products as well as beta Met-55 to methionine sulfoxide. These findings may therefore explain the premature collapse of the beta subunits as a result of the H2O2 attack. Analysis of a tryptic digest of the main reversed phase-high pressure liquid chromatography fraction revealed two a-peptide fragments (alpha 128 - alpha 139) and a heme moiety with the loss of iron, cross-linked between alpha Ser-138 and the porphyrin ring. The novel oxidative pathway of HbA(0) modification detailed here may explain the diverse oxidative, toxic, and potentially immunogenic effects associated with the release of hemoglobin from red blood cells during hemolytic diseases and/or when cell-free Hb is used as a blood substitute. C1 Food & Drug Adm, Ctr Biol Evaluat & Res, Lab Biochem & Vasc Biol, Div Hematol, Bethesda, MD 20892 USA. Food & Drug Adm, Ctr Biol Evaluat & Res, Biophys Lab, Div Bacterial Parasit & Allergen Prod, Bethesda, MD 20892 USA. NHLBI, Membrane Biophys Sect, Lab Computat Biol, NIH, Bethesda, MD 20892 USA. RP Alayash, AI (reprint author), Food & Drug Adm, Ctr Biol Evaluat & Res, Lab Biochem & Vasc Biol, Div Hematol, Bethesda, MD 20892 USA. EM abdu.alayash@fda.hhs.gov NR 47 TC 58 Z9 58 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 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 16 PY 2007 VL 282 IS 7 BP 4894 EP 4907 DI 10.1074/jbc.M609955200 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 140CX UT WOS:000244482000072 PM 17178725 ER PT J AU Burnett, JC Ruthel, G Stegmann, CM Panchal, RG Nguyen, TL Hermone, AR Stafford, RG Lane, DJ Kenny, TA McGrath, CF Wipf, P Stahl, AM Schmidt, JJ Gussio, R Brunger, AT Bavari, S AF Burnett, James C. Ruthel, Gordon Stegmann, Christian M. Panchal, Rekha G. Nguyen, Tam L. Hermone, Ann R. Stafford, Robert G. Lane, Douglas J. Kenny, Tara A. McGrath, Connor F. Wipf, Peter Stahl, Andrea M. Schmidt, James J. Gussio, Rick Brunger, Axel T. Bavari, Sina TI Inhibition of metalloprotease botulinum serotype A from a pseudo-peptide binding mode to a small molecule that is active in primary neurons SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TOXIN TYPE-A; NEUROTOXIN SEROTYPE; ZINC ENDOPEPTIDASE; NEUROTRANSMITTER RELEASE; COMMON PHARMACOPHORE; CRYSTAL-STRUCTURE; PROTEASE ACTIVITY; POISONOUS POISON; IDENTIFICATION; PROTEINS AB An efficient research strategy integrating empirically guided, structure-based modeling and chemoinformatics was used to discover potent small molecule inhibitors of the botulinum neurotoxin serotype A light chain. First, a modeled binding mode for inhibitor 2-mercapto-3-phenylpropionyl-RATKML (K-i = 330 nM) was generated, and required the use of a molecular dynamic conformer of the enzyme displaying the reorientation of surface loops bordering the substrate binding cleft. These flexible loops are conformationally variable in x-ray crystal structures, and the model predicted that they were pivotal for providing complementary binding surfaces and solvent shielding for the pseudo-peptide. The docked conformation of 2-mercapto-3-phenylpropionyl-RATKML was then used to refine our pharmacophore for botulinum serotype A light chain inhibition. Data base search queries derived from the pharmacophore were employed to mine small molecule (non-peptidic) inhibitors from the National Cancer Institute's Open Repository. Four of the inhibitors possess K, values ranging from 3.0 to 10.0 mu m. Of these, NSC 240898 is a promising lead for therapeutic development, as it readily enters neurons, exhibits no neuronal toxicity, and elicits dose-dependent protection of synaptosomal-associated protein (of 25 kDa) in a primary culture of embryonic chicken neurons. Isothermal titration calorimetry showed that the interaction between NSC 240898 and the botulinum A light chain is largely entropy-driven, and occurs with a 1:1 stoichiometry and a dissociation constant of 4.6 mu M. C1 Stanford Univ, Sch Med, HHMI, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Cellular & Mol Physiol, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Dept Neurol & Neurol Sci, Stanford, CA 94305 USA. Stanford Univ, Sch Med, Stanford Synchrotron Radiat Lab, Stanford, CA 94305 USA. NCI Frederick, Informat Technol Branch, Dev Therapeut Program, Ft Detrick, MD 21702 USA. USA, Med Res Inst Infect Dis, Ft Detrick, MD 21702 USA. SAIC Frederick, Target Struct Based Drug Discovery Grp, Frederick, MD USA. Univ Pittsburgh, Combinatorial Chem Ctr, Pittsburgh, PA 15260 USA. RP Brunger, AT (reprint author), Stanford Univ, Sch Med, HHMI, 318 Campus Dr,Rm E300, Stanford, CA 94305 USA. EM brunger@stanford.edu; sina.bavari@us.army.mil OI Brunger, Axel/0000-0001-5121-2036 NR 46 TC 50 Z9 50 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 16 PY 2007 VL 282 IS 7 BP 5004 EP 5014 DI 10.1074/jbc.M608166200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 140CX UT WOS:000244482000083 ER PT J AU Saad, JS Loeliger, E Luncsford, P Liriano, M Tai, J Kim, A Miller, J Joshi, A Freed, EO Summers, MF AF Saad, Jamil S. Loeliger, Erin Luncsford, Paz Liriano, Mellisa Tai, Janet Kim, Andrew Miller, Jaime Joshi, Anjali Freed, Eric O. Summers, Michael F. TI Point mutations in the HIV-1 matrix protein turn off the myristyl switch SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE human immunodeficiency virus type-1; Gag; myristyl; matrix; phosphatidylinositol-4,5-bisphosphate ID IMMUNODEFICIENCY-VIRUS TYPE-1; PLASMA-MEMBRANE; TERMINAL REGION; GAG PRECURSOR; BINDING; MYRISTOYLATION; DOMAIN; NMR; IDENTIFICATION; REPLICATION AB During the late phase of human immunodeficiency virus type-1 (HIV-1) replication, newly synthesized retroviral Gag proteins are targeted to lipid raft regions of specific cellular membranes, where they assemble and bud to form new virus particles. Gag binds preferentially to the plasma membrane (PM) of most hematopoietic cell types, a process mediated by interactions between the cellular PM marker phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P-2) and Gag's N-terminally myristoylated matrix (MA) domain. We recently demonstrated that PI(4,5)P2 binds to a conserved cleft on MA and promotes myristate exposure, suggesting a role as both a direct membrane anchor and myristyl switch trigger. Here we show that PI(4,5)P2 is also capable of binding to MA proteins containing point mutations that inhibit membrane binding in vitro, and in vivo, including V7R, L8A and L8I. However, these mutants do not exhibit PI(4,5)P2 or concentration-dependent myristate exposure. NMR studies of V7R and LSA MA reveal minor structural changes that appear to be responsible for stabilizing the myristate-sequestered (myr(s)) species and inhibiting exposure. Unexpectedly, the myristyl group of a revertant mutant with normal PM targeting properties (V7R, L21K) is also tightly sequestered and insensitive to PI(4,5)P2 binding. This mutant binds PI(4,5)P2 with twofold higher affinity compared with the native protein, suggesting a potential compensatory mechanism for membrane binding. (c) 2006 Elsevier Ltd. All rights reserved. C1 Univ Maryland Baltimore Cty, Howard Hughes Med Inst, Baltimore, MD 21250 USA. Univ Maryland Baltimore Cty, Dept Chem & Biochem, Baltimore, MD 21250 USA. NCI, Virus Cell Interact Sect, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Summers, MF (reprint author), Univ Maryland Baltimore Cty, Howard Hughes Med Inst, 1000 Hilltop Circle, Baltimore, MD 21250 USA. EM summers@hhmi.umbc.edu FU Intramural NIH HHS; NIAID NIH HHS [R37 AI030917, AI30917]; NIGMS NIH HHS [T32 GM007753] NR 48 TC 66 Z9 66 U1 0 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD FEB 16 PY 2007 VL 366 IS 2 BP 574 EP 585 DI 10.1016/j.jmb.2006.11.068 PG 12 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 135WH UT WOS:000244184100020 PM 17188710 ER PT J AU Oelschlaeger, P Klahn, M Beard, WA Wilson, SH Warshel, A AF Oelschlaeger, Peter Klahn, Marco Beard, William A. Wilson, Samuel H. Warshel, Arieh TI Magnesium-cationic dummy atom molecules enhance representation of DNA polymerase beta in molecular dynamics simulations: Improved accuracy in studies of structural features and mutational effects SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE metalloenzyme; DNA polymerase; molecular dynamics; magnesium ion; mutation ID FREE-ENERGY RELATIONSHIPS; COMPUTER-SIMULATION; ACTIVE-SITE; FORCE-FIELD; MECHANISM; PROTEINS; FIDELITY; BINDING; COMPLEXES; CATALYSIS AB Human DNA polymerase beta (pol beta) fills gaps in DNA as part of base excision DNA repair. Due to its small size it is a convenient model enzyme for other DNA polymerases. Its active site contains two Mg2+ ions, of which one binds an incoming dNTP and one catalyzes its condensation with the DNA primer strand. Simulating such binuclear metalloenzymes accurately but computationally efficiently is a challenging task. Here, we present a magnesium-cationic dummy atom approach that can easily be implemented in molecular mechanical force fields such as the ENZYMIX or the AMBER force fields. All properties investigated here, namely, structure and energetics of both Michaelis complexes and transition state (TS) complexes were represented more accurately using the magnesium-cationic dummy atom model than using the traditional one-atom representation for Mg2+ ions. The improved agreement between calculated free energies of binding of TS models to different pol variants and the experimentally determined activation free energies indicates that this model will be useful in studying mutational effects on catalytic efficiency and fidelity of DNA polymerases. The model should also have broad applicability to the modeling of other magnesium-containing proteins. (c) 2006 Elsevier Ltd. All rights reserved. C1 Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Oelschlaeger, P (reprint author), Univ So Calif, Dept Chem, Los Angeles, CA 90089 USA. EM poelschl@usc.edu; warshel@usc.edu RI Klahn, Marco/A-6022-2008 FU Intramural NIH HHS; NCI NIH HHS [5U19CA105010, U19 CA105010, U19 CA105010-040001]; NIGMS NIH HHS [R01 GM021422-23, R01 GM021422, R01GM21422] NR 43 TC 49 Z9 49 U1 2 U2 16 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 16 PY 2007 VL 366 IS 2 BP 687 EP 701 DI 10.1016/j.jmb.2006.10.095 PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 135WH UT WOS:000244184100029 PM 17174326 ER PT J AU Galbraith, CG Yamada, KM Galbraith, JA AF Galbraith, Catherine G. Yamada, Kenneth M. Galbraith, James A. TI Polymerizing actin fibers position integrins primed to probe for adhesion sites SO SCIENCE LA English DT Article ID CELL-MIGRATION; GROWTH CONES; MOTILITY; CYTOSKELETON; LAMELLIPODIA; FIBROBLASTS; LINKAGES; PROTEINS; LOCOMOTION; MOVEMENTS AB Migrating cells extend protrusions, probing the surrounding matrix in search of permissive sites to form adhesions. We found that actin fibers polymerizing along the leading edge directed local protrusions and drove synchronous sideways movement of beta(1) integrin adhesion receptors. These movements lead to the clustering and positioning of conformationally activated, but unligated, beta(1) integrins along the leading edge of fibroblast lamellae and growth cone filopodia. Thus, rapid actin-based movement of primed integrins along the leading edge suggests a "sticky fingers" mechanism to probe for new adhesion sites and to direct migration. C1 Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD 20892 USA. RP Yamada, KM (reprint author), Natl Inst Dent & Craniofacial Res, NIH, Bethesda, MD 20892 USA. EM kyamada@dir.nidcr.nih.gov OI Yamada, Kenneth/0000-0003-1512-6805 NR 26 TC 160 Z9 164 U1 1 U2 17 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 16 PY 2007 VL 315 IS 5814 BP 992 EP 995 DI 10.1126/science.1137904 PG 4 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 136MW UT WOS:000244229800043 PM 17303755 ER PT J AU Ahmed, A Zile, MR Rich, MW Fleg, JL Adams, KF Love, TE Young, JB Aronow, WS Kitzman, DW Gheorghiade, M Dell'Italia, LJ AF Ahmed, Ali Zile, Michael R. Rich, Michael W. Fleg, Jerome L. Adams, Kirkwood F., Jr. Love, Thomas E. Young, James B. Aronow, Wilbert S. Kitzman, Dalane W. Gheorghiade, Mihai Dell'Italia, Louis J. TI Hospitalizations due to unstable angina pectoris in diastolic and systolic heart failure SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID LEFT-VENTRICULAR HYPERTROPHY; MYOCARDIAL-INFARCTION; ISCHEMIC CARDIOMYOPATHY; HYPERTENSIVE PATIENTS; BETA-BLOCKERS; OLDER-ADULTS; MORTALITY; DYSFUNCTION; PREVALENCE; SURVIVAL AB Patients with diastolic heart failure (HF), i.e., clinical HF with normal or near normal left ventricular ejection fraction (LVEF), may develop unstable angina pectoris (UAP) due to epicardial atherosclerotic coronary artery disease and/or to subendocardial ischemia, even in the absence of coronary artery disease. However, the risk of UAP in ambulatory patients with diastolic HF has not been well studied. We examined incident hospitalizations due to UAP in 916 patients with diastolic HF (LVEF > 45%) without significant valvular heart disease and 6,800 patients with systolic HF (LVEF <= 45%) in the Digitalis Investigation Group trial. During a 38-month median follow-up, 12% of patients (797 of 6,800) with systolic HF (incidence rate 435 per 10,000 person-years) and 15% of patients (138 of 916) with diastolic HF (incidence rate 536 per 10,000 person-years) were hospitalized for UAP (adjusted hazard ratio for diastolic HF 1.22, 95% confidence interval [CI] 1.02 to 1.47, p = 0.032). There was a graded increase in incident hospital admissions for UAP with increasing LVEF. Hospitalizations for UAP occurred in 11% (520 of 4,808, incidence rate 407 per 10,000 person-years), 14% (355 of 2,556, incidence rate 496 per 10,000 person-years), and 17% (60 of 352, incidence rate 613 per 10,000 person-years) of patients with HF, respectively, with LVEF values < 35%, 35% to 55%, and > 55%. Compared with patients with HF and an LVEF < 35%, the adjusted hazard ratios for UAP hospitalization in those with LVEF values 35% to 55% and > 55% were, respectively, 1.17 (95% Cl 1.02 to 1.34, p = 0.028) and 1.57 (95% Cl 1.20 to 2.07, p = 0.026). In conclusion, in ambulatory patients with chronic HF, a higher LVEF was associated with increased risk of hospitalizations due to UAP. As in patients with systolic HF, those with diastolic HF should be routinely evaluated for myocardial ischemia and managed accordingly. (c) 2007 Elsevier Inc. All rights reserved. C1 Univ Alabama, Birmingham, AL 35294 USA. VA Med Ctr, Birmingham, AL USA. Med Univ S Carolina, Charleston, SC 29425 USA. RHJ VA Med Ctr, Charleston, SC USA. Washington Univ, St Louis, MO USA. NHLBI, Bethesda, MD 20892 USA. Univ N Carolina, Chapel Hill, NC USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. Cleveland Clin Fdn, Cleveland, OH 44195 USA. New York Med Coll, Valhalla, NY 10595 USA. Wake Forest Univ, Winston Salem, NC 27109 USA. Northwestern Univ, Chicago, IL 60611 USA. RP Ahmed, A (reprint author), Univ Alabama, Birmingham, AL 35294 USA. EM aahmed@uab.edu RI Ahmed, Ali/A-2934-2008 OI Ahmed, Ali/0000-0002-6832-6424 FU NHLBI NIH HHS [P50-HL077100, 1-R01-HL085561-01, P50 HL077100, R01 HL085561, R01 HL085561-01]; NIA NIH HHS [1-K23-AG19211-04, K23 AG019211, K23 AG019211-03, R37 AG018915, K23 AG019211-04, R01 AG018915] NR 26 TC 17 Z9 19 U1 0 U2 1 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD FEB 15 PY 2007 VL 99 IS 4 BP 460 EP 464 DI 10.1016/j.amjcard.2006.08.056 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 140OH UT WOS:000244514500007 PM 17293184 ER PT J AU McGlynn, KA Sakoda, LC Rubertone, MV Sesterhenn, IA Lyu, C Graubard, BI Erickson, RL AF McGlynn, Katherine A. Sakoda, Lori C. Rubertone, Mark V. Sesterhenn, Isabel A. Lyu, Christopher Graubard, Barry I. Erickson, Ralph L. TI Body size, dairy consumption, puberty, and risk of testicular germ cell tumors SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE body height; diet; puberty; testicular neoplasms ID PHYSICAL-ACTIVITY; TESTIS CANCER; BIRTH COHORT; UNITED-STATES; ADULT HEIGHT; TRENDS; MEN; ASSOCIATION; CARCINOMA; PROSTATE AB The etiology of testicular germ cell tumors (TGCTs) is poorly understood, with cryptorchidism and family history being the only well-established risk factors. Body size, age at puberty, and dairy consumption, however, have been suggested to be related to TGCTs. To clarify the relation of these variables to TGCT risk and to one another, the authors analyzed data from 767 cases and 928 controls enrolled in the Servicemen's Testicular Tumor Environmental and Endocrine Determinants Study (2002-2005). Overall, increased height was significantly related to risk (odds ratio (OR) = 1.83, 95% confidence interval (CI): 1.36, 2.45), though body mass index was not (OR = 1.06, 95% CI: 0.66, 1.69). There was no association with age at puberty, based on ages at first shaving (OR = 1.29, 95% CI: 0.96, 1.73), voice changing (OR = 0.97, 95% CI: 0.71, 1.32), and nocturnal emissions (OR = 1.00, 95% CI: 0.73, 1.37). Similarly, there was no relation with dairy consumption at any age between birth and 12th grade. These results suggest that height is a risk factor for TGCTs, but the relation is unlikely explained by childhood dairy consumption. As adult height is largely determined in the first 2 years of life, increased attention to events in this interval may help elucidate the etiology of TGCTs. C1 Natl Canc Inst, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Rockville, MD 20892 USA. US Army Ctr Hlth Promot & Prevent Med, Washington, DC USA. Armed Forces Inst Pathol, Washington, DC 20306 USA. Battelle Inst Ctr Publ Hlth Res & Evaluat, Durham, NC USA. Walter Reed Army Inst Res, Dept Prevent Med, Dept Def, Silver Spring, MD USA. RP McGlynn, KA (reprint author), Natl Canc Inst, Hormonal & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, EPS 7060,6120 Execut Blvd, Rockville, MD 20892 USA. EM mcglynnk@mail.nih.gov FU Intramural NIH HHS NR 37 TC 38 Z9 38 U1 1 U2 2 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 15 PY 2007 VL 165 IS 4 BP 355 EP 363 DI 10.1093/aje/kwk019 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 134ZQ UT WOS:000244123800001 PM 17110638 ER PT J AU Kamel, F Tanner, CM Umbach, DM Hoppin, JA Alavanja, MCR Blair, A Comyns, K Goldman, SM Korell, M Langston, JW Ross, GW Sandler, DP AF Kamel, F. Tanner, C. M. Umbach, D. M. Hoppin, J. A. Alavanja, M. C. R. Blair, A. Comyns, K. Goldman, S. M. Korell, M. Langston, J. W. Ross, G. W. Sandler, D. P. TI Pesticide exposure and self-reported Parkinson's disease in the agricultural health study SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE case-control studies; herbicides; insecticides; Parkinson disease; pesticides ID ENVIRONMENTAL RISK-FACTORS; LIFE-STYLE; APPLICATORS; POPULATION; METAANALYSIS; ASSOCIATION; PARAQUAT; CYP2D6; SYSTEM; TWINS AB Previous studies based on limited exposure assessment have suggested that Parkinson's disease (PD) is associated with pesticide exposure. The authors used data obtained from licensed private pesticide applicators and spouses participating in the Agricultural Health Study to evaluate the relation of self-reported PD to pesticide exposure. Cohort members, who were enrolled in 1993-1997, provided detailed information on lifetime pesticide use. At follow-up in 1999-2003, 68% of the cohort was interviewed. Cases were defined as participants who reported physician-diagnosed PD at enrollment (prevalent cases, n = 83) or follow-up (incident cases, n = 78). Cases were compared with cohort members who did not report PD (n = 79,557 at enrollment and n = 55,931 at follow-up). Incident PD was associated with cumulative days of pesticide use at enrollment (for highest quartile vs. lowest, odds ratio (OR) = 2.3, 95% confidence interval: 1.2, 4.5; p-trend = 0.009), with personally applying pesticides more than half the time (OR = 1.9, 95% confidence interval: 0.7, 4.7), and with some specific pesticides (ORs >= 1.4). Prevalent PD was not associated with overall pesticide use. This study suggests that exposure to certain pesticides may increase PD risk. Findings for specific chemicals may provide fruitful leads for further investigation. C1 NIEHS, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Parkinsons Inst, Sunnyvale, CA USA. Natl Canc Inst, Bethesda, MD USA. Pacific Isl VA Hlth Care Syst, Honolulu, HI USA. RP Kamel, F (reprint author), NIEHS, Epidemiol Branch, MD A3-05,POB 12233, Res Triangle Pk, NC 27709 USA. EM kamel@mail.nih.gov OI Kamel, Freya/0000-0001-5052-6615; Sandler, Dale/0000-0002-6776-0018 FU Intramural NIH HHS; NIEHS NIH HHS [01-ES10803, U54-ES12077] NR 51 TC 146 Z9 149 U1 2 U2 23 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 2007 VL 165 IS 4 BP 364 EP 374 DI 10.1093/aje/kwk024 PG 11 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 134ZQ UT WOS:000244123800002 PM 17116648 ER PT J AU Goodwin, RD Chuang, S Simuro, N Davies, M Pine, DS AF Goodwin, Renee D. Chuang, Shirley Simuro, Nicole Davies, Mark Pine, Daniel S. TI Association between lung function and mental health problems among adults in the United States: Findings from the First National Health and Nutrition Examination Survey SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE adult; asthma; mental health; respiratory function tests ID PANIC-ATTACKS; CIGARETTE-SMOKING; ASTHMA; DISORDERS; COMMUNITY; COMORBIDITY; DEPRESSION; DEPENDENCE; SYMPTOMS; ANXIETY AB The objective of this study was to determine the association between lung function and mental health problems among adults in the United States. Data were drawn from the First National Health and Nutrition Examination Survey (1971-1975), with available information on a representative sample of US adults aged 25-74 years. Lung function was assessed by spirometry, and provisional diagnoses of restrictive and obstructive airway disease were assigned based on percentage of expected forced expiratory volume. Mental health problems were assessed with the General Well-Being scales. Restrictive lung function and obstructive lung function, compared with normal lung function, were each associated with a significantly increased likelihood of mental health problems. After adjustment for differences in demographic characteristics, obstructive lung function was associated with significantly lower overall well-being (p = 0.025), and restrictive lung function was associated with significantly lower overall well-being (p < 0.001), general health (p < 0.0001), vitality (p < 0.0001), and self-control (p = 0.001) and with higher depression (p = 0.002) subscale scores compared with no lung function problems. Consistent with previous findings from clinical and community-based studies, these results extend available data by providing evidence of a link between objectively measured lung function and self-reported mental health problems in a representative sample of community adults. Future studies are needed to determine the mechanisms of these associations. C1 Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, New York, NY 10032 USA. Columbia Univ, Coll Phys & Surg, Dept Child Psychiat, New York, NY USA. NIMH, Div Intramural Res, Bethesda, MD 20892 USA. RP Goodwin, RD (reprint author), Columbia Univ, Mailman Sch Publ Hlth, Dept Epidemiol, 722 W 168th St,Room 1706, New York, NY 10032 USA. EM rdg66@columbia.edu FU NIMH NIH HHS [MH-64736] NR 26 TC 28 Z9 29 U1 1 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 15 PY 2007 VL 165 IS 4 BP 383 EP 388 DI 10.1093/aje/kwk026 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 134ZQ UT WOS:000244123800004 PM 17158187 ER PT J AU Howards, PP Hertz-Picciotto, I Poole, C AF Howards, Penelope P. Hertz-Picciotto, Irva Poole, Charles TI Conditions for bias from differential left truncation SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE abortion; spontaneous; bias (epidemiology); logistic models; survival analysis; trihalomethanes ID LOGISTIC-REGRESSION; PROPORTIONAL HAZARDS; SPONTANEOUS-ABORTION; PRENATAL-CARE; EMPIRICAL COMPARISONS; SURVIVAL ANALYSIS; DRINKING-WATER; MODELS; MORTALITY; PREGNANCY AB Spontaneous abortion studies that recruit pregnant women are left truncated because an unknown proportion of the source population experiences losses prior to enrollment. Unconditional logistic regression, commonly used in such studies, ignores left truncation, whereas survival analysis can accommodate left truncation and is therefore more appropriate. This study assessed the magnitude of bias introduced by fitting logistic versus Cox models using left-truncated data from a 1998 US pregnancy cohort study (n = 5,104) of trihalomethanes and spontaneous abortion. In addition, the conditions producing bias were explored by using simulated exposure data. The odds ratios and hazard ratios from the actual study differed by 10% or less. However, when the exposed women entered observation earlier on average than those unexposed, the hazard ratio was closer to the null than the odds ratio, whereas the reverse was true when the exposed entered later. The simulation suggests that bias in the odds ratio will exceed 20% when average gestational age at entry for the exposed versus the unexposed differs by 10 days or more, as has been observed regarding some socioeconomic factors, such as education and ethnicity. Cox regression can correct for left truncation and is no more difficult to perform than logistic regression. C1 Natl Inst Child Hlth & Human Dev, Div Epidemiol Stat & Prevent Res, Rockville, MD 20852 USA. Univ Calif Davis, Dept Publ Hlth Sci, Div Epidemiol, Davis, CA 95616 USA. Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA. RP Howards, PP (reprint author), Natl Inst Child Hlth & Human Dev, Div Epidemiol Stat & Prevent Res, 6100 Execut Blvd,Room 7B03C MSC 7510, Rockville, MD 20852 USA. EM howardsp@mail.nih.gov FU Intramural NIH HHS; NICHD NIH HHS [T32 HD07168-22]; NIEHS NIH HHS [ES07018, P30 ES10126] NR 30 TC 34 Z9 34 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 15 PY 2007 VL 165 IS 4 BP 444 EP 452 DI 10.1093/aje/kwk027 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 134ZQ UT WOS:000244123800011 PM 17150983 ER PT J AU Semba, RD Lauretani, F Ferrucci, L AF Semba, Richard D. Lauretani, Fulvio Ferrucci, Luigi TI Carotenoids as protection against sarcopenia in older adults SO ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS LA English DT Review DE aging; carotene; carotenoids; cryptoxanthin; inflammation; lutein; lycopene; muscle; sarcopenia; zeaxanthin ID HUMAN SKELETAL-MUSCLE; RANDOMIZED CONTROLLED TRIAL; DNA DELETION MUTATIONS; MITOCHONDRIAL-DNA; OXIDATIVE STRESS; CARDIOVASCULAR-DISEASE; BLOOD-PRESSURE; HANDGRIP STRENGTH; KAPPA-B; VEGETABLE CONSUMPTION AB Sarcopenia, or loss of muscle mass and strength, plays a major role in the disablement process in older adults and increases the risk of impaired physical performance, falls, physical disability, frailty, and death. Oxidative stress is a major mechanism implicated in the pathogenesis of sarcopenia; aging muscle shows increased oxidative damage to DNA, protein, and lipids. Carotenoids quench free radicals, reduce damage from reactive oxygen species, and appear to modulate redox-sensitive transcription factors such as NF-kappa B that are involved in the upregulation of IL-6 and other proinflammatory cytokines. Recent epidemiological studies in community-dwelling older adults show that low serum/plasma carotenoids are independently associated with low skeletal muscle strength and the development of walking disability. These observations are consistent with a growing number of studies showing that a diet with high intake of fruits and vegetables is associated with a reduced risk of inflammation, hypertension, diabetes, cardiovascular disease, and mortality. (c) 2007 Published by Elsevier Inc. C1 Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. Tuscany Reg Agcy, Florence, Italy. NIA, Longitudinal Studies Sect, Clin Res Branch, Baltimore, MD 21224 USA. RP Semba, RD (reprint author), Johns Hopkins Univ, Sch Med, Baltimore, MD 21205 USA. EM rdsemba@jhmi.edu RI Lauretani, Fulvio/K-5115-2016 OI Lauretani, Fulvio/0000-0002-5287-9972 FU Intramural NIH HHS [Z99 AG999999]; NIA NIH HHS [N01-AG-5-0002, N01-AG-821336, N01-AG-916413, R01 AG027012] NR 81 TC 55 Z9 66 U1 1 U2 10 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0003-9861 J9 ARCH BIOCHEM BIOPHYS JI Arch. Biochem. Biophys. PD FEB 15 PY 2007 VL 458 IS 2 BP 141 EP 145 DI 10.1016/j.abb.2006.11.025 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 138TI UT WOS:000244385000007 PM 17196927 ER PT J AU Lopez, AB Wang, CP Huang, CC Yaman, I Li, Y Chakravarty, K Johnson, PF Chiang, CM Snider, MD Wek, RC Hatzoglou, M AF Lopez, Alex B. Wang, Chuanping Huang, Charlie C. Yaman, Ibrahim Li, Yi Chakravarty, Kaushik Johnson, Peter F. Chiang, Cheng-Ming Snider, Martin D. Wek, Ronald C. Hatzoglou, Maria TI A feedback transcriptional mechanism controls the level of the arginine/lysine transporter cat-1 during amino acid starvation SO BIOCHEMICAL JOURNAL LA English DT Article DE activating transcription factor; amino acid response element; amino acid transporter; eIF2 phosphorylation; stress response gene; transcriptional regulation ID ENDOPLASMIC-RETICULUM STRESS; UNFOLDED PROTEIN RESPONSE; ASPARAGINE SYNTHETASE PROMOTER; SITE-MEDIATED TRANSLATION; OPEN READING FRAMES; GENE-EXPRESSION; MAMMALIAN-CELLS; INDUCIBLE GENE; GLUCOSE-HOMEOSTASIS; NUTRITIONAL CONTROL AB The adaptive response to amino acid limitation in mammalian cells inhibits global protein synthesis and promotes the expression of proteins that protect cells from stress. The arginine/lysine transporter, cat-1, is induced during amino acid starvation by transcriptional and post-transcriptional mechanisms. It is shown in the present study that the transient induction of cat-1 transcription is regulated by the stress response pathway that involves phosphorylation of the translation initiation factor, eIF2 (eukaryotic initiation factor-2). This phosphorylation induces expression of the bZIP (basic leucine zipper protein) transcription factors C/ EBP (CCAAT/enhancer-binding protein)-beta and ATF (activating transcription factor) 4, which in turn induces ATF3. Transfection experiments in control and mutant cells, and chromatin immuno-precipitations showed that ATF4 activates, whereas ATF3 represses cat-1 transcription, via an AARE (amino acid response element), TGATGAAAC, in the first exon of the cat-1 gene, which functions both in the endogenous and in a heterologous promoter. ATF4 and C/EBP beta activated transcription when expressed in transfected cells and they bound as heterodimers to the AARE in vitro. The induction of transcription by ATF4 was inhibited by ATF3, which also bound to the AARE as a heterodimer with C/EBP beta. These results suggest that the transient increase in cat-1 transcription is due to transcriptional activation caused by ATF4 followed by transcriptional repression by ATF3 via a feedback mechanism. C1 Case Western Reserve Univ, Sch Med, Dept Nutr, Cleveland, OH 44106 USA. Case Western Reserve Univ, Sch Med, Dept Biochem, Cleveland, OH 44106 USA. NCI, Lab Prot Dynam & Signaling, Frederick, MD 21702 USA. Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. RP Hatzoglou, M (reprint author), Case Western Reserve Univ, Sch Med, Dept Nutr, Cleveland, OH 44106 USA. EM mxh8@case.edu RI Johnson, Peter/A-1940-2012; yaman, ibrahim/A-7192-2016 OI Johnson, Peter/0000-0002-4145-4725; FU NCI NIH HHS [R01 CA103867, R01-CA103867]; NIDDK NIH HHS [R01 DK053307, 5T32-DK07319, R01 DK060596, R01-DK53307, R01-DK60596, T32 DK007319] NR 52 TC 50 Z9 50 U1 0 U2 4 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0264-6021 J9 BIOCHEM J JI Biochem. J. PD FEB 15 PY 2007 VL 402 BP 163 EP 173 DI 10.1042/BJ20060941 PN 1 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 137HT UT WOS:000244284400017 PM 17042743 ER PT J AU Giri, S Krausz, KW Idle, JR Gonzalez, FJ AF Giri, Sarbani Krausz, Kristopher W. Idle, Jeffrey R. Gonzalez, Frank J. TI The metabolomics of (+/-)-arecoline 1-oxide in the mouse and its formation by human flavin-containing monooxygenases SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE arecoline; metabolomics; flavin-containing monooxygenase; ultra-performance liquid chromatography; tandem mass spectrometry; coupled time-of-flight mass spectrometry ID CARBOXYLIC-ACID REDUCTASE; MASS-SPECTROMETRY; N-OXIDES; METABOLISM; ARECOLINE; ARECAIDINE; IONIZATION; OXIDATION; AMINES; HEALTH AB The alkaloid arecoline is a main constituent of areca nuts that are chewed by approximately 600 million persons worldwide. A principal metabolite of arecoline is arecoline 1-oxide whose metabolism has been poorly studied. To redress this, synthetic (+/-)-arecoline 1-oxide was administered to mice (20 mg/kg p.o.) and a metabolomic study performed on 0-12 h urine using ultra-performance liquid chromatography-coupled time-of-flight mass spectrometry (UPLC-TOFMS) with multivariate data analysis. A total of 16 mass/retention time pairs yielded 13 metabolites of (+/-)-arecoline 1-oxide, most of them novel. identity of metabolites was confirmed by tandem mass spectrometry. The principal pathways of metabolism of ()arecoline 1-oxide were mercapturic acid formation, with catabolism to mercaptan and methylmercaptan metabolites, apparent C=C double-bond reduction, carboxylic acid reduction to the aldehyde (a novel pathway in mammals), N-oxide reduction, and de-esterification. Relative percentages of metabolites were determined directly from the metabolomic data. Approximately, 50% of the urinary metabolites corresponded to unchanged ()-arecoline 1-oxide, 25% to other N-oxide metabolites, while approximately, 30% corresponded to mercapturic acids or their metabolites. Many metabolites, principally mercapturic acids and their derivatives, were excreted as diastereomers that could be resolved by UPLC-TOFMS. Arecoline was converted to arecoline 1-oxide in vitro by human flavin-containing monooxygenases FMO1 (K-M: 13.6 +/- 4.9 mu M; V-MAX: 0.114 +/- 0.01 nmol min(-1) mu g(-1) protein) and FMO3 (K-M: 44.5 +/- 8.0 mu M; V-MAX: 0.014 +/- 0.001 nmol min(-1) mu g(-1) protein), but not by FMO5 or any of 11 human cytochromes P450. This report underscores the power of metabolomics in drug metabolite mining. (c) 2006 Published by Elsevier Inc. C1 NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Assam Univ, Dept Life Sci, Assam 788011, India. Charles Univ Prague, Fac Med 1, Inst Pharmacol, Prague 12800 2, Czech Republic. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bldg 37,Room 3106, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov OI Idle, Jeff/0000-0002-6143-1520 FU Intramural NIH HHS NR 26 TC 32 Z9 36 U1 1 U2 8 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 2007 VL 73 IS 4 BP 561 EP 573 DI 10.1016/j.bcp.2006.10.017 PG 13 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 134BQ UT WOS:000244058000010 PM 17123469 ER PT J AU Li, H Sun, Y Zhan, M AF Li, Huai Sun, Yu Zhan, Ming TI The discovery of transcriptional modules by a two-stage matrix decomposition approach SO BIOINFORMATICS LA English DT Article ID INDEPENDENT COMPONENT ANALYSIS; GENE-EXPRESSION DATA; BLIND SOURCE SEPARATION; MICROARRAY DATA; FACTORIZATION; NETWORK; RECONSTRUCTION; IDENTIFICATION; ANNOTATION; ALGORITHMS AB Motivation: We address the problem of identifying gene transcriptional modules from gene expression data by proposing a new approach. Genes mostly interact with each other to form transcriptional modules for context-specific cellular activities or functions. Unraveling such transcriptional modules is important for understanding biological network, deciphering regulatory mechanisms and identifying biomarkers. Method: The proposed algorithm is based on two-stage matrix decomposition. We first model microarray data as non-linear mixtures and adopt the non-linear independent component analysis to reduce the non-linear distortion and separate the data into independent latent components. We then apply the probabilistic sparse matrix decomposition approach to model the 'hidden' expression profiles of genes across the independent latent components as linear weighted combinations of a small number of transcriptional regulator profiles. Finally, we propose a general scheme for identifying gene modules from the outcomes of the matrix decomposition. Results: The proposed algorithm partitions genes into non-mutually exclusive transcriptional modules, independent from expression profile similarity measurement. The modules contain genes with not only similar but different expression patterns, and show the highest enrichment of biological functions in comparison with those by other methods. The usefulness of the algorithm was validated by a yeast microarray data analysis. Availability: The software is available upon request to the authors. Contact: zhanmi@mail.nih.gov C1 NIA, Bioinformat Unit, Branch Res Resources, Baltimore, MD 21224 USA. RP Zhan, M (reprint author), NIA, Bioinformat Unit, Branch Res Resources, Baltimore, MD 21224 USA. EM zhanmi@mail.nih.gov FU Intramural NIH HHS NR 34 TC 19 Z9 19 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 1367-4803 J9 BIOINFORMATICS JI Bioinformatics PD FEB 15 PY 2007 VL 23 IS 4 BP 473 EP 479 DI 10.1093/bioinformatics/btl640 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Computer Science, Interdisciplinary Applications; Mathematical & Computational Biology; Statistics & Probability SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Computer Science; Mathematical & Computational Biology; Mathematics GA 136YE UT WOS:000244259200011 PM 17189296 ER PT J AU Vitiello, B Wagner, A AF Vitiello, Benedetto Wagner, Ann TI The rapidly expanding field of autism research SO BIOLOGICAL PSYCHIATRY LA English DT Editorial Material ID RISPERIDONE C1 NIMH, Child & Adolescent Treatment & Prevent Intervent, Bethesda, MD 20892 USA. RP Vitiello, B (reprint author), NIMH, Child & Adolescent Treatment & Prevent Intervent, 6001 Execut Blvd,Room 7147,MSC 9633, Bethesda, MD 20892 USA. EM bvitiell@mail.nih.gov NR 23 TC 2 Z9 3 U1 7 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 2007 VL 61 IS 4 BP 427 EP 428 DI 10.1016/j.biopsych.2006.11.024 PG 2 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 138DX UT WOS:000244344400001 PM 17276745 ER PT J AU Wagner, A Lecavalier, L Arnold, LE Aman, MG Scahill, L Stigler, KA Johnson, CR McDougle, CJ Vitiello, B AF Wagner, Ann Lecavalier, Luc Arnold, L. Eugene Aman, Michael G. Scahill, Lawrence Stigler, Kimberly A. Johnson, Cynthia R. McDougle, Christopher J. Vitiello, Benedetto TI Developmental disabilities modification of the Children's Global Assessment Scale SO BIOLOGICAL PSYCHIATRY LA English DT Article DE assessment; autism; children; functioning; pervasive developmental disorder; psychometrics ID INTENSIVE BEHAVIORAL TREATMENT; OBSESSIVE-COMPULSIVE SCALE; ADAPTIVE-BEHAVIOR; YOUNG-CHILDREN; AUTISM; DISORDERS; INDIVIDUALS; CHECKLIST; DOMAINS; TRIALS AB Background Interventions for pervasive developmental disorders (PDD) aim to alleviate symptoms and improve functioning. To measure global functioning in treatment studies, the Children's Global Assessment Scale was modified and psychometric properties of the revised version (DD-CGAS) were assessed in children with PDD. Methods: Developmental disabilities-relevant descriptors were developed for the DD-CGAS, and administration procedures were established to enhance rater consistency, Ratings of clinical case vignettes were used to assess inter-rater reliability and temporal stability. Validity was assessed by correlating the DD-CGAS with measures of functioning and symptoms in 83 youngsters with PDD. Sensitivity to change was assessed by comparing change from baseline to post-treatment with change on the Aberrant Behavior Checklist-Irritability and Clinical Global Impressions-Improvement subscale scores in a subset of 14 children. Results: Inter-rater reliability (intraclass correlation coefficient [ICC] = .79) and temporal stability (average ICC = .86) were excellent. The DD-CGAS scores correlated with measures of functioning and symptoms with moderate to large effect sizes. Changes on the DD-CGAS correlated with changes on the Aberrant Behavior Checklist-I (r = -.71) and Global Impressions Scale-I (r = -.52). The pre-post DD-CGAS change bad an effect size of .72. Conclusions. The DD-CGAS is a reliable instrument with apparent convergent validity,for measuring global functioning of children with PDD in treatment studies. C1 NIMH, NIH, Bethesda, MD 20892 USA. Ohio State Univ, Columbus, OH 43210 USA. Yale Univ, New Haven, CT 06520 USA. Indiana Univ, Sch Med, Indianapolis, IN 46202 USA. Univ Pittsburgh, Sch Med, Pittsburgh, PA 15260 USA. RP Wagner, A (reprint author), NIMH, NIH, Room 6184,6001 Executive Blvd, Bethesda, MD 20892 USA. EM awagner@mail.nih.gov OI Scahill, Lawrence/0000-0001-5073-1707 FU NIMH NIH HHS [U10 MH066766-03, U10 MH066764, U10 MH066764-01, U10 MH066764-02, U10 MH066764-03, U10 MH066764-04, U10 MH066764-05, U10 MH066766, U10 MH066766-01, U10 MH066766-02, U10 MH066766-02S1, U10 MH066766-04, U10 MH066766-05, U10 MH066768, U10 MH066768-01, U10 MH066768-02, U10 MH066768-03, U10 MH066768-04, U10 MH066768-05, U10MH66764, U10MH66766, U10MH66768] NR 35 TC 22 Z9 23 U1 3 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 2007 VL 61 IS 4 BP 504 EP 511 DI 10.1016/j.biopsych.2007.01.001 PG 8 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 138DX UT WOS:000244344400012 PM 17276748 ER PT J AU Posey, DJ Aman, MG McCracken, JT Scahill, L Tierney, E Arnold, LE Vitiello, B Chuang, SZ Davies, M Ramadan, Y Witwer, AN Swiezy, NB Cronin, P Shah, B Carroll, DH Young, C Wheeler, C McDougle, CJ AF Posey, David J. Aman, Michael G. McCracken, James T. Scahill, Lawrence Tierney, Elaine Arnold, L. Eugene Vitiello, Benedetto Chuang, Shirley Z. Davies, Mark Ramadan, Yaser Witwer, Andrea N. Swiezy, Naomi B. Cronin, Pegeen Shah, Bhavik Carroll, Deirdre H. Young, Christopher Wheeler, Courtney McDougle, Christopher J. TI Positive effects of methylphenidate on inattention and hyperactivity in pervasive developmental disorders: An analysis of secondary measures SO BIOLOGICAL PSYCHIATRY LA English DT Article DE Asperger's disorder; autism; hyperactivity; inattention; methylphenidate; pervasive developmental disorder; stimulants ID ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; ABERRANT BEHAVIOR CHECKLIST; OBSESSIVE-COMPULSIVE SCALE; AUTISTIC DISORDER; DOUBLE-BLIND; SCHIZOPHRENIC CHILDREN; STIMULANT-DRUGS; CROSSOVER TRIAL; RISPERIDONE; SYMPTOMS AB Background: Methylphenidate has been shown elsewhere to improve hyperactivity in about half of treated children who have pervasive developmental disorders (PDD) and significant hyperactive-inattentive symptoms. We present secondary analyses to better define the scope of effects of methylphenidate on symptoms that define attention-deficit/hyperactivity disorder (ADHD) and oppositional dqfiant disorder (ODD), as well as the core autistic symptom domain qf repetitive behavior. Methods: Sixty-six children (mean age 7.5 y) with autistic disorder, Asperger's disorder, and PDD not otherwise specified, were randomized to varying sequences of placebo and three different doses of methylphenidate during a 4-week blinded, crossover study. Methylphenidate doses used approximated .125, .25, and .5 mg/kg per dose, twice daily, with an additional half-dose in the late afternoon. Outcome measures included the Swanson, Nolan, and Pelham Questionnaire revised for DSM-IV(ADHD and ODD scales) and the Children's Yale-Brown Obsessive Compulsive Scales for PDD. Results: Methylphenidate was associated with significant improvement that was most evident at the .25- and .5-mg/kg doses. Hyperactivity and impulsivity improved more than inattention. There were not significant effects on ODD or stereotyped and repetitive behavior. Conclusions: Convergent evidence from different assessments and raters confirms methyliobenidate's efficacy in relieving ADHD symptoms in some children with PDD. Optimal dose analyses suggested significant interindividual variability in close response. C1 Indiana Univ, Dept Psychiat, Bloomington, IN 47405 USA. Ohio State Univ, UCEDD, Nisonger Ctr, Columbus, OH 43210 USA. Univ Calif Los Angeles, Los Angeles, CA 90024 USA. Yale Univ, Child Study Ctr, New Haven, CT 06520 USA. Johns Hopkins Univ, Kennedy Krieger Inst, Baltimore, MD 21218 USA. Natl Inst Mental Hlth, Bethesda, MD USA. Columbia Univ, New York, NY 10027 USA. RP Posey, DJ (reprint author), Riley Hosp Children, Room 430,702 Barnhill Dr, Indianapolis, IN 46202 USA. EM dposey@iupui.edu OI Witwer, Andrea/0000-0002-1268-4222; Scahill, Lawrence/0000-0001-5073-1707 FU NCRR NIH HHS [M01 RR-06022, M01 RR-00750, M01 RR-00034, M01 RR-00052]; NIMH NIH HHS [N01 MH-70009, N01 MH-70001, MH-01805, MH-68627, N01 MH 80011, N01 MH-70070] NR 35 TC 53 Z9 55 U1 0 U2 10 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 2007 VL 61 IS 4 BP 538 EP 544 DI 10.1016/j.biopsych.2006.09.028 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 138DX UT WOS:000244344400015 PM 17276750 ER PT J AU Anderson, GM Scahill, L McCracken, JT McDougle, CJ Aman, MG Tierney, E Arnold, LE Martin, A Katsovich, L Posey, DJ Shah, B Vitiello, B AF Anderson, George M. Scahill, Lawrence McCracken, James T. McDougle, Christopher J. Aman, Michael G. Tierney, Elaine Arnold, L. Eugene Martin, Andres Katsovich, Liliya Posey, David J. Shah, Bhavik Vitiello, Benedetto TI Effects of short- and long-term risperidone treatment on prolactin levels in children with autism SO BIOLOGICAL PSYCHIATRY LA English DT Article; Proceedings Paper CT 51st Annual Meeting of the American-Academy-of-Child-and-Adolescent-Psychiatry CY OCT 19-24, 2004 CL Washington, DC SP Amer Acad Child & Adolescent Psychiat DE adolescents; autism; children; DRD2; hyperprolactinemia; prolactin ID ATYPICAL ANTIPSYCHOTIC AGENTS; D2 RECEPTOR GENE; SCHIZOPHRENIC-PATIENTS; INDUCED HYPERPROLACTINEMIA; DISRUPTIVE BEHAVIORS; ELEVATED PROLACTIN; CLINICAL-TRIALS; DRD2 GENE; ADOLESCENTS; DISORDER AB Background: The effects of short- and long-term risperidone treatment on serum prolactin were assessed in children and adolescents with autism. Methods: Patients with autism (N = 101, 5-17 years of age) were randomized to an 8-week trial of risperidone or placebo and 63 then took part in a 4-month open-label follow-up phase. Serum samples were obtained at Baseline and Week-8 (N = 78), and at 6-month (N = 43) and 22-month (N = 30) follow-up. Serum prolactin was determined by immunoradiometric assay; dopamine type-2 receptor (DRD2) polymorphisms were genotyped. Results: Baseline prolactin levels were similar in the risperidone (N = 42) and placebo (N = 36) groups (9.3 +/- 7.5 and 9.3 +/- 7.6 ng/ml, respectively). After 8 weeks of risperidone, prolactin increased to 39.0 +/- 19.2 ng/ml, compared with 10.1 +/- 8.8 ng/ml for placebo (p < .0001). Prolactin levels were also significantly increased at 6 months (32.4 +/- 17.8 ng/ml; N = 43, p < .0001) and at 22 months (N = 30, 25.3 +/- 15.6 ng/ml, p < .0001). Prolactin levels were not associated with adverse effects and DRD2 alleles (Taq1A, - 141C Ins/Del, C957T) did not significantly influence baseline levels or risperidone-induced increases in prolactin. Conclusions: Risperidone treatment was associated with two- to four-fold mean increases in serum prolactin in children with autism. Although risperidone-induced increases tended to diminish with time, further research on the consequences of long-term prolactin elevations in children and adolescents is needed. C1 Yale Univ, Ctr Child Study, New Haven, CT 06520 USA. Univ Calif Los Angeles, Dept Psychiat, Los Angeles, CA 90024 USA. Indiana Univ, Dept Psychiat, Bloomington, IN 47405 USA. Ohio State Univ, Dept Psychiat, Columbus, OH 43210 USA. Kennedy Krieger Inst, Autism Metab Res Program, Baltimore, MD USA. NIMH, Child & Adolescent Treatment & Prevent Intervent, Bethesda, MD 20892 USA. RP Anderson, GM (reprint author), Yale Univ, Ctr Child Study, 230 S Frontage Rd, New Haven, CT 06520 USA. EM anderson@yale.edu OI Scahill, Lawrence/0000-0001-5073-1707 FU NCRR NIH HHS [M01 RR-00034, M01 RR-00052, M01 RR-00750, M01 RR-06022]; NIMH NIH HHS [N01 MH-70001, MH-01805, N01 MH-70009, N01 MH-70010, N01 MH-80011] NR 44 TC 72 Z9 74 U1 3 U2 9 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 15 PY 2007 VL 61 IS 4 BP 545 EP 550 DI 10.1016/j.biopsych.2006.02.032 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 138DX UT WOS:000244344400016 PM 16730335 ER PT J AU Mente, NR Wiemer, AJ Neighbors, JD Beutler, JA Hohl, RJ Wiemer, DF AF Mente, Nolan R. Wiemer, Andrew J. Neighbors, Jeffrey D. Beutler, John A. Hohl, Raymond J. Wiemer, David F. TI Total synthesis of (R,R,R)- and (S,S,S)-schweinfurthin F: Differences of bioactivity in the enantiomeric series SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article ID MACARANGA-SCHWEINFURTHII; STILBENE AB Total synthesis of the (R,R,R)- and (S,S,S)-enantiomers of the natural product schweinfurthin F has been completed. Comparisons of spectral data and optical rotations with those reported for the natural product, as well as a variety of bioassay data, allow assignment of the natural material as the (R,R,R)-isomer. (c) 2006 Elsevier Ltd. All rights reserved. C1 Univ Iowa, Dept Chem, Iowa City, IA 52242 USA. Univ Iowa, Mol & Cellular Biol Program, Iowa City, IA 52242 USA. Univ Iowa, Dept Pharmacol, Iowa City, IA 52242 USA. Univ Iowa, Dept Internal Med, Iowa City, IA 52242 USA. NCI, Mol targets Dev Program, Canc Res Ctr, Frederick, MD 21702 USA. RP Wiemer, DF (reprint author), Univ Iowa, Dept Chem, Iowa City, IA 52242 USA. EM david-wiemer@uiowa.edu RI Wiemer, Andrew/C-2257-2009; Beutler, John/B-1141-2009 OI Wiemer, Andrew/0000-0002-3029-1780; Beutler, John/0000-0002-4646-1924 FU Intramural NIH HHS; NCI NIH HHS [2 T32 CA79445]; NIGMS NIH HHS [2 T32 GM067795, T32 GM067795] NR 17 TC 29 Z9 29 U1 0 U2 8 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 2007 VL 17 IS 4 BP 911 EP 915 DI 10.1016/j.bmcl.2006.11.096 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 142GF UT WOS:000244636700010 PM 17236766 ER PT J AU Nakayama, T Mutsuga, N Tosato, G AF Nakayama, Takayuki Mutsuga, Noriko Tosato, Giovanna TI FGF2 posttranscriptionally down-regulates expression of SDF1 in bone marrow stromal cells through FGFR1 IIIc SO BLOOD LA English DT Article ID FIBROBLAST-GROWTH-FACTOR; HEMATOPOIETIC PROGENITOR CELLS; CHEMOKINE RECEPTOR CXCR4; MESSENGER-RNA STABILITY; STIMULATING FACTOR; FACTOR-I; MOLECULAR-CLONING; G-CSF; B-LYMPHOPOIESIS; FACTOR FAMILY AB The chemokine stromal cell-derived factor-1 (SDF-1) is constitutively expressed by bone marrow stromal cells and plays key roles in hematopolesis. Fibroblast growth factor 2 (FGF2), a member of the FGF family that plays important roles in developmental morphogenic processes, is abnormally elevated in the bone marrow from patients with clonal myeloid disorders and other disorders where normal hematopoiesis is impaired. Here, we report that FGF2 reduces SDF-1 secretion and protein content in bone marrow stromal cells. By inhibiting SDF-1 production, FGF2 compromises stromal cell support of hematopoietic progenitor cells. Reverse-transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that bone marrow stromal cells express 5 FGF receptors (FGFRs) among the 7 known FGFR subtypes. Blocking experiments identified FGFR1 IIIc as the receptor mediating FGF2 inhibition of SDF-1 expression in bone marrow stromal cells. Analysis of the mechanisms underlying FGF2 inhibition of SDF-1 production in bone marrow stromal cells revealed that FGF2 reduces the SDF-1 mRNA content by post-transcriptionally accelerating SDF-1 mRNA decay. Thus, we identify FGF2 as an inhibitor of SDF-1 production in bone marrow stromal cells and a regulator of stromal cell supportive functions for hematopoietic progenitor cells. C1 NCI, Basic Res Lab, Ctr Canc Res, Bethesda, MD 20892 USA. NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. RP Tosato, G (reprint author), NCI, Basic Res Lab, Ctr Canc Res, Bethesda, MD 20892 USA. EM tosatog@mail.nih.gov FU Intramural NIH HHS NR 84 TC 21 Z9 23 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 15 PY 2007 VL 109 IS 4 BP 1363 EP 1372 DI 10.1182/blood-2006-06-028217 PG 10 WC Hematology SC Hematology GA 136JW UT WOS:000244219400010 PM 17077327 ER PT J AU Lancet, JE Gojo, I Gotlib, J Feldman, EJ Greer, J Liesveld, JL Bruzek, LM Morris, L Park, Y Adjei, AA Kaufmann, SH Garrett-Mayer, E Greenberg, PL Wright, JJ Karp, JE AF Lancet, Jeffrey E. Gojo, Ivana Gotlib, Jason Feldman, Eric J. Greer, Jacqueline Liesveld, Jane L. Bruzek, Laura M. Morris, Lawrence Park, Youn Adjei, Alex A. Kaufmann, Scott H. Garrett-Mayer, Elizabeth Greenberg, Peter L. Wright, John J. Karp, Judith E. TI A phase 2 study of the farnesyltransferase inhibitor tipifarnib in poor-risk and elderly patients with previously untreated acute myelogenous leukemia SO BLOOD LA English DT Article ID ACUTE MYELOID-LEUKEMIA; FARNESYL TRANSFERASE INHIBITOR; SOUTHWEST-ONCOLOGY-GROUP; COLONY-STIMULATING FACTOR; MYELODYSPLASTIC SYNDROME MDS; TUMOR-CELL LINES; EUROPEAN ORGANIZATION; POSTREMISSION THERAPY; DOSE CYTARABINE; OLDER PATIENTS AB Outcomes for older adults with acute myelogenous leukemia (AML) are poor due to both disease and host-related factors. In this phase 2 study, we tested the oral farnesyltransferase inhibitor tipifarnib in 158 older adults with previously untreated, poor-risk AML. The median age was 74 years, and a majority of patients had antecedent myelodysplastic syndrome. Complete remission (CR) was achieved in 22 patients (14%); partial remission or hematologic improvement occurred in 15 patients, for an overall response rate of 23%. The median duration of CR was 7.3 months and the median survival of complete responders was 18 months. Adverse karyotype, age 75 years or older, and poor performance status correlated negatively with survival. Early death in the absence of progressive disease was rare, and drug-related nonhematologic serious adverse events were observed in 74 patients (47%). Inhibition of farnesylation of the surrogate protein HDJ-2 occurred in the large majority of marrow samples tested. Baseline levels of phosphorylated mitogen-activated protein kinase and AKT did not correlate with clinical response. Tipifarnib is active and well tolerated in older adults with poor-risk AML and may impart a survival advantage in those patients who experience a clinical response. C1 Univ S Florida, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. Univ Maryland, Greenebaum Canc Ctr, Baltimore, MD 21201 USA. Stanford Canc Ctr, Div Hematol, Stanford, CA USA. Cornell Univ, Weill Med Coll, New York, NY 10021 USA. Univ Rochester, James P Wilmot Canc Ctr, Rochester, NY USA. Blood & Marrow Transplant Grp, Atlanta, GA USA. Mayo Clin, Rochester, MN USA. Johnson & Johnson Pharmaceut Res & Dev, Raritan, NJ USA. NCI, IDB CTEP, Bethesda, MD 20892 USA. Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD USA. RP Lancet, JE (reprint author), Univ S Florida, H Lee Moffitt Canc Ctr & Res Inst, Tampa, FL USA. EM lancetje@moffitt.org FU NCI NIH HHS [U01 CA70095, U01 CA070095, U01 CA69854] NR 44 TC 127 Z9 134 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 15 PY 2007 VL 109 IS 4 BP 1387 EP 1394 DI 10.1182/blood-2006-04-014357 PG 8 WC Hematology SC Hematology GA 136JW UT WOS:000244219400013 PM 17082323 ER PT J AU Chintala, S Tan, J Gautam, R Rusiniak, ME Guo, XL Li, W Gahl, WA Huizing, M Spritz, RA Hutton, S Novak, EK Swank, RT AF Chintala, Sreenivasulu Tan, Jian Gautam, Rashi Rusiniak, Michael E. Guo, Xiaoli Li, Wei Gahl, William A. Huizing, Marjan Spritz, Richard A. Hutton, Saunie Novak, Edward K. Swank, Richard T. TI The Slc35d3 gene, encoding an orphan nucleotide sugar transporter, regulates platelet-dense granules SO BLOOD LA English DT Article ID HERMANSKY-PUDLAK-SYNDROME; LYSOSOME-RELATED ORGANELLES; STORAGE POOL DEFICIENCY; GRISCELLI-SYNDROME; PUDIAK-SYNDROME; MOUSE; ACIDOCALCISOMES; IDENTIFICATION; BIOGENESIS; MUTATIONS AB Platelet dense granules are lysosome-related organelles which contain high concentrations of several biologically important low-molecular-weight molecules. These include calcium, serotonin, adenine nucleotides, pyrophosphate, and polyphosphate, which are necessary for normal blood hemostasis. The synthesis of dense granules and other lysosome-related organelles is defective in inherited diseases such as Hermansky-Pudiak syndrome (HPS) and Chediak-Higashi syndrome (CHS). HIPS and CHS mutations in 8 human and at least 16 murine genes have been identified. Previous studies produced contradictory findings for the function of the murine ashen (Rab27a) gene in platelet-dense granules. We have used a positional cloning approach with one line of ashen mutants to establish that a new mutation in a second gene, Slc35d3, on mouse chromosome 10 is the basis of this discrepancy. The platelet-dense granule defect is rescued in BAC transgenic mice containing the normal Slc35d3 gene. Thus, Slc35d3, an orphan member of a nucleotide sugar transporter family, specifically regulates the contents of platelet-dense granules. Unlike HIPS or CHS genes, it has no apparent effect on other lysosome-related organelles such as melanosomes or lysosomes. The ash-Roswell mouse mutant is an appropriate model for human congenital-isolated delta-storage pool deficiency. C1 Roswell Pk Canc Inst, Dept Mol & Cellular Biol, Buffalo, NY 14263 USA. Chinese Acad Sci, Inst Genet & Dev Biol, Key Lab Mol & Dev Biol, Beijing, Peoples R China. NIH, Sect Human Biochem Genet, Bethesda, MD 20892 USA. Univ Colorado, Hlth Sci Ctr, Human Med Genet Program, Denver, CO 80202 USA. RP Swank, RT (reprint author), Roswell Pk Canc Inst, Dept Mol & Cellular Biol, Elm & Carlton Sts, Buffalo, NY 14263 USA. EM richard.swank@roswellpark.org RI Guo, Xiaoli/O-3906-2014 FU NCI NIH HHS [P30 CA016056]; NEI NIH HHS [R01 EY012104, EY-12104, R01 EY015626, EY015626]; NHLBI NIH HHS [HL-31698, R01 HL031698, HL-51480, R01 HL051480]; NIAMS NIH HHS [R01 AR039892, AR39892] NR 37 TC 18 Z9 20 U1 2 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 2007 VL 109 IS 4 BP 1533 EP 1540 DI 10.1182/blood-2006-08-040196 PG 8 WC Hematology SC Hematology GA 136JW UT WOS:000244219400031 PM 17062724 ER PT J AU Wright, ME Chang, SC Schatzkin, A Albanes, D Kipnis, V Mouw, T Hurwitz, P Hollenbeck, A Leitzmann, MF AF Wright, Margaret E. Chang, Shih-Chen Schatzkin, Arthur Albanes, Demetrius Kipnis, Victor Mouw, Traci Hurwitz, Paul Hollenbeck, Albert Leitzmann, Michael F. TI Prospective study of adiposity and weight change in relation to prostate cancer incidence and mortality SO CANCER LA English DT Article DE adiposity; body mass index; cohort study; prostate cancer; weight change ID BODY-MASS INDEX; PHYSICAL-ACTIVITY; NORWEGIAN MEN; UNITED-STATES; RISK-FACTORS; FOLLOW-UP; US ADULTS; OBESITY; COHORT; HEALTH AB BACKGROUND. Adiposity has been linked inconsistently with prostate cancer, and few Studies have evaluated whether such associations vary by disease aggressiveness. METHODS. The authors prospectively examined body mass index (BMI) and adult weight change in relation to prostate cancer incidence and mortality in 287,760 men ages 50 years to 71 years at enrollment (1995-1996) in the National Institutes of Health-AARP Diet and Health Study. At baseline, participants completed questionnaires regarding height, weight, and cancer screening practices, including digital rectal examinations and prostate-specific antigen tests. Cox regression analysis was used to calculate relative risks (RR) and 95% confidence intervals (95% CIs). RESULTS. in total, 9986 incident prostate cancers were identified during 5 years of follow-up, and 173 prostate cancer deaths were ascertained during 6 years of follow-up. In multivariate models, higher baseline BMI was associated with significantly reduced total prostate cancer incidence, largely because of the relationship with localized tumors (for men in the highest BMI category [>= 40 kg/m(2)] vs men in the lowest BMI category [< 25 kg/m(2)]: RR, 0.67; 95% CI, 0.50-0.89;P=.0006). Conversely, a significant elevation in prostate cancer mortality was observed at higher BMI levels (BMI < 25 kg/m(2) : RR, 1.0 [referent group]; BMI 25-29.9 kg/m(2) : RR, 1.25; 95% CI, 0.871.80; BMI 30-34. 9 kg/m(2) : RR, 1.46; 95% CI, 0.92-2.33; and BMI >= 35 kg/m(2) : RR, 2.12; 95% CI, 1.08-4.15; P=.02). Adult weight gain from age 18 years to baseline also was associated positively with fatal prostate cancer (P=.009), but not with incident disease. CONCLUSIONS. Although adiposity was not related positively to prostate cancer incidence, higher BMI and adult weight gain increased the risk of dying from prostate cancer. C1 NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Div Canc Prevent, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Westat Corp, Rockville, MD USA. AARP, Washington, DC USA. RP Wright, ME (reprint author), Univ Illinois, Dept Pathol, MC847,840 S Wood St,Room 130 CSN, Chicago, IL 60612 USA. EM mewright@uic.edu RI Albanes, Demetrius/B-9749-2015 FU Intramural NIH HHS NR 47 TC 175 Z9 181 U1 1 U2 10 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0008-543X J9 CANCER JI Cancer PD FEB 15 PY 2007 VL 109 IS 4 BP 675 EP 684 DI 10.1002/cncr.22443 PG 10 WC Oncology SC Oncology GA 135EJ UT WOS:000244136600005 PM 17211863 ER PT J AU Das, S Hahn, Y Nagata, S Willingham, MC Bera, TK Lee, B Pastan, I AF Das, Sudipto Hahn, Yoonsoo Nagata, Satoshi Willingham, Mark C. Bera, Tapan K. Lee, Byungkook Pastan, Ira TI NGEP, a prostate-specific plasma membrane protein that promotes the association of LNCaP cells SO CANCER RESEARCH LA English DT Article ID RADICAL PROSTATECTOMY; CANCER; COMMUNICATION; EXPRESSION; FAMILY AB NGEP is a prostate-specific gene identified by analysis of expressed sequence tag databases. RNA analysis revealed two spliced forms of NGEP mRNA: a short form encoding a soluble protein (NGEP-S) and a long form encoding a polytopic membrane protein (NGEP-L). Transient expression of myc epitope-tagged NGEP-L showed that it was localized to the plasma membrane. We have now produced a specific antibody to the COOH terminus of NGEP-L and showed that it detects an similar to 100-kDa protein in extracts of normal prostate and prostate cancers that contain high levels of NGEP mRNA. The antibody detects a protein that is highly expressed on the apical and the lateral surfaces of normal prostate and prostate cancer cells by immunohistochemistry. The antibody does not detect a protein in the prostate cancer cell line LNCaP, which has very low NGEP mRNA levels. To study NGEP function, two stable LNCaP cell lines were prepared by transfection with NGEP-L and shown to contain similar amounts of NGEP-L protein as human prostate. Confocal immunofluorescence showed that NGEP-L is present on the plasma membrane of the transfected LNCaP cells and is highly concentrated at cell:cell contact regions. Furthermore, as the cell density increased, the cells formed large aggregates. A specific RNA interference that lowered NGEP-L levels prevented formation of cell aggregates. Our results suggest that NGEP-L has a role in promoting cell contact-dependent interactions of LNCaP prostate cancer cells and also that NGEP is a promising immunotherapy target for prostate cancer. C1 NCI, Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Wake Forest Univ, Sch Med, Dept Pathol, Winston Salem, NC 27109 USA. RP Pastan, I (reprint author), NCI, Mol Biol Lab, Ctr Canc Res, NIH, 37 Convent Dr,Room 5106, Bethesda, MD 20892 USA. EM pastani@mail.nih.gov FU Intramural NIH HHS NR 17 TC 28 Z9 31 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 15 PY 2007 VL 67 IS 4 BP 1594 EP 1601 DI 10.1158/0008-5472.CAN-06-2673 PG 8 WC Oncology SC Oncology GA 137JP UT WOS:000244289200025 PM 17308099 ER PT J AU Lu, CH Bonome, T Li, Y Kamat, AA Han, LY Schmandt, R Coleman, RL Gershenson, DM Jaffe, RB Birrer, MJ Sood, AK AF Lu, Chunhula Bonome, Tomas Li, Yang Kamat, Aparna A. Han, Liz Y. Schmandt, Rosemarie Coleman, Robert L. Gershenson, David M. Jaffe, Robert B. Birrer, Michael J. Sood, Anil K. TI Gene alterations identified by expression profiling in tumor-associated endothelial cells from invasive ovarian carcinoma SO CANCER RESEARCH LA English DT Article ID FOCAL ADHESION KINASE; GROWTH-FACTOR; BREAST-CANCER; ANGIOGENESIS; EZH2; PROLIFERATION; MIGRATION; PATHWAYS; THERAPY; MODEL AB Therapeutic strategies based on antiangiogenic approaches are beginning to show great promise in clinical studies. However, full realization of these approaches requires identification of key differences in gene expression between endothelial cells from tumors versus their normal counterparts. Here, we examined gene expression differences in purified endothelial cells from 10 invasive epithelial ovarian cancers and 5 normal ovaries using Affymetrix U133 Plus 2.0 microarrays. More than 400 differentially expressed genes were identified in tumor-associated endothelial cells. We selected and validated 23 genes that were overexpressed by 3.6- to 168-fold using real-time reverse transcription-PCR and/or immunohistochemistry. Among these, the polycomb group protein enhancer of Zeste homologue 2 (EZH2), the Notch ligand Jagged1, and PTK2 were elevated 3- to 4.3-fold in tumor-associated endothelial cells. Silencing these genes individually with small interfering RNA blocked endothelial cell migration and tube formation in vitro. The present study shows that tumor and normal endothelium differ at the molecular level, which may have significant implications for the development of antiangiogenic therapies. C1 Univ Texas, MD Anderson Canc Ctr, Dept Gynecol Oncol, Houston, TX 77030 USA. Univ Texas, MD Anderson Canc Ctr, Dept Canc Biol, Houston, TX 77030 USA. NCI, Cell & Canc Biol Branch, Bethesda, MD 20892 USA. Univ Calif San Francisco, Ctr Reprod Sci, San Francisco, CA 94143 USA. RP Sood, AK (reprint author), Univ Texas, MD Anderson Canc Ctr, Dept Gynecol Oncol, Unit 1362, Houston, TX 77030 USA. EM asood@mdanderson.org FU NCI NIH HHS [CA 110793-01, CA 109298-01, P50 CA 083639] NR 50 TC 96 Z9 103 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 15 PY 2007 VL 67 IS 4 BP 1757 EP 1768 DI 10.1158/0008-5472.CAN-06-3700 PG 12 WC Oncology SC Oncology GA 137JP UT WOS:000244289200044 PM 17308118 ER PT J AU Oh, WJ Rishi, V Orosz, A Gerdes, NJ Vinson, C AF Oh, Won Jun Rishi, Vikas Orosz, Andras Gerdes, Michael J. Vinson, Charles TI Inhibition of CCAAT/enhancer binding protein family DNA binding in mouse epidermis prevents and regresses papillomas SO CANCER RESEARCH LA English DT Article ID TRANSCRIPTION FACTORS C/EBP; GENE-EXPRESSION; ADIPOCYTE DIFFERENTIATION; IN-VIVO; SKIN TUMORIGENESIS; MAMMALIAN-CELLS; NUCLEAR FACTOR; HUMAN CANCER; COILED-COIL; BETA AB The CCAAT/enhancer binding proteins (C/EBP) are a family of B-ZIP DNA binding proteins that act as transcription factors to regulate growth and differentiation of many cell types, including keratinocytes. To examine the consequences of inhibiting the C/EBP family of transcription factors in skin, we generated transgenic mice that use the tetracycline system to conditionally express A-C/EBP, a dominant negative that inhibits the DNA binding of C/EBP family members. We expressed A-C/EBP in the basal layer of the skin epidermis during a two-step skin carcinogenesis protocol. A-C/EBP expression caused hyperplasia of the basal epidermis and increased apoptosis in the suprabasal epidermis. The mice developed fewer papillomas and had systemic hair loss. A-C/EBP expression caused C/FBPP protein to disappear whereas C/EBP alpha p53, Bax, and caspase-3 protein levels were dramatically up-regulated in the suprabasal layer. Primary keratinocytes recapitulate the A-C/EBP induction of cell growth and increase in p53 protein. A-C/EBP expression after papilloma development caused the papillomas to regress with an associated increase in apoptosis and up-regulation of p53 protein. Furthermore, A-C/EBP-expressing mice heterozygous for p53 were more susceptible to papilloma formation, suggesting that the suppression of papilloma formation has a p53-dependent mechanism. These results implicate DNA binding of C/EBP family members as a potential molecular therapeutic target. C1 NCI, Lab Metab, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. GE Global Res, New York, NY USA. RP Vinson, C (reprint author), NCI, Lab Metab, Canc Res Ctr, NIH, Bldg 37,Room 3128, Bethesda, MD 20892 USA. EM Vinsonc@dc37a.nci.nih.gov NR 45 TC 18 Z9 18 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 2007 VL 67 IS 4 BP 1867 EP 1876 DI 10.1158/0008-5472.CAN-06-2746 PG 10 WC Oncology SC Oncology GA 137JP UT WOS:000244289200056 PM 17308129 ER PT J AU Park, DM Li, J Okamoto, H Akeju, O Kim, SH Lubensky, I Vortmeyer, A Dambrosia, J Weil, RJ Oldfield, EH Park, JK Zhuang, ZP AF Park, Deric M. Li, Jie Okamoto, Hiroaki Akeju, Oluwaseun Kim, Stephanie H. Lubensky, Irina Vortmeyer, Alexander Dambrosia, James Weil, Robert J. Oldfield, Edward H. Park, John K. Zhuang, Zhengping TI N-CoR pathway targeting induces glioblastoma derived cancer stem cell differentiation SO CELL CYCLE LA English DT Article DE N-CoR; glioma; cancer stem cell; differentiation; retinoic acid ID RETINOIC ACID; IDENTIFICATION; RECEPTORS; REPRESSOR; DISEASE; PROTEIN; GLIOMAS AB Nuclear receptor corepressor (N-CoR) is a critical regulator of neural stem cell differ entiation. Nuclear localization of N-CoR is a feature of undifferentiated neural stem cells and cytoplasmic translocation of N-CoR leads to astrocytic differentiation. Comparative proteomic analysis of microdissected glioblastoma multiforme (GBM) specimens and matched normal glial tissue reveals increased expression of N-CoR in GBM. In GBM primary cell cultures, tumor cells with nuclear localization of N-CoR demonstrate an undifferentiated phenotype, but are subject to astroglial differentiation upon exposure to agents promoting phosphorylation of N-CoR and its subsequent translocation to the cytoplasm. Treatment of glioma cell lines with a combination of retinoic acid and low-dose okadaic acid decreases the corepressor effect of N-CoR and has a striking synergistic effect on growth inhibition. The identification of N-CoR in GBM provides insights into the tumorigenesis process and supports the development of differentiation-based therapeutic strategies. C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NINDS, Surg & Mol Neurooncol Unit, NIH, Bethesda, MD 20892 USA. RP Park, JK (reprint author), NINDS, Surg Neurol Branch, NIH, Bldg 10,Room 5D37, Bethesda, MD 20892 USA. EM parkjk@ninds.nih.gov; zhuangp@ninds.nih.gov RI Park, Deric/C-5675-2013 FU Intramural NIH HHS NR 20 TC 33 Z9 39 U1 1 U2 5 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD FEB 15 PY 2007 VL 6 IS 4 BP 467 EP 470 PG 4 WC Cell Biology SC Cell Biology GA 154GT UT WOS:000245495600016 PM 17312396 ER PT J AU Van Waes, C AF Van Waes, Carter TI Nuclear factor-kappa 13 in development, prevention, and therapy of cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID NF-KAPPA-B; SQUAMOUS-CELL CARCINOMA; PROTEASOME INHIBITOR BORTEZOMIB; PHASE-II TRIAL; PROINFLAMMATORY CYTOKINE EXPRESSION; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; ADVANCED SOLID TUMORS; BREAST-CANCER; HUMAN HEAD; CONSTITUTIVE ACTIVATION AB Nuclear factor-kappa B (NF-kappa B) is a signal transcription factor that has emerged as an important modulator of altered gene programs and malignant phenotype in development of cancer. Major carcinogens and oncogenic viruses induce NF-kappa B activation, and a variety of subsequent oncogenic events contribute to a progressive increase in constitutive NF-kappa B activation as an important common pathway in most forms of cancer. NF-kappa B target genes promote tumor cell proliferation, survival, migration, inflammation, and angiogenesis. Inhibition of NF-kappa B has been found to be an important mechanism of action of steroids, nonsteroidal anti-inflammatory drugs, and natural and synthetic compounds that show therapeutic and preventive activity. Newer agents targeting the proteasome, inhibitor-kappa B kinase, and other upstream kinases involved in NF-kappa B activation have shown anticancer activity in clinical or preclinical studies. C1 Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, Bethesda, MD 20892 USA. NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Van Waes, C (reprint author), Natl Inst Deafness & Other Commun Disorders, Head & Neck Surg Branch, CRC Room 4-2732,10 Ctr Dr, Bethesda, MD 20892 USA. EM vanwaesc@nidcd.nih.gov FU NIDCD NIH HHS [Z01-DC-00016] NR 99 TC 206 Z9 211 U1 1 U2 5 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2007 VL 13 IS 4 BP 1076 EP 1082 DI 10.1158/1078-0432.CCR-06-2221 PG 7 WC Oncology SC Oncology GA 140JO UT WOS:000244501100003 PM 17317814 ER PT J AU Jia, HL Ye, QH Qin, LX Budhu, A Forgues, M Chen, YD Liu, YK Sun, HC Wang, L Lu, HZ Shen, F Tang, ZY Wang, XW AF Jia, Hu-Liang Ye, Qing-Hai Qin, Lun-Xiu Budhu, Anuradha Forgues, Marshorma Chen, Yidong Liu, Yin-Kun Sun, Hui-Chuan Wang, Lu Lu, Hong-Zhou Shen, Fang Tang, Zhao-You Wang, Xin Wei TI Gene expression profiling reveals potential biomarkers of human hepatocellular carcinoma SO CLINICAL CANCER RESEARCH LA English DT Article ID GLOBAL CANCER STATISTICS; PRIMARY LIVER-CANCER; ALPHA-FETOPROTEIN; GLYPICAN-3; MIDKINE; MARKER; EXPERIENCE; DIAGNOSIS; RESECTION; STRATEGY AB Purpose: Hepatocellular carcinoma (HCC), a common cancer worldwide, has a dismal outcome partly due to the poor identification of early-stage HCC. Currently, one third of HCC patients present with low serum alpha-fetoprotein (AFP) levels, the only clinically available diagnostic marker for HCC. The aim of this study was to identify new diagnostic molecular markers for HCC, especially for individuals with low serum AFP. Experimental Design: We used the microarray technique to determine the expression profiles of 218 HCC specimens from patients with either high or low serum AFP. From the microarray study, we selected five candidate genes (i.e., GPC3, PEG10, MDK, SERPINI1, and QP-C), which were overexpressed in HCCs. Using quantitative real-time PCR analyses, we validated the expression of these five genes in 50 AFP-normal and 8 AFP-positive HCC specimens and 36 cirrhotic noncancerous hepatic specimens, which include 52 independent specimens not used in microarray analysis. Results: A significant increase in the expression of the five candidate genes could be detected in most of the HCC samples, including those with normal serum AFP and small tumors. GPC3, MDK, and SERPINI1 encode known serum proteins. Consistently, a significant increase in serum midkine, encoded by MDK, was associated with HCC patients, including those with normal serum AFP. Using prediction analysis of microarray, we showed that a combined score of these five genes can accurately classify noncancerous hepatic tissues (100%) and HCC (71%). Conclusions: We suggest that a diagnostic signature approach using a combined score of these five biomarkers rather than a single marker may improve the prediction accuracy of HCC patients, including those with normal serum AFP and smaller-sized tumors. C1 NCI, Human Carcinogenesis Lab, Canc Res Ctr, NIH,Liver Carcinogenesis Sect, Bethesda, MD 20892 USA. NHGRI, Canc Genet Lab, Bethesda, MD 20892 USA. Fudan Univ, Liver Canc Inst, Shanghai 200433, Peoples R China. Fudan Univ, Zhongshan Hosp, Shanghai 200433, Peoples R China. Shanghai Publ Hlth Ctr, Shanghai, Peoples R China. RP Wang, XW (reprint author), NCI, Human Carcinogenesis Lab, Canc Res Ctr, NIH,Liver Carcinogenesis Sect, 37 Convent Dr,MSC 4258,Bldg 37,Room 3044A, Bethesda, MD 20892 USA. EM xw3uc@nih.gov RI Wang, Xin/B-6162-2009 FU Intramural NIH HHS NR 29 TC 103 Z9 113 U1 1 U2 7 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 15 PY 2007 VL 13 IS 4 BP 1133 EP 1139 DI 10.1158/1078-0432.CCR-06-1025 PG 7 WC Oncology SC Oncology GA 140JO UT WOS:000244501100010 PM 17317821 ER PT J AU Mitre, E Talaat, KR Sperling, MR Nash, TE AF Mitre, Edward Talaat, Kawsar R. Sperling, Michael R. Nash, Theodore E. TI Methotrexate as a corticosteroid-sparing agent in complicated neurocysticercosis SO CLINICAL INFECTIOUS DISEASES LA English DT Article ID RHEUMATOID-ARTHRITIS; PERILESIONAL EDEMA; DOUBLE-BLIND; SUPPLEMENTATION; MANAGEMENT AB Background. A subset of patients with neurocysticercosis developed chronic or recurrent perilesional inflammation and required long-term and high-dose corticosteroid therapy. Such therapy frequently results in severe adverse effects. The purpose of this study was to determine whether methotrexate can be used as an effective corticosteroid-sparing or replacement agent in patients with complicated neurocysticercosis. Methods. This study was a nonblinded, prospective, observational trial. Patients with neurocysticercosis who required prednisone (15 mg/day) or its equivalent for >= 2 months, were likely to require long-term corticosteroid therapy by nature of their disease, developed serious complications due to corticosteroid use, or presented with a long-term history of corticosteroid use and had continued evidence of ongoing inflammation were eligible for methotrexate treatment. Results. Four patients are described in this study: 2 with subarachnoid neurocysticercosis, 1 with severe intraventricular and parenchymal disease, and 1 with recurrent perilesional edema around calcified lesions. Chronic inflammation due to neurocysticercosis resulted in lacunar infarcts, visual impairment, hydrocephalus, and seizures in these patients and necessitated long-term treatment with corticosteroids, which resulted in multiple adverse effects. The addition of methotrexate, prescribed at <= 20 mg/week, allowed for the successful reduction of corticosteroid use in all 4 patients and resulted in the improvement of many corticosteroid-associated adverse effects. Conclusions. Methotrexate is a beneficial corticosteroid-sparing or replacement agent for patients with neurocysticercosis who develop chronic or recurrent perilesional inflammation C1 NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Microbiol & Immunol, Bethesda, MD 20814 USA. Thomas Jefferson Univ, Jefferson Med Coll, Dept Neurol, Philadelphia, PA 19107 USA. RP Nash, TE (reprint author), NIAID, Parasit Dis Lab, NIH, 4 Ctr Dr,Rm 4-B1-01, Bethesda, MD 20892 USA. EM tnash@niaid.nih.gov FU Intramural NIH HHS NR 17 TC 22 Z9 22 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD FEB 15 PY 2007 VL 44 IS 4 BP 549 EP 553 DI 10.1086/511040 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 127PB UT WOS:000243597700014 PM 17243058 ER PT J AU Wilkin, TJ Su, ZH Kuritzkes, DR Hughes, M Flexner, C Gross, R Coakley, E Greaves, W Godfrey, C Skolnik, PR Timpone, J Rodriguez, B Gulick, RM AF Wilkin, Timothy J. Su, Zhaohui Kuritzkes, Daniel R. Hughes, Michael Flexner, Charles Gross, Robert Coakley, Eoin Greaves, Wayne Godfrey, Catherine Skolnik, Paul R. Timpone, Joseph Rodriguez, Benigno Gulick, Roy M. TI HIV type 1 chemokine coreceptor use among antiretroviral-experienced patients screened for a clinical trial of a CCR5 inhibitor: AIDS Clinical Trial Group A5211 SO CLINICAL INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 13th Conference on Retroviruses and Opportunistic Infections CY FEB 05-09, 2006 CL Denver, CO ID ENFUVIRTIDE; EPIDEMIOLOGY; POPULATION; PREVALENCE; INFECTION; EFFICACY; RECEPTOR; FUSION; ENTRY; R5 AB Background. Chemokine coreceptor use impacts both the natural history of human immunodeficiency virus type 1 (HIV-1) disease and the potential use of a new class of antiretroviral agents, the CCR5 inhibitors. Methods. We analyzed HIV-infected patients who were screened for participation in Acquired Immunodeficiency Syndrome (AIDS) Clinical Trial Group protocol A5211, a phase 2b study of the investigational CCR5 inhibitor vicriviroc involving antiretroviral-experienced subjects. Screening CD4(+) cell count, HIV-1 plasma RNA level, HIV-1 genotype, and chemokine coreceptor use phenotype were determined. The univariate and multivariate association of subject characteristics with coreceptor use was assessed by logistic regression. Results. Coreceptor use was determined for 391 subjects: 197 (50%) had virus that used the CCR5 coreceptor (the R5 group), 176 (46%) had dual-tropic or mixed HIV-1 populations that used both CCR5 and CXCR4 coreceptors (the D/M group), and 16 (4%) had virus that used the CXCR4 coreceptor (the X4 group). The D/M group had a significantly lower median CD4(+) cell count than the R5 virus group (103 cells/mu L vs. 170 cells/mu L;). No other characteristics were independently associated. Among 118 subjects who entered A5211 having R5 virus, 12 ( 10%) had D/ M virus according to the results of a second coreceptor test conducted prior to starting treatment with the study drug. Conclusions. Infection with dual-tropic or mixed HIV-1 populations that use both CCR5 and CXCR4 is common among highly treatment-experienced patients, but infection with virus using CXCR4 alone is uncommon. Subjects in the D/ M group had significantly lower CD4+ cell counts than subjects in the R5 group. Evaluating coreceptor use will be important in the clinical development of CCR5 and CXCR4 inhibitors. C1 Weill Cornell Med Coll, Div Int Med & Infect Dis, New York, NY USA. Harvard Univ, Sch Publ Hlth, Dept Biostat, Boston, MA 02115 USA. Harvard Univ, Sch Med, Sect Retroviral Therapeut, Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Sch Med, Div AIDS, Boston, MA 02115 USA. Boston Univ, Sch Med, Ctr HIV AIDS Care & Res, Boston, MA 02215 USA. Johns Hopkins Univ, Baltimore, MD USA. NIH, Natl Inst Allergy & Infect Dis, Div AIDS, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Div Infect Dis, Philadelphia, PA 19104 USA. Monogram Biosci, San Francisco, CA USA. Schering Plough Res Inst, Kenilworth, NJ USA. Georgetown Univ, Sch Med, Div Infect Dis, Washington, DC USA. Univ Hosp Cleveland, Div Infect Dis, Cleveland, OH 44106 USA. RP Wilkin, TJ (reprint author), 119 W 24th St,Ground Fl, New York, NY 10011 USA. EM tiw2001@med.cornell.edu RI Rodriguez, Benigno/C-3365-2009 OI Rodriguez, Benigno/0000-0001-9736-7957 FU NCRR NIH HHS [M01RR00096, RR00044, RR00046, RR00047, RR00051]; NIAID NIH HHS [AI025879, AI027666, AI25868, AI25903, AI27658, AI27659, AI27660-18S2, AI27661, AI27664, AI27665, AI27668, AI27670, AI32770, AI38858, AI46339, AI46370, AI46386, AI50410, K23 AI55038, K24 AI51966, P30-AI45008, U01 AI25915, U01-AI32783, U01AI32782]; PHS HHS [U01 A125924-18] NR 16 TC 137 Z9 141 U1 0 U2 1 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD FEB 15 PY 2007 VL 44 IS 4 BP 591 EP 595 DI 10.1086/511035 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 127PB UT WOS:000243597700022 PM 17243065 ER PT J AU Yun, CH Choi, SC Park, E Kim, SJ Chung, AS Lee, HK Lee, HJ Han, JK AF Yun, Chang-Hyun Choi, Sun-Cheol Park, Eunjoo Kim, Seong-Jin Chung, An-Sik Lee, Hyeong-Kyu Lee, Ho-Jae Han, Jin-Kwan TI Negative regulation of Activin/Nodal signaling by SRF during Xenopus gastrulation SO DEVELOPMENT LA English DT Article DE SRF; germ-layer formation; Activin and Nodal signaling; Xenopus ID SERUM RESPONSE FACTOR; GENE-EXPRESSION; NON-CELL; EMBRYOS; EMBRYOGENESIS; DIFFERENTIATION; IDENTIFICATION; SPECIFICATION; TRANSCRIPTION; ORGANIZER AB Activin/Nodal signaling is essential for germ-layer formation and axial patterning during embryogenesis. Recent evidence has demonstrated that the intra-or extracellular inhibition of this signaling is crucial for ectoderm specification and correct positioning of mesoderm and endoderm. Here, we analyzed the function of Xenopus serum response factor (XSRF) in establishing germ layers during early development. XSRF transcripts are restricted to the animal pole ectoderm in Xenopus early embryos. Ectopic expression of XSRF RNA suppresses mesoderm induction, both in the marginal zone in vivo and caused by Activin/ Nodal signals in animal caps. Dominant-negative mutant or antisense morpholino oligonucleotide-mediated inhibition of XSRF function expands the expression of mesendodermal genes toward the ectodermal territory and enhances the inducing activity of the Activin signal. SRF interacts with Smad2 and FAST-1, and inhibits the formation of the Smad2-FAST-1 complex induced by Activin. These results suggest that XSRF might act to ensure proper mesoderm induction in the appropriate region by inhibiting the mesoderm-inducing signals during early embryogenesis. C1 Pohang Univ Sci & Technol, Div Mol & Life Sci, Pohang, Kyungbuk, South Korea. KRIBB, Nat Med Res Ctr, Taejon 305333, South Korea. Korea Adv Inst Sci & Technol, Dept Biol Sci, Taejon 305701, South Korea. NCI, Lab Cell Regulat & Carcinogenesis, Bethesda, MD 20892 USA. RP Lee, HJ (reprint author), Pohang Univ Sci & Technol, Div Mol & Life Sci, Pohang, Kyungbuk, South Korea. EM hjlee@kribb.re.kr; jkh@postech.ac.kr FU Intramural NIH HHS NR 43 TC 11 Z9 11 U1 0 U2 1 PU COMPANY OF BIOLOGISTS LTD PI CAMBRIDGE PA BIDDER BUILDING CAMBRIDGE COMMERCIAL PARK COWLEY RD, CAMBRIDGE CB4 4DL, CAMBS, ENGLAND SN 0950-1991 J9 DEVELOPMENT JI Development PD FEB 15 PY 2007 VL 134 IS 4 BP 769 EP 777 DI 10.1242/dev.02778 PG 9 WC Developmental Biology SC Developmental Biology GA 130IU UT WOS:000243794100013 PM 17259304 ER PT J AU Cho, HY Kleeberger, SR AF Cho, Hye-Youn Kleeberger, Steven R. TI Genetic mechanisms of susceptibility to oxidative lung injury in mice SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Review DE susceptibility; linkage analysis; inbred mice; quantitative trait locus; lung; candidate gene ID OIL FLY-ASH; INDUCED PULMONARY-FIBROSIS; TOLL-LIKE RECEPTOR-4; RESPIRATORY-DISTRESS-SYNDROME; NRF2 ENHANCES SUSCEPTIBILITY; ADENOVIRUS-MEDIATED TRANSFER; QUANTITATIVE TRAIT ANALYSIS; OZONE-INDUCED INFLAMMATION; INBRED MOUSE STRAINS; AIR-POLLUTION AB Genetic background is a known predisposing risk factor for many acute and chronic pulmonary disorders and responses to environmental oxidants. Variation in lung injury responses to oxidative stimuli such as ozone, particles, hyperoxia, and chemotherapeutic agents between genetically standardized inbred mouse strains has been demonstrated. In this review, we discuss quantitative trait loci (QTLs) which contain candidate genes that confer differential susceptibility to oxidative stimuli between strains in mouse models of airway toxicity and disease. We addressed multiple inflammatory, immunity, and antioxidant genes identified as candidate genetic determinants following these strategies, which include tumor necrosis factor (Tnf), toll-like receptor 4,(Tlr4), and the transcription factor NF-E2, related factor 2 (Nrf2). Mice with targeted deletion of these and related genes have provided initial proof of concept for their importance in the respective models. Interestingly, a few regions of the genome appear to have important roles in determining susceptibility to a number of stimuli which may suggest common genetic mechanisms in mice. Though more complete examination of functional association is required, results have potential implications for the role of these candidate genes in the pathogenesis of human pulmonary diseases including asthma, acute respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IPF), and emphysema. (c) 2006 Elsevier Inc. All rights reserved. C1 NIEHS, Lab Resp Biol, NIH, Res Triangle Pk, NC 27709 USA. RP Cho, HY (reprint author), NIEHS, Lab Resp Biol, NIH, POB 12233, Res Triangle Pk, NC 27709 USA. EM cho2@niehs.nih.gov NR 118 TC 64 Z9 67 U1 0 U2 4 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD FEB 15 PY 2007 VL 42 IS 4 BP 433 EP 445 DI 10.1016/j.freeradbiomed.2006.11.021 PG 13 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 137FU UT WOS:000244279200001 PM 17275675 ER PT J AU Bonini, MG Siraki, AG Atanassov, BS Mason, RP AF Bonini, Marcelo G. Siraki, Arno G. Atanassov, Boyko S. Mason, Ronald P. TI Immunolocalization of hypochlorite-induced, catalase-bound free radical formation in mouse hepatocytes SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE catalase; immunospin-trapping; hypochlorite; EPR; protein radical; free radicals ID NITROGEN-CENTERED RADICALS; MYELOPEROXIDASE COMPOUND-I; PROSTAGLANDIN-H SYNTHASE; HYDROGEN-PEROXIDE; TYROSYL RADICALS; INDUCED DAMAGE; PROTEIN FRAGMENTATION; DENSITY-LIPOPROTEIN; HUMAN NEUTROPHILS; INDUCED OXIDATION AB The establishment of oxidants as mediators of signal transduction has renewed the interest of investigators in oxidant production and metabolism. In particular, H2O2 has been demonstrated to play pivotal roles in mediating cell differentiation, proliferation, and death, Intracellular concentrations of H2O2 are modulated by its rate of production and its rate of decomposition by catalase and peroxidases. In inflammation and infection, some of the H2O2 is converted to hypochlorous acid, a key mediator of the host immune response against pathogens. In vivo HOCl production is mediated by myeloperoxidase, which uses excess H2O2 to oxidize Cl-. Mashino and Fridovich (Biochim. Biophys. Acta 956:63-69; 1988) observed that a high excess of HOCl over catalase inactivated the enzyme by mechanisms that remain unclear. The potential relevance of this as an alternative mechanism for catalase activity control and its potential impact on H2O2-mediated signaling and HOCl production compelled us to explore in depth the HOCl-mediated catalase inactivation pathways. Here, we demonstrate that HOCl induces formation of catalase protein radicals and carbonyls, which are temporally correlated with catalase aggregation. Hypochlorite-induced catalase aggregation and free radical formation that paralleled the enzyme loss of function in vitro were also detected in mouse hepatocytes treated with the oxidant. Interestingly, the novel immuno-spin-trapping technique was applied to image radical production in the cells. Indeed, in HOCl-treated hepatocytes, catalase and protein-DMPO nitrone adducts were colocalized in the cells' peroxisomes. In contrast, when hepatocytes from catalase-knockout mice were treated with hypochlorous acid, there was extensive production of free radicals in the plasma membrane. Because free radicals are short-lived species with fundamental roles in biology, the possibility of their detection and localization to cell compartments is expected to open new and stimulating research venues in the interface of chemistry, biology, and medicine. (c) 2006 Elsevier Inc. All rights reserved. C1 NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. NCI, NIH, Res Triangle Pk, NC 27709 USA. RP Bonini, MG (reprint author), NIEHS, Lab Pharmacol & Chem, 111 TW Alexander Dr,MD F0-02, Res Triangle Pk, NC 27709 USA. EM bonini@niehs.nih.gov FU Intramural NIH HHS [Z01 ES050139-11] NR 49 TC 36 Z9 36 U1 1 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD FEB 15 PY 2007 VL 42 IS 4 BP 530 EP 540 DI 10.1016/j.freeradbiomed.2006.11.019 PG 11 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 137FU UT WOS:000244279200011 PM 17275685 ER PT J AU Bloom, GC Eschrich, S Zhou, JX Coppola, D Yeatman, TJ AF Bloom, Gregory C. Eschrich, Steven Zhou, Jeff X. Coppola, Domenico Yeatman, Timothy J. TI Elucidation of a protein signature discriminating six common types of adenocarcinoma SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE 2D gel electrophoresis; proteomics; classification; cancer; artificial neural network ID B-CELL LYMPHOMA; GENE-EXPRESSION; PREDICT SURVIVAL; UNKNOWN PRIMARY; BREAST-CANCER; CARCINOMA; IDENTIFICATION; LUNG; SITE AB Pathologists are commonly facing the problem of attempting to identify the site of origin of a metastatic cancer when no primary tumor has been identified, yet few markers have been identified to date. Multitumor classifiers based on microarray based RNA expression have recently been described. Here we describe the first approximation of a tumor classifier based entirely on protein expression quantified by two-dimensional gel electrophoresis (2DE). The 2DE was used to analyze the proteomic expression pattern of 77 similarly appearing (using histomorphology) adenocareinomas encompassing 6 types or sites of origin: ovary, colon, kidney, breast, lung and stomach. Discriminating sets of proteins were identified and used to train an artificial neural network (ANN). A leave-one-out cross validation (LOOCV) method was used to test the ability of the constructed network to predict the single held out sample from each iteration with a maximum predictive accuracy of 87% and an average predictive accuracy of 82% over the range of proteins chosen for its construction. These findings demonstrate the use of proteomics to construct a highly accurate ANN-based classifier for the detection of an individual tumor type, as well as distinguishing between 6 common tumor types in an unknown primary diagnosis setting. (c) 2006 Wiley-Liss. Inc. C1 H Lee Moffitt Canc Ctr & Res Inst, Biostat Program, Tampa, FL 33612 USA. Large Scale Biol Corp, Germantown, MD USA. NIH, Rockville, MD USA. H Lee Moffitt Canc Ctr & Res Inst, Dept Interdisciplinary Oncol, Tampa, FL USA. Univ S Florida, Coll Med, Dept Surg, Tampa, FL 33612 USA. Univ S Florida, Coll Med, Dept Pathol, Tampa, FL 33612 USA. RP Yeatman, TJ (reprint author), H Lee Moffitt Canc Ctr & Res Inst, Biostat Program, 12902 Magnolia Dr,SRB 2, Tampa, FL 33612 USA. EM yeatman@moffitt.usf.edu RI Eschrich, Steven/K-6848-2013 FU NCI NIH HHS [R01 CA112215, K24-CA85429, R01 CA112215-03, R01-CA098522, R21-CA101355, U01-CA85052] NR 19 TC 25 Z9 26 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 15 PY 2007 VL 120 IS 4 BP 769 EP 775 DI 10.1002/ijc.22041 PG 7 WC Oncology SC Oncology GA 129BT UT WOS:000243704100006 PM 17131332 ER PT J AU Prueitt, RL Boersma, BJ Howe, TM Goodman, JE Thomas, DD Ying, L Pfiester, CM Yfantis, HG Cottre, JR Lee, DH Remaley, AT Hofseth, LJ Wink, DA Ambs, S AF Prueitt, Robyn L. Boersma, Brenda J. Howe, Tiffany M. Goodman, Julie E. Thomas, Douglas D. Ying, Lei Pfiester, Candice M. Yfantis, Harris G. Cottre, John R. Lee, Dong H. Remaley, Alan T. Hofseth, Lorne J. Wink, David A. Ambs, Stefan TI Inflammation and IGF-I activate the Akt pathway in breast cancer SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE breast cancer; Akt; inflammation; insulin-like growth factor; survival ID PROTEIN-KINASE-B; COX-2 MESSENGER-RNA; NITRIC-OXIDE; SIGNALING PATHWAYS; TUMOR PROGRESSION; INDUCED APOPTOSIS; GENE-EXPRESSION; CELL-GROWTH; INSULIN; P53 AB Akt signaling may promote breast cancer progression and poor disease outcome. We hypothesized that serum insulin-like growth factor I (IGF-I) and a proinflammatory tumor environment induce phosphorylation of Akt and downstream targets of Akt in breast cancer. We studied the relationship between Akt pathway activation, IGF-I and markers of inflammation, e.g., nitric oxide synthase-2 (NOS2), cyclooxygenase-2 (COX2) and tumor phagocyte density, in 248 breast tumors. We also examined the association of Akt phosphorylation with breast cancer survival. We observed that phosphorylation of Akt, BAD and caspase-9 correlated strongly with the expression of the 2 proinflammatory enzymes, NOS2 and COX2, in breast tumors (p < 0.001; Spearman rank correlation). Both NOS2 and COX2 expression were independently associated with Akt phosphorylation in the multivariate analysis. Serum IGF-I concentrations and the IGF-I/IGFBP3 ratio correlated with Akt phosphorylation at Thr308 and Ser473 in breast tumors (p <= 0.05; Spearman rank correlation). The association with Akt phosphorylation at Thr308 remained statistically significant in the multivariate analysis. Akt pathway activation was not associated with overall survival in the unstratified analysis, but we observed a statistical interaction between Akt phosphorylation and tumor phagocyte density on breast cancer survival (P-interaction < 0.05). We further corroborated our findings in cell culture models by demonstrating that ANA-1 macrophages, nitric oxide and prostaglandin E-2 induce Akt phosphorylation in human breast cancer cells. In summary, a proinflammatory environment was found to activate the Akt pathway in breast cancer, and may modify the association between the Akt phosphorylation status and breast cancer survival. (c) 2006 Wiley-Liss, Inc. C1 NCI, Human Carcinogenesis Lab, Canc Res Ctr, Bethesda, MD 20892 USA. Gradient Corp, Cambridge, MA 02138 USA. NCI, Radiat Biol Branch, Ctr Canc Res, Bethesda, MD 20892 USA. S Carolina Coll Pharm, Lab Inflammatory Driven Carcinogenesis, Dept Basic Pharmaceut Sci, Columbia, SC USA. Baltimore VA Med Ctr, Baltimore, MD USA. Univ Maryland, Sch Med, Dept Pathol, Baltimore, MD 21201 USA. NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA. RP Ambs, S (reprint author), NCI, Human Carcinogenesis Lab, Canc Res Ctr, Bldg 37,Room 3050B, Bethesda, MD 20892 USA. EM ambss@mail.nih.gov RI Boersma, Brenda/A-9270-2009 OI Boersma, Brenda/0000-0002-8992-2735 FU Intramural NIH HHS NR 59 TC 52 Z9 58 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 15 PY 2007 VL 120 IS 4 BP 796 EP 805 DI 10.1002/ijc.22336 PG 10 WC Oncology SC Oncology GA 129BT UT WOS:000243704100010 PM 17096325 ER PT J AU Klopot, A Hance, KW Peleg, S Barsony, J Fleet, JC AF Klopot, Anna Hance, Kenneth W. Peleg, Sara Barsony, Julia Fleet, James C. TI Nucleo-cytoplasmic cycling of the vitamin D receptor in the enterocyte-like cell line, Caco-2 SO JOURNAL OF CELLULAR BIOCHEMISTRY LA English DT Article DE intestine; nuclear trafficking; 1,25 dihydroxyvitamin D-3 ID RETINOID-X-RECEPTOR; MEMBRANE PHOSPHOINOSITIDE TURNOVER; INTESTINAL CALCIUM-ABSORPTION; NUCLEAR EXPORT; KNOCKOUT MICE; LIGAND; D-3; 1,25-DIHYDROXYVITAMIN-D; IDENTIFICATION; TRANSLOCATION AB We examined the effects of 1,25 dihydroxyvitamin D-3 (1,25(OH)(2)D-3) on the distribution and mobility of the vitamin D receptor (VDR) in the enterocyte-like Caco-2 cell. Confocal microscopy showed that a green fluorescent protein-vitamin D receptor (GFP-VDR) fusion protein is predominantly nuclear (58%) and it does not associate with the apical or basolateral membrane of proliferating or polarized, differentiated cells. In contrast to the previously studied cell types, neither endogenous VDR nor GFP-VDR levels accumulate in the nucleus following 1,25(OH)(2)D-3 treatment (100 nM, 30 min). However, in nuclear photobleaching experiments nuclear GFP-VDR import was significantly increased by 1,25(OH)(2)D-3 during both an early (0-5 min) and later (30-35 min) period (20% per 5 min). Compared to the natural ligand, nuclear import of GFP-VDR was 60% lower in cells treated with the 1,25(OH)(2)D-3 analog, 1-alpha-fluoro-16-ene20-epi-23-ene-26,27-bishomo-25-hydroxyvitamin D-3 (Ro-26-9228, 5 min, 100 nM). Downstream events like ligand-induced association of VDR with chromatin at 1 h and the accumulation of CYP24 mRNA were significantly lower in Ro-26-9228 treated cells compared to 1,25(OH)(2)D-3 (60 and 95% lower, respectively). Collectively our data are consistent with a role for ligand-induced nuclear VDR import in receptor activation. In addition, ligand-dependent VDR nuclear import appears to be balanced by export, thus accounting for the lack of nuclear VDR accumulation even when VDR import is significantly elevated. C1 Purdue Univ, Dept Foods & Nutr, W Lafayette, IN 47907 USA. Purdue Univ, Interdept Nutr Program, W Lafayette, IN 47907 USA. Univ Texas, MD Anderson Canc Ctr, Dept Endocrine Neoplasia & Hormonal Disorders, Houston, TX 77030 USA. NIDDK, Lab Cell Biochem & Biol, NIH, Bethesda, MD 20892 USA. RP Fleet, JC (reprint author), Purdue Univ, Dept Foods & Nutr, 700 W State St, W Lafayette, IN 47907 USA. EM fleet@purdue.edu FU NCI NIH HHS [CA23168, P30 CA023168]; NIDDK NIH HHS [DK50583, R01 DK054111, DK54111, R01 DK054111-10, R01 DK050583] NR 36 TC 8 Z9 8 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0730-2312 J9 J CELL BIOCHEM JI J. Cell. Biochem. PD FEB 15 PY 2007 VL 100 IS 3 BP 617 EP 628 DI 10.1002/jcb.21087 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 130CB UT WOS:000243775700006 PM 16960876 ER PT J AU Veenstra, TD AF Veenstra, Timothy D. TI Global and targeted quantitative proteomics for biomarker discovery SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article; Proceedings Paper CT Symposium on Biomarker Discovery by Mass Spectrometry CY MAY 18-19, 2006 CL Amsterdam, NETHERLANDS DE biomarker discovery; mass spectrometry; quantitative proteomics; targeted quantitation ID MASS-SPECTROMETRY; PROTEIN IDENTIFICATION; SERUM; DISEASE; CANCER AB The extraordinary developments made in proteomic technologies in the past decade have enabled investigators to consider designing studies to search for diagnostic and therapeutic biomarkers by scanning complex proteome samples using unbiased methods. The major technology driving these studies is mass spectrometry (MS). The basic premises of most biomarker discovery studies is to use the high data-gathering capabilities of MS to compare biological samples obtained from healthy and disease-afflicted patients and identify proteins that are differentially abundant between the two specimen. To meet the need to compare the abundance of proteins in different samples, a number of quantitative approaches have been developed. In this article, many of these will be described with an emphasis on their advantageous and disadvantageous for the discovery of clinically useful biomarkers. (c) 2006 Elsevier B.V. All rights reserved. C1 SAIC Frederick Inc, Natl Canc Inst, Ft Detrick, MD 21702 USA. RP Veenstra, TD (reprint author), SAIC Frederick Inc, Natl Canc Inst, POB B, Ft Detrick, MD 21702 USA. EM veenstra@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 25 TC 70 Z9 72 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD FEB 15 PY 2007 VL 847 IS 1 BP 3 EP 11 DI 10.1016/j.jchromb.2006.09.004 PG 9 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 142DK UT WOS:000244629200002 PM 17023222 ER PT J AU Schwarz, BA Sambandam, A Maillard, I Harman, BC Love, PE Bhandoola, A AF Schwarz, Benjamin A. Sambandam, Arivazhagan Maillard, Ivan Harman, Benjamin C. Love, Paul E. Bhandoola, Avinash TI Selective thymus settling regulated by cytokine and chemokine receptors SO JOURNAL OF IMMUNOLOGY LA English DT Article ID HEMATOPOIETIC STEM-CELLS; MOUSE BONE-MARROW; COMMON LYMPHOID PROGENITORS; T-CELL; LINEAGE COMMITMENT; C-KIT; THYMOCYTE PRECURSORS; UP-REGULATION; IN-VITRO; DIFFERENTIATION AB To generate T cells throughout adult life, the thymus must import hemopoietic progenitors from the bone marrow via the blood. In this study, we establish that thymus settling is selective. Using nonirradiated recipient mice, we found that hemopoietic stem cells were excluded from the thymus, whereas downstream multipotent progenitors (MPP) and common lymphoid progenitors rapidly generated T cells following i.v. transfer. This cellular specificity correlated with the expression of the chemokine receptor CCR9 by a subset of MPP and common lymphoid progenitors but not hemopoietic stem cells. Furthermore, CCR9 expression was required for efficient thymus settling. Finally, we demonstrate that a prethymic signal through the cytokine receptor fms-like tyrosine kinase receptor-3 was required for the generation of CCR9-expressing early lymphoid progenitors, which were the most efficient progenitors of T cells within the NIPP population. We conclude that fms-like tyrosine kinase receptor-3 signaling is required for the generation of T lineage-competent progenitors, which selectively express molecules, including CCR9, that allow them to settle within the thymus. The Journal of Immunology, 2007, 178: 2008-2017. C1 Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA. Univ Penn, Sch Med, Div Hematol Oncol, Philadelphia, PA 19104 USA. NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. RP Bhandoola, A (reprint author), Univ Penn, Sch Med, Dept Pathol & Lab Med, 264-266 John Morgan Bldg,37th & Hamilton Walk, Philadelphia, PA 19104 USA. EM bhandooa@mail.med.upenn.edu RI Schwarz, Benjamin/A-1069-2007 FU NIAID NIH HHS [AI059621, T32 AI055428, T32-AI-055428] NR 65 TC 116 Z9 123 U1 1 U2 6 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 15 PY 2007 VL 178 IS 4 BP 2008 EP 2017 PG 10 WC Immunology SC Immunology GA 133QF UT WOS:000244026800006 PM 17277104 ER PT J AU Karaolis, DKR Means, TK Yang, D Takahashi, M Yoshimura, T Muraille, E Philpott, D Schroeder, JT Hyodo, M Hayakawa, Y Talbot, BG Brouillette, E Malouin, F AF Karaolis, David K. R. Means, Terry K. Yang, De Takahashi, Munehisa Yoshimura, Teizo Muraille, Eric Philpott, Dana Schroeder, John T. Hyodo, Mamoru Hayakawa, Yoshihiro Talbot, Brian G. Brouillette, Eric Malouin, Francois TI Bacterial c-di-GMP is an immunostimulatory molecule SO JOURNAL OF IMMUNOLOGY LA English DT Article ID ACTIVATED PROTEIN-KINASE; CYCLIC DIGUANYLIC ACID; NECROSIS-FACTOR-ALPHA; NF-KAPPA-B; SIGNAL-TRANSDUCTION PATHWAYS; AUREUS-INDUCED MASTITIS; STAPHYLOCOCCUS-AUREUS; DENDRITIC CELLS; ACETOBACTER-XYLINUM; CELLULOSE SYNTHESIS AB Cyclic diguanylate (c-di-GMP) is a bacterial intracellular signaling molecule. We have shown that treatment with exogenous c-di-GMP inhibits Staphylococcus aureus infection in a mouse model. We now report that c-di-GMP is an immodulator and immunostimulatory molecule. Intramammary treatment of mice with c-di-GMP 12 and 6 h before S. aureus challenge gave a protective effect and a 10,000-fold reduction in CFUs in tissues (p < 0.001). Intramuscular vaccination of mice with c-di-GMP coinjected with S. aureus clumping factor A (ClfA) Ag produced serum with significantly higher anti-ClfA IgG Ab titers (p < 0.001) compared with ClfA alone. Intraperitoneal injection of mice with c-di-GMP activated monocyte and granulocyte recruitment. Human immature dendritic cells (DCs) cultured in the presence of c-di-GMP showed increased expression of costimulatory molecules CD80/CD86 and maturation marker CD83, increased MHC class II and cytokines and chemokines such as IL-12, IFN-gamma, IL-8, MCP-1, IFN-gamma-inducible protein 10, and RANTES, and altered expression of chemokine receptors including CCR1, CCR7, and CXCR4. c-di-GMP-matured DCs demonstrated enhanced T cell stimulatory activity. c-di-GMP activated p38 MAPK in human DCs and ERK phosphorylation in human macrophages. c-di-GMP is stable. in human serum. We propose that cyclic dinucleotides like c-di-GMP can be used clinically in humans and animals as an immunomodulator, immune enhancer, immunotherapeutic, immunoprophylactic, or vaccine adjuvant. The Journal of Immunology, 2007, 178: 2171-2181. C1 Intragen Res Inst, Havre De Grace, MD 21078 USA. Karagen Pharmaceut, Baltimore, MD 21210 USA. Univ Maryland, Sch Med, Dept Epidemiol & Prevent Med, Baltimore, MD 21201 USA. Harvard Univ, Ctr Immunol & Inflammatory Dis, Boston, MA 02129 USA. NCI, Ctr Canc Res, Frederick, MD 21702 USA. NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. Univ Libre Bruxelles, Fac Med, Brussels, Belgium. Univ Toronto, Dept Immunol, Toronto, ON, Canada. Johns Hopkins Univ, Dept Med, Baltimore, MD 21224 USA. Nagoya Univ, Grad Sch Informat Sci, Nagoya, Aichi, Japan. Univ Sherbrooke, Dept Biol, Sherbrooke, PQ J1K 2R1, Canada. RP Karaolis, DKR (reprint author), Intragen Res Inst, 415 Oakington Rd, Havre De Grace, MD 21078 USA. EM dkaraolis@intragenics.org RI Hyodo, Mamoru/D-5496-2012; OI Hyodo, Mamoru/0000-0002-1766-3949; Malouin, Francois/0000-0001-5031-345X NR 58 TC 113 Z9 116 U1 0 U2 10 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 2007 VL 178 IS 4 BP 2171 EP 2181 PG 11 WC Immunology SC Immunology GA 133QF UT WOS:000244026800024 PM 17277122 ER PT J AU Gorbachev, AV Kobayashi, H Kudo, D Tannenbaum, CS Finke, JH Shu, S Farber, JM Fairchild, RL AF Gorbachev, Anton V. Kobayashi, Hirobito Kudo, Daisuke Tannenbaum, Charles S. Finke, James H. Shu, Suyu Farber, Joshua M. Fairchild, Robert L. TI CXC chemokine ligand 9/monokine induced by IFN-gamma production by tumor cells is critical for T cell-mediated suppression of cutaneous tumors SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NECROSIS IN-VIVO; INTERFERON-GAMMA; INDUCIBLE PROTEIN-10; CHEMOKINE LIGAND-9; NKT CELLS; EXPRESSION; IP-10; MIG; CARCINOMA; INTERLEUKIN-12 AB The role of tumor-produced chemokines in the growth of malignancies remains poorly understood. We retrieved an in vivo growing MCA205 fibrosarcoma and isolated tumor cell clones that produce both CXCL9/monokine induced by IFN-gamma (Mig) and CXCL10/IFN-gamma-inducible protein 10 following stimulation with IFN-gamma and clones that produce IFN-gamma-inducible protein 10 but not Mig. The Mig-deficient variants grew more aggressively as cutaneous tumors in wild-type mice than the Mig-producing tumor cells. The growth of Mig-expressing, but not Mig-deficient, tumor cells was suppressed by NK and T cell activity. Transduction of Mig-negative variants to generate constitutive tumor cell production of Mig resulted in T cell-dependent rejection of the tumors and in induction of protective tumor-specific CD8(+) T cell responses to Mig-deficient tumors. The results indicate a critical role for tumor-derived Mig in T cell-mediated responses to cutaneous fibrosarcomas and suggest the loss of Mig expression as a mechanism used by tumor cells to evade these responses. C1 Cleveland Clin Fdn, Lerner Res Inst, Dept Immunol, Cleveland, OH 44195 USA. Cleveland Clin Fdn, Surg Res Ctr, Cleveland, OH 44195 USA. NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. RP Gorbachev, AV (reprint author), Cleveland Clin Fdn, Lerner Res Inst, Dept Immunol, 9500 Euclid Ave, Cleveland, OH 44195 USA. EM gorbaca@ccf.org FU NIAID NIH HHS [R01AI45888] NR 31 TC 25 Z9 25 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 2007 VL 178 IS 4 BP 2278 EP 2286 PG 9 WC Immunology SC Immunology GA 133QF UT WOS:000244026800035 PM 17277133 ER PT J AU Frossi, B Rivera, J Hirsch, E Pucillo, C AF Frossi, Barbara Rivera, Juan Hirsch, Emilio Pucillo, Carlo TI Selective activation of Fyn/PI3K and p38 MAPK regulates IL-4 production in BMMC under nontoxic-stress condition SO JOURNAL OF IMMUNOLOGY LA English DT Article ID MAST-CELL ACTIVATION; OXYGEN SPECIES GENERATION; CYTOKINE PRODUCTION; HYDROGEN-PEROXIDE; ALLERGIC RESPONSE; OXIDATIVE STRESS; GENE-EXPRESSION; NUCLEAR FACTOR; T-CELLS; IGE AB Mast cells have the ability to react to multiple stimuli, implicating these cells in many immune responses. Specific signals from the microenvironment in which mast cells reside can activate different molecular events that govern distinct mast cells responses. We previously demonstrated that hydrogen peroxide (H(2)O(2)) promotes IL-4 and IL-6 mRNA production and potentates Fc epsilon RI-induced cytokine release in rat basophilic leukemia RBL-2H3 cells. To further evaluate the effect of an oxidative microenvironment (which is physiologically present in an inflammatory site) on mast cell function and the molecular events responsible for mast cell cytokine production in this environment, we analyzed the effect of H(2)O(2) treatment on IL-4 production in bone marrow-derived, cultured mast cells. Our findings show that nanomolar concentrations of H(2)O(2) induce cytokine secretion and enhance IL-4 production upon Fc epsilon RI triggering. Oxidative stimulation activates a distinct signal transduction pathway that induces Fyn/PI3K/Akt activation and the selective phosphorylation of p38 MAP kinase. Moreover, H(2)O(2) induces AP-1 and NFAT complexes that recognize the IL-4 promoter. The absence of Fyn and PI3K or the inhibition of p38 MAPK activity demonstrated that they are essential for H(2)O(2)-driven IL-4 production. These findings show that mast cells can respond to an oxidative microenvironment by initiating specific signals capable of eliciting a selective response. The findings also demonstrate the dominance of the Fyn/p38 MAPK pathway in driving IL-4 production. C1 Univ Udine, Dept Biomed Sci & Technol, Immunol Sect, I-33100 Udine, Italy. Univ Udine, Micrograv Ageing Training Immobil Ctr Excellence, I-33100 Udine, Italy. NIAMSD, Mol Inflammat Sect, Arthritis & Rheumatism Branch, NIH, Bethesda, MD 20892 USA. Univ Turin, Dipartimento Genet Biol & Biochim, Turin, Italy. RP Pucillo, C (reprint author), Univ Udine, Dept Biomed Sci & Technol, Immunol Sect, Piazzale Kolbe 4, I-33100 Udine, Italy. EM carlo.pucillo@uniud.it RI Pucillo, Carlo/A-5515-2008; Hirsch, Emilio/F-4848-2013; OI Hirsch, Emilio/0000-0002-9073-6024; Pucillo, Carlo/0000-0002-4872-6156 NR 40 TC 59 Z9 63 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 2007 VL 178 IS 4 BP 2549 EP 2555 PG 7 WC Immunology SC Immunology GA 133QF UT WOS:000244026800066 PM 17277164 ER PT J AU Valencia, X Yarboro, C Illei, G Lipsky, PE AF Valencia, Xavier Yarboro, Cheryl Illei, Gabor Lipsky, Peter E. TI Deficient CD4(+)CD25(high) T regulatory cell function in patients with active systemic lupus erythematosus SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TUMOR-NECROSIS-FACTOR; IMMUNOLOGICAL SELF-TOLERANCE; REVISED CRITERIA; FOXP3; ACTIVATION; EXPRESSION; RECEPTOR; CLASSIFICATION; INTERLEUKIN-2; ABNORMALITIES AB CD4(+)CD25(+) T regulatory cells (Tregs) play an essential role in maintaining immunologic homeostasis and preventing autoimmunity. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a loss of tolerance to nuclear components. We hypothesized that altered function of CD4(+)CD25(high) Tregs might play a role in the breakdown of immunologic self-tolerance in patients with SLE. In this study, we report a significant decrease in the suppressive function of CD4(+)CD25(high) Tregs from peripheral blood of patients with active SLE as compared with normal donors and patients with inactive SLE. Notably, CD4(+)CD25(high) Tregs isolated from patients with active SLE expressed reduced levels of FoxP3 mRNA and protein and poorly suppressed the proliferation and cytokine secretion of CD4(+) effector T cells in vitro. In contrast, the expression of FoxP3 mRNA and protein and in vitro suppression of the proliferation of CD4(+) effector T cells by Tregs isolated from inactive SLE patients, was comparable to that of normal individuals. In vitro activation of CD4(+)CD25(high) Tregs from patients with active SLE increased FoxP3 mRNA and protein expression and restored their suppressive function. These data are the first to demonstrate a reversible defect in CD4(+)CD25(high) Treg function in patients with active SLE, and suggest that strategies to enhance the function of these cells might benefit patients with this autoimmune disease. C1 NIAMSD, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. NIAMSD, Off Clin Director, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, NIH, Bethesda, MD 20892 USA. RP Valencia, X (reprint author), NIAMSD, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. EM xvalencia@mail.nih.gov FU Intramural NIH HHS NR 44 TC 334 Z9 356 U1 3 U2 10 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 2007 VL 178 IS 4 BP 2579 EP 2588 PG 10 WC Immunology SC Immunology GA 133QF UT WOS:000244026800070 PM 17277168 ER PT J AU Estes, JD Wietgrefe, S Schacker, T Southern, P Beilman, G Reilly, C Milush, JM Lifson, JD Sodora, DL Carlis, JV Haase, AT AF Estes, Jacob D. Wietgrefe, Stephen Schacker, Timothy Southern, Peter Beilman, Greg Reilly, Cavan Milush, Jeffrey M. Lifson, Jeffrey D. Sodora, Donald L. Carlis, John V. Haase, Ashley T. TI Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by transforming growth factor beta 1-positive regulatory T cells and begins in early infection SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT Keystone Symposium on HIV Pathogenesis CY MAR 27-APR 02, 2006 CL Keystone, CO ID HIV TYPE-1 INFECTION; SOOTY MANGABEYS; ANTIRETROVIRAL THERAPY; LYMPHOID-TISSUES; DISEASE PROGRESSION; IMMUNE FUNCTION; FACTOR-BETA; AIDS; SIV; ACTIVATION AB In human immunodeficiency virus (HIV) infection, collagen deposition and fibrosis within the T cell zone disrupt the lymphatic tissue architecture, contributing to depletion of CD4(+) T cells and limiting immune reconstitution. We used relevant animal and in vitro models to investigate the kinetics and possible underlying mechanism(s) of this process. In the lymphatic tissue of simian immunodeficiency virus (SIV)-infected rhesus macaques, we observed parallel increases in immune activation, transforming growth factor (TGF) beta 1-positive regulatory T (T-reg) cells, and collagen type I deposition by 7 days after inoculation, consistent with the hypothesis that early immune activation elicits a countering Treg cell response associated with TGF beta 1 expression and collagen deposition. In support of this hypothesis and the possible role of fibrosis in viral pathogenesis, we show (1) spatial colocalization and temporal concordance in levels of TGF beta 1(+) Treg cells and collagen deposition; (2) TGF beta 1(+) inducible T-reg cell stimulation of primary lymphatic tissue fibroblasts to produce collagen type I in vitro; and (3) high levels of immune activation, TGF beta 1(+) T-reg cells, and collagen deposition in pathogenic SIV infection of macaques, in contrast to apathogenic SIV infection in sooty mangabeys in which levels of immune activation, TGF beta 1(+) T-reg cells, and collagen deposition were low. We thus conclude that the response of TGF beta 1(+) Treg cells to immune activation in early SIV/HIV infection is a double-edged sword: TGF beta 1(+) T-reg cells normally have a positive effect by limiting immunopathological and autoreactive immune responses, but they also have a negative effect by dampening the antiviral immune response and, as we show here, causing deleterious effects on CD4(+) T cell homeostasis by inducing collagen deposition in lymphatic tissues. C1 Univ Minnesota, Dept Microbiol, Sch Med, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Med, Sch Med, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Surg, Sch Med, Minneapolis, MN 55455 USA. Univ Minnesota, Sch Publ Hlth, Div Biostat, Minneapolis, MN 55455 USA. Univ Minnesota, Dept Comp Sci & Engn, Inst Technol, Minneapolis, MN 55455 USA. Univ Texas, SW Med Ctr, Dept Internal Med, Dallas, TX 75230 USA. NCI, AIDS Vaccine Program, SAIC Frederick Inc, Frederick, MD 21701 USA. RP Haase, AT (reprint author), Univ Minnesota, Dept Microbiol, Sch Med, MMC 196,420 Delaware St SE, Minneapolis, MN 55455 USA. EM haase001@umn.edu FU NCI NIH HHS [N01-CO-12400]; NIAID NIH HHS [R01-AI056997, R01-AI48484, 5R01-AI054232-04, R21-AI060451, T32-AI07421, R01-AI035522]; NIDCR NIH HHS [R21-DE15090]; PHS HHS [5K24-A1056986-04] NR 44 TC 100 Z9 107 U1 0 U2 4 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 2007 VL 195 IS 4 BP 551 EP 561 DI 10.1086/510852 PG 11 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 127DP UT WOS:000243565800013 PM 17230415 ER PT J AU Cui, XZ Li, Y Li, XM Laird, MW Subramanian, M Moayeri, M Leppla, SH Fitz, Y Su, JW Sherer, K Eichacker, PQ AF Cui, Xizhong Li, Yan Li, Xuemei Laird, Michael W. Subramanian, Mani Moayeri, Mahtab Leppla, Stephen H. Fitz, Yvonne Su, Junwu Sherer, Kevin Eichacker, Peter Q. TI Bacillus anthracis edema and lethal toxin have different hemodynamic effects but function together to worsen shock and outcome in a rat model SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 102nd International Conference of the American-Thoracic-Society CY MAY 19-24, 2006 CL San Diego, CA SP Amer Thorac Soc ID INHALATIONAL ANTHRAX; PROTECTIVE ANTIGEN; ESCHERICHIA-COLI; CYCLIC-AMP; CELLS; PURIFICATION; MICE; PATHOGENESIS; COMPONENTS; TOXICITY AB Introduction. To better define the contribution of edema toxins (ETx) and lethal toxins (LeTx) to shock with Bacillus anthracis, recombinant preparations of each were investigated alone or together in rats. Methods and results. Lethal dose ranges (0%-100% lethality) of ETx (200-800 mu g/kg as a 24-h infusion) were higher than those of LeTx (12.5-200 mu g/ kg) (p < .0001). However, compared with LeTx, similarly lethal ETx doses produced earlier and greater reductions in mean blood pressure (MBP) and increased, rather than decreased, heart rate (HR) (P < .05 for all). Combining either similar weight or lethal doses of ETx and LeTx increased the hazard ratio for death (log +/- standard error) similar to the sum calculated with the toxin's effects alone (2.6 +/- 1.1 observed 2.9 vs. 1.0 calculated for similar weight and 3.1 +/- 1.0 vs. 3.9 +/- 1.5 for similar lethal doses; P = .5 for both). Early (<= 10 h) and late during infusion, ETx and LeTx together also altered MBP and HR in patterns consistent with the sum of their individual effects. Conclusions. ETx was similar to 10 times less lethal than LeTx but produced greater hypotension and added to the latter's harmful effects. These findings suggest that it may be appropriate for antitoxin therapies for B. anthracis to target both ETx and LeTx. C1 NIH, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. NIAID, NIH, Bethesda, MD 20892 USA. Human Genome Sci, Rockville, MD USA. RP Eichacker, PQ (reprint author), NIH, Dept Crit Care Med, Ctr Clin, Bldg 10,Rm 2C145, Bethesda, MD 20892 USA. EM peichacker@mail.cc.nih.gov NR 32 TC 43 Z9 45 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 2007 VL 195 IS 4 BP 572 EP 580 DI 10.1086/510856 PG 9 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 127DP UT WOS:000243565800015 PM 17230417 ER PT J AU Huang, XM Chen, HL Miller, WC Mailman, RB Woodard, JL Chen, PC Xiang, D Murrow, RW Wang, YZ Poole, C AF Huang, Xuemei Chen, Honglei Miller, William C. Mailman, Richard B. Woodard, Jennifer L. Chen, Peter C. Xiang, Dong Murrow, Richard W. Wang, Yi-Zhe Poole, Charles TI Lower low-density lipoprotein cholesterol levels are associated with Parkinson's disease SO MOVEMENT DISORDERS LA English DT Article DE Parkinson's disease; low-density lipoprotein cholesterol; apolipoprotein E; statin; case control study ID CIGARETTE-SMOKING; SERUM-CHOLESTEROL; APOLIPOPROTEIN-E; CONTROLLED TRIAL; RISK; HYPOCHOLESTEROLEMIA; INDIVIDUALS; MORTALITY; PROFILES; DEMENTIA AB The apolipoprotein E (APOE) epsilon 2 allele has been associated with both Parkinson's disease (PD) and lower low-density lipoprotein cholesterol (LDL-C). We tested the hypothesis that lower LDL-C may be associated with PD. This case-control study used fasting lipid profiles obtained from 124 PD cases and 112 controls. The PD cases were recruited from consecutive cases presenting at our tertiary Movement Disorder Clinic, and the controls were recruited from the Spouse populations of the same clinic. Multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated from unconditional logistic regressions, adjusting for age gender, smoking status, and use of cholesterol-lowering agents. Lower LDL-C concentrations were associated with a higher occurrence of PD. Compared with participants with the highest LDL-C (>= 138 mg/dL), the OR was 2.2 (95% Cl = 0.9-5.1) for participants with LDL-C of 115 to 137,3.5 (95% Cl = 1.6-8.1) for LDL-C of 93 to 114, and 2.6 (95% Cl - 1.1-5.9) for LDL-C of <= 92. Interestingly, use of either cholesterol-lowering drugs, or statins alone, was related to lower PD occurrence. Thus, our data provide preliminary evidence that low LDL-C may be associated with higher Occurrence of PD, and/or that statin use may lower PD occurrence, either of which finding warrants further investigation. (C) 2006 Movement Disorder Society. C1 Univ N Carolina, Sch Med, Dept Neurol, Chapel Hill, NC 27599 USA. NIEHS, Res Triangle Pk, NC 27709 USA. Univ N Carolina, Sch Publ Hlth, Dept Epidemiol, Chapel Hill, NC USA. Univ N Carolina, Sch Med, Dept Pharmacol, Ctr Neurosci, Chapel Hill, NC USA. Univ N Carolina, Sch Med, Dept Psychiat, Ctr Neurosci, Chapel Hill, NC USA. Univ N Carolina, Sch Med, Dept Med Chem, Ctr Neurosci, Chapel Hill, NC USA. RP Huang, XM (reprint author), Univ N Carolina, Sch Med, Dept Neurol, 3104 Bioinformat Bldg, Chapel Hill, NC 27599 USA. EM xuemei@med.unc.edu RI Miller, William/H-4800-2014; OI Miller, William/0000-0002-1934-7827; Mailman, Richard/0000-0003-1353-2738; Chen, Honglei/0000-0003-3446-7779 FU Intramural NIH HHS [Z01 ES101986-02, Z99 ES999999]; NCRR NIH HHS [M01 RR000046, M01 RR000046-41, RR000046]; NIA NIH HHS [K23 AG021491, K23 AG021491-04, K23-AG21491] NR 30 TC 86 Z9 95 U1 0 U2 3 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 FEB 15 PY 2007 VL 22 IS 3 BP 377 EP 381 DI 10.1002/mds.21290 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 147OQ UT WOS:000245012700014 PM 17177184 ER PT J AU Toft, M Mata, IF Ross, OA Kachergus, J Hulihan, MM Haugarvoll, K Stone, JT Blazquez, M Gibson, JM Aasly, JO White, LR Lynch, T Adler, CH Gwinn-Hardy, K Farrer, MJ AF Toft, Mathias Mata, Ignacio F. Ross, Owen A. Kachergus, Jennifer Hulihan, Mary M. Haugarvoll, Kristoffer Stone, Jeremy T. Blazquez, Marta Gibson, J. Mark Aasly, Jan O. White, Linda R. Lynch, Timothy Adler, Charles H. Gwinn-Hardy, Katrina Farrer, Matthew J. TI Pathogenicity of the Lrrk2 R1514Q substitution in Parkinson's disease SO MOVEMENT DISORDERS LA English DT Article DE Lrrk2; R1514Q; pathogenicity; genetic testing ID AUTOSOMAL-DOMINANT PARKINSONISM; GENE; MUTATIONS; ASSOCIATION; FAMILIES; LINKAGE AB An increasing number of nonsynonymous LRRK2 variants are being reported as putative pathogenic mutations. We identified one large kindred harboring the Lrrk2 R1514Q substitution; however, the variant did not segregate fully with disease. Combined analyses of three case-control series demonstrate that the R1514Q substitution is not associated with increased risk of disease (OR: 1.3; 95 % Cl: 0.6-2.8; P = 0.45). These findings highlight the importance of using family-based studies and multiple population screenings when examining the association of these polymorphic LRRK2 gene variants with Parkinson's disease. (C) 2007 Movement Disorder Society. C1 Mayo Clin Coll Med, Dept Neurosci, Jacksonville, FL 32224 USA. Norwegian Univ Sci & Technol, Dept Neurosci, N-7034 Trondheim, Norway. Hosp Univ Cent Asturias, Genet Mol Lab, Inst Invest Befrol IRSIN FRIAT, Oviedo, Spain. Hosp Univ Cent Asturias, Serv Neurol, Oviedo, Spain. Royal Victoria Hosp, Dept Neurol, Belfast BT12 6BA, Antrim, North Ireland. St Olavs Hosp, Dept Neurol, Trondheim, Norway. Mater Misericordiae Univ Hosp, Dept Neurol, Dublin 7, Ireland. Univ Coll Dublin, Dublin 2, Ireland. NINDS, NIH, Bethesda, MD 20892 USA. RP Ross, OA (reprint author), Mayo Clin, Mol Genet Lab & Core, Morris K Udall Parkinsons Dis Res Ctr Excellence, Dept Neurosci, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM ross.owen@mayo.edu RI Gwinn, Katrina/C-2508-2009; Ross, Owen/D-7573-2013; Haugarvoll, Kristoffer/L-1486-2015; OI Haugarvoll, Kristoffer/0000-0001-9381-1109; Fernandez Mata, Ignacio/0000-0003-1198-0633; Toft, Mathias/0000-0002-6723-6865; Gwinn, Katrina/0000-0002-8277-651X FU NINDS NIH HHS [P01 #NS40256] NR 15 TC 5 Z9 5 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0885-3185 J9 MOVEMENT DISORD JI Mov. Disord. PD FEB 15 PY 2007 VL 22 IS 3 BP 389 EP 392 DI 10.1002/mds.21217 PG 4 WC Clinical Neurology SC Neurosciences & Neurology GA 147OQ UT WOS:000245012700017 PM 17216639 ER PT J AU Zhou, TQ Xu, L Dey, B Hessell, AJ Van Ryk, D Xiang, SH Yang, XZ Zhang, MY Zwick, MB Arthos, J Burton, DR Dimitrov, DS Sodroski, J Wyatt, R Nabel, GJ Kwong, PD AF Zhou, Tongqing Xu, Ling Dey, Barna Hessell, Ann J. Van Ryk, Donald Xiang, Shi-Hua Yang, Xinzhen Zhang, Mei-Yun Zwick, Michael B. Arthos, James Burton, Dennis R. Dimitrov, Dimiter S. Sodroski, Joseph Wyatt, Richard Nabel, Gary J. Kwong, Peter D. TI Structural definition of a conserved neutralization epitope on HIV-1 gp120 SO NATURE LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; ENVELOPE GLYCOPROTEIN; BINDING SITES; RECEPTOR; RECOGNITION; ANTIGEN; PROTEIN; DOMAIN; GP41 AB The remarkable diversity, glycosylation and conformational flexibility of the human immunodeficiency virus type 1 (HIV-1) envelope (Env), including substantial rearrangement of the gp120 glycoprotein upon binding the CD4 receptor, allow it to evade antibody-mediated neutralization. Despite this complexity, the HIV-1 Env must retain conserved determinants that mediate CD4 binding. To evaluate how these determinants might provide opportunities for antibody recognition, we created variants of gp120 stabilized in the CD4-bound state, assessed binding of CD4 and of receptor-binding-site antibodies, and determined the structure at 2.3 angstrom resolution of the broadly neutralizing antibody b12 in complex with gp120. b12 binds to a conformationally invariant surface that overlaps a distinct subset of the CD4-binding site. This surface is involved in the metastable attachment of CD4, before the gp120 rearrangement required for stable engagement. A site of vulnerability, related to a functional requirement for efficient association with CD4, can therefore be targeted by antibody to neutralize HIV-1. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA. Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA. Scripps Res Inst, Dept Mol Biol, La Jolla, CA 92037 USA. Harvard Univ, Sch Med, Dept Canc Immunol & AIDS, Dana Farber Canc Inst, Boston, MA 02115 USA. NCI, Ctr Canc Res, Frederick, MD 21702 USA. RP Kwong, PD (reprint author), NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM pdkwong@nih.gov RI Zhou, Tongqing/A-6880-2010 OI Zhou, Tongqing/0000-0002-3935-4637 FU Intramural NIH HHS; NIAID NIH HHS [U19 AI067854, U19 AI067854-03] NR 50 TC 541 Z9 552 U1 5 U2 70 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 15 PY 2007 VL 445 IS 7129 BP 732 EP 737 DI 10.1038/nature05580 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 136EK UT WOS:000244205200037 PM 17301785 ER PT J AU Gavin, MA Rasmussen, JP Fontenot, JD Vasta, V Manganiello, VC Beavo, JA Rudensky, AY AF Gavin, Marc A. Rasmussen, Jeffrey P. Fontenot, Jason D. Vasta, Valeria Manganiello, Vincent C. Beavo, Joseph A. Rudensky, Alexander Y. TI Foxp3-dependent programme of regulatory T-cell differentiation SO NATURE LA English DT Article ID TRANSCRIPTION FACTOR FOXP3; HELPER-CELLS; INFLAMMATION; ACTIVATION; RECEPTORS AB Regulatory CD4(+) T cells (T-R cells), the development of which is critically dependent on X-linked transcription factor Foxp3 ( forkhead box P3), prevent self-destructive immune responses(1). Despite its important role, molecular and functional features conferred by Foxp3 to T-R precursor cells remain unknown. It has been suggested that Foxp3 expression is required for both survival of T-R precursors as well as their inability to produce interleukin (IL)-2 and independently proliferate after T-cell-receptor engagement, raising the possibility that such 'anergy' and T-R suppressive capacity are intimately linked(2-4). Here we show, by dissociating Foxp3-dependent features from those induced by the signals preceding and promoting its expression in mice, that the latter signals include several functional and transcriptional hallmarks of T-R cells. Although its function is required for T-R cell suppressor activity, Foxp3 to a large extent amplifies and fixes pre-established molecular features of T-R cells, including anergy and dependence on paracrine IL-2. Furthermore, Foxp3 solidifies T-R cell lineage stability through modification of cell surface and signalling molecules, resulting in adaptation to the signals required to induce and maintain T-R cells. This adaptation includes Foxp3-dependent repression of cyclic nucleotide phosphodiesterase 3B, affecting genes responsible for T-R cell homeostasis. C1 Univ Washington, Dept Immunol, Seattle, WA 98195 USA. Univ Washington, Dept Pharmacol, Seattle, WA 98195 USA. Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Rudensky, AY (reprint author), Amgen Corp, Seattle, WA 98101 USA. EM aruden@u.washington.edu OI Rasmussen, Jeffrey/0000-0001-6997-3773 NR 23 TC 626 Z9 672 U1 4 U2 25 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 15 PY 2007 VL 445 IS 7129 BP 771 EP 775 DI 10.1038/nature05543 PG 5 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 136EK UT WOS:000244205200046 PM 17220874 ER PT J AU Zhou, Z Bai, YW AF Zhou, Zheng Bai, Yawen TI Structural biology - Analysis of protein-folding cooperativity SO NATURE LA English DT Letter ID DOWNHILL C1 NCI, Biochem & Mol Biol Lab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Zhou, Z (reprint author), NCI, Biochem & Mol Biol Lab, Ctr Canc Res, NIH, Bldg 37,Room 6114E, Bethesda, MD 20892 USA. EM yawen@helix.nih.gov NR 4 TC 30 Z9 30 U1 1 U2 7 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 15 PY 2007 VL 445 IS 7129 BP E16 EP E17 DI 10.1038/nature05644 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 136EK UT WOS:000244205200034 PM 17301743 ER PT J AU Esposito, G Giovacchini, G Der, M Liow, JS Bhattacharjee, AK Ma, K Herscovitch, P Channing, M Eckelman, WC Hallett, M Carson, RE Rapoport, SI AF Esposito, Giuseppe Giovacchini, Giampiero Der, Margaret Liow, Jeih-San Bhattacharjee, Abesh K. Ma, Kaizong Herscovitch, Peter Channing, Michael Eckelman, William C. Hallett, Mark Carson, Richard E. Rapoport, Stanley I. TI Imaging signal transduction via arachidonic acid in the human brain during visual stimulation, by means of positron emission tomography SO NEUROIMAGE LA English DT Article DE positron emission tomography; brain; human; arachidonic acid; stimulation; phospholipase A(2); signal; transduction; blood flow; visual; flash; sensory ID PHOSPHOLIPASE A(2) ACTIVATION; CEREBRAL BLOOD-FLOW; UNANESTHETIZED RATS; FATTY-ACIDS; CHOLINERGIC STIMULATION; SELECTIVE ATTENTION; PARKINSONS-DISEASE; ALZHEIMERS-DISEASE; AWAKE RATS; CORTEX AB Background. Arachidonic acid (AA, 20:4n-6), an important second messenger, is released from membrane phospholipid following receptor mediated activation of phospholipase A(2) (PLAD(2)). This signaling process can be imaged in brain as a regional brain AA incorporation coefficient K*. Hypothesis: K* will be increased in brain visual areas of subjects submitted to visual stimulation. Subjects and methods: Regional values of K* were measured with positron emission tomography (PET), following the intravenous injection of [1-C-11]AA, in 16 healthy volunteers subjected to visual stimulation at flash frequencies 2.9 Hz (8 subjects) or 7.8 Hz (8 subjects), compared with the dark (0 Hz) condition. Regional cerebral blood flow (rCBF) was measured with intravenous [O-15]water under comparable conditions. Results: During flash stimulation at 2.9 Hz or 7.8 Hz vs. 0 Hz, K* was increased significantly by 2.3-8.9% in Brodmann areas 17, 18 and 19, and in additional frontal, parietal and temporal cortical regions. rCBF was increased significantly by 3.1-22%, often in comparable regions. Increments at 7.8 Hz often exceeded those at 2.9 Hz for both K* and rCBF. Decrements in both parameters also were produced, particularly in frontal brain regions. Conclusions: AA plays a role in signaling processes provoked by visual stimulation, since visual stimulation at flash frequencies of 2.9 and 7.8 Hz compared to 0 Hz modifies both K* for AA and rCBF in visual and related areas of the human brain. The two-stimulus condition paradigm of this study might be used with PET to image effects of other functional activations and of drugs on brain signaling via AA. Published by Elsevier Inc. C1 NIA, Brain Physiol & Metab Sect, NIH, Bethesda, MD 20892 USA. NINDS, PET Dept, Warren Magnusson Clin Ctr, Med Neurol Branch,NIH, Bethesda, MD 20892 USA. NINDS, Human Motor Control Sect, Med Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Rapoport, SI (reprint author), NIA, Brain Physiol & Metab Sect, NIH, Bldg 9,Rm 1S128,9 Mem Dr, Bethesda, MD 20892 USA. EM sir@helix.nih.gov RI Carson, Richard/H-3250-2011 OI Carson, Richard/0000-0002-9338-7966 FU Intramural NIH HHS [Z99 NS999999] NR 55 TC 29 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 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2007 VL 34 IS 4 BP 1342 EP 1351 DI 10.1016/j.neuroimage.2006.11.018 PG 10 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 138GA UT WOS:000244349900003 PM 17196833 ER PT J AU Vaupel, DB Stein, EA Mukhin, AG AF Vaupel, D. Bruce Stein, Elliot A. Mukhin, Alexey G. TI Quantification of alpha 4 beta 2*nicotinic receptors in the rat brain with microPET (R) and 2-[F-18]F-A-85380 SO NEUROIMAGE LA English DT Article ID NICOTINIC ACETYLCHOLINE-RECEPTORS; POSITRON-EMISSION-TOMOGRAPHY; RADIATION-DOSIMETRY; GRAPHICAL ANALYSIS; C-11 RACLOPRIDE; PET DATA; QUANTITATION; INFUSION; HUMANS; TOXICITY AB The radioligand 2-[F]F-A-85380 has been used for PET studies of the alpha 4 beta 2* subtype of nicotinic acetylcholine receptors (nAChRs) in the living brain of humans and nonhuman primates. In order to extend the capacity of microPET to quantify neuroreceptors in rat brain, we carried out studies of 2-[F-18]F-A-85380 to measure the apparent binding potential BP* in individual rats, which were studied repeatedly over several months. Using a bolus-plus-infusion paradigm, 2-[F-18]F-A-85380 (specific activity 20-1300 GBq/mu mol) was administered intravenously over 8 to 9 h with K-bol values of 350 to 440 min and a mean infusion rate of 0.03 +/- 0.01 nmol/kg/h. Studies included a 2-h nicotine infusion initiated 2 h before the end of scanning to displace specifically bound radioactivity. Steady state binding in brain was obtained within 5 h as defined by the occurrence of constant radioactivity concentrations in brain regions and constant, free arterial plasma levels of nonmetabolized radioligand. BP* averages ( SEM) for thalamus, forebrain, and cerebellum were 5.9 +/- 0.7, 2.6 +/- 0.4, and 1.0 +/- 0.1, respectively, which are consistent with the alpha 4 beta 2* nAChR distribution in rat brain measured in vitro. Studies of receptor occupancy determined the ED50 to be 0.29 nmol/kg/h. The demonstration that alpha 4 beta 2* nAChRs are quantifiable in the rat brain using PET measurements, coupled with the ability to conduct longitudinal studies over several months in the same rats, suggests potential applications to studies of chronic nicotine use, its treatment, and abnormal functioning of alpha 4 beta 2* receptors in a rat model. Published by Elsevier Inc. C1 NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. RP Vaupel, DB (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH,Dept Hlth & Human Serv, Baltimore, MD 21224 USA. EM bvaupel@intra.nida.nih.gov RI Stein, Elliot/C-7349-2008 FU Intramural NIH HHS [Z99 DA999999] NR 39 TC 16 Z9 17 U1 0 U2 1 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2007 VL 34 IS 4 BP 1352 EP 1362 DI 10.1016/j.neuroimage.2006.10.036 PG 11 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 138GA UT WOS:000244349900004 PM 17187994 ER PT J AU Sitaram, R Zhang, HH Guan, CT Thulasidas, M Hoshi, Y Ishikawa, A Shimizu, K Birbaumer, N AF Sitaram, Ranganatha Zhang, Haihong Guan, Cuntai Thulasidas, Manoj Hoshi, Yoko Ishikawa, Akihiro Shimizu, Koji Birbaumer, Niels TI Temporal classification of multichannel near-infrared spectroscopy signals of motor imagery for developing a brain-computer interface SO NEUROIMAGE LA English DT Article DE brain-computer interface (BCI); near-infrared spectroscopy (NIRS); amyotrophic lateral sclerosis (ALS); Motor Imagery; Support Vector Machine (SVM); Hidden Markov Model (HMM) ID RESONANCE-IMAGING FMRI; TRANSLATION DEVICE TTD; HIDDEN MARKOV-MODELS; FAST NEURONAL SIGNAL; MOVEMENT SIGNAL; SELF-REGULATION; CORTEX; TIME; EEG; ACTIVATION AB There has been an increase in research interest for brain-computer interface (BCI) technology as an alternate mode of communication and environmental control for the disabled, such as patients suffering from amyotrophic lateral sclerosis (ALS), brainstem stroke and spinal cord injury. Disabled patients with appropriate physical care and cognitive ability to communicate with their social environment continue to live with a reasonable quality of life over extended periods of time. Near-infrared spectroscopy is a non-invasive technique which utilizes light in the near-infrared range (700 to 1000 nm) to determine cerebral oxygenation, blood flow and metabolic status of localized regions of the brain. In this paper, we describe a study conducted to test the feasibility of using multichannel NIRS in the development of a BCI. We used a continuous wave 20-channel NIRS system over the motor cortex of 5 healthy volunteers to measure oxygenated and deoxygenated hemoglobin changes during left-hand and right-hand motor imagery. We present results of signal analysis indicating that there exist distinct patterns of hemodynamic responses which could be utilized in a pattern classifier towards developing a BCI. We applied two different pattern recognition algorithms separately, Support Vector Machines (SVM) and Hidden Markov Model (HMM), to classify the data offline. SVM classified left-hand imagery from right-hand imagery with an average accuracy of 73 % for all volunteers, while HMM performed better with an average accuracy of 89%. Our results indicate potential application of NIRS in the development of BCIs. We also discuss here future extension of our system to develop a word speller application based on a cursor control paradigm incorporating online pattern classification of single-trial NIRS data. (c) 2006 Elsevier Inc. All rights reserved. C1 Univ Tubingen, Inst Med Psychol & Behav Neurobiol, D-72074 Tubingen, Germany. Inst Infocomm Res, Singapore, Singapore. Tokyo Inst Psychiat, Tokyo, Japan. NIH, Bethesda, MD 20892 USA. RP Sitaram, R (reprint author), Univ Tubingen, Inst Med Psychol & Behav Neurobiol, Gartenstr 29, D-72074 Tubingen, Germany. EM sitaram.ranganatha@uni-tuebingen.de RI Guan, Cuntai/G-7835-2016; THULASIDAS, Manoj/A-9920-2017; OI Guan, Cuntai/0000-0002-0872-3276; Sitaram, Ranganatha/0000-0002-8577-8035 NR 43 TC 262 Z9 272 U1 12 U2 67 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1053-8119 EI 1095-9572 J9 NEUROIMAGE JI Neuroimage PD FEB 15 PY 2007 VL 34 IS 4 BP 1416 EP 1427 DI 10.1016/j.neuroimage.2006.11.005 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 138GA UT WOS:000244349900009 PM 17196832 ER PT J AU Budhani, S Marsh, AA Pine, DS Blair, RJR AF Budhani, S. Marsh, A. A. Pine, D. S. Blair, R. J. R. TI Neural correlates of response reversal: Considering acquisition SO NEUROIMAGE LA English DT Article DE caudate; anterior cingulate; probabilistic reversal learning; psychopathy; inferior frontal cortex ID ANTERIOR CINGULATE CORTEX; HUMAN ORBITOFRONTAL CORTEX; EVENT-RELATED FMRI; PREFRONTAL CORTEX; FRONTAL-CORTEX; PSYCHOPATHIC TENDENCIES; CAUDATE-NUCLEUS; ERROR-DETECTION; LEARNING-TASK; TEMPORAL-LOBE AB Previous work on response reversal has typically used a single pair of stimuli that serially reverse. This conflation of acquisition and reversal processes has prevented an examination of the functional role of neural systems implicated in response reversal during acquisition despite the relevance of such data in evaluating accounts of response reversal. In the current study, participants encountered 16 independent reversing stimulus pairs in the context of a probabilistic response reversal paradigm. Functional regions of interest identified as involved in response reversal through a contrast used in the previous literature (punished errors made in the reversal phase versus rewarded correct responses), were interrogated across conditions. Consistent with suggestions that middle frontal cortex codes reward, this region showed significantly greater responses to rewarded rather than punished trials irrespective of accuracy or learning phase (acquisition or reversal). Consistent with the suggestion that this coding of the expectation of reinforcement is acquired via input from the amygdala, we observed significant positive connectivity between activity within the amygdala and a region of rostral anterior cingulate cortex highly proximal to this region of middle frontal/mesial prefrontal cortex. In contrast, inferior frontal cortex, anterior cingulate cortex and caudate showed greater responses to punished errors than to the rewarded correct responses. These three regions also showed significant activation to rewarded errors during acquisition, in contrast to positions suggesting that inferior frontal cortex represents punishment or suppresses previously rewarded responses. Moreover, a connectivity analysis with an anterior cingulate cortex seed revealed highly significant positive connectivity among them. The implications of these data for recent accounts of response reversal and of response reversal impairments in specific neuropsychiatric populations are discussed. Published by Elsevier Inc. C1 Nalt Inst Mental Hlth, Mood & Anxiety Disorders, Unit Affect Cognit Neurosci, NIH, Bethesda, MD 20892 USA. UCL, Dept Psychol, London WC1E 6BT, England. RP Blair, RJR (reprint author), Nalt Inst Mental Hlth, Mood & Anxiety Disorders, Unit Affect Cognit Neurosci, NIH, Bethesda, MD 20892 USA. EM James.Blair@mail.nih.gov FU Intramural NIH HHS NR 77 TC 63 Z9 63 U1 4 U2 14 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 2007 VL 34 IS 4 BP 1754 EP 1765 DI 10.1016/j.neuroimage.2006.08.060 PG 12 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 138GA UT WOS:000244349900042 PM 17188518 ER PT J AU Staudt, LM AF Staudt, Louis M. TI A closer look at follicular lymphoma SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Editorial Material ID HEALTHY-INDIVIDUALS; B-CELLS C1 NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Staudt, LM (reprint author), NCI, Metab Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. NR 4 TC 35 Z9 35 U1 0 U2 2 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 15 PY 2007 VL 356 IS 7 BP 741 EP 742 DI 10.1056/NEJMcibr067155 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 135ZV UT WOS:000244193300016 PM 17301308 ER PT J AU Berg, CD Aberle, DR AF Berg, Christine D. Aberle, Denise R. CA Natl Lung Screening Trial Exec TI CT screening for lung cancer SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Letter C1 NCI, Bethesda, MD 20892 USA. Univ Calif Los Angeles, David Geffen Sch Med, Los Angeles, CA 90095 USA. RP Berg, CD (reprint author), NCI, Bethesda, MD 20892 USA. EM bergc@mail.nih.gov NR 1 TC 4 Z9 5 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 15 PY 2007 VL 356 IS 7 BP 743 EP 744 PG 2 WC Medicine, General & Internal SC General & Internal Medicine GA 135ZV UT WOS:000244193300018 PM 17310522 ER PT J AU Cieslak, J Kauffman, JS Kolodziejski, MJ Lloyd, JR Beaucage, SL AF Cieslak, Jacek Kauffman, Jon S. Kolodziejski, Michelle J. Lloyd, John R. Beaucage, Serge L. TI Assessment of 4-nitrogenated benzyloxymethyl groups for 2 '-hydroxyl protection in solid-phase RNA synthesis SO ORGANIC LETTERS LA English DT Article ID CHEMICAL-SYNTHESIS; 2'-O-PROTECTING FUNCTIONS; OLIGORIBONUCLEOTIDES; INTERFERENCE; NUCLEOTIDES; ACETALS AB The search for a 2'-OH protecting group that would impart ribonucleoside phosphoramidites with coupling kinetics and coupling efficiencies comparable to those of deoxyribonucleoside phosphoramidites led to an assessment of 2'-O-(4-nitrogenated benzyloxy)methyl groups through solid-phase RNA synthesis using phosphoramidites 2a-d, 12a, and 14a. These phosphoramidites exhibited rapid and efficient coupling properties. Particularly noteworthy is the cleavage of the 2'-O-[4-(N-methylamino)benzyloxy]methyl groups in 0.1 M AcOH, which led to U(19)dT within 15 min at 90 degrees C. C1 US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prot, Bethesda, MD 20892 USA. Lancaster Labs, Lancaster, PA 17605 USA. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Cieslak, J (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prot, 8800 Rockville Pike, Bethesda, MD 20892 USA. EM serge.beaucage@fda.hhs.gov NR 25 TC 16 Z9 16 U1 2 U2 8 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 1523-7060 J9 ORG LETT JI Org. Lett. PD FEB 15 PY 2007 VL 9 IS 4 BP 671 EP 674 DI 10.1021/ol0629824 PG 4 WC Chemistry, Organic SC Chemistry GA 133UQ UT WOS:000244039800032 PM 17256869 ER PT J AU Yu, YK AF Yu, Yi-Kuo TI A metric measure for weight matrices of variable lengths - with applications to clustering and classification of hidden Markov models SO PHYSICA A-STATISTICAL MECHANICS AND ITS APPLICATIONS LA English DT Article DE information theory; metric; weight matrices; clustering AB We construct a metric measure among weight matrices that are commonly used in non-interacting statistical physics systems, computational biology problems, as well as in general applications such as hidden Markov models. The metric distance between two weight matrices is obtained via aligning the matrices and thus can be evaluated by dynamic programming. Capable of allowing reverse complements in distance evaluation, this metric accommodates both gapless and gapped alignments between two weight matrices. The distance statistics among random motifs is also studied. We find that the average square distance and its standard error grow with different powers of motif length, and the normalized square distance follows a Gaussian distribution for large motif lengths. (c) 2006 Published by Elsevier B.V. C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Yu, YK (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM yyu@ncbi.nlm.nih.gov NR 8 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-4371 J9 PHYSICA A JI Physica A PD FEB 15 PY 2007 VL 375 IS 1 BP 212 EP 220 DI 10.1016/j.physa.2006.08.061 PG 9 WC Physics, Multidisciplinary SC Physics GA 134LM UT WOS:000244084500020 ER PT J AU Sharifi, N Hurt, EM Kawasaki, BT Farrar, WL AF Sharifi, Nima Hurt, Elaine M. Kawasaki, Brian T. Farrar, William L. TI TGFBR3 loss and consequences in prostate cancer SO PROSTATE LA English DT Article DE TGF-beta; prostate cancer; angiogenesis; stem cells; betaglycan; prostate intraepithelial neoplasia ID GROWTH-FACTOR-BETA; EPITHELIUM-DERIVED FACTOR; GENE-EXPRESSION ANALYSIS; STEM-CELLS; MUTATIONAL ANALYSIS; III RECEPTOR; DISEASE; INHIBIN; DEAFNESS; MICE AB BACKGROUND. Resistance to transforming growth factor-beta (TGF-beta) is important in tumorigenesis. TGF-beta resistance mechanisms in prostate cancer are not well understood. METHODS. We have conducted a systematic analysis of TGF-beta pathway components with a meta-analysis of seven microarray studies using Oncomine and evaluated the results of TGFBR3 expression in prostate cell lines. Furthermore, we knocked down TGFBR3 in prostate epithelial cells and analyzed the consequences of TGFBR3 knockdown. RESULTS. We found that TGFBR3 is the TGF-beta component most commonly downregulated among localized human prostate cancer studies. TGFBR3 knockdown led to focus formation and enhanced expression of CD133, a marker found on prostate cancer Stem cells. DNA microarray analysis of TGFBR3 knockdown cells identified 101 genes regulated by TGFBR3. Seven of these genes show a corresponding decrease in clinical prostate cancer specimens, which include genes involved in prostate mass and vasculature. CONCLUSIONS. TGFBR3 downregulation is an important step in prostate tumorigenesis. C1 Natl Canc Inst, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Frederick, MD 21702 USA. NCI, Med Oncol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. RP Sharifi, N (reprint author), Natl Canc Inst, Canc Stem Cell Sect, Lab Canc Prevent, Ctr Canc Res,NIH, Bldg 560,Room 21-81, Frederick, MD 21702 USA. EM nima.sharifi@nih.gov NR 41 TC 34 Z9 35 U1 2 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0270-4137 J9 PROSTATE JI Prostate PD FEB 15 PY 2007 VL 67 IS 3 BP 301 EP 311 DI 10.1002/pros.20526 PG 11 WC Endocrinology & Metabolism; Urology & Nephrology SC Endocrinology & Metabolism; Urology & Nephrology GA 134PF UT WOS:000244094600009 PM 17192875 ER PT J AU Bumbaca, D Littlejohn, JE Nayakanti, H Lucas, AH Rigden, DJ Galperin, MY Jedrzejas, MJ AF Bumbaca, Daniela Littlejohn, James E. Nayakanti, Hannah Lucas, Alexander H. Rigden, Daniel J. Galperin, Michael Y. Jedrzejas, Mark J. TI Genome-based identification and characterization of a putative mucin-binding protein from the surface of Streptococcus pneumoniae SO PROTEINS-STRUCTURE FUNCTION AND BIOINFORMATICS LA English DT Article DE adhesin; carbohydrate; mucin; mucin-binding protein; Streptococcus pneumoniae; gram-positive bacteria ID SECONDARY STRUCTURE; VIRULENCE FACTORS; FUNCTIONAL FORM; SEQUENCE; PREDICTION; MODELS; PURIFICATION; PNEUMOLYSIN; ANTIBODIES; EMERGENCE AB Streptococcus pneumoniae open reading frame SP1492 encodes a surface protein that contains a novel conserved domain similar to the repeated fragments of mucin-binding proteins from lactobacilli and lactococci. To investigate the functional role(s) of this protein and its potential adhesive properties, the surface-exposed region of SP1492 was expressed in Escherichia coli, purified to homogeneity, and partially characterized by biophysical and immunological methods. Circular dichroism and sedimentation measurements confirmed that SP1492 is an all-P protein that exists in solution as a monomer. The SP1492 protein has been shown to be expressed by S. pneumoniae and was experimentally localized to its surface. The protein functional domain binds to mucins II and III from porcine stomach and to purified submaxillary bovine gland mucin. It appears to be one of the very few unambiguous pneumococcal adhesin molecules known to date. A hypothetical model constructed by ab initio techniques predicts a novel P-sandwich protein structure. Proteins 2007; 66:547-558. (c) 2006 Wiley-Liss, Inc. C1 Childrens Hosp Oakland, Res Inst, Ctr Immunobiol & Vaccine Dev, Oakland, CA 94609 USA. Univ Liverpool, Sch Biol Sci, Liverpool L69 7ZB, Merseyside, England. Natl Lib Med, NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. RP Jedrzejas, MJ (reprint author), Childrens Hosp Oakland, Res Inst, Ctr Immunobiol & Vaccine Dev, 5700 Martin Luther King Jr Way, Oakland, CA 94609 USA. EM MJedrzejas@chori.org RI Galperin, Michael/B-5859-2013; OI Galperin, Michael/0000-0002-2265-5572; Rigden, Daniel/0000-0002-7565-8937 FU NIAID NIH HHS [AI44079] NR 56 TC 13 Z9 14 U1 0 U2 3 PU WILEY-BLACKWELL PI HOBOKEN PA 111 RIVER ST, HOBOKEN 07030-5774, NJ USA SN 0887-3585 EI 1097-0134 J9 PROTEINS JI Proteins PD FEB 15 PY 2007 VL 66 IS 3 BP 547 EP 558 DI 10.1002/prot.21205 PG 12 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 126BR UT WOS:000243487700005 PM 17115425 ER PT J AU Tycko, R AF Tycko, Robert TI Symmetry-based constant-time homonuclear dipolar recoupling in solid state NMR SO JOURNAL OF CHEMICAL PHYSICS LA English DT Article ID NUCLEAR-MAGNETIC-RESONANCE; ANGLE-SPINNING NMR; BETA-AMYLOID FIBRILS; HIGH-RESOLUTION NMR; CHEMICAL-SHIFT; ROTATING SOLIDS; EXPERIMENTAL CONSTRAINTS; STRUCTURAL MEASUREMENTS; DISTANCE MEASUREMENTS; SECONDARY-STRUCTURE AB Constant-time dipolar recoupling pulse sequences are advantageous in structural studies by solid state nuclear magnetic resonance (NMR) with magic-angle spinning (MAS) because they yield experimental data that are relatively insensitive to radio-frequency pulse imperfections and nuclear spin relaxation processes. A new approach to the construction of constant-time homonuclear dipolar recoupling sequences is described, based on symmetry properties of the recoupled dipole-dipole interaction Hamiltonian under cyclic displacements in time with respect to the MAS sample rotation period. A specific symmetry-based pulse sequence called PITHIRDS-CT is introduced and demonstrated experimentally. C-13 NMR data for singly-C-13-labeled amino acid powders and amyloid fibrils indicate the effectiveness of PITHIRDS-CT in measurements of intermolecular distances in solids. N-15-detected and C-13-detected measurements of intramolecular N-15-N-15 distances in peptides with alpha-helical and beta-sheet structures indicate the utility of PITHIRDS-CT in studies of molecular conformations, especially measurements of backbone psi torsion angles in peptides containing uniformly N-15- and C-13-labeled amino acids. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Tycko, R (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. EM robertty@mail.nih.gov FU Intramural NIH HHS NR 51 TC 57 Z9 57 U1 4 U2 26 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 14 PY 2007 VL 126 IS 6 AR 064506 DI 10.1063/1.2437194 PG 9 WC Chemistry, Physical; Physics, Atomic, Molecular & Chemical SC Chemistry; Physics GA 136US UT WOS:000244250200024 PM 17313228 ER PT J AU Cheng, AW Arumugam, TV Liu, D Khatri, RG Mustafa, K Kwak, S Ling, HP Gonzales, C Xin, OY Jo, DG Guo, ZH Mark, RJ Mattson, MP AF Cheng, Aiwu Arumugam, Thiruma V. Liu, Dong Khatri, Rina G. Mustafa, Khadija Kwak, Seung Ling, Huai-Ping Gonzales, Cathleen Xin, Ouyang Jo, Dong-Gyu Guo, Zhihong Mark, Robert J. Mattson, Mark P. TI Pancortin-2 interacts with WAVE1 and Bcl-xL in a mitochondria-associated protein complex that mediates ischemic neuronal death SO JOURNAL OF NEUROSCIENCE LA English DT Article DE pancortin; WAVE1; cerebral ischemia; stroke; neuronal cell death; Bcl-xL ID FAMILY PROTEINS; BAX TRANSLOCATION; INDUCED APOPTOSIS; ACTIN-FILAMENTS; ARP2/3 COMPLEX; CELL-DEATH; WASP; EXCITOTOXICITY; A2-PANCORTINS; VULNERABILITY AB The actin-modulating protein Wiskott-Aldrich syndrome protein verprolin homologous-1 (WAVE1) and a novel CNS-specific protein, pancortin, are highly enriched in adult cerebral cortex, but their functions are unknown. Here we show that WAVE1 and pancortin-2 interact in a novel cell death cascade in adult, but not embryonic, cerebral cortical neurons. Focal ischemic stroke induces the formation of a protein complex that includes pancortin-2, WAVE1, and the anti-apoptotic protein Bcl-xL. The three-protein complex is associated with mitochondria resulting in increased association of Bax with mitochondria, cytochrome c release, and neuronal apoptosis. In pancortin null mice generated using a Cre-loxP system, ischemia-induced WAVE1-Bcl-xL interaction is diminished, and cortical neurons in these mice are protected against ischemic injury. Thus, pancortin-2 is a mediator of ischemia-induced apoptosis of neurons in the adult cerebral cortex and functions in a novel mitochondrial/actin-associated protein complex that sequesters Bcl-xL. C1 NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. Wyeth Res, Neurosci Discovery Res, Princeton, NJ 08543 USA. Sungkyunkwan Univ, Coll Pharm, Suwon, South Korea. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Mark, RJ (reprint author), Merck Res Labs, WP 26-265,770 Sumneytown Pike, West Point, PA 19486 USA. EM robert_mark@merck.com RI Arumugam, Thiruma/C-7969-2009; Arumugam, Thiruma/B-4898-2011; Mattson, Mark/F-6038-2012 FU Intramural NIH HHS NR 39 TC 26 Z9 28 U1 0 U2 0 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 14 PY 2007 VL 27 IS 7 BP 1519 EP 1528 DI 10.1523/JNEUROSCI.5154-06.2007 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 136QQ UT WOS:000244239600004 PM 17301160 ER PT J AU Buckholtz, JW Meyer-Lindenberg, A Honea, RA Straub, RE Pezawas, L Egan, MF Vakkalanka, R Kolachana, B Verchinski, BA Sust, S Mattay, VS Weinberger, DR Callicott, JH AF Buckholtz, Joshua W. Meyer-Lindenberg, Andreas Honea, Robyn A. Straub, Richard E. Pezawas, Lukas Egan, Michael F. Vakkalanka, Radhakrishna Kolachana, Bhaskar Verchinski, Beth A. Sust, Steven Mattay, Venkata S. Weinberger, Daniel R. Callicott, Joseph H. TI Allelic variation in RGS4 impacts functional and structural connectivity in the human brain SO JOURNAL OF NEUROSCIENCE LA English DT Article DE G-protein; schizophrenia; genetics; fMRI; VBM; human ID GTPASE-ACTIVATING PROTEINS; DORSOLATERAL PREFRONTAL CORTEX; INFERIOR FRONTAL-CORTEX; SHORT-TERM-MEMORY; WORKING-MEMORY; WHITE-MATTER; SIGNALING RGS; MESSENGER-RNA; ONSET SCHIZOPHRENIA; RESPONSE-INHIBITION AB Regulator of G-protein signaling 4 (RGS4) modulates postsynaptic signal transduction by affecting the kinetics of G alpha-GTP binding. Linkage, association, and postmortem studies have implicated the gene encoding RGS4 (RGS4) as a schizophrenia susceptibility factor. Using a multimodal neuroimaging approach, we demonstrate that genetic variation in RGS4 is associated with functional activation and connectivity during working memory in the absence of overt behavioral differences, with regional gray and white matter volume and with gray matter structural connectivity in healthy human subjects. Specifically, variation at one RGS4 single nucleotide polymorphism that has been associated previously with psychosis (rs951436) impacts frontoparietal and frontotemporal blood oxygenation level-dependent response and network coupling during working memory and results in regionally specific reductions in gray and white matter structural volume in individuals carrying the A allele. These findings suggest mechanisms in brain for the association of RGS4 with risk for psychiatric illness. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. NIMH, Unit Dynam Imaging Genet, NIH, Bethesda, MD 20892 USA. NIMH, Neuroimaging Core Facil, NIH, Bethesda, MD 20892 USA. NIMH, Unit Syst Neurosci Psychiat, Genes Cognit & Psychosis Program, NIH, Bethesda, MD 20892 USA. RP Callicott, JH (reprint author), Bldg 10,Ctr Dr,Room 4C-216,MSC 1364, Bethesda, MD 20892 USA. EM callicottj@mail.nih.gov RI Buckholtz, Joshua /E-7299-2010; Callicott, Joseph/C-9102-2009; Meyer-Lindenberg, Andreas/H-1076-2011 OI Pezawas, Lukas/0000-0002-1329-6352; Buckholtz, Joshua /0000-0002-9418-8686; Callicott, Joseph/0000-0003-1298-3334; Meyer-Lindenberg, Andreas/0000-0001-5619-1123 FU Intramural NIH HHS NR 99 TC 69 Z9 73 U1 2 U2 5 PU SOC NEUROSCIENCE PI WASHINGTON PA 11 DUPONT CIRCLE, NW, STE 500, WASHINGTON, DC 20036 USA SN 0270-6474 J9 J NEUROSCI JI J. Neurosci. PD FEB 14 PY 2007 VL 27 IS 7 BP 1584 EP 1593 DI 10.1523/JNEUROSCI.5112-06.2007 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 136QQ UT WOS:000244239600011 PM 17301167 ER PT J AU Berezhkovskii, AM Bezrukov, SM AF Berezhkovskii, Alexander M. Bezrukov, Sergey M. TI Site model for channel-facilitated membrane transport: invariance of the translocation time distribution with respect to direction of passage SO JOURNAL OF PHYSICS-CONDENSED MATTER LA English DT Article AB A particle entering a membrane channel either returns to the initial reservoir from which it entered or goes through to escape on the opposite side. We prove that the probability density of the translocation time is invariant with respect to the direction of passage. This invariance holds at arbitrary asymmetry of the intra-channel potential, i.e., independently of how different the translocation probabilities are in the two directions. Assuming that the particle motion is described as a continuous-time random walk between neighbouring sites representing the channel, we give three proofs of the invariance. The present analysis complements a recent proof of the invariance where we assumed Langevin dynamics of the particle in the channel. C1 NIH, Math & Stat Comp Lab, Div Computat Biosci, CIT, Bethesda, MD 20892 USA. NICHD, Lab Phys & Struct Biol, NIH, Bethesda, MD 20892 USA. RP Berezhkovskii, AM (reprint author), NIH, Math & Stat Comp Lab, Div Computat Biosci, CIT, Bethesda, MD 20892 USA. NR 9 TC 7 Z9 7 U1 0 U2 0 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0953-8984 J9 J PHYS-CONDENS MAT JI J. Phys.-Condes. Matter PD FEB 14 PY 2007 VL 19 IS 6 AR 065148 DI 10.1088/0953-8984/19/6/065148 PG 10 WC Physics, Condensed Matter SC Physics GA 130OU UT WOS:000243809700049 ER PT J AU Gopich, IV AF Gopich, Irina V. TI Long-time kinetics of the excited-state association-dissociation reaction with different lifetimes SO JOURNAL OF PHYSICS-CONDENSED MATTER LA English DT Article ID DIFFUSION-INFLUENCED REACTIONS; REVERSIBLE BIMOLECULAR REACTIONS; ASYMPTOTIC RELAXATION; GEMINATE REACTION; ARROW-C; EQUILIBRIUM; SIMULATION; BINDING AB We consider the long-time behaviour of the reversible diffusion-influenced reaction A + B (<-)(<-) C when A and C are immobile electronically excited states and B particles are in excess. A and C have different lifetimes. When C decays faster than A, the two leading terms of the asymptotic behaviour are obtained analytically by mapping this problem onto an effective irreversible reaction. The first term is exponential, and it coincides with that obtained from conventional rate equations with steady-state diffusion-influenced rate constants. The second term in the exponent is root t, as in the Smoluchowski irreversible kinetics. C1 NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Gopich, IV (reprint author), NIDDK, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. NR 28 TC 1 Z9 1 U1 2 U2 4 PU IOP PUBLISHING LTD PI BRISTOL PA DIRAC HOUSE, TEMPLE BACK, BRISTOL BS1 6BE, ENGLAND SN 0953-8984 J9 J PHYS-CONDENS MAT JI J. Phys.-Condes. Matter PD FEB 14 PY 2007 VL 19 IS 6 AR 065135 DI 10.1088/0953-8984/19/6/065135 PG 5 WC Physics, Condensed Matter SC Physics GA 130OU UT WOS:000243809700036 ER PT J AU Fishelovitch, D Hazan, C Shaik, S Wolfson, HJ Nussinov, R AF Fishelovitch, Dan Hazan, Carina Shaik, Sason Wolfson, Haim J. Nussinov, Ruth TI Structural dynamics of the cooperative binding of organic molecules in the human cytochrome P450 3A4 SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID DRUG-DRUG INTERACTIONS; CYP3A4 ACTIVE-SITE; ALPHA-NAPHTHOFLAVONE; CRYSTAL-STRUCTURES; LIGAND-BINDING; IN-VITRO; METABOLISM; OXIDATION; PROTEINS; ISOFORMS AB Cytochrome P450 3A4 (CYP3A4) is a key enzyme responsible for the metabolism of 50% of all orally administered drugs which exhibit an intriguing kinetic behavior typified by a sigmoidal dependence of the reaction velocity on the substrate concentration. There is evidence for the binding of two substrates in the active site of the enzyme, but the mechanism of this cooperative binding is unclear. Diazepam is such a drug that undergoes metabolism by CYP3A4 with sigmoidal dependence. Metabolism is initiated by hydrogen atom abstraction from the drug. To understand the factors that determine the cooperative binding and the juxtaposition of the C-H bond undergoing abstraction, we carried out molecular dynamics simulations for two enzymatic conformers and examined the differences between the substrate-free and the bound enzymes, with one and two diazepam molecules. Our results indicate that the effector substrate interacts both with the active substrate and with the enzyme, and that this interaction results in side chain reorientation with relatively minor long-range effects. In accord with experiment, we find that F304, in the interface between the active and effector binding sites, is a key residue in the mechanism of cooperative binding. The addition of the effector substrate stabilizes F304 and its environment, especially F213, and induces a favorable orientation of the active substrate, leading to a short distance between the targeted hydrogen for abstraction and the active species of the enzyme. In addition, in one conformer of the enzyme, residue R212 may strongly interact with F304 and counteract the effector's impact on the enzyme. C1 Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, Dept Human Genet, IL-69978 Tel Aviv, Israel. Hebrew Univ Jerusalem, Inst Chem, IL-91904 Jerusalem, Israel. Hebrew Univ Jerusalem, Lise Meitner Minerva Ctr Computat Quantum Chem, IL-91904 Jerusalem, Israel. Tel Aviv Univ, Sch Comp Sci, IL-69978 Tel Aviv, Israel. NCI Frederick, Ctr Canc Res Nanobiol Program, Frederick, MD 21702 USA. RP Nussinov, R (reprint author), Tel Aviv Univ, Sackler Fac Med, Sackler Inst Mol Med, Dept Human Genet, IL-69978 Tel Aviv, Israel. EM ruthn@ncifcrf.gov RI Wolfson, Haim/A-1837-2011 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 54 TC 33 Z9 33 U1 1 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD FEB 14 PY 2007 VL 129 IS 6 BP 1602 EP 1611 DI 10.1021/ja066007j PG 10 WC Chemistry, Multidisciplinary SC Chemistry GA 133GF UT WOS:000244000700041 PM 17284003 ER PT J AU Wolf, Y Madej, T Babenko, V Shoemaker, B Panchenko, AR AF Wolf, Yuri Madej, Thomas Babenko, Vladimir Shoemaker, Benjamin Panchenko, Anna R. TI Long-term trends in evolution of indels in protein sequences SO BMC EVOLUTIONARY BIOLOGY LA English DT Article ID MAMMALIAN GENOMES; DNA-SEQUENCES; INSERTIONS; DELETIONS; RATES; DATABASE; GENE; CLASSIFICATION; CONSTRAINTS; ALIGNMENTS AB Background: In this paper we describe an analysis of the size evolution of both protein domains and their indels, as inferred by changing sizes of whole domains or individual unaligned regions or "spacers". We studied relatively early evolutionary events and focused on protein domains which are conserved among various taxonomy groups. Results: We found that more than one third of all domains have a statistically significant tendency to increase/decrease in size in evolution as judged from the overall domain size distribution as well as from the size distribution of individual spacers. Moreover, the fraction of domains and individual spacers increasing in size is almost twofold larger than the fraction decreasing in size. Conclusion: We showed that the tolerance to insertion and deletion events depends on the domain's taxonomy span. Eukaryotic domains are depleted in insertions compared to the overall test set, namely, the number of spacers increasing in size is about the same as the number of spacers decreasing in size. On the other hand, ancient domain families show some bias towards insertions or spacers which grow in size in evolution. Domains from several Gene Ontology categories also demonstrate certain tendencies for insertion or deletion events as inferred from the analysis of spacer sizes. C1 NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. Russian Acad Sci, Inst Cytol & Genet, Novosibirsk 630090, Russia. RP Panchenko, AR (reprint author), NIH, Natl Ctr Biotechnol Informat, Bethesda, MD 20894 USA. EM wolf@ncbi.nlm.nih.gov; madej@ncbi.nlm.nih.gov; vl_babenko@yahoo.com; shoemake@ncbi.nlm.nih.gov; panch@ncbi.nlm.nih.gov RI Babenko, Vladimir/K-5609-2014; OI Babenko, Vladimir/0000-0002-3077-9559 FU Intramural NIH HHS NR 51 TC 19 Z9 21 U1 1 U2 4 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 13 PY 2007 VL 7 AR 19 DI 10.1186/1471-2148-7-19 PG 10 WC Evolutionary Biology; Genetics & Heredity SC Evolutionary Biology; Genetics & Heredity GA 140GW UT WOS:000244493700001 PM 17298668 ER PT J AU DeJong, RJ Miller, LM Molina-Cruz, A Gupta, L Kumar, S Barillas-Mury, C AF DeJong, Randall J. Miller, Lisa M. Molina-Cruz, Alvaro Gupta, Lalita Kumar, Sanjeev Barillas-Mury, Carolina TI Reactive oxygen species detoxification by catalase is a major determinant of fecundity in the mosquito Anopheles gambiae SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE insect; malaria; Plasmodium; reproduction; single-nucleotide polymorphism ID SUPEROXIDE DISMUTASE/CATALASE MIMETICS; DROSOPHILA-MELANOGASTER; OXIDATIVE STRESS; LIFE-SPAN; MOLECULAR CHARACTERIZATION; CAENORHABDITIS-ELEGANS; ACATALASEMIC MUTANTS; MALARIA VECTOR; SENSU-STRICTO; COPPER-ZINC AB The mosquito Anopheles gambiae is a primary vector of Plasmodium parasites in Africa. The effect of aging on reproductive output in A. gambiae females from three strains that differ in their ability to melanize Plasmodium and in their systemic levels of hydrogen peroxide (H2O2), a reactive oxygen species (ROS), was analyzed. The number of eggs oviposited after the first blood meal decreases with age in all strains; however, this decline was much more pronounced in the G3 (unselected) and R (refractory to Plasmodium infection) strains than in the S (highly susceptible to Plasmodium) strain. Reduction of ROS levels in G3 and R females by administration of antioxidants reversed this age-related decline in fecundity. The S and G3 strains were fixed for two functionally different catalase alleles that differ at the second amino acid position (Ser2Trp). Biochemical analysis of recombinant proteins revealed that the Trp isoform has lower specific activity and higher K. than the Ser isoform, indicating that the former is a less efficient enzyme. The Trp-for-Ser substitution appears to destabilize the functional tetrameric form of the enzyme. Both alleles are present in the R strain, and Ser/Ser females had significantly higher fecundity than Trp/Trp females. Finally, a systemic reduction in catalase activity by dsRNA-mediated knockdown significantly reduced the reproductive output of mosquito females, indicating that catalase plays a central role in protecting the oocyte and early embryo from ROS damage. C1 Natl Inst Allergy & Infect Dis, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA. Natl Inst Allergy & Infect Dis, Lab Malaria & Vector Res, NIH, Rockville, MD 20892 USA. Colorado State Univ, Dept Microbiol Immunol & Pathol, Ft Collins, CO 80523 USA. RP Barillas-Mury, C (reprint author), Natl Inst Allergy & Infect Dis, Lab Malaria & Vector Res, NIH, MSC 8132 Twinbrook 3,Room 2E-20, Bethesda, MD 20892 USA. EM cbarillas@niaid.nih.gov FU Intramural NIH HHS NR 38 TC 53 Z9 56 U1 1 U2 17 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 13 PY 2007 VL 104 IS 7 BP 2121 EP 2126 DI 10.1073/pnas.0608407104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 139NJ UT WOS:000244438500018 PM 17284604 ER PT J AU Parrish, S Resch, W Moss, B AF Parrish, Susan Resch, Wolfgang Moss, Bernard TI Vaccinia virus D10 protein has mRNA decapping activity, providing a mechanism for control of host and viral gene expression SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE mRNA metabolism; MutT motif; Nudix hydrolase; poxvirus; mRNA turnover ID CAP STRUCTURE; SACCHAROMYCES-CEREVISIAE; MICROARRAY ANALYSIS; NUDIX HYDROLASES; YEAST-CELLS; ENZYME; TRANSCRIPTION; INFECTION; SEQUENCE; HDCP2 AB Previous studies indicated that the vaccinia virus D10 protein, which is conserved in all sequenced poxviruses, participates in the rapid turnover of host and viral mRNAs. D10 contains a motif present in the family of Nudix/MutT enzymes, a subset of which has been shown to enhance mRNA turnover in eukaryotic cells through cleavage of the 5' cap (m(7)GpppNm-). Here, we demonstrate that a purified recombinant D10 fusion protein possesses an intrinsic activity that liberates m(7)GDP from capped RNA substrates. Furthermore, point mutations in the Nudix/MutT motif abolished decapping activity. D10 has a strong affinity for capped RNA substrates (K-m approximate to 3 nm). RNAs of 24-309 nt were clecapped to comparable extents, whereas the cap of a 12-nt RNA was uncleaved. At large molar ratios relative to capped RNA substrate, competitor m(7)GpppG, m(7)GTP, or m(7)GDP inhibited clecapping, whereas even higher concentrations of unmethylated analogs did not. High concentrations of uncapped RNA were also inhibitory, suggesting that D10 recognizes its substrate through interaction with both cap and RNA moieties. Thus far, poxviruses represent the only virus family shown to encode a Nudix hydrolase-decapping enzyme. Although it may seem self-destructive for a virus to encode a decapping and a capping enzyme, accelerated mRNA turnover helps eliminate competing host mRNAs and allows stage-specific synthesis of viral proteins. C1 Natl Inst Allergy & Infect Dis, Lab Viral Dis, NIH, Bethesda, MD 20892 USA. RP Moss, B (reprint author), Natl Inst Allergy & Infect Dis, Lab Viral Dis, NIH, Bethesda, MD 20892 USA. EM bmoss@nih.gov FU Intramural NIH HHS NR 42 TC 46 Z9 48 U1 0 U2 1 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 13 PY 2007 VL 104 IS 7 BP 2139 EP 2144 DI 10.1073/pnas.0611685104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 139NJ UT WOS:000244438500021 PM 17283339 ER PT J AU Kim, YC Wikstrom, M Hummer, G AF Kim, Young C. Wikstrom, Marten Hummer, Gerhard TI Kinetic models of redox-coupled proton pumping SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE bioenergetics; kinetic master equation; respiration; biological machines; motors ID CYTOCHROME-C-OXIDASE; HEME-COPPER OXIDASES; PARACOCCUS-DENITRIFICANS; MOLECULAR MOTORS; D-PATHWAY; TRANSLOCATION; OXYGEN; MECHANISM; ELECTRON; ENERGY AB Cytochrome c oxidase, the terminal enzyme of the respiratory chain, pumps protons across the inner mitochondrial membrane against an opposing electrochemical gradient by reducing oxygen to water. To explore the fundamental mechanisms of such redox-coupled proton pumps, we develop kinetic models at the singlemolecule level consistent with basic physical principles. We demonstrate that pumping against potentials > 150 mV can be achieved purely through electrostatic couplings, given an asymmetric arrangement of charge centers; however, nonlinear gates are essential for highly efficient real enzymes. The fundamental requirements for proton pumping identified here highlight a possible evolutionary origin of cytochrome c oxidase pumping. The general design principles are relevant also for other molecular machines and suggest future applications in biology-inspired fuel cells. C1 NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. Univ Helsinki, Helsinki Bioenerget Grp, Inst Biotechnol, FI-00014 Helsinki, Finland. Univ Helsinki, Bioctr Helsinki, FI-00014 Helsinki, Finland. RP Hummer, G (reprint author), NIDDK, Phys Chem Lab, NIH, Bethesda, MD 20892 USA. EM hummer@helix.nih.gov RI Wikstrom, Marten/A-4403-2008; Hummer, Gerhard/A-2546-2013 OI Hummer, Gerhard/0000-0001-7768-746X NR 35 TC 39 Z9 39 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 13 PY 2007 VL 104 IS 7 BP 2169 EP 2174 DI 10.1073/pnas.0611114104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 139NJ UT WOS:000244438500026 PM 17287344 ER PT J AU Chi, A Huttenhower, C Geer, LY Coon, JJ Syka, JEP Bai, DL Shabanowitz, J Burke, DJ Troyanskaya, OG Hunt, DF AF Chi, An Huttenhower, Curtis Geer, Lewis Y. Coon, Joshua J. Syka, John E. P. Bai, Dina L. Shabanowitz, Jeffrey Burke, Daniel J. Troyanskaya, Olga G. Hunt, Donald F. TI Analysis of phosphorylation sites on proteins from Saccharomyces cerevisiae by electron transfer dissociation (ETD) mass spectrometry SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE yeast phosphoproteome; network analysis ID FREE-FLOW ELECTROPHORESIS; TYROSINE PHOSPHORYLATION; GENOME DATABASE; YEAST; IDENTIFICATION; KINASE; PROTEOME; CELLS; PHOSPHOPROTEOMICS; ORGANIZATION AB We present a strategy for the analysis of the yeast phosphoproteome that uses endo-Lys C as the proteolytic enzyme, immobilized metal affinity chromatography for phosphopeptide enrichment, a 90-min nanoflow-HPLC/electrospray-ionization MS/MS experiment for phosphopeptide fractionation and detection, gas phase ion/ion chemistry, electron transfer dissociation for peptide fragmentation, and the Open Mass Spectrometry Search Algorithm for phosphoprotein identification and assignment of phosphorylation sites. From a 30-mu g (approximate to 600 pmol) sample of total yeast protein, we identify 1,252 phosphorylation sites on 629 proteins. Identified phosphoproteins have expression levels that range from < 50 to 1,200,000 copies per cell and are encoded by genes involved in a wide variety of cellular processes. We identify a consensus site that likely represents a motif for one or more uncharacterized kinases and show that yeast kinases, themselves, contain a disproportionately large number of phosphorylation sites. Detection of a pHis containing peptide from the yeast protein, Cdc10, suggests an unexpected role for histidine phosphorylation in septin biology. From diverse functional genomics data, we show that phosphoproteins have a higher number of interactions than an average protein and interact with each other more than with a random protein. They are also likely to be conserved across large evolutionary distances. C1 Univ Virginia, Dept Chem, Charlottesville, VA 22904 USA. Univ Virginia, Engn Phys Program, Charlottesville, VA 22904 USA. Princeton Univ, Dept Comp Sci, Princeton, NJ 08540 USA. Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ 08540 USA. Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. Thermo Fisher Sci, San Jose, CA 95134 USA. Univ Virginia, Dept Biochem & Mol Genet, Hlth Sci Ctr, Charlottesville, VA 22908 USA. Univ Virginia, Dept Pathol, Hlth Sci Ctr, Charlottesville, VA 22908 USA. RP Hunt, DF (reprint author), Merck Res Labs, Boston, MA 02115 USA. EM dfh@virginia.edu RI Troyanskaya, Olga/B-1968-2010; Hunt, Donald/I-6936-2012; Geer, Lewis/H-2714-2014; OI Hunt, Donald/0000-0003-2815-6368; Huttenhower, Curtis/0000-0002-1110-0096 FU NIGMS NIH HHS [GM37537, R01 GM037537] NR 35 TC 385 Z9 869 U1 10 U2 94 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 13 PY 2007 VL 104 IS 7 BP 2193 EP 2198 DI 10.1073/pnas.0607084104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 139NJ UT WOS:000244438500030 PM 17287358 ER PT J AU Vassena, L Proschan, M Fauci, AS Lusso, P AF Vassena, Lia Proschan, Michael Fauci, Anthony S. Lusso, Paolo TI Interleukin 7 reduces the levels of spontaneous apoptosis in CD4(+) and CD8(+) T cells from HIV-1-infected individuals SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE T lymphocytes; immunodeficiency; immune reconstitution; programmed cell death; cytokines ID HUMAN-IMMUNODEFICIENCY-VIRUS; HIV-INFECTED PATIENTS; ANTIRETROVIRAL THERAPY; LYMPHOCYTE APOPTOSIS; RECEPTOR EXPRESSION; DISEASE PROGRESSION; IL-7; DEATH; ACTIVATION; BCL-2 AB Apoptosis has been suggested as one of the major mechanisms of CD4(+) T cell depletion during the course of HIV type 1 (HIV-1) infection. Here, we show that interleukin 7 (IL-7), a nonredundant cytokine that plays essential roles in the generation and homeostasis of the T cell compartment of the immune system, exerts strong antiapoptotic effects ex vivo on both CD4(+) and CD8(+) T cells derived from HIV-1-infected subjects. The level of IL-7-mediated reduction of apoptosis was inversely correlated with the number of circulating CD4(+) T cells, indicating a higher sensitivity to IL-7 effects in patients with more advanced disease. The antiapoptotic effect of IL-7 was uncoupled from the induction of cellular proliferation or endogenous HIV-1 replication. These results provide a further rationale for consideration of IL-7 as an agent of immune reconstitution in HIV-1 infection. C1 NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. RP Fauci, AS (reprint author), NIAID, Immunoregulat Lab, NIH, Bldg 10,Room 6A11,9000 Rockville Pike, Bethesda, MD 20892 USA. EM afauci@niaid.nih.gov; plusso@niaid.nih.gov NR 39 TC 40 Z9 42 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 13 PY 2007 VL 104 IS 7 BP 2355 EP 2360 DI 10.1073/pnas.0610775104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 139NJ UT WOS:000244438500057 PM 17284597 ER PT J AU Chowers, Y Kirschner, J Keller, N Barshack, I Bar-Meir, S Ashkenazi, S Schneerson, R Robbins, J Passwell, JH AF Chowers, Yehuda Kirschner, Joachim Keller, Nathan Barshack, Iris Bar-Meir, Simon Ashkenazi, Shai Schneerson, Rachel Robbins, John Passwell, Justen H. TI Specific polysaccharide conjugate vaccine-induced IgG antibodies prevent invasion of Shigella into Caco-2 cells and may be curative SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE vaccination ID O-SPECIFIC POLYSACCHARIDE; EPITHELIAL-CELLS; SERUM ANTIBODIES; FLEXNERI TYPE-2A; LIPOPOLYSACCHARIDE; SONNEI; IMMUNOGENICITY; INTERLEUKIN-8; PATHOGENESIS; EXPRESSION AB The O-specific polysaccharide (O-SP) domain of Shigella LIPS is both an essential virulence factor and a protective antigen for this genus. A critical level of serum IgG anti-O-SP was shown to confer immunity to shigellosis, likely by complement-mediated bacteriolysis of the inoculum. Conjugate Shigella O-SP vaccines were shown to be safe and immunogenic in children, and, in a preliminary study, Shigella sonnei vaccine was protective in young adults. Characteristic of shigellosis is bacterial invasion of intestinal cells. Incubation of shigellae with postimmunization but not preimmunization sera of children vaccinated with S. sonnei or Shigella flexneri 2a O-SP conjugate vaccines inhibited in a type-specific and dose-dependent manner in vitro invasion of intestinal epithelial cells (Caco-2) and the infection-associated increases in IL-1 beta and IL-8 mRNA and extracellular cytokine levels. Pretreatment of these sera or of Caco-2 cells with O-SP abrogated these effects also in a type-specific and dose-dependent manner. Confocal microscopy demonstrated antibody-specific inhibition of bacterial adhesion to HeLa cells. These protective effects were duplicated by IgG purified from these sera. These results suggest a dual role for IgG anti-O-SP. In addition to lysis of the inoculum in immune individuals, the newly synthesized IgG anti-O-SP in patients may terminate an established infection by inhibiting shigellae released from epithelial cells from invading new ones. A critical level of IgG anti-O-SP could, therefore, have a protective as well as a curative role in shigellosis. C1 Chaim Sheba Med Ctr, Edmond & Lily Safra Childrens Hosp, Dept Gastroenterol, IL-52621 Tel Hashomer, Israel. Chaim Sheba Med Ctr, Edmond & Lily Safra Childrens Hosp, Dept Bacteriol, IL-52621 Tel Hashomer, Israel. Chaim Sheba Med Ctr, Edmond & Lily Safra Childrens Hosp, Dept Pathol, IL-52621 Tel Hashomer, Israel. Chaim Sheba Med Ctr, Edmond & Lily Safra Childrens Hosp, Samuel Jared Kushnick Pediat Immunol Lab, IL-52621 Tel Hashomer, Israel. Weizmann Inst Sci, Dept Cell Biol, IL-76100 Rehovot, Israel. Schneider Childrens Med Ctr, IL-49202 Petah Tiqwa, Israel. NICHHD, Lab Dev & Mol Immun, NIH, Bethesda, MD 20892 USA. Tel Aviv Univ, Sackler Sch Med, IL-69978 Tel Aviv, Israel. RP Chowers, Y (reprint author), Chaim Sheba Med Ctr, Edmond & Lily Safra Childrens Hosp, Dept Gastroenterol, IL-52621 Tel Hashomer, Israel. EM ychowers@post.tau.ac.il; robbinsjo@mail.nih.gov FU Intramural NIH HHS; NICHD NIH HHS [N01-HD-5-3226] NR 24 TC 15 Z9 15 U1 1 U2 2 PU NATL ACAD SCIENCES PI WASHINGTON PA 2101 CONSTITUTION AVE NW, WASHINGTON, DC 20418 USA SN 0027-8424 J9 P NATL ACAD SCI USA JI Proc. Natl. Acad. Sci. U. S. A. PD FEB 13 PY 2007 VL 104 IS 7 BP 2396 EP 2401 DI 10.1073/pnas.0610833104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 139NJ UT WOS:000244438500064 PM 17287349 ER PT J AU Dreher, JC Schmidt, PJ Kohn, P Furman, D Rubinow, D Berman, KF AF Dreher, Jean-Claude Schmidt, Peter J. Kohn, Philip Furman, Daniella Rubinow, David Berman, Karen Faith TI Menstrual cycle phase modulates reward-related neural function in women SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article ID OVARIAN HORMONES INFLUENCE; CENTRAL-NERVOUS-SYSTEM; ORBITOFRONTAL CORTEX; ESTROUS-CYCLE; BASOLATERAL AMYGDALA; PREFRONTAL CORTEX; RHESUS-MONKEYS; GENDER-DIFFERENCES; DOPAMINE RELEASE; COCAINE-SEEKING AB There is considerable evidence from animal studies that the mesolimbic and mesocortical dopamine systems are sensitive to circulating gonadal steroid hormones. Less is known about the influence of estrogen and progesterone on the human reward system. To investigate this directly, we used functional MRI and an event-related monetary reward paradigm to study women with a repeated-measures, counterbalanced design across the menstrual cycle. Here we show that during the midfollicular phase (days 4-8 after onset of menses) women anticipating uncertain rewards activated the orbitofrontal cortex and amygdala more than during the luteal phase (6-10 days after luteinizing hormone surge). At the time of reward delivery, women in the follicular phase activated the midbrain, striatum, and left fronto-polar cortex more than during the luteal phase. These data demonstrate augmented reactivity of the reward system in women during the midfollicular phase when estrogen is unopposed by progesterone. Moreover, investigation of between-sex differences revealed that men activated ventral putamen more than women during anticipation of uncertain rewards, whereas women more strongly activated the anterior medial prefrontal cortex at the time of reward delivery. Correlation between brain activity and gonadal steroid levels also revealed that the amygdalo-hippocampal complex was positively correlated with estradiol level, regardless of menstrual cycle phase. Together, our findings provide evidence of neurofunctional modulation of the reward system by gonadal steroid hormones in humans and establish a neurobiological foundation for understanding their impact on vulnerability to drug abuse, neuropsychiatric diseases with differential expression across males and females, and hormonally mediated mood disorders. C1 NIMH, Sect Integrat Neuroimaging, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NIMH, Behav Endocrinol Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Dreher, JC (reprint author), Univ Lyon 1, CNRS, Inst Cognit Sci, F-69675 Lyon, France. EM dreher@isc.cnrs.fr FU Intramural NIH HHS NR 46 TC 221 Z9 227 U1 4 U2 27 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 13 PY 2007 VL 104 IS 7 BP 2465 EP 2470 DI 10.1073/pnas.0605569104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 139NJ UT WOS:000244438500076 PM 17267613 ER PT J AU Lu, HB Xi, ZX Gitajn, L Rea, W Yang, YH Stein, EA AF Lu, Hanbing Xi, Zheng-Xiong Gitajn, Leah Rea, William Yang, Yihong Stein, Elliot A. TI Cocaine-induced brain activation detected by dynamic manganese-enhanced magnetic resonance imaging (MEMRI) SO PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA LA English DT Article DE Ca2+ channel; dopamine; drug abuse ID CEREBRAL BLOOD-FLOW; RAT-BRAIN; GLUCOSE-UTILIZATION; FUNCTIONAL MRI; DRUG-ADDICTION; BOLD FMRI; REWARD; MOTIVATION; DOPAMINE; CONSEQUENCES AB Dynamic manganese-enhanced magnetic resonance imaging (MEMRI) detects neuronal activity based on the passage of Mn2+ into active neurons. Because this mechanism is independent of any hemodynamic response, it is potentially ideal for pharmacological studies and was applied to investigate the acute CNS effects of cocaine in the rat. Dose-dependent, region-specific MEMRI signals were seen mostly in cortical and subcortical mesocorticolimbic structures. To verify the spatial accuracy and physiological mechanisms of MEMRI, neuronal activation following electrical forepaw stimulation revealed somatotopic signal enhancement in the primary and secondary somatosensory cortices, which was blocked by diltiazem, a Ca2+ channel antagonist. These data suggest that MEMRI may serve as a tool for investigating the effects of pharmacological agents and opens an application of MRI to study CNS drug effects at a systems level. C1 NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. NIDA, Behav Neurosci Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. RP Stein, EA (reprint author), NIDA, Neuroimaging Res Branch, Intramural Res Program, NIH, Baltimore, MD 21224 USA. EM estein@intra.nida.nih.gov RI Stein, Elliot/C-7349-2008 FU Intramural NIH HHS NR 54 TC 70 Z9 71 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 13 PY 2007 VL 104 IS 7 BP 2489 EP 2494 DI 10.1073/pnas.0606983104 PG 6 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 139NJ UT WOS:000244438500080 PM 17287361 ER PT J AU Kalueff, AV Keisala, T Minasyan, A Tuohimaa, P AF Kalueff, Allan V. Keisala, Tiina Minasyan, Anna Tuohimaa, Pentti TI Influence of paternal genotypes on F1 behaviors: Lessons from several mouse strains SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE behavioral phenotypes; F1 hybrid inice; 129S1; BALB/c; NMRI; C57BL/6 strains; aternal genotype ID CONTRASTING GROOMING PHENOTYPES; ANXIETY-RELATED BEHAVIORS; F-1 HYBRIDS IMPLICATIONS; TRAIT LOCI ANALYSES; INBRED STRAINS; LOCOMOTOR-ACTIVITY; OPEN-FIELD; MARKED DIFFERENCES; C57BL/6 MICE; SINGLE-GENE AB F1 and F2 mouse hybrids derived from different parental strains are becoming a useful tool in behavioral research, underlining the importance of their in-depth behavioral phenotyping. 129S1/SvlmJ (S1), C57BL/6 (B6), NMRI (N) and BALB/c (BC) mice are commonly used in behavioral neuroscience. demonstrating marked behavioral differences. Here, we assess behavioral phenotypes of male mice of S1 and several hybrid strains (S1B6, S1N, S1BC) in a battery of behavioral tests, including the open field, novel odor exposure, novelty-induced grooming, horizontal rod (Suok) and the elevated plus maze tests. In addition, we assessed aggression and social barbering in these strains. Overall, the substantial differences observed here between these strains allow us to determine the influence of different genetic backgrounds on mouse behaviors, and more fully understand how different strain-specific behaviors overlap in the F1 progeny. Our results imply complex interplay between parental genotypes in anxiety, activity, grooming, aggression and barbering of their F1 progeny, further confirming the utility of F1 hybrids in behavioral neurogenetics. (c) 2006 Elsevier B.V. All rights reserved. C1 Univ Tampere, Sch Med, Dept Anat, FIN-33101 Tampere, Finland. Tampere Univ Hosp, Dept Clin Chem, FIN-33101 Tampere, Finland. RP Kalueff, AV (reprint author), NIMH, Clin Sci Lab, Bldg 10,Room 3D41,10 Ctr Dr,MSC 1264, Bethesda, MD 20892 USA. EM avkalueff@inbox.ru NR 59 TC 14 Z9 14 U1 0 U2 3 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD FEB 12 PY 2007 VL 177 IS 1 BP 45 EP 50 DI 10.1016/j.bbr.2006.11.005 PG 6 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 135BO UT WOS:000244129000007 PM 17141884 ER PT J AU Bjork, JM Hommer, DW AF Bjork, James M. Hommer, Daniel W. TI Anticipating instrumentally obtained and passively-received rewards: A factorial fMRI investigation SO BEHAVIOURAL BRAIN RESEARCH LA English DT Article DE reward; incentive motivation; fMRI; instrumental behavior ID DOPAMINE NEURONS; STRIATUM; HUMANS; EXPECTATION; RESPONSES; NUCLEUS; CORTEX AB During functional magnetic resonance imaging (fMRI), subjects saw cues signaling probabilities of 1.0, 0.5, and 0 of winning $1 for hitting a subsequent target, and cues signaling similar probabilities of reward delivery requiring no instrumental response. Non-instrumental reward anticipation did not elicit activation. Instrumental reward anticipation activated multiple nodes of the basal ganglia-thalamocortical motor circuit. Ventromesial striatum was activated by joint requirement for an instrumental response together with uncertain (but not certain) reward. (c) 2006 Elsevier B.V. All rights reserved. C1 NIAAA, Lab Clin & Translat Studies, NIH, Bethesda, MD 20892 USA. RP Bjork, JM (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, 10 Ctr Dr,CRC Rm 1-5330, Bethesda, MD 20892 USA. EM jbjork@mail.nih.gov OI Bjork, James/0000-0003-0593-3291 FU Intramural NIH HHS; NCCIH NIH HHS [PRATPHARMACOLOGY FELLOWSHIP]; PHS HHS [PRATPHARMACOLOGY FELLOWSHIP] NR 19 TC 60 Z9 60 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0166-4328 J9 BEHAV BRAIN RES JI Behav. Brain Res. PD FEB 12 PY 2007 VL 177 IS 1 BP 165 EP 170 DI 10.1016/j.bbr.2006.10.034 PG 6 WC Behavioral Sciences; Neurosciences SC Behavioral Sciences; Neurosciences & Neurology GA 135BO UT WOS:000244129000021 PM 17140674 ER PT J AU Tolentino, HD Matters, MD Walop, W Law, B Tong, W Liu, F Fontelo, P Kohl, K Payne, DC AF Tolentino, Herman D. Matters, Michael D. Walop, Wikke Law, Barbara Tong, Wesley Liu, Fang Fontelo, Paul Kohl, Katrin Payne, Daniel C. TI A UMLS-based spell checker for natural language processing in vaccine safety SO BMC MEDICAL INFORMATICS AND DECISION MAKING LA English DT Article ID TEXT PROCESSOR; INFORMATION; SYSTEM; RADIOLOGY AB Background: The Institute of Medicine has identified patient safety as a key goal for health care in the United States. Detecting vaccine adverse events is an important public health activity that contributes to patient safety. Reports about adverse events following immunization (AEFI) from surveillance systems contain free-text components that can be analyzed using natural language processing. To extract Unified Medical Language System ( UMLS) concepts from free text and classify AEFI reports based on concepts they contain, we first needed to clean the text by expanding abbreviations and shortcuts and correcting spelling errors. Our objective in this paper was to create a UMLS-based spelling error correction tool as a first step in the natural language processing (NLP) pipeline for AEFI reports. Methods: We developed spell checking algorithms using open source tools. We used de-identified AEFI surveillance reports to create free-text data sets for analysis. After expansion of abbreviated clinical terms and shortcuts, we performed spelling correction in four steps: ( 1) error detection, ( 2) word list generation, ( 3) word list disambiguation and ( 4) error correction. We then measured the performance of the resulting spell checker by comparing it to manual correction. Results: We used 12,056 words to train the spell checker and tested its performance on 8,131 words. During testing, sensitivity, specificity, and positive predictive value (PPV) for the spell checker were 74% ( 95% CI: 74 - 75), 100% ( 95% CI: 100 - 100), and 47% ( 95% CI: 46% - 48%), respectively. Conclusion: We created a prototype spell checker that can be used to process AEFI reports. We used the UMLS Specialist Lexicon as the primary source of dictionary terms and the WordNet lexicon as a secondary source. We used the UMLS as a domain-specific source of dictionary terms to compare potentially misspelled words in the corpus. The prototype sensitivity was comparable to currently available tools, but the specificity was much superior. The slow processing speed may be improved by trimming it down to the most useful component algorithms. Other investigators may find the methods we developed useful for cleaning text using lexicons specific to their area of interest. C1 Ctr Dis Control & Prevent, Natl Immunizat Program, Bacterial Vaccine Preventable Dis Branch, Atlanta, GA 30333 USA. Ctr Dis Control & Prevent, Publ Hlth Informat Fellowship Program, Off Workforce & Career Dev, Atlanta, GA 30333 USA. Ctr Dis Control & Prevent, Div Heart Dis & Stroke Prevent, Natl Ctr Chron Dis Prevent & Hlth Promot, Atlanta, GA 30341 USA. Ctr Infect Dis Prevent & Control, Immunizat & Resp Infect Div, Publ Hlth Agcy Canada, Ottawa, ON K1A 0K9, Canada. McMaster Univ, Honours Biol & Pharmacol Programme, Hamilton, ON L8S 4L8, Canada. NIH, Off High performance Comp & commun, Natl Lib Med, Bethesda, MD 20894 USA. Ctr Dis Control & Prevent, Immunizat Safety Off, Off Chief Sci Officer, Atlanta, GA 30333 USA. RP Tolentino, HD (reprint author), Ctr Dis Control & Prevent, Natl Immunizat Program, Bacterial Vaccine Preventable Dis Branch, Atlanta, GA 30333 USA. EM htolentino@cdc.gov; mmatters@cdc.gov; Wikke_Walop@phac-aspc.gc.ca; barbara_law@hc-sc.gc.ca; wesley_tong@hc-sc.gc.ca; fliu@mail.nih.gov; fontelo@nlm.nih.gov; KKohl@cdc.gov; dpayne@cdc.gov NR 31 TC 7 Z9 7 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA MIDDLESEX HOUSE, 34-42 CLEVELAND ST, LONDON W1T 4LB, ENGLAND SN 1472-6947 J9 BMC MED INFORM DECIS JI BMC Med. Inform. Decis. Mak. PD FEB 12 PY 2007 VL 7 AR 3 DI 10.1186/1472-6947-7-3 PG 13 WC Medical Informatics SC Medical Informatics GA 168IA UT WOS:000246516100001 PM 17295907 ER PT J AU Sudarshan, S Linehan, WM Neckers, L AF Sudarshan, S. Linehan, W. M. Neckers, L. TI HIF and fumarate hydratase in renal cancer SO BRITISH JOURNAL OF CANCER LA English DT Review DE hereditary leiomyomatosis and renal cell cancer; kidney cancer; fumarate hydratase; hypoxia inducible factor ID TUMOR-SUPPRESSOR GENE; HIPPEL-LINDAU PROTEIN; CELL-CANCER; HEREDITARY LEIOMYOMATOSIS; SUCCINATE-DEHYDROGENASE; PROLINE HYDROXYLATION; UTERINE LEIOMYOMAS; COMPLEX II; MUTATIONS; FH AB Hereditary leiomyomatosis and renal cell cancer is a recently described hereditary cancer syndrome in which affected individuals are predisposed to the development of leiomyomas of the skin and uterus. In addition, this clinical entity also can result in the development of biologically aggressive kidney cancer. Affected individuals harbour a germline mutation of the fumarate hydratase (FH) gene, which encodes an enzyme that catalyses conversion of fumarate to malate in the Kreb's cycle. Thus far, proposed mechanisms for carcinogeneis associated with this syndrome include aberrant apoptosis, oxidative stress, and pseudohypoxic drive. At this time, the majority of accumulating data support a role for pseudohypoxic drive in tumour development. The link between FH mutation and pseudohypoxic drive may reside in the biochemical alterations resulting from diminished/absent FH activity. These biochemical derangements may interfere with oxygen homeostasis and result in a cellular environment conducive to tumour formation. C1 NCI, Urol Oncol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. RP Neckers, L (reprint author), NCI, Urol Oncol Branch, Canc Res Ctr, 10 Ctr Dr,Bldg 10,CRC Room I-5940, Bethesda, MD 20892 USA. EM len@helix.nih.gov FU Intramural NIH HHS NR 38 TC 31 Z9 33 U1 2 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0007-0920 J9 BRIT J CANCER JI Br. J. Cancer PD FEB 12 PY 2007 VL 96 IS 3 BP 403 EP 407 DI 10.1038/sj.bjc.6603547 PG 5 WC Oncology SC Oncology GA 134RA UT WOS:000244100300001 PM 17211469 ER PT J AU Melnick, RL Nyska, A Foster, PM Roycroft, JH Kissling, GE AF Melnick, Ronald L. Nyska, Abraham Foster, Paul M. Roycroft, Joseph H. Kissling, Grace E. TI Toxicity and carcinogenicity of the water disinfection byproduct, dibromoacetic acid, in rats and mice SO TOXICOLOGY LA English DT Article DE dibromoacetic acid; water disinfection byproduct; delayed spermiation; mesothelioma; hepatoblastoma; leukemia; hepatocellular adenoma/carcinoma ID GLUTATHIONE TRANSFERASE ZETA; HALOGENATED ACETIC-ACIDS; MALE B6C3F1 MOUSE; DICHLOROACETIC ACID; DRINKING-WATER; TRICHLOROACETIC-ACID; F344 RATS; LIVER; CHLORINATION; METABOLISM AB Dibromoacetic acid (DBA) is a water disinfection byproduct formed by the reaction of chlorine oxidizing compounds with natural organic matter in water containing bromide. Male and female F344/N rats and B6C3F(1) mice were exposed to DBA in drinking water for 2 weeks (N=5), 3 months (N=10), or 2 years (N=50). Concentrations of DBA in drinking water were 0, 125, 250, 500, 1000, and 2000 mg/L in the 2-week and 3-month studies, and 0, 50, 500, and 1000 mg/L in the 2-year studies. Toxic effects of DBA in the prechronic studies were detected in the liver (hepatocellular cytoplasmic vacuolization in rats and mice) and testes (delayed spermiation and atypical residual bodies in male rats and mice, and atrophy of the germinal epithelium in rats). In the 2-year studies, neoplasms were induced at multiple sites in rats and mice exposed to DBA; these included mononuclear cell leukemia and abdominal cavity mesothliomas in rats, and neoplasms of the liver (hepatocellular adenoma or carcinoma and hepatoblastoma) and lung (alveolar adenoma or carcinoma) in mice. The increase in incidence of hepatocellular neoplasms in male mice was significant even at the lowest exposure concentration of 50 mg/L, which is equivalent to an average daily dose of approximately 4 mg/kg. These studies provide critical information for future re-evaluations of health-based drinking water standards for haloacetic acids. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 NIEHS, Environm Toxicol Program, Res Triangle Pk, NC 27709 USA. NIEHS, Environm Dis & Med Program, Res Triangle Pk, NC 27709 USA. RP Melnick, RL (reprint author), NIEHS, Environm Toxicol Program, POB 12233, Res Triangle Pk, NC 27709 USA. EM melnickr@niehs.nih.gov FU Intramural NIH HHS [Z99 ES999999] NR 56 TC 30 Z9 35 U1 2 U2 17 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD FEB 12 PY 2007 VL 230 IS 2-3 BP 126 EP 136 DI 10.1016/j.tox.2006.11.006 PG 11 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 138QI UT WOS:000244376900003 PM 17157429 ER PT J AU Moser, VC Phillips, PM McDaniel, KL Sills, RC AF Moser, Virginia C. Phillips, Pamela M. McDaniel, Katherine L. Sills, Robert C. TI Neurotoxicological evaluation of two disinfection by-products, bromodichloromethane and dibromoacetonitrile, in rats SO TOXICOLOGY LA English DT Article DE bromodichloromethane; dibromoacetonitrile; disinfection by-products; neurotoxicity; behavior; neuropathology; rats ID 2-GENERATION REPRODUCTIVE TOXICITY; DRINKING-WATER; DICHLOROACETIC ACID; TRIHALOMETHANES; CHLOROFORM; EXPOSURE; MICE; HALOACETONITRILES; SPERMATOTOXICITY; BROMOFORM AB The Safe Drinking Water Act requires that the U.S. EPA consider noncancer endpoints for the assessment of adverse human health effects of disinfection by-products (DBPs). As an extension of our studies in which we demonstrated neurotoxicity at relatively low levels of dibromo- and dichloroacetic acids, we examined the potential neurotoxicity of other classes of DBPs. Bromodichloromethane (BDCM) and dibromoacetonitrile (DBAN) were administered to male and female F-344 rats via drinking water for 6 months. During exposure, rats were tested for neurobehavioral effects using a functional observational battery and motor activity, followed by perfusion fixation for neuropathological evaluation at the end of exposure. Calculating for chemical loss. fluid consumption. and body weight, average intakes were approximately: 9, 27, and 72 mg/(kg day) BDCM, and 5, 12, and. 29 mg/(kg day) DBAN. Fluid consumption was decreased in most treatment groups, but body weight gain was altered only at the high concentrations. There were few neurobehavioral changes, and these were not considered toxicologically relevant. Of the general observations, there was only minimally decreased body tone in DBAN-treated high-dose males. Treatment-related neuropathological findings were not observed. Lowered fluid consumption was the most sensitive and consistent endpoint in the present studies. Thus, unlike the haloacetic acids, neurotoxicity may not be a concern for toxicity of halomethanes or haloacetonitriles. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 US EPA, Neurotoxicol Div, NHEERL ORD, Res Triangle Pk, NC 27711 USA. Natl Inst Environm Hlth Sci, NTP, Res Triangle Pk, NC USA. RP Moser, VC (reprint author), US EPA, Neurotoxicol Div, NHEERL ORD, MD B105-04, Res Triangle Pk, NC 27711 USA. EM moser.ginger@epa.gov NR 32 TC 2 Z9 2 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0300-483X J9 TOXICOLOGY JI Toxicology PD FEB 12 PY 2007 VL 230 IS 2-3 BP 137 EP 144 DI 10.1016/j.tox.2006.11.007 PG 8 WC Pharmacology & Pharmacy; Toxicology SC Pharmacology & Pharmacy; Toxicology GA 138QI UT WOS:000244376900004 PM 17157428 ER PT J AU Nam, JM AF Nam, Jun-mo TI Comparison of validity of assessment methods using indices of adjusted agreement SO STATISTICS IN MEDICINE LA English DT Article DE adjusted agreement; comparison of raters; sensitivity; specificity; Yule's index ID ASBESTOS EXPOSURE; CATEGORICAL DATA; 2 PARADOXES; KAPPA AB For comparing the validity of rating methods, the adjusted kappa (S coefficient) and Yule's Y index are better than Cohen's kappa which is affected by marginal probabilities. We consider a validity study in which a subject is assessed as exposed or not-exposed by two competing rating methods and the gold standard. We are interested in one of the methods, which is closer in agreement with the gold standard. We present statistical methods taking correlations into account for comparing the validity of the rating methods using S coefficient and Y index. We show how the S coefficient and Yule's Y index are related to sensitivity and specificity. In comparing the two rating methods, the preference is clear when the inference is the same for both S and Y. If the inference using S differs from that using Y, then it is not obvious how to decide a preference. This may occur when one rating method is better than the other in sensitivity but not in specificity. Numerical examples for comparing asbestos-exposure assessment methods are illustrated. Copyright (c) 2006 John Wiley & Sons, Ltd. C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Nam, JM (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Execut Plaza S,Room 8028,6120 Execut Blvd,MSC 724, Bethesda, MD 20892 USA. EM namj@mail.nih.gov FU Intramural NIH HHS NR 28 TC 4 Z9 5 U1 1 U2 2 PU JOHN WILEY & SONS LTD PI CHICHESTER PA THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W SUSSEX, ENGLAND SN 0277-6715 J9 STAT MED JI Stat. Med. PD FEB 10 PY 2007 VL 26 IS 3 BP 620 EP 632 DI 10.1002/sim.2562 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 126KI UT WOS:000243511400011 PM 16612836 ER PT J AU Nakayama, T Illoh, K Ruetzler, C Auh, S Sokoloff, L Hallenbeck, J AF Nakayama, Toshiyuki Illoh, Kachikwu Ruetzler, Christi Auh, Sungyoung Sokoloff, Louis Hallenbeck, John TI Intranasal administration of E-selectin to induce immunological tolerization can suppress subarachnoid hemorrhage-induced vasospasm implicating immune and inflammatory mechanisms in its genesis SO BRAIN RESEARCH LA English DT Article DE vasospasm; subarachnoid hemorrhage; immunomodulation; E-selectin; mucosal tolerance; basilar artery ID ORAL TOLERANCE; CEREBROSPINAL-FLUID; CEREBRAL VASOSPASM; MUCOSAL TOLERANCE; AUTOIMMUNE ENCEPHALOMYELITIS; HYPERSENSITIVITY; ENDOTHELIN-1; MACROPHAGES; CYTOKINES; RESPONSES AB Evidence that inflammatory and immune mechanisms may have a critical role in the development of vasospasm after subarachnoid hemorrhage is accumulating. We examined, therefore, whether induction of immunological tolerance to the adhesion molecule that is uniquely expressed on activated endothelium, E-selectin, could inhibit the vasospasm provoked by subarachnoid blood in a rat subarachnoid hemorrhage model. We found that intranasal instillation of E-selectin every other day for 10 days on a mucosal tolerization schedule suppressed delayed type hypersensitivity to E-selectin confirming tolerance to that molecule and markedly suppressed basilar artery spasm after subarachnoid hemorrhage. The results of this proof-of-concept study suggest that agents that can mimic the local effects of the mediators of mucosal tolerance could have therapeutic potential for the management of post-subarachnoid hemorrhage vasospasm. (c) 2006 Published by Elsevier B.V. C1 NINDS, Stroke Branch, NIH, Bethesda, MD 20892 USA. NINDS, Cerebral Metab Lab, NIH, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Dept Neurol, Houston, TX 77225 USA. NINDS, Off Clin Director, NIH, Bethesda, MD 20892 USA. RP Hallenbeck, J (reprint author), NINDS, Stroke Branch, NIH, 49 Room 2A10,49 Convent Dr,MSC 4476, Bethesda, MD 20892 USA. EM Hallenbj@ninds.nih.gov FU Intramural NIH HHS [Z99 NS999999] NR 31 TC 9 Z9 10 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD FEB 9 PY 2007 VL 1132 IS 1 BP 177 EP 184 DI 10.1016/j.brainres.2006.09.116 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 135RJ UT WOS:000244170400020 PM 17188657 ER PT J AU Sugiyama, T Cam, HP Sugiyama, R Noma, K Zofall, M Kobayashi, R Grewal, SIS AF Sugiyama, Tomoyasu Cam, Hugh P. Sugiyama, Rie Noma, Ken-ichi Zofall, Martin Kobayashi, Ryuji Grewal, Shiv I. S. TI SHREC, an effector complex for heterochromatic transcriptional silencing SO CELL LA English DT Article ID DIRECTED DNA METHYLATION; H3 LYSINE-9 METHYLATION; GENOME-WIDE ANALYSIS; MATING-TYPE LOCI; FISSION YEAST; HISTONE H3; SCHIZOSACCHAROMYCES-POMBE; DOMAIN PROTEIN; RNA-POLYMERASE; PERICENTRIC HETEROCHROMATIN AB Transcriptional gene silencing (TGS) is the mechanism generally thought by which heterochromatin effects silencing. However, recent discovery in fission yeast of a cis-acting posttranscriptional gene-silencing (cis-PTGS) pathway operated by the RNAi machinery at heterochromatin challenges the role of TGS in heterochromatic silencing. Here, we describe a multienzyme effector complex (termed SHREC) that mediates heterochromatic TGS in fission yeast. SHREC consists of a core quartet of proteins-Clr1, Clr2, Clr3, and Mit1-which distribute throughout all major heterochromatin domains to effect TGS via distinct activities associated with the histone deacetylase Clr3 and the SNF2 chromatin-remodeling factor homolog Mit1. SHREG is also recruited to the telomeres by multiple independent mechanisms involving telomere binding protein Ccq1 cooperating with Taz1 and the RNAi machinery, and to euchromatic sites, via mechanism(s) distinct from its heterochromatin localization aided by Swi6/HP1. Our analyses suggest that SHREC regulates nucleosome positioning to assemble higher-order chromatin structures critical for heterochromatin functions. C1 NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. Univ Texas, MD Anderson Canc Ctr, Dept Mol Pathol, Houston, TX 77030 USA. RP Grewal, SIS (reprint author), NCI, Mol Cell Biol Lab, NIH, Bethesda, MD 20892 USA. EM grewals@mail.nih.gov OI Sugiyama, Tomoyasu/0000-0001-5704-6606 FU Intramural NIH HHS NR 71 TC 164 Z9 173 U1 1 U2 8 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 0092-8674 J9 CELL JI Cell PD FEB 9 PY 2007 VL 128 IS 3 BP 491 EP 504 DI 10.1016/j.cell.2006.12.035 PG 14 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 145CK UT WOS:000244842700016 PM 17289569 ER PT J AU Oguariri, RM Brann, TW Imamichi, T AF Oguariri, Raphael M. Brann, Terrence W. Imamichi, Tomozumi TI Hydroxyurea and interleukin-6 synergistically reactivate HIV-1 replication in a latently infected promonocytic cell line via SP1/SP3 transcription factors SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; ACTIVE ANTIRETROVIRAL THERAPY; NF-KAPPA-B; TUMOR NECROSIS FACTOR; LONG TERMINAL REPEAT; CD4(+) T-CELLS; IN-VIVO; HIV-1-INFECTED PATIENTS; PROMOTER ACTIVITY; ACTINOMYCIN-D AB The existence of viral latency limits the success of highly active antiretroviral therapy. With the therapeutic intention of reactivating latent virus to induce a cure, in this study we assessed the impact of cell synchronizers on HIV gene activation in latently infected U1 cells and investigated the molecular mechanisms responsible for such effect. Latently infected U1 cells were treated with 10 drugs including hydroxyurea (HU) and HIV-1 replication monitored using a p24 antigen capture assay. We found that HU was able to induce HIV-1 replication by 5-fold. HU has been used in the clinical treatment of HIV-1-infected patients in combination with didanosine; therefore, we investigated the impact of HU on HIV-1 activation in the presence of the proinflammatory cytokines, interleukin 6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). IL-6 or TNF-alpha alone induced HIV replication by 18- and similar to 500-fold, respectively. Of interest, in the presence of HU, IL-6-mediated HIV-1 activation was enhanced by > 90-fold, whereas TNF-alpha-mediated activation was inhibited by > 30%. A reporter gene assay showed that HU and IL-6 synergized to activate HIV promoter activity via the Sp1 binding site. Electrophoretic mobility shift and supershift assays revealed increased binding of the Sp1 and Sp3 transcription factors to this region. Western blot analysis showed that HU and IL-6 co-stimulation resulted in increased levels of Sp1 and Sp3 proteins. In contrast, treatment with HU plus TNF-alpha down-regulated the expression of NF-kappa B. These findings suggest that Sp1/Sp3 is involved in controlling the HU/IL-6-induced reactivation of HIV-1 in latently infected cells. C1 SAIC Frederick Inc, Clin Serv Program, Lab Human Retrovirol, NCI Frederick,NIH, Frederick, MD 21702 USA. RP Imamichi, T (reprint author), SAIC Frederick Inc, Clin Serv Program, Lab Human Retrovirol, NCI Frederick,NIH, POB B,Bldg 550,Rm 126, Frederick, MD 21702 USA. EM timamichi@mail.nih.gov FU NCI NIH HHS [N01-CO-12400] NR 62 TC 15 Z9 15 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 9 PY 2007 VL 282 IS 6 BP 3594 EP 3604 DI 10.1074/jbc.M608150200 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 140CW UT WOS:000244481900021 PM 17150965 ER PT J AU Munshi, UM Kim, J Nagashima, K Hurley, JH Freed, EO AF Munshi, Utpal M. Kim, Jaewon Nagashima, Kunio Hurley, James H. Freed, Eric O. TI An Alix fragment potently inhibits HIV-1 budding - Characterization of binding to retroviral YPXL late domains SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID INFECTIOUS-ANEMIA VIRUS; RECEPTOR DOWN-REGULATION; PROTEIN-SORTING PATHWAY; MULTIVESICULAR-BODY; SACCHAROMYCES-CEREVISIAE; PARTICLE-PRODUCTION; GAG PROTEIN; LIFE-CYCLE; ESCRT-I; UBIQUITIN AB The retroviral structural protein, Gag, contains small peptide motifs known as late domains that promote efficient virus release from the infected cell. In addition to the well characterized PTAP late domain, the p6 region of HIV-1 Gag contains a binding site for the host cell protein Alix. To better understand the functional role of the Gag/Alix interaction, we overexpressed an Alix fragment composed of residues 364-716 (Alix 364-716) and examined the effect on release of wild type (WT) and Alix binding site mutant HIV-1. We observed that Alix 364-716 expression significantly inhibited WT virus release and Gag processing and that mutation of the Alix binding site largely relieved this inhibition. Furthermore, Alix 364-716 expression induced a severe defect on WT but not mutant particle morphology. Intriguingly, the impact of Alix 364-716 expression on HIV-1 release and Gag processing was markedly different from that induced by mutation of the Alix binding site in p6. The association of Alix 364-716 with HIV-1 and equine infectious anemia virus late domains was quantitatively evaluated by isothermal titration calorimetry and surface plasmon resonance techniques, and the effects of mutations in these viral sequences on Alix 364-716 binding was determined. This study identifies a novel Alix-derived dominant negative inhibitor of HIV-1 release and Gag processing and provides quantitative information on the interaction between Alix and viral late domains. C1 NCI Frederick, HIV Drug Resistance Program, Virus Cell Interact Sect, Frederick, MD 21702 USA. NIDDK, Mol Biol Lab, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, SAIC Frederick, Res Technol Program, Image Anal Lab, Frederick, MD 21702 USA. RP Freed, EO (reprint author), NCI Frederick, HIV Drug Resistance Program, Virus Cell Interact Sect, Bldg 535,Rm 108, Frederick, MD 21702 USA. EM efreed@nih.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 51 TC 67 Z9 67 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 9 PY 2007 VL 282 IS 6 BP 3847 EP 3855 DI 10.1074/jbc.M607489200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 140CW UT WOS:000244481900048 PM 17158451 ER PT J AU Beyl, S Timin, EN Hohaus, A Stary, A Kudrnac, M Guy, RH Hering, S AF Beyl, Stanislav Timin, Eugen N. Hohaus, Annette Stary, Anna Kudrnac, Michaela Guy, Robert H. Hering, Steffen TI Probing the architecture of an L-type calcium channel with a charged phenylalkylamine - Evidence for a widely open pore and drug trapping SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MOLECULAR DETERMINANTS; RETINAL DISORDER; BLOCK; MUSCLE; INACTIVATION; ANTAGONISTS; ACTIVATION; DEPENDENCE; MEMBRANE; CURRENTS AB Voltage-gated calcium channels are in a closed conformation at rest and open temporarily when the membrane is depolarized. To gain insight into the molecular architecture of Ca(v)1.2, we probed the closed and open conformations with the charged phenylalkylamine (-)devapamil ((-)qD888). To elucidate the access pathway of (-)D888 to its binding pocket from the intracellular side, we used mutations replacing a highly conserved Ile-781 by threonine/proline in the pore-lining segment IIS6 of Ca(v)1.2 (1). The shifted channel gating of these mutants (by 30 - 40 mV in the hyperpolarizing direction) enabled us to evoke currents with identical kinetics at different potentials and thus investigate the effect of the membrane potentials on the drug access per se. We show here that under these conditions the development of channel block by (-)qD888 is not affected by the transmembrane voltage. Recovery from block at rest was, however, accelerated at more hyperpolarized voltages. These findings support the conclusion that Ca(v)1.2 must be opening widely to enable free access of the charged (-)D888 molecule to its binding site, whereas drug dissociation from the closed channel conformation is restricted by bulky channel gates. The functional data indicating a location of a trapped (-)D888 molecule close to the central pore region are supported by a homology model illustrating that the closed Ca(v)1.2 is able to accommodate a large cation such as (-)D888. C1 Univ Vienna, Inst Pharmacol & Toxicol, A-1090 Vienna, Austria. Univ Vienna, Inst Theoret Chem, A-1090 Vienna, Austria. NCI, NIH, Cell Biol Lab, Bethesda, MD 20892 USA. RP Hering, S (reprint author), Univ Vienna, Inst Pharmacol & Toxicol, Althanstr 14, A-1090 Vienna, Austria. EM steffen.hering@univie.ac.at RI Stary-Weinzinger, Anna/A-3629-2014 OI Stary-Weinzinger, Anna/0000-0002-9202-0484 FU Austrian Science Fund FWF [P 15914]; Intramural NIH HHS NR 26 TC 15 Z9 15 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 9 PY 2007 VL 282 IS 6 BP 3864 EP 3870 DI 10.1074/jbc.M609153200 PG 7 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 140CW UT WOS:000244481900050 PM 17138559 ER PT J AU Mazurov, D Heidecker, G Derse, D AF Mazurov, Dmitriy Heidecker, Gisela Derse, David TI The inner loop of tetraspanins CD82 and CD81 mediates interactions with human T cell lymphotrophic virus type 1 Gag protein SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TRANSMEMBRANE-4 SUPERFAMILY; PLASMA-MEMBRANE; METASTASIS SUPPRESSOR; ENRICHED MICRODOMAINS; SYNCYTIUM FORMATION; MOLECULAR CLONE; MATRIX PROTEIN; C33 ANTIGEN; HTLV-1 GAG; PALMITOYLATION AB The tetraspanin superfamily proteins play important roles in organizing membrane protein complexes, modulating integrin function, and controlling T cell adhesion. Tetraspanins such as CD82 contain two extracellular loops with its N terminus, C terminus, and inner loop exposed to the cytoplasm. The matrix (MA) domain of human T cell lymphotrophic virus, type 1 (HTLV-1), Gag interacts with the cytoplasmic face of the plasma membrane and is concentrated at tetraspanin-enriched microdomains. To understand the basis of this association, we generated site-directed mutations in the various domains of CD82 and used coimmunoprecipitation and colocalization approaches to examine interactions with HTLV-1 MA. The large extracellular loop of CD82, which is important for interactions with integrins, was not required for the association with HTLV-1 MA. The cytoplasmic N terminus and C terminus of CD82 were also dispensable for CD82-MA interactions. In contrast, mutations of conserved amino acids in the inner loop of CD82 or of palmitoylated cysteines that flank the inner loop diminished CD82 association with MA. HTLV-1 MA also interacted with the inner loop of CD81. Thus, association of HTLV-1 Gag with tetraspanin-enriched microdomains is mediated by the inner loops of CD81 and CD82. C1 NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. RP Derse, D (reprint author), NCI, HIV Drug Resistance Program, Frederick, MD 21702 USA. EM derse@ncifcrf.gov FU Intramural NIH HHS NR 45 TC 33 Z9 33 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 9 PY 2007 VL 282 IS 6 BP 3896 EP 3903 DI 10.1074/jbc.M607322200 PG 8 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 140CW UT WOS:000244481900054 PM 17166843 ER PT J AU Liang, MH Chuang, DM AF Liang, Min-Huei Chuang, De-Maw TI Regulation and function of glycogen synthase kinase-3 isoforms in neuronal survival SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID TYROSINE PHOSPHORYLATION; CELL-SURVIVAL; DIFFERENTIAL REGULATION; NUCLEAR ACCUMULATION; NEGATIVE REGULATOR; CIRCADIAN CLOCK; XENOPUS EMBRYOS; LITHIUM; INHIBITION; INSULIN AB Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase consisting of two isoforms, alpha and beta. The activities of GSK-3 are regulated negatively by serine phosphorylation but positively by tyrosine phosphorylation. GSK-3 inactivation has been proposed as a mechanism to promote neuronal survival. We used GSK-3 isoform-specific small interfering RNAs, dominant-negative mutants, or pharmacological inhibitors to search for functions of the two GSK-3 isoforms in regulating neuronal survival in cultured cortical neurons in response to glutamate insult or during neuronal maturation/aging. Surprisingly, RNA interference-induced depletion of either isoform was sufficient to block glutamate-induced excitotoxicity, and the resulting neuroprotection was associated with enhanced N-terminal serine phosphorylation in both GSK-3 isoforms. However, GSK-3 beta depletion was more effective than GSK-3 alpha depletion in suppressing spontaneous neuronal death in extended culture. This phenomenon is likely due to selective and robust inhibition of GSK-3 beta activation resulting from GSK-3 beta Ser(9) dephosphorylation during the course of spontaneous neuronal death. GSK-3 alpha silencing resulted in reduced tyrosine phosphorylation of GSK-3 beta, suggesting that tyrosine phosphorylation is also a critical autoregulatory event. Interestingly, GSK-3 inhibitors caused a rapid and long-lasting increase in GSK-3 alpha Ser(21) phosphorylation levels, followed by a delayed increase in GSK-3 beta Ser(9) phosphorylation and a decrease in GSK-3 alpha Tyr(279) and GSK-3 beta Tyr(216) phosphorylation, thus implying additional levels of GSK-3 autoregulation. Taken together, our results underscore important similarities and dissimilarities of GSK-3 alpha and GSK-3 beta in the roles of cell survival as well as their distinct modes of regulation. The development of GSK-3 isoform-specific inhibitors seems to be warranted for treating GSK-3-mediated pathology. C1 NIMH, Mol Neurobiol Sect, Bethesda, MD 20892 USA. RP Chuang, DM (reprint author), NIMH, Mol Neurobiol Sect, Bldg 10,Room 4C-206,10 Ctr Dr,MSC 1363, Bethesda, MD 20892 USA. EM chuang@mail.nih.gov FU Intramural NIH HHS NR 63 TC 97 Z9 102 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 9 PY 2007 VL 282 IS 6 BP 3904 EP 3917 DI 10.1074/jbc.M605178200 PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 140CW UT WOS:000244481900055 PM 17148450 ER PT J AU Nakamura, Y Umehara, T Nakano, K Jang, MK Shirouzu, M Morita, S Uda-Tochio, H Hamana, H Terada, T Adachi, N Matsumoto, T Tanaka, A Horikoshi, M Ozato, K Padmanabhan, B Yokoyama, S AF Nakamura, Yoshihiro Umehara, Takashi Nakano, Kazumi Jang, Moon Kyoo Shirouzu, Mikako Morita, Satoshi Uda-Tochio, Hiroko Hamana, Hiroaki Terada, Takaho Adachi, Naruhiko Matsumoto, Takehisa Tanaka, Akiko Horikoshi, Masami Ozato, Keiko Padmanabhan, Balasundaram Yokoyama, Shigeyuki TI Crystal structure of the human BRD2 bromodomain - Insights into dimerization and recognition of acetylated histone H4 SO JOURNAL OF BIOLOGICAL CHEMISTRY LA English DT Article ID MITOTIC CHROMOSOMES; MYELOID-LEUKEMIA; RING3 GENE; CHROMATIN; PROTEIN; DROSOPHILA; MITOSIS; CBP; DNA; ACETYLTRANSFERASES AB The BET (bromodomains and extra terminal domain) family proteins recognize acetylated chromatin through their bromodomain and act as transcriptional activators. One of the BET proteins, BRD2, associates with the transcription factor E2F, the mediator components CDK8 and TRAP220, and RNA polymerase II, as well as with acetylated chromatin during mitosis. BRD2 contains two bromodomains (BD1 and BD2), which are considered to be responsible for binding to acetylated chromatin. The BRD2 protein specifically recognizes the histone H4 tail acetylated at Lys(12). Here, we report the crystal structure of the N-terminal bromodomain (BD1, residues 74-194) of human BRD2. Strikingly, the BRD2 BD1 protein forms an intact dimer in the crystal. This is the first observation of a homodimer among the known bromodomain structures, through the buried hydrophobic core region at the interface. Biochemical studies also demonstrated BRD2 BD1 dimer formation in solution. The two acetyllysine-binding pockets and a negatively charged secondary binding pocket, produced at the dimer interface in BRD2 BD I, may be the unique features that allow BRD2 BD1 to selectively bind to the acetylated H4 tail. C1 RIKEN, Genom Sci Ctr, Yokohama, Kanagawa 2300045, Japan. Japan Sci & Technol Corp, Horikoshi Gene Selector Project Exploratory Res A, Tsukuba, Ibaraki 3002635, Japan. Univ Tokyo, Inst Mol & Cellular Biosci, Lab Dev Biol, Bunkyo Ku, Tokyo 1130032, Japan. Univ Tokyo, Grad Sch Sci, Dept Biophys & Biochem, Tokyo 1130033, Japan. NICHD, Lab Mol Growth Regulat, NIH, Bethesda, MD 20892 USA. RP Padmanabhan, B (reprint author), RIKEN, Genom Sci Ctr, 1-7-22 Suehiro Cho, Yokohama, Kanagawa 2300045, Japan. EM paddy@gsc.riken.jp; yokoyama@biochem.s.u-tokyo.ac.jp RI Shirouzu, Mikako/A-6521-2016; Yokoyama, Shigeyuki/N-6911-2015; Umehara, Takashi/N-5683-2015 OI Yokoyama, Shigeyuki/0000-0003-3133-7338; Umehara, Takashi/0000-0003-3464-2960 NR 48 TC 53 Z9 54 U1 1 U2 4 PU AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3996 USA SN 0021-9258 J9 J BIOL CHEM JI J. Biol. Chem. PD FEB 9 PY 2007 VL 282 IS 6 BP 4193 EP 4201 DI 10.1074/jbc.M605971200 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 140CW UT WOS:000244481900082 PM 17148447 ER PT J AU Fong, JH Geer, LY Panchenko, AR Bryant, SH AF Fong, Jessica H. Geer, Lewis Y. Panchenko, Anna R. Bryant, Stephen H. TI Modeling the evolution of protein domain architectures using maximum parsimony SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE protein domain architecture; multi-domain proteins; domain recombination; domain evolution; protein family ID MULTIDOMAIN PROTEINS; GENE FUSION; GENOME; DATABASE; FISSION; ASSIGNMENTS; ALIGNMENTS; SEQUENCES; NETWORKS; FAMILIES AB Domains are basic evolutionary units of proteins and most proteins have more than one domain. Advances in domain modeling and collection are making it possible to annotate a large fraction of known protein sequences by a linear ordering of their domains, yielding their architecture. Protein domain architectures link evolutionarily related proteins and underscore their shared functions. Here, we attempt to better understand this association by identifying the evolutionary pathways by which extant architectures may have evolved. We propose a model of evolution in which architectures arise through rearrangements of inferred precursor architectures and acquisition of new domains. These pathways are ranked using a parsimony principle, whereby scenarios requiring the fewest number of independent recombination events, namely fission and fusion operations, are assumed to be more likely. Using a data set of domain architectures present in 159 proteomes that represent all three major branches of the tree of life allows us to estimate the history of over 85% of all architectures in the sequence database. We find that the distribution of rearrangement classes is robust with respect to alternative parsimony rules for inferring the presence of precursor architectures in ancestral species. Analyzing the most parsimonious pathways, we find 87% of architectures to gain complexity over time through simple changes, among which fusion events account for 5.6 times as many architectures as fission. Our results may be used to compute domain architecture similarities, for example, based on the number of historical recombination events separating them. Domain architecture "neighbors" identified in this way may lead to new insights about the evolution of protein function. Published by Elsevier Ltd. C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Bryant, SH (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, 8600 Rockville Pike, Bethesda, MD 20894 USA. EM bryant@ncbi.nlm.nih.gov RI Geer, Lewis/H-2714-2014 FU Intramural NIH HHS [Z01 LM000161-04] NR 37 TC 63 Z9 63 U1 0 U2 2 PU ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD FEB 9 PY 2007 VL 366 IS 1 BP 307 EP 315 DI 10.1016/j.jmb.2006.11.017 PG 9 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 135NV UT WOS:000244161200025 PM 17166515 ER PT J AU Ciccia, A Ling, C Coulthard, R Yan, ZJ Xue, YT Meetei, AR Laghmani, EH Joenje, H McDonald, N de Winter, JP Wang, WD West, SC AF Ciccia, Alberto Ling, Chen Coulthard, Rachel Yan, Zhijiang Xue, Yutong Meetei, Amom Ruhikanta Laghmani, El Houari Joenje, Hans McDonald, Neil de Winter, Johan P. Wang, Weidong West, Stephen C. TI Identification of FAAP24, a Fanconi anemia core complex protein that interacts with FANCM SO MOLECULAR CELL LA English DT Article ID NUCLEOTIDE EXCISION-REPAIR; DNA-REPAIR; ENDONUCLEASE XPF-ERCC1; HELICASE BRIP1; PATHWAY; MUS81-EME1; DOMAINS; BACH1; ACCUMULATION; DEFICIENT AB The Fanconi anemia (FA) core complex plays a crucial role in a DNA damage response network with BRCA1 and BRCA2. How this complex interacts with damaged DNA is unknown, as only the FA core protein FANCM (the homolog of an archaeal helicase/nuclease known as HEF) exhibits DNA binding activity. Here, we describe the identification of FAAP24, a protein that targets FANCM to structures that mimic intermediates formed during the replication/repair of damaged DNA. FAAP24 shares homology with the XPF family of flap/fork endonucleases, associates with the C-terminal region of FANCM, and is a component of the FA core complex. FAAP24 is required for normal levels of FANCD2 monoubiquitylation following DNA damage. Depletion of FAAP24 by siRNA results in cellular hypersensitivity to DNA crosslinking agents and chromosomal instability. Our data indicate that the FANCM/FAAP24 complex may play a key role in recruitment of the FA core complex to damaged DNA. C1 London Res Inst, Clare Hall Labs, Canc Res UK, S Mimms EN6 3LD, Herts, England. NIA, Genet Lab, NIH, TRIAD Ctr, Baltimore, MD 21224 USA. Canc Res UK, London Res Inst, London WC2A 3PX, England. Cincinnati Childrens Hosp, Res Fdn, Div Expt Hematol, Cincinnati, OH 45229 USA. Univ Cincinnati, Coll Med, Cincinnati, OH 45229 USA. VU, Med Ctr, Dept Clin Genet, NL-1081 BT Amsterdam, Netherlands. RP Wang, WD (reprint author), London Res Inst, Clare Hall Labs, Canc Res UK, S Mimms EN6 3LD, Herts, England. EM stephen.west@cancer.org.uk; wangw@grc.nia.nih.gov OI West, Stephen/0000-0001-8848-9418 FU Intramural NIH HHS NR 45 TC 173 Z9 182 U1 4 U2 12 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB 9 PY 2007 VL 25 IS 3 BP 331 EP 343 DI 10.1016/j.molcel.2007.01.003 PG 13 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 138FZ UT WOS:000244349800003 PM 17289582 ER PT J AU Luk, E Vu, ND Patteson, K Mizuguchi, G Wu, WH Ranjan, A Backus, J Sen, S Lewis, M Bai, YW Wu, C AF Luk, Ed Vu, Ngoc-Diep Patteson, Kern Mizuguchi, Gaku Wu, Wei-Hua Ranjan, Anand Backus, Jonathon Sen, Subhojit Lewis, Marc Bai, Yawen Wu, Carl TI Chz1, a nuclear chaperone for histone H2AZ SO MOLECULAR CELL LA English DT Article ID RNA-POLYMERASE-II; CRYSTAL-STRUCTURE; ASSEMBLY PATHWAY; DNA-REPLICATION; VARIANT H2A.Z; CHROMATIN; NUCLEOSOME; PROTEIN; YEAST; CORE AB The histone variant H2AZ marks nucleosomes flanking the promoters of most genes of budding yeast. The incorporation of H2AZ into chromatin is dependent on the SWR1 complex, which catalyses the replacement of conventional histone H2A with H2AZ. In cells, the pool of unincorporated histone H2AZ has previously been found in association with Nap1, a chaperone for conventional histone H2A-H2B. Here, we report the discovery of Chz1, a histone chaperone that has preference for H2AZ and can also deliver a source of the histone variant for SWR1-dependent histone replacement. Bacterially expressed Chz1 forms a heterotrimer with H2AZ-H2B, stabilizing the association of the histone dimer. We have identified a conserved motif important for histone variant recognition within the H2AZ-interacting domain of Chz1. The presence of this motif in other metazoan proteins suggests that H2AZ-specific chaperones may be widely conserved. C1 NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. NIH, Div Bioengn & Phys Sci, Off Res Serv, Off Director, Bethesda, MD 20892 USA. RP Luk, E (reprint author), NCI, Biochem & Mol Biol Lab, NIH, Bethesda, MD 20892 USA. EM luked@mail.nih.gov; carlwu@helix.nih.gov RI Sen, Subhojit/I-9033-2012; OI Sen, Subhojit/0000-0001-8457-915X; Luk, Ed/0000-0002-6619-2258 FU Intramural NIH HHS NR 50 TC 94 Z9 97 U1 0 U2 4 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1097-2765 J9 MOL CELL JI Mol. Cell PD FEB 9 PY 2007 VL 25 IS 3 BP 357 EP 368 DI 10.1016/j.molcel.2006.12.015 PG 12 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 138FZ UT WOS:000244349800005 PM 17289584 ER PT J AU Weickert, CS Webster, MJ Gondipalli, P Rothmond, D Fatula, RJ Herman, MM Kleinman, JE Akil, M AF Weickert, C. S. Webster, M. J. Gondipalli, P. Rothmond, D. Fatula, R. J. Herman, M. M. Kleinman, J. E. Akil, M. TI Postnatal alterations in dopaminergic markers in the human prefrontal cortex SO NEUROSCIENCE LA English DT Article DE development; dopamine receptors; tyrosine hydroxylase; cerebral cortex; adolescence; aging ID PRIMATE CEREBRAL-CORTEX; QUANTITATIVE AUTORADIOGRAPHIC ANALYSIS; POSITRON-EMISSION-TOMOGRAPHY; AGE-DEPENDENT DECLINE; HUMAN-BRAIN; TYROSINE-HYDROXYLASE; MESSENGER-RNA; D1 RECEPTORS; LIFE-SPAN; BIOCHEMICAL DEVELOPMENT AB Dopamine in the prefrontal cortex plays a critical role in normal cognition throughout the lifespan and has been implicated in the pathophysiology of neuropsychiatric disorders such as schizophrenia and attention deficit disorder. Little is known, however, about the postnatal development of the dopaminergic system in the human prefrontal cortex. In this study, we examined pre- and post-synaptic markers of the dopaminergic system in postmortem tissue specimens from 37 individuals ranging in age from 2 months to 86 years. We measured the levels of tyrosine hydroxylase, the rate limiting enzyme in dopamine biosynthesis, using Western immunoblotting. We also examined the gene expression of the three most abundant dopamine receptors (DARs) in the human prefrontal cortex: DAR1, DAR2 and DAR4, by in situ hybridization. We found that tyrosine hydroxylase concentrations and DAR2 mRNA levels were highest in the cortex of neonates. In contrast, the gene expression of DAR1 was highest in adolescents and young adults. No significant changes across age groups were detected in mRNA levels of DAR4. Both DAR1 and DAR2 mRNA were significantly lower in the aged cortex. Taken together, our data suggest dynamic changes in markers of the dopamine system in the human frontal cortex during postnatal development at both pre-and post-synaptic sites. The peak in DAR1 mRNA levels around adolescence/early adulthood may be of particular relevance to neuropsychiatric disorders such as schizophrenia in which symptoms manifest during the same developmental period. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved. C1 NIMH, Clin Brain Disorders Branch, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Psychiat, Stanley Fdn, Brain Res Lab, Bethesda, MD 20892 USA. RP Akil, M (reprint author), NIMH, Clin Brain Disorders Branch, NIH, 9000 Rockville Blvd,Bldg 10,CRC6-5340, Bethesda, MD 20892 USA. EM makil@mail.nih.gov RI Shannon Weickert, Cynthia/G-3171-2011 NR 66 TC 65 Z9 66 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0306-4522 J9 NEUROSCIENCE JI Neuroscience PD FEB 9 PY 2007 VL 144 IS 3 BP 1109 EP 1119 DI 10.1016/j.neuroscience.2006.10.009 PG 11 WC Neurosciences SC Neurosciences & Neurology GA 131ZX UT WOS:000243912600033 PM 17123740 ER PT J AU Youle, RJ AF Youle, Richard J. TI Cellular demolition and the rules of engagement SO SCIENCE LA English DT Editorial Material ID BH3-ONLY PROTEINS; BCL-2; BAX; OLIGOMERIZATION; APOPTOSIS; DEATH; MCL-1 AB Does cell death occur by pulling the plug on Bcl-2 life support or pulling the trigger on Bax activation? C1 NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. RP Youle, RJ (reprint author), NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. EM youler@ninds.nih.gov NR 11 TC 39 Z9 41 U1 0 U2 0 PU AMER ASSOC ADVANCEMENT SCIENCE PI WASHINGTON PA 1200 NEW YORK AVE, NW, WASHINGTON, DC 20005 USA SN 0036-8075 J9 SCIENCE JI Science PD FEB 9 PY 2007 VL 315 IS 5813 BP 776 EP 777 DI 10.1126/science.1138870 PG 2 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 134FN UT WOS:000244069000035 PM 17289967 ER PT J AU Shu, Y Winfrey, S Yang, ZY Xu, L Rao, SS Srivastava, I Barnett, SW Nabel, GJ Mascola, JR AF Shu, Yuuei Winfrey, Sarah Yang, Zhi-yong Xu, Ling Rao, Srinivas S. Srivastava, Indresh Barnett, Susan W. Nabel, Gary J. Mascola, John R. TI Efficient protein boosting after plasmid DNA or recombinant adenovirus immunization with HIV-1 vaccine constructs SO VACCINE LA English DT Article DE HIV; neutralizing antibodies; adjuvant ID HUMAN-IMMUNODEFICIENCY-VIRUS; T-CELL RESPONSES; 2ND HYPERVARIABLE REGION; NEUTRALIZING ANTIBODIES; IMMUNE-RESPONSES; ENVELOPE GLYCOPROTEIN; NONHUMAN-PRIMATES; PARTIAL DELETION; TYPE-1 ISOLATE; SUBTYPE-B AB DNA plasmids and recombinant adenovirus serotype-5 (rAd5) vectors are being studied in human clinical trials as HIV-1 vaccine candidates. Each elicits robust T-cell responses and modest antibody levels. Since protein immunization alone elicits antibody but not CD8 T-cell responses, we studied protein boosting of DNA and rAd5 HIV-1 vaccine vectors. A single Env protein immunization provided a marked boost in antibody titer in guinea pigs primed with either DNA or rAd5 vaccines, and the resulting antibody binding and neutralization levels were similar to those attained after thee sequential protein immunizations. Since both T-cell immunity and neutralizing antibodies are thought to be required for protection against HIV-1, it may be possible to establish a balanced T-cell and antibody response with appropriate vectored vaccines and improve the neutralizing antibody titer with protein boosting. (c) 2006 Elsevier Ltd. All rights reserved. C1 NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA. Novartis Vaccine, Emeryville, CA 94608 USA. RP Mascola, JR (reprint author), NIAID, Vaccine Res Ctr, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jmascola@nih.gov FU NIAID NIH HHS [Z01 AI005012-04] NR 59 TC 61 Z9 65 U1 2 U2 2 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD FEB 9 PY 2007 VL 25 IS 8 BP 1398 EP 1408 DI 10.1016/j.vaccine.2006.10.046 PG 11 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 136PJ UT WOS:000244236300006 PM 17113201 ER PT J AU Parrino, J McCurdy, LH Larkin, BD Gordon, IJ Rucker, SE Enama, ME Koup, RA Roederer, M Bailer, RT Moodie, Z Gu, L Yan, L Graham, BS AF Parrino, Janie McCurdy, Lewis H. Larkin, Brenda D. Gordon, Ingelise J. Rucker, Steven E. Enama, Mary E. Koup, Richard A. Roederer, Mario Bailer, Robert T. Moodie, Zoe Gu, Lin Yan, Lihan Graham, Barney S. CA VRC 201 203 Study Team TI Safety, immunogenicity and efficacy of modified vaccinia Ankara (MVA) against Dryvax (R) challenge in vaccinia-naive and vaccinia-immune individuals SO VACCINE LA English DT Article DE smallpox; orthopoxvirus; vaccine ID SMALLPOX VACCINE; MONKEYPOX VIRUS; PROTECTION; MACAQUES; TRIAL AB Modified vaccinia Ankara (MVA) was evaluated as an alternative to Dryvax (R) in vaccinia-naive and vaccinia-immune adult volunteers. Subjects received intramuscular MVA or placebo followed by Dryvax (R) challenge at 3 months. Two or more doses of MVA prior to Dryvax (R) reduced severity of lesion formation, decreased magnitude and duration of viral shedding, and augmented post-Dryvax (R) vaccinia-specific CD8+ T cell responses and extracellular enveloped virus protein-specific antibody responses. MVA vaccination is safe and immunogenic and improves the safety and immunogenicity of subsequent Dryvax (R) vaccination supporting the potential for using MVA as a vaccine in the general population to improve immunity to orthopox viruses. Published by Elsevier Ltd. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Stat Ctr HIV AIDS Res & Prevent, Seattle, WA USA. EMMEs Corp, Rockville, MD USA. RP Graham, BS (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,MSC-3017,Bldg 40,Room 2502, Bethesda, MD 20892 USA. EM bgraham@nih.gov RI Roederer, Mario/G-1887-2011 FU Intramural NIH HHS; NIAID NIH HHS [Z01 AI005062-03] NR 21 TC 63 Z9 63 U1 0 U2 1 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 0264-410X J9 VACCINE JI Vaccine PD FEB 9 PY 2007 VL 25 IS 8 BP 1513 EP 1525 DI 10.1016/j.vaccine.2006.10.047 PG 13 WC Immunology; Medicine, Research & Experimental SC Immunology; Research & Experimental Medicine GA 136PJ UT WOS:000244236300020 PM 17126963 ER PT J AU Scholzova, E Malik, R Sevcik, J Kleibl, Z AF Scholzova, Eva Malik, Radek Sevcik, Jan Kleibl, Zdenek TI RNA regulation and cancer development SO CANCER LETTERS LA English DT Review DE nonsense-mediated decay; RNA editing; alternative splicing; RNA interference; microRNA; cancer ID B MESSENGER-RNA; I-EDITED RNAS; MAMMALIAN-CELLS; GENE-EXPRESSION; SUBCELLULAR-DISTRIBUTION; REDUCED EXPRESSION; MISSENSE MUTATIONS; NONCODING RNAS; DECAY PATHWAY; BREAST-CANCER AB Cancer is viewed as a genetic disease. According to the currently accepted model of carcinogenesis, several consequential mutations in oncogenes or tumor suppressor genes are necessary for cancer development. In this model, mutated DNA sequence is transcribed to mRNA that is finally translated into functionally aberrant protein. mRNA is viewed solely as an intermediate between DNA (with 'coding' potential) and protein (with 'executive' function). However, recent findings suggest that (m)RNA is actively regulated by a variety of processes including nonsense-mediated decay, alternative splicing, RNA editing or RNA interference. Moreover, RNA molecules can regulate a variety of cellular functions through interactions with RNA, DNA as well as protein molecules. Although, the precise contribution of RNA molecules by themselves and RNA-regulated processes on cancer development is currently unknown, recent data suggest their important role in carcinogenesis. Here, we summarize recent knowledge on RNA-related processes and discuss their potential role in cancer development. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 Charles Univ Prague, Fac Med 1, Inst Biochem & Expt Oncol, Prague 12853 2, Czech Republic. Natl Canc Inst, Lab Prot Dynam & Signaling, Eukaryot Transcript Regulat Sect, Frederick, MD USA. RP Scholzova, E (reprint author), Charles Univ Prague, Fac Med 1, Inst Biochem & Expt Oncol, Nemocnice 5, Prague 12853 2, Czech Republic. EM escho@lf1.cuni.cz RI Malik, Radek/G-3578-2014; OI Kleibl, Zdenek/0000-0003-2050-9667 NR 122 TC 32 Z9 33 U1 1 U2 13 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD FEB 8 PY 2007 VL 246 IS 1-2 BP 12 EP 23 DI 10.1016/j.canlet.2006.03.021 PG 10 WC Oncology SC Oncology GA 135LK UT WOS:000244154900002 PM 16675105 ER PT J AU Yim, HW Slebos, RJC Randell, SH Umbach, DM Parsons, AM Rivera, MP Detterbeck, FC Taylor, JA AF Yim, Hyeon Woo Slebos, Robbert J. C. Randell, Scott H. Umbach, David M. Parsons, Alden M. Rivera, M. Patricia Detterbeck, Frank C. Taylor, Jack A. TI Smoking is associated with increased telomerase activity in short-term cultures of human bronchial epithelial cells SO CANCER LETTERS LA English DT Article DE telomerase activity; bronchial epithelial cells; smoking ID LUNG-CANCER; STEM-CELL; LIFE-SPAN; SMOKERS; METHYLATION; GROWTH; HTERT; HYPERMETHYLATION; IMMORTALIZATION; PROLIFERATION AB Telomerase plays an important role in the maintenance of telomere ends in normal and tumor cells and ectopic expression can immortalize human bronchial epithelial (HBE) cells. We assessed telomerase activation, growth proper-ties and methylation status in the hTERT promoter in a panel of HBE cell cultures in relation to smoking and previous lung cancer history. HBE cells were obtained from a total of 26 subjects, six of whom were lifelong non-smokers, while 20 subjects had a smoking history, including seven who had lung carcinoma. Telomerase activity was determined using the telomeric repeat amplification protocol (TRAP). Maximum passage number and time to senescence were also determined through extended culturing. The distribution of the telomerase activity between ever-smokers and never-smokers was significantly different (P = 0.03, F-test), and there was a strong correlation between telomerase activity and the number of pack-years smoked (P=0.0012, F-test for slope). A small difference in telomerase activity was observed according to lung cancer status (P=0.02, F-test). Telomerase activity was not correlated with maximum passage number after extended culturing or with time to senescence. None of the HBE cultures demonstrated methylation of the hTERT promoter. Our results indicate an association between tobacco carcinogen exposure and telomerase activity in normal bronchial epithelium, although a causative role of tobacco smoking in the (re)activation of telomerase can not be proven. An increase in telomerase activity in normal bronchial epithelium might extend the lifespan of cells at risk for malignant transformation, and thus contribute to lung carcinogenesis. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 Natl Inst Environm Hlth Sci, Epidemiol Branch, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Mol Carcinogenesis Lab, Res Triangle Pk, NC 27709 USA. Natl Inst Environm Hlth Sci, Biostat Branch, Res Triangle Pk, NC 27709 USA. Catholic Univ Korea, Dept Prevent Med, Seoul, South Korea. Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Dept Canc Biol, Nashville, TN USA. Vanderbilt Univ, Vanderbilt Ingram Canc Ctr, Dept Otolaryngol, Nashville, TN USA. Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA. RP Taylor, JA (reprint author), Natl Inst Environm Hlth Sci, Epidemiol Branch, Mail Drop A3-01,Box 12233, Res Triangle Pk, NC 27709 USA. EM taylor@niehs.nih.gov OI taylor, jack/0000-0001-5303-6398 FU Intramural NIH HHS NR 32 TC 10 Z9 10 U1 0 U2 1 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD FEB 8 PY 2007 VL 246 IS 1-2 BP 24 EP 33 DI 10.1016/j.canlet.2006.01.023 PG 10 WC Oncology SC Oncology GA 135LK UT WOS:000244154900003 PM 16517060 ER PT J AU Bates, MN Hopenhayn, C Rey, OA Moore, LE AF Bates, Michael N. Hopenhayn, Claudia Rey, Omar A. Moore, Lee E. TI Bladder cancer and mate consumption in Argentina: A case-control study SO CANCER LETTERS LA English DT Article DE Argentina; bladder cancer; case-control study; epidemiology; Mate; tobacco smoking ID ESOPHAGEAL CANCER; SOUTHERN BRAZIL; RISK; DRINKING; URUGUAY; TOBACCO; EXPOSURE; ALCOHOL; SMOKING; DIET AB Mate is a 'tea', made from Ilex paraguariensis, widely consumed in South America, as mate con bombilla and mate cocido. Mate consumption has been associated with esophageal, oral, lung, and bladder cancers. This bladder cancer case-control study involved 114 Argentinean case-control pairs. Mate consumption was recorded for time of interview, and 20 and 40 years previously. Mate con bombilla consumed 20 years ago was associated with bladder cancer in ever-smokers (odds ratio = 3.77, 95% confidence interval: 1.17-12.1), but not in never-smokers. Mate cocido was not associated with bladder cancer. These results are consistent with a previous study in Uruguay. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 Univ Calif Berkeley, Sch Publ Hlth, Berkeley, CA 94720 USA. Univ Kentucky, Sch Publ Hlth, Lexington, KY USA. Univ Kentucky, Canc Control Program, Lexington, KY USA. Univ Catolica Cordoba, Fac Med, Cordoba, Argentina. NCI, Occupat Epidemiol Branch, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. RP Bates, MN (reprint author), Univ Calif Berkeley, Sch Publ Hlth, 140 Warren Hall, Berkeley, CA 94720 USA. EM m_bates@berkeley.edu FU NIEHS NIH HHS [P30 ES01896-22, P42 ES04705] NR 21 TC 22 Z9 24 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3835 J9 CANCER LETT JI Cancer Lett. PD FEB 8 PY 2007 VL 246 IS 1-2 BP 268 EP 273 DI 10.1016/j.canlet.2006.03.005 PG 6 WC Oncology SC Oncology GA 135LK UT WOS:000244154900032 PM 16616809 ER PT J AU Bax, A Torchia, DA AF Bax, Ad Torchia, Dennis A. TI Structural biology - Molecular machinery in action SO NATURE LA English DT Editorial Material ID SPECTROSCOPY C1 NIH, Bethesda, MD 20892 USA. RP Bax, A (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM bax@nih.gov; dtorchia@mail.nih.gov NR 4 TC 0 Z9 0 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 8 PY 2007 VL 445 IS 7128 BP 609 EP 609 DI 10.1038/445609a PG 1 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA 133UM UT WOS:000244039400032 PM 17237759 ER PT J AU Legro, RS Barnhart, HX Schlaff, WD Carr, BR Diamond, MP Carson, SA Steinkampf, MP Coutifaris, C McGovern, PG Cataldo, NA Gosman, GG Nestler, JE Giudice, LC Leppert, PC Myers, ER AF Legro, Richard S. Barnhart, Huiman X. Schlaff, William D. Carr, Bruce R. Diamond, Michael P. Carson, Sandra A. Steinkampf, Michael P. Coutifaris, Christos McGovern, Peter G. Cataldo, Nicholas A. Gosman, Gabriella G. Nestler, John E. Giudice, Linda C. Leppert, Phyllis C. Myers, Evan R. CA Cooperative Multicenter Reprod Med TI Clomiphene, metformin, or both for infertility in the polycystic ovary syndrome SO NEW ENGLAND JOURNAL OF MEDICINE LA English DT Article ID EXTENDED-RELEASE METFORMIN; PLACEBO-CONTROLLED TRIAL; CITRATE-RESISTANT WOMEN; SURROGATE END-POINTS; EARLY-PREGNANCY LOSS; DOUBLE-BLIND; OVULATION INDUCTION; INSULIN-RESISTANCE; CLINICAL-TRIAL; OBESITY AB BACKGROUND: The polycystic ovary syndrome is a common cause of infertility. Clomiphene and insulin sensitizers are used alone and in combination to induce ovulation, but it is unknown whether one approach is superior. METHODS: We randomly assigned 626 infertile women with the polycystic ovary syndrome to receive clomiphene citrate plus placebo, extended-release metformin plus placebo, or a combination of metformin and clomiphene for up to 6 months. Medication was discontinued when pregnancy was confirmed, and subjects were followed until delivery. RESULTS: The live-birth rate was 22.5% (47 of 209 subjects) in the clomiphene group, 7.2% (15 of 208) in the metformin group, and 26.8% (56 of 209) in the combination-therapy group (P<0.001 for metformin vs. both clomiphene and combination therapy; P=0.31 for clomiphene vs. combination therapy). Among pregnancies, the rate of multiple pregnancy was 6.0% in the clomiphene group, 0% in the metformin group, and 3.1% in the combination-therapy group. The rates of first-trimester pregnancy loss did not differ significantly among the groups. However, the conception rate among subjects who ovulated was significantly lower in the metformin group (21.7%) than in either the clomiphene group (39.5%, P=0.002) or the combination-therapy group (46.0%, P<0.001). With the exception of pregnancy complications, adverse-event rates were similar in all groups, though gastrointestinal side effects were more frequent, and vasomotor and ovulatory symptoms less frequent, in the metformin group than in the clomiphene group. CONCLUSIONS: Clomiphene is superior to metformin in achieving live birth in infertile women with the polycystic ovary syndrome, although multiple birth is a complication. C1 Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Obstet & Gynecol, Hershey, PA 17033 USA. Duke Univ, Med Ctr, Durham, NC USA. Univ Colorado, Denver, CO 80202 USA. Univ Texas, SW Med Ctr, Dallas, TX USA. Wayne State Univ, Detroit, MI USA. Baylor Coll Med, Houston, TX 77030 USA. Univ Alabama, Birmingham, AL USA. Univ Penn, Sch Med, Philadelphia, PA 19104 USA. Univ Med & Dent New Jersey, Newark, NJ 07103 USA. Stanford Univ, Stanford, CA 94305 USA. Univ Pittsburgh, Pittsburgh, PA USA. Virginia Commonwealth Univ, Sch Med, Richmond, VA USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. NICHHD, Bethesda, MD 20892 USA. RP Legro, RS (reprint author), Penn State Univ, Milton S Hershey Med Ctr, Coll Med, Dept Obstet & Gynecol, 500 Univ Dr,H103, Hershey, PA 17033 USA. EM rsl1@psu.edu OI Diamond, Michael/0000-0001-6353-4489 FU NCRR NIH HHS [M01RR00056, M01RR10732, C06 RR016499]; NICHD NIH HHS [U01 HD38997, U10 HD27011, U10 HD27049, U10 HD33172, U10 HD38988, U10 HD38992, U10 HD38998, U10 HD38999, U10 HD39005, U54-HD29834] NR 39 TC 398 Z9 425 U1 1 U2 25 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 8 PY 2007 VL 356 IS 6 BP 551 EP 566 DI 10.1056/NEJMoa063971 PG 16 WC Medicine, General & Internal SC General & Internal Medicine GA 133KV UT WOS:000244012700004 PM 17287476 ER PT J AU Ivanov, SV Salnikow, K Ivanova, AV Bai, L Lerman, MI AF Ivanov, S. V. Salnikow, K. Ivanova, A. V. Bai, L. Lerman, M. I. TI Hypoxic repression of STAT1 and its downstream genes by a pVHL/HIF-1 target DEC1/STRA13 SO ONCOGENE LA English DT Article DE VHL; HIF-1; hypoxia; STRA13; STAT1; CASP1 ID RENAL-CELL CARCINOMA; TUMOR-SUPPRESSOR PROTEIN; INTERFERON-GAMMA; DEACETYLASE ACTIVITY; DOWN-REGULATION; TRANSCRIPTIONAL REPRESSOR; INDEPENDENT MECHANISMS; STRA13 EXPRESSION; INDUCED APOPTOSIS; CLASS-I AB DEC1/STRA13 is a bHLH type transcriptional regulator involved with immune regulation, hypoxia response and carcinogenesis. We recently demonstrated that STRA13 interacts with STAT3 in the transcriptional activation of STAT-dependent promoters. Here, we pursue STRA13 involvement in the JAK/STAT pathway by studying its role in STAT1 expression. First, we showed that VHL deficiency or HIF-1 activation resulted in the repression of endogenous STAT1 mediated by STRA13. We then characterized the STAT1 proximal promoter to assess its response to STRA13 by transient coexpression in a luciferase reporter assay. Using sequential truncation and site-directed mutagenesis of the STAT1 promoter with STRA13 deletion constructs, we showed that the STRA13 C-terminal trans-activation domain, which is known to bind HDAC1, mostly determines the repressive activity. Involvement of HDAC activity in STAT1 regulation was validated by TSA inhibition and chromatin immuno-precipitation (ChIP) assay. Thus, we demonstrate that STRA13-mediated repression of STAT1 transcription utilizes an HDAC1-dependent mechanism. Furthermore, we show that targets of unphosphorylated STAT1, such as antigen presenting genes and CASP1, are also repressed by hypoxia possibly through the same STRA13-mediated mechanism. Thus, the newly discovered link between HIF-1 and STAT1 reveals a previously unknown role of STRA13 in hypoxia and carcinogenesis. C1 SAIC Frederick, Basic Res Program, Ft Detrick, MD 21702 USA. NCI, NIH, Frederick, MD 21701 USA. NYU, Med Ctr, Dept Cardiothorac Surg, New York, NY 10016 USA. Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA. RP Ivanov, SV (reprint author), SAIC Frederick, Basic Res Program, B 560,POB B, Ft Detrick, MD 21702 USA. EM Sergey.Ivanov@med.nyu.edu OI Ivanov, Sergey/0000-0001-9770-7237 FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 55 TC 35 Z9 36 U1 1 U2 7 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 8 PY 2007 VL 26 IS 6 BP 802 EP 812 DI 10.1038/sj.onc.1209842 PG 11 WC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredity GA 134DT UT WOS:000244063800002 PM 16878149 ER PT J AU Dupuis, J O'Donnell, CJ AF Dupuis, Josee O'Donnell, Christopher J. TI Interpreting results of large-scale genetic association studies - Separating gold from fool's gold SO JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION LA English DT Editorial Material ID GENOME-WIDE ASSOCIATION; FALSE DISCOVERY; EFFICIENT; VARIANT; POWER; MAP C1 Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA. NHLBI, Boston, MA USA. NHLBI Framingham Heart Study, Boston, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Cardiol Div, Boston, MA USA. RP O'Donnell, CJ (reprint author), Framingham Heart Dis Epidemiol Study, 73 Mt Wayte Ave 2, Framingham, MA 01702 USA. EM codonnell@nih.gov NR 17 TC 14 Z9 15 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0098-7484 J9 JAMA-J AM MED ASSOC JI JAMA-J. Am. Med. Assoc. PD FEB 7 PY 2007 VL 297 IS 5 BP 529 EP 531 DI 10.1001/jama.297.5.529 PG 3 WC Medicine, General & Internal SC General & Internal Medicine GA 133FP UT WOS:000243999100032 PM 17284705 ER PT J AU Burton, RA Tjandra, N AF Burton, Robert A. Tjandra, Nico TI Residue-specific C-13' CSA tensor principal components for ubiquitin: Correlation between tensor components and hydrogen bonding SO JOURNAL OF THE AMERICAN CHEMICAL SOCIETY LA English DT Article ID CHEMICAL-SHIFT ANISOTROPY; SOLID-STATE NMR; PROTEIN-STRUCTURE; BONDED STRUCTURE; ALIGNMENT MEDIA; TORSION ANGLES; N-15; PEPTIDES; CARBONYL; RELAXATION AB The residue-specific C-13' CSA tensor principal components, sigma(11), sigma(22), sigma(33), and the tensor orientation defined by the rotation angles beta and gamma have been determined by solution NMR for uniformly labeled ubiquitin partially aligned in four different media. Spurious chemical shift deviations due to solvent effects were corrected with an offset calculated by linear regression of the residual dipolar couplings and chemical shifts at increasing alignment strengths. Analysis of this effect revealed no obvious correlation to solvent exposure. Data obtained in solution from a protein offer a better sampling of C-13' CSA for different amino acid types in a complex heterogeneous environment, thereby allowing for the evaluation of structural variables that would be challenging to achieve by other methods. The C-13' CSA principal components cluster about the average values previously determined, and experimental correlations observed between sigma(11), sigma(22) tensorial components and C'O center dot center dot center dot H-N hydrogen bonding are discussed. The inverse association of sigma(11) and sigma(22) exemplify the calculated and solid-state NMR observed effect on the tensor components by hydrogen bonding. We also show that C-13' CSA tensors are sensitive to hydrogen-bond length but not hydrogen-bond angle. This differentiation was previously unavailable. Similarly, hydrogen bonding to the conjugated NH of the same peptide plane has no detectable effect. Importantly, the observed weak correlations signify the presence of confounding influences such as nearest-neighbor effects, side-chain conformation, electrostatics, and other long-range factors to the C-13' CSA tensor. These analyses hold future potential for exploration provided that more accurate data from a larger number of proteins and alignments become available. C1 NHLBI, Lab Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Tjandra, N (reprint author), NHLBI, Lab Mol Biophys, NIH, 50 S Dr, Bethesda, MD 20892 USA. EM tjandran@nhlbi.nih.gov FU Intramural NIH HHS NR 35 TC 12 Z9 12 U1 0 U2 11 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0002-7863 J9 J AM CHEM SOC JI J. Am. Chem. Soc. PD FEB 7 PY 2007 VL 129 IS 5 BP 1321 EP 1326 DI 10.1021/ja066835c PG 6 WC Chemistry, Multidisciplinary SC Chemistry GA 131AL UT WOS:000243840100051 PM 17263416 ER PT J AU Hisada, M Chen, BE Jaffe, ES Travis, LB AF Hisada, Michie Chen, Bingshu E. Jaffe, Elaine S. Travis, Lois B. TI Second cancer incidence and cause-specific mortality among 3104 patients with hairy cell leukemia: A population-based study SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CHRONIC LYMPHOCYTIC-LEUKEMIA; TERM-FOLLOW-UP; ACID-PHOSPHATASE; CLADRIBINE; 2-CHLORODEOXYADENOSINE; MALIGNANCIES; EXPERIENCE; RISK; RETICULOENDOTHELIOSIS; LYMPHOMA AB Background The introduction of new treatments for hairy cell leukemia has resulted in improved patient survival but also engendered increasing concern about the possibility of excess second cancers. The available evidence is conflicting, with most risk estimates based on sparse numbers. To our knowledge, no study has evaluated cause-specific mortality in patients with hairy cell leukemia. Methods We quantified second cancer incidence and cause-specific mortality among 3104 two-month survivors of hairy cell leukemia who were reported to 16 population-based registries in the Surveillance, Epidemiology and End Results (SEER) Program between 1973 and 2002. Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were used to quantify the risk of second cancers and causes of death, respectively. The cumulative probability of a second cancer among survivors of hairy cell leukemia was calculated using a competing risk model. All statistical tests were two-sided. Results Mean follow-up of hairy cell leukemia survivors was 6.5 years (range, 2 months-29.3 years). Second cancer risk was statistically significantly elevated (SIR = 1.24, 95% confidence interval [CI] = 1.11 to 1.37) compared with the general population. Survivors had statistically significantly higher risks of Hodgkin lymphoma (SIR 6.61, 95% CI = 2.13 to 15.42), non-Hodgkin lymphoma (SIR = 5.03, 95% CI = 3.77 to 6.58), and thyroid cancer (SIR = 3.56, 95% CI = 1.30 to 7.74) and a lower risk of lung cancer (SIR = 0.63, 95% CI = 0.42 to 0.90). The cumulative probability of all second cancers was estimated to be 31.9% (95% Cl = 26.2 to 37.6) 25 years after hairy cell leukemia diagnosis. Among 10000 hairy cell leukemia patients, a total excess of about 34 cancers, including 21 non-Hodgkin lymphomas, 2 Hodgkin lymphomas, and 7 solid tumors (including 2 thyroid cancers), might be observed per year. Deaths due to solid tumors were not elevated compared with the general population (SMR = 0.9), and there were statistically significant deficits in mortality due to both cardiovascular (SMR = 0.67, 95% CI = 0.56 to 0.80) and cerebrovascular (SMR = 0.61, 95% CI = 0.38 to 0.93) disease. Conclusions Patients with hairy cell leukemia are at increased risk of Hodgkin lymphoma, non-Hodgkin lymphoma, and thyroid cancer. The decrease in lung cancer incidence and smoking-associated vascular mortality may reflect an inverse association of tobacco use with hairy cell leukemia. Future studies should address the roles of immunologic impairment inherent to hairy cell leukemia, treatment modalities, and other factors as codeterminants of morbidity and mortality in hairy cell leukemia survivors. C1 NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. NCI, Pathol Lab, Canc Res Ctr, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Hisada, M (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, 6120 Execut Blvd,EPS 8008, Bethesda, MD 20892 USA. EM hisadam@mail.nih.gov FU Intramural NIH HHS NR 35 TC 46 Z9 51 U1 0 U2 1 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 7 PY 2007 VL 99 IS 3 BP 215 EP 222 DI 10.1093/jnci/djk030 PG 8 WC Oncology SC Oncology GA 136LG UT WOS:000244223400009 PM 17284716 ER PT J AU Nakayama, T Mutsuga, N Tosato, G AF Nakayama, Takayuki Mutsuga, Noriko Tosato, Giovanna TI Effect of fibroblast growth factor 2 on stromal cell-derived factor 1 production by bone marrow stromal cells and hematopoiesis SO JOURNAL OF THE NATIONAL CANCER INSTITUTE LA English DT Article ID CHEMOKINE RECEPTOR CXCR4; FACTOR-I; PROGENITOR CELLS; MYELOPROLIFERATIVE DISORDERS; MYELOID METAPLASIA; STIMULATING FACTOR; CORD BLOOD; MYELOFIBROSIS; MOBILIZATION; MYELOPOIESIS AB Background Reduction of intramedullary hematopoiesis and the development of myelofibrosis and splenic hematopoiesis are frequent complications of CIonal myeloid disorders that cause severe morbidity and death and present a therapeutic challenge. However, the pathogenesis of these complications is still unknown. We evaluated the effect of fibroblast growth factor 2 (FGF-2), the level of which is elevated in patients with CIonal myeloid disorders, on bone marrow stromal cell expression of stromal cell-derived factor 1 (SDF-1), a chemokine that is essential for normal hematopoiesis. Methods Reverse transcription-polymerase chain reaction analysis, immunoblot analysis, and enzyme-linked immunosorbent assays were used to examine effects of human recombinant FGF-2 exposure on SDF-1 expression in mouse stromal MS-5 and S-17 cells. Cocultures of human CD34-positive peripheral blood stem cells or mouse pre-B DW34 cells with mouse stromal cells were used to characterize the functional relevance of the effects of FGF-2 on SDF-1 expression. The in vivo hematologic effects of FGF-2 were determined by systemic administration to mice (n = 10). All statistical tests were two-sided. Results FGF-2 reduced constitutive SDF-1 mRNA expression and secretion in stromal cells (SDF-1 levels in supernatants: MS-5 cells cultured for 3 days in medium only versus in medium with FGF-2, 95.4 ng/mL versus 22.2 ng/mL, difference = 73.2 ng/mL, 95% confidence interval [CI] = 60.52 to 85.87 ng/mL; P=.002, two-sided Student's t test; S-17 cultured in medium only versus in medium with FGF-2, 203.53 ng/mL versus 32.36 ng/mL, difference = 171.17 ng/mL, 95% CI = 161.8 to 180.6 ng/mL; P < 001). These effects of FGF-2 were reversible. FGF-2 compromised stromal cell support of the growth and survival of pre-13 DW34 and myeloid lineage cells, and these effects were reversed in part by exogenous recombinant SDF-1 alpha (rSDF-1 alpha) QW34 pre-B cells recovery on S-17 stromal cells, expressed as a percentage of DW34 cells recovered from medium only: with FGF-2 versus without FGF-2, 27.6% versus 100%, difference = 72.4%, 95% CI = 45.34% to 99.51%, P=.008; with FGF-2 plus rSDF1 versus with FGF-2 only, 60.3% versus 27.6%, difference = 32.7%, 95% CI = 9.35% to 56.08%, P=.034; fold increase in number of myeloid lineage cells after culture on S-17 stromal cells: with FGF-2 versus without FGF-2, 0.25-fold versus 3.8-fold, difference = 3.55-fold, 95% CI = 2.66- to 4.44-fold, P < 001; recovery of myeloid cells on S-17 stromal cells, expressed as a percentage of myeloid cells recovered from medium only: FGF-2 plus rSDF-1 alpha versus FGF-2 only, 76.5% versus 32.4%, difference = 44.1%, 95% CI = 32.58% to 55.68%, P < 001). Administration of FGF-2 to mice reversibly reduced bone marrow levels of SDF-1 and cellularity and induced immature myeloid cell mobilization, extramedullary hematopoiesis, and splenomegaly. Conclusions Systemic administration of FGF-2 in mice disrupts normal bone marrow hematopoiesis in part through reduced expression of SDF-1. Thus, endogenous FGF-2 may represent a potential therapeutic target in CIonal myeloid disorders characterized by bone marrow failure. C1 NCI, Canc Res Ctr, Basic Res Lab, Bethesda, MD 20892 USA. Natl Inst Neurol Disorders & Stroke, Neurochem Lab, NIH, Bethesda, MD USA. RP Tosato, G (reprint author), NCI, Canc Res Ctr, Basic Res Lab, Bldg 10,Rm 12C205,10 Ctr Dr, Bethesda, MD 20892 USA. EM tosatog@mail.nih.gov FU Intramural NIH HHS NR 45 TC 21 Z9 24 U1 0 U2 2 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 7 PY 2007 VL 99 IS 3 BP 223 EP 235 DI 10.1093/jnci/djk031 PG 13 WC Oncology SC Oncology GA 136LG UT WOS:000244223400010 PM 17284717 ER PT J AU Sengupta, K Upender, MB Barenboim-Stapleton, L Nguyen, QT Wincovitch, SM Garfield, SH Difilippantonio, MJ Ried, T AF Sengupta, Kundan Upender, Madhvi B. Barenboim-Stapleton, Linda Nguyen, Quang Tri Wincovitch, Stephen M., Sr. Garfield, Susan H. Difilippantonio, Michael J. Ried, Thomas TI Artificially Introduced Aneuploid Chromosomes Assume a Conserved Position in Colon Cancer Cells SO PLOS ONE LA English DT Article AB Background. Chromosomal aneuploidy is a defining feature of carcinomas. For instance, in colon cancer, an additional copy of Chromosome 7 is not only observed in early pre-malignant polyps, but is faithfully maintained throughout progression to metastasis. These copy number changes show a positive correlation with average transcript levels of resident genes. An independent line of research has also established that specific chromosomes occupy a well conserved 3D position within the interphase nucleus. Methodology/Principal Findings. We investigated whether cancer-specific aneuploid chromosomes assume a 3D-position similar to that of its endogenous homologues, which would suggest a possible correlation with transcriptional activity. Using 3D-FISH and confocal laser scanning microscopy, we show that Chromosomes 7, 18, or 19 introduced via microcell-mediated chromosome transfer into the parental diploid colon cancer cell line DLD-1 maintain their conserved position in the interphase nucleus. Conclusions. Our data is therefore consistent with the model that each chromosome has an associated zip code (possibly gene density) that determines its nuclear localization. Whether the nuclear localization determines or is determined by the transcriptional activity of resident genes has yet to be ascertained. C1 [Sengupta, Kundan; Upender, Madhvi B.; Barenboim-Stapleton, Linda; Nguyen, Quang Tri; Difilippantonio, Michael J.; Ried, Thomas] NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. [Wincovitch, Stephen M., Sr.; Garfield, Susan H.] NCI, Expt Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA. RP Ried, T (reprint author), NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. EM riedt@mail.nih.gov FU NIH; National Cancer Institute FX This research was supported by the intramural research program of the NIH, National Cancer Institute. NR 25 TC 16 Z9 16 U1 0 U2 0 PU PUBLIC LIBRARY SCIENCE PI SAN FRANCISCO PA 185 BERRY ST, STE 1300, SAN FRANCISCO, CA 94107 USA SN 1932-6203 J9 PLOS ONE JI PLoS One PD FEB 7 PY 2007 VL 2 IS 2 AR e199 DI 10.1371/journal.pone.0000199 PG 9 WC Multidisciplinary Sciences SC Science & Technology - Other Topics GA V10DI UT WOS:000207444300011 PM 17332847 ER PT J AU Wu, YT Beddall, MH Marsh, JW AF Wu, Yuntao Beddall, Margaret H. Marsh, Jon W. TI Rev-dependent lentiviral expression vector SO RETROVIROLOGY LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; IN-SITU HYBRIDIZATION; LONG-TERMINAL REPEAT; MESSENGER-RNA; T-CELL; TRANS-ACTIVATION; MOLECULAR CLONE; GENE-PRODUCT; TYPE-1; HIV-1 AB Background: HIV-responsive expression vectors are all based on the HIV promoter, the long terminal repeat (LTR). While responsive to an early HIV protein, Tat, the LTR is also responsive to cellular activation states and to the local chromatin activity where the integration has occurred. This can result in high HIV-independent activity, and has restricted the use of LTR-based reporter vectors to cloned cells, where aberrantly high expressing (HIV-negative) cells can be eliminated. Enhancements in specificity would increase opportunities for expression vector use in detection of HIV as well as in experimental gene expression in HIV-infected cells. Results: We have constructed an expression vector that possesses, in addition to the Tat-responsive LTR, numerous HIV DNA sequences that include the Rev-response element and HIV splicing sites that are efficiently used in human cells. It also contains a reading frame that is removed by cellular splicing activity in the absence of HIV Rev. The vector was incorporated into a lentiviral reporter virus, permitting detection of replicating HIV in living cell populations. The activity of the vector was measured by expression of green fluorescence protein (GFP) reporter and by PCR of reporter transcript following HIV infection. The vector displayed full HIV dependency. Conclusion: As with the earlier developed Tat-dependent expression vectors, the Rev system described here is an exploitation of an evolved HIV process. The inclusion of Rev-dependency renders the LTR-based expression vector highly dependent on the presence of replicating HIV. The application of this vector as reported here, an HIV-dependent reporter virus, offers a novel alternative approach to existing methods, in situ PCR or HIV antigen staining, to identify HIV-positive cells. The vector permits examination of living cells, can express any gene for basic or clinical experimentation, and as a pseudo-typed lentivirus has access to most cell types and tissues. C1 NIMH, Sect Mol Virol, Cellular & Mol Regulat Lab, Bethesda, MD 20892 USA. George Mason Univ, Ctr Biodefense & Infect Dis, Dept Mol & Microbiol, Manassas, VA 20110 USA. RP Marsh, JW (reprint author), NIMH, Sect Mol Virol, Cellular & Mol Regulat Lab, Bethesda, MD 20892 USA. EM ywu8@gmu.edu; margaretbeddall@mail.nih.gov; marshj@mail.nih.gov FU Intramural NIH HHS; NINDS NIH HHS [R21 NS051130, 5R21NS51130-2] NR 45 TC 24 Z9 25 U1 1 U2 4 PU BIOMED CENTRAL LTD PI LONDON PA 236 GRAYS INN RD, FLOOR 6, LONDON WC1X 8HL, ENGLAND SN 1742-4690 J9 RETROVIROLOGY JI Retrovirology PD FEB 7 PY 2007 VL 4 AR 12 DI 10.1186/1742-4690-4-12 PG 7 WC Virology SC Virology GA 138MT UT WOS:000244367400002 PM 17286866 ER PT J AU Schwieters, CD Clore, GM AF Schwieters, Charles D. Clore, G. Marius TI A physical picture of atomic motions within the Dickerson DNA dodecamer in solution derived from joint ensemble refinement against NMR and large-angle X-ray scattering data SO BIOCHEMISTRY LA English DT Article ID INTERPROTON DISTANCE RESTRAINTS; NUCLEAR-MAGNETIC-RESONANCE; MACROMOLECULAR STRUCTURE DETERMINATION; MOLECULAR-DYNAMICS SIMULATION; CHEMICAL-SHIFT ANISOTROPY; SMALL ALPHA/BETA PROTEIN; DIPOLAR COUPLINGS; CROSS-VALIDATION; 3-DIMENSIONAL STRUCTURES; STRUCTURAL BASIS AB The structure and dynamics of the Dickerson DNA dodecamer [5'd(CGCGAATTCGCG)(2)] in solution have been investigated by joint simulated annealing refinement against NMR and large-angle X-ray scattering data (extending from 0.25 to 3 A(-1)). The NMR data comprise an extensive set of hetero- and homonuclear residual dipolar coupling and P-31 chemical shift anisotropy restraints in two alignment media, supplemented by NOE and (3)J coupling data. The NMR and X-ray scattering data cannot be fully ascribed to a single structure representation, indicating the presence of anisotropic motions that impact the experimental observables in different ways. Refinement with ensemble sizes (N-e) of >= 2 to represent the atomic motions reconciles all the experimental data within measurement error. Cross validation against both the dipolar coupling and X-ray scattering data suggests that the optimal ensemble size required to account for the current data is 4. The resulting ensembles permit one to obtain a detailed view of the conformational space sampled by the dodecamer in solution and permit one to analyze fluctuations in helicoidal parameters, sugar puckers, and BI-BII backbone transitions and to obtain quantitative metrics of atomic motion such as generalized order parameters and thermal B factors. The calculated order parameters are in good agreement with experimental order parameters obtained from C-13 relaxation measurements. Although DNA behaves as a relatively rigid rod with a persistence length of similar to 150 bp, dynamic conformational heterogeneity at the base pair level is functionally important since it readily permits optimization of intermolecular protein-DNA interactions. C1 NIH, DIv computat Biosci, Ctr Informat Technol, Bethesda, MD 20892 USA. NIDDKD, Chem Phys Lab, NIH, Bethesda, MD 20892 USA. RP Schwieters, CD (reprint author), NIH, DIv computat Biosci, Ctr Informat Technol, Bldg 12A, Bethesda, MD 20892 USA. EM charles.schwieters@nih.gov; mariusc@mail.nih.gov RI Clore, G. Marius/A-3511-2008 OI Clore, G. Marius/0000-0003-3809-1027 FU Intramural NIH HHS NR 63 TC 69 Z9 69 U1 1 U2 13 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 6 PY 2007 VL 46 IS 5 BP 1152 EP 1166 DI 10.1021/bi061943.x PG 15 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 131AG UT WOS:000243839500004 PM 17260945 ER PT J AU Zheng, J Zanuy, D Haspel, N Tsai, CJ Aleman, C Nussinov, R AF Zheng, Jie Zanuy, David Haspel, Nurit Tsai, Chung-Jung Aleman, Carlos Nussinov, Ruth TI Nanostructure design using protein building blocks enhanced by conformationally constrained synthetic residues SO BIOCHEMISTRY LA English DT Article ID BETA-HELIX PROTEINS; CYCLOPROPANE ANALOG; C-ALPHA,ALPHA-DIALKYLATED GLYCINES; CRYSTALLOGRAPHIC CHARACTERIZATION; NANOTECHNOLOGICAL APPLICATIONS; STRUCTURAL VERSATILITY; LINEAR OLIGOPEPTIDES; MOLECULAR-DYNAMICS; PEPTIDE NANOTUBES; CRYSTAL-STRUCTURE AB Increasing efforts are being invested in the construction of nanostructures with desired shapes and physical and chemical properties. Our strategy involves nanostructure design using naturally occurring protein building blocks. Inspection of the protein structural database (PDB) reveals the richness of the conformations, shapes, and chemistries of proteins and their building blocks. To increase the population of the native fold in the selected building block, we mutate natural residues by engineered, constrained residues that restrict the conformational freedom at the targeted site and have favorable interactions, geometry, and size. Here, as a model system, we construct nanotubes using building blocks from left-handed beta-helices which are commonly occurring repeat protein architectures. We pick two-turn beta-helical segments, duplicate and stack them, and using all-atom molecular dynamics simulations (MD) with explicit solvent probe the structural stability of these nanotubular structures as indicated by their capacity to retain the initial organization and their conformational dynamics. Comparison of the results for the wild-type and mutated sequences shows that the introduction of the conformationally restricted 1-aminocyclopropanecarboxylic acid (Ac(3)c) residue in loop regions greatly enhances the stability of beta-helix nanotubes. The Ac(3)c geometrical confinement effect is sequence-specific and position-specific. The achievement of high stability of nanotubular structures originates not only from the reduction of mobility at the mutation site induced by Ac(3)c but also from stabilizing association forces between building blocks such as hydrogen bonds and hydrophobic contacts. For the selected synthetic residue, similar size, hydrophobicity, and backbone conformational tendencies are desirable as in the Ac(3)c. C1 NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol,FCRDC, Frederick, MD 21702 USA. Univ Politecn Cataluna, Dept Engn Quim, ETS Engn Ind Barcelona, E-08028 Barcelona, Spain. Tel Aviv Univ, Sackler Sch Med, Dept Human Genet & Mol Med, Sackler Inst Mol Med, IL-69978 Tel Aviv, Israel. RP Nussinov, R (reprint author), NCI, Basic Res Program, SAIC Frederick Inc, Ctr Canc Res Nanobiol,FCRDC, Bldg 469,Room 151, Frederick, MD 21702 USA. EM ruthn@ncifcrf.gov RI Zheng, Jie/B-5057-2013; Zanuy, David/G-3930-2014; Haspel, Nurit/D-1961-2017 OI Zheng, Jie/0000-0003-1547-3612; Zanuy, David/0000-0001-7704-2178; FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 70 TC 29 Z9 30 U1 1 U2 6 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 6 PY 2007 VL 46 IS 5 BP 1205 EP 1218 DI 10.1021/bi061674a PG 14 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 131AG UT WOS:000243839500009 PM 17260950 ER PT J AU Boesze-Battaglia, K Song, HM Sokolov, M Lillo, C Pankoski-Walker, L Gretzula, C Gallagher, B Rachel, RA Jenkins, NA Copeland, NG Morris, F Jacob, J Yeagle, P Williams, DS Damek-Poprawa, M AF Boesze-Battaglia, Kathleen Song, Hongman Sokolov, Maxim Lillo, Concepcion Pankoski-Walker, Lisa Gretzula, Cheryl Gallagher, Bridget Rachel, Rivka A. Jenkins, Nancy A. Copeland, Neal G. Morris, Francine Jacob, Jerry Yeagle, Philip Williams, David S. Damek-Poprawa, Monika TI The tetraspanin protein peripherin-2 forms a complex with melanoregulin, a putative membrane fusion regulator SO BIOCHEMISTRY LA English DT Article ID RDS MUTANT MICE; OUTER SEGMENT MEMBRANES; INTRINSICALLY UNSTRUCTURED PROTEINS; PHOTORECEPTOR CELL PERIPHERIN/RDS; DOMINANT RETINITIS-PIGMENTOSA; COAT-COLOR PHENOTYPE; SUPPRESSOR GENE DSU; DILUTE SUPPRESSOR; ROD PHOTORECEPTORS; DISK MEMBRANES AB Peripherin-2, the product of the rds gene, is a tetraspanin protein. In this study, we show that peripherin-2 forms a complex with melanoregulin (MREG), the product of the Mreg locus. Genetic studies suggest that MREG is involved in organelle biogenesis. In this study, we explore the role of this protein in processes associated with the formation of disk membranes, specialized organelles of photoreceptor rod cells. MREG antibodies were generated and found to be immunoreactive with a 28 kDa protein in retinal extracts, bovine OS, ARPE-19 cells, and rat RPE. MREG colocalized with peripherin-2 in WT (CB6F1/J) and in rds+/- retinas. Western blots of serial tangential sections confirmed the close association of these two proteins within the IS and basal outer segment of rods. Immunoprecipitation (IP) of OS extracts showed formation of a complex between MREG and peripherin-2-ROM-1 hetero-oligomers. This interaction was confirmed with pulldown analyses in which the GST-PerCter protein selectively pulled down (His-)MREG and (His-)MREG selectively pulled down PerCter. Biacore analysis using peptide inhibitors and per-2 truncation mutant studies allowed us to map the MREG binding site on per-2 to the last five residues of the C-terminus (Gln(341)-Gly(346)), and kinetic data predicted a K-D of 80 nM for PerCter-MREG binding. Finally, the effect of MREG on photoreceptor specific membrane fusion was assayed using a disk-plasma membrane cell free assay. Preincubation of target membranes with MREG resulted in a dose-dependent inhibition of fusion with an IC50 in the submicromolar range. Collectively, these results suggest that this newly identified protein regulates peripherin-2 function. C1 Univ Penn, Sch Dent Med, Dept Biochem, Philadelphia, PA 19104 USA. Univ Penn, Sch Dent Med, Dept Pathol, Philadelphia, PA 19104 USA. W Virginia Univ, Ctr Hlth Sci, Dept Mol Pharmacol & Biochem, Morgantown, WV 26506 USA. W Virginia Univ, Inst Eye, Dept Ophthalmol, Morgantown, WV 26506 USA. Univ Calif San Diego, Sch Med, Dept Pharmacol, La Jolla, CA 92093 USA. NCI, Mouse Canc Genet Program, Frederick, MD 21702 USA. Univ Connecticut, Dept Mol & Cell Biol, Storrs, CT 06269 USA. RP Boesze-Battaglia, K (reprint author), Univ Penn, Sch Dent Med, Dept Biochem, 240 S 40th St, Philadelphia, PA 19104 USA. EM battagli@biochem.dental.upenn.edu RI Lillo, Concepcion/A-6321-2009; 2007, Secribsal/A-1556-2012; OI Lillo, Concepcion/0000-0001-5814-9826; Yeagle, Philip/0000-0003-4157-8506 FU NCRR NIH HHS [S10 RR026365, P20 RR015574, S10 RR026365-01]; NEI NIH HHS [EY07042, EY10420, P30 EY001583, R01 EY007042, R01 EY007042-20, R01 EY007042-21, R01 EY010420, R01 EY010420-06, R01 EY010420-07, R01 EY010420-08, R01 EY010420-09, R01 EY010420-10A2, R01 EY010420-11, R01 EY010420-12, R01 EY010420-13A2, R01 EY010420-14, R01 EY010420-15, R01 EY010420-16, R21 EY018705, R21 EY018705-01A1, R21 EY018705-02, R29 EY010420, R29 EY010420-03] NR 69 TC 26 Z9 32 U1 2 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 6 PY 2007 VL 46 IS 5 BP 1256 EP 1272 DI 10.1021/bi061466i PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 131AG UT WOS:000243839500014 PM 17260955 ER PT J AU Dimitrov, AS Jacobs, A Finnegan, CM Stiegler, G Katinger, H Blumenthal, R AF Dimitrov, Antony S. Jacobs, Amy Finnegan, Catherine M. Stiegler, Gabriela Katinger, Hermann Blumenthal, Robert TI Exposure of the membrane-proximal external region of HIV-1 gp41 in the course of HIV-1 envelope glycoprotein-mediated fusion SO BIOCHEMISTRY LA English DT Article ID IMMUNODEFICIENCY-VIRUS TYPE-1; HUMAN MONOCLONAL-ANTIBODY; CELL-CELL FUSION; PEPTIDE INHIBITOR; SYNTHETIC PEPTIDE; ATOMIC-STRUCTURE; COILED-COIL; ECTODOMAIN; EPITOPE; DESIGN AB The membrane-proximal external region (MPER) of HIV-1 gp41 is highly conserved and critical for the fusogenic ability of the virus. However, little is known about the activity of this region in the context of viral fusion. In this study we investigate the temporal exposure of MPER during the course of HIV-1 Env-mediated fusion. We employed the broadly neutralizing monoclonal antibodies 2F5 and 4E10, whose epitopes localize to this region as indicators for accessibility to this region. Time of addition experiments indicated that escape of HIV-1 infection inhibition by 2F5 and 4E10 occurred concomitantly with that of C34, a peptide that blocks the six-helix bundle formation and fusion, which was about 20 min later than escape of inhibition by the mAb b12 that blocks CD4-gp120 attachment. We also probed accessibility of the MPER region on fusion intermediates by measuring the binding of the monoclonal antibodies at different time points during the fusion reaction. Immunofluorescence and in-cell Western assays showed that binding of 2F5 and 4E10 decreased upon triggering HIV-1 Env-expressing cells with appropriate target cells. Addition of C34 did not counteract the loss of antibody binding, suggesting that changes in exposure of MPER occur independently of six-helix bundle formation. C1 NCI, Ctr Canc Res, Nanobiol Program, NIH, Frederick, MD 21702 USA. Univ Nat Resources & Appl Life Sci Vienna, Inst Appl Microbiol, Vienna, Austria. RP Blumenthal, R (reprint author), NCI, Ctr Canc Res, Nanobiol Program, NIH, Frederick, MD 21702 USA. EM blumen@helix.nih.gov FU Intramural NIH HHS NR 34 TC 64 Z9 64 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0006-2960 J9 BIOCHEMISTRY-US JI Biochemistry PD FEB 6 PY 2007 VL 46 IS 5 BP 1398 EP 1401 DI 10.1021/bi062245f PG 4 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 131AG UT WOS:000243839500028 PM 17260969 ER PT J AU Han, SH Quon, MJ Kim, J Koh, KK AF Han, Seung Hwan Quon, Michael J. Kim, Jeong-a Koh, Kwang Kon TI Adiponectin and cardiovascular disease - Response to therapeutic interventions SO JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY LA English DT Article ID CORONARY-ARTERY-DISEASE; DEPENDENT DIABETES-MELLITUS; PLASMA-PROTEIN ADIPONECTIN; ADIPOSE-SPECIFIC PROTEIN; INSULIN-RESISTANCE; HYPERTENSIVE PATIENTS; 3T3-L1 ADIPOCYTES; GENE-EXPRESSION; PPAR-GAMMA; ENDOTHELIAL DYSFUNCTION AB Adiponectin is a protein secreted specifically by adipose cells that may couple regulation of insulin sensitivity with energy metabolism and serve to link obesity with insulin resistance. Obesity-related disorders including the metabolic syndrome, diabetes, atherosclerosis, hypertension, and coronary artery disease are associated with decreased plasma levels of adiponectin, insulin resistance, and endothelial dysfunction. Adiponectin has insulin-sensitizing effects as well as antiatherogenic properties. Lifestyle modifications and some drug therapies to treat atherosclerosis, hypertension, and coronary heart disease have important effects to simultaneously increase adiponectin levels, decrease insulin resistance, and improve endothelial dysfunction. In this review, we discuss insights into the relationships between adiponectin levels, insulin resistance, and endothelial dysfunction that are derived from various therapeutic interventions. The effects of lifestyle modifications and cardiovascular drugs on adiponectin levels and insulin resistance suggest plausible mechanisms that may be important for treating atherosclerosis and coronary heart disease. C1 Gachon Med Sch, Gil Heart Ctr, Div Cardiol, Inchon, South Korea. NIH, Diabet Unit, Clin Invest Lab, NCCAM, Bethesda, MD 20892 USA. RP Koh, KK (reprint author), Gachon Med Sch, Gil Heart Ctr, Div Cardiol, Inchon, South Korea. EM kwangk@gilhospital.com RI Quon, Michael/B-1970-2008; OI Quon, Michael/0000-0002-9601-9915; Quon , Michael /0000-0002-5289-3707 NR 79 TC 168 Z9 190 U1 0 U2 7 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 FEB 6 PY 2007 VL 49 IS 5 BP 531 EP 538 DI 10.1016/j.jacc.2006.08.061 PG 8 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 134CJ UT WOS:000244059900001 PM 17276175 ER PT J AU Wiklund, PG Brown, WM Brott, TG Stegmayr, B Brown, RD Nilsson-Ardnor, S Hardy, JA Kissela, BM Singleton, A Holmberg, D Rich, SS Meschia, JF AF Wiklund, P. G. Brown, W. M. Brott, T. G. Stegmayr, B. Brown, R. D., Jr. Nilsson-Ardnor, S. Hardy, J. A. Kissela, B. M. Singleton, A. Holmberg, D. Rich, S. S. Meschia, J. F. TI Lack of aggregation of ischemic stroke subtypes within affected sibling pairs SO NEUROLOGY LA English DT Article ID FAMILY-HISTORY; GENE; QUESTIONNAIRE; POPULATION; RISK; CLASSIFICATION; RELIABILITY; TRIAL AB Objective: To establish whether subtypes of ischemic stroke aggregate within ischemic stroke - affected sibling pairs more than expected by chance alone. Methods: This retrospective family study was based on a pooled analysis of two cohorts of male and female adult sibling pairs with symptomatic ischemic stroke. One hospital-based cohort of 404 individuals (first proband seen August 30, 1999) was recruited from the United States and Canada, and another population-based cohort of 198 individuals (first proband seen April 17, 1997) was recruited from Umea, Sweden. Subtype diagnoses were based on Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. Results: Agreement for subtype diagnoses within families was poor (mean +/- asymptotic SE kappa = 0.17 +/- 0.04). Occurrence of one ischemic stroke subtype in a proband was not associated with a greater likelihood of that subtype being the qualifying stroke subtype in the sibling. Comparable levels of agreement were seen when restricting the analysis to same-sex sibling pairs (kappa = 0.22 +/- 0.05) to sibling pairs in which the proband's stroke occurred before the age of 65 years (kappa = 0.16 +/- 0.05) or to pairs in which the proband's stroke occurred at or after the age of 65 years (kappa = 0.19 +/- 0.05). Conclusions: The subtype of ischemic stroke in a proband was a poor determinant of the subtype of ischemic stroke in the respective sibling. This suggests that many genetic risk factors for ischemic stroke may not be specific for one subtype. C1 Mayo Clin, Dept Neurol, Jacksonville, FL 32224 USA. Umea Univ, Dept Med, Umea, Sweden. Umea Univ, Dept Med Biosci, Umea, Sweden. Wake Forest Univ, Sch Med, Dept Biostat, Winston Salem, NC 27109 USA. Mayo Clin, Dept Neurol, Rochester, MN USA. NIA, Bethesda, MD 20892 USA. Univ Cincinnati, Dept Neurol, Cincinnati, OH USA. RP Meschia, JF (reprint author), Mayo Clin, Dept Neurol, 4500 San Pablo Rd, Jacksonville, FL 32224 USA. EM meschia.james@mayo.edu RI Singleton, Andrew/C-3010-2009; Hardy, John/C-2451-2009; OI Kissela, Brett/0000-0002-9773-4013 FU Medical Research Council [G0701075]; NINDS NIH HHS [R01 NS039987, R01 NS39987] NR 24 TC 15 Z9 16 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0028-3878 J9 NEUROLOGY JI Neurology PD FEB 6 PY 2007 VL 68 IS 6 BP 427 EP 431 DI 10.1212/01.wnl.0000252955.17126.6a PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 133EZ UT WOS:000243996800008 PM 17283317 ER PT J AU Resch, W Hixson, KK Moore, RJ Lipton, MS Moss, B AF Resch, Wolfgang Hixson, Kim K. Moore, Ronald J. Lipton, Mary S. Moss, Bernard TI Protein composition of the vaccinia virus mature virion SO VIROLOGY LA English DT Review DE vaccinia virus; poxvirus; mass spectrometry; proteomics ID DEPENDENT RNA-POLYMERASE; TEMPERATURE-SENSITIVE MUTANTS; EARLY TRANSCRIPTION FACTOR; CELL-CELL FUSION; DISULFIDE BOND FORMATION; VIRAL MEMBRANE-PROTEIN; FORM IMMATURE VIRIONS; AMINO-ACID-SEQUENCES; Z-DNA-BINDING; MESSENGER-RNA AB The protein content of vaccinia virus mature virions, purified by rate zonal and isopycnic centrifugations and solubilized by SDS or a solution of urea and thiourea, was determined by the accurate mass and time tag technology which uses both tandem mass spectrometry and Fourier transform-ion cyclotron resonance mass spectrometry to detect tryptic peptides separated by high-resolution liquid chromatography. Eighty vaccinia virus-encoded proteins representing 37% of the 218 genes annotated in the complete genome sequence were detected in at least three analyses. Ten proteins accounted for approximately 80% of the virion mass. Thirteen identified proteins were not previously reported as components of virions. On the other hand, 8 previously described virion proteins were not detected here, presumably due to technical reasons including small size and hydrophobicity. In addition to vaccinia virus-encoded proteins, 24 host proteins omitting isoforms were detected. The most abundant of these were cytoskeletal proteins, heat shock proteins and proteins involved in translation. Published by Elsevier Inc. C1 NIAID, Viral Dis Lab, NIH, Bethesda, MD 20892 USA. Battelle Pacific NW Natl Lab, Environm Mol Sci Lab, Richland, WA 99352 USA. RP Moss, B (reprint author), NIAID, Viral Dis Lab, NIH, 4 Ctr Dr,MSC 0445, Bethesda, MD 20892 USA. EM bmoss@nih.gov NR 182 TC 95 Z9 98 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0042-6822 J9 VIROLOGY JI Virology PD FEB 5 PY 2007 VL 358 IS 1 BP 233 EP 247 DI 10.1016/j.virol.2006.08.025 PG 15 WC Virology SC Virology GA 131LS UT WOS:000243871100023 PM 17005230 ER PT J AU Arana, ME Takata, K Garcia-Diaz, M Wood, RD Kunkel, TA AF Arana, Mercedes E. Takata, Kei-ichi Garcia-Diaz, Miguel Wood, Richard D. Kunkel, Thomas A. TI A unique error signature for human DNA polymerase v SO DNA REPAIR LA English DT Article DE error-prone polymerase; infidelity; base substitutions ID NUCLEOTIDE-EXCISION-REPAIR; ACTIVE-SITE TIGHTNESS; I KLENOW FRAGMENT; CROSS-LINK REPAIR; CRYSTAL-STRUCTURES; HIGH-FIDELITY; SOMATIC HYPERMUTATION; TRANSLESION SYNTHESIS; REPLICATION FIDELITY; KINETIC MECHANISM AB Human DNA polymerase v (pol v) is one of three A family polymerases conserved in vertebrates. Although its biological functions are unknown, pol v has been implicated in DNA repair and in translesion. DNA synthesis (TLS). Pol v lacks intrinsic exonucleolytic proofreading activity and discriminates poorly against misinsertion of dNTP opposite template thymine or guanine, implying that it should copy DNA with low base substitution fidelity. To test this prediction and to comprehensively examine pol v DNA synthesis fidelity as a clue to its function, here we describe human pol v error rates for all 12 single base-base mismatches and for insertion and deletion errors during synthesis to copy the lacZ alpha-complementation sequence in M13mp2 DNA. Pol v copies this DNA with average single-base insertion and deletion error rates of 7 x 10(-5) and 17 x 10(-5), respectively. This accuracy is comparable to that of replicative polymerases in the B family, lower than that of its A family homolog, human pol gamma, and much higher than that of Y family TLS polymerases. In contrast, the average single-base substitution error rate of human pol v is 3.5 x 10(-3), which is inaccurate compared to the replicative polymerases and comparable to Y family polymerases. Interestingly, the vast majority of errors made by pol v reflect stable misincorporation of dTMP opposite template G, at average rates that are much higher than for homologous A family members. This pol v error is especially prevalent in sequence contexts wherein the template G is preceded by a C-G or G-C base pair, where error rates can exceed 10%. Amino acid sequence alignments based on the structures of more accurate A family polymerases suggest substantial differences in the O-helix of pol v that could contribute to this unique error signature. (c) 2006 Elsevier B.V. All rights reserved. C1 NIEHS, Genet Mol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. NIEHS, Struct Biol Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. Univ Pittsburgh, Sch Med, Dept Pharmacol, Hillman Canc Ctr, Pittsburgh, PA 15213 USA. RP Kunkel, TA (reprint author), NIEHS, Genet Mol Lab, NIH, DHHS, POB 12233, Res Triangle Pk, NC 27709 USA. EM kunkel@niehs.nih.gov RI Wood, Richard/E-7855-2011 OI Wood, Richard/0000-0002-9495-6892 FU Intramural NIH HHS [Z01 ES065070-15, Z01 ES065070-17]; NCI NIH HHS [CA101980, R01 CA101980] NR 73 TC 36 Z9 36 U1 0 U2 3 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 4 PY 2007 VL 6 IS 2 BP 213 EP 223 DI 10.1016/j.dnarep.2006.09.012 PG 11 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 133PI UT WOS:000244024400007 PM 17118716 ER PT J AU Poltoratsky, V Prasad, R Horton, JK Wilson, SH AF Poltoratsky, Vladimir Prasad, Rajendra Horton, Julie K. Wilson, Samuel H. TI Down-regulation of DNA polymerase beta accompanies somatic hypermutation in human BL2 cell lines SO DNA REPAIR LA English DT Article DE B lymphocytes; mutagenesis; somatic hypermutation; base excision repair; DNA polymerase beta; activation-induced cytidine deaminase ID BASE-EXCISION-REPAIR; CLASS-SWITCH RECOMBINATION; MOUSE FIBROBLASTS; LYASE ACTIVITY; POL-IOTA; IN-VITRO; IG GENES; IMMUNOGLOBULIN; LAMBDA; AID AB Somatic hypermutation (SHM) is a fundamental process in immunoglobulin gene maturation that results in increased affinity of antibodies toward antigens. In one hypothesis explaining SHM in human B cells, the process is initiated by enzymatic deamination of cytosine to uracil in the immunoglobulin gene V-region and this in turn triggers mutation-prone forms of uracil-DNA base excision repair (BER). Yet, an uncertainty with this model is that BER of uracil-DNA in mammalian cells is generally error-free, wherein DNA polymerase beta (pol beta) conducts gap-filling synthesis by insertion of bases according to Watson-Crick rules. To evaluate this inconsistency, we examined pol beta expression in various SHM proficient human BL2 cell line subcIones. We report that expression of pol beta in SHM proficient cell lines was strongly down-regulated. in contrast, in other BL2 subclones, we found that SHM was deficient and that pol beta expression was much higher than in the SHM proficient subclones. We also found that overexpression of recombinant human pol beta in a SHM proficient subclone abrogated its capacity for SHM. These results suggest that down-regulation of the normal BER gap-filling DNA polymerase, pol beta, accompanies induced SHM in BL2 cells. This is consistent with the hypothesis that normal error-free BER must be silenced to make way for an error-prone BER process that may be required during somatic hypermutation. (c) 2006 Elsevier B.V. All rights reserved. C1 NIEHS, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Wilson, SH (reprint author), NIEHS, Struct Biol Lab, NIH, 111 TW Alexander Dr,POB 12233,MD B2-06, Res Triangle Pk, NC 27709 USA. EM wilson5@niehs.nih.gov FU Intramural NIH HHS [Z01 ES050159-11] NR 42 TC 23 Z9 24 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 4 PY 2007 VL 6 IS 2 BP 244 EP 253 DI 10.1016/j.dnarep.2006.10.003 PG 10 WC Genetics & Heredity; Toxicology SC Genetics & Heredity; Toxicology GA 133PI UT WOS:000244024400010 PM 17127106 ER PT J AU Burlinson, B Tice, RR Speit, G Agurell, E Brendler-Schwaab, SY Collins, AR Escobar, P Honma, M Kumaravel, TS Nakajima, M Sasaki, YF Thybaud, V Uno, Y Vasquez, M Hartmann, A AF Burlinson, Brian Tice, Raymond R. Speit, Gunter Agurell, Eva Brendler-Schwaab, Susanne Y. Collins, Andrew R. Escobar, Patricia Honma, Masamitsu Kumaravel, Tirukalikundram S. Nakajima, Madoka Sasaki, Yu F. Thybaud, Veronique Uno, Yoshifumi Vasquez, Marie Hartmann, Andreas TI Fourth International Workgroup on Genotoxicity Testing: Results of the in vivo Comet assay workgroup SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE single cell gel assay; Comet assay; DNA damage; genotoxicity; alkaline electrophoresis ID GEL-ELECTROPHORESIS ASSAY; MULTIPLE MOUSE ORGANS; DNA-DAMAGE; CELLS; RADIATION; PHENYLPHENOL; CHEMICALS; REPAIR AB As part of the Fourth International Workshop on Genotoxicity Testing (IWGT), held 9-10 September 2005 in San Francisco, California, an expert working group on the Comet assay was convened to review and discuss some of the procedures and methods recommended in previous documents. Particular attention was directed at the in vivo rodent, alkaline (pH > 13) version of the assay. The aim was to review those protocol areas which were unclear or which required more detail in order to produce a standardized protocol with maximum acceptability by international regulatory agencies. The areas covered were: number of dose levels required, cell isolation techniques, measures of cytotoxicity, scoring of comets (i.e., manually or by image analysis), and the need for historical negative/positive control data. It was decided that a single limit dose was not sufficient although the required number of dose levels was not stipulated. The method of isolating cells was thought not to have a qualitative effect on the assay but more data were needed before a conclusion could be drawn. Concurrent measures of cytotoxicity were required with histopathological examination of tissues for necrosis or apoptosis as the "Gold Standard". As for analysing the comets, the consensus was that image analysis was preferred but not required. Finally, the minimal number of studies required to generate a historical positive or negative control database was not defined; rather the emphasis was placed on demonstrating the stability of the negative/positive control data. It was also agreed that a minimum reporting standard would be developed which would be consistent with OECD in vivo genotoxicity test method guidelines. (c) 2006 Elsevier B.V. All rights reserved. C1 Huntingdon Life Sci, Cellular & Mol Toxicol, Huntington PE28 4HS, Cambs, England. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. Univ Ulm Klinikum, Abt Humangenet, D-7900 Ulm, Germany. Med Prod Agcy, Uppsala, Sweden. Fed Inst Drugs & Med Devices, Bonn, Germany. Univ Oslo, Dept Nutr, Oslo, Norway. BioReliance, Invitrogen Bioserv, Rockville, MD USA. Natl Inst Hlth Sci, Tokyo 158, Japan. Bio Safety Res Ctr, Shizuoka, Japan. Hachinohe Inst Technol, Hachinohe, Japan. Sanofi Aventis, Vitry Sur Seine, France. Mitsubishi Chem Safety Inst Ltd, Minato Ku, Tokyo, Japan. Novartis Pharma AG, Safety Profiling & Assessment, Basel, Switzerland. RP Burlinson, B (reprint author), Huntingdon Life Sci, Cellular & Mol Toxicol, Woolley Rd, Huntington PE28 4HS, Cambs, England. EM burlinsb@ukorg.huntingdon.com NR 30 TC 273 Z9 281 U1 0 U2 12 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 3 PY 2007 VL 627 IS 1 SI SI BP 31 EP 35 DI 10.1016/j.mrgentox.2006.08.011 PG 5 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 134KG UT WOS:000244081300004 PM 17118697 ER PT J AU Tweats, DJ Blakey, D Heflich, RH Jacobs, A Jacobsen, SD Morita, T Nohmi, T O'Donovan, MR Sasaki, YF Sofuni, T Tice, R AF Tweats, D. J. Blakey, D. Heflich, R. H. Jacobs, A. Jacobsen, S. D. Morita, T. Nohmi, T. O'Donovan, M. R. Sasaki, Y. F. Sofuni, T. Tice, R. TI Report of the IWGT working group on strategies and interpretation of regulatory in vivo tests - I. Increases in micronucleated bone marrow cells in rodents that do not indicate genotoxic hazards SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE IWGT; genotoxicity tests; in vivo; rodent bone marrow; micronucleus; specificity; false positive; changes in physiology; hypothermia; hyperthermia; spindle disruption; erythropoiesis; bone marrow cell toxicity; pharmacologically related changes; regulatory implications ID HAMSTER OVARY CELLS; HYDRAZINE DERIVATIVES; ANILINE HYDROCHLORIDE; ERYTHROPOIETIN; HYPERTHERMIA; HYPOTHERMIA; INDUCTION; ASSAY; RATS; MICE AB In vivo genotoxicity tests play a pivotal role in genotoxicity testing batteries. They are used both to determine if potential genotoxicity observed in vitro is realised in vivo and to detect any genotoxic carcinogens that are poorly detected in vitro. It is recognised that individual in vivo genotoxicity tests have limited sensitivity but good specificity. Thus, a positive result from the established in vivo assays is taken as strong evidence for genotoxic carcinogenicity of the compound tested. However, there is a growing body of evidence that compound-related disturbances in the physiology of the rodents used in these assays can result in increases in micronucleated cells in the bone marrow that are not related to the intrinsic genotoxicity of the compound under test. For rodent bone marrow or peripheral blood micronucleus tests, these disturbances include changes in core body temperature (hypothermia and hyperthermia) and increases in erythropoiesis following prior toxicity to erythroblasts or by direct stimulation of cell division in these cells. This paper reviews relevant data from the literature and also previously unpublished data obtained from a questionnaire devised by the IWGT working group. Regulatory implications of these findings are discussed and flow diagrams have been provided to aid in interpretation and decision-making when such changes in physiology are suspected. (c) 2006 Elsevier B.V. All rights reserved. C1 Univ Coll Swansea, Ctr Mol Genet & Toxicol, Swansea, W Glam, Wales. Hlth Canada, Safe Environm Programme, Ottawa, ON K1A 0L2, Canada. US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. US FDA, Ctr Drug Evaluat & Res, Off New Drugs, Rockville, MD 20852 USA. Novo Nordisk AS, Malov, Denmark. Natl Inst Hlth Sci, Div Safety Informat Drug Food & Chem, Tokyo 158, Japan. Natl Inst Hlth Sci, Div Genet & Mutagenesis, Setagaya Ku, Tokyo 158, Japan. Safety Assessment UK, Macclesfield, Cheshire, England. Hachinohe Inst Technol, Hachinohe, Aomori, Japan. Natl Inst Hlth Sci, Div Genet & Mutagenesis, Setagaya Ku, Tokyo 158, Japan. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Tweats, DJ (reprint author), Univ Coll Swansea, Ctr Mol Genet & Toxicol, Swansea, W Glam, Wales. EM djtweats@fish.co.uk NR 45 TC 56 Z9 57 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 3 PY 2007 VL 627 IS 1 SI SI BP 78 EP 91 DI 10.1016/j.mrgentox.2006.10.005 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 134KG UT WOS:000244081300008 PM 17116417 ER PT J AU Tweats, DJ Blakey, D Heflich, RH Jacobs, A Jacobsen, SD Morita, T Nohmi, T O'Donovan, MR Sasaki, YF Sofuni, T Tice, R AF Tweats, D. J. Blakey, D. Heflich, R. H. Jacobs, A. Jacobsen, S. D. Morita, T. Nohmi, T. O'Donovan, M. R. Sasaki, Y. F. Sofuni, T. Tice, R. TI Report of the IWGT working group on strategy/interpretation for regulatory in vivo tests - II. Identification of in vivo-only positive compounds in the bone marrow micronucleus test SO MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS LA English DT Article DE IWGT; genotoxicity tests; in vivo; rodent bone marrow; micronucleus test; in vivo-only positive compounds; ADME; in vitro versus in vivo metabolism; sex-specific metabolism; influence of gut flora; pharmacological mechanisms; kinase inhibitors; regulatory implication; pharmaceuticals; cosmetics; food additives; in vitro-only genotoxicity test batteries ID ETHYL CARBAMATE URETHANE; CHROMOSOMAL DAMAGE; HUMAN-LYMPHOCYTES; TRANSGENIC MICE; GENOTOXICITY; SALICYLAZOSULFAPYRIDINE; MUTAGENICITY; METABOLISM; INDUCTION; CELLS AB A survey conducted as part of an International Workshop on Genotoxicity Testing (IWGT) has identified a number of compounds that appear to be more readily detected in vivo than in vitro. The reasons for this property varies from compound to compound and includes metabolic differences; the influence of gut flora; higher exposures in vivo compared to in vitro; effects on pharmacology, in particular folate depletion or receptor kinase inhibition. It is possible that at least some of these compounds are detectable in vitro if a specific in vitro test is chosen as part of the test battery, but the 'correct' choice of test may not always be obvious when testing a compound of unknown genotoxicity. It is noted that many of the compounds identified in this study interfere with cell cycle kinetics and this can result in either aneugenicity or chromosome breakage. A decision tree is outlined as a guide for the evaluation of compounds that appear to be genotoxic agents in vivo but not in vitro. The regulatory implications of these findings are discussed. (c) 2006 Elsevier B.V. All rights reserved. C1 Univ Coll Swansea, Ctr Mol Genet & Toxicol, Swansea, W Glam, Wales. Hlth Canada, Safe Environm Programme, Ottawa, ON K1A 0L2, Canada. US FDA, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA. US FDA, Ctr Drug Evaluat & Res, Off New Drugs, Rockville, MD 20852 USA. Novo Nordisk AS, Malov, Denmark. Natl Inst Hlth Sci, Div Safety Informat Drug Food & Chem, Setagaya Ku, Tokyo, Japan. Natl Inst Hlth Sci, Div Genet & Mutagenesis, Setagaya Ku, Tokyo 158, Japan. Safety Assessment UK, Macclesfield, Cheshire, England. Hachinohe Inst Technol, Hachinohe, Aomori, Japan. Natl Inst Hlth Sci, Div Genet & Mutagenesis, Setagaya Ku, Tokyo 158, Japan. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC 27709 USA. RP Tweats, DJ (reprint author), Univ Coll Swansea, Ctr Mol Genet & Toxicol, Swansea, W Glam, Wales. EM djtweats@fish.co.uk FU Intramural NIH HHS [Z99 ES999999] NR 40 TC 29 Z9 32 U1 0 U2 1 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 3 PY 2007 VL 627 IS 1 SI SI BP 92 EP 105 DI 10.1016/j.mrgentox.2006.10.006 PG 14 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology SC Biotechnology & Applied Microbiology; Genetics & Heredity; Toxicology GA 134KG UT WOS:000244081300009 PM 17113817 ER PT J AU Sanchez-Alavez, M Chan, SL Mattson, MP Criado, JR AF Sanchez-Alavez, Manuel Chan, Sic L. Mattson, Mark P. Criado, Jose R. TI Electrophysiological and cerebrovascular effects of the alpha-secretase-derived form of amyloid precursor protein in young and middle-aged rats SO BRAIN RESEARCH LA English DT Article DE EEG; blood flow; aging; hippocampus; sAPP; Alzheimer's disease ID CORTICAL ACETYLCHOLINE-RELEASE; ALZHEIMERS-DISEASE; BASAL FOREBRAIN; HIPPOCAMPAL-NEURONS; BLOOD-FLOW; ACTIVATION; MEMORY; MODULATION; BRAIN; TRANSMISSION AB Cleavage of the p-amyloid precursor protein (APP) by a-secretase releases a secreted form of APP (SAPP) from cells. sAPP is released from neurons in an activity-dependent manner and is believed to play roles in synaptic plasticity and neuroprotection. We determined whether sAPP modulates electrophysiological and cerebrovascular processes in vivo. The effects of recombinant sAPP, applied by intracerebroventricular infusion, on hippocampal and cortical electroencephalographic (EEG) activity and hippocampal blood flow in young adult and middle-aged Long-Evans rats were measured. sAPP increased the power spectrum density of low frequency EEG bands in the hippocampus and cortex of middle-aged rats without affecting hippocampal blood flow. The neurophysiological effects of sAPP were observed in middle-aged, but not in young rats. The results of this study indicate that hippocampal and cortical electrophysiological processes are sensitive to sAPP, whereas the cerebral vasculature may not be regulated by sAPP. The age-dependent change in the sensitivity of neuronal activity to sAPP suggests the possibility of an important role for this APP product in brain functioning in mid life. (c) 2006 Elsevier B.V. All rights reserved. C1 Scripps Clin, Brain Res & Treatment Ctr, La Jolla, CA 92037 USA. Scripps Res Inst, Mol & Integrat Neurosci Dept, La Jolla, CA 92037 USA. NIA, Intramural Res Program, Neurosci Lab, Baltimore, MD 21224 USA. RP Criado, JR (reprint author), Scripps Clin, Brain Res & Treatment Ctr, 10666 N Torrey Pines Rd, La Jolla, CA 92037 USA. EM criado.jose@scrippshealth.org RI Mattson, Mark/F-6038-2012 FU Intramural NIH HHS; NIDA NIH HHS [DA12669] NR 39 TC 11 Z9 12 U1 0 U2 0 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0006-8993 J9 BRAIN RES JI Brain Res. PD FEB 2 PY 2007 VL 1131 IS 1 BP 112 EP 117 DI 10.1016/j.brainres.2006.10.074 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 133KN UT WOS:000244011900013 PM 17157827 ER PT J AU Chavakis, E Hain, A Vinci, M Carmona, G Bianchi, ME Vajkoczy, P Zeiher, AM Chavakis, T Dimmeler, S AF Chavakis, Emmanouil Hain, Andreas Vinci, Maria Carmona, Guillaume Bianchi, Marco E. Vajkoczy, Peter Zeiher, Andreas M. Chavakis, Triantafyllos Dimmeler, Stefanie TI High-mobility group box 1 activates integrin-dependent homing of endothelial progenitor cells SO CIRCULATION RESEARCH LA English DT Article DE high-mobility group box 1; endothelial progenitor cells; homing; integrins; migration ID CHROMATIN PROTEIN HMGB1; NITRIC-OXIDE SYNTHASE; NEOVASCULARIZATION CAPACITY; TUMOR ANGIOGENESIS; AVIDITY REGULATION; NEURITE OUTGROWTH; MIGRATION; RECRUITMENT; ADHESION; TRANSPLANTATION AB Endothelial progenitor cells (EPCs) are recruited to ischemic regions and improve neovascularization. Integrins contribute to EPC homing. High-mobility group box 1 (HMGB1) is a nuclear protein that is released extracellularly on cell necrosis and tissue damage, eliciting a proinflammatory response and stimulating tissue repair. In the present study, we investigated the effects of HMGB1 on EPC homing. EPCs express the HMGB1 receptors RAGE ( receptor for advanced glycation end products) and TLR2 (Toll-like receptor 2). EPC migration was stimulated by HMGB1 in a RAGE-dependent manner. In addition, the HMGB1-induced migration of EPCs on fibronectin and fibrinogen was significantly inhibited by antibodies against beta(1) and beta(2) integrins, respectively. Short-term prestimulation of EPCs with HMGB1 also increased EPC adhesion to endothelial cell monolayers, and this effect was blocked by antibodies to beta(2) integrins or RAGE. HMGB1 increased EPC adhesion to the immobilized integrin ligands intercellular adhesion molecule-1 and fibronectin in a RAGE-dependent manner. Strikingly, HMGB1 rapidly increased integrin affinity and induced integrin polarization. Using intravital microscopy in a tumor model of neovascularization, prestimulation of EPCs with HMGB1 enhanced the initial in vivo adhesion of EPCs to microvessels and the recruitment of EPCs in the tumor tissue. In addition, prestimulation of EPCs with HMGB1 increased the homing of EPCs to ischemic muscles. In conclusion, these data represent a link between HMGB1 and integrin functions of EPCs and demonstrate that HMGB1 stimulates EPC homing to ischemic tissues. These results may provide a platform for the development of novel therapeutic approaches to improve EPC homing. C1 Univ Frankfurt, Dept Internal Med 3, D-60590 Frankfurt, Germany. Univ Heidelberg, Fac Med, Dept Neurosurg, D-6800 Mannheim, Germany. San Raffaele Univ, Dept Mol Biol & Funct Genom, Milan, Italy. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Dimmeler, S (reprint author), Univ Frankfurt, Dept Internal Med 3, Theodor Stern Kai 7, D-60590 Frankfurt, Germany. EM Dimmeler@em.uni-frankfurt.de OI Bianchi, Marco Emilio/0000-0002-5329-6445 FU Intramural NIH HHS NR 54 TC 194 Z9 204 U1 1 U2 10 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 2 PY 2007 VL 100 IS 2 BP 204 EP 212 DI 10.1161/01.RES.0000257774.55970.f4 PG 9 WC Cardiac & Cardiovascular Systems; Hematology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Hematology GA 132KT UT WOS:000243942400007 PM 17218606 ER PT J AU Baron, S Hernandez, J Bekisz, J Poast, J Goldman, N Clouse, K Fields, K Bacot, S Wang, J Zoon, K AF Baron, Samuel Hernandez, Jessica Bekisz, Joseph Poast, Joyce Goldman, Neil Clouse, Kathleen Fields, Karen Bacot, Sylvia Wang, Jiun Zoon, Kathryn TI Clinical model: Interferons activate human monocytes to an eradicative tumor cell level in vitro SO JOURNAL OF INTERFERON AND CYTOKINE RESEARCH LA English DT Article ID CENTRIFUGAL ELUTRIATION CCE; NECROSIS-FACTOR-ALPHA; NF-KAPPA-B; ADOPTIVE IMMUNOTHERAPY; MACROPHAGE ACTIVATION; EFFECTOR-CELLS; PERITONEAL-MACROPHAGES; ENRICHED FRACTIONS; MONONUCLEAR-CELLS; DENDRITIC CELLS AB Eradicative levels of antitumor activity by cytokines and leukocytes have not yet been reached experimentally and are needed clinically. Only a limited number of human cancers respond to therapy with interferon (IFN), other cytokines, or mononuclear leukocytes despite significant antitumor activity in vitro. We studied the IFN and monocytic cell conditions that would lead to an eradicative effect using human cells in vitro. Targets of the IFN-activated monocytic cells were either four human tumor cell lines (human osteosarcoma [HOS], LOX melanoma, A549 lung tumor, and SNB-19 glioblastoma) or two diploid cell lines (W138 and MRC5). An average of 30-90 colony-forming tumor target cells were cultured overnight in 96-well tissue culture plates prior to treatment with serially diluted IFN with or without activated elutriation-purified monocytes or lymphocytes. The target cell colonies were treated for 3 days. The colonies were then stained with crystal violet to determine the levels of antitumor activity. IFN-activated human monocytes reached an eradicative level (95%-100%) against three of four tumor cell lines. The eradicative level (1) was induced best in human monocytes activated by combined type I and II IFNs, (2) was effective against tumor cells that were growing for 24 h, (3) was specific for human tumors, as diploid human cells were not inhibited, and (4) required contact between the macrophage and the tumor cells. Also, for the first time, the minimal effective concentration (MEC) of IFNs to activate monocytes can approach those needed for antiviral activity. To our knowledge, this is the first report of near total eradication of many tumor cells, but not diploid cells, by IFN-activated monocytes. Because of its potency and specificity, the IFN-activated monocyte arm of the innate immune system may be a candidate for therapy of established tumors. C1 Univ Texas, Med Branch, Galveston, TX 77555 USA. NCI, NIH, Bethesda, MD 20892 USA. Food & Drug Adm, Bethesda, MD 20892 USA. RP Baron, S (reprint author), Univ Texas, Med Branch, Galveston, TX 77555 USA. EM sabaron@utmb.edu NR 65 TC 7 Z9 9 U1 0 U2 1 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1079-9907 J9 J INTERF CYTOK RES JI J. Interferon Cytokine Res. PD FEB 2 PY 2007 VL 27 IS 2 BP 157 EP 163 DI 10.1089/jir.2006.0083 PG 7 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 140SG UT WOS:000244526400010 PM 17316143 ER PT J AU Mulky, A Vu, BC Conway, JA Hughes, SH Kappes, JC AF Mulky, Alok Vu, B. Christie Conway, Joan A. Hughes, Stephen H. Kappes, John C. TI Analysis of amino acids in the beta 7-beta 8 loop of human immunodeficiency virus type 1 reverse transcriptase for their role in virus replication SO JOURNAL OF MOLECULAR BIOLOGY LA English DT Article DE HIV-1; reverse transcriptase; reverse transcription ID TRYPTOPHAN-REPEAT MOTIF; CRYSTAL-STRUCTURE; PRIMER GRIP; NONNUCLEOSIDE INHIBITORS; ANGSTROM RESOLUTION; INFECTIOUS VIRIONS; TSAO DERIVATIVES; DNA-SYNTHESIS; P51 SUBUNIT; RNASE-H AB The HIV-1 p51/p66 reverse transcriptase (RT) heterodimer interface comprises, in part, intermolecular interaction of the loop region between beta-strands 7 and 8 (beta 7-beta 8 loop) in the p51 fingers subdomain with the p66 palm subdomain. In this study, for the first time in the context of infectious HIV-1 particles, we analyzed the contribution of amino acid residues (S134, I135, N136, N137, T139 and P140) in the beta 7-beta 8 loop for RT heterodimerization, enzymatic activity, and virus infectivity. Mutating asparagine 136 to alanine (N136A) reduced viral infectivity and enzyme activity dramatically. The N136A mutation appeared to destabilize the RT heterodimer and render both the p66 and p51 subunits susceptible to aberrant cleavage by the viral protease. Subunit-specific mutagenesis demonstrated that the presence of the N136A mutation in the p51 subunit alone was sufficient to cause degradation of RT within the virus particle. Alanine mutation at other residues of the beta 7-beta 8 loop did not affect either RT stability or virus infectivity significantly. None of the beta 7-beta 8 loop alanine mutations affected the sensitivity of virus to inhibition by NNRTIs. In the context of infectious virions, our results indicate a critical role of the p51 N136 residue within the beta 7-beta 8 loop for RT heterodimer stability and function. These findings suggest the interface comprising N136 in p51 and interacting residues in p66 as a possible target for rational drug design. (c) 2006 Published by Elsevier Ltd. C1 Univ Alabama, Dept Med, Birmingham, AL 35294 USA. Univ Alabama, Dept Microbiol, Birmingham, AL 35294 USA. NCI, HIV Drug Resistance Program, Ft Detrick, MD 21702 USA. Birmingham Vet Affairs Med Ctr, Res Serv, Birmingham, AL 35233 USA. RP Kappes, JC (reprint author), Univ Alabama, Dept Med, Birmingham, AL 35294 USA. EM kappesjc@uab.edu FU Intramural NIH HHS; NIAID NIH HHS [P30 AI 27767, R01 AI 47714]; NIDDK NIH HHS [R24 DK 64400] NR 47 TC 11 Z9 12 U1 0 U2 2 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 0022-2836 J9 J MOL BIOL JI J. Mol. Biol. PD FEB 2 PY 2007 VL 365 IS 5 BP 1368 EP 1378 DI 10.1016/j.jmb.2006.10.089 PG 11 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 129SE UT WOS:000243749600011 PM 17141805 ER PT J AU Grajkowski, A Ausin, C Kauffman, JS Snyder, J Hess, S Lloyd, JR Beaucage, SL AF Grajkowski, Andrzej Ausin, Cristina Kauffman, Jon S. Snyder, John Hess, Sonja Lloyd, John R. Beaucage, Serge L. TI Solid-phase synthesis of thermolytic DNA oligonucleotides functionalized with a single 4-hydroxy-1-butyl or 4-phosphato-/thiophosphato-1-butyl thiophosphate protecting group SO JOURNAL OF ORGANIC CHEMISTRY LA English DT Article ID SULFUR-TRANSFER REAGENT; OLIGODEOXYRIBONUCLEOSIDE PHOSPHOROTHIOATES; 3H-1,2-BENZODITHIOL-3-ONE 1,1-DIOXIDE; 2'-TETRAHYDROFURANYL PROTECTION; 3-(PIVALOYLOXY)PROPYL GROUPS; PROOLIGONUCLEOTIDE APPROACH; PHOSPHORAMIDITE APPROACH; EFFICIENT REAGENT; PRODRUGS; PHOSPHODIESTER AB Several thermolytic CpG-containing DNA oligonucleotides analogous to 1 have been synthesized to serve as potential immunotherapeutic oligonucleotide prodrug formulations for the treatment of infectious diseases in animal models. Specifically, the CpG motif (GACGTT) of each DNA oligonucleotide has been functionalized with either the thermolabile 4-hydroxy-1-butyl or the 4-phosphato-/thiophosphato-1-butyl thiophosphate protecting group. This functionalization was achieved through incorporation of activated deoxyribonucleoside phosphoramidite 8b into the oligonucleotide chain during solid-phase synthesis and, optionally, through subsequent phosphorylation effected by phosphoramidite 9. Complete conversion of CpG ODNs hbu1555, psb1555, and pob1555 to CpG ODN 1555 (homologous to 2) occurred under elevated temperature conditions, thereby validating the function of these diastereomeric oligonucleotides as prodrugs in vitro. Noteworthy is the significant increase in solubility of CpG ODN psb1555 and CpG pob1555 in water when compared to that of neutral CpG ODN fma1555 (homologous to 1). C1 US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prot, Bethesda, MD 20892 USA. Lancaster Labs, Lancaster, PA 17605 USA. NIDDKD, Bioorgan Chem Lab, NIH, Bethesda, MD 20892 USA. RP Beaucage, SL (reprint author), US FDA, Ctr Biol Evaluat & Res, Div Therapeut Prot, 8800 Rockville Pike, Bethesda, MD 20892 USA. EM Serge.Beaucage@fda.hhs.gov RI Hess, Sonja/K-4842-2013 OI Hess, Sonja/0000-0002-5904-9816 NR 44 TC 11 Z9 11 U1 2 U2 12 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 2 PY 2007 VL 72 IS 3 BP 805 EP 815 DI 10.1021/jo062087y PG 11 WC Chemistry, Organic SC Chemistry GA 129NF UT WOS:000243735500017 PM 17253799 ER PT J AU Popp, MP Liu, L Timmers, A Esson, DW Shiroma, L Meyers, C Berceli, S Tao, M Wistow, G Schultz, GS Sherwood, MB AF Popp, Michael P. Liu, Li Timmers, Adrian Esson, Douglas W. Shiroma, Lineu Meyers, Craig Berceli, Scott Tao, Ming Wistow, Graeme Schultz, Gregory S. Sherwood, Mark B. TI Development of a microarray chip for gene expression in rabbit ocular research SO MOLECULAR VISION LA English DT Article ID CELLS; IDENTIFICATION; LYSOZYME; SURGERY; MODEL AB PURPOSE: To develop a microarray for the rabbit that can be used for ocular gene expression research. METHODS: Messenger RNA was isolated from anterior segment tissues (cornea, conjunctiva, and iris) and posterior segment tissues (lens, retina, and sclera) of rabbit eyes and used to create two independent cDNA libraries through the NEIBank project. Clones from each of these libraries were sequenced from both the 5' and 3' ends. These sequences and those from the National Center for Biotechnology Information (NCBI) taxonomy database for rabbit were combined and electronically assembled into a set of unique nonoverlapping continuous sequences (contigs). For each contig, a homology search was performed using BLASTX and BLASTN against both the NCBI NR and NT databases to provide gene annotation. Unique contigs were sent to Agilent Technologies, where 60 base oligonucleotide probes were designed and synthesized, in situ, on two different arrays in an 8 array x 1900 element format. Glaucoma filtration surgery was performed on one eye of six rabbits. After 14 days, tissue was harvested from the conjunctiva and Tenon's capsule of both the surgically treated and untreated control eyes. Total RNA from each sample was labeled with cyanine dyes and hybridized to our custom microarrays. RESULTS: Of the 3,154 total probes present on the two arrays, 2,522 had a signal value above the background. The expression of 315 genes was significantly altered by glaucoma filtration surgery. Genes whose expression was altered included proteins associated with inflammatory response, defense response, and proteins involved in synthesis of the extracellular matrix. CONCLUSIONS: The results of this rabbit microarray study are consistent with those from other wound healing studies, indicating that this array can provide valid information on broad patterns of gene expression. This is the first microarray available for rabbit studies and is a valuable tool that can be used to study molecular events in the eye. C1 Univ Florida, Dept Obstet & Gynecol, Interdisciplinary Ctr Biotechnol Res, Gainesville, FL 32610 USA. Univ Florida, Dept Ophthalmol, Gainesville, FL USA. Univ Florida, Inst Wound Healing, Gainesville, FL USA. Univ Florida, Vis Res Ctr, Gainesville, FL USA. Univ Florida, Dept Surg, Gainesville, FL USA. NEI, NIH, Bethesda, MD 20892 USA. RP Popp, MP (reprint author), Univ Florida, Dept Obstet & Gynecol, Interdisciplinary Ctr Biotechnol Res, POB 100294, Gainesville, FL 32610 USA. EM mpopp@obgyn.ufl.edu NR 25 TC 11 Z9 11 U1 0 U2 2 PU MOLECULAR VISION PI ATLANTA PA C/O JEFF BOATRIGHT, LAB B, 5500 EMORY EYE CENTER, 1327 CLIFTON RD, N E, ATLANTA, GA 30322 USA SN 1090-0535 J9 MOL VIS JI Mol. Vis. PD FEB 2 PY 2007 VL 13 IS 18-19 BP 164 EP 173 PG 10 WC Biochemistry & Molecular Biology; Ophthalmology SC Biochemistry & Molecular Biology; Ophthalmology GA 134RN UT WOS:000244101700002 PM 17293780 ER PT J AU Kanungo, J Li, BS Goswami, M Zheng, YL Ramchandran, R Pant, HC AF Kanungo, Jyotshnabala Li, Bing-Sheng Goswami, Moloy Zheng, Ya-Li Ramchandran, Ramani Pant, Harish C. TI Cloning and characterization of zebrafish (Danio rerio) cyclin-dependent kinase 5 SO NEUROSCIENCE LETTERS LA English DT Article DE neurogenesis; protein kinase; siRNA; zebrafish ID CYCLIN-DEPENDENT KINASE-5; NEURONAL DIFFERENTIATION; NERVOUS-SYSTEM; REGULATORY SUBUNIT; NEURITE OUTGROWTH; XENOPUS-LAEVIS; MESSENGER-RNA; CDK5; EXPRESSION; ACTIVATOR AB Cyclin-dependent kinase 5 (cdk5) is a ubiquitous protein activated by neuron-specific activators, p35 and p39. Cdk5 regulates neuronal migration, differentiation, axonogenesis, synaptic transmission and apoptosis. However, its role in primary neurogenesis remains unexplored. Here, we have cloned and characterized the zebrafish cdk5 ortholog. Zebrafish cdk5 is 96% identical to its human counterpart. In situ hybridization analyses demonstrated that zebrafish cdk5 transcripts are ubiquitously expressed as early as the blastula stage. At 11.5 h of development, cdk5 transcripts were present in the neural plate at the domains where primary neurons begin to be specified. RT-PCR analyses showed equal levels of cdk5 transcripts up to 72 h of development. SiRNA-mediated cdk5 knockdown resulted in a reduction in primary sensory neurons of the trigeminal ganglia of the peripheral nervous system, suggesting that cdk5 plays a crucial role in the development of the peripheral nervous system. (c) 2006 Elsevier Ireland Ltd. All rights reserved. C1 NINDS, Neurochem Lab, NIH, Bethesda, MD 20892 USA. NICHD, Unit Vertebrate Neural Dev, Genet Mol Lab, Bethesda, MD 20892 USA. NCI, NIH, Pathol Lab, Bethesda, MD 20892 USA. RP Pant, HC (reprint author), NINDS, Neurochem Lab, NIH, Bldg 49,Rm 2A28,9000 Rockville Pike, Bethesda, MD 20892 USA. EM panth@ninds.nih.gov FU Intramural NIH HHS [, NIH0011072097]; NCI NIH HHS [K22 CA095325-02, K22 CA095325, K22 CA095325-01]; PHS HHS [NIH0011072097] NR 25 TC 12 Z9 13 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD FEB 2 PY 2007 VL 412 IS 3 BP 233 EP 238 DI 10.1016/j.neulet.2006.11.016 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 138WC UT WOS:000244393000010 PM 17178437 ER PT J AU Pannacciulli, N Le, DSNT Chen, KW Reiman, EM Krakoff, J AF Pannacciulli, Nicola Le, Duc Son N. T. Chen, Kewei Reiman, Eric M. Krakoff, Jonathan TI Relationships between plasma leptin concentrations and human brain structure: A voxel-based morphometric study SO NEUROSCIENCE LETTERS LA English DT Article DE grey matter volume; leptin; obesity ID BODY-WEIGHT; FOLLOW-UP; OBESE; ABNORMALITIES; SATIATION; APOPTOSIS; ADULTS; MOUSE; MECHANISMS; OVERWEIGHT AB We have previously demonstrated that obese people have reduced grey matter (GM) in several brain areas, including regions implicated in the regulation of taste (i.e., inferior frontal operculum and postcentral gyrus), reward (i.e., putamen), and behavioural processing (i.e., middle frontal gyrus), compared with their lean counterparts. It is well established that the brain may serve as a direct target for adiposity signals, one of the most important being leptin. We investigated the relationships between fasting plasma leptin concentrations and brain tissue composition in a group of 32 young adult Caucasians (12M/20F, age 32 +/- 1 years, body fat 29 +/- 1%, mean +/- S.E.) with normal glucose tolerance by using voxel-based morphometry of magnetic resonance imaging scans. Fasting plasma leptin concentrations were positively correlated with GM volumes of the left cerebellum and left inferior temporal gyrus and negatively associated with GM volumes of the left inferior frontal operculum, left postcentral gyrus, and right putamen (P < 0.001, uncorrected for multiple comparisons) after adjustment for sex, percent body fat, age, fasting plasma insulin concentrations (i.e., the major determinants of plasma leptin), and global GM volume (thus allowing for an assessment of regional effects only). This study showed an independent, negative correlation between fasting plasma leptin concentrations, which are increased in obesity, and the volumes of GM in brain areas where obese people have reduced GM compared to their lean counterparts. These relationships may explain some of the abnormalities in brain morphology recently found to be associated with excess body fatness. Published by Elsevier Ireland Ltd. C1 NIDDKD, Obes & Diabet Clin Res Stn, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. Banner Good Samaritan Med Ctr, Banner Alzheimer Inst & Positron Emiss Tomog Ctr, Phoenix, AZ USA. Univ Arizona, Dept Psychiat, Phoenix, AZ USA. Translat Genom Res Inst, Neurogenom Program, Phoenix, AZ USA. RP Pannacciulli, N (reprint author), NIDDKD, Obes & Diabet Clin Res Stn, Phoenix Epidemiol & Clin Res Branch, NIH, 4212 N 16Th St, Phoenix, AZ 85016 USA. EM nicolap@mail.nih.gov RI Chen, kewei/P-6304-2015 OI Chen, kewei/0000-0001-8497-3069 FU Intramural NIH HHS [Z99 DK999999] NR 43 TC 43 Z9 44 U1 0 U2 3 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0304-3940 J9 NEUROSCI LETT JI Neurosci. Lett. PD FEB 2 PY 2007 VL 412 IS 3 BP 248 EP 253 DI 10.1016/j.neulet.2006.11.019 PG 6 WC Neurosciences SC Neurosciences & Neurology GA 138WC UT WOS:000244393000013 PM 17123711 ER PT J AU Hildebrand, EJ Buice, MA Chow, CC AF Hildebrand, Eric J. Buice, Michael A. Chow, Carson C. TI Kinetic theory of coupled oscillators SO PHYSICAL REVIEW LETTERS LA English DT Article ID INTERACTING OSCILLATORS; NEURONAL NETWORKS; PHASE-TRANSITION; MEAN-FIELD; SYNCHRONIZATION; POPULATIONS; DYNAMICS; SYSTEMS; NOISE AB We present an approach for the description of fluctuations that are due to finite system size induced correlations in the Kuramoto model of coupled oscillators. We construct a hierarchy for the moments of the density of oscillators that is analogous to the Bogoliubov-Bom-Green-Mrkwood-Yvon hierarchy in the kinetic theory of plasmas and gases. To calculate the lowest order system size effect, we truncate this hierarchy at second order and solve the resulting closed equations for the two-oscillator correlation function around the incoherent state. We use this correlation function to compute the fluctuations of the order parameter, including the effect of transients, and compare this computation with numerical simulations. C1 Univ Pittsburgh, Dept Phys & Astron, Pittsburgh, PA 15260 USA. NIDDK, Lab Biol Modeling, NIH, Bethesda, MD USA. RP Hildebrand, EJ (reprint author), Univ Pittsburgh, Dept Phys & Astron, Pittsburgh, PA 15260 USA. RI Chow, Carson/A-7970-2009 FU Intramural NIH HHS [Z01 DK013024-01] NR 27 TC 35 Z9 35 U1 0 U2 6 PU AMERICAN PHYSICAL SOC PI COLLEGE PK PA ONE PHYSICS ELLIPSE, COLLEGE PK, MD 20740-3844 USA SN 0031-9007 J9 PHYS REV LETT JI Phys. Rev. Lett. PD FEB 2 PY 2007 VL 98 IS 5 AR 054101 DI 10.1103/PhysRevLett.98.054101 PG 4 WC Physics, Multidisciplinary SC Physics GA 142JR UT WOS:000244646100035 PM 17358861 ER PT J AU Yedavalli, VRK Jeang, KT AF Yedavalli, Venkat R. K. Jeang, Kuan-Teh TI Methylation: a regulator of HIV-1 replication? SO RETROVIROLOGY LA English DT Editorial Material ID DNA CPG METHYLATION; HUMAN-IMMUNODEFICIENCY-VIRUS; ARGININE METHYLATION; PROTEIN METHYLATION; MESSENGER-RNA; BINDING; TRANSCRIPTION; EXPRESSION; LTR; REACTIVATION AB Recent characterizations of methyl transferases as regulators of cellular processes have spurred investigations into how methylation events might influence the HIV-1 life cycle. Emerging evidence suggests that protein-methylation can positively and negatively regulate HIV-1 replication. How DNA- and RNA-methylation might impact HIV-1 is also discussed. C1 NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. RP Jeang, KT (reprint author), NIAID, Mol Virol Sect, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. EM vyedavalli@mail.nih.gov; kj7e@nih.gov RI Jeang, Kuan-Teh/A-2424-2008 NR 25 TC 13 Z9 14 U1 1 U2 3 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 2 PY 2007 VL 4 AR 9 DI 10.1186/1742-4690-4-9 PG 3 WC Virology SC Virology GA 138MS UT WOS:000244367300001 PM 17274823 ER PT J AU Saugstad, OD Hansen, TWR Ronnestad, A Nakstad, B Tollofsrud, PA Reinholt, F Hamvas, A Cole, FS Dean, M Wert, SE Whitsett, JA Nogee, LM AF Saugstad, Ola D. Hansen, Thor Willy Ruud Ronnestad, Arild Nakstad, Britt Tollofsrud, Per Arne Reinholt, Finn Hamvas, Aaron Cole, F. Sessions Dean, Michael Wert, Susan E. Whitsett, Jeffrey A. Nogee, Lawrence M. TI Novel mutations in the gene encoding ATP binding cassette protein member A3 (ABCA3) resulting in fatal neonatal lung disease SO ACTA PAEDIATRICA LA English DT Article DE ABCA3 deficiency; human genetic disorders; neonatal lung failure; pulmonary surfactant; respiratory distress syndrome ID C GENE; SURFACTANT DEFICIENCY; LAMELLAR BODIES; II CELLS; ALVEOLAR PROTEINOSIS; RESPIRATORY-DISEASE; MEMBRANE-PROTEIN; SP-B; IDENTIFICATION AB Aim: To investigate whether intractable respiratory distress syndrome in three Norwegian term infants was due to mutations in the ABCA3 gene. Methods: The genes encoding SP-B (SFTPB), SP-C (SFTPC), and ABCA3 (ABCA3) were sequenced from the parents of one infant and two unrelated infants with fatal neonatal lung disease. Lung tissue was examined by histology, immunohistochemistry and electron microscopy. Results: Novel ABCA3 mutations were identified in each family. One patient had a phenotype differing from previous descriptions of this disease with an initial uneventful period. The diagnosis was established 19 years after death by analysing DNA material from the parents, with an ABCA3 mutation identified on one allele in each parent. The other two infants had more typical clinical courses with the onset of respiratory symptoms immediately after birth. ABCA3 mutations were identified on both alleles from these two infants, and electron microscopy of alveolar type 2 cells demonstrated abnormal lamellar body formation characteristic of this disorder. Conclusion: ABCA3 mutations were the basis for lung disease in all three patients. Children with lung disease due to ABCA3 deficiency may not have symptoms at birth. The finding of five novel mutations indicates allelic heterogeneity for ABCA3 mutations within the Norwegian population. C1 Univ Oslo, Rikshosp, Dept Pediat Res, Radiumhosp Hlth Trust, N-0027 Oslo, Norway. Univ Oslo, Rikshosp, Dept Pediat, Radiumhosp Hlth Trust, N-0027 Oslo, Norway. Univ Oslo, Aker Univ Hosp, Dept Pediat, Oslo, Norway. Univ Oslo, Rikshosp, Dept Pathol, Radiumhosp Hlth Trust, N-0027 Oslo, Norway. Washington Univ, Sch Med, Dept Pediat, Div Newborn Med, St Louis, MO 63110 USA. St Louis Childrens Hosp, St Louis, MO 63178 USA. NCI, Human Genet Sect, Frederick, MD 21701 USA. Cincinnati Childrens Hosp, Div Neonatol, Cincinnati, OH USA. Cincinnati Childrens Hosp, Div Pulm Biol, Cincinnati, OH USA. Univ Cincinnati, Coll Med, Cincinnati, OH USA. Johns Hopkins Univ, Sch Med, Dept Pediat, Div Neonatol, Baltimore, MD 21205 USA. RP Saugstad, OD (reprint author), Pediat Forsknings Inst Rikshosp, N-0027 Oslo, Norway. EM o.d.saugstad@medisin.uio.no RI Dean, Michael/G-8172-2012 OI Dean, Michael/0000-0003-2234-0631 FU NHLBI NIH HHS [HL-56387, HL-54703, HL-65174] NR 24 TC 20 Z9 21 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0803-5253 J9 ACTA PAEDIATR JI Acta Paediatr. PD FEB PY 2007 VL 96 IS 2 BP 185 EP 190 DI 10.1111/j.1651-2227.00016.x PG 6 WC Pediatrics SC Pediatrics GA 133DZ UT WOS:000243993800010 PM 17429902 ER PT J AU Osmanov, S Ackland, J Allen, S Barth-Jones, D Birx, D Chomba, E Churchyard, G Duerr, A Jin, SG Johnston, M Fast, PE Fix, A Foulkes, M Follmann, D Hutubessy, R Malone, S Gray, R Indrayan, A Levin, J Mathieson, BJ Mastro, TD McNeil, J Pitisuttithum, P Peters, B Karita, E Robertson, MN Ramakrishnan, R Rees, H Rida, W Ruan, YH Sandstrom, E Schmidt, C Smith, P Self, S Thiry, G Wasserheit, J Priddy, F Thior, I Warren, M Cooper, D Kaleebu, P Macklin, R Tangwa, G AF Osmanov, Saladin Ackland, Jim Allen, Susan Barth-Jones, Daniel Birx, Deborah Chomba, Elwyn Churchyard, Gavin Duerr, Ann Jin, Shiugao Johnston, Margaret Fast, Patricia E. Fix, Alan Foulkes, Mary Follmann, Dean Hutubessy, Raymond Malone, Siobhan Gray, Ronald Indrayan, Abhay Levin, Jonathan Mathieson, Bonnie J. Mastro, Timothy D. McNeil, John Pitisuttithum, Punnee Peters, Barry Karita, Etienne Robertson, Michael N. Ramakrishnan, R. Rees, Helen Rida, Wasima Ruan, Yuhua Sandstrom, Eric Schmidt, Claudia Smith, Peter Self, Steven Thiry, Georges Wasserheit, Judith Priddy, Frances Thior, Ibou Warren, Mitchell Cooper, David Kaleebu, Pontiano Macklin, Ruth Tangwa, Godfrey CA WHO UNAIDS IAVI Intl Expert Grp TI Executive summary and recommendations from the WHO/UNAIDS/IAVI expert group consultation on 'Phase IIB-TOC trials as a novel strategy for evaluation of preventive HIV vaccines', 31 January-2 February 2006, IAVI, New York, USA SO AIDS LA English DT Article DE clinical trial design; HIV vaccines; phase IIB trials; proof of concept trials; test of concept trials; vaccine efficacy ID RANDOMIZED CONTROLLED-TRIAL; HUMAN-PAPILLOMAVIRUS TYPE-16; PARTICLE VACCINE; YOUNG-WOMEN; EFFICACY; INFECTION; WORKSHOP AB This report summarizes the discussions and recommendations from a consultation held in New York City, USA (31 January-2 February 2006) organized by the joint World Health Organization-United Nations Programme on HIV/AIDS HIV Vaccine Initiative and the International AIDS Vaccine Initiative. The consultation discussed issues related to the design and implementation of phase IIB 'test of concept' trials (phase IIB-TOC), also referred to as 'proof of concept' trials, in evaluating candidate HIV vaccines and their implications for future approval and licensure. The results of a single phase IIB-TOC trial would not be expected to provide sufficient evidence of safety or efficacy required for licensure. In many instances, phase IIB-TOC trials may be undertaken relatively early in development, before manufacturing processes and capacity are developed sufficiently to distribute the vaccine on a large scale. However, experts at this meeting considered the pressure that could arise, particularly in regions hardest hit by AIDS, if a phase IIB-TOC trial showed high levels of efficacy. The group largely agreed that full-scale phase III trials would still be necessary to demonstrate that the vaccine candidate was safe and effective, but emphasized that governments and organizations conducting trials should consider these issues in advance. The recommendations from this meeting should be helpful for all organizations involved in HIV vaccine trials, in particular for the national regulatory authorities in assessing the utility of phase IIB-TOC trials in the overall HIV vaccine research and development process. (c) 2007 Lippincott Williams & Wilkins. C1 Global BioSolut, Craigieburn, Vic, Australia. Emory Univ, Rollins Sch Publ Hlth, Atlanta, GA 30322 USA. Wayne State Univ, Sch Med, Pediat Prevent Res Ctr, Detroit, MI 48202 USA. Ctr Dis Control & Prevent, GAP, Global AIDS Program, Atlanta, GA USA. Zambia Emory HIV Res Project, Lusaka, Zambia. Ernest Oppenheimer Hosp, Welkom, South Africa. HIV Vaccine Trials Network, Sci Support Unit, Seattle, WA USA. Chinese Ctr Dis Control & Prevent, Beijing, Peoples R China. NIAID, Vaccine & Prevent Res Program, Seattle, WA USA. Int AIDS Vaccine Initiat, New York, NY USA. NIAID, Div Aids, NIH, Bethesda, MD 20892 USA. US FDA, Off Biostat & Epidemiol, Ctr Biol Evaluat & Res, Rockville, MD 20857 USA. WHO, UNAIDS HIV Vaccine Initiat, CH-1211 Geneva, Switzerland. Bill & Melinda Gates Fdn, Global Hlth Program, Seattle, WA USA. Johns Hopkins Bloomberg Sch Publ Hlth, Baltimore, MD USA. Univ Coll Med Sci, Div Biostat & Med Informat, New Delhi, India. Med Res Council S Africa, Pretoria, South Africa. OAR HIV AIDS Vaccine Coordinating Comm, Bethesda, MD USA. Ctr Dis Control & Prevent, Div HIV AIDS Prevent, Atlanta, GA USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Mahidol Univ, Fac Trop Med, Dept Clin Trop Med, Bangkok 10700, Thailand. St Thomas Hosp, London, England. Projet San Francisco IAVI, Kigali, Rwanda. Natl Inst Epidemiol, Madras, Tamil Nadu, India. Univ Witwatersrand, Reprod Hlth Res Unit, Dept Obstet & Gynecol, Johannesburg, South Africa. Stat Collaborat, Washington, DC USA. Karolinska Univ Hosp, Dept Infect Dis, Stockholm, Sweden. IAVI, New York, NY USA. Univ London London Sch Hyg & Trop Med, Dept Infect & Trop Dis, London WC1E 7HT, England. Stat Ctr HIV AIDS Res & Prevent, Seattle, WA USA. HIV Vaccine Trials Network, Seattle, WA USA. Emory Vaccine Ctr, Hope Clin, Decatur, GA USA. Princess Marina Hosp, Botswana Harvard Partnership, Gaborone, Botswana. AIDS Vaccine Advocacy Coalit, New York, NY USA. Univ New S Wales, Natl Ctr HIV Epidemiol & Clin Res, Sydney, NSW, Australia. Uganda Virus Res Inst, Entebbe, Uganda. Albert Einstein Coll Med, Dept Epidemiol & Social Med, Bronx, NY 10467 USA. Univ Yaounde, Yaounde, Cameroon. RP Osmanov, S (reprint author), WHO, UNAIDS HIV Vaccine Initiat, 20 Ave Appia, CH-1211 Geneva, Switzerland. EM osmanovs@who.int NR 9 TC 11 Z9 12 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0269-9370 J9 AIDS JI Aids PD FEB 1 PY 2007 VL 21 IS 4 BP 539 EP 546 PG 8 WC Immunology; Infectious Diseases; Virology SC Immunology; Infectious Diseases; Virology GA 146BR UT WOS:000244910000026 ER PT J AU Nicholas, PK Kemppainen, JK Canaval, GE Corless, IB Sefcik, EF Nokes, KM Bain, CA Kirksey, KM Eller, LS Dole, PJ Hamilton, MJ Coleman, CL Holzemer, WL Reynolds, NR Portillo, CJ Bunch, EH Wantland, DJ Voss, J Phillips, R Tsai, YF Mendez, MR Lindgren, TG Davis, SM Gallagher, DM AF Nicholas, P. K. Kemppainen, J. K. Canaval, G. E. Corless, I. B. Sefcik, E. F. Nokes, K. M. Bain, C. A. Kirksey, K. M. Eller, L. Sanzero Dole, P. J. Hamilton, M. J. Coleman, C. L. Holzemer, W. L. Reynolds, N. R. Portillo, C. J. Bunch, E. H. Wantland, D. J. Voss, J. Phillips, R. Tsai, Y. -F. Mendez, M. Rivero Lindgren, T. G. Davis, S. M. Gallagher, D. M. TI Symptom management and self-care for peripheral neuropathy in HIV/AIDS SO AIDS CARE-PSYCHOLOGICAL AND SOCIO-MEDICAL ASPECTS OF AIDS/HIV LA English DT Article ID DISTAL SENSORY POLYNEUROPATHY; QUALITY-OF-LIFE; HIV-INFECTION; ANTIRETROVIRAL THERAPY; NEUROLOGIC MANIFESTATIONS; RISK-FACTORS; HAT-QOL; COHORT; AIDS; PATHOPHYSIOLOGY AB Peripheral neuropathy is the most common neurological complication in HIV and is often associated with antiretroviral therapy. As part of a larger study on self-care for symptoms in HIV disease, this study analyzed the prevalence and characteristics of peripheral neuropathy in HIV disease, sociodemographic and disease-related correlates and self-care strategies. A convenience sample of 1,217 respondents was recruited from data collection sites in several US cities, Puerto Rico, Colombia and Taiwan. Results of the study indicated that respondents with peripheral neuropathy (n = 450) identified 20 self-care behaviors including complementary therapies, use of medications, exercise and rest and/or elevation of extremities. Ratings of frequency and effectiveness were also included. An activities checklist summarized into five categories of self-care behaviors including activities/thoughts, exercise, medications, complementary therapies and substance was used to determine self-care behaviors. Taking a hot bath was the most frequent strategy used by those with peripheral neuropathy (n = 292) and received the highest overall rating of effectiveness of any self-management strategies included in this study at 8.1 (scale 1-10). Other self-care strategies to manage this symptom included: staying off the feet (n = 258), rubbing the feet with cream (n = 177), elevating the feet (n = 236), walking (n = 262), prescribed antiepileptic agent (n = 80), prescribed analgesics (n = 84), over-the-counter medications (n = 123), vitamin B (n = 122), calcium supplements (n = 72), magnesium (n = 48), massage (n = 156), acupuncture (n = 43), reflexology (n = 23) and meditation (n = 80). Several behaviors that are often deemed unhealthy were included among the strategies reported to alleviate peripheral neuropathy including use of marijuana (n = 67), cigarette smoking (n = 139), drinking alcohol (n = 81) and street drugs (n = 30). C1 Brigham & Womens Hosp, MGH Inst Hlth Profess, Grad Program Nursing, Boston, MA 02129 USA. Univ N Carolina, Wilmington, NC 28401 USA. Univ Valle, Cali, Colombia. Texas A&M Univ, Corpus Christi, TX USA. CUNY Hunter Coll, New York, NY 10021 USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. Ben Taub Gen Hosp, Houston, TX 77030 USA. Rutgers State Univ, Newark, NJ 07102 USA. Greenwich House, New York, NY USA. Univ Penn, Philadelphia, PA 19104 USA. Ohio State Univ, Columbus, OH 43210 USA. Univ Oslo, N-0316 Oslo, Norway. Natl Inst Hlth, Natl Inst Neuromuscular Dis Sect, Bethesda, MD USA. Chang Gung Univ, Tao Yuan, Taiwan. Univ Puerto Rico, San Juan, PR 00936 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. New England AIDS Educ & Training Ctr, Boston, MA USA. RP Nicholas, PK (reprint author), Brigham & Womens Hosp, MGH Inst Hlth Profess, Grad Program Nursing, 36 1st Ave, Boston, MA 02129 USA. EM pnicholas@mghihp.edu RI Canaval, Gladys/F-7284-2015; OI Canaval, Gladys/0000-0001-9841-5084; Corless, Inge/0000-0003-0438-2037 NR 47 TC 32 Z9 32 U1 2 U2 6 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 0954-0121 J9 AIDS CARE JI Aids Care-Psychol. Socio-Med. Asp. Aids-Hiv PD FEB PY 2007 VL 19 IS 2 BP 179 EP 189 DI 10.1080/09540120600971083 PG 11 WC Health Policy & Services; Public, Environmental & Occupational Health; Psychology, Multidisciplinary; Respiratory System; Social Sciences, Biomedical SC Health Care Sciences & Services; Public, Environmental & Occupational Health; Psychology; Respiratory System; Biomedical Social Sciences GA 130FY UT WOS:000243786400005 PM 17364396 ER PT J AU Ducci, F Enoch, MA Funt, S Virkkunen, M Albaugh, B Goldman, D AF Ducci, Francesca Enoch, Mary-Anne Funt, Samuel Virkkunen, Matti Albaugh, Bernard Goldman, David TI Increased anxiety and other similarities in temperament of alcoholics with and without antisocial personality disorder across three diverse populations SO ALCOHOL LA English DT Article DE harm avoidance; novelty seeking; alcohol use disorders; ASPD ID SUBSTANCE USE DISORDERS; NATIONAL EPIDEMIOLOGIC SURVEY; MAJOR DEPRESSION; ENVIRONMENTAL STRUCTURE; AMERICAN-INDIANS; COMORBIDITY; DIMENSIONS; DEPENDENCE; COOCCURRENCE; LINKAGE AB According to Cloninger's model, type I alcoholics are thought to be innately vulnerable to anxiety and depression. In contrast, type II alcoholics are thought to have increased likelihood of antisocial personality disorder (ASPD) and reduced anxiety. However, allostatic activations of stress, anxiety, and dysphoria may be a common thread in alcohol use disorders (AUDs). Our aim was to find commonalities and differences in temperament of alcoholics with and without ASPD in three diverse populations. By sib-sib comparisons, we also evaluated the extent to which the temperament traits were moderated by familial factors including inheritance. We compared harm avoidance (HA), novelty seeking (NS), and reward dependence (RD) in alcoholics with ASPD, alcoholics without ASPD, and controls. Correlations for each temperament dimension were evaluated in pairs of siblings concordant and discordant for AUD. Participants were derived from three independent populations: Finnish Caucasians (N = 453, men = 100%, including a sample of alcoholic criminals), a Plains American Indian community sample (N = 378; men = 42%), and a subset of the familial and predominantly Caucasian Collaborative Study on the Genetics of Alcoholism (COGA) sample (N = 967, men = 47%). In all the three populations, both alcoholics with and without ASPD were higher in HA than controls. The increase of HA among alcoholics as compared to controls ranged from 54% to 12%. In two populations (COGA and Finns), NS was highest in alcoholics with ASPD, intermediate in alcoholics without ASPD, and lowest in controls. HA levels were correlated in sib-pairs concordant (either affected or unaffected) for AUD but not in discordant pairs. In conclusions, despite cultural diversity and different modes of ascertainment we found a consistent pattern of elevated HA in all groups of alcoholics, including alcoholics with ASPD. Even in alcoholics with long-term exposure to the anxiogenic effects of repeated cycles of alcohol withdrawal, genetic and other familial influences seem to play a role in moderating anxiety. (c) 2007 Elsevier Inc. All rights reserved. C1 NIAAA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. Univ Helsinki, Dept Psychiat, SF-00180 Helsinki, Finland. Ctr Human Behav Studies Inc, Weatherford, OK 73096 USA. RP Ducci, F (reprint author), NIAAA, Neurogenet Lab, NIH, 5625 Fishers Lane,Room 3S32,MSC 9412, Bethesda, MD 20892 USA. EM duccif@mail.nih.gov RI Goldman, David/F-9772-2010 OI Goldman, David/0000-0002-1724-5405 FU Intramural NIH HHS [, NIH0011559571]; PHS HHS [NIH0011559571] NR 43 TC 26 Z9 26 U1 7 U2 7 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0741-8329 J9 ALCOHOL JI Alcohol PD FEB PY 2007 VL 41 IS 1 BP 3 EP 12 DI 10.1016/j.alcohol.2007.02.005 PG 10 WC Substance Abuse; Pharmacology & Pharmacy; Toxicology SC Substance Abuse; Pharmacology & Pharmacy; Toxicology GA 164MF UT WOS:000246237200002 PM 17452294 ER PT J AU Schwandt, ML Barr, CS Suomi, SJ Higley, JD AF Schwandt, Melanie L. Barr, Christina S. Suomi, Stephen J. Higley, James D. TI Age-dependent variation in behavior following acute ethanol administration in male and female adolescent rhesus macaques (Macaca mulatta) SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE nonhuman primate; alcohol; adolescence; sex differences; development ID LONG-TERM POTENTIATION; SPRAGUE-DAWLEY RATS; ADULT RATS; SEX-DIFFERENCES; ALCOHOL SENSITIVITY; GENDER-DIFFERENCES; DEVELOPMENTAL DIFFERENCES; INDIVIDUAL-DIFFERENCES; MATURE HIPPOCAMPUS; NUCLEUS-ACCUMBENS AB Background: There has been considerable focus on the adolescent stage of development in the study of alcohol use and the etiology of alcohol-related problems. Because adolescence is a process of dynamic change rather than a discrete or static stage of development, it is important to consider ontogenetic changes in the response to ethanol within the adolescent time period. In rodents, levels of ethanol-induced motor impairment have been shown to increase from early to late adolescence. This study investigated associations between behavior following acute ethanol administration and age, rearing condition (mother-reared vs nursery-reared), and serotonin transporter (rh5-HTTLPR) genotype in a sample of alcohol-naive adolescent rhesus macaques. Methods: Rhesus macaques (n=97; 41 males, 56 females), ranging in age from 28 to 48 months, were administered intravenous (IV) doses of ethanol (2.2 g/kg for males, 2.0 g/kg for females) twice in 2 separate testing sessions. A saline/ethanol group (n=16; 8 males, 6 females) was administered saline in 1 testing session and ethanol in the second session. Following each IV injection, subjects underwent a 30-minute general motor behavioral assessment. Behavior in the saline/ethanol group was compared between the saline and ethanol-testing sessions using analysis of variance. Behavioral data for the larger study sample were averaged between the 2 testing sessions and summarized using factor analysis. Rotated factor scores were used as dependent variables in multiple regression analyses to test for relationships between behavior and age, rearing condition, and rh5-HTTLPR genotype. Results:During the ethanol-testing session, behaviors indicative of motor impairment (stumbles, falls, sways, bumping the wall, and unsuccessful jumps) were frequently observed in the saline/ethanol group, while they did not occur under the saline-testing session. Factor analysis of behavior following ethanol administration in the larger study sample yielded 3 factors: Ataxia, Impaired Jumping Ability, and Stimulation. Significant negative correlations between age and Ataxia were found for both males and females. Females also exhibited positive correlations between age and Impaired Jumping Ability and age and Stimulation. No significant correlations were found with either rearing condition or rh5-HTTLPR genotype. Conclusions: These findings suggest that ontogenetic changes during adolescence in the behavioral response to ethanol differ between rodents and primates. Furthermore, sex differences in the behavioral response to ethanol appear to develop during adolescence. C1 NIAAA, Lab Clin & Translat Studies, NIH, Anim Ctr, Poolesville, MD 20837 USA. NICHHD, Lab Comparat Ethol, NIH, Anim Ctr, Poolesville, MD USA. RP Schwandt, ML (reprint author), NIAAA, Lab Clin & Translat Studies, NIH, Anim Ctr, POB 529, Poolesville, MD 20837 USA. EM melanies@mail.nih.gov RI Schwandt, Melanie/L-9866-2016 FU Intramural NIH HHS NR 69 TC 10 Z9 10 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD FEB PY 2007 VL 31 IS 2 BP 228 EP 237 DI 10.1111/j.1530-0277.2006.00300.x PG 10 WC Substance Abuse SC Substance Abuse GA 128QW UT WOS:000243674200007 PM 17250614 ER PT J AU Chen, CM Yoon, YH Yi, HY Lucas, DL AF Chen, Chiung M. Yoon, Young-Hee Yi, Hsiao-ye Lucas, Diane L. TI Alcohol and hepatitis C mortality among males and females in the United States: A life table analysis SO ALCOHOLISM-CLINICAL AND EXPERIMENTAL RESEARCH LA English DT Article DE hepatitis C; alcohol drinking; alcohol-induced disorders; mortality; life table; gender ID CHRONIC LIVER-DISEASE; TRANSFUSION-ASSOCIATED HEPATITIS; VIRUS-INFECTION; NATURAL-HISTORY; RISK-FACTORS; HEPATOCELLULAR-CARCINOMA; FIBROSIS PROGRESSION; INTERFERON THERAPY; DEATH CERTIFICATES; DRINKING HABITS AB Background: Evidence from previous studies suggests that heavy alcohol use (HAU) exacerbates the rate of fibrosis progression in the liver and results in increased probability for premature death among patients with hepatitis C virus (HCV) infection. The current study uses population-based mortality data to investigate whether heavy drinking affects the age of death among individuals with HCV and, if so, whether this effect differs between men and women. Methods: A total of 7,263,163 death records in the United States between 2000 and 2002 were drawn from the Multiple Cause of Death (MCD) public-use data files compiled by the National Center for Health Statistics (NCHS). International Classification of Diseases, Tenth Revision (ICD-10) codes were used to identify the presence of HCV (B17.1 and B18.2) and HAU (as indicated by alcohol-induced medical conditions, F10 and K70) either as the underlying cause or as one of the contributing causes of death. The deaths were divided into 4 distinctive cause-of-death categories: HCV without HAU, HAU without HCV, HCV plus HAU, and all others. The mean ages of death and the cumulative probabilities of death derived from multiple-cause life table were compared across these categories. Results: Hepatitis C virus deaths showed an excessive prevalence of HAU when compared with non-HCV deaths. Compared with deaths of HCV without HAU, the mean age of death was shortened for deaths of HCV plus HAU (from 55.1 to 50.0 years among males, and from 61.0 to 49.1 years among females). The cumulative probability of death before age 65 was much higher for the latter than the former group (0.91 vs 0.68 among males, and 0.88 vs 0.47 among females). While HCV alone showed a disproportionate effect on premature death in males, HAU presented a stronger effect in females, resulting in a "catching-up" effect that diminished the gender difference in age of HCV death. Conclusions: This study provides mortality-based evidence to further establish heavy alcohol consumption as one of the key risk factors contributing to premature deaths from HCV in the United States. More importantly, this study, for the first time, presents empirical evidence that alcohol consumption affects men and women differently in HCV mortality. C1 CSR Inc, Arlington, VA 22201 USA. NIAAA, Bethesda, MD USA. RP Chen, CM (reprint author), CSR Inc, 2107 Wilson Blvd,Suite 1000, Arlington, VA 22201 USA. EM cchen@csrincorporated.com FU NIAAA NIH HHS [N0AA32007] NR 64 TC 37 Z9 38 U1 0 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0145-6008 J9 ALCOHOL CLIN EXP RES JI Alcoholism (NY) PD FEB PY 2007 VL 31 IS 2 BP 285 EP 292 DI 10.1111/j.1530-0277.2006.00304.x PG 8 WC Substance Abuse SC Substance Abuse GA 128QW UT WOS:000243674200014 PM 17250621 ER PT J AU Punturieri, A Croxton, TL Weinmann, G Kiley, JP AF Punturieri, Antonello Croxton, Thomas L. Weinmann, Gail Kiley, James P. TI The changing face of COPD SO AMERICAN FAMILY PHYSICIAN LA English DT Editorial Material ID OBSTRUCTIVE PULMONARY-DISEASE; NUTRITION-EXAMINATION-SURVEY; UNITED-STATES; NATIONAL-HEALTH; ADULTS; MORTALITY; SMOKING; TRIAL C1 NHLBI, Bethesda, MD 20892 USA. RP Kiley, JP (reprint author), NHLBI, Bldg 10, Bethesda, MD 20892 USA. EM kileyj@nhlbi.nih.gov NR 15 TC 5 Z9 5 U1 2 U2 2 PU AMER ACAD FAMILY PHYSICIANS PI KANSAS CITY PA 8880 WARD PARKWAY, KANSAS CITY, MO 64114-2797 USA SN 0002-838X J9 AM FAM PHYSICIAN JI Am. Fam. Physician PD FEB 1 PY 2007 VL 75 IS 3 BP 315 EP 316 PG 2 WC Primary Health Care; Medicine, General & Internal SC General & Internal Medicine GA 133QP UT WOS:000244027800006 PM 17304861 ER PT J AU Whellan, DJ O'Connor, CM Lee, KL Keteyian, SJ Cooper, LS Ellis, SJ Leifer, ES Kraus, WE Kitzman, DW Blumenthal, JA Rendall, DS Houston-Miller, N Fleg, JL Schulman, KA Pina, IL AF Whellan, David J. O'Connor, Christopher M. Lee, Kerry L. Keteyian, Steven J. Cooper, Lawton S. Ellis, Stephen J. Leifer, Eric S. Kraus, William E. Kitzman, Dalane W. Blumenthal, James A. Rendall, David S. Houston-Miller, Nancy Fleg, Jerome L. Schulman, Kevin A. Pina, Ileana L. CA HF-ACTION Trial Investigators TI Heart failure and a controlled trial investigating outcomes of exercise TraiNing (HF-ACTION): Design and rationale SO AMERICAN HEART JOURNAL LA English DT Article ID ACUTE MYOCARDIAL-INFARCTION; HEALTH-CARE-PROFESSIONALS; QUALITY-OF-LIFE; RANDOMIZED-TRIAL; CLINICAL-TRIALS; DILATED CARDIOMYOPATHY; PHYSICAL EXERTION; 6-MINUTE WALK; RISK PATIENTS; DOUBLE-BLIND AB Background Although there are limited clinical data to support the use of exercise training as a means to reduce mortality and morbidity in patients with heart failure, current guidelines state that exercise is beneficial. Trial Design The objective of this trial is to determine whether exercise training reduces all-cause mortality or all-cause hospitalization for patients with left ventricular systolic dysfunction and. heart failure symptoms. After undergoing baseline assessments to determine whether they can safely exercise, patients are randomized to either usual care or exercise training. Patients in the exercise training arm attend 36 supervised facility-based exercise training sessions. Exercise modalities are cycling or walking. After completing 18 sessions, patients initiate home-based exercise and then transition to solely home-based exercise after completing all 36 sessions. Patients return for facility-based training every 3 months to reinforce their exercise training program. Patients are followed for up to A years. Physiologic, quality-of-life, and economic end points that characterize the effect of exercise training in this patient population will be measured at baseline and at intervals throughout the trial. Blood samples will be collected to examine biomarkers such as brain natriuretic peptide, tumor necrosis'-factor, and C-reactive protein. Conclusions Because of its relatively low cost, high availability, and ease of use, exercise training is an intervention that could be accessible to most patients with heart failure. The HF-ACTION trial is designed to definitively assess the effect of exercise training on the clinically relevant end points of mortality, hospitalization, and quality of life in patients with heart failure. C1 Jefferson Med Coll, Dept Med, Philadelphia, PA 19107 USA. Duke Univ, Ctr Med, Durham, NC 27706 USA. Henry Ford Hosp, Detroit, MI 48202 USA. NHLBI, Bethesda, MD 20892 USA. Wake Forest Univ, Sch Med, Winston Salem, NC 27109 USA. Stanford Univ, Stanford, CA 94305 USA. Case Western Reserve Univ, Cleveland, OH 44106 USA. RP Whellan, DJ (reprint author), Jefferson Med Coll, Dept Med, Mezzanine Level,925 Chestnut St, Philadelphia, PA 19107 USA. EM david.whellan@jefferson.edu OI Kraus, William E/0000-0003-1930-9684 FU NHLBI NIH HHS [5U01-HL063747, 5U01-HL066461, HL064250, HL064257, HL064264, HL064265, HL066482, HL066491, HL066494, HL066497, HL066501, HL068973, HL068980] NR 64 TC 130 Z9 134 U1 0 U2 4 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD FEB PY 2007 VL 153 IS 2 BP 201 EP 211 DI 10.1016/j.ahj.2006.11.007 PG 11 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 133XQ UT WOS:000244047600008 PM 17239677 ER PT J AU Fox, ER Taylor, J Taylor, H Han, H Samdarshi, T Arnett, D Myerson, M AF Fox, Ervin R. Taylor, Jason Taylor, Herman Han, Hui Samdarshi, Tandaw Arnett, Donna Myerson, Merle TI Left ventricular geometric patterns in the Jackson cohort of the atherosclerotic risk in communities (ARIC) study: Clinical correlates and influences on systolic and diastolic dysfunction SO AMERICAN HEART JOURNAL LA English DT Article ID CONGESTIVE-HEART-FAILURE; WHITE ADULT MEN; ESSENTIAL-HYPERTENSION; CARDIOVASCULAR HEALTH; AFRICAN-AMERICANS; EJECTION FRACTION; MYOCARDIAL-INFARCTION; ELDERLY COHORT; BLOOD-PRESSURE; YOUNG-ADULTS AB Background The distribution and determinants of left ventricular (LV) geometric patterns and their relation to LV function in African Americans is not well described despite higher rates of LV hypertrophy and cardiovascular mortality reported in this group. Purpose This study investigates the distribution and clinical correlates of LV geometric patterns and how these patterns relate to function in a population-based African American cohort. Methods The study population included participants in the Jackson cohort of ARIC, who underwent echocardiograms between 1993 and 1995. We defined 4 geometric patterns (normal geometry, concentric remodeling [CR], eccentric hypertrophy [EH], and concentric hypertrophy [CH]) according to LV mass index and relative wall thickness. Multiple logistic regression was used to assess the association of geometric patterns to systolic dysfunction and diastolic dysfunction, adjusting for traditional coronary risk factors. Results There were 1849 participants in the study population (mean age 59 years, 65% women). Concentric remodeling and CH were highly prevalent. Concentric hypertrophy and EH groups had the highest rates of hypertension, obesity, and diabetes mellitus. Compared to the normal geometric pattern, EH was related to systolic dysfunction (OR 24.27, Cl 6.71-87.80), and CH was related to diastolic dysfunction 1.58 (1.04-2.39). Concentric remodeling was not related to systolic or diastolic dysfunction. Conclusion In this large middle-aged African American cohort, CR and CH are prevalent. Hypertension, diabetes mellitus, and obesity are associated with both CH and EH. Concentric hypertrophy is strongly associated with diastolic dysfunction; EH is strongly associated with systolic dysfunction. Concentric remodeling, however, is not related to either systolic or diastolic dysfunction. C1 Univ Mississippi, Med Ctr, Jackson Heart Study, NHLBI, Jackson, MS 39216 USA. Univ Alabama, Birmingham, AL 35233 USA. NHLBI, Bethesda, MD 20892 USA. RP Fox, ER (reprint author), Univ Mississippi, Med Ctr, Jackson Heart Study, NHLBI, 2500 N State St, Jackson, MS 39216 USA. EM efox@medicine.umsmed.edu FU NHLBI NIH HHS [N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022] NR 43 TC 43 Z9 48 U1 0 U2 1 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0002-8703 J9 AM HEART J JI Am. Heart J. PD FEB PY 2007 VL 153 IS 2 BP 238 EP 244 DI 10.1016/j.ahj.2006.09.013 PG 23 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 133XQ UT WOS:000244047600012 PM 17239683 ER PT J AU Emanuel, EJ Miller, FG AF Emanuel, Ezekiel J. Miller, Franklin G. TI Money and distorted ethical judgments about research: Ethical assessment of the TeGenero TGN1412 trial SO AMERICAN JOURNAL OF BIOETHICS LA English DT Article ID CLINICAL-RESEARCH; UNDUE INDUCEMENT; VOLUNTEERS; RISK AB Money in clinical research creates ethical concerns because of its potential to distort judgments (Thompson 1993). Nowhere has money's potential to distort judgments been more obvious than in the reaction to the tragic adverse reactions in the trial of TGN1412-the TeGenero drug tested by Parexel (Associated Press 2006; Caplan 2006; Panja 2006; Waldman 2006; Goodyear 2006). Six participants were stricken by a massive inflammatory reaction (Suntharalingam 2002). Almost all press reports and commentaries have mentioned that the healthy research participants were paid 12000 for enrolling in a phase one trial of a new agent produced by a for-profit company, as if this necessarily signified the trial was ethically questionable (Associated Press 2006; Caplan 2006; Waldman 2006; Goodyear 2006). The payment and profit status of the company alone, however do not make the trial ethically suspect (Emanuel 2004). Rather than relying on financial considerations as indicators of ethical problems, ethical analysis should focus on pertinent substantive issues, such as the research design, the risk/benefit ratio, and the informed consent process. C1 Ctr Clin, Dept Clin Bioeth, NIH, Bethesda, MD 20892 USA. RP Emanuel, EJ (reprint author), Ctr Clin, Dept Clin Bioeth, NIH, Bldg 10,Room 1C118, Bethesda, MD 20892 USA. EM eemanuel@nih.gov NR 30 TC 23 Z9 23 U1 0 U2 1 PU ROUTLEDGE JOURNALS, TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXFORDSHIRE, ENGLAND SN 1526-5161 J9 AM J BIOETHICS JI Am. J. Bioeth. PD FEB PY 2007 VL 7 IS 2 BP 76 EP 81 DI 10.1080/15265160601111800 PG 6 WC Ethics; Medical Ethics; Social Issues; Social Sciences, Biomedical SC Social Sciences - Other Topics; Medical Ethics; Social Issues; Biomedical Social Sciences GA 142ZE UT WOS:000244689000025 PM 17366206 ER PT J AU Kathiresan, S Larson, MG Keyes, MJ Polak, JF Wolf, PA D'Agostino, RB Jaffer, FA Clouse, ME Levy, D Manning, WJ O'Donnell, CJ AF Kathiresan, Sekar Larson, Martin G. Keyes, Michelle J. Polak, Joseph F. Wolf, Philip A. D'Agostino, Ralph B. Jaffer, Farouc A. Clouse, Melvin E. Levy, Daniel Manning, Warren J. O'Donnell, Christopher J. TI Assessment by cardiovascular magnetic resonance, electron beam computed tomography, and carotid ultrasonography of the distribution of subclinical atherosclerosis across Framingham risk strata SO AMERICAN JOURNAL OF CARDIOLOGY LA English DT Article ID CORONARY-HEART-DISEASE; ARTERY CALCIUM; AORTIC ATHEROSCLEROSIS; MEDIA THICKNESS; ADULTS; INTIMA AB Screening for subclinical atherosclerosis has been advocated for individuals at intermediate global risk for coronary heart disease (CHD). However, the distribution of subclinical atherosclerosis test values across CHD risk strata is unknown. We studied a stratified random sample of 292 participants (mean age 59.5 years, 50% women) from the offspring cohort of the Framingham Heart Study who were free of clinically apparent cardiovascular disease. We assessed abdominal and thoracic aortic plaque burden by cardiovascular magnetic resonance (CMR), coronary artery calcification (CAC) and thoracic aortic calcification (TAC) by electron beam computed tomography, and common carotid intima-media thickness (C-IMT) by ultrasonography. We categorized the upper 20% of each measurement as a high level of atherosclerosis and evaluated these variables across clinically relevant Framingham CHD risk score strata (low, intermediate, and high risk). In age-adjusted analyses in men and women, correlations across CMR aortic plaque, CAC, TAC, and C-IMT were low (maximum r = 0.30 for CAC:TAC in women, p < 0.005). In men and women, the proportion of subjects with high atherosclerosis test results for any of these measurements increased significantly across Framingham CHD risk score strata (Kruskal-Wallis test, p < 0.0001). In the intermediate Framingham CHD risk score category, 14% of men and 25% of women had a high atherosclerosis result on 2 measurements. However, different participants were identified as having high atherosclerosis by each modality. For example, in a comparison of the overlap across CMR aortic plaque, CAC, and C-IMT, only 4% of men and 16% of women were classified as having high atherosclerosis on all 3 measurements. In conclusion, in a community-based sample, correlations among subclinical atherosclerosis test results are low, and a substantial proportion has high levels of subclinical atherosclerosis detected on >= 2 imaging tests. (c) 2007 Elsevier Inc. All rights reserved. C1 Framingham Heart Dis Epidemiol Study, Framingham, MA USA. Harvard Univ, Massachusetts Gen Hosp, Sch Med, Dept Med,Div Cardiol, Boston, MA USA. Boston Univ, Sch Med, Dept Neurol, Boston, MA 02118 USA. Boston Univ, Sch Med, Dept Med, Boston, MA 02118 USA. Boston Univ, Dept Math & Stat, Boston, MA 02118 USA. Tufts Univ, New England Med Ctr, Dept Radiol, Boston, MA 02111 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Dept Radiol, Boston, MA 02215 USA. NHLBI, Bethesda, MD 20892 USA. RP O'Donnell, CJ (reprint author), Framingham Heart Dis Epidemiol Study, Framingham, MA USA. EM codonell@nih.gov OI Larson, Martin/0000-0002-9631-1254; Jaffer, Farouc/0000-0001-7980-384X FU NHLBI NIH HHS [N01-HC-25195] NR 14 TC 33 Z9 33 U1 0 U2 0 PU EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC PI BRIDGEWATER PA 685 ROUTE 202-206, BRIDGEWATER, NJ 08807 USA SN 0002-9149 J9 AM J CARDIOL JI Am. J. Cardiol. PD FEB PY 2007 VL 99 IS 3 BP 310 EP 314 DI 10.1016/j.amjcard.2006.08.028 PG 5 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 132MW UT WOS:000243947900004 PM 17261388 ER PT J AU Manini, TM Clark, BC Nalls, MA Goodpaster, BH Ploutz-Snyder, LL Harris, TB AF Manini, Todd M. Clark, Brian C. Nalls, Michael A. Goodpaster, Bret H. Ploutz-Snyder, Lori L. Harris, Tamara B. TI Reduced physical activity increases intermuscular adipose tissue in healthy young adults SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE unilateral limb suspension; bed rest; physical inactivity; intermuscular adipose tissue ID NECROSIS-FACTOR-ALPHA; SKELETAL-MUSCLE CONTRACTILE; LIPOPROTEIN-LIPASE ACTIVITY; LOWER-LIMB SUSPENSION; INSULIN-RESISTANCE; BED REST; NONCONTRACTILE COMPONENTS; LIPID-ACCUMULATION; HIV-LIPODYSTROPHY; INTRAMUSCULAR FAT AB Background: Recent findings suggest that higher levels of intermuscular adipose tissue (IMAT) are associated with glucose dysregulation, lower levels of muscle strength, and a heightened risk of disability. Although several studies have described adaptations in muscle after reduced physical activity, the change in IMAT in healthy young adults is unknown. Objective: The objective was to determine whether reduced lower limb activity alters IMAT in healthy young adults and to assess whether this change affects muscle strength loss. Design: The subjects (6 men and 12 women aged 19-28 y) underwent a 4-wk control period, which was followed by 4wk of unilateral lower limb suspension. Volumes of whole muscle, subcutaneous adipose tissue, and IMAT were assessed by using magnetic resonance imaging in the thigh and calf. Muscle strength was assessed during maximal voluntary isometric contractions. Results: No changes were observed in the control,period. Reduced physical activity decreased thigh and calf muscle volumes by 7.4% and 7.9% (P < 0.001), respectively; no significant change in subcutaneous adipose tissue was observed. Additionally, IMAT increased in both regions; the increase was larger in the calf (20%) than in the thigh (14.5%) (P < 0.005) and was partially explained by the loss in muscle (R-2 = 26%). The loss in strength was greater in the thigh (20.4%) than in the calf (15%). Strength loss was associated with increases in IMAT (P = 0.039) after adjustment for the loss in muscle, initial strength, initial IMAT, and initial muscle volume. Conclusions: IMAT accumulates markedly after reduced activity in healthy young adults. Increases in IMAT may contribute to losses in muscle strength associated with reduced physical activity, but the mechanism responsible is yet to be determined. C1 Univ Florida, Inst Aging, Dept Aging & Geriatr Res, Gainesville, FL 32611 USA. Ohio Univ, Coll Osteopath Med, Dept Biomed Sci, Interdisciplinary Inst Neuromuscloskeletal Res, Athens, OH 45701 USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. Univ Pittsburgh, Med Ctr, Div Endocrinol & Metab, Pittsburgh, PA 15260 USA. Syracuse Univ, Dept Exercise Sci, Musculoskeletal Res Lab, Syracuse, NY USA. RP Manini, TM (reprint author), Univ Florida, Inst Aging, Dept Aging & Geriatr Res, POB 112610, Gainesville, FL 32611 USA. EM tmanini@aging.ufl.edu NR 50 TC 81 Z9 83 U1 3 U2 9 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 2007 VL 85 IS 2 BP 377 EP 384 PG 8 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 137JZ UT WOS:000244290200008 PM 17284732 ER PT J AU Ding, JZ Kritchevsky, SB Newman, AB Taaffe, DR Nicklas, BJ Visser, M Lee, JS Nevitt, M Tylavsky, FA Rubin, SM Pahor, M Harris, TB AF Ding, Jingzhong Kritchevsky, Stephen B. Newman, Anne B. Taaffe, Dennis R. Nicklas, Barbara J. Visser, Marjolein Lee, Jung Sun Nevitt, Michael Tylavsky, Frances A. Rubin, Susan M. Pahor, Marco Harris, Tamara B. CA Hlth ABC Study TI Effects of birth cohort and age on body composition in a sample of community-based elderly SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE birth cohort; age; body composition; elderly; fat; lean ID FAT-FREE MASS; SKELETAL-MUSCLE MASS; WEIGHT CHANGE; OLDER MEN; PHYSICAL-DISABILITY; MOBILITY DISABILITY; SARCOPENIC OBESITY; NHANES-I; WOMEN; ADULTS AB Background: The effect of the recent obesity epidemic on body composition remains unknown. Furthermore, age-related changes in body composition are still unclear. Objective: The objective was to simultaneously examine the effects of birth cohort and age on body composition. Design: A total of 1786 well-functioning, community-based whites and blacks (52% women and 35% blacks) aged 70-79 y from the Health, Aging, and Body Composition Study underwent dual-energy X-ray absorptiometry annually from 1997 to 2003. Results: At baseline, mean SD percentage body fat, fat mass, and lean mass (bone-free) were 28 +/- 5%, 24 +/- 7 kg, and 56 +/- 7 kg, respectively, for men and 39 +/- 6%, 28 +/- 9 kg, and 40 +/- 6 kg for women. Mixed models were used to assess the effects of cohort and age-related changes on body composition. Later cohorts in men had a greater percentage body fat(0.32% per birth year, P < 0.0001) than did earlier cohorts. This cohort effect was due to a greater increase in fat mass than in lean mass (0.45 kg and 0. 17 kg/birth year, respectively). With increasing age, percentage body fat in men initially increased and then leveled off. This age-related change was due to an accelerated decrease in lean mass and an initial increase and a later decrease in fat mass. Similar but less extreme effects of cohort and age were observed in women. Conclusions: The combination of effects of both birth cohort and age leads to bigger body size and less lean mass in the elderly. C1 Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27157 USA. Univ Pittsburgh, Dept Epidemiol, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. Univ Pittsburgh, Dept Med, Grad Sch Publ Hlth, Pittsburgh, PA 15261 USA. Univ Queensland, Sch Human Movement Studies, Brisbane, Qld, Australia. Vrije Univ Amsterdam, Inst Hlth Sci, Fac Earth & Life Sci, Amsterdam, Netherlands. Vrije Univ Amsterdam, Med Ctr, Inst Res & Extramural Med, Amsterdam, Netherlands. Univ N Carolina, Dept Biostat, Chapel Hill, NC USA. Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA 94143 USA. Univ Tennessee, Ctr Hlth Sci, Dept Prevent Med, Memphis, TN 38163 USA. Univ Florida, Dept Aging & Geriatr Res, Coll Med, Inst Aging, Gainesville, FL USA. Malcom Randall Vet Affairs Med Ctr, Geriatr Res Educ & Clin Ctr, N Florida S Georgia Vet Hlth Syst, Gainesville, FL USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. RP Ding, JZ (reprint author), Wake Forest Univ, Sch Med, Sticht Ctr Aging, Med Ctr Blvd, Winston Salem, NC 27157 USA. EM jding@wfubmc.edu RI Newman, Anne/C-6408-2013 OI Newman, Anne/0000-0002-0106-1150 FU Intramural NIH HHS; NIA NIH HHS [N01-AG-6-2106, N01-AG-6-2101, N01-AG-6-2103, P30-AG21332] NR 30 TC 50 Z9 52 U1 1 U2 3 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD FEB PY 2007 VL 85 IS 2 BP 405 EP 410 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 137JZ UT WOS:000244290200012 PM 17284736 ER PT J AU Ortega, E Pannacciulli, N Bogardus, C Krakoff, J AF Ortega, Emilio Pannacciulli, Nicola Bogardus, Clifton Krakoff, Jonathan TI Plasma concentrations of free triiodothyronine predict weight change in euthyroid persons SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE thyroid hormones; energy expenditure; lipid oxidation; obesity; respiratory chamber ID THYROID-HORMONE METABOLISM; 24-HOUR ENERGY-EXPENDITURE; TYPE-2 IODOTHYRONINE DEIODINASE; BROWN ADIPOSE-TISSUE; BODY-MASS INDEX; SYMPATHETIC ACTIVITY; PREMENOPAUSAL WOMEN; FUEL UTILIZATION; OBESE WOMEN; LEPTIN AB Background: Factors that influence energy metabolism and substrate oxidation, such as thyroid hormones (THs), may be important regulators of body weight. Objective: We investigated associations of THs cross-sectionally with obesity, energy expenditure, and substrate oxidation and prospectively with weight change. Design: Euthyroid, nondiabetic, healthy, adult Pima Indians (n = 89; 47 M, 42 F) were studied. Percentage body fat (%BF) was measured by using dual-energy X-ray absorptiometry; sleeping metabolic rate (SMR), respiratory quotient, and substrate oxidation rates were measured in a respiratory chamber. Thyroid-stimulating hormone (TSH), free thyroxine (T-4), free triiodothyronine (T-3), and leptin concentrations were measured in fasting plasma samples. Results: TSH, but neither free T-3 nor free T-4 was associated with %BF and leptin concentrations (r = 0.27 and 0.29, respectively; both: P <= 0.01). In multiple regression analyses adjusted for age, sex, fat mass, and fat-free mass, free T-3 was a positive predictor of SMR (P = 0.02). After adjustment for age, sex, %BF, and energy balance, free T-3 was a negative predictor of 24-h respiratory quotient (P < 0.05) and a positive predictor of 24-h lipid oxidation rate (P = 0.006). Prospectively, after an average follow-up of 4 +/- 2 y, the mean increase in weight was 3 +/- 9 kg. Baseline T-3 concentrations were associated with absolute and annual percentage of changes in weight (r = -0.27, P = 0.02, and r = -0.28, P = 0.009, for the ageand sex-adjusted associations, respectively). Conclusions: In euthyroid Pima Indians, lower free T-3 but not free T-4 concentrations were an independent predictor of SMR and lipid oxidation and a predictor of weight gain. This finding indicates that control of T-4-to-T-3 conversion may play a role in body weight regulation. C1 NIDDKD, Clin Diabet & Nutr Sect, Obes & Diabet Clin Res Sect,Dept Human & Hlth Ser, NIH,Phoenix Epidemiol Clin & Res Branch, Phoenix, AZ 85016 USA. RP Ortega, E (reprint author), NIDDKD, Clin Diabet & Nutr Sect, Obes & Diabet Clin Res Sect,Dept Human & Hlth Ser, NIH,Phoenix Epidemiol Clin & Res Branch, 4212 N 16Th St,Room 5-35, Phoenix, AZ 85016 USA. EM emilioo@mail.nih.gov FU Intramural NIH HHS [Z99 DK999999] NR 56 TC 20 Z9 21 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 2007 VL 85 IS 2 BP 440 EP 445 PG 6 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 137JZ UT WOS:000244290200017 PM 17284741 ER PT J AU Tsai, CJ Leitzmann, MF Willett, WC Giovannucci, EL AF Tsai, Chung-Jyi Leitzmann, Michael F. Willett, Walter C. Giovannucci, Edward L. TI Heme and non-heme iron consumption and risk of gallstone disease in men SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Article DE iron; gallstone; gallbladder; heme iron; non-heme iron; men ID MALE HEALTH-PROFESSIONALS; DIETARY IRON; LIPID-PEROXIDATION; STORES; POPULATION; FAT; SUPPLEMENTATION; REPRODUCIBILITY; QUESTIONNAIRE; DETERMINANTS AB Background: Excessive iron intake can promote biliary cholesterol crystal formation in experimental studies. The absorption of heme iron is more complete than that of non-heme iron in humans; however, the effect of long-term consumption of heme and non-heme iron on the risk of gallstones is unknown. Objective: The objective of the study was to examine long-term iron intake in relation to the occurrence of gallstone disease. Design: We prospectively studied intakes of heme and non-heme iron and the risk of gallstone disease in a cohort of 44 758 US men from 1986 to 2002. Iron consumption was assessed by using a validated semiquantitative food-frequency questionnaire. Newly diagnosed gallstone disease was ascertained biennially. Results: We documented 2468 incident cases of symptomatic gallstones during 597 699 person-years of follow-up. The age-adjusted relative risks (RRs) for men with intakes of heme iron and non-heme iron, when the highest and lowest quintiles were compared, were 1.21 (95% CI: 1.06, 1.37; P for trend = 0.0008) and 1.02 (95% CI: 0.90, 1.16; P for trend = 0.45), respectively. After adjustment for multiple potential confounding variables, when extreme quintiles were compared, the multivariate RR of heme iron intake was not significantly changed and remained significant with a dose-response relation (RR = 1.21; 95% CI: 1.03, 1.42; P for trend 0.01), and that of non-heme iron intake was not significant (RR = 1.14; 95% CI: 0.99, 1.31; P for trend = 0.18). Conclusion: Our findings suggest that a higher consumption of heme iron is associated with a greater risk of gallstone disease among men. C1 Univ Kentucky, Div Digest Dis & Nutr, Med Ctr, Lexington, KY 40536 USA. Brigham & Womens Hosp, Channing Lab, Dept Med, Boston, MA 02115 USA. Harvard Univ, Sch Med, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Nutr, Boston, MA 02115 USA. Harvard Univ, Sch Publ Hlth, Dept Epidemiol, Boston, MA 02115 USA. NCI, NIH, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Tsai, CJ (reprint author), Univ Kentucky, Div Digest Dis & Nutr, Med Ctr, 800 Rose St, Lexington, KY 40536 USA. EM hpcjt@channing.harvard.edu FU NCI NIH HHS [CA55075]; NIDDK NIH HHS [DK46200] NR 36 TC 2 Z9 2 U1 3 U2 4 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 2007 VL 85 IS 2 BP 518 EP 522 PG 5 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 137JZ UT WOS:000244290200028 PM 17284752 ER PT J AU Raiten, DJ Kalhan, SC Hay, WW AF Raiten, Daniel J. Kalhan, Satish C. Hay, William W., Jr. TI Maternal nutrition and optimal infant feeding practices: executive summary SO AMERICAN JOURNAL OF CLINICAL NUTRITION LA English DT Editorial Material DE maternal nutrition; infant feeding; NIH/USDA conference AB Much recent attention has been paid to the effect of the fetal environment on not only healthy birth outcomes but also long-term health outcomes, including a role as an antecedent to adult diseases. A major gap in our understanding of these relations, however, is the effect of maternal nutrition and nutrient transport on healthy fetal growth and development. In addition, this gap precludes evidence-based recommendations about how to best feed preterm infants. The biological role of the mother and the effect of her nutritional status on infant feeding extend to postnatal infant feeding practices. Currently, evidence is incomplete about not only the composition of human milk, but also the maternal nutritional needs to support extended lactation and the appropriate nutrient composition of foods that will be used to complement breastfeeding at least through the first year of life. Consequently, a conference, organized by the National Institute of Child Health and Human Development, the National Institutes of Health Office of Dietary Supplements, and the US Department of Agriculture Children's Nutrition Research Center was held to explore current knowledge and develop a research agenda to address maternal nutrition and infant feeding practices. These proceedings contain presentations about the effect of maternal nutrition and the placental environment on fetal growth and birth outcomes, as well as issues pertaining to feeding preterm and fullterm infants. C1 NICHD, Off Prevent Res & Int Programs, Endocrinol Nutr & Growth Branch, Ctr Res Mothers & Children,DHHS NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Cleveland Clin Fdn, Cleveland Clin, Lerner Coll Med,Dept Med, Cleveland, OH 44106 USA. Univ Colorado, Ctr Hlth Sci, Prenatal Res Ctr, Aurora, CO USA. RP Raiten, DJ (reprint author), NICHD, Off Prevent Res & Int Programs, Endocrinol Nutr & Growth Branch, Ctr Res Mothers & Children,DHHS NIH, 6100 Execut Blvd, Bethesda, MD 20892 USA. EM raitend@mail.nih.gov NR 14 TC 11 Z9 12 U1 0 U2 3 PU AMER SOC CLINICAL NUTRITION PI BETHESDA PA 9650 ROCKVILLE PIKE, SUBSCRIPTIONS, RM L-3300, BETHESDA, MD 20814-3998 USA SN 0002-9165 J9 AM J CLIN NUTR JI Am. J. Clin. Nutr. PD FEB PY 2007 VL 85 IS 2 BP 577S EP 583S PG 7 WC Nutrition & Dietetics SC Nutrition & Dietetics GA 137JZ UT WOS:000244290200036 PM 17284759 ER PT J AU Mannisto, S Yaun, SS Hunter, DJ Spiegelman, D Adami, HO Albanes, D van den Brandt, PA Buring, JE Cerhan, JR Colditz, GA Freudenheim, JL Fuchs, CS Giovannucci, E Goldbohm, RA Harnack, L Leitzmann, M McCullough, ML Miller, AB Rohan, TE Schatzkin, A Virtamo, J Willett, WC Wolk, A Zhang, SM Smith-Warner, SA AF Mannisto, Satu Yaun, Shiaw-Shyuan Hunter, David J. Spiegelman, Donna Adami, Hans-Olov Albanes, Demetrius van den Brandt, Piet A. Buring, Julie E. Cerhan, James R. Colditz, Graham A. Freudenheim, Jo L. Fuchs, Charles S. Giovannucci, Edward Goldbohm, R. Alexandra Harnack, Lisa Leitzmann, Michael McCullough, Marjorie L. Miller, Anthony B. Rohan, Thomas E. Schatzkin, Arthur Virtamo, Jarmo Willett, Walter C. Wolk, Alicja Zhang, Shumin M. Smith-Warner, Stephanie A. TI Dietary carotenoids and risk of colorectal cancer in a pooled analysis of 11 cohort studies SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE carotenoids; cohort studies; colonic neoplasms; colorectal neoplasms; diet; meta-analysis; rectal neoplasms ID FOOD FREQUENCY QUESTIONNAIRE; BETA-CAROTENE; COLON-CANCER; ALPHA-TOCOPHEROL; WOMENS HEALTH; NEW-YORK; MICRONUTRIENT INTAKE; RECTAL-CANCER; MALE SMOKERS; LUNG-CANCER AB Dietary carotenoids have been hypothesized to protect against epithelial cancers. The authors analyzed the associations between intakes of specific carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein + zeaxanthin, and lycopene) and risk of colorectal cancer using the primary data from 11 cohort studies carried out in North America and Europe. Carotenoid intakes were estimated from food frequency questionnaires administered at baseline in each study. During 6-20 years of follow-up between 1980 and 2003, 7,885 incident cases of colorectal cancer were diagnosed among 702,647 participants. The authors calculated study-specific multivariate relative risks and then combined them using a random-effects model. In general, intakes of specific carotenoids were not associated with colorectal cancer risk. The pooled multivariate relative risks of colorectal cancer comparing the highest quintile of intake with the lowest ranged from 0.92 for lutein + zeaxanthin to 1.04 for lycopene; only for lutein + zeaxanthin intake was the result borderline statistically significant (95% confidence interval: 0.84, 1.00). The associations observed were generally similar across studies, for both sexes, and for colon cancer and rectal cancer. These pooled data did not suggest that carotenoids play an important role in the etiology of colorectal cancer. C1 Natl Inst Publ Hlth, Dept Hlth Promot & Chron Dis Prevent, Helsinki 00300, Finland. Harvard Univ, Sch Publ Hlth, Boston, MA 02115 USA. Harvard Univ, Sch Med, Brigham & Womens Hosp, Boston, MA 02115 USA. Harvard Univ, Ctr Canc Prevent, Boston, MA 02115 USA. Karolinska Inst, Stockholm, Sweden. NCI, Bethesda, MD 20892 USA. Maastricht Univ, Fac Hlth Sci, Maastricht, Netherlands. Mayo Clin, Coll Med, Rochester, MN USA. SUNY Buffalo, Univ Buffalo, Buffalo, NY 14260 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. TNO Qual Life, Zeist, Netherlands. Univ Minnesota, Sch Publ Hlth, Minneapolis, MN USA. Amer Canc Soc, Atlanta, GA 30329 USA. Univ Toronto, Fac Med, Toronto, ON, Canada. Albert Einstein Coll Med, Bronx, NY 10467 USA. RP Mannisto, S (reprint author), Natl Inst Publ Hlth, Dept Hlth Promot & Chron Dis Prevent, Mannerheimintie 166, Helsinki 00300, Finland. EM satu.mannisto@ktl.fi RI Albanes, Demetrius/B-9749-2015; Colditz, Graham/A-3963-2009; OI Colditz, Graham/0000-0002-7307-0291; Cerhan, James/0000-0002-7482-178X; Mannisto, Satu/0000-0002-8668-3046 FU NCI NIH HHS [CA78548, CA55075, N01 CN45035, N01 CN45165] NR 74 TC 28 Z9 29 U1 0 U2 6 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 2007 VL 165 IS 3 BP 246 EP 255 DI 10.1093/aje/kwk009 PG 10 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 130PK UT WOS:000243811300002 PM 17158857 ER PT J AU Perkins, NJ Schisterman, EF Vexler, A AF Perkins, Neil J. Schisterman, Enrique F. Vexler, Albert TI Receiver operating characteristic curve inference from a sample with a limit of detection SO AMERICAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE censoring; curve estimation; detection; maximum likelihood; receiver operating characteristic ID ROC CURVE; POPULATIONS; PARAMETERS AB The receiver operating characteristic curve is a commonly used tool for evaluating biomarker usefulness in clinical diagnosis of disease. Frequently, biomarkers being assessed have immeasurable or unreportable samples below some limit of detection. Ignoring observations below the limit of detection leads to negatively biased estimates of the area under the curve. Several correction methods are suggested in the areas of mean estimation and testing but nothing regarding the receiver operating characteristic curve or its summary measures. In this paper, the authors show that replacement values below the limit of detection, including those suggested, result in the same biased area under the curve when properly accounted for, but they also provide guidance on the usefulness of these values in limited situations. The authors demonstrate maximum likelihood techniques leading to asymptotically unbiased estimators of the area under the curve for both normally and gamma distributed biomarker levels. Confidence intervals are proposed, the coverage probability of which is scrutinized by simulation study. An example using polychlorinated biphenyl levels to classify women with and without endometriosis illustrates the potential benefits of these methods. C1 NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, Rockville, MD 20852 USA. American Univ, Dept Math & Stat, Washington, DC 20016 USA. RP Schisterman, EF (reprint author), NICHHD, Div Epidemiol Stat & Prevent Res, NIH, Dept Hlth & Human Serv, 6100 Execut Blvd, Rockville, MD 20852 USA. EM schistee@mail.nih.gov OI Perkins, Neil/0000-0002-6802-4733; Schisterman, Enrique/0000-0003-3757-641X FU Intramural NIH HHS NR 17 TC 23 Z9 24 U1 0 U2 5 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0002-9262 J9 AM J EPIDEMIOL JI Am. J. Epidemiol. PD FEB 1 PY 2007 VL 165 IS 3 BP 325 EP 333 DI 10.1093/aje/kwk011 PG 9 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 130PK UT WOS:000243811300012 PM 17110640 ER PT J AU DeChristoforo, R Gamble-Bowen, S Daniels, CE AF DeChristoforo, Robert Gamble-Bowen, Sharon Daniels, Charles E. TI Improving communication using an electronic bulletin board SO AMERICAN JOURNAL OF HEALTH-SYSTEM PHARMACY LA English DT Editorial Material C1 NIH, Dept Pharm, Ctr Clin, Bethesda, MD 20892 USA. NIH, Dept Clin Res & Informat, Ctr Clin, Bethesda, MD 20892 USA. Univ Calif San Diego, Skaggs Sch Pharm & Pharmaceut Sci, San Diego, CA 92093 USA. RP DeChristoforo, R (reprint author), NIH, Dept Pharm, Ctr Clin, Bldg 10,Room 1N-257,MSC-1196, Bethesda, MD 20892 USA. EM rdechristo@nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU AMER SOC HEALTH-SYSTEM PHARMACISTS PI BETHESDA PA 7272 WISCONSIN AVE, BETHESDA, MD 20814 USA SN 1079-2082 J9 AM J HEALTH-SYST PH JI Am. J. Health-Syst. Pharm. PD FEB 1 PY 2007 VL 64 IS 3 BP 245 EP + DI 10.2146/ajhp060457 PG 4 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 134IB UT WOS:000244075600013 PM 17244873 ER PT J AU Bryant, BJ Alperin, JB Elghetany, MT AF Bryant, Barbara J. Alperin, Jack B. Elghetany, M. Tarek TI Paraplegia as the presenting manifestation of extramedullary megakaryoblastic transformation of previously undiagnosed chronic myelogenous leukemia SO AMERICAN JOURNAL OF HEMATOLOGY LA English DT Article DE paraplegia; chronic myelogenous leukemia; granulocytic sarcoma; mega-karyocytic leukemia ID SPINAL-CORD COMPRESSION; MYELOID-LEUKEMIA; GRANULOCYTIC SARCOMA; CHLOROMA; SYMPTOMS AB Extramedullary tumors, also known as granulocytic sarcomas (GS), occur most frequently in acute myelogenous leukemia (AML). They may signal the onset of the accelerated phase of chronic myelogenous leukemia (CIVIL) or the blastic transformation of a myeloproliferative disorder. Occasionally, a GS may be the presenting sign of undiagnosed AML, and rarely the presenting sign of undiagnosed CIVIL or aleukemic leukemia. Paraplegia due to a spinal cord GS is an extremely rare presentation of undiagnosed leukemia. This is the first case report of paraplegia as the presenting manifestation of extramedullary megakaryoblastic transformation of previously undiagnosed CIVIL A 53-year-old woman reported back pain for 6 days, rapidly progressing to paraplegia. Physical examination noted a large abdominal mass and flaccid paralysis in both lower extremities. Spinal MRI revealed a T4-T6 vertebral mass causing spinal stenosis and cord compression. Tumor clebulking and laminectomy were performed emergently. The tumor consisted of noncohesive blast cells. The CBC revealed a leukocyte count of 238,300/mu l and a differential consistent with CIVIL Reexamination of the patient found that the abdominal mass was a giant spleen. Further immunohistochemical studies of the tumor were consistent with extramedullary acute megakaryoblastic blast transformation of CIVIL. Although extramedullary blast crises herald the accelerated phases in similar to 10% of CIVIL cases, megakaryoblastic blast transformation of CIVIL accounts for less than 3% of these cases. The combination of acute paraplegia and megakaryoblastic transformation in a previously undiagnosed patient with CIVIL is extremely rare and may pose a diagnostic dilemma. (c) 2006 Wiley-Liss, Inc. C1 Univ Texas, Med Branch, Dept Pathol, Galveston, TX 77550 USA. Univ Texas, Med Branch, Dept Internal Med, Galveston, TX 77550 USA. RP Bryant, BJ (reprint author), Warren G Magnuson Clin Ctr, Dept Transfus Med, NIH, 10 Ctr Dr,MSC-1184,Bldg 10,Room 1C711, Bethesda, MD 20892 USA. EM bryantb2@cc.nih.gov NR 38 TC 4 Z9 5 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0361-8609 J9 AM J HEMATOL JI Am. J. Hematol. PD FEB PY 2007 VL 82 IS 2 BP 150 EP 154 DI 10.1002/ajh.20777 PG 5 WC Hematology SC Hematology GA 127GN UT WOS:000243573600009 PM 17019692 ER PT J AU Sharabi, Y Oron-Herman, M Kamari, Y Avni, I Peleg, E Shabtay, Z Grossman, E Shamiss, A AF Sharabi, Yehonatan Oron-Herman, Mor Kamari, Yehuda Avni, Irit Peleg, Edna Shabtay, Zehava Grossman, Ehud Shamiss, Arie TI Effect of PPAR-gamma agonist on adiponectin levels in the metabolic syndrome: Lessons from the high fructose fed rat model SO AMERICAN JOURNAL OF HYPERTENSION LA English DT Article DE metabolic syndrome; adiponectin; PPAR gamma; rosiglitazone ID INSULIN-RESISTANCE SYNDROME; TYPE-2 DIABETES-MELLITUS; CARDIOVASCULAR-DISEASE; OBESITY; RISK; HYPERTENSION; EXPRESSION; ADIPOCYTOKINES; ADOLESCENTS; PROTEIN AB Background: The health hazard of the metabolic syndrome (MS) is increasing, yet there is no effective pharmacologic treatment to this entity as a whole. Recently, hypoadiponectinemia was found to play an important role in the development of MS. We studied the effect of the PPAR-gamma agonist rosiglitazone on adiponectin and the metabolic profile in the fructose-induced hypertensive, hyperinsulinemic, hypertriglyceridemic rat model. Methods: Thirty male Sprague-Dawley rats were divided into three groups. Ten were fed standard rat chow for 5 weeks, 10, a fructose-enriched diet for 5 weeks, and 10, a fructose-enriched diet for 5 weeks, with rosiglitazone 10 mg/kg/d added during the last 2 weeks. Blood pressure (BP), oral glucose tolerance test (OGTT), plasma insulin, triglycerides, and adiponectin were recorded, as well as mRNA levels of the adiponectin gene in visceral adipose tissue. Results: Fructose-fed rats developed MS as manifested by the increase in systolic BP (from 139 +/- 3 to 158 4 turn Hg, P < .05), insulin (from 26 +/- 1.6 to 40 +/- 2.5 mu U/mL, P < .05), triglycerides (from 91 +/- 9 to 304 +/- 24 mg/dL, P < .05), and impaired OGTT (area under the curve from 13,894 +/- 246 to 17,725 +/- 700 mg/dL/min). Treatment with rosiglitazone reversed these effects and reduced BP to 133 +/- 7 mm Hg, insulin levels to 30 +/- 2.8 mu U/mL, triglycerides to 116 +/- 9 mg/dL, and the OGTT to 15,415 372 mg/dL/min (P < .05 for all variables). In addition, rosiglitazone increased plasma levels of adiponectin fourfold from 4.3 +/- 0.1 to 18.4 +/- 0.6 mu g/mL (P < .05). This increase was coupled with 3.8-fold increase in adiponectin mRNA in visceral adipose tissue. Conclusions: This study shows for the first time that in an animal model of MS, the insulin sensitizer, rosiglitazone, improves the metabolic profile and increases plasma levels of adiponectin and its gene expression. It is possible therefore that rosiglitazone exerts its beneficial effects by increasing the levels of adiponectin. Am J Hypertens 2007;20:206-210 (c) 2007 American Journal of Hypertension, Ltd. C1 C Sheba Med Ctr, Hypertens Unit, IL-52621 Tel Hashomer, Israel. Natl Inst Neurol Disorders & Stroke, NIH, Bethesda, MD USA. RP Sharabi, Y (reprint author), C Sheba Med Ctr, Hypertens Unit, IL-52621 Tel Hashomer, Israel. EM sharabiy@sheba.health.gov.il OI Grossman, Ehud/0000-0001-8353-0661 NR 30 TC 55 Z9 59 U1 0 U2 3 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0895-7061 J9 AM J HYPERTENS JI Am. J. Hypertens. PD FEB PY 2007 VL 20 IS 2 BP 206 EP 210 DI 10.1016/j.amjhyper.2006.08.002 PG 5 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 138TA UT WOS:000244384200016 PM 17261469 ER PT J AU Peplonska, B Stewart, P Szeszenia-Dabrowska, N Rusiecki, J Garcia-Closas, M Lissowska, J Bardin-Mikolajczak, A Zatonski, W Gromiec, J Brzeznicki, S Brinton, LA Blair, A AF Peplonska, Beata Stewart, Patricia Szeszenia-Dabrowska, Neonila Rusiecki, Jennifer Garcia-Closas, Montserrat Lissowska, Jolanta Bardin-Mikolajczak, Alicja Zatonski, Witold Gromiec, Jan Brzeznicki, Slawomir Brinton, Louise A. Blair, Aaron TI Occupation and breast cancer risk in Polish women: A population-based case-control study SO AMERICAN JOURNAL OF INDUSTRIAL MEDICINE LA English DT Article DE breast cancer; occupation; industry; risk factors ID CAPACITOR MANUFACTURING WORKERS; PLASMA ORGANOCHLORINE LEVELS; POLYCHLORINATED-BIPHENYLS; UNITED-STATES; PHYSICAL-ACTIVITY; MAGNETIC-FIELDS; ELECTROMAGNETIC-FIELDS; REGISTERED NURSES; PRINTING INDUSTRY; BRITISH-COLUMBIA AB Background The etiology of breast cancer is not well understood and the role of occupational exposures in breast carcinogenesis is still uncertain. Methods The population-based case-control study included 2,386 incident breast cancer cases diagnosed in 2000-2003, and 2,502 controls. Lifetime occupational histories and information on other potential breast cancer riskjactors were obtained through personal interviews. Conditional logistic regression analyses calculated odds ratios (ORs) associated with various occupations and industries after control for potential confounders. Results We found statistically significant excesses of breast cancer among engineers (OR=2.0; 95% CP 1.0-3.8), economists (2.1; 1.1-3.8), sales occupations-retail (1.2; 1.0-1.5), and other sales occupations (1.2; 1.0-1.5). Industries showing significantly elevated risks included special trade contractors (2.2; 1.2-4.3), electronic and electric equipment manufacturers (1.7; 1.1-2.7); and public administration/general government n.e.c. (2.7; 1.3-5.7). Each of these findings was supported by a statistically significant positive trend for duration of employment (P < 0.05). A decreased breast cancer risk was observed in janitors and cleaners (0. 7; 0.5-0.8). Conclusions In this study, we found few associationsfor breast cancer and occupations or industries. The suggestive findings for the electronic and electric equipment manufacturing industry and for the occupations with potential exposure to magnetic fields deserve further evaluation. C1 Nofer Inst Occupat Med, Dept Occupat & Environm Epidemiol, PL-91348 Lodz, Poland. NCI, Occupat & Environm Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Dept Prevent Med & Biometr, Bethesda, MD USA. NCI, Hormonal & Reprod Epidemiol Branch, NIH, Bethesda, MD 20892 USA. Ctr Canc, Div Canc Epidemiol & Prevent, Warsaw, Poland. M Sklodowska Curie Inst Oncol, Warsaw, Poland. Nofer Inst Occupat Med, Dept Chem Hazards, Lodz, Poland. RP Peplonska, B (reprint author), Nofer Inst Occupat Med, Dept Occupat & Environm Epidemiol, 8 Teresy St, PL-91348 Lodz, Poland. EM beatap@imp.lodz.pl RI BRZEZNICKI, SLAWOMIR/G-4762-2010; Gromiec, Jan/G-4938-2010; Peplonska, Beata/F-6004-2010; Szeszenia-Dabrowska, Neonila/F-7190-2010; Garcia-Closas, Montserrat /F-3871-2015; Brinton, Louise/G-7486-2015; OI Garcia-Closas, Montserrat /0000-0003-1033-2650; Brinton, Louise/0000-0003-3853-8562; Lissowska, Jolanta/0000-0003-2695-5799 FU Intramural NIH HHS; NCI NIH HHS [N01-CP-91013] NR 65 TC 10 Z9 11 U1 1 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0271-3586 J9 AM J IND MED JI Am. J. Ind. Med. PD FEB PY 2007 VL 50 IS 2 BP 97 EP 111 DI 10.1002/ajim.20420 PG 15 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 134KB UT WOS:000244080800003 PM 17238140 ER PT J AU Zhu, XL Wu, SH Dahut, WL Parikh, CR AF Zhu, Xiaolei Wu, Shenhong Dahut, William L. Parikh, Chirag R. TI Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: Systematic review and meta-analysis SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE bevacizumab; vascular enclothelial growth factor (VEGF); anti-VEGF antibody; cancer; hypertension; proteinuria ID METASTATIC COLORECTAL-CANCER; PHASE-II TRIAL; RANDOMIZED-TRIAL; FLUOROURACIL; LEUCOVORIN; THERAPY; ANGIOGENESIS; PREECLAMPSIA; COMBINATION; RECEPTOR-1 AB Background: Angiogenesis inhibitors have emerged as an effective targeted therapy in the treatment of patients with many cancers. One of the most widely used angiogenesis inhibitors is bevacizumab, a neutralizing antibody against vascular endothelial growth factor. The overall risk of proteinuria and hypertension in patients with cancer on bevacizumab therapy is unclear. We performed a systematic review and meta-analysis of published clinical trials of bevacizumab to quantify the risk of proteinuria and hypertension. Methods: The databases MEDLINE (OVID, 1966 to June 2006) and Web of Science and abstracts presented at the American Society of Clinical Oncology annual meetings from 2004 through 2006 were searched to identify relevant studies. Eligible studies were randomized controlled trials of patients with cancer treated with bevacizumab that described the incidence of proteinuria and hypertension. Relative risk (RR) was calculated by using the fixed-effects model. Results: A total of 1,850 patients were included in the 7 trials identified from the literature. Bevacizumab was associated with a significant increased risk of proteinuria (RR, 1.4 with low-dose bevacizumab; 95% confidence interval [Cl], 1.1 to 1.7; FIR, 2.2 with high dose; 95% Cl, 1.6 to 2.9). Hypertension also was increased significantly among patients receiving bevacizumab (FIR, 3.0 for low dose; 95% Cl, 2.2 to 4.2; FIR, 7.5 for high dose; 95% Cl, 4.2 to 13.4). Conclusion: There was a significant dose-dependent increase in risk of proteinuria and hypertension in patients with cancer who received bevacizumab. C1 Stony Brook Univ Hosp, Hlth Sci Ctr, Stony Brook, NY 11794 USA. SUNY Stony Brook, Div Nephrol & Oncol, New York, NY USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. Yale Univ, Nephrol Sect, West Haven, CT USA. VAMC, West Haven, CT USA. RP Zhu, XL (reprint author), Stony Brook Univ Hosp, Hlth Sci Ctr, T16,Rm080, Stony Brook, NY 11794 USA. EM xiaolei.zhu@stonybrook.edu NR 29 TC 317 Z9 336 U1 1 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD FEB PY 2007 VL 49 IS 2 BP 186 EP 193 DI 10.1053/j.ajkd.2006.11.039 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 197PJ UT WOS:000248567500004 PM 17261421 ER PT J AU Xu, JQ Knowler, WC Devereux, RB Yeh, JL Umans, JG Begum, M Fabsitz, RR Lee, ET AF Xu, Jiaqiong Knowler, William C. Devereux, Richard B. Yeh, Jeunliang Umans, Jason G. Begum, Momotaz Fabsitz, Richard R. Lee, Elisa T. TI Albuminuria within the "Normal" range and risk of cardiovascular disease and death in American Indians: The strong heart study SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE albuminuria; urinary albumin-creatinine; cardiovascular disease; death ID ALL-CAUSE MORTALITY; LEFT-VENTRICULAR HYPERTROPHY; NONDIABETIC INDIVIDUALS; DIABETES-MELLITUS; MICROALBUMINURIA; HYPERTENSION; EVENTS; LIFE; PROTEINURIA; POPULATION AB Background: "Normal" albuminuria has been defined as urinary albumin-creatinine ratio (UACR) less than 30 mg/g (3.4 mg/mmol). Whether higher UACR within this range independently predicts cardiovascular disease (CVD) and CVD death is uncertain. Methods: A total of 3,000 participants aged 45 to 74 years with a UACR less than 30 mg/g and free of CVD at the baseline examination of the Strong Heart Study (SHS) were evaluated. Survival time was calculated from the baseline examination to the first nonfatal CVD, fatal CVD, or December 31, 2002. Results: During follow-up (average, 10.4 years), 383 incident nonfatal CVD and 145 fatal CVD cases were ascertained. After adjustment for conventional CVD risk factors, participants with a UACR in the third (UACR >= 5.4 to < 10.2 mg/g [>= 0.6 to < 1.1 mg/mmol] in men, >= 7.6 to < 12.9 mg/g [>= 0.9 to < 1.4 mg/mmol] in women) and the fourth (UACR >= 10.2 to < 30 mg/g in men, >= 12.9 to < 30 mg/g in women) quartiles had 41% and 72% greater risks of all CVD events and 118% and 199% greater risks of CVD mortality than those in the lowest quartile (UACR < 2.7 mg/g [< 0.3 mg/mmol] in men, < 4.3 mg/g [< 0.5 mg/mmol] in women), respectively. In subgroup analysis, these associations were more pronounced in persons with diabetes. Conclusion: In the SHS cohort of middle-aged to elderly American Indians, albuminuria levels less than the traditional cutoff value predict CVD. Our findings agree with a growing number of studies questioning the concept that UACR less than 30 mg/g is normal. C1 Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, Oklahoma City, OK 73190 USA. NIDDK, NIH, Phoenix, AZ USA. Cornell Univ, Med Ctr, New York, NY 10021 USA. MedStar Res Inst, Penn Med Lab, Washington, DC USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Xu, JQ (reprint author), Univ Oklahoma, Hlth Sci Ctr, Coll Publ Hlth, Ctr Amer Indian Hlth Res, 801 NE 13st St,Rm 112, Oklahoma City, OK 73190 USA. EM susan-xu@ouhsc.edu FU Intramural NIH HHS; NHLBI NIH HHS [U01-HL-41642, U01-HL-41652, UL01-HL-41654] NR 27 TC 29 Z9 29 U1 1 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD FEB PY 2007 VL 49 IS 2 BP 208 EP 216 DI 10.1053/j.ajkd.2006.10.017 PG 9 WC Urology & Nephrology SC Urology & Nephrology GA 197PJ UT WOS:000248567500006 PM 17261423 ER PT J AU Cho, ME Hurley, JK Kopp, JB AF Cho, Monique E. Hurley, John K. Kopp, Jeffrey B. TI Sirolimus therapy of focal segmental glomerulosclerosis is associated with nephrotoxicity SO AMERICAN JOURNAL OF KIDNEY DISEASES LA English DT Article DE proteinuria; fibrosis; glomerular filtration rate; drug toxicity ID ACUTE RAPAMYCIN NEPHROTOXICITY; RENAL-TRANSPLANT RECIPIENTS; CELL-PROLIFERATION; IN-VITRO; PROTEINURIA; CYCLOSPORINE; FIBROSIS; MODEL; TURNOVER; INJURY AB To evaluate the safety and efficacy of sirolimus in treating patients with focal segmental glomerulosclerosis (FSGS), we performed a phase 2, open-label clinical trial. Inclusion criteria were adults and children 13 years and older with biopsy-proven idiopathic FSGS, proteinuria with protein of 3.5 g/d or greater while on angiotensin antagonist therapy, glomerular filtration rate(GFR)of 30mL/min/1.73 m(2) or greater (>= 0.50 mL/s), and failure to achieve sustained remission with at least 1 immunosuppressive agent. Eligible patients received sirolimus doses adjusted to achieve trough levels of 5 to 15 ng/mL during the first 4 months and 10 to 20 ng/mL for the subsequent 8 months. The primary outcome was decrease in proteinuria, expressed as complete remission (protein < 0.3 g/d) or partial remission (protein >= 50% decrease and < 3.5 g/d). Six adult patients with FSGS were enrolled in the study; they had median disease duration of 4.0 years, mean age of 39 +/- 11 years, mean baseline Modification of Diet in Renal Disease-estimated GFR of 52 +/- 15 mL/min/1.73 m(2) (0.87 +/- 0.25 mL/s), and median baseline proteinuria with protein of 6.6 g/d (interquartile range, 4.2 to 9.4). Five patients had received cyclosporine. No patient experienced a complete or partial remission. Sirolimus therapy was stopped prematurely in 5 patients for the following reasons: (1) precipitous decrease in GFR in 4 patients after 7 to 9 months of therapy with a greater than 2-fold increase in proteinuria in 3 patients and (2) hypertriglyceridemia with triglyceride levels greater than 1,600 mg/dL (> 18 mmol/L) at 5 months in 1 patient. Because of a rapid decrease in GFR with worsening proteinuria, the protocol was closed to further recruitment. We conclude that sirolimus may be associated with nephrotoxicity in some patients with FSGS, particularly those with prolonged disease duration and prior cyclosporine therapy. C1 NIDDK, NIH, Kidney Dis Sect, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Cho, ME (reprint author), NIDDK, NIH, Kidney Dis Sect, Dept Hlth & Human Serv, 10-3N112, Bethesda, MD 20892 USA. EM moniquec@intra.niddk.nih.gov OI Kopp, Jeffrey/0000-0001-9052-186X FU Intramural NIH HHS NR 32 TC 37 Z9 43 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0272-6386 J9 AM J KIDNEY DIS JI Am. J. Kidney Dis. PD FEB PY 2007 VL 49 IS 2 BP 310 EP 317 DI 10.1053/j.ajkd.2006.10.020 PG 8 WC Urology & Nephrology SC Urology & Nephrology GA 197PJ UT WOS:000248567500017 PM 17261434 ER PT J AU Parravicini, E Baccarelli, A Wung, JT Kolobow, T Lorenz, JM AF Parravicini, Elvira Baccarelli, Andrea Wung, Jen Tien Kolobow, Theodor Lorenz, John M. TI A comparison of a new, ultrathin-walled two-stage twin endotracheal tube and a conventional endotracheal tube in very premature infants with respiratory distress syndrome: A pilot study SO AMERICAN JOURNAL OF PERINATOLOGY LA English DT Article ID MECHANICAL VENTILATION AB This was a pilot study to test the feasibility of use of the ultrathin-walled two-stage twin endotracheal tube (UTTS-T-ETT), with one half to one third the resistance to gas flow and one third to one seventh the dead space of a conventional tracheal tube, in very premature infants. Twenty-eight infants with gestational age 24 to 28 weeks and birthweight >= 500 g with respiratory distress syndrome requiring intubation and mechanical ventilation were randomly assigned to be intubated with either the UTTS-T-ETT (13 infants) or with a conventional ETT (15 infants). The infants in the two groups were similar in GA, birthweight, age of entry in the study, and initial ventilator settings. Indications for intubation and extubation were standardized. To evaluate the feasibility of the UTTS-T-ETT, complications with insertion of the endotracheal tube, traumatic injury of the upper airway, number of accidental extubations, number of re-intubations after attempted extubation, number of x-ray/days of mechanical ventilation, prevalence of atelectasis, prevalence of air-leak syndrome, duration of ventilation, bronchopulmonary dysplasia, length of stay, and mortality in the two groups were compared. No significant differences in the outcomes were observed. Specifically, no complications during intubation or traumatic injury of the upper airway due to indwelling ETT were observed in either group. The proportion of failed extubation attempts was 7% in the UTTS-T-ETT v 40% in the conventional ETT group (p = 0.08). The use of the UTTS-T-ETT is feasible in preterm infants. There was no difference in adverse events associated with its use compared with a conventional ETT. Given the proven in vitro advantages and a favorable trend toward facilitation of extubation in this pilot study, a larger randomized trial to assess clinical benefit and confirm safety is indicated. C1 Columbia Univ, Coll Phys & Surg, Dept Pediat, New York, NY 10032 USA. New York Presbyterian, Morgan Stanley Childrens Hosp, New York, NY USA. Univ Milan, Osped Maggiore, IRCCS, EPOCA Epidemiol Res Ctr, Milan, Italy. Harvard Univ, Sch Publ Hlth, Exposure Epidemiol & Risk Program, Boston, MA 02115 USA. NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. RP Parravicini, E (reprint author), Columbia Univ, Coll Phys & Surg, Dept Pediat, 3959 Broadway,CHN 1213, New York, NY 10032 USA. OI Baccarelli, Andrea/0000-0002-3436-0640 NR 8 TC 5 Z9 5 U1 0 U2 1 PU THIEME MEDICAL PUBL INC PI NEW YORK PA 333 SEVENTH AVE, NEW YORK, NY 10001 USA SN 0735-1631 J9 AM J PERINAT JI Am. J. Perinatol. PD FEB PY 2007 VL 24 IS 2 BP 117 EP 122 DI 10.1055/s-2007-970082 PG 6 WC Obstetrics & Gynecology; Pediatrics SC Obstetrics & Gynecology; Pediatrics GA 142KH UT WOS:000244647800008 PM 17304419 ER PT J AU Johnson, DT Harris, RA Blair, PV Balaban, RS AF Johnson, D. Thor Harris, Robert A. Blair, Paul V. Balaban, Robert S. TI Functional consequences of mitochondrial proteome heterogeneity SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE oxidative phosphorylation; liquid chromatography; mass spectrometry; electrophoresis; histone; liver; heart; kidney; brain ID PYRUVATE-DEHYDROGENASE COMPLEX; COA-TRANSFERASE; INNER MEMBRANE; AMINO-ACIDS; ARGINASE-II; PHOSPHORYLATION; METABOLISM; PROTEINS; PATHWAY; UREA AB Potential functional consequences of the differences in protein distribution between the mitochondria of the rat liver, heart, brain, and kidney, as determined in the companion paper in this issue (Johnson DT, French S, Blair PV, You JS, Bemis KG, Wang M, Harris RA, and Balaban RS. The tissue heterogeneity of the mammalian mitochondrial proteome. Am J Physiol Cell Physiol 292: C689 - C697, 2006), were analyzed using a canonical metabolic pathway approach as well as a functional domain homology analysis. These data were inserted into the Kyoto Encyclopedia of Genes and Genomes pathway framework to give global and metabolic pathway-specific information on the impact of the differential protein distribution on mitochondrial function. Custom pathway analysis was also performed using pathways limited to the mitochondrion. With the use of this approach, several well-known functional differences between these mitochondrial populations were confirmed. These included GABA metabolism in the brain, urea synthesis in the liver, and the domination of oxidative phosphorylation in the heart. By comparing relative protein amounts of mitochondria across tissues, a greater understanding of functional emphasis is possible as well as the nuclear "programming" required to enhance a given function within the mitochondria. For proteins determined to be mitochondrial and lacking a defined role functional domain BLAST analyses were performed. Several proteins associated with DNA structural modification and a novel CoA transferase were identified. A protein was also identified capable of catalyzing the first three steps of de novo pyrimidine synthesis. This analysis demonstrates that the distribution of nuclear encoded proteins significantly modifies the overall functional emphasis of the mitochondria to meet tissue-specific needs. These studies demonstrate the existence of mitochondrial biochemical functions that at present are poorly defined. C1 NHLBI, Lab Cardiac Energet, NIH, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA. RP Johnson, DT (reprint author), NHLBI, Lab Cardiac Energet, NIH, 10 Ctr Dr,Room B1D416, Bethesda, MD 20892 USA. EM johnsondt@nhlbi.nih.gov FU Intramural NIH HHS; NIDDK NIH HHS [DK-47844] NR 51 TC 48 Z9 50 U1 1 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD FEB PY 2007 VL 292 IS 2 BP C698 EP C707 DI 10.1152/ajpcell.00109.2006 PG 10 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 135RQ UT WOS:000244171100007 PM 16971502 ER PT J AU Johnson, DT Harris, RA French, S Blair, PV You, J Bemis, KG Wang, M Balaban, RS AF Johnson, D. Thor Harris, Robert A. French, Stephanie Blair, Paul V. You, Jinsam Bemis, Kerry G. Wang, Mu Balaban, Robert S. TI Tissue heterogeneity of the mammalian mitochondrial proteome SO AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY LA English DT Article DE structural proteins; oxidative phosphorylation; liquid chromatography; mass spectrometry; electrophoresis; histone; liver; heart; kidney; brain ID ACID DEHYDROGENASE COMPLEX; SACCHAROMYCES-CEREVISIAE; BOVINE HEART; ALPHA; YEAST; PROTEINS; IMPORT; PURIFICATION; CONTRACTION; MUTATION AB The functionality of the mitochondrion is primarily determined by nuclear encoded proteins. The mitochondrial functional requirements of different tissues vary from a significant biosynthetic role (liver) to a primarily energy metabolism-oriented organelle (heart). The purpose of this study was to compare the mitochondrial proteome from four different tissues of the rat, brain, liver, heart, and kidney, to provide insight into the extent of mitochondrial heterogeneity and to further characterize the overall mitochondrial proteome. Mitochondria were isolated, solubilized, digested, and subjected to quantitative liquid chromatography-mass spectroscopy. Of the 16,950 distinct peptides detected, 8,045 proteins were identified. High-confidence identification threshold was reached by 1,162 peptides, which were further analyzed. Of these 1,162 proteins, 1,149 were significantly different in content (P and q values < 0.05) between at least 2 tissues, whereas 13 were not significantly different between any tissues. Confirmation of the mitochondrial origin of proteins was determined from the literature or via NH(2)-terminal mitochondrial localization signals. With these criteria, 382 proteins in the significantly different groups were confirmed to be mitochondrial, and 493 could not be confirmed to be mitochondrial but were not definitively localized elsewhere in the cell. A total of 145 proteins were assigned to the rat mitochondrial proteome for the first time via their NH(2)-terminal mitochondrial localization signals. Among the proteins that were not significantly different between tissues, three were confirmed to be mitochondrial. Most notable of the significantly different proteins were histone family proteins and several structural proteins, including tubulin and intermediate filaments. The mitochondrial proteome from each tissue had very specific characteristics indicative of different functional emphasis. These data confirm the notion that mitochondria are tuned by the nucleus for specific functions in different tissues. C1 NHLBI, Lab Cardiac Energet, NIH, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46204 USA. RP Balaban, RS (reprint author), NHLBI, Lab Cardiac Energet, NIH, 10 Ctr Cr,Room B1D416, Bethesda, MD 20892 USA. EM rsb@nih.gov RI Balaban, Robert/A-7459-2009 OI Balaban, Robert/0000-0003-4086-0948 NR 36 TC 99 Z9 105 U1 1 U2 5 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0363-6143 J9 AM J PHYSIOL-CELL PH JI Am. J. Physiol.-Cell Physiol. PD FEB PY 2007 VL 292 IS 2 BP C689 EP C697 DI 10.1152/ajpcell.00108.2006 PG 9 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 135RQ UT WOS:000244171100006 PM 16928776 ER PT J AU Shah, YM Morimura, K Gonzalez, FJ AF Shah, Yatrik M. Morimura, Keiichirou Gonzalez, Frank J. TI Expression of peroxisome proliferator-activated receptor-gamma in macrophage suppresses experimentally induced colitis SO AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY LA English DT Article DE CC chemokine receptor 2; macrophages ID INFLAMMATORY-BOWEL-DISEASE; NITRIC-OXIDE SYNTHASE; SULFATE-MEDIATED COLITIS; PPAR-GAMMA; INSULIN-RESISTANCE; GENE-EXPRESSION; DEFICIENT MICE; IN-VIVO; INTESTINAL INFLAMMATION; CHEMOKINE RECEPTOR-2 AB Peroxisome proliferatoractivated receptor-gamma ( PPAR-gamma) has been shown to be a protective transcription factor in mouse models of inflammatory bowel disease ( IBD). PPAR-gamma is expressed in several different cell types, and mice with a targeted disruption of the PPAR-gamma gene in intestinal epithelial cells demonstrated increased susceptibility to dextran sulfate sodium ( DSS)- induced IBD. However, the highly selective PPAR-gamma ligand rosiglitazone decreased the severity of DSS-induced colitis and suppressed cytokine production in both PPAR-gamma intestinal specific null mice and wild-type littermates. Therefore the role of PPAR-gamma in different tissues and their contribution to the pathogenesis of IBD still remain unclear. Mice with a targeted disruption of PPAR-gamma in macrophages (PPAR-gamma(Delta M phi)) and wild-type littermates (PPAR-gamma(F/F)) were administered 2.5% DSS in drinking water to induce IBD. Typical clinical symptoms were evaluated on a daily basis, and proinflammatory cytokine analysis was performed. PPAR-gamma(Delta M phi) mice displayed an increased susceptibility to DSS-induced colitis compared with wildtype littermates, as defined by body weight loss, diarrhea, rectal bleeding score, colon length, and histology. IL-1 beta, CCR2, MCP-1, and inducible nitric oxide synthase mRNA levels in colons of PPAR gamma(Delta M phi) gamma(Delta M phi) mice treated with DSS were higher than in similarly treated PPAR-gamma(F/F) mice. The present study has identified a novel protective role for macrophage PPAR-gamma in the DSS- induced IBD model. The data suggest that PPAR-gamma regulates recruitment of macrophages to inflammatory foci in the colon. C1 NCI, Canc Res Ctr, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Gonzalez, FJ (reprint author), NCI, Canc Res Ctr, Lab Metab, NIH, Bldg 37,Rm 3106, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov FU Intramural NIH HHS; NCI NIH HHS [Z01 BC005708-14] NR 53 TC 63 Z9 65 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0193-1857 J9 AM J PHYSIOL-GASTR L JI Am. J. Physiol.-Gastroint. Liver Physiol. PD FEB PY 2007 VL 292 IS 2 BP G657 EP G666 DI 10.1152/ajpgi.00381.2006 PG 10 WC Gastroenterology & Hepatology; Physiology SC Gastroenterology & Hepatology; Physiology GA 134NT UT WOS:000244090800025 PM 17095756 ER PT J AU Shen, JB Cronin, C Sonin, D Joshi, BV Nieto, MG Harrison, D Jacobson, KA Liang, BT AF Shen, Jian-Bing Cronin, Chunxia Sonin, Dmitry Joshi, Bhalchandra V. Nieto, Maria Gongora Harrison, David Jacobson, Kenneth A. Liang, Bruce T. TI P2X purinergic receptor-mediated ionic current in cardiac myocytes of calsequestrin model of cardiomyopathy: implications for the treatment of heart failure SO AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY LA English DT Article DE ion channels; membrane current; mouse; heart ID ADENINE-NUCLEOTIDE ANALOGS; VENTRICULAR MYOCYTES; EXTRACELLULAR ATP; OVEREXPRESSING CALSEQUESTRIN; POTENCY ANTAGONIST; HYPERTROPHY; CALCIUM; MICE; CONFORMATION; EXPRESSION AB P2X purinergic receptor-mediated ionic current in cardiac myocytes of calsequestrin model of cardiomyopathy: implications for the treatment of heart failure. Am J Physiol Heart Circ Physiol 292: H1077 - H1084, 2007. First published October 13, 2006; doi: 10.1152/ajpheart. 00515.2006. - P2X purinergic receptors, activated by extracellular ATP, mediate a number of cardiac cellular effects and may be important under pathophysiological conditions. The objective of the present study was to characterize the P2X receptor-mediated ionic current and determine its role in heart failure using the calsequestrin (CSQ) model of cardiomyopathy. Membrane currents under voltage clamp were determined in myocytes from both wild-type (WT) and CSQ mice. The P2X agonist 2-methylthio-ATP (2-meSATP) induced an inward current that was greater in magnitude in CSQ than in WT ventricular cells. The novel agonist, MRS-2339, an N-methanocarba derivative of 2-chloro- AMP relatively resistant to nucleotidase, induced a current in the CSQ myocyte similar to that by 2-meSATP. When administered via a miniosmotic pump (Alzet), it significantly increased longevity compared with vehicle-injected mice ( log rank test, P = 0.02). The improvement in survival was associated with decreases in the heart weight-to-body weight ratio and in cardiac myocyte cross-sectional area [MRS-2339-treated mice: 281 +/- 15.4 (SE) mu m(2), n = 6 mice vs. vehicle-treated mice: 358 +/- 27.8 mu m(2), n = 6 mice, P < 0.05]. MRS-2339 had no vasodilator effect in mouse aorta ring preparations, indicating that its salutary effect in heart failure is not because of any vascular unloading. The cardiac P2X current is upregulated in the CSQ heart failure myocytes. Chronic administration of a nucleotidase-resistant agonist confers a beneficial effect in the CSQ model of heart failure, apparently via an activation of the cardiac P2X receptor. Cardiac P2X receptors represent a novel and potentially important therapeutic target for the treatment of heart failure. C1 Univ Connecticut, Ctr Hlth, Dept Cardiol, Pat & Jim Calhoun Cardiol Ctr, Farmington, CT 06030 USA. NIDDK, Mol Recognit Sect, Bioorgan Chem Lab, NIH, Bethesda, MD USA. Emory Univ, Sch Med, Div Cardiovasc, Atlanta, GA 30322 USA. RP Liang, BT (reprint author), Univ Connecticut, Ctr Hlth, Dept Cardiol, Pat & Jim Calhoun Cardiol Ctr, MC-3946, Farmington, CT 06030 USA. EM bliang@uchc.edu RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS [ZIA DK031127-03]; NHLBI NIH HHS [R01-HL-48225] NR 34 TC 23 Z9 24 U1 0 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 2007 VL 292 IS 2 BP H1077 EP H1084 PG 8 WC Cardiac & Cardiovascular Systems; Physiology; Peripheral Vascular Disease SC Cardiovascular System & Cardiology; Physiology GA 134FK UT WOS:000244068700044 PM 17040972 ER PT J AU Steagall, WK Lin, JP Moss, J AF Steagall, Wendy K. Lin, Jing-Ping Moss, Joel TI The C/A(-18) polymorphism in the surfactant protein B gene influences transcription and protein levels of surfactant protein B SO AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY LA English DT Article DE electrophoretic mobility shift assay; enzyme-linked immunosorbent assay; respiratory function; SFTPB ID HUMAN SP-A; PULMONARY SURFACTANT; RESPIRATORY-FAILURE; MARKER ALLELES; PROMOTER; SP1; DEFICIENCY; ACTIVATION; MICE; ASSOCIATION AB Surfactant protein B (SP-B) is an essential component of surfactant that promotes adsorption and spreading of surfactant phospholipids and stabilizes the phospholipid monolayer. SP-B is essential for respiratory function in newborn humans and mice; adult mice with levels of SP-B below 25% of wild-type develop fatal respiratory distress syndrome. A potential regulatory function of the C/A(-18) single nucleotide polymorphism (SNP) in the promoter of the SP-B gene was examined. Transcriptional analysis and ELISA on bronchoalveolar lavage fluid revealed that the presence of the C allele correlated with more SP-B promoter activity and protein. There was approximately threefold difference in amounts of SP-B in bronchoalveolar lavage fluid from CA(-18) and AA(-18) individuals. By EMSA, Sp1 bound more tightly to the C allele sequence than to the A allele sequence, perhaps accounting for the differences in transcription. Genotyping of a normal volunteer population showed similar to 31% of the population were AA homozygotes, suggesting that these individuals produce less SP-B. Differences in amounts of SP-B resulting from the promoter SNP could affect the clinical presentation of pulmonary disease. C1 NHLBI, Pulm Crit Care Med Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Moss, J (reprint author), NHLBI, Pulm Crit Care Med Branch, NIH, Bldg 10,Rm 6D03,MSC 1590, Bethesda, MD 20892 USA. EM mossj@nhlbi.nih.gov NR 33 TC 11 Z9 15 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1040-0605 J9 AM J PHYSIOL-LUNG C JI Am. J. Physiol.-Lung Cell. Mol. Physiol. PD FEB PY 2007 VL 292 IS 2 BP L448 EP L453 DI 10.1152/ajplung.00307.2006 PG 6 WC Physiology; Respiratory System SC Physiology; Respiratory System GA 134NV UT WOS:000244091000011 PM 17071721 ER PT J AU Hoffert, JD Nielsen, J Yu, MJ Pisitkun, T Schleicher, SM Nielsen, S Knepper, MA AF Hoffert, Jason D. Nielsen, Jakob Yu, Ming-Jiun Pisitkun, Trairak Schleicher, Stephen M. Nielsen, Soren Knepper, Mark A. TI Dynamics of aquaporin-2 serine-261 phosphorylation in response to short-term vasopressin treatment in collecting duct SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE IMCD; water transport; serine-256; channel; inner medullary ID NEPHROGENIC DIABETES-INSIPIDUS; WATER CHANNEL; RAT-KIDNEY; AQP2; MEMBRANE; IDENTIFICATION; LOCALIZATION; CELLS; PERMEABILITY; PROTEINS AB We recently identified a novel phosphorylation site, serine-261 (pS261), in the COOH-terminus of the vasopressin-regulated water channel, aquaporin-2 (AQP2). To address whether phosphorylation at this site is regulated by vasopressin, a rabbit polyclonal phospho-specific antibody was generated. Dot blot and immunoblot analysis demonstrated that this antibody specifically recognizes AQP2 phosphorylated at pS261, and that phosphorylation of S256 (pS256), a site already known to be regulated by vasopressin, does not interfere with antibody recognition. Immunohistochemical analysis revealed intense pS261 labeling of inner medullary collecting duct (IMCD) from wild-type mice, while sections from AQP2 knockout animals showed a general absence of labeling. AQP2 pS261 was present in principal cells of all mouse and rat distal tubule segments from the connecting tubule to the terminal IMCD. Co-immunolabeling of collecting duct with phospho-specific and total AQP2 antibodies revealed that pS261 and pS256 have distinct subcellular distributions. Levels of pS256 increased, while the amount of pS261 significantly decreased in freshly isolated rat IMCD samples incubated with 1 nM [ deamino-Cys(1), D-Arg(8)] vasopressin for 30 min. Similarly, based on immunohistochemical labeling, the amount of pS261 was reduced in all collecting duct segments of Brattleboro rats treated with [deamino-Cys(1), D-Arg(8)] vasopressin for 2 h. This study reveals a reciprocal change in S256 and S261 phosphorylation in response to short-term vasopressin exposure, suggesting that these residues may serve distinct roles in regulation of AQP2 subcellular distribution and collecting duct water permeability. C1 NHLBI, Kidney & Electrolyte Metab Lab, Bethesda, MD 20892 USA. Univ Aarhus, Water & Salt Res Ctr, Aarhus, Denmark. RP Knepper, MA (reprint author), NIH, Bldg 10,Rm 6N260,10 Ctr Dr,MSC 1603, Bethesda, MD 20892 USA. EM knep@helix.nih.gov OI Pisitkun, Trairak/0000-0001-6677-2271; YU, MING-JIUN/0000-0003-0393-4696 FU Intramural NIH HHS [Z99 HL999999, Z01 HL001285-21] NR 21 TC 83 Z9 85 U1 1 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD FEB PY 2007 VL 292 IS 2 BP F691 EP F700 DI 10.1152/ajprenal.00284.2006 PG 10 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 133FC UT WOS:000243997200023 PM 16985212 ER PT J AU Kleta, R Gahl, WA AF Kleta, Robert Gahl, William A. TI Collecting evidence: the case of collectrin (Tmem27) and amino acid transport SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Editorial Material ID ALKAPTONURIA C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Kleta, R (reprint author), NHGRI, NIH, Bldg 10,Rm 10C103,10 Ctr Dr, Bethesda, MD 20892 USA. EM kletar@mail.nih.gov NR 9 TC 2 Z9 2 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD FEB PY 2007 VL 292 IS 2 BP F531 EP F532 DI 10.1152/ajprenal.00409.2006 PG 2 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 133FC UT WOS:000243997200004 PM 17077384 ER PT J AU Malakauskas, SM Quan, H Fields, TA McCall, SJ Yu, MJ Kourany, WM Frey, CW Le, TH AF Malakauskas, Sandra M. Quan, Hui Fields, Timothy A. McCall, Shannon J. Yu, Ming-Jiun Kourany, Wissam M. Frey, Campbell W. Le, Thu H. TI Aminoaciduria and altered renal expression of luminal amino acid transporters in mice lacking novel gene collectrin SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE proximal tubule; crystalluria; osmotic diuresis ID NEURONAL GLUTAMATE TRANSPORTER; I CYSTINURIA; OSMOTIC DIURESIS; FANCONI SYNDROME; KIDNEY; PROTEIN; RBAT; MUTATIONS; REABSORPTION; TRAFFICKING AB Defects in renal proximal tubule transport manifest in a number of human diseases. Although variable in clinical presentation, disorders such as Hartnup disease, Dent's disease, and Fanconi syndrome are characterized by wasting of solutes commonly recovered by the proximal tubule. One common feature of these disorders is aminoaciduria. There are distinct classes of amino acid transporters located in the apical and basal membranes of the proximal tubules that reabsorb > 95% of filtered amino acids, yet few details are known about their regulation. We present our physiological characterization of a mouse line with targeted deletion of the gene collectrin that is highly expressed in the kidney. Collectrin-deficient mice display a reduced urinary concentrating capacity due to enhanced solute clearance resulting from profound aminoaciduria. The aminoaciduria is generalized, characterized by loss of nearly every amino acid, and results in marked crystalluria. Furthermore, in the kidney, collectrin-deficient mice have decreased plasma membrane populations of amino acid transporter subtypes B(0)AT1, rBAT, and b(0), (+) AT, as well as altered cellular distribution of EAAC1. Our data suggest that collectrin is a novel mediator of renal amino acid transport and may provide further insight into the pathogenesis of a number of human disease correlates. C1 Duke Univ, Med Ctr, Div Nephrol, Dept Med, Durham, NC 27710 USA. Duke Univ, Dept Pathol, Durham, NC USA. Durham Vet Affairs Med Ctr, Durham, NC USA. CIIT Ctr Hlth Res, Res Triangle Pk, NC USA. NHLBI, Kidney & Electrolyte Metab Lab, NIH, Bethesda, MD 20892 USA. RP Le, TH (reprint author), Duke Univ, Med Ctr, Div Nephrol, Dept Med, Durham, NC 27710 USA. EM thu.le@duke.edu OI McCall, Shannon/0000-0003-3957-061X; YU, MING-JIUN/0000-0003-0393-4696 FU NIDDK NIH HHS [2T32-DK-007731-12] NR 44 TC 51 Z9 52 U1 0 U2 3 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD FEB PY 2007 VL 292 IS 2 BP F533 EP F544 DI 10.1152/ajprenal.00325.2006 PG 12 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 133FC UT WOS:000243997200005 PM 16985211 ER PT J AU Topcu, SO Pedersen, M Norregaard, R Wang, GX Knepper, M Djurhuus, JC Nielsen, S Jorgensen, TM Frokiaer, J AF Topcu, Sukru Oguzkan Pedersen, Michael Norregaard, Rikke Wang, Guixian Knepper, Mark Djurhuus, Jens Christian Nielsen, Soren Jorgensen, Troels Munch Frokiaer, Jorgen TI Candesartan prevents long-term impairment of renal function in response to neonatal partial unilateral ureteral obstruction SO AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY LA English DT Article DE congenital ureteral obstruction; newborn rat; aquaporin water channels; sodium transporter; AT(1) receptor blockage ID URETEROPELVIC JUNCTION OBSTRUCTION; AQUAPORIN WATER CHANNELS; RENIN-ANGIOTENSIN SYSTEM; KAPPA-B ACTIVATION; DOWN-REGULATION; SODIUM TRANSPORTERS; RATS; KIDNEY; EXPRESSION; CILEXETIL AB Angiotensin II ( ANG II) plays an important role in the development of obstructive nephropathy. Here, we examined the effects of the ANG II receptor type 1 ( AT1R) blockade using candesartan on long-term renal molecular and functional changes in response to partial unilateral ureteral obstruction (PUUO). Newborn rats were subjected to severe PUUO or sham operation ( Sham) within the first 48 h of life. Candesartan was provided in the drinking water ( 10 mg(.)kg(-1) (.)day(-1)) from day 21 of life until 10 wk of age. Renal blood flow (RBF) was evaluated by MRI, glomerular filtration rate (GFR) was measured using the renal clearance of (51)Cr-EDTA, and the renal expression of Na-K-ATPase and the collecting duct water channel aquaporin-2 (AQP2) was examined by immunoblotting and immunocytochemistry. At 10 wk of age, PUUO significantly reduced RBF (0.8 +/- 0.1 vs. 1.6 +/- 0.1 ml (.) min(-1) (.) 100 g body wt(-1); P < 0.05) and GFR ( 37 +/- 16 vs. 448 +/- 111 mu l(.)min(-1) (.)100 g body wt(-1); P < 0.05) compared with Sham. Candesartan prevented the RBF reduction ( PUUO + CAN: 1.6 +/- 0.2 vs. PUUO: 0.8 +/- 0.1 ml (.) min(-1) (.) 100 g body wt(-1); P < 0.05) and attenuated the GFR reduction ( PUUO similar to CAN: 265 +/- 68 vs. PUUO: 37 +/- 16 mu l(.)min(-1) (.)100 g body wt(-1); P < 0.05). PUUO was also associated with a significant downregulation in the expression of Na-K-ATPase ( 75 +/- 12 vs. 100 +/- 5%, P < 0.05) and AQP2 ( 52 +/- 15 vs. 100 +/- 4%, P < 0.05), which were also prevented by candesartan (Na-K-ATPase: 103 +/- 8 vs. 100 +/- 5% and AQP2: 74 +/- 13 vs. 100 +/- 4%). These findings were confirmed by immunocytochemistry. Consistent with this, candesartan treatment partly prevented the reduction in solute free water reabsorption and attenuated fractional sodium excretion in rats with PUUO. In conclusion, candesartan prevents or attenuates the reduction in RBF, GFR and dysregulation of AQP2 and Na-K-ATPase in response to congenital PUUO in rats, suggesting that AT1R blockade may protect the neonatally obstructed kidney against development of obstructive nephropathy. C1 Univ Aarhus, Hosp Skejby, Inst Clin Med, Water & Salt Res Ctr, DK-8200 Aarhus, Denmark. Univ Aarhus, Inst Anat, DK-8000 Aarhus C, Denmark. Univ Aarhus, Hosp Skejby, MR Res Ctr, DK-8200 Aarhus, Denmark. Univ Aarhus, Hosp Skejby, Dept Urol, DK-8200 Aarhus, Denmark. Univ Aarhus, Hosp Skejby, Dept Clin Physiol, DK-8200 Aarhus, Denmark. NHLBI, Lab Kidney & Electrolyte Metab, NIH, Bethesda, MD 20892 USA. RP Frokiaer, J (reprint author), Univ Aarhus, Hosp Skejby, Inst Clin Med, Water & Salt Res Ctr, DK-8200 Aarhus, Denmark. EM JF@ki.au.dk FU Intramural NIH HHS [Z01 HL001285-21, Z99 HL999999] NR 50 TC 14 Z9 14 U1 0 U2 2 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 1931-857X J9 AM J PHYSIOL-RENAL JI Am. J. Physiol.-Renal Physiol. PD FEB PY 2007 VL 292 IS 2 BP F736 EP F748 DI 10.1152/ajprenal.00241.2006 PG 13 WC Physiology; Urology & Nephrology SC Physiology; Urology & Nephrology GA 133FC UT WOS:000243997200027 PM 17032940 ER PT J AU Goes, FS Zandi, PP Miao, K McMahon, FJ Steele, J Willour, VL MacKinnon, DF Mondimore, FM Schweizer, B Nurnberger, JI Rice, JP Scheftner, W Coryell, W Berrettini, WH Kelsoe, JR Byerley, W Murphy, DL Gershon, ES DePaulo, JR McInnis, MG Potash, JB AF Goes, Fernando S. Zandi, Peter P. Miao, Kuangyi McMahon, Francis J. Steele, Jo Willour, Virginia L. MacKinnon, Dean F. Mondimore, Francis M. Schweizer, Barbara Nurnberger, John I., Jr. Rice, John P. Scheftner, William Coryell, William Berrettini, Wade H. Kelsoe, John R. Byerley, William Murphy, Dennis L. Gershon, Elliot S. DePaulo, J. Raymond, Jr. McInnis, Melvin G. Potash, James B. CA Bipolar Disorder Phenome Grp TI Mood-incongruent psychotic features in bipolar disorder: Familial aggregation and suggestive linkage to 2p11-q14 and 13q21-33 SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID GENOME SCAN METAANALYSIS; SCHIZOAFFECTIVE DISORDER; SUSCEPTIBILITY LOCUS; MAJOR DEPRESSION; SCHIZOPHRENIA; PEDIGREES; CONGRUENT; GENETICS; 13Q32; ASSOCIATION AB Objective: Mood-incongruent psychotic features in bipolar disorder may signify a more severe form of the illness and might represent phenotypic manifestations of susceptibility genes shared with schizophrenia. This study attempts to characterize clinical correlates, familial aggregation, and genetic linkage in subjects with these features. Method: Subjects were drawn from The National Institute of Mental Health (NIMH) Genetics Initiative Bipolar Disorder Collaborative cohort, consisting of 708 families recruited at 10 academic medical centers. Subjects with mood-incongruent and mood-congruent psychotic features were compared on clinical variables. Familial aggregation was tested using a proband-predictive model and generalized estimating equations. A genome-wide linkage scan incorporating a mood-incongruence covariate was performed. Results: Mood-incongruent psychotic features were associated with an increased rate of hospitalization and attempted suicide. A proband with mood-incongruence predicted mood-incongruence in relatives with bipolar I disorder when compared with all other subjects and when compared with subjects with mood-congruent psychosis. The presence of mood-incongruent psychotic features increased evidence for linkage on chromosomes 13q21-33 and 2p11-q14. These logarithm of the odds ratio (LOD) scores and their increase from baseline met empirical genome-wide suggestive criteria for significance. Conclusions: Mood-incongruent psychotic features showed evidence of a more severe course, familial aggregation, and suggestive linkage to two chromosomal regions previously implicated in major mental illness susceptibility. The 13q21-33 finding supports prior evidence of bipolar disorder/schizophrenia overlap in this region, while the 2p11-q14 finding is, to the authors' knowledge, the first to suggest that this schizophrenia linkage region might also harbor a bipolar disorder susceptibility gene. C1 Johns Hopkins Sch Med, Dept Psychiat, Baltimore, MD USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Mental Hlth, Baltimore, MD USA. NIMH, Genet Basis Mood & Anxiety Disorders Unit, Mood & Anxiety Porgram, NIH, Bethesda, MD 20892 USA. NIMH, Clin Sci Lab, NIH, Bethesda, MD 20892 USA. Indiana Univ, Sch Med, Inst Psychiat Res, Indianapolis, IN 46202 USA. Washington Univ, Sch Med, Dept Psychiat, St Louis, MO 63110 USA. Rush Univ, Med Ctr, Dept Psychiat, Chicago, IL 60612 USA. Univ Iowa, Sch Med, Dept Psychiat, Iowa City, IA 52242 USA. Univ Penn, Sch Med, Dept Psychiat, Ctr Neurobiol & Behav, Philadelphia, PA 19104 USA. Univ Calif San Diego, Dept Psychiat, La Jolla, CA 92093 USA. Univ Calif San Francisco, Dept Psychiat, San Francisco, CA 94143 USA. Univ Chicago, Dept Psychiat, Chicago, IL 60637 USA. Univ Michigan, Sch Med, Dept Psychiat, Ann Arbor, MI 48109 USA. RP Potash, JB (reprint author), Johns Hopkins Univ Hosp, 600 N Wolfe St,Meyer 4-119, Baltimore, MD 21287 USA. EM jpotash@jhmi.edu RI McMahon, Francis/A-7290-2009; McInnis, Melvin/F-6963-2012; OI McInnis, Melvin/0000-0002-0375-6247; Nurnberger, John/0000-0002-7674-1767; McMahon, Francis/0000-0002-9469-305X FU NIMH NIH HHS [K01 MH072866, K01 MH072866-01] NR 40 TC 53 Z9 54 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 2007 VL 164 IS 2 BP 236 EP 247 DI 10.1176/appi.ajp.164.2.236 PG 12 WC Psychiatry SC Psychiatry GA 131XM UT WOS:000243905700014 PM 17267786 ER PT J AU Grillon, C Lissek, S McDowell, D Levenson, J Pine, DS AF Grillon, Christian Lissek, Shmuel McDowell, Dana Levenson, Jessica Pine, Daniel S. TI Reduction of trace but not delay eyeblink conditioning in panic disorder SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID CEREBRAL GLUCOSE-METABOLISM; ANXIETY DISORDERS; AWARENESS; CONTEXT; FEAR; ACQUISITION; PERSPECTIVE; EXPLICIT AB Objective: Individuals with panic disorder perceive panic attacks as unpredictable. Because predictability is fundamental to Pavlovian conditioning, failure to predict panic attacks could be due to a basic deficit in conditioning. The present study examined trace eyeblink conditioning in order to test the hypothesis that individuals with panic disorder are impaired in associative learning tasks that depend on declarative memory. Method: Delay and trace eyeblink conditioning were tested in separate experimental sessions in 19 individuals meeting DSM-IV criteria for panic disorder and 19 sex- and age-matched healthy comparison subjects. In the delay paradigm, a mild puff was delivered to the eye at the end of a 500-msec tone; in the trace paradigm, the puff was delivered after a 700-msec empty "trace" interval that followed the end of the tone. Results: Patients and comparison subjects showed similar rates of conditioned responses in the delay paradigm, but patients showed reduced rates of conditioned responses in the trace paradigm. Conclusions: These results suggest that individuals with panic disorder suffer from a deficit in declarative associative learning. Such a deficit points to impaired hippocampal function that may disrupt cognitive processing of internal and external cues predictive of a panic attack. C1 NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. RP Grillon, C (reprint author), NIMH, Mood & Anxiety Disorders Program, 15 K N Dr,MSC 2670, Bethesda, MD 20892 USA. EM grillonc@intra.nimh.nih.gov RI Lissek, Shmuel/B-6577-2008; Levenson, Jessica/O-5448-2015 NR 33 TC 14 Z9 14 U1 1 U2 2 PU AMER PSYCHIATRIC PUBLISHING, INC PI ARLINGTON PA 1000 WILSON BOULEVARD, STE 1825, ARLINGTON, VA 22209-3901 USA SN 0002-953X J9 AM J PSYCHIAT JI Am. J. Psychiat. PD FEB PY 2007 VL 164 IS 2 BP 283 EP 289 DI 10.1176/appi.ajp.164.2.283 PG 7 WC Psychiatry SC Psychiatry GA 131XM UT WOS:000243905700020 PM 17267792 ER PT J AU Rich, BA Schmajuk, M Perez-Edgar, KE Fox, NA Pine, DS Leibenluft, E AF Rich, Brendan A. Schmajuk, Mariana Perez-Edgar, Koraly E. Fox, Nathan A. Pine, Daniel S. Leibenluft, Ellen TI Different psychophysiological and behavioral responses elicited by frustration in pediatric bipolar disorder and severe mood dysregulation SO AMERICAN JOURNAL OF PSYCHIATRY LA English DT Article ID DEFICIT HYPERACTIVITY DISORDER; SPECTRUM DISORDERS; CHILDREN; ATTENTION; ADOLESCENTS; PHENOTYPE; MANIA; P300; SCHIZOPHRENIA; PHENOMENOLOGY AB Objective: Researchers disagree as to whether irritability is a diagnostic indicator for pediatric mania in bipolar disorder. The authors compared the behavioral and psychophysiological correlates of irritability among children with severe mood dysregulation (i.e., nonepisodic irritability and hyperarousal without episodes of euphoric mood) and narrow-phenotype bipolar disorder (i. e., a history of at least one manic or hypomanic episode with euphoric mood) as well as those with no diagnosis (i. e., healthy comparison children). Method: Subjects with severe mood dysregulation (N = 21) or narrow-phenotype bipolar disorder (N = 35) and comparison subjects (N = 26) completed the affective Posner task, an attentional task that manipulated emotional demands and induced frustration. Mood response, behavior (reaction time and accuracy), and brain activity (event-related potentials) were measured. Results: The severe mood dysregulation and narrow-phenotype bipolar disorder groups both reported significantly more arousal than comparison subjects during frustration, but behavioral and psychophysiological performance differed between the patient groups. In the frustration condition, children with narrow-phenotype bipolar disorder had lower P3 amplitude than children with severe mood dysregulation or comparison subjects, reflecting impairments in executive attention. Regardless of emotional context, children with severe mood dysregulation had lower N1 event-related potential amplitude than comparison subjects or children with narrow-phenotype bipolar disorder, reflecting impairments in the initial stages of attention. Post hoc analyses demonstrated that the N1 deficit in children with severe mood dysregulation is associated with oppositional defiant disorder symptom severity. Conclusions: Results indicate that while irritability is an important feature of severe mood dysregulation and narrow-phenotype bipolar disorder, the pathophysiology of irritability may differ among the groups and is influenced by oppositional defiant disorder severity. C1 NIMH, Pediat & Dev Neuropsychiat Branch, Sect Dev & Affect Neurosci, Mood & Anxiety Program, Bethesda, MD 20892 USA. George Mason Univ, Dept Psychol, Fairfax, VA 22030 USA. Univ Maryland, Child Dev Lab, College Pk, MD 20742 USA. RP Rich, BA (reprint author), NIH, Bldg 10,MSC 2670, Bethesda, MD 20892 USA. EM brendanrich@mail.nih.gov OI Perez-Edgar, Koraly/0000-0003-4051-9563 FU Intramural NIH HHS NR 32 TC 72 Z9 73 U1 4 U2 10 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 2007 VL 164 IS 2 BP 309 EP 317 DI 10.1176/appi.ajp.164.2.309 PG 9 WC Psychiatry SC Psychiatry GA 131XM UT WOS:000243905700023 PM 17267795 ER PT J AU Blum, N Fee, E AF Blum, Nava Fee, Elizabeth TI The polio epidemic in Israel in the 1950s SO AMERICAN JOURNAL OF PUBLIC HEALTH LA English DT Editorial Material C1 Univ Haifa, Sch Publ Hlth, Fac Social Welf & Hlth Studies, IL-31905 Haifa, Israel. Natl Lib Med, NIH, Bethesda, MD 20209 USA. RP Blum, N (reprint author), Univ Haifa, Sch Publ Hlth, Fac Social Welf & Hlth Studies, IL-31905 Haifa, Israel. EM navablum@hotmail.com NR 4 TC 1 Z9 1 U1 0 U2 1 PU AMER PUBLIC HEALTH ASSOC INC PI WASHINGTON PA 800 I STREET, NW, WASHINGTON, DC 20001-3710 USA SN 0090-0036 J9 AM J PUBLIC HEALTH JI Am. J. Public Health PD FEB PY 2007 VL 97 IS 2 BP 218 EP 218 DI 10.2105/AJPH.2006.103986 PG 1 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 132NO UT WOS:000243949700012 PM 17194848 ER PT J AU Sherer, K Li, Y Cui, XZ Eichacker, PQ AF Sherer, Kevin Li, Yan Cui, Xizhong Eichacker, Peter Q. TI Lethal and edema toxins in the pathogenesis of Bacillus anthracis septic shock - Implications for therapy SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE anthrax; toxin; shock; treatment ID CAPILLARY MORPHOGENESIS PROTEIN-2; T-LYMPHOCYTE ACTIVATION; PROTECTIVE ANTIGEN; MONOCLONAL-ANTIBODY; IN-VIVO; CRYSTAL-STRUCTURE; CYCLIC-AMP; ADENYLATE-CYCLASE; ESCHERICHIA-COLI; EUKARYOTIC CELLS AB Recent research regarding the structure and function of Bacillus anthrocis lethal (LeTx) and edema (ETx) toxins provides growing insights into the pathophysiology and treatment of shock with this lethal bacteria. These are both binary-type toxins composed of protective antigen necessary for their cellular uptake and either lethal or edema factors, the toxigenic moieties. The primary cellular receptors for protective antigen have been identified and constructed and key steps in the extracellular processing and internalization of the toxins clarified. Consistent with the lethal factor's primary action as an intracellular endopepticlase targeting mitogen-activated protein kinase kinases, growing evidence indicates that shock with this toxin does not result from an excessive inflammatory response. In fact, the potent immunosuppressive effects of LeTx may actually contribute to the establishment and persistence of infection. Instead, shock with LeTx may be related to the direct injurious effects of lethal factor on endothelial cell function. Despite the importance of LeTx, very recent studies show that edema factor, a potent adenyl cyclase, has the ability to make a substantial contribution to shock caused by B. anthracis and works additively with LeTx. Furthermore, ETx may contribute to the immunosuppressive effects of LeTx. Therapies under development that target several different steps in the cellular uptake and function of these two toxins have been effective in in vitro and in vivo systems. Understanding how best to apply these agents clinically and how they interact with conventional treatments should be goals for future research. C1 Crit Care Med Dept, Clin Ctr, NIH, Bethesda, MD 20892 USA. RP Eichacker, PQ (reprint author), Crit Care Med Dept, Clin Ctr, NIH, Bldg 10,Room 2C145, Bethesda, MD 20892 USA. EM peichacker@cc.nih.gov FU Intramural NIH HHS NR 92 TC 31 Z9 33 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 1 PY 2007 VL 175 IS 3 BP 211 EP 221 DI 10.1164/rccm.200608-1239CP PG 11 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 132NK UT WOS:000243949300004 PM 17095744 ER PT J AU Whitehead, GS Wang, T DeGraff, LM Card, JW Lira, SA Graham, GJ Cook, DN AF Whitehead, Gregory S. Wang, Tie DeGraff, Laura M. Card, Jeffrey W. Lira, Sergio A. Graham, Gerard J. Cook, Donald N. TI The chemokine receptor D6 has opposing effects on allergic inflammation and airway reactivity SO AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE LA English DT Article DE chemokines; lung; D6; allergic; transforming growth factor-beta ID ACTIVATION-REGULATED CHEMOKINE; MACROPHAGE-DERIVED CHEMOKINE; ATOPIC ASTHMATICS; MOLECULAR-CLONING; DECOY RECEPTOR; T-CELLS; EXPRESSION; THYMUS; MICE; CCR4 AB Rationale: The D6 chemokine receptor can bind and scavenge several chemokines, including the T-helper 2 (Th2)-associated chemokines CCL17 and CCL22. Although D6 is constitutively expressed in the lung, its pulmonary function is unknown. Objectives: This study tested whether D6 regulates pulmonary chemokine levels, inflammation, or airway responsiveness during allergen-induced airway disease. Methods: D6-deficient and genetically matched C57BL/6 mice were sensitized and challenged with ovalbumin. ELISA and flow cytometry were used to measure levels of cytokines and leukocytes, respectively. Mechanical ventilation was used to measure airway reactivity. Results: The ability of D6 to diminish chemokine levels in the lung was chemokine concentration dependent. CCL17 and CCL22 were abundant in the airway, and their levels were attenuated by D6 when they were within a defined concentration range. By contrast, airway concentrations of CCL3, CCL5, and CCL11 were low and unaffected by D6. Allergen-challenged D6-deficient mice had more dendritic cells, T cells, and eosinophils in the lung parenchyma and more eosinophils in the airway than similarly challenged C57BL/6 mice. By contrast, D6-deficient mice had reduced airway responses to methacholine compared with C57BL/6 mice. Thus, D6 has opposing effects on inflammation and airway reactivity. Conclusions: The ability of D6 to scavenge chemokines in the lung is dependent on chemokine concentration. The absence of D6 increases inflammation, but reduces airway reactivity. These findings suggest that inhibiting D6 function might be a novel means to attenuate airway responses in individuals with allergic asthma. C1 Natl Inst Environm Hlth Sci, Lab Resp Biol, Res Triangle Pk, NC 27709 USA. Mt Sinai Sch Med, Immunobiol Ctr, New York, NY USA. Univ Glasgow, Div Immunol Infect & Inflammat, Glasgow, Lanark, Scotland. RP Cook, DN (reprint author), Natl Inst Environm Hlth Sci, Lab Resp Biol, 111 TW Alexander Dr,Bldg 101,Room E244, Res Triangle Pk, NC 27709 USA. EM cookd@niehs.nih.gov RI Graham, Gerard/D-1240-2009; OI Graham, Gerard/0000-0002-7801-204X FU Intramural NIH HHS NR 34 TC 56 Z9 57 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 1 PY 2007 VL 175 IS 3 BP 243 EP 249 DI 10.1164/rccm.200606-839OC PG 7 WC Critical Care Medicine; Respiratory System SC General & Internal Medicine; Respiratory System GA 132NK UT WOS:000243949300008 PM 17095748 ER PT J AU Sawyer, RT Fontenot, AP Barnes, TA Parsons, CE Tooker, BC Maier, LA Gillespie, MM Gottschall, EB Silveira, L Hagman, J Newman, LS AF Sawyer, Richard T. Fontenot, Andrew P. Barnes, Tristan A. Parsons, Charles E. Tooker, Brian C. Maier, Lisa A. Gillespie, May M. Gottschall, E. Brigitte Silveira, Lori Hagman, James Newman, Lee S. TI Beryllium-induced TNF-alpha production is transcription-dependent in chronic beryllium disease SO AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY LA English DT Review DE granuloma; T lymphocytes; cytokines; gene regulation; lung ID TUMOR-NECROSIS-FACTOR; CD4(+) T-CELLS; PERIPHERAL-BLOOD MONONUCLEAR; BACTERIAL-INFECTION; DENDRITIC CELLS; MESSENGER-RNA; TARGET ORGAN; HLA-DP; PENTOXIFYLLINE; PROMOTER AB Beryllium (Be)-antigen presentation to Be-specific CD4(+) T cells from the lungs of patients with chronic beryllium disease (CBD) results in T cell proliferation and TNF-alpha secretion. We tested the hypothesis that Be-induced, CBD bronchoalveolar lavage (BAL) T cell, transcription-dependent, TNF-alpha secretion was accompanied by specific transcription factor upregulation. After 6 h of Be stimulation, CBD BAL cells produced a median of 883 pg/ml TNF-alpha (range, 608-1,275 pg/ml) versus 198 pg/ml (range, 116-245 pg/ml) by unstimulated cells. After 12 h CBD BAL cells produced a median of 2,963 pg/ml (range, 99-9,424 pg/ml) TNF-1 versus 55 pg/ml (range, 0-454) by unstimulated cells. Using real-time RT-PCIR, Be-stimulated TNF-alpha production at 6 h was preceded by a 5-fold increase in TNF-alpha pre-mRNA copy number:p-actin copy number (Be median ratio 0.21; unstimulated median ratio 0.04). The median ratio of mature TNF-alpha mRNA:P-actin mRNA was upregulated 1.4-fold (Be median ratio 0.17; unstimulated median ratio 0.12). Be exposure in the presence of the transcription inhibitor pentoxifylline (PTX) decreased CBD BAL cell TNF-alpha pre-mRNA levels > 60%, whereas treatment with the mRNA splicing inhibitor 2-aminopurine (2AP) decreased levels 40% relative to Be exposure alone. PTX treatment decreased mature TNF-a mRNA levels 50% while 2AP decreased levels > 80%, relative to Be exposure alone. Beryllium exposure specifically upregulated transcription factors AP-1 and NF-kappa B. The data suggest that Be exposure induces transcription-dependent TNF-alpha production, potentially due to upregulation of specific transcription factors. C1 Univ Colorado, Hlth Sci Ctr, Dept Med, Div Pulm Sci & Crit Care Med,Dept Immunol, Denver, CO 80202 USA. Univ Colorado, Hlth Sci Ctr, Dept Prevent Med & Biometr, Denver, CO 80202 USA. Natl Jewish Med & Res Ctr, Robert H Hollis Lab Environm & Occupat Hlth, Div Environm & Occupat Hlth Sci, Dept Med, Denver, CO USA. Natl Jewish Med & Res Ctr, Integrated Dept Immunol, Denver, CO USA. RP Sawyer, RT (reprint author), NIAID, Div Allergy Immunol & Transportat, DHHS, 6610 Rockledge Dr,Room 3103, Bethesda, MD 20892 USA. EM sawyerr@niaid.nih.gov FU NCRR NIH HHS [M01 RR00051]; NHLBI NIH HHS [K08 HL03887, R01 HL62410]; NIEHS NIH HHS [P01 ES11810, R01 ES06538] NR 38 TC 7 Z9 13 U1 0 U2 1 PU AMER THORACIC SOC PI NEW YORK PA 1740 BROADWAY, NEW YORK, NY 10019-4374 USA SN 1044-1549 J9 AM J RESP CELL MOL JI Am. J. Respir. Cell Mol. Biol. PD FEB PY 2007 VL 36 IS 2 BP 191 EP 200 DI 10.1165/rcmd.2006-0021TR PG 10 WC Biochemistry & Molecular Biology; Cell Biology; Respiratory System SC Biochemistry & Molecular Biology; Cell Biology; Respiratory System GA 135GP UT WOS:000244142400010 PM 16980557 ER PT J AU Carney, PA Abraham, LA Miglioretti, DL Yabroff, KR Sickles, EA Buist, DSM Kasales, CJ Geller, BM Rosenberg, RD Dignan, MB Weaver, DL Kerlikowske, K AF Carney, Patricia A. Abraham, Linn A. Miglioretti, Diana L. Yabroff, K. Robin Sickles, Edward A. Buist, Diana S. M. Kasales, Claudia J. Geller, Berta M. Rosenberg, Robert D. Dignan, Mark B. Weaver, Donald L. Kerlikowske, Karla CA Breast Canc Surveillance Co TI Factors associated with imaging and procedural events used to detect breast cancer after screening mammography SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE breast biopsy; breast cancer screening; breast neoplasms; mammography; sonography ID HORMONE REPLACEMENT THERAPY; DIAGNOSTIC MAMMOGRAPHY; DETECTION RATES; UNITED-STATES; WOMEN; DENSITY; PERFORMANCE; RECALL; SYMPTOMS; AGE AB OBJECTIVE. The purpose of this study was to characterize the type and frequency of diagnostic evaluations after screening mammography and to summarize their association with the likelihood of biopsy and subsequent breast cancer diagnosis. MATERIALS AND METHODS. The data source was 584,470 women with no previous breast cancer from six states in the Breast Cancer Surveillance Consortium. In this observational study, we linked data from 1,207,631 routine screening mammograms performed between January 1, 1996, and December 31, 2002, to data on additional imaging, interventional procedures, and biopsy outcome ( benign or malignant). Additional examinations were categorized into diagnostic mammography, sonography, or both. Events were further subdivided by whether they were performed on the same day as the screening examination and whether patients reported breast symptoms. Logistic regression analysis was used to examine the association between additional evaluation performed and the likelihood of biopsy and the likelihood of subsequent breast cancer diagnosis after adjustment for patient and screening mammographic characteristics. RESULTS. Most (92%) of the screening examinations did not include additional imaging. The probability of biopsy ranged from 0.4% for examinations with no follow-up to 20.1% for those with diagnostic mammography and sonography on the same day as screening among women without symptoms and from 2.1% for those with no follow-up to 18.9% for those with diagnostic mammography and sonography on a day different from screening among women with symptoms. Thirty percent of women without symptoms who underwent biopsy had cancer, whereas 27.1% of women with symptoms who underwent biopsy had cancer. Women who underwent biopsy after screening mammography with diagnostic mammography and sonography on the same day had the highest probability of breast cancer (37.6% among women without symptoms, 36.4% among women with symptoms), whereas those who underwent only sonography performed at a later date had the lowest probability of breast cancer (11.9% among women without symptoms, 17.1% among women with symptoms). CONCLUSION. Women who undergo screening mammography followed by diagnostic mammography and sonography have a high probability of undergoing biopsy and having the biopsy result of breast cancer when follow-up imaging is performed on the same day as screening mammography whether or not breast symptoms are present. Biopsy performed after sonography in the absence of diagnostic mammography had a low yield of breast cancer. C1 Oregon Hlth & Sci Univ, Dept Family Med, Portland, OR 97239 USA. Dartmouth Coll Sch Med, Norris Cotton Canc Ctr, Lebanon, NH 03756 USA. Grp Hlth Cooperat Puget Sound, Ctr Hlth Studies, Seattle, WA 98101 USA. NCI, Appl Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Univ Calif San Francisco, Dept Radiol, San Francisco, CA 94115 USA. Univ Vermont, Burlington, VT 05401 USA. Univ New Mexico, Dept Radiol, Albuquerque, NM 87131 USA. Cooper Inst, Golden, CO 80401 USA. Univ Vermont, Sch Med, Dept Pathol, Burlington, VT 05405 USA. Univ Calif San Francisco, Dept Med, San Francisco, CA 94115 USA. RP Carney, PA (reprint author), Oregon Hlth & Sci Univ, Dept Family Med, 3181 SW Sam Jackson Pk Rd, Portland, OR 97239 USA. EM carneyp@ohsu.edu OI Yabroff, K. Robin/0000-0003-0644-5572 FU NCI NIH HHS [R01 CA080888, U01 CA086076, U01 CA086076-06, U01 CA086082, U01CA36736, U01CA63731, U01CA63740, U01CA69976, U01CA70013, U01CA70040, U01CA86076, U01CA86082] NR 31 TC 8 Z9 8 U1 0 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD FEB PY 2007 VL 188 IS 2 BP 385 EP 392 DI 10.2214/AJR.05.1718 PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 156QB UT WOS:000245663000017 PM 17242246 ER PT J AU Yao, L Pitts, JT Thomasson, D AF Yao, Lawrence Pitts, John T. Thomasson, David TI Isotropic 3D fast spin-echo with proton-density-like contrast: A comprehensive approach to musculoskeletal MRI SO AMERICAN JOURNAL OF ROENTGENOLOGY LA English DT Article DE ankle; high resolution; MRI; MR technique ID ARTICULAR-CARTILAGE; DRIVEN EQUILIBRIUM; KNEE; SEQUENCE; PULSE AB OBJECTIVE. Scanning time considerations have restricted routine use of 3D Fourier transform (3DFT)-encoded MRI to gradient-recalled echo sequences. We sought to combine isotropic 3DFT acquisition with fast spin-echo at a practical scan duration. This strategy offers versatile image contrast for musculoskeletal evaluation and facilitates image reformation tailored to the depiction of small anatomic features. CONCLUSION. Isotropic 3DFT fast spin-echo is feasible on current MRI scanners and has the potential to improve musculoskeletal evaluation. C1 NIH, Ctr Clin, Dept Diagnost Radiol, Bethesda, MD 20892 USA. InVivo Corp, Orlando, FL USA. RP Yao, L (reprint author), NIH, Ctr Clin, Dept Diagnost Radiol, 10 Ctr Dr,Rm 1C360, Bethesda, MD 20892 USA. NR 9 TC 17 Z9 18 U1 0 U2 1 PU AMER ROENTGEN RAY SOC PI RESTON PA 1891 PRESTON WHITE DR, SUBSCRIPTION FULFILLMENT, RESTON, VA 22091 USA SN 0361-803X J9 AM J ROENTGENOL JI Am. J. Roentgenol. PD FEB PY 2007 VL 188 IS 2 BP W199 EP W201 DI 10.2214/AJR.06.0556 PG 3 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 156QB UT WOS:000245663000060 PM 17242228 ER PT J AU Haque, R Mondal, D Shu, JF Roy, S Kabir, M Davis, AN Duggal, P Petri, WA AF Haque, Rashidul Mondal, Dinesh Shu, Jianfen Roy, Shantanu Kabir, Mamun Davis, Andrea N. Duggal, Priya Petri, William A., Jr. TI Correlation of interferon-gamma production by peripheral blood mononuclear cells with childhood malnutrition and susceptibility to amebiasis SO AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE LA English DT Article ID ENTAMOEBA-HISTOLYTICA TROPHOZOITES; LIVER-ABSCESS; BANGLADESHI CHILDREN; INNATE IMMUNITY; INHIBITABLE LECTIN; PRESCHOOL-CHILDREN; ANOREXIA-NERVOSA; ADHERENCE LECTIN; NITRIC-OXIDE; INFECTION AB The contribution of interferon-gamma (IFN-gamma) to immunity from amebiasis was assessed in a three-year prospective study of children 2-5 years of age in an urban slum of Dhaka, Bangladesh. IFN-gamma produced by peripheral blood mononuclear cells stimulated with soluble amebic antigen was measured upon enrollment. Thirty-one of the 209 enrolled children had Entamoeba histolytica-associated diarrhea. Children who produced higher than the median level of IFN-gamma (median 580 pg/mL) had longer survival without E. histolytica diarrhea/dysentery (log rank test P = 0.03) and a reduction in the risk of E. histolytica diarrhea/dysentery by more than half (Cox proportional hazard regression 0.45, P = 0.04). When adjusted for stunting, the association between IFN-gamma and the time to the first episode of E. histolytica-associated diarrhea remained marginally significant (Cox proportional hazard regression = 0.49, P = 0.07). We conclude that production of IFN-gamma is linked to nutritional status and predicts future susceptibility to symptomatic amebiasis. C1 Univ Virginia, Div Infect Dis & Int Hlth, Dept Internal Med, Charlottesville, VA 22908 USA. Univ Virginia, Div Biostat & Epidemiol, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA. Int Ctr Diarrhoeal Dis Res, Dhaka 1000, Bangladesh. NHGRI, NIH, Bethesda, MD 20892 USA. RP Petri, WA (reprint author), Univ Virginia, Div Infect Dis & Int Hlth, Dept Internal Med, Room 2115 MR4 Bldg,POB 801340,Lane Rd, Charlottesville, VA 22908 USA. EM wap3g@virginia.edu FU Intramural NIH HHS; NIAID NIH HHS [AI-43596] NR 34 TC 32 Z9 32 U1 0 U2 1 PU AMER SOC TROP MED & HYGIENE PI MCLEAN PA 8000 WESTPARK DR, STE 130, MCLEAN, VA 22101 USA SN 0002-9637 J9 AM J TROP MED HYG JI Am. J. Trop. Med. Hyg. PD FEB PY 2007 VL 76 IS 2 BP 340 EP 344 PG 5 WC Public, Environmental & Occupational Health; Tropical Medicine SC Public, Environmental & Occupational Health; Tropical Medicine GA 135GN UT WOS:000244142200022 PM 17297046 ER PT J AU Wang, WJ Guo, T Rudnick, PA Song, T Li, J Zhuang, ZP Zheng, WX Devoe, DL Lee, CS Balgley, BM AF Wang, Weijie Guo, Tong Rudnick, Paul A. Song, Tao Li, Jie Zhuang, Zhengping Zheng, Wenxin Devoe, Don L. Lee, Cheng S. Balgley, Brian M. TI Membrane proteome analysis of microdissected ovarian tumor tissues using capillary isoelectric focusing/reversed-phase liquid chromatography-tandem MS SO ANALYTICAL CHEMISTRY LA English DT Article ID LARGE-SCALE ANALYSIS; MASS-SPECTROMETRY; SHOTGUN PROTEOMICS; IDENTIFICATION TECHNOLOGY; WIDE ANALYSIS; LC-MS/MS; PROTEINS; GENOME; CELLS; 1ST-DIMENSION AB This work expands our tissue proteome capabilities from the analysis of soluble proteins in previous studies to the examination of membrane proteins within the pellets of enriched and selectively isolated tumor cells procured from microdissected tissue specimens. The pellets of targeted ovarian tumor cells are treated by two different membrane protein extraction methods, including the use of detergent and organic solvent. The detergent-based membrane protein preparation protocol not only extracts proteins effectively from cell pellets but also is compatible with subsequent proteome analysis using combined capillary isoelctric focusing/nano reversed-phase liquid chromatography separations coupled with nano electrospray ionization mass spectrometry. Among proteins identified from an amount of pellet equivalent to 20 000 cells, 773 proteins are predicted to contain one or more transmembrane domains, corresponding to 22% membrane proteome coverage within the SwissProt Human protein sequence entries. C1 Calibrant Biosyst, Gaithersburg, MD 20878 USA. Univ Maryland, Dept Chem & Biochem, College Pk, MD 20742 USA. NINDS, Mol Pathogenesis Unit, Surg Neurol Branch, Bethesda, MD 20892 USA. Univ Arizona, Dept Pathol, Tucson, AZ 85724 USA. Univ Maryland, Dept Mech Engn, College Pk, MD 20742 USA. Univ Maryland, Bioengn Program, College Pk, MD 20742 USA. RP Balgley, BM (reprint author), Calibrant Biosyst, 910 Clopper Rd,Suite 220N, Gaithersburg, MD 20878 USA. EM brian.balgley@calibrant.com RI DeVoe, Don/A-2891-2011; OI DeVoe, Don/0000-0002-7740-9993; Balgley, Brian/0000-0002-3509-4567 FU NCI NIH HHS [CA107988, CA103086]; NCRR NIH HHS [RR021239, RR021862] NR 43 TC 47 Z9 47 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0003-2700 J9 ANAL CHEM JI Anal. Chem. PD FEB 1 PY 2007 VL 79 IS 3 BP 1002 EP 1009 DI 10.1021/ac061613i PG 8 WC Chemistry, Analytical SC Chemistry GA 131AK UT WOS:000243839900023 PM 17263328 ER PT J AU Basile, BM Hampton, RR Chaudhry, AM Murray, EA AF Basile, B. M. Hampton, R. R. Chaudhry, A. M. Murray, E. A. TI Presence of a privacy divider increases proximity in pair-housed rhesus monkeys SO ANIMAL WELFARE LA English DT Article DE animal welfare; macaque; pair-housing; primate; privacy; social ID ENVIRONMENTAL ENRICHMENT; BEHAVIOR; MACAQUES AB Use of a privacy panel in the home cage of female pair-housed rhesus monkeys has been reported to increase time spent in close proximity and time spent in affiliative behaviours. In the current study we measured these behaviours in more diverse populations; including male-male and male-female pairs of monkeys actively participating in cognitive experiments. We observed twenty-five pairs of rhesus macaques (Macaca mulatta) both with and without the presence of a privacy divider. Monkeys spent significantly more time in the same half of the pair-cage when the divider was in place. A significant increase in affiliative behaviour was not observed. The effects of privacy dividers previously reported for female monkeys partially extend to male pairs and mixed sex pairs under conditions typical of an active research setting. C1 Emory Univ, Dept Psychol, Atlanta, GA 30322 USA. NIMH, Vet Med & Resources Branch, NIH, Bethesda, MD 20892 USA. NIMH, Neuropsychol Lab, NIH, Bethesda, MD 20892 USA. RP Basile, BM (reprint author), Emory Univ, Dept Psychol, 532 Kilgo Circle, Atlanta, GA 30322 USA. EM bbasile@emory.edu OI Murray, Elisabeth/0000-0003-1450-1642 NR 16 TC 4 Z9 4 U1 0 U2 2 PU UNIV FEDERATION ANIMAL WELFARE PI WHEATHAMPSTEAD PA OLD SCHOOL, BREWHOUSE HILL, WHEATHAMPSTEAD AL4 8AN, HERTS, ENGLAND SN 0962-7286 J9 ANIM WELFARE JI Anim. Welf. PD FEB PY 2007 VL 16 IS 1 BP 37 EP 39 PG 3 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 132NN UT WOS:000243949600004 ER PT J AU Zhang, Y Graubard, BI Longnecker, MP Stanczyk, FZ Klebanoff, MA McGlynn, KA AF Zhang, Yawei Graubard, Barry I. Longnecker, Matthew P. Stanczyk, Frank Z. Klebanoff, Mark A. McGlynn, Katherine A. TI Maternal hormone levels and perinatal characteristics: Implications for testicular cancer SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE testicular cancer; maternal hormones; perinatal factors ID GERM-CELL TUMORS; RISK-FACTORS; UNITED-STATES; PREGNANCY ESTRIOL; BIRTH-WEIGHT; BINDING GLOBULIN; SERUM ESTRIOL; MALES BORN; CRYPTORCHIDISM; ESTRADIOL AB PURPOSE: It was hypothesized that the risk for testicular germ cell tumors (TGCTs) is associated with maternal hormone levels. To examine the hypothesis, some studies used perinatal factors as surrogates for hormone levels. To determine the validity of this assumption, hormone-perinatal factor relationships were examined in the Collaborative Perinatal Project. METHODS: Maternal estradiol, estriol, and testosterone levels in first- and third-trimester serum samples were correlated with perinatal factors in 300 mothers representative of populations at high (white Americans) or low (black Americans) risk for TGCT. RESULTS: For white participants, testosterone levels were associated negatively with maternal height (P < 0.01) and age (p = 0.02) and positively with maternal weight (p = 0.02) and body mass index (BMI; p < 0.01), whereas estradiol levels were associated negatively with height (p = 0.03) and positively with son's birth weight (P = 0.04). For black participants, estriol levels were associated negatively with maternal weight (p = 0.01), BMI (p = 0.02), and gestational age p < 0.01) and positively with son's birth weight (p < 0.01), length (p = 0.04), and head circumference (P = 0.03). CONCLUSIONS: These findings indicate that use of perinatal characteristics as surrogates for hormone levels should be limited to a specific ethnic group. For white men, previously reported associations of TGCT with maternal weight and age may be caused by lower maternal testosterone levels. C1 NCI, Div Canc Epidemiol & Genet, DHHS, NIH, Rockville, MD 20852 USA. NICHHD, Rockville, MD USA. NIH, Dept Hlth & Human Serv, Rockville, MD USA. Natl Inst Environm Hlth Sci, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC USA. Yale Univ, Sch Med, Dept Epidemiol & Publ Hlth, New Haven, CT USA. Univ So Calif, Keck Sch Med, Reproduct Endocrine Res Lab, Los Angeles, CA USA. RP McGlynn, KA (reprint author), NCI, Div Canc Epidemiol & Genet, DHHS, NIH, 6120 Execut Blvd,EPS-7060, Rockville, MD 20852 USA. EM mcglynnk@mail.nih.gov OI Longnecker, Matthew/0000-0001-6073-5322 FU Intramural NIH HHS [ZIA CP010128-17] NR 49 TC 8 Z9 8 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD FEB PY 2007 VL 17 IS 2 BP 85 EP 92 DI 10.1016/j.annepidem.2006.03.006 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 132CM UT WOS:000243919700001 PM 16882463 ER PT J AU Chodick, G Freedman, MD Kwok, RK Fears, TR Linet, MS Alexander, BH Kleinerman, RA AF Chodick, Gabriel Freedman, Michal D. Kwok, Richard K. Fears, Thomas R. Linet, Martha S. Alexander, Bruce H. Kleinerman, Ruth A. TI Agreement between contemporaneously recorded and subsequently recalled time spent outdoors: Implications for environmental exposure studies SO ANNALS OF EPIDEMIOLOGY LA English DT Article DE questionnaires; human activities; solar exposures; validity ID SUN EXPOSURE; RELIABILITY; REPRODUCIBILITY; QUESTIONNAIRE; VALIDITY AB PURPOSE: The aim of the study is to evaluate the agreement between contemporaneously recorded and subsequently recalled time spent outdoors during I week among members of an occupational cohort. METHODS: One hundred twenty-five radiologic technologists from northern and southern geographic areas in the United States recorded time spent outdoors for 7 consecutive days in a daily diary. Six months later, study participants completed a mailed self-administered questionnaire of the number of outdoor hours during the same 7-day period. We tested the agreement between questionnaire responses and diary entries. Logistic regression models were used to identify variables significantly affecting agreement. RESULTS: Time spent outdoors comprised one fifth of the total time recorded in the diaries. Agreement (weighted kappa [kappa(w)]) between reported outdoor time during weekdays (kappa(w) = 0.49; 95% confidence interval [CI], 0.39-0.59) was significantly (p < 0.05) higher than for weekends (kappa(w) = 0.23; 95% CI, 0.12-0.34). Similarly, agreement was lower for weekends compared with weekdays in multivariate analyses, reaching statistical significance (p = 0.05) in only the southern regions. CONCLUSIONS: Although our investigation was carried out among volunteers from the US radiologic technologist cohort, we believe retrospective questionnaires may be more accurate in reporting time spent outdoors for weekdays compared with weekends in any group of indoor workers. These differences have implications for the wording in future questionnaires about time spent outdoors and level and sources of uncertainty characterizing estimated time spent outdoors on weekdays versus weekend days. C1 NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Rockville, MD 20852 USA. RTI Int, Res Triangle Pk, NC USA. Univ Minnesota, Div Occupat & Environm Hlth, Minneapolis, MN USA. RP Chodick, G (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, 6120 Execut Blvd,EPS-7049, Rockville, MD 20852 USA. EM chodickg@mail.nih.gov RI Kwok, Richard/B-6907-2017; OI Kwok, Richard/0000-0002-6794-8360; Kleinerman, Ruth/0000-0001-7415-2478 NR 24 TC 7 Z9 7 U1 0 U2 2 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1047-2797 J9 ANN EPIDEMIOL JI Ann. Epidemiol. PD FEB PY 2007 VL 17 IS 2 BP 106 EP 111 DI 10.1016/j.annepidem.2006.06.004 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 132CM UT WOS:000243919700004 PM 16882464 ER PT J AU Smith, FM Gallagher, WM Fox, E Stephens, RB Rexhepaj, E Petricoin, EF Liotta, L Kennedy, MJ Reynolds, JV AF Smith, Fraser M. Gallagher, William M. Fox, Edward Stephens, Richard B. Rexhepaj, Elton Petricoin, Emanuel F., III Liotta, Lance Kennedy, M. John Reynolds, John V. TI Combination of SELDI-TOF-MS and data mining provides early-stage response prediction for rectal tumors undergoing multimodal neoadjuvant therapy SO ANNALS OF SURGERY LA English DT Article ID TOTAL MESORECTAL EXCISION; NF-KAPPA-B; PREOPERATIVE CHEMORADIATION; COLORECTAL-CANCER; PROTEOMIC PATTERNS; INDUCED APOPTOSIS; BREAST-CANCER; CARCINOMA; CHEMORADIOTHERAPY; CHEMOTHERAPY AB Objective: We investigated whether proteomic analysis of the low molecular weight region of the serum proteome could predict histologic response of locally advanced rectal cancer to neoadjuvant radiochemotherapy (RCT). Summary Background Data: Proteomic analysis of serum is emerging as a powerful new modality in cancer, in terms of both screening and monitoring response to treatment. No study has yet assessed its ability to predict and monitor the response of rectal cancer to RCT. Methods: Sequential serum samples from 20 patients undergoing RCT were prospectively collected. Time points sampled were as follows: pretreatment, 24/48 hours, 1 week, 2 weeks, 3 weeks, 5 weeks (last day of RCT), and presurgery. Response to treatment was measured using a 5-point tumor regression grade (TRG) based on the degree of residual tumor to fibrosis. All serum samples were analyzed in duplicate using surface-enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF-MS). Support vector machine (SVM) analysis of spectra was used to generate a predictive algorithm for each time point based on proteins that were maximally differentially expressed between good and poor responders. This algorithm was then tested using leave-one-out cross validation. Results: In total, 230 spectra were generated representing all available time points from 9 good responders (TRG 1+2) and 11 poor responders (TRG 3-5). SVM analysis indicated that changes within the serum proteome at the 24/48 hours time point into treatment provided optimal classification accuracy. In more detail, a cohort of 14 protein peaks were identified that collectively differentiated between good and poor responders, with 87.5% sensitivity and 80% specificity. Conclusions: Serum proteomic analysis may represent an early response predictor in multimodal treatment regimens of rectal cancer. These data suggest that this novel, minimally invasive modality may be a useful adjunct in the multimodal management of rectal cancer, and in the design of future clinical trials. C1 St James Hosp, Dept Surg, Dublin 8, Ireland. St James Hosp, Acad Unit Clin & Mol Oncol, Dublin 8, Ireland. Trinity Coll Dublin, Dublin, Ireland. Natl Univ Ireland Univ Coll Dublin, Conway Inst, UCD Sch Biomol & Biomed Sci, Dublin 4, Ireland. NCI, Pathol Lab, Ctr Canc Res, Clin Proteom Program, Bethesda, MD 20892 USA. RP Reynolds, JV (reprint author), St James Hosp, Dept Surg, Dublin 8, Ireland. EM reynoljv@tcd.ie RI Fox, Edward/A-4675-2011; OI Fox, Edward/0000-0002-3740-651X; Gallagher, William/0000-0002-4307-5999 NR 49 TC 49 Z9 57 U1 0 U2 2 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0003-4932 J9 ANN SURG JI Ann. Surg. PD FEB PY 2007 VL 245 IS 2 BP 259 EP 266 DI 10.1097/01.sla.0000245577.68151.bd PG 8 WC Surgery SC Surgery GA 131GR UT WOS:000243857400016 PM 17245180 ER PT J AU Alexander, H Pingpank, JF Libutti, SK Bartlett, DL Fraker, DL Royal, RE Steinberg, SM Beresnev, TH Helsabeck, CB AF Alexander, H. Pingpank, J. F. Libutti, S. K. Bartlett, D. L. Fraker, D. L. Royal, R. E. Steinberg, S. M. Beresnev, T. H. Helsabeck, C. B. TI Analysis of factors associated with outcome in patients undergoing isolated hepatic perfusion (IHP) for unresectable liver metastases (LM) from colorectal cancer (CRC) SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 60th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 15-18, 2007 CL Washington, DC SP Soc Surg Oncol C1 Univ Maryland, Med Ctr, Baltimore, MD 21201 USA. Natl Canc Inst, Bethesda, MD USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Penn, Philadelphia, PA 19104 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 2007 VL 14 IS 2 SU S BP 5 EP 6 PG 2 WC Oncology; Surgery SC Oncology; Surgery GA 134PU UT WOS:000244096200015 ER PT J AU Julian, TB Anderson, S Fourchotte, V Zieger, S Mamounas, E Bear, H Costantino, J Wolmark, N AF Julian, T. B. Anderson, S. Fourchotte, V. Zieger, S. Mamounas, E. Bear, H. Costantino, J. Wolmark, N. TI Predictive factors associated with invasive lobular breast cancer after neoadjuvant chemotherapy SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 60th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 15-18, 2007 CL Washington, DC SP Soc Surg Oncol C1 NSABP, Ctr Biostat, Pittsburgh, PA USA. Aultman Hosp, Canton, OH USA. Virginia Commonwealth Univ, Richmond, VA USA. Operat Ctr & Allegheny Gen Hosp, NSABP, Pittsburgh, PA USA. NR 0 TC 1 Z9 1 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 2007 VL 14 IS 2 SU S BP 17 EP 17 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 134PU UT WOS:000244096200051 ER PT J AU Greer, SE Alexander, HR Libutti, SK Royal, RE Hughes, MS Ohl, SH Beresneva, T Pingpank, JF AF Greer, S. E. Alexander, H. R. Libutti, S. K. Royal, R. E. Hughes, M. S. Ohl, S. H. Beresneva, T. Pingpank, J. F. TI Prolonged survival in 101 patients with malignant peritoneal mesothelioma undergoing systematic surgical cytoreduction, continuous hyperthermic peritoneal perfusion (CHPP) and early post-operative intraperitoneal (IP) chemotherapy SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 60th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 15-18, 2007 CL Washington, DC SP Soc Surg Oncol C1 NCI, NIH, Surg Branch, Surg Metab Sect, Bethesda, MD 20892 USA. Univ Maryland, Dept Surg, Baltimore, MD 21201 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 2007 VL 14 IS 2 SU S BP 29 EP 29 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 134PU UT WOS:000244096200087 ER PT J AU Blansfield, JA Alexander, HR Morita, S Libutti, SK AF Blansfield, J. A. Alexander, H. R., III Morita, S. Libutti, S. K. TI Targeting the tumor microenviroment to treat human ocular melanoma in nude mice using the tyrosine kinase inhibitors (TKIs) sunitinib or sorafenib alone and in combination with metronomic doses of cyclophosphamide (CTX) SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 60th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 15-18, 2007 CL Washington, DC SP Soc Surg Oncol C1 NIH, Natl Canc Inst, Surg Branch, Tumor Angiogenesis Sect, 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 2007 VL 14 IS 2 SU S BP 33 EP 33 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 134PU UT WOS:000244096200097 ER PT J AU Gallagher, K Varghese, S Pingpank, JF Libutti, SK Alexander, HR AF Gallagher, K. Varghese, S. Pingpank, J. F. Libutti, S. K. Alexander, H. R. TI Pro-inflammatory and angiogenic serum and tumor profiles in patients with malignant peritoneal mesothelioma (MPM) SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 60th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 15-18, 2007 CL Washington, DC SP Soc Surg Oncol C1 Univ Maryland, Baltimore, MD 21201 USA. Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2007 VL 14 IS 2 SU S BP 78 EP 78 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 134PU UT WOS:000244096200250 ER PT J AU Soballe, PW Gergich, N Washington, F Pfalzer, C Mcgarvey, CL AF Soballe, P. W. Gergich, N. Washington, F. Pfalzer, C. Mcgarvey, C. L. TI Pre-operative assessment improves early diagnosis and treatment of lymphedema: a case-control series SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 60th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 15-18, 2007 CL Washington, DC SP Soc Surg Oncol C1 Natl Naval Med Ctr, Sch Med, Bethesda, MD 20889 USA. Univ Maryland, Baltimore, MD 21201 USA. Univ Michigan, Flint, MI 48503 USA. NIH, 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 EI 1534-4681 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2007 VL 14 IS 2 SU S BP 89 EP 89 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 134PU UT WOS:000244096200285 ER PT J AU Pierobon, M Calvert, VS Lipsky, M Sheehan, KM Speer, R Mammano, E Belluco, C Nitti, D Liotta, LA Petricoin, EF AF Pierobon, M. Calvert, V. S. Lipsky, M. Sheehan, K. M. Speer, R. Mammano, E. Belluco, C. Nitti, D. Liotta, L. A. Petricoin, E. F. TI Phosphoproteomic analysis of metastatic colorectal cancer: Insights for new therapeutic targets SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 60th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 15-18, 2007 CL Washington, DC SP Soc Surg Oncol C1 Dept Oncol & Surg Sci, Padua, Italy. George Mason Univ, Manassas, VA USA. Univ Maryland, Baltimore, MD 21201 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. CRO Hosp, Aviano, Italy. 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 2007 VL 14 IS 2 SU S BP 99 EP 100 PG 2 WC Oncology; Surgery SC Oncology; Surgery GA 134PU UT WOS:000244096200321 ER PT J AU Abad, JD Morgan, RA Rosenberg, SA AF Abad, J. D. Morgan, R. A. Rosenberg, S. A. TI T cell receptor gene therapy targeting a native melanoma antigen can impact established tumor growth in a murine model SO ANNALS OF SURGICAL ONCOLOGY LA English DT Meeting Abstract CT 60th Annual Cancer Symposium of the Society-of-Surgical-Oncology CY MAR 15-18, 2007 CL Washington, DC SP Soc Surg Oncol C1 Natl Canc Inst, Surg Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1068-9265 J9 ANN SURG ONCOL JI Ann. Surg. Oncol. PD FEB PY 2007 VL 14 IS 2 SU S BP 111 EP 111 PG 1 WC Oncology; Surgery SC Oncology; Surgery GA 134PU UT WOS:000244096200354 ER PT J AU Deeken, JF Figg, WD Bates, SE Sparreboom, A AF Deeken, John F. Figg, William D. Bates, Susan E. Sparreboom, Alex TI Toward individualized treatment: prediction of anticancer drug disposition and toxicity with pharmacogenetics SO ANTI-CANCER DRUGS LA English DT Review DE anticancer drugs; pharmacogenetics; pharmacokinetics; toxicity ID CANCER RESISTANCE PROTEIN; THIOPURINE S-METHYLTRANSFERASE; DIHYDROPYRIMIDINE DEHYDROGENASE-DEFICIENCY; SINGLE NUCLEOTIDE POLYMORPHISMS; CYTOCHROME P4502C9 POLYMORPHISMS; REVERSE-TRANSCRIPTASE INHIBITORS; ACUTE LYMPHOBLASTIC-LEUKEMIA; P-GLYCOPROTEIN EXPRESSION; HUMAN LIVER-MICROSOMES; BREAST-CANCER AB A great deal of effort has been spent in defining the pharmacokinetics and pharmacodynamics of investigational and registered anticancer agents. Often, there is a marked variability in drug handling between individual patients, which contributes to variability in the pharmacodynamic effects of a given dose of a drug. A combination of physiological variables, genetic characteristics (pharmacogenetics) and environmental factors is known to alter the relationship between the absolute dose and the concentration-time profile in plasma. A variety of strategies are now being evaluated in patients with cancer to improve the therapeutic index of anticancer drugs by implementation of pharmacogenetic imprinting through genotyping or phenotyping individual patients. The efforts have mainly focused on variants in genes encoding the drug-metabolizing enzymes thiopurine S-methyltransferase, dihydropyrimidine dehydrogenase, members of the cytochrome P450 family, including the CYP2B, 2C, 2D and 3A subfamilies, members of the UDP glucuronosyltransferase family, as well as the ATP-binding cassette transporters ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein). Several of these genotyping strategies have been shown to have substantial impact on therapeutic outcome and should eventually lead to improved anticancer chemotherapy. C1 NCI, Med Oncol Branch, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Clin Pharmacol Res Core, Bethesda, MD 20892 USA. RP Sparreboom, A (reprint author), St Jude Childrens Hosp, Dept Pharmaceut Sci, DTRC, Mail Stop 314,Room D1034B,332 N Lauderdale St, Memphis, TN 38105 USA. EM alex.sparreboom@stjude.org RI Sparreboom, Alex/B-3247-2008; Figg Sr, William/M-2411-2016 FU Intramural NIH HHS NR 154 TC 41 Z9 46 U1 0 U2 3 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 2007 VL 18 IS 2 BP 111 EP 126 DI 10.1097/CAD.0b013e3280109411 PG 16 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 127GY UT WOS:000243574700003 PM 17159598 ER PT J AU Unadkat, JD Wara, DW Hughes, MD Mathias, AA Holland, DT Paul, ME Connor, J Huang, S Nguyen, BY Watts, DH Mofenson, LM Smith, E Deutsch, P Kaiser, KA Tuomala, RE AF Unadkat, Jashvant D. Wara, Diane W. Hughes, Michael D. Mathias, Anita A. Holland, Diane T. Paul, Mary E. Connor, James Huang, Sharon Nguyen, Bach-Yen Watts, D. Heather Mofenson, Lynne M. Smith, Elizabeth Deutsch, Paul Kaiser, Kathleen A. Tuomala, Ruth E. TI Pharmacokinetics and safety of indinavir in human immunodeficiency virus-infected pregnant women SO ANTIMICROBIAL AGENTS AND CHEMOTHERAPY LA English DT Article AB Human immunodeficiency virus-infected women (n = 16) received indinavir (800 mg three times a day) plus zidovudine plus lamivudine from 14 to 28 weeks of gestation to 12 weeks postpartum. Two women and eight infants experienced grade 3 or 4 toxicities that were possibly treatment related. Indinavir area under the plasma concentration-time curve was 68% lower antepartum versus postpartum, suggesting increased intestinal and/or hepatic CYP3A activity during pregnancy. C1 Univ Washington, Dept Pharmaceut, Seattle, WA 98195 USA. Univ Calif San Francisco, Dept Pediat, San Francisco, CA USA. Harvard Univ, Sch Publ Hlth, Ctr Biostat AIDS Res, Boston, MA USA. Univ Calif San Diego, Div Clin Pharmacol & Dev Therapeut, San Diego, CA USA. Baylor Coll Med, Houston, TX 77030 USA. Merck Res Labs, West Point, PA USA. Natl Inst Child Hlth & Human Dev, Pediat Adolescent & Maternal AIDS Branch, Bethesda, MD USA. Natl Inst Allergy & Infect Dis, Div AIDS, Pediat Med Branch, Bethesda, MD USA. Frontier Sci & Technol Res Fdn Inc, Boston, MA USA. Brigham & Womens Hosp, Dept Obstet & Gynecol, Boston, MA USA. RP Unadkat, JD (reprint author), Univ Washington, Dept Pharmaceut, Box 357610, Seattle, WA 98195 USA. EM jash@u.washington.edu OI Mofenson, Lynne/0000-0002-2818-9808 FU NIAID NIH HHS [U01 AI41089, U01 AI041089]; NICHD NIH HHS [N01-HD-3-3345, P50 HD044404, P50 HD44404] NR 13 TC 50 Z9 50 U1 0 U2 0 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0066-4804 J9 ANTIMICROB AGENTS CH JI Antimicrob. Agents Chemother. PD FEB PY 2007 VL 51 IS 2 BP 783 EP 786 DI 10.1128/AAC.00420-06 PG 4 WC Microbiology; Pharmacology & Pharmacy SC Microbiology; Pharmacology & Pharmacy GA 131WB UT WOS:000243900600058 PM 17158945 ER PT J AU Liu, J Pedersen, LC AF Liu, Jian Pedersen, Lars C. TI Anticoagulant heparan sulfate: structural specificity and biosynthesis SO APPLIED MICROBIOLOGY AND BIOTECHNOLOGY LA English DT Review DE heparin; heparan sulfate; sulfotransferase; anticoagulant; oligosaccharide; herpes simplex virus ID D-GLUCOSAMINYL 3-O-SULFOTRANSFERASE; HERPES-SIMPLEX-VIRUS; HAMSTER OVARY CELLS; SUBSTRATE SPECIFICITIES; N-SULFOTRANSFERASE; ANTITHROMBIN-III; TERNARY COMPLEX; ENTRY RECEPTOR; HUMAN CDNAS; BINDING AB Heparan sulfate (HS) is present on the surface of endothelial and surrounding tissues in large quantities. It plays important roles in regulating numerous functions of the blood vessel wall, including blood coagulation, inflammation response, and cell differentiation. HS is a highly sulfated polysaccharide containing glucosamine and glucuronic/iduronic acid repeating disaccharide units. The unique sulfated saccharide sequences of HS determine its specific functions. Heparin, an analog of HS, is the most commonly used anticoagulant drug. Because of its wide range of biological functions, HS has become an interesting molecule to biochemists, medicinal chemists, and developmental biologists. In this review, we summarize recent progress toward understanding the interaction between HS and blood- coagulating factors, the biosynthesis of anticoagulant HS and the mechanism of action of HS biosynthetic enzymes. Furthermore, knowledge of the biosynthesis of HS facilitates the development of novel enzymatic approaches to synthesize HS from bacterial capsular polysaccharides and to produce polysaccharide end products with high specificity for the biological target. These advancements provide the foundation for the development of polysaccharide-based therapeutic agents. C1 Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Chapel Hill, NC 27599 USA. Natl Inst Environm Hlth Sci, Struct Biol Lab, NIH, Res Triangle Pk, NC 27709 USA. RP Liu, J (reprint author), Univ N Carolina, Sch Pharm, Div Med Chem & Nat Prod, Rm 309,Beard Hall, Chapel Hill, NC 27599 USA. EM jian_liu@unc.edu FU Intramural NIH HHS; NIAID NIH HHS [AI050050, R01 AI050050] NR 62 TC 57 Z9 64 U1 1 U2 14 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0175-7598 J9 APPL MICROBIOL BIOT JI Appl. Microbiol. Biotechnol. PD FEB PY 2007 VL 74 IS 2 BP 263 EP 272 DI 10.1007/s00253-006-0722-x PG 10 WC Biotechnology & Applied Microbiology SC Biotechnology & Applied Microbiology GA 132SC UT WOS:000243961500001 PM 17131147 ER PT J AU Huang, TTK Ball, GDC Franks, PW AF Huang, Terry T. -K. Ball, Geoff D. C. Franks, Paul W. TI Metabolic syndrome in youth: current issues and challenges SO APPLIED PHYSIOLOGY NUTRITION AND METABOLISM-PHYSIOLOGIE APPLIQUEE NUTRITION ET METABOLISME LA English DT Review DE metabolic syndrome; obesity; cardiovascular risk; children; adolescents ID CARDIOVASCULAR RISK-FACTORS; INSULIN-RESISTANCE SYNDROME; NUTRITION EXAMINATION SURVEY; 3RD NATIONAL-HEALTH; AMERICAN-HEART-ASSOCIATION; PHYSICAL-ACTIVITY; DANISH CHILDREN; BLOOD-PRESSURE; SCIENTIFIC STATEMENT; PREADOLESCENT GIRLS AB The current paper reviews the important issues and challenges facing children and adolescents with the metabolic syndrome (MetS). Studies suggest that the MetS and its risk components may be on the rise in children along with rising rates of obesity; however, further study remains warranted. The topics reviewed encompass the definition of the syndrome, its prevalence, clustering and tracking of metabolic risk factors, the role of physical activity and diet in the development of the MetS, criticisms and utility of the MetS definition, and special considerations needed in the pediatric population. Physical activity and diet may play important roles in the MetS; however, research with precise measurements of activity, diet, and metabolic outcomes is needed. The paper concludes by emphasizing that regardless of one's position in the ongoing debate about the MetS, the long-term risks attributable to each individual risk component are real. The abnormality of one component should automatically prompt the screening of other components. Among children and adolescents, lifestyle modification should always serve as the frontline strategy. Prevention during childhood is key to the largest possible impact on adult health at the population level. C1 NICHHD, Ctr Res Mothers & Childrens, Endocrinol Nutr & Growth Branch, Rockville, MD 20852 USA. Univ Alberta, Dept Pediat & Child Hlth, Edmonton, AB, Canada. Univ Cambridge, MRC, Epidemiol Unit, Cambridge, England. Univ Umea Hosp, Inst Publ Hlth & Clin Med, Dept Med, Genet Epidemiol & Clin Res Grp, S-90185 Umea, Sweden. RP Huang, TTK (reprint author), NICHHD, Ctr Res Mothers & Childrens, Endocrinol Nutr & Growth Branch, 6100 Execut Blvd,4B11, Rockville, MD 20852 USA. EM huangter@mail.nih.gov OI Franks, Paul/0000-0002-0520-7604 NR 77 TC 33 Z9 35 U1 0 U2 5 PU CANADIAN SCIENCE PUBLISHING, NRC RESEARCH PRESS PI OTTAWA PA 1200 MONTREAL ROAD, BUILDING M-55, OTTAWA, ON K1A 0R6, CANADA SN 1715-5312 J9 APPL PHYSIOL NUTR ME JI Appl. Physiol. Nutr. Metab. PD FEB PY 2007 VL 32 IS 1 BP 13 EP 22 DI 10.1139/H06-094 PG 10 WC Nutrition & Dietetics; Physiology; Sport Sciences SC Nutrition & Dietetics; Physiology; Sport Sciences GA 144ZY UT WOS:000244836300003 ER PT J AU Territo, PR Heil, J Bose, S Evans, FJ Balaban, RS AF Territo, Paul R. Heil, Jeremy Bose, Salil Evans, Frank J. Balaban, Robert S. TI Fluorescence absorbance inner-filter decomposition: The role of emission shape on estimates of free Ca2+ using Rhod-2 SO APPLIED SPECTROSCOPY LA English DT Article DE fluorescence; absorbance; inner filter; spectral decomposition; Rhod-2; calcium; algorithms ID MITOCHONDRIAL OXIDATIVE-PHOSPHORYLATION; SINGULAR-VALUE DECOMPOSITION; CYTOCHROME-C; HEMOGLOBIN; KINETICS; LIGHT; FLUOROMETER; ABSORPTION; ACTIVATION; SCATTERING AB A method for decomposing complex emission spectra by correcting for known inner-filter effects is described. This approach builds on previous work using a linear combination of model emission spectra and combines the known absorption characteristics of the system to fit the composite emission spectrum. Rhod-2, which has a small Stokes shift and significant self-absorption, was used as the model system. By adding the absorption characteristics of Rhod-2 to the model, the degree of fit was significantly improved, thus minimizing residuals, and accurately predicted the spectral shape changes with increasing concentration, [Rhod-2]. More complex studies were conducted with Rhod-2 in isolated cardiac mitochondria with multiple emission and absorption elements. By including known absorbances to the spectral decomposition, the overall precision increased almost four fold. Moreover, this approach eliminated the significant [Rhod-2] dependence on the apparent K-50 and therefore improved the accuracy of free [Ca2+] calculations. These data demonstrate that secondary inner-fitter correction can significantly improve spectral decomposition of complex emission spectra, which are used in a variety of biological applications. C1 Eli Lilly & Co, Lilly Res Labs, Lilly Ctr Mol & Anat Imaging, Greenfield, IN 46140 USA. NHLBI, Cardiac Energet Lab, NIH, Bethesda, MD 20892 USA. RP Territo, PR (reprint author), Eli Lilly & Co, Lilly Res Labs, Lilly Ctr Mol & Anat Imaging, 2001 W Main St,B220-GL54, Greenfield, IN 46140 USA. EM territop@lilly.com NR 31 TC 3 Z9 3 U1 0 U2 4 PU SOC APPLIED SPECTROSCOPY PI FREDERICK PA 201B BROADWAY ST, FREDERICK, MD 21701 USA SN 0003-7028 J9 APPL SPECTROSC JI Appl. Spectrosc. PD FEB PY 2007 VL 61 IS 2 BP 138 EP 147 DI 10.1366/000370207779947530 PG 10 WC Instruments & Instrumentation; Spectroscopy SC Instruments & Instrumentation; Spectroscopy GA 137CJ UT WOS:000244270100003 PM 17331304 ER PT J AU Hasler, G van der Veen, JW Tumonis, T Meyers, N Shen, J Drevets, WC AF Hasler, Gregor van der Veen, Jan Willem Tumonis, Toni Meyers, Noah Shen, Jun Drevets, Wayne C. TI Reduced prefrontal glutamate/glutamine and gamma-aminobutyric acid levels in major depression determined using proton magnetic resonance spectroscopy SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID ANTERIOR CINGULATE CORTEX; GLIAL-CELL DENSITY; MOOD DISORDERS; HUMAN BRAIN; ELECTROCONVULSIVE-THERAPY; GABA LEVELS; NEURONAL SIZE; GLUTAMATE; MR; HIPPOCAMPUS AB Context: Increasing evidence indicates that major depressive disorder (MDD) is associated with altered function of the major excitatory and inhibitory neurotransmitters glutamate and gamma-aminobutyric acid (GABA), respectively. A recently developed magnetic resonance spectroscopy method allows for reliable measurement of glutamate/glutamine (Glx) and GABA concentrations in prefrontal brain regions that have been implicated in the pathophysiologic mechanisms of MDD by studies using other neuroimaging and postmortem techniques. Objective: To measure Glx and GABA levels in 2 regions of the prefrontal brain tissue in unmedicated adults with MDD. Design: Cross-sectional study for association. Setting: Psychiatric outpatient clinic. Participants: Twenty unmedicated, depressed patients with MDD and 20 age- and sex-matched controls. Intervention: Participants underwent scanning using a 3-T whole-body scanner with a transmit-receive head coil, providing a homogeneous radiofrequency field and the capability of obtaining spectroscopic measurements in a dorsomedial/dorsal anterolateral prefrontal region of interest (ROI) and a ventromedial prefrontal ROI. Main Outcome Measures: Glx and GABA levels derived from magnetic resonance spectroscopy signals. Results: Depressed patients had reduced Glx levels in both ROIs. The GABA levels were reduced in the dorsomedial/dorsal anterolateral prefrontal ROI. Levels of GABA and Glx were positively correlated in both ROIs. Conclusions: For the first time, GABA and Glx concentrations were compared between unmedicated depressed adults and controls in prefrontal ROIs. The abnormal reductions in Glx and GABA concentrations found in the MDD sample were compatible with findings from postmortem histopathologic studies, indicating that glial cell density is reduced in the same areas in MDD. C1 Univ Zurich Hosp, Dept Psychiat, CH-8091 Zurich, Switzerland. NIMH, Magnet Resonance Spect Core, NIH, Bethesda, MD 20892 USA. NIMH, Mood & Anxiety Disorders Program, Sect Neuroimaging Mood & Anxiety Disorders, NIH, Bethesda, MD 20892 USA. RP Hasler, G (reprint author), Univ Zurich Hosp, Dept Psychiat, Culmannstr 8, CH-8091 Zurich, Switzerland. EM g.hasler@bluewin.ch RI Hasler, Gregor/E-4845-2012 OI Hasler, Gregor/0000-0002-8311-0138 NR 54 TC 342 Z9 355 U1 6 U2 28 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD FEB PY 2007 VL 64 IS 2 BP 193 EP 200 DI 10.1001/archpsyc.64.2.193 PG 8 WC Psychiatry SC Psychiatry GA 133DD UT WOS:000243990900006 PM 17283286 ER PT J AU Oquendo, MA Hastings, RS Huang, YY Simpson, N Ogden, RT Hu, XZ Goldman, D Arango, V Van Heertum, RL Mann, JJ Parsey, RV AF Oquendo, Maria A. Hastings, Ramin S. Huang, Yung-yu Simpson, Norman Ogden, R. Todd Hu, Xian-zhang Goldman, David Arango, Victoria Van Heertum, Ronald L. Mann, J. John Parsey, Ramin V. TI Brain serotonin transporter binding in depressed patients with bipolar disorder using positron emission tomography SO ARCHIVES OF GENERAL PSYCHIATRY LA English DT Article ID DORSAL RAPHE NUCLEUS; MAJOR DEPRESSION; MOOD DISORDERS; TRYPTOPHAN-HYDROXYLASE; COMPUTED-TOMOGRAPHY; GRAPHICAL ANALYSIS; BLOOD-PLATELETS; PET; GENE; PATHOPHYSIOLOGY AB Context: Depression in bipolar disorder is clinically indistinguishable from that observed in major depressive disorder. As in major depression, selective serotonin reuptake inhibitors targeting brain serotonin transporters are first-line treatments for bipolar depression. Associations of serotonin transporter promoter polymorphisms and bipolarity have been reported; however, research on alterations in serotonergic neuro transmission in bipolar depression remains scant. Objectives: To assess in vivo brain serotonin transporter binding potential (BP1, proportional to serotonin transporter number) in patients with bipolar depression and controls and to examine the relationship between serotonin transporter binding and genotype. Design: Case-control study. Setting: University hospital. Participants: A sample of 18 medication-free patients with bipolar depression and 41 controls. Main Outcome Measures: In vivo brain serotonin transporter binding was measured using positron emission tomography and radiolabeled trans-1,2,3,5,6, 10-beta-hexahydro-6-[4-(methylthio) phenyl]pyrrolo-[2,1-a]-isoquinoline ([C-11] (+)-McNeil 5652). Participants were genotyped assessing biallelic and triallefic 5-HTTLPR polymorphisms. Results: Patients with bipolar disorder had 16% to 26% lower serotonin transporter BP1 in the midbrain, amygdala, hippocampus, thalamus, putamen, and anterior cingulate cortex. Triallelic 5-HTTLPR genotypes were unrelated to serotonin transporter BP1. Conclusions: Lower serotonin transporter BP1 in bipolar depression overlaps with that observed in major depression and suggests that serotonergic dysfunction is common to depressive conditions. C1 New York State Psychiat Inst & Hosp, Dept Neurosci, New York, NY 10032 USA. Columbia Univ, Coll Phys & Surg, Dept Psychiat, New York, NY USA. Columbia Univ, Coll Phys & Surg, Dept Radiol, New York, NY USA. NIAAA, Neurogenet Lab, NIH, Rockville, MD 20852 USA. Columbia Univ, Sch Publ Hlth, Dept Biostat, New York, NY USA. RP Oquendo, MA (reprint author), New York State Psychiat Inst & Hosp, Dept Neurosci, 1051 Riverside Dr,Box 42, New York, NY 10032 USA. EM moquendo@neuron.cpmc.columbia.edu RI Ogden, Todd/H-7946-2012; Arango, Victoria/K-9377-2015; Goldman, David/F-9772-2010 OI Arango, Victoria/0000-0001-8811-400X; Goldman, David/0000-0002-1724-5405 FU NIMH NIH HHS [P50 MH062185, MH59710, MH62185, R01 MH059710] NR 60 TC 75 Z9 76 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-990X J9 ARCH GEN PSYCHIAT JI Arch. Gen. Psychiatry PD FEB PY 2007 VL 64 IS 2 BP 201 EP 208 DI 10.1001/archpsyc.64.2.201 PG 8 WC Psychiatry SC Psychiatry GA 133DD UT WOS:000243990900007 PM 17283287 ER PT J AU Voon, V Thomsen, T Miyasaki, JM de Souza, M Shafro, A Fox, SH Duff-Canning, S Lang, AE Zurowski, M AF Voon, Valerie Thomsen, Teri Miyasaki, Janis M. de Souza, Minella Shafro, Ariel Fox, Susan H. Duff-Canning, Sarah Lang, Anthony E. Zurowski, Mateusz TI Factors associated with dopaminergic drug-related pathological gambling in Parkinson disease SO ARCHIVES OF NEUROLOGY LA English DT Article ID NOVELTY SEEKING; PERSONALITY; DISORDERS; ALCOHOL; ONSET AB Objective: To evaluate factors associated with pathological gambling (PG) in Parkinson disease (PD). Design: Case-control study. Setting: Outpatient tertiary clinic. Patients: Twenty-one patients with idiopathic PD with PG after the patients began receiving medications compared with a consecutive sample of 42 patients with idiopathic PD without compulsive behaviors. Main Outcome Measures: Clinical features, comorbid psychiatric and substance use disorders, personality traits, and impulsivity scores. Results: Patients with PG had a younger age at PD onset (P=.006), higher novelty seeking (P <.001), medication-induced hypomania or mania (P=.001), impaired planning (P=.002), or a personal or immediate family history of alcohol use disorders (P=.002). Novelty seeking, a personal or immediate family history of alcohol use disorders, and younger age at PD onset accurately predicted PG at 83.7% in a logistic regression model, with the model accounting for 62% of the variance. Conclusions: Patients with PD having a younger age at PD onset, higher novelty seeking traits, and a personal or family history of alcohol use disorders may have a greater risk for PG with dopamine agonists. C1 NINDS, NIH, Bethesda, MD 20892 USA. Toronto Western Hosp, Dept Psychiat, Toronto, ON M5T 2S8, Canada. Toronto Western Hosp, Div Neurol, Toronto, ON M5T 2S8, Canada. RP Voon, V (reprint author), NINDS, NIH, 10 Ctr Dr,MSC 1428,Bldg 10,Room 5S213, Bethesda, MD 20892 USA. EM voonv@ninds.nih.gov RI zurowski, mateusz/D-1536-2010; OI zurowski, mateusz/0000-0002-6407-4629; Miyasaki, Janis/0000-0002-6372-6007 NR 18 TC 195 Z9 201 U1 2 U2 5 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9942 J9 ARCH NEUROL-CHICAGO JI Arch. Neurol. PD FEB PY 2007 VL 64 IS 2 BP 212 EP 216 DI 10.1001/archneur.64.2.212 PG 5 WC Clinical Neurology SC Neurosciences & Neurology GA 135OK UT WOS:000244162700008 PM 17296836 ER PT J AU Shiels, A Hejtmancik, JF AF Shiels, Alan Hejtmancik, J. Fielding TI Genetic origins of cataract SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID ALPHA-B-CRYSTALLIN; AGE-RELATED CATARACT; RECESSIVE CONGENITAL CATARACTS; POSTERIOR POLAR CATARACT; BEAVER DAM EYE; MISSENSE MUTATION; RISK-FACTORS; NONSENSE MUTATION; CORTICAL CATARACT; OXIDATIVE STRESS C1 NEI, Ophthalmol Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Ophthalmol & Visual Sci, St Louis, MO 63110 USA. RP Hejtmancik, JF (reprint author), NEI, Ophthalmol Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA. EM f3h@helix.nih.gov NR 61 TC 91 Z9 91 U1 0 U2 6 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD FEB PY 2007 VL 125 IS 2 BP 165 EP 173 DI 10.1001/archopht.125.2.165 PG 9 WC Ophthalmology SC Ophthalmology GA 134FR UT WOS:000244069400003 PM 17296892 ER PT J AU Blain, D Brooks, BP AF Blain, Delphine Brooks, Brian P. TI Molecular diagnosis and genetic counseling in ophthalmology SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID COMPARATIVE GENOMIC HYBRIDIZATION; FACTOR-H POLYMORPHISM; MACULAR DEGENERATION; LOW-VISION; IMBALANCES; DISTRESS; CHILDREN; DISEASE; IMPACT C1 NEI, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. MedStar Res Inst, Hyattsville, MD USA. RP Brooks, BP (reprint author), NEI, NIH, Dept Hlth & Human Serv, Bldg 10,Room 10N226,MSC 1860,10 Ctr Dr, Bethesda, MD 20892 USA. EM brooksb@mail.nih.gov FU Intramural NIH HHS NR 44 TC 7 Z9 7 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD FEB PY 2007 VL 125 IS 2 BP 196 EP 203 DI 10.1001/archopht.125.2.196 PG 8 WC Ophthalmology SC Ophthalmology GA 134FR UT WOS:000244069400006 PM 17296895 ER PT J AU Wong, WT Agron, E Coleman, HR Reed, GF Csaky, K Peterson, J Glenn, G Linehan, WM Albert, P Chew, EY AF Wong, Wai T. Agron, Elvira Coleman, Hanna R. Reed, George F. Csaky, Karl Peterson, James Glenn, Gladys Linehan, W. Marston Albert, Paul Chew, Emily Y. TI Genotype-phenotype correlation in von Hippel-Lindau disease with retinal angiomatosis SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID TUMOR-SUPPRESSOR GENE; GERMLINE MUTATIONS; CLINICAL-FEATURES; IDENTIFICATION AB Objectives: To characterize the germline mutations found in a large population of persons having von Hippel-Lindau (VHL) disease mutations with the clinical characteristics of associated retinal capillary hemangioblastomas (RCHs), to measure the prevalence of RCHs among patients with VHL disease generally and specifically for each genotype category, to establish genotype-phenotype correlations between genotype category and phenotypic features of ocular VHL disease, and to establish genotype-phenotype correlations between genotype category and visual function. Methods: Cross-sectional and molecular genetic study. Of 890 patients with VHL disease, 335 had ocular involvement in the form of RCHs. Statistical analysis was used to correlate the structure of the mutated VHL protein with the ocular phenotype. Results: Three genotype categories (amino acid substitutions, protein-truncating mutations, and complete deletions of VHL protein) were defined in all patients. The prevalence of RCHs was lowest (14.5%) among patients with complete deletions; the overall prevalence of retinal angiomatosis was 37.2%. Genotype category had no correlation with the unilaterality or bilaterality of ocular disease or with the number or extent of peripheral RCHs. The prevalence of RCHs at the juxtapapillary location was lower among patients with protein-truncating mutations compared with those with amino acid substitutions. Complete deletions were associated with the highest mean visual acuity compared with the other 2 genotype categories. Conclusion: Patients with complete deletions of VHL protein have the lowest prevalence of ocular disease and the most favorable visual outcome. Clinical Relevance: The VHL mutation genotype may be used to predict the prevalence and outcome of ocular VHL disease and to guide ophthalmic follow-up. C1 NEI, Div Epidemiol & Clin Res, NIH, Clin Res Ctr, Bethesda, MD 20892 USA. NEI, Off Sci Director, NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, Canc Res Ctr, NIH, Bethesda, MD 20892 USA. NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. RP Chew, EY (reprint author), NEI, Div Epidemiol & Clin Res, NIH, Clin Res Ctr, Bldg 10,Room 3-2531,10 Ctr Dr,MSC 1204, Bethesda, MD 20892 USA. RI Wong, Wai/B-6118-2017 OI Wong, Wai/0000-0003-0681-4016 FU Intramural NIH HHS [Z01 EY000463-01, ZIE EY000487-01, Z99 EY999999] NR 24 TC 31 Z9 33 U1 0 U2 0 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD FEB PY 2007 VL 125 IS 2 BP 239 EP 245 DI 10.1001/archopht.125.2.239 PG 7 WC Ophthalmology SC Ophthalmology GA 134FR UT WOS:000244069400012 PM 17296901 ER PT J AU Downs, K Zacks, DN Caruso, R Karoukis, AJ Branham, K Yashar, BM Haimann, MH Trzupek, K Meltzer, M Blain, D Richards, JE Weleber, RG Heckenlively, JR Sieving, PA Ayyagari, R AF Downs, Katy Zacks, David N. Caruso, Rafael Karoukis, Athanasios J. Branham, Kari Yashar, Beverly M. Haimann, Mark H. Trzupek, Karmen Meltzer, Meira Blain, Delphine Richards, Julia E. Weleber, Richard G. Heckenlively, John R. Sieving, Paul A. Ayyagari, Radha TI Molecular testing for hereditary retinal disease as part of clinical care SO ARCHIVES OF OPHTHALMOLOGY LA English DT Article ID LEBER CONGENITAL AMAUROSIS; DOMINANT MACULAR DYSTROPHY; CONE-ROD DYSTROPHY; ABCA4 ABCR GENE; RETINITIS-PIGMENTOSA; STARGARDT-DISEASE; BASIC RESEARCH; MUTATION; DEGENERATION; THERAPY AB Objective: To describe clinical molecular testing for hereditary retinal degenerations, highlighting results, interpretation, and patient education. Methods: Mutation analysis of 8 retinal genes was performed by dideoxy sequencing. Pretest and posttest genetic counseling was offered to patients. The laboratory report listed results and provided individualized interpretation. Results: A total of 350 tests were performed. The molecular basis of disease was determined in 133 of 266 diagnostic tests; the disease-causing mutations were not identified in the remaining 133 diagnostic tests. Predictive and carrier tests were requested for 9 and 75 nonsymptomatic patients with known familial mutations, respectively. Conclusions: Molecular testing can confirm a clinical diagnosis, identify carrier status, and confirm or rule out the presence of a familial mutation in nonsymptomatic at-risk relatives. Because causative mutations cannot be identified in all patients with retinal diseases, it is essential that patients are counseled before testing regarding the benefits and limitations of this emerging diagnostic tool. Clinical Relevance: The molecular definition of the genetic basis of disease provides a unique adjunct to the clinical care of patients with hereditary retinal degenerations. C1 Univ Michigan, WK Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, Ann Arbor, MI 48105 USA. Univ Michigan, Dept Otolaryngol Head & Neck Surg, Ann Arbor, MI 48105 USA. Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48105 USA. NEI, NIH, Bethesda, MD 20892 USA. Retina Consultants Michigan, Southfield, MI USA. Oregon Hlth Sci Univ, Casey Eye Inst, Portland, OR 97201 USA. MedStar Res Inst, Hyattsville, MD USA. RP Ayyagari, R (reprint author), Univ Michigan, WK Kellogg Eye Ctr, Dept Ophthalmol & Visual Sci, 1000 Wall St,Room 325, Ann Arbor, MI 48105 USA. EM ayyagari@umich.edu RI Zacks, David/I-4394-2013; OI Zacks, David/0000-0001-8592-5165 FU NEI NIH HHS [EY 07003, EY 07060, EY 11671, EY 13198] NR 48 TC 22 Z9 25 U1 0 U2 2 PU AMER MEDICAL ASSOC PI CHICAGO PA 515 N STATE ST, CHICAGO, IL 60610-0946 USA SN 0003-9950 J9 ARCH OPHTHALMOL-CHIC JI Arch. Ophthalmol. PD FEB PY 2007 VL 125 IS 2 BP 252 EP 258 DI 10.1001/archopht.125.2.252 PG 7 WC Ophthalmology SC Ophthalmology GA 134FR UT WOS:000244069400014 PM 17296903 ER PT J AU Sims, G Lipsky, P AF Sims, Gary Lipsky, Peter TI The existence of human TII B cells remains unproven: comment on the article by Daridon et al SO ARTHRITIS AND RHEUMATISM LA English DT Letter ID SJOGRENS-SYNDROME; IDENTIFICATION C1 NIH, Bethesda, MD 20892 USA. RP Sims, G (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 5 TC 0 Z9 0 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0004-3591 J9 ARTHRITIS RHEUM JI Arthritis Rheum. PD FEB PY 2007 VL 56 IS 3 BP 1035 EP 1036 DI 10.1002/art.22438 PG 2 WC Rheumatology SC Rheumatology GA 144XI UT WOS:000244829400045 PM 17330259 ER PT J AU Davis, RE Zhang, YQ Southall, N Staudt, LM Austin, CP Inglese, J Auld, DS AF Davis, R. Eric Zhang, Ya-Qin Southall, Noel Staudt, Louis M. Austin, Christopher P. Inglese, James Auld, Douglas S. TI A cell-based assay for I kappa B alpha stabilization using a two-color dual luciferase-based sensor SO ASSAY AND DRUG DEVELOPMENT TECHNOLOGIES LA English DT Article ID SMALL-MOLECULE INHIBITORS; GENE-EXPRESSION; GLUCOCORTICOID-RECEPTOR; LYMPHOMA; KINASE; MECHANISMS; SURVIVAL; VECTOR; SCREEN; SYSTEM AB A cell-sensor assay for stabilization of I kappa B alpha was developed in the activated B cell-like diffuse large B-cell lymphoma cell line OCI-Ly3. This cell line expresses known nuclear factor kappa B (NF kappa B) target genes due to high constitutive activity of I kappa B kinase (IKK), which phosphorylates the protein I kappa B alpha leading to proteasomal degradation of I kappa B alpha and activation of NF kappa B. The cell-sensor assay uses green and red light-emitting beetle luciferases, with the green luciferase fused to I kappa B alpha (I kappa B alpha-CBG68) and the red luciferase (CBR) present in its native state. The I kappa B alpha-CBG68 reporter functions as a sensor of IKK and proteasome activity, while CBR serves to normalize for cell number and nonspecific effects. Both reporter constructs were stably integrated and placed under the control of an inducible promoter system, which increased fold responsiveness to inhibitors when assay incubations were performed simultaneous to reporter induction by doxycycline. The assay was miniaturized to a 1,536-well plate format and showed a Z' of 0.6; it was then used to panel 2,677 bioactive compounds by a concentration-response-based screening strategy. The concentration-effect curves for the I kappa B alpha-CBG68 and CBR signals were then used to identify specific stabilizers of I kappa B alpha, such as IKK inhibitors or proteasome inhibitors, which increased the doxycycline-induced rise in I kappa B alpha-CBG68 without affecting the rise in CBR. Known and unexpected inhibitors of NF kappa B signaling were identified from the bioactive collection. We describe here the development and performance of this assay, and discuss the merits of its specific features. C1 NHGRI, NIH Chem Genom Ctr, NIH, Bethesda, MD 20892 USA. NCI, Canc Res Ctr, Metab Branch, Bethesda, MD 20892 USA. RP Auld, DS (reprint author), NHGRI, NIH Chem Genom Ctr, NIH, 9800 Med Ctr Dr, Bethesda, MD 20892 USA. EM dauld@mail.nih.gov RI Southall, Noel/H-8991-2012 OI Southall, Noel/0000-0003-4500-880X FU Intramural NIH HHS NR 29 TC 26 Z9 26 U1 2 U2 6 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1540-658X J9 ASSAY DRUG DEV TECHN JI ASSAY DRUG DEV. TECHNOL. PD FEB PY 2007 VL 5 IS 1 BP 85 EP 103 DI 10.1089/adt.2006.048 PG 19 WC Biochemical Research Methods; Pharmacology & Pharmacy SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 147VL UT WOS:000245030700006 PM 17355202 ER PT J AU Glover, CJ Rabow, AA Isgor, YG Shoemaker, RH Covell, DG AF Glover, Constance J. Rabow, Alfred A. Isgor, Yasemin G. Shoemaker, Robert H. Covell, David G. TI Data mining of NCI's anticancer screening database reveals mitochondrial complex I inhibitors cytotoxic to leukemia cell lines SO BIOCHEMICAL PHARMACOLOGY LA English DT Article DE apoptosis; mitochondria; NADH : coenzyme Q oxidoreductase; enzyme inhibition; drug discovery; self-organized maps; K562 leukemia cells ID NADH-UBIQUINONE OXIDOREDUCTASE; ESSENTIAL STRUCTURAL FACTORS; BOVINE HEART-MITOCHONDRIA; COENZYME-Q OXIDOREDUCTASE; DRUG DISCOVERY DATABASES; ELECTRON-TRANSPORT CHAIN; ANNONACEOUS ACETOGENINS; RESPIRATORY-CHAIN; CYTOCHROME-C; SYNTHETIC UBIQUINONES AB Mitochondria are principal mediators of apoptosis and thus can be considered molecular targets for new chemotherapeutic agents in the treatment of cancer. Inhibitors of mitochondrial complex I of the electron transport chain have been shown to induce apoptosis and exhibit antitumor activity. In an effort to find novel complex I inhibitors which exhibited anticancer activity in the NCI's tumor cell line screen, we examined organized tumor cytotoxicity screening data available as SOM (self-organized maps) (http//www.spheroid.ncifcrf.gov) at the developmental therapeutics program (DTP) of the National Cancer Institute (NCI). Our analysis focused on an SOM cluster comprised of compounds which included a number of known mitochondrial complex I (NADH:CoQ oxidoreductase) inhibitors. From these clusters 10 compounds whose mechanism of action was unknown were tested for inhibition of complex I activity in bovine heart sub-mitochondrial particles (SMP) resulting in the discovery that 5 of the 10 compounds demonstrated significant inhibition with IC50's in the nM range for three of the five. Examination of screening profiles of the five inhibitors toward the NCI's tumor cell lines revealed that they were cytotoxic to the leukemia subpanel (particularly K562 cells). Oxygen consumption experiments with permeabilized K562 cells revealed that the five most active compounds inhibited complex I activity in these cells in the same rank order and similar potency as determined with bovine heart SMP. Our findings thus fortify the appeal of mitochondrial complex I as a possible anticancer molecular target and provide a data mining strategy for selecting candidate inhibitors for further testing. (c) 2006 Elsevier Inc. All rights reserved. C1 Natl Canc Inst Frederick, Div Canc Treatment & Diagnosis, Dev Therapeut Program, Screening Technol Branch, Frederick, MD 21702 USA. NCI, SAIC, Frederick, MD 21702 USA. RP Glover, CJ (reprint author), Natl Canc Inst Frederick, Div Canc Treatment & Diagnosis, Dev Therapeut Program, Screening Technol Branch, Frederick, MD 21702 USA. EM cglover@mail.ncifcrf.gov RI Isgor, Yasemin/B-3322-2010 OI Isgor, Yasemin/0000-0002-6021-257X FU Intramural NIH HHS [Z99 CA999999] NR 75 TC 14 Z9 14 U1 0 U2 6 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 1 PY 2007 VL 73 IS 3 BP 331 EP 340 DI 10.1016/j.bcp.2006.10.005 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 134GP UT WOS:000244071800002 PM 17109823 ER PT J AU Ambudkar, IS AF Ambudkar, I. S. TI TRPC1: a core component of store-operated calcium channels SO BIOCHEMICAL SOCIETY TRANSACTIONS LA English DT Article; Proceedings Paper CT Conference on Cell and Molecular Biology of TRP Channels CY SEP 07-08, 2006 CL Univ Bath, Bath, ENGLAND SP Biochem Soc HO Univ Bath DE calcium-release activated calcium channel (CRAC channel); calcium signalling; endoplasmic reticulum; regulatory protein complex; store-operated calcium entry (SOCE); transient receptor potential canonical 1 (TRPC1) ID CAPACITATIVE CA2+ ENTRY; SALIVARY-GLAND CELLS; ENDOPLASMIC-RETICULUM; ENDOTHELIAL PERMEABILITY; T-LYMPHOCYTES; RECEPTOR; INFLUX; INHIBITION; DEPLETION; PROTEIN AB The TRPC (transient receptor potential canonical) proteins are activated in response to agonist-stimulated PIP2 (phosphatidylinositol 4,5-bisphosphate) hydrolysis and have been suggested as candidate components of the elusive SOC (store-operated calcium channel). TRFC1 is currently the strongest candidate component of SOC. Enclogenous TRPC1 has been shown to contribute to SOCE (store-operated calcium entry) in several different cell types. However, the mechanisms involved in the regulation of TRFC1 and its exact physiological function have yet to be established. Studies from our laboratory and several others have demonstrated that TRPC1 is assembled in a signalling complex with key calcium signalling proteins in functionally specific plasma membrane microdomains. Furthermore, critical interactions between TRPC1 monomers as well as interactions between TRPC1 and other proteins determine the surface expression and function of TRFC1-containing channels. Recent studies have revealed novel regulators of TRFC1 -containing SOCs and have demonstrated a common molecular basis for the regulation of CRAC (calcium-release-activated calcium) and SOC channels. In the present paper, we will revisit the role of TRPC1 in SOCE and discuss how studies with TRPC1 provide an experimental basis for validating the mechanism of SOCE. C1 NIDCR, Secretory Physiol Sect, GTTB, NIH, Bethesda, MD 20892 USA. RP Ambudkar, IS (reprint author), NIDCR, Secretory Physiol Sect, GTTB, NIH, Bldg 10,Room 1N-113, Bethesda, MD 20892 USA. EM indu.ambudkar@nih.gov NR 52 TC 50 Z9 50 U1 0 U2 1 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0300-5127 J9 BIOCHEM SOC T JI Biochem. Soc. Trans. PD FEB PY 2007 VL 35 BP 96 EP 100 PN 1 PG 5 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 136IJ UT WOS:000244215500024 PM 17233611 ER PT J AU Pummill, PE Kane, TA Kempner, ES DeAngelis, PL AF Pummill, Philip E. Kane, Tasha A. Kempner, Ellis S. DeAngelis, Paul L. TI The functional molecular mass of the Pasteurella hyaluronan synthase is a monomer SO BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS LA English DT Article DE glycosaminoglycan; glycosyltransferase; hyaluronan; hyaluronan synthase; Pasteurella multocida; radiation inactivation ID 2 ACTIVE-SITES; RADIATION INACTIVATION; STREPTOCOCCUS-PYOGENES; CHEMOENZYMATIC SYNTHESIS; SYNTHESIZE HYALURONAN; DG42 GENE; IN-VITRO; MULTOCIDA; PROTEIN; XENOPUS AB Hyaluronan (HA), a linear polysaccharide composed of beta 1,3-GlcNAc-beta 1,4-GIcUA repeats, is found in the extracellular matrix of vertebrate tissues as well as the capsule of several pathogenic bacteria. All known HA synthases (HASs) are dual-action glycosyltransferases that catalyze the addition of two different sugars from UDP-linked precursors to the growing HA chain. The bacterial hyaluronan synthase, PmHAS from Gram-negative Pasteurella multocida, is a 972-residue membrane-associated protein. Previously, the Gram-positive Streptococcus pyogenes enzyme, SpHAS (419 residues), and the vertebrate enzyme, XlHAS1 (588 residues), were found to function as monomers of protein, but the PmHAS is not similar at the protein sequence level and has quite different enzymological properties. We have utilized radiation inactivation to measure the target size of recombinant full-length and truncated PmHAS. The target size of HAS activity was confirmed using internal enzyme standards of known molecular weight. We found that the Pasteurella HA synthase protein functions catalytically as a monomer. Functional truncated soluble PmHAS also behaves as a polypeptide monomer as assessed by gel filtration chromatography and light scattering. (c) 2006 Elsevier B.V All rights reserved. C1 Univ Oklahoma, Hlth Sci Ctr, Oklahoma Ctr Med Glycobiol, Dept Biochem & Mol Biol, Oklahoma City, OK 73104 USA. Hyalose LLC, Oklahoma City, OK 73104 USA. Natl Inst Arthritis & Musculoskeletal & Skin Dis, Off Sci & Technol, NIIH, Bethesda, MD 20892 USA. RP DeAngelis, PL (reprint author), Univ Oklahoma, Hlth Sci Ctr, Oklahoma Ctr Med Glycobiol, Dept Biochem & Mol Biol, 940 Stanton L Young Blvd, Oklahoma City, OK 73104 USA. EM paul-deangelis@ouhsc.edu FU NIAMS NIH HHS [Z01 AR027003-46]; NIGMS NIH HHS [R01 GM056497-04S1] NR 28 TC 0 Z9 1 U1 1 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0304-4165 J9 BBA-GEN SUBJECTS JI Biochim. Biophys. Acta-Gen. Subj. PD FEB PY 2007 VL 1770 IS 2 BP 286 EP 290 DI 10.1016/j.bbagen.2006.09.020 PG 5 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 129DZ UT WOS:000243709900016 PM 17095162 ER PT J AU Dalen, KT Dahl, T Holter, E Arntsen, B Londos, C Sztalryd, C Nebb, HI AF Dalen, Knut Tomas Dahl, Tuva Holter, Elin Arntsen, Borghild Londos, Constantine Sztalryd, Carole Nebb, Hilde I. TI LSDP5 is a PAT protein specifically expressed in fatty acid oxidizing tissues SO BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS LA English DT Article DE LSDP5; adipophilin; ADFP; S3-12; perilipin; TIP47; PAT; TAG; fatty acid; PPAR ID DIFFERENTIATION-RELATED PROTEIN; ACTIVATED-RECEPTOR-ALPHA; HORMONE-SENSITIVE LIPASE; MURINE PERILIPIN GENE; A-MEDIATED LIPOLYSIS; LIPID DROPLETS; ADIPOSE-TISSUE; CELL-LINE; POSTTRANSLATIONAL REGULATION; PEROXISOME PROLIFERATORS AB The PAT family (originally named for Perilipin, ADFP and TIP47) now includes four members: Perilipins, ADFP, TIP47 and S3-12. Significant primary sequence homology and the ability to associate with lipid storage droplets (LSDs) are well conserved within this family and across species. In this study, we have characterized a novel PAT protein, lipid storage droplet protein 5 (LSDP5) of 463 residues. A detailed sequence analysis of all murine PAT proteins reveals that LSDP5, TIP47 and ADFP share the highest order of sequence similarity, whereas perilipin and S3-12 have more divergent carboxyl- and amino-termini, respectively. Ectopically-expressed YFP-LSDP5 or flag-LSDP5 fusion proteins associate with LSDs. In accord with recent published data for perilipin, forced expression of LSDP5 in CHO cells inhibits lipolysis of intracellular LSDs. The LSDP5 gene is primarily transcribed in cells that actively oxidize fatty acids, such as heart, red muscle and liver. Expression of LSDP5 is stimulated by ligand activation of peroxisomal proliferator-activated receptor alpha (PPAR alpha), and significantly reduced in liver and heart in the absence of this transcription factor. PPAR alpha is generally required for regulation of fatty acid metabolism during fasting, but fasting induces LSDP5 mRNA in liver even in the absence of PPAR alpha. (c) 2006 Elsevier B.V. All rights reserved. C1 NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. Univ Oslo, Inst Basic Med Sci, Dept Nutr, N-0316 Oslo, Norway. Univ Maryland, Sch Med, Dept Med, Educ & Clin Ctr,Baltimore Vet Affairs Hlth Care C, Baltimore, MD 21201 USA. RP Dalen, KT (reprint author), NIDDK, Lab Cellular & Dev Biol, NIH, Bethesda, MD 20892 USA. EM dalenk@mail.nih.gov; h.i.nebb@medisin.uio.no RI Dalen, Knut Tomas/C-4719-2016 OI Dalen, Knut Tomas/0000-0002-0270-5982 FU NIDDK NIH HHS [R01 DK075017-01A2, R01 DK075017] NR 67 TC 107 Z9 113 U1 2 U2 9 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1388-1981 J9 BBA-MOL CELL BIOL L JI Biochim. Biophys. Acta Mol. Cell Biol. Lipids PD FEB PY 2007 VL 1771 IS 2 BP 210 EP 227 DI 10.1016/j.bbalip.2006.11.011 PG 18 WC Biochemistry & Molecular Biology; Biophysics; Cell Biology SC Biochemistry & Molecular Biology; Biophysics; Cell Biology GA 142HD UT WOS:000244639100010 PM 17234449 ER PT J AU Pardo, VG Facchinetti, MM Curino, A Boland, R de Boland, AR AF Gonzalez Pardo, Veronica Facchinetti, Maria Marta Curino, Alejandro Boland, Ricardo Russo de Boland, Ana TI Age-related alteration of 1 alpha,25(OH)(2)-vitamin D-3-dependent activation of p38 MAPK in rat intestinal cells SO BIOGERONTOLOGY LA English DT Article DE 1 alpha,25(OH)(2)D-3; enterocytes; p38 MAPK; calcium; c-Src; c-fos; ageing ID MEMBRANE-INITIATED ACTIONS; PROTEIN-KINASE; SIGNAL-TRANSDUCTION; CALCIUM-TRANSPORT; RECEPTOR KINETICS; BINDING-PROTEIN; SKELETAL-MUSCLE; D-3; 1,25(OH)(2)-VITAMIN-D-3; EXPRESSION AB In intestinal cells, 1 alpha,25(OH)(2)-vitamin D-3 (1 alpha,25(OH)(2)D-3) regulates gene expression via the specific intracellular vitamin D receptor and induces fast non-transcriptional responses involving stimulation of transmembrane signal transduction pathways. In the present study, we analyzed, for the first time, alterations in p38 MAPK response to 1 alpha,25(OH)(2)D-3 in rat enterocytes with ageing. In enterocytes from young rats, the hormone increased, in a time- and dose-dependent fashion, the phosphorylation of p38 MAPK, peaking at 3 min (+2-fold). Basal levels of p38 MAPK phosphorylation were lower in enterocytes from old rats and the hormone response was greatly diminished (+0.5-fold at 3 min). p38 MAPK phosphorylation impairment in old animals was not related to significant changes of the kinase protein expression and do not explain the decreased response to 1 alpha,25(OH)(2)D-3. Extracellular and intracellular Ca2+ chelation or c-Src pharmacological inhibition suppressed hormone activation of p38 MAPK in both, young and aged rats, demonstrating that Ca2+ and the non-receptor tyrosine kinase c-Src are required for full activation of p38 MAPK in cells stimulated with 1 alpha,25(OH)(2)D-3. Two other vitamin D-3 metabolites, 25(OH)D-3 and 24,25(OH)(2)D-3,D- also enhanced p38 phosphorylation, and to a similar extent than 1 alpha,25(OH)(2)D-3, an ability that is lost with ageing. Enterocyte exposure to the hormone also resulted in the rapid induction of c-fos protein (peaking at 5 min, +3-fold) and to a greater extent than that of mRNA induction. With ageing, 1 alpha,25(OH)(2)D-3-dependent increase of c-fos protein level was diminished, but c-fos mRNA expression was not different from young animals. Impairment of 1 alpha,25(OH)(2)D-3 activation of p38 MAPK upon ageing and abnormal hormone regulation of the c-fos oncoprotein synthesis may affect intestinal cell function. C1 Univ Nacl Sur, Dept Biol Bioquim & Farm, RA-8000 Bahia Blanca, Buenos Aires, Argentina. NCI, Neurooncol Branch, NIH, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Oral & Pharyngeal Canc Branch, NIH, Bethesda, MD 20892 USA. RP de Boland, AR (reprint author), Univ Nacl Sur, Dept Biol Bioquim & Farm, San Juan 670, RA-8000 Bahia Blanca, Buenos Aires, Argentina. EM aboland@criba.edu.ar NR 49 TC 5 Z9 5 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1389-5729 J9 BIOGERONTOLOGY JI Biogerontology PD FEB PY 2007 VL 8 IS 1 BP 13 EP 24 DI 10.1007/s10522-006-9031-0 PG 12 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 123UO UT WOS:000243321800002 PM 16855859 ER PT J AU Murphy, TK Snider, LA Mutch, PJ Harden, E Zaytoun, A Edge, PJ Storch, EA Yang, MCK Mann, G Goodman, WK Swedo, SE AF Murphy, Tanya K. Snider, Lisa A. Mutch, P. Jane Harden, Elaine Zaytoun, Annette Edge, Paula J. Storch, Eric A. Yang, Mark C. K. Mann, Giselle Goodman, Wayne K. Swedo, Susan E. TI Relationship of movements and behaviors to group A streptococcus infections in elementary school children SO BIOLOGICAL PSYCHIATRY LA English DT Article DE ADHD; behavior; choreiform; group A streptococcus; PANDAS; tics ID OBSESSIVE-COMPULSIVE DISORDER; ACUTE RHEUMATIC-FEVER; PRIVATE PEDIATRIC PRACTICE; SEASONAL-VARIATION; TIC DISORDERS; CHOREA; EXACERBATIONS; PREVALENCE; ANTIBODIES; SYMPTOMS AB Background: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcus (PANDAS) research is based on the hypothesis that infections trigger changes in behavior and movement in children. Methods: We enrolled 693 children (ages 3 to 12 years) into a systematic, longitudinal study. Data were collected monthly for 8 months (October-May) to determine point prevalence of Group A Streptococcal (GAS) infections, tics, behavior, and choreiform movements. Simultaneous throat cultures were obtained, and relational analyses were made between GAS and movement/observation ratings. Results: Combined behavior/GAS associations (concurrent with or 3 subsequent months to GAS) revealed a strong relationship, relative risk (RR) of 1.71 (p <.0001). Detailed analysis revealed that balance/swaying and non-tic grimacing wen, reponsible for a significant proportion of this association (RR = 2.92, p <.0001). A strong seasonal pattern was found, with fall being more significant for GAS infections and observation ratings (p <.0001) compared with winter/spring. Children with repeated streptococcus (n = 64) showed higher rates of behavior and distal choreiform observations (p =.005). Conclusions: Motor/behavior changes were noted to occur in relationship to positive GAS culture with support that repeated GAS increases risk. C1 Univ Florida, Dept Psychiat, Coll Med, Gainesville, FL 32610 USA. Univ Florida, Dept Stat, Gainesville, FL 32610 USA. NIMH, Pediat & Dev Neuropsychiat Branch, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Murphy, TK (reprint author), Univ Florida, Dept Psychiat, Coll Med, POB 100256, Gainesville, FL 32610 USA. EM tmurphy@psychiatry.ufl.edu RI Storch, Eric/I-4935-2012 NR 35 TC 29 Z9 30 U1 3 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 2007 VL 61 IS 3 BP 279 EP 284 DI 10.1016/j.biopsych.2006.08.031 PG 6 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 131MM UT WOS:000243873100004 PM 17126304 ER PT J AU Winslow, JT Noble, PL Davis, M AF Winslow, James T. Noble, Pamela L. Davis, Michael TI Modulation of fear-potentiated startle and vocalizations in juvenile rhesus monkeys by morphine, diazepam, and buspirone SO BIOLOGICAL PSYCHIATRY LA English DT Article DE acoustic startle; amygdala; anxiety; fear; memory; vocalization ID GENERALIZED ANXIETY DISORDER; ACOUSTIC STARTLE; RECEPTOR LIGANDS; MACACA-MULATTA; ULTRASONIC VOCALIZATION; CONDITIONED FEAR; ANXIOLYTIC DRUG; LONG-TERM; RATS; PARADIGM AB Background: Modulation of the acoustic startle response by aversive sensory stimulation is a simple and objective indicator of emotionality in rodents and human beings that has been extremely valuable for the analysis of neural systems associated with fear and anxiety. We have described a paradigm for measuring fear-potentiated, whole-body acoustic startle in nonhuman primates and have developed a protocol for maintaining fear-potentiated startle over repeated sessions with minimal extinction to allow measurement of pharmacological effects on fear-potentiated startle by using within-subjects designs in relatively small groups of monkeys. Methods: A novel, within-subjects testing protocol was used to examine the effects of three compounds in rhesus monkeys that have anxiolytic effects in rodents on fear-potentiated startle but that differ in their mechanism of action. Spontaneous vocalizations during testing also were recorded. Juvenile monkeys that were trained to associate a visual stimulus with a fear-inducing air blast to the face were tested after acute administration of different doses of buspirone diazepam, morphine, or vehicle. Results: Monkeys rapidly developed a robust and persistent elevation of startle response in the presence of the CS during repeated testing sessions. Diazepam and morphine produced dose-related reductions of fear-potentiated startle. Buspirone did not significantly reduce fear-potentiated startle at the doses tested, although a trend was evident at the highest dose. All drugs reduced rates of coo vocalizations during startle testing. Conclusions: These fear-potentiated startle results suggest that rhesus monkeys have a pharmacological profile with respect to these compounds that is closer to humans than to rats. This demonstrates the value of examining the effects of drugs on fear-potentiated startle in nonhuman primates. C1 Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30322 USA. Emory Univ, Ctr Behav Neurosci, Atlanta, GA 30322 USA. RP Winslow, JT (reprint author), NIMH, IRP, NHP Core, NIHAC Bldg 110,9000 Rockville Pike, Bethesda, MD 20892 USA. EM jameswinslow@mail.nih.gov FU NIMH NIH HHS [MH47840, MH57704, MH58922] NR 47 TC 34 Z9 34 U1 4 U2 6 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0006-3223 J9 BIOL PSYCHIAT JI Biol. Psychiatry PD FEB 1 PY 2007 VL 61 IS 3 BP 389 EP 395 DI 10.1016/j.biopsych.2006.03.012 PG 7 WC Neurosciences; Psychiatry SC Neurosciences & Neurology; Psychiatry GA 131MM UT WOS:000243873100019 PM 16730332 ER PT J AU Rezvani, K Yong, ASM Price, DA Mielke, S Savani, B Gostick, E Douek, D Barrett, AJ AF Rezvani, K. Yong, A. S. M. Price, D. A. Mielke, S. Savani, B. Gostick, E. Douek, D. Barrett, A. J. TI WTI-specific T lymphocytes participate in the elimination of acute lymphoblastic leukemia following allogeneic stem cell transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT Meeting 2007 CY FEB 08-12, 2007 CL Keystone, CO SP Amer Soc Blood & Marrow Transplantat, Ctr Int Blood & Marrow Transplantat Res, Pfizer Inc C1 NIH, Bethesda, MD 20892 USA. Univ Oxford, Nuffield Dept Clin Med, Oxford, England. RI Price, David/C-7876-2013 OI Price, David/0000-0001-9416-2737 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2007 VL 13 IS 2 SU 2 MA 3 BP 1 EP 2 DI 10.1016/j.bbmt.2006.12.004 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 133QU UT WOS:000244028300004 ER PT J AU Chu, YW Schmitz, S Choudhury, B Gress, RE AF Chu, Y. -W. Schmitz, S. Choudhury, B. Gress, R. E. TI Insulin-like growth factor I positively regulates thymic function by expansion of thymocyte precursors and thymic epithelial cells SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT Meeting 2007 CY FEB 08-12, 2007 CL Keystone, CO SP Amer Soc Blood & Marrow Transplantat, Ctr Int Blood & Marrow Transplantat Res, Pfizer Inc C1 Natl Canc Inst, Expt Transplantat, Immunol Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2007 VL 13 IS 2 SU 2 MA 42 BP 18 EP 18 DI 10.1016/j.bbmt.2006.12.045 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 133QU UT WOS:000244028300043 ER PT J AU Williams, KM Chu, YW Tayler, E Gress, RE AF Williams, K. M. Chu, Y. -W. Tayler, E. Gress, R. E. TI Androgen withdrawal modulates thymopoiesis by inducing thymic epithelial cell proliferation and enhancing thymocyte development prior to increasing precursor immigration SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT Meeting 2007 CY FEB 08-12, 2007 CL Keystone, CO SP Amer Soc Blood & Marrow Transplantat, Ctr Int Blood & Marrow Transplantat Res, Pfizer Inc C1 NIH, NCI, Expt Transplant & Immunol Branch, Bethesda, MD 20892 USA. NR 0 TC 1 Z9 1 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2007 VL 13 IS 2 SU 2 MA 51 BP 21 EP 21 DI 10.1016/j.bbmt.2006.12.054 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 133QU UT WOS:000244028300052 ER PT J AU Donohue, TB Savani, BN Shenoy, A Kozanas, E Singh, AK Childs, RW Barrett, AJ AF Donohue, T. B. Savani, B. N. Shenoy, A. Kozanas, E. Singh, A. K. Childs, R. W. Barrett, A. J. TI High prevalence of bone loss in long term survivors following allogeneic bone marrow and peripheral blood stem cell transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT Meeting 2007 CY FEB 08-12, 2007 CL Keystone, CO SP Amer Soc Blood & Marrow Transplantat, Ctr Int Blood & Marrow Transplantat Res, Pfizer Inc C1 Natl Inst Hlth, NHLBI, Stem Cell Transplant Sect, Bethesda, MD USA. NCI, Natl Inst Hlth, Radiat Biol Sect, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2007 VL 13 IS 2 SU 2 MA 128 BP 49 EP 49 DI 10.1016/j.bbmt.2006.12.132 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 133QU UT WOS:000244028300129 ER PT J AU Savani, BN Shenoy, A Kozanas, E Wisch, L Singh, AK Childs, R Barrett, AJ AF Savani, B. N. Shenoy, A. Kozanas, E. Wisch, L. Singh, A. K. Childs, R. Barrett, A. J. TI Hypothyroidism in long-term survivors after TBI based allogeneic stem cell transplantations - Impact of chronic graft versus host disease and TBI dose SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT Meeting 2007 CY FEB 08-12, 2007 CL Keystone, CO SP Amer Soc Blood & Marrow Transplantat, Ctr Int Blood & Marrow Transplantat Res, Pfizer Inc C1 NIH, NHLBI, Bethesda, MD 20892 USA. NIH, Natl Canc Inst, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2007 VL 13 IS 2 SU 2 BP 52 EP 52 DI 10.1016/j.bbmt.2006.12.142 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 133QU UT WOS:000244028300139 ER PT J AU Bociek, RG Talmadge, JE Loberiza, F Kuszynski, CA Bierman, PJ Vose, JM Devetten, MP Maness, LJ Armitage, JO Joshi, S Wisecarver, JL Enke, CA McGuire, T Bernal, K Pavletic, SZ AF Bociek, R. G. Talmadge, J. E. Loberiza, F. Kuszynski, C. A. Bierman, P. J. Vose, J. M. Devetten, M. P. Maness, L. J. Armitage, J. O. Joshi, S. Wisecarver, J. L. Enke, C. A. McGuire, T. Bernal, K. Pavletic, S. Z. TI Nonmyeloablative allogeneic stem cell transplantation (NST) for hematologic malignancies (HM) using pentostatin/low-dose total body irradiation (PT-TBI) SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT Meeting 2007 CY FEB 08-12, 2007 CL Keystone, CO SP Amer Soc Blood & Marrow Transplantat, Ctr Int Blood & Marrow Transplantat Res, Pfizer Inc C1 Univ Nebraska Med Ctr, Omaha, NE USA. NIH, Washington, DC USA. RI Talmadge, James/A-5916-2008 OI Talmadge, James/0000-0002-6328-6056 NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2007 VL 13 IS 2 SU 2 MA 228 BP 83 EP 84 DI 10.1016/j.bbmt.2006.12.233 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 133QU UT WOS:000244028300229 ER PT J AU Mariotti, J Foley, J Wong, E Borenstein, T Hanson, J Fowler, DH AF Mariotti, J. Foley, J. Wong, E. Borenstein, T. Hanson, J. Fowler, D. H. TI Rapamycin generated donor Th2/Tc2 cells prevent graft rejection by inhibition of alloreactivity and not by deletion of alloreactive T cells SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT Meeting 2007 CY FEB 08-12, 2007 CL Keystone, CO SP Amer Soc Blood & Marrow Transplantat, Ctr Int Blood & Marrow Transplantat Res, Pfizer Inc C1 NIH, Natl Canc Inst, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2007 VL 13 IS 2 SU 2 MA 234 BP 86 EP 86 DI 10.1016/j.bbmt.2006.12.239 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 133QU UT WOS:000244028300235 ER PT J AU Baird, K Fry, TJ Love, C Layton, P Rager, A Cordoza-Salzman, T Mackall, CL Wayne, AS AF Baird, K. Fry, T. J. Love, C. Layton, P. Rager, A. Cordoza-Salzman, T. Mackall, C. L. Wayne, A. S. TI Manifestations of acute and chronic graft-versus- host-disease in reduced-intensity allogeneic stem cell transplantation (RISCT) for pediatric cancer SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT Meeting 2007 CY FEB 08-12, 2007 CL Keystone, CO SP Amer Soc Blood & Marrow Transplantat, Ctr Int Blood & Marrow Transplantat Res, Pfizer Inc C1 NIH, Natl Canc Inst, Pediat Branch, Bethesda, MD 20892 USA. Duke Univ, Sch Med, Durham, NC USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2007 VL 13 IS 2 SU 2 MA 285 BP 104 EP 104 DI 10.1016/j.bbmt.2006.12.290 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 133QU UT WOS:000244028300286 ER PT J AU Foley, JE Mariotti, J Borenstein, T Han, S Eckhaus, M Fowler, D AF Foley, J. E. Mariotti, J. Borenstein, T. Han, S. Eckhaus, M. Fowler, D. TI Rapamycin-generated Th2 cell therapy of established acute murine GVHD requires Th2 cell secretion of both IL-4 and IL-10 SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT Meeting 2007 CY FEB 08-12, 2007 CL Keystone, CO SP Amer Soc Blood & Marrow Transplantat, Ctr Int Blood & Marrow Transplantat Res, Pfizer Inc C1 NIH, Natl Canc Inst, Experimental Transplant & Immunol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2007 VL 13 IS 2 SU 2 MA 290 BP 105 EP 105 DI 10.1016/j.bbmt.2006.12.295 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 133QU UT WOS:000244028300291 ER PT J AU Herby, S Davis, J Wayne, AS Fry, TJ AF Herby, S. Davis, J. Wayne, A. S. Fry, T. J. TI Dendritic cell vaccination expands antigen specific T cells following allogeneic transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT Meeting 2007 CY FEB 08-12, 2007 CL Keystone, CO SP Amer Soc Blood & Marrow Transplantat, Ctr Int Blood & Marrow Transplantat Res, Pfizer Inc C1 NIH, NCI, CCR, Pediat Oncol Branch, Bethesda, MD 20892 USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2007 VL 13 IS 2 SU 2 MA 292 BP 106 EP 106 DI 10.1016/j.bbmt.2006.12.297 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 133QU UT WOS:000244028300293 ER PT J AU Mielke, S Nunes, R Rezvani, K Fellowes, VS Fan, Y Scotto, C Solomon, SP Read, EJ Barrett, AJ AF Mielke, S. Nunes, R. Rezvani, K. Fellowes, V. S. Fan, Y. Scotto, C. Solomon, S. P. Read, E. J. Barrett, A. J. TI Selective depletion of alloreacting T cells by TH9402-based photodepletion as a translational strategy for GVHD control in HLA-mismatched and matched donor-recipient pairs SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT Meeting 2007 CY FEB 08-12, 2007 CL Keystone, CO SP Amer Soc Blood & Marrow Transplantat, Ctr Int Blood & Marrow Transplantat Res, Pfizer Inc C1 NIH, NHLBI, Hematol Branch, Stem Cell Allotransplantat Sect, Bethesda, MD USA. NIH, Dept Transfus Med, Cell Proc Sect, Bethesda, MD USA. Celmed Biosci Inc, St Laurent, PQ, Canada. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2007 VL 13 IS 2 SU 2 MA 314 BP 114 EP 114 DI 10.1016/j.bbmt.2006.12.319 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 133QU UT WOS:000244028300315 ER PT J AU Savani, BN Wielke, S Rezvani, K Yong, A Shenoy, A Read, EJ Hensel, N Childs, R Barrett, AJ AF Savani, B. N. Wielke, S. Rezvani, K. Yong, A. Shenoy, A. Read, E. J. Hensel, N. Childs, R. Barrett, A. J. TI Day 30 post-transplant absolute lymphocyte and natural killer cell count strongly predict outcome after allogeneic stem cell transplantation for hematological malignancy SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT Meeting 2007 CY FEB 08-12, 2007 CL Keystone, CO SP Amer Soc Blood & Marrow Transplantat, Ctr Int Blood & Marrow Transplantat Res, Pfizer Inc C1 NHLBI, NIH, Hematol Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2007 VL 13 IS 2 SU 2 MA 323 BP 117 EP 118 DI 10.1016/j.bbmt.2006.12.328 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 133QU UT WOS:000244028300324 ER PT J AU Yong, ASM Rezvani, K Savani, RN Eniafe, R Mielke, S Goldman, JM Barett, J AF Yong, A. S. M. Rezvani, K. Savani, R. N. Eniafe, R. Mielke, S. Goldman, J. M. Barett, J. TI Cytotoxic T lymphocyte responses to pri peptide in CML patients inversely correlate with proteinase 3 and elastase expression but donor PRI-responses determine molecular remission and disease eradication after stem cell transplantation SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT Meeting 2007 CY FEB 08-12, 2007 CL Keystone, CO SP Amer Soc Blood & Marrow Transplantat, Ctr Int Blood & Marrow Transplantat Res, Pfizer Inc C1 NHLBI, NIH, Hematol Branch, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2007 VL 13 IS 2 SU 2 MA 333 BP 121 EP 121 DI 10.1016/j.bbmt.2006.12.338 PG 1 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 133QU UT WOS:000244028300334 ER PT J AU Babb, R Shelburne, N Castro, K Krumlauf, M Pavletic, SZ AF Babb, R. Shelburne, N. Castro, K. Krumlauf, M. Pavletic, S. Z. TI Hematopoietic stem cell transplantation for systemic lupus erythematosus: Unique challenges and strategies for the nursing care team SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT Meeting 2007 CY FEB 08-12, 2007 CL Keystone, CO SP Amer Soc Blood & Marrow Transplantat, Ctr Int Blood & Marrow Transplantat Res, Pfizer Inc C1 Natl Canc Inst, Ctr Canc Res, Expt Transplantat & Immunol Branch, Bethesda, MD USA. Natl Inst Hlth, Mark O Hatfield Clin Res Ctr, Nursing & Patient Care Service, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2007 VL 13 IS 2 SU 2 MA 375 BP 136 EP 137 DI 10.1016/j.bbmt.2007.01.005 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 133QU UT WOS:000244028300376 ER PT J AU Bevans, MF Mitchell, SA Marden, S AF Bevans, M. F. Mitchell, S. A. Marden, S. TI An exploratory analysis of symptom experience at days 30 and 100 following allogeneic hematopoietic stem cell transplantation (AHSCT) SO BIOLOGY OF BLOOD AND MARROW TRANSPLANTATION LA English DT Meeting Abstract CT Tandem BMT Meeting 2007 CY FEB 08-12, 2007 CL Keystone, CO SP Amer Soc Blood & Marrow Transplantat, Ctr Int Blood & Marrow Transplantat Res, Pfizer Inc C1 Natl Inst Hlth, Ctr Clin, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1083-8791 J9 BIOL BLOOD MARROW TR JI Biol. Blood Marrow Transplant. PD FEB PY 2007 VL 13 IS 2 SU 2 MA 378 BP 137 EP 138 DI 10.1016/j.bbmt.2007.01.008 PG 2 WC Hematology; Immunology; Transplantation SC Hematology; Immunology; Transplantation GA 133QU UT WOS:000244028300379 ER PT J AU Li, TY Jinsmaa, Y Nedachi, M Miyazaki, A Tsuda, Y Ambo, A Sasaki, Y Bryant, SD Marczak, E Li, Q Swartzwelder, HS Lazarus, LH Okada, Y AF Li, Tingyou Jinsmaa, Yunden Nedachi, Masahiro Miyazaki, Anna Tsuda, Yuko Ambo, Akihiro Sasaki, Yusuke Bryant, Sharon D. Marczak, Ewa Li, Qiang Swartzwelder, H. Scott Lazarus, Lawrence H. Okada, Yoshio TI Transformation of mu-opioid receptor agonists into biologically potent mu-opioid receptor antagonists SO BIOORGANIC & MEDICINAL CHEMISTRY LA English DT Article DE opioid; mu-opioid receptor antagonists; endomorphin; Dmt; antinociception; ethanol; spontaneous IPSC ID ETHANOL-CONSUMPTION; MEDIATED ANALGESIA; OPIATE RECEPTOR; DELTA-RECEPTOR; KNOCKOUT MICE; ANALOGS; DMT; SUBSTITUTION; NALTRINDOLE; NALTREXONE AB N-Allylation (-CH2-CH=CH2) of [Dmt(1)]endomorphins yielded the following: (i) [N-allyl-Dmt(1)]endomorphin-2 (Dmt = 2',6'-dimethyl-L-tyrosine) (12) and [N-allyl-Dmt(1)]endomorphin-1 (15) (K-i mu = 0.45 and 0.26 nM, respectively) became p-antagonists (pA(2) = 8.59 and 8.18, respectively) with weak delta-antagonism (pA(2) = 6.32 and 7.32, respectively); (ii) intracerebroventricularly administered 12 inhibited morphine-induced CNS-mediated antinociception in mice [AD(50) (0.148 ng/mouse) was 16-fold more potent than naloxone], but not spinal antinociception, and (iii) 15 reversed the alcohol-elevated frequency in spontaneous inhibitory post-synaptic currents (IPSC) in hippocampal CA1 pyramidal cells in rat brain slices (P = 0.0055). Similarly, N-allylation of the potent mu-opioidmimetic agonists, 1,6-bis-[H-Dmt-NH]-hexane and 3,6-bis-[Dmt-NH-propyl]-2(1H)-pyrazinone, converted them into p-antagonists (pA(2) = 7.23 and 7.17 for the N-allyl-derivatives 17 and 19, respectively), and exhibited weak delta-antagonism. Thus, N-allylation of Dmt containing opioid peptides or opioidmimetics; continues to provide a facile means to convert selective mu-opioid agonists into potent mu-opioid antagonists. (c) 2006 Elsevier Ltd. All rights reserved. C1 Kobe Gakuin Univ, Grad Sch Food & Med Sci, Nishi Ku, Kobe, Hyogo 6512180, Japan. NIEHS, Lab Pharmacol & Chem, Med Chem Grp, Res Triangle Pk, NC 27709 USA. Kobe Gakuin Univ, Fac Pharmaceut Sci, Nishi Ku, Kobe, Hyogo 6512180, Japan. Tohoku Pharmaceut Univ, Dept Biochem, Aoba Ku, Sendai, Miyagi 9818558, Japan. Duke Univ, Med Ctr, Dept Pharmacol & Canc Biol, Durham, NC 27710 USA. Duke Univ, Med Ctr, Dept Psychiat, Durham, NC 27710 USA. Vet Adm Med Ctr, Neurobiol Res Lab, Durham, NC 27705 USA. RP Lazarus, LH (reprint author), Kobe Gakuin Univ, Grad Sch Food & Med Sci, Nishi Ku, Kobe, Hyogo 6512180, Japan. EM lazarus@niehs.nih.gov; okada@pharm.kobegakuin.ac.jp FU Intramural NIH HHS; PHS HHS [12478, 14894] NR 35 TC 15 Z9 16 U1 1 U2 4 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0968-0896 J9 BIOORGAN MED CHEM JI Bioorg. Med. Chem. PD FEB 1 PY 2007 VL 15 IS 3 BP 1237 EP 1251 DI 10.1016/j.bmc.2006.11.019 PG 15 WC Biochemistry & Molecular Biology; Chemistry, Medicinal; Chemistry, Organic SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy; Chemistry GA 132RE UT WOS:000243959100005 PM 17142049 ER PT J AU Nishizawa, R Nishiyama, T Hisaichi, K Matsunaga, N Minamoto, C Habashitaa, H Takaoka, Y Toda, M Shibayama, S Tada, H Sagawa, K Fukushima, D Maeda, K Mitsuya, H AF Nishizawa, Rena Nishiyama, Toshihiko Hisaichi, Katsuya Matsunaga, Naoki Minamoto, Chiaki Habashitaa, Hiromu Takaoka, Yoshikazu Toda, Masaaki Shibayama, Shiro Tada, Hideaki Sagawa, Kenji Fukushima, Daikichi Maeda, Kenji Mitsuya, Hiroaki TI Spirodiketopiperazine-based CCR5 antagonists: Lead optimization from biologically active metabolite SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE CCR5; HIV-1; active metabolite ID CHEMOKINE RECEPTOR; HIV-1 INFECTION; DISCOVERY; INHIBITORS; CORECEPTOR; POTENT; ENTRY AB Hydroxylated derivatives were designed and synthesized based on the information of oxidative metabolites. Compounds derived from beta-substituted (2R,3R)-2-amino-3-hydroxypropionic acid showed improved inhibitory activities against the binding of MIP-1 alpha to human CCR5, compared with the non-hydroxylated derivatives and the other isomers. (c) 2006 Elsevier Ltd. All rights reserved. C1 Ono Pharmaceut Co Ltd, Med Chem Res Labs, Osaka 6188585, Japan. Ono Pharmaceut Co Ltd, Explorat Res Labs, Ibaraki 300424, Japan. Kumamoto Univ, Sch Med, Dept Internal Med 2, Kumamoto 8600811, Japan. NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, NIH, Bethesda, MD 20892 USA. RP Nishizawa, R (reprint author), Ono Pharmaceut Co Ltd, Med Chem Res Labs, Osaka 6188585, Japan. EM r.nishizawa@ono.co.jp NR 18 TC 38 Z9 39 U1 1 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 1 PY 2007 VL 17 IS 3 BP 727 EP 731 DI 10.1016/j.bmcl.2006.10.084 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 135RM UT WOS:000244170700031 PM 17118654 ER PT J AU Grundt, P Husband, SLJ Luedtke, RR Taylor, M Newman, AH AF Grundt, Peter Husband, Sarah Little Jane Luedtke, Robert R. Taylor, Michelle Newman, Amy Hauck TI Analogues of the dopamine D2 receptor antagonist L741,626: Binding, function, and SAR SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE dopamine d2 receptor antagonists ID THERAPEUTIC AGENTS; HIGH-AFFINITY; D3 RECEPTOR; DRUG-ABUSE; HALOPERIDOL; LIGANDS AB A series of analogues of the dopamine D2 receptor antagonist L741,626 were synthesized and evaluated for binding and function at D2 family receptor subtypes. Several analogues showed comparable binding profiles to the parent ligand, however, in general, chemical modification served to reduce D2 binding affinity and selectivity. (c) 2006 Elsevier Ltd. All rights reserved. C1 NIDA, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Univ N Texas, Ctr Hlth Sci, Dept Pharmacol & Neurosci, Miki, Kagawa 76107, Japan. RP Newman, AH (reprint author), NIDA, Intramural Res Program, NIH, 5500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM anewman@intra.nida.nih.gov FU Intramural NIH HHS; NIDA NIH HHS [1 DA 13584, Z01 DA000424-07, R01 DA013584] NR 20 TC 24 Z9 25 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 1 PY 2007 VL 17 IS 3 BP 745 EP 749 DI 10.1016/j.bmcl.2006.10.076 PG 5 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 135RM UT WOS:000244170700035 PM 17095222 ER PT J AU Ivanov, AA Fricks, I Harden, TK Jacobson, KA AF Ivanov, Andrei A. Fricks, Ingrid Harden, T. Kendall Jacobson, Kenneth A. TI Molecular dynamics simulation of the P2Y(14) receptor. Ligand docking and identification of a putative binding site of the distal hexose moiety SO BIOORGANIC & MEDICINAL CHEMISTRY LETTERS LA English DT Article DE nucleotide; G protein-coupled receptor; pyrimidine; UDP-glucose; homology modeling; Monte Carlo ID CHARGED AMINO-ACIDS; EXTRACELLULAR LOOPS; UDP-GLUCOSE; GRAMICIDIN; BILAYER; NUCLEOTIDES; RECOGNITION; MUTAGENESIS; POTENCY; CHANNEL AB A rhodopsin-based homology model of the P2Y(14) receptor was inserted into a phospholipid bilayer and refined by molecular dynamics (MD) simulation. The binding modes of several known agonists, namely UDP-glucose and its analogues, were proposed using automatic molecular docking combined with Monte Carlo Multiple Minimum calculations. Compared to other P2Y receptors, the P2Y(14) receptor has an atypical binding mode of the nucleobase, ribose, and phosphate moieties. The diphosphate moiety interacts with only one cationic residue, namely Lys171 of EL2, while in other P2Y receptor subtypes three Arg or Lys residues interact with the phosphate chain. Two other conserved cationic residues, namely Arg253 (6.55) and Lys277 (7.35) of the P2Y(14) receptor together with two anionic residues (Glu166 and Glul74, located in EL2), are likely involved in interactions with the distal hexose moiety. (c) 2006 Elsevier Ltd. All rights reserved. C1 NIDDKD, Mol Recognit Sect, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. Univ N Carolina, Dept Pharmacol, Sch Med, Chapel Hill, NC 27599 USA. RP Jacobson, KA (reprint author), NIDDKD, Mol Recognit Sect, Lab Bioorgan Chem, NIH, Bethesda, MD 20892 USA. EM kajacobs@helix.nih.gov RI Jacobson, Kenneth/A-1530-2009 OI Jacobson, Kenneth/0000-0001-8104-1493 FU Intramural NIH HHS NR 25 TC 16 Z9 16 U1 0 U2 2 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0960-894X J9 BIOORG MED CHEM LETT JI Bioorg. Med. Chem. Lett. PD FEB 1 PY 2007 VL 17 IS 3 BP 761 EP 766 DI 10.1016/j.bmcl.2006.10.081 PG 6 WC Chemistry, Medicinal; Chemistry, Organic SC Pharmacology & Pharmacy; Chemistry GA 135RM UT WOS:000244170700038 PM 17088057 ER PT J AU Fowler, DH AF Fowler, Daniel H. TI B-ware of allosensitized graft rejection SO BLOOD LA English DT Editorial Material ID TRANSPLANTATION; RECIPIENTS AB In elegant murine experiments, Taylor and colleagues have demonstrated that preformed antibody represents the primary engraftment barrier in allosensitized hosts, and have identified interventions to target this biology for potential clinical benefit. C1 NIH, Bethesda, MD 20892 USA. RP Fowler, DH (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. NR 6 TC 3 Z9 4 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 1 PY 2007 VL 109 IS 3 BP 851 EP 852 PG 2 WC Hematology SC Hematology GA 135CX UT WOS:000244132800003 ER PT J AU Roederer, M Mattapallil, J AF Roederer, Mario Mattapallil, Joseph TI CCR5 and HIV: the less, the better SO BLOOD LA English DT Editorial Material AB Two reports in this issue of Blood underscore the central importance of the regulation of chemokine receptor CCR5 expression to the pathogenic infection of SIV and associated destruction of gut mucosa in nonnatural hosts. CCR5 is the obligate coreceptor for infection by SIV and most transmitted forms of HIV; humans who lack CCR5 expression (CCR5 Delta 32) are highly resistant to HIV infection. Now it appears that a selection for low expression of CCR5 in natural hosts of SIV has evolved as one mechanism to escape the pathogenic consequences of infection. C1 NIAID, Bethesda, MD 20892 USA. Uniformed Serv Univ Hlth Sci, Bethesda, MD 20814 USA. RP Roederer, M (reprint author), NIAID, 9000 Rockville Pike, Bethesda, MD 20892 USA. RI Roederer, Mario/G-1887-2011 NR 1 TC 1 Z9 1 U1 1 U2 1 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 1 PY 2007 VL 109 IS 3 BP 854 EP 854 PG 1 WC Hematology SC Hematology GA 135CX UT WOS:000244132800006 ER PT J AU Ng, D Toure, O Wei, MH Arthur, DC Abbasi, F Fontaine, L Marti, GE Fraumeni, JF Goldin, LR Caporaso, N Toro, JR AF Ng, David Toure, Ousmane Wei, Ming-Hui Arthur, Diane C. Abbasi, Fatima Fontaine, Laura Marti, Gerald E. Fraumeni, Joseph F., Jr. Goldin, Lynn R. Caporaso, Neil Toro, Jorge R. TI Identification of a novel chromosome region, 13q21.33-q22.2, for susceptibility genes in familial chronic lymphocytic leukemia SO BLOOD LA English DT Article ID TUMOR-SUPPRESSOR LOCUS; BREAST-CANCER; FLOW-CYTOMETRY; TRANSCRIPTION FACTOR; UNIPARENTAL DISOMY; BAND 13Q14; DELETIONS; CLL; PREDISPOSITION; ABNORMALITIES AB Chronic lymphocytic leukemia (CLL) is the most prevalent form of leukemia in adults in western countries. A genome scan of CLL-prone families revealed a lod score of one in band 13q22.1. To investigate this finding, we selected 6 CLL families consisting of 63 individuals (CLL affected, n = 19; unaffected, n = 44) for fine mapping of a 23-megabase region in 13q14.2-q22.2. Interphase fluorescence in situ hybridization (FISH) revealed 13q14 deletion in 85% (11/13) of CLL patients. Four CLL families shared a 3.68-Mb minimal region in 13q21.33-q22.2. Two asymptomatic siblings who shared the 13q2l.33q22.2 at-risk haplotype exhibited CD5+ monoclonal B-cell lymphocytosis (MBL) on flow cytometry. One of these individuals also had a 13q14 deletion by FISH. These 2 individuals with MBL shared the at-risk haplotype with their CLL-affected relatives, providing further evidence of the relationship between CLL and MBL, as well as of the biologic significance of this novel region. Using direct DNA sequencing analysis, we screened 13 genes for mutations, but no frameshift or nonsense mutations were detected. Our studies revealed that 11 of the 13 genes in the candidate region were expressed in immune tissues, supporting their functional relevance in investigations of familial CLL. In conclusion, we identified a novel candidate region that may predispose to familial CLL. C1 NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Sci Applicat Int Corp, Program Div Canc Epidemiol & Genet, Frederick, MD USA. NCI, Pathol Lab, Canc Res Ctr, NIH,DHHS, Bethesda, MD 20892 USA. US FDA, Flow & Image Cytometry Lab, Cellular Therapy & Tissues Branch, Div Gene & Cell Therapy,Ctr Biol Evaluat & Res, Bethesda, MD 20014 USA. WESTAT Corp, Rockville, MD 20850 USA. NCI, Off Director, Div Canc Epidemiol & Genet, NIH,DHHS, Rockville, MD USA. RP Toro, JR (reprint author), NCI, Genet Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, 6120 Execut Blvd,Execut Plaza S,Rm 7012, Bethesda, MD 20892 USA. EM toroj@mail.nih.gov FU Intramural NIH HHS NR 49 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 2007 VL 109 IS 3 BP 916 EP 925 DI 10.1182/blood-2006-03-011825 PG 10 WC Hematology SC Hematology GA 135CX UT WOS:000244132800020 PM 17047154 ER PT J AU Orr, SJ Morgan, NM Elliott, J Burrows, JF Scott, CJ McVicar, DW Johnston, JA AF Orr, Selinda J. Morgan, Nuala M. Elliott, Joanne Burrows, James F. Scott, Christopher J. McVicar, Daniel W. Johnston, James A. TI CD33 responses are blocked by SOCS3 through accelerated proteasomal-mediated turnover SO BLOOD LA English DT Article ID PROTEIN-TYROSINE-PHOSPHATASE; CYTOKINE SIGNALING-3; NEGATIVE REGULATION; BOX MOTIF; RECEPTOR; BINDING; DEGRADATION; FAMILY; PHOSPHORYLATION; PROLIFERATION AB CD33 is a member of the sialic acid-binding immunoglobulin-like lectin (Siglec) family of inhibitory receptors and a therapeutic target for acute myeloid leukemia (AML). CD33 contains a cytoplasmic Immunoreceptor tyrosine-based inhibitory motif (ITIM), which can recruit SHP-1 and SHP-2. How CD33 expression is regulated is unclear. Suppressor of cytokine signaling 3 (SOCS3) is expressed in response to cytokines, LIPS, and other PAMPs, and competes with SHP-1/2 binding to ITIMs of cytokine receptors, thereby inhibiting signaling. In this study, using peptide pull-down experiments, we found that SOCS3 can specifically bind to the phosphorylated ITIM of CD33. Additionally, following cross-linking SOCS3 can recruit the ECS E3 ligase resulting in accelerated proteasomal degradation of both CD33 and SOCS3. Our data suggest that the tyrosine motifs in CD33 are not important for internalization, while they are required for degradation. Moreover, SOCS3 inhibited the CD33-induced block on cytokine-induced proliferation. This is the first receptor shown to be degraded by SOCS3 and where SOCS3 and its target protein are degraded concomitantly. Our findings clearly suggest that during an inflammatory response, the inhibitory receptor CD33 is lost by this mechanism. Moreover, this has important clinical implications as tumors expressing SOCS3 may be refractory to alpha-CD33 therapy. C1 Queens Univ Belfast, Ctr Canc Res & Cell Biol, Belfast BT9 7BL, Antrim, North Ireland. Queens Univ Belfast, Sch Pharm, Belfast BT9 7BL, Antrim, North Ireland. NCI, Frederick Canc Res & Dev Ctr, Expt Immunol Lab, Div Basic Sci, Frederick, MD USA. RP Johnston, JA (reprint author), Queens Univ Belfast, Ctr Canc Res & Cell Biol, 2nd Floor,Whitla Med Bldg,97 Lisburn Rd, Belfast BT9 7BL, Antrim, North Ireland. EM jim.johnston@qub.ac.uk RI McVicar, Daniel/G-1970-2015; OI Orr, Selinda/0000-0001-8539-7825 FU Wellcome Trust [07034/Z/03/Z] NR 47 TC 45 Z9 49 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 2007 VL 109 IS 3 BP 1061 EP 1068 DI 10.1182/blood-2006-05-023556 PG 8 WC Hematology SC Hematology GA 135CX UT WOS:000244132800038 PM 17008544 ER PT J AU Pandrea, I Apetrei, C Gordon, S Barbercheck, J Dufour, J Bohm, R Sumpter, B Roques, P Marx, PA Hirsch, VM Kaur, A Lackner, AA Veazey, RS Silvestri, G AF Pandrea, Ivona Apetrei, Cristian Gordon, Shari Barbercheck, Joseph Dufour, Jason Bohm, Rudolf Sumpter, Beth Roques, Pierre Marx, Preston A. Hirsch, Vanessa M. Kaur, Amitinder Lackner, Andrew A. Veazey, Ronald S. Silvestri, Guido TI Paucity of CD4(+)CCR5(+) T cells is a typical feature of natural SIV hosts SO BLOOD LA English DT Article ID SIMIAN IMMUNODEFICIENCY VIRUS; AFRICAN-GREEN MONKEYS; IN-VIVO REPLICATION; SOOTY MANGABEYS; GASTROINTESTINAL-TRACT; VIRAL REPLICATION; MANDRILLUS-SPHINX; HIV-1 INFECTION; RHESUS MACAQUES; CORECEPTOR USAGE AB In contrast to lentiviral infections of humans and macaques, simian immunodeficiency virus (SIV) infection of natural hosts is nonpathogenic despite high levels of viral replication. However, the mechanisms underlying this absence of disease are unknown. Here we report that natural hosts for SIV infection express remarkably low levels of CCR5 on CD4(+) T cells isolated from blood, lymph nodes, and mucosal tissues. Given that this immunologic feature is found in 5 different species of natural SIV hosts (sooty mangabeys, African green monkeys, mandrills, sun-tailed monkeys, and chimpanzees) but is absent in 5 normatural/recent hosts (humans, rhesus, pigtail, cynomolgus macaques, and baboons), it may represent a key feature of the coevolution between the virus and its natural hosts that led to a nonpathogenic infection. Beneficial effects of low CCR5 expression on CD4(+) T cells may include the reduction of target cells for viral replication and a decreased homing of activated CD4(+) T cells to inflamed tissue. C1 Tulane Natl Primate Res Ctr, Dept Comparat Pathol, Covington, LA 70433 USA. Univ Penn, Dept Pathol, Philadelphia, PA 19104 USA. Yerkes Natl Primate Res Ctr, Atlanta, GA USA. Ctr Int Rech Med, Franceville, Gabon. NIAID, Mol Microbiol Lab, NIH, Bethesda, MD 20892 USA. New England Reg Primate Res Ctr, Southborough, MA 01772 USA. RP Pandrea, I (reprint author), Tulane Natl Primate Res Ctr, Dept Comparat Pathol, 18703 3 Rivers Rd, Covington, LA 70433 USA. EM ipandrea@tulane.edu RI Roques, Pierre/M-2212-2013 OI Roques, Pierre/0000-0003-1825-1054 FU NCRR NIH HHS [P51 RR000164, P51 RR000165, RR00164, RR00165]; NIAID NIH HHS [R01 AI052755, AI66998, R01 AI049080, R01 AI049809, R01 AI064066, R01 AI065325, R01 AI066998, R01 AI49080, R01 AI49809, R01 AI52755, R01 AI64066, R01 AI65325, R37 AI066998] NR 56 TC 120 Z9 121 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 2007 VL 109 IS 3 BP 1069 EP 1076 DI 10.1182/blood-2006-05-024364 PG 8 WC Hematology SC Hematology GA 135CX UT WOS:000244132800039 PM 17003371 ER PT J AU Payne, SG Oskeritzian, CA Griffiths, P Subramanian, P Barbour, SE Chalfant, CE Milstien, S Spiegel, S AF Payne, Shawn G. Oskeritzian, Carole A. Griffiths, Plachael Subramanian, Preeti Barbour, Suzanne E. Chalfant, Charles E. Milstien, Sheldon Spiegel, Sarah TI The immunosuppressant drug FTY720 inhibits cytosohc phospholipase A2 independently of sphingosine-1-phosphate receptors SO BLOOD LA English DT Article ID FC-EPSILON-RI; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; SPHINGOSINE 1-PHOSPHATE RECEPTORS; ACTIVATED MAST-CELLS; PROSTAGLANDIN D-2; INFLAMMATORY RESPONSES; MULTIPLE-SCLEROSIS; LYMPHOCYTE EGRESS; P388D(1) CELLS; T-CELLS AB FrY720 is a potent immunomodulator drug that inhibits the egress of lymphocytes from secondary lymphoid tissues and thymus. FrY720 is phosphorylated in vivo by sphingosine kinase 2 to FTY720-phosphate, which acts as a potent sphingosine-1-phosphate (SI P) receptor agonist. However, in contrast to S1P, FTY720 has no effect on mast-cell degranulation, yet significantly reduces antigen-induced secretion of PGD(2) and cysteinyl-leukotriene. Unexpectedly, this effect of FTY720 was independent of its phosphorylation and S1P receptor functions. The rate-limiting step in the blosynthesis of all elcosanolds is the phospholipase A(2) (PLA(2))-mediated release of arachidonic acid from glycerol phospholipids. Although FTY720 also reduced arachidonic acid release in response to antigen, it had no effect on translocation of cPLA(2) or ERK1/2 activation, suggesting that it does not interfere with Fc epsilon RI-mediated events leading to cPLA2 activation. Remarkably, however, FTY720 drastically inhibited recombinant cPLA(2)alpha activity, whereas FrY720-phosphate, sphin-gosine, or S1P had no effect. This study has uncovered a unique action of FTY720 as an inhibitor of cPLA(2)alpha and hence on production of all eicosanoids. Our results have important implications for the potential therapeutic mechanism of action of FrY720 in eicosanold-driven inflammatory disorders such as asthma and multiple sclerosis. C1 Virginia Commonwealth Univ, Sch Med, Dept Biochem, Richmond, VA 23298 USA. NIMH, NIH, Bethesda, MD 20892 USA. RP Spiegel, S (reprint author), Virginia Commonwealth Univ, Sch Med, Dept Biochem, Med Coll Virginia Campus, Richmond, VA 23298 USA. EM sspiegel@vcu.edu FU Intramural NIH HHS; NCRR NIH HHS [C06 RR017393, 1C06RR17393]; NHLBI NIH HHS [R01 HL072925]; NIGMS NIH HHS [R37 GM043880]; PHS HHS [R01AIS0094] NR 69 TC 101 Z9 104 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 1 PY 2007 VL 109 IS 3 BP 1077 EP 1085 DI 10.1182/blood-2006-03-011437 PG 9 WC Hematology SC Hematology GA 135CX UT WOS:000244132800040 PM 17008548 ER PT J AU Fessler, MB Arndt, PG Just, I Nick, JA Malcolm, KC Worthen, GS AF Fessler, Michael B. Arndt, Patrick G. Just, Ingo Nick, Jerry A. Malcolm, Kenneth C. Worthen, G. Scott TI Dual role for RhoA in suppression and induction of cytokines in the human neutrophil SO BLOOD LA English DT Article ID NF-KAPPA-B; ACTIVATED PROTEIN-KINASE; TUMOR-NECROSIS-FACTOR; HUMAN ENDOTHELIAL-CELLS; GTP-BINDING PROTEINS; ACTIN STRESS FIBERS; POLYMORPHONUCLEAR LEUKOCYTES; GENE-EXPRESSION; RAC ACTIVATION; CYTOCHALASIN-D AB Production of tumor necrosis factor-alpha (TNF alpha) by the neutrophil (PMN) is a pivotal event in innate immunity, but the signals regulating TNFa induction in this primary cell are poorly understood. Herein, we use protein transduction to identify novel, opposing anti- and procytokine-inducing roles for RhoA in the resting and lipopolysaccharide (LPS)-stimulated human PMN, respectively. In the resting cell, RhoA suppresses Cdc42 activation, I kappa B alpha degradation, nuclear factor-kappa B (NF-kappa B) activation, and induction of TNF alpha and NF-kappa B-dependent chemokines. Suppression of TNF alpha induction by RhoA is Rho kinase alpha (ROCK alpha) independent, but Cdc42 dependent, because TNF alpha-induction by C3 transferase is attenuated by inhibition of Cdc42, and constitutively active Cdc42 suffices to activate NF-kappa B and induce TNF alpha. By contrast, we also place RhoA downstream of p38 mitogen-activated protein kinase and Cdc42 in a novel LPS-activated pathway in which p38, Cdc42, and ROCK alpha all promote TNF alpha protein expression. The p65 subunit of NF-kappa B coprecipitates with RhoA in a manner sensitive to the RhoA activation state. Our findings suggest a new, 2-faced role for RhoA as a checkpoint in innate immunity. C1 Natl Jewish Med & Res Ctr, Dept Med, Denver, CO USA. Univ Colorado, Sch Med, Dept Med, Denver, CO USA. Hannover Med Sch, Dept Toxicol, D-3000 Hannover, Germany. Natl Jewish Med & Res Ctr, Dept Pediat, Div Cell Biol, Denver, CO USA. RP Fessler, MB (reprint author), Natl Inst Environm Hlth Sci, 111 TW Alexander Dr,POB 12233,MD D2-01, Res Triangle Pk, NC 27709 USA. EM fesslerm@niehs.nih.gov FU NHLBI NIH HHS [P01 HL068743, 5R01HL061407-08, K08 HL067179, HL67179, R01 HL105834, 5P01HL68743-04, R01 HL061407] NR 71 TC 9 Z9 10 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 1 PY 2007 VL 109 IS 3 BP 1248 EP 1256 DI 10.1182/blood-2006-03-012898 PG 9 WC Hematology SC Hematology GA 135CX UT WOS:000244132800063 PM 17018860 ER PT J AU Dib, A Barlogie, B Shaughnessy, JD Kuehl, M AF Dib, Amel Barlogie, Bart Shaughnessy, John D., Jr. Kuehl, Michael TI Methylation and expression of the p1 61NK4A tumor suppressor gene in multiple myeloma SO BLOOD LA English DT Letter ID P16(INK4A); EVENT C1 USN Hosp, Natl Canc Inst, Bethesda, MD 20889 USA. RP Kuehl, M (reprint author), USN Hosp, Natl Canc Inst, Bldg 8,Rm 5101, Bethesda, MD 20889 USA. EM wmk@helix.nih.gov NR 10 TC 21 Z9 23 U1 0 U2 0 PU AMER SOC HEMATOLOGY PI WASHINGTON PA 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA SN 0006-4971 J9 BLOOD JI Blood PD FEB 1 PY 2007 VL 109 IS 3 BP 1337 EP 1338 PG 2 WC Hematology SC Hematology GA 135CX UT WOS:000244132800078 PM 17244692 ER PT J AU Harrington, SM Buller, RS Storch, GA Li, L Fischer, SH Murray, PR Gea-Banacloche, JC AF Harrington, S. M. Buller, R. S. Storch, G. A. Li, L. Fischer, S. H. Murray, P. R. Gea-Banacloche, J. C. TI The effect of quantification standards used in real-time CMV PCR assays on guidelines for initiation of therapy in allogeneic stem cell transplant patients SO BONE MARROW TRANSPLANTATION LA English DT Letter ID POLYMERASE-CHAIN-REACTION; MARROW TRANSPLANTATION; PREEMPTIVE THERAPY; PERIPHERAL-BLOOD; PP65 ANTIGENEMIA; CYTOMEGALOVIRUS; GANCICLOVIR; INFECTION; DNA C1 NCI, Dept Lab Med, Warren Grant Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA. NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Harrington, SM (reprint author), NCI, Dept Lab Med, Warren Grant Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. EM HarrinS@mail.amc.edu NR 9 TC 8 Z9 8 U1 1 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0268-3369 J9 BONE MARROW TRANSPL JI Bone Marrow Transplant. PD FEB PY 2007 VL 39 IS 4 BP 237 EP 238 DI 10.1038/sj.bmt.1705558 PG 2 WC Biophysics; Oncology; Hematology; Immunology; Transplantation SC Biophysics; Oncology; Hematology; Immunology; Transplantation GA 134KL UT WOS:000244081800008 PM 17211434 ER PT J AU Low, N Singleton, A AF Low, Nancy Singleton, Andrew TI Establishing the genetic heterogeneity of familial hemiplegic migraine SO BRAIN LA English DT Editorial Material ID COMORBIDITY; MUTATION; ATAXIA; TYPE-2 C1 NIMH, Sect Dev Genet Epidemiol, NIH, Bethesda, MD 20892 USA. NIA, Mol Genet Unit, NIH, Bethesda, MD 20892 USA. RP Low, N (reprint author), NIMH, Sect Dev Genet Epidemiol, NIH, Bethesda, MD 20892 USA. EM lown@mail.nih.gov; singleta@mail.nih.gov RI Singleton, Andrew/C-3010-2009 NR 10 TC 0 Z9 0 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0006-8950 J9 BRAIN JI Brain PD FEB PY 2007 VL 130 BP 312 EP 313 DI 10.1093/brain/awl381 PN 2 PG 2 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 130PC UT WOS:000243810500008 PM 17235123 ER PT J AU Floel, A Cohen, LG AF Floel, A. Cohen, L. G. TI Contribution of noninvasive cortical stimulation to the study of memory functions SO BRAIN RESEARCH REVIEWS LA English DT Review DE episodic memory; procedural memory; transcranial magnetic stimulation; transcranial direct current stimulation; long-term potentiation ID TRANSCRANIAL MAGNETIC STIMULATION; HUMAN MOTOR CORTEX; USE-DEPENDENT PLASTICITY; LONG-TERM POTENTIATION; SPATIAL WORKING-MEMORY; HUMAN EPISODIC MEMORY; PREFRONTAL CORTEX; BRAIN POLARIZATION; CHRONIC STROKE; FRONTAL LOBES AB In the memory domain, a large body of experimental evidence about subsystems of memory has been collected from classic lesion studies and functional brain imaging. Animal studies have provided information on molecular mechanisms of memory formation. Compared to this work, transcranial magnetic stimulation and transcranial direct current stimulation have made their own unique contribution. Here, we describe how noninvasive brain stimulation has been used to study the functional contribution of specific cortical areas during a given memory task, how these techniques can be used to assess LTP- and LTD-like plasticity in the living human brain, and how they can be employed to modulate memory formation in humans, suggesting an adjuvant role in neurorehabilitative treatments following brain injury. (c) 2006 Elsevier B.V. All rights reserved. C1 Univ Munster, Dept Neurol, D-48129 Munster, Germany. NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20892 USA. RP Floel, A (reprint author), Univ Munster, Dept Neurol, Albert Schweitzer Str 33, D-48129 Munster, Germany. EM floeel@uni-muenster.de RI Floel, Agnes/A-9426-2017 NR 91 TC 23 Z9 24 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0173 J9 BRAIN RES REV JI Brain Res. Rev. PD FEB PY 2007 VL 53 IS 2 BP 250 EP 259 DI 10.1016/j.brainresrev.2006.08.006 PG 10 WC Neurosciences SC Neurosciences & Neurology GA 141BU UT WOS:000244552200003 PM 17023050 ER PT J AU Kalueff, AV Zimbardo, PG AF Kalueff, Allan V. Zimbardo, Philip G. TI Behavioral neuroscience, exploration, and K.C. Montgomery's legacy SO BRAIN RESEARCH REVIEWS LA English DT Review DE KC Montgomery; exploration; fear; motivation; experimental model; novelty; behavior ID ELEVATED PLUS-MAZE; NOVELTY SEEKING; ANIMAL-MODELS; ZERO-MAZE; ANXIETY; MICE; MOUSE; FEAR; RATS; RESPONSES AB Exploration is a key animal and human behavior. Kay C. Montgomery (1921-1956) has made an important contribution to behavioral neuroscience of exploration, as well as motivation and learning. His works have many important applications to current experimental models of stress, fear and memory, continuing to influence research in this field. This paper, dedicated to the 85th anniversary of Montgomery's birth, and 50 years since his tragic death, summarizes Montgomery's contribution to behavioral neuroscience, and discusses its current importance for further progress in this field. it is aimed at neuroscientists with strong interests in both theory of animal exploration and motivation, and the history of behavioral neuroscience. (c) 2006 Elsevier B.V. All rights reserved. C1 NIMH, Clin Sci Lab, Bethesda, MD 20892 USA. Stanford Univ, Dept Psychol, Stanford, CA 94305 USA. RP Kalueff, AV (reprint author), NIMH, Clin Sci Lab, Bldg 10,Room 3D41,10 Ctr Dr MSC 1264, Bethesda, MD 20892 USA. EM avkalueff@inbox.ru FU Intramural NIH HHS NR 58 TC 5 Z9 5 U1 0 U2 2 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0165-0173 J9 BRAIN RES REV JI Brain Res. Rev. PD FEB PY 2007 VL 53 IS 2 BP 328 EP 331 DI 10.1016/j.brainresrev.2006.09.003 PG 4 WC Neurosciences SC Neurosciences & Neurology GA 141BU UT WOS:000244552200009 PM 17095097 ER PT J AU Brittain, NJ Erexson, C Faucette, L Ward, J Fujioka, H Wellems, TE Fairhurst, RM AF Brittain, Nathaniel J. Erexson, Cindy Faucette, Lawrence Ward, Jerrold Fujioka, Hisashi Wellems, Thomas E. Fairhurst, Rick M. TI Non-opsonising aggregates of IgG and complement in haemoglobin C erythrocytes SO BRITISH JOURNAL OF HAEMATOLOGY LA English DT Article DE haemoglobin C; haemoglobin S; sickle cell; erythrocyte senescence; autologous IgG ID RED-BLOOD-CELLS; INTEGRAL MEMBRANE-PROTEINS; SICKLE ERYTHROCYTES; HEINZ BODIES; HEMOLYTIC ANEMIA; BETA-THALASSEMIA; AA-ERYTHROCYTES; AUTOLOGOUS IGG; SEVERE MALARIA; SC DISEASE AB Haemoglobin C (HbC) differs from normal HbA by a lysine for glutamate substitution at position 6 of beta-globin. Heterozygous AC and homozygous CC phenotypes are associated with shortened erythrocyte life spans and mild anaemia. AC and CC erythrocytes contain elevated amounts of membrane-associated haemichromes, band 3 clusters, and immunoglobulin G (IgG) in vivo. These findings led us to investigate whether AC and CC erythrocytes might expose elevated levels of IgG and complement, two opsonins that have been implicated in the phagocytic clearance of senescent and sickle erythrocytes. Surprisingly, we found IgG, complement, and other plasma proteins co-localised in aggregates beneath the membrane of circulating AC and CC erythrocytes. These observations, and our finding of similar aggregates in erythrocytes heterozygous or homozygous for haemoglobin S (sickle-cell haemoglobin), suggest that the vast majority of membrane-associated IgG and complement detected in these abnormal erythrocytes is intracellular and does not contribute to the eventual opsonic clearance of these cells. Phagocytosis studies with macrophages provide evidence in support of this suggestion. Studies of erythrocyte clearance that involve the detection of membrane-associated IgG and complement as putative opsonins should investigate the possibility that these plasma proteins reside in the erythrocyte interior, and not on the cell surface. C1 NIAID, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. NIAID, Infect Dis Pathogenesis Sect, Comparat Med Branch, NIH, Bethesda, MD 20892 USA. Case Western Reserve Univ, Inst Pathol, Cleveland, OH 44106 USA. RP Fairhurst, RM (reprint author), NIAID, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy,Room 3E-18A, Rockville, MD 20852 USA. EM rfairhurst@niaid.nih.gov FU Intramural NIH HHS NR 58 TC 5 Z9 5 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0007-1048 J9 BRIT J HAEMATOL JI Br. J. Haematol. PD FEB PY 2007 VL 136 IS 3 BP 491 EP 500 DI 10.1111/j.1365-2141.2006.06446.x PG 10 WC Hematology SC Hematology GA 133UG UT WOS:000244038800015 PM 17156402 ER PT J AU Garland, MR Hallahan, B McNamara, M Carney, PA Grimes, H Hibbeln, JR Harkin, A Conroy, RM AF Garland, Malcolm R. Hallahan, Brian McNamara, Mairead Carney, Philip A. Grimes, Helen Hibbeln, Joseph R. Harkin, Andrew Conroy, Ronan M. TI Lipids and essential fatty acids in patients presenting with self-harm SO BRITISH JOURNAL OF PSYCHIATRY LA English DT Article ID SERUM-CHOLESTEROL LEVELS; SEROTONIN TRANSPORTER; FRONTAL-CORTEX; DEPRESSION; SUICIDE; METAANALYSIS; CONSUMPTION; DEFICIENCY; REDUCTION; MORTALITY AB Background Low cholesterol has been reliably demonstrated in people who self-harm. Aims To determine whether people who self-harm also have low levels of essential fatty acids (EFAs) and to examine associations between the EFAs and serotonergic function. Method Depression, impulsivity and suicidal intent were measured in patients with self-harm (n=40) and matched controls, together with plasma lipids and EFAs. Platelet serotonergic studies were carried out in a subgroup (n=27). Results Patients with self-harm had significantly more pathology on all psychometric measures, lower mean total cholesterol levels (4.18 (s. d. = 0.93) v. 4.87 (s.d.=0.83) mmol/l, P=0.003) and lower mean total EFA levels (89.5 (15.6) v. 103.7 (17.1) mu g/ml, P=0.0001) than controls after adjustment for confounding variables. Total n-3 and n-6 EFA levels were also significantly lower. Impulsivity and depression scores were significantly inversely correlated with both n-6 EFAs and n-3 EFAs, but were not associated with total or low-density lipoprotein cholesterol levels. Platelet serotonergic measures did not differ between groups, and were not related to psychobiological measures. Conclusions Lower plasma EFA levels combined with low cholesterol concentrations were associated with self-harm as well as impulsivity and affect. This was not related to platelet serotonergic measures. Declaration of interest None. C1 Natl Univ Ireland Univ Coll Galway, Galway Univ Hosp, Dept Adult Psychiat, Galway, Ireland. Natl Univ Ireland Univ Coll Galway, Inst Clin Sci, Galway, Ireland. Natl Univ Ireland Univ Coll Galway, Dept Expt Pharmacol, Galway, Ireland. Galway Univ Hosp, Dept Clin Biochem, Galway, Ireland. NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. Royal Coll Surgeons Ireland, Dept Epidemiol & Biostat, Dublin 2, Ireland. RP Garland, MR (reprint author), St Itas Hosp, Dublin, Ireland. EM mgarland@ireland.com RI Conroy, Ronan/C-6416-2008; Mcnamara, Mairead/J-1621-2015; OI Conroy, Ronan/0000-0001-5983-8682; Mcnamara, Mairead/0000-0002-2272-3678; Harkin, Andrew/0000-0001-9734-216X; Hallahan, Brian/0000-0003-0518-9757 NR 40 TC 40 Z9 41 U1 0 U2 2 PU ROYAL COLLEGE OF PSYCHIATRISTS PI LONDON PA BRITISH JOURNAL OF PSYCHIATRY 17 BELGRAVE SQUARE, LONDON SW1X 8PG, ENGLAND SN 0007-1250 J9 BRIT J PSYCHIAT JI Br. J. Psychiatry PD FEB PY 2007 VL 190 BP 112 EP 117 DI 10.1192/bjp.bp.105.019562 PG 6 WC Psychiatry SC Psychiatry GA 139CZ UT WOS:000244411200006 PM 17267926 ER PT J AU Hallahan, B Hibbeln, JR Davis, JM Garland, MR AF Hallahan, Brian Hibbeln, Joseph R. Davis, John M. Garland, Malcolm R. TI Omega-3 fatty acid supplementation in patients with recurrent self-harm - Single-centre double-blind randomised controlled trial SO BRITISH JOURNAL OF PSYCHIATRY LA English DT Article ID ESSENTIAL FATTY-ACIDS; DOCOSAHEXAENOIC ACID; DEPRESSION; AGGRESSION; BEHAVIOR; STRESS; SCALE AB Background Trials have demonstrated benefits of long-chain omega-3 essential fatty acid (n-3 EFA) supplementation in a variety of psychiatric disorders. Aims To assess the efficacy of n-3 EFAs in improving psychological well-being in patients with recurrent self-harm. Method Patients (n=49) presenting after an act of repeated self-harm were randomised to receive 1.2 g eicosapentaenoic acid plus 0.9 g decosahexaenoic acid (n=22) or placebo (n=27) for 12 weeks in addition to standard psychiatric care. Six psychological domains were measured at baseline and end point. Results At 12 weeks, the n-3 EFA group had significantly greater improvements in scores for depression, suicidality and daily stresses. Scores for impulsivity, aggression and hostility did not differ. Conclusions Supplementation achieved substantial reductions in surrogate markers of suicidal behaviour and improvements in well-being. Larger studies are warranted to determine if insufficient dietary intake of n-3 EFAs is a reversible risk factor for self-harm. Declaration of interest Pronova (now Epax) AS, Lysaker, Norway, provided the active preparation and placebo but were not otherwise involved in the study Funding detailed in Acknowledgements. C1 Beaumont Hosp, Dept Psychiat, Beaumont, TX USA. Royal Coll Surgeons Ireland, Dublin 2, Ireland. NIAAA, Lab Membrane Biochem & Biophys, Rockville, MD 20852 USA. Univ Illinois, Inst Psychiat, Chicago, IL USA. RP Garland, MR (reprint author), St Itas Hosp, Dublin, Ireland. EM mgarland@ireland.com OI Hallahan, Brian/0000-0003-0518-9757 NR 21 TC 85 Z9 89 U1 0 U2 7 PU ROYAL COLLEGE OF PSYCHIATRISTS PI LONDON PA BRITISH JOURNAL OF PSYCHIATRY 17 BELGRAVE SQUARE, LONDON SW1X 8PG, ENGLAND SN 0007-1250 J9 BRIT J PSYCHIAT JI Br. J. Psychiatry PD FEB PY 2007 VL 190 BP 118 EP 122 DI 10.1192/bjp.bp.106.022707 PG 5 WC Psychiatry SC Psychiatry GA 139CZ UT WOS:000244411200007 PM 17267927 ER PT J AU Howerton, MW Gibbons, MC Baffi, CR Gary, TL Lai, GY Bolen, S Tilburt, J Tanpitukpongse, TP Wilson, RF Powe, NR Bass, EB Ford, JG AF Howerton, Mollie W. Gibbons, M. Chris Baffi, Charles R. Gary, Tiffany L. Lai, Gabriel Y. Bolen, Shari Tilburt, Jon Tanpitukpongse, Teerath Peter Wilson, Renee F. Powe, Neil R. Bass, Eric B. Ford, Jean G. TI Provider roles in the recruitment of underrepresented populations to cancer clinical trials SO CANCER LA English DT Review DE clinical trials; recruitment; accrual; underrepresented populations; underserved; minorities; providers; cancer; systematic review ID COOPERATIVE-ONCOLOGY-GROUP; BREAST-CANCER; PHYSICIAN PERSPECTIVES; BARRIERS; PARTICIPATION; ENROLLMENT; PATTERNS; WOMEN AB BACKGROUND. Providers play a vital role in the successful recruitment of underrepresented patients to cancer clinical trials because they often introduce the opportunity of clinical trials. The purpose of the current systematic review was to describe provider-related factors influencing recruitment of underrepresented populations to cancer clinical trials. METHODS. To find original studies on the recruitment of underrepresented populations to cancer clinical trials, electronic databases from January 1966 to December 2005 were searched; hand-searched titles in 34 journals from January 2003 to January 2006; and reference lists were examined of eligible articles. Title and abstract reviews were conducted to identify relevant studies. Potential articles were then abstracted using a structured instrument and a serial review process by 2 investigators. RESULTS. Eighteen studies were eligible for review: 13 targeted healthcare providers, 3 targeted patients/participants, and 2 targeted both providers and patients. The study designs included randomized controlled trial, concurrent controlled trial, case-control, descriptive, and qualitative. A lack of available protocols and/or a lack of provider awareness about clinical trials prevented providers from discussing the opportunity of clinical trials in 2 studies. In 14 studies, patient accrual was affected by provider attitudinal barriers relating to patient adherence to the study protocol, patient mistrust of research, patient costs, data collection costs, and/or patient eligibility Providers' communication methods were barriers in 5 studies and promoters in 1 study. CONCLUSIONS. A heterogeneous body of evidence suggests that several provider-related factors influence recruitment of underrepresented groups to clinical trials. Future recruitment efforts should address these factors. C1 Johns Hopkins Univ Sch Med, Dept Oncol, Baltimore, MD 21205 USA. Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Hlth Dispar Res Program, Baltimore, MD 21218 USA. Johns Hopkins Sch Med, Dept Med, Baltimore, MD 21205 USA. Johns Hopkins Univ, Urban Hlth Inst, Baltimore, MD 21218 USA. CCH, Baltimore, MD USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Hlth Policy & Management, Baltimore, MD USA. NCI, Canc Prevent Fellowship Program, Off Prevent Oncol, Div Canc Prevent, Bethesda, MD 20892 USA. NCI, Hlth Promot Res Branch, Behav Res Program, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Johns Hopkins Univ Sch Med, Dept Med Gen Internal, Baltimore, MD USA. Johns Hopkins Univ, Welch Ctr Prevent Epidemiol & Clin Res, Baltimore, MD 21218 USA. NYU, Sch Med, New York, NY USA. Johns Hopkins Sch Medt, Phoebe R Berman Bioeth Inst, Baltimore, MD USA. Johns Hopkins Univ, Evidence Based Practice Ctr, Baltimore, MD USA. RP Howerton, MW (reprint author), Johns Hopkins Univ Sch Med, Dept Oncol, 615 N Wolfe St,Rm E6005, Baltimore, MD 21205 USA. EM mhowert2@jhmi.edu NR 33 TC 57 Z9 57 U1 0 U2 3 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 2007 VL 109 IS 3 BP 465 EP 476 DI 10.1002/cncr.22436 PG 12 WC Oncology SC Oncology GA 131LF UT WOS:000243869700002 PM 17200964 ER PT J AU Gatto, NM Longnecker, MP Press, MF Sullivan-Halley, J McKean-Cowdin, R Bernstein, L AF Gatto, Nicole M. Longnecker, Matthew P. Press, Michael F. Sullivan-Halley, Jane McKean-Cowdin, Roberta Bernstein, Leslie TI Serum organochlorines and breast cancer: a case-control study among African-American women SO CANCER CAUSES & CONTROL LA English DT Article DE organochlorines; breast cancer; African-Americans; DDT; DDE; PCBs; pesticides; cancer; women ID HORMONE REPLACEMENT THERAPY; POLYCHLORINATED-BIPHENYLS; ADIPOSE-TISSUE; P53 MUTATIONS; BLOOD-LEVELS; LONG-ISLAND; RISK; RECEPTOR; RESIDUES; ESTROGEN AB This population-based case-control study of African-American women (355 breast cancer case patients, 327 controls) examined the association between breast cancer and circulating levels of PCBs and dichlorodiphenyldichloroethene (DDE), a metabolite of DDT. Case patients were diagnosed with invasive breast carcinoma and interviewed between June 1995 and July 1998, and control subjects were identified by random digit dialing methods. Serum levels of DDE and total PCBs were adjusted for total lipid content. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable unconditional logistic regression methods. Effect modification by tumor receptor status and cancer treatment was investigated. Breast cancer risk was not associated with increasing quintiles of lipid-adjusted PCBs or DDE (highest versus lowest quintile adjusted for age, body mass index (BMI) and breastfeeding for DDE: OR = 1.02, 95% CI = (0.61, 1.72), p-trend = 0.74; for PCBs: OR = 1.01, 95% CI = (0.63, 1.63), p-trend = 0.56). Risk did not differ by strata of BMI, breastfeeding, parity, menopausal status or tumor receptor status. This study, the largest study of African-American women to date, does not support a role of DDE and total PCBs in breast cancer risk at the levels measured. C1 Univ So Calif, Keck Sch Med, USC Norris Comprehens Ctr, Dept Prevent Med, Los Angeles, CA 90033 USA. NIEHS, US Dept HHS, NIH, Res Triangle Pk, NC 27709 USA. Univ So Calif, Keck Sch Med, Dept Pathol, Los Angeles, CA 90033 USA. RP Bernstein, L (reprint author), Univ So Calif, Keck Sch Med, USC Norris Comprehens Ctr, Dept Prevent Med, 1441 Eastlake Ave,Room 4449, Los Angeles, CA 90033 USA. EM Lbern@usc.edu OI Longnecker, Matthew/0000-0001-6073-5322 FU Intramural NIH HHS; NCI NIH HHS [N01-CN-67010]; NICHD NIH HHS [N01 HD3-3175]; NIEHS NIH HHS [ES07084, Z01 ES049016-10] NR 68 TC 31 Z9 33 U1 1 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD FEB PY 2007 VL 18 IS 1 BP 29 EP 39 DI 10.1007/s10552-006-0070-2 PG 11 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 119RW UT WOS:000243031800003 PM 17186420 ER PT J AU Meissner, HI Breen, N Taubman, ML Vernon, SW Graubard, BI AF Meissner, Helen I. Breen, Nancy Taubman, Michele L. Vernon, Sally W. Graubard, Barry I. TI Which women aren't getting mammograms and why? (United States) SO CANCER CAUSES & CONTROL LA English DT Article DE mammography; communications barriers; access to health care; breast neoplasms ID CANCER SCREENING PRACTICES; HEALTH INTERVIEW SURVEYS; ETHNIC-GROUPS; BREAST; METAANALYSIS; PHYSICIAN; SERVICES; PROGRESS; CARE AB Objective This study investigates why women who reported no recent mammogram did not get the test. Methods Using data from the 2000 National Health Interview Survey (NHIS), we examine correlates of mammography use among women 40 years and older (n = 10,212), with particular focus on the 30% (n = 3,188) who reported no recent mammogram. Non-screening is examined in the context of two important correlates of mammography use-access to health care and a physician's recommendation to get a mammogram. Results In total, 80% of non-screeners who reported having access to healthcare did not receive a recommendation for a mammogram. Women age 65 years and older were more likely than younger women to report not receiving a recommendation (OR 1.77, 95% CI 1.25-2.50). For women who reported having access, non-screening was significantly more likely among younger women (40-49), those with less education, incomes less than $20,000, residence outside Metropolitan Statistical Areas (MSAs) and no family history of breast cancer. Among women with access problems, those who had not visited a primary care provider in the past year were much more likely to be non-screeners (80%) compared with those who had seen a provider (46%). Among women with access, those who reported put it off as the main reason for non-screening were significantly more likely to be younger and to be born in the U.S. than women who said that they didn't know they needed a mammogram. Conclusions Most non-screeners report not receiving a physician recommendation for mammography. Although a minority reported access problems, the effect of lacking access on utilization was strong and is accentuated when women without access do not see a doctor. These findings confirm the importance of a mammography recommendation and raise questions concerning whether this information is being conveyed by physicians or heard by patients. C1 NCI, Div Canc Control & Populat Sci, Appl Canc Screening Res Branch, Bethesda, MD 20892 USA. NCI, Div Canc Control & Populat Sci, Hlth Serv & Econ Branch, Bethesda, MD 20892 USA. Univ Texas, Hlth Sci Ctr, Div Hlth Promot & Behav Sci, Houston, TX USA. NCI, Div Canc Control & Populat Sci, Biostat Branch, Bethesda, MD 20892 USA. RP Meissner, HI (reprint author), NCI, Div Canc Control & Populat Sci, Appl Canc Screening Res Branch, 6130 Execut blvd,EPN 4102 MSC 7331, Bethesda, MD 20892 USA. EM hm36d@nih.gov FU NCI NIH HHS [R01 CA76330, R01 CA97263] NR 31 TC 84 Z9 86 U1 0 U2 8 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0957-5243 J9 CANCER CAUSE CONTROL JI Cancer Causes Control PD FEB PY 2007 VL 18 IS 1 BP 61 EP 70 DI 10.1007/s10552-006-0078-7 PG 10 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 119RW UT WOS:000243031800006 PM 17186422 ER PT J AU Ma, C Mandrekar, SJ Alberts, SR Croghan, GA Jatoi, A Reid, JM Hanson, LJ Bruzek, L Tan, AD Pitot, HC Erlichman, C Wright, JJ Adjei, AA AF Ma, Cynthia Mandrekar, Sumithra J. Alberts, Steven R. Croghan, Gary A. Jatoi, Aminah Reid, Joel M. Hanson, Lorelei J. Bruzek, Laura Tan, Angelina D. Pitot, Henry C. Erlichman, Charles Wright, John J. Adjei, Alex A. TI A phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib (PS-341, Velcade (TM)), in combination with paclitaxel and carboplatin in patients with advanced malignancies SO CANCER CHEMOTHERAPY AND PHARMACOLOGY LA English DT Article DE PS-341; ubiquitin-proteasome system; chemotherapy ID PANCREATIC-CANCER; SOLID TUMORS; TRIAL; THERAPY; APOPTOSIS; MYELOMA AB Purpose Bortezomib, a selective inhibitor of the 20S proteasome with activity in a variety of cancers, exhibits sequence-dependent synergistic cytotoxicity with taxanes and platinum agents. Two different treatment schedules of bortezomib in combination with paclitaxel and carboplatin were tested in this phase I study to evaluate the effects of scheduling on toxicities, pharmacodynamics and clinical activity. Methods Patients with advanced malignancies were alternately assigned to receive ( schedule A) paclitaxel and carboplatin (IV d1) followed by bortezomib (IV d2, d5, d8) or (schedule B) bortezomib (IV d1, d4, d8) followed by paclitaxel and carboplatin ( IV d2) on a 21-day cycle. Results Fifty-three patients (A 25, B 28) were treated with a median of 3 cycles (range 1-8) for schedule A and 3.5 cycles (range 1-10) for schedule B. Grade 3 or higher treatment related hematologic adverse events in all cycles of treatment included neutropenia (A 52%, B 50%), anemia (A 12%, B 7.1%) and thrombocytopenia (A 16%, B 17.9%). Non-hematologic treatment related adverse events were fairly mild (primarily grades 1 and 2). The maximum tolerated dose and the recommended doses for future phase II trials are bortezomib 1.2 mg/m(2), paclitaxel 135 mg/m(2) and carboplatin AUC=6 for schedule A and bortezomib 1.2 mg/ m(2), paclitaxel 175 mg/m(2) and carboplatin AUC=6 for schedule B. Six (21.4%) partial responses (PR) were seen with schedule B. In contrast, only 1 (4%) PR was achieved with schedule A. Similar proteasome inhibition was achieved at MTD for both schedules. Conclusion Administration of sequential bortezomib followed by chemotherapy (schedule B) was well tolerated and associated with an encouraging number of objective responses in this small group of patients. Further studies with this administration schedule are warranted. C1 Mayo Clin & Mayo Fdn, Div Med Oncol, Rochester, MN 55905 USA. NCI, Bethesda, MD 20892 USA. RP Adjei, AA (reprint author), Mayo Clin & Mayo Fdn, Div Med Oncol, 200 1st St SW, Rochester, MN 55905 USA. EM adjei.alex@mayo.edu FU NCI NIH HHS [CA69912]; NCRR NIH HHS [RR00585] NR 25 TC 30 Z9 30 U1 0 U2 2 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 2007 VL 59 IS 2 BP 207 EP 215 DI 10.1007/s00280-006-0259-9 PG 9 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 110ZK UT WOS:000242419900007 PM 16763792 ER PT J AU Hawk, E Viner, JL AF Hawk, Ernest Viner, Jaye L. TI The adenoma prevention with celecoxib and prevention of colorectal sporadic adenomatous polyps trials: Stepping stones to progress SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material ID RANDOMIZED-TRIAL; CYCLOOXYGENASE-2 INHIBITOR; CARDIOVASCULAR RISK; COLON-CANCER; RECURRENCE; ASPIRIN; DIET; RATS C1 NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Hawk, E (reprint author), NCI, Div Canc Prevent, EPN Suite 2141,6130 Execut Blvd,MSC 7317, Bethesda, MD 20892 USA. EM eh51p@nih.gov NR 24 TC 8 Z9 8 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2007 VL 16 IS 2 BP 185 EP 187 DI 10.1158/1055-9965.EPI-06-1086 PG 3 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 137LF UT WOS:000244293400001 PM 17301246 ER PT J AU Boffetta, P Armstrong, B Linet, M Kasten, C Cozen, W Hartge, P AF Boffetta, Paolo Armstrong, Bruce Linet, Martha Kasten, Carol Cozen, Wendy Hartge, Patricia TI Consortia in cancer epidemiology: Lessons from InterLymph SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Editorial Material ID NON-HODGKIN-LYMPHOMA; POOLED ANALYSIS; RISK C1 IARC, Gene Environm Epidemiol Grp, F-69008 Lyon, France. Univ Sydney, Sydney, NSW 2006, Australia. NCI, Bethesda, MD 20892 USA. Univ So Calif, Los Angeles, CA USA. RP Boffetta, P (reprint author), IARC, Gene Environm Epidemiol Grp, 150 Cours Albert Thomas, F-69008 Lyon, France. EM boffetta@iarc.fr RI Armstrong, Bruce/K-9464-2015 OI Armstrong, Bruce/0000-0001-8940-7525 NR 11 TC 17 Z9 19 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2007 VL 16 IS 2 BP 197 EP 199 DI 10.1158/1055-9965.EPI-06-0786 PG 3 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 137LF UT WOS:000244293400005 PM 17301250 ER PT J AU Mechanic, LE Bowman, ED Welsh, JA Khan, MA Hagiwara, N Enewold, L Shields, PG Burdette, L Chanock, S Harris, CC AF Mechanic, Leah E. Bowman, Elise D. Welsh, Judith A. Khan, Mohammed A. Hagiwara, Nobutoshi Enewold, Lindsey Shields, Peter G. Burdette, Laurie Chanock, Stephen Harris, Curtis C. TI Common genetic variation in TP53 is associated with lung cancer risk and prognosis in African Americans and somatic mutations in lung tumors SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID SQUAMOUS-CELL CARCINOMA; POLYMORPHIC VARIANTS; CODON-72 POLYMORPHISM; P53 POLYMORPHISMS; BREAST-CANCER; HAPLOTYPE; SUSCEPTIBILITY; EPIDEMIOLOGY; POPULATION; FREQUENCY AB Lung cancer is primarily caused by tobacco smoking, but susceptibility is likely modified by common genetic variation. In response to many forms of cellular stress, including DNA damage, the p53 protein functions to induce cell cycle arrest, DNA repair, senescence, or apoptosis. We hypothesized that common TP53 haplotypes modulate pathways of lung carcinogenesis and lung cancer susceptibility or prognosis. To investigate our hypothesis, 14 polymorphisms in TP53, including haplotype tagging and coding single nucleotide polymorphisms, were genotyped in two studies from the greater Baltimore, Maryland area. One study is a case-control study and the second is a case-only study for which TP53 mutational spectra data are available. African Americans with Pro-T-A-G-G haplotypes of the combined TP53 polymorphisms TP53_01 (rs1042522), TP53_65 (rs9895829), TP53_66 (rs2909430), TP53_16 (rs1625895), and TP53_11 (rs12951053) had both an increased risk for lung cancer (odds ratio, 2.32; 95% confidence interval, 1.18-4.57) and a worsened lung cancer prognosis (hazards ratio, 2.38; 95% confidence interval, 1.38-4.10) compared with those with Arg-T-A-G-T haplotypes. No associations of TP53 polymorphisms with lung cancer were observed in Caucasians. In the case-only study, several polymorphisms in TP53 and TP53 haplotypes, overlapping regions of TP53 associated with risk and prognosis in African Americans, were associated with increased odds of somatic TP53 mutation in lung tumors in Caucasians. In conclusion, common genetic variation in TP53 could modulate lung cancer pathways, as suggested by the association with lung cancer in African Americans and somatic TP53 mutation frequency in lung tumors. C1 NCI, Human Carcinogenesis Lab, NIH, Ctr Canc Res, Bethesda, MD 20892 USA. Nippon Med Coll Hosp, Dept Surg 1, Tokyo, Japan. Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Washington, DC 20007 USA. NCI, Frederick Canc Res & Dev Ctr, Ctr Adv Technol,Sci Applicat Int Corp Frederick, Intramural Res Support Program, Frederick, MD USA. NCI, Pediat Oncol Branch, Ctr Canc Res, Rockville, MD USA. NCI, Dept Canc Epidemiol & Genet, Rockville, MD USA. RP Harris, CC (reprint author), NCI, Human Carcinogenesis Lab, NIH, Ctr Canc Res, Room 3068,Bldg 37,37 Convent Dr, Bethesda, MD 20892 USA. EM Curtis_Harris@nih.gov RI Shields, Peter/I-1644-2012 FU Intramural NIH HHS NR 57 TC 40 Z9 42 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 2007 VL 16 IS 2 BP 214 EP 222 DI 10.1158/1055-9965.EPI-06-0790 PG 9 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 137LF UT WOS:000244293400008 PM 17301252 ER PT J AU Chalut, KJ Kresty, LA Pyhtila, JW Nines, R Baird, M Steele, VE Wax, A AF Chalut, Kevin J. Kresty, Laura A. Pyhtila, John W. Nines, Ronald Baird, Maureen Steele, Vernon E. Wax, Adam TI In situ assessment of intraepithelial neoplasia in hamster trachea epithelium using angle-resolved low-coherence interferometry SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID TOMOGRAPHY AB Optical spectroscopy was used to evaluate the transformation of nuclear morphology associated with intraepithelial neoplasia in an animal model of carcinogenesis. In this pilot study, we have assessed the capability of angle-resolved low-coherence interferometry (a/LCI) to monitor in situ the neoplastic progression of hamster trachea epithelial tissue. By using the depth resolution made possible by coherence gating, the a/LCI system has been adapted to the unique geometry of the hamster trachea to allow us to extract useful nuclear morphometric information from cells in the epithelial layer without the need for exogenous staining or tissue fixation. Analysis of a/LCI nuclear morphology measurements has identified two important biomarkers of neoplastic transformation in hamster trachea epithelium, the size and the refractive index of epithelial cell nuclei. By comparing the a/LCI measurements of these two biomarkers to pathologic classification, we distinguished nuclear morphology changes for normal tissue, low-grade dysplasia, and high-grade dysplasia. Given its previous usefulness for tracking neoplastic change through nuclear morphometry measurements, the a/LCI technique may prove to be a useful tool in evaluating chemopreventive agents in future studies of hamster trachea epithelium. C1 Duke Univ, Dept Biomed Engn, Durham, NC 27708 USA. Ohio State Univ, Ctr Comprehens Canc, Columbus, OH 43210 USA. NCI, Div Canc Prevent, Bethesda, MD 20892 USA. RP Wax, A (reprint author), Duke Univ, Dept Biomed Engn, Box 90281, Durham, NC 27708 USA. EM a.wax@duke.edu RI Wax, Adam/A-4760-2008; OI Wax, Adam/0000-0002-1827-5112 FU NCI NIH HHS [CN43308-13, N01-CN-43308] NR 14 TC 18 Z9 19 U1 0 U2 1 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2007 VL 16 IS 2 BP 223 EP 227 DI 10.1158/1055-9965.EPI-06-0418 PG 5 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 137LF UT WOS:000244293400009 PM 17301253 ER PT J AU Lillie, SE Brewer, NT O'Neill, SC Morrill, EF Dees, EC Carey, LA Rimer, BK AF Lillie, Sarah E. Brewer, Noel T. O'Neill, Suzanne C. Morrill, Edward F. Dees, E. Claire Carey, Lisa A. Rimer, Barbara K. TI Retention and use of breast cancer recurrence risk information from genomic tests: The role of health literacy SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID MEDICAL DECISION-MAKING; ADJUVANT THERAPY; PATIENTS PERCEPTIONS; NEEDS; WOMEN; PREFERENCES; CARE; PARTICIPATION; CHEMOTHERAPY; MAMMOGRAPHY AB Background: New genomic technology now allows physicians to provide women with individualized and highly accurate breast cancer recurrence risk estimates that are a key factor in adjuvant (after surgery) therapy decisions. Because these genomic tests are so new, little is known about how well patients understand the tests and their results. Method: We interviewed 163 stage I or II breast cancer patients at a routine follow-up appointment. We assessed their health literacy (using the Rapid Estimate of Adult Learning in Medicine) as well as their knowledge of and attitudes towards a genomic test that identifies risk of recurrence in hormone receptor-positive, node-negative breast cancer (the OncoType Dx Recurrence Score). Results: Women with lower health literacy recalled less of the information provided about the recurrence risk test than women with higher health literacy. Health literacy was not related to the amount of additional information women desired. Women with higher health literacy preferred to have a more active role in decisions about the test. Implications: Health literacy may affect women's capacity to learn about the new genomic tests as well as their desire for informed participation in their medical care. C1 Univ N Carolina, Sch Publ Hlth, Chapel Hill, NC 27599 USA. NIH, Bethesda, MD 20892 USA. RP Brewer, NT (reprint author), Univ N Carolina, Sch Publ Hlth, Rosenau Hall 306,CB 7440, Chapel Hill, NC 27599 USA. EM ntb1@unc.edu RI Brewer, Noel/C-4375-2008; OI Lillie, Sarah/0000-0001-9854-7191 NR 50 TC 50 Z9 50 U1 2 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 2007 VL 16 IS 2 BP 249 EP 255 DI 10.1158/1055-9965.EPI-06-0525 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 137LF UT WOS:000244293400013 PM 17267389 ER PT J AU Tiro, JA Meissner, HI Kobrin, S Chollette, V AF Tiro, Jasmin A. Meissner, Helen I. Kobrin, Sarah Chollette, Veronica TI What do women in the US know about human papillomavirus and cervical cancer? SO CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION LA English DT Article ID YOUNG-WOMEN; TELEPHONE SURVEY; RISK BEHAVIORS; KNOWLEDGE; INFECTION; NONRESPONSE; ADOLESCENTS; POPULATION; NEOPLASIA; AWARENESS AB Background: Women need to understand the link between human papillornavirus (HPV) and cervical cancer in order to make appropriate, evidence-based choices among existing prevention strategies (Pap test, HPV DNA test, and HPV vaccine). Assessment of the public's knowledge in nationally representative samples is a high priority for cervical cancer control. Objectives: To assess factors associated with U.S. women's awareness of HPV and knowledge about its link to cervical cancer. Methods: Analyzed cross-sectional data from women ages 18 to 75 years old responding to the 2005 Health Information National Trends Survey (n = 3,076). Results: Among the 40% of women who had ever heard about HPV, < 50% knew it caused cervical cancer; knowledge that HPV was sexually transmitted and caused abnormal Paptests was higher (64% and 79%, respectively). Factors associated with having heard about HPV included: younger age, being non-Hispanic White, higher educational attainment, exposure to multiple health information sources, trusting health information, regular Pap tests, awareness of changes in cervical cancer screening guidelines, and having tested positive for HPV. Accurate knowledge of the HPV-cervical cancer link was associated with abnormal Pap and positive HPV test results. Conclusions: Awareness about HPV among U.S. women is low. Having heard about HPV did not ensure accurate knowledge. Strategies for communicating accurate information about HPV transmission, prevention, and detection as well as risk and treatment of cervical cancer are needed. C1 NCI, Div Canc Control & Populat Sci, Appl Canc Screening Res Branch, Bethesda, MD 20892 USA. NCI, Canc Prevent Fellowship Program, Div Canc Prevent, Bethesda, MD 20892 USA. RP Tiro, JA (reprint author), NCI, Div Canc Control & Populat Sci, Appl Canc Screening Res Branch, 6130 Execut Blvd,EPN 4103A,MSC 7331, Bethesda, MD 20892 USA. EM tiroj@mail.nih.gov OI Tiro, Jasmin/0000-0001-8300-0441 FU NCI NIH HHS [N02-PC-3523] NR 49 TC 122 Z9 125 U1 1 U2 8 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1055-9965 J9 CANCER EPIDEM BIOMAR JI Cancer Epidemiol. Biomarkers Prev. PD FEB PY 2007 VL 16 IS 2 BP 288 EP 294 DI 10.1158/1055-9965.EPI-06-0756 PG 7 WC Oncology; Public, Environmental & Occupational Health SC Oncology; Public, Environmental & Occupational Health GA 137LF UT WOS:000244293400019 PM 17267388 ER PT J AU Niederhuber, JE AF Niederhuber, John E. TI A look inside the National Cancer Institute budget process: Implications for 2007 and beyond SO CANCER RESEARCH LA English DT Article C1 NCI, Bethesda, MD 20892 USA. RP Niederhuber, JE (reprint author), NCI, Bldg 31,Room 11A48,31 Ctr Dr,MSC 2590, Bethesda, MD 20892 USA. EM niederj@mail.nih.gov NR 2 TC 1 Z9 1 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 1 PY 2007 VL 67 IS 3 BP 856 EP 862 DI 10.1158/0008-5472.CAN-06-4472 PG 7 WC Oncology SC Oncology GA 135EQ UT WOS:000244137300004 PM 17283113 ER PT J AU Yeager, N Klein-Szanto, A Kimura, S Di Cristofano, A AF Yeager, Nicole Klein-Szanto, Andres Kimura, Shioko Di Cristofano, Antonio TI Pten loss in the mouse thyroid causes goiter and follicular adenomas: Insights into thyroid function and Cowden disease pathogenesis SO CANCER RESEARCH LA English DT Article ID PROTEIN-KINASE-B; TRANSGENIC MICE; TUMOR SUPPRESSION; PHOSPHATIDYLINOSITOL 3-KINASE; P27(KIP1) EXPRESSION; CELL PROLIFERATION; SIGNALING PATHWAYS; GROWTH-FACTORS; CANCER; RECEPTOR AB Inactivation and silencing of the tumor suppressor PTEN are found in many different epithelial tumors, including thyroid neoplasia. Cowden Disease patients, who harbor germ-line PTEN mutations, often display thyroid abnormalities, including multinodular goiter and follicular adenomas, and are at increased risk of thyroid cancer. To gain insights into the role PTEN plays in thyroid function and disease, we have generated a mouse strain, in which Cre-mediated recombination is used to specifically delete Pten in the thyrocytes. We found that Pten mutant mice develop diffuse goiter characterized by extremely enlarged follicles, in the presence of normal thyroid-stimulating hormone and T4 hormone levels. Loss of Pten resulted in a significant increase in the thyrocyte proliferative index, which was more prominent in the female mice, and in increased cell density in the female thyroid glands. Surprisingly, goitrogen treatment did not cause a substantial increase of the mutant thyroid size and increased only to some extent the proliferation index of the female thyrocytes, suggesting that a relevant part of the thyroidstimulating hormone-induced proliferation signals are funneled through the phosphatidylinositol-3-kinase (PI3K)/ Akt cascade. Although complete loss of Pten was not sufficient to cause invasive tumors, over two thirds of the mutant females developed follicular adenomas by 10 months of age, showing that loss of Pten renders the thyroid highly susceptible to neoplastic transformation through mechanisms that include increased thyrocyte proliferation. Our findings show that constitutive activation of the PI3K/Akt cascade is sufficient to stimulate continuous autonomous growth and provide novel clues to the pathogenesis of Cowden Disease and sporadic nontoxic goiter. C1 Fox Chase Canc Ctr, Human Genet Program, Philadelphia, PA 19111 USA. Fox Chase Canc Ctr, Dept Pathol, Philadelphia, PA 19111 USA. NCI, Lab Metab, NIH, Bethesda, MD 20892 USA. RP Di Cristofano, A (reprint author), Fox Chase Canc Ctr, Human Genet Program, 333 Cottman Ave, Philadelphia, PA 19111 USA. EM antonio.dicristofano@fccc.edu RI Klein-Szanto, Andres/E-6218-2010; Di Cristofano, Antonio/B-4148-2016 NR 44 TC 66 Z9 68 U1 1 U2 2 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 1 PY 2007 VL 67 IS 3 BP 959 EP 966 DI 10.1158/0008-5472.CAN-06-3524 PG 8 WC Oncology SC Oncology GA 135EQ UT WOS:000244137300018 PM 17283127 ER PT J AU Markus, J Garin, MT Bies, J Galili, N Raza, A Thirman, MJ Le Beau, MM Rowley, JD Liu, PP Wolff, L AF Markus, Jan Garin, Matthew T. Bies, Juraj Galili, Naomi Raza, Azra Thirman, Michael J. Le Beau, Michelle M. Rowley, Janet D. Liu, P. Paul Wolff, Linda TI Methylation-independent silencing of the tumor suppressor INK4b (p15) by CBF beta-SMMHC in acute myelogenous leukemia with inv(16) SO CANCER RESEARCH LA English DT Article ID ACUTE MYELOID-LEUKEMIA; CPG ISLAND METHYLATION; FUSION GENE CBFB-MYH11; DNA-METHYLATION; MYELODYSPLASTIC SYNDROMES; DISEASE PROGRESSION; CELL-PROLIFERATION; P15(INK4B) GENE; IN-VIVO; C-MYC AB The tumor suppressor gene INK4b (p15) is silenced by CpG island hypermethylation in most acute myclogenous leukemias (AML), and this epigenetic phenomenon can be reversed by treatment with hypomethylating agents. Thus far, it was not investigated whether INK4b is hypermethylated in all cytogenetic subtypes of AML. A comparison of levels of INK4b methylation in AML with the three most common cytogenetic alterations, inv(16), t(8;21), and t(15;17), revealed a strikingly low level of methylation in all leukemias with inv(16) compared with the other types. Surprisingly, the expression level of INK4b in inv(16)+ AML samples was low and comparable with that of the other subtypes. An investigation into an alternative mechanism of INK4b silencing determined that the loss of INK4b expression was caused by inv(16)-encoded core binding factor beta-smooth muscle myosin heavy chain (CBF beta-SMMHC). The silencing was manifested in an inability to activate the normal expression of INK4b RNA as shown in vitamin D3-treated U937 cells expressing CBF beta-SMMHC. CBF beta-SMMHC was shown to displace RUNXl from a newly determined CBF site in the promoter of INK4b. Importantly, this study (a) establishes that the gene encoding the tumor suppressor p15(INK4b) is a target of CBF beta-SMMHC, a finding relevant to the leukemogenesis process, and (b) indicates that, in patients with inv(16)-containing AML, reexpression from the INK4b locus in the leukemia would not be predicted to occur using hypomethylating drugs. C1 NCI, Cellular Oncol Lab, NIH, Bethesda, MD 20892 USA. NHGRI, NIH, Bethesda, MD 20892 USA. Univ Chicago, Rush Canc Inst, Chicago, IL 60637 USA. Univ Chicago, Dept Med, Chicago, IL 60637 USA. RP Wolff, L (reprint author), NCI, Cellular Oncol Lab, NIH, Bldg 37,Room 4124,37 Convent Dr,MSC 4263, Bethesda, MD 20892 USA. EM lwolff@helix.nih.gov RI Liu, Paul/A-7976-2012 OI Liu, Paul/0000-0002-6779-025X FU Intramural NIH HHS; NCI NIH HHS [CA 84405] NR 50 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 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2007 VL 67 IS 3 BP 992 EP 1000 DI 10.1158/0008-5472.CAN-06-2964 PG 9 WC Oncology SC Oncology GA 135EQ UT WOS:000244137300022 PM 17283131 ER PT J AU Chin, KT Chun, ACS Ching, YP Jeang, KT Jin, DY AF Chin, King-Tung Chun, Abel C. S. Ching, Yick-Pang Jeang, Kuan-Teh Jin, Dong-Yan TI Human T-cell leukemia virus oncoprotein tax represses nuclear receptor-dependent transcription by targeting coactivator TAX1BP1 SO CANCER RESEARCH LA English DT Article ID NF-KAPPA-B; TYPE-1 TAX; GLUCOCORTICOID-RECEPTOR; POTENTIAL MECHANISM; UBIQUITIN LIGASE; DNA-DAMAGE; HTLV-1 TAX; PROTEIN; ACTIVATION; P53 AB Human T-cell leukemia virus type 1 oncoprotein Tax is a transcriptional regulator that interacts with a large number of host cell factors. Here, we report the novel characterization of the interaction of Tax with a human cell protein named Tax1-binding protein 1 (TAXIBP1). We show that TAX1BP1 is a nuclear receptor coactivator that forms a complex with the glucocorticoid receptor. TAX1BP1 and Tax colocalize into intranuclear speckles that partially overlap with but are not identical to the PML oncogenic domains. Tax binds TAX1BP1 directly, induces the dissociation of TAX1BP1 from the glucocorticoid receptor-containing protein complex, and represses the coactivator function of TAX1BP1. Genetic knockout of Tax1bp1 in mice abrogates the influence of Tax on the activation of nuclear receptors. We propose that Tax-TAX1BP1 interaction mechanistically explains the previously reported repression of nuclear receptor activity by Tax. C1 Univ Hong Kong, Dept Biochem, Hong Kong, Hong Kong, Peoples R China. Univ Hong Kong, Dept Pathol, Hong Kong, Hong Kong, Peoples R China. NIAID, Mol Microbiol Lab, Bethesda, MD 20892 USA. RP Jin, DY (reprint author), Univ Hong Kong, Dept Biochem, 3-F Lab Block,Fac Med Bldg,21 Sassoon Rd, Hong Kong, Hong Kong, Peoples R China. EM dyjin@hkucc.hku.hk RI Ching, Yick Pang/C-4244-2009; Jeang, Kuan-Teh/A-2424-2008 NR 50 TC 25 Z9 26 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2007 VL 67 IS 3 BP 1072 EP 1081 DI 10.1158/0008-5472.CAN-06-3053 PG 10 WC Oncology SC Oncology GA 135EQ UT WOS:000244137300031 PM 17283140 ER PT J AU Berndt, SI Huang, WY Fallin, MD Helzlsouer, KJ Platz, EA Weissfeld, JL Church, TR Welch, R Chanock, SJ Hayes, RB AF Berndt, Sonja I. Huang, Wen-Yi Fallin, M. Daniele Helzlsouer, Kathy J. Platz, Elizabeth A. Weissfeld, Joel L. Church, Timothy R. Welch, Robert Chanock, Stephen J. Hayes, Richard B. TI Genetic variation in base excision repair genes and the prevalence of advanced colorectal adenoma SO CANCER RESEARCH LA English DT Article ID STRAND BREAK REPAIR; JUN DNA-BINDING; MONONUCLEAR LEUKOCYTES; CANCER SUSCEPTIBILITY; XRCC1 POLYMORPHISMS; MUTAGEN SENSITIVITY; RIBOSYL TRANSFERASE; HUMAN-LYMPHOCYTES; LINKAGE PHASE; XPD GENES AB Base excision repair (BER) corrects DNA damage caused by oxidative stress and low folate intake, which are putative risk factors for colorectal neoplasia. To examine the relationship between genetic variation in BER genes and colorectal adenoma risk, we conducted a case-control study of 767 cases of advanced colorectal adenoma and 773 controls from the baseline screening exam of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cases included participants diagnosed with advanced left-sided adenoma, and controls were subjects without evidence of a left-sided polyp by sigmoidoscopy, frequency-matched to cases on race and gender. Twenty single nucleotide polymorphisms were genotyped in four BER genes (APEX1, PARP1, POLB, and XRCC1), and conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95% CI) for the association with colorectal adenoma. Two variants with possible functional significance were associated with risk. The APEX1 51H variant was associated with a borderline significant decreased risk of colorectal adenoma (OR, 0.66; 95% CI, 0.44-1.00), and the XRCC1 399Q variant was inversely associated with risk among Caucasians (OR, 0.80; 95% CI, 0.64-0.99). Homozygotes at two PARP1 loci (A284A and IVS13+118G > A) were also associated with a decreased risk of colorectal adenoma compared with wild-type carriers (OR, 0.70; 95% CI, 0.49-0.98 for both), which was restricted to advanced adenomas displaying histologically aggressive characteristics (OR, 0.51; 95% Cl, 0.33-0.78, P = 0.002 for PARP1 A284A). This study suggests that polymorphisms in APEX1, XRCC1, and PARP1 may be associated with advanced colorectal adenoma. C1 NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. Johns Hopkins Bloomberg Sch Publ Hlth, Dept Epidemiol, Baltimore, MD USA. Mercy Med Ctr, Weinberg Ctr Womens Hlth & Med, Prevent & Res Ctr, Baltimore, MD USA. Univ Pittsburgh, Pittsburgh, PA USA. Univ Minnesota, St Paul, MN 55108 USA. RP Berndt, SI (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, 6120 Execut Blvd,EPS 8111,MSC 7240, Bethesda, MD 20892 USA. EM berndts@mail.nih.gov OI Hayes, Richard/0000-0002-0918-661X; Church, Timothy R./0000-0003-3292-5035 FU Intramural NIH HHS NR 52 TC 39 Z9 39 U1 0 U2 3 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 0008-5472 J9 CANCER RES JI Cancer Res. PD FEB 1 PY 2007 VL 67 IS 3 BP 1395 EP 1404 DI 10.1158/0008-5472.CAN-06-1390 PG 10 WC Oncology SC Oncology GA 135EQ UT WOS:000244137300069 PM 17283177 ER PT J AU McCormick, DL Johnson, WD Kozub, NM Rao, KVN Lubet, RA Steele, VE Bosland, MC AF McCormick, David L. Johnson, William D. Kozub, Nicole M. Rao, K. V. N. Lubet, Ronald A. Steele, Vernon E. Bosland, Maarten C. TI Chemoprevention of rat prostate carcinogenesis by dietary 16 alpha-fluoro-5-androsten-17-one (fluasterone), a minimally androgenic analog of dehydroepiandrosterone SO CARCINOGENESIS LA English DT Article ID SKIN PAPILLOMA FORMATION; LONG-TERM TREATMENT; MAMMARY-GLAND; F344 RATS; MICE; INHIBITION; CANCER; TUMORIGENESIS; LUNG; DHEA AB Dehydroepiandrosterone (DHEA) is a potent inhibitor of prostate carcinogenesis in rats. However, concerns related to the possible androgenicity of DHEA may preclude its use for chemoprevention of human prostate cancer. Studies were performed to compare the androgenicity of DHEA and a fluorinated DHEA analog, 16 alpha-fluoro-5-androsten-17-one (fluasterone), and to determine the chemopreventive activity of fluasterone in the rat prostate. Comparisons of accessory sex gland weight and histology in gonadectomized male rats demonstrated that fluasterone is less androgenic than is DHEA. Fluasterone conferred significant protection against prostate carcinogenesis induced in Wistar-Unilever rats by a sequential regimen of N-methyl-N-nitrosourea + testosterone. Chronic administration of fluasterone at levels of 2000 and 1000 mg/kg diet reduced the incidence of adenocarcinoma in the dorsolateral/anterior prostate from 64% in dietary controls to 28 and 31%, respectively. Other than a dose-related suppression of body weight gain, chronic exposure to fluasterone induced no clinical evidence of toxicity; suppression of body weight gain may be either a pharmacological effect or a minimally toxic effect of the compound. These data demonstrate that a minimally androgenic analog of DHEA protects against prostate carcinogenesis induced in rats by a chemical carcinogen + androgen. The reduced androgenicity of fluasterone may obviate toxicities associated with the androgenicity of the parent compound. On this basis, fluasterone merits consideration for evaluation in clinical trials for prostate cancer prevention. The chemopreventive activity of a non-androgenic DHEA analog suggests that at least a portion of the chemopreventive activity of DHEA in the rat prostate is unrelated to hormonal effects. C1 IIT, Res Inst, Life Sci Grp, Chicago, IL 60616 USA. NCI, Chemoprevent Agent Dev Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. NYU, Sch Med, Dept Environm Med & Urol, New York, NY 10016 USA. RP McCormick, DL (reprint author), IIT, Res Inst, Life Sci Grp, 10 W 35th St, Chicago, IL 60616 USA. EM dmccormick@iitri.org FU NCI NIH HHS [N01-CN-65120, CA016087]; NIEHS NIH HHS [ES000260] NR 29 TC 12 Z9 13 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 2007 VL 28 IS 2 BP 398 EP 403 DI 10.1093/carcin/bgl141 PG 6 WC Oncology SC Oncology GA 134ZZ UT WOS:000244124800019 PM 16952912 ER PT J AU Fenton, JI Hursting, SD Perkins, SN Hord, NG AF Fenton, Jenifer I. Hursting, Stephen D. Perkins, Susan N. Hord, Norman G. TI Leptin induces an Apc genotype-associated colon epithelial cell chemokine production pattern associated with macrophage chemotaxis and activation SO CARCINOGENESIS LA English DT Article ID ENDOPEROXIDE H SYNTHASE-2; TOLL-LIKE RECEPTORS; GROWTH-FACTOR; INTESTINAL INFLAMMATION; CANCER DEVELOPMENT; IMMUNE-SYSTEM; FACTOR-I; OBESITY; MICE; EXPRESSION AB Leptin is an adipocyte-derived cytokine associated with obesity and inflammation recently shown to influence colon epithelial cell fate and colon inflammation. Thus, the purpose of this study is to investigate the influences of leptin exposure on the production of proinflammatory signals by a model of normal [YAMC (Apc(+/+))] and preneoplastic [IMCE (Apc(Min/+))] colon epithelial cells. Here, we characterize the production of specific CC and CXC chemokines by IMCE and YAMC cells using an antibody-based cytokine array. Further, since epithelial cells are hypothesized to be accessory to the inflammatory response, we assessed the ability of supernants from leptin-exposed colon epithelial cells to activate macrophage chemotaxis and nitric oxide production. Both YAMC and IMCE cells produced the following chemokines from the CC family; MCP-1, MIP-3 alpha, TCA-3, CTACK and RANTES. These cell lines also produced the following CXC chemokines; MIP-2, CXCL18, KC and LIX. Conditioned media from leptin-treated YAMC and IMCE cells induced nitric oxide production by macrophages (P < 0.05). However, only conditioned media from leptin-treated IMCE cells induced macrophage chemotaxis (P < 0.05). These data imply that preneoplastic but not normal cells may selectively attract immune cells that promote their survival and transformation. Taken together with our previous data, we conclude that leptin promotes the proliferation of a model of preneoplastic cells (IMCE) and induces the production of chemokines which may activate macrophages and promote macrophage cell chemotaxis. These data provide a rational basis for leptin-induced cross-talk between preneoplastic epithelial cells and immune cells that may influence the promotional phase of carcinogenesis. C1 Michigan State Univ, Dept Food Sci & Human Nutr, E Lansing, MI 48824 USA. NCI, Canc Prevent Fellowship Program, Div Canc Prevent, Bethesda, MD 20892 USA. NCI, Lab Biosyst & Canc, Bethesda, MD 20892 USA. Univ Texas, Div Nutr Sci, Austin, TX 78712 USA. RP Fenton, JI (reprint author), Michigan State Univ, Dept Food Sci & Human Nutr, 210 GM Trout Bldg, E Lansing, MI 48824 USA. EM imigjeni@msu.edu OI Fenton, Jenifer/0000-0002-8875-3239 NR 50 TC 16 Z9 16 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 2007 VL 28 IS 2 BP 455 EP 464 DI 10.1093/carcin/bgl137 PG 10 WC Oncology SC Oncology GA 134ZZ UT WOS:000244124800026 PM 16891627 ER PT J AU Liu, T Zhang, XY So, CK Wang, S Wang, P Yan, LY Myers, R Chen, ZG Patterson, AP Yang, CS Chen, XX AF Liu, Tong Zhang, Xinyan So, Chi-Kwong Wang, Su Wang, Peng Yan, Liying Myers, Rene Chen, Zhigang Patterson, Amy P. Yang, Chung S. Chen, Xiaoxin TI Regulation of Cdx2 expression by promoter methylation, and effects of Cdx2 transfection on morphology and gene expression of human esophageal epithelial cells SO CARCINOGENESIS LA English DT Article ID HEPATOCYTE NUCLEAR FACTOR-1-ALPHA; ACTIVATED PROTEIN-KINASE; COLUMNAR-LINED ESOPHAGUS; BARRETTS-ESOPHAGUS; HOMEOBOX GENE; INTESTINAL METAPLASIA; TRANSCRIPTION FACTOR; IMMUNOHISTOCHEMICAL SURVEY; DEVELOPMENTAL REGULATION; ECTOPIC EXPRESSION AB Caudal-related homeobox 2 (Cdx2) has been suggested as an early marker of Barrett's esophagus (BE), which is the premalignant lesion of esophageal adenocarcinoma (EAC). However, the mechanism of ectopic Cdx2 expression in the esophageal epithelial cells and its role in the development of BE remained unclear. RT-PCR, pyrosequencing and methylation-specific PCR were used to determine expression and promoter methylation of Cdx2 in human esophageal epithelial cells (HET1A and SEG1) after treatment with 5-aza-2'-deoxycytidine (DAC), acid, bile acids and their combination. HET1A cells with stable transfection of Cdx2 were characterized for morphology and gene expression profiles with Affymetrix array. We found Cdx2 was expressed in most human EAC cell lines, but not in squamous epithelial cell lines. DAC-induced demethylation and expression of Cdx2 in HET1A and SEG1 cells, and treatment with a DNA methylating agent counteracted the effect of DAC. Treatment of HET1A and SEG1 cells with acid, bile acids or both also resulted in promoter demethylation and expression of Cdx2. HET1A cells with stable transfection of human Cdx2 formed crypt-like structures in vitro. Microarray analysis and quantitative real-time PCR showed that stable transfection of Cdx2 up-regulated differentiation markers of intestinal columnar epithelial cells and goblet cells in HET1A cells. This may be partially due to modulation of Notch signaling pathway, as western blotting confirmed down-regulation of Hes1 and up-regulation of Atoh1 and Muc2. Our data suggest that exposure to acid and/or bile acids may activate Cdx2 expression in human esophageal epithelial cells through promoter demethylation, and ectopic Cdx2 expression in esophageal squamous epithelial cells may contribute to intestinal metaplasia of the esophagus. C1 N Carolina Cent Univ, Canc Res Program, Julius L Chambers Biomed Biotechnol Res Inst, Durham, NC 27707 USA. Rutgers State Univ, Susan Lehman Cullman Lab Canc Res, Dept Biol Chem, Piscataway, NJ 08854 USA. Biotage Inc, Foxboro, MA 02035 USA. NHLBI, NIH, Bethesda, MD 20892 USA. RP Chen, XX (reprint author), N Carolina Cent Univ, Canc Res Program, Julius L Chambers Biomed Biotechnol Res Inst, 700 George St, Durham, NC 27707 USA. EM lchen@nccu.edu FU NCI NIH HHS [CA092077, CA75683]; NIDDK NIH HHS [DK63650]; NIEHS NIH HHS [5T32ES07148] NR 59 TC 91 Z9 96 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 2007 VL 28 IS 2 BP 488 EP 496 DI 10.1093/carcin/bgl176 PG 9 WC Oncology SC Oncology GA 134ZZ UT WOS:000244124800030 PM 16990345 ER PT J AU Sudheendra, D Leger, R Groppo, ER Sun, D Durrani, AK Neeman, Z Wood, BJ AF Sudheendra, Deepak Leger, Rosanne Groppo, Eli R. Sun, David Durrani, Amir K. Neeman, Ziv Wood, Bradford J. TI Comparison of three different needles for percutaneous injections SO CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY LA English DT Letter C1 NIH, Dept Radiol, Warren G Magnuson Clin Ctr, Bethesda, MD 20892 USA. RP Sudheendra, D (reprint author), NIH, Dept Radiol, Warren G Magnuson Clin Ctr, Bldg 10,Room 1C-660, Bethesda, MD 20892 USA. EM woodbradford@netscape.net FU Intramural NIH HHS [Z99 CL999999] NR 1 TC 5 Z9 5 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0174-1551 J9 CARDIOVASC INTER RAD JI Cardiovasc. Interv. Radiol. PD FEB PY 2007 VL 30 IS 1 BP 151 EP 152 DI 10.1007/s00270-005-0387-3 PG 2 WC Cardiac & Cardiovascular Systems; Radiology, Nuclear Medicine & Medical Imaging SC Cardiovascular System & Cardiology; Radiology, Nuclear Medicine & Medical Imaging GA 112BS UT WOS:000242500800030 PM 16988874 ER PT J AU Palevitch, O Kight, K Abraham, E Wray, S Zohar, Y Gothilf, Y AF Palevitch, Ori Kight, Katherine Abraham, Eytan Wray, Susan Zohar, Yonathan Gothilf, Yoav TI Ontogeny of the GnRH systems in zebrafish brain: in situ hybridization and promoter-reporter expression analyses in intact animals SO CELL AND TISSUE RESEARCH LA English DT Article DE gonadotropin-releasing hormone; in situ hybridization; reporter protein; neuronal migration; Danio rerio (Teleostei) ID GONADOTROPIN-RELEASING-HORMONE; OLFACTORY PLACODE; MESSENGER-RNA; DANIO-RERIO; NEURONAL MIGRATION; CHICK-EMBRYO; CELLS; FISH; NEUROBLASTS; GOLDFISH AB The ontogeny of two gonadotropin-releasing-hormone (GnRH) systems, salmon GnRH (sGnRH) and chicken GnRH-II (cGnRH-II), was investigated in zebrafish (Danio rerio). In situ hybridization (ISH) first detected sGnRH mRNA-expressing cells at 1 day post-fertilization (pf) anterior to the developing olfactory organs. Subsequently, cells were seen along the ventral olfactory organs and the olfactory bulbs, reaching the terminal nerve (TN) ganglion at 5-6 days pf. Some cells were detected passing posteriorly through the ventral telencephalon (10-25 days pf), and by 25-30 days pf, sGnRH cells were found in the hypothalamic/preoptic area. Continuous documentation in live zebrafish was achieved by a promoter-reporter expression system. The expression of enhanced green fluorescent protein (EGFP) driven by the sGnRH promoter allowed the earlier detection of cells and projections and the migration of sGnRH neurons. This expression system revealed that long leading processes, presumably axons, preceded the migration of the sGnRH neuron somata. cGnRH-II mRNA expressing cells were initially detected (1 day pf) by ISH analysis at lateral aspects of the midbrain and later on (starting at 5 days pf) at the midline of the midbrain tegmentum. Detection of red fluorescent protein (DsRed) driven by the cGnRH-II promoter confirmed the midbrain expression domain and identified specific hindbrain and forebrain cGnRH-II-cells that were not identified by ISH. The forebrain DsRed-expressing cells seemed to emerge from the same site as the sGnRH-EGFP-expressing cells, as revealed by co-injection of both constructs. These studies indicate that zebrafish TN and hypothalamic sGnRH cell populations share a common embryonic origin and migratory path, and that midbrain cGnRH-II cells originate within the midbrain. C1 Tel Aviv Univ, George S Wise Fac Life Sci, Dept Neurobiochem, IL-69978 Tel Aviv, Israel. Tel Aviv Univ, George S Wise Fac Life Sci, Dept Zool, IL-69978 Tel Aviv, Israel. Univ Maryland, Ctr Marine Biotechnol, Inst Biotechnol, Baltimore, MD 21202 USA. NINDS, Cellular & Dev Neurobiol Sect, Bethesda, MD 20892 USA. RP Gothilf, Y (reprint author), Tel Aviv Univ, George S Wise Fac Life Sci, Dept Neurobiochem, IL-69978 Tel Aviv, Israel. EM yoavg@tauex.tau.ac.il RI Palevitch, Ori/B-1870-2010; OI wray, susan/0000-0001-7670-3915 NR 32 TC 54 Z9 57 U1 1 U2 12 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0302-766X J9 CELL TISSUE RES JI Cell Tissue Res. PD FEB PY 2007 VL 327 IS 2 BP 313 EP 322 DI 10.1007/s00441-006-0279-0 PG 10 WC Cell Biology SC Cell Biology GA 119GB UT WOS:000242999700009 PM 17036230 ER PT J AU Weerth, SH Holtzclaw, LA Russell, JT AF Weerth, Susanna H. Holtzclaw, Lynne A. Russell, James T. TI Signaling proteins in raft-like microdomains are essential for Ca2+ wave propagation in glial cells SO CELL CALCIUM LA English DT Article DE calcium signaling; lipid rafts; wave propagation; glial cells ID ENDOPLASMIC-RETICULUM PROTEINS; INTRACELLULAR CA2+; CALCIUM WAVES; INOSITOL TRISPHOSPHATE; CULTURED ASTROCYTES; CAVEOLAE MEMBRANE; PLASMA-MEMBRANE; XENOPUS OOCYTES; KINASE-C; RECEPTORS AB The hypothesis that calcium signaling proteins segregate into lipid raft-like microdomains was tested in isolated membranes of rat oligodendrocyte progenitor (OP) cells and astrocytes using Triton X-100 solubilization and density gradient centrifugation. Western blot analysis of gradient fractions showed co-localization of caveolin-1 with proteins involved in the Ca2+ signaling cascade. These included agonist receptors, P2Y(1), and M-1, TRPC1, IP(3)R2, ryanodine receptor, as well as the G protein G alpha(q) and Homer. Membranes isolated from agonist-stimulated astrocytes showed an enhanced recruitment of phospholipase C (PLC beta 1), IP(3)R2 and protein kinase C (PKC-alpha) into lipid raft fractions. IP3R2, TRPC1 and Homer co-immunoprecipitated, suggesting protein-protein interactions. Disruption of rafts by cholesterol depletion using methyl-p-cyclodextrin (beta-MCD) altered the distribution of caveolin-1 and GM1 to non-raft fractions with higher densities. beta-MCD-induced disruption of rafts inhibited agonist-evoked Ca2+ wave propagation in astrocytes and attenuated wave speeds. These results indicate that in glial cells, Ca2+ signaling proteins might exist in organized membrane microdomains, and these complexes may include proteins from different cellular membrane systems. Such an organization is essential for Ca2+ wave propagation. (c) 2006 Elsevier Ltd. All rights reserved. C1 NICHD, Sect Cell Biol & Signal Transduct, NIH, Bethesda, MD 20892 USA. RP Russell, JT (reprint author), NICHD, Sect Cell Biol & Signal Transduct, NIH, Bldg 49,Room 5A-22,49 Convent Dr, Bethesda, MD 20892 USA. EM james@helix.nih.gov FU Intramural NIH HHS NR 50 TC 53 Z9 54 U1 0 U2 6 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 0143-4160 EI 1532-1991 J9 CELL CALCIUM JI Cell Calcium PD FEB PY 2007 VL 41 IS 2 BP 155 EP 167 DI 10.1016/j.ceca.2006.06.006 PG 13 WC Cell Biology SC Cell Biology GA 135QG UT WOS:000244167500006 PM 16905188 ER PT J AU Schwartz, EI Smilenov, LB Price, MA Osredkar, T Baker, RA Ghosh, S Shi, FD Vollmer, TL Lencinas, A Stearns, DM Gorospe, M Kruman, II AF Schwartz, Elena I. Smilenov, Lubomir B. Price, Mary A. Osredkar, Tracy Baker, Ronald A. Ghosh, Soma Shi, Fu-Dong Vollmer, Timothy L. Lencinas, Alejandro Stearns, Diane M. Gorospe, Myriam Kruman, Inna I. TI Cell cycle activation in postmitotic neurons is essential for DNA repair SO CELL CYCLE LA English DT Article DE cell cycle; DNA damage; DNA repair; neuron; apoptosis ID DOUBLE-STRAND BREAKS; TERMINALLY DIFFERENTIATED CELLS; DEPENDENT KINASE INHIBITORS; ALZHEIMERS-DISEASE; COMET ASSAY; GEL-ELECTROPHORESIS; INDIVIDUAL CELLS; OXIDATIVE STRESS; PROTEIN-KINASE; HISTONE H2AX AB Increasing evidence indicates that maintenance of neuronal homeostasis involves the activation of the cell cycle machinery in postmitotic neurons. Our recent findings suggest that cell cycle activation is essential for DNA damage-induced neuronal apoptosis. However, whether the cell division cycle also participates in DNA repair and survival of postmitotic, terminally differentiated neurons is unknown. Here, we tested the hypothesis that G(1) phase components contribute to the repair of DNA and are involved in the DNA damage response of postmitotic neurons. In cortical terminally differentiated neurons, treatment with subtoxic concentrations of hydrogen peroxide (H2O2) caused repairable DNA double strand breaks (DSBs) and the activation of G(1) components of the cell cycle machinery. Importantly, DNA repair was attenuated if cyclin-dependent kinases CDK4 and CDK6, essential elements of G(0) -> G(1) transition, were suppressed. Our data suggest that G(1) cell cycle components are involved in DNA repair and survival of postmitotic neurons. C1 Sun Hlth Res Inst, Sun City, AZ 85351 USA. Georgetown Univ, Med Ctr, Dept Pathol & Oncol, Washington, DC 20007 USA. Columbia Univ, Coll Phys & Surg, Ctr Radiol Res, New York, NY USA. Barrow Neurol Inst, Div Neurol, Phoenix, AZ 85013 USA. NICHHD, NIH, Lab Mol Growth Regulat, Bethesda, MD 20892 USA. NAU, Dept Chem & Biochem, Flagstaff, AZ USA. NIA, Cellular & Mol Biol Lab, NIH, Baltimore, MD 21224 USA. RP Kruman, II (reprint author), Sun Hlth Res Inst, 10515 W Santa Fe Dr, Sun City, AZ 85351 USA. EM inna.kruman@sunhealth.org NR 74 TC 38 Z9 42 U1 0 U2 2 PU LANDES BIOSCIENCE PI GEORGETOWN PA 810 SOUTH CHURCH STREET, GEORGETOWN, TX 78626 USA SN 1538-4101 J9 CELL CYCLE JI Cell Cycle PD FEB 1 PY 2007 VL 6 IS 3 BP 318 EP 329 DI 10.4161/cc.6.3.3752 PG 12 WC Cell Biology SC Cell Biology GA 154GQ UT WOS:000245495300015 PM 17297309 ER PT J AU Li, Z Zhang, J Liu, Z Woo, CW Thiele, CJ AF Li, Z. Zhang, J. Liu, Z. Woo, C. -W. Thiele, C. J. TI Downregulation of Bim by brain-derived neurotrophic factor activation of TrkB protects neuroblastoma cells from paclitaxel but not etoposide or cisplatin-induced cell death SO CELL DEATH AND DIFFERENTIATION LA English DT Article DE neuroblastoma; Bim; BDNF; TrkB; paclitaxel; etoposide; cisplatin ID FORKHEAD TRANSCRIPTION FACTOR; FAMILY-MEMBER BIM; SIGNAL-TRANSDUCTION; PROAPOPTOTIC ACTIVITY; KINASE-B; APOPTOSIS; SURVIVAL; EXPRESSION; BCL-2; AKT AB Chemoresistance and increased expression of TrkB and brain-derived neurotrophic factor (BDNF) are biomarkers of poor prognosis in tumors from patients with neuroblastoma (NB). Previously, we found BDNF activation of TrkB through PI3K/Akt protects NB from etoposide/cisplatin-induced cell death. In this study, the role of Bim, a proapoptotic protein, was investigated. Bim was involved in paclitaxel but not etoposide or cisplatin-induced cell death in NB cells. Pharmacological and genetic studies showed that BDNF-induced decreases in Bim were regulated by MAPK and not PI3K/Akt pathway. Both MAPK and PI3K pathways were involved in BDNF protection of NB cells from paclitaxel-induced cell death, while PI3K predominantly mediated BDNF protection of NB cells from etoposide or cisplatin-induced cell death. These data indicate that different chemotherapeutic drugs induce distinct death pathways and growth factors utilize different signal transduction pathways to modulate the effects of chemotherapy on cells. C1 NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. China Med Univ, Affiliated Hosp 2, Shenyang, Peoples R China. Korea Univ, Anam Hosp, Dept Pediat, Seoul, South Korea. RP Thiele, CJ (reprint author), NCI, Cell & Mol Biol Sect, Pediat Oncol Branch, NIH, 10 Ctr Dr,MSC 1928,Bldg 10-CRC 1-3940, Bethesda, MD 20892 USA. EM ct47a@nih.gov FU Intramural NIH HHS NR 46 TC 44 Z9 47 U1 0 U2 5 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 1350-9047 J9 CELL DEATH DIFFER JI Cell Death Differ. PD FEB PY 2007 VL 14 IS 2 BP 318 EP 326 DI 10.1038/sj.cdd.4401983 PG 9 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 126DS UT WOS:000243493000012 PM 16778834 ER PT J AU Cheung, KJ Tzameli, I Pissios, P Rovira, I Gavrilova, O Ohtsubo, T Chen, Z Finkel, T Flier, JS Friedman, JM AF Cheung, Kevin J. Tzameli, Iphigenia Pissios, Pavlos Rovira, Ilsa Gavrilova, Oksana Ohtsubo, Toshio Chen, Zhu Finkel, Toren Flier, Jeffrey S. Friedman, Jeffrey M. TI Xanthine oxidoreductase is a regulator of adipogenesis and PPAR gamma activity SO CELL METABOLISM LA English DT Article ID CHRONIC HEART-FAILURE; BINDING PROTEIN-BETA; ADIPOCYTE DIFFERENTIATION; C/EBP-BETA; URIC-ACID; STIMULATES ADIPOGENESIS; CARDIOVASCULAR-DISEASE; ECTOPIC EXPRESSION; MAMMARY-GLAND; OXIDIZED LDL AB In an effort to identify novel candidate regulators of adipogenesis, gene profiling of differentiating 3T3-L1 preadipocytes was analyzed using a novel algorithm. We report here the characterization of xanthine oxidoreductase (XOR) as a novel regulator of adipogenesis. XOR lies downstream of C/EBP beta and upstream of PPAR gamma, in the cascade of factors that control adipogenesis, and it regulates PPAR gamma activity. In vitro, knockdown of XOR inhibits adipogenesis and PPAR gamma activity while constitutive overexpression increases activity of the PPAR gamma receptor in both adipocytes and preadipocytes. In vivo, XOR -/- mice demonstrate 50% reduction in adipose mass versus wild-type littermates while obese ob/ob mice exhibit increased concentrations of XOR mRNA and urate in the adipose tissue. We propose that XOR is a novel regulator of adipogenesis and of PPAR gamma activity and essential for the regulation of fat accretion. Our results identify XOR as a potential therapeutic target for metabolic abnormalities beyond hyperuricemia. C1 Rockefeller Univ, Genet Mol Lab, New York, NY 10021 USA. Harvard Univ, Beth Israel Deaconess Med Ctr, Sch Med, Div Endocrinol, Boston, MA 02215 USA. NHLBI, Mol Biol Sect, Cardiol Branch, Bethesda, MD 20892 USA. RP Friedman, JM (reprint author), Rockefeller Univ, Genet Mol Lab, 1230 York Ave, New York, NY 10021 USA. EM friedj@mail.rockefeller.edu NR 47 TC 79 Z9 83 U1 1 U2 2 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 2007 VL 5 IS 2 BP 115 EP 128 DI 10.1016/j.cmet.2007.01.005 PG 14 WC Cell Biology; Endocrinology & Metabolism SC Cell Biology; Endocrinology & Metabolism GA 135HW UT WOS:000244145700007 PM 17276354 ER PT J AU Lee, KS Scanga, CA Bachelder, EM Chen, QY Snapper, CM AF Lee, Katherine S. Scanga, Charles A. Bachelder, Eric M. Chen, Quanyi Snapper, Clifford M. TI TLR2 synergizes with both TLR4 and TLR9 for induction of the MyD88-dependent splenic cytokine and chemokine response to Streptococcus pneumoniae SO CELLULAR IMMUNOLOGY LA English DT Article DE toll-like receptor; Streptococcus pneumoniae; innate immunity; cytokine; chemokine; MyD88; bacteria; mouse; in vitro ID TOLL-LIKE RECEPTORS; NECROSIS-FACTOR-ALPHA; INDUCED IMMUNE ACTIVATION; BACILLUS-CALMETTE-GUERIN; HUMAN DENDRITIC CELLS; LIPOTEICHOIC ACID; CUTTING EDGE; CPG-DNA; STAPHYLOCOCCUS-AUREUS; SIGNALING PATHWAY AB We previously demonstrated that induction of splenic cytokine and chemokine secretion in response to Streptococcus pneumoniae (Pn) is MyD88-, but not critically TLR2-dependent, suggesting a role for additional TLRs. In this study, we investigated the role of TLR2, TLR4, and/or TLR9 in mediating this response. We show that a single deficiency in TLR2, TLR4, or TLR9 has only modest, selective effects on cytokine and chemokine secretion, whereas substantial defects were observed in TLR2(-/-) x TLR9(-/-) and TLR2(-/-) x TLR4(-/-) mice, though not as severe as in MyD88(-/-) mice. Chloroquine, which inhibits the function of intracellular TLRs, including TLR9, completely abrogated detectable cytokine and chemokine release in spleen cells from TLR2(-/-) x TLR4(-/-) mice, similar to what is observed for mice deficient in MyD88. These data demonstrate significant synergy between TLR2 and both TLR4 and TLR9 for induction of the MyD88-dependent splenic cytokine and chemokine response to Pn. (c) 2007 Elsevier Inc. All rights reserved. C1 Uniformed Serv Univ Hlth Sci, Dept Pathol, Bethesda, MD 20814 USA. NIAID, Parasit Dis Lab, Immunobiol Sect, Bethesda, MD 20892 USA. NIAID, Ghost Lab, Cellular & Mol Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Snapper, CM (reprint author), Uniformed Serv Univ Hlth Sci, Dept Pathol, 4301 Jones Bridge Rd, Bethesda, MD 20814 USA. EM csnapper@usuhs.mil FU NIAID NIH HHS [R01 AI049192-09, 1R01 AI49192, R01 AI049192] NR 67 TC 58 Z9 59 U1 3 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0008-8749 J9 CELL IMMUNOL JI Cell. Immunol. PD FEB PY 2007 VL 245 IS 2 BP 103 EP 110 DI 10.1016/j.cellimm.2007.04.003 PG 8 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 186IJ UT WOS:000247772100005 PM 17521621 ER PT J AU Che, Y Brooks, BR Riley, DP Reaka, AJH Marshall, GR AF Che, Ye Brooks, Bernard R. Riley, Dennis P. Reaka, Andrea J. H. Marshall, Garland R. TI Engineering metal complexes of chiral pentaazacrowns as privileged reverse-turn scaffolds SO CHEMICAL BIOLOGY & DRUG DESIGN LA English DT Article DE density functional theory; pentaazacrown; peptidomimetics; principal component analysis; privileged structure; protein-protein interaction; reverse turn; template design; transition metal ID SUPEROXIDE-DISMUTASE MIMICS; PROTEIN-COUPLED RECEPTORS; GAUSSIAN-BASIS SETS; AIDED-DESIGN CAD; CONFORMATIONAL TEMPLATES; CATALYTIC ACTIVITY; RATIONAL DESIGN; ATOMS LI; PEPTIDES; ALPHA-V-BETA-3 AB Reverse turns are common structural motifs and recognition sites in protein/protein interactions. The design of peptidomimetics is often based on replacing the amide backbone of peptides by a non-peptidic scaffold while retaining the biologic mode of action. This study evaluates the potential of metal complexes of chiral pentaazacrowns conceptually derived by reduction of cyclic pentapeptides as reverse-turn mimetics. The possible conformations of metal complexes of chiral pentaazacrown scaffolds have been probed by analysis of 28 crystal structures complexed with six different metals (Mn, Fe, Co, Ni, Cu, and Zn). The solvated structures as well as the impact of complexation with different metals/oxidation states have been examined with density functional theory (DFT) calculation as explicitly represented by interactions with a single water molecule. The results suggest that most reverse-turn motifs seen in proteins could be mimicked effectively with a subset of metal complexes of chiral pentaazacrown scaffolds with an RMSD of approximately 0.3 angstrom. Due to the relatively fixed orientation of the pendant chiral side groups in these metal complexes, one can potentially elicit information about the receptor-bound conformation of the parent peptide from their binding affinities. The presence of 20 H-atoms on the pentaazacrown ring that could be functionalized as well as the conformational perturbations available from complexation with different metals offer a desirable diversity to probe receptors for reverse-turn recognition. C1 NHLBI, NIH, Lab Computat Biol, Bethesda, MD 20892 USA. Kereos Inc, St Louis, MO 63108 USA. Washington Univ, Ctr Computat Biol, St Louis, MO 63110 USA. Washington Univ, Dept Biochem & Mol Biophys, St Louis, MO 63110 USA. RP Che, Y (reprint author), NHLBI, NIH, Lab Computat Biol, Bethesda, MD 20892 USA. EM chey@nhlbi.nih.gov RI Che, Ye/A-3449-2008; OI Marshall, Garland/0000-0002-3098-0332 FU Intramural NIH HHS; NIGMS NIH HHS [GM68460] NR 32 TC 8 Z9 8 U1 1 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1747-0277 J9 CHEM BIOL DRUG DES JI Chem. Biol. Drug Des. PD FEB PY 2007 VL 69 IS 2 BP 99 EP 110 DI 10.1111/j.1747-0285.2007.00484.x PG 12 WC Biochemistry & Molecular Biology; Chemistry, Medicinal SC Biochemistry & Molecular Biology; Pharmacology & Pharmacy GA 148UJ UT WOS:000245100800001 PM 17381723 ER PT J AU Bourdi, M Eiras, DP Holt, MP Webster, MR Reilly, TP Welch, KD Pohl, LR AF Bourdi, Mohammed Eiras, Daniel P. Holt, Michael P. Webster, Marie R. Reilly, Timothy P. Welch, Kevin D. Pohl, Lance R. TI Role of IL-6 in an IL-10 and IL-4 double knockout mouse model uniquely susceptible to acetaminophen-induced liver injury SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article; Proceedings Paper CT 55th Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases (AASLD) CY OCT 29-NOV 02, 2004 CL Boston, MA SP Amer Assoc Study Liver Dis ID NITRIC-OXIDE SYNTHASE; INDUCED HEPATOTOXICITY; MACROPHAGE-MIGRATION; HEPATIC-INJURY; HEPATOCYTE PROLIFERATION; INTERLEUKIN-6 PROTECTS; MICE; EXPRESSION; CYTOKINE; GLUTATHIONE AB Drug-induced hepatitis remains a challenging problem for drug development and safety because of the lack of animal models. In the current work, we discovered a unique interaction that makes mice deficient in both IL-10 and IL-4 (IL-10/4(-/-)) highly sensitive to the hepatotoxic effects of acetaminophen (APAP). Male C57Bl/6 wild type (WT) and mice deficient in one or more cytokines were treated with 120 mg/kg APAP. Within 24 h after WT, IL-10(-/-), IL-4(-/-), or IL-10/4(-/-) mice were administered APAP, 75% of the IL-10/4(-/-) mice died of massive hepatic injury while all other genotypes were resistant to liver toxicity at this dose of APAP. The unique susceptibility of IL-10/4(-/-) mice was associated with reduced levels of liver glutathione and remarkably high serum levels of IL-6 and several proinflammatory factors including TNF-alpha, IFN-gamma, macrophage inflammatory protein-1 alpha (MIP-1 alpha), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-2 (MIP-2), and osteopontin (OPN) as well as nitric oxide (NO). IL-6 appeared to have a causal role in controlling the unique susceptibility of IL-10/4(-/-) mice to APAP-induced liver disease (AILD) because IL-6 neutralizing antibody reversed the high sensitivity of these mice to AILD. Moreover, IL-10/4/6(-/-) mice were also resistant to the enhanced susceptibility to AILD and expressed relatively low levels of most proinflammatory factor genes that were elevated in the IL-10/4(-/-) mice. In conclusion, liver homeostasis following AILD appears to be highly dependent on the activities of both IL-10 and IL-4, which together help prevent overexpression of IL-6 and other potential hepatotoxic factors. C1 NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, Dept Hlth & Human Serv,NIH, Bethesda, MD 20892 USA. RP Bourdi, M (reprint author), NHLBI, Mol & Cellular Toxicol Sect, Lab Mol Immunol, Dept Hlth & Human Serv,NIH, Bldg 10, Bethesda, MD 20892 USA. EM bourdim@nih.gov FU Intramural NIH HHS NR 63 TC 46 Z9 49 U1 0 U2 5 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD FEB PY 2007 VL 20 IS 2 BP 208 EP 216 DI 10.1021/tx0602281 PG 9 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 136UA UT WOS:000244248400006 PM 17305405 ER PT J AU Iyer, PC Yagi, H Sayer, JM Jerina, DM AF Iyer, Prema C. Yagi, Haruhiko Sayer, Jane M. Jerina, Donald M. TI 3 '-H-phosphonate synthesis of chiral benzo[a]pyrene diol epoxide adducts at N-2 of deoxyguanosine in oligonucleotides SO CHEMICAL RESEARCH IN TOXICOLOGY LA English DT Article ID DNA-POLYMERASE; POSTOLIGOMERIZATION SYNTHESIS; H-PHOSPHONATES; CIS; BENZOPYRENE; DEOXYADENOSINE; OLIGODEOXYNUCLEOTIDES; DEOXYRIBONUCLEOSIDE; POSITION; BINDING AB A synthetic route to oligonucleotides containing N-2-deoxyguanosine adducts at C-10 of the enantiomeric 7,8-diol 9,10-epoxides of 7,8,9,10-tetrahydrobenzo[a]pyrene in which the epoxide oxygen and the 7-hydroxyl group are trans is described. The present adducts result from the trans addition of N-2 of deoxyguanosine to the epoxide at C-10. Our synthesis proceeds via preparation of the 3'-H-phosphonate of a suitably protected deoxyguanosine N-2-adduct. The blocking groups consisted of O-6-allyl on the deoxyguanosine, acetates on the 7-, 8-, and 9-hydroxyl groups of the hydrocarbon moiety, and dimethoxytrityl on the 5'-hydroxyl group of the sugar. These blocking groups are well suited to oligonucleotide synthesis on solid supports. The free 3'-hydroxyl group of this nucleoside adduct was readily converted to its 3'-H-phosphonate with diphenyl phosphite in pyridine in high yield for both the 10R and 10S isomers. For synthesis of oligonucleotides, the first several nucleotides were incorporated onto the solid support with an automated synthesizer using standard phosphoramidite chemistry. The adducted deoxyguanilic acid residue was introduced as the H-phosphonate in a manual step (80% yield), followed by completion of the sequence on the synthesizer. Although a 10-fold excess of the 3'-H-phosphonate was used in the manual coupling step, as much as 70% of the reactant could be recovered. The 3'-H-phosphonate of the protected 10S nucleoside adduct was converted to the unblocked nucleotide adduct, various salts of which failed to form crystals suitable for X-ray analysis. Although submilligram quantities of this compound have been formed as mixed diastereomers by direct reaction of deoxyguanylic acid with racemic diol epoxide, the present study represents the first actual synthesis of the major DNA adduct formed from benzo[a]pyrene in mammals as its 3'-phosphate. C1 NIDDK, Bioorgan Chem Lab, DHHS, NIH, Bethesda, MD 20892 USA. RP Jerina, DM (reprint author), NIDDK, Bioorgan Chem Lab, DHHS, NIH, Bethesda, MD 20892 USA. EM dmjerina@nih.gov FU Intramural NIH HHS NR 28 TC 2 Z9 2 U1 1 U2 3 PU AMER CHEMICAL SOC PI WASHINGTON PA 1155 16TH ST, NW, WASHINGTON, DC 20036 USA SN 0893-228X J9 CHEM RES TOXICOL JI Chem. Res. Toxicol. PD FEB PY 2007 VL 20 IS 2 BP 311 EP 315 DI 10.1021/tx600282y PG 5 WC Chemistry, Medicinal; Chemistry, Multidisciplinary; Toxicology SC Pharmacology & Pharmacy; Chemistry; Toxicology GA 136UA UT WOS:000244248400017 PM 17305411 ER PT J AU Walter, MF Biessmann, MR Benitez, C Torok, T Mason, JM Biessmann, H AF Walter, Marika F. Biessmann, Max R. Benitez, Cecil Torok, Tibor Mason, James M. Biessmann, Harald TI Effects of telomere length in Drosophila melanogaster on life span, fecundity, and fertility SO CHROMOSOMA LA English DT Article ID HET-A; HETEROCHROMATIN PROTEIN-1; SACCHAROMYCES-CEREVISIAE; DIFFERENT MECHANISMS; CELL-PROLIFERATION; MAINTAIN TELOMERES; CHROMOSOME ENDS; GAG PROTEINS; RETROTRANSPOSONS; ELONGATION AB Chromosome length in Drosophila is maintained by targeted transposition of three non-long terminal repeat retrotransposons, HeT-A, TART, and TAHRE, to the chromosome ends. The length and composition of these retrotransposon arrays can vary significantly between chromosome tips and between fly stocks, but the significance and consequences of these length differences are not understood. A dominant genetic factor, Tel, has been described, which causes a severalfold elongation of the retrotransposon arrays at all telomeres. We used this strain to assess possible affects of extended telomeres on the organism. While we found no effect on life span of the adults, we could demonstrate a correlation between long telomeres and reduced fertility and fecundity in individual females, which is also reflected in abnormal oocyte development. C1 Univ Calif Irvine, Ctr Dev Biol, Irvine, CA 92697 USA. Univ Szeged, Dept Genet & Mol Biol, Szeged, Hungary. NIEHS, Mol Genet Lab, Res Triangle Pk, NC 27709 USA. RP Biessmann, MR (reprint author), Univ Calif Irvine, Ctr Dev Biol, Irvine, CA 92697 USA. EM hbiessma@uci.edu FU Intramural NIH HHS [Z01 ES021054-14]; NIGMS NIH HHS [GM-56729, R01 GM056729] NR 45 TC 13 Z9 15 U1 1 U2 7 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0009-5915 J9 CHROMOSOMA JI Chromosoma PD FEB PY 2007 VL 116 IS 1 BP 41 EP 51 DI 10.1007/s00412-006-0081-5 PG 11 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 130MG UT WOS:000243803100005 PM 17089138 ER PT J AU Gannot, G Tangrea, MA Richardson, AM Flaig, MJ Hewitt, SM Marcus, EM Emmert-Buck, MR Chuaqui, RF AF Gannot, Gallya Tangrea, Michael A. Richardson, Annely M. Flaig, Michael J. Hewitt, Stephen M. Marcus, Elizabeth M. Emmert-Buck, Michael R. Chuaqui, Rodrigo F. TI Layered expression scanning: Multiplex molecular analysis of diverse life science platforms SO CLINICA CHIMICA ACTA LA English DT Review DE layered expression scanning; multiplex; high throughput; layered peptide arrays ID PROTEIN EXPRESSION; ANTIBODY ARRAYS; HIGH-THROUGHPUT; TISSUE; THERAPIES; SAMPLES; CANCER AB With the advent of the genomic era, there is an increasing use of high-throughput techniques to generate transcriptome- and proteome-based profiles of biological specimens. Each of these methodologies offers a unique window into the inner workings of cell and tissue samples. Often, these studies generate large data sets and provide investigators with a substantial number of candidate dysregulated genes and pathways. Followup studies are then undertaken to independently validate the original findings and to extend the study to additional samples or more quantitative measurements. Although there are several methods available for these validation efforts, they are often tedious and laborious to perform; thus, additional tools that enable this task are needed. One such approach is layered expression scanning (LES), a new technique developed via a cooperative research and development agreement (CRADA) between the National Cancer Institute and 20/20 GeneSystems, Inc. The technique is based on the movement of biomolecules from a two-dimensional life science platform (histological tissue section, electrophoresis gel, multi-well plate, etc.) through a set of analysis membranes while maintaining the original distribution pattern of the molecules. Each membrane measures one analyte and the data are then mapped back to the original specimen, permitting each component of the life science platform to be studied in detail. LES can be configured in several different ways depending on the goals of the study. In this review, we summarize the use of the LES technique for a variety of biological applications. (c) 2006 Elsevier B.V. All rights reserved. C1 NCI, Pathogenesis Unit, Adv Technol Ctr, Lab Pathol,NIH, Bethesda, MD 20892 USA. NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. Univ Munich, Dept Dermatol, D-80137 Munich, Germany. NCI, Tissue Array Res Program, Pathol Lab, NIH, Bethesda, MD 20892 USA. GeneSyst Inc 2020 20 20, Rockville, MD USA. RP Chuaqui, RF (reprint author), US Postal Serv, Bethesda, MD 20892 USA. EM chuaquir@mail.nih.gov OI Hewitt, Stephen/0000-0001-8283-1788 FU Intramural NIH HHS NR 24 TC 13 Z9 13 U1 0 U2 1 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD FEB 1 PY 2007 VL 376 IS 1-2 BP 9 EP 16 DI 10.1016/j.cca.2006.08.007 PG 8 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 127KS UT WOS:000243585300002 PM 16996046 ER PT J AU Sardy, M Csikos, M Geisen, C Preisz, K Kornsee, Z Tomsits, E Tox, U Hunzelmann, N Wieslander, J Karpati, S Paulsson, M Smyth, N AF Sardy, Miklos Csikos, Marta Geisen, Christof Preisz, Klaudia Kornsee, Zoltan Tomsits, Erika Toex, Ulrich Hunzelmann, Nicolas Wieslander, Jorgen Karpati, Sarolta Paulsson, Mats Smyth, Neil TI Tissue transglutaminase ELISA positivity in autoimmune disease independent of gluten-sensitive disease SO CLINICA CHIMICA ACTA LA English DT Article DE tissue transglutaminase; celiac disease; gluten-sensitive disease; autoimmunity; ELISA ID CELIAC-DISEASE; DERMATITIS-HERPETIFORMIS; REVISED CRITERIA; ANTIBODIES; AUTOANTIBODIES; IGA; CLASSIFICATION; PREVALENCE; DIAGNOSIS; CIRRHOSIS AB Background: Our aim was to understand why some sera from patients with a broad spectrum of autoimmune diseases or non-autoimmune diseases involving enhanced apoptosis, cell lysis and/or putative secondary autoimmune processes show reactions in the tissue transglutaminase (TGc) ELISA used for diagnosis of gluten-sensitive disease. Methods: Sera were compared from groups of patients with autoimmune diseases, diseases involving organ specific enhanced cell death, celiac disease or dermatitis herpetiformis, diseases of non-autoimmune origin, and a group without known disease. IgA antibodies against TGc were detected using human antigen (produced recombinantly in bacterial or human cells) in different systems (non-commercial ELISA with buffers of differing NaCl concentrations, and anti-TGc sandwich ELISA). Anti-gliadin and anti-endomysium antibodies were also determined. Results: Many sera from patients with autoimmune disorders gave a positive signal in the human TGc ELISAs. The signal appeared related to minor impurities in the recombinant human TGc used and to raised serum IgA antibody levels rather than to the occurrence of TGc specific antibodies in these patients. Conclusions: No association of anti-TGc Abs and autoimmune conditions independent of gluten-sensitive disease could be shown. Care should be taken to exclude copurification of chaperones, like heat shock protein 70, where preparing antigens for TGc ELISAs. (c) 2006 Elsevier B.V. All rights reserved. C1 Semmelweis Univ, Dept Dermatoveneorol & Oncol, H-1085 Budapest, Hungary. Univ Cologne, Fac Med, Inst Clin Chem, D-50924 Cologne, Germany. Semmelweis Univ, Dept Pediat 2, H-1094 Budapest, Hungary. Univ Cologne, Fac Med, Dept Internal Med 4, D-50924 Cologne, Germany. Univ Cologne, Fac Med, Dept Dermatol, D-50924 Cologne, Germany. Wieslab Co, Ideon, S-22370 Lund, Sweden. Univ Cologne, Fac Med, Ctr Biochem, D-50931 Cologne, Germany. Univ Cologne, Fac Med, Ctr Mol Med, D-50931 Cologne, Germany. RP Sardy, M (reprint author), NCI, NIH, Dermatol Branch, 10 Ctr Dr,Bldg 10,Room 5A30, Bethesda, MD 20892 USA. EM sardym@mail.nih.gov NR 34 TC 22 Z9 22 U1 0 U2 7 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0009-8981 J9 CLIN CHIM ACTA JI Clin. Chim. Acta PD FEB 1 PY 2007 VL 376 IS 1-2 BP 126 EP 135 DI 10.1016/j.cca.2006.08.006 PG 10 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 127KS UT WOS:000243585300021 PM 16987503 ER PT J AU Scagnolari, C Bellomi, F Trombetti, S Casato, M Carlesimo, M Bagnato, F Lavolpe, V Bruno, R Millefiorini, E Antonelli, L Girardi, E Turriziani, O Antonelli, G AF Scagnolari, C. Bellomi, F. Trombetti, S. Casato, M. Carlesimo, M. Bagnato, F. Lavolpe, V. Bruno, R. Millefiorini, E. Antonelli, L. Girardi, E. Turriziani, O. Antonelli, G. TI Expression of biomarkers of interferon type I in patients suffering from chronic diseases SO CLINICAL AND EXPERIMENTAL IMMUNOLOGY LA English DT Article DE 2-5 oligoadenylate synthetase; beta2microglobulin; interferon; markers of IFN; neopterin ID CHRONIC HEPATITIS-C; BLOOD MONONUCLEAR-CELLS; MXA MESSENGER-RNA; MULTIPLE-SCLEROSIS; PERIPHERAL-BLOOD; STIMULATED GENES; MIXED CRYOGLOBULINEMIA; PEGYLATED INTERFERON; VIRAL-INFECTIONS; VIRUS-INFECTION AB Interferons (IFNs) are used widely in the treatment of viral infections, tumours and neurological disorders. The aim of this study was to evaluate the endogenous expressions of various IFN-induced compounds [specifically: neopterin (NPT), beta2microglobulin (beta 2mg) and 2-5 oligoadenylate synthetase (2-5 OAS)] in patients with various chronic diseases requiring treatment with IFN type I. The results showed that patients with such chronic diseases as hepatitis C virus-associated type II mixed cryoglobulinaemia (MC), chronic hepatitis C (CHC) and relapsing-remitting multiple sclerosis (RRMS) are characterized by different activations of the IFN system. Furthermore, the interindividual variability in baseline levels of IFN-induced biomarkers was higher in patients with chronic diseases than in healthy individuals. When levels of the above biomarkers were measured 24 h after the first injection of IFN in patients with CHC or RRMS, significant increases in expression levels of IFN-induced compounds were recorded but, again, there is a broad range of variability in the degree of increase. Further, a significant inverse correlation between baseline levels of NPT, beta 2mg and 2-5 OAS activity and their relative increases after IFN administration was found in patients with CHC or RRMS. Together, the results are consistent with the observation that there is considerable interindividual heterogeneity in the clinical response to IFNs, which suggests that host factors other than disease markers must be taken into account in order to manage and optimize the IFN therapy. C1 Univ Roma La Sapienza, Dept Expt Med, Virol Sect, I-00185 Rome, Italy. Univ Roma La Sapienza, Dept Clin Med, I-00185 Rome, Italy. Univ Roma La Sapienza, Dept Neurol Sci, I-00185 Rome, Italy. NINDS, Neuroimmunol Branch, NIH, Bethesda, MD 20892 USA. Univ Bari, Dept Neurol & Psychiat Sci, I-70121 Bari, Italy. Univ Pavia, S Matteo Hosp, IRCCS, Div Infect & Trop Dis, I-27100 Pavia, Italy. Policlin Umberto 1, Dept Infect Dis, Rome, Italy. Natl Inst Infect Dis L Spallanzani, Rome, Italy. RP Antonelli, G (reprint author), Univ Roma La Sapienza, Dept Expt Med, Virol Sect, Viale Porta Tiburtina 28, I-00185 Rome, Italy. EM guido.antonelli@uniroma1.it RI SCAGNOLARI, CAROLINA/G-3837-2011; OI SCAGNOLARI, CAROLINA/0000-0003-1044-1478; millefiorini, enrico/0000-0001-5318-3849; Bruno, Raffaele/0000-0002-0235-9207; CASATO, MILVIA/0000-0003-1841-6808 NR 32 TC 10 Z9 10 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0009-9104 J9 CLIN EXP IMMUNOL JI Clin. Exp. Immunol. PD FEB PY 2007 VL 147 IS 2 BP 270 EP 276 DI 10.1111/j.1365-2249.2006.03280.x PG 7 WC Immunology SC Immunology GA 125KP UT WOS:000243441100010 PM 17223968 ER PT J AU Roberts, DD Isenberg, JS Ridnour, LA Wink, DA AF Roberts, David D. Isenberg, Jeffery S. Ridnour, Lisa A. Wink, David A. TI Nitric oxide and its gatekeeper thrombospondin-1 in tumor angiogenesis SO CLINICAL CANCER RESEARCH LA English DT Article ID ARGININE DEIMINASE TREATMENT; ENDOTHELIAL PRECURSOR CELLS; CURATIVE RADIATION-THERAPY; HUMAN-MELANOMA XENOGRAFTS; PHASE-I; INHIBITOR ABT-510; HEPATOCELLULAR-CARCINOMA; PREVENTS GROWTH; SYNTHASE; CANCER AB Nitric oxide (NO) plays a central role in angiogenesis as a mediator of signaling by vascular endothelial growth factor and other angiogenic factors. Low concentrations of NO produced in response to angiogenic factors stimulate angiogenesis, whereas higher concentrations typical of inflammatory responses inhibit angiogenesis, The proangiogenic activity of NO is mediated by activation of soluble guanylyl cyclase, leading to cyclic guanosine 3',5'-monophosphate accumulation and activation of its target kinases and ion channels. The four angiogenesis inhibitors currently approved for clinical use target components of the signaling cascade upstream of NO. New research has identified components downstream of NO as the primary target of the endogenous angiogenesis inhibitor thrombospondin-1 and has shown that circulating levels of thrombospondin-1 are sufficient to limit angiogenic responses by antagonizing NO signaling. This provides new insights into the significance of the widespread loss of thrombospondin-1 expression during malignant progression. Although clinical trials suggest that blocking NO signaling can inhibit tumor angiogenesis, this approach also inactivates inhibitory signaling from thrombospondin-1. We discuss the implications of the balance between these pathways for applying thrombospondin-1 mimetics and redox modifiers as cancer therapeutics. C1 NCI, Radiat Biol Branch, NIH, Bethesda, MD 20892 USA. NCI, Pathol Lab, NIH, Bethesda, MD 20892 USA. RP Roberts, DD (reprint author), NCI, Radiat Biol Branch, NIH, Room B3-B69,Bldg 10, Bethesda, MD 20892 USA. EM droberts@helix.nih.gov RI Roberts, David/A-9699-2008 OI Roberts, David/0000-0002-2481-2981 FU Intramural NIH HHS NR 67 TC 42 Z9 42 U1 0 U2 0 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 1 PY 2007 VL 13 IS 3 BP 795 EP 798 DI 10.1158/1078-0432.CCR-06-1758 PG 4 WC Oncology SC Oncology GA 137JR UT WOS:000244289400005 PM 17289869 ER PT J AU Agalliu, I Kwon, EM Zadory, D McIntosh, L Thompson, J Stanford, JL Ostrander, EA AF Agalliu, Ilir Kwon, Erika M. Zadory, Daniel McIntosh, Laura Thompson, Joseph Stanford, Janet L. Ostrander, Elaine A. TI Germline mutations in the BRCA2 gene and susceptibility to hereditary prostate cancer SO CLINICAL CANCER RESEARCH LA English DT Article ID BREAST-CANCER; EARLY-ONSET; HOMOLOGOUS RECOMBINATION; OVARIAN-CANCER; FAMILIES; RELATIVES; RISK; SEQUENCE; REPEATS; PREDISPOSITION AB Purpose: Several epidemiologic studies have reported that carriers of germline mutations in the BRCA2 gene have an increased risk of prostate cancer, with the highest risk observed in men diagnosed at earlier ages. However, studies of the contribution of BRCA2 mutations to the etiology of hereditary prostate cancer (HPC) have been inconsistent. Experimental Design: To further address this issue, 266 subjects from 194 HPC families participating in the Seattle-based Prostate Cancer Genetic Research Study were screened for BRCA2 mutations by sequencing the coding regions, intron-exon boundaries, and suspected regulatory elements of this gene. Of selected HPC families, 32 had multiple breast or ovarian cancer cases, 16 were Jewish, 8 had a pancreatic cancer case, and 138 had at least one affected man diagnosed with prostate cancer at an early age (<60 years). Results: No disease-associated protein truncating BRCA2 mutations were found in 266 subjects from HPC families. There were 61 DNA sequence variants, of which 31 (50.8%)changed the predicted amino acids. No associations were found between these missense changes and family characteristics. Among affected men with prostate cancer, there were no statistically significant differences between the genotype frequencies of DNA variants with a minor allele frequency of 1% or higher and between the strata defined by median age at diagnosis or by clinical features. Conclusion: No evidence was found in this study for an association between BRCA2 mutations and susceptibility to HPC in men selected from high-risk families. C1 NHGRI, Canc Genet Branch, Bethesda, MD 20892 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. RP Ostrander, EA (reprint author), NHGRI, Canc Genet Branch, 50 South Dr,MSC 8000,Room 5351,Bldg 50, Bethesda, MD 20892 USA. EM eostrand@mail.nih.gov OI Ostrander, Elaine/0000-0001-6075-9738 FU Intramural NIH HHS; NCI NIH HHS [R01-CA80122] NR 37 TC 22 Z9 22 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 1 PY 2007 VL 13 IS 3 BP 839 EP 843 DI 10.1158/1078-0432.CCR-06-2164 PG 5 WC Oncology SC Oncology GA 137JR UT WOS:000244289400011 PM 17289875 ER PT J AU O'Mahony, D Morris, JC Quinn, C Gao, W Wilson, WH Gause, B Pittaluga, S Neelapu, S Brown, M Fleisher, TA Gulley, JL Schlom, J Nussenblatt, R Albert, P Davis, TA Lowy, I Petrus, M Waldmann, TA Janik, JE AF O'Mahony, Deirdre Morris, John C. Quinn, Cate Gao, Wendy Wilson, Wyndham H. Gause, Barry Pittaluga, Stefania Neelapu, Sattva Brown, Margaret Fleisher, Thomas A. Gulley, James L. Schlom, Jeffrey Nussenblatt, Robert Albert, Paul Davis, Thomas A. Lowy, Israel Petrus, Mike Waldmann, Thomas A. Janik, John E. TI A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy SO CLINICAL CANCER RESEARCH LA English DT Article; Proceedings Paper CT 45th Annual Meeting and Exhibition of the American-Society-of-Hematology CY DEC 06-09, 2003 CL San Diego, CA SP Amer Soc Hematol ID LYMPHOCYTE-ASSOCIATED ANTIGEN-4; T-CELL RESPONSES; COLONY-STIMULATING FACTOR; PROSTATE-CANCER; METASTATIC MELANOMA; COMBINATION IMMUNOTHERAPY; CARCINOMA PATIENTS; ANTIBODY BLOCKADE; AUTOIMMUNITY; REGRESSION AB Purpose: Eleven patients with progressive advanced malignancy after administration of a cancer vaccine received a fully human anti-CTLA-4 monoclonal antibody (ipilimumab). The primary end point was to determine drug toxicity. Tumor response, tumor-specific CD8(+) T-cell immune responses, and modulation of CD4(+) CD25(+) FoxP3(+) regulatory T-cell (Treg) numbers were secondary end points. Experimental Design: Three patients with colon cancer, four with non - Hodgkin's lymphoma, and four with prostate cancer were treated. The first dose was given at 3 mg/kg and subsequent doses were administered monthly at 1.5 mg/kg for a total of four cycles. Results: Tumor regression was observed in two patients with lymphoma; one of which obtained a partial response of 14-month duration. Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One drug-related grade 3 toxicity was observed. One patient died within 30 days of treatment due to progressive colon cancer. No increase in vaccine-specific T-cell responses was observed after therapy. Tregs as detected by expression of CD4(+)CD25(+)CD62L(+) declined at early time points but rebounded to levels at or above baseline values at the time of the next infusion. Conclusions: Ipilimumab treatment depressed Treg numbers at early time points in the treatment cycle but was not accompanied by an increase in vaccine-specific CD8+ T-cell responses in these patients previously treated with a variety of investigational anticancer vaccines. A partial response was observed in one patient with follicular lymphoma. A phase I/II trial evaluating ipilimumab in patients with follicular lymphoma is currently ongoing. C1 NCI, Metab Branch, Ctr Canc Res, Bethesda, MD 20892 USA. NCI, Med Oncol Branch, Bethesda, MD 20892 USA. NCI, Pathol Lab, Bethesda, MD 20892 USA. NCI, Dept Lab Med, Bethesda, MD 20892 USA. NCI, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. NCI, NEI, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Div Canc Treatment & Diag, Bethesda, MD 20892 USA. Medarex Inc, Bloomsbury, NJ USA. RP Janik, JE (reprint author), NCI, Metab Branch, Ctr Canc Res, Room 4E-5330, Bethesda, MD 20892 USA. EM janikj@mail.nih.gov RI Gulley, James/K-4139-2016 OI Gulley, James/0000-0002-6569-2912 FU Intramural NIH HHS NR 32 TC 106 Z9 107 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 1 PY 2007 VL 13 IS 3 BP 958 EP 964 DI 10.1158/1078-0432.CCR-06-1974 PG 7 WC Oncology SC Oncology GA 137JR UT WOS:000244289400027 PM 17289891 ER PT J AU Creighton-Gutteridge, M Cardellina, JH Stephen, AG Rapisarda, A Uranchimeg, B Hite, K Denny, WA Shoemaker, RH Melillo, G AF Creighton-Gutteridge, Mark Cardellina, John H., II Stephen, Andrew G. Rapisarda, Annamaria Uranchimeg, Badarch Hite, Karen Denny, William A. Shoemaker, Robert H. Melillo, Giovanni TI Cell type-specific, topoisomerase II-dependent inhibition of hypoxia-inducible factor-1 alpha protein accumulation by NSC 644221 SO CLINICAL CANCER RESEARCH LA English DT Article ID POTENTIAL ANTITUMOR AGENTS; DNA TOPOISOMERASE; CANCER-THERAPY; PATHWAY; ALPHA; HIF-1; BETA; DEGRADATION; TARGET; GROWTH AB Purpose: The discovery and development of small-molecule inhibitors of hypoxia-inducible factor-1 (HIF-1) is an attractive, yet challenging, strategy for the development of new cancer therapeutic agents. Here, we report on a novel tricyclic carboxamide inhibitor of HIF-1 alpha, NSC 644221. Experimental Design: We investigated the mechanism by which the novel compound NSC 644221 inhibited HIF-1 alpha. Results: NSC 644221 inhibited HIF-1 -dependent, but not constitutive, luciferase expression in U251-HRE and U251-pGL3 cells, respectively, as well as hypoxic induction of vascular endothelial growth factor mRNA expression in U251 cells. HIF-1 alpha, but not HIF-1 beta, protein expression was inhibited by NSC 644221 in a time- and dose-dependent fashion. Interestingly, NSC 644221 was unable to inhibit HIF-1 alpha protein accumulation in the presence of the proteasome inhibitors MG132 or PS341, yet it did not directly affect the degradation of HIF-1 alpha as shown by experiments done in the presence of cyclohexamide or pulse-chase labeling using [S-35] methionine. In contrast, NSC 644221 decreased the rate of HIF-1 alpha translation relative to untreated controls. Silencing of topoisomerase (topo) II alpha, but not topo I, by specific small interfering RNA completely blocked the ability of NSC 644221 to inhibit HIF-1 alpha. The data presented show that topo II is required for the inhibition of HIF-1 alpha by NSC 644221. Furthermore, although NSC 644221 induced p21 expression, gamma H2A.X, and G(2)-M arrest in the majority of cell lines tested, it only inhibited HIF-1 alpha in a distinct subset of cells, raising the possibility of pathway-specific "resistance" to HIF-1 inhibition in cancer cells. Conclusions: NSC 644221 is a novel HIF-1 inhibitor with potential for use as both an analytic tool and a therapeutic agent. Our data provide a strong rationale for pursuing the preclinical development of NSC 644221 as a HIF-1 inhibitor. C1 NCI, Dev Therapeut Program, SAIC Frederick Inc, Tumor Hypoxia Lab, Frederick, MD 21702 USA. NCI, Screening Technol Branch, Dev Therapeut Program, Frederick, MD 21702 USA. Univ Auckland, Fac Med & Hlth Sci, Auckland Canc Soc Res Ctr, Auckland 1, New Zealand. RP Melillo, G (reprint author), NCI, Dev Therapeut Program, SAIC Frederick Inc, Tumor Hypoxia Lab, Bldg 432,Room 218, Frederick, MD 21702 USA. EM melillog@ncifcrf.gov FU NCI NIH HHS [N01-CO-12400] NR 27 TC 37 Z9 41 U1 0 U2 4 PU AMER ASSOC CANCER RESEARCH PI PHILADELPHIA PA 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA SN 1078-0432 J9 CLIN CANCER RES JI Clin. Cancer Res. PD FEB 1 PY 2007 VL 13 IS 3 BP 1010 EP 1018 DI 10.1158/1078-0432.CCR-06-2301 PG 9 WC Oncology SC Oncology GA 137JR UT WOS:000244289400034 PM 17289897 ER PT J AU Grube, M Moritz, S Obermann, EC Rezvani, K Mackensen, A Andreesen, R Holler, E AF Grube, Matthias Moritz, Stephanie Obermann, Ellen C. Rezvani, Katayoun Mackensen, Andreas Andreesen, Reinhard Holler, Ernst TI CD8(+) T cells reactive to survivin antigen in patients with multiple myeloma SO CLINICAL CANCER RESEARCH LA English DT Article ID BLOOD MONONUCLEAR-CELLS; BONE-MARROW; PERIPHERAL-BLOOD; CANCER-PATIENTS; TUMOR-ANTIGEN; HEALTHY-INDIVIDUALS; PROTEIN SURVIVIN; DENDRITIC CELLS; EFFECTOR-CELLS; EX-VIVO AB Purpose: Survivin is a member of the inhibitors of apoptosis family and is overexpressed in different types of malignancies. Cytotoxic T cells recognizing survivin epitopes can be elicited in vitro and by vaccination in patients with leukemia, breast cancer, and melanoma. We did this study to investigate whether survivin-specific CD8(+) T cells occur in patients with multiple myeloma. Experimental Design: An HLA-A2.1 - binding survivin peptide was used to detect peptide-specific T cells by a quantitative real-time PCR to measure antigen-specific IFN-gamma mRNA expression in 23 patients with myeloma and 21 healthy volunteers. T cells producing IFN-gamma in response to survivin were further analyzed for expression of CD45RA and CCR7 to determine phenotypic characterization. Additional immunohistochemical analyses of survivin antigen expression in bone marrow specimens of patients was done. Results: T cells recognizing HLA-A2.1 - binding survivin peptide were detected in 9 of 23 patients and in 1 of 21 healthy volunteers. Survivin-reactive T cells were identified as terminally differentiated effector T cells (CD8(+), CD45RA(+), and CCR7(-)). Positive survivin expression of myeloma cells in bone marrow specimens was shown in 7 of 11 patients. Conclusion: We provide, for the first time, evidence of T cell reactivity against survivin antigen in patients with multiple myeloma. Our data suggest the immunogenicity of survivin antigen in multiple myeloma and that immunotherapeutic strategies using survivin as a target antigen might be an option for patients with this disease. C1 Univ Regensburg, Dept Hematol & Oncol, D-93042 Regensburg, Germany. Univ Regensburg, Inst Pathol, D-93042 Regensburg, Germany. NHLBI, NIH, Bethesda, MD 20892 USA. RP Grube, M (reprint author), Univ Regensburg, Dept Hematol & Oncol, Franz Josef Strauss Allee 11, D-93042 Regensburg, Germany. EM matthias.grube@klinik.uni-regensburg.de RI Obermann, Ellen/E-7802-2011; Obermann, Ellen/E-2656-2013 NR 49 TC 28 Z9 29 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 1 PY 2007 VL 13 IS 3 BP 1053 EP 1060 DI 10.1158/1078-0432.CCR-06-1722 PG 8 WC Oncology SC Oncology GA 137JR UT WOS:000244289400039 PM 17289902 ER PT J AU Wessel, TR Arant, CB McGorray, SP Sharaf, BL Reis, SE Kerensky, RA von Mering, GO Smith, KM Pauly, DF Handberg, EM Mankad, S Olson, MB Johnson, BD Merz, CNB Sopko, G Pepine, CJ AF Wessel, Timothy R. Arant, Christopher B. McGorray, Susan P. Sharaf, Barry L. Reis, Steven E. Kerensky, Richard A. von Mering, Gregory O. Smith, Karen M. Pauly, Daniel F. Handberg, Eileen M. Mankad, Sunil Olson, Marian B. Johnson, B. Delia Merz, C. Noel Bairey Sopko, George Pepine, Carl J. TI Coronary microvascular reactivity is only partially predicted by atherosclerosis risk factors or coronary artery disease in women evaluated for suspected ischemia: Results from the NHLBI Women's Ischemia Syndrome Evaluation (WISE) SO CLINICAL CARDIOLOGY LA English DT Article DE women; risk factors; microcirculation; adenosine ID DENSITY-LIPOPROTEIN CHOLESTEROL; CHEST-PAIN; CARDIOVASCULAR EVENTS; SYNDROME-X; HEART-DISEASE; PILOT PHASE; BLOOD-FLOW; FOLLOW-UP; RESERVE; DYSFUNCTION AB Background: Altered coronary reactivity is frequent in women with findings of myocardial ischemia without significant obstructive disease. This suggests a defect in coronary microvascular function. The adenosine-related component of this altered reactivity has been described in male and mixed gender populations, while the factors influencing this component of coronary reactivity in symptomatic women have received limited attention. Accordingly, the relationship between adenosine-related microvascular coronary reactivity and risk factors in symptomatic women evaluated for suspected ischemia remains uncertain. Hypothesis: Abnormal coronary microvascular reactivity to adenosine is predicted by atherosclerosis risk factors in women. Methods: As part of the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE), we investigated the relationship between risk factors and coronary microvascular reactivity as flow velocity reserve to intracoronary adenosine (CFVRAdo) in 210 women referred for angiography to evaluate suspected ischemia. Results: Univariate analyses identified associations between CFVRAdo and multiple risk conditions; however, after adjusting for age, none remained significant. The best multivariable model using combinations of risk conditions to predict CFVRAdo yielded an R-2 of only 0.18. Conclusions: Among women with suspected ischemia, risk factors account for < 20% of observed variability in CFVRAdo. Therefore, other as yet unidentified factors must primarily account for coronary microvascular reactivity to adenosine. C1 Univ Florida, Coll Med, Div Cardiovasc Med, Gainesville, FL 32610 USA. Rhode Isl Hosp, Div Cardiol, Providence, RI USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Allegheny Gen Hosp, Div Cardiol, Pittsburgh, PA 15212 USA. Cedars Sinai Med Ctr, Div Cardiol, Los Angeles, CA 90048 USA. NHLBI, NIH, Div Heart & Vasc Dis, Bethesda, MD 20892 USA. RP Pepine, CJ (reprint author), Univ Florida, Coll Med, Div Cardiovasc Med, POB 100277, Gainesville, FL 32610 USA. EM pepincj@medicine.ufl.edu RI Reis, Steven/J-3957-2014 FU NCRR NIH HHS [M01-RR00425]; NHLBI NIH HHS [N01-HV-68162, N01-HV-68163, N01-HV-68164, U01-HL64829-01, U01-HL64914-01, U01-HL65924-01]; PHS HHS [N01 NV-68161] NR 29 TC 24 Z9 27 U1 0 U2 2 PU JOHN WILEY & SONS INC PI HOBOKEN PA 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0160-9289 J9 CLIN CARDIOL JI Clin. Cardiol. PD FEB PY 2007 VL 30 IS 2 BP 69 EP 74 DI 10.1002/clc.19 PG 6 WC Cardiac & Cardiovascular Systems SC Cardiovascular System & Cardiology GA 135ZO UT WOS:000244192600003 PM 17326061 ER PT J AU Lenders, JWM Willemsen, JJ Eisenhofer, G Ross, HA Pacak, K Timmers, HJLM Sweep, CGJF AF Lenders, Jacques W. M. Willemsen, Jacques J. Eisenhofer, Graeme Ross, H. Alec Pacak, Karel Timmers, Henri J. L. M. Sweep, C. G. J. (Fred) TI Is supine rest necessary before blood sampling for plasma metanephrines? SO CLINICAL CHEMISTRY LA English DT Article ID BIOCHEMICAL-DIAGNOSIS; PHEOCHROMOCYTOMA; CATECHOLAMINES AB Background: The impact of blood sampling in sitting vs supine positions on measurements of plasma metanephrines for diagnosis of pheochromocytoma is unknown. Methods: We compared plasma concentrations of free metanephrines in samples from patients with primary hypertension obtained after supine rest with those obtained in the sitting position without preceding rest. We also assessed the effects on diagnostic test performance retrospectively in patients with and without pheochromocytoma, and we calculated cost-effectiveness for pheochromocytoma testing. Results: Upper reference limits of plasma free metanephrines were higher in samples obtained from seated patients without preceding rest than from supine patients with preceding rest. Application of these higher upper reference limits to samples from supine patients with pheochromocytoma decreased the diagnostic sensitivity from 99% to 96%. In patients without pheochromocytoma, adjusting the plasma concentration for the effects of sitting while preserving the 99% sensitivity by use of the supine upper reference limits increased the number of false-positive test results from 9% to 25%. Conclusions: To preserve high diagnostic sensitivity we recommend the use of upper reference limits determined from blood samples collected in the supine position. Under these conditions, negative test results for blood samples obtained with patients sitting are as effective for ruling out pheochromocytoma as negative results from samples obtained after supine rest. Repeat testing with samples obtained in the supine position offers a cost-effective approach for dealing with the increased numbers of false-positive results expected after initial sampling in the sitting position. (c) 2007 American Association for Clinical Chemistry C1 Radboud Univ Nijmegen Med Ctr, Dept Internal Med, NL-6500 HB Nijmegen, Netherlands. Radboud Univ Nijmegen Med Ctr, Dept Chem Endocrinol, NL-6500 HB Nijmegen, Netherlands. Radboud Univ Nijmegen Med Ctr, Dept Endocrinol, NL-6500 HB Nijmegen, Netherlands. Natl Inst Neurol Disoders & Stroke, Clin Neurocardiol Sect, Bethesda, MD USA. NICHHD, Reprod Biol & Med Branch, NIH, Bethesda, MD 20892 USA. RP Lenders, JWM (reprint author), Radboud Univ Nijmegen Med Ctr, Dept Internal Med, Geert Grootepl,POB 9101, NL-6500 HB Nijmegen, Netherlands. EM j.lenders@aig.umcn.nl RI Sweep, C.G.J./H-8096-2014; Lenders, J.W.M./L-4487-2015; Ross, H.A./L-4613-2015 NR 10 TC 49 Z9 50 U1 0 U2 1 PU AMER ASSOC CLINICAL CHEMISTRY PI WASHINGTON PA 2101 L STREET NW, SUITE 202, WASHINGTON, DC 20037-1526 USA SN 0009-9147 J9 CLIN CHEM JI Clin. Chem. PD FEB PY 2007 VL 53 IS 2 BP 352 EP 354 DI 10.1373/clinchem.2006.076489 PG 3 WC Medical Laboratory Technology SC Medical Laboratory Technology GA 132TQ UT WOS:000243965500027 PM 17200132 ER PT J AU Lok, ASF Everhart, JE Chung, RT Padmanabhan, L Greenson, JK Shiffman, ML Everson, GT Lindsay, KL Bonkovsky, HL Di Bisceglie, AM Lee, WM Morgan, TR Ghany, MG Morishima, C AF Lok, Anna S. F. Everhart, James E. Chung, Raymond T. Padmanabhan, Latha Greenson, Joel K. Shiffman, Mitchell L. Everson, Gregory T. Lindsay, Karen L. Bonkovsky, Herbert L. Di Bisceglie, Adrian M. Lee, William M. Morgan, Timothy R. Ghany, Marc G. Morishima, Chihiro CA HALT C Trial Grp TI Hepatic steatosis in hepatitis C: Comparison of diabetic and nondiabetic patients in the hepatitis C antiviral long-term treatment against cirrhosis trial SO CLINICAL GASTROENTEROLOGY AND HEPATOLOGY LA English DT Article ID FATTY LIVER-DISEASE; BODY-MASS INDEX; INSULIN-RESISTANCE; FIBROSIS PROGRESSION; VIRUS GENOTYPE-3; NONALCOHOLIC STEATOHEPATITIS; CRYPTOGENIC CIRRHOSIS; HEPATOCYTE STEATOSIS; NATURAL-HISTORY; HCV GENOTYPE AB Background & Aims: Hepatic steatosis often is observed in patients with chronic hepatitis C and has been reported to be associated with hepatic fibrosis and impaired treatment response in some studies. Our aim was to determine the prevalence of and risk factors for hepatic steatosis among Hepatitis C Antiviral Long-term Treatment against Cirrhosis patients, and to determine the relationship between steatosis, fibrosis, and sustained virologic response (SVR) to re-treatment with pegylated interferon and ribavirin. Methods: Baseline data from 1143 Hepatitis C Antiviral Long-term Treatment against Cirrhosis patients, with a mean body mass index of 30, 5% with genotype 3, 38% with cirrhosis, and 24% with diabetes were analyzed. Results: Steatosis scores of 0, 1, 2, 3, and 4 were observed in 19%, 42%, 30%, 8%, and 1% of patients, respectively. High body mass index, triglyceride and alanine aminotransferase levels, and genotype 3 were associated with higher grades of steatosis. Among nondiabetic patients, steatosis scores of 0-2 but not scores of 3-4 were associated significantly with cirrhosis. For diabetic patients, there was no association between steatosis and cirrhosis. Similarly, steatosis scores of 2-4 were associated with a lack of SVR among nondiabetic but not among diabetic patients. Conclusions: in this cohort with predominantly hepatitis C virus genotype I infection, steatosis was associated strongly with metabolic factors that contribute to nonalcoholic fatty liver disease. Steatosis correlated with increasing stages of fibrosis up to but not including cirrhosis. Steatosis had a negative impact on SVR among nondiabetic but not diabetic patients. The discordant findings between nondiabetic and diabetic patients indicate that these 2 groups should be considered separately when analyzing metabolic factors and liver disease outcomes. C1 Univ Michigan, Ctr Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. Univ Michigan, Ctr Med, Dept Pathol, Ann Arbor, MI 48109 USA. NIDDKD, Liver Dis Branch, Div Digest Dis & Nutr, NIH, Bethesda, MD 20892 USA. NIDDKD, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Massachusetts Gen Hosp, Gastrointestinal Unit, Med Serv, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA 02115 USA. New England Res Inst, Watertown, MA 02172 USA. Virginia Commonwealth Univ, Hlth Syst, Hepatol Sect, Richmond, VA USA. Univ Colorado, Sch Med, Sect Hepatol, Div Gastroenterol & Hepatol, Denver, CO 80202 USA. Univ So Calif, Keck Sch Med, Div Gastrointestinal & Liver Dis, Los Angeles, CA USA. Univ Connecticut, Ctr Hlth, Liver Biliary Pancreat Ctr, Farmington, CT USA. Univ Connecticut, Ctr Hlth, Dept Med, Farmington, CT USA. Univ Connecticut, Ctr Hlth, Dept Mol & Struct Biol, Farmington, CT USA. St Louis Univ, Sch Med, Div Gastroenterol & Hepatol, St Louis, MO 63103 USA. Univ Texas, SW Med Ctr, Div Digest & Liver Dis, Dallas, TX USA. Univ Calif Irvine, Div Gastroenterol, Irvine, CA USA. Univ Washington, Dept Lab Med, Seattle, WA 98195 USA. RP Lok, ASF (reprint author), Univ Michigan, Ctr Med, Div Gastroenterol, Ann Arbor, MI 48109 USA. EM aslok@umich.edu RI Lok, Anna /B-8292-2009; OI Yang, Shuman/0000-0002-9638-0890 FU NCRR NIH HHS [M01RR-00042, M01RR-00043, M01RR-00051, M01RR-00065, M01RR-00633, M01RR-00827, M01RR-01066, M01RR-06192]; NIDDK NIH HHS [N01-DK-9-2319, N01-DK-9-2318, N01-DK-9-2320, N01-DK-9-2321, N01-DK-9-2322, N01-DK-9-2323, N01-DK-9-2324, N01-DK-9-2325, N01-DK-9-2326, N01-DK-9-2327, N01-DK-9-2328, P60 DK020572-28] NR 43 TC 26 Z9 28 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1542-3565 J9 CLIN GASTROENTEROL H JI Clin. Gastroenterol. Hepatol. PD FEB PY 2007 VL 5 IS 2 BP 245 EP 254 DI 10.1016/j.cgh.2006.11.002 PG 10 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 140NH UT WOS:000244511700020 PM 17296533 ER PT J AU Kitajiri, S Makishima, T Friedman, TB Griffith, AJ AF Kitajiri, S. Makishima, T. Friedman, T. B. Griffith, A. J. TI A novel mutation at the DFNA36 hearing loss locus reveals a critical function and potential genotype-phenotype correlation for amino acid-572 of TMC1 SO CLINICAL GENETICS LA English DT Article DE deafness; dominant; dominant-negative; gain-of-function; genetic; hearing; hotspot; mutation; TMC1 ID DEAFNESS DN/DN MICE; GENE FAMILY; MOUSE MODEL; DOMINANT; DEGENERATION; BEETHOVEN; INNER; DN AB We ascertained a North American Caucasian family (LMG248) segregating autosomal dominant, non-syndromic, post-lingual, progressive sensorineural hearing loss. The hearing loss begins in the second decade of life and initially affects high frequencies. It progresses to profound deafness at all frequencies by the fourth or fifth decade. The phenotype co-segregates with short-tandem repeat markers flanking the TMC1 gene at the DFNA36 locus on chromosome 9q31-q21. The affected individuals carry a novel missense substitution, p.D572H (c.G1714C), of the TMC1 gene. This mutation is at the same nucleotide and amino acid position as the only other reported DFNA36 mutation, p.D572N (c.G1714A). Our observations implicate a critical function for amino acid-572 for wild-type TMC1 function or the pathogenesis of DFNA36 hearing loss. The slower progression of hearing loss associated with p.D572H, in comparison with that caused by p.D572N, may reflect a correlation of DFNA36 phenotype with TMC1 genotype. C1 Natl Inst Deafness & Other Commun Disorders, NIH, Otolaryngol Branch, Rockville, MD 20850 USA. Univ Texas, Med Branch, Dept Otolaryngol, Galveston, TX 77550 USA. Natl Inst Deafness & Other Commun Disorders, NIH, Lab Mol Genet, Rockville, MD 20850 USA. RP Griffith, AJ (reprint author), Natl Inst Deafness & Other Commun Disorders, NIH, Otolaryngol Branch, 5 Res Court,Room 2A01, Rockville, MD 20850 USA. EM griffita@nidcd.nih.gov FU Intramural NIH HHS NR 21 TC 19 Z9 21 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0009-9163 J9 CLIN GENET JI Clin. Genet. PD FEB PY 2007 VL 71 IS 2 BP 148 EP 152 DI 10.1111/j.1399-0004.2007.00739.x PG 5 WC Genetics & Heredity SC Genetics & Heredity GA 135UN UT WOS:000244179500006 PM 17250663 ER PT J AU Viorritto, ICB Nikolov, NP Siegel, RM AF Viorritto, Irene C. B. Nikolov, Nikolay P. Siegel, Richard M. TI Autoimmunity versus tolerance: Can dying cells tip the balance? SO CLINICAL IMMUNOLOGY LA English DT Review DE apoptosis; autoimmunity; phagocytosis; dentritic cell; Toll-like receptor ID SYSTEMIC-LUPUS-ERYTHEMATOSUS; RECEPTOR TYROSINE KINASE; CD8 T-CELLS; MHC CLASS-I; APOPTOTIC CELLS; DENDRITIC CELLS; PHOSPHATIDYLSERINE RECEPTOR; INNATE IMMUNITY; AUTOANTIBODY PRODUCTION; VITRONECTIN RECEPTOR AB Apoptosis is a physiological process of self-destruction for cells that are damaged or programmed to die. Apoptosis occurs through a series of regulated events that allow cellular debris to be contained and efficiently phagocytosed without initiating a proinflammatory immune response. Recent data have linked physiological apoptosis and the uptake of apoptotic cells by macrophages and some subsets of dendritic cells to the maintenance of peripheral immune tolerance. However, when cells die through necrosis, spilling their intracellular contents, or are infected with various pathogens, activation of antigenpresenting cells and induction of an immune response can occur. Receptors for extrinsic pathogen-associated structures, such as membrane bound Toll-like receptors (TLRs) or intracellular Nod-like receptors (NLRs) can also respond to cross-reactive host molecules from dying cells and may focus autoimmune responses onto these antigens. Several autoimmune disorders have been linked to defects in the apoptotic process. Defective apoptosis of immune cells leads to autoimmunity, as in autoimmune lymphoproliferative syndrome (ALPS) associated with mutations in the death receptor Fas. Defective clearance of apoptotic cell debris can also lead to autoantibody production. We will discuss how cell death and apoptotic cell clearance may affect the finely tuned balance between peripheral immune tolerance and autoimmunity. Published by Elsevier Inc. C1 NHGRI, Genet Dis Res Branch, Cell Signaling Sect, Bethesda, MD 20892 USA. Univ Penn, Sch Med, Immunol Grad Grp, Philadelphia, PA 19104 USA. NIAMS, Immunoregulat Unit, Autoimmun Branch, NIH, Bethesda, MD 20892 USA. RP Siegel, RM (reprint author), Bld 10 Rm 9N238, Bethesda, MD 20892 USA. EM rsiegel@nih.gov RI Siegel, Richard/C-7592-2009 OI Siegel, Richard/0000-0001-5953-9893 FU NIAMS NIH HHS [Z01 AR041133-04] NR 68 TC 44 Z9 51 U1 0 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1521-6616 J9 CLIN IMMUNOL JI Clin. Immunol. PD FEB PY 2007 VL 122 IS 2 BP 125 EP 134 DI 10.1016/j.clim.2006.07.012 PG 10 WC Immunology SC Immunology GA 130DJ UT WOS:000243779300002 PM 17029966 ER PT J AU Greene, RE Schlamm, HT Oestmann, JW Stark, P Durand, C Lortholary, O Wingard, JR Herbrecht, R Ribaud, P Patterson, TF Troke, PF Denning, DW Bennett, JE de Pauw, BE Rubin, RH AF Greene, Reginald E. Schlamm, Haran T. Oestmann, Joerg -W. Stark, Paul Durand, Christine Lortholary, Olivier Wingard, John R. Herbrecht, Raoul Ribaud, Patricia Patterson, Thomas F. Troke, Peter F. Denning, David W. Bennett, John E. de Pauw, Ben E. Rubin, Robert H. TI Imaging findings in acute invasive pulmonary aspergillosis: Clinical significance of the halo sign SO CLINICAL INFECTIOUS DISEASES LA English DT Article; Proceedings Paper CT 13th European Congress of Clinical Microbiology and Infectious Diseases CY MAY 10-13, 2003 CL GLASGOW, SCOTLAND SP Belgian Fonds Format Rech Ind Agr, Belgian Fonds Natl Rech Sci, Belgian Fonds Rech Sci Med ID RECEIVING PIPERACILLIN-TAZOBACTAM; NEUTROPENIC PATIENTS; IMMUNOCOMPROMISED PATIENTS; EARLY-DIAGNOSIS; HEMATOLOGICAL MALIGNANCIES; BRONCHOALVEOLAR LAVAGE; TOMOGRAPHIC SCAN; ACUTE-LEUKEMIA; CT; GALACTOMANNAN AB Background. Computed tomography ( CT) of the chest may be used to identify the halo sign, a macronodule surrounded by a perimeter of ground- glass opacity, which is an early sign of invasive pulmonary aspergillosis ( IPA). This study analyzed chest CT findings at presentation from a large series of patients with IPA, to assess the prevalence of these imaging findings and to evaluate the clinical utility of the halo sign for early identification of this potentially life- threatening infection. Methods. Baseline chest CT imaging findings from 235 patients with IPA who participated in a previously published study were systematically analyzed. To evaluate the clinical utility of the halo sign for the early identification and treatment of IPA, we compared response to treatment and survival after 12 weeks of treatment in 143 patients who presented with a halo sign and in 79 patients with other imaging findings. Results. At presentation, most patients ( 94%) had >= 1 macronodules, and many ( 61%) also had halo signs. Other imaging findings at presentation, including consolidations ( 30%), infarct- shaped nodules ( 27%), cavitary lesions ( 20%), and air- crescent signs ( 10%), were less common. Patients presenting with a halo sign had significantly better responses to treatment ( 52% vs. 29%;) and greater survival to 84 days ( 71% vs. 53%;) than P <= .001 P <= .01 did patients who presented with other imaging findings. Conclusions. Most patients presented with a halo sign and/ or a macronodule in this large imaging study of IPA. Initiation of antifungal treatment on the basis of the identification of a halo sign by chest CT is associated with a significantly better response to treatment and improved survival. C1 Massachusetts Gen Hosp, Dept Radiol, Boston, MA 02114 USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Pfizer Global Res & Dev, New York, NY USA. Univ Calif San Diego, La Jolla, CA 92093 USA. Univ Florida, Coll Med, Gainesville, FL 32611 USA. Univ Texas, Hlth Sci Ctr, San Antonio, TX 78285 USA. NIAID, Bethesda, MD 20892 USA. Charite Univ Med Berlin, Berlin, Germany. Hop Bocage, Dijon, France. Inst Pasteur, Paris, France. Hop St Louis, Paris, France. Hop Hautepierre, Strasbourg, France. Pfizer Global Res & Dev, Sandwich, Kent, England. Univ Manchester, Manchester M13 9PL, Lancs, England. Univ Nijmegen, Med Ctr, Nijmegen, Netherlands. RP Greene, RE (reprint author), Massachusetts Gen Hosp, Dept Radiol, Founders 202, Boston, MA 02114 USA. EM greene.reginald@mgh.harvard.edu RI Herbrecht, Raoul/D-3471-2013; OI Herbrecht, Raoul/0000-0002-9381-4876; Denning, David/0000-0001-5626-2251 NR 54 TC 279 Z9 315 U1 0 U2 6 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD FEB 1 PY 2007 VL 44 IS 3 BP 373 EP 379 DI 10.1086/509917 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 123SE UT WOS:000243315100016 PM 17205443 ER PT J AU Segal, BH Almyroudis, NG Battiwalla, M Herbrecht, R Perfect, JR Walsh, TJ Wingard, JR AF Segal, Brahm H. Almyroudis, Nikolaos G. Battiwalla, Minoo Herbrecht, Raoul Perfect, John R. Walsh, Thomas J. Wingard, John R. TI Prevention and early treatment of invasive fungal infection in patients with cancer and neutropenia and in stem cell transplant recipients in the era of newer broad-spectrum antifungal agents and diagnostic adjuncts SO CLINICAL INFECTIOUS DISEASES LA English DT Editorial Material ID BONE-MARROW-TRANSPLANTATION; LIPOSOMAL AMPHOTERICIN-B; ACUTE MYELOGENOUS LEUKEMIA; BETA-D-GLUCAN; PERSISTENT FEVER; RISK-FACTORS; IN-VITRO; GALACTOMANNAN ANTIGENEMIA; RANDOMIZED-TRIAL; CLINICAL-TRIALS AB Invasive fungal infection ( IFI) is a leading cause of infection- related mortality among patients with cancer and prolonged neutropenia and among allogeneic hematopoietic stem cell transplant recipients with graft- versus- host disease. Invasive candidiasis was the principal IFI in the period predating fluconazole prophylaxis, whereas today, invasive aspergillosis and other mold infections cause the majority of deaths from fungal infection in this patient population. The changing epidemiology of IFI, in addition to advances made in antifungal therapeutics and early diagnosis of IFI, warrant a reevaluation of earlier strategies aimed at prevention and early treatment of IFI that were developed several years ago. Here, we propose that persistent neutropenic fever is nonspecific for an IFI and should not be used as the sole criterion for empirical modification in the antifungal regimen in a patient receiving mold- active prophylaxis. We explore the potential benefits and gaps in knowledge associated with employing chest CT scans and laboratory markers as diagnostic adjuncts for IFI. Finally, we discuss the implications of newer antifungal agents and diagnostic adjuncts in the design of future clinical trials to evaluate prophylaxis and early prevention strategies. C1 Roswell Pk Canc Inst, Dept Med, Div Infect Dis, Buffalo, NY 14263 USA. Roswell Pk Canc Inst, Dept Immunol, Buffalo, NY 14263 USA. Duke Univ, Med Ctr, Dept Med, Durham, NC 27710 USA. NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. Univ Florida, Shands Canc Ctr, Dept Med, Div Hematol Oncol, Gainesville, FL USA. Univ Hosp, Dept Hematol & Oncol, Strasbourg, France. RP Segal, BH (reprint author), Roswell Pk Canc Inst, Dept Med, Div Infect Dis, Elm & Carlton Sts, Buffalo, NY 14263 USA. EM brahm.segal@roswell.park.org RI Herbrecht, Raoul/D-3471-2013; OI Herbrecht, Raoul/0000-0002-9381-4876 NR 74 TC 94 Z9 103 U1 0 U2 2 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 1058-4838 J9 CLIN INFECT DIS JI Clin. Infect. Dis. PD FEB 1 PY 2007 VL 44 IS 3 BP 402 EP 409 DI 10.1086/510677 PG 8 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 123SE UT WOS:000243315100021 PM 17205448 ER PT J AU Pritsch, T Bickels, J Winberg, T Malawer, MM AF Pritsch, Tamir Bickels, Jacob Winberg, Tierney Malawer, Martin M. TI Popliteal sarcomas - Presentation, prognosis, and limb salvage SO CLINICAL ORTHOPAEDICS AND RELATED RESEARCH LA English DT Article ID SOFT-TISSUE SARCOMA; SCIATIC-NERVE RESECTION; FLEXOR FOSSAE; POSTOPERATIVE RADIOTHERAPY; LOCAL RECURRENCE; SPARING SURGERY; LOWER-EXTREMITY; SURVIVAL; RADIATION; THERAPY AB Soft tissue sarcomas of the popliteal fossa are rare diseases. Resection is challenging because of their extracompartmental location and proximity to neurovascular structures. Their prognosis is inferior to intracompartmental extremity soft tissue sarcomas. We ascertained the mode of initial presentation, the rates of local recurrence and distant metastasis, and the morbidity and complications of limb salvage procedures. We retrospectively analyzed the data of 29 consecutive patients operated on between 1989 and 2003. The median followup was 79 months. Sixteen, five, and eight patients were diagnosed with high-, intermediate-, and low-grade tumors, respectively. High-grade tumors were smaller than low- and intermediate-grade tumors. Thirty-one percent of patients presented with localized pain. Of the 26 patients who had primary limb salvage resections, 14 had negative surgical margins, six had close margins, and six had positive margins. Seventeen patients were treated with radiotherapy and 10 patients received chemotherapy. The local recurrence rate was 10.3%, four patients with high-grade tumors had distant metastasis, and the limb-salvage rate was 86.2%. Postoperatively, six patients experienced wound dehiscence and four had mild flexion contractures. Soft tissue sarcomas of the popliteal fossa have an atypical presentation. Limb salvage can be accomplished in most patients with low morbidity and good systemic and local control. Level of Evidence: Level IV, therapeutic study. See the guidelines for Authors for a complete description of level of evidence. C1 Washington Hosp Ctr, Dept Orthoped Oncol, Washington Canc Inst, Washington, DC 20010 USA. Tel Aviv Sourasky Med Ctr, Natl Unit Orthoped Oncol, Tel Aviv, Israel. Georgetown Univ, Washington, DC USA. NCI, Pediat & Surg Branch, Bethesda, MD 20892 USA. RP Pritsch, T (reprint author), Washington Hosp Ctr, Dept Orthoped Oncol, Washington Canc Inst, C2173,110 Irving St NW, Washington, DC 20010 USA. EM Pritscht@yahoo.com NR 37 TC 1 Z9 1 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0009-921X EI 1528-1132 J9 CLIN ORTHOP RELAT R JI Clin. Orthop. Rel. Res. PD FEB PY 2007 IS 455 BP 225 EP 233 DI 10.1097/01.blo.0000238812.95035.52 PG 9 WC Orthopedics; Surgery SC Orthopedics; Surgery GA 135HO UT WOS:000244144900036 PM 16957647 ER PT J AU Cohn, SE Park, JG Watts, DH Stek, A Hitti, J Clax, PA Yu, S Lertora, JJL AF Cohn, S. E. Park, J-G Watts, D. H. Stek, A. Hitti, J. Clax, P. A. Yu, S. Lertora, J. J. L. CA ACTG A5093 Protocol Team TI Depo-medroxyprogesterone in women on antiretroviral therapy: Effective contraception and lack of clinically significant interactions SO CLINICAL PHARMACOLOGY & THERAPEUTICS LA English DT Article; Proceedings Paper CT 12th Conference on Retroviruses and Opportunistic Infections CY FEB 22-25, 2005 CL Boston, MA ID HIV; PHARMACOKINETICS; TRIALS; AGENTS; DRUGS; RISK; 3A4 AB We conducted an open-label, steady-state pharmacokinetic (PK) study of drug interactions among HIV-infected women treated with depo-medroxyprogesterone acetate (DMPA) while on nucleoside analogues plus nelfinavir (N = 21), efavirenz (N = 17), or nevirapine (N = 16); or nucleosides only or no antiretroviral therapy as a control group (N = 16). PK parameters were estimated using non-compartmental analysis, with between-group comparisons of medroxyprogesterone acetate (MPA) PKs and within-subject comparisons of ARV PKs before and 4 weeks after DMPA dosing. Plasma progesterone levels were measured at baseline and at 2, 4, 6, 8, 10, and 12 weeks after DMPA dosing. There were no significant changes in MPA area under the concentration curve, peak or trough concentrations, or apparent clearance in the nelfinavir, efavirenz, or nevirapine groups compared to the control group. Minor changes in nelfinavir and nevirapine drug exposure were seen after DMPA, but were not considered clinically significant. Suppression of ovulation was maintained. C1 Univ Rochester, Ctr Med, Dept Med, Rochester, NY USA. Harvard Univ, Sch Publ Hlth & Frontier Sci, Ctr Biostat AIDS Res, Boston, MA 02115 USA. Harvard Univ, Technol Res Fdn, Boston, MA 02115 USA. NICHHD, Ctr Res Mothers & Children, NIH, Bethesda, MD 20892 USA. Univ So California, Sch Med, Dept Obstet Gynecol, Los Angeles, CA USA. Univ Washington, Sch Med, Dept Obstet Gynecol, Seattle, WA 98195 USA. Pfizer Inc, US Med, Pfizer Global Pharmaceut, New York, NY USA. Tulane Univ, Ctr Hlth Sci, Dept Med & Pharmacol, Tulane LSU Char Hosp GCRC, New Orleans, LA 70118 USA. RP Cohn, SE (reprint author), Univ Rochester, Ctr Med, Dept Med, 601 Elmwood Ave, Rochester, NY USA. EM Susan_Cohn@urmc.rochester.edu FU NCRR NIH HHS [5M01 RR00044, M01 RR05096]; NIAID NIH HHS [AI27664, UO1 AI27658, U01 AI38855, AI38858, IU01AI3844]; NICHD NIH HHS [N01-HD-3-3345] NR 22 TC 37 Z9 38 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0009-9236 J9 CLIN PHARMACOL THER JI Clin. Pharmacol. Ther. PD FEB PY 2007 VL 81 IS 2 BP 222 EP 227 DI 10.1038/sj.clpt.6100040 PG 6 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 132TR UT WOS:000243965600013 PM 17192768 ER PT J AU Littman, BH Di Mario, L Plebani, M Marincola, FM AF Littman, Bruce H. Di Mario, Linda Plebani, Mario Marincola, Francesco M. TI What's next in translational medicine? SO CLINICAL SCIENCE LA English DT Review DE clinical research; drug target; translational medicine; translational research ID CLINICAL-RESEARCH ENTERPRISE; BIOMEDICAL-RESEARCH; SCIENCE; PROPOSAL; CANCER; CHALLENGES; OBSTACLES; EDUCATION; MELANOMA; DISEASE AB Translational medicine is the integrated application of innovative pharmacology tools, biomarkers, clinical methods, clinical technologies and study designs to improve disease understanding, confidence in human drug targets and increase confidence in drug candidates, understand the therapeutic index in humans, enhance cost-effective decision making in exploratory development and increase phase 11 success. Translational research is one of the most important activities of translational medicine as it supports predictions about probable drug activities across species and is especially important when compounds with unprecedented drug targets are brought to humans for the first time. Translational research has the potential to deliver many practical benefits for patients and justify the extensive investments placed by the private and public sector in biomedical research. Translational research encompasses a complexity of scientific, financial, ethical, regulatory, legislative and practical hurdles that need to be addressed at several levels to make the process efficient. Several have resisted the idea of supporting translational research because of its high costs and the fear that it may re-direct funds from other biomedical disciplines. Resistance also comes from those more familiar with traditional clinical research methods. In this review, we argue that translational research should be seen as enabled by ongoing efforts in basic and clinical research and not competing with them. Translational research provides the knowledge necessary to draw important conclusions from clinical testing regarding disease and the viability of novel drug mechanisms. Advancing translational research requires education and new sources of funding. This could be achieved through public and congressional education by a joint coalition of patients' advocacy groups, academia, drug regulatory agencies and industry. C1 NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bethesda, MD 20892 USA. Pfizer Inc, Pfizer Global Res & Dev, Global Translat Med, New London, CT USA. BioAdvance, Clin Strategies, Philadelphia, PA 19104 USA. Univ Hosp Padova, Dept Lab Med, Padua, Italy. RP Marincola, FM (reprint author), NIH, Immunogenet Sect, Dept Transfus Med, Ctr Clin, Bldg 10, Bethesda, MD 20892 USA. EM FMarincola@cc.nih.gov NR 54 TC 68 Z9 84 U1 0 U2 28 PU PORTLAND PRESS LTD PI LONDON PA THIRD FLOOR, EAGLE HOUSE, 16 PROCTER STREET, LONDON WC1V 6 NX, ENGLAND SN 0143-5221 J9 CLIN SCI JI Clin. Sci. PD FEB PY 2007 VL 112 IS 3-4 BP 217 EP 227 DI 10.1042/CS20060108 PG 11 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 137JG UT WOS:000244288300008 PM 17223795 ER PT J AU Fleg, JL AF Fleg, Jerome L. TI Exercise therapy for elderly heart failure patients SO CLINICS IN GERIATRIC MEDICINE LA English DT Article ID QUALITY-OF-LIFE; VENTRICULAR SYSTOLIC FUNCTION; SKELETAL-MUSCLE ATROPHY; OLDER CORONARY-PATIENTS; CARDIAC REHABILITATION; CONTROLLED-TRIAL; CARDIOVASCULAR PERFORMANCE; MYOCARDIAL-INFARCTION; FUNCTIONAL-CAPACITY; OXYGEN-CONSUMPTION AB Exercise intolerance is one of the hallmark symptoms of heart failure (HF). Exercise training in this condition was not explored as a therapeutic modality until the past two decades. In fact, bed rest was promoted as a treatment for certain forms of HF in the 1970s. Over the past two decades, however, data have shown convincingly that exercise training can be implemented safely in patients who have HF, with significant improvement in functional capacity, various other physiologic variables, and quality of life. This article reviews the accumulated literature in this area, with specific emphasis on the effects of exercise training in older patients who have HF, a subset that may have the most to gain from such training. C1 NHLBI, Div Cardiovasc Dis, Bethesda, MD 20892 USA. RP Fleg, JL (reprint author), NHLBI, Div Cardiovasc Dis, 6701 Rockledge Dr,Room 8126, Bethesda, MD 20892 USA. EM flegj@nhlbi.nih.gov NR 70 TC 3 Z9 3 U1 1 U2 4 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0749-0690 J9 CLIN GERIATR MED JI Clin. Geriatr. Med. PD FEB PY 2007 VL 23 IS 1 BP 221 EP + DI 10.1016/j.cger.2006.08.011 PG 15 WC Geriatrics & Gerontology SC Geriatrics & Gerontology GA 119YG UT WOS:000243049800014 PM 17126764 ER PT J AU Marsh, AA Ambady, N AF Marsh, Abigail A. Ambady, Nalini TI The influence of the fear facial expression on prosocial responding SO COGNITION & EMOTION LA English DT Article ID PSYCHOPATHIC TENDENCIES; EMOTION; CHILDREN; DOMINANCE; RESPONSES; ATTRACTIVENESS; UNIVERSALITY; RECOGNITION; AGGRESSION; MOTIVATION AB Perceiving distress cues appears to be associated with prosocial responding. This being the case, it was hypothesised that the fear facial expression would elicit prosocial responding in perceivers. In Study 1, participants indicated that fear and sadness expressions would be associated with greater sympathy and willingness to help the expresser than would neutral expressions. In Study 2, participants were primed with fear or neutral expressions before reading vignettes featuring protagonists in mild distress. Fear-primed participants reported more sympathy and desire to help the protagonists than neutral-primed participants. Moreover, participants who recognised fear most accurately, as measured by a standard facial expression recognition task, showed the greatest increases in prosocial responding following fear expression primes. This corroborates the notion, supported by research as disparate as behavioural research on bystander intervention and clinical research on psychopaths, that exposure to and correct interpretation of certain distress cues may predict an individual's likelihood of behaving prosocially. C1 NIMH, Mood & Anxiety Disorders Program, Bethesda, MD 20892 USA. Tufts Univ, Medford, MA 02155 USA. RP Marsh, AA (reprint author), NIMH, Mood & Anxiety Disorders Program, 15K North Dr,MSC 2670, Bethesda, MD 20892 USA. EM marsha@mail.nih.gov NR 57 TC 28 Z9 29 U1 2 U2 26 PU PSYCHOLOGY PRESS PI HOVE PA 27 CHURCH RD, HOVE BN3 2FA, EAST SUSSEX, ENGLAND SN 0269-9931 J9 COGNITION EMOTION JI Cogn. Emot. PD FEB PY 2007 VL 21 IS 2 BP 225 EP 247 DI 10.1080/02699930600652234 PG 23 WC Psychology, Experimental SC Psychology GA 141GZ UT WOS:000244568100001 ER PT J AU Thomas, ML Morse, BC O'Malley, J Davis, JA St Claire, MB Cole, MN AF Thomas, Marvin L., III Morse, Brent C. O'Malley, James Davis, Judith A. St Claire, Mark B. Cole, Marlene N. TI Gender influences infectivity in C57BL/6 mice exposed to mouse minute virus SO COMPARATIVE MEDICINE LA English DT Article ID LINKED-IMMUNOSORBENT-ASSAY; PARVOVIRUS INFECTIONS; ORPHAN PARVOVIRUS; STABILITY; AGENTS AB Two natural outbreaks of mouse minute virus (MMV) are described. Observations during management of the naturally infected colonies led to a study in which 4-wk-old C57BL/6NCr and C57BL/6Tac mice were inoculated oronasally with an immunosuppressive variant of MMV (MMVi), as were adult C57BL/6NCr lactating dams or their pups (age, 10 d). By day 28 postinoculation, 100% of the 4-wk-old male C57BL/6NCr and C57BL/6Tac mice, 56.2% of 4-wk-old C57BL/6NCr female and 62.5% of 4-wk-old C57BL/6Tac female mice, 100% of adult lactating C57BL/6NCr dams, and 100% of inoculated pups (10 d) had seroconverted. Serologically positive nursing dams did not infect their nursing pups. In contrast, when nursing pups were inoculated, 100% of their dams seroconverted by 28 d postinoculation. Only 1 of 4 facility sentinels (Tac:SW female mice) seroconverted to MMVi and none of the 4 research sentinels (Tac:SW female mice) seroconverted under a once-weekly bedding transfer program. Consequently, 4 new research Tac:SW sentinels of each gender (n = 8) were placed in known-positive cages at cage-change; 100% of the male mice but 0% of the females seroconverted by day 48. Study results suggest gender influences both infectivity and the ability to detect subclinical infections of MMVi. Other factors that may influence detection of MMV include mouse strain or stock, short shedding period, and prolonged time between cage changes. In light of the data from both the natural infections and the experimental cases, cessation of breeding likely will be beneficial when trying to eradicate this virus. C1 NIH, Bethesda, MD 20892 USA. RP Thomas, ML (reprint author), NIH, Bldg 10, Bethesda, MD 20892 USA. EM mt98h@nih.gov FU Intramural NIH HHS NR 24 TC 5 Z9 5 U1 0 U2 0 PU AMER ASSOC LABORATORY ANIMAL SCIENCE PI MEMPHIS PA 9190 CRESTWYN HILLS DR, MEMPHIS, TN 38125 USA SN 1532-0820 J9 COMPARATIVE MED JI Comparative Med. PD FEB PY 2007 VL 57 IS 1 BP 74 EP 81 PG 8 WC Veterinary Sciences; Zoology SC Veterinary Sciences; Zoology GA 140KZ UT WOS:000244505300009 PM 17348294 ER PT J AU Yu, BB Barrett, MJ Kim, HJ Feuer, EJ AF Yu, Binbing Barrett, Michael J. Kim, Hyune-Ju Feuer, Eric J. TI Estimating joinpoints in continuous time scale for multiple change-point models SO COMPUTATIONAL STATISTICS & DATA ANALYSIS LA English DT Article DE constrained least square; cancer incidence and mortality; joinpoint regression; SEER ID 2-PHASE REGRESSION; CANCER RATES; INFERENCE AB Joinpoint models have been applied to the cancer incidence and mortality data with continuous change points. The current estimation method [Lerman, P.M., 1980. Fitting segmented regression models by grid search. Appl. Statist. 29, 77-84] assumes that the joinpoints only occur at discrete grid points. However, it is more realistic that the joinpoints take any value within the observed data range. Hudson [ 1966. Fitting segmented curves whose join points have to be estimated. J. Amen Statist. Soc. 6 1. 1097-1129] provides an algorithm to find the weighted least square estimates of the joinpoint on the continuous scale. Hudson described the estimation procedure in detail for a model with only one joinpoint, but its extension to a multiple joinpoint model is not straightforward. In this article, we describe in detail Hudson's method for the multiple joinpoint model and discuss issues in the implementation. We compare the computational efficiencies of the LGS method and Hudson's method. The comparisons between the proposed estimation method and several alternative approaches, especially the Bayesian joinpoint models, are discussed. Hudson's method is implemented by C ++ and applied to the colorectal cancer incidence data for men under age 65 from SEE R nine registries. (c) 2006 Elsevier B.V. All rights reserved. C1 Informat Management Serv Inc, Silver Spring, MD 20904 USA. Syracuse Univ, Dept Math, Syracuse, NY 13244 USA. NCI, Stat Res & Applicat Branch, Bethesda, MD 20892 USA. RP Yu, BB (reprint author), Informat Management Serv Inc, 12501 Prosper Dr,Suite 200, Silver Spring, MD 20904 USA. EM yub@imsweb.com NR 15 TC 23 Z9 24 U1 1 U2 11 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-9473 J9 COMPUT STAT DATA AN JI Comput. Stat. Data Anal. PD FEB 1 PY 2007 VL 51 IS 5 BP 2420 EP 2427 DI 10.1016/j.csda.2006.07.044 PG 8 WC Computer Science, Interdisciplinary Applications; Statistics & Probability SC Computer Science; Mathematics GA 130SN UT WOS:000243819400004 ER PT J AU DerSimonian, R Kacker, R AF DerSimonian, Rebecca Kacker, Raghu TI Random-effects model for meta-analysis of clinical trials: An update SO CONTEMPORARY CLINICAL TRIALS LA English DT Article DE clinical trials; meta-analysis; random effects model; restricted maximum likelihood; variance components ID MYOCARDIAL-INFARCTION; VARIANCE AB The random-effects model is often used for meta-analysis of clinical studies. The method explicitly accounts for the heterogeneity of studies through a statistical parameter representing the inter-study variation. We discuss several iterative and non-iterative alternative methods for estimating the inter-study variance and hence the overall population treatment effect. We show that the leading methods for estimating the inter-study variance are special cases of a general method-of-moments estimate of the inter-study variance. The general method suggests two new two-step methods. The iterative estimate is statistically optimal and it can be easily calculated on a spreadsheet program, such as Microsoft Excel, available on the desktop of most researchers. The two-step methods approximate the optimal iterative method better than the earlier one-step non-iterative methods. (c) 2006 Elsevier Inc. All rights reserved. C1 NIAID, Biostat Res Branch, Div Clin Res, Bethesda, MD 20892 USA. Natl Inst Stand & Technol, Div Math & Comp Sci, Gaithersburg, MD 20899 USA. RP DerSimonian, R (reprint author), NIAID, Biostat Res Branch, Div Clin Res, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM DerSimonian@nih.gov NR 18 TC 556 Z9 572 U1 2 U2 25 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1551-7144 J9 CONTEMP CLIN TRIALS JI Contemp. Clin. Trials PD FEB PY 2007 VL 28 IS 2 BP 105 EP 114 DI 10.1016/j.cct.2006.04.004 PG 10 WC Medicine, Research & Experimental; Pharmacology & Pharmacy SC Research & Experimental Medicine; Pharmacology & Pharmacy GA 129GH UT WOS:000243716100001 PM 16807131 ER PT J AU Shimomura, Y Deai, T Fukuda, M Higaki, S Hooper, LC Hayashi, K AF Shimomura, Yoshikazu Deai, Tatsunori Fukuda, Masahiko Higaki, Shiro Hooper, Laura C. Hayashi, Kozaburo TI Corneal buttons obtained from patients with HSK harbor high copy numbers of the HSV genome SO CORNEA LA English DT Article DE herpes simplex virus-1; herpes simplex virus DNA; real-time polymerase chain reaction; herpetic stromal keratitis ID HERPES-SIMPLEX-VIRUS; POLYMERASE-CHAIN-REACTION; STROMAL KERATITIS; DONOR CORNEAS; T-CELLS; DNA; INFECTION; CULTURE; QUANTIFICATION; TRANSMISSION AB Purpose: To detect herpes simplex virus (HSV) genome in the cornea, we sampled the limbal corneas and scleras of the imported eye bank eyes and recipient's corneal buttons and quantitated HSV genome in them by real-time polymerase chain reaction (PCR). Methods: Forty-four recipient corneas including 7 corneas with and 37 corneas without a history of herpetic keratitis, 70 eye bank donor limbal corneas, and 35 eye bank donor scleras were obtained. Primers for real-time PCR were synthesized using the HSV-1 and -2 common regions of the viral DNA polymerase. Primers for conventional PCR were designed to detect HSV-1 and -2 and varicella zoster virus (VZV). Results: Significantly higher copy number of HSV DNA was detected in corneas with a history of herpetic keratitis 85.7% (6/7), with an average of 1.6 X 10(4) copies/mg tissue weight than in corneas without a history of herpetic keratitis 10.8% (4/37), with an average of 8.7 copies/mg tissue weight (P < 0.05, Mann-Whitney U test). HSV DNA was detected in 5.7% (4/70) of the eye bank donor corneas, with an average of 4.9 X 10(2) copies/mg tissue weight, and in 8.6% (3/35) of the donor scleras, with an average of 10.6 copies/mg tissue weight. HSV-2 and VZV-DNA were not detected in these samples. Conclusions: Real-time PCR quantitated HSV genome in the cornea even at a quiescent phase of infection. HSV genome was detected in the corneas and scleras without a past history of herpetic keratitis by this method. C1 Kinki Univ, Sch Med, Dept Ophthalmol, Osaka 5898511, Japan. NEI, Immunol & Virol Sect, Immunol Lab, NIH, Bethesda, MD 20892 USA. RP Shimomura, Y (reprint author), Kinki Univ, Sch Med, Dept Ophthalmol, 377-2 Ohno Higashi, Osaka 5898511, Japan. EM yoshis@med.kindai.ac.jp NR 26 TC 18 Z9 21 U1 0 U2 0 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0277-3740 J9 CORNEA JI Cornea PD FEB PY 2007 VL 26 IS 2 BP 190 EP 193 DI 10.1097/ICO.0b013e31802eaee6 PG 4 WC Ophthalmology SC Ophthalmology GA 131VT UT WOS:000243899800016 PM 17251811 ER PT J AU Machado, RF AF Machado, Roberto F. TI Nitric oxide-based therapies in sickle cell disease: The evidence continues to mount SO CRITICAL CARE MEDICINE LA English DT Editorial Material DE sickle cell disease; acute chest syndrome; vasoocclusive pain crisis; nitric oxide; arginase; sepsis ID ACUTE CHEST SYNDROME; MOUSE C1 NHLBI, Vasc Med Brach, NIH, Bethesda, MD 20892 USA. RP Machado, RF (reprint author), NHLBI, Vasc Med Brach, NIH, Bldg 10, Bethesda, MD 20892 USA. NR 16 TC 2 Z9 2 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0090-3493 J9 CRIT CARE MED JI Crit. Care Med. PD FEB PY 2007 VL 35 IS 2 BP 654 EP 655 DI 10.1097/01.CCM.0000251844.19490.3B PG 2 WC Critical Care Medicine SC General & Internal Medicine GA 129OP UT WOS:000243739100057 PM 17251718 ER PT J AU Laouar, L Fishbein, K McGann, LE Horton, WE Spencer, RG Jomha, NM AF Laouar, Leila Fishbein, Ken McGann, Locksley E. Horton, Walter E. Spencer, Richard G. Jomha, Nadr M. TI Cryopreservation of porcine articular cartilage: MRI and biochemical results after different freezing protocols SO CRYOBIOLOGY LA English DT Article DE articular cartilage; cryopreservation; MRI; dimethyl sulfoxide; biochemical; porcine ID OSTEOCHONDRAL ALLOGRAFT TRANSPLANTATION; MAGNETIC-RESONANCE MICROSCOPY; CULTURE CELLS FROZEN; OSTEOARTICULAR ALLOGRAFTS; FEMORAL CONDYLES; 2-STEP PROCEDURE; TISSUE; FRESH; DIFFUSION; SURVIVAL AB The objective of this study was to investigate the effects of cryopreservation on the components of articular cartilage (AC) matrix by utilizing magnetic resonance imaging (MRI) and biochemical assessments. Porcine AC (10 mm osteochondral dowels) was collected into four groups - (1) phosphate buffered saline (PBS) control, (2) PBS snap frozen in liquid nitrogen, (3) slow-cooled in dimethyl sulfoxide (DMSO), and (4) slow cooled in PBS (in absence of DMSO). MRI results demonstrated three distinct zones in the cartilage. After exposure to ice formation during cryopreservation procedures, alterations in MRI determined matrix fixed charged density and magnetization transfer rate were noted. In addition, biochemical assays demonstrated significant alterations in chondroitin sulfate and hydroxyproline content over time without differences in hydration or DNA content. In conclusion, MRI was able to detect some changes in the intact cartilage matrix structure consistent with biochemical assessments after ice formation during cryopreservation of intact porcine AC. Furthermore, biochemical assessments supported some of these findings and changed significantly after incubating the cartilage matrix for 36-72 h in PBS in terms of chondroitin sulfate and hydroxyproline content. (c) 2006 Elsevier Inc. All rights reserved. C1 NIA, Nucl Magnet Resonance Unit, NIA, Intramural Res Program, Baltimore, MD 21224 USA. Univ Alberta Hosp, Dept Surg, Edmonton, AB T6G 2B7, Canada. Northeastern Ohio Univ Coll Med & Pharm, Dept Anat, Rootstown, OH 44272 USA. RP Spencer, RG (reprint author), NIA, Nucl Magnet Resonance Unit, NIA, Intramural Res Program, GRC 4D-08,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM spencerri@grc.nia.nih.gov; njomha@ualberta.ca OI Fishbein, Kenneth/0000-0002-6353-4603 FU Intramural NIH HHS NR 36 TC 20 Z9 20 U1 0 U2 5 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0011-2240 J9 CRYOBIOLOGY JI Cryobiology PD FEB PY 2007 VL 54 IS 1 BP 36 EP 43 DI 10.1016/j.cryobiol.2006.10.193 PG 8 WC Biology; Physiology SC Life Sciences & Biomedicine - Other Topics; Physiology GA 152DY UT WOS:000245342300005 PM 17174945 ER PT J AU Maudsley, S Martin, B Luttrell, LM AF Maudsley, Stuart Martin, Bronwen Luttrell, Louis M. TI G protein-coupled receptor signaling complexity in neuronal tissue: Implications for novel therapeutics SO CURRENT ALZHEIMER RESEARCH LA English DT Review ID METABOTROPIC GLUTAMATE RECEPTORS; IMMUNODEFICIENCY-VIRUS TYPE-1; BETA(2) ADRENERGIC-RECEPTOR; MU-OPIOID RECEPTOR; MUSCARINIC ACETYLCHOLINE-RECEPTORS; AMYLOID-PRECURSOR PROTEIN; ADENOSINE A(1) RECEPTOR; 3RD INTRACELLULAR LOOP; GENE-RELATED PEPTIDE; ALZHEIMERS-DISEASE AB The manipulation of transmembrane signaling by G protein-coupled receptors (GPCRs) constitutes perhaps the single most important therapeutic target in medicine. Therapeutics acting on GPCRs have traditionally been classified as agonists, partial agonists, or antagonists based on a two state model of receptor function embodied in the ternary complex model. Over the past decade, however, many lines of investigation have shown that GPCR signaling exhibits greater diversity and 'texture' than previously appreciated. Signal diversity arises from numerous factors, among them the ability of receptors to adopt multiple 'active' states with different effector coupling profiles, the formation of receptor dimers that exhibit unique pharmacology, signaling, and trafficking, the dissociation of receptor 'activation' from desensitization and internalization, and the discovery that non-G protein effectors mediate some aspects of GPCR signaling. At the same time, clustering of GPCRs with their downstream effectors in membrane microdomains, and interactions between receptors and a plethora of multidomain scaffolding proteins and accessory/chaperone molecules confers signal preorganization, efficiency, and specificity. More importantly it is likely that alteration in the interactions of these proteins with GPCRs may occur in aging or neurodegenerative disorders, thus defining a distinct 'pharmacology' from that seen in young organisms or normal physiology. In this context, the concept of agonist selective trafficking of receptor signaling, which recognizes that a bound ligand may select between a menu of 'active' receptor conformations and induce only a subset of the possible response profile, presents the opportunity to develop drugs that change the quality as well as the quantity of efficacy and enhance these qualities for specific disorders or other paradigms. As a more comprehensive understanding of the complexity of GPCR signaling is developed, the rational design of ligands possessing increased specific efficacy and attenuated side effects may become the standard mode of drug development. C1 NIA, Lab Neurosci, Intramural Res Program, Gerontol Res Ctr,Johns Hopkins Med Ctr, Baltimore, MD 21224 USA. Med Univ S Carolina, Dept Med, Charleston, SC 29425 USA. Med Univ S Carolina, Dept Biochem & Mol Biol, Charleston, SC 29425 USA. Ralph H Johnson Vet Affairs Med Ctr, Charleston, SC 29401 USA. RP Maudsley, S (reprint author), NIA, Lab Neurosci, Intramural Res Program, Gerontol Res Ctr,Johns Hopkins Med Ctr, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM maudsleyst@grc.nia.nih.gov RI X, Simon/F-4678-2011 NR 186 TC 29 Z9 29 U1 0 U2 5 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2050 J9 CURR ALZHEIMER RES JI Curr. Alzheimer Res. PD FEB PY 2007 VL 4 IS 1 BP 3 EP 19 DI 10.2174/156720507779939850 PG 17 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 149AU UT WOS:000245119800002 PM 17316162 ER PT J AU Driscoll, I Resnick, SM AF Driscoll, Ira Resnick, Susan M. TI Testosterone and cognition in normal aging and Alzheimer's disease: An update SO CURRENT ALZHEIMER RESEARCH LA English DT Review ID MORRIS WATER TASK; CONGENITAL ADRENAL-HYPERPLASIA; RANDOMIZED CONTROLLED-TRIAL; HEALTHY OLDER MEN; MIDDLE-AGED MEN; SPATIAL MEMORY; ELDERLY-MEN; SEX-DIFFERENCES; PLACE NAVIGATION; GROWTH-FACTOR AB There is evidence to suggest that testosterone loss constitutes a risk for cognitive decline and possibly dementia, and that elderly men might benefit from exogcnous supplementation of testosterone. Studies in non-human animals repeatedly report neuroexcitatory and neuroprotective properties of testosterone and enhanced memory performance after acute or chronic treatment. Positive effects of testosterone supplementation in older men have been reported in several, but not all, studies and require replication in larger randomized clinical trials before recommendations for clinical practice can be made. The current review summarizes recent studies on the neurobiological connection between testosterone and cognitive function in humans and non-human animals. When appropriate, we use the hippocampus as a model structure given it's involvement in sexually dymorphic spatial ability and sensitivity to both androgens and aging. In addition, a number of potential explanations of the discrepancy between data obtained in humans and non-human animals are discussed.. C1 NIA, LPC, GRC, Baltimore, MD 21224 USA. RP Driscoll, I (reprint author), NIA, LPC, GRC, 6500 Nathan Shock Dr, Baltimore, MD 21224 USA. EM driscolli@mail.nih.gov NR 142 TC 21 Z9 21 U1 6 U2 10 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1567-2050 J9 CURR ALZHEIMER RES JI Curr. Alzheimer Res. PD FEB PY 2007 VL 4 IS 1 BP 33 EP 45 DI 10.2174/156720507779939878 PG 13 WC Clinical Neurology; Neurosciences SC Neurosciences & Neurology GA 149AU UT WOS:000245119800004 PM 17316164 ER PT J AU Fox, NA Hane, AA Pine, DS AF Fox, Nathan A. Hane, Amie A. Pine, Daniel S. TI Plasticity for affective neurocircuitry - How the environment affects gene expression SO CURRENT DIRECTIONS IN PSYCHOLOGICAL SCIENCE LA English DT Article DE temperament; gene x environment interaction; attention bias to threat; parenting ID GENERALIZED ANXIETY DISORDER; BEHAVIORAL-INHIBITION; ATTENTIONAL BIAS; FACIAL EXPRESSIONS; DEPRESSION; LIFE; POLYMORPHISM; TEMPERAMENT; ADOLESCENTS; STRESS AB We (Fox et al., 2005) recently described a gene-by-environment interaction involving child temperament and maternal social support, finding heightened behavioral inhibition in children homozygous or heterozygous for the serotonin transporter (5HTTLPR) gene short allele whose mothers reported low social support. Here, we propose a model, Plasticity for Affective Neurocircuitry, that describes the manner in which genetic disposition and environmental circumstances may interact. Children with a persistently fearful temperament (and the 5HTTLPR short allele) are more likely to experience caregiving environments in which threat is highlighted. This in turn will exacerbate an attention bias that alters critical affective neurocircuitry to threat and enhances and maintains anxious behavior in the child. C1 Univ Maryland, Dept Human Dev, College Pk, MD 20742 USA. Williams Coll, Williamstown, MA 01267 USA. NIH, Bethesda, MD 20892 USA. RP Fox, NA (reprint author), Univ Maryland, Dept Human Dev, College Pk, MD 20742 USA. EM fox@umd.edu NR 26 TC 54 Z9 56 U1 3 U2 10 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0963-7214 J9 CURR DIR PSYCHOL SCI JI Curr. Dir. Psychol. PD FEB PY 2007 VL 16 IS 1 BP 1 EP 5 DI 10.1111/j.1467-8721.2007.00464.x PG 5 WC Psychology, Multidisciplinary SC Psychology GA 146NQ UT WOS:000244941600001 ER PT J AU Srivastava, S AF Srivastava, Sudhir TI Cancer genetics in the post genomic era SO CURRENT MOLECULAR MEDICINE LA English DT Editorial Material C1 Natl Canc Inst, Canc Biomarkers Res Grp, Div Canc Prevent, Rockville, MD 20852 USA. RP Srivastava, S (reprint author), Natl Canc Inst, Canc Biomarkers Res Grp, Div Canc Prevent, 6130 Execut Blvd,Suite 3142, Rockville, MD 20852 USA. EM srivasts@mail.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 0 PU BENTHAM SCIENCE PUBL LTD PI SHARJAH PA EXECUTIVE STE Y26, PO BOX 7917, SAIF ZONE, 1200 BR SHARJAH, U ARAB EMIRATES SN 1566-5240 J9 CURR MOL MED JI Curr. Mol. Med. PD FEB PY 2007 VL 7 IS 1 BP 1 EP 2 DI 10.2174/156652407779940422 PG 2 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 128QX UT WOS:000243674300001 PM 17311528 ER PT J AU Wahl, SM AF Wahl, Sharon M. TI Transforming growth factor-beta: innately bipolar SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID REGULATORY T-CELLS; TOLL-LIKE RECEPTORS; TGF-BETA; SYNOVIAL INFLAMMATION; AUTOIMMUNE-DISEASE; DENDRITIC CELLS; MAST-CELLS; TGF-BETA-1; MICE; DIFFERENTIATION AB Widely heralded for depressing ongoing immune responses, renewed interest in the proficiency by which transforming growth factor beta (TGF-beta) not only engages but also might drive an over-reactive innate response highlights its bipolar nature. Although coordination of the development and function of Treg, in addition to direct inhibition of cellular activation, are prominent pathways by which TGF-beta controls adaptive immunity, paradoxically TGF-beta appears instrumental in initiation of host responses to invasion through recruitment and activation of immune cells and persuasion of Th17 lineage commitment. Nevertheless, true to its manic-depressive behavior, new evidence links TGF-beta with depression of innate cells, including INK cells, and by way of a potential bridge between mast cells and Treg. Disruption of the tenuous balance between these opposing actions of TGF-beta underlies immunopathogenicity. C1 NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. RP Wahl, SM (reprint author), NIDCR, Oral Infect & Immun Branch, NIH, Bethesda, MD 20892 USA. EM smwahl@dir.nidcr.nih.gov FU Intramural NIH HHS NR 52 TC 103 Z9 111 U1 1 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD FEB PY 2007 VL 19 IS 1 BP 55 EP 62 DI 10.1016/j.coi.2006.11.008 PG 8 WC Immunology SC Immunology GA 132UZ UT WOS:000243969200009 PM 17137775 ER PT J AU Yewdell, JW AF Yewdell, Jonathan W. TI Plumbing the sources of endogenous MHC class I peptide ligands SO CURRENT OPINION IN IMMUNOLOGY LA English DT Review ID ANTIGEN-PROCESSING PATHWAY; NEWLY SYNTHESIZED PROTEINS; DEFECTIVE RIBOSOMAL PRODUCTS; T-CELL EPITOPE; ENDOPLASMIC-RETICULUM; RAPID DEGRADATION; MAMMALIAN-CELLS; CUTTING EDGE; PROTEASOME; CANCER AB From fish to fowl to pharaohs, nearly all cells in jawed vertebrates constitutively process and present peptides derived from endogenously synthesized polypeptides. Such peptides, snug in the binding groove of cell surface MHC class I molecules, enable CD8(+)T cell mediated immunosurveillance of viruses, other intracellular pathogens, and spontaneously arising tumors. The MHC class I system also plays an important role in olfactory-based vertebrate mate selection and perhaps even in preventing direct transmission of tumors between individuals. Recent findings indicate that MHC class I bound peptides are generated at higher efficiency from rapidly degraded polypeptides (including defective ribosomal products) than from old proteins. Intimately linking translation and antigen presentation makes perfect sense for immunosurveillance of acute virus infections, in which speed is of the essence to minimize viral replication, pathogenesis and transmission. The intriguing question of how translation is linked to presentation has prompted the immunoribosome hypothesis of immunosurveillance, which posits that MHC class I peptide ligands are preferentially generated from a subset of translation products. C1 NIAID, Cellular Biol Sect, Viral Dis Lab, Bethesda, MD 20892 USA. RP Yewdell, JW (reprint author), NIAID, Cellular Biol Sect, Viral Dis Lab, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM jyewdell@nih.gov RI yewdell, jyewdell@nih.gov/A-1702-2012 FU Intramural NIH HHS NR 55 TC 48 Z9 48 U1 0 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0952-7915 J9 CURR OPIN IMMUNOL JI Curr. Opin. Immunol. PD FEB PY 2007 VL 19 IS 1 BP 79 EP 86 DI 10.1016/j.coi.2006.11.010 PG 8 WC Immunology SC Immunology GA 132UZ UT WOS:000243969200013 PM 17140786 ER PT J AU Quinn, TC AF Quinn, Thomas C. TI Circumcision and HIV transmission SO CURRENT OPINION IN INFECTIOUS DISEASES LA English DT Review DE AIDS; circumcision; epidemiology; HIV; prevention; transmission ID SEXUALLY-TRANSMITTED INFECTIONS; SUB-SAHARAN AFRICA; TARGET-CELLS; KENYAN MEN; RISK; PREVENTION; ACCEPTABILITY; INTERVENTION; EPIDEMIOLOGY; POPULATION AB Purpose of review To review the recent literature on male circumcision and its effect on HIV acquisition. Recent findings The report from the randomized clinical trial of male circumcision in South Africa demonstrating a 60% protective effect in preventing HIV acquisition provided the first clinical trial evidence of efficacy of male circumcision in protecting men against HIV infection. This protective effect was consistent with both ecological and epidemiologic studies which also show a protective effect of 50-70% in men at high risk for HIV infection. Biological studies also demonstrate an increased number of HIV receptor cells in the mucosa of foreskin providing additional evidence of HIV susceptibility in the uncircumcised male. Male circumcision may also have a beneficial effect in preventing HIV acquisition in women and lowering selected sexually transmitted infections in both sexes. Summary The results of two ongoing randomized clinical trials of male circumcision in Kenya and Uganda are awaited with interest, however male circumcision should be carefully considered as a potential public health tool in preventing HIV acquisition. If other trials confirm the results of the South African trial, implementation of this surgical procedure will need to be carefully scaled up and integrated into other prevention programs with emphasis on surgical training, aseptic techniques, acceptability, availability and cultural considerations. C1 Johns Hopkins Univ, Div Infect Dis, Sch Med, Baltimore, MD 21205 USA. NIAID, Bethesda, MD 20892 USA. RP Quinn, TC (reprint author), Johns Hopkins Univ, Div Infect Dis, Sch Med, 720 Rutland Ave Ross 1159, Baltimore, MD 21205 USA. EM tquinn@jhmi.edu NR 46 TC 25 Z9 26 U1 0 U2 1 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0951-7375 J9 CURR OPIN INFECT DIS JI Curr. Opin. Infect. Dis. PD FEB PY 2007 VL 20 IS 1 BP 33 EP 38 DI 10.1097/QCO.0b013e328012c5bc PG 6 WC Infectious Diseases SC Infectious Diseases GA 130PG UT WOS:000243810900006 PM 17197879 ER PT J AU Han, SH Quon, MJ Koh, KK AF Han, Seung Hwan Quon, Michael J. Koh, Kwang Kon TI Reciprocal relationships between abnormal metabolic parameters and endothelial dysfunction SO CURRENT OPINION IN LIPIDOLOGY LA English DT Review DE endothelial dysfunction; insulin resistance; metabolic syndrome ID RANDOMIZED CONTROLLED-TRIAL; TYPE-2 DIABETES-MELLITUS; INSULIN-RESISTANCE; DEPENDENT VASODILATION; HYPERTENSIVE PATIENTS; NITRIC-OXIDE; THERAPEUTIC INTERVENTIONS; CARDIOVASCULAR EVENTS; SECONDARY PREVENTION; VASCULAR FUNCTION AB Purpose of review Endothelial dysfunction plays a crucial role in the pathogenesis of atherosclerosis and related cardiovascular diseases. Glucotoxicity, lipotoxicity, and inflammation all independently contribute to development of both endothelial dysfunction and insulin resistance. We review pathophysiological mechanisms underlying reciprocal relationships between endothelial dysfunction and insulin resistance and recent insights from therapeutic interventions to improve both metabolic and vascular interventions to improve both metabolic and vascular function. Recent findings Shared causal factors such as glucotoxicity, lipotoxicity, and inflammation interact at multiple levels creating reciprocal relationships between insulin resistance and endothelial dysfunction that help to explain frequent clustering of metabolic and cardiovascular disorders. Metabolic abnormalities implicated in the development of insulin resistance, including hyperglycemia, elevated levels of free fatty acids, accumulation of advanced glycation end products, dyslipidemias, and decreased levels of adiponectin, also contribute importantly to endothelial dysfunction. Diet, exercise, cardiovascular drugs, and insulin sensitizers simultaneously improve endothelium dependent vascular function, reduce inflammation, and improve insulin sensitivity by both distinct and interrelated mechanisms. Summary Pathophysiological mechanisms underlying reciprocal relationships between endothelial dysfunction and insulin resistance contribute to clustering of metabolic and cardiovascular diseases represented by the metabolic syndrome. Therapeutic interventions that target endothelial dysfunction or insulin resistance often simultaneously improve both metabolic and vascular function. C1 Gachon Med Sch, Div Cardiol, Vasc Med & Atherosclerosis Unit, Gil Heart Ctr,Gachon Med Sch, Inchon 405760, South Korea. NCCAM, NIH, Diabet Unit, Bethesda, MD USA. RP Koh, KK (reprint author), Gachon Med Sch, Div Cardiol, Vasc Med & Atherosclerosis Unit, Gil Heart Ctr,Gachon Med Sch, 1198 Kuwol Dong, Inchon 405760, South Korea. EM kwangk@gilhospital.com RI Quon, Michael/B-1970-2008; OI Quon, Michael/0000-0002-9601-9915; Quon , Michael /0000-0002-5289-3707 NR 56 TC 51 Z9 58 U1 0 U2 3 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0957-9672 J9 CURR OPIN LIPIDOL JI Curr. Opin. Lipidology PD FEB PY 2007 VL 18 IS 1 BP 58 EP 65 DI 10.1097/MOL.0b013e328012b627 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Peripheral Vascular Disease SC Biochemistry & Molecular Biology; Endocrinology & Metabolism; Cardiovascular System & Cardiology GA 133DJ UT WOS:000243991500012 PM 17218834 ER PT J AU McClarty, G Caldwell, HD Nelson, DE AF McClarty, Grant Caldwell, Harlan D. Nelson, David E. TI Chlamydial interferon gamma immune evasion influences infection tropism SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID PELVIC-INFLAMMATORY-DISEASE; FIBROBLASTS L-CELLS; TRYPTOPHAN SYNTHASE; BACTERIAL VAGINOSIS; INTRACELLULAR PATHOGENS; LYMPHOCYTE-ACTIVATION; TRACHOMATIS INFECTION; GENOME SEQUENCE; GENITAL-TRACT; P47 GTPASES AB Chlamydia trachomatis is a human pathogen and Chlamydia muridarum is a mouse pathogen but paradoxically, they share near genomic synteny. The majority of strain-variable genes are located primarily in a hyper-variable region termed the plasticity zone. Tryptophan synthase and cytotoxin are plasticity zone genes unique to the human and murine strains, respectively. Tryptophan synthase is a virulence factor that differentiates C. trachomatis strains into genital and ocular disease pathotypes, whereas cytotoxin(s) is a virulence factor linked to murine infection tropism. Divergence in these loci is strongly correlated with host-specific interferon gamma effector activities, suggesting that these virulence genes have co-evolved with their respective hosts as a primary mechanism to evade innate immunity. These findings have important implications for chlamydial animal modeling studies. C1 Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. Univ Manitoba, Dept Med Microbiol, Winnipeg, MB R3E 3R2, Canada. NIAID, Rocky Mt Labs, Intracellular Parasites Lab, Hamilton, MT 59840 USA. RP Nelson, DE (reprint author), Indiana Univ, Dept Biol, Bloomington, IN 47405 USA. EM nelsonde@indiana.edu NR 56 TC 41 Z9 41 U1 0 U2 4 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD FEB PY 2007 VL 10 IS 1 BP 47 EP 51 DI 10.1016/j.mib.2006.12.003 PG 5 WC Microbiology SC Microbiology GA 144QB UT WOS:000244809900008 PM 17208039 ER PT J AU Freeman, AF Holland, SM AF Freeman, Alexandra F. Holland, Steven M. TI Persistent bacterial infections and primary immune disorders SO CURRENT OPINION IN MICROBIOLOGY LA English DT Review ID HELICOBACTER-PYLORI; IFN-GAMMA; MYCOBACTERIAL INFECTION; INTERFERON-GAMMA; IL-12 PRODUCTION; SALMONELLA; TUBERCULOSIS; SUSCEPTIBILITY; MICE; AUTOANTIBODIES AB Mycobacteria, Salmonella and Helicobacter species have all evolved mechanisms to evade host defenses and cause persistent infection in humans. Host control of mycobacteria and Salmonella is largely achieved by the IFN-gamma/IL-12 pathway. Immune disorders affecting this pathway are characterized by disseminated infections with environmental or nontuberculous mycobacteria. Helicobacter is a predominantly extracellular bacterium that uses its remarkable genetic diversity (as well as other mechanisms) in order to evade host defenses. The importance of humoral immunity in containing Helicobacter infections to the mucosal surface is illustrated by the primary immune disorder, X-linked agammaglobulinemia in which patients are prone to chronic bacteremia and skin infections by Helicobacter and related species such as Flexispira and Campylobacter. Exploration of these particular infections in their specific immune defects sheds light on both host and bacterial mechanisms that have implications for pathogenesis and therapy. C1 NIAID, NIH, Bethesda, MD 20892 USA. RP Holland, SM (reprint author), NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA. EM smh@nih.gov FU Intramural NIH HHS NR 37 TC 12 Z9 12 U1 0 U2 2 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 1369-5274 J9 CURR OPIN MICROBIOL JI Curr. Opin. Microbiol. PD FEB PY 2007 VL 10 IS 1 BP 70 EP 75 DI 10.1016/j.mib.2006.11.005 PG 6 WC Microbiology SC Microbiology GA 144QB UT WOS:000244809900012 PM 17208513 ER PT J AU Epstein, JE Giersing, B Mullen, G Moorthy, V Richie, TL AF Epstein, Judith E. Giersing, Birgitte Mullen, Gregory Moorthy, Vasee Richie, Thomas L. TI Malaria vaccines: Are we getting closer? SO CURRENT OPINION IN MOLECULAR THERAPEUTICS LA English DT Review DE attenuated; immunity; malaria; Plasmodium falciparum; subunit; vaccine ID PLASMODIUM-FALCIPARUM MALARIA; MEROZOITE SURFACE PROTEIN-1; APICAL MEMBRANE ANTIGEN-1; GROWTH-INHIBITORY ANTIBODIES; RANDOMIZED CONTROLLED-TRIAL; LIVER-STAGE ANTIGEN-1; T-CELL; PROTECTIVE IMMUNITY; CLINICAL-TRIAL; VIRUS ANKARA AB Forty years ago, researchers first demonstrated that immunization with irradiated sporozoites could protect against malaria infection, providing the impetus for the development of a malaria vaccine. Twenty five years ago, the circumsporozoite protein (CSP), a sporozoite surface antigen that is required to establish infection, became the first Plasmodium falciparum gene to be cloned, and a vaccine based on this antigen appeared imminent. However, today we are still without a highly effective malaria vaccine, despite considerable progress achieved during many years of research and development. This review highlights the most recent test-of-concept studies involving subunit vaccines; to illustrate this field of research, five antigens - CSP, TRAP/SSP2, LSA1, MSP1 and AMA1 - are discussed. These antigens have all entered clinical trials evaluating efficacy against experimental sporozoite challenge ( phase IIa) and/or exposure to natural infection (phase IIb). Challenges facing the development of subunit-based vaccines are discussed, and strategies for improving their efficacy above that observed with the current leading vaccine candidate, RTS, S, are described. In addition, recent progress in the development of whole-organism vaccines is presented. C1 Naval Med Res Ctr, Malaria Program, Silver Spring, MD 20910 USA. PATH Malaria Vaccine Initiat, Bethesda, MD 20814 USA. NIAID, Natl Inst Hlth, Malaria Vaccine Dev Branch, Rockville, MD 20852 USA. Univ Oxford, Churchill Hosp, Malaria Ctr Clin Vaccinol & Trop Med, Oxford OX3 7LJ, England. RP Epstein, JE (reprint author), Naval Med Res Ctr, Malaria Program, 503 Robert Grant Ave, Silver Spring, MD 20910 USA. EM epsteinj@nmrc.navy.mil RI Richie, Thomas/A-8028-2011 NR 95 TC 53 Z9 55 U1 0 U2 7 PU THOMSON REUTERS (SCIENTIFIC) LTD PI LONDON PA 77 HATTON GARDEN, LONDON, EC1N 8JS, ENGLAND SN 1464-8431 J9 CURR OPIN MOL THER JI Curr. Opin. Mol. Ther. PD FEB PY 2007 VL 9 IS 1 BP 12 EP 24 PG 13 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 201ZG UT WOS:000248870600002 PM 17330398 ER PT J AU Ting, CY Lee, CH AF Ting, Chun-Yuan Lee, Chi-Hon TI Visual circuit development in Drosophila SO CURRENT OPINION IN NEUROBIOLOGY LA English DT Article ID PHOTORECEPTOR AXON GUIDANCE; SH2/SH3 ADAPTER PROTEIN; RETINAL AXONS; TARGET SELECTION; SYNAPTIC PARTNERS; KINASE MISSHAPEN; LAYER-SELECTION; LIPRIN-ALPHA; GLIAL-CELLS; OPTIC LOBE AB Fly visual circuits are organized into lattice-like arrays and layers. Recent genetic studies have provided insights into how these reiterated structures are assembled through stepwise processes and how precise connections are established during development. Afferent-derived morphogens, such as Hedgehog, play a key role in organizing the overall structure by inducing and recruiting target neurons and glia. In turn, the target-derived ligand DWnt4 guides Frizzled2-expressing photoreceptor afferents to their proper destination. Photoreceptor afferents select specific synaptic targets by forming adhesive interactions and regulating actin cytoskeleton in growth cones. Target specificity is probably achieved by restricting the expression of adhesive molecules, such as Capricious, to appropriate presynaptic and postsynaptic partners, and by differentially regulating the function of broadly expressed adhesive molecules such as N-cadherin. C1 NICHHD, Unit Neuronal Connectiv, Lab Gene Regualt & Dev, NIH, Bethesda, MD 20817 USA. RP Lee, CH (reprint author), NICHHD, Unit Neuronal Connectiv, Lab Gene Regualt & Dev, NIH, Bethesda, MD 20817 USA. EM leechih@mail.nih.gov RI Lee, Chi-Hon/G-9190-2012; Ting, chun-yuan/F-6448-2013 FU Intramural NIH HHS NR 48 TC 43 Z9 43 U1 0 U2 5 PU CURRENT BIOLOGY LTD PI LONDON PA 84 THEOBALDS RD, LONDON WC1X 8RR, ENGLAND SN 0959-4388 J9 CURR OPIN NEUROBIOL JI Curr. Opin. Neurobiol. PD FEB PY 2007 VL 17 IS 1 BP 65 EP 72 DI 10.1016/j.conb.2006.12.004 PG 8 WC Neurosciences SC Neurosciences & Neurology GA 144BV UT WOS:000244771100010 PM 17204415 ER PT J AU Shaltiel, G Chen, G Manji, HK AF Shaltiel, Galit Chen, Guang Manji, Husseini K. TI Neurotrophic signaling cascades in the pathophysiology and treatment of bipolar disorder SO CURRENT OPINION IN PHARMACOLOGY LA English DT Review ID GLYCOGEN-SYNTHASE KINASE-3-BETA; EMERGING EXPERIMENTAL THERAPEUTICS; MOOD STABILIZERS; CELLULAR PLASTICITY; PROTEIN BCL-2; ANIMAL-MODELS; LITHIUM; NEUROBIOLOGY; DEPRESSION; VALPROATE AB Increasing evidence suggests that bipolar disorder (BPD) is associated with regional brain volumetric reductions, accompanied by cellular atrophy and/or loss. Considerable data suggest that the protypical drugs for BPD - lithium and valproate - when administered in therapeutically relevant paradigms regulate neurotrophic signaling cascades. Notably, brain-derived neurotrophic factor, the extracellular signal-regulated kinase pathway, the glycogen synthase kinase-3-mediated pathway and Bcl-2 are major targets for mood stabilizers. Further data suggest that agents which directly target neurotrophic signaling cascades may have considerable utility for the treatment of this devastating illness. C1 NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Res Program, NIH, Bethesda, MD 20892 USA. RP Manji, HK (reprint author), NIMH, Mol Pathophysiol Lab, Mood & Anxiety Disorders Res Program, NIH, Bethesda, MD 20892 USA. EM manjih@mail.nih.gov RI Chen, Guang/A-2570-2017 FU Intramural NIH HHS NR 33 TC 72 Z9 77 U1 0 U2 3 PU ELSEVIER SCI LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, OXON, ENGLAND SN 1471-4892 J9 CURR OPIN PHARMACOL JI Curr. Opin. Pharmacol. PD FEB PY 2007 VL 7 IS 1 BP 22 EP 26 DI 10.1016/j.coph.2006.07.005 PG 5 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 135QJ UT WOS:000244167800005 PM 17055337 ER PT J AU Spooner, CJ Sebastian, T Shuman, JD Durairaj, S Guo, XR Johnson, PF Schwartz, RC AF Spooner, Chauncey J. Sebastian, Thomas Shuman, Jon D. Durairaj, Srinivasan Guo, Xiangrong Johnson, Peter F. Schwartz, Richard C. TI C/EBP beta serine 64, a phosphoacceptor site, has a critical role in LPS-induced IL-6 and MCP-1 transcription SO CYTOKINE LA English DT Article DE gene regulation; C/EBP beta; IL-6; MCP-1; lipopolysaccharide ID MONOCYTE CHEMOATTRACTANT PROTEIN-1; CCAAT/ENHANCER-BINDING-PROTEINS; NITRIC-OXIDE SYNTHASE; LYMPHOBLASTIC CELL-LINE; ACUTE-PHASE RESPONSE; SMOOTH-MUSCLE-CELLS; FACTOR-KAPPA-B; NUCLEAR-FACTOR; INDUCIBLE EXPRESSION; SIGNAL-TRANSDUCTION AB C/EBPP is a member of the CCAAT/enhancer binding protein family of transcription factors and has been shown to be a critical transcriptional regulator of various proinflammatory genes, including IL-6 and MCP-1. Serine 64 in the transactivation domain of QEHP has recently been identified as a Ras-induced phosphoacceptor site. The integrity of serine 64 along with threonine 189 is important for the Ha-ras (V12)-induced transformation of NIH3T3 cells, however no target genes dependent upon serine 64 for their expression have been reported. In order to evaluate a potential role of serine 64 in C/EBP beta-regulated cytokine expression, we expressed a form of C/EEIP beta with an alanine substitution at serine 64 (C/EBP beta(S64A)) in P388 murine B lymphoblasts, which lack endogenous C/EBP beta expression and are normally unresponsive to LPS for expression of IL-6 and MCP-1. In comparison to wild type C/EBP beta, which robustly supports the LPS-induced expression of IL-6 and MCP-1, C/EBP beta(S64A) was severely impaired in its ability to support the LPS-induced transcription of IL-6 and MCP-1. Furthermore, LPS stimulation increased the level of phosphorylation detected at serine 64. Thus, serine 64, probably through its phospborylation, is a critical determinant of C/EBP beta activity in the transcription of IL-6 and MCP-1. (c) 2007 Elsevier Ltd. All rights reserved. C1 Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA. NCI, Lab Prot Dynam & Signaling, Ft Detrick, MD 21702 USA. Michigan State Univ, Dept Physiol, E Lansing, MI 48824 USA. RP Schwartz, RC (reprint author), Michigan State Univ, Dept Microbiol & Mol Genet, E Lansing, MI 48824 USA. EM schwart9@msu.edu RI Johnson, Peter/A-1940-2012; OI Johnson, Peter/0000-0002-4145-4725; Shuman, Jon/0000-0001-8412-9087 FU Intramural NIH HHS NR 58 TC 8 Z9 8 U1 0 U2 0 PU ACADEMIC PRESS LTD ELSEVIER SCIENCE LTD PI LONDON PA 24-28 OVAL RD, LONDON NW1 7DX, ENGLAND SN 1043-4666 J9 CYTOKINE JI Cytokine PD FEB PY 2007 VL 37 IS 2 BP 119 EP 127 DI 10.1016/j.cyto.2007.03.001 PG 9 WC Biochemistry & Molecular Biology; Cell Biology; Immunology SC Biochemistry & Molecular Biology; Cell Biology; Immunology GA 174FJ UT WOS:000246927000003 PM 17433708 ER PT J AU Perfetto, SP Roederer, M AF Perfetto, Stephen P. Roederer, Mario TI Increased immunofluorescence sensitivity using 532 nm laser excitation SO CYTOMETRY PART A LA English DT Article DE new green laser technology; polychromatic flow cytometry; phycobiliproteins ID FLOWMETRIX(TM) SYSTEM; PHYCOBILISOMES AB Objective: We evaluated the use of a high power, diode pulsed solid-state laser emitting 532 run light for immunofluorescence applications. We compared the sensitivity and utility of this laser with the standard 488 run excitation. Methods: A flow cytometer was equipped With both a 488 rim and a 532 nm laser; fluorescence emissions from each laser were collected using the Same filters and the same detector system. Cells or compensation beads (e.g. latex beads coated with anti-kappa antibodies) were stained with monoclonal antibodies conjugated to phycoerythrin (PE) as well as the PE tandem dyes TRPE, Cy5PE, Cy5.5PE, and Cy7PE. The sensitivity of detection of these reagents as well as those in heavily compensated channels was quantified by measuring the spreading error for a primary detector into a secondary detector. Results: Measurement of the fluorescence emission of PE and PE-tandem dyes was considerably more sensitive when using 532 nut excitation (150 mW) as compared with 488 nm excitation (20 mW). In addition, as the absolute number of photoelectrons collected was greater, there was less measurement-error-induced spread into the compensated channels. As in example, when comparing the spreading error of PE labeled cells into the TRPE detector, the green laser was found to be 15-fold more sensitive as compared with the blue laser. In addition, the blue laser produced more autofluoresent signal from cells as compared with the green laser. Together, these advantages of the 532 nm excitation line provides for a significantly improved detection of immunofluorescence staining. Published 2007 Wiley-Liss, Inc. C1 NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Perfetto, SP (reprint author), NIAID, Vaccine Res Ctr, NIH, 40 Convent Dr,Room 5509, Bethesda, MD 20892 USA. EM sperfetto@nih.gov NR 11 TC 20 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 1552-4922 J9 CYTOM PART A JI Cytom. Part A PD FEB PY 2007 VL 71A IS 2 BP 73 EP 79 DI 10.1002/cyto.a.20358 PG 7 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 132RK UT WOS:000243959700002 PM 17200955 ER PT J AU Liu, J Roederer, M AF Liu, Jie Roederer, Mario TI Differential susceptibility of leukocyte subsets to cytotoxic T cell killing: Implications for HIV immunopathogenesis SO CYTOMETRY PART A LA English DT Article DE cytotoxic T cells; CCR5; HIV; leukocytes ID CYTOMEGALOVIRUS LATENT INFECTION; FLOW CYTOMETRIC ASSAY; DENDRITIC CELLS; MEDIATED CYTOTOXICITY; IN-VIVO; CYTOLYTIC ACTIVITY; SIV INFECTION; MEMORY; ANTIGEN; CD4(+) AB Background: Cytotoxic T lymphocytes (CTL) are crucial for the host defense against viral infection. In many cases, this anti-viral immune response contributes to host pathogenesis, through inflammation and tissue destruction. Few studies have explored the relative susceptibility of infected cells to CTL killing, and the range of cell types that may be effectively killed by CTLs in vivo, both of which are key to understanding both immune control of infection and immune-related pathogenesis. Methods: We developed and optimized a highly sensitive method to quantify the relative susceptibility of leukocyte subsets to CTL-mediated killing. Maximal sensitivity was achieved by uniquely measuring cell death occurring during the assay culture. Results: We found that leukocyte subsets have a wide range of susceptibility to antigen-specific CTL-mediated lysis. Generally, T cells were more susceptible than B or NK cells, with CD4 T cells being more susceptible than CD8 T cells. In all lymphocyte lineages, susceptibility was greater for more differentiated subsets compared with their naive counterparts; however, for dendritic cells, immature cells are more susceptible than mature cells. We focused on the susceptibility of T cell subsets, and found that naive cells are far more resistant than memory cells, and in particular, CCR5+ or HLA-DR+ memory cells are highly susceptible to CTL-mediated killing. Conclusions: These results provide an explanation for the observation that certain subsets of CD4 T cells are ablated during chronic HIV infection, and indicate which Subsets are most likely to contain the persistent viral reservoir. Published 2007 Wiley-Liss, Inc. C1 NIAID, Immunotechnol Sect, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. RP Roederer, M (reprint author), 40 Convent Dr,Room 5509, Bethesda, MD 20895 USA. EM roederer@nih.gov NR 53 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 1552-4922 J9 CYTOM PART A JI Cytom. Part A PD FEB PY 2007 VL 71A IS 2 BP 94 EP 104 DI 10.1002/cyto.a.20363 PG 11 WC Biochemical Research Methods; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 132RK UT WOS:000243959700005 PM 17200952 ER PT J AU Komatsu, Y Scott, G Nagy, A Kaartinen, V Mishina, Y AF Komatsu, Yoshihiro Scott, Gregory Nagy, Andre Kaartinen, Vesa Mishina, Yuji TI BMP type I receptor ALK2 is essential for proper patterning at late gastrulation during mouse embryogenesis SO DEVELOPMENTAL DYNAMICS LA English DT Article DE Alk2; bone morphogenetic protein; gastrulation; mouse ID GROWTH-FACTOR-BETA; NEURAL CREST CELLS; TGF-BETA; MESODERM FORMATION; ACTIVIN RECEPTOR; MULTIPLE ROLES; SMAD PROTEINS; EXPRESSION; EMBRYO; GENE AB Bone morphogenetic proteins (BMPs) have multiple functions during vertebrate development. Previously, it was shown that BMP type I receptor ALK2 (also known as ACVR1, ActR1, or ActRIA) was important for normal mouse gastrulation by deleting exon 4 or exon 5 of AM. Recently, flanking exon 7 by loxP sites generated a conditional allele for Alk2. To assess whether the deletion of exon 7 causes functional null of ALK2, and does not produce a dominant negative form or a partially functional form of ALK2, we performed a comparative analysis between Alk2 homozygous mutant embryos with an exon 5 deletion (Alk2 (Delta 5/Delta 5)) and embryos with an exon 7 deletion (Alk2 (Delta 7/Delta 7)). Both Alk2(Delta 5/Delta 5) and Alk2(Delta 7/Delta 7) mutants showed identical morphological gastrulation defects. Histological examinations and molecular marker analyses revealed identical abnormal gastrulation phenotypes in Alk2(Delta 5/Delta 5) and Alk2(Delta 7/Delta 7) mutants. Although FgfS was expressed in the primitive streak of Alk2(Delta 5/Delta 5) and Alk2 (Delta 7/Delta 7) mutants, Brachyury, Wnt3a, and Tbx6 were dramatically downregulated in Alk2 (Delta 5/Delta 5) and Alk2(Delta 7/Delta 7) mutants. These results indicate that deletion of exon 7 for Alk2 leads to a functionally null mutation in vivo, and Alk2 is crucial for sustaining the proper gastrulation events in early mouse embryogenesis. Developmental Dynamics 236.512-517, 2007. Published 2006 Wiley-Liss, Inc. C1 NIEHS, Mol Dev Biol Grp, Reprod & Dev Toxicol Lab, NIH, Res Triangle Pk, NC 27709 USA. Childrens Hosp Los Angeles, Res Inst, Dept Pathol, Dev Biol Program, Los Angeles, CA 90027 USA. Univ So Calif, Keck Sch Med, Los Angeles, CA USA. RP Mishina, Y (reprint author), NIEHS, Mol Dev Biol Grp, Reprod & Dev Toxicol Lab, NIH, Knock Out Core, Res Triangle Pk, NC 27709 USA. EM mishina@niehs.nih.gov OI Kaartinen, Vesa/0000-0002-9432-510X FU NHLBI NIH HHS [R01 HL074862, HL074862]; NIDCR NIH HHS [R01 DE013085, DE013085] NR 37 TC 16 Z9 17 U1 0 U2 3 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1058-8388 J9 DEV DYNAM JI Dev. Dyn. PD FEB PY 2007 VL 236 IS 2 BP 512 EP 517 DI 10.1002/dvdy.21021 PG 6 WC Anatomy & Morphology; Developmental Biology SC Anatomy & Morphology; Developmental Biology GA 132SG UT WOS:000243961900017 PM 17117439 ER PT J AU Hirtz, D AF Hirtz, Deborah TI Classification of cerebral palsy: collaborative study perspective SO DEVELOPMENTAL MEDICINE AND CHILD NEUROLOGY LA English DT Article; Proceedings Paper CT Workshop on Definition and Classification of Cerebral Palsy CY 2004 CL Bethesda, MD ID GROSS MOTOR FUNCTION; CHILDREN C1 NINDS, NIH, Rockville, MD 20852 USA. RP Hirtz, D (reprint author), NINDS, NIH, Rockville, MD 20852 USA. NR 4 TC 1 Z9 1 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0012-1622 J9 DEV MED CHILD NEUROL JI Dev. Med. Child Neurol. PD FEB PY 2007 VL 49 SU 109 BP 23 EP 23 PG 1 WC Clinical Neurology; Pediatrics SC Neurosciences & Neurology; Pediatrics GA 135KP UT WOS:000244152800010 ER PT J AU Florez, JC Jablonski, KA Kahn, SE Franks, PW Dabelea, D Hamman, RF Knowler, WC Nathan, DM Altshuler, D AF Florez, Jose C. Jablonski, Kathleen A. Kahn, Steven E. Franks, Paul W. Dabelea, Dana Hamman, Richard F. Knowler, William C. Nathan, David M. Altshuler, David CA Diabetes Prevention Program Res Gr TI Type 2 diabetes-associated missense polymorphisms KCNJ11 E23K and ABCC8 A1369S influence progression to diabetes and response to interventions in the diabetes prevention program SO DIABETES LA English DT Article ID IMPAIRED GLUCOSE-TOLERANCE; LIFE-STYLE INTERVENTION; CHANNEL SUBUNIT KIR6.2; SENSITIVE K+ CHANNELS; INSULIN-RESISTANCE; INCREASED RISK; SUR1 ABCC8; GENE; VARIANTS; METFORMIN AB The common polymorphisms KCNJ11 E23K and ABCC A1369S have been consistently associated with type diabetes. We examined whether these variants are also associated with progression from impaired glucose tolerance (IGT) to diabetes and responses to preventive interventions in the Diabetes Prevention Program. We genotyped both variants in 3,534 participants and performed Cox regression analysis using genotype, intervention, and their interactions as predictors of diabetes incidence over similar to 3 years. We also assessed the effect of genotype on insulin secretion and insulin sensitivity at I year. As previously shown in other studies, lysine carriers at KCNJ11 E23K had reduced insulin secretion at baseline; however, they were less likely to develop diabetes than E/E homozygotes. Lysine carriers were less protected by 1-year metformin treatment than E/E homozygotes (P < 0.02). Results for ABCC8 A1369S were essentially identical to those for KCNJ11 E23K. We conclude that the lysine variant in KCNJ11 E23K leads to diminished insulin secretion in individuals with IGT. Given our contrasting results compared with case-control analyses, we hypothesize that its effect on diabetes risk may occur before the IGT-todiabetes transition. We further hypothesize that the diabetes-preventive effect of metformin may interact with the impact of these variants on insulin regulation. C1 George Washington Univ, Ctr Biostat, Diabet Prevent Program, Coordinat Ctr, Rockville, MD 20852 USA. Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA. Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Harvard Univ, Sch Med, Dept Med, Boston, MA USA. Broad Inst Harvard, Program Med & Populat Genet, Cambridge, MA USA. MIT, Cambridge, MA 02139 USA. VA Puget Sound Hlth Care Syst, Dept Med, Div Metab Endocrinol & Nutr, Seattle, WA USA. Univ Washington, Seattle, WA 98195 USA. Univ Umea Hosp, Inst Publ Hlth & Clin Med, Genet Epidemiol & Clin Res Grp, S-90185 Umea, Sweden. NIDDK, Diabet Epidemiol & Clin Res Sect, Phoenix, AZ USA. Univ Colorado, Dept Prevent Med & Biostat, Denver, CO 80202 USA. Hlth Sci Ctr, Denver, CO USA. Harvard Univ, Sch Med, Dept Genet, Boston, MA 02115 USA. RP Florez, JC (reprint author), George Washington Univ, Ctr Biostat, Diabet Prevent Program, Coordinat Ctr, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. EM dppmail@biostat.bsc.gwu.edu RI Altshuler, David/A-4476-2009; OI Altshuler, David/0000-0002-7250-4107; Franks, Paul/0000-0002-0520-7604; Kahn, Steven/0000-0001-7307-9002 FU Intramural NIH HHS; NIDDK NIH HHS [U01 DK048489-06, K23 DK065978, 1K23 DK 65978-03, U01 DK048489] NR 30 TC 70 Z9 74 U1 1 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2007 VL 56 IS 2 BP 531 EP 536 DI 10.2337/db06-0966 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 133CQ UT WOS:000243989600033 PM 17259403 ER PT J AU Kovac, IP Havlik, RJ Foley, D Peila, R Hernandez, D Wavrant-De Vrieze, F Singleton, A Egan, J Taub, D Rodriguez, B Masaki, K Curb, JD Fujimoto, WY Wilson, AF AF Kovac, Ilija P. Havlik, Richard J. Foley, Daniel Peila, Rita Hernandez, Dena Wavrant-De Vrieze, Fabienne Singleton, Andrew Egan, Josephine Taub, Dennis Rodriguez, Beatriz Masaki, Kamal Curb, J. David Fujimoto, Wilfred Y. Wilson, Alexander F. TI Linkage and association analyses of type 2 diabetes/impaired glucose metabolism and adiponectin serum levels in Japanese Americans from Hawaii SO DIABETES LA English DT Article ID ADIPOSE-SPECIFIC PROTEIN; SUSCEPTIBILITY LOCI; DIABETES-MELLITUS; MAPPING GENES; OBESITY; SCAN; POPULATION; PEDIGREES; SEARCH; MEN AB Type 2 diabetes is a common disorder associated with obesity. Lower plasma levels of adiponectin were associated with type 2 diabetes. Candidate regions on chromosomes 1 (similar to 70 cM) and 14 (similar to 30 cM) were evaluated for replication of suggestive linkage results for type 2 diabetes/impaired glucose homeostasis in an independent sample of Japanese Americans. Replication of independent linkage evidence for serum levels of adiponectin on chromosome 14 was also evaluated. We investigated. 529 subjects from 175 sibships who were originally part of the Honolulu Heart Program. Analyses included nonparametric linkage and association using SAGE (Statistical Analysis for Genetic Epidemiology) and FBAT (family-based test of association) programs and Monte Carlo simulation of Fisher's exact test in SAS. For type 2 diabetes/impaired glucose metabolism, nominal linkage evidence (P < 0.02) followed-up by genotypic association (P = 0.016) was found with marker D14S297 at 31.8 cM; linkage analyses using only diabetes phenotype were also nominally significant at this marker (P < 0.02). Nominal evidence for genotypic association to adiponectin serum level phenotype (P = 0.04) was found with the marker D14S1032 at 23.2 cM. The present study was limited by relatively small sample size. Nevertheless, these results corroborate earlier studies suggesting that further research is warranted in the candidate region similar to 30 cM on chromosome 14. C1 NHGRI, Genometr Sect, NIH, Baltimore, MD USA. NIA, Lab Epidemiol Demog & Biometry, Bethesda, MD 20892 USA. NIA, Mol Genet Unit, Bethesda, MD 20892 USA. NIA, Clin Invest Lab, Baltimore, MD 21224 USA. NIA, Immunol Lab, Baltimore, MD USA. Univ Hawaii, John A Burns Sch Med, Dept Geriatr Med, Honolulu, HI 96822 USA. Pacific Hlth Res Inst, Honolulu, HI USA. Univ Washington, Div Metab Endocrinol & Nutr, Dept Med, Seattle, WA 98195 USA. RP Kovac, IP (reprint author), McGill Univ, Alan Mem Inst, Dept Psychiat, R&T Bldg,1033 Pine Ave, Montreal, PQ H3A 1A1, Canada. EM ilija.kovac@mail.mcgill.ca RI Singleton, Andrew/C-3010-2009; Wilson, Alexander/C-2320-2009 FU Intramural NIH HHS [Z01 AG000758-10]; NCRR NIH HHS [P41 RR003655, RR 03655]; NHLBI NIH HHS [N01 HC 05102, N01 HC005102]; NIA NIH HHS [N01 AG 42149] NR 20 TC 9 Z9 9 U1 0 U2 0 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0012-1797 J9 DIABETES JI Diabetes PD FEB PY 2007 VL 56 IS 2 BP 537 EP 540 DI 10.2337/db06-0443 PG 4 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 133CQ UT WOS:000243989600034 PM 17259404 ER PT J AU Shultis, WA Weil, EJ Looker, HC Curtis, JM Shlossman, M Genco, RJ Knowler, WC Nelson, RG AF Shultis, Wendy A. Weil, E. Jennifer Looker, Helen C. Curtis, Jeffrey M. Shlossman, Marc Genco, Robert J. Knowler, William C. Nelson, Robert G. TI Effect of periodontitis on overt nephropathy and end-stage renal disease in type 2 diabetes SO DIABETES CARE LA English DT Article ID CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; PIMA-INDIANS; ATHEROSCLEROSIS RISK; TOOTH LOSS; MELLITUS; COMMUNITIES; PREVALENCE; SMOKING; MARKERS AB OBJECTIVE - The purpose of this study was to investigate the effect of periodontitis on development of overt nephropathy, defined as macroalbuminuria, and end-stage renal disease (ESRD) in type 2 diabetes. RESEARCH DESIGN AND METHODS - individuals residing in the Gila River Indian Community aged >= 25 years with type 2 diabetes, one or more periodontal examination, estimated glomerular filtration rate >= 60 ml/min per 1.73 m(2), and no macroalbuminuria (urinary albumin-to-creatinine ratio >= 300 mg/g) were identified. Periodontitis was classified as none/mild, moderate, severe, or edentulous using number of teeth and alveolar bone score. Subjects were followed to development of macroalbuminuria or ESRD, defined as onset of renal replacement therapy or death attributed to diabetic nephropathy. RESULTS - Of the 529 individuals, 107 (20%) had none/mild periodontitis, 200 (38%) had moderate periodontitis, 117 (22%) had severe periodontitis, and 105 (20%) were edentulous at baseline. During follow-up of up to 22 years, 193 individuals developed macroalbuminuria and 68 developed ESRD. Age- and sex-adjusted incidence of macroalbuminuria and ESRD increased with severity of periodontitis. After adjustment for age, sex, diabetes duration, BMI, and smoking in a proportional hazards model, the incidences of macroalbuminuria were 2.0, 2.1, and 2.6 Limes as high in individuals With moderate or severe periodontitis or those Who were edentulous, respectively, compared with those with none/mild periodontitis (P = 0.01). Incidences of ESRD in individuals with moderate or severe periodontitis or in those who were edentulous were 2.3, 3.5, and 4.9 times as high, respectively, compared with those with none/mild periodontitis (P 0.02). CONCLUSIONS - Periodontitis predicts development of overt nephropathy and ESRD in individuals with type 2 diabetes. Whether treatment of periodontitis will reduce the risk of diabetic kidney disease remains to be determined. C1 Natl Inst Hlth, Diabet Epidemiol & Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIDDKD, Phoenix, AZ 85014 USA. SUNY Buffalo, Dept Oral Biol, Buffalo, NY 14260 USA. Arizona Sch Dent & Oral Hlth, Mesa, AZ USA. RP Shultis, WA (reprint author), Natl Inst Hlth, Diabet Epidemiol & Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIDDKD, 1550 E Indian Sch Rd, Phoenix, AZ 85014 USA. EM shultisw@mail.nih.gov RI Nelson, Robert/B-1470-2012 FU Intramural NIH HHS; NIDCR NIH HHS [DE 06514] NR 37 TC 106 Z9 112 U1 1 U2 4 PU AMER DIABETES ASSOC PI ALEXANDRIA PA 1701 N BEAUREGARD ST, ALEXANDRIA, VA 22311-1717 USA SN 0149-5992 J9 DIABETES CARE JI Diabetes Care PD FEB PY 2007 VL 30 IS 2 BP 306 EP 311 DI 10.2337/dc06-1184 PG 6 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 133PF UT WOS:000244024100018 PM 17259499 ER PT J AU Nathan, DM Chew, E Christophi, CA Davis, MD Fowler, S Goldstein, BJ Hamman, RF Hubbard, LD Knowler, WC Molitch, ME AF Nathan, D. M. Chew, E. Christophi, C. A. Davis, M. D. Fowler, S. Goldstein, B. J. Hamman, R. F. Hubbard, L. D. Knowler, W. C. Molitch, M. E. CA Diabetes Prevention Program R TI The prevalence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program SO DIABETIC MEDICINE LA English DT Article DE impaired glucose tolerance; retinopathy; Type 2 diabetes ID RETINAL MICROVASCULAR ABNORMALITIES; DIAGNOSIS; RISK; COMPLICATIONS; MELLITUS; TRIAL; NIDDM AB Aims Retinopathy is considered the complication most closely associated with and characteristic of diabetes mellitus. Hyperglycaemia below levels diagnostic of diabetes, so called pre-diabetes, is associated with a low prevalence of 'diabetic' retinopathy. However, few longitudinal studies of non-diabetic populations have performed repeated measures of glycaemia and screened for retinopathy to determine its occurrence in the non-diabetic population and the onset of retinopathy in new-onset diabetic patients. We determined the prevalence of retinopathy characteristically seen in diabetes in persons with impaired glucose tolerance and in patients with new-onset diabetes of known duration in the Diabetes Prevention Program (DPP) cohort. Methods The DPP recruited persons with elevated fasting glucose (5.3-6.9 mmol/l) and impaired glucose tolerance, and no history of diagnosed diabetes, other than gestational diabetes not persisting after pregnancy. Seven-field, stereoscopic fundus photography was completed a mean of 3.1 years after the development of diabetes in 594 of 878 participants who had developed diabetes during the DPP, and in a random sample of 302 participants who remained non-diabetic. Results Retinopathy consistent with diabetic retinopathy was detected in 12.6 and 7.9% of the diabetic and non-diabetic participants, respectively (P = 0.03, comparing prevalence in the two groups). Systolic blood pressure and HbA(1c) were higher at baseline in the diabetic participants who had retinopathy compared with the diabetic participants without retinopathy. Conclusions Retinopathy characteristic of diabetes is present in persons with elevated fasting glucose and impaired glucose tolerance and no known history of diabetes. The prevalence of retinopathy is significantly higher in persons who develop diabetes, even within 3 years of diagnosis. C1 George Washington Univ, Ctr Biostat, Diabet Prevent Program Res Grp, Rockville, MD 20852 USA. Massachusetts Gen Hosp, Boston, MA 02114 USA. NEI, Bethesda, MD 20892 USA. Univ Wisconsin, Madison, WI USA. Thomas Jefferson Univ, Jefferson Med Coll, Philadelphia, PA 19107 USA. Univ Colorado, Hlth Sci Ctr, Denver, CO USA. NIDDKD, Phoenix, AZ 85016 USA. Northwestern Univ, Feinberg Sch Med, Chicago, IL 60611 USA. RP Nathan, DM (reprint author), George Washington Univ, Ctr Biostat, Diabet Prevent Program Res Grp, 6110 Execut Blvd,Suite 750, Rockville, MD 20852 USA. EM dppmail@biostat.bsc.gwu.edu NR 24 TC 138 Z9 139 U1 0 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0742-3071 J9 DIABETIC MED JI Diabetic Med. PD FEB PY 2007 VL 24 IS 2 BP 137 EP 144 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 130HO UT WOS:000243790900006 ER PT J AU Nikolova, T Wu, M Brumbarov, K Alt, R Opitz, H Boheler, KR Cross, M Wobus, AM AF Nikolova, Teodora Wu, Minyao Brumbarov, Krassimir Alt, Ruediger Opitz, Heike Boheler, Kenneth R. Cross, Michael Wobus, Anna M. TI WNT-conditioned media differentially affect the proliferation and differentiation of cord blood-derived CD133(+) cells in vitro SO DIFFERENTIATION LA English DT Article DE CD133 cells; umbilical cord blood; mouse embryonic fibroblast feeder cells; WNT; nestin; CD31; von Willebrand factor; conditioned medium ID ENDOTHELIAL PROGENITOR CELLS; HEMATOPOIETIC STEM-CELLS; EX-VIVO EXPANSION; POSITIVE CELLS; MUSCLE-CELLS; EXPRESSION; BIOLOGY; MURINE; GENE; IDENTIFICATION AB Cord blood-derived CD133(+) cells have a degree of non-hematopoietic potential and express transcripts of pluripotency markers including Oct-4, Sox-2, Rex-1, and leukemia inhibitory factor (LIF) receptor, as well as markers of progenitor cells, such as HoxB4, brachyury, and nestin. Having shown by transcriptome analysis that the mouse embryonic fibroblast (MEF) cells routinely used to maintain pluripotent embryonic stem cells express transcripts of the WNT/BMP families of signaling factors, we have assessed the effects on proliferation and differentiation of CD133(+) cells of medium conditioned (CM) by MEF, by NIH3T3, and by NIH3T3 cells stably expressing WNT1, WNT3a, WNT4, WNT5a, and WNT11. Cultivation of CD133(+) cells in MEF-CM led to a significant increase in cell number after 7 days of culture, while WNT-1, WNT3a-, and WNT11-CM increased the cell number significantly by 14 days of culture. During this period, WNT3a-CM increased the proportion of nestin-expressing cells and increased the ratio of blast-like cells to macrophages, suggesting that these signaling molecules contribute to the maintenance of an undifferentiated, blast-like phenotype. The number of cells expressing the endothelial-related marker CD31(+) was significantly increased following culture in WNT5a- and WNT11-CM, whereas the number of cells positive for von Willebrand (vW) factor was maintained during 14 days of culture only in the presence of WNT4-CM. In addition, WNT5a-CM led to increased beta-catenin mRNA levels and the presence of beta-catenin protein in the cytoplasm and nucleus, consistent with the activation of the WNT signaling pathway. We conclude that in vitro conditioning of CD133(+) cells by media containing specific WNT signaling factors influences the non-hematopoietic potential of CD133(+) cells and dynamically alters the expression of the neural stem/progenitor cell marker nestin and the endothelial-related cell surface markers CD31 and vW factor. C1 Leibniz Inst Plant Genet, Differentiat Grp, IPK, Gatersleben, Germany. Univ Leipzig, Dept Hematol, IZKF, D-7010 Leipzig, Germany. NIA, Cardiovasc Sci Lab, NIH, Baltimore, MD 21224 USA. RP Wobus, AM (reprint author), Leibniz Inst Plant Genet, Differentiat Grp, IPK, Gatersleben, Germany. EM wobusam@ipk-gatersleben.de FU Intramural NIH HHS NR 45 TC 33 Z9 37 U1 0 U2 19 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0301-4681 J9 DIFFERENTIATION JI Differentiation PD FEB PY 2007 VL 75 IS 2 BP 100 EP 111 DI 10.1111/j.1432-0436.2006.00119.x PG 12 WC Cell Biology; Developmental Biology SC Cell Biology; Developmental Biology GA 136MI UT WOS:000244227500002 PM 17316380 ER PT J AU Hanaoka, R Dawid, IB Kawahara, A AF Hanaoka, Ryuki Dawid, Igor B. Kawahara, Atsuo TI Cloning and expression of zebrafish genes encoding the heme synthesis enzymes uroporphyrinogen III synthase (UROS) and protoporphyrinogen oxidase (PPO) SO DNA SEQUENCE LA English DT Article DE heme synthesis; UROS; PPO; zebrafish ID CONGENITAL ERYTHROPOIETIC PORPHYRIA; FULL-LENGTH CDNA; VARIEGATE PORPHYRIA; NUCLEOTIDE-SEQUENCE; MOLECULAR-CLONING; MUTATIONS; MODEL; IDENTIFICATION; DISEASE; ORGANIZATION AB Heme is synthesized from glycine and succinyl CoA by eight heme synthesis enzymes. Although genetic defects in any of these enzymes are known to cause severe human blood diseases, their developmental expression in mammals is unknown. In this paper, we report two zebrafish heme synthesis enzymes, uroporphyrinogen III synthase (UROS) and protoporphyrinogen oxidase (PPO) that are well conserved in comparison to their human counterparts. Both UROS and PPO formed pairs of bilateral stripes in the lateral plate mesoderm at the 15-somite stage. At 24 h post-fertilization (hpf), UROS and PPO were predominantly expressed in the intermediate cell mass (ICM) that is the major site of primitive hematopoiesis. The expression of UROS and PPO was drastically suppressed in the bloodless mutants cloche and vlad tepes/gata 1 from 15-somite to 24 hpf stages, indicating that both cloche and vlad tepes/gata 1 are required for the induction and maintenance of UROS and PPO expression in the ICM. C1 Kyoto Univ, Lab Dev Mol Genet, Horizontal Med Res Org, Grad Sch Med,Sakyo Ku, Kyoto 6068501, Japan. NICHHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. RP Kawahara, A (reprint author), Kyoto Univ, Lab Dev Mol Genet, Horizontal Med Res Org, Grad Sch Med,Sakyo Ku, Yoshida Konoe Cho, Kyoto 6068501, Japan. EM atsuo@hmro.med.kyoto-u.ac.jp NR 30 TC 1 Z9 1 U1 0 U2 2 PU INFORMA HEALTHCARE-TAYLOR & FRANCIS PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON, OXFORSHIRE OX14 4RN, ENGLAND SN 1042-5179 J9 DNA SEQUENCE JI DNA Seq. PD FEB PY 2007 VL 18 IS 1 BP 54 EP 60 DI 10.1080/10425170601060848 PG 7 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 138HW UT WOS:000244354700008 PM 17364814 ER PT J AU Elsasser, TH Capuco, AV Caperna, TJ Martinez, A Cuttitta, F Kahl, S AF Elsasser, Ted H. Capuco, Anthony V. Caperna, Thomas J. Martinez, Alfredo Cuttitta, Frank Kahl, Stanislaw TI Adrenomedullin (AM) and adrenomedullin binding protein (AM-BP) in the bovine mammary gland and milk: Effects of stage of lactation and experimental intramammary E. coli infection SO DOMESTIC ANIMAL ENDOCRINOLOGY LA English DT Article DE adrenomedullin; adrenomedullin binding protein; mammary gland; inflammation; lactation ID NECROSIS-FACTOR-ALPHA; NITRIC-OXIDE PRODUCTION; COMPLEMENT FACTOR-H; DAIRY-COWS; HYPOTENSIVE PEPTIDE; INSULIN-SECRETION; INDUCED MASTITIS; DISEASE STRESS; GROWTH-HORMONE; EXPRESSION AB Adrenomedullin (AM) has been characterized as an endogenous tissue survival factor and modulator of many inflammatory processes. Because of the increased susceptibility of the mammary gland to infection during the time surrounding parturition in the cow, we investigated how milk and tissue content of AM and its binding protein (AM-BP) might be affected by the stage of lactation and the udder health status. Milk and mammary biopsy samples were obtained from Holstein cows 21 days prior to and at various times after calving to represent the dry period and early and midstages of lactation. Additional cows received an intramammary challenge with Escherichia coli for immunohistochemical characterization of AM and AM-BP. Milk AM concentrations were relatively constant across the stages of lactation while AM-BP increased two-fold (P < 0.04) between early and mid-lactation. Milk AM (P < 0.04) and AM-BP (P < 0.03) increased as somatic cell counts (SCCs) increased within a given stage of lactation. Tissue content of both (AM and AM-BP) were significantly affected by stage of lactation, lowest in the dry period and progressively increasing to peak at mid-lactation as well as increasing in association with higher levels of SCCs. Following E. coli challenge, AM increased in epithelial cells surrounding mammary alveoli presenting high levels of SCCs. The data suggest that AM and AM-BP are cooperatively regulated in the mammary gland during lactation; changes in localized tissue AM and AM-BP content reflect a dynamic regulation of these tissue factors in the bovine mammary gland consistent with their protective effects within inflamed tissue. Published by Elsevier Inc. C1 USDA ARS, BARC E, Growth Biol Lab, Beltsville, MD 20705 USA. USDA ARS, Bovine Funct Genom Lab, Beltsville, MD 20705 USA. NCI, Dept Cell & Canc Biol, NIH, Bethesda, MD 20892 USA. RP Elsasser, TH (reprint author), USDA ARS, BARC E, Growth Biol Lab, Beltsville, MD 20705 USA. EM elsasser@anri.barc.usda.gov RI Martinez, Alfredo/A-3077-2013; Cuttitta, Frank/B-4758-2016 OI Martinez, Alfredo/0000-0003-4882-4044; NR 54 TC 2 Z9 2 U1 0 U2 5 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0739-7240 J9 DOMEST ANIM ENDOCRIN JI Domest. Anim. Endocrinol. PD FEB PY 2007 VL 32 IS 2 BP 138 EP 154 DI 10.1016/j.domaniend.2006.02.004 PG 17 WC Agriculture, Dairy & Animal Science; Endocrinology & Metabolism SC Agriculture; Endocrinology & Metabolism GA 134VH UT WOS:000244111900006 PM 16569490 ER PT J AU Ma, X Shah, Y Cheung, C Guo, GL Feigenbaum, L Krausz, KW Idle, JR Gonzalez, FJ AF Ma, Xiaochao Shah, Yatrik Cheung, Connie Guo, Grace L. Feigenbaum, Lionel Krausz, Kristopher W. Idle, Jeffrey R. Gonzalez, Frank J. TI The pregnane X receptor gene-humanized mouse: A model for investigating drug-drug interactions mediated by cytochromes P450 3A SO DRUG METABOLISM AND DISPOSITION LA English DT Article ID CONSTITUTIVE ANDROSTANE RECEPTOR; IN-VITRO METABOLISM; NUCLEAR RECEPTOR; CYTOCHROME-P-450 3A4; XENOBIOTIC RECEPTOR; ORAL-CONTRACEPTIVES; SIGNALING PATHWAY; HUMAN HEPATOCYTES; CYP3A INDUCTION; TRANSGENIC MICE AB The most common clinical implication for the activation of the human pregnane X receptor (PXR) is the occurrence of drug-drug interactions mediated by up-regulated cytochromes P450 3A (CYP3A) isozymes. Typical rodent models do not predict drug-drug interactions mediated by human PXR because of species differences in response to PXR ligands. In the current study, a PXRhumanized mouse model was generated by bacterial artificial chromosome (BAC) transgenesis in Pxr-null mice using a BAC clone containing the complete human PXR gene and 5'- and 3'-flanking sequences. In this PXR-humanized mouse model, PXR is selectively expressed in the liver and intestine, the same tissue expression pattern as CYP3A. Treatment of PXR-humanized mice with the PXR ligands mimicked the human response, since both hepatic and intestinal CYP3As were strongly induced by rifampicin, a human-specific PXR ligand, but not by pregnenolone 16 alpha-carbonitrile, a rodent-specific PXR ligand. In rifampicin-pretreated PXR-humanized mice, an similar to 60% decrease was observed for both the maximal midazolam serum concentration (C-max) and the area under the concentration-time curve, as a result of a 3-fold increase in midazolam 1'-hydroxylation. These results illustrate the potential utility of the PXR-humanized mice in the investigation of drug-drug interactions mediated by CYP3A and suggest that the PXR-humanized mouse model would be an appropriate in vivo tool for evaluation of the overall pharmacokinetic consequences of human PXR activation by drugs. C1 NCI, Lab Metab, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Univ Kansas, Med Ctr, Dept Pharmacol Toxicol & Therapeut, Kansas City, KS 66103 USA. NCI, Lab Anim Sci Program, SAIC, Frederick, MD 21701 USA. Charles Univ Prague, Fac Med 1, Inst Pharmacol, Prague, Czech Republic. RP Gonzalez, FJ (reprint author), NCI, Lab Metab, Ctr Canc Res, NIH, Bldg 37,Room 3106, Bethesda, MD 20892 USA. EM fjgonz@helix.nih.gov OI Idle, Jeff/0000-0002-6143-1520 FU Intramural NIH HHS; NIAID NIH HHS [U19 AI067773-02] NR 44 TC 83 Z9 86 U1 0 U2 1 PU AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3995 USA SN 0090-9556 J9 DRUG METAB DISPOS JI Drug Metab. Dispos. PD FEB PY 2007 VL 35 IS 2 BP 194 EP 200 DI 10.1124/dmd.106.012831 PG 7 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 128UR UT WOS:000243685000003 PM 17093002 ER PT J AU Duesberg, P Li, RH Sachs, R Fabarius, A Upender, MB Hehlmann, R AF Duesberg, Peter Li, Ruhong Sachs, Rainer Fabarius, Alice Upender, Madhvi B. Hehlmann, Ruediger TI Cancer drug resistance: The central role of the karyotype SO DRUG RESISTANCE UPDATES LA English DT Editorial Material DE drug resistance; cancer; karyotype; aneuploidy; mutations; imatinib ID COMPARATIVE GENOMIC HYBRIDIZATION; CHRONIC MYELOGENOUS LEUKEMIA; GENE-EXPRESSION; MULTIDRUG-RESISTANCE; BREAST-CANCER; CELL-LINES; CHROMOSOME REASSORTMENTS; COLORECTAL-CANCER; ANEUPLOIDY; AMPLIFICATION AB Current genetic and epigenetic theories of cancer-specific drug resistance do not adequately explain: (i) the karyotypic changes that coincide with resistance, (ii) the high rates at which cancer cells acquire and enhance resistance compared to the rates of conventional mutation, (iii) the wide ranges of resistance such as multidrug resistance, (iv) the frequent occurrence of intrinsic drug resistance. We have recently proposed, that specific karyotypic alterations are sufficient for drug resistance via new transcriptomes of cooperative genes, independent of gene mutation. This mechanism generates new phenotypes just like trisomy 21 generates Down syndrome. These karyotypic changes are generated by cancer-specific aneuploidy autocatalytically, because aneuploidy destabilizes the karyotype by misbalancing teams of proteins that synthesize, repair and segregate chromosomes. Evidence for this chromosomal mechanism is as follows: (i) resistance is proportional to the number of clonal chromosomal alterations compared to drug-sensitive precursors. (ii) The high rates at which cancer cells acquire drug resistance are comparable with the rates, as high as 10(-2) per cell generation, at which their karyotypes change-dimming hopes for gene-specific therapies. (iii) Multidrug resistance probably reflects un-selected transcriptomes of karyotypes selected for resistance against specific drugs. (iv) Intrinsic drug resistance probably reflects unselected transcriptomes of karyotypes selected for oncogenicity. We also adduce evidence that resistance of chronic myeloid leukemia against the drug imatimb is chromosomal, although it is widely believed to be due to mutation of a kinase. (c) 2007 Elsevier Ltd. All rights reserved. C1 Univ Calif Berkeley, Donner Lab, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. Univ Calif Berkeley, Dept Math & Phys, Berkeley, CA 94720 USA. Univ Heidelberg, Med Klin 3, D-68305 Mannheim, Germany. NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Duesberg, P (reprint author), Univ Calif Berkeley, Donner Lab, Dept Mol & Cell Biol, Berkeley, CA 94720 USA. EM duesberg@berkeley.edu NR 60 TC 66 Z9 72 U1 0 U2 5 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1368-7646 J9 DRUG RESIST UPDATE JI Drug Resist. Update PD FEB-APR PY 2007 VL 10 IS 1-2 BP 51 EP 58 DI 10.1016/j.drup.2007.02.003 PG 8 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 170UW UT WOS:000246692400004 PM 17387035 ER PT J AU Fojo, T AF Fojo, Tito TI Multiple paths to a drug resistance phenotype: Mutations, translocations, deletions and amplification of coding genes or promoter regions, epigenetic changes and microRNAs SO DRUG RESISTANCE UPDATES LA English DT Editorial Material DE drug resistance; mutations; translocation; amplification; rearrangements; p53; imatimb; gefitinib; erlotimb; microRNAs; epigenetics; CpG ID CHRONIC LYMPHOCYTIC-LEUKEMIA; GROWTH-FACTOR-RECEPTOR; CHRONIC MYELOID-LEUKEMIA; CELL LUNG-CANCER; OVARIAN-CANCER; BREAST-CANCER; IN-VITRO; CHROMOSOME TRANSLOCATIONS; CLINICAL RESISTANCE; HUMAN NEUROBLASTOMA AB The remarkable responses observed with imatinib (Gleevec (R)) in the therapy of CML led many scientists to think that drug resistance, long recognized as a problem with "cytotoxic" agents, would soon become a thing of the past. But then reality set in. We learned that imatinib, a wonderful drug by any measure, was also susceptible to the development of resistance, as was gefitinib (Iressa (R)), and then erlotinib (Tarceva (R)). This evidence on resistance to "novel agents" together with new data on the complexity of cancer, the rapidly evolving story of microRNAs and their diverse roles, as well as evidence of the importance of epigenetic changes have allowed us to refine our models of drug resistance and how cells acquire these phenotypes. In this overview I will look at examples of how drug resistance develops including older and more recent data on the role of mutations, translocations, deletions, and amplification. The role of epigenetic changes and microRNAs will be discussed, as examples of different mechanisms by which a cell achieves the same end. Recurrent themes that have emerged will be underscored as we seek to understand how drug resistance occurs. (c) 2007 Published by Elsevier Ltd. C1 NCI, Ctr Canc Res, Bethesda, MD 20892 USA. RP Fojo, T (reprint author), NCI, Ctr Canc Res, Bldg 10,Room 12N226,9000 Rockville Pike, Bethesda, MD 20892 USA. EM tfojo@helix.nih.gov NR 80 TC 106 Z9 113 U1 0 U2 4 PU CHURCHILL LIVINGSTONE PI EDINBURGH PA JOURNAL PRODUCTION DEPT, ROBERT STEVENSON HOUSE, 1-3 BAXTERS PLACE, LEITH WALK, EDINBURGH EH1 3AF, MIDLOTHIAN, SCOTLAND SN 1368-7646 J9 DRUG RESIST UPDATE JI Drug Resist. Update PD FEB-APR PY 2007 VL 10 IS 1-2 BP 59 EP 67 DI 10.1016/j.drup.2007.02.002 PG 9 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 170UW UT WOS:000246692400005 PM 17350322 ER PT J AU Insel, TR AF Insel, Thomas R. TI The arrival of preemptive psychiatry SO EARLY INTERVENTION IN PSYCHIATRY LA English DT Editorial Material C1 NIMH, NIH, Bethesda, MD 20892 USA. RP Insel, TR (reprint author), NIMH, NIH, Bethesda, MD 20892 USA. NR 0 TC 37 Z9 37 U1 0 U2 0 PU WILEY-BLACKWELL PUBLISHING, INC PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 1751-7885 J9 EARLY INTERV PSYCHIA JI Early Interv. Psychiatry PD FEB PY 2007 VL 1 IS 1 BP 5 EP 6 DI 10.1111/j.1751-7893.2007.00017.x PG 2 WC Psychiatry SC Psychiatry GA V04II UT WOS:000207051700003 PM 21352102 ER PT J AU Chrambach, A AF Chrambach, Andreas TI A productive and happy research laboratory: Conditions for its creation and management SO ELECTROPHORESIS LA English DT Article AB It is rare to find a research laboratory that is productive and in which investigators are happy; the two adjectives appear to be antagonistic. Productive scientists are frequently driven, compulsive people who are not happy. There are productive slave shops of exceedingly unhappy, harshly driven, junior investigators doing the work for their master. However, only in rare cases is such unhappy productivity creative and original. To foster creative productivity, the management of the laboratory should provide a number of ingredients that combine to foster happiness: peace of mind, mutual intellectual stimulation and its emotional underpinnings of friendship, mutual respect, egalitarianism, absence of interference and micromanagement, freedom in the choice of research subject and methodology, and a minimum of rules. C1 NIH, Bethesda, MD 20892 USA. RP Chrambach, A (reprint author), 9923 Dickens Ave, Bethesda, MD 20814 USA. NR 0 TC 0 Z9 0 U1 3 U2 5 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD FEB PY 2007 VL 28 IS 4 BP 495 EP 498 DI 10.1002/elps.200600378 PG 4 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 148GJ UT WOS:000245062300002 PM 17304490 ER PT J AU Antal, J Banyasz, B Buzas, Z AF Antal, Jozsef Banyasz, Borbala Buzas, Zsuzsanna TI Shotgun electroelution: A proteomic tool for simultaneous sample elution from whole SDS-polyacrylamide gel slabs SO ELECTROPHORESIS LA English DT Article DE electroelution; high throughput; shotgun; proteomics ID PROTEIN MIXTURES; ELECTROPHORESIS; MATRIX AB A high-throughput device has been constructed which allows parallel electroelution of separated SDS-protein bands directly from intact unsectioned polyacrylamide gel slabs as well as single electroelution of certain protein spots into a 384-well standard flat-bottom multiwell plate. The prototype provides complete, quick elution for proteomics from 1-D or from 2-D gels without gel sectioning. Since the elution chamber matrix requires no assembly, sample handling can be easily carried out by existing robotic workstations. The current design is a good candidate for automation of spot elution since there are no moving liquid containing components in the apparatus. Eight SDS-proteins were eluted in test runs and an average 70% sample recovery was achieved by re-electrophoresis of the electroeluates. C1 Agr Biotechnol Ctr, H-2100 Godollo, Hungary. NICHHD, Sect Metab Anal & Mass Spectrometry, Lab Cellular & Mol Biophys, NIH, Bethesda, MD 20892 USA. RP Buzas, Z (reprint author), Agr Biotechnol Ctr, Szent Gyorgyi Albert 4, H-2100 Godollo, Hungary. EM zbuzas@yahoo.com NR 9 TC 4 Z9 4 U1 0 U2 1 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0173-0835 J9 ELECTROPHORESIS JI Electrophoresis PD FEB PY 2007 VL 28 IS 4 BP 508 EP 511 DI 10.1002/elps.200600634 PG 4 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 148GJ UT WOS:000245062300006 PM 17226757 ER PT J AU Hardy, J AF Hardy, John TI Putting presenilins centre stage - Introduction to the Talking Point on the role of presenilin mutations in Alzheimer disease SO EMBO REPORTS LA English DT Article DE Alzheimer disease; presenilins; intramembranous cleavage; aspartyl protease; APP ID AMYLOID PRECURSOR PROTEIN; GAMMA-SECRETASE ACTIVITY C1 NIA, Neurogenet Lab, NIH, Bethesda, MD 20892 USA. RP Hardy, J (reprint author), NIA, Neurogenet Lab, NIH, Main Campus,Porter Neurosci Bldg, Bethesda, MD 20892 USA. EM hardyj@mail.nih.gov RI Hardy, John/C-2451-2009 FU Medical Research Council [G0701075] NR 13 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 1469-221X J9 EMBO REP JI EMBO Rep. PD FEB PY 2007 VL 8 IS 2 BP 134 EP 135 DI 10.1038/sj.embor.7400899 PG 2 WC Biochemistry & Molecular Biology; Cell Biology SC Biochemistry & Molecular Biology; Cell Biology GA 145LL UT WOS:000244866500007 PM 17268503 ER PT J AU Parrino, J Hotchkiss, RS Bray, M AF Parrino, Janie Hotchkiss, Richard S. Bray, Mike TI Prevention of immune cell apoptosis as potential therapeutic strategy for severe infections SO EMERGING INFECTIOUS DISEASES LA English DT Article ID DECREASES LYMPHOCYTE APOPTOSIS; IMPROVES SURVIVAL; IN-VIVO; CASPASE INHIBITORS; HEMORRHAGIC-FEVER; BIOLOGICAL WEAPON; T-LYMPHOCYTES; SEPTIC MICE; SEPSIS; EBOLA AB Some labile cell types whose numbers are normally controlled through programmed cell death are subject to markedly increased destruction during some severe infections. Lymphocytes, in particular, undergo massive and apparently unregulated apoptosis in human patients and laboratory animals with sepsis, potentially playing a major role in the severe immunosuppression that characterizes the terminal phase of fatal illness. Extensive lymphocyte apoptosis has also occurred in humans and animals infected with several exotic agents, including Bacillus anthracis, the cause of anthrax; Yersinia pestis, the cause of plague; and Ebola virus. Prevention of lymphocyte apoptosis, through either genetic modification of the host or treatment with specific inhibitors, markedly improves survival in murine sepsis models. These findings suggest that interventions aimed at reducing the extent of immune cell apoptosis could improve outcomes for a variety of severe human infections, including those caused by emerging pathogens and bioterrorism agents. C1 NIAID, Biodef Clin Res Branch, NIH, Bethesda, MD 20892 USA. Washington Univ, Sch Med, St Louis, MO 63130 USA. RP Bray, M (reprint author), NIAID, Biodef Clin Res Branch, NIH, 6700A Rockledge Dr,Rm 5128, Bethesda, MD 20892 USA. EM mbray@niaid.nih.gov NR 40 TC 27 Z9 33 U1 0 U2 1 PU CENTERS DISEASE CONTROL PI ATLANTA PA 1600 CLIFTON RD, ATLANTA, GA 30333 USA SN 1080-6040 J9 EMERG INFECT DIS JI Emerg. Infect. Dis PD FEB PY 2007 VL 13 IS 2 BP 191 EP 198 PG 8 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 134UY UT WOS:000244111000001 PM 17479879 ER PT J AU Lolait, SJ Stewart, LQ Jessop, DS Young, WS O'Carroll, AM AF Lolait, Stephen J. Stewart, Lesley Q. Jessop, David S. Young, W. Scott, III O'Carroll, Anne-Marie TI The hypothalamic-pituitary-adrenal axis response to stress in mice lacking functional vasopressin V1b receptors SO ENDOCRINOLOGY LA English DT Article; Proceedings Paper CT 35th Congress of the International-Society-for-Psychoneuroendocrinology CY JUL, 2004 CL Glasgow, SCOTLAND SP Int Soc Psychoneuroendocrinol ID CORTICOTROPIN-RELEASING HORMONE; INSULIN-INDUCED HYPOGLYCEMIA; ARGININE-VASOPRESSIN; PARAVENTRICULAR NUCLEUS; ACTH-SECRETION; MESSENGER-RNA; ADRENOCORTICOTROPIN SECRETION; MAGNOCELLULAR NEURONS; REPEATED RESTRAINT; RAT AB The role of arginine vasopressin (Avp) as an ACTH secretagogue is mediated by the Avp 1b receptor (Avpr1b) found on anterior pituitary corticotropes. Avp also potentiates the actions of CRH (Crh) and appears to be an important mediator of the hypothalamic-pituitary-adrenal axis response to chronic stress. To investigate the role of Avp in the hypothalamicpituitary- adrenal axis response to stress, we measured plasma ACTH and corticosterone (CORT) levels in Avpr1b knockout (KO) mice and wild-type controls in response to two acute (restraint and insulin administration) and one form of chronic (daily restraint for 14 d) stress. No significant difference was found in the basal plasma levels of ACTH and CORT between the two genotypes. Acute restraint (30 min) increased plasma ACTH and CORT to a similar level in both the Avpr1b mutant and wild-type mice. In contrast, plasma ACTH and CORT levels induced by hypoglycemia were significantly decreased in the Avpr1b KO mice when compared with wild-type littermates. There was no difference in the ACTH response to acute and chronic restraint in wild-type mice. In the Avpr1b KO group subjected to 14 sessions of daily restraint, plasma ACTH was decreased when compared with wild-type mice. On the other hand, the CORT elevations induced by restraint did not adapt in the Avpr1b KO or wild-type mice. The data suggest that the Avpr1b is required for the normal pituitary and adrenal response to some acute stressful stimuli and is necessary only for a normal ACTH response during chronic stress. C1 Univ Bristol, Henry Wellcome Labs Integrat Neurosci & Endocrino, Bristol BS1 3NY, Avon, England. NIMH, Sect Neural Gene Express, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. RP Lolait, SJ (reprint author), Univ Bristol, Henry Wellcome Labs Integrat Neurosci & Endocrino, Dorothy Hodgkin Bldg,Whitson St, Bristol BS1 3NY, Avon, England. EM s.j.lolait@bristol.ac.uk RI Young, W Scott/A-9333-2009; chen, xuanlan/H-4158-2011 OI Young, W Scott/0000-0001-6614-5112; FU Intramural NIH HHS; NIMH NIH HHS [Z01 MH002498]; Wellcome Trust [, 063049] NR 71 TC 77 Z9 80 U1 1 U2 9 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0013-7227 J9 ENDOCRINOLOGY JI Endocrinology PD FEB PY 2007 VL 148 IS 2 BP 849 EP 856 DI 10.1210/en.2006-1309 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 126NV UT WOS:000243520500041 PM 17122081 ER PT J AU Lee, SA Dai, Q Zheng, W Gao, YT Blair, A Tessari, JD Ji, BT Shu, XO AF Lee, Sang-Ah Dai, Qi Zheng, Wei Gao, Yu-Tang Blair, Aaron Tessari, John D. Ji, Bu Tian Shu, Xiao-Ou TI Association of serum concentration of organochlorine pesticides with dietary intake and other lifestyle factors among urban Chinese women SO ENVIRONMENT INTERNATIONAL LA English DT Article DE organochlorine pesticides; dietary intake; lifestyle factors; Chinese women ID BREAST-CANCER RISK; DICHLORODIPHENYL DICHLOROETHENE DDE; POLYCHLORINATED-BIPHENYLS PCBS; NEW-YORK; BETA-HEXACHLOROCYCLOHEXANE; ADIPOSE-TISSUE; LONG-ISLAND; HUMAN-MILK; LACTATION; EXPOSURE AB Concerns about the carcinogenic and endocilne-disrupting characteristics of organochlorine pesticides (OCPs) have led to a global ban on OCP use. However, OCPs persist in the environment for decades because of their long half-life. We evaluated serum levels of OCPs and their correlations with usual dietary intake and other lifestyle factors among 250 healthy women who participated as controls in the Shanghai Breast Cancer Study. Serum levels of hexachlorocyclohexane isomers (alpha-HCH, beta-HCIL gamma-HCH), dichloro-di-phenyl-trichloroethane (DDT) isomers (p,p'-DDE and p,p'-DDT), hexachlorobenzene (HCB), trans-nonachlor (TNC), and eight polychlorinated biphenyls (PCB) congeners (IUPAC no. 74, 118, 138, 153, 170, 180, 183, and 187) were measured. Lifestyle factors and usual dietary habits over the past 5 years were assessed through an in-person interview. With the exception of PCB, total OCP levels in our study population were significantly higher than those observed in other countries. Age, income, body mass index, waist-to-hip ratio, number of pregnancies, and/or total duration of breastfeeding were all significantly correlated with all types of OCPs. Of the 20 food groups evaluated, correlations with serum total OCPs were observed for eggs (r=0.13), fresh beans (r=-0.17), tea (r=0.14), and animal fat (r=0.18). Multiple regression analyses showed that age and animal fat intake were positively associated with serum total level OCPs, while leafy vegetable and fresh bean consumption was negatively associated with OCPs level. Our study suggests that dietary intake may be an important contributor of serum levels of OCPs in Chinese women. (c) 2006 Elsevier Ltd. All rights reserved. C1 Vanderbilt Univ, Ctr Med, Ctr Hlth Serv Res, Dept Med, Nashville, TN 37232 USA. Vanderbilt Univ, Ctr Med, Vanderbilt Ingram Canc Ctr, Nashville, TN 37232 USA. NCI, Div Canc Epidemiol & Genet, Rockville, MD USA. Shanghai Canc Inst, Dept Epidemiol, Shanghai, Peoples R China. Colorado State Univ, Dept Environm Hlth, Ft Collins, CO 80523 USA. RP Shu, XO (reprint author), Vanderbilt Univ, Ctr Med, Ctr Hlth Serv Res, Dept Med, 6009 Med Ctr E,1215 21st Ave S, Nashville, TN 37232 USA. EM Xiao-Ou.Shu@vanderbilt.edu FU Intramural NIH HHS; NCI NIH HHS [R01 CA64277] NR 32 TC 44 Z9 48 U1 0 U2 20 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0160-4120 J9 ENVIRON INT JI Environ. Int. PD FEB PY 2007 VL 33 IS 2 BP 157 EP 163 DI 10.1016/j.envint.2006.08.010 PG 7 WC Environmental Sciences SC Environmental Sciences & Ecology GA 130LA UT WOS:000243799900004 PM 17055057 ER PT J AU Baccarelli, A Zanobetti, A Martinelli, I Grillo, P Hou, L Lanzani, G Mannucci, PM Bertazzi, PA Schwartz, J AF Baccarelli, Andrea Zanobetti, Antonella Martinelli, Ida Grillo, Paolo Hou, Lifang Lanzani, Guido Mannucci, Pier o Mannucci Bertazzi, Pier Alberto Schwartz, Joel TI Air pollution, smoking, and plasma homocysteine SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE air pollution; cardiovascular risk; generalized additive models; homocysteine; particulate matter; smoking ID CASE-CROSSOVER ANALYSIS; CARDIOVASCULAR-DISEASE; HORDALAND HOMOCYSTEINE; MYOCARDIAL-INFARCTION; HOSPITAL ADMISSIONS; AMBIENT PARTICLES; CIGARETTE-SMOKING; HEART-DISEASE; TIME-SERIES; RISK-FACTOR AB BACKGROUND: Mild hyperhomocysteinemia is independently associated with an increased risk of cardiovascular disease. Air pollution exposure induces short-term inflammatory changes that may determine hyperhomocysteinemia, particularly in the presence of a preexisting proinflammatory status such as that found in cigarette smokers. OBJECTIVE: We examined the relation of air pollution levels with fasting and postmethionine-load total homocysteine (tHcy) in 1,213 normal subjects from Lombardia, Italy. METHODS, We obtained hourly concentrations of particulate matter < 10 mu m, in aerodynamic diameter (PM(10)) and gaseous pollutants (carbon monoxide, nitrogen dioxide, sulfur dioxide, ozone) from 53 monitoring sites covering the study area. We applied generalized additive models to compute standardized regression coefficients controlled for age, sex, body mass index, smoking, alcohol, hormone use, temperature, day of the year, and long-term trends. RESULTS: The estimated difference in tHcy associated with an interquartile increase in average PM10 concentrations in the 24 hr before the study was nonsignificant [0.4%; 95% confidence interval (CI), -2.4 to 3.3 for fasting; and 1.1%, 95% CI, -1.5 to 3.7 for postmethionine-load tHcy]. In smokers, 24-hr PM10 levels were associated with 6.3% (95% CI, 1.3 to 11.6; p < 0.05) and 4.9% (95% CI, 0.5 to 9.6; p < 0.05) increases in fasting and postmethionine-load tHcy, respectively, but no association was seen in nonsmokers (p interaction = 0.005 far fasting and 0.039 for postmethionine-load tHcy). Average 24-hr 03 concentrations were associated with significant differences in fasting tHcy (6.7%; 95% CI, 0.9 to 12.8; p < 0.05), but no consistent associations were found when postmethionine-load tHcy and/or 7-day average 03 concentrations were considered. CONCLUSIONS: Air particles may interact with cigarette smoking and increase plasma homocysteine in healthy subjects. C1 Harvard Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA 02115 USA. IRCCS, Maggiore Hosp, Mangiagalli & Regina Elena Fdn, Dept Environm & Occupat Hlth, Milan, Italy. Univ Milan, A Bianchi Bonomi Hemophilia & Thrombosis Ctr, Dept Internal Med & Med Special, I-20122 Milan, Italy. NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Reg Environm Protect Agcy ARPA Lombardia, Air Qual Unit, Milan, Italy. RP Baccarelli, A (reprint author), Harvard Univ, Sch Publ Hlth, Exposure Epidemiol & Risk Program, Landmark Ctr, 401 Pk Dr,Suite 412F W,POB 15698, Boston, MA 02215 USA. EM abaccare@hsph.harvard.edu RI Mannucci, Pier/C-3102-2014; Martinelli, ida/J-2287-2015; bertazzi, pietro alberto/D-5039-2017; OI Martinelli, ida/0000-0001-9218-3622; bertazzi, pietro alberto/0000-0003-3475-2449; Baccarelli, Andrea/0000-0002-3436-0640 FU NIEHS NIH HHS [27306C2005] NR 54 TC 40 Z9 44 U1 0 U2 5 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2007 VL 115 IS 2 BP 176 EP 181 DI 10.1289/ehp.9517 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 132ML UT WOS:000243946800022 PM 17384761 ER PT J AU Elliott, L Arbes, SJ Harvey, ES Lee, RC Salo, PM Cohn, RD London, SJ Zeldin, DC AF Elliott, Leslie Arbes, Samuel J., Jr. Harvey, Eric S. Lee, Robert C. Salo, Paivi M. Cohn, Richard D. London, Stephanie J. Zeldin, Darryl C. TI Dust weight and asthma prevalence in the National Survey of Lead and Allergens in Housing (NSLAH) SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE allergens; cross-sectional; environmental; house dust; respiratory ID OCCUPATIONAL ASTHMA; CHILDHOOD ASTHMA; RISK-FACTORS; EXPOSURE; MITE; HEALTH; ASSOCIATION; ENDOTOXIN; POLLUTION; SYMPTOMS AB BACKGROUND: Settled dust has been used in studies to assess exposures to allergens and other biologically active components, but it has not been considered in the aggregate in relation to respiratory health outcomes in the general population. OBJECTIVE: We addressed whether total house dust weight, an index of total dust exposure, was associated with respiratory health outcomes in the National Survey of Lead and Allergens in Housing (1998-1999) (NSLAH). METHODS: NSLAH was a cross-sectional survey designed to represent permanently occupied housing units in the United States. In each household, a questionnaire was administered and settled dust was vacuumed from five locations. Linear regression models were used to identify predictors of dust weight; logistic regression models were used to examine the relationship between dust weight and asthma and wheeze. RESULTS: Dust weight samples were available for 829 households, and survey information was available for 2,456 participants (children and adults). Lower income, older homes, household pets, having a smoker in the house, and less frequent cleaning predicted higher dust weight levels in U.S. households. Higher levels of dust weight were associated with greater odds of current asthma and wheeze. The strongest associations were seen for wheeze [adjusted odds ratio (OR) = 1.99; 95% confidence interval (CI), 1.21-3.28 for bedroom bed dust; OR = 2.81; 95% CI, 1.52-5.21 for upholstery dust). These associations persisted when adjusting for allergen and endotoxin exposures. CONCLUSIONS: Dust weight, an index of total dust exposure in the home, may contribute to respiratory outcomes independently of the exposure to specific components. C1 NIEHS, NIH, Lab Resp Biol, Div Intramural Res,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. Constella Grp LLC, Durham, NC USA. RP Zeldin, DC (reprint author), NIEHS, NIH, Lab Resp Biol, Div Intramural Res,Dept Hlth & Human Serv, 111 TW Alexander Dr,Bldg 101,D236, Res Triangle Pk, NC 27709 USA. EM zeldin@niehs.nih.gov OI London, Stephanie/0000-0003-4911-5290 NR 44 TC 27 Z9 27 U1 1 U2 3 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2007 VL 115 IS 2 BP 215 EP 220 DI 10.1289/ehp.9412 PG 6 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 132ML UT WOS:000243946800028 PM 17384767 ER PT J AU Demchuk, E Yucesoy, B Johnson, VJ Andrew, M Weston, A Germolec, DR De Rosa, CT Luster, MI AF Demchuk, Eugene Yucesoy, Berran Johnson, Victor J. Andrew, Michael Weston, Ainsley Germolec, Dori R. De Rosa, Christopher T. Luster, Michael I. TI A statistical model for assessing genetic susceptibility as a risk factor in multifactorial diseases: Lessons from occupational asthma SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE asthma; genetics; polygenic diseases; risk assessment; susceptibility genes ID PROMOTER POLYMORPHISM; ALLERGIC-ASTHMA; ASSOCIATION; RECEPTOR; METAANALYSIS; VARIANTS; ATOPY AB BACKGROUND: Incorporating the influence of genetic variation in the risk assessment process is often considered, but no generalized approach exists. Many common human diseases such as asthma, cancer, and cardiovascular disease are complex in nature, as they are influenced variably by environmental, physiologic, and genetic factors. The genetic components most responsible for differences in individual disease risk are thought to be DNA variants (polymorphisms) that influence the expression or function of mediators involved in the pathological processes. OBJECTIVE: The purpose of this study was to estimate the combinatorial contribution of multiple genetic variants to disease risk. METHODS: We used a logistic regression model to help estimate the joint contribution that multiple genetic variants would have on disease risk. This model was developed using data collected from molecular epidemiology studies of allergic asthma that examined variants in 16 susceptibility genes. RESULTS: Based on the product of single gene variant odds ratios, the risk of developing asthma was assigned to genotype profiles, and the frequency of each profile was estimated for the general population. Our model predicts that multiple disease variants broaden the risk distribution, facilitating the identification of susceptible populations. This model also allows for incorporation of exposure information as an independent variable, which will be important for risk variants associated with specific exposures. CONCLUSION: The present model provided an opportunity to estimate the relative change in risk associated with multiple genetic variants. This will facilitate identification of susceptible populations and help provide a framework to model the genetic contribution in probabilistic risk assessment. C1 NIOSH, Ctr Dis Control & Prevent, Chron Inflammatory & Immune Dis Team, Toxicol & Mol Biol Branch,Lab Div, Morgantown, WV 26505 USA. NIOSH, Ctr Dis Control & Prevent, Biostat & Epidemiol Branch, Hlth Effects Lab Div, Morgantown, WV 26505 USA. Ctr Dis Control & Prevent, Div Toxicol & Environm Med, Agcy Tox Subst & Dis Registry, Atlanta, GA USA. NIEHS, Toxicol Operat Branch, Environm Toxicol Program, NIH,Dept Hlth & Human Serv, Res Triangle Pk, NC 27709 USA. RP Yucesoy, B (reprint author), NIOSH, Ctr Dis Control & Prevent, Chron Inflammatory & Immune Dis Team, Toxicol & Mol Biol Branch,Lab Div, 1095 Willowdale Rd,M-S 3014, Morgantown, WV 26505 USA. EM byucesoy@cdc.gov RI Johnson, Victor/A-7910-2009; Yucesoy, Berran/B-4497-2009 FU Intramural NIH HHS; NIEHS NIH HHS [Y1-ES-69277266]; OFP OPHS HHS [921Z4FP] NR 29 TC 12 Z9 13 U1 0 U2 5 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2007 VL 115 IS 2 BP 231 EP 234 DI 10.1289/ehp.8870 PG 4 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 132ML UT WOS:000243946800031 PM 17384770 ER PT J AU Benbrahim-Tallaa, L Webber, MM Waalkes, MP AF Benbrahim-Tallaa, Lamia Webber, Mukta M. Waalkes, Michael P. TI Mechanisms of acquired androgen independence during arsenic-induced malignant transformation of human prostate epithelial cells SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE androgen-independent; androgen receptor; arsenic; cancer progression; hormone refractory; malignant transformation; MAP kinase; prostate; Ras ID CANCER-CELLS; HER-2/NEU EXPRESSION; TYROSINE KINASE; RECEPTOR GENE; GROWTH-FACTOR; WELL WATER; PROGRESSION; ACTIVATION; AMPLIFICATION; MORTALITY AB BACKGROUND: Prostate cancer progression often occurs with overexpression of growth factors and receptors, many of which engage the Ras/mitogen-activated protein MAP kinase (MAPK) pathway. OBJECTIVES: In this study we used arsenic-transformed human prostate epithelial cells, which also show androgen-independent growth, to study the possibility that chronic activation of Ras/MAPK signaling may contribute to arsenic-induced prostate cancer progression. METHODS: Control and chronic arsenic-transformed prostate epithelial cells (CAsE-PE) were compared for Ras/MAPK signaling capacities using reverse transcription-polymerase chain reaction and Western blot analyses. RESULTS: We found activation of HER-2/neu oncogene in transformed CAsE-PE cells, providing molecular evidence of androgen independence in the transformed cells. CAsE-PE cells displayed constitutively increased expression of unmutated K-Ras (6-fold), and the downstream MAP kinases A-Raf and B-Raf (2.2-fold and 3.2-fold, respectively). There was also increased expression of phosphorylated MEK1/2 and Elk1 in the transformant cells. The MEK1/2 inhibitor, U0126, blocked PSA overexpression in CAsE-PE cells. CONCLUSION: Thus, arsenic-induced malignant transformation and acquired androgen independence are linked to Ras signaling activation in human prostate epithelial cells. Chronic activation of this pathway can sensitize the androgen receptor to subphysiologic levels of androgen. This may be important in arsenic carcinogenesis and provide a mechanism that may be common for prostate cancer progression driven by diverse agents. C1 NIEHS, NCI, Inorgan Carcinogenesis Sect, Lab Comparat Carcinogenesis,NIH,Dept Hlth & Human, Res Triangle Pk, NC 27709 USA. Michigan State Univ, Dept Med, E Lansing, MI 48824 USA. Michigan State Univ, Dept Zool, E Lansing, MI 48824 USA. RP Waalkes, MP (reprint author), NIEHS, NCI, Inorgan Carcinogenesis Sect, Lab Comparat Carcinogenesis,NIH,Dept Hlth & Human, POB 12233,Mail Drop F0-09,111 Alexander Dr, Res Triangle Pk, NC 27709 USA. EM waalkes@niehs.nih.gov NR 50 TC 20 Z9 21 U1 0 U2 2 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2007 VL 115 IS 2 BP 243 EP 247 DI 10.1289/ehp.9630 PG 5 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 132ML UT WOS:000243946800033 PM 17384772 ER PT J AU Colt, JS Cyr, MJ Zahm, SH Tobias, GS Hartge, P AF Colt, Joanne S. Cyr, Mancer J. Zahm, Shelia H. Tobias, Geoffrey S. Hartge, Patricia TI Inferring past pesticide exposures: A matrix of individual active ingredients in home and garden pesticides used in past decades SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Article DE exposure assessment; herbicides; insecticides; pesticides; residential ID RISK AB BACKGROUND: In retrospective studies of the health effects of home and garden pesticides, self-reported information typically forms the basis for exposure assessment. Study participants generally find it easier to remember the types of pests treated than the specific pesticides used. However, if the goal of the study is to assess disease risk from specific chemicals, the investigator must be able to link the pest type treated with specific chemicals or products. OBJECTIVES: Our goal was to develop a "pesticide-exposure matrix" that would list active ingredients on the market for treating different types of pests in past years, and provide an estimate of the probability that each active ingredient was used. METHODS: We used several different methods for deriving the active ingredient lists and estimating the probabilities. These methods are described in this article, along with a sample calculation and data sources for each. RESULTS: The pesticide-exposure matrix lists active ingredients and their probabilities of use for 96 distinct scenarios defined by year (1976, 1980, 1990, 2000), applicator type (consumer, professional), and pest type (12 categories). Calculations and data sources for all 96 scenarios are provide online. CONCLUSIONS: Although we are confident that the active ingredient lists are reasonably accurate for most scenarios, we acknowledge possible sources of error in the probability estimates. Despite these limitations, the pesticide-exposure matrix should provide valuable information to researchers interested in the chronic health effects of residential pesticide exposure. C1 NCI, NIH, Dept Hlth & Human Serv, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Kline & Co Inc, Little Falls, NJ USA. RP Colt, JS (reprint author), NCI, Occupat & Environm Epidemiol Branch, 6120 Execut Blvd,Room 8112, Rockville, MD 20852 USA. EM coltj@mail.nih.gov RI Tobias, Geoffrey/M-4135-2016 OI Tobias, Geoffrey/0000-0002-2878-8253 FU Intramural NIH HHS; PHS HHS [MQ609394, MQ207208, MQ219223, MQ318225, MQ414366, MQ513892] NR 33 TC 5 Z9 5 U1 0 U2 3 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2007 VL 115 IS 2 BP 248 EP 254 DI 10.1289/ehp.9538 PG 7 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 132ML UT WOS:000243946800034 PM 17384773 ER PT J AU Schwartz, DA AF Schwartz, David A. TI New pathways to disease prevention SO ENVIRONMENTAL HEALTH PERSPECTIVES LA English DT Editorial Material C1 NIEHS, Bethesda, MD USA. RP Schwartz, DA (reprint author), NIEHS, Bethesda, MD USA. EM david.schwartz@niehs.nih.gov NR 0 TC 0 Z9 0 U1 0 U2 1 PU US DEPT HEALTH HUMAN SCIENCES PUBLIC HEALTH SCIENCE PI RES TRIANGLE PK PA NATL INST HEALTH, NATL INST ENVIRONMENTAL HEALTH SCIENCES, PO BOX 12233, RES TRIANGLE PK, NC 27709-2233 USA SN 0091-6765 J9 ENVIRON HEALTH PERSP JI Environ. Health Perspect. PD FEB PY 2007 VL 115 IS 2 BP A68 EP A68 PG 1 WC Environmental Sciences; Public, Environmental & Occupational Health; Toxicology SC Environmental Sciences & Ecology; Public, Environmental & Occupational Health; Toxicology GA 132ML UT WOS:000243946800001 ER PT J AU Galperin, MY AF Galperin, Michael Y. TI Using archaeal genomics to fight global warming and clostridia to fight cancer SO ENVIRONMENTAL MICROBIOLOGY LA English DT Article ID BACILLUS-CEREUS GROUP; METHANE EMISSION; NOVYI-NT; ACIDOTHERMUS-CELLULOLYTICUS; MYCOBACTERIUM-SMEGMATIS; MAGNETOTACTIC BACTERIUM; CENARCHAEUM-SYMBIOSUM; BACTERIOLYTIC THERAPY; EXPERIMENTAL-TUMORS; RICE PLANTS C1 Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. RP Galperin, MY (reprint author), Natl Lib Med, Natl Ctr Biotechnol Informat, NIH, Bethesda, MD 20894 USA. EM galperin@ncbi.nlm.nih.gov RI Galperin, Michael/B-5859-2013 OI Galperin, Michael/0000-0002-2265-5572 FU Intramural NIH HHS NR 49 TC 3 Z9 3 U1 0 U2 3 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 1462-2912 J9 ENVIRON MICROBIOL JI Environ. Microbiol. PD FEB PY 2007 VL 9 IS 2 BP 279 EP 286 DI 10.1111/j.1462-2920.2006.01223.x PG 8 WC Microbiology SC Microbiology GA 124OF UT WOS:000243376800001 PM 17222127 ER PT J AU Levy, S Shechtman, S Zhu, BZ Stadtman, ER Stadler, R Chevion, M AF Levy, Smadar Shechtman, Svetlana Zhu, Ben-Zhan Stadtman, Earl R. Stadler, Richard Chevion, Mordechai TI Synergism between the toxicity of chlorophenols and iron complexes SO ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY LA English DT Article DE pentachlorophenol; ternary complex; bacterial survival; protein carbonyl content; phase partitioning ID OXIDATIVE STRESS; DNA-DAMAGE; ESCHERICHIA-COLI; FREE-RADICALS; PENTACHLOROPHENOL; METALS; COPPER; CARCINOGENESIS; CELLS; 1,10-PHENANTHROLINE AB Synergistic interactions could prove to be relevant when evaluating the toxicity of environmental pollutants in a complex mixture, especially when organic and inorganic substances co-occur at concentrations currently considered to be low-toxic or sublethal. Escherichia coli cells (SR-9 strain) were used as a model system for studying the cellular toxicity of environmental pollutants. Exposure of bacterial cells to a combination of pentachlorophenol (PCP) and a positively charged complex of iron or copper caused a dramatic inhibition of growth and an increase in cell death. Incubation of bacterial cells with PCP and either ferric-1, 10-phenanthroline complex [Fe3+(OP)(3)](3+) (500 and 5 mu M, respectively) or cupric-1,10-phenanthroline complex [Cu2+(OP)(2)](2+) (400 and 0.05 mu M, respectively) showed two and four log units of cell death, respectively, in 30 min. In contrast, only minor amounts of cell death were observed with each component alone. Similar effects have been shown for other positively charged complexes of transition metals and for other biocides. The observed synergism was associated with the formation of novel noncharged and lipophilic ternary complexes, which contain PCP anions (or other polychlorinated anions) and the iron (or copper) complex. The ternary complexes demonstrated effective transport of their components into the cells. C1 Hebrew Univ Jerusalem, Dept Cellular Biochem, IL-91120 Jerusalem, Israel. NHLBI, Biochem Lab, Natl Inst Hlth, Bethesda, MD 20892 USA. Nestle Res Ctr, CH-1000 Lausanne, Switzerland. RP Chevion, M (reprint author), Hebrew Univ Jerusalem, Dept Cellular Biochem, IL-91120 Jerusalem, Israel. EM chevion@cc.huji.ac.il RI Zhu, Ben-Zhan/G-4798-2010 NR 47 TC 5 Z9 6 U1 1 U2 7 PU SOCIETY ENVIRONMENTAL TOXICOLOGY & CHEMISTRY-SETAC PI PENSACOLA PA 1010 NORTH 12TH AVE, PENSACOLA, FL 32501-3367 USA SN 0730-7268 J9 ENVIRON TOXICOL CHEM JI Environ. Toxicol. Chem. PD FEB PY 2007 VL 26 IS 2 BP 218 EP 224 DI 10.1897/06-306R.1 PG 7 WC Environmental Sciences; Toxicology SC Environmental Sciences & Ecology; Toxicology GA 126BA UT WOS:000243486000006 PM 17713207 ER PT J AU Rosales, T Georget, V Malide, D Smirnov, A Xu, JH Combs, C Knutson, JR Nicolas, JC Royer, CA AF Rosales, Tilman Georget, Virginie Malide, Daniela Smirnov, Aleksandr Xu, Jianhua Combs, Christian Knutson, Jay R. Nicolas, Jean-Claude Royer, Catherine A. TI Quantitative detection of the ligand-dependent interaction between the androgen receptor and the co-activator, Tif2, in live cells using two color, two photon fluorescence cross-correlation spectroscopy SO EUROPEAN BIOPHYSICS JOURNAL WITH BIOPHYSICS LETTERS LA English DT Article ID SIGNAL-TRANSDUCTION PATHWAYS; PROTEIN-PROTEIN INTERACTIONS; REFRACTORY PROSTATE-CANCER; PHOTON-COUNTING HISTOGRAM; LIVING CELLS; FLUCTUATION SPECTROSCOPY; IN-VIVO; ANTIANDROGENS; RECRUITMENT; EXCITATION AB Two-photon, two-color fluorescence cross-correlation spectroscopy (TPTCFCCS) was used to directly detect ligand-dependent interaction between an eCFP-fusion of the androgen receptor (eCFP-AR) and an eYFP fusion of the nuclear receptor co-activator, Tif2 (eYFP-Tif2) in live cells. As expected, these two proteins were co-localized in the nucleus in the presence of ligand. Analysis of the cross-correlation amplitude revealed that AR was on average 81% bound to Tif2 in the presence of agonist, whereas the fractional complex formation decreased to 56% in the presence of antagonist. Residual AR-Tif2 interaction in presence of antagonist is likely mediated by its ligand-independent activation function. These studies demonstrate that using TPTCFCCS it is possible to quantify ligand-dependent interaction of nuclear receptors with co-regulator partners in live cells, making possible a vast array of structure-function studies for these important transcriptional regulators. C1 INSERM, U554, Montpellier, France. NHLBI, Opt Spect Sect, LBC, NIH, Bethesda, MD 20892 USA. INSERM, U540, Montpellier, France. NHLBI, Light Microscopy Core Facil, NIH, Bethesda, MD 20892 USA. RP Royer, CA (reprint author), INSERM, U554, Montpellier, France. EM royer@cbs.cnrs.fr RI Royer, Catherine/E-5266-2016 OI Royer, Catherine/0000-0002-2670-3391 NR 38 TC 11 Z9 12 U1 1 U2 5 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0175-7571 J9 EUR BIOPHYS J BIOPHY JI Eur. Biophys. J. Biophys. Lett. PD FEB PY 2007 VL 36 IS 2 BP 153 EP 161 DI 10.1007/s00249-006-0095-1 PG 9 WC Biophysics SC Biophysics GA 130MN UT WOS:000243803800008 PM 17021805 ER PT J AU Valent, P Akin, C Metcalfe, DD AF Valent, P. Akin, C. Metcalfe, D. D. TI FIP1L1/PDGFRA is a molecular marker of chronic eosinophilic leukaemia but not for systemic mastocytosis SO EUROPEAN JOURNAL OF CLINICAL INVESTIGATION LA English DT Letter ID IDENTIFICATION; CLASSIFICATION; DISORDERS; THERAPY; FUSION; CELLS C1 Med Univ Vienna, Div Haematol & haemostaseol, Dept Internal Med 1, A-1090 Vienna, Austria. Univ Michigan, Div Allergy & Immunol, Dept Internal Med, Ann Arbor, MI 48109 USA. NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Valent, P (reprint author), Med Univ Vienna, Div Haematol & haemostaseol, Dept Internal Med 1, Wahringer Gurtel 18-20, A-1090 Vienna, Austria. EM peter.valent@meduniwien.ac.at NR 11 TC 10 Z9 10 U1 0 U2 1 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0014-2972 J9 EUR J CLIN INVEST JI Eur. J. Clin. Invest. PD FEB PY 2007 VL 37 IS 2 BP 153 EP 154 DI 10.1111/j.1365-2362.2007.01757.x PG 2 WC Medicine, General & Internal; Medicine, Research & Experimental SC General & Internal Medicine; Research & Experimental Medicine GA 123KL UT WOS:000243294700011 PM 17217382 ER PT J AU Alguacil, J Pfeiffer, RM Moore, LE del Fresno, MR Medina-Lopez, R Kogevinas, M Vermeulen, R Dosemeci, M Silverman, DT Rothman, N Garcia-Closas, M AF Alguacil, Juan Pfeiffer, Ruth M. Moore, Lee E. Rivas del Fresno, Manuel Medina-Lopez, Rafael Kogevinas, Manolis Vermeulen, Roel Dosemeci, Mustafa Silverman, Debra T. Rothman, Nathaniel Garcia-Closas, Montserrat TI Measurement of urine pH for epidemiological studies on bladder cancer SO EUROPEAN JOURNAL OF EPIDEMIOLOGY LA English DT Article DE aromatic amines; bladder cancer; hydrogen ion concentration; kidney stones; methods; urine pH ID N-HYDROXY METABOLITES; DIURNAL-VARIATION; ACETYLBENZIDINE; GLUCURONIDATION; 4-AMINOBIPHENYL; LIVER; DOGS AB Methods for efficiently identifying subjects with constantly acidic pH in epidemiological and clinical studies have not been assessed. We recruited 30 volunteers to estimate the minimum number of urine pH measurements using pH strips needed to identify subjects with "constantly acidic urine pH''. Spearman's correlation coefficients between urine pH measured with a pH meter and with the four pH strips ranged from 0.94 to 0.95 ( p < 0.001 for all four strips). Overall agreement within +/- 0.5 pH units between the four strips and the pH meter ranged from 62.2% to 74.4%. When using a spot urine sample from a single morning to classify participants with respect to their urine pH, 80% of individuals fell into the acidic urine pH ( pH equal to or lower than 6.0) group. When we required subjects to have urine pH equal to or lower than 6.0 in six consecutive AM spot urine samples and seven spot PM urine samples, only 20% of participants fulfilled this criterion. Measuring urine pH twice a day ( early in the morning and early in the evening) during four consecutive days classified individuals in the same way as two daily measurements for one week. A single pH measurement from a spot urine sample is not reliable to identify individuals with constantly acidic pH. Morning and evening urine pH measurements with pH strips during four consecutive days identify individuals with constantly acidic urine pH individuals as well as one week of measurements, and thus might be useful to identify subjects with constantly acidic urine pH in epidemiological and clinical studies. C1 Univ Huelva, Dept Biol Ambiental & Salud Publ, Huelva 21071, Spain. NCI, Div Canc Epidemiol & Genet, Bethesda, MD 20892 USA. Hosp Cabuenes, Urol Serv, Gijon, Spain. Hosp Virgen Del Rocio, Serv Urol, Seville, Spain. Municipal Inst Med Res, Resp & Environm Hlth Res Unit, Barcelona, Spain. Univ Utrecht, Inst Risk Assessment Sci, Utrecht, Netherlands. RP Alguacil, J (reprint author), Univ Huelva, Dept Biol Ambiental & Salud Publ, Avda Fuerzas Armadas SN, Huelva 21071, Spain. EM alguacil@dbasp.uhu.es RI Pfeiffer, Ruth /F-4748-2011; Vermeulen, Roel/F-8037-2011; Garcia-Closas, Montserrat /F-3871-2015; IBIS, UROLOGIA/H-6497-2016; Kogevinas, Manolis/C-3918-2017 OI Vermeulen, Roel/0000-0003-4082-8163; Garcia-Closas, Montserrat /0000-0003-1033-2650; NR 21 TC 7 Z9 8 U1 2 U2 8 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 0393-2990 J9 EUR J EPIDEMIOL JI Eur. J. Epidemiol. PD FEB PY 2007 VL 22 IS 2 BP 91 EP 98 DI 10.1007/s10654-006-9101-2 PG 8 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 149FI UT WOS:000245132100003 PM 17334820 ER PT J AU Kennedy, AD Willment, JA Dorward, DW Williams, DL Brown, GD Deleo, FR AF Kennedy, Adam D. Willment, Janet A. Dorward, David W. Williams, David L. Brown, Gordon D. DeLeo, Frank R. TI Dectin-1 promotes fungicidal activity of human neutrophils SO EUROPEAN JOURNAL OF IMMUNOLOGY LA English DT Article DE cell surface molecules; fungal; human; neutrophils; phagocytosis ID BETA-GLUCAN RECEPTOR; HUMAN POLYMORPHONUCLEAR LEUKOCYTES; STAPHYLOCOCCUS-AUREUS; PATHOGEN RECOGNITION; SECRETORY VESICLES; LECTIN SITE; MACROPHAGES; ACTIVATION; EXPRESSION; PHAGOCYTOSIS AB Human polymorphonuclear leukocytes (PMN) are a first line of defense against fungal infections. PMN express numerous pattern recognition receptors (PRR) that facilitate identification of invading microorganisms and ultimately promote resolution of disease. Dectin-1 (beta-glucan receptor) is a PRR expressed on several cell types and has been studied on monocytes and macrophages. However, the role played by dectin-1 in the recognition and killing of fungi by PMN is unknown. We investigated the ability of dectin-1 to mediate human PMN phagocytosis and fungicidal activity. Dectin-1 was expressed on the surface of PMN from all subjects tested (n=29) and in an intracellular compartment that co-sedimented with azurophilic granules in Percoll density gradients. Soluble beta-glucan and mAb GE2 (anti-dectin-1) inhibited binding and phagocytosis of zymosan by human PMN (e.g., ingestion was inhibited 40.1% by 30 min, p < 0.001), and blocked reactive oxygen species production. Notably, soluble beta-glucan and GE2 inhibited phagocytosis and killing of Candida albicans by PMN (inhibition of killing was 54.8% for beta-glucan and 36.2% for GE2, p < 0.01). Our results reveal a mechanism whereby PMN dectin-1 plays a key role in the recognition and killing of fungal pathogens by the innate immune system. C1 NIAID, Rocky Mt Lab, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. Univ Cape Town, Fac Hlth Sci, Inst Infect Dis & Mol Med, ZA-7925 Cape Town, South Africa. NIAID, Rocky Mt Lab, RTB Res Technol Sect, Microscopy Unit,NIH, Hamilton, MT 59840 USA. E Tennessee State Univ, James H Quillen Coll Med, Dept Surg, Johnson City, TN 37614 USA. RP Deleo, FR (reprint author), NIAID, Rocky Mt Lab, Lab Human Bacterial Pathogenesis, NIH, Hamilton, MT 59840 USA. EM fdeleo@niaid.nih.gov RI brown, gordon/B-4249-2012; OI DeLeo, Frank/0000-0003-3150-2516 FU Intramural NIH HHS NR 51 TC 66 Z9 74 U1 0 U2 1 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 0014-2980 J9 EUR J IMMUNOL JI Eur. J. Immunol. PD FEB PY 2007 VL 37 IS 2 BP 467 EP 478 DI 10.1002/eji.200636653 PG 12 WC Immunology SC Immunology GA 139HG UT WOS:000244422300023 PM 17230442 ER PT J AU Ragavendran, JV Sriram, D Patel, SK Reddy, IV Bharathwajan, N Stables, J Yogeeswari, P AF Ragavendran, Jegadeesan Vaigunda Sriram, Dharmarajan Patel, Sravan Kumar Reddy, Ingala Vikram Bharathwajan, Narayanan Stables, James Yogeeswari, Perumal TI Design and synthesis of anticonvulsants from a combined phthalimide-GABA-anilide and hydrazone pharmacophore SO EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY LA English DT Article DE anticonvulsants; phthalimides; GABA; pentylenetetrazole; picrotoxin; strychnine; acid hydrazones; amides ID CENTRAL-NERVOUS-SYSTEM; ANTIEPILEPTIC DRUG DEVELOPMENT; AMINO-ACIDS; DERIVATIVES; MICE; SEMICARBAZONES; RATS AB Two series of pharmacophoric hybrids of phthalimide-GABA-anilides/hydrazones were designed and synthesized and evaluated for their anticonvulsant and neurotoxic properties. The structures of the synthesized compounds were confirmed by the use of their spectral data besides elemental analysis. Initial anticonvulsant screening was performed using intraperitoneal (i.p.) maximal electroshock-induced seizure (MES), subcutaneous pentylenetetrazole (scPTZ), subcutaneous strychnine (scSTY), and intraperitoneal picrotoxin (ipPIC)-induced seizure threshold tests. All of the compounds were ineffective in the MES test. Most of the compounds were found to be effective in the scSTY and ipPIC models and very few compounds showed protection in the scPTZ model. (c) 2006 Elsevier Masson SAS. All rights reserved. C1 Birla Inst Technol & Sci, Med Chem Res Lab, Pharm Grp, Pilani 333031, Rajasthan, India. NIH, Epilepsy Branch, Bethesda, MD 20892 USA. RP Yogeeswari, P (reprint author), Birla Inst Technol & Sci, Med Chem Res Lab, Pharm Grp, Pilani 333031, Rajasthan, India. EM pyogee@bits-pilani.ac.in OI Patel, Sravan Kumar/0000-0002-1235-3458 NR 28 TC 102 Z9 106 U1 0 U2 9 PU ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER PI PARIS PA 23 RUE LINOIS, 75724 PARIS, FRANCE SN 0223-5234 J9 EUR J MED CHEM JI Eur. J. Med. Chem. PD FEB PY 2007 VL 42 IS 2 BP 146 EP 151 DI 10.1016/j.ejmech.2006.08.010 PG 6 WC Chemistry, Medicinal SC Pharmacology & Pharmacy GA 150VS UT WOS:000245248300003 PM 17011080 ER PT J AU Liu, ZH Ikemoto, S AF Liu, Zhong-Hua Ikemoto, Satoshi TI The midbrain raphe nuclei mediate primary reinforcement via GABA(A) receptors SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE conditioned place preference; intracranial self-administration; muscimol; rat; reward ID VENTRAL TEGMENTAL AREA; SELF-STIMULATION; SUPRAMAMMILLARY NUCLEUS; ASCENDING PROJECTIONS; INHIBITORY INFLUENCE; LOCOMOTOR-ACTIVITY; RAT; ACCUMBENS; MUSCIMOL; REWARD AB Because rats learn to lever-press for brief electrical stimulation of the median and dorsal raphe nuclei (MRN and DRN, respectively), these brain sites have long been implicated in reward processes. However, it is not clear whether the MRN and DRN integrate reward-related signals or merely contain fibers of passage involved in reward processes. To shed light on this issue, the present study employed chemicals that selectively modulate neurotransmission, in particular the GABA(A) receptor agonist muscimol. Rats quickly learned to lever-press for muscimol infusions (50 and 100 mu M) into the MRN or DRN. Muscimol was not self-administered when cannulae were placed just outside these nuclei. The reinforcing effects of muscimol appeared to be greater when the drug was administered into the MRN than into the DRN, as demonstrated by higher infusion rates and better response discrimination. These observations are consistent with the additional finding that muscimol administration into the MRN, but not the DRN, induced conditioned place preference. The reinforcing effects of muscimol administration into the MRN were blocked by coadministration of the GABA(A) antagonist picrotoxin (100 mu M) and by pretreatment with the dopamine receptor antagonist SCH 23390 (0.025 mg/kg, i.p.). The present results suggest that median and dorsal raphe neurons presumably inhibited by muscimol via GABA(A) receptors are involved in integration of primary reinforcement, and that median raphe neurons exert tonic inhibition over dopamine-dependent reward circuitry. The midbrain raphe nuclei may be involved in a variety of reward-related phenomena including drug addiction. C1 NIDA, Behav Neurosci Branch, NIH, US Dept Hlth & Human Serv, Baltimore, MD USA. RP Ikemoto, S (reprint author), NIDA, Behav Neurosci Branch, NIH, US Dept Hlth & Human Serv, 5500 Nathan Shock Dr, Baltimore, MD USA. EM sikemoto@intra.nida.nih.gov OI Ikemoto, Satoshi/0000-0002-0732-7386 FU Intramural NIH HHS; NIDA NIH HHS [Z01 DA000439-06] NR 37 TC 23 Z9 24 U1 1 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD FEB PY 2007 VL 25 IS 3 BP 735 EP 743 DI 10.1111/j.1460-9568.2007.05319.x PG 9 WC Neurosciences SC Neurosciences & Neurology GA 137DS UT WOS:000244273800013 PM 17328772 ER PT J AU Hertzano, R Dror, AA Montcouquiol, M Ahmed, ZM Ellsworth, B Camper, S Friedman, TB Kelley, MW Avraham, KB AF Hertzano, Ronna Dror, Amiel A. Montcouquiol, Mireille Ahmed, Zubair M. Ellsworth, Buffy Camper, Sally Friedman, Thomas B. Kelley, Matthew W. Avraham, Karen B. TI Lhx3, a LIM domain transcription factor, is regulated by Pou4f3 in the auditory but not in the vestibular system SO EUROPEAN JOURNAL OF NEUROSCIENCE LA English DT Article DE cochlea; inner ear; hair cell; Gfi1; deafness; mouse ID HOMEOBOX GENE LHX3; INNER-EAR; PROTEIN-INTERACTION; CELL LINEAGES; HAIR-CELLS; ACTIVATION; MUTATIONS; NEURONS; UNC-86; BRN-3C AB A dominant mutation of the gene encoding the POU4F3 transcription factor underlies human non-syndromic progressive hearing loss DFNA15. Using oligonucleotide microarrays to generate expression profiles of inner ears of Pou4f3(ddl/ddl) mutant and wild-type mice, we have identified and validated Lhx3, a LIM domain transcription factor, as an in vivo target gene regulated by Pou4f3. Lhx3 is a hair cell-specific gene expressed in all hair cells of the auditory and vestibular system as early as embryonic day 16. The level of Lhx3 mRNA is greatly reduced in the inner ears of embryonic Pou4f3 mutant mice. Our data also show that the expression of Lhx3 is regulated differently in auditory and vestibular hair cells. This is the first example of a hair cell-specific gene expressed both in auditory and in vestibular hair cells, with differential regulation of expression in these two closely related systems. C1 Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. NIDCD, Sect Dev Neurosci, NIH, Bethesda, MD 20892 USA. Univ Bordeaux 2, Ctr Rech INSERM Francois Magendie, Lav Dev Neurosci, Avenir Team, F-33077 Bordeaux, France. NIDCD, Sect Human Genet, Mol Genet Lab, NIH, Rockville, MD 20850 USA. Univ Michigan, Sch Med, Dept Human Genet, Ann Arbor, MI 48109 USA. RP Avraham, KB (reprint author), Tel Aviv Univ, Sackler Sch Med, Dept Human Mol Genet & Biochem, IL-69978 Tel Aviv, Israel. EM karena@post.tau.ac.il OI montcouquiol, mireille/0000-0001-8739-6519; Camper, Sally/0000-0001-8556-3379 FU NIDCD NIH HHS [R01 DC005641, R01DC041557] NR 32 TC 27 Z9 30 U1 0 U2 0 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0953-816X J9 EUR J NEUROSCI JI Eur. J. Neurosci. PD FEB PY 2007 VL 25 IS 4 BP 999 EP 1005 DI 10.1111/j.1460-9568.2007.05332.x PG 7 WC Neurosciences SC Neurosciences & Neurology GA 139GC UT WOS:000244419300008 PM 17331196 ER PT J AU Tokugawa, J Ravasi, L Nakayama, T Lang, LX Schmidt, KC Seidel, J Green, MV Sokoloff, L Eckelman, WC AF Tokugawa, Joji Ravasi, Laura Nakayama, Toshiyuki Lang, Lixin Schmidt, Kathleen C. Seidel, Jurgen Green, Michael V. Sokoloff, Louis Eckelman, William C. TI Distribution of the 5-HT1A receptor antagonist [F-18]FPWAY in blood and brain of the rat with and without isoflurane anesthesia SO EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING LA English DT Article DE FPWAY; 5-HT1A receptor; anesthesia; small animal PET; arterial blood sampling ID H-3 WAY-100635; PET; BINDING; SENSITIVITY AB Purpose: To determine whether brain and plasma equilibrium of a proposed PET tracer for 5-HT1A, [F-18] FPWAY, can be achieved in a sufficiently short time for practical use of the brain to plasma equilibrium distribution ratio (DR) to monitor receptor availability with and without isoflurane anesthesia. Methods: Awake (n= 4) and isoflurane-anesthetized ( n= 4) rats were administered a continuous 60 min intravenous infusion of [F-18] FPWAY with timed arterial blood sampling. Brains of the isoflurane- anesthetized rats were scanned with the ATLAS small animal PET scanner; awake rats were not. All rats were killed at 60 min and scanned postmortem for 15 min, followed by brain slicing for autoradiography. Several regions of interest (ROIs) were defined in the PET images as well as in the autoradiographic images. Regional DRs were calculated as total activity in the brain ROI divided by plasma [F-18] FPWAY activity. Results: DRs in the anesthetized animals were constant between 30 and 60 min, indicating that near equilibrium between brain and plasma had been achieved by similar to 30 min. DRs determined from postmortem PET data were higher in the isoflurane- anesthetized rats by 24% ( not significant) and 33% ( p= 0.065) in whole brain and hippocampus, respectively. DRs determined from autoradiographic data were greater in isoflurane- anesthetized rats in medial hippocampus, lateral hippocampus, and cerebellum by 33% ( p= 0.054), 63% ( p< 0.01), and 32% ( p< 0.05), respectively. Conclusion: [F-18] FPWAY could be an appropriate ligand for monitoring changes in receptor availability in the serotonergic system using a bolus/infusion paradigm. One possible explanation for higher DRs in anesthetized rats may be a reduction in endogenous 5-HT secretion under isoflurane anesthesia. C1 Mol Tracer LLC, Bethesda, MD 20814 USA. NIH, Positron Emiss Tomog Dept, Warren Grant Magnuson Clin Ctr, Bethesda, MD 20892 USA. Univ Milan, Inst Radiol Sci, Milan, Italy. NIMH, Cerebral Metab Lab, NIH, Bethesda, MD 20892 USA. NIH, Dept Nucl Med, Warren Grant Magnuson Clin Ctr, Bethesda, MD USA. RP Eckelman, WC (reprint author), Mol Tracer LLC, Snow Point Dr, Bethesda, MD 20814 USA. EM wceckelman@comcast.net NR 20 TC 12 Z9 12 U1 0 U2 0 PU SPRINGER PI NEW YORK PA 233 SPRING STREET, NEW YORK, NY 10013 USA SN 1619-7070 J9 EUR J NUCL MED MOL I JI Eur. J. Nucl. Med. Mol. Imaging PD FEB PY 2007 VL 34 IS 2 BP 259 EP 266 DI 10.1007/s00259-006-0228-x PG 8 WC Radiology, Nuclear Medicine & Medical Imaging SC Radiology, Nuclear Medicine & Medical Imaging GA 128BU UT WOS:000243631700014 PM 17021813 ER PT J AU Adamo, R Kovac, P AF Adamo, Roberto Kovac, Pavol TI Glycosylation under thermodynamic control: Synthesis of the di- and the hexasaccharide fragments of the O-SP of Vibrio cholerae O : 1 serotype Ogawa from fully functionalized building blocks SO EUROPEAN JOURNAL OF ORGANIC CHEMISTRY LA English DT Article DE carbohydrates; oligosaccharides; synthetic methods; thioglycosides; cholera vaccine ID METHYL ALPHA-GLYCOSIDES; BRUCELLA-A ANTIGEN; C-13-NMR SPECTRA; POLYSACCHARIDE; INABA; OLIGOSACCHARIDES; LIPOPOLYSACCHARIDE; PENTASACCHARIDE; THIOGLYCOSIDE; DETERMINANTS AB The known 5-(methoxycarbonyl)pentyl alpha-glycoside of the hexasaccharide of the O-SP of Vibrio cholerae 0:1, serotype Ogawa 31 was newly prepared from side-chain-equipped disaccharide building blocks. The intermediate tetrasaccharide 25 was prepared from the disaccharide glycosyl acceptor 11 and the (1 -> 2)-linked disaccharide thioglycoside glycosyl donor 8, having a (non-participating) saccharide moiety at C-2 in the downstream end. When performed conventionally (at room or at sub 0 degrees C temperatures), glycosylations with 11, carried out without anchimeric assistance, showed poor stereoselectivity but the formation of the 1,2-trans-glycosidic linkage could be markedly improved through thermodynamic control. This synthetic strategy towards 31 was more efficient than the step-wise approach, which was based on iterative glycosylation of 11 with 5 followed by delevulinoylation. Thermodynamic control improved considerably the yields of glycosylation of tetrasaccharide glycosyl acceptor 26 with disaccharide donor 18, to give the fully protected hexasaccharide 28, and also a similar reaction of the thioglycoside 18 with methyl 5-hydroxyhexanoate, to afford the linker-equipped disaccharide 19. Sequential deacetylation and debenzylation of the hexasaccharide 28, and deprotection of one of its intermediates, 19, gave the target hexasaccharide 31, and the wanted disaccharide 22, respectively. ((C) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007). C1 NIDDK, LBC, Sect Carbohydrates, NIH, Bethesda, MD 20892 USA. RP Adamo, R (reprint author), NIDDK, LBC, Sect Carbohydrates, NIH, Bethesda, MD 20892 USA. NR 36 TC 9 Z9 9 U1 0 U2 5 PU WILEY-V C H VERLAG GMBH PI WEINHEIM PA PO BOX 10 11 61, D-69451 WEINHEIM, GERMANY SN 1434-193X J9 EUR J ORG CHEM JI Eur. J. Org. Chem. PD FEB PY 2007 IS 6 BP 988 EP 1000 DI 10.1002/ejoc.200600851 PG 13 WC Chemistry, Organic SC Chemistry GA 141LB UT WOS:000244578900013 ER PT J AU Kleinau, G Claus, M Jaschke, H Muller, S Neumann, S Paschke, R Krause, G AF Kleinau, G. Claus, M. Jaeschke, H. Mueller, S. Neumann, S. Paschke, R. G., Krause TI Molecular mechanism at the TSH receptor: Modulation of signalling activity via extracellular loop 2 SO EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY & DIABETES LA English DT Meeting Abstract C1 Leibniz Inst Mol Pharm, Berlin, Germany. Univ Leipzig, Dept Med, Leipzig, Germany. NIH, NIDDK, Bethesda, MD USA. NR 0 TC 2 Z9 2 U1 0 U2 1 PU JOHANN AMBROSIUS BARTH VERLAG MEDIZINVERLAGE HEIDELBERG GMBH PI STUTTGART PA RUEDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0947-7349 J9 EXP CLIN ENDOCR DIAB JI Exp. Clin. Endocrinol. Diabet. PD FEB PY 2007 VL 115 SU 1 BP S75 EP S76 PG 2 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 145LC UT WOS:000244865600284 ER PT J AU Krause, G Neumann, S Kleinau, G Moore, S Jaeschke, H Paschke, R Thomas, CJ Gershengorn, MC AF Krause, G. Neumann, S. Kleinau, G. Moore, S. Jaeschke, H. Paschke, R. Thomas, C. J. Gershengorn, M. C. TI Design of low molecular weight ligands for the TSH receptor utilizing its sequence homology to the LH receptor SO EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY & DIABETES LA English DT Meeting Abstract C1 Leibniz Inst Mol Pharmkol, Berlin, Germany. NIH, NIDDKD, Bethesda, MD USA. Univ Leipzig, Dept Med, D-7010 Leipzig, Germany. NR 0 TC 1 Z9 1 U1 0 U2 0 PU JOHANN AMBROSIUS BARTH VERLAG MEDIZINVERLAGE HEIDELBERG GMBH PI STUTTGART PA RUEDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0947-7349 J9 EXP CLIN ENDOCR DIAB JI Exp. Clin. Endocrinol. Diabet. PD FEB PY 2007 VL 115 SU 1 BP S7 EP S7 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 145LC UT WOS:000244865600024 ER PT J AU Muller, S Kleinau, G Jaschke, H Neumann, S Krause, G Paschke, R AF Mueller, S. Kleinau, G. Jaeschke, H. Neumann, S. Krause, G. Paschke, R. TI Significance of the hinge region of the TSHR for receptor activation and hormone binding SO EXPERIMENTAL AND CLINICAL ENDOCRINOLOGY & DIABETES LA English DT Meeting Abstract C1 Univ Leipzig, Med Klin 3 Endocrinol, D-7010 Leipzig, Germany. Leibniz Inst Mol Pharmacol, Berlin, Germany. Natl Inst Hlth, NIDDK, CEB, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 1 U2 1 PU JOHANN AMBROSIUS BARTH VERLAG MEDIZINVERLAGE HEIDELBERG GMBH PI STUTTGART PA RUEDIGERSTR 14, D-70469 STUTTGART, GERMANY SN 0947-7349 J9 EXP CLIN ENDOCR DIAB JI Exp. Clin. Endocrinol. Diabet. PD FEB PY 2007 VL 115 SU 1 BP S33 EP S33 PG 1 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 145LC UT WOS:000244865600125 ER PT J AU Prakash, S Paul, WE Robbins, PW AF Prakash, S. Paul, W. E. Robbins, P. W. TI Fibrosin, a novel fibrogenic cytokine, modulates expression of myofibroblasts SO EXPERIMENTAL AND MOLECULAR PATHOLOGY LA English DT Article DE cytokine; fibrosin; myofibroblasts; alpha smooth muscle actin; fibrosis; tissue repair ID SMOOTH MUSCLE ACTIN; GRANULATION-TISSUE MYOFIBROBLASTS; SCHISTOSOMAL EGG GRANULOMAS; GROWTH-FACTOR-BETA; TRANSFORMING GROWTH-FACTOR-BETA-1; FIBROBLAST STIMULATION; CULTURED FIBROBLASTS; CONTROL ELEMENT; DIFFERENTIATION; LYMPHOKINE AB Granulation tissue fibroblasts, or myofibroblasts are characterized by the presence of alpha smooth muscle actin fibers (alpha SMA). These specialized cells are involved in wound contraction and in retractile phenomena observed during fibrotic disease. Myofibroblasts have also been shown to play a role in embryonic development. Growth factors such as Transforming growth factors TGF beta and Nerve growth factor beta (NGF) can modulate the differentiation of myofibroblasts. In this report, we show that in vitro application of fibrosin, a novel fibrogenic cytokine, stimulates expression of alpha SMA-producing cells at least four-fold above that observed in control cultures. In addition, administration of fibrosin in a wound healing model in mice stimulates increased numbers of myofibroblasts 7 days after injury, when compared with untreated, or, control, wounded mice. These results suggest that fibrosin plays an important role in up regulating the appearance of myofibroblasts during wound healing, and possibly in fibrotic diseases. It may, therefore, be important in the process of scarring. (c) 2006 Elsevier Inc. All rights reserved. C1 Boston Univ, Sch Dent Med, MIT, Ctr Canc Res, Boston, MA 02118 USA. Natl Inst Allergy & Infect Dis, Lab Immunol, NIH, Bethesda, MD 20892 USA. Boston Univ, Dent Sch, Dept Mol & Cell Biol, Boston, MA 02118 USA. RP Prakash, S (reprint author), Boston Univ, Sch Dent Med, MIT, Ctr Canc Res, 850 Harrison Ave, Boston, MA 02118 USA. EM sadhanap@comcast.net FU Intramural NIH HHS NR 44 TC 6 Z9 6 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 0014-4800 J9 EXP MOL PATHOL JI Exp. Mol. Pathol. PD FEB PY 2007 VL 82 IS 1 BP 42 EP 48 DI 10.1016/j.yexmp.2006.06.008 PG 7 WC Pathology SC Pathology GA 129WL UT WOS:000243760700005 PM 17083929 ER PT J AU Davis, CD AF Davis, Cindy D. TI Nutritional interactions: Credentialing of molecular targets for cancer prevention SO EXPERIMENTAL BIOLOGY AND MEDICINE LA English DT Review DE bioactive dietary components; cancer; prevention; molecular targets ID TEA BIOACTIVE COMPONENTS; TUMOR-NECROSIS-FACTOR; PROSTATE-CANCER; DNA-DAMAGE; FATTY-ACIDS; GENE-EXPRESSION; CELL-CYCLE; KAPPA-B; APOPTOSIS; CARCINOGENESIS AB Dietary behavior has been identified as one of the most important modifiable determinants of cancer risk. Which personalized modifications are needed remains an area of considerable controversy. Part of this uncertainty may arise from interactions among dietary bioactive compounds and/or food combinations. These interactions may either enhance or negate the response to specific foods. Evidence suggests that the cancer-protective effects of an individual's diet may reflect the combined effects of various vitamins, minerals, and other bioactive components such as flavonoids, isothiocyanates, and/or allium compounds rather than from the effect of a single ingredient. A better understanding of physiologically important interactions is needed to determine the merit of combining foods for maximum efficacy for cancer prevention. Furthermore, the response is complicated, since multiple cellular processes associated with carcinogenesis can be modified simultaneously, including sites such as drug metabolism, DNA repair, cell proliferation, apoptosis, inflammation, differentiation, and angiogenesis. Current evidence suggests that bioactive food components can typically influence more than one process. It is essential to have a better understanding of how the response relates to exposures and credentialing which process is most involved in bringing about a change in tumor incidence and/or tumor behavior. Credentialing is being defined as a determination of which cellular process(es) and which bioactive food components are most important for bringing about a phenotypic change. Additional attention is needed to determine the critical intake of dietary components, their duration, and when they should be provided to optimize the desired physiological response. Further research is also needed on the molecular targets for bioactive components and whether genetic and epigenetic events dictate the direction and magnitude of the response. C1 NCI, Nutr Sci Res Grp, Div Canc Prevent, Bethesda, MD 20892 USA. RP Davis, CD (reprint author), NCI, Nutr Sci Res Grp, Div Canc Prevent, 6130 Execut Blvd,Suite 3159, Bethesda, MD 20892 USA. EM davisci@mail.nih.gov NR 70 TC 35 Z9 38 U1 0 U2 5 PU SOC EXPERIMENTAL BIOLOGY MEDICINE PI MAYWOOD PA 195 WEST SPRING VALLEY AVE, MAYWOOD, NJ 07607-1727 USA SN 1535-3702 J9 EXP BIOL MED JI Exp. Biol. Med. PD FEB PY 2007 VL 232 IS 2 BP 176 EP 183 PG 8 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 129WU UT WOS:000243761600002 PM 17259324 ER PT J AU Weeraratna, AT Kalehua, A DeLeon, I Bertak, D Maher, G Wade, MS Lustig, A Becker, KG Wood, W Walker, DG Beach, TG Taub, DD AF Weeraratna, Ashani T. Kalehua, Audrey DeLeon, Isoke Bertak, Dorothy Maher, Gregory Wade, Michael S. Lustig, Ana Becker, Kevin G. Wood, William, III Walker, Douglas G. Beach, Thomas G. Taub, Dennis D. TI Alterations in immunological and neurological gene expression patterns in Alzheimer's disease tissues SO EXPERIMENTAL CELL RESEARCH LA English DT Article DE Alzheimer's disease; endothelin converting enzyme; inflammation; aging; chemokine ID RECEPTOR-RELATED PROTEIN; ENDOTHELIN-CONVERTING ENZYME; HERPES-SIMPLEX-VIRUS; AMYLOID-BETA PEPTIDE; UP-REGULATION; EXON 3; SKIN; LRP; TRANSCRIPTION; POLYMORPHISM AB Microarray technology was utilized to isolate disease-specific changes in gene expression by sampling across inferior parietal lobes of patients suffering from late onset AD or non-AD-associated dementia and non-demented controls. Primary focus was placed on understanding how inflammation plays a role in AD pathogenesis. Gene ontology analysis revealed that the most differentially expressed genes related to nervous system development and function and neurological disease followed by genes involved in inflammation and immunological signaling. Pathway analysis also implicated a role for chemokines and their receptors, specifically CXCR4 and CCR3, in AD. Immunohistological analysis revealed that these chemokine receptors are upregulated in AD patients. Western analysis demonstrated an increased activation of PKC, a downstream mediator of chemokine receptor signaling, in the majority of AD patients. A very specific cohort of genes related to amyloid beta accumulation and clearance were found to be significantly altered in AD. The most significantly downregulated gene in this data set was the endothelin converting enzyme 2 (ECE2), implicated in amyloid beta clearance. These data were subsequently confirmed by real-time PCR and Western blot analysis. Together, these findings open up new avenues of investigation and possible therapeutic strategies targeting inflammation and amyloid clearance in AD patients. (c) 2006 Elsevier Inc. All rights reserved. C1 NIA, Clin Immunol Sect, Immunol Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. NIA, Res Resources Branch, NIH, Baltimore, MD 21224 USA. Sun Hlth Res Inst, Sun City, AZ 85372 USA. RP Taub, DD (reprint author), NIA, Clin Immunol Sect, Immunol Lab, Intramural Res Program,NIH, 5600 Nathan Shock Dr,Room 4C02, Baltimore, MD 21224 USA. EM taubd@grc.nia.nih.gov OI Becker, Kevin/0000-0002-6794-6656 FU Intramural NIH HHS [Z01 AG000759-10]; NIA NIH HHS [P30 AG19610, P30 AG019610] NR 38 TC 60 Z9 63 U1 0 U2 1 PU ELSEVIER INC PI SAN DIEGO PA 525 B STREET, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4827 J9 EXP CELL RES JI Exp. Cell Res. PD FEB 1 PY 2007 VL 313 IS 3 BP 450 EP 461 DI 10.1016/j.yexcr.2006.10.028 PG 12 WC Oncology; Cell Biology SC Oncology; Cell Biology GA 137HH UT WOS:000244283200003 PM 17188679 ER PT J AU Padilla-Nash, HM Wu, KD Just, H Ried, T Thestrup-Pedersen, K AF Padilla-Nash, Hesed M. Wu, Kaida Just, Helle Ried, Thomas Thestrup-Pedersen, Kristian TI Spectral karyotyping demonstrates genetically unstable skin-homing T lymphocytes in cutaneous T-cell lymphoma SO EXPERIMENTAL DERMATOLOGY LA English DT Article DE cutaneous T-cell lymphoma; cytogenetic analysis; genomic instability; mycosis fungoides; spectral karyotyping ID MOLECULAR CYTOGENETIC ANALYSIS; MYCOSIS-FUNGOIDES; SEZARY-SYNDROME; CHROMOSOMAL-ABNORMALITIES; IDENTIFICATION; CANCER; 10Q AB We initially established cell lines from skin biopsies from four patients (MF8, MF18, MF19 and MF31) in early stages of cutaneous T-cell lymphoma (CTCL) in 1999. After 3 weeks of culture, skin-homing T lymphocytes were stimulated with phytohaemagglutinin. Metaphase spreads were analysed using spectral karyotyping (SKY), a molecular cytogenetic technique. MF18 and MF19 had predominantly normal karyotypes. MF8 had recurrent numerical aberrations resulting in two T lymphocyte clones: one with trisomy 21 (12/20 cells) and the other with monosomy chromosome 22 (3/20 cells). MF8 also exhibited a clonal deletion, del(5)(p15.1), as well as multiple non-clonal structural aberrations. MF31 had a clonal deletion, del(17)(p12) and other non-clonal deletions involving chromosomes 2, 5, 10, 11. MF18 had a single abnormal cell that contained two reciprocal translocations t(1;2)(q32;p21) and t(4;10)(p15.2;q24). In 2001, three of the original patients had new skin biopsies taken and cell lines were established. SKY analysis revealed the continued presence of a T-cell clone in MF8 with trisomy 21 (4/20 cells). Additionally, a new clone was seen with a del(18)(p11.2) (17/20 cells). MF31 had only one aberrant cell with a del(17)(p12). MF18 had a clonal deletion, [del(1)(p36.1) in 3/20 cells] and non-clonal aberrations involving chromosomes 3, 4, 5, 6, 12, 13, 17 and 18. Thus, three of four patients continued to show numerous numerical and structural aberrations, both clonal and non-clonal, with only MF8 having a recurring T lymphocyte clone (+21). Our findings demonstrate high genetic instability among skin-homing T lymphocytes even in early stages of CTCL. We did not see genetic instability or evidence of clones in cell lines from a patient with atopic dermatitis and one with psoriasis. C1 NCI, Genet Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. Aarhus Univ Hosp, Dept Dermatol, Aarhus C, Denmark. RP Padilla-Nash, HM (reprint author), NCI, Genet Branch, Ctr Canc Res, NIH, Bldg 50,Room 1408,50 South Dr, Bethesda, MD 20892 USA. EM nashh@mail.nih.gov FU Intramural NIH HHS NR 24 TC 7 Z9 7 U1 0 U2 0 PU WILEY-BLACKWELL PI MALDEN PA COMMERCE PLACE, 350 MAIN ST, MALDEN 02148, MA USA SN 0906-6705 J9 EXP DERMATOL JI Exp. Dermatol. PD FEB PY 2007 VL 16 IS 2 BP 98 EP 103 DI 10.1111/j.1600-0625.2006.00507.x PG 6 WC Dermatology SC Dermatology GA 122NZ UT WOS:000243235000004 PM 17222222 ER PT J AU Imanguli, MM Atkinson, JC Harvey, KE Hoehn, GT Ryu, OH Wu, TX Kingman, A Barrett, AJ Bishop, MR Childs, RW Fowler, DH Pavletic, SZ Hart, TC AF Imanguli, Matin M. Atkinson, Jane C. Harvey, Kristen E. Hoehn, Gerard T. Ryu, Ok Hee Wu, Tianxia Kingman, Albert Barrett, A. John Bishop, Michael R. Childs, Richard W. Fowler, Daniel H. Pavletic, Steven Z. Hart, Thomas C. TI Changes in salivary proteome following allogeneic hematopoietic stem cell transplantation SO EXPERIMENTAL HEMATOLOGY LA English DT Article ID VERSUS-HOST-DISEASE; LEUKOCYTE PROTEASE INHIBITOR; DIFFERENCE GEL-ELECTROPHORESIS; BONE-MARROW-TRANSPLANTATION; SJOGRENS-SYNDROME; ORAL CAVITY; LACTOFERRIN; LIPOPOLYSACCHARIDE; BETA-DEFENSIN-2; IDENTIFICATION AB Objective. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is frequently complicated by severe infections and graft-vs-host disease (GVHD). Saliva contains many components of adaptive and innate immune response crucial for local host defenses. Changes in salivary constituents could reflect systemic processes such as immune reconstitution and development of GVHD that occur posttransplant. This study was an initial evaluation of salivary protein changes that occur after allo-HCT. Patients and Methods. Serially collected saliva samples from 41 patients undergoing allo-HCT were evaluated. Changes in salivary proteome were initially examined by SELDI-TOF mass spectrometry. Individual protein changes were identified by 2-dimensional differential in-gel electrophoresis (2D-DIGE) with subsequent MS/MS sequencing and ELISA. Results. Significant increases and decreases in multiple salivary proteins that lasted at least 2 months posttransplant were detected by SELDI-TOF mass spectrometry. Lactoferrin and secretory leukocyte protease inhibitor demonstrated elevations 1 month post-HCT that persisted at least 6 months. Secretory IgA (sIgA) levels were decreased 1 month posttransplant, with recovery at approximately 6 months. Levels of salivary beta(2)-microglobulin were elevated at 6 months and correlated with sIgA levels. Conclusion. Allo-HCT is associated with long-term changes in several salivary proteins important for innate immune responses. These results support further studies on the association of salivary proteins with posttransplant complications including infections and GVHD. (c) 2007 International Society for Experimental Hematology. Published by Elsevier Inc. C1 Natl Inst Dent & Craniofacial Res, Clin Res Core, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Human Craniofacial Genet Sect, Bethesda, MD 20892 USA. Natl Inst Dent & Craniofacial Res, Div Clin Res & Hlth Promot, Bethesda, MD 20892 USA. NHLBI, Dept Crit Care Med, Ctr Clin, Bethesda, MD 20892 USA. NHLBI, Hematol Branch, Bethesda, MD 20892 USA. NCI, Expt Transplantat & Immunol Branch, NIH, Bethesda, MD 20892 USA. RP Atkinson, JC (reprint author), Natl Inst Dent & Craniofacial Res, Clin Res Core, 10 Ctr Dr,1N-117,MSC 1191, Bethesda, MD 20892 USA. EM jatkinso@mail.nih.gov FU Intramural NIH HHS [Z99 DE999999] NR 41 TC 34 Z9 36 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0301-472X J9 EXP HEMATOL JI Exp. Hematol. PD FEB PY 2007 VL 35 IS 2 BP 184 EP 192 DI 10.1016/j.exphem.2006.10.009 PG 9 WC Hematology; Medicine, Research & Experimental SC Hematology; Research & Experimental Medicine GA 134HC UT WOS:000244073100002 PM 17258067 ER PT J AU Perry, T Holloway, HW Weerasuriya, A Mouton, PR Duffy, K Mattison, JA Greig, NH AF Perry, TracyAnn Holloway, Harold W. Weerasuriya, Ananda Mouton, Peter R. Duffy, Kara Mattison, Julie A. Greig, Nigel H. TI Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy SO EXPERIMENTAL NEUROLOGY LA English DT Article DE GLP-1; exendin-4; behavior; diabetes; morphology; neuropathy; neuroprotection; neurotrophic; pyroxidine; rat; stereometry ID GLUCAGON-LIKE PEPTIDE-1; RECEPTOR; RATS; NEURONOPATHY; EXPRESSION; EXENDIN-4; CELLS AB Pyridoxine (vitamin 136) intoxicated rodents develop a peripheral neuropathy characterized by sensory nerve conduction deficits associated disturbances of nerve fiber geometry and axonal atrophy. To investigate the possibility that glucagon-like peptide-1(7-36)-amide (GLP-1) receptor agonism may influence axonal structure and function through neuroprotection neurotrophic support, effects of GLP-1 and its long acting analog, Exendin-4 (Ex4) treatment on pyridoxine-induced peripheral neuropathy were examined in rats using behavioral and morphometric techniques. GLP-1 is an endogenous insulinotropic peptide secreted from the gut in response to the presence of food. GLP-1 receptors (GLP-1) are coupled to the cAMP second messenger pathway, and are expressed widely throughout neural tissues of humans and rodents. Recent studies have established that GLP-1 and Ex4, have multiple synergistic effects on glucose-dependent insulin secretion pathways of pancreatic beta-cells and on neural plasticity. Data reported here suggest that clinically relevant doses of GLP-1 and Ex4 may offer some protection against the sensory peripheral neuropathy induced by pyridoxine. Our findings suggest a potential role for these peptides in the treatment of neuropathies, including that associated with type II diabetes mellitus. Published by Elsevier Inc. C1 NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, Baltimore, MD 21224 USA. NIA, Lab Expt Gerontol, Intramural Res Program, NIH, Baltimore, MD 21224 USA. Mercer Univ, Sch Med, Div Basic Med Sci, Macon, GA 31207 USA. RP Greig, NH (reprint author), NIA, Drug Design & Dev Sect, Neurosci Lab, Intramural Res Program,NIH, Room 2C13,Gerontol Res Ctr,5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM Greign@grc.nia.nih.gov FU Intramural NIH HHS; NIA NIH HHS [Z01 AG000311-05] NR 26 TC 106 Z9 114 U1 3 U2 9 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0014-4886 J9 EXP NEUROL JI Exp. Neurol. PD FEB PY 2007 VL 203 IS 2 BP 293 EP 301 DI 10.1016/j.expneurol.2006.09.028 PG 9 WC Neurosciences SC Neurosciences & Neurology GA 133XA UT WOS:000244046000002 PM 17125767 ER PT J AU Dalgleish, A Emerich, D Glassy, M Kreitman, RJ Mironov, V Morse, M Santini, D AF Dalgleish, Angus Emerich, Dwaine Glassy, Mark Kreitman, Robert J. Mironov, Vladimir Morse, Michael Santini, Daniele TI Editorial Board focus - February 2007 SO EXPERT OPINION ON BIOLOGICAL THERAPY LA English DT Article ID CANCER-PATIENTS; STEM-CELL AB From our panel of expert Editorial Board members, an update on the developments and activities ongoing in thier laboratories and institutions, as well as recommendations of other groups whose work is of considerable interest to the readers of EOBT. C1 St George Hosp, Sch Med, Div Oncol, London SW17 0RE, England. LCT Biopharma, Glocester, RI 02857 USA. Rajko Medenica Res Fdn, San Diego, CA 92121 USA. NCI, NIH, Clin Immunotherapy Sect, Mol Biol Lab, Bethesda, MD 20892 USA. Med Univ S Carolina, Charleston, SC 29464 USA. Duke Univ, Med Ctr, Div Med Oncol, Durham, NC 27710 USA. RP Dalgleish, A (reprint author), St George Hosp, Sch Med, Div Oncol, 2nd Floor Jenner Wing,Cranmer Terrace, London SW17 0RE, England. EM daigleis@sghms.ac.uk; ED3FJM@aol.com; Markglassy@aol.com; kreitmar@mail.nih.gov; mironovv@musc.edu; morse004@mc.duke.edu; d.santini@unicampus.it NR 10 TC 0 Z9 0 U1 0 U2 0 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1471-2598 J9 EXPERT OPIN BIOL TH JI Expert Opin. Biol. Ther. PD FEB PY 2007 VL 7 IS 2 BP 157 EP 160 DI 10.1517/14712598.7.2.157 PG 4 WC Biotechnology & Applied Microbiology; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Research & Experimental Medicine GA 130KD UT WOS:000243797600001 ER PT J AU Camandola, S Mattson, MP AF Camandola, Simonetta Mattson, Mark P. TI NF-kappa B as a therapeutic target in neurodegenerative diseases SO EXPERT OPINION ON THERAPEUTIC TARGETS LA English DT Review DE Alzheimer's disease; neurodegeneration; NF-kappa B; NSAID ID TUMOR-NECROSIS-FACTOR; AMYLOID BETA-PEPTIDE; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; AMYOTROPHIC-LATERAL-SCLEROSIS; SPORADIC PARKINSONS-DISEASE; CEREBRAL-ARTERY OCCLUSION; NERVE GROWTH-FACTOR; SPINAL-CORD-INJURY; LONG-TERM-MEMORY; FACTOR C-REL AB NF-kappa B is a transcription factor that regulates numerous physiological functions, and that is involved in the pathogenesis of various diseases. In the nervous system there is evidence supporting a dual role of NF-kappa B in neurodegenerative diseases; activation of NF-kappa B in neurons promotes their survival, whereas activation in glial and immune cells mediates pathological inflammatory processes. The reason for such a dichotomy lies in the complexity of the NF-kappa B system. Emerging research has begun to dissect the pathways leading to the activation of the different NF-kappa B proteins, and the gene targets of NF-kappa B, in cells of the nervous system. in this article the authors discuss recent findings concerning the roles of NF-kappa B in the pathogenesis of several neurodegenerative disorders, and its potential as a pharmaceutical target for these disorders. C1 NIA, Neurosci Lab, Intramural Res Program, Baltimore, MD 21224 USA. Johns Hopkins Univ, Sch Med, Dept Neurosci, Baltimore, MD 21205 USA. RP Camandola, S (reprint author), NIA, Neurosci Lab, Intramural Res Program, 5600 Nathan Shock Dr, Baltimore, MD 21224 USA. EM camandolasi@grc.nia.nih.gov RI Mattson, Mark/F-6038-2012 FU Intramural NIH HHS NR 102 TC 83 Z9 91 U1 0 U2 4 PU INFORMA HEALTHCARE PI LONDON PA TELEPHONE HOUSE, 69-77 PAUL STREET, LONDON EC2A 4LQ, ENGLAND SN 1472-8222 J9 EXPERT OPIN THER TAR JI Expert Opin. Ther. Targets PD FEB PY 2007 VL 11 IS 2 BP 123 EP 132 DI 10.1517/14728222.11.2.123 PG 10 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 127IL UT WOS:000243579000003 PM 17227229 ER PT J AU Kwon, O Eck, P Chen, SL Corpe, CP Lee, JH Kruhlak, M Levine, M AF Kwon, Oran Eck, Peter Chen, Shenglin Corpe, Christopher P. Lee, Je-Hyuk Kruhlak, Michael Levine, Mark TI Inhibition of the intestinal glucose transporter GLUT2 by flavonoids SO FASEB JOURNAL LA English DT Article DE intestinal sugar transporter; polyphenols; intraluminal flavonoids; Xenopus laevis ID BRUSH-BORDER-MEMBRANE; DEHYDROASCORBIC ACID; DIFFUSIVE COMPONENT; DIETARY FLAVONOIDS; FRUCTOSE TRANSPORT; METABOLIC SYNDROME; KINASE INHIBITORS; SUGAR ABSORPTION; RAT ADIPOCYTES; CACO-2 CELLS AB We tested whether the dominant intestinal sugar transporter GLUT2 was inhibited by intestinal luminal compounds that are inefficiently absorbed and naturally present in foods. Because of their abundance in fruits and vegetables, flavonoids were selected as model compounds. Robust inhibition of glucose and fructose transport by GLUT2 expressed in Xenopus laevis oocytes was produced by the flavonols myricetin, fisetin, the widely consumed flavonoid quercetin, and its glucoside precursor isoquercetrin. IC(50)s for quercetin, myricetin, and isoquercetirin were similar to 200- to 1000-fold less than glucose or fructose concentrations, and noncompetitive inhibition was observed. The two other major intestinal sugar transporters, GLUT5 and SGLT1, were unaffected by flavonoids. Sugar transport by GLUT2 overexpressed in pituitary cells and naturally present in Caco-2E intestinal cells was similarly inhibited by quercetin. GLUT2 was detected on the apical side of Caco-2E cells, indicating that GLUT2 was in the correct orientation to be inhibited by luminal compounds. Quercetin itself was not transported by the three major intestinal glucose transporters. Because the flavonoid quercetin, a food component with an excellent pharmacology safety profile, might act as a potent luminal inhibitor of sugar absorption independent of its own transport, flavonols show promise as new pharmacologic agents in the obesity epidemic. C1 NIDDKD, NIH, Mol & Clin Nutr Sect, Digest Dis Branch,Intramural Res Program, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, Intramural Res Program, Bethesda, MD 20892 USA. RP Levine, M (reprint author), NIDDKD, NIH, Mol & Clin Nutr Sect, Digest Dis Branch,Intramural Res Program, Bethesda, MD 20892 USA. EM markl@mail.nih.gov RI Chen, Shenglin/B-4049-2010; OI Eck, Peter/0000-0003-2371-9774 FU Intramural NIH HHS NR 51 TC 139 Z9 143 U1 3 U2 37 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD FEB PY 2007 VL 21 IS 2 BP 366 EP 377 DI 10.1096/fj.06-6620com PG 12 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 142YD UT WOS:000244686300010 PM 17172639 ER PT J AU Taniguchi, F Couse, JF Rodriguez, KF Emmen, JMA Poirier, D Korach, KS AF Taniguchi, Fuminori Couse, John F. Rodriguez, Karina F. Emmen, Judith M. A. Poirier, Donald Korach, Kenneth S. TI Estrogen receptor-alpha mediates an intraovarian negative feedback loop on thecal cell steroidogenesis via modulation of Cyp17a1 (cytochrome P450, steroid 17 alpha-hydroxylase/17,20 lyase) expression SO FASEB JOURNAL LA English DT Article DE hydroxysteroid (17 beta) dehydrogenase; hyperandrogenemia; folliculogenesis; aromatase ID POLYCYSTIC-OVARY-SYNDROME; 17-BETA-HYDROXYSTEROID DEHYDROGENASE TYPE-1; TRANSFORMING GROWTH FACTOR-BETA-1; ANDROGEN PRODUCTION; LUTEINIZING-HORMONE; INTERSTITIAL CELLS; FACTOR-I; TESTOSTERONE PRODUCTION; HYPOPHYSECTOMIZED RATS; AUTOREGULATORY PROCESS AB Excess androgen synthesis by thecal cells is invariably detrimental to preovulatory follicles in the ovary and is considered a fundamental characteristic of polycystic ovary syndrome in women. Investigators have long postulated that granulosa cell-derived estrogens modulate thecal cell steroidogenesis via a short negative-feedback loop within the follicle. To test this hypothesis, we assessed the steroidogenic capacity of individual wild-type (WT) and estrogen receptor-alpha (ER alpha-)-null follicles when cultured in vitro under comparable conditions. Late-stage ER alpha-null follicles exhibited markedly increased expression of the thecal cell enzyme CYP17A1 and secreted much greater amounts of its end product, androstenedione. This phenotype was reproduced in WT follicles when exposed to an aromatase inhibitor or ER-antagonist, and prevented when the former treatment was supplemented with an ER alpha-specific agonist. ER alpha-null follicles also exhibited increased testosterone synthesis due to ectopic expression of hydroxysteroid (17 beta) dehydrogenase type 3 (HSD17B3), a testis-specific androgenic enzyme. These data indicate that ER alpha functions within thecal cells to negatively modulate the capacity for androgen synthesis by repressing Cyp17a1 expression, and the biological activity of androgens produced by inhibiting Hsd17b3 expression. Hence, these findings provide novel evidence of an intraovarian ER alpha function that may be critical to the latter stages of folliculogenesis and overall ovarian function. C1 NIEHS, Reprod & Dev Toxicol Lab, Receptor Biol Sect, NIH, Res Triangle Pk, NC 27709 USA. Tottori Univ Hosp, Dept Obstet & Gynecol, Yonago, Tottori, Japan. CHUQ, Oncol & Mol Endocrinol Res Ctr, Div Med Chem, Quebec City, PQ, Canada. RP Korach, KS (reprint author), NIEHS, Reprod & Dev Toxicol Lab, Receptor Biol Sect, NIH, MD B3-02,POB 12233, Res Triangle Pk, NC 27709 USA. EM korach@nichs.nih.gov OI Korach, Kenneth/0000-0002-7765-418X FU Intramural NIH HHS [NIH0010047172, ]; PHS HHS [NIH0010047172] NR 51 TC 35 Z9 38 U1 0 U2 1 PU FEDERATION AMER SOC EXP BIOL PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814-3998 USA SN 0892-6638 J9 FASEB J JI Faseb J. PD FEB PY 2007 VL 21 IS 2 BP 586 EP 595 DI 10.1096/fj.06-6681com PG 10 WC Biochemistry & Molecular Biology; Biology; Cell Biology SC Biochemistry & Molecular Biology; Life Sciences & Biomedicine - Other Topics; Cell Biology GA 142YD UT WOS:000244686300031 PM 17158782 ER PT J AU Woods, CG Burns, AM Maki, A Bradford, BU Cunningham, ML Connor, HD Kadiiska, MB Mason, RP Peters, JM Rusyn, I AF Woods, Courtney G. Burns, Amanda M. Maki, Akira Bradford, Blair U. Cunningham, Michael L. Connor, Henry D. Kadiiska, Maria B. Mason, Ronald P. Peters, Jeffrey M. Rusyn, Ivan TI Sustained formation of alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone radical adducts in mouse liver by peroxisome proliferators is dependent upon peroxisome proliferator-activated receptor-alpha, but not NADPH oxidase SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article ID ACYL-COA OXIDASE; IN-VIVO; RAT-LIVER; HEPATOCYTE PROLIFERATION; LIPID-PEROXIDATION; H2O2 PRODUCTION; KUPFFER CELLS; DNA-DAMAGE; WY-14,643; CLOFIBRATE AB Reactive oxygen species are thought to be crucial for peroxisome proliferator-induced liver carcinogenesis. Free radicals have been shown to mediate-the production of mitogenic cytokines by Kupffer cells and cause DNA damage in rodent liver. Previous in vivo experiments demonstrated that acute administration of the peroxisome proliferator di(2-ethylhexyl) phthalate (DEHP) led to an increase in production of alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone (POBN) radical adducts in liver, an event that was dependent on Kupffer cell NADPH oxidase, but not peroxisome proliferator-activated receptor (PPAR)alpha. Here, we hypothesized that continuous treatment with peroxisome proliferators will cause a sustained formation in POBN radical adducts in liver. Mice were fed diets containing either 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY-14,643, 0.05% w/w) or DEHP (0.6% w/w) for up to 3 weeks. Liver-derived radical production was assessed in bile samples by measuring POBN radical adducts using electron spin resonance. Our data indicate that WY-14,643 causes a sustained increase in POBN radical adducts in mouse liver and that this effect is greater than that of DEHP. To understand the molecular source of these radical species, NADPH oxidase-deficient (p47(phox)-null) and PPAR alpha-null mice were examined after treatment with WY-14,643. No increase in radicals was observed in PPAR alpha-null mice that were treated with WY-14,643 for 3 weeks, while the response in p47(phox)-nulls was similar to that of wild-type mice. These results show that PPAR alpha, not NADPH oxidase. is critical for a sustained increase in POBN radical production caused by peroxisome proliferators in rodent liver. Therefore, peroxisome proliferator-induced POBN radical production in Kupffer cells may be limited to an acute response to these compounds in mouse liver. (c) 2006 Elsevier Inc. All rights reserved. C1 Univ N Carolina, Dept Environm Sci & Engn, Michael Hooker Res Ctr 0031, Chapel Hill, NC 27599 USA. Natl Toxicol Program, Res Triangle Pk, NC 27709 USA. NIEHS, Lab Pharmacol & Chem, Res Triangle Pk, NC 27709 USA. Penn State Univ, Dept Vet & Biomed Sci, State Coll, PA 16802 USA. RP Rusyn, I (reprint author), Univ N Carolina, Dept Environm Sci & Engn, Michael Hooker Res Ctr 0031, Chapel Hill, NC 27599 USA. EM iir@unc.edu RI Peters, Jeffrey/D-8847-2011; Rusyn, Ivan/S-2426-2016 FU NIEHS NIH HHS [F31 ES013342, F32-ES13342, K22 ES011660, K22-ES11660, P30 ES010126, P30-ES10126, P42 ES005948, R01 ES012686, R01-ES12686, U19 ES011391, U19-ES11391] NR 48 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 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD FEB 1 PY 2007 VL 42 IS 3 BP 335 EP 342 DI 10.1016/j.freeradbiomed.2006.10.053 PG 8 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 129XX UT WOS:000243764500003 PM 17210446 ER PT J AU Kim, SH Lee, S Suk, K Bark, H Jun, CD Kim, DK Choi, CH Yoshimura, T AF Kim, Sang-Hyun Lee, Soyoung Suk, Kyoungho Bark, Hyun Jun, Chang-Duk Kim, Dae-Ki Choi, Cheol-Hee Yoshimura, Teizo TI Discoidin domain receptor 1 mediates collagen-induced nitric oxide production in J774A.1 murine macrophages SO FREE RADICAL BIOLOGY AND MEDICINE LA English DT Article DE discoidin domain receptor 1; nitric oxide; macrophages; nuclear factor-kappa B; p38 kinase; c-jun N-terminal kinase ID NF-KAPPA-B; DISCOIDIN DOMAIN RECEPTOR-1; ACTIVATED PROTEIN-KINASE; TYROSINE KINASE; SIGNALING PATHWAYS; MESANGIAL CELLS; ISOFORM-B; P38 MAPK; SYNTHASE; EXPRESSION AB Nitric oxide (NO) is an important regulator of immune responses. Effects of cytokines, such as tumor necrosis factor (TNF)-alpha or IFN-gamma, and bacterial products, such as lipopolysaccharide, on macrophage NO production have been well documented; however, the role of the extracellular matrix proteins, including collagen, in this process remains unclear. We previously reported that discoidin domain receptor 1 (DDR1), a nonintegrin collagen receptor, was expressed in human macrophages, and its activation facilitated their differentiation as well as cytokine/ chemokine production. Here, we examined the role for DDR1 in collagen- induced NO production using the murine macrophage cell line J774 cells that endogenously express DDR1. Activation of J774 cells with collagen induced the expression of inducible NO synthase (iNOS) and NO production. Inhibition of DDR1, but not beta 1-integrins, abolished collagen-induced iNOS and NO production. Activation of J774 cells with collagen-activated nuclear factor-kappa B, p38 mitogen-activated protein kinase (MAPK), and c-jun N-terminal kinase (JNK) and a pharmacological inhibitor of each signaling molecule significantly reduced collagen-induced NO production. Thus, we have demonstrated, for the first time, that the interaction of DDR1 with collagen induces iNOS expression and subsequent NO synthesis in J774 cells through activation of NF-kappa B, p38 MAPK, and JNK and suggest that intervention of DDR1 signaling in macrophages may be useful in controlling inflammatory diseases in which NO plays a critical role. (c) 2006 Elsevier Inc. All rights reserved. C1 Kyungpook Natl Univ, Sch Med, Dept Pharmacol, Taegu 700422, South Korea. Chosun Univ, Coll Med, Dept Pharmacol, Kwangju 501759, South Korea. Gwangju Inst Sci & Technol, Dept Life Sci, Kwangju 500712, South Korea. Chonbuk Natl Univ, Sch Med, Dept Immunol, Jeonju 561108, South Korea. NCI, Mol Immunoregulat Lab, Frederick, MD 21702 USA. RP Kim, SH (reprint author), Kyungpook Natl Univ, Sch Med, Dept Pharmacol, Taegu 700422, South Korea. EM shkim72@knu.ac.kr NR 32 TC 47 Z9 47 U1 0 U2 1 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 0891-5849 J9 FREE RADICAL BIO MED JI Free Radic. Biol. Med. PD FEB 1 PY 2007 VL 42 IS 3 BP 343 EP 352 DI 10.1016/j.freeradbiomed.2006.10.052 PG 10 WC Biochemistry & Molecular Biology; Endocrinology & Metabolism SC Biochemistry & Molecular Biology; Endocrinology & Metabolism GA 129XX UT WOS:000243764500004 PM 17210447 ER PT J AU Von Hahn, T Yoon, JC Alter, H Rice, CM Rehermann, B Balfe, P Mckeating, JA AF Von Hahn, Thomas Yoon, Joo Chun Alter, Harvey Rice, Charles M. Rehermann, Barbara Balfe, Peter Mckeating, Jane A. TI Hepatitis C virus continuously escapes from neutralizing antibody and T-cell responses during chronic infection in vivo SO GASTROENTEROLOGY LA English DT Article ID HUMORAL IMMUNE-RESPONSE; HYPERVARIABLE REGION-1; NATURAL-HISTORY; UNITED-STATES; GLYCOPROTEINS; EVOLUTION; ENVELOPE; HCV; PERSISTENCE; DISEASE AB Background & Aims: Broadly reactive neutralizing antibodies (nAbs) and multispecific T-cell responses are generated during chronic hepatitis C virus (HCV) infection and yet fail to clear the virus. This study investigated the development of autologous nAb and HCV-glycoprotein-specific T-cell responses and their effects on viral sequence evolution during chronic infection in order to understand the reasons for their lack of effectiveness. Methods: Numerous E1E2 sequences were amplified and sequenced from serum samples collected over a 26-year period from patient H, a uniquely well-characterized, chronically infected individual. HCV pseudoparticles (HCVpp) expressing the patient-derived glycoproteins were generated and tested for their sensitivity to neutralization by autologous and heterologous serum antibodies. Results: A strain-specific nAb response developed early in infection (8 weeks postinfection), whereas cross-reactive antibodies able to neutralize HCVpp-bearing heterologous glycoproteins developed late in infection (> 33 wk postinfection). The humoral response continuously failed to neutralize viruses bearing autologous glycoprotein sequences that were present in the serum at a given time. The amplified glycoprotein sequences displayed high variability, particularly in regions corresponding to defined linear B-cell epitopes. Mutations in defined neutralizing epitopes were associated with a loss of recognition by monoclonal antibodies against these epitopes and with decreased neutralization of corresponding HCVpp. Viral escape from CD4 and CD8 T-cell responses also was shown for several novel epitopes throughout the glycoprotein region. Conclusions: During chronic infection HCV is subjected to selection pressures from both humoral and cellular immunity, resulting in the continuous generation of escape variants. C1 Rockefeller Univ, Ctr Study Hepatitis C, New York, NY 10021 USA. NIH, Immunol Sect, Liver Dis Branch, Bethesda, MD 20892 USA. NIH, Warren Grant Magnuson Clin Ctr, Dept Transfus Med, Bethesda, MD 20892 USA. Columbia Univ, Div Infect Dis, New York, NY USA. Univ Birmingham, Sch Med, Div Immun & Infect, Biomed Res Inst, Birmingham, W Midlands, England. RP Von Hahn, T (reprint author), Rockefeller Univ, Ctr Study Hepatitis C, 1230 York Ave, New York, NY 10021 USA. EM vonhaht@rockefeller.edu RI Yoon, Joo Chun/D-3675-2012; OI Yoon, Joo Chun/0000-0001-9395-8418; McKeating, Jane/0000-0002-7229-5886 FU Intramural NIH HHS; Medical Research Council [G0400802, G0801976]; NCI NIH HHS [CA57973]; NIAID NIH HHS [AI50798, U19 AI40034] NR 59 TC 228 Z9 236 U1 0 U2 7 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD FEB PY 2007 VL 132 IS 2 BP 667 EP 678 DI 10.1053/j.gastro.2006.12.008 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 141UL UT WOS:000244604200026 PM 17258731 ER PT J AU Huang, Y Feld, JJ Sapp, RK Nanda, S Lin, JH Blatt, LM Fried, MW Murthy, K Liang, TJ AF Huang, Ying Feld, Jordan J. Sapp, Ronda K. Nanda, Santosh Lin, Jiing-Huey Blatt, Lawrence M. Fried, Michael W. Murthy, Krishna Liang, T. Jake TI Defective hepatic response to interferon and activation of suppressor of cytokine signaling 3 in chronic hepatitis C SO GASTROENTEROLOGY LA English DT Article ID VIRUS CORE PROTEIN; GENE-EXPRESSION; CYTOKINE SIGNALING-3; CONSENSUS INTERFERON; INHIBITS INTERFERON; NEGATIVE REGULATION; HUMAN HEPATOCYTES; UP-REGULATION; IN-VITRO; INFECTION AB Background & Aims: Approximately half of hepatitis C virus (HCV)-infected patients do not respond to current interferon (IFN)-alpha combination therapy. To understand IFN-alpha resistance in vivo, we examined the dynamic responses to both type I and type II IFNs, human IFN (hIFN)-alpha, -gamma, and consensus IFN, in the chimpanzee model. Methods: Naive and HCV-infected chimpanzees were treated with 3 forms of hIFNs in vivo. Quantitative real-time polymerase chain reaction was performed to evaluate the expression of IFN-stimulated genes (ISGs) in both peripheral blood mononuclear cells and liver to compare the responses to hIFN between naive and infected chimpanzees. The hepatic expression of IFN signaling components and inhibitory regulators including suppressor of cytokine signaling 3 (SOCS3) were assessed. SOCS3 expression was also evaluated in the liver of HCV-infected patients undergoing IFN treatment. Results: The in vivo responses to all 3 hIFNs were much lower in the HCV-infected chimpanzees than those in the naive chimpanzees. This defect was particularly evident in the liver because induction of hepatic ISGs was barely detectable in the infected animals. Following IFN administration, the expression of SOCS3 was significantly up-regulated, possibly through induction of interleukin-6, in the liver of HCV-infected chimpanzees. HCV-infected humans also showed a differential pattern of hepatic SOCS3 expression in response to IFN that is associated with treatment response. Conclusions: Our data indicate a predominantly defective hepatic response to IFN in HCV-infected chimpanzees, which is probably mediated through the activation of SOCS3 and may explain the nonresponse of many HCV patients to IFN-based therapy. C1 NIDDKD, Liver Dis Branch, NIH, Bethesda, MD 20892 USA. InterMune Inc, Brisbane, CA USA. Univ N Carolina, Div Gastroenterol & Hepatol, Chapel Hill, NC USA. SW Fdn Biomed Res, Dept Virol & Immunol, San Antonio, TX USA. RP Liang, TJ (reprint author), NIDDKD, Liver Dis Branch, NIH, Bldg 10,Room 9B16,10 Ctr Dr, Bethesda, MD 20892 USA. EM jliang@nih.gov FU Intramural NIH HHS; NHLBI NIH HHS [N01-HB-27091, N01HB27091]; NIDDK NIH HHS [Z01 DK054505-09] NR 44 TC 70 Z9 75 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD FEB PY 2007 VL 132 IS 2 BP 733 EP 744 DI 10.1053/j.gastro.2006.11.045 PG 12 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 141UL UT WOS:000244604200032 PM 17258724 ER PT J AU Habermann, JK Luke, BT Ried, T AF Habermann, Jens K. Luke, Brian T. Ried, Thomas TI Identifying new biomarkers associated with invasive colorectal cancer and colorectal polyps - Reply SO GASTROENTEROLOGY LA English DT Letter ID LASER DESORPTION/IONIZATION-TIME; MASS-SPECTROMETRY C1 NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. RP Habermann, JK (reprint author), NCI, Genet Branch, NIH, Bethesda, MD 20892 USA. NR 3 TC 0 Z9 0 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0016-5085 J9 GASTROENTEROLOGY JI Gastroenterology PD FEB PY 2007 VL 132 IS 2 BP 824 EP 824 DI 10.1053/j.gastro.2006.12.044 PG 1 WC Gastroenterology & Hepatology SC Gastroenterology & Hepatology GA 141UL UT WOS:000244604200042 ER PT J AU Yiu, WH Pan, CJ Allamarvdasht, M Kim, SY Chou, JY AF Yiu, W. H. Pan, C-J Allamarvdasht, M. Kim, S. Y. Chou, J. Y. TI Glucose-6-phosphate transporter gene therapy corrects metabolic and myeloid abnormalities in glycogen storage disease type Ib mice SO GENE THERAPY LA English DT Article DE glycogen storage disease type Ib; adenoviral vector; glucose-6-phosphate transporter; bone marrow transduction; spleen transduction ID COLONY-STIMULATING FACTORS; LIVER-TRANSPLANTATION; ADENOVIRAL VECTOR; 1B; NEUTROPHIL; TRANSDUCTION; GRANULOCYTE; DELIVERY; SYSTEM; MOUSE AB Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate transporter (G6PT), an endoplasmic reticulum-associated transmembrane protein that is ubiquitously expressed. GSD-Ib patients suffer from disturbed glucose homeostasis and myeloid dysfunctions. To evaluate the feasibility of gene replacement therapy for GSD-Ib, we have infused adenoviral (Ad) vector containing human G6PT (Ad-hG6PT) into G6PT-deficient (G6PT(/)) mice that manifest symptoms characteristics of the human disorder. Ad-hG6PT infusion restores significant levels of G6PT mRNA expression in the liver, bone marrow and spleen, and corrects metabolic as well as myeloid abnormalities in G6PT(/) mice. The G6PT(/) mice receiving gene therapy exhibit improved growth; normalized serum profiles for glucose, cholesterol, triglyceride, uric acid and lactic acid; and reduced hepatic glycogen deposition. The therapy also corrects neutropenia and lowers the elevated serum levels of granulocyte colony-stimulating factor. The development of bone and spleen in the infused G6PT(/) mice is improved and accompanied by increased cellularity and normalized myeloid progenitor cell frequencies in both tissues. This effective use of gene therapy to correct metabolic imbalances and myeloid dysfunctions in GSD-Ib mice holds promise for the future of gene therapy in humans. C1 NICHHD, Heritable Disorders Branch, Sect Cellular Differentiat, NIH, Bethesda, MD 20892 USA. RP Chou, JY (reprint author), NICHHD, Heritable Disorders Branch, Sect Cellular Differentiat, NIH, Bldg 10,Room 9D42,9000 Rockville Pike, Bethesda, MD 20892 USA. EM chouja@mail.nih.gov FU Intramural NIH HHS [Z01 HD000912-28] NR 34 TC 19 Z9 19 U1 0 U2 1 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD FEB PY 2007 VL 14 IS 3 BP 219 EP 226 DI 10.1038/sj.gt.3302869 PG 8 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 127OZ UT WOS:000243597500004 PM 17006547 ER PT J AU Yoshimitsu, M Higuchi, K Ramsubir, S Nonaka, T Rasaiah, VI Siatskas, C Liang, SB Murray, GJ O Brady, R Medin, JA AF Yoshimitsu, M. Higuchi, K. Ramsubir, S. Nonaka, T. Rasaiah, V. I. Siatskas, C. Liang, S. -B Murray, G. J. O Brady, R. Medin, J. A. TI Efficient correction of Fabry mice and patient cells mediated by lentiviral transduction of hematopoietic stem/progenitor cells SO GENE THERAPY LA English DT Article DE lysosomal storage diseases; hematopoiesis; bone marrow transplantation; globotriaosylceramide; mobilized peripheral blood ID SEVERE COMBINED IMMUNODEFICIENCY; HUMAN ALPHA-GALACTOSIDASE; BONE-MARROW-CELLS; GENE-THERAPY; FUNCTIONAL CORRECTION; REPLACEMENT THERAPY; GAUCHER-DISEASE; MULTIPLE ORGANS; DEFICIENT MICE; HUMAN GENOME AB A deficiency in alpha-galactosidase A (alpha-gal A) activity causes Fabry disease. Virus-based delivery of genes can correct cells and establish a sustained supply of therapeutic proteins. Recombinant lentiviral vectors (LVs) show promise in this context. We first demonstrate LV-mediated marking of peripheral blood (PB) cells by transduction/transplantation of hematopoietic stem/progenitor cells. Stable enGFP expression was observed in PB for 37 weeks. Next, we transplanted Fabry mice with bone marrow mononuclear cells (BMMNCs) transduced a single time with a LV encoding the human alpha-gal A cDNA. Sustained expression of functional alpha-gal A in Fabry mice was observed over 24 weeks. Plasma alpha-gal A activity from treated Fabry mice was two-fold higher than wild-type controls. Increased a-gal A activity, often to supra-normal levels, and reduction of globotriaosylceramide, a glycolipid that accumulates in Fabry disease, was observed in all organs assessed. In secondary bone marrow transplantations, Fabry mice showed multilineage marking of PB, splenocytes and BMMNCs, along with therapeutic levels of alpha-gal A activity in plasma and organs over 20 weeks. Lastly, we transduced mobilized PB CD34(+) cells from a Fabry patient and observed corresponding enzymatic increases. Thus a single LV-mediated transduction of primitive hematopoietic cells can result in sustained correction for Fabry disease. C1 Univ Toronto, Hlth Network, Dept Med Biophys, Toronto, ON M5G 2M1, Canada. Univ Toronto, Hlth Network, Ontario Canc Inst, Div Stem Cell & Dev Biol, Toronto, ON M5G 2M1, Canada. NINDS, Dev & Metab Neurol Branch, NIH, Bethesda, MD 20892 USA. Univ Toronto, Inst Med Sci, Toronto, ON M5S 1A1, Canada. RP Medin, JA (reprint author), Univ Toronto, Hlth Network, Dept Med Biophys, Canadian Blood Serv Bldg,67 Coll St,Room 406, Toronto, ON M5G 2M1, Canada. EM jmedin@uhnres.utoronto.ca FU NHLBI NIH HHS [HL70569] NR 45 TC 25 Z9 25 U1 0 U2 2 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0969-7128 J9 GENE THER JI Gene Ther. PD FEB PY 2007 VL 14 IS 3 BP 256 EP 265 DI 10.1038/sj.gt.3302839 PG 10 WC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 127OZ UT WOS:000243597500008 PM 16929352 ER PT J AU Guo, CY Lunetta, KL DeStefano, AL Ordovas, JM Cupples, LA AF Guo, Chao-Yu Lunetta, Kathryn L. DeStefano, Anita L. Ordovas, Jose M. Cupples, L. Adrienne TI Informative-transmission disequilibrium test (i-TDT): Combined linkage and association mapping that includes unaffected offspring as well as affected offspring SO GENETIC EPIDEMIOLOGY LA English DT Article DE TDT; multiple affecteds; unaffected siblings; nuclear families; linkage; association; APOE; cholesterol ID APOLIPOPROTEIN-E GENOTYPE; FAMILY-BASED TESTS; DENSITY-LIPOPROTEIN-CHOLESTEROL; SIBSHIP TEST; FRAMINGHAM; AGE; DISEASE; DESIGN AB To date, there is no test valid for the composite null hypothesis of no linkage or no association that utilizes transmission information from heterozygous parents to their unaffected offspring as well as the affected offspring from ascertained nuclear families. Since the unaffected siblings also provide information about linkage and association, we introduce a new strategy called the informative-transmission disequilibrium test (i-TDT), which uses transmission information from heterozygous parents to all of the affected and unaffected offspring in ascertained nuclear families and provides a valid ch-isquare test for both linkage and association. The i-TDT can be used in various study designs and can accommodate all types of independent nuclear families with at least one affected offspring. We show that the transmission/ disequilibrium test (TDT) (Spielman et al. [1993] Am. J. Hum. Genet. 52:506-516) is a special case of the i-TDT, if the study sample contains only case-parent trios. If the sample contains only affected and unaffected offspring without parental genotypes, the i-TDT is equivalent to the sibship disequilibrium test (SDT) (Horvath and Laird [1998] Am. J. Hum. Genet. 63:1886-1897. In addition, the test statistic of i-TDT is simple, explicit and can be implemented easily without intensive computing. Through computer simulations, we demonstrate that power of the i-TDT can be higher in many circumstances compared to a method that uses affected offspring only. Applying the i-TDT to the Framingham Heart Study data, we found that the apolipoprotein E (APOE) gene is significantly linked and associated with cross-sectional measures and longitudinal changes in total cholesterol. Genet. Epidemiol. 31:115-133, 2007. (c) 2006 Wiley-Liss, Inc. C1 Boston Univ, Framingham Heart Study, NHLBI, Dept Math & Stat,Stat & Consulting Unit, Boston, MA 02215 USA. Boston Univ, Dept Biostat, Sch Publ Hlth, Boston, MA 02215 USA. NHLBI, Framingham Heart Study, Framingham, MA USA. Tufts Univ, Jean Mayer USDA, Human Nutr Res Ctr, Nutr & Genom Lab, Medford, MA 02155 USA. RP Guo, CY (reprint author), Boston Univ, Framingham Heart Study, NHLBI, Dept Math & Stat,Stat & Consulting Unit, 111 Cummington St, Boston, MA 02215 USA. EM chaoyu@bu.edu OI Lunetta, Kathryn/0000-0002-9268-810X; Cupples, L. Adrienne/0000-0003-0273-7965; Ordovas, Jose/0000-0002-7581-5680 FU NHLBI NIH HHS [N01-HC-25195] NR 27 TC 9 Z9 9 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0741-0395 J9 GENET EPIDEMIOL JI Genet. Epidemiol. PD FEB PY 2007 VL 31 IS 2 BP 115 EP 133 DI 10.1002/gepi.20195 PG 19 WC Genetics & Heredity; Mathematical & Computational Biology SC Genetics & Heredity; Mathematical & Computational Biology GA 127FK UT WOS:000243570500003 PM 17123304 ER PT J AU Feng, JX Wang, HS Morse, HC AF Feng, Jianxun Wang, Hongsheng Morse, Herbert C., III TI Functional deficiency in IL-7 caused by an N-ethyl-N-nitrosourea-induced point mutation SO GENETICS LA English DT Article ID B-CELL DEVELOPMENT; MARGINAL-ZONE; INTERLEUKIN-7 RECEPTOR; MURINE; MICE; EXPRESSION; LYMPHOPOIESIS; REGION; LOCUS; LYMPHOCYTES AB N-ethyl-N-nitrosourea (ENU)-induced mutagenesis provides a powerful approach for identifying genes involved-immune regulation and diseases. Here we describe a new mutant strain, HLB368, with hereditary leukopenia.At necropsy, the mutant mice had very small thymuses and spleens. All but the inguinal nodes were absent and there were no Peyer's patches. By flow cytometry, the ratios of T-cell subsets were normal, but B-cell development was blocked at the pre-pro-B-cell stage. The development of B1 and marginal zone B cells was relatively normal. The mutation was mapped to chromosome 3 between D3Mit221 and D3Mit224, a region that contains the Il7gene. cDNA and genomic DNA sequences of Il7 revealed a T-to-C missense transition resulting in a change of Leu to Pro within the leader peptide that would be predicted to inhibit secretion. In keeping with this concept, We found that in vitro treatment of B-cell progenitors from mutant mice with IL-7 induced them to differentiate into pre-BII cells. Phenotypic comparisons of HLB368 with genetically targeted Il7 null mice showed many similarities along with a few differences, indicating that this ENU-induced mutant carries a novel allele. This new strain thus provides a new model for studying the functions of IL-7 on a pure C57BL/6 background. C1 NIAID, Immunopathol Lab, NIH, Rockville, MD 20852 USA. RP Wang, HS (reprint author), NIAID, Immunopathol Lab, NIH, Twinbrook 1,5640 Fishers Lane, Rockville, MD 20852 USA. EM wanghongs@niaid.nih.gov OI Morse, Herbert/0000-0002-9331-3705 FU Intramural NIH HHS; NHLBI NIH HHS [HL66611, U01 HL066611] NR 33 TC 6 Z9 6 U1 0 U2 1 PU GENETICS PI BALTIMORE PA 428 EAST PRESTON ST, BALTIMORE, MD 21202 USA SN 0016-6731 J9 GENETICS JI Genetics PD FEB PY 2007 VL 175 IS 2 BP 545 EP 551 DI 10.1534/genetics.106.066043 PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 142ZK UT WOS:000244689600011 PM 17179092 ER PT J AU Taioli, E Benhamou, S Bouchardy, C Cascorbi, I Cajas-Salazar, N Dally, H Fong, KM Larsen, JE Le Marchand, L London, SJ Risch, A Spitz, MR Stucker, I Weinshenker, B Wu, XF Yang, P AF Taioli, Emanuela Benhamou, Simone Bouchardy, Christine Cascorbi, Ingolf Cajas-Salazar, Nohelia Dally, Heike Fong, Kwun M. Larsen, Jill E. Le Marchand, Loic London, Stephanie J. Risch, Angela Spitz, Margaret R. Stucker, Isabelle Weinshenker, Brian Wu, Xifeng Yang, Ping TI Myeloperoxidase G-463A polymorphism and lung cancer: A huge genetic susceptibility to environmental carcinogens pooled analysis SO GENETICS IN MEDICINE LA English DT Review DE epidemiology; cooperative studies; metabolic gene polymorphisms; smoking ID HUMAN SKIN FIBROBLASTS; ACID RESPONSE ELEMENT; DNA ADDUCT LEVELS; HYPOCHLOROUS ACID; REDUCED RISK; MISSENSE MUTATION; MPO; ASSOCIATION; DEFICIENCY; METAANALYSIS AB Myeloperoxidase is a phase I metabolic enzyme that converts the metabolites of benzo[a]pyrene from tobacco smoke into highly reactive epoxides. A polymorphism in the promoter region of myeloperoxidase (463G -> A) has been found to be inversely associated with lung cancer; differences in the association with age and gender have been suggested. We conducted a pooled analysis of individual data from 10 studies (3688 cases and 3874 controls) from the Genetic Susceptibility to Environmental Carcinogens database. The odds ratio for lung cancer was 0.88 (95% confidence interval: 0.80-0.97) for the AG variant of myeloperoxidase G-463A polymorphism, and 0.71 (95% confidence interval: 0.57-0.88) for the AA variant after adjusting for smoking, age, gender, and ethnicity. The inverse association between lung cancer and myeloperoxidase G-463A polymorphism was equally found in males and females (odds ratio for the AA genotype 0.73 [95% confidence interval: 0.56-0.96] and 0.67 [95% confidence interval: 0.46-0.98], respectively), without differences in the association according to age in the two genders. The myeloperoxicase G-463A polymorphism was significantly protective in "ever" smokers but not in "never" smokers. Myeloperoxidase is a key enzyme in tobacco-induced carcinogenesis. C1 Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15232 USA. INSERM, U794, Evry, France. Geneva Canc Registry, Geneva, Switzerland. Univ Kiel, Hosp Schleswig Holstein, Inst Pharmacol, Kiel, Germany. Univ Texas, Med Branch, Dept Prevent Med & Community Hlth, Galveston, TX 77550 USA. Deutsch Krebsforschungszentrum, Abt Toxikol & Krebsrisikofaktoren, D-6900 Heidelberg, Germany. Prince Charles Hosp, Dept Thorac Med, Brisbane, Qld 4032, Australia. Univ Hawaii, Canc Res Ctr Hawaii, Honolulu, HI 96813 USA. Natl Inst Environm Hlth Sci, Res Triangle Pk, NC USA. Univ Texas, MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA. INSERM, U170, Villejuif, France. Mayo Clin, Coll Med, Ctr Canc, Rochester, MN USA. RP Taioli, E (reprint author), Univ Pittsburgh, Inst Canc, 5150 Ctr Ave, Pittsburgh, PA 15232 USA. RI Cascorbi, Ingolf/A-4519-2009; Fong, Kwun/G-6369-2010; Larsen, Jill/G-3787-2010; Benhamou, Simone/K-6554-2015; Risch, Angela/H-2669-2013; OI Larsen, Jill/0000-0001-7806-3931; Risch, Angela/0000-0002-8026-5505; London, Stephanie/0000-0003-4911-5290 NR 53 TC 29 Z9 29 U1 0 U2 5 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1098-3600 J9 GENET MED JI Genet. Med. PD FEB PY 2007 VL 9 IS 2 BP 67 EP 73 DI 10.1097/GIM.0b013e31803068bI PG 7 WC Genetics & Heredity SC Genetics & Heredity GA 140FX UT WOS:000244491100003 PM 17304047 ER PT J AU Murphy, WJ Davis, B David, VA Agarwala, R Schaffer, AA Wilkerson, AJP Neelam, B O'Brien, SJ Menotti-Raymond, M AF Murphy, William J. Davis, Brian David, Victor A. Agarwala, Richa Schaffer, Alejandro A. Wilkerson, Alison J. Pearks Neelam, Beena O'Brien, Stephen J. Menotti-Raymond, Marilyn TI A 1.5-Mb-resolution radiation hybrid map of the cat genome and comparative analysis with the canine and human genomes SO GENOMICS LA English DT Article DE domestic cat; radiation hybrid map; canine genome; genome evolution; synteny; chromosome rearrangement ID MAMMALIAN CHROMOSOME EVOLUTION; DOMESTIC CAT; HIGH-RESOLUTION; FELIS-CATUS; PSEUDOAUTOSOMAL REGION; MUTATION; TYROSINASE; LOCI; DOG; BOUNDARY AB We report the construction of a 1.5-Mb-resolution radiation hybrid map of the domestic cat genome. This new map includes novel microsatellite loci and markers derived from the 2X genome sequence that target previous gaps in the feline-human comparative map. Ninety-six percent of the 1793 cat markers we mapped have identifiable orthologues in the canine and human genome sequences. The updated autosomal and X-chromosome comparative maps identify 152 cat-human and 134 cat-dog hornologous synteny blocks. Comparative analysis shows the marked change in chromosomal evolution in the canid lineage relative to the felid lineage since divergence from their carnivoran ancestor. The canid lineage has a 30-fold difference in the number of interchromosomal rearrangements relative to felids, while the felid lineage has primarily undergone intrachromosomal rearrangements. We have also refined the pseudoautosomal region and boundary in the cat and show that it is markedly longer than those of human or mouse. This improved RH comparative map provides a useful tool to facilitate positional cloning studies in the feline model. (c) 2006 Elsevier Inc. All rights reserved. C1 Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, College Stn, TX 77843 USA. NCI, Lab Genome Divers, Frederick, MD 21702 USA. Natl Lib Med, Informat Engn Branch, Natl Ctr Biotechnol Informat, NIH,Dept Hlth & Human Serv, Bethesda, MD 20894 USA. Natl Lib Med, Computat Biol Branch, Natl Ctr Biotechnol Informat, NIH,Dept Hlth & Human Serv, Bethesda, MD 20894 USA. NCI, Adv Biomed Comp Ctr, Frederick, MD 21702 USA. RP Murphy, WJ (reprint author), Texas A&M Univ, Coll Vet Med & Biomed Sci, Dept Vet Integrat Biosci, Mail Stop 4458, College Stn, TX 77843 USA. EM wmurphy@cvm.tamu.edu RI Schaffer, Alejandro/F-2902-2012 FU Intramural NIH HHS [Z01 BC005385-24, Z01 LM000097-06]; NCI NIH HHS [N01-CO-12400, N01CO12400] NR 39 TC 44 Z9 44 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD FEB PY 2007 VL 89 IS 2 BP 189 EP 196 DI 10.1016/j.ygeno.2006.08.007 PG 8 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 127RP UT WOS:000243604300003 PM 16997530 ER PT J AU Peters, LM Belyantseva, IA Lagziel, A Battey, JF Friedman, TB Morell, RJ AF Peters, Linda M. Belyantseva, Inna A. Lagziel, Ayala Battey, James F. Friedman, Thomas B. Morell, Robert J. TI Signatures from tissue-specific MPSS libraries identify transcripts preferentially expressed in the mouse inner ear SO GENOMICS LA English DT Article DE ear; inner; MPSS; transcription; genetic; Vmo1; Slc26a5 ID OUTER HAIR-CELLS; GENE-EXPRESSION; ANTISENSE TRANSCRIPTION; MATRIX PROTEINS; SEQUENCING MPSS; MESSENGER-RNAS; MOTOR PROTEIN; HUMAN GENOME; HEARING-LOSS; DEAFNESS AB Specialization in cell function and morphology is influenced by the differential expression of mRNAs, many of which are expressed at low abundance and restricted to certain cell types. Detecting such transcripts in cDNA libraries may require sequencing millions of clones. Massively parallel signature sequencing (MPSS) is well suited to identifying transcripts that are expressed in discrete cell types and in low abundance. We have made MPSS libraries from microdissections of three inner ear tissues. By comparing these MPSS libraries to those of 87 other tissues included in the Mouse Reference Transcriptome online resource, we have identified genes that are highly enriched in, or specific to, the inner ear. We show by RT-PCR and in situ hybridization that signatures unique to the inner ear libraries identify transcripts with highly specific cell-type localizations. These transcripts serve to illustrate the utility of a resource that is available to the research community. Utilization of these resources will increase the number of known transcription units and expand our knowledge of the tissue-specific regulation of the transcriptome. (c) 2006 Elsevier Inc. All rights reserved. C1 Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Mol Genet Lab, NIGMS, Rockville, MD 20850 USA. Natl Inst Neurol Disorders & Stroke, G Prot Coupled Receptors Sect, NIH, Bethesda, MD 20892 USA. RP Morell, RJ (reprint author), Natl Inst Deafness & Other Commun Disorders, Sect Human Genet, Mol Genet Lab, NIGMS, Rockville, MD 20850 USA. EM morellr@nidcd.nih.gov OI Morell, Robert/0000-0003-1537-7356 FU Intramural NIH HHS; NIDCD NIH HHS [Z01 DC000039-09, Z01 DC000039, T32 DC000035] NR 49 TC 21 Z9 23 U1 0 U2 7 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD FEB PY 2007 VL 89 IS 2 BP 197 EP 206 DI 10.1016/j.ygeno.2006.09.006 PG 10 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 127RP UT WOS:000243604300004 PM 17049805 ER PT J AU Phue, JN Kedem, B Jaluria, P Shiloach, J AF Phue, Je-Nie Kedem, Benjamin Jaluria, Pratik Shiloach, Joseph TI Evaluating microarrays using a serniparametric approach: Application to the central carbon metabolism of Escherichia coli BL21 and JM109 SO GENOMICS LA English DT Article DE Microarray; E. coli; glucose metabolism; semiparametric algorithm ID GENE-EXPRESSION; ACETATE ACCUMULATION; GLUCOSE-UTILIZATION; PATHWAYS; PATTERNS; GROWTH; MODELS AB Escherichia coli K (JM 109) and E. coli B (BL21) are strains used routinely for recombinant protein production. These two strains grow and respond differently to environmental factors such as glucose and oxygen concentration. The differences have been attributed to differential expression of individual genes that constitute certain metabolic pathways that are part of the central carbon metabolism. By implementing a semiparametric algorithm, which is based on a density ratio model, it was possible to compare and quantify the expression patterns of groups of genes involved in several central carbon metabolic pathways. The groups comprising the glyoxylate shunt, TCA cycle, fatty acid, and gluconeogenesis and anaplerotic pathways were expressed differently between the two strains, whereas no differences were apparent for the groups comprising either glycolysis or the pentose phosphate pathway. These results further characterized differences between the two E. coli strains and illustrated the potency of the semiparametric algorithm. (c) 2006 Elsevier Inc. All rights reserved. C1 NIDDK, Biotechnol Unit, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Math, College Pk, MD 20742 USA. RP Shiloach, J (reprint author), NIDDK, Biotechnol Unit, NIH, Bldg 14A,Room 170,Rockville Pike, Bethesda, MD 20892 USA. EM yossi@nih.gov FU NIDDK NIH HHS [Z01 DK015500-44] NR 22 TC 10 Z9 10 U1 1 U2 4 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 0888-7543 J9 GENOMICS JI Genomics PD FEB PY 2007 VL 89 IS 2 BP 300 EP 305 DI 10.1016/j.ygeno.2006.10.004 PG 6 WC Biotechnology & Applied Microbiology; Genetics & Heredity SC Biotechnology & Applied Microbiology; Genetics & Heredity GA 127RP UT WOS:000243604300014 PM 17125967 ER PT J AU Kim, MJ Liu, IH Song, YQ Lee, JA Halfter, W Balice-Gordon, RJ Linney, E Cole, GJ AF Kim, Min Jung Liu, I-Hsuan Song, Yuanquan Lee, Ju-Ahng Halfter, Willi Balice-Gordon, Rita J. Linney, Elwood Cole, Gregory J. TI Agrin is required for posterior development and motor axon outgrowth and branching in embryonic zebrafish SO GLYCOBIOLOGY LA English DT Article DE agrin; heparan sulfate proteoglycan; axon outgrowth; zebrafish; posterior development; Fgf; neuromuscular synaptogenesis ID HEPARAN-SULFATE PROTEOGLYCAN; GLOMERULAR-BASEMENT-MEMBRANE; CELL-ADHESION MOLECULE; NEURITE OUTGROWTH; OTIC PLACODE; IN-VIVO; NEUROMUSCULAR SYNAPTOGENESIS; HIPPOCAMPAL-NEURONS; GENE-EXPRESSION; XENOPUS-EMBRYOS AB Although recent studies have extended our understanding of agrin's function during development, its function in the central nervous system (CNS) is not clearly understood. To address this question, zebrafish agrin was identified and characterized. Zebrafish agrin is expressed in the developing CNS and in nonneural structures such as somites and notochord. In agrin morphant embryos, acetylcholine receptor (AChR) cluster number and size on muscle fibers at the choice point were unaffected, whereas AChR clusters on muscle fibers in the dorsal and ventral regions of the myotome were reduced or absent. Defects in the axon outgrowth by primary motor neurons, subpopulations of branchiomotor neurons, and Rohon-Beard sensory neurons were also observed, which included truncation of axons and increased branching of motor axons. Moreover, agrin morphants exhibit significantly inhibited tail development in a dose-dependent manner, as well as defects in the formation of the midbrain-hindbrain boundary and reduced size of eyes and otic vesicles. Together these results show that agrin plays an important role in both peripheral and CNS development and also modulates posterior development in zebrafish. C1 NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. N Carolina Cent Univ, Julius L Chambers Biomed Biotechnol Res Inst, Durham, NC 27707 USA. Univ Penn, Sch Med, Dept Neurosci, Philadelphia, PA 19104 USA. Univ Pittsburgh, Dept Neurobiol, Pittsburgh, PA 15261 USA. Duke Univ, Med Ctr, Dept Mol Genet & Microbiol, Durham, NC 27710 USA. RP Cole, GJ (reprint author), NICHD, Mol Genet Lab, NIH, Bethesda, MD 20892 USA. EM gcole@nccu.edu RI Song, Yuanquan/E-2603-2012; OI LIU, I-HSUAN/0000-0002-4524-3263 FU NINDS NIH HHS [NS 050524, NS 33981] NR 85 TC 20 Z9 20 U1 0 U2 3 PU OXFORD UNIV PRESS INC PI CARY PA JOURNALS DEPT, 2001 EVANS RD, CARY, NC 27513 USA SN 0959-6658 J9 GLYCOBIOLOGY JI Glycobiology PD FEB PY 2007 VL 17 IS 2 BP 231 EP 247 DI 10.1093/glycob/cw1069 PG 17 WC Biochemistry & Molecular Biology SC Biochemistry & Molecular Biology GA 127NH UT WOS:000243592500010 PM 17110391 ER PT J AU Simons-Morton, B AF Simons-Morton, Bruce TI Defined by publication: A commentary on health education and health promotion publication trends SO HEALTH EDUCATION & BEHAVIOR LA English DT Editorial Material DE research design; statistical methods; surveys C1 NICHD, DESPR, NIH, Prevent Res Branch, Bethesda, MD 20892 USA. RP Simons-Morton, B (reprint author), NICHD, DESPR, NIH, Prevent Res Branch, 6100 Execut Blvd 7B13M, Bethesda, MD 20892 USA. EM Mortonb@mail.nih.gov OI Simons-Morton, Bruce/0000-0003-1099-6617 NR 12 TC 1 Z9 1 U1 0 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1090-1981 J9 HEALTH EDUC BEHAV JI Health Educ. Behav. PD FEB PY 2007 VL 34 IS 1 BP 26 EP 30 DI 10.1177/1090198106288567 PG 5 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 128HN UT WOS:000243648900002 PM 16803944 ER PT J AU Shaw, BR Han, JY Baker, T Witherly, J Hawkins, RP McTavish, F Gustafson, DH AF Shaw, Bret R. Han, Jeong Yeob Baker, Timothy Witherly, Jeffre Hawkins, Robert P. McTavish, Fiona Gustafson, David H. TI How women with breast cancer learn using interactive cancer communication systems SO HEALTH EDUCATION RESEARCH LA English DT Article ID COMPUTER SUPPORT; SMOKING CESSATION; TAILORED MESSAGES; MULTICOLLINEARITY; NONLINEARITY; INFORMATION; SETTINGS; CHESS; CARE AB To provide insights about how women with breast cancer learn from interactive cancer communication systems (ICCSs), this study examined how use of different types of services that employ conceptually distinct pedagogical methods relates to learning outcomes. The study sample included 231 recently diagnosed, lower income breast cancer patients. Participants were provided a free computer, Internet access and training in how to use an ICCS called the Comprehensive Health Enhancement Support System 'Living with Breast Cancer' program. Data comprised survey information collected at pre-test and 4 months after using the system and computer records of how women used the system (use data). The findings suggest that use of the information and interactive services independently contributed to perceived information competence, though the communication services, including both discussion group and ask an expert, did not. Consistent with expectations, use of discussion group and interactive services amplified the learning effects of using the information services. However, use of the ask an expert service did not amplify the learning effects of using the information services as predicted. Some constructivist pedagogical methods-specifically online support groups and intelligently designed, computer-driven interactive services-may supplement and extend the learning potential of information services delivered via a transmission-oriented pedagogical approach. C1 Univ Wisconsin, Ctr Excellence Canc Commun Res, Madison, WI USA. Univ Wisconsin, Dept Psychol, Madison, WI USA. NCI, Div Canc Control & Populat Sci, Bethesda, MD 20892 USA. RP Shaw, BR (reprint author), Univ Wisconsin, Ctr Excellence Canc Commun Res, 1136 WARF Bldg,610 Walnut St, Madison, WI USA. EM bretshaw@chsra.wisc.edu NR 41 TC 41 Z9 42 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1153 EI 1465-3648 J9 HEALTH EDUC RES JI Health Educ. Res. PD FEB PY 2007 VL 22 IS 1 BP 108 EP 119 DI 10.1093/her/cyl051 PG 12 WC Education & Educational Research; Public, Environmental & Occupational Health SC Education & Educational Research; Public, Environmental & Occupational Health GA 127NC UT WOS:000243592000010 PM 16829544 ER PT J AU Coffin, AB Dabdoub, A Kelley, MW Popper, AN AF Coffin, Allison B. Dabdoub, Alain Kelley, Matthew W. Popper, Arthur N. TI Myosin VI and VIIa distribution among inner ear epithelia in diverse fishes SO HEARING RESEARCH LA English DT Article DE teleost; hearing; hair cell; saccule; utricle; lagena; myosin ID SENSORY HAIR-CELLS; NONSYNDROMIC HEARING-LOSS; SNELLS-WALTZER MICE; UNCONVENTIONAL MYOSIN; HEREDITARY DEAFNESS; STRUCTURAL INTEGRITY; CROSS-LINKS; MUTATIONS; STEREOCILIA; ZEBRAFISH AB Unconventional myosins are critical motor proteins in the vertebrate inner ear. Mutations in any one of at least six different myosins can lead to human hereditary deafness, but the precise functions of these proteins in the ear are unknown. This study uses a comparative approach to better understand the role of myosins VI and VIIa in vertebrate ears by examining protein distribution for these two myosins in the ears of evolutionarily diverse fishes and the aquatic clawed toad Xenopus laevis. Both myosins are expressed in the inner ears of all species examined in this study. Myo7a localizes to hair cells, particularly the actin-rich hair bundle, in all species studied. Myo6 also localizes to hair cells, but its distribution differs between species and end organs. Myo6 is found in hair bundles of most fish and frog epithelia examined here but not in anterior and posterior utricular hair bundles of American shad. These results show that myo7a distribution is highly conserved in diverse vertebrates and suggest functional conservation as well. The finding of myo6 in fish and Xenopus hair bundles, however, suggests a novel role for this protein in anamniotic hair cells. The lack of myo6 in specific American shad utricular hair bundles indicates a unique quality of these cells among fishes, perhaps relating to ultrasound detection capability that is found in this species. (c) 2006 Elsevier B.V. All rights reserved. C1 Univ Maryland, Dept Biol, College Pk, MD 20742 USA. Natl Inst Deafness & Other Commun Disorders, Sect Dev Neurosci, NIH, Bethesda, MD 20892 USA. Univ Maryland, Neurosci & Cognit Sci Program, College Pk, MD 20742 USA. Univ Maryland, Ctr Comparat & Evolutionary Biol Hearing, College Pk, MD 20742 USA. RP Coffin, AB (reprint author), Queens Univ, Dept Biol, Kingston, ON K7L 3N6, Canada. EM coffina@biology.queensu.ca; dabdouba@nidcd.nih.gov; kelleymt@nidcd.nih.gov; apopper@umd.edu FU Intramural NIH HHS; NIDCD NIH HHS [P30 DC004664, F31 DC005724, T32 DC000046, T32-DC-00046] NR 74 TC 9 Z9 9 U1 3 U2 6 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0378-5955 J9 HEARING RES JI Hear. Res. PD FEB PY 2007 VL 224 IS 1-2 BP 15 EP 26 DI 10.1016/j.heares.2006.11.004 PG 12 WC Audiology & Speech-Language Pathology; Neurosciences; Otorhinolaryngology SC Audiology & Speech-Language Pathology; Neurosciences & Neurology; Otorhinolaryngology GA 139JE UT WOS:000244427300002 PM 17204383 ER PT J AU Kim, J Zhu, W Chang, L Bentler, PM Ernst, T AF Kim, Jieun Zhu, Wei Chang, Linda Bentler, Peter M. Ernst, Thomas TI Unified structural equation modeling approach for the analysis of multisubject, multivariate functional MRI data SO HUMAN BRAIN MAPPING LA English DT Article DE dynamic causal modeling; fMRI; general linear model; multivariate autoregressive; structural equation modeling; subject-level covariates; visual attention study ID TIME-SERIES; EFFECTIVE CONNECTIVITY; CORTICAL INTERACTIONS; GRANGER CAUSALITY; VISUAL PATHWAYS; WORKING-MEMORY; HUMAN BRAIN; FMRI DATA; ATTENTION; NETWORK AB The ultimate goal of brain connectivity studies is to propose, test, modify, and compare certain directional brain pathways. Path analysis or structural equation modeling (SEM) is an ideal statistical method for such studies. In this work, we propose a two-stage unified SEM plus GLM (General Linear Model) approach for the analysis of multisubject, multivariate functional magnetic resonance imaging (fMRI) time series data with subject-level covariates. In Stage 1, we analyze the fMRI multivariate time series for each subject individually via a unified SEM model by combining longitudinal pathways represented by a multivariate autoregressive (MAR) model, and contemporaneous pathways represented by a conventional SEM. In Stage 2, the resulting subject-level path coefficients are merged with subject-level covariates such as gender, age, IQ, etc., to examine the impact of these covariates on effective connectivity via a GLM. Our approach is exemplified via the analysis of an fMRI visual attention experiment. Furthermore, the significant path network from the unified SEM analysis is compared to that from a conventional SEM analysis without incorporating the longitudinal information as well as that from a Dynamic Causal Modeling (DCM) approach. C1 SUNY Stony Brook, Dept Appl Math & Stat, Stony Brook, NY 11794 USA. Univ Hawaii, Dept Med, John A Burns Sch Med, Honolulu, HI 96822 USA. Univ Calif Los Angeles, Dept Psychol, Los Angeles, CA 90024 USA. Univ Calif Los Angeles, Dept Stat, Los Angeles, CA 90024 USA. NYU, Dept Psychiat, New York, NY 10016 USA. RP Kim, J (reprint author), NIDCD, Brain Imaging & Modeling Sect, NIH, Bldg 10,Rm 8S235C, Bethesda, MD 20892 USA. EM kimjieun@nidcd.nih.gov FU NCRR NIH HHS [3M01 RR0101710-06S1]; NIA NIH HHS [2P30AG08051-11]; NIDA NIH HHS [DA00017, DA01070, K02 DA16991, K24 DA16170] NR 45 TC 83 Z9 84 U1 3 U2 8 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 1065-9471 J9 HUM BRAIN MAPP JI Hum. Brain Mapp. PD FEB PY 2007 VL 28 IS 2 BP 85 EP 93 DI 10.1002/hbm.20259 PG 9 WC Neurosciences; Neuroimaging; Radiology, Nuclear Medicine & Medical Imaging SC Neurosciences & Neurology; Radiology, Nuclear Medicine & Medical Imaging GA 129WG UT WOS:000243760200001 PM 16718669 ER PT J AU Voutetakis, A Zheng, CY Mineshiba, F Cotrim, AP Goldsmith, CM Schmidt, M Afione, S Roescher, N Metzger, M Eckhaus, MA Chiorini, JA Dunbar, CE Donahue, RE Baum, BJ AF Voutetakis, Antonis Zheng, Changyu Mineshiba, Fumi Cotrim, Ana P. Goldsmith, Corinne M. Schmidt, Michael Afione, Sandra Roescher, Nienke Metzger, Mark Eckhaus, Michael A. Chiorini, John A. Dunbar, Cynthia E. Donahue, Robert E. Baum, Bruce J. TI Adeno-associated virus serotype 2-mediated gene transfer to the parotid glands of nonhuman primates SO HUMAN GENE THERAPY LA English DT Article ID HUMAN AQUAPORIN-1 CDNA; SALIVARY-GLANDS; IN-VIVO; ENDOCRINE SECRETION; PROTEIN SECRETION; MEDIATED TRANSFER; TRANSFER VECTOR; VIRAL VECTORS; SAFETY; THERAPEUTICS AB Salivary glands (SGs) are promising gene transfer targets with potential clinical applicability. Previous experiments in rodents using recombinant serotype 2 adeno-associated viral (rAAV2) vectors have demonstrated relatively stable transgene-encoded protein levels after SG gene transfer. In the present study, we examine direct SG administration of rAAV2 vectors encoding rhesus macaque erythropoietin (RhEPO) to the parotid glands of nonhuman primates using two different doses (n = 3 per group; 1 x 10(10) or 3 x 10(11) particles/gland, respectively). Gene transfer had no negative effects on general macaque physiology (e. g., weight, complete blood count, and serum chemistry). Macaques were euthanized 6 months after vector administration and complete necropsy and pathology assessments were performed, revealing no vector-related pathological lesions in any of the examined organs. In the high-dose group, RhEPO expression increased quickly (i.e., by week 1) and levels remained relatively stable both in serum and saliva until the end of the study. Serum-to-saliva ratios of RhEPO revealed secretion of the transgene product into the bloodstream, but not to the extent previously observed in mice. Furthermore, the kinetic results were not predicted by those observed in murine SGs. With respect to viral biodistribution, at necropsy vector was found overwhelmingly in the targeted parotid gland (similar to 100 times more than levels in other tissues, most of which were similar to tissue levels in nontreated animals). We conclude that administration of modest doses of rAAV2 vectors to SGs for therapeutic purposes can be accomplished without significant or permanent injury to the targeted gland or to distant organs of nonhuman primates. C1 Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, Bethesda, MD 20892 USA. Natl Heart Lung & Blood Inst, Hematol Branch, NIH, Dept Human Hlth Serv, Bethesda, MD 20892 USA. NIH, Div Vet Resources, Dept Human Hlth Serv, Bethesda, MD 20892 USA. RP Baum, BJ (reprint author), Natl Inst Dent & Craniofacial Res, Gene Therapy & Therapeut Branch, Bldg 10,Room 1A01,MSC-1190,9000 Rockville Pike, Bethesda, MD 20892 USA. EM bbaum@nidcr.nih.gov FU Intramural NIH HHS NR 43 TC 20 Z9 20 U1 0 U2 0 PU MARY ANN LIEBERT INC PI NEW ROCHELLE PA 140 HUGUENOT STREET, 3RD FL, NEW ROCHELLE, NY 10801 USA SN 1043-0342 J9 HUM GENE THER JI Hum. Gene Ther. PD FEB PY 2007 VL 18 IS 2 BP 142 EP 150 DI 10.1089/hum.2006.154 PG 9 WC Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental SC Biotechnology & Applied Microbiology; Genetics & Heredity; Research & Experimental Medicine GA 147VR UT WOS:000245031400006 PM 17328682 ER PT J AU Yao, YG Ellison, FM McCoy, JP Chen, JC Young, NS AF Yao, Yong-Gang Ellison, Felicia M. McCoy, J. Philip Chen, Jichun Young, Neal S. TI Age-dependent accumulation of mtDNA mutations in murine hematopoietic stem cells is modulated by the nuclear genetic background SO HUMAN MOLECULAR GENETICS LA English DT Article ID MITOCHONDRIAL-DNA MUTATIONS; POINT MUTATIONS; DEGENERATIVE DISEASES; OXIDATIVE STRESS; SKELETAL-MUSCLE; CONTROL REGION; MICE; REPLICATION; SEQUENCE; SENESCENCE AB Alterations in mitochondrial DNA (mtDNA) and consequent loss of mitochondrial function underlie the mitochondrial theory of aging. In this study, we systematically analyzed the mtDNA control region somatic mutation pattern in 2864 single hematopoietic stem cells (HSCs) and progenitors, isolated by flow cytometry sorting on Lin(-)Kit(+)CD34(-) parameters from young and old C57BL/6 (B6) and BALB/cBy (BALB) mice, to test the hypothesis that the accumulated mtDNA mutations in HSCs were strain-correlated and associated with HSC functional senescence during aging. An increased level of mtDNA mutations in single HSCs was observed in old B6 when compared with young B6 mice (P=0.003); in contrast, no significant age-dependent accumulation of mutations was observed in BALB mice (old versus young, P=0.202) and the level of mutations in both young and old BALB mice was close to that of old B6 mice (P > 0.280). Cellular reactive oxygen species (ROS) in mouse HSCs could not be correlated with the level of mtDNA mutations in these cells, although B6 mice had a higher proportion of ROS- cells when compared with the BALB mice. Propagation assays of single HSCs showed B6 cells form larger colonies compared with cells from BALB mice, irrespective of age and mtDNA mutation load. We infer from our data that age-related mtDNA somatic mutation accumulation in mouse HSCs is influenced by the nuclear genetic background and that these mutations may not obviously correlate to either cellular ROS content or HSC senescence. C1 NHLBI, Hematol Branch, NIH, Bethesda, MD 20892 USA. NHLBI, Flow Cytometry Core Facil, NIH, Bethesda, MD 20892 USA. RP Yao, YG (reprint author), NHLBI, Hematol Branch, NIH, Bldg 10 CRC,Rm 3E-5140,10 Ctr Dr, Bethesda, MD 20892 USA. EM yaoy3@nhlbi.nih.gov NR 47 TC 20 Z9 24 U1 0 U2 3 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 1 PY 2007 VL 16 IS 3 BP 286 EP 294 DI 10.1093/hmg/ddl457 PG 9 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 135AK UT WOS:000244126000005 PM 17185390 ER PT J AU Hancock, AL Brown, KW Moorwood, K Moon, H Holmgren, C Mardikar, SH Dallosso, AR Klenova, E Loukinov, D Ohlsson, R Lobanenkov, VV Malik, K AF Hancock, Anne L. Brown, Keith W. Moorwood, Kim Moon, Hanlim Holmgren, Claes Mardikar, Sudhanshu H. Dallosso, Anthony R. Klenova, Elena Loukinov, Dmitri Ohlsson, Rolf Lobanenkov, Victor V. Malik, Karim TI A CTCF-binding silencer regulates the imprinted genes AWT1 and WT1-AS and exhibits sequential epigenetic defects during Wilms' tumourigenesis SO HUMAN MOLECULAR GENETICS LA English DT Article ID GROWTH-FACTOR-II; CHROMOSOME ARM 16Q; TUMOR GENE; TRANSCRIPTIONAL REGULATION; NEPHROGENIC RESTS; CONTROL REGION; DNA-SEQUENCE; PROMOTER; MUTATIONS; PROTEIN AB We have shown previously that AWT1 and WT1-AS are functionally imprinted in human kidney. In the adult kidney, expression of both transcripts is restricted to the paternal allele, with the silent maternal allele retaining methylation at the WT1 antisense regulatory region (WT1 ARR). Here, we report characterization of the WT1 ARR differentially methylated region and show that it contains a transcriptional silencer element acting on both the AWT1 and WT1-AS promoters. DNA methylation of the silencer results in increased transcriptional repression, and the silencer is also shown to be an in vitro and in vivo target site for the imprinting regulator protein CTCF. Binding of CTCF is methylation-sensitive and limited to the unmethylated silencer. Potentiation of the silencer activity is demonstrated after CTCF protein is knocked down, suggesting a novel silencer-blocking activity for CTCF. We also report assessment of WT1 ARR methylation in developmental and tumour tissues, including the first analysis of Wilms' tumour precursor lesions, nephrogenic rests. Nephrogenic rests show increases in methylation levels relative to foetal kidney and reductions relative to the adult kidney, together with biallelic expression of AWT1 and WT1-AS. Notably, the methylation status of CpG residues within the CTCF target site appears to distinguish monoallelic and biallelic expression states. Our data suggest that failure of methylation spreading at the WT1 ARR early in renal development, followed by imprint erasure, occurs during Wilms' tumourigenesis. We propose a model wherein imprinting defects at chromosome 11p13 may contribute to Wilms' tumourigenesis. C1 Univ Bristol, Sch Med Sci, Dept Cellular & Mol Med, CLCI Sargent Res Unit, Bristol BS8 1TD, Avon, England. NIAID, Immunopathol Lab, NIH, Bethesda, MD 20892 USA. Uppsala Univ, Dept Dev & Genet, S-75236 Uppsala, Sweden. Univ Essex, Dept Biol Sci, Colchester CQ4 3SQ, Essex, England. RP Malik, K (reprint author), Univ Bristol, Sch Med Sci, Dept Cellular & Mol Med, CLCI Sargent Res Unit, Univ Walk, Bristol BS8 1TD, Avon, England. EM k.t.a.malik@bris.ac.uk RI dallosso, anthony/A-8335-2008; Brown, Keith/C-3355-2009; OI Brown, Keith/0000-0002-4258-5129; Dallosso, Anthony/0000-0002-1460-2550 FU Medical Research Council [G0401088] NR 50 TC 23 Z9 25 U1 1 U2 4 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 1 PY 2007 VL 16 IS 3 BP 343 EP 354 DI 10.1093/hmg/ddl478 PG 12 WC Biochemistry & Molecular Biology; Genetics & Heredity SC Biochemistry & Molecular Biology; Genetics & Heredity GA 135AK UT WOS:000244126000010 PM 17210670 ER PT J AU Richani, K Romero, R Soto, E Nien, JK Cushenberry, E Kim, YM Espinoza, J Kim, CJ AF Richani, Karina Romero, Roberto Soto, Eleazar Nien, Jyh Kae Cushenberry, Enota Kim, Yeon Mee Espinoza, Jimmy Kim, Chong Jai TI Genetic origin and proportion of basal plate surface-lining cells in normal and abnormal pregnancies SO HUMAN PATHOLOGY LA English DT Article DE placenta; basal plate; trophoblast; endothelium; morphometry; immunohistochemistry ID INTRAUTERINE GROWTH RESTRICTION; LASER-SCANNING MICROSCOPY; PLACENTAL BED; ENDOTHELIAL-CELLS; SPIRAL ARTERIES; PREECLAMPSIA; HYPERTENSION; PATHOGENESIS; ACTIVATION; MEMBRANES AB The human placenta is a transient organ, the villous surface of which is in direct contact with the maternal circulation during pregnancy. Thus, the syncytiotrophoblast and the basal plate-lining cells are considered continuous with the endothelial layer of the maternal vasculature. Two types of cells are found on the surface of the basal plate: trophoblasts (of fetal origin) and endothelial cells of putative maternal origin. Histologic abnormalities have been described in the basal plate of the placenta obtained from patients with preeclampsia and intrauterine growth restriction. Moreover, endothelial cell dysfunction and intravascular inflammation are key features of preeclampsia. The objectives of this study were to: (1) determine the origin of the endothelial cells located in the basal plate surface of the placenta (from male fetuses); and (2) analyze the relative proportion of the intervillous surface of the basal plate occupied by trophoblasts and endothelial cells. Immunohistochemistry and morphometry were performed in placentas from women in the following clinical groups: (1) normal-term pregnancies (n = 15); (2) severe preeclampsia at term (n = 15); (3) small-for-gestational-age (SGA) neonates delivered at term (n = 15); (4) preterm deliveries (< 37 weeks) without inflammation (n = 5); and (5) preterm preeclampsia (n = 5). Laser capture microdissection and polymerase chain reaction were used to determine the allelic pattern of the amelogenin gene of the endothelial cells on the intervillous surface of the basal plate. Our results showed that: (1) the endothelial cells lining the basal plate in placentas of male fetuses were uniformly of maternal origin; and (2) in placentas from uncomplicated pregnancies, the median proportion of trophoblasts and endothelial cells covering the surface of the basal plate were 27.7% and 46.5%, respectively. The remaining area of the intervillous surface of the basal plate was composed of fibrin and anchoring villi. Of interest, placentas from women who delivered an SGA neonate had a higher proportion of trophoblasts and a lower proportion of endothelial cells lining the basal plate than those from normal pregnancies (P < .05). The same tendency was observed in placentas from patients with preeclampsia. This study demonstrates that endothelial cells of maternal origin cover the intervillous surface of the basal plate of the placenta, along with trophoblasts of fetal origin. The proportion of this surface lined by trophoblasts is greater in placentas from SGA and preeclampsia than in normal pregnancy. We propose that this change reflects a compensatory mechanism whereby the basal plate surface covered by injured endothelial cells is replaced by trophoblasts or results from a failure of trophoblastic involution in abnormal pregnancies. Our observations also suggest that the lining of the basal plate can provide information about the pathology of endothelial cells in complications of pregnancy. (c) 2007 Published by Elsevier Inc. C1 Wayne State Univ, Perinatol Res Branch, NICHD,Hutzel Womens Hosp, NIH,DHHS, Detroit, MI 48201 USA. Wayne State Univ, Ctr Mol Med & Genet, Detroit, MI 48201 USA. Wayne State Univ, Dept Pathol, Detroit, MI 48201 USA. Wayne State Univ, Dept Obstet & Gynecol, Detroit, MI 48201 USA. RP Kim, CJ (reprint author), Wayne State Univ, Perinatol Res Branch, NICHD,Hutzel Womens Hosp, NIH,DHHS, 3990 John R,4th Floor, Detroit, MI 48201 USA. EM warfiela@mail.nih.gov; cjki@med.wayne.edu FU Intramural NIH HHS NR 35 TC 6 Z9 7 U1 0 U2 1 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD FEB PY 2007 VL 38 IS 2 BP 269 EP 275 DI 10.1016/j.humpath.2006.08.007 PG 7 WC Pathology SC Pathology GA 131QB UT WOS:000243883700009 PM 17059842 ER PT J AU Fukuoka, J Dracheva, T Shih, JH Hewitt, SM Fujii, T Kishor, A Mann, F Shilo, K Franks, TJ Travis, WD Jen, J AF Fukuoka, Junya Dracheva, Tatiana Shih, Joanna H. Hewitt, Stephen M. Fujii, Takashi Kishor, Aparna Mann, Felecia Shilo, Konstantin Franks, Teri J. Travis, William D. Jen, Jin TI Desmoglein 3 as a prognostic factor in lung cancer SO HUMAN PATHOLOGY LA English DT Article DE tissue microarray; gene expression; carcinoid tumors; desmosome; outcome ID PULMONARY NEUROENDOCRINE TUMORS; PEMPHIGUS-VULGARIS ANTIGEN; BRONCHIAL CARCINOID-TUMORS; SQUAMOUS-CELL CARCINOMA; E-CADHERIN; TISSUE MICROARRAY; BETA-CATENIN; ADHESION; EXPRESSION; SURVIVAL AB Desmoglein 3 is a desmosomal protein of the cadherin family. Our cDNA expression profile demonstrated that desmoglein 3 was highly expressed in squamous cell carcinoma of the lung but not detected in pulmonary adenocarcinoma or normal lung. To investigate the clinical significance of desmoglein 3 in lung cancer, we surveyed its expression in primary non-small-cell lung cancers and neuroendocrine tumors. We used immunohistochemical analysis to examine the expression of desmoglein 3 by using tissue microarrays containing samples from 300 surgical non-small-cell lung cancer and 183 lung neuroendocrine tumor. Staining status was determined based on the sum of the distribution score (0, 1, or 2) and the intensity score (0, 1, 2, or 3) of the staining signal. Follow-up was available for 346 cases (median follow-up of 2.8 years). We determined the survival statistical significance of desmoglein 3 by using the log-rank test, and we plotted Kaplan-Meier curves. Negative immunohistochemical staining with desmoglein 3 was associated with shorter survival for all lung cancer patients regardless of the histologic subtype (5-year survival of 20.9% versus 49.5%, P < .001) in our series. In patients with atypical carcinoid tumors, lacking desmoglein 3 expression showed a 5-year survival of 0% compared with 36.8% for desmoglein 3-positive cases (P < .001). Desmoglein 3 status indicated a poor prognosis in lung cancers and portends a more aggressive behavior for atypical carcinoid tumors. Published by Elsevier Inc. C1 NCI, Lab Populat Genet, Canc Res Ctr, Bethesda, MD 20892 USA. NCI, Biometr Res Branch, Bethesda, MD 20892 USA. NCI, Tissue Array Res Program, Pathol Lab, Bethesda, MD 20892 USA. Toyama Univ Hosp, Anat Pathol Lab, Toyama Tissue Micorarray Lab, Toyama 9300194, Japan. Armed Forces Inst Pathol, Dept Pulm & Mediastinal Pathol, Washington, DC 20306 USA. Mem Sloan Kettering Canc Ctr, Dept Pathol, New York, NY 10021 USA. RP Fukuoka, J (reprint author), NCI, Lab Populat Genet, Canc Res Ctr, Bethesda, MD 20892 USA. EM fukuokaj@med.u-toyama.ac.jp; jenj@mail.nih.gov RI Shilo, Konstantin/E-4084-2011; Fujii, Takeshi/D-5877-2014; OI Fujii, Takeshi/0000-0001-7237-1183; Hewitt, Stephen/0000-0001-8283-1788; S, K/0000-0002-6702-3130 FU Intramural NIH HHS NR 30 TC 31 Z9 31 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD FEB PY 2007 VL 38 IS 2 BP 276 EP 283 DI 10.1016/j.humpath.2006.08.006 PG 8 WC Pathology SC Pathology GA 131QB UT WOS:000243883700010 PM 17084439 ER PT J AU Engels, EA Mbulaiteye, SM Othieno, E Gomez, M Mathew, S Cesarman, E Knowles, DM Chadburn, A AF Engels, Eric A. Mbulaiteye, Sam M. Othieno, Emmanuel Gomez, Mario Mathew, Susan Cesarman, Ethel Knowles, Daniel M. Chadburn, Amy TI Kaposi sarcoma-associated herpesvirus in non-Hodgkin lymphoma and reactive lymphadenopathy in Uganda SO HUMAN PATHOLOGY LA English DT Article DE Kaposi sarcoma-associated herpesvirus (human herpesvirus 8); non-Hodgkin lymphoma; multicentric Castleman disease; follicular involution; Africa; Epstein-Barr virus; human immunodeficiency virus ID MULTICENTRIC CASTLEMANS-DISEASE; PRIMARY EFFUSION LYMPHOMA; HUMAN-HERPESVIRUS-8 INFECTION; HIV-INFECTION; DNA-SEQUENCES; AIDS; KSHV; ANTIBODIES; VIRUS; INTERLEUKIN-6 AB Kaposi sarcoma-associated herpesvirus (KSHV) causes Kaposi sarcoma and is also associated with primary effusion lymphoma, a subset of diffuse large B-cell lymphomas, and multicentric Castleman disease. Because KSHV infection is endemic in sub-Saharan Africa, we sought to identify cases of KSHV-positive non-Hodgkin lymphomas (NHLs) and reactive lymphadenopathy in this region. One hundred forty-four cases (80 NHLs, 64 reactive lymph nodes) from the major pathology laboratory in Uganda were reviewed. One NHL was KSHV-positive, as indicated by staining for the viral latent nuclear antigen. This NHL was a diffuse large B-cell lymphoma in a 5-year-old boy. The tumor was also Epstein-Barr virus-positive. In addition, 2 reactive lymph nodes, both classified histologically as follicular involution, stained KSHV latent nuclear antigen-positive and thus most likely represent multicentric Castleman disease. In all 3 KSHV-positive cases, a minority of cells expressed KSHV viral interleukin 6, a biologically active cytokine homolog. In conclusion, we show that KSHV is rarely associated with lymphoproliferative disorders in sub-Saharan Africa. We describe the first case of a KSHV-positive NHL from this region; this case is also the first reported pediatric lymphoma associated with KSHV infection. (c) 2007 Elsevier Inc. All rights reserved. C1 NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. Makerere Univ, Dept Pathol, Kampala, Uganda. Weill Cornell Med Coll, Dept Pathol & Lab Med, New York, NY 10021 USA. RP Engels, EA (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Dept Hlth & Human Serv, Bethesda, MD 20892 USA. EM engelse@exchange.nih.gov NR 27 TC 12 Z9 12 U1 0 U2 0 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0046-8177 J9 HUM PATHOL JI Hum. Pathol. PD FEB PY 2007 VL 38 IS 2 BP 308 EP 314 DI 10.1016/j.humpath.2006.08.009 PG 7 WC Pathology SC Pathology GA 131QB UT WOS:000243883700014 PM 17097130 ER PT J AU Ferrari, RM Cooney, MA Vexler, A Liu, A Louis, GMB AF Ferrari, R. M. Cooney, M. A. Vexler, A. Liu, A. Louis, G. M. Buck TI Time to pregnancy and multiple births SO HUMAN REPRODUCTION LA English DT Article DE fecundity; multiple births; time-to-pregnancy; twinning ID OVULATION INDUCTION; HUMAN-FERTILITY; TWINNING RATE; TO-PREGNANCY; FECUNDITY; TRENDS; FECUNDABILITY; CONCEPTION; DURATION; IMPACT AB BACKGROUND: Mothers of multiples are alleged to be more fecund than mothers of singletons. Some authors have suggested monitoring twinning rates for assessing temporal changes in a population's reproductive health. METHODS: Using a nested case-control design, we estimated the odds of a multiple birth in relation to fecundity in the US Collaborative Perinatal Project inclusive of 8546 pregnant women who reported a known time-to-pregnancy (TTP) upon enrolment in the cohort, 1959-1966. Case mothers comprised 81 women giving birth to twins/triplets; control mothers comprised 243 women giving birth to singletons matched to case mothers on maternal age at a ratio of 3:1. The odds ratio (OR) for a multiple birth within 6 months of trying adjusting for maternal age and prior pregnancies was estimated using logistic regression. Discrete time Cox regression analysis was also utilized to estimate the fecundability OR. RESULTS: Women with a TTP of <= 6 months were more likely to have a multiple birth than women reporting a TTP of > 6 months [OR = 1.95; 95% confidence interval (95% CI) = 1.09-3.51]. Excluding pregnancies after 13+ months resulted in a loss of precision (OR = 2.14; 95% CI = 0.90-5.04). CONCLUSIONS: These data support higher fecundity among mothers of multiples than mothers of singletons. C1 NICHHD, Epidemiol Branch, Rockville, MD 20852 USA. NICHHD, Biometry Branch, Rockville, MD 20852 USA. Univ N Carolina, Dept Maternal & Child Hlth, Chapel Hill, NC USA. RP Louis, GMB (reprint author), NICHHD, Epidemiol Branch, 6100 Execut Blvd,Room 7B03, Rockville, MD 20852 USA. EM louisg@mail.nih.gov OI Liu, Aiyi/0000-0002-6618-5082; Buck Louis, Germaine/0000-0002-1774-4490 FU Intramural NIH HHS NR 37 TC 6 Z9 6 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD FEB PY 2007 VL 22 IS 2 BP 407 EP 413 DI 10.1093/humrep/de1374 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 127MU UT WOS:000243591200013 PM 17000648 ER PT J AU Law, DCG Maclehose, RF Longnecker, MP AF Law, D. C. Gesink Maclehose, R. F. Longnecker, M. P. TI Obesity and time to pregnancy SO HUMAN REPRODUCTION LA English DT Article DE fecundity; fertility; obesity; reproduction ID BODY-MASS INDEX; POLYCYSTIC-OVARY-SYNDROME; OVULATORY DISORDER; WEIGHT-LOSS; WOMEN; INFERTILITY; IMPROVEMENT; FERTILITY; LIFE; REPRODUCTION AB BACKGROUND: Obesity may reduce fecundity. We examined the obesity-fecundity association in relation to menstrual cycle regularity, parity, smoking habits and age to gain insight into mechanisms and susceptible subgroups. METHODS: Data were provided by 7327 pregnant women enrolled in the Collaborative Perinatal Project at 12 study centres in the United States from 1959 to 1965. Prepregnancy body mass index (BMI) was analysed continuously and categorically [underweight (< 18.5 kg/m(2)), optimal weight (18.5-24.9 kg/m(2)), overweight (25.0-29.9 kg/m(2)) and obese (>= 30.0 kg/m(2))]. Adjusted fecundability odds ratios (FORs) were estimated using Cox proportional hazards modelling for discrete time data. RESULTS: Fecundity was reduced for overweight [OR = 0.92, 95% confidence interval (95% CI): 0.84, 1.01] and obese (OR = 0.82, 95% CI: 0.72, 0.95) women compared with optimal weight women and was more evident for obese primiparous women (OR = 0.66, 95% CI: 0.49, 0.89). Fecundity remained reduced for overweight and obese women with normal menstrual cycles. Neither smoking habits nor age modified the association. CONCLUSIONS: Obesity was associated with reduced fecundity for all subgroups of women and persisted for women with regular cycles. Our results suggest that weight loss could increase fecundity for overweight and obese women, regardless of menstrual cycle regularity, parity, smoking habits and age. C1 Montana State Univ, Dept Microbiol, Bozeman, MT 59717 USA. NIEHS, Epidemiol Branch, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC USA. NIEHS, Biostat Branch, Dept Hlth & Human Serv, NIH, Res Triangle Pk, NC 27709 USA. RP Law, DCG (reprint author), Montana State Univ, Dept Microbiol, POB 173520, Bozeman, MT 59717 USA. EM dionne.gesinklaw@montana.edu OI Longnecker, Matthew/0000-0001-6073-5322 FU Intramural NIH HHS; NIEHS NIH HHS [Z01 ES049016-10] NR 44 TC 79 Z9 82 U1 1 U2 8 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0268-1161 J9 HUM REPROD JI Hum. Reprod. PD FEB PY 2007 VL 22 IS 2 BP 414 EP 420 DI 10.1093/humrep/de1400 PG 7 WC Obstetrics & Gynecology; Reproductive Biology SC Obstetrics & Gynecology; Reproductive Biology GA 127MU UT WOS:000243591200014 PM 17095518 ER PT J AU Takemori, K Gao, YJ Ding, LL Lu, C Su, LY An, WS Vinson, C Lee, RMKW AF Takemori, Kumiko Gao, Yu-Jing Ding, Lili Lu, Chao Su, Li-Ying An, Wen-Sheng Vinson, Charles Lee, Robert M. K. W. TI Elevated blood pressure in transgenic lipoatrophic mice and altered vascular function SO HYPERTENSION LA English DT Article DE lipoatrophy; hypertension; vascular fat function; adipose tissue ID ADIPOSE-TISSUE; ENDOCRINE; FAT AB The role of perivascular fat in the control of vascular function was studied using lipoatrophic A-ZIP/F1 transgenic mice. Only a small amount of brown fat was found around the aorta but not around mesenteric arteries. Blood pressure of A-ZIP/F1 mice became higher than wild-type (WT) mice from 10 weeks of age. The presence of perivascular fat reduced the contraction of WT aorta to phenylephrine and serotonin, whereas this effect was either absent or less prominent in A-ZIP/F1 aorta. In WT mice, transfer of solution incubated with aorta with fat to aorta with fat removed caused a relaxation response, but not in A-ZIP/F1 mice, indicating the release of a relaxation factor from perivascular fat in WT aorta. This factor was acting through the activation of calcium-dependent potassium channels. Perfusion of phenylephrine to the isolated mesenteric bed caused a higher increase in perfusion pressure in A-ZIP/F1 than in WT mice. Contractile response of aorta to angiotensin II (Ang II) was mediated by Ang II type I receptors and was higher in A-ZIP/F1 than in WT mice. Expression of Ang II type I receptors but not Ang II type 2 receptors was higher in aorta of A-ZIP/F1 than WT mice. Treatment with an Ang II type I receptor antagonist (TCV 116, 10 mg/kg per day) for 2 weeks normalized the blood pressure of A-ZIP/F1 mice. These results suggest that the absence of perivascular fat tissue, which enhances the contractile response of the blood vessels to agonists, and an upregulation of vascular Ang II type I receptors in A-ZIP/F1 mice, are some of the mechanisms underlying the blood pressure elevation in these lipoatrophic mice. C1 McMaster Univ, Dept Anaesthesia, Hamilton, ON L8N 3Z5, Canada. McMaster Univ, Smooth Muscle Res Program, Hamilton, ON L8N 3Z5, Canada. Kinki Univ, Sch Med, Dept Pathol, Osaka, Japan. NCI, NIH, Bethesda, MD 20892 USA. RP Lee, RMKW (reprint author), McMaster Univ, Dept Anaesthesia, 1200 Main St W, Hamilton, ON L8N 3Z5, Canada. EM rmkwlee@mcmaster.ca NR 14 TC 45 Z9 47 U1 0 U2 4 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 0194-911X J9 HYPERTENSION JI Hypertension PD FEB PY 2007 VL 49 IS 2 BP 365 EP 372 DI 10.1161/01.HYP.0000255576.16089.b9 PG 8 WC Peripheral Vascular Disease SC Cardiovascular System & Cardiology GA 127PN UT WOS:000243598900022 PM 17200435 ER PT J AU Li, M Ishii, M Taylor, RH AF Li, Ming Ishii, Masaru Taylor, Russell H. TI Spatial motion constraints using virtual fixtures generated by anatomy SO IEEE TRANSACTIONS ON ROBOTICS LA English DT Article; Proceedings Paper CT IEEE International Conference on Robotics and Automation (ICRA) CY APR 18-22, 2005 CL Barcelona, SPAIN SP IEEE DE anatomy-based constraint; optimization robot control; surgical robot assistant; virtual fixtures (VFs) ID KINEMATICALLY REDUNDANT MANIPULATORS; ROBOT MANIPULATORS; SINUS SURGERY; RHINOSINUSITIS AB This paper describes a spatial-motion-constraints-generation approach for a human-machine collaborative surgical-assistant system from registered computer tomography models. We extend constrained optimization formulation incorporating task goals, anatomy-based constraints, "no fly zones," etc. We use a fast potential-collision-constraint-detection method based on a 3-D surface model and covariance tree data structure. These boundary constraints, along with task behaviors and joint limits, serve as constraint conditions for constrained robot control. We are able to follow a complex path inside a human skull, phantom represented by a surface model composed of 99000 vertices and 182 000 triangles in real time. Our approach enables real-time task-based control of a surgical robot in a precise interactive minimally invasive surgery task. We illustrate our approach based on two example tasks which are analogous to the procedures in endoscopic sinus surgery, and analyze the user's performance on both teleoperation and cooperative control for one of the example tasks. The experimental results show that a robotic assistant employing our approach on spatial motion constraints can assist the user in skilled manipulation tasks, while maintaining desired properties. Our approach is equally applicable to teleoperative and cooperative controlled robots. C1 NIH, Bethesda, MD 20892 USA. Johns Hopkins Bayview Med Ctr, Dept Otolaryngol Head & Neck Surg, Baltimore, MD 21224 USA. Johns Hopkins Univ, Dept Comp Sci, Baltimore, MD 21218 USA. RP Li, M (reprint author), NIH, Bethesda, MD 20892 USA. EM lim2@mail.nih.gov; mishii3@jhmi.edu; rht@jhu.edu NR 48 TC 45 Z9 47 U1 0 U2 6 PU IEEE-INST ELECTRICAL ELECTRONICS ENGINEERS INC PI PISCATAWAY PA 445 HOES LANE, PISCATAWAY, NJ 08855-4141 USA SN 1552-3098 EI 1941-0468 J9 IEEE T ROBOT JI IEEE Trans. Robot. PD FEB PY 2007 VL 23 IS 1 BP 4 EP 19 DI 10.1109/TRO.2006.886838 PG 16 WC Robotics SC Robotics GA 137SD UT WOS:000244311500002 ER PT J AU Schwartzberg, PL AF Schwartzberg, Pamela L. TI Formin the way SO IMMUNITY LA English DT Editorial Material ID T-CELL-ACTIVATION; IMMUNOLOGICAL SYNAPSE; COMPLEX AB Reorganization of the actin cytoskeleton requires nucleating factors, which initiate actin fiber formation. In this issue of Immunity, the functions of two classes of actin nucleators are examined in T lymphocytes, giving insight into the regulation of T cell polarity (Gomez et al., 2007). C1 NHGRI, NIH, Bethesda, MD 20892 USA. RP Schwartzberg, PL (reprint author), NHGRI, NIH, Bethesda, MD 20892 USA. EM pams@mail.nih.gov NR 9 TC 5 Z9 6 U1 0 U2 1 PU CELL PRESS PI CAMBRIDGE PA 1100 MASSACHUSETTS AVE, CAMBRIDGE, MA 02138 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD FEB PY 2007 VL 26 IS 2 BP 139 EP 141 DI 10.1016/j.immuni.2007.02.007 PG 3 WC Immunology SC Immunology GA 142DE UT WOS:000244628600003 PM 17307700 ER PT J AU Hasenkrug, KJ AF Hasenkrug, Kim J. TI The leptin connection: Regulatory T cells and autoimmunity SO IMMUNITY LA English DT Editorial Material ID IMMUNE-RESPONSE AB Leptin is a cytokine-like hormone with proinflammatory properties linked to autoimmune diseases. In this issue of Immunity, De Rosa et al. (2007) elucidate an important new role for leptin in the anergy and hyporesponsiveness of regulatory T cells. C1 NIAID, NIH, Lab Persistent Viral Dis, Hamilton, MT 59840 USA. RP Hasenkrug, KJ (reprint author), NIAID, NIH, Lab Persistent Viral Dis, Hamilton, MT 59840 USA. EM khasenkrug@nih.gov NR 9 TC 16 Z9 16 U1 0 U2 0 PU CELL PRESS PI CAMBRIDGE PA 600 TECHNOLOGY SQUARE, 5TH FLOOR, CAMBRIDGE, MA 02139 USA SN 1074-7613 J9 IMMUNITY JI Immunity PD FEB PY 2007 VL 26 IS 2 BP 143 EP 145 DI 10.1016/j.immuni.2007.02.002 PG 3 WC Immunology SC Immunology GA 142DE UT WOS:000244628600005 PM 17307702 ER PT J AU Hayes, SM Love, PE AF Hayes, Sandra M. Love, Paul E. TI A retrospective on the requirements for gamma delta T-cell development SO IMMUNOLOGICAL REVIEWS LA English DT Review DE gamma delta T cells; T-cell development; alpha beta versus gamma delta T-cell development; developmental; signaling pathways ID RECEPTOR-DEFICIENT MICE; PROTEIN-TYROSINE-PHOSPHATASE; INTESTINAL INTRAEPITHELIAL LYMPHOCYTES; DEFECTIVE LYMPHOID DEVELOPMENT; ALPHA-BETA; INTERLEUKIN-7 RECEPTOR; THYMOCYTE DEVELOPMENT; TRANSCRIPTION FACTOR; V(D)J RECOMBINATION; DIFFERENTIAL REQUIREMENTS AB Since the discovery of gamma delta T cells two decades ago, considerable effort has been made to understand their developmental program, their antigen specificity, and their contribution to the immune response. In this review, we focus on what is known about gamma delta T-cell development and on the advances that have been made in determining which genes are required. In addition, we compare the genetic requirements for alpha beta and gamma delta T-cell development with the hope of gaining a better picture of the signaling pathways that govern the development of gamma delta lineage cells. C1 NICHHD, Lab Mammalian Genes & Dev, NIH, Bethesda, MD 20892 USA. SUNY Upstate Med Univ, Dept Microbiol & Immunol, Syracuse, NY USA. RP Love, PE (reprint author), NICHHD, Lab Mammalian Genes & Dev, NIH, Bldg 6B,Room 2B-210,9000 Rockville Pike, Bethesda, MD 20892 USA. EM lovep@mail.nih.gov NR 100 TC 11 Z9 12 U1 2 U2 2 PU BLACKWELL PUBLISHING PI OXFORD PA 9600 GARSINGTON RD, OXFORD OX4 2DQ, OXON, ENGLAND SN 0105-2896 J9 IMMUNOL REV JI Immunol. Rev. PD FEB PY 2007 VL 215 BP 8 EP 14 DI 10.1111/j.1600-065X.2006.00476.x PG 7 WC Immunology SC Immunology GA 132WM UT WOS:000243973600002 PM 17291275 ER PT J AU Dharajiya, NG Bacsi, A Boldogh, I Sur, S AF Dharajiya, Nilesh G. Bacsi, Attila Boldogh, Istvan Sur, Sanjiv TI Pollen NAD(P)H oxidases and their contribution to allergic inflammation SO IMMUNOLOGY AND ALLERGY CLINICS OF NORTH AMERICA LA English DT Article ID CHRONIC GRANULOMATOUS-DISEASE; RESPIRATORY BURST OXIDASE; PHAGOCYTE NADPH OXIDASE; SUPEROXIDE PRODUCTION; OXIDATIVE BURST; HYDROGEN-PEROXIDE; PHYTOPHTHORA-INFESTANS; CYTOCHROME B(558); PLASMA-MEMBRANE; ACTIVE OXYGEN AB This article provides an overview of NADPH oxidase and its role in allergic inflammation. A background and historical perspectives of NADPH oxidase are first provided, followed by a detailed overview of mammalian NADPH oxidase subunits and their functional organization. Plant NADPH oxidase, the authors' discovery of NADPH oxidase in pollens, and their contribution to allergic inflammation are then discussed, concluding with a discussion of future directions and outstanding questions that require attention. C1 Univ Texas, Med Branch,NHLBI,Proteom Ctr, Dept Internal Med, Div Allergy Pulm Immunol Crit Ccare & Sleep, Galveston, TX 77555 USA. Univ Texas, Med Branch, Dept Internal Med, NHLBI Proteom Ctr,Div Sleep, Galveston, TX 77555 USA. Univ Texas, Med Branch, Dept Microbiol & Immunol, Galveston, TX 77555 USA. Univ Debrecen, Inst Immunol, H-4021 Debrecen, Hungary. Univ Texas, Med Branch, Dept Biochem & Mol Biol, NHLBI Proteom Ctr, Galveston, TX 77555 USA. RP Sur, S (reprint author), Univ Texas, Med Branch,NHLBI,Proteom Ctr, Dept Internal Med, Div Allergy Pulm Immunol Crit Ccare & Sleep, 301 Univ Blvd, Galveston, TX 77555 USA. EM sasur@utmb.edu FU NHLBI NIH HHS [1R01 HL 071163, N01 HV 28184]; NIAID NIH HHS [P01 AI062885, 1P01 AI 062885]; NIEHS NIH HHS [P30 ES006676] NR 97 TC 6 Z9 6 U1 0 U2 2 PU W B SAUNDERS CO-ELSEVIER INC PI PHILADELPHIA PA 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA SN 0889-8561 J9 IMMUNOL ALLERGY CLIN JI Immunol. Allerg. Clin. North Am. PD FEB PY 2007 VL 27 IS 1 BP 45 EP + DI 10.1016/j.iac.2006.11.007 PG 20 WC Allergy; Immunology SC Allergy; Immunology GA 140AC UT WOS:000244473300005 PM 17276878 ER PT J AU Wilson, MS Mentink-Kane, MM Pesce, JT Ramalingam, TR Thompson, R Wynn, TA AF Wilson, Mark S. Mentink-Kane, Margaret M. Pesce, John T. Ramalingam, Thirumalai R. Thompson, Robert Wynn, Thomas A. TI Immunopathology of schistosomiasis SO IMMUNOLOGY AND CELL BIOLOGY LA English DT Review DE schistosomiasis; inflammation; pathology; immune regulation; Treg; decoy receptor ID REGULATORY T-CELLS; ALTERNATIVE MACROPHAGE ACTIVATION; MANSONI-INFECTED MICE; RECEPTOR ALPHA-CHAINS; MURINE SCHISTOSOMIASIS; PERIPORTAL FIBROSIS; GRANULOMA-FORMATION; HELMINTH INFECTION; HEPATIC-FIBROSIS; CUTTING EDGE AB Waterborne parasitic diseases plague tropical regions of the world with the development of water resources often increasing transmission. Skin-penetrating cercariae (infectious stages of schistosome parasites) mature within their mammalian host, form sexual pairs and produce several hundred eggs per day. Many eggs are swept within the circulation and in the case of Schistosoma mansoni and S. japonicum, become lodged within hepatic sinusoids, invoking a fibrotic granulomatous response. Animal studies have identified a moderate type 1 helper (Th1) response to parasite antigens; however, a robust Th2 response to egg-derived antigens dominates and propagates fibrogenesis within the liver. Elegant T helper cell polarization studies have highlighted that critical control of Th1, Th2 and interleukin (IL)-17-secretingly mphocytes is necessary to prevent severe liver pathology. Alternatively activated macrophages develop in the Th2 milieu and upregulate Fizz1, Ym-1 and Arg-1. The possible contribution of macrophages to fibrogenesis and their role in immune regulation are discussed. Within the liver, natural (CD4(+)CD25(+) Forkhead box protein 3 (Foxp3)(+)) and inducible (CD4(+) Foxp3(-)) Treg's are recruited, providing an essential regulatory arm to stabilize the immune response and limit immunopathology. This review ties together current thinking of how the granulomatous response develops, causing much of the associated immunopathology, with extensive discussions on how regulatory cells and cytokine decoy receptors serve to limit the extent of immune-mediated pathology during schistosomiasis. C1 NIAID, Parasit Dis Lab, Immunopathogenesis Sect, NIH, Bethesda, MD 20892 USA. RP Wilson, MS (reprint author), NIAID, Parasit Dis Lab, Immunopathogenesis Sect, NIH, Bethesda, MD 20892 USA. EM wilsonmar@niaid.nih.gov RI Wynn, Thomas/C-2797-2011 FU Intramural NIH HHS [Z01 AI000829-10, Z01 AI000829-11] NR 89 TC 196 Z9 225 U1 1 U2 32 PU NATURE PUBLISHING GROUP PI NEW YORK PA 75 VARICK STREET, 9TH FLOOR, NEW YORK, NY 10013-1917 USA SN 0818-9641 J9 IMMUNOL CELL BIOL JI Immunol. Cell Biol. PD FEB-MAR PY 2007 VL 85 IS 2 BP 148 EP 154 DI 10.1038/sj.icb.7100014 PG 7 WC Cell Biology; Immunology SC Cell Biology; Immunology GA 148UR UT WOS:000245102500011 PM 17160074 ER PT J AU Huskins, WC O'Grady, NP Samore, M Wallace, D Goldmann, DA Pappas, PG AF Huskins, W. Charles O'Grady, Naomi P. Samore, Matthew Wallace, Dennis Goldmann, Donald A. Pappas, Peter G. TI Design and methodology of the strategies to reduce transmission of antimicrobial resistant bacteria in intensive care units (STAR-ICU) trial SO INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY LA English DT Letter C1 Mayo Clin, Coll Med, Rochester, MN USA. NIH, Ctr Clin, Bethesda, MD 20892 USA. Univ Utah, Salt Lake City, UT 84112 USA. Rho Fed Syst Div, Chapel Hill, NC USA. Harvard Med Sch, Boston, MA USA. Univ Alabama, Birmingham, AL USA. RP Huskins, WC (reprint author), Mayo Clin, 200 First Ave SW, Rochester, MN 55905 USA. EM huskins.charles@mayo.edu NR 4 TC 4 Z9 5 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0899-823X J9 INFECT CONT HOSP EP JI Infect. Control Hosp. Epidemiol. PD FEB PY 2007 VL 28 IS 2 BP 245 EP 246 DI 10.1086/510988 PG 2 WC Public, Environmental & Occupational Health; Infectious Diseases SC Public, Environmental & Occupational Health; Infectious Diseases GA 205NL UT WOS:000249120700026 PM 17301944 ER PT J AU Arca, B Lombardo, F Francischetti, IMB Pham, VM Mestres-Simon, M Andersen, JF Ribeiro, JMC AF Arca, Bruno Lombardo, Fabrizio Francischetti, Ivo M. B. Pham, Van My Mestres-Simon, Montserrat Andersen, John F. Ribeiro, Jose M. C. TI An insight into the sialome of the adult female mosquito Aedes albopictus SO INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE saliva; transcriptome; hematophagy; salivary proteins; mosquito; Aedes albopictus ID VECTOR ANOPHELES-GAMBIAE; RICH SECRETORY PROTEINS; SALIVARY-GLAND; SEQUENCE ALIGNMENT; AEGYPTI; VENOM; FAMILY; TRANSCRIPTOME; DATABASE; GENE AB To gain insight into the molecular repertoire of the adult female salivary glands of the tiger mosquito Aedes albopictus, we performed transcriptome and proteome analysis. cDNA clones were sequenced and assembled in clusters of related sequences and the corresponding genes assigned to one of three categories: housekeeping (H; 31%), secreted (S; 34%), or unknown (U; 35%) function. Among the putative secreted factors are proteins known to be widely distributed in the saliva of-blood-sucking Diptera, such as D7 and antigen 5 family members, as well as proteins that are mosquito- or culicine-specific, i.e., the 30-kDa allergen or the 62-kDa and 34-kDa families, respectively. Expression of 15 of these salivary proteins was confirmed by Edman degradation. Tissue and sex specificity of selected transcripts were evaluated by RT-PCR and identified at least 32 genes whose expression is restricted or enriched in the female salivary glands of Ae. albopictus, whereas 17 additional genes were expressed in female glands and adult males but not in other tissues of adult females. For approximately one third of the genes analyzed, involvement in blood-feeding, sugar digestion, immune response, or other more generic physiological roles can be postulated; however, no functions can be suggested for the remaining sequences, which therefore likely represent either novel functions or novel molecules recruited during the evolution of hematophagy. Supplemental spreadsheets with hyperlinks to all sequences used in this manuscript are hyperlinked throughout the text and can be found at http:// www.ncbi.nlm.nih.gov/projects/omes/#salivarytranscriptomes. Published by Elsevier Ltd. C1 Natl Inst Allergy & Infect Dis, Sect Vector Biol, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. Univ Naples Federico II, Dept Struct & Funct Biol, Naples, Italy. Univ Roma La Sapienza, Parasitol Sect, Dept Publ Hlth, Rome, Italy. RP Ribeiro, JMC (reprint author), Natl Inst Allergy & Infect Dis, Sect Vector Biol, Lab Malaria & Vector Res, NIH, 12735 Twinbrook Pkwy, Rockville, MD 20852 USA. EM jribeiro@niaid.nih.gov RI Lombardo, Fabrizio/J-8511-2014; OI Lombardo, Fabrizio/0000-0002-8563-0612; Arca, Bruno/0000-0002-4029-0984; Ribeiro, Jose/0000-0002-9107-0818 FU Intramural NIH HHS NR 67 TC 66 Z9 77 U1 3 U2 15 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0965-1748 J9 INSECT BIOCHEM MOLEC JI Insect Biochem. Mol. Biol. PD FEB PY 2007 VL 37 IS 2 BP 107 EP 127 DI 10.1016/j.ibmb.2006.10.007 PG 21 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 136QR UT WOS:000244239700002 PM 17244540 ER PT J AU Calvo, E Dao, A Pham, VM Ribeiro, JMC AF Calvo, Eric Dao, Adama Pham, Van M. Ribeiro, Jose M. C. TI An insight into the sialome of Anopheles funestus reveals an emerging pattern in anopheline salivary protein families SO INSECT BIOCHEMISTRY AND MOLECULAR BIOLOGY LA English DT Article DE malaria; hematophagy; salivary glands; vector; saliva ID ADULT FEMALE MOSQUITO; AEDES-AEGYPTI; SEQUENCE ALIGNMENT; PSI-BLAST; MALARIA; GLANDS; DATABASE; VECTOR; GAMBIAE; TRANSCRIPTOME AB Anopheles funestus, together with Anopheles gambiae, is responsible for most malaria transmission in sub-Saharan Africa, but little is known about molecular aspects of its biology. To investigate the salivary repertoire of this mosquito, we randomly sequenced 916 clones from a salivary-gland cDNA library from adult female F1 offspring of field-caught An. funestus. Thirty-three protein sequences, mostly full-length transcripts, are predicted to be secreted salivary proteins. We additionally describe 25 full-length housekeeping-associated transcripts. In accumulating mosquito sialotranscriptome information-which includes An. gambiae, Anopheles stephensi, Anopheles darlingi, Aedes aegypti, Aedes albopictus, Culex pipiens quinquefasciatus, and now An. funestus-a pattern is emerging. First, ubiquitous protein families are recruited for a salivary role, such as members of the antigen-5 family and enzymes of nucleotide and carbohydrate catabolism. Second, a group of protein families exclusive to blood-feeding Nematocera includes the abundantly expressed D7 proteins also found in sand flies and Culicoides. A third group of proteins, only found in Culicidae, includes the 30 kDa allergen family and several mucins. Finally, 10 protein and peptide families, five of them multigenic, are exclusive to anophelines. Among these proteins may reside good epidemiological markers to measure human exposure to anopheline species such as An. funestus and An. gambiae. Published by Elsevier Ltd. C1 Natl Inst Allergy & Infect Dis, Lab Malaria & Vector Res, NIH, Rockville, MD 20852 USA. Univ Bamako, Malaria Res & Training Ctr, Dept Epidemiol Parasit Dis, Fac Med Pharm & Odontostomatol, Bamako, Mali. RP Ribeiro, JMC (reprint author), Natl Inst Allergy & Infect Dis, Lab Malaria & Vector Res, NIH, Twinbrook 3,12735 Twinbrook Pkwy,Room 2E32D, Rockville, MD 20852 USA. EM jribeiro@niaid.nih.gov OI Calvo, Eric/0000-0001-7880-2730; Ribeiro, Jose/0000-0002-9107-0818 FU Intramural NIH HHS; NIAID NIH HHS [Z01 AI000810-09] NR 46 TC 63 Z9 66 U1 0 U2 6 PU PERGAMON-ELSEVIER SCIENCE LTD PI OXFORD PA THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND SN 0965-1748 J9 INSECT BIOCHEM MOLEC JI Insect Biochem. Mol. Biol. PD FEB PY 2007 VL 37 IS 2 BP 164 EP 175 DI 10.1016/j.ibmb.2006.11.005 PG 12 WC Biochemistry & Molecular Biology; Entomology SC Biochemistry & Molecular Biology; Entomology GA 136QR UT WOS:000244239700007 PM 17244545 ER PT J AU Konno, A Kirby, M Anderson, SA Schwartzberg, PL Candotti, F AF Konno, Akihiro Kirby, Martha Anderson, Stacie A. Schwartzberg, Pamela L. Candotti, Fabio TI The expression of Wiskott-Aldrich syndrome protein (WASP) is dependent on WASP-interacting protein (WIP) SO INTERNATIONAL IMMUNOLOGY LA English DT Article DE post-translational regulation; Wiskott-Aldrich syndrome; Wiskott-Aldrich syndrome protein; Wiskott-Aldrich syndrome protein-interacting protein ID MEDIATED GENE-TRANSFER; B-CELL ACTIVATION; T-CELL; ACTIN POLYMERIZATION; N-WASP; LENTIVIRAL VECTOR; CYTOSKELETAL REARRANGEMENT; IMMUNOLOGICAL SYNAPSE; FUNCTIONAL CORRECTION; HEMATOPOIETIC-CELLS AB The Wiskott-Aldrich syndrome protein (WASP) is a key molecule for transduction of extracellular signals that induce a variety of critical biological events involving actin cytoskeleton rearrangement. Among the cellular partners of WASP, the Wiskott-Aldrich syndrome protein-interacting protein (WIP) has been speculated to play a critical role in the pathophysiology of Wiskott-Aldrich syndrome since WASP mutation hot spots map to the WIP-binding region. The notion that WIP promotes WASP function, however, conflicts with evidence that WIP inhibits WASP-mediated actin polymerization and IL-2 production and suggests a complex regulation of WASP function by WIP. Here we show that WASP gene transfer results in high WASP expression only when WIP is concomitantly expressed in K562 cells. Furthermore, WIP-knockdown experiments demonstrated that T cells with reduced WIP expression show a concordant reduction of WASP levels. Mapping studies using WIP mutants showed that the minimal WIP region able to rescue WASP expression in WIP-knockdown cells was the WASP-binding domain. However, expression of such a minimal domain of WIP failed to rescue WASP-dependent, nuclear factor of activated T-cells-mediated IL-2 transcriptional activity. These results demonstrate that expression of WIP is necessary for functional WASP expression in human cells and provide a new paradigm for understanding the function of these two molecules. C1 NHGRI, Genet & Mol Biol Branch, NIH, Bethesda, MD 20892 USA. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Candotti, F (reprint author), NHGRI, Genet & Mol Biol Branch, NIH, 49 Convent Dr, Bethesda, MD 20892 USA. EM fabio@nhgri.nih.gov FU Intramural NIH HHS NR 55 TC 24 Z9 24 U1 0 U2 2 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0953-8178 J9 INT IMMUNOL JI Int. Immunol. PD FEB PY 2007 VL 19 IS 2 BP 185 EP 192 DI 10.1093/intimm/dxl135 PG 8 WC Immunology SC Immunology GA 130NI UT WOS:000243805900008 PM 17205972 ER PT J AU Miyoshi, N Uchida, K Osawa, T Nakamura, Y AF Miyoshi, Noriyuki Uchida, Koji Osawa, Toshihiko Nakamura, Yoshimasa TI Selective cytotoxicity of benzyl isothiocyanate in the proliferating fibroblastoid cells SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE benzyl isothiocyanate; apoptosis; p53; human colon fibroblastoid cell; cell cycle ID ACTIVATED PROTEIN-KINASES; CANCER-CELLS; INDUCED APOPTOSIS; CYCLE ARREST; DNA-DAMAGE; ALLYL-ISOTHIOCYANATE; ANTICARCINOGENIC ISOTHIOCYANATES; PHENETHYL ISOTHIOCYANATE; CRUCIFEROUS VEGETABLES; CHECKPOINT FUNCTION AB In the present study, experiments using presynchronization culture cells demonstrated that benzyl ITC (BITC), previously isolated from a tropical papaya fruit extract, induced the cytotoxic effect preferentially in the proliferating human colon CCD-18Co cells to the quiescent ones. Quiescent CCD-18Co cells were virtually unaffected by BITC and marginal cytotoxicity was observed at 15 mu M. We observed that BITC dramatically induced the p53 phosphorylation and stabilization only in the quiescent (G(0)/G(1) phase-arrested) cells, but not significantly in the proliferating human colon CCD-18Co cells when compared with quiescent ones. We also observed ataxia telangiectasia-mutated (ATM) phosphorylation in the quiescent cells. The BITC-induced p53 phosphorylation was counteracted by caffeine treatment, implying the involvement of an ATM/ataxia telangiectasia and Rad3-related kinase signaling pathway. Moreover, downregulation of p53 by a siRNA resulted in the enhancement of susceptibility to undergo apoptosis by BITC. We also showed here that depletion of p53 abrogated G(0)/G(1), arrest accompanied by the declined expression of p21(waf1/cip1) and p27(kip1) in CCD-18Co cells. In conclusion, we identified p53 as a potential negative regulator of the apoptosis induction by BITC in the normal colon CCD-18Co cells through the inhibition of cell-cycle progression at the G(0)/G(1) phase. (c) 2006 Wiley-Liss, Inc. C1 Okayama Univ, Dept Biofunct Chem, Div Biosci, Grad Sch Nat Sci & Technol, Okayama 7008530, Japan. NHLBI, Biochem Lab, NIH, Bethesda, MD 20892 USA. Nagoya Univ, Lab Food & Biodynam, Grad Sch Bioagr Sci, Nagoya, Aichi, Japan. RP Nakamura, Y (reprint author), Okayama Univ, Dept Biofunct Chem, Div Biosci, Grad Sch Nat Sci & Technol, Okayama 7008530, Japan. EM yossan@cc.okayama-u.ac.jp RI Miyoshi, Noriyuki/F-4554-2010 NR 64 TC 22 Z9 22 U1 1 U2 5 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 1 PY 2007 VL 120 IS 3 BP 484 EP 492 DI 10.1002/ijc.22350 PG 9 WC Oncology SC Oncology GA 117JI UT WOS:000242869000005 PM 17096346 ER PT J AU Booth, BW Jhappan, C Merlino, G Smith, GH AF Booth, Brian W. Jhappan, Chamelli Merlino, Glenn Smith, Gilbert H. TI TGF beta 1 and TGF alpha contrarily affect alveolar survival and tumorigenesis in mouse mammary epithelium SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cancer; mammary; TGF; transgenic ID TRANSFORMING GROWTH-FACTOR-BETA-1 TRANSGENE; GROWTH-FACTOR-ALPHA; MESENCHYMAL TRANSITION; SIGNALING PATHWAYS; FACTOR-BETA; EXPRESSION; MICE; GLAND; INDUCTION; NEOPLASIA AB Growth factors and hormones are responsible for development of the mammary gland and can contribute to mammary carcinogenesis. The transforming growth factors (TGF) alpha and beta 1 demonstrate opposing effects on the mammary epithelium. TGF alpha is a mitogen and survival factor for mammary secretory cells and is often upregulated in cancer, while TGF beta 1 may act as a growth suppressor and has been shown to inhibit alveolar development and lactogenesis. To examine the contradistinct effects of TGFa and TGF beta 1 on normal mammary epithelium, we crossed MT-TGF alpha mice with WAP-TGF beta 1 transgenic mice. The newly generated bitransgenic mice failed to nurse their pups and were resistant to mammary tumorigenesis (0% at 12 months of age), compared to single transgenic MT-TGFa in which the majority (65% at 12 months of age) of the mice developed hyperplastic alveolar mammary lesions. Transplantation studies showed that bitransgenic tissue was highly resistant to tumor formation even after multiple pregnancies. WAP-TGF beta 1 mammary transplants often failed to grow and fully fill cleared mammary fat pads upon transplantation. This repression of growth was completely reversed in the bitransgenic implants, which grew as well as normal epithelium upon transplantation. In addition, TGF and bitransgenic TGF alpha/TGF beta 1 mice had reduced rates of apoptosis during involution as compared to wild type and TGF beta 1. These data demonstrate that TGF beta 1 and TGF alpha exhibit opposing effects upon the proliferation and survival of mammary epithelium when expressed alone but when expressed together result in reciprocally suppressive effects upon one another in the context of mammary development and tumorigenesis. (c) 2006 Wiley-Liss, Inc. C1 NCI, Mammary Biol & Tumorigenesis Lab, NIH, Bethesda, MD 20892 USA. NCI, Lab Cell Regulat & Carcinogenesis, NIH, Bethesda, MD 20892 USA. RP Smith, GH (reprint author), NCI, Mammary Biol & Tumorigenesis Lab, NIH, 37 Convent Dr,Room 1112B MSC 4254, Bethesda, MD 20892 USA. EM gs4d@nih.gov FU Intramural NIH HHS NR 29 TC 5 Z9 5 U1 0 U2 0 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 1 PY 2007 VL 120 IS 3 BP 493 EP 499 DI 10.1002/ijc.22310 PG 7 WC Oncology SC Oncology GA 117JI UT WOS:000242869000006 PM 17096338 ER PT J AU Tomii, K Tsukuda, K Toyooka, S Dote, H Hanafusa, T Asano, H Naitou, M Doihara, H Kisimoto, T Katayama, H Pass, HI Date, H Shimizu, N AF Tomii, Kunitoshi Tsukuda, Kazunori Toyooka, Shinichi Dote, Hideaki Hanafusa, Tadashi Asano, Hiroaki Naitou, Minoru Doihara, Hiroyoshi Kisimoto, Takumi Katayama, Hideki Pass, Harvery I. Date, Hiroshi Shimizu, Nobuyoshi TI Aberrant promoter methylation of insulin-like growth factor binding protein-3 gene in human cancers SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE IGFBP-3; methylation; gastric cancer; coloretal cancer; breast cancer; malignant mesothelioma ID FACTOR-BINDING PROTEIN-3; CELL LUNG-CANCER; HUMAN HEPATOCELLULAR-CARCINOMA; INSULIN-RECEPTOR SUBSTRATE-1; BREAST-CANCER; GASTRIC-CANCER; DNA METHYLATION; GROWTH; EXPRESSION; RISK AB Insulin-like growth factor binding protein-3 (IGFBP-3) is postulated to be a mediator of growth suppression signals. Here, we examined the methylation status of IGFBP-3 to correlate to clinicopathological factors in human cancers. The methylation status of IGFBP-3 was determined by bisulfite DNA sequencing and was correlated with expression semi-quantified by real-time RT-PCR to develop a methylation-specific PCR (MSP) assay for IGFBP-3. Using the MSP assay, we examined the methylation status of IGFBP-3 in gastric cancer (GC), colorectal cancer (CRC), breast cancer (BC) and malignant mesothelioma (MM). IGFBP-3 methylation was detected in 6 of 13 (46%) and 16 of 24 (67%) GC cell lines and tumors, respectively; 4 of 8 (50%) and 15 of 26 (58%) CRC cell lines and tumors, respectively; 3 of 11 (27%) and 7 of 39 (18%) BC cell lines and tumors, respectively and 1 of 5 (20%) and 18 of 56 (32%) MM cell lines and tumors, respectively. Interestingly, the methylation status of MM specimens from Japanese patients (75%, 12 out of 16 patients) was significantly higher than those from the USA (15%, 6 out of 40 patients) (p < 0.0001), suggesting the presence of ethnic differences in the IGFBP-3 methylation status. We also found that IGFBP-3 methylation was preferentially present in GCs arising in the lower-third of the stomach (p = 0.079). In summary, our results showed that IGFBP-3 methylation played an important role in the silencing of its expression, suggesting that IGFBP-3 may act as a tumor suppressor gene in several human cancers examined. (c) 2006 Wiley-Liss, Inc. C1 Okayama Univ, Dept Canc & Thorac Surg, Grad Sch Med Dent & Pharmaceut Sci, Shikata Lab,Adv Sci Res Ctr, Okayama 7008558, Japan. Okayama Univ, Dept Radiat Res, Grad Sch Med Dent & Pharmaceut Sci, Shikata Lab,Adv Sci Res Ctr, Okayama 7008558, Japan. Okayama Rousai Hosp, Dept Internal Med, Okayama, Japan. Natl Sanyo Hosp, Resp Dis Ctr, Dept Resp Med, Ube, Yamaguchi, Japan. NYU, Sch Med, Div Thorac Surg & Thorac Oncol, Dept Cardiothorac Surg, New York, NY USA. NCI, Ctr Canc, New York, NY USA. RP Toyooka, S (reprint author), Okayama Univ, Dept Canc & Thorac Surg, Grad Sch Med Dent & Pharmaceut Sci, Shikata Lab,Adv Sci Res Ctr, 2-5-1 Shikata Cho, Okayama 7008558, Japan. EM s_toyooka@nigeka2.hospital.okayama-u.ac.jp NR 48 TC 57 Z9 59 U1 0 U2 2 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 1 PY 2007 VL 120 IS 3 BP 566 EP 573 DI 10.1002/ijc.22341 PG 8 WC Oncology SC Oncology GA 117JI UT WOS:000242869000016 PM 17096329 ER PT J AU Welzel, TM Mellemkjaer, L Gloria, G Sakoda, LC Hsing, AW El Ghormli, L Olsen, JH McGlynn, KA AF Welzel, Tania M. Mellemkjaer, Lene Gloria, Gridley Sakoda, Lori C. Hsing, Ann W. El Ghormli, Laure Olsen, Jorgen H. McGlynn, Katherine A. TI Risk factors for intrahepatic cholangiocarcinoma in a low-risk population: A nationwide case-control study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE intrahepatic cholangiocarcinoma; risk factors; population-based case control study ID PRIMARY SCLEROSING CHOLANGITIS; DIABETES-MELLITUS; UNITED-STATES; LIVER-CANCER; HISTORY; DISEASE AB Recently, the incidence of intrahepatic cholangiocarcinoma (ICC) has been increasing in a number of developed (Western) countries. However, risk factors in these low-risk populations are poorly understood. In this nationwide population based case-control study in Denmark, we examined the relationship between selected medical conditions and subsequent ICC risk to provide additional clues to etiopathogenesis. All histologically confirmed ICC cases diagnosed in Denmark between 1978 and 1991 were identified from the Danish cancer registry. Population controls were selected from the central population registry and were matched 4:1 to cases on sex and year of birth. Cases and controls were linked to the Danish hospital discharge registry to obtain information on prior hospital diagnoses. Odds ratios (OR) and 95% confidence intervals (95% CI) were derived using conditional logistic regression. A total of 764 ICC cases and 3,056 population controls were included in the study. Chronic liver diseases were significantly related to ICC: alcoholic liver disease (OR = 19.22, 95% CI = 5.55-66.54), unspecified cirrhosis (OR = 75.9, 95% CI 10.2-565.7). Bile duct diseases were also associated with risk: cholangitis (OR = 6.3, 95 % CI = 2.3-17.5), choledocholithiasis (OR = 23.97, 95 % CI = 2.9-198.9), cholecystolithiasis (OR = 4.0, 95% CI = 2.0-7.99), though gallbladder removal did not change risk (OR = 1.6, 95 % CI = 0.653.7). Among other conditions, chronic inflammatory bowel disease (OR = 4.7, 95% CI = 1.65-13.9) was significantly associated with ICC. Diabetes was associated with risk in the year prior to diagnosis of ICC (OR = 3.02, 95% CI = 1.05-8.69). Obesity was unrelated to risk. These results confirm that prior bile duct diseases increase risk of ICC and suggest that alcoholic liver disease and diabetes may also increase risk. (c) 2006 Wiley-Liss, Inc. C1 NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. Danish Canc Soc, Inst Canc Epidemiol, Copenhagen, Denmark. RP Welzel, TM (reprint author), NCI, Div Canc Epidemiol & Genet, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA. EM welzlt@mail.nih.gov OI Olsen, Jorgen Helge/0000-0001-9633-5662 FU Intramural NIH HHS NR 28 TC 73 Z9 78 U1 1 U2 4 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0020-7136 J9 INT J CANCER JI Int. J. Cancer PD FEB 1 PY 2007 VL 120 IS 3 BP 638 EP 641 DI 10.1002/ijc.22283 PG 4 WC Oncology SC Oncology GA 117JI UT WOS:000242869000024 PM 17109384 ER PT J AU Purdue, MP Hoppin, JA Blair, A Dosemeci, M Alavanja, MCR AF Purdue, Mark P. Hoppin, Jane A. Blair, Aaron Dosemeci, Mustafa Alavanja, Michael C. R. TI Occupational exposure to organochlorine insecticides and cancer incidence in the Agricultural Health Study SO INTERNATIONAL JOURNAL OF CANCER LA English DT Article DE cancer; pesticides; organochlorines; agriculture; cohort study ID NON-HODGKINS-LYMPHOMA; PROSTATE-CANCER; PESTICIDE APPLICATORS; PANCREATIC-CANCER; HUMAN-LYMPHOCYTES; BLOOD DYSCRASIAS; RISK-FACTORS; LIFE-STYLE; MORTALITY; FARMERS AB Organochlorine (OC) insecticides have been regulated as possible human carcinogens primarily on the basis of animal studies. However, the epidemiologic evidence is inconsistent. We investigated the relationship between cancer incidence and OC insecticide use among pesticide applicators enrolled in the Agricultural Health Study, a prospective cohort study of 57,311 licensed applicators in Iowa and North Carolina enrolled between 1993 and 1997. Information on ever use of 7 OC insecticides (aldrin, chlordane, DDT, dieldrin, heptachlor, lindane, toxaphene) was collected from a selfadministered questionnaire at enrollment. Lifetime exposure-days to OC insecticides were calculated using additional data from a take-home questionnaire completed by 25,291 participants (44% of total). We found no clear evidence of an association between use of OC insecticides and incident cancers (N = 1,150) ascertained through December, 2002. When we focused on individual insecticides and structurally similar groups (aldrin and dieldrin; chlordane and heptachlor), significantly increased relative risks of some cancers were observed for use of some chemicals (rectal cancer and chlordane, lung cancer and dieldrin, non-Hodgkin lymphoma (NHL) and lindane, melanoma and toxaphene, leukemia and chlordane/heptachlor). Some significant decreased relative risks were also observed (colon cancer and aldrin; overall cancer and heptachlor). In conclusion, we did not observe any clear relationship between cancer risk and the use of OC insecticides. Our chemicalspecific findings are based on small numbers and multiple comparisons, and should be interpreted with caution; however, some observed associations (lindane and NHL, chlordane/heptachlor and leukemia) are supported by previous evidence. (c) 2006 Wiley-Liss. Inc. C1 NCI, Occupat & Environm Engn Branch, Div Canc Epidemiol & Genet, NIH, Rockville, MD 20852 USA. NIEHS, Epidemiol Branch, NIH, Res Triangle Pk, NC 27709 USA. RP Purdue, MP (reprint author), NCI, Occupat & Environm Engn Branch, Div Canc Epidemiol & Genet, NIH, EPS 8109, Rockville, MD 20852 USA. EM purduem@mail.nih.gov RI Purdue, Mark/C-9228-2016 OI Purdue, Mark/0000-0003-1177-3108 FU Intramural NIH HHS [001-0167-612, 001-1600-195, Z99 CA999999, Z99 ES999999] NR 55 TC 80 Z9 88 U1 3 U2 18 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 1 PY 2007 VL 120 IS 3 BP 642 EP 649 DI 10.1002/ijc.22258 PG 8 WC Oncology SC Oncology GA 117JI UT WOS:000242869000025 PM 17096337 ER PT J AU Olden, K AF Olden, Kenneth TI Commentary: From phenotype, to genotype, to gene-environment interaction and risk for complex diseases SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material C1 NIEHS, Mol Carcinogenesis Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. RP Olden, K (reprint author), NIEHS, Mol Carcinogenesis Lab, NIH, DHHS, Res Triangle Pk, NC 27709 USA. EM olden@niehs.nih.gov NR 10 TC 9 Z9 11 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD FEB PY 2007 VL 36 IS 1 BP 18 EP 20 DI 10.1093/ije/dyl292 PG 3 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 174TQ UT WOS:000246966100004 PM 17510072 ER PT J AU Rothman, N Garcia-Closas, M Hein, DW AF Rothman, Nathaniel Garcia-Closas, Montserrat Hein, David W. TI Commentary: Reflections on G. M. Lower and colleagues' 1979 study associating slow acetylator phenotype with urinary bladder cancer: meta-analysis, historical refinements of the hypothesis, and lessons learned SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Editorial Material DE bladder neoplasms; genetic susceptibility; NAT2; N-acetylation; tobacco ID BENZIDINE-EXPOSED WORKERS; N-ACETYLATION; DNA-REPAIR; MOLECULAR EPIDEMIOLOGY; CIGARETTE-SMOKING; AROMATIC-AMINES; POOLED ANALYSIS; RISK; GENOTYPE; ADDUCTS C1 NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, NIH,DHHS, Bethesda, MD 20892 USA. Univ Louisville, Sch Med, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. Univ Louisville, Sch Med, James Graham Brown Canc Ctr, Louisville, KY 40292 USA. RP Rothman, N (reprint author), NCI, Div Canc Epidemiol & Genet, Occupat & Environm Epidemiol Branch, NIH,DHHS, EPS 8116, Bethesda, MD 20892 USA. EM rothmann@mail.nih.gov RI Hein, David/A-9707-2008; Garcia-Closas, Montserrat /F-3871-2015 OI Garcia-Closas, Montserrat /0000-0003-1033-2650 FU Intramural NIH HHS; NCI NIH HHS [R01 CA034627, R01 CA034627-21] NR 39 TC 20 Z9 21 U1 0 U2 0 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD FEB PY 2007 VL 36 IS 1 BP 23 EP 28 DI 10.1093/ije/dym026 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 174TQ UT WOS:000246966100006 PM 17510073 ER PT J AU Lubin, JH Kogevinas, M Silverman, D Malats, N Garcia-Closas, M Tardon, A Hein, DW Garcia-Closas, R Serra, C Dosemeci, M Carrato, A Rothman, N AF Lubin, Jay H. Kogevinas, Manolis Silverman, Debra Malats, Nuria Garcia-Closas, Montserrat Tardon, Adonina Hein, David W. Garcia-Closas, Reina Serra, Consol Dosemeci, Mustafa Carrato, Alfredo Rothman, Nathaniel TI Evidence for an intensity-dependent interaction of NAT2 acetylation genotype and cigarette smoking in the Spanish Bladder Cancer Study SO INTERNATIONAL JOURNAL OF EPIDEMIOLOGY LA English DT Article DE bladder neoplasms; smoking; dose response; interaction ID RISK; GLUCURONIDATION; 4-AMINOBIPHENYL; EXPOSURE; LIVER; LUNG AB Background The N-acetyltransferase 2 (NAT2) enzyme detoxifies aromatic arnines, an important class of carcinogens in tobacco smoke. Slow acetylation phenotype individuals have reduced detoxification capacity compared with those with a rapid/intermediate phenotype. Analysis of the Spanish Bladder Cancer Study found an odds ratio (OR) for slow acetylators relative to rapid/intermediate acetylators of 0.9 in never-smokers and 1.6 in ever-smokers, a 1.8-fold enhancement in smokers. Evidence indicates that acetylation is an exposure-dependent process, and thus the magnitude of the interaction may also depend on exposure level. Methods We extend a comprehensive three-parameter linear-exponential model for the excess odds ratio (EOR) for smoking to include effects of NAT2 status, and reanalyse smoking and NAT2 status for the bladder cancer data. Results We show that variations in intensity (cigarettes per day) and not total pack-years of exposure. In addition, the relative increase in smoking risk in NAT2 slo acetylators increases with smoking intensity. Conclusions Analyses reveal an enhanced effect for smoking intensity and bladder cancer in NAT2 slow acetylators which increases with intensity. C1 NCI, Biostat Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Municipal Inst Med Res, IMIM, Ctr Res Environm Epidemiol, Barcelona, Spain. Univ Crete, Sch Med, Dept Social Med, Iraklion, Greece. NCI, Occupat & Environm Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. NCI, Hormone & Reprod Epidemiol Branch, Div Canc Epidemiol & Genet, Rockville, MD 20852 USA. Univ Oviedo, Oviedo, Spain. Univ Louisville, Sch Med, James Graham Brown Canc Ctr, Dept Pharmacol & Toxicol, Louisville, KY 40292 USA. Univ La Laguna, Hosp Canarias, Unidad Invest, E-38207 San Cristobal la Laguna, Spain. Consorci Hosp Parc Tauli, Sabadell, Spain. Univ Pompeu Fabra, Barcelona, Spain. Hosp Gen Elche, Elche, Spain. RP Lubin, JH (reprint author), NCI, Biostat Branch, Div Canc Epidemiol & Genet, 6120 Execut Blvd, Rockville, MD 20852 USA. EM lubinj@mail.nih.gov RI Hein, David/A-9707-2008; Serra, C/E-6879-2014; Garcia-Closas, Montserrat /F-3871-2015; Kogevinas, Manolis/C-3918-2017; OI Serra, C/0000-0001-8337-8356; Garcia-Closas, Montserrat /0000-0003-1033-2650; Malats, Nuria/0000-0003-2538-3784 FU Intramural NIH HHS; NCI NIH HHS [R01 CA034627, R01 CA034627-21] NR 11 TC 25 Z9 25 U1 0 U2 3 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0300-5771 J9 INT J EPIDEMIOL JI Int. J. Epidemiol. PD FEB PY 2007 VL 36 IS 1 BP 236 EP 241 DI 10.1093/ije/dym043 PG 6 WC Public, Environmental & Occupational Health SC Public, Environmental & Occupational Health GA 174TQ UT WOS:000246966100040 PM 17510079 ER PT J AU Yang, MQ Yang, JY Ersoy, OK AF Yang, Mary Q. Yang, Jack Y. Ersoy, Okan K. TI Classification of proteins multiple-labelled and single-labelled with protein functional classes SO INTERNATIONAL JOURNAL OF GENERAL SYSTEMS LA English DT Article DE computational intelligence; machine learning; classification; multifunctional proteins; bioinformatics ID DATABASE AB Advances in high-throughput genome sequencing technology have led to an explosion in the amount of sequence data that are available. The determination of protein function using experimental techniques is time-consuming and expensive; the use of machine-learning techniques rapidly to assess protein function may be useful in streamlining this process. The problem of assigning functional classes to proteins is complicated by the fact that a single protein can participate in several different pathways and thus can have multiple functions. We have developed a tree-based classifier that is capable of handling multiple-labelled data and gaining an insight into the multi-functional nature of proteins. We call the resulting tree a recursive maximum contrast tree (RMCT) and the resulting classifier a multiple-labelled instance classifier (MLIC). We investigate the synergy of machine-learning-based ensemble methods and physiochemical-based feature augments. We test our algorithm on protein phylogenetic profiles generated from 60 completely sequenced genomes and we compare our results with those achieved by algorithms such as support vector machines and decision trees. C1 Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47907 USA. US Dept HHS, NHGRI, NIH, Rockville, MD 20852 USA. Harvard Univ, Sch Med, Dept Radiat Oncol, Boston, MA 02114 USA. Harvard Univ, Massachusetts Gen Hosp, Boston, MA 02114 USA. RP Yang, JY (reprint author), Purdue Univ, Sch Elect & Comp Engn, W Lafayette, IN 47907 USA. EM jyang@hadron.mgh.harvard.edu NR 29 TC 4 Z9 5 U1 0 U2 0 PU TAYLOR & FRANCIS LTD PI ABINGDON PA 4 PARK SQUARE, MILTON PARK, ABINGDON OX14 4RN, OXON, ENGLAND SN 0308-1079 EI 1563-5104 J9 INT J GEN SYST JI Int. J. Gen. Syst. PD FEB PY 2007 VL 36 IS 1 BP 91 EP 109 DI 10.1080/03081070600950868 PG 19 WC Computer Science, Theory & Methods; Ergonomics SC Computer Science; Engineering GA 115XN UT WOS:000242767200005 ER PT J AU Korner, A Ma, L Franks, PW Kiess, W Baier, LJ Stumvoll, M Kovacs, P AF Koerner, A. Ma, L. Franks, P. W. Kiess, W. Baier, L. J. Stumvoll, M. Kovacs, P. TI Sex-specific effect of the Val1483Ile polymorphism in the fatty acid synthase gene (FAS) on body mass index and lipid profile in Caucasian children SO INTERNATIONAL JOURNAL OF OBESITY LA English DT Article DE genetics; children; fatty acid synthase ID PIMA-INDIANS; OBESITY; ADOLESCENTS; OXIDATION; FOXC2 AB Objective: A Val 1483 Ile polymorphism in the human fatty acid sythase gene (FAS) has recently been shown to be associated with lower percentage of body fat and substrate oxidation rates in Pima Indians, but its role in other populations has not been described. Here, we investigate the effect of this variant on obesity in Caucasian children and adolescents. Subjects and methods: In total, 738 Caucasian children and adolescents aged 6 - 17 years of the Leipzig Schoolchildren cohort, which constitutes an unselected representative German population and 205 obese children (body mass index (BMI) 2.71 +/- 0.04 SDS) were genotyped for genotype-phenotype associations. Results: The frequency of the Ile-allele was lower in German Caucasians compared with Pima Indians (0.03 compared to 0.10). Using generalized linear regression models, there was no effect of the polymorphism on BMI in the whole normal population. However, we identified a significant interaction effect between sex and genotype (P = 0.004). Subsequent sex stratified analyses revealed a lower BMI SDS in boys with Ile/Val genotype compared to Val/Val (-0.36 +/- 0.29 vs 0.09 +/- 0.05, P < 0.05), while an opposite effect was observed in girls (0.48 +/- 0.19 vs 0.09 +/- 0.05, P < 0.05). In genotype-phenotype associations in obese children, the polymorphism did not affect parameters of insulin, glucose, or lipid metabolism in the whole population. Again, however, obese boys with Ile/Val genotype had significantly higher high-density lipoprotein (HDL) cholesterol levels (1.46 +/- 0.07 vs 1.23 +/- 0.03 mmol/l, P < 0.05). Conclusion: In conclusion, our findings suggest a sex-specific protective effect of the Val 1483 Ile polymorphism in FAS for obesity in Caucasian boys. In addition, the polymorphism may be associated with a beneficial lipid profile in obese boys. C1 Univ Leipzig, Dept Med 3, D-04103 Leipzig, Germany. Univ Leipzig, Hosp Children & Adolescents, D-04103 Leipzig, Germany. NIDDK, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ USA. Univ Umea Hosp, Med Dept Publ Hlth & Clin Med, S-90185 Umea, Sweden. Univ Leipzig, Dept Med 3, D-7010 Leipzig, Germany. RP Kovacs, P (reprint author), Univ Leipzig, Dept Med 3, Philipp Rosenthal Str 27, D-04103 Leipzig, Germany. EM peter.kovacs@medizin.uni-leipzig.de RI Korner, Antje/B-3988-2015; OI Korner, Antje/0000-0001-6001-0356; Franks, Paul/0000-0002-0520-7604 FU Intramural NIH HHS NR 22 TC 18 Z9 20 U1 0 U2 0 PU NATURE PUBLISHING GROUP PI LONDON PA MACMILLAN BUILDING, 4 CRINAN ST, LONDON N1 9XW, ENGLAND SN 0307-0565 J9 INT J OBESITY JI Int. J. Obes. PD FEB PY 2007 VL 31 IS 2 BP 353 EP 358 DI 10.1038/sj.ijo.0803428 PG 6 WC Endocrinology & Metabolism; Nutrition & Dietetics SC Endocrinology & Metabolism; Nutrition & Dietetics GA 134KI UT WOS:000244081500023 PM 16788566 ER PT J AU Bandettini, P AF Bandettini, Peter TI Functional MRI today SO INTERNATIONAL JOURNAL OF PSYCHOPHYSIOLOGY LA English DT Article DE fMRI; BOLD; cognitive neuroscience ID TASK-INDUCED DEACTIVATION; VASCULAR-SPACE-OCCUPANCY; HUMAN VISUAL-CORTEX; BOLD SIGNAL; HUMAN BRAIN; HIGH-FIELD; HIGH-RESOLUTION; RESTING-STATE; DEFAULT MODE; FMRI AB Most brain imaging researchers would agree with the assertion that functional MRI (fMRI) is progressing. Since fMRI began in 1991, the number of people, papers, and abstracts related to fMRI has been increasing; the technology and methodology has shown advances in robustness and sophistication; the physiology of the signal is better understood; and, even though it hasn't yet made significant headway into the clinical setting, applications are widening. Questions that stem from this optimistic and perhaps overly general set of observations include those that ask what the ultimate theoretical and practical limits of fMRI are and how close are we to approaching these limits. In this commentary, I attempt to provide a snapshot of fMRI as it exists at the end of 2005, and to give a clear impression that not only are we progressing by "dotting the i's and crossing the t's" but that fundamental changes in fMRI methodology and processing are being put forth as the field matures. Published by Elsevier B.V. C1 NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, Bethesda, MD 20892 USA. RP Bandettini, P (reprint author), NIMH, Sect Funct Imaging Methods, Lab Brain & Cognit, Bethesda, MD 20892 USA. EM bandettini@nih.gov RI Bandettini, Peter/F-5871-2012 NR 64 TC 40 Z9 43 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 0167-8760 J9 INT J PSYCHOPHYSIOL JI Int. J. Psychophysiol. PD FEB PY 2007 VL 63 IS 2 BP 138 EP 145 DI 10.1016/j.ijpsycho.2006.03.016 PG 8 WC Psychology, Biological; Neurosciences; Physiology; Psychology; Psychology, Experimental SC Psychology; Neurosciences & Neurology; Physiology GA 138LP UT WOS:000244364400002 PM 16842871 ER PT J AU Denduluri, N Lee, JJ Walshe, J Berman, AW Vatas, U Chow, CK Steinberg, SM Cox, MC Low, JA Swain, SM AF Denduluri, Neelima Lee, James J. Walshe, Janice Berman, Arlene W. Vatas, Ujala Chow, Catherine K. Steinberg, Seth M. Cox, Michael C. Low, Jennifer A. Swain, Sandra M. TI Phase II trial of ixabepilone, an epothilone B analog, given daily for three days every three weeks, in metastatic breast cancer SO INVESTIGATIONAL NEW DRUGS LA English DT Article ID MICROTUBULE-STABILIZING AGENTS; PROSPECTIVE RANDOMIZED-TRIAL; CLINICAL-TRIAL; DAILY SCHEDULE; SOLID TUMORS; BMS-247550; PACLITAXEL; DOCETAXEL AB Twelve patients with metastatic breast cancer previously exposed to taxanes were treated on a Phase II trial with ixabepilone. Eligible patients had histologically confirmed metastatic breast cancer with measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST), and adequate hematopoietic, renal, and hepatic function. Ixabepilone 8 mg/m(2)/day was given intravenously daily for 3 days for the first 3-week cycle and increased to 10 mg/m(2)/day for subsequent cycles if patients did not have hematologic or other toxicity after the first cycle. Patients continued treatment until progressive disease or unacceptable toxicity. Three, 29, and 33 of 65 cycles administered were at the 7 mg/m(2), 8 mg/m(2) and 10 mg/m(2) dose levels respectively. Grade 4 leukopenia (n=1), grade 3 neutropenia (n=2), grade 2 neuropathy (n=3), and grade 2 transaminase elevation (n=2) were the most notable toxicities. Ten patients had stable disease for at least 6 weeks. No complete or partial responses were observed in 12 evaluable patients treated with ixabepilone daily for 3 days. Although ixabepilone was well-tolerated, the dose of 8-10 mg/m(2) daily for 3 days is not an effective therapy in metastatic breast cancer previously exposed to taxanes. C1 NCI, Breast Canc Sect, Med Oncol Branch, Ctr Canc Res,NIH, Bethesda, MD 20889 USA. Yale Univ, Sch Med, Yale Canc Ctr, New Haven, CT 06520 USA. NCI, Dept Diagnost Radiol, Warrant G Magnuson Clin Ctr, NIH, Bethesda, MD 20889 USA. NCI, Biostat & Data Management Sect, Off Clin Director, NIH, Bethesda, MD 20889 USA. NCI, Canc Therapy Evaluat Program, Div Canc Treatment & Diagnosis, NIH, Bethesda, MD 20889 USA. RP Swain, SM (reprint author), NCI, Breast Canc Sect, Med Oncol Branch, Ctr Canc Res,NIH, Bldg 8,Rm 5101,8901 Wisconsin Ave, Bethesda, MD 20889 USA. EM swains@mail.nih.gov OI Swain, Sandra/0000-0002-1320-3830 FU Intramural NIH HHS NR 28 TC 32 Z9 32 U1 0 U2 1 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 J9 INVEST NEW DRUG JI Invest. New Drugs PD FEB PY 2007 VL 25 IS 1 BP 63 EP 67 DI 10.1007/s10637-006-9006-7 PG 5 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 099QC UT WOS:000241609400008 PM 16933153 ER PT J AU Jhawer, M Rosen, L Dancey, J Hochster, H Hamburg, S Tempero, M Clendeninn, N Mani, S AF Jhawer, Minaxi Rosen, Lee Dancey, Janet Hochster, Howard Hamburg, Solomon Tempero, Margaret Clendeninn, Neil Mani, Sridhar TI Phase II trial of nolatrexed dihydrochloride [Thymitaq (TM), AG 337] in patients with advanced hepatocellular carcinoma SO INVESTIGATIONAL NEW DRUGS LA English DT Article DE hepatocellular carcinoma; thymidylate synthase inhibitors; Thymitaq; phase II clinical trial ID THYMIDYLATE SYNTHASE INHIBITOR; CHEMOTHERAPY; DOXORUBICIN; ADRIAMYCIN; CANCER AB Background: To evaluate the tolerability and efficacy of nolatrexed in patients with advanced hepatocellular carcinoma. Patients and methods: Forty-eight patients were entered onto this study. Nolatrexed was administered every 3 weeks as a 24-h continuous intravenous infusion of 725 mg/m(2)/day for 5 days. Doses were adjusted to maintain a dose level that produced grade 2 toxicity. Response was assessed after every two cycles. Plasma pharmacokinetic samples were assayed using a validated high performance liquid chromatography ultraviolet method. Results: Thirty-nine (81%) patients were evaluable for response. The mean number of cycles received was 2.8 (range 1-12). The mean dose intensity was 700 mg/m(2)/day (SD of 71). One patient had a partial response (2.6%) for 7 months. Eighteen (46%) patients had SD, 20 (51%) patients had progressive disease. The median duration of SD was 93 days. The median overall survival was 32 weeks [95% CI (22-37)]. The most frequent Grade 3 or 4 adverse events were stomatitis (25%), dehydration (23%) and asthenia (21%). There was no evidence of cumulative toxicity. The overall median plasma concentration (C (max)) was 14.20 mu g/mL (range 1.41 to 119 mu g /mL) with no accumulation observed between cycles 1-6. Conclusion: This phase II study of nolatrexed in advanced HCC patients, demonstrated minimal activity and significant stomatitis. Hence, it does not warrant further study as a single agent for this disease. C1 Montefiore Med Ctr, Bronx, NY USA. NCI, Bethesda, MD 20892 USA. NYU, Med Ctr, New York, NY USA. Univ Calif San Francisco, San Francisco, CA 94143 USA. RP Jhawer, M (reprint author), Montefiore Med Ctr, Bronx, NY USA. EM mjhawer@montefiore.org NR 35 TC 6 Z9 8 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0167-6997 J9 INVEST NEW DRUG JI Invest. New Drugs PD FEB PY 2007 VL 25 IS 1 BP 85 EP 94 DI 10.1007/s10637-006-9003-x PG 10 WC Oncology; Pharmacology & Pharmacy SC Oncology; Pharmacology & Pharmacy GA 099QC UT WOS:000241609400011 PM 16957834 ER PT J AU Kim, SH Galban, CJ Lutz, RJ Dedrick, RL Csaky, KG Lizak, MJ Wang, NS Tansey, G Robinson, MR AF Kim, Stephanie H. Galban, Craig J. Lutz, Robert J. Dedrick, Robert L. Csaky, Karl G. Lizak, Martin J. Wang, Nam Sun Tansey, Ginger Robinson, Michael R. TI Assessment of subconjunctival and intrascleral drug delivery to the posterior segment using dynamic contrast-enhanced magnetic resonance imaging SO INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE LA English DT Article ID EXPERIMENTAL RETINAL-DETACHMENT; HUMAN SCLERAL PERMEABILITY; TRANSSCLERAL DELIVERY; MACULAR DEGENERATION; GANCICLOVIR IMPLANT; ANECORTAVE ACETATE; RABBIT EYE; SUBFOVEAL NEOVASCULARIZATION; SUPRACHOROIDAL SPACE; SUBRETINAL SPACE AB PURPOSE. Sustained-release intravitreal drug implants for posterior segment diseases are associated with significant complications. As an alternative, subconjunctival infusions of drug to the episclera of the back of the eye have been performed, but results in clinical trials for macular diseases showed mixed results. To improve understanding of transscleral drug delivery to the posterior segment, the distribution and clearance of gadolinium-diethylenetriaminopentaacetic acid (Gd-DTPA) infused in the subconjunctival or intrascleral space was investigated by means of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). METHODS. In anesthetized rabbits, catheters were placed anteriorly in the subconjunctival or intrascleral space and infused with Gd-DTPA at 1 and 10 mu L/min. Distribution and clearance of Gd-DTPA were measured using DCE-MRI. Histologic examination was performed to assess ocular toxicity of the delivery system. RESULTS. Subconjunctival infusions failed to produce detectable levels of Gd-DTPA in the back of the eye. In contrast, intrascleral infusions expanded the suprachoroidal layer and delivered Gd- DTPA to the posterior segment. Suprachoroidal clearance of Gd- DTPA followed first-order kinetics with an average half-life of 5.4 and 11.8 minutes after intrascleral infusions at 1 and 10 mu L/min, respectively. Histologic examination demonstrated expansion of the tissues in the suprachoroidal space that normalized after infusion termination. CONCLUSIONS. An intrascleral infusion was successful in transporting Gd- DTPA to the posterior segment from an anterior infusion site with limited anterior segment exposure. The suprachoroidal space appears to be an expandible conduit for drug transport to the posterior segment. Further studies are indicated to explore the feasibility of clinical applications. C1 NINDS, MRI Res Facil, NIH, Bethesda, MD 20892 USA. Univ Maryland, Dept Chem & Biomol Engn, College Pk, MD 20742 USA. NEI, Div Bioengn & Phys Sci, Off Res Serv, NIH, Bethesda, MD 20892 USA. RP Kim, SH (reprint author), NINDS, MRI Res Facil, NIH, 9000 Rockville Pike,Bldg 13-3N07, Bethesda, MD 20892 USA. EM kimstep@mail.nih.gov RI Wang, Nam Sun/E-4253-2016 NR 61 TC 35 Z9 37 U1 1 U2 4 PU ASSOC RESEARCH VISION OPHTHALMOLOGY INC PI ROCKVILLE PA 12300 TWINBROOK PARKWAY, ROCKVILLE, MD 20852-1606 USA SN 0146-0404 J9 INVEST OPHTH VIS SCI JI Invest. Ophthalmol. Vis. Sci. PD FEB PY 2007 VL 48 IS 2 BP 808 EP 814 DI 10.1167/iovs.06-0670 PG 7 WC Ophthalmology SC Ophthalmology GA 129KV UT WOS:000243729300044 PM 17251481 ER PT J AU Russell, ND Graham, BS Keefer, MC McElrath, MJ Self, SG Weinhold, KJ Montefiroi, DC Ferrari, G Horton, H Tomaras, GD Gurunathan, SV Baglyos, L Frey, SE Mulligan, MJ Harro, CD Buchbinder, SP Baden, LR Blattner, WA Koblin, BA Corey, L AF Russell, Nina D. Graham, Barney S. Keefer, Michael C. McElrath, M. Juliana Self, Steve G. Weinhold, Kent J. Montefiroi, David C. Ferrari, Guido Horton, Helen Tomaras, Georgia D. Gurunathan, Sanjay Baglyos, Lynn Frey, Sharon E. Mulligan, Mark J. Harro, Clayton D. Buchbinder, Susan P. Baden, Lindsey R. Blattner, William A. Koblin, Beryl A. Corey, Lawrence CA Natl Inst Allergy Infect Dis HIV V TI Phase 2 study of an HIV-1 canarypox vaccine (vCP1452) alone and in combination with rgp120 - Negative results fail to trigger a phase 3 correlates trial SO JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES LA English DT Article; Proceedings Paper CT HIV Vaccines - Current Challenges and Future Prospects Keystone Symposia CY APR 09-15, 2005 CL Banff, CANADA DE canarypox vector; cytotoxic T lymphocyte; enzyme-linked immunospot assay; HIV vaccine; rgp120 subunit protein; vCP1452 ID HUMAN-IMMUNODEFICIENCY-VIRUS; RECOMBINANT GLYCOPROTEIN-120 VACCINE; CD8(+) T-CELLS; IMMUNE-RESPONSES; HIV-1-POSITIVE INDIVIDUALS; NEUTRALIZING ANTIBODY; TYPE-1 VACCINE; ELISPOT ASSAY; VOLUNTEERS; INFECTION AB Background: A goal of T-cell HIV vaccines is to define the correlation between a vaccine-induced immune response and protection from HIV infection. We conducted a phase 2 trial to determine if a canarypox vaccine candidate (vCP1452) administered with rgp120 subunit protein would "qualify" for a trial to define a correlate of efficacy. Methods: A total of 330 healthy volunteers were enrolled into 4 groups: 120 received vCP1452 alone (0, 1, 3, and 6 months), 120 received vCP1452 with 2 different regimens of rgp120 coadministration, and 90 received placebo. HIV-specific antibody responses were measured by enzyme-linked immunoassay (ELISA) and neutralizing activity. T-cell responses were measured by chromium release and interferon-gamma (IFN-gamma) enzyme-linked immunospot (ELISpot) assays Results: Significant neutralizing antibody responses to the HIV MN strain were detected in all vaccine groups, with net responses ranging from 57% (95% confidence interval [CI]: 40% to 71%) to 94% (95% CI: 85% to 99%). Net cumulative HIV-specific CD8(+) IFN-gamma ELISpot assay responses were 13% (95% CI: -1% to 26%) for recipients of vCP1452 alone and 16% (95% CI: 2% to 29%) for recipients of vCP1452 plus rgp120. Conclusions: Overall, the HIV-specific CD8(+) cytotoxic T lymphocyte (CTL) response was not sufficient to qualify the regimen for a subsequent trial designed to detect an immune correlate of protection requiring a minimum CD8(+) CTL frequency of 30%. C1 Fred Hutchinson Canc Res Ctr, Clin Res Div, Program Infect Dis, Seattle, WA 98104 USA. Univ Washington, Dept Med, Seattle, WA 98195 USA. NIAID, Vaccine Res Ctr, NIH, Bethesda, MD 20892 USA. Univ Rochester, Med Ctr, Rochester, NY 14627 USA. Fred Hutchinson Canc Res Ctr, Program Biostat, Publ Hlth Sci Div, Seattle, WA 98104 USA. Fred Hutchinson Canc Res Ctr, Stat Ctr HIV AIDS Res & Prevent, Seattle, WA 98104 USA. Duke Univ, Med Ctr, Durham, NC 27706 USA. Sanofi Pasteur Inc, Swiftwater, PA USA. St Louis Univ, Sch Med, St Louis, MO 63103 USA. Univ Alabama, Sch Med, Birmingham, AL 35233 USA. Johns Hopkins Univ, Sch Med, Baltimore, MD 21218 USA. San Francisco Dept Publ Hlth, San Francisco, CA USA. Brigham & Womens Hosp, Boston, MA 02115 USA. Univ Maryland, Inst Human Virol, Baltimore, MD 21201 USA. New York Blood Ctr, New York, NY 10021 USA. RP Russell, ND (reprint author), Bill & Melinda Gates Fdn, POB 23350, Seattle, WA 98102 USA. EM nina.russell@gatesfoundation.org RI Ferrari, Guido/A-6088-2015; Tomaras, Georgia/J-5041-2016 FU Intramural NIH HHS [Z99 AI999999]; NIAID NIH HHS [U01 AI046747, UO1 AI 46747] NR 34 TC 78 Z9 80 U1 0 U2 7 PU LIPPINCOTT WILLIAMS & WILKINS PI PHILADELPHIA PA 530 WALNUT ST, PHILADELPHIA, PA 19106-3621 USA SN 1525-4135 J9 JAIDS-J ACQ IMM DEF JI JAIDS PD FEB 1 PY 2007 VL 44 IS 2 BP 203 EP 212 DI 10.1097/01.qai.0000248356.48501.ff PG 10 WC Immunology; Infectious Diseases SC Immunology; Infectious Diseases GA 131RZ UT WOS:000243888900012 PM 17106277 ER PT J AU Kushnir-Sukhov, NM Brown, JM Wu, YL Kirshenbaum, A Metcalfe, DD AF Kushnir-Sukhov, Nataliya M. Brown, Jared M. Wu, Yalin Kirshenbaum, Arnold Metcalfe, Dean D. TI Human mast cells are capable of serotonin synthesis and release SO JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY LA English DT Letter ID MASTOCYTOSIS C1 NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. RP Kushnir-Sukhov, NM (reprint author), NIAID, Lab Allerg Dis, NIH, Bethesda, MD 20892 USA. EM nkushnir@niaid.nih.gov FU Intramural NIH HHS NR 10 TC 84 Z9 85 U1 0 U2 3 PU MOSBY-ELSEVIER PI NEW YORK PA 360 PARK AVENUE SOUTH, NEW YORK, NY 10010-1710 USA SN 0091-6749 J9 J ALLERGY CLIN IMMUN JI J. Allergy Clin. Immunol. PD FEB PY 2007 VL 119 IS 2 BP 498 EP 499 DI 10.1016/j.jaci.2006.09.003 PG 2 WC Allergy; Immunology SC Allergy; Immunology GA 137YB UT WOS:000244327900031 PM 17291861 ER PT J AU Antachopoulos, C Meletiadis, J Sein, T Roilides, E Walsh, TJ AF Antachopoulos, Charalampos. Meletiadis, Joseph Sein, Tin Roilides, Emmanuel Walsh, Thomas J. TI Use of high inoculum for early metabolic signalling and rapid susceptibility testing of Aspergillus species SO JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY LA English DT Article DE XTT; metabolic activity; Aspergillus spp ID ANTIFUNGAL DRUG-RESISTANCE; FILAMENTOUS FUNGI; TRANSPLANT RECIPIENTS; COLORIMETRIC ASSAY; AMPHOTERICIN-B; IN-VITRO; FUMIGATUS; MENADIONE; ACTIVATION; CELLS AB Objectives: To develop and evaluate a new method for rapid susceptibility testing of Aspergillus spp. based on early metabolic signalling of high-inoculum biomass. Methods: Susceptibility to amphotericin B and voriconazole was studied in 39 clinical isolates of Aspergillus spp. (16 Aspergillus fumigatus, 11 Aspergillus flavus, 12 Aspergillus terreus). At 6 or 8 h after inoculation for A. fumigatus and A. flavus, and at 8 or 12 h after inoculation for A. terreus, 100 mu g/mL of the tetrazolium salt XTT and 25 mu M menadione were added and absorbance measured at 450 nm after 2 h of incubation at 37 degrees C. Inocula used were 106 conidia/mL for A. fumigatus and A. terreus and 105 conidia/mL for A. flavus, as lower inocula exhibited very low metabolic activity at these time points. Data were analysed with the sigmoid E-max model and compared with visual (lowest drug concentration showing no growth) and spectrophotometric MIC determination at 48 h (CLSI M38-A method). Results: The E-max model described well the concentration -effect relationship for early metabolic activity and 48 h fungal biomass (median r(2): 0.97 and 0.93, respectively). Use of the model allowed characterization and quantification of species- and drug-related differences in pharmacological inhibition of early metabolic activity as well as calculation of appropriate cutoff levels for MIC determination with the XTT assay. Using these cutoff levels, for A. fumigatus and A. flavus at both time points (6 and 8 h) and for A. terreus at 12 h, the agreement ( one dilution) of the XTT assay with the CLSI method was 91-100% and its reproducibility was 97-100%. Conclusions: This newly developed high-inoculum-based method provides rapid and reproducible MIC determinations for Aspergillus spp. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. Aristotle Univ Thessaloniki, Hippokrat Hosp, Dept Pediat 3, Thessaloniki, Greece. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov FU Intramural NIH HHS NR 32 TC 17 Z9 17 U1 0 U2 1 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0305-7453 J9 J ANTIMICROB CHEMOTH JI J. Antimicrob. Chemother. PD FEB PY 2007 VL 59 IS 2 BP 230 EP 237 DI 10.1093/jac/dkl488 PG 8 WC Infectious Diseases; Microbiology; Pharmacology & Pharmacy SC Infectious Diseases; Microbiology; Pharmacology & Pharmacy GA 147OH UT WOS:000245011800010 PM 17185296 ER PT J AU Ruan, XY Gallagher, D Harris, T Albu, J Heymsfield, S Kuznia, P Heshka, S AF Ruan, Xiang Yan Gallagher, Dympna Harris, Tamara Albu, Jeanine Heymsfield, Steven Kuznia, Patrick Heshka, Stanley TI Estimating whole body intermuscular adipose tissue from single cross-sectional magnetic resonance images SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Article DE race; body composition; fat distribution; muscle fat; imaging ID AFRICAN-AMERICAN; FAT DISTRIBUTION; SKELETAL-MUSCLE; INSULIN-RESISTANCE; METABOLIC SYNDROME; CLINICAL-TRIALS; LARGER AMOUNTS; THIGH MUSCLE; RISK-FACTORS; HEALTH ABC AB Estimating whole body intermuscular adipose tissue from single cross-sectional magnetic resonance images. J Appl Physiol 102: 748-754, 2007. First published October 19, 2006; doi:10.1152/japplphysiol.00304.2006.-Intermuscular adipose tissue (IMAT), a novel fat depot linked with metabolic abnormalities, has been measured by whole body MRI. The cross-sectional slice location with the strongest relation to total body IMAT volume has not been established. The aim was to determine the predictive value of each slice location and which slice locations provide the best estimates of whole body IMAT. MRI quantified total adipose tissue of which IMAT, defined as adipose tissue visible within the boundary of the muscle fascia, is a subcomponent. Single-slice IMAT areas were calculated for the calf, thigh, buttock, waist, shoulders, upper arm, and forearm locations in a sample of healthy adult women, African-American [n = 39; body mass index (BMI) 28.5 +/- 5.4 kg/m(2); 41.8 +/- 14.8 yr], Asian (n = 21; BMI 21.6 +/- 3.2 kg/m(2); 40.9 +/- 16.3 yr), and Caucasian (n = 43; BMI 25.6 +/- 5.3 kg/m(2); 43.2 +/- 15.3 yr), and Caucasian men (n = 39; BMI 27.1 +/- 3.8 kg/m(2); 45.2 +/- 14.6 yr) and used to estimate total IMAT groups using multiple-regression equations. Midthigh was the best, or near best, single predictor in all groups with adjusted R-2 ranging from 0.49 to 0.84. Adding a second and third slice further increased R-2 and reduced the error of the estimate. Menopausal status and degree of obesity did not affect the location of the best single slice. The contributions of other slice locations varied by sex and race, but additional slices improved predictions. For group studies, it may be more cost-effective to estimate IMAT based on one or more slices than to acquire and segment for each subject the numerous images necessary to quantify whole body IMAT. C1 St Lukes Roosevelt Hosp, Dept Med, Obes Res Ctr, New York, NY 10025 USA. Columbia Univ, Inst Human Nutr, New York, NY 10032 USA. NIA, Lab Epidemiol Demog & Biometry, Geriatr Epidemiol Sect, Bethesda, MD 20892 USA. Capital Univ Med Sci, Beijing Obstet & Gynecol Hosp, Endocrinol Ctr Gynecol, Beijing, Peoples R China. RP Gallagher, D (reprint author), Obes Res Ctr, 1090 Amsterdam Ave, New York, NY 10025 USA. EM dg108@columbia.edu OI Gallagher, Dympna/0000-0003-1769-9754 FU NCRR NIH HHS [RR00645, M01 RR000645]; NIA NIH HHS [R29 AG014715-05, R29 AG014715, AG14715]; NIDDK NIH HHS [P01 DK042618, P01 DK042618-120006, R01 DK040414, R01 DK040414-12, DK42618, DK40414] NR 35 TC 25 Z9 29 U1 0 U2 1 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD FEB PY 2007 VL 102 IS 2 BP 748 EP 754 DI 10.1152/japplphysiol.00304.2006 PG 7 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 133SM UT WOS:000244033500034 PM 17053107 ER PT J AU McGuinness, OP AF McGuinness, Owen P. TI Untitled SO JOURNAL OF APPLIED PHYSIOLOGY LA English DT Editorial Material ID INSULIN; HUMANS C1 Vanderbilt Univ, Sch Med, Dept Physiol & Mol Biophys, Nashville, TN 37212 USA. Vanderbilt Univ, Sch Med, Mouse Metab Phenotyping Ctr, Nashville, TN 37212 USA. RP McGuinness, OP (reprint author), Vanderbilt Univ, Sch Med, Dept Physiol & Mol Biophys, Nashville, TN 37212 USA. FU NIDDK NIH HHS [R01 DK078188] NR 6 TC 0 Z9 0 U1 0 U2 0 PU AMER PHYSIOLOGICAL SOC PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 8750-7587 J9 J APPL PHYSIOL JI J. Appl. Physiol. PD FEB PY 2007 VL 102 IS 2 BP 823 EP 823 PG 1 WC Physiology; Sport Sciences SC Physiology; Sport Sciences GA 133SM UT WOS:000244033500053 PM 17323468 ER PT J AU Jomaa, A Damjanovic, D Leong, V Ghirlando, R Iwanczyk, J Ortega, J AF Jomaa, Ahmad Damjanovic, Daniela Leong, Vivian Ghirlando, Rodolfo Iwanczyk, Jack Ortega, Joaquin TI The inner cavity of Escherichia coli DegP protein is not essential for molecular chaperone and proteolytic activity SO JOURNAL OF BACTERIOLOGY LA English DT Article ID HEAT-SHOCK-PROTEIN; PDZ DOMAIN; CRYSTAL-STRUCTURE; STRESS-RESPONSE; QUALITY-CONTROL; CLPAP PROTEASE; HTRA PROTEASE; CELL-ENVELOPE; TEMPERATURES; DEGRADATION AB The Escherichia coli DegP protein is an essential periplasmic protein for bacterial survival at high temperatures. DegP has the unusual property of working as a chaperone below 28 degrees C, but efficiently degrading unfolded proteins above 28 degrees C. Monomeric DegP contains a protease domain and two PDZ domains. It oligomerizes into a hexameric cage through the staggered association of trimers. The active sites are located in a central cavity that is only accessible laterally, and the 12 PDZ domains act as mobile sidewalls that mediate opening and closing of the gates. As access to the active sites is restricted, DegP is an example of a self-compartmentalized protease. To determine the essential elements of DegP that maintain the integrity of the hexameric cage, we constructed several deletion mutants of DegP that formed trimers rather than hexamers. We found that residues 39 to 78 within the LA loops, as well as the PDZ2 domains are essential for the integrity of the DegP hexamer. In addition, we asked whether an enclosed cavity or cage of specific dimensions is required for the protease and chaperone activities in DegP. Both activities were maintained in the trimeric DegP mutants without an enclosed cavity and in deletion DegP mutants with significantly reduced dimensions of the cage. We conclude that the functional unit for the protease and chaperone activities of DegP is a trimer and that neither a cavity of specific dimensions nor the presence of an enclosed cavity appears to be essential for the protease and chaperone activities of DegP. C1 McMaster Univ, Hlth Sci Ctr, Dept Biochem & Biomed Sci, Hamilton, ON L8N 3Z5, Canada. NIDDK, Mol Biol Lab, NIH, Bethesda, MD 20892 USA. RP Ortega, J (reprint author), McMaster Univ, Hlth Sci Ctr, Dept Biochem & Biomed Sci, Room 4H24,1200 Main St W, Hamilton, ON L8N 3Z5, Canada. EM ortegaj@mcmaster.ca RI Ghirlando, Rodolfo/A-8880-2009 FU Canadian Institutes of Health Research [64342, 76594]; Intramural NIH HHS NR 29 TC 36 Z9 37 U1 0 U2 5 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD FEB PY 2007 VL 189 IS 3 BP 706 EP 716 DI 10.1128/JB.01334-06 PG 11 WC Microbiology SC Microbiology GA 134VJ UT WOS:000244112100005 PM 17122339 ER PT J AU Makarova, KS Koonin, EV AF Makarova, Kira S. Koonin, Eugene V. TI Evolutionary genomics of lactic acid bacteria SO JOURNAL OF BACTERIOLOGY LA English DT Review ID HORIZONTAL GENE-TRANSFER; LACTOCOCCUS-LACTIS; STREPTOCOCCUS-THERMOPHILUS; COG DATABASE; LACTOBACILLUS-PLANTARUM; MOLECULAR CLOCK; SEQUENCE; METABOLISM; BIFIDOBACTERIA; SUSCEPTIBILITY C1 NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. RP Makarova, KS (reprint author), NIH, Natl Ctr Biotechnol Informat, Natl Lib Med, Bethesda, MD 20894 USA. EM makarova@ncbi.nlm.nih.gov NR 63 TC 71 Z9 85 U1 2 U2 22 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0021-9193 J9 J BACTERIOL JI J. Bacteriol. PD FEB PY 2007 VL 189 IS 4 BP 1199 EP 1208 DI 10.1128/JB.01351-06 PG 10 WC Microbiology SC Microbiology GA 137FY UT WOS:000244279600004 ER PT J AU Nguyen, DM Hussain, M AF Nguyen, Dao M. Hussain, Mustafa TI The role of the mitochondria in mediating cytotoxicity of anti-cancer therapies SO JOURNAL OF BIOENERGETICS AND BIOMEMBRANES LA English DT Review DE mitochondria; cancer; chemotherapy; Apo2L/TRAIL; Bc12 superfamily; apoptosis; caspase ID APOPTOSIS-INDUCING LIGAND; HISTONE DEACETYLASE INHIBITORS; CELL LUNG-CANCER; TRAIL-INDUCED APOPTOSIS; BCL-X-L; SUBEROYLANILIDE HYDROXAMIC ACID; CISPLATIN-INDUCED APOPTOSIS; MALIGNANT PLEURAL MESOTHELIOMA; DEPENDENT CASPASE ACTIVATION; PROSTATE-CANCER AB Optimal cytotoxic anticancer therapy, at the cellular level, requires effective and selective induction of cell death to achieve a net reduction of biomass of malignant tissues. Standard cytotoxic chernotherapeutics have been developed based on the observations that mitotically active cancer cells are more susceptible than quiescent normal cells to chromosornal, microtubular or metabolic poisons. More recent development of molecularly targeted drugs for cancer focuses on exploiting biological differentials between normal and transformed cells for selective eradication of cancers. The common thread of "standard" and "novel" cytotoxic drugs is their ability to activate the apoptosis-inducing machinery mediated by mitochondria, also known as the intrinsic death signaling cascade. The aim of this article is to provide an overview of the role of the mitochondria, an energy-generating organelle essential for life, in mediating death when properly activated by cytotoxic stresses. C1 NCI, Sect Thorac Oncol, Surg Branch, Ctr Canc Res,NIH, Bethesda, MD 20892 USA. RP Nguyen, DM (reprint author), NCI, Sect Thorac Oncol, Surg Branch, Ctr Canc Res,NIH, Room 4W-4-3940,10 Ctr Dr, Bethesda, MD 20892 USA. EM dao_nguyen@nih.gov FU Intramural NIH HHS NR 129 TC 13 Z9 13 U1 0 U2 7 PU SPRINGER/PLENUM PUBLISHERS PI NEW YORK PA 233 SPRING ST, NEW YORK, NY 10013 USA SN 0145-479X J9 J BIOENERG BIOMEMBR JI J. Bioenerg. Biomembr. PD FEB PY 2007 VL 39 IS 1 BP 13 EP 21 DI 10.1007/s10863-006-9055-9 PG 9 WC Biophysics; Cell Biology SC Biophysics; Cell Biology GA 180OS UT WOS:000247375900002 PM 17294132 ER PT J AU Tavakoli-Nezhad, M Tao-Cheng, JH Weavert, DR Schwartz, WJ AF Tavakoli-Nezhad, Mahboubeh Tao-Cheng, Jung-Hwa Weavert, David R. Schwartz, William J. TI PERI-like immunoreactivity in oxytocin cells of the hamster hypothalamo-neurohypophyseal system SO JOURNAL OF BIOLOGICAL RHYTHMS LA English DT Letter ID CIRCADIAN CLOCK; SUPRACHIASMATIC NUCLEUS; PARAVENTRICULAR NUCLEUS; SYRIAN-HAMSTERS; EXPRESSION; GENE C1 Univ Massachusetts, Sch Med, Dept Neurol, Worcester, MA 01655 USA. NINDS, Electron Microscop Facil, Bethesda, MD USA. Univ Massachusetts, Sch Med, Dept Neurobiol, Worcester, MA 01605 USA. RP Schwartz, WJ (reprint author), Univ Massachusetts, Sch Med, Dept Neurol, 55 Lake Ave N, Worcester, MA 01655 USA. EM william.schwartz@umassmed.edu RI Jelinek, Milan/C-8515-2011 FU Intramural NIH HHS; NINDS NIH HHS [R01 NS46605] NR 11 TC 4 Z9 4 U1 1 U2 1 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0748-7304 J9 J BIOL RHYTHM JI J. Biol. Rhythms PD FEB PY 2007 VL 22 IS 1 BP 81 EP 84 DI 10.1177/0748730406296717 PG 4 WC Biology; Physiology SC Life Sciences & Biomedicine - Other Topics; Physiology GA 126CM UT WOS:000243489800008 PM 17229927 ER PT J AU Sioutos, N de Coronado, S Haber, MW Hartel, FW Shaiu, WL Wright, LW AF Sioutos, Nicholas de Coronado, Sherri Haber, Margaret W. Hartel, Frank W. Shaiu, Wen-Ling Wright, Lawrence W. TI NCI Thesaurus: A semantic model integrating cancer-related clinical and molecular information SO JOURNAL OF BIOMEDICAL INFORMATICS LA English DT Article DE biomedical vocabulary; ontology development; cancer research; disease model; cancer terminology ID ACUTE LYMPHOBLASTIC-LEUKEMIA; B-CELL LYMPHOMA; TEL-AML1 FUSION; C-KIT; CHILDREN; GENE; THERAPY; EXPRESSION; PREDICTION; RISK AB Over the last 8 years, the National Cancer Institute (NCI) has launched a major effort to integrate molecular and clinical cancer-related information within a unified biomedical informatics framework, with controlled terminology as its foundational layer. The NCI Thesaurus is the reference terminology underpinning these efforts. It is designed to meet the growing need for accurate, comprehensive, and shared terminology, covering topics including: cancers, findings, drugs, therapies, anatomy, genes, pathways, cellular and subcellular processes, proteins, and experimental organisms. The NCI Thesaurus provides a partial model of how these things relate to each other, responding to actual user needs and implemented in a deductive logic framework that can help maintain the integrity and extend the informational power of what is provided. This paper presents the semantic model for cancer diseases and its uses in integrating clinical and molecular knowledge, more briefly examines the models and uses for drug, biochemical pathway, and mouse terminology, and discusses limits of the current approach and directions for future work. (c) 2006 Elsevier Inc. All rights reserved. C1 NCI, Ctr Bioinformat, Bethesda, MD 20892 USA. RP de Coronado, S (reprint author), 113 Brookline St, Moraga, CA 94556 USA. EM decorons@mail.nih.gov NR 54 TC 123 Z9 124 U1 1 U2 6 PU ACADEMIC PRESS INC ELSEVIER SCIENCE PI SAN DIEGO PA 525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA SN 1532-0464 EI 1532-0480 J9 J BIOMED INFORM JI J. Biomed. Inform. PD FEB PY 2007 VL 40 IS 1 BP 30 EP 43 DI 10.1016/j.jbi.2006.02.013 PG 14 WC Computer Science, Interdisciplinary Applications; Medical Informatics SC Computer Science; Medical Informatics GA 122HI UT WOS:000243216000004 PM 16697710 ER PT J AU Ruocco, KM Goncharova, EI Young, MR Colburn, NH McMahon, JB Henrich, CJ AF Ruocco, Katie M. Goncharova, Ekaterina I. Young, Matthew R. Colburn, Nancy H. McMahon, James B. Henrich, Curtis J. TI A high-throughput cell-based assay to identify specific inhibitors of transcription factor AP-1 SO JOURNAL OF BIOMOLECULAR SCREENING LA English DT Article DE AP-1; high-throughput assay; natural products; beta-lactamase ID PROTEIN-KINASE-C; INDUCED TRANSFORMATION; ACTIVATOR PROTEIN-1; JUN; POTENT; TRANSACTIVATION; EXPRESSION; CALCIUM; COMPLEX; BINDING AB The oncogenic transcription factor AP-1 (activator protein-1) is required for tumor promotion and progression. Identification of novel and specific AP-1 inhibitors would be beneficial for cancer prevention and therapy. The authors have developed a high-throughput assay to screen synthetic and natural product libraries for noncytotoxic inhibitors of mitogen-activated AP-1 activity. The cell-based high-throughput screen is conducted in a 384-well format using a fluorescent resonance energy transfer (FRET) substrate to quantify the activity of a beta-lactamase reporter under the control of an AP-1-dependent promoter. The ratiometric FRET readout makes this assay extremely robust and reproducible, particularly for use with natural product extracts. To eliminate false positives due to cell killing, a cytotoxicity assay was incorporated. The AP-1 beta-lactamase reporter was validated with inhibitors of kinases located upstream of AP-1 and with known natural product inhibitors of AP-1 (nordihydroguaiaretic acid and curcumin). The assay was able to identify other known AP-1 inhibitors and protein kinase C modulators, as well as a number of chemically diverse compounds with unknown mechanisms of action from natural products libraries. Application to natural product extracts identified hits from a range of taxonomic groups. Screening of synthetic compounds and natural products should identify novel AP-1 inhibitors that may be useful in the prevention and treatment of cancers. C1 NCI, SAIC Frederick Inc, Basic Res Program, Frederick, MD 21702 USA. NCI, Lab Canc Prevent, Gene Regulat Sect, Frederick, MD 21702 USA. NCI, Mol Targets Dev Program, Frederick, MD 21702 USA. NCI, Data Management Serv Inc, Frederick, MD 21702 USA. RP Henrich, CJ (reprint author), NCI, SAIC Frederick Inc, Basic Res Program, Bldg 560,Room 32-63A, Frederick, MD 21702 USA. EM henrichc@ncifcrf.gov FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 31 TC 13 Z9 13 U1 1 U2 7 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 1087-0571 J9 J BIOMOL SCREEN JI J. Biomol. Screen PD FEB PY 2007 VL 12 IS 1 BP 133 EP 139 DI 10.1177/1087057106296686 PG 7 WC Biochemical Research Methods; Biotechnology & Applied Microbiology; Chemistry, Analytical SC Biochemistry & Molecular Biology; Biotechnology & Applied Microbiology; Chemistry GA 136UG UT WOS:000244249000014 PM 17175522 ER PT J AU Yingling, YG Shapiro, BA AF Yingling, Yaroslava G. Shapiro, Bruce A. TI The impact of dyskeratosis congenita mutations on the structure and dynamics of the human telomerase RNA pseudoknot domain SO JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS LA English DT Article DE dyskeratosis congenita; telomerase; RNA; molecular modeling; and pseudoknot ID EXPLICIT SOLVENT SIMULATIONS; GENERALIZED BORN MODELS; MOLECULAR-DYNAMICS; NUCLEIC-ACIDS; REVERSE-TRANSCRIPTASE; CONTINUUM SOLVENT; APLASTIC-ANEMIA; SOLVATION MODEL; PROTEIN BINDING; DNA AB The pseudoknot domain is a functionally crucial part of telomerase RNA and influences the activity and stability of the ribonucleoprotein complex. Autosomal dominant dyskeratosis congenita (DKC) is an inherited disease that is linked to mutations in telomerase RNA and impairs telomerase function. In this paper, we present a computational prediction of the influence of two base DKC mutations on the structure, dynamics, and stability of the pseudoknot domain. We use molecular dynamics simulations, MM-GBSA free energy calculations, static analysis, and melting simulations analysis. Our results show that the DKC mutations stabilize the hairpin form and destabilize the pseudoknot form of telomerase RNA. Moreover, the P3 region of the predicted DKC-mutated pseudoknot structure is unstable and fails to form as a defined helical stem. We directly compare our predictions with experimental observations by calculating the enthalpy of folding and melting profiles for each structure. The enthalpy values are in very good agreement with values determined by thermal denaturation experiments. The melting simulations and simulations at elevated temperatures show the existence of an intermediate structure, which involves the formation of two UU base pairs observed in the hairpin form of the pseudoknot domain. C1 NCI, Canc Res Ctr, Nanobiol Program, NIH, Ft Detrick, MD 21702 USA. RP Shapiro, BA (reprint author), NCI, Canc Res Ctr, Nanobiol Program, NIH, Bldg 469,Room 150, Ft Detrick, MD 21702 USA. EM bshapiro@ncifcrf.gov RI Yingling, Yaroslava/B-2901-2008 OI Yingling, Yaroslava/0000-0002-8557-9992 FU Intramural NIH HHS NR 63 TC 9 Z9 10 U1 0 U2 4 PU ADENINE PRESS PI SCHENECTADY PA 2066 CENTRAL AVE, SCHENECTADY, NY 12304 USA SN 0739-1102 J9 J BIOMOL STRUCT DYN JI J. Biomol. Struct. Dyn. PD FEB PY 2007 VL 24 IS 4 BP 303 EP 319 PG 17 WC Biochemistry & Molecular Biology; Biophysics SC Biochemistry & Molecular Biology; Biophysics GA 137GU UT WOS:000244281900001 PM 17206847 ER PT J AU Kuznetsov, S Pellegrini, M Shuda, K Fernandez-Capetillo, O Liu, YL Martin, BK Burkett, S Southon, E Pati, D Tessarollo, L West, SC Donovan, PJ Nussenzweig, A Sharan, SK AF Kuznetsov, Sergey Pellegrini, Manuela Shuda, Kristy Fernandez-Capetillo, Oscar Liu, Yilun Martin, Betty K. Burkett, Sandra Southon, Eileen Pati, Debananda Tessarollo, Lino West, Stephen C. Donovan, Peter J. Nussenzweig, Andre Sharan, Shyam K. TI RAD51C deficiency in mice results in early prophase I arrest in males and sister chromatid separation at metaphase II in females SO JOURNAL OF CELL BIOLOGY LA English DT Article ID MEIOTIC CHROMOSOME SYNAPSIS; DNA STRAND EXCHANGE; AIR-DRYING METHOD; SYNAPTONEMAL COMPLEX; MAMMALIAN OOCYTES; BREAK REPAIR; MEIOSIS I; RECOMBINATION; PROTEIN; MOUSE AB RAD51C is a member of the RecA/RAD51 protein family, which is known to play an important role in DNA repair by homologous recombination. In mice, it is essential for viability. Therefore, we have generated a hypomorphic allele of Rad51c in addition to a null allele. A subset of mice expressing the hypomorphic allele is infertile. This infertility is caused by sexually dimorphic defects in meiotic recombination, revealing its two distinct functions. Spermatocytes undergo a developmental arrest during the early stages of meiotic prophase I, providing evidence for the role of RAD51C in early stages of RAD51mediated recombination. In contrast, oocytes can progress normally to metaphase I after superovulation but display precocious separation of sister chromatids, aneuploidy, and broken chromosomes at metaphase II. These defects suggest a possible late role of RAD51C in meiotic recombination. Based on the marked reduction in Holliday junction (HJ) resolution activity in Rad51c-null mouse embryonic. broblasts, we propose that this late function may be associated with HJ resolution. C1 NCI, Mouse Canc Genet Program, Canc Res Ctr, Frederick, MD 21702 USA. NCI, Expt Immunol Branch, Bethesda, MD 20892 USA. Thomas Jefferson Univ, Kimmerl Canc Ctr, Philadelphia, PA 19107 USA. Imperial Canc Res Fund, Clare Hall Labs, London Res Inst, Canc Res UK, S Mimms EN6 3LD, Herts, England. Baylor Coll Med, Dept Pediat, Texas Childrens Canc Ctr, Houston, TX 77030 USA. Johns Hopkins Univ, Inst Cell Engn, Baltimore, MD 21205 USA. RP Sharan, SK (reprint author), NCI, Mouse Canc Genet Program, Canc Res Ctr, Frederick, MD 21702 USA. EM ssharan@mail.ncifcrf.gov RI Fernandez-Capetillo, Oscar/H-3508-2015; OI Fernandez-Capetillo, Oscar/0000-0002-2690-6885; Kuznetsov, Sergey/0000-0002-5662-9700; West, Stephen/0000-0001-8848-9418 NR 61 TC 68 Z9 71 U1 1 U2 9 PU ROCKEFELLER UNIV PRESS PI NEW YORK PA 1114 FIRST AVE, 4TH FL, NEW YORK, NY 10021 USA SN 0021-9525 J9 J CELL BIOL JI J. Cell Biol. PD FEB PY 2007 VL 176 IS 5 BP 581 EP 592 DI 10.1083/jcb.200608130 PG 12 WC Cell Biology SC Cell Biology GA 140EN UT WOS:000244487100017 PM 17312021 ER PT J AU Xiao, Z Camalier, CE Nagashima, K Chan, KC Lucas, DA De la Cruz, MJ Gignac, M Lockett, S Issaq, HJ Veenstra, TD Conrads, TP Beck, GR AF Xiao, Zhen Camalier, Corinne E. Nagashima, Kunio Chan, King C. Lucas, David A. De la Cruz, M. Jason Gignac, Michelle Lockett, Stephen Issaq, Haleem J. Veenstra, Timothy D. Conrads, Thomas P. Beck, George R., Jr. TI Analysis of the extracellular matrix vesicle proteome in mineralizing osteoblasts SO JOURNAL OF CELLULAR PHYSIOLOGY LA English DT Article ID ALKALINE-PHOSPHATASE ACTIVITY; CELL MEMBRANE GLYCOPROTEIN-1; MURINE MC3T3-E1 CELLS; TERMINAL DIFFERENTIATION; FINE-STRUCTURE; ASCORBIC-ACID; GROWTH; CARTILAGE; CALCIFICATION; BONE AB Many key processes central to bone formation and homeostasis require the involvement of osteoblasts, cells responsible for accumulation and mineralization of the extracellular matrix (ECM). During this complex and only partially understood process, osteoblasts generate and secrete matrix vesicles (MVs) into the ECM to initiate mineralization. Although they are considered an important component of mineralization process, MVs still remain a mystery. To better understand their function and biogenesis, a proteomic analysis of MVs has been conducted. MVs were harvested by two sample preparation approaches and mass spectrometry was utilized for protein identification. A total of 133 proteins were identified in common from the two MV preparations, among which were previously known proteins, such as annexins and peptidases, along with many novel proteins including a variety of enzymes, osteoblast-specific factors, ion channels, and signal transduction molecules, such as 14-3-3 family members and Rab-related proteins. To compare the proteome of MV with that of the ECM we conducted a large-scale proteomic analysis of collagenase digested mineralizing osteoblast matrix. This analysis resulted in the identification of 1,327 unique proteins. A comparison of the proteins identified from the two MV preparations with the ECM analysis revealed 83 unique, non-redundant proteins identified in all three samples. This investigation represents the first systematic proteomic analysis of MVs and provides insights into both the function and origin of these important mineralization-regulating vesicles. C1 NCI, SAIC Frederick Inc, Mass Spectrometry Ctr, Lab Proteom & Analyt Technol, Frederick, MD 21702 USA. Emory Univ, Sch Med, Div Endocrinol Metab & Lipids, Atlanta, GA 30322 USA. NCI, SAIC Frederick Inc, Image Anal Lab, Frederick, MD 21702 USA. RP Beck, GR (reprint author), NCI, SAIC Frederick Inc, Mass Spectrometry Ctr, Lab Proteom & Analyt Technol, POB B, Frederick, MD 21702 USA. EM george.beck@emory.edu FU NCI NIH HHS [N01-CO12400, CA84573] NR 55 TC 72 Z9 73 U1 3 U2 19 PU WILEY-LISS PI HOBOKEN PA DIV JOHN WILEY & SONS INC, 111 RIVER ST, HOBOKEN, NJ 07030 USA SN 0021-9541 J9 J CELL PHYSIOL JI J. Cell. Physiol. PD FEB PY 2007 VL 210 IS 2 BP 325 EP 335 DI 10.1002/jcp.20826 PG 11 WC Cell Biology; Physiology SC Cell Biology; Physiology GA 117MD UT WOS:000242876400006 PM 17096383 ER PT J AU Burger, AM Loadman, PM Thurston, DE Schultz, R Fiebig, H Bibby, MC AF Burger, A. M. Loadman, P. M. Thurston, D. E. Schultz, R. Fiebig, H. Bibby, M. C. CA European Org Res Treatment Canc E TI Preclinical pharmacology of the pyrrolobenzodiazepine (PBD) monomer DRH-417 (NSC 709119) SO JOURNAL OF CHEMOTHERAPY LA English DT Article DE PBD monomer; anti-tumor activity; minor groove DNA binder; plasma pharmacokinetics ID CROSS-LINKING AGENT; MURINE COLON ADENOCARCINOMA; SPECTRUM ANTITUMOR-ACTIVITY; HUMAN TUMOR XENOGRAFTS; SJG-136 NSC-694501; DNA-BINDING; IN-VITRO; TRANSCRIPTION FACTORS; CLONOGENIC-ASSAY; PHOSPHATE AB The pyrrolobenzodiazepine monomer DRH-417 is a member of the anthramycin group of anti-tumor antibiotics that bind covalently to the N2 of guanine within the minor groove of DNA. DRH-417 emerged from the EORTC-Drug Discovery Committee and NCI 60 cell line in vitro screening programs as a potent antiproliferative agent with differential sensitivity towards certain cancer types such as melanoma, breast and renal cell carcinoma (mean IC50 = 3 nM). DRH-417 was therefore tested for in vivo activity. The maximum tolerated dose (MTD) was established as 0.5 mg/kg given i.p. Marked anti-tumor activity was seen in two human renal cell cancers, one breast cancer and a murine colon tumor model (p < 0.01). A selective HPLC (LC/MS) analytical method was developed and plasma pharmacokinetics determined. At a dose of 0.5 mg kg(-1), the plasma AUC was 540 nM h (197.1 ng h ml(-1)) and the peak plasma concentration (171 nM [62.4 ng ml(-1)]) occurred at 30 min., reaching doses levels well above those needed for in vitro antiproliferative activity. Genomic profiling of in vivo sensitive tumors revealed that the latter have an activated insulin-like growth factor signalling pathway. C1 Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Dept Pharmacol & Expt Therapeut, Baltimore, MD 21201 USA. Univ Bradford, Tom Connors Canc Res Ctr, Bradford BD7 1DP, W Yorkshire, England. Univ London, Sch Pharm, Gene Targeted Drug Design Res Grp, Canc Res UK, London WC1E 7HU, England. Univ London, Sch Pharm, Spirogen Ltd, London WC1E 7HU, England. NCI, Dev Therapeut Program, Bethesda, MD 20892 USA. Oncotest GmbH, Inst Expt Oncol, Freiburg, Germany. RP Burger, AM (reprint author), Univ Maryland, Sch Med, Marlene & Stewart Greenebaum Canc Ctr, Dept Pharmacol & Expt Therapeut, Bressler Res Bldg,Rm 9-0369,655 W Baltimore St, Baltimore, MD 21201 USA. EM aburger@som.umaryland.edu OI Loadman, Paul/0000-0002-4259-8616 NR 29 TC 10 Z9 10 U1 0 U2 3 PU ESIFT SRL PI FLORENCE PA VIA CARLO DEL GRECO 36,, 50141 FLORENCE, ITALY SN 1120-009X J9 J CHEMOTHERAPY JI J. Chemother. PD FEB PY 2007 VL 19 IS 1 BP 66 EP 78 PG 13 WC Oncology; Infectious Diseases; Pathology; Pharmacology & Pharmacy SC Oncology; Infectious Diseases; Pathology; Pharmacology & Pharmacy GA 135CD UT WOS:000244130500009 PM 17309854 ER PT J AU Zhao, M Rudek, MA He, P Hafner, FT Radtke, M Wright, JJ Smith, BD Messersmith, WA Hidalgo, M Baker, SD AF Zhao, Ming Rudek, Michelle A. He, Ping Hafner, Frank-Thorsten Radtke, Martin Wright, John J. Smith, B. Douglas Messersmith, Wells A. Hidalgo, Manuel Baker, Sharyn D. TI A rapid and sensitive method for determination of sorafenib in human plasma using a liquid chromatography/tandem mass spectrometry assay SO JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES LA English DT Article DE sorafenib; LC/MS/MS; pharmacokinetics ID REFRACTORY SOLID TUMORS; FACTOR RECEPTOR INHIBITOR; DAYS ON/7 DAYS; RAF KINASE; PHASE-I; BAY-43-9006; PHARMACOKINETICS; PATHWAY; SAFETY; VALIDATION AB A rapid, sensitive and specific method was developed and validated using LC/MS/MS for determination of sorafenib in human plasma. Sample preparation involved a single protein precipitation step by the addition of 0.1 mL of plasma with 0.5 mL acetonitrile. Analysis of the compounds of interest including the internal standard ([H-2(8) N-15] sorafenib) was achieved on a Waters X-Terra (TM) C-18 (150 mm x 2.1 mm i.d., 3.5 mu m) analytical column using a mobile phase consisting of acetonitrile/10mM ammonium acetate (65:35, v/v) containing 0.1% formic acid and isocratic flow at 0.2 mL/min for 6 min. The analytes were monitored by tandem mass spectrometry with electrospray positive ionization. Linear calibration curves were generated over the range of 7.3-7260 ng/mL for the human plasma samples with values for the coefficient of determination of > 0.96. The values for both within day and between day precision and accuracy were well within the generally accepted criteria for analytical methods (< 15%). (c) 2006 Elsevier B.V. All rights reserved. C1 Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Baltimore, MD 21231 USA. Bayer HealthCare, Preclin Pharmacokinet Bioanalyt, Wuppertal, Germany. Bayer HealthCare, Drug Metab & Isotope Chem, Wuppertal, Germany. NCI, Invest Drug Branch, CTEP, Rockville, MD USA. RP Baker, SD (reprint author), Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr Johns Hopkins, Bunting Blaustein Canc Res Bldg,Room 1M87,1650 Or, Baltimore, MD 21231 USA. EM sbaker7@jhmi.edu RI HIDALGO, MANUEL/I-4995-2015 OI HIDALGO, MANUEL/0000-0002-3765-3318 FU NCI NIH HHS [P30CA069773, U01CA70095] NR 19 TC 37 Z9 37 U1 0 U2 4 PU ELSEVIER SCIENCE BV PI AMSTERDAM PA PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS SN 1570-0232 J9 J CHROMATOGR B JI J. Chromatogr. B PD FEB 1 PY 2007 VL 846 IS 1-2 BP 1 EP 7 DI 10.1016/j.jchromb.2006.06.005 PG 7 WC Biochemical Research Methods; Chemistry, Analytical SC Biochemistry & Molecular Biology; Chemistry GA 137GN UT WOS:000244281100001 PM 16798122 ER PT J AU Cappola, AR Ratcliffe, SJ Bhasin, S Blackman, MR Cauley, J Robbins, J Zmuda, JM Harris, T Fried, LP AF Cappola, Anne R. Ratcliffe, Sarah J. Bhasin, Shalender Blackman, Marc R. Cauley, Jane Robbins, John Zmuda, Joseph M. Harris, Tamara Fried, Linda P. TI Determinants of serum total and free testosterone levels in women over the age of 65 years SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID HUMAN-IMMUNODEFICIENCY-VIRUS; SURGICALLY MENOPAUSAL WOMEN; ENDOGENOUS SEX-HORMONES; POSTMENOPAUSAL WOMEN; ANDROGEN DEFICIENCY; DEHYDROEPIANDROSTERONE-SULFATE; CIRCULATING ANDROGENS; ESTROGEN REPLACEMENT; ENDOCRINE FUNCTION; CONTROLLED-TRIAL AB Context: Little is known about testosterone ( T) levels and their determinants in women of late postmenopausal age. Objective: We describe levels of total and free T and selected factors that influence these levels in a random sample of older women. Design: Levels of serum total T and free T by microdialysis were measured using ultrasensitive assays in 347 community-dwelling women aged 65-98 yr enrolled in the Cardiovascular Health Study. Cross-sectional analyses were performed to define factors associated with total and free T levels. Results: In adjusted models: 1) total T levels declined with age until 80, whereas free T levels did not vary by age; 2) women with bilateral oophorectomy had 23% lower total T and 16% lower free T levels than those with at least one intact ovary; 3) oral estrogen users had total and free T levels that were 47% lower than never users; 4) obese women had 47% higher total T and 20% higher free T levels, and overweight women had 24% higher total T and 14% higher free T levels, than normal weight women; and 5) free T levels were 51% higher in black women. Corticosteroid users had 75% lower total T and 43% lower free T levels than nonusers. Conclusions: Bilateral oophorectomy, estrogen use, corticosteroid use, and low body mass index are independent risk factors for lower T levels in women aged 65 yr and over. Although highly prevalent in women of this age, the physiological significance of low T levels in late postmenopausal women requires further investigation. C1 Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Div Endocrinol Diabet & Metab, Philadelphia, PA 19104 USA. Boston Univ, Endocrinol Sect, Boston, MA 02118 USA. NIA, Endocrine Sect, Lab Clin Invest, Natl Ctr Complementary & Alternat Med,NIH, Bethesda, MD 20892 USA. NIA, Lab Epidemiol Demog & Biometry, NIH, Bethesda, MD 20892 USA. Univ Pittsburgh, Dept Epidemiol, Pittsburgh, PA 15261 USA. Univ Calif Davis, Div Gen Internal Med, Sacramento, CA 95817 USA. Johns Hopkins Med Inst, Div Geriatr Med & Gerontol, Baltimore, MD 21205 USA. Johns Hopkins Med Inst, Ctr Aging & Hlth, Baltimore, MD 21205 USA. RP Cappola, AR (reprint author), Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Div Endocrinol Diabet & Metab, 718 Blockley,423 Guardian Dr, Philadelphia, PA 19104 USA. EM acappola@cceb.med.upenn.edu RI Cauley, Jane/N-4836-2015; OI Cauley, Jane/0000-0003-0752-4408; Ratcliffe, Sarah/0000-0002-6644-8284 FU Intramural NIH HHS; NHLBI NIH HHS [N01 HC-15103, N01-HC-35129, N01-HC-85079, N01-HC-85086]; NIA NIH HHS [K23 AG19161] NR 45 TC 31 Z9 32 U1 1 U2 1 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2007 VL 92 IS 2 BP 509 EP 516 DI 10.1210/jc.2006-1399 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 134ED UT WOS:000244064900026 PM 17090636 ER PT J AU Mulligan, K Zackin, R Von Roenn, JH Chesney, MA Egorin, MJ Sattler, FR Benson, CA Liu, T Umbleja, T Shriver, S Auchus, RJ Schambelan, M AF Mulligan, Kathleen Zackin, Robert Von Roenn, Jamie H. Chesney, Margaret A. Egorin, Merrill J. Sattler, Fred R. Benson, Constance A. Liu, Tun Umbleja, Triin Shriver, Sharon Auchus, Richard J. Schambelan, Morris CA ACTG 313 Study Team TI Testosterone supplementation of megestrol therapy does not enhance lean tissue accrual in men with human immunodeficiency virus-associated weight loss: A randomized, double-blind, placebo-controlled, multicenter trial SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID ACTIVE ANTIRETROVIRAL THERAPY; HIV-INFECTED PATIENTS; BIOELECTRICAL-IMPEDANCE ANALYSIS; AIDS WASTING SYNDROME; HUMAN GROWTH-HORMONE; QUALITY-OF-LIFE; BODY-COMPOSITION; ADRENAL SUPPRESSION; HYPOGONADAL MEN; ACETATE THERAPY AB Context: Reduced energy intake is a primary factor in HIV-associated wasting. Megestrol acetate (MA) stimulates appetite and weight gain. However, much of the weight gained is fat, possibly as a result of MA-induced hypogonadism. Objective: The objective of the study was to determine whether coadministration of testosterone with MA could enhance lean body mass (LBM) accrual and evaluate the effects of MA, alone or combined with testosterone, on sexual functioning and the hypothalamic-pituitary-adrenal axis. Design: This was a randomized, double-blind, placebo-controlled, multicenter trial. Setting: Fourteen AIDS Clinical Trials Units in the United States participated in the study. Subjects: Seventy-nine HIV-positive men with 5% or more weight loss or body mass index less than 20 kg/m(2) took part in the study. Intervention: Subjects were randomized to receive MA (800 mg daily) plus testosterone enanthate (200 mg; MA/TE; n=41) or placebo (MA/PL; n = 38) biweekly for 12 wk. Main Outcome Measures: Weight, body composition ( bioelectric impedance analysis), adrenal and gonadal hormones, and sexual functioning (questionnaire) were measured. Results: Both groups experienced robust increases in weight (median 5.3 and 7.3 kg in MA/TE and MA/PL, respectively), LBM (3.3 and 3.3 kg), and fat (3.0 and 3.8 kg). There were no significant differences between groups in the magnitude or composition of weight gain (P=0.44, 0.90, and 0.11 for weight, LBM, and fat, respectively). Trough testosterone concentrations decreased to a greater extent in MA/PL (-12.3 vs. -6.1 nmol/liter in MA/TE; P=0.04). Cortisol levels became nearly undetectable in subjects with plasma MA levels greater than 150 ng/ml. Sexual functioning was preserved with MA/TE but worsened in MA/PL. Conclusions: MA produced robust weight gain. Coadministration of testosterone preserved sexual functioning but did not enhance LBM accrual. C1 Univ Calif San Francisco, Div Endocrinol, San Francisco Gen Hosp, Dept Med, San Francisco, CA 94110 USA. Harvard Univ, Stat & Data Anal Ctr, Boston, MA 02115 USA. NIH, Bethesda, MD 20892 USA. Northwestern Univ, Med Ctr, Chicago, IL 60611 USA. Univ Pittsburgh, Dept Med, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Dept Pharmacol, Pittsburgh, PA 15213 USA. Univ Pittsburgh, Inst Canc, Pittsburgh, PA 15213 USA. Univ So Calif, Keck Sch Med, Los Angeles, CA 90033 USA. Univ Calif San Diego, San Diego, CA 92103 USA. Social & Sci Syst Inc, Silver Spring, MD 20910 USA. Univ Texas, SW Med Ctr, Dallas, TX 75390 USA. RP Mulligan, K (reprint author), Univ Calif San Francisco, Div Endocrinol, San Francisco Gen Hosp, Dept Med, Bldg 30,Room 3501K,1001 Potrero Ave, San Francisco, CA 94110 USA. EM kmulligan@sfghgcrc.ucsf.edu FU NCRR NIH HHS [RR-00051, RR-05096, RR-00083, RR-00043, RR-00052]; NIAID NIH HHS [AI34853, AI38855, AI27673, AI38844, AI32770, AI27663, AI25859, AI27670, AI38858, AI27668, AI25915]; NIDDK NIH HHS [DK45833] NR 58 TC 18 Z9 18 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2007 VL 92 IS 2 BP 563 EP 570 DI 10.1210/jc.2006-0954 PG 8 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 134ED UT WOS:000244064900034 PM 17090640 ER PT J AU Salbe, AD Lindsay, RS Collins, CB Tataranni, PA Krakoff, J Bunt, JC AF Salbe, A. D. Lindsay, R. S. Collins, C. B. Tataranni, P. A. Krakoff, J. Bunt, J. C. TI Comparison of plasma insulin levels after a mixed-meal challenge in children with and without intrauterine exposure to diabetes SO JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM LA English DT Article ID BETA-CELL FUNCTION; IMPAIRED GLUCOSE-TOLERANCE; PIMA-INDIAN CHILDREN; OVERWEIGHT LATINO CHILDREN; BIRTH-WEIGHT; LONGITUDINAL CHANGES; FAMILY-HISTORY; SECRETION; RESISTANCE; OBESITY AB Background: The diabetic intrauterine environment is a known risk factor for the development of diabetes in the offspring. Objective: We compared anthropometric and metabolic characteristics of 41 nondiabetic children whose mothers developed diabetes either before (ODM, n = 19, 9.3 +/- 1.1 yr) or after (OPDM, n = 22, 9.5 +/- 1.3 yr) the pregnancy of interest. Maternal diabetes status was established from OGTT results before, during, and after the pregnancy of interest. Design: After consuming a standardized diet for 2 d, a mixed-meal breakfast was given after an overnight fast. Fasting concentrations and responses of plasma glucose and insulin were evaluated using linear regression analyses to assess potential independent determinants of plasma insulin concentration at each time point. Results: After adjustment for age and sex, there were no differences between ODM and OPDM children for maternal age at diagnosis, height, weight, body mass index, BMI z score, or percent body fat (dual energy x-ray absorptiometry). After adjusting for age, sex, percent body fat, and the corresponding glucose level at each time point, ODM had a lower plasma insulin level at the 15-min time point during the meal test than OPDM (P = 0.01). Conclusion: A lower initial insulin response to a standard mixed-meal challenge can be detected in nondiabetic ODM compared with OPDM children as early as 9 yr of age. This response may be another indicator for an attenuated early insulin response and explain the increased risk for diabetes in these children. C1 NIDDK, Obes & Diabet Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIH, Phoenix, AZ 85016 USA. Univ Glasgow, BHF Glasgow Cardiovasc Res Ctr, Glasgow G12 8TA, Lanark, Scotland. Sanofi Aventis Pharmaceut, F-75601 Paris, France. RP Bunt, JC (reprint author), NIDDK, Obes & Diabet Clin Res Sect, Phoenix Epidemiol & Clin Res Branch, NIH, 4212 N 16th St,Room 541, Phoenix, AZ 85016 USA. EM JBunt@mail.nih.gov FU Intramural NIH HHS NR 41 TC 9 Z9 9 U1 0 U2 0 PU ENDOCRINE SOC PI CHEVY CHASE PA 8401 CONNECTICUT AVE, SUITE 900, CHEVY CHASE, MD 20815-5817 USA SN 0021-972X J9 J CLIN ENDOCR METAB JI J. Clin. Endocrinol. Metab. PD FEB PY 2007 VL 92 IS 2 BP 624 EP 628 DI 10.1210/jc.2006-1179 PG 5 WC Endocrinology & Metabolism SC Endocrinology & Metabolism GA 134ED UT WOS:000244064900045 PM 17148565 ER PT J AU Wrzesinski, C Paulos, CM Gattinoni, L Palmer, DC Kaiser, A Yu, ZY Rosenberg, SA Restifo, NP AF Wrzesinski, Claudia Paulos, Chrystal M. Gattinoni, Luca Palmer, Douglas C. Kaiser, Andrew Yu, Zhiya Rosenberg, Steven A. Restifo, Nicholas P. TI Hematopoietic stem cells promote the expansion and function of adoptively transferred antitumor CD8(+) T cells SO JOURNAL OF CLINICAL INVESTIGATION LA English DT Article ID ALLOGENEIC BONE-MARROW; NATURAL-KILLER-CELLS; IN-VIVO; HOMEOSTATIC PROLIFERATION; TRANSPLANT RECIPIENTS; METASTATIC MELANOMA; CANCER REGRESSION; MULTIPLE-MYELOMA; GROWTH-HORMONE; OVARIAN-CANCER AB Depleting host immune elements with nonmyeloablative regimens prior to the adoptive transfer of tumor-specific CD8(+) T cells significantly enhances tumor treatment. In the current study, superior antitumor efficacy was achieved by further increasing the intensity of lymphodepletion to a level that required HSC transplantation. Surprisingly, the HSC transplant and not the increased lymphodepletion caused a robust expansion of adoptively transferred tumor-specific CD8(+) T cells. The HSC-driven cell expansion of effector, but not of naive, CD8(+) T cells was independent of in vivo restimulation. by MHC class I-expressing APCs. Simultaneously, HSCs also facilitated the reconstitution of the host lymphoid compartment, including inhibitory elements, not merely via the production of progeny cells but by enhancing the expansion of cells that had survived lymphodepletion. Profound lymphodepletion, by myeloablation or by genetic means, focused the nonspecific HSC boost preferentially toward the transferred tumor-specific T cells, leading to successful tumor treatment. These findings indicate that CD8(+) T cell-mediated tumor responses can be efficiently driven by HSCs in the myeloablative setting and have substantial implications for the design of new antitumor immunotherapies. C1 NCI, NIH, Bethesda, MD 20892 USA. RP Wrzesinski, C (reprint author), NCI, NIH, Bethesda, MD 20892 USA. EM wrzesinc@mail.nih.gov; restifo@nih.gov RI Gattinoni, Luca/A-2281-2008; Wrzesinski, Claudia/A-3077-2008; Palmer, Douglas/B-9454-2008; Restifo, Nicholas/A-5713-2008; Kaiser, Andrew/C-2617-2012; OI Gattinoni, Luca/0000-0003-2239-3282; Palmer, Douglas/0000-0001-5018-5734; Restifo, Nicholas P./0000-0003-4229-4580 FU Intramural NIH HHS [Z01 BC010763-01, Z99 CA999999] NR 62 TC 114 Z9 119 U1 0 U2 1 PU AMER SOC CLINICAL INVESTIGATION INC PI ANN ARBOR PA 35 RESEARCH DR, STE 300, ANN ARBOR, MI 48103 USA SN 0021-9738 J9 J CLIN INVEST JI J. Clin. Invest. PD FEB PY 2007 VL 117 IS 2 BP 492 EP 501 DI 10.1172/JCI30414 PG 10 WC Medicine, Research & Experimental SC Research & Experimental Medicine GA 133ZD UT WOS:000244051500029 PM 17273561 ER PT J AU McNulty, A Jennings, C Bennett, D Fitzgibbon, J Bremer, JW Ussery, M Kalish, ML Heneine, W Garcia-Lerma, JG AF McNulty, Amanda Jennings, Cheryl Bennett, Diane Fitzgibbon, Joseph Bremer, James W. Ussery, Michael Kalish, Marcia L. Heneine, Walid Garcia-Lerma, J. Gerardo TI Evaluation of dried blood spots for human immunodeficiency virus type 1 drug resistance testing SO JOURNAL OF CLINICAL MICROBIOLOGY LA English DT Article ID REVERSE-TRANSCRIPTASE INHIBITORS; ANTIRETROVIRAL THERAPY; MONONUCLEAR-CELLS; FILTER-PAPER; HIV SURVEILLANCE; WHOLE-BLOOD; SUBTYPE-B; PLASMA; MUTATIONS; RNA AB Dried blood spots (DBS) are simpler to prepare, store, and transport than plasma or serum and may represent a good alternative for drug resistance genotyping, particularly in resource-limited settings. However, the utility of DBS for drug resistance testing is unknown. We investigated the efficiency of amplification of large human immunodeficiency virus type 1 (HIV-1) pol fragments (1,023 bp) from DBS stored at different temperatures, the type of amplified product(s) (RNA and/or DNA), and the similarity between plasma and DBS sequences. We evaluated two matched plasma/DBS panels stored for 5 to 6 years at several temperatures and 40 plasma/DBS specimens collected from untreated persons in Cameroon and stored for 2 to 3 years at -20 degrees C. The amplification of HIV-1 pol was done using an in-house reverse transcriptase-nested PCR assay. Reactions were done with and without reverse transcription to evaluate the contribution of HIV DNA to pol sequences from DBS. Amplification was successful for the DBS samples stored for 5 to 6 years at -20 degrees C or at -70 degrees C but not for those stored at room temperature. Thirty-seven of the 40 (92.5%) DBS from Cameroon were amplifiable, including 8/11 (72.7%) with plasma virus loads of < 10,000 RNA copies/ml and all 29 with plasma virus loads of > 10,000. Proviral DNA contributed significantly to DBS sequences in 24 of the 37 (65%) specimens from Cameroon. The overall similarity between plasma and DBS sequences was 98.1%. Our results demonstrate the feasibility of DBS for drug resistance testing and indicate that -20 degrees C is a suitable temperature for long-term storage of DBS. The amplification of proviral DNA from DBS highlights the need for a wider evaluation of the concordance of resistance genotypes between plasma and DBS. C1 Ctr Dis Control & Prevent, Lab Branch, Div HIV AIDS Prevent, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, Atlanta, GA 30333 USA. Rush Med Coll, Chicago, IL 60612 USA. NIAID, Div AIDS, Bethesda, MD 20892 USA. RP Garcia-Lerma, JG (reprint author), Ctr Dis Control & Prevent, Lab Branch, Div HIV AIDS Prevent, Natl Ctr HIV AIDS Viral Hepatitis STD & TB Preven, 1600 Clifton Rd, Atlanta, GA 30333 USA. EM GGarcia-Lerma@cdc.gov FU NIAID NIH HHS [N01-AI-85354, N01AI85354] NR 25 TC 61 Z9 63 U1 1 U2 3 PU AMER SOC MICROBIOLOGY PI WASHINGTON PA 1752 N ST NW, WASHINGTON, DC 20036-2904 USA SN 0095-1137 J9 J CLIN MICROBIOL JI J. Clin. Microbiol. PD FEB PY 2007 VL 45 IS 2 BP 517 EP 521 DI 10.1128/JCM.02016-06 PG 5 WC Microbiology SC Microbiology GA 137CI UT WOS:000244270000041 PM 17166967 ER PT J AU Fang, LY Holford, NHG Hinkle, G Cao, XH Xiao, JJ Bloomston, M Gibbs, S Al Saif, OH T Dalton, J Chan, KK Schlom, J Martin, EW Sun, DX AF Fang, Lanyan Holford, Nicholas H. G. Hinkle, George Cao, Xianhua Xiao, Jim J. Bloomston, Mark Gibbs, Seth Al Saif, Osama Habib T Dalton, James Chan, Kenneth K. Schlom, Jeffery Martin, Edward W., Jr. Sun, Duxin TI Population pharmacokinetics of humanized monoclonal antibody HuCC49 Delta CH2 and murine antibody CC49 in colorectal cancer patients SO JOURNAL OF CLINICAL PHARMACOLOGY LA English DT Article DE population pharmacokinetics; bayesian estimation; RIGS ID RADIOIMMUNOGUIDED SURGERY RIGS; CARCINOEMBRYONIC ANTIGEN; DECISION-MAKING; COLON-CANCER; CARCINOMA; RECURRENT; B72.3; RADIOIMMUNOTHERAPY; BRACHYTHERAPY; XENOGRAFTS AB To predict the optimal time for surgery after antibody administration, the population pharmacokinetics of (125)HuCC49 Delta CH2 and I-125-CC49 were characterized in 55 patients with colorectal cancers. A 2-compartment linear model was used to fit the pharmacokinetic data. Model stability and performance were assessed using a visual predictive check procedure. Different clinical trial designs were evaluated by simulation in combination with Boyesian estimation method to predict the optimal time for surgery. The results showed that HuCC49 Delta CH2 had 65% faster clearance from blood circulation and 24% shorter mean residence time than CC49. Population pharmacokinetic analysis identified body weight as the only covariate to explain between-subject variability in clearance, intercompartmental flow rate, and volume of distribution. Model predictions indicated a wide interval for the optimal time of surgery, suggesting that it would be beneficial to individualize the time of surgery for each patient by measurement of antibody disposition. Clinical trial designs with at least 3 measurements of antibody disposition were found to be better than an empirical direct observation method for the optimal prediction of surgery time. C1 Ohio State Univ, Coll Pharm, Div Pharmaceut, Columbus, OH 43210 USA. James Canc Hosp, Columbus, OH USA. Ohio State Univ, Solove Res Inst, Columbus, OH 43210 USA. Univ Auckland, Dept Pharmacol & Clin Pharmacol, Auckland 1, New Zealand. Amgen Inc, Thousand Oaks, CA 91320 USA. NIH, Tumor Immunol & Biol Lab, Bethesda, MD 20892 USA. RP Sun, DX (reprint author), Ohio State Univ, Coll Pharm, Div Pharmaceut, 232 Pks Hall,500 W 12th Ave, Columbus, OH 43210 USA. RI Martin Jr, Edward/E-3604-2011; Bloomston, Mark/E-2767-2011 FU Intramural NIH HHS NR 36 TC 20 Z9 20 U1 0 U2 2 PU SAGE PUBLICATIONS INC PI THOUSAND OAKS PA 2455 TELLER RD, THOUSAND OAKS, CA 91320 USA SN 0091-2700 J9 J CLIN PHARMACOL JI J. Clin. Pharmacol. PD FEB PY 2007 VL 47 IS 2 BP 227 EP 237 DI 10.1177/0091270006293758 PG 11 WC Pharmacology & Pharmacy SC Pharmacology & Pharmacy GA 131ZO UT WOS:000243911700010 PM 17244774 ER PT J AU Duque, J Murase, N Celnik, P Hummel, F Harris-Love, M Mazzocchio, R Olivier, E Cohen, LG AF Duque, Julie Murase, Nagako Celnik, Pablo Hummel, Friedhelm Harris-Love, Michelle Mazzocchio, Riccardo Olivier, Etienne Cohen, Leonardo G. TI Intermanual differences in movement-related interhemispheric inhibition SO JOURNAL OF COGNITIVE NEUROSCIENCE LA English DT Article ID HUMAN MOTOR CORTEX; TRANSCRANIAL MAGNETIC STIMULATION; FOCAL HAND DYSTONIA; HEMISPHERIC-ASYMMETRY; INTRACORTICAL INHIBITION; CORPUS-CALLOSUM; TRANSCALLOSAL INHIBITION; VOLUNTARY CONTRACTION; SURROUND INHIBITION; FINGER MOVEMENTS AB Interhemispheric inhibition (IHI) between motor cortical areas is thought to play a critical role in motor control and could influence dexterity. The purpose of this study was to investigate IHI preceding movements of the dominant and nondominant hands of healthy volunteers, Movement-related IHI was Studied by means of a double-pulse transcranial magnetic stimulation protocol in right-handed individuals in a simple reaction time paradigm. IHI targeting the motor cortex contralateral (IHIC) and ipsilateral (IHIi) to each moving finger was determined. IHIC was comparable after the go signal, a long time preceding movement onset, in both hands. Closet, to movement onset, IHIC reversed into facilitation for the right dominant hand but remained inhibitory for left nondominant hand movements. IHIi displayed a nearly constant inhibition with a trough early in the premovement period in both hands. In conclusion, our results unveil a more important modulation of interhemispheric interactions during generation of dominant than nondominant hand movements. This modulation essentially consisted of a shift from a balanced IHI at rest to an IHI predominant directed to toward the ipsilateral primary motor cortex at movement onset. Such a mechanism might release muscles front inhibition in the contralateral primary motor cortex while preventing the occurrence of the mirror activity in ipsilateral primary motor cortex and could therefore contribute to intermanual differences in dexterity. C1 NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20817 USA. Catholic Univ Louvain, B-3000 Louvain, Belgium. Univ Tokushima, Tokushima 770, Japan. Univ Siena, I-53100 Siena, Italy. RP Cohen, LG (reprint author), NINDS, Human Cort Physiol Sect, NIH, Bethesda, MD 20817 USA. EM cohenl@ninds.nih.gov RI Harris-Love, Michelle/J-1388-2014; Mazzocchio, Riccardo/H-4223-2012 OI Harris-Love, Michelle/0000-0001-5571-3858; Mazzocchio, Riccardo/0000-0002-0628-2868 FU NICHD NIH HHS [5K12HD001097] NR 75 TC 116 Z9 120 U1 0 U2 2 PU M I T PRESS PI CAMBRIDGE PA 238 MAIN STREET, STE 500, CAMBRIDGE, MA 02142-1046 USA SN 0898-929X J9 J COGNITIVE NEUROSCI JI J. Cogn. Neurosci. PD FEB PY 2007 VL 19 IS 2 BP 204 EP 213 DI 10.1162/jocn.2007.19.2.204 PG 10 WC Neurosciences; Psychology, Experimental SC Neurosciences & Neurology; Psychology GA 138FJ UT WOS:000244348200003 PM 17280510 ER PT J AU Pottick, KJ Kirk, SA Hsieh, DK Tian, X AF Pottick, Kathleen J. Kirk, Stuart A. Hsieh, Derek K. Tian, Xin TI Judging mental disorder in youths: Effects of client, clinician, and contextual differences SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE adolescent mental health; clinical judgment; conduct disorder; Diagnostic and Statistical Manual of Mental Disorders; race/ethnicity bias ID SOCIAL-CONTEXT; CONDUCT DISORDER; DSM-III; JUDGMENT; DIAGNOSIS; BEHAVIOR; CHILDREN; PATIENT; GENDER; BIAS AB Using a vignette-based, mailed survey of 1,401 experienced psychologists, psychiatrists, and social workers, the authors examined how clients' race/ethnicity and clinicians' professional and social characteristics affect their judgment of mental disorder among antisocially behaving youths. Vignettes described problematic behaviors meeting the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) criteria for conduct disorder but contained contextual information suggesting either disorder or nondisorder, following DSM-IV guidelines. Clinicians depended on contextual information to decide whether a mental disorder existed, and they judged White youths to have a disorder more frequently than Black or Hispanic youths. Clinicians' occupation, theoretical orientation, and age also were associated with disorder judgments, whereas their gender, race, and experience were not. Research and training implications of these variations in clinical judgments are discussed. C1 Rutgers State Univ, Inst Hlth Hlth Care Policy & Aging Res, New Brunswick, NJ 08901 USA. Univ Calif Los Angeles, Sch Publ Affairs, Los Angeles, CA USA. Los Angeles Cty Dept Mental Hlth, Emergency Outreach Bur, Torrance, CA USA. NHLBI, Off Biostat Res, NIH, Bethesda, MD 20892 USA. RP Pottick, KJ (reprint author), Rutgers State Univ, Inst Hlth Hlth Care Policy & Aging Res, 30 Coll Ave, New Brunswick, NJ 08901 USA. EM pottick@rci.rutgers.edu NR 35 TC 15 Z9 15 U1 0 U2 7 PU AMER PSYCHOLOGICAL ASSOC/EDUCATIONAL PUBLISHING FOUNDATION PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD FEB PY 2007 VL 75 IS 1 BP 1 EP 8 DI 10.1037/0022-006x.75.1.1 PG 8 WC Psychology, Clinical SC Psychology GA 131VI UT WOS:000243898500001 PM 17295558 ER PT J AU Brown, DA Pipe, ME Lewis, C Lamb, ME Orbach, Y AF Brown, Deirdre A. Pipe, Margaret-Ellen Lewis, Charlie Lamb, Michael E. Orbach, Yael TI Supportive or suggestive: Do human figure drawings help 5-to 7-year old children to report touch? SO JOURNAL OF CONSULTING AND CLINICAL PSYCHOLOGY LA English DT Article DE children; drawing; eyewitness testimony; forensic interviews; body maps ID EMOTIONALLY LADEN EVENTS; SEXUAL-ABUSE; NARRATIVE ELABORATION; INTERVIEWING CHILDREN; EYEWITNESS MEMORY; ANATOMICAL DOLLS; YOUNG-CHILDREN; VERBAL REPORTS; REPRESENTATION; EXPERIENCES AB The authors examined the accuracy of information elicited from seventy-nine 5- to 7-year-old children about a staged event that included physical contact-touching. Four to six weeks later, children's recall for the event was assessed using an interview protocol analogous to those used in forensic investigations with children. Following the verbal interview, children were asked about touch when provided with human figure drawings (drawings only), following practice using the human figure drawings (drawings with instruction), or without drawings (verbal questions only). In this touch-inquiry phase of the interview, most children provided new information. Children in the drawings conditions reported more incorrect information than those in the verbal questions condition. Forensically relevant errors were infrequent and were rarely elaborated on. Although asking children to talk about innocuous touch may plead them to report unreliable information, especially when human figure drawings are used as aids, errors are reduced when open-ended prompts are used to elicit further information about reported touches. C1 Univ Lancaster, Dept Psychol, Lancaster LA1 4YF, England. CUNY, Dept Psychol, New York, NY USA. CUNY, Childrens Studies Ctr, New York, NY USA. Univ Cambridge, Fac Social & Polit Sci, Cambridge, England. NICHHD, Bethesda, MD 20892 USA. RP Brown, DA (reprint author), Univ Lancaster, Dept Psychol, Lancaster LA1 4YF, England. EM d.a.brown@lancaster.ac.uk NR 46 TC 27 Z9 27 U1 0 U2 8 PU AMER PSYCHOLOGICAL ASSOC/EDUCATIONAL PUBLISHING FOUNDATION PI WASHINGTON PA 750 FIRST ST NE, WASHINGTON, DC 20002-4242 USA SN 0022-006X J9 J CONSULT CLIN PSYCH JI J. Consult. Clin. Psychol. PD FEB PY 2007 VL 75 IS 1 BP 33 EP 42 DI 10.1037/0022-006X.75.1.33 PG 10 WC Psychology, Clinical SC Psychology GA 131VI UT WOS:000243898500004 PM 17295561 ER PT J AU Ohyama, M Amagai, M Vogel, JC AF Ohyama, Manabu Amagai, Masayuki Vogel, Jonathan C. TI Gene ontology analysis of human hair follicle bulge molecular signature SO JOURNAL OF DERMATOLOGICAL SCIENCE LA English DT Letter ID STEM-CELL NICHE; POPULATIONS; EPIDERMIS; SKIN C1 Keio Univ, Sch Med, Dept Dermatol, Shinjuku Ku, Tokyo 1608582, Japan. NCI, Dermatol Branch, Ctr Canc Res, NIH, Bethesda, MD 20892 USA. RP Ohyama, M (reprint author), Keio Univ, Sch Med, Dept Dermatol, Shinjuku Ku, 35 Shinanomachi, Tokyo 1608582, Japan. EM maboym@sc.itc.keio.ac.jp RI Ohyama, Manabu/J-5524-2014 OI Ohyama, Manabu/0000-0002-2662-5717 NR 10 TC 8 Z9 9 U1 0 U2 0 PU ELSEVIER IRELAND LTD PI CLARE PA ELSEVIER HOUSE, BROOKVALE PLAZA, EAST PARK SHANNON, CO, CLARE, 00000, IRELAND SN 0923-1811 J9 J DERMATOL SCI JI J. Dermatol. Sci. PD FEB PY 2007 VL 45 IS 2 BP 147 EP 150 DI 10.1016/j.jdermsci.2006.09.009 PG 4 WC Dermatology SC Dermatology GA 138SR UT WOS:000244383300012 PM 17071058 ER PT J AU Demartini, DR Wlodawer, A Carlini, CR AF Demartini, Diogo Ribeiro Wlodawer, Alexander Carlini, Celia Regina TI A comparative study of the expression of serine proteinases in quiescent seeds and in developing Canavalia ensiformis plants SO JOURNAL OF EXPERIMENTAL BOTANY LA English DT Article DE benzamidine; Canavalia ensiformis; characterization; cotyledons; germination; proteinase; purification; roots; seeds; serine proteinase ID JACK BEAN-SEEDS; CLEAVAGE SPECIFICITY; CYSTEINE PROTEINASES; STORAGE PROTEIN; CONCANAVALIN-A; TOXIC PROTEIN; PROTEASES; PURIFICATION; MOBILIZATION; GERMINATION AB An alkaline proteinase activity is present in quiescent seeds and up to the 24th day of development of Canavalia ensiformis DC (L.) plants. By a simple protocol consisting of cation exchange chromatography, followed by an anion exchange column, a serine proteinase (Q-SP) was purified to homogeneity from quiescent seeds. Q-SP consists of a 33 kDa chain with an optimum pH between 8.0 and 9.0. Arginine residues at P1 and P2 subsites favour binding to the substrate, as shown by the K-M assay with N-alpha-benzoyl-DL-arginine-4-nitroanilide-hydrochloride and N-benzoylcarboxyl-L-arginyl-L-arginine-7-amido-4-methylcoumarin. The same protocol was used for partial purification of benzamidine-sensitive enzymes from the developing plant. On the 7th day, a new benzamidine-sensitive enzyme is synthesized in the seedling, seen as the second active peak appearing in anion exchange chromatography. A benzamidine-sensitive enzyme purified from cotyledons presented a similar gel filtration profile as Q-SP, although it was eluted at different salt concentrations in the anion exchange chromatography. None of the enzymes was inhibited by PMSF, APMSF, or SBTI, but they were inactivated by benzamidine, TLCK, and leupeptin. Q-SP did not cleave in vitro C. ensiformis urease, concanavalin A, or its main storage protein, canavalin. In conclusion, a ubiquitous benzamidine-sensitive proteolytic activity was found in C. ensiformis from quiescent seeds up to 24 d of growth, which apparently is not involved in the hydrolysis of storage proteins and might participate in an as yet unidentified limited proteolysis event. C1 Univ Fed Rio Grande do Sul, Ctr Biotechnol, Grad Program Cellular & Mol Biol, BR-91501970 Porto Alegre, RS, Brazil. NCI, Prot Struct Sect, Macromol Crystallog Lab, Frederick, MD 21702 USA. Univ Fed Rio Grande do Sul, Dept Biophys, BR-91501970 Porto Alegre, RS, Brazil. RP Carlini, CR (reprint author), Univ Fed Rio Grande do Sul, Ctr Biotechnol, Grad Program Cellular & Mol Biol, Ave Bento Goncalves 9500,Predio 43422, BR-91501970 Porto Alegre, RS, Brazil. EM ccarlini@ufrgs.br RI DEMARTINI, DIOGO/F-6029-2013; OI DEMARTINI, DIOGO/0000-0001-5294-3666; Carlini, Celia R/0000-0002-7027-2445 FU Intramural NIH HHS NR 36 TC 8 Z9 8 U1 0 U2 4 PU OXFORD UNIV PRESS PI OXFORD PA GREAT CLARENDON ST, OXFORD OX2 6DP, ENGLAND SN 0022-0957 EI 1460-2431 J9 J EXP BOT JI J. Exp. Bot. PD FEB PY 2007 VL 58 IS 3 BP 521 EP 532 DI 10.1093/jxb/erl223 PG 12 WC Plant Sciences SC Plant Sciences GA 139JP UT WOS:000244428400014 PM 17158110 ER PT J AU Pipeling, MR West, EE Osborne, CM Migueles, SA Connors, M McDyer, JF AF Pipeling, M. R. West, E. E. Osborne, C. M. Migueles, S. A. Connors, M. McDyer, J. F. TI Acquisition of CMV-specific CD8+ T cell memory during primary CMV infection in lung transplant recipients SO JOURNAL OF HEART AND LUNG TRANSPLANTATION LA English DT Meeting Abstract C1 Johns Hopkins Univ, Baltimore, MD USA. Natl Inst Hlth, NIAID, Bethesda, MD USA. NR 0 TC 0 Z9 0 U1 0 U2 0 PU ELSEVIER SCIENCE INC PI NEW YORK PA 360 PARK AVE SOUTH, NEW YORK, NY 10010-1710 USA SN 1053-2498 J9 J HEART LUNG TRANSPL JI J. Heart Lung Transplant. PD FEB PY 2007 VL 26 IS 2 SU S MA 240 BP S146 EP S146 DI 10.1016/j.healun.2006.11.258 PG 1 WC Cardiac & Cardiovascular Systems; Respiratory System; Surgery; Transplantation SC Cardiovascular System & Cardiology; Respiratory System; Surgery; Transplantation GA 138DB UT WOS:000244342200241 ER PT J AU Anderson, MJ Shafer-Weaver, K Greenberg, NM Hurwitz, AA AF Anderson, Michael J. Shafer-Weaver, Kimberly Greenberg, Norman M. Hurwitz, Arthur A. TI Tolerization of tumor-specific T cells despite efficient initial priming in a primary murine model of prostate cancer SO JOURNAL OF IMMUNOLOGY LA English DT Article ID DENDRITIC CELLS; IN-VIVO; CROSS-PRESENTATION; SELF-ANTIGEN; PERIPHERAL TOLERANCE; IMMUNE-RESPONSES; TRANSGENIC MICE; DELETION; MOUSE; PROGRESSION AB In this report, we studied T cell responses to a prostate cancer Ag by adoptively transferring tumor Ag-specific T cells into prostate tumor-bearing mice. Our findings demonstrate that CD8(+) T cells initially encountered tumor Ag in the lymph node and underwent an abortive proliferative response. Upon isolation from the tumor, the residual tumor-specific T cells were functionally tolerant of tumor Ag as measured by their inability to degranulate and secrete IFN-gamma and granzyme B. We next sought to determine whether providing an ex vivo-matured, peptide-pulsed dendritic cell (DC) vaccine could overcome the tolerizing mechanisms of tumor-bearing transgenic adenocarcinoma of the mouse prostate model mice. We demonstrate that tumor Ag-specific T cells were protected from tolerance following provision of the DC vaccine. Concurrently, there was a reduction in prostate tumor size. However, even when activated DCs initially present tumor Ag, T cells persisting within the tolerogenic tumor environment gradually lost Ag reactivity. These results suggest that even though a productive antitumor response can be initiated by a DC vaccine, the tolerizing environment created by the tumor still exerts suppressive effects on the T cells. Furthermore, our results demonstrate that when trying to elicit an effective antitumor immune response, two obstacles must be considered: to maintain tumor Ag responsiveness, T cells must be efficiently primed to overcome tumor Ag presented in a tolerizing manner and protected from the suppressive mechanisms of the tumor microenvironment. C1 NCI, Tumor Immun & Tolerance Sect, Mol Immunoregulat Lab, NIH, Frederick, MD 21701 USA. SUNY Upstate Med Univ, Dept Microbiol & Immunol, Syracuse, NY 13210 USA. SAIC Frederick, Clin Serv Program, Lab Cell Mediated Immun, Frederick, MD 21701 USA. Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA. RP Hurwitz, AA (reprint author), NCI, Tumor Immun & Tolerance Sect, Mol Immunoregulat Lab, NIH, Frederick, MD 21701 USA. FU Intramural NIH HHS NR 40 TC 67 Z9 71 U1 2 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 1 PY 2007 VL 178 IS 3 BP 1268 EP 1276 PG 9 WC Immunology SC Immunology GA 130TC UT WOS:000243820900007 PM 17237372 ER PT J AU Gao, JL Guillabert, A Hu, JY Le, YY Urizar, E Seligman, E Fang, KJ Yuan, X Imbault, V Communi, D Wang, JM Parmentier, M Murphy, PM Migeotte, F AF Gao, Ji-Liang Guillabert, Aude Hu, Jinyue Le, Yingying Urizar, Eneko Seligman, Eva Fang, Kevin J. Yuan, Xiaoning Imbault, Virginie Communi, David Wang, Ji Ming Parmentier, Marc Murphy, Philip M. Migeotte, Isabelle TI F2L, a peptide derived from heme-binding protein, chemoattracts mouse neutrophils by specifically activating Fpr2, the low-affmity N-formylpeptide receptor SO JOURNAL OF IMMUNOLOGY LA English DT Article ID LIPOXIN A(4) RECEPTOR; DENDRITIC CELLS; MOLECULAR CHARACTERIZATION; CHEMOTACTIC AGONIST; COUPLED RECEPTOR; FORMYL; IDENTIFICATION; GENE; DIFFERENTIATION; PHAGOCYTES AB F2L (formylpeptide receptor (FPR)-like (FPRL)-2 ligand), a highly conserved acetylated peptide derived from the amino-terminal cleavage of heme-binding protein, is a potent chemoattractant for human monocytes and dendritic cells, and inhibits LPS-induced human dendritic cell maturation. We recently reported that F2L is able to activate the human receptors FPRL-1 and FPRL2, two members of the FPR family, with highest selectivity and affinity for FPRL2. To facilitate delineation of mechanisms of F2L action in vivo, we have now attempted to define its mouse receptors. This is complicated by the nonequivalence of the human and mouse FPR gene families (three vs at least eight members, respectively). When cell lines were transfected with plasmids encoding the eight mouse receptors, only the one expressing the receptor Fpr2 responded to F2L (EC50 similar to 400 nM for both human and mouse F2L in both calcium flux and cAMP inhibition assays). This value is similar to F2L potency at human FPRL1. Consistent with this, mouse neutrophils, which like macrophages and dendritic cells express Fpr2, responded to human and mouse F2L in both calcium flux and chemotaxis assays with EC50 values similar to those found for Fpr2-expressing cell lines (similar to 500 nM). Moreover, neutrophils from mice genetically deficient in Fpr2 failed to respond to F2L. Thus, Fpr2 is a mouse receptor for F2L, and can be targeted for the study of F2L action in mouse models. C1 NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. Univ Libre Bruxelles, Inst Rech Interdisciplinaire Biol Humaine & Mol, B-1070 Brussels, Belgium. NCI, Frederick Canc Res & Dev Ctr, Mol Immunoregulat Lab, Frederick, MD 21702 USA. RP Murphy, PM (reprint author), NIAID, Lab Mol Immunol, NIH, Bethesda, MD 20892 USA. EM pmm@nih.gov; migeotti@mskcc.org NR 38 TC 41 Z9 42 U1 1 U2 5 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2007 VL 178 IS 3 BP 1450 EP 1456 PG 7 WC Immunology SC Immunology GA 130TC UT WOS:000243820900028 PM 17237393 ER PT J AU Aiello, FB Keller, JR Klarmann, KD Dranoff, G Mazzucchelli, R Durum, SK AF Aiello, Francesca B. Keller, Jonathan R. Klarmann, Kimberly D. Dranoff, Glenn Mazzucchelli, Renata Durum, Scott K. TI IL-7 induces myelopoiesis and erythropoiesis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID COLONY-STIMULATING FACTOR; RECOMBINANT HUMAN INTERLEUKIN-7; HEMATOPOIETIC STEM-CELLS; MURINE FLT3 LIGAND; CD4(+) T-CELLS; KAPPA-B LIGAND; DEFICIENT MICE; BONE-MARROW; GM-CSF; PROGENITOR CELLS AB IL-7 administration to mice was previously reported to increase the mobilization of progenitor cells from marrow to peripheral sites. We now report that IL-7 increases the number of mature myeloid and monocytic cells in spleen and peripheral blood. This effect required T cells, and we show that IL-7 treatment in vivo induced GNI-CSF and IL-3 production by T cells with memory phenotype. However, additional myelopoietic cytokines were shown to be involved because mice deficient in both GNI-CSF and IL-3 also responded to IL-7 with increased myelopoiesis. Candidate cytokines included IFN-gamma and Flt3 ligand, which were also produced in response to IL-7. Because IFN-gamma-deficient mice also increased myelopoiesis, it was suggested that IL-7 induced production of redundant myelopoietic cytokines. In support of this hypothesis, we found that the supernatant from IL-7-treated, purified T cells contained myelopoietic activity that required a combination of Abs against GNI-CSF, IL-3, and anti-Flt3 ligand to achieve maximum neutralization. IL-7 administration increased the number of splenic erythroid cells in either normal, Ragl or GM-CSF-IL-3-deficient mice, suggesting that IL-7 might directly act on erythroid progenitors. In support of this theory, we detected a percentage of TER-119(+) erythroid cells that expressed the IL-7R alpha-chain and common gamma-chain. Bone marrow cells expressing IL-7R and B220 generated erythroid colonies in vitro in response to IL-7, erythropoietin, and stem cell factor. This study demonstrates that IL-7 can promote nonlymphoid hemopoiesis and production of cytokines active in the host defense system in vivo, supporting its possible clinical utility. C1 NCI, Sect Cytokines & Immun, Mol Immunoregulat Lab, Frederick, MD 21702 USA. Univ Chieti, Dept Oncol & Neurosci, Chieti, Italy. NCI, SAIC Frederick, Canc & Dev Biol Lab, Frederick, MD 21701 USA. Dana Farber Canc Inst, Boston, MA 02115 USA. RP Durum, SK (reprint author), NCI, Sect Cytokines & Immun, Mol Immunoregulat Lab, Bldg 560,Room 31-56, Frederick, MD 21702 USA. EM durum@nciferf.gov FU Intramural NIH HHS NR 88 TC 18 Z9 18 U1 0 U2 1 PU AMER ASSOC IMMUNOLOGISTS PI BETHESDA PA 9650 ROCKVILLE PIKE, BETHESDA, MD 20814 USA SN 0022-1767 J9 J IMMUNOL JI J. Immunol. PD FEB 1 PY 2007 VL 178 IS 3 BP 1553 EP 1563 PG 11 WC Immunology SC Immunology GA 130TC UT WOS:000243820900039 PM 17237404 ER PT J AU Sumpter, B Dunham, R Gordon, S Engram, J Hennessy, M Kinter, A Paiardini, M Cervasi, B Klatt, N McClure, H Milush, JM Staprans, S Sodora, DL Silvestri, G AF Sumpter, Beth Dunham, Richard Gordon, Shari Engram, Jessica Hennessy, Margaret Kinter, Audrey Paiardini, Mirko Cervasi, Barbara Klatt, Nichole McClure, Harold Milush, Jeffrey M. Staprans, Silvija Sodora, Donald L. Silvestri, Guido TI Correlates of preserved CD4(+) T cell homeostasis during natural, nonpathogenic simian immunodeficiency virus infection of sooty mangabeys: Implications for AIDS pathogenesis SO JOURNAL OF IMMUNOLOGY LA English DT Article ID TRANSCRIPTION FACTOR FOXP3; HIV-1 INFECTION; RHESUS MACAQUE; DISEASE; PLASMA; REPLICATION; LYMPHOCYTES; ACTIVATION; EXPRESSION; INDUCTION AB In contrast to HIV-infected humans, naturally SIV-infected sooty mangabeys (SMs) very rarely progress to AIDS. Although the mechanisms underlying this disease resistance are unknown, a consistent feature of natural SIV infection is the absence of the generalized immune activation associated with HIV infection. To define the correlates of preserved CD4(+) T cell counts in SMs, we conducted a cross-sectional immunological study of 110 naturally SIV-infected SMs. The nonpathogenic nature of the infection was confirmed by an average CD4(+) T cell count of 1,076 +/- 589/mm(3) despite chronic infection with a highly replicating virus. No correlation was found between CD4(+) T cell counts and either age (used as a surrogate marker for length of infection) or viremia. The strongest correlates of preserved CD4(+) T cell counts were a low percentage of circulating effector T cells (CD28(-)CD95(+) and/or IL-7R/CD127(-)) and a high percentage of CD4(+)CD25(+) T cells. These findings support the hypothesis that the level of immune activation is a key determinant of CD4' T cell counts in SIV-infected SMs. Interestingly, we identified 14 animals with CD4(+) T cell counts of < 500/mm(3), of which two show severe and persistent CD4(+) T cell depletion (< 50/mm(3)). Thus, significant CD4(+) T cell depletion does occasionally follow SIV infection of SMs even in the context of generally low levels of immune activation, lending support to the hypothesis of multifactorial control of CD4(+) T cell homeostasis in this model of infection. The absence of AIDS in these "CD4(low)" naturally SIV-infected SMs defines a protective role of the reduced immune activation even in the context of a significant CD4(+) T cell depletion. C1 Univ Penn, Sch Med, Dept Pathol & Lab Med, Stellar Chance Labs 705, Philadelphia, PA 19104 USA. Emory Univ, Sch Med, Dept Med, Atlanta, GA 30322 USA. Emory Univ, Sch Med, Emory Vaccine Ctr, Atlanta, GA 30322 USA. NIAID, Immunoregulat Lab, NIH, Bethesda, MD 20892 USA. Emory Univ, Yerkes Natl Primate Res Ctr, Atlanta, GA 30329 USA. SW Texas State Univ, Dept Med, Dallas, TX 75390 USA. RP Silvestri, G (reprint author), Univ Penn, Sch Med, Dept Pathol & Lab Med, Stellar Chance Labs 705, 422 Curie Blvd, Philadelphia, PA 19104 USA. EM gsilvest@mail.med.upenn.edu RI Dunham, Richard/B-2012-2009 OI Dunham, Richard/0000-0003-4542-2330 NR 31 TC 83 Z9 87 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 1 PY 2007 VL 178 IS 3 BP 1680 EP 1691 PG 12 WC Immunology SC Immunology GA 130TC UT WOS:000243820900053 PM 17237418 ER PT J AU Kim, IJ Burkum, CE Cookenham, T Schwartzberg, PL Woodland, DL Blackman, MA AF Kim, In-Jeong Burkum, Claire E. Cookenham, Tres Schwartzberg, Pamela L. Woodland, David L. Blackman, Marcia A. TI Perturbation of B cell activation in SLAM-associated protein-deficient mice is associated with changes in gammaherpesvirus latency reservoirs SO JOURNAL OF IMMUNOLOGY LA English DT Article ID EPSTEIN-BARR-VIRUS; LINKED LYMPHOPROLIFERATIVE-DISEASE; CD4(+) T-CELLS; GAMMA-HERPESVIRUS INFECTION; MURINE GAMMAHERPESVIRUS-68; IN-VIVO; GENE-PRODUCT; TERMINAL DIFFERENTIATION; LYMPHOCYTE-RESPONSES; PERSISTENT INFECTION AB Signaling lymphocyte activation molecule (SLAM)-associated protein (SAP)) interactions with SLAM family proteins play important roles in immune function. SAP-deficient mice have defective B cell function, including impairment of germinal center formation, production of class-switched Ig, and development of memory B cells. B cells are the major reservoir of latency for both EBV and the homologous murine gammaherpesvirus, gammaherpesvirus 68. There is a strong association between the B cell life cycle and viral latency in that the virus preferentially establishes latency in activated germinal center B cells, which provides access to memory B cells, a major reservoir of long-term latency. In the current studies, we have analyzed the establishment and maintenance of gamma HV68 latency in wild-type and SAP-deficient mice. The results show that, despite SAP-associated defects in germinal center and memory B cell formation, latency was established and maintained in memory B cells at comparable frequencies to wild-type mice, although the paucity of memory B cells translated into a 10-fold reduction in latent load. Furthermore, there were defects in normal latency reservoirs within the germinal center cells and IgD(+)"naive" B cells in SAP-deficient mice, showing a profound effect of the SAP mutation on latency reservoirs. C1 Trudeau Inst Inc, Saranac Lake, NY 12983 USA. NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA. RP Blackman, MA (reprint author), Trudeau Inst Inc, 159 Algonquin Ave, Saranac Lake, NY 12983 USA. EM mblackman@trudeauinstitute.org FU Intramural NIH HHS; NIAID NIH HHS [AI51602, AI42927] NR 70 TC 6 Z9 7 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 1 PY 2007 VL 178 IS 3 BP 1692 EP 1701 PG 10 WC Immunology SC Immunology GA 130TC UT WOS:000243820900054 PM 17237419 ER PT J AU Chen, KQ Iribarren, P Huang, J Zhang, LZ Gong, WH Cho, EH Lockett, S Dunlop, NM Wang, JM AF Chen, Keqiang Iribarren, Pablo Huang, Jian Zhang, Lingzhi Gong, Wanghua Cho, Edward H. Lockett, Stephen Dunlop, Nancy M. Wang, Ji Ming TI Induction of the formyl peptide receptor 2 in microglia by IFN-gamma and synergy with CD40 ligand SO JOURNAL OF IMMUNOLOGY LA English DT Article ID NITRIC-OXIDE SYNTHASE; NECROSIS-FACTOR-ALPHA; AMYLOID-BETA-PEPTIDE; NF-KAPPA-B; INTERFERON-GAMMA; ALZHEIMERS-DISEASE; GENE-EXPRESSION; CELL UPTAKE; TNF-ALPHA; A-BETA AB Human formyl peptide receptor (FPR)-like 1 (FPRL1) and its mouse homologue mFPR2 are functional receptors for a variety of exogenous and host-derived chemotactic peptides, including amyloid beta 1-42 (A beta(42)), a pathogenic factor in Alzheimer's disease. Because mFPR2 in microglial cells is regulated by proinflammatory stimulants including TLR agonists, in this study we investigated the capacity of IFN-gamma and the CD40 ligand (CD40L) to affect the expression and function of mFPR2. We found that IFN-gamma, when used alone, induced mFPR2 mRNA expression in a mouse microglial cell line and primary microglial cells in association with increased cell migration in response to mFPR2 agonists, including A beta(42). IFN-gamma also increased the endocytosis of A beta(42) by microglial cells via mFPR2. The effect of IFN-gamma on mFPR2 expression in microglial cells was dependent on activation of MAPK and I kappa B-alpha. IFN-gamma additionally increased the expression of CD40 by microglial cells and soluble CD40L significantly promoted cell responses to IFN-gamma during a 6-h incubation period by enhancing the activation of MAPK and I kappa B-alpha signaling pathways. We additionally found that the effect of IFN-gamma and its synergy with CD40L on mFPR2 expression in microglia was mediated in part by TNF-alpha. Our results suggest that IFN-gamma and CD40L, two host-derived factors with increased concentrations in inflammatory central nervous system diseases, may profoundly affect microglial cell responses in the pathogenic process in which mFPR2 agonist peptides are elevated. C1 NCI, Ctr Canc Res, Mol Immunoregulat Lab, Frederick, MD 21702 USA. NCI, Image Anal Lab, Sci Applicat Int Corp, Frederick, MD 21702 USA. NCI, Basic Res Program, Sci Applicat Int Corp, Frederick, MD 21702 USA. Shanghai Jiao Tong Univ, Sch Agr & Biotechnol, Shanghai 200030, Peoples R China. Shanghai Asia United Antibody Med, Shanghai, Peoples R China. RP Wang, JM (reprint author), NCI, Ctr Canc Res, Mol Immunoregulat Lab, Bldg 560,Room 31-76, Frederick, MD 21702 USA. EM wangji@mail.ncifcrf.gov RI Cho, Edward/B-3727-2012 OI Cho, Edward/0000-0002-0278-334X FU Intramural NIH HHS; NCI NIH HHS [N01-CO-12400] NR 56 TC 22 Z9 23 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 1 PY 2007 VL 178 IS 3 BP 1759 EP 1766 PG 8 WC Immunology SC Immunology GA 130TC UT WOS:000243820900060 PM 17237425 ER PT J AU Morse, C Maldarelli, F AF Morse, Caryn Maldarelli, Frank TI Enfuvirtide antiviral activity despite rebound viremia and resistance mutations: Fitness tampering or a case of persistent braking on entering? SO JOURNAL OF INFECTIOUS DISEASES LA English DT Editorial Material ID IMMUNODEFICIENCY-VIRUS TYPE-1; PROTEASE INHIBITOR THERAPY; EXPERIENCED HIV-1-INFECTED PATIENTS; HIV-INFECTED PATIENTS; FUSION INHIBITOR; BASE-LINE; INITIAL TREATMENT; SALVAGE THERAPY; TREATMENT FAILURE; DRUG-RESISTANCE C1 NCI, HIV Drug Resistance Program, NIH, Bethesda, MD 20892 USA. NCI, Dept Crit Care Med, Warren Grant Magnuson Clin Ctr, NIH, Bethesda, MD 20892 USA. RP Maldarelli, F (reprint author), NCI, HIV Drug Resistance Program, NIH, Bldg 10,Rm 12S245,9000 Rockville Pike, Bethesda, MD 20892 USA. EM fmalli@mail.nih.gov OI Morse, Caryn/0000-0002-1177-4365 NR 40 TC 7 Z9 7 U1 0 U2 0 PU UNIV CHICAGO PRESS PI CHICAGO PA 1427 E 60TH ST, CHICAGO, IL 60637-2954 USA SN 0022-1899 J9 J INFECT DIS JI J. Infect. Dis. PD FEB 1 PY 2007 VL 195 IS 3 BP 318 EP 321 DI 10.1086/510539 PG 4 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 122PA UT WOS:000243237700003 PM 17205468 ER PT J AU Fotheringham, J Akhyani, N Vortmeyer, A Donati, D Williams, E Oh, U Bishop, M Barrett, J Gea-Banacloche, J Jacobson, S AF Fotheringham, Julie Akhyani, Nahid Vortmeyer, Alexander Donati, Donatella Williams, Elizabeth Oh, Unsong Bishop, Michael Barrett, John Gea-Banacloche, Juan Jacobson, Steven TI Detection of active human herpesvirus-6 infection in the brain: Correlation with polymerase chain reaction detection in cerebrospinal fluid SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID BONE-MARROW-TRANSPLANT; STEM-CELL TRANSPLANTATION; CLINICAL-FEATURES; HUMAN-HERPESVIRUS-6; ENCEPHALITIS; RECIPIENTS; PLASMA AB One-half of bone-marrow transplant (BMT) and stem-cell transplant recipients have reactivation of latent human herpesvirus (HHV)-6 2-4 weeks after transplant. Although the detection of viral DNA, RNA, and antigen in brain material confirmed active HHV-6 variant B infection, peak viral loads in cerebrospinal fluid (CSF) and serum occurred 2-4 weeks before death and decreased to low levels before or at autopsy. All autopsy samples consistently demonstrated HHV-6 active infection in the hippocampus. Astrocytic cells positive for viral antigen provided support for an HHV-6-specific tropism for hippocampal astrocytes. HHV-6 DNA in CSF and serum may not reflect the level of active viral infection in the brain after BMT. C1 NINDS, Viral Immunol Sect, NIH, Bethesda, MD 20892 USA. NINDS, Surg Neurol Branch, NIH, Bethesda, MD 20892 USA. NCI, NIH, Bethesda, MD 20892 USA. NHLBI, NIH, Bethesda, MD 20892 USA. Azienda Osped Univ Senese, Siena, Italy. RP Jacobson, S (reprint author), NINDS, Viral Immunol Sect, NIH, 10 Ctr Dr,Bldg 10 Rm 5B16, Bethesda, MD 20892 USA. EM jacobsons@ninds.nih.gov NR 16 TC 46 Z9 51 U1 0 U2 3 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 1 PY 2007 VL 195 IS 3 BP 450 EP 454 DI 10.1086/510757 PG 5 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 122PA UT WOS:000243237700020 PM 17205485 ER PT J AU Hope, WW Kruhlak, MJ Lyman, CA Petraitiene, R Petraitis, V Francesconi, A Kasai, M Mickiene, D Sein, T Peter, J Kelaher, AM Hughes, JE Cotton, MP Cotten, CJ Bacher, J Tripathi, S Bermudez, L Maugel, TK Zerfas, PM Wingard, JR Drusano, GL Walsh, TJ AF Hope, William W. Kruhlak, Michael J. Lyman, Caron A. Petraitiene, Ruta Petraitis, Vidmantas Francesconi, Andrea Kasai, Miki Mickiene, Diana Sein, Tin Peter, Joanne Kelaher, Amy M. Hughes, Johanna E. Cotton, Margaret P. Cotten, Catherine J. Bacher, John Tripathi, Sanjay Bermudez, Louis Maugel, Timothy K. Zerfas, Patricia M. Wingard, John R. Drusano, George L. Walsh, Thomas J. TI Pathogenesis of Aspergillus fumigatus and the kinetics of galactomannan in an in vitro model of early invasive pulmonary aspergillosis: Implications for antifungal therapy SO JOURNAL OF INFECTIOUS DISEASES LA English DT Article ID AMPHOTERICIN-B DEOXYCHOLATE; ALVEOLAR EPITHELIAL-CELLS; FUNGAL-INFECTIONS; MYCOBACTERIUM-TUBERCULOSIS; EARLY DIAGNOSIS; POTENTIAL ROLE; MURINE MODEL; PROTEIN-D; PHARMACOKINETICS; PHARMACODYNAMICS AB Background. Little is known about the pathogenesis of invasive pulmonary aspergillosis and the relationship between the kinetics of diagnostic markers and the outcome of antifungal therapy. Methods. An in vitro model of the human alveolus, consisting of a bilayer of human alveolar epithelial and endothelial cells, was developed. An Aspergillus fumigatus strain expressing green fluorescent protein was used. Invasion of the cell bilayer was studied using confocal and electron microscopy. The kinetics of culture, polymerase chain reaction, and galactomannan were determined. Galactomannan was used to measure the antifungal effect of macrophages and amphotericin B. A mathematical model was developed, and results were bridged to humans. Results. A. fumigatus penetrated the cellular bilayer 14 - 16 h after inoculation. Galactomannan levels were inextricably tied to fungal invasion and were a robust measure of the antifungal effect of macrophages and amphotericin B. Neither amphotericin nor macrophages alone was able to suppress the growth of A. fumigatus; rather, the combination was required. Monte Carlo simulations showed that human dosages of amphotericin B of at least 0.6 mg/kg were required to achieve adequate drug exposure. Conclusions. This model provides a strategy by which relationships among pathogenesis, immunological effectors, and antifungal drug therapy for invasive pulmonary aspergillosis may be further understood. C1 NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA. NCI, Expt Immunol Branch, NIH, Bethesda, MD 20892 USA. NIH, Vet Resources Program, Off Res Serv, Bethesda, MD 20892 USA. SAIC Frederick Inc, Frederick, MD USA. Univ Maryland, Dept Biol, College Pk, MD 20742 USA. Oregon State Univ, Coll Vet Med, Dept Biomed Sci, Corvallis, OR 97331 USA. Univ Florida, Coll Med, Gainesville, FL USA. Ordway Res Inst, Emerging Infect Dis Unit, Albany, NY USA. RP Walsh, TJ (reprint author), NCI, Immunocompromised Host Sect, Pediat Oncol Branch, NIH, Bldg 10-CRC,Rm 1-5750, Bethesda, MD 20892 USA. EM walsht@mail.nih.gov OI Hope, William/0000-0001-6187-878X FU Intramural NIH HHS NR 33 TC 67 Z9 68 U1 0 U2 3 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 1 PY 2007 VL 195 IS 3 BP 455 EP 466 DI 10.1086/510535 PG 12 WC Immunology; Infectious Diseases; Microbiology SC Immunology; Infectious Diseases; Microbiology GA 122PA UT WOS:000243237700021 PM 17205486 ER PT J AU Heare, T Alp, NJ Priestman, DA Kulkarni, AB Qasba, P Butters, TD Dwek, RA Clarke, K Channon, KM Platt, FM AF Heare, T. Alp, N. J. Priestman, D. A. Kulkarni, A. B. Qasba, P. Butters, T. D. Dwek, R. A. Clarke, K. Channon, K. M. Platt, F. M. TI Severe endothelial dysfunction in the aorta of a mouse model of Fabry disease; partial prevention by N-butyldeoxynojirimycin treatment SO JOURNAL OF INHERITED METABOLIC DISEASE LA English DT Article ID NITRIC-OXIDE PATHWAY; ALPHA-GALACTOSIDASE; ENZYME REPLACEMENT; KNOCKOUT MICE; L-ARGININE; HYPERCHOLESTEROLEMIA; BIOSYNTHESIS; BRADYKININ; REVERSAL AB Objective: Fabry disease results from alpha-gala- ctosidase A deficiency and is characterized by the lysosomal accumulation of globotriaosylceramide. Globotriaosylceramide storage predominantly affects endothelial cells, altering vascular wall morphology and vasomotor function. Our objective was to investigate aortic globotriaosylceramide levels, morphology and function in a mouse model of Fabry disease, and the effect of substrate reduction therapy, using the glycosphingolipid biosynthesis inhibitor N-butyldeoxynojirimycin. Methods and results: Mice used were C57BL/6J and alpha-galactosidase A knockout (Fabry). We show progressive accumulation of aortic globotriaosylceramide throughout the lifespan of untreated Fabry mice (55-fold elevation at 2 months increasing to 187-fold by 19 months), localized to endothelial and vascular smooth-muscle cells; there was no effect on vascular wall morphology in young Fabry mice. In old mice, storage resulted in intimal thickening. Endothelial function declined with age in Fabry mouse aorta. Aortae from N-butyldeoxynojirimycin-treated Fabry mice at 19 months of age had reduced endothelial globotriaosylceramide storage, fewer morphological abnormalities and less severe vasomotor dysfunction compared with untreated littermates. Conclusion: We provide evidence of a novel vascular phenotype in the Fabry mouse that has relevance to vascular disease in Fabry patients. N-Butyldeoxynojirimycin treatment partially prevented the phenotype in the Fabry mouse by reducing endothelial globotriaosylceramide storage. C1 Univ Oxford, Dept Biochem, Glycobiol Inst, Oxford OX1 3QT, England. Univ Oxford, John Radcliffe Hosp, Dept Cardiovasc Med, Oxford OX1 3QT, England. Natl Inst Dental & Craniofacial Res, Funct Genom Unit, NIH, Bethesda, MD USA. NHLBI, Blood Dis Program, Bethesda, MD 20892 USA. Univ Oxford, Physiol Lab, Burdon Sanderson Cardiac Sci Ctr, Oxford OX1 3QT, England. RP Platt, FM (reprint author), Univ Oxford, Dept Pharmacol, S Parks Rd, Oxford OX1 3QT, England. EM Frances.platt@pharm.ox.ac.uk RI Platt, Frances/G-1004-2010 FU British Heart Foundation [RG/07/004/22659, PS/02/002/14893] NR 35 TC 23 Z9 23 U1 0 U2 0 PU SPRINGER PI DORDRECHT PA VAN GODEWIJCKSTRAAT 30, 3311 GZ DORDRECHT, NETHERLANDS SN 0141-8955 J9 J INHERIT METAB DIS JI J. Inherit. Metab. Dis. PD FEB PY 2007 VL 30 IS 1 BP 79 EP 87 DI 10.1007/s10545-006-0473-y PG 9 WC Endocrinology & Metabolism; Genetics & Heredity; Medicine, Research & Experimental SC Endocrinology & Metabolism; Genetics & Heredity; Research & Experimental Medicine GA 127VD UT WOS:000243613500010 PM 17189993 ER EF